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"abstract": "Phenytoin sodium intoxication of subacute onset may occur in cases of nonepileptic patients who receive phenytoin for suppression of cardiac arrhythmias. The case reported here is of a syndrome that consisted of dementia, cerebellar dysfunction, and peripheral neuropathy. Withdrawal of phenytoin was followed by a slow improvement in the syndrome. Awareness of the features of subacute phenytoin intoxication in cardiac patients is important because this entity may mimic cerebrovascular disease. Periodic monitoring of serum phenytoin concentrations is advisable.",
"affiliations": null,
"authors": "Tindall|R S|RS|;Willerson|J|J|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9926",
"issue": "138(7)",
"journal": "Archives of internal medicine",
"keywords": null,
"medline_ta": "Arch Intern Med",
"mesh_terms": "D001145:Arrhythmias, Cardiac; D002526:Cerebellar Diseases; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases; D010672:Phenytoin",
"nlm_unique_id": "0372440",
"other_id": null,
"pages": "1168-9",
"pmc": null,
"pmid": "208480",
"pubdate": "1978-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Subacute phenytoin intoxication syndrome.",
"title_normalized": "subacute phenytoin intoxication syndrome"
} | [
{
"companynumb": "US-PFIZER INC-2015227131",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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"drugadditional": null,
... |
{
"abstract": "The clinical epidemiology of BK virus (BKV) disease after allogeneic hematopoietic stem cell transplantation (HSCT) is not well defined. We evaluated 491 patients transplanted from January 2010 to December 2011 at a single transplant center to assess incidence, severity, and risk factors for BKV disease after HSCT. BKV disease was defined as BKV detection in urine by PCR testing in association with genitourinary symptoms without other concurrent genitourinary conditions. BKV disease occurred in 78 patients (15.9%), for an incidence rate of .47/1000 patient-days (95% confidence interval [CI], .37 to .59); BKV disease was considered severe in 27 patients (5.5%). In multivariate Cox modeling, time-dependent acute graft-versus-host disease (aGVHD) grades II to IV (adjusted hazard ratio [aHR] 4.25; 95% CI, 2.51 to 7.21), cord blood HSCT (aHR 2.28; 95% CI, 1.01 to 5.15), post-transplant mycophenolate use (aHR 3.31; 95% CI, 1.83 to 5.99), and high-dose cyclophosphamide conditioning (aHR 2.34, 95% CI 1.45 to 3.77) were significant predictors of BKV disease. Time-dependent aGVHD grades III to IV (aHR 10.5; 95% CI, 4.44 to 25.0) and cord blood HSCT (aHR 5.40; 95% CI, 1.94 to 15.0) were independent risk factors for severe BKV disease. BKV disease is common and is associated with significant and prolonged morbidity after HSCT. Prospective studies are needed to better define the morbidity of post-HSCT BKV disease and inform the design of prophylaxis and treatment trials.",
"affiliations": "Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; University of Groningen Medical School, Groningen, The Netherlands.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Division of Infectious Diseases, Brigham and Women's Hospital, Boston, Massachusetts; Division of Hematologic Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. Electronic address: fmarty@partners.org.",
"authors": "Rorije|Nienke M G|NM|;Shea|Margaret M|MM|;Satyanarayana|Gowri|G|;Hammond|Sarah P|SP|;Ho|Vincent T|VT|;Baden|Lindsey R|LR|;Antin|Joseph H|JH|;Soiffer|Robert J|RJ|;Marty|Francisco M|FM|",
"chemical_list": "D019653:Myeloablative Agonists; D003520:Cyclophosphamide; D009173:Mycophenolic Acid",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-8791",
"issue": "20(4)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Allogeneic stem cell transplantation; BK virus; Cord blood transplantation; Graft-versus-host disease; Human BK polyomavirus",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D001739:BK Virus; D002908:Chronic Disease; D036101:Cord Blood Stem Cell Transplantation; D003520:Cyclophosphamide; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D019653:Myeloablative Agonists; D027601:Polyomavirus Infections; D011446:Prospective Studies; D012720:Severity of Illness Index; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014412:Tumor Virus Infections",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "564-70",
"pmc": null,
"pmid": "24462984",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "BK virus disease after allogeneic stem cell transplantation: a cohort analysis.",
"title_normalized": "bk virus disease after allogeneic stem cell transplantation a cohort analysis"
} | [
{
"companynumb": "US-ROCHE-1488429",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugaddition... |
{
"abstract": "Hand-foot syndrome is a common cutaneous adverse effect associated with certain systemic chemotherapy drugs. It is characterized by erythema, edema, and burning sensation, especially over palmoplantar surfaces. We report the case of an elderly patient undergoing chemotherapy after a breast cancer surgery who developed symptoms two months after the start of the regimen. There are no studies that explore specific therapies. Suggestive therapy include reducing agent dosage, increasing the interval between cycles, or even stopping chemotherapy. Emollients, analgesics, and cold packs are described as effective. After alopecia and mucositis, hand-foot syndrome is the most common adverse dermatologic reaction to chemotherapeutic agents.",
"affiliations": "Department of Dermatology and Radiotherapy, Medical School of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu (SP), Brazil.;Department of Dermatology and Radiotherapy, Medical School of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu (SP), Brazil.;Department of Dermatology and Radiotherapy, Medical School of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu (SP), Brazil.;Department of Pathology, Medical School of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu (SP), Brazil.;Department of Dermatology and Radiotherapy, Medical School of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu (SP), Brazil.",
"authors": "Braghiroli|Cintia Santos|CS|;Ieiri|Rodrigo|R|;Ocanha|Juliana Polizel|JP|;Paschoalini|Rafael Bispo|RB|;Miot|Hélio Amante|HA|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Spain",
"delete": false,
"doi": "10.1590/abd1806-4841.20174602",
"fulltext": "\n==== Front\nAn Bras DermatolAn Bras DermatolabdAnais Brasileiros de Dermatologia0365-05961806-4841Sociedade Brasileira de Dermatologia 10.1590/abd1806-4841.20174602Syndrome in QuestionDo you know this syndrome? Hand-foot syndrome*\n Braghiroli Cintia Santos 1Ieiri Rodrigo 1Ocanha Juliana Polizel 1Paschoalini Rafael Bispo 2Miot Hélio Amante 11 Department of Dermatology and Radiotherapy, Medical\nSchool of Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\"\n(Unesp) - Botucatu (SP), Brazil2 Department of Pathology, Medical School of Botucatu -\nUniversidade Estadual Paulista \"Júlio de Mesquita Filho\" (Unesp) - Botucatu\n(SP), BrazilMailing address: Hélio Amante Miot, Departamento de\nDermatologia e Radioterapia, Faculdade de Medicina de Botucatu - Unesp SN,\n18618-000 Botucatu, SP, Brazil. E-mail: heliomiot@fmb.unesp.brJan-Feb 2017 Jan-Feb 2017 92 1 131 133 01 4 2015 13 7 2015 ©2017 by Anais Brasileiros de\nDermatologia2017Anais Brasileiros de DermatologiaThis is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium provided the original work is properly cited.Hand-foot syndrome is a common cutaneous adverse effect associated with certain\nsystemic chemotherapy drugs. It is characterized by erythema, edema, and burning\nsensation, especially over palmoplantar surfaces. We report the case of an\nelderly patient undergoing chemotherapy after a breast cancer surgery who\ndeveloped symptoms two months after the start of the regimen. There are no\nstudies that explore specific therapies. Suggestive therapy include reducing\nagent dosage, increasing the interval between cycles, or even stopping\nchemotherapy. Emollients, analgesics, and cold packs are described as effective.\nAfter alopecia and mucositis, hand-foot syndrome is the most common adverse\ndermatologic reaction to chemotherapeutic agents.\n\nAdjuvant chemotherapyChemotherapyDrug eruptionHand-foot syndrome\n==== Body\nCASE REPORT\nWe report a 73-year-old woman under post-surgical chemotherapy (breast ductal\ncarcinoma) who presented with transudation and pain on the lower limbs 20 days after\nthe first cycle with doxorubicin and cyclophosphamide and no improvement with\nfurosemide.\n\nDue to treatment failure after four cycles of adjuvant regimen, the patient was\nstarted on herceptin and paclitaxel. From the 45th day of this new\nregimen, we observed the development of an edema and considerable erythema on the\nhands, wrists, legs, and feet. We also observed desquamation, ulceration,\nvesicopustules, and intense burning sensation. Little improvement was observed after\nanalgesia, topical corticosteroids and cephalexin (Figures 1 and 2).\n\nFigure 1 Erythema and acral edema on the lower limbs, with flaking and areas of\nulceration\n\n\n\nFigure 2 Detail of scaly erythematous lesions of the posterior region of the\nankles with areas of ulceration and vesicopustules\n\n\n\nLaboratory tests were normal. Histopathological examination showed areas of epidermal\nnecrosis with small clefts, keratinocyte apoptosis, parakeratosis foci, and basal\nvacuolar degeneration with extensive involvement of the acrosyringium without\nsquamous syringometaplasia.\n\nWe opted for hospitalization, suspension of chemotherapy, and administration of\nopioids, prednisone (0.5 mg/kg), potassium permanganate compresses, and application\nof occlusive dressing with fludroxycortide. The patient was discharged five days\nlater with significant improvement in pain and lesions.\n\nDISCUSSION\nHand-foot syndrome (HFS) - or palmar-plantar erythrodysesthesia, acral erythema, or\nBurgdorf reaction - is an adverse event of many chemotherapeutic agents, especially\nliposomal doxorubicin, capecitabine, 5-fluorouracil, cytarabine, docetaxel,\nsorafenib, sunitinib, cyclophosphamide, etoposide, vinorelbine, methotrexate,\nhydroxyurea, tegafur, mercaptopurine, and paclitaxel.1,2\n\nAfter alopecia and mucositis, HFS is the most common adverse dermatologic reaction to\nchemotherapy, with an incidence of 3%-64%. The highest incidences occur with\ndoxorubicin (40%-50%) and capecitabine (50%-60%). The risk of HFS seems to be\ndose-dependent: formulations that prolong the serum level or that concentrate the\ndrug at the affected sites have the highest association rates.1\n\nThe pathogenesis of HFS is not known. It is believed to be a toxic reaction due to\nthe local accumulation of the drug with consequent degeneration and necrosis of the\nsweat glands. That is because its microscopic features resemble squamous eccrine\nsyringometaplasia and neutrophilic eccrine hidradenitis patterns.2,3\n\nHFS presents with prodromal dysesthesia and palmar-plantar tingling. Within days, the\nreaction progresses to burning pain, well-defined edema and erythema with a tendency\nto symmetry and flaking, and limitation of daily activities. Extreme cases involve\nulceration and blisters, palmoplantar keratoderma, nail dystrophy, inflammation of\nactinic keratoses, and may affect the folds of the skin (axillary, inguinal,\nperineal, and inframammary).1,2,4-6\n\nDifferent classifications grade the severity of HFS. The two most commonly used\ncriteria are provided by the World Health Organization and by the National Cancer\nInstitute (Chart 1).7\n\nChart 1 Clinical description of severity for hand-foot syndrome according to\nNCI-CTCAE (National Cancer Institute - Common Terminology Criteria for\nAdverse Events) and WHO (World Health Organization) and associated\nhistologic findings\n\nGrade\tNCI-CTCAE (version 4.03)\tWHO\tHistological findings\t\n1\tminimal skin changes OR dermatitis (e.g.\nerythema,\n edema, or hyperkeratosis) NO pain\tDysesthesia/paresthesia, tingling in hands and\n\nfeet\tDilated vessels in the\n superficial\ndermal\n plexus\t\n2\tCutaneous lesions (e.g. flaking, blistering,\nbleeding,\n swelling, and hyperkeratosis) WITH pain,\nbut\n with minimum limitation\tDiscomfort when holding objects and walking,\n\npainless swelling, or erythema\t \t\n3\tUlcerative dermatitis or serious painful\ncutaneous\n lesions (e.g. flaking, blistering, bleeding,\nswelling,\n and hyperkeratosis) interfering with function\nand\n self-care\tPainful erythema and swelling of the palms and\n\nsoles; erythema and periungual swelling\tIsolated keratinocytes\n necrosis in the\n\nouter layers of the\n epidermis\t\n4\t \tDesquamation, ulceration, blistering, and\nsevere\n pain\tComplete epidermal\n necrosis\t\nThere are no longitudinal studies that explore specific treatments. Suggestive\ntherapy include reducing chemotherapy dosage, increasing the interval between\ncycles, or even stopping chemotherapy, which would lead to remission of the picture\nin up to two weeks. Dressings, rigorous analgesia, emollients, cold compresses, and\npotent topical corticosteroids associated with emollients or systemic\ncorticosteroids are reported as efficient. Cooling of the hands and feet and use of\nemollients and antiperspirants (aluminum chloride hydroxide) during infusions can\nprevent the reaction. Oral pyridoxine showed no preventive efficacy in\nHFS.2,8-10\n\nWith an aging population and greater access to health care and oncological diagnosis,\ncutaneous reactions to chemotherapy should become more frequent. Prevention,\nidentification, and early intervention is essential for clinicians in cases of\nHFS.\n\nConflict of Interest: None\n\nFinancial Support: None\n\n* Study conducted at the Department of Dermatology and Radiotherapy, Medical School\nof Botucatu - Universidade Estadual Paulista \"Júlio de Mesquita Filho\"\n(Unesp) - Botucatu (SP), Brazil\n==== Refs\nReferences\n1 Webster-Gandy JD How C Harrold K Palmar-plantar erythrodysesthesia (PPE): a literature review with\ncommentary on experience in a cancer centre Eur J Oncol Nurs 2007 11 238 246 17350337 \n2 Miller KK Gorcey L McLellan BN Chemotherapy-induced hand-foot syndrome and nail changes: a\nreview of clinical presentation, etiology, pathogenesis, and\nmanagement J Am Acad Dermatol 2014 71 787 794 24795111 \n3 Martschick A Sehouli J Patzelt A Richter H Jacobi U Oskay-Ozcelik G The pathogenetic mechanism of anthracycline-induced\npalmar-plantar erythrodysesthesia Anticancer Res 2009 29 2307 2313 19528496 \n4 Suwattee P Chow S Berg BC Warshaw EM Sunitinib: a cause of bullous palmoplantar erythrodysesthesia,\nperiungual erythema, and mucositis Arch Dermatol 2008 144 123 125 18209189 \n5 Sapp CM DeSimone P Palmar-plantar erythrodysesthesia associated with scrotal and\npenile involvement with capecitabine Clin Colorectal Cancer 2007 6 382 385 17311704 \n6 Siqueira CR Miot HA Inflammation of multiple seborrheic keratoses induced by\nchemotherapy with gemcitabine An Bras Dermatol 2009 84 410 413 19851675 \n7 Sanches Junior JA Brandt HR Moure ER Pereira GL Criado PR Adverse mucocutaneous reactions to chemotherapeutic agentes: part\nI An Bras Dermatol 2010 85 425 437 20944902 \n8 Templeton AJ Ribi K Surber C Sun H Hsu Schmitz SF Beyeler M Prevention of palmar-plantar erythrodysesthesia with an\nantiperspirant in breast cancer patients treated with pegylated liposomal\ndoxorubicin (SAKK 92/08) Breast 2014 23 244 249 24656636 \n9 Lademann J Martschick A Kluschke F Richter H Fluhr JW Patzelt A Efficient prevention strategy against the development of a\npalmar-plantar erythrodysesthesia during chemotherapy Skin Pharmacol Physiol 2014 27 66 70 23969763 \n10 Jo SJ Shin H Jo S Kwon O Myung SK Prophylactic and therapeutic efficacy of pyridoxine supplements\nin the management of hand-foot syndrome during chemotherapy: a\nmeta-analysis Clin Exp Dermatol 2015 40 260 270 25557587\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0365-0596",
"issue": "92(1)",
"journal": "Anais brasileiros de dermatologia",
"keywords": null,
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D001943:Breast Neoplasms; D005260:Female; D060831:Hand-Foot Syndrome; D006801:Humans",
"nlm_unique_id": "0067662",
"other_id": null,
"pages": "131-133",
"pmc": null,
"pmid": "28225974",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "25557587;19851675;17350337;23969763;17311704;24795111;20944902;24656636;19528496;18209189",
"title": "Do you know this syndrome? Hand-foot syndrome.",
"title_normalized": "do you know this syndrome hand foot syndrome"
} | [
{
"companynumb": "BR-FRESENIUS KABI-FK201702764",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
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... |
{
"abstract": "To identify clinical characteristics common among epileptic patients prescribed levetiracetam who report suicidal ideation or who exhibit suicidal behavior. A case is also provided that highlights the need for increased vigilance for neuropsychiatric sequelae in fragile epileptic patients prescribed levetiracetam, especially post dosage adjustment.\nPubMed was queried with no time limitation to December 2018 using a combination of controlled terms. Using the Boolean operators \"AND\" and \"OR,\" the authors searched PubMed for case reports and case series on levetiracetam-related suicidal behavior. The search terms used were [levetiracetam] OR [Keppra] AND in combination with suicidal, suicide, suicidal ideation, suicide attempt, and suicidality.\nRelevant English-language human studies on levetiracetam and its effect on suicidal behavior were included. The search terms generated 78 results from the databases. After excluding all duplicates and applying the inclusion and exclusion criteria, a total of 14 clinical studies were retained for review.\nTwo reviewers independently extracted relevant data and assessed the methodological quality of each study.\nThe included studies reveal a number of risk factors for suicide ideation, suicide-related behavior, and suicide attempt among individuals taking levetiracetam. These risk factors include a prior psychiatric disorder, a history of traumatic brain injury, a history of substance use disorder, and a structural brain abnormality. Patients with these risk factors constitute a specific subgroup of patients with epilepsy who have an increased vulnerability to suicidal ideation or behavior if prescribed levetiracetam. These patients should, therefore, be monitored closely.\nSuicidal behavior in epileptic patients appears to be multifactorial in etiology. Psychiatric disorders are more prevalent in epileptic patients than in the general population and contribute to this risk. In spite of the high risk of suicidal behavior with the use of antiepileptic drugs, studies have shown that the benefits of anticonvulsant therapy often outweigh the risks. Nevertheless, timely consultation with a psychiatrist is invaluable in the care of these patients, particularly those with multiple risk factors, as in the index case. The risk of suicidality should be balanced with the risk of uncontrolled seizures. Specifically, in the case of levetiracetam, it is important to be aware of the subgroup of individuals with prior severe psychiatric illness, a history of traumatic brain injury, or a history of substance use disorder who might be at an increased risk of developing suicide-related behavior and suicidal ideations once levetiracetam is started.",
"affiliations": "Clarion Psychiatric Center, 2 Hospital Dr, Clarion, PA 16214. silversensorium@gmail.com.;Department of Psychiatry & Behavioral Sciences, Nassau University Medical Center, East Meadow, New York, USA.;Department of Psychiatry & Behavioral Sciences, Nassau University Medical Center, East Meadow, New York, USA.",
"authors": "Esang|Michael|M|;Santos|Melody G|MG|;Ahmed|Saeed|S|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2155-7780",
"issue": "22(4)",
"journal": "The primary care companion for CNS disorders",
"keywords": null,
"medline_ta": "Prim Care Companion CNS Disord",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D004827:Epilepsy; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D059020:Suicidal Ideation; D013406:Suicide, Attempted",
"nlm_unique_id": "101547532",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32731314",
"pubdate": "2020-07-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Levetiracetam and Suicidality: A Case Report and Literature Review.",
"title_normalized": "levetiracetam and suicidality a case report and literature review"
} | [
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"companynumb": "NVSC2020US231424",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALPRAZOLAM"
},
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{
"abstract": "Toxicity from the intentional misuse of over-the-counter (OTC) combination cold products has been widely recognized. Adolescents are most frequently involved and dextromethorphan containing products are the most popular. Desired symptoms include stimulatory effects, euphoria, hallucinations, and dissociation. Potential adverse effects include tachycardia, agitation, hyperthermia, acidosis, and coma. However, mortality is rare [ 1-3]. Co-formulated ingredients such as acetaminophen, pseudoephedrine, and antihistamines may also be present and potentiate dangerous effects. We report a case of an adolescent decedent with markedly elevated postmortem chlorpheniramine (CPA) and dextromethorphan (DXM) blood concentrations and no other identifiable cause of death.",
"affiliations": "UC San Diego Medical Center, Dept. of Emergency Medicine, 200 W. Arbor Drive, San Diego, CA 92103-8676, USA. Electronic address: lcantrell@calpoison.org.;California Poison Control System, San Diego Division, 200 W. Arbor Dr., San Diego, CA, 92103-8925, USA.",
"authors": "Ontiveros|Sam|S|;Cantrell|Lee|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajem.2021.08.043",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-6757",
"issue": null,
"journal": "The American journal of emergency medicine",
"keywords": "Chlorpheniramine; Dextromethorphan; Fatal; Poisoning",
"medline_ta": "Am J Emerg Med",
"mesh_terms": null,
"nlm_unique_id": "8309942",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34454805",
"pubdate": "2021-08-21",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fatal cold medication poisoning in an adolescent.",
"title_normalized": "fatal cold medication poisoning in an adolescent"
} | [
{
"companynumb": "US-BAYER-2021-208780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CHLORPHENIRAMINE MALEATE\\DEXTROMETHORPHAN HYDROBROMIDE"
},
... |
{
"abstract": "BACKGROUND\nPsoriasis is one of several systemic diseases that presents chiefly with cutaneous symptoms and has the potential to negatively impact patients' overall health and quality of life. Physicians who treat patients with psoriasis must be cognizant of the chronic, lifelong character of the disease and of the potential for multisystem pathology. According to the National Institutes of Health (NIH), between 5.8 and 7.5 million persons in the U.S.--approximately 2.2% of the population--have psoriasis; worldwide, it affects an estimated 125 million people. The annual cost of treating psoriasis may exceed $3 billion annually. Immunologic mechanisms are now accepted as the pathophysiologic basis for the development of psoriatic disease. Treatment strategies--which include topical treatment, phototherapy, methtrexate, cyclosporine and acitretin--also encompass several biologic agents that target immune mediators associated with the condition.\n\n\nCONCLUSIONS\nPatients with mild disease may obtain symptomatic relief with topical agents and targeted phototherapy. Patients with moderate-to-severe disease are likely to benefit from systemic therapy. Shortcomings of the traditional agents, particularly their adverse event profiles, have motivated research and development of biologic agents. Currently three anti-TNF agents--etanercept, infliximab and adalimumab--are FDA-approved for treatment of psoriasis. Differences exist among study designs and, therefore, in interpretation of data; however, the improvements observed in the psoriasis study populations participating in clinical trials are dramatic. Long-term clinical data continue to accumulate and demonstrate sustained benefits with anti-TNF agents. Safety data also continue to be collected over the long-term; key safety considerations are infection, cytopenia, demyelinating disease, lupus-like syndromes, congestive heart failure and malignancies. Combination therapy should also be considered when managing psoriasis for such reasons as augmenting an inadequate response to monotherapy or improving tolerability. Combination therapy with an anti-TNF agent and phototherapy has shown considerably higher rates of response compared with either intervention alone.\n\n\nOBJECTIVE\nThe objective of this paper is to critically examine the anti-TNF studies to assess the efficacy and safety of the agents in patients with psoriasis and determine applicability of the data in clinical practice. In light of the chronic nature of this disease, the emphasis will be on the longest-term data available.\n\n\nCONCLUSIONS\nThe treatment of plaque psoriasis with TNF-alpha antagonists is still a relatively recent addition to the pharmacologic armamentarium available to clinicians. The collection of long-term data is, therefore, small but growing as results from newer studies emerge. From the data reviewed here, the clinician can attempt to arrive at a satisfactory assessment of the benefits and risks of treatment with these agents.",
"affiliations": "Indiana University Medical Center, Indianapolis, Indiana, USA. wedoderma@bellsouth.net",
"authors": "Kircik|Leon H|LH|;Del Rosso|James Q|JQ|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "8(6)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D000068879:Adalimumab; D000893:Anti-Inflammatory Agents; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000068800:Etanercept; D006801:Humans; D007074:Immunoglobulin G; D000069285:Infliximab; D011565:Psoriasis; D018124:Receptors, Tumor Necrosis Factor; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "546-59",
"pmc": null,
"pmid": "19537380",
"pubdate": "2009-06",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Anti-TNF agents for the treatment of psoriasis.",
"title_normalized": "anti tnf agents for the treatment of psoriasis"
} | [
{
"companynumb": "FR-JNJFOC-20031200222",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "The current evidence regarding immunotherapy plus targeted therapy in esophageal neuroendocrine carcinoma (NEC) is lacking. Camrelizumab is a programmed cell death protein 1 inhibitor. Apatinib is a selective tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2. A 50-year-old female was initially diagnosed as primary esophageal NEC. Neoadjuvant chemotherapy and Ivor Lewis esophagectomy were performed (ypT3N0M0, stage Ⅱ). Twenty months after the surgery, an isolated mediastinal lymph node recurrence of NEC was recorded. The specimen revealed a positive expression of vascular endothelial growth factor and programmed cell death ligand 1. The diseased lymph node was slightly enlarged after two cycles of first-line paclitaxel liposome and S-1. Second-line apatinib and S-1 for 2 months also resulted in progressive disease. Subsequently, third-line camrelizumab plus apatinib was continued for 5 months. The patient demonstrated a progression-free status for more than 10 months following the combination therapy. Meanwhile, relevant studies of camrelizumab in gastric or esophageal cancer were briefly reviewed. Based on the current evidence, camrelizumab is a promising agent for esophageal cancer. More prospective trials are warranted before a definite recommendation could be drawn.",
"affiliations": "Institute of Digestive Disease, China Three Gorges University , Yichang, China.;Department of Surgical Oncology, Xuzhou Central Hospital , Xuzhou, China.;Department of Surgical Oncology, Xuzhou Central Hospital , Xuzhou, China.;Department of Surgical Oncology, Xuzhou Central Hospital , Xuzhou, China.;Department of Surgical Oncology, Xuzhou Central Hospital , Xuzhou, China.",
"authors": "Liu|Lei|L|0000-0002-4384-0005;Liu|Yuanyuan|Y|0000-0002-7273-0358;Gong|Longbo|L|0000-0003-2071-4548;Zhang|Miao|M|0000-0001-7431-5986;Wu|Wenbin|W|0000-0002-8183-1687",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D011725:Pyridines; C553458:apatinib; C000631724:camrelizumab",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2020.1829265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "21(11)",
"journal": "Cancer biology & therapy",
"keywords": "apatinib; camrelizumab (SHR-1210); immune checkpoint inhibitor (ICI); neuroendocrine carcinoma (NEC); programmed cell death ligand 1 (PD-L1); programmed cell death protein 1 (PD-1); vascular endothelial growth factor receptor (VEGFR)",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D018278:Carcinoma, Neuroendocrine; D004938:Esophageal Neoplasms; D016629:Esophagectomy; D005260:Female; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D011725:Pyridines; D016879:Salvage Therapy",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "983-989",
"pmc": null,
"pmid": "33092443",
"pubdate": "2020-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "31017739;31380271;29755117;30508306;30348638;29340724;30207593;31619265;29508855;27810391;29358502;30653123;31149547;29182797;32256049;32581041;28453803;31561465;26918886;31317008;30755403;29320654;31014519;31269806;31451841;31794158;31516736;31313098;30677306;32416073",
"title": "Salvage camrelizumab plus apatinib for relapsed esophageal neuroendocrine carcinoma after esophagectomy: a case report and review of the literature.",
"title_normalized": "salvage camrelizumab plus apatinib for relapsed esophageal neuroendocrine carcinoma after esophagectomy a case report and review of the literature"
} | [
{
"companynumb": "CN-ACCORD-208744",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
"drugad... |
{
"abstract": "We aimed to evaluate the efficacy and safety of carboplatin plus weekly paclitaxel with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC).\n\n\n\nPatients with stage IIIB/IV or postoperative recurrent NSCLC (n=33) were treated with carboplatin (area under the curve of 6) on day 1; paclitaxel (80 mg/m2) on days 1, 8, and 15; and bevacizumab (15 mg/kg) on day 1 repeated every 4 weeks, for four to six cycles; followed by maintenance bevacizumab (15 mg/kg) every 3 weeks.\n\n\n\nThe overall response rate was 76%. The median progression-free survival and overall survival were 8.4 months and 22.2 months, respectively. Grade 3-4 toxicities included neutropenia in 55% of patients, anemia in 18%, febrile neutropenia in 12%, and anorexia in 9%. No treatment-related deaths were observed.\n\n\n\nCarboplatin plus weekly paclitaxel with bevacizumab was effective and well tolerated by patients with advanced NSCLC.",
"affiliations": "Department of Respiratory Disease, Hiroshima Red Cross Hospital & Atomic Bomb Survivors Hospital, Hiroshima, Japan myamasanjp@yahoo.co.jp.;Department of Respiratory Medicine, Higashi-Hiroshima Medical Center, Higashi-Hiroshima, Japan.;Department of Respiratory Medicine, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.;Division of Clinical Oncology, Hiroshima Prefectural Hospital, Hiroshima, Japan.;Department of Medical Oncology, Hiroshima City Asa Citizens' Hospital, Hiroshima, Japan.;Department of Respiratory Medicine, JA Hiroshima General Hospital, Hiroshima, Japan.;Sakurai Clinic, Hiroshima, Japan.;Department of Molecular and Internal Medicine, Institute of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Respiratory Medicine, Mihara Red Cross Hospital, Mihara, Japan.",
"authors": "Yamasaki|Masahiro|M|;Murakami|Isao|I|;Nakano|Kikuo|K|;Doi|Mihoko|M|;Kitaguchi|Souichi|S|;Kondo|Tomohiro|T|;Sakurai|Joji|J|;Hattori|Noboru|N|;Arita|Ken-Ichi|KI|",
"chemical_list": "D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11400",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "37(2)",
"journal": "Anticancer research",
"keywords": "Non-squamous non-small cell lung cancer; bevacizumab; carboplatin; phase II study; weekly paclitaxel",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D003967:Diarrhea; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D064147:Febrile Neutropenia; D005260:Female; D006801:Humans; D007239:Infections; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "923-928",
"pmc": null,
"pmid": "28179353",
"pubdate": "2017-02",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Carboplatin plus Weekly Paclitaxel Combined with Bevacizumab as First-line Treatment for Non-small Cell Lung Cancer.",
"title_normalized": "carboplatin plus weekly paclitaxel combined with bevacizumab as first line treatment for non small cell lung cancer"
} | [
{
"companynumb": "JP-ROCHE-1904935",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "OBJECTIVE\nTo compare treatment failure and survival associated with ultrasound-guided radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) for early-stage HCC in Child-Pugh A cirrhosis patients.\n\n\nMETHODS\n122 cirrhotic patients (RFA: 61; TACE: 61) were well matched according to cirrhosis severity; tumor size and serum alpha-fetoprotein. TACE was performed in case of inconspicuous nodule on US or nodule with \"at risk location\". Treatment failure was defined as local tumor progression (LTP) and primary treatment failure (failing to obtain complete response after two treatment session). Treatment failure and overall survival (OS) were compared after coarsened exact matching. Cox proportional model to assess independent predictive factors was performed.\n\n\nRESULTS\nNo significant difference was seen for baseline characteristics between the two groups. Mean tumor size was 3cm in both group with 41% HCC>3cm. Treatment failure rates after TACE was 42.6% (14 primary treatment failures and 12 LTP) and 9.8% after RFA (no primary treatment failure and 6 LTP) P < 0.001. TACE was the only predictive factor of treatment failure (Hazard ratio: 5.573). The 4-years OS after RFA and TACE were 54.1% and 31.5% (P = 0.042), respectively.\n\n\nCONCLUSIONS\nFor Child-Pugh A patients with early-stage HCC, alternative treatment as supra-selective TACE to RFA regarded as too challenging using common US guidance decrease significantly the local tumor control and overall survival. Efforts to improve feasibility of RFA especially for inconspicuous target have to be made.",
"affiliations": "Department of Diagnostic and Interventional Imaging, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Department of Radiology, Hôpital Jean Verdier (Assistance Publique-Hôpitaux de Paris), Bondy, France.;Department of HepatoGastroenterology and Digestive oncology, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Department of Diagnostic and Interventional Imaging, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Department of Diagnostic and Interventional Imaging, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Inserm, Génomique Fonctionelle des Tumeurs Solides, Paris, France.;Department of Diagnostic and Interventional Imaging, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.",
"authors": "Hocquelet|Arnaud|A|;Seror|Olivier|O|;Blanc|Jean-Frédéric|JF|;Frulio|Nora|N|;Salut|Cécile|C|;Nault|Jean-Charles|JC|;Trillaud|Hervé|H|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.12921",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 277930271292110.18632/oncotarget.12921Clinical Research PaperTransarterial chemoembolization for early stage hepatocellular carcinoma decrease local tumor control and overall survival compared to radiofrequency ablation Hocquelet Arnaud 12Seror Olivier 3Blanc Jean-Frédéric 4Frulio Nora 1Salut Cécile 1Nault Jean-Charles 5Hervé Trillaud 121 Department of Diagnostic and Interventional Imaging, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France2 EA IMOTION (Imagerie Moléculaire et Thérapies Innovantes en Oncologie) Université de Bordeaux, Bordeaux, France3 Department of Radiology, Hôpital Jean Verdier (Assistance Publique-Hôpitaux de Paris), Bondy, France4 Department of HepatoGastroenterology and Digestive oncology, Hôpital Saint-André, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France5 Inserm, Génomique Fonctionelle des Tumeurs Solides, Paris, FranceCorrespondence to: Arnaud Hocquelet, arnaud.hocquelet@gmail.com9 5 2017 26 10 2016 8 19 32190 32200 7 6 2016 21 10 2016 Copyright: © 2017 Hocquelet et al.2017This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background & Aims\nTo compare treatment failure and survival associated with ultrasound-guided radiofrequency ablation (RFA) and trans-arterial chemoembolization (TACE) for early-stage HCC in Child-Pugh A cirrhosis patients.\n\nMethods\n122 cirrhotic patients (RFA: 61; TACE: 61) were well matched according to cirrhosis severity; tumor size and serum alpha-fetoprotein. TACE was performed in case of inconspicuous nodule on US or nodule with “at risk location”. Treatment failure was defined as local tumor progression (LTP) and primary treatment failure (failing to obtain complete response after two treatment session). Treatment failure and overall survival (OS) were compared after coarsened exact matching. Cox proportional model to assess independent predictive factors was performed.\n\nResults\nNo significant difference was seen for baseline characteristics between the two groups. Mean tumor size was 3cm in both group with 41% HCC>3cm. Treatment failure rates after TACE was 42.6% (14 primary treatment failures and 12 LTP) and 9.8% after RFA (no primary treatment failure and 6 LTP) P < 0.001. TACE was the only predictive factor of treatment failure (Hazard ratio: 5.573). The 4-years OS after RFA and TACE were 54.1% and 31.5% (P = 0.042), respectively.\n\nConclusion\nFor Child-Pugh A patients with early-stage HCC, alternative treatment as supra-selective TACE to RFA regarded as too challenging using common US guidance decrease significantly the local tumor control and overall survival. Efforts to improve feasibility of RFA especially for inconspicuous target have to be made.\n\nchemoembolizationtherapeuticradiofrequency ablationcarcinomahepatocellular\n==== Body\nINTRODUCTION\nHepatocellular carcinoma (HCC) is the fifth most common cancer and the second cause of cancer-related deaths [1]. As recommended by EASL clinical practice guidelines [1] single hepatocellular carcinoma and up to three hepatocellular carcinoma < 3cm should be treated by transplantation, surgery resection (SR) or radiofrequency ablation (RFA). Due to the lack of transplants from cadaveric donors RFA is the first-line treatment for unresectable Child Pugh A HCC patients. Although TACE is recommended only for BCLC B HCC [1], this treatment is the most performed worldwide and it is frequently used for early-stage HCC. Indeed, thirty per cent of RFA can't be performed under ultrasound guidance because of tumor invisibility [2] and 15% of RFA are not performed due to the “high-risk” location of the tumor [3]. Recent progress in imaging guidance as imaging fusion [4, 5] or cone-beam CT [6, 7] and using artificial pleural effusion or ascitis [3, 8], [9] have drastically reduced the RFA infeasibility rate. However these devices are mainly available on specialized tertiary centers, When not available, supra-selective transarterial chemoembolization (segmental or subsegmental tumor feeding embolization) (TACE) [10] is frequently used as first-line treatment [11]. Furthermore several studies concluded that supra-selective TACE allows achievement of long-term survival rates comparable to RFA for early-HCC [12–14]. These studies explained the similar outcome by a less satisfactory effect of RFA on medium tumors (3-5 cm in diameter) and the ability of TACE treating satellite nodules. Indeed monopolar radiofrequency device offered a weak local disease control and complete necrosis for HCC larger than 3cm [15, 16]. RFA technologies have been improved. No touch multi-bipolar RFA offered a larger complete necrosis rate than monopolar devices for medium HCC [16–19] and avoids the need of intra tumorous puncture. So it appeared as more suitable ablative technique for inconspicuous target with ultrasound or medium size HCC on condition to use proper advanced guidance imaging. Thus because main causes of infeasibility of RFA are nowadays resolved, it is of major interest to value if supra-selective TACE can compete with RFA as first line treatment in curative intent for HCC ≤5cm. The aim of this study was to compare the treatment failure (defined as local tumor progression and failing to obtain complete response) and the following overall survival in Child-Pugh A cirrhotic patients after RFA versus supra-selective TACE as first line treatment for HCC ≤5cm criteria using coarsened exact matching.\n\nRESULTS\nAmong the 234 patients with HCC≤5cm (Figure 1), 122 Child A cirrhotic patients treated either by RFA (n = 61) or TACE (n = 61) were matched.\n\nFigure 1 Flow-chart\nBaseline characteristics of RFA and TACE group\nThe mean tumor size was 30.2 (±10) mm in RFA group and 31 (±10) mm in TACE group (p = 0.399). 41% of patients in each treatment groups had HCC > 30mm. No significant difference between both groups was seen for baseline characteristics and patients were perfectly matched according to tumor size and serum AFP strata (Table 1). TACE was chosen as first-line treatment due to: inconspicuous nodule on US for 33 patients (54%); subcapsular location for 10 patients (16.4%) and “at risk location” for 18 patients (29.5%) [13 near hepatic hilum; 2 near colon; <1 near stomach; 1 near the inferior vena cava and one near a sus-hepatic venous].\n\nTable 1 Demographics and clinical characteristics of Child-Pugh A patients who received radiofrequency ablation (RFA) and transaterial chemoembolization (TACE) for hepatocellular carcinoma (N = 122)\n\tRFA group (n = 61)\tTACE group (n= 61)\tP value\t\nAge**\t67 (11)\t67 (11)\t0.919\t\nMale\nn\n(%)\t50 (82)\t47 (77)\t0.501\t\nBMI**\t27.8 (4.7)\t27.6 (5)\t0.892\t\nPlatelet count (G/L)*\t122 (86-162)\t121 (81-160)\t0.706\t\nEtiologies:\n∙ HCV\n∙ Non-viral\n∙ Mixed\t13 (21)\n42 (69)\n6 (10)\t14 (23)\n40 (66)\n7 (11)\t0.922\t\nAFP (ng/ml)*\t10 (5-42)\t10 (4-43)\t0.350\t\nAFP (categorical)\nn\n(%)\n- <10 ng/ml\n- 10-100 ng/ml\n- >100ng/ml\t30 (49)\n19 (31)\n12 (20)\t30 (49)\n19 (31)\n12 (20)\t1\t\nTumor size (cm)**\t30.2 (10)\t31 (10)\t0.399\t\nTumor size (categorical)\nn\n(%)\n-\n<2 cm\n- 2-3 cm\n- 3.1-5 cm\t8 (13)\n28 (46)\n25 (41)\t8 (13)\n28 (46)\n25 (41)\t1\t\nMultiple nodules: n\n(%)\t14 (23)\t19 (31)\t0.308\t\n*median (1 and 3 quartiles) and compared with Wilcoxon rank-sum test\n\n** Mean (Standard Deviation) and compared with two sided T-test\n\nCategorical variables are: n (%).\n\nAbbreviations: BMI= Body Mass Index; HCV= Hepatitis C virus; AFP= Alpha-Foeto-protein;\n\nIn RFA group, Monopolar device was used for 19 patients (31%) and multipolar devices for 42 patients (69%) (including the 25 patients with HCC > 3cm).\n\nThe mean follow-up was 2.7 years (±1.9); the median follow-up was 2.25 years.\n\nSurvival status at the end of the study was available for 121/122 patients. One patient was lost to follow-up in RFA group after 5.58 years. The rate of liver transplantation did not differ between the two groups, 13% (8/61) in RFA group and 11% (7/61) in TACE group, p = 0.783. The mean and median time to transplantation were 2.01 years (range: 0.42-5.44) and 2.03 years (1-3 quartiles: 0.98-2.8), respectively.\n\nMedian hospitalization duration was 2 days (range: 2-6) in RFA group and 2 days (range 2-7) in TACE group, p = 0.902.\n\nTreatments failure and predictive factor\nA complete response (CR) was achieved in 100% of patients in RFA group, with 4 patients (6.5%) requiring two ablative sessions. A CR was observed for 47 patients (77%) in TACE group, after one session for 28 patients (59.5%), two sessions for 19 patients (40.5%). The rates of CR and the number of treatment session to achieve it were significantly different between both groups, p < 0.001 for both. Eight patients (13.1%) treated by TACE experienced partial response, two (3.2%) stable diseases and four (6.5%) progressive diseases as best treatment response.\n\nLocal tumor progression was observed in 9.8% of patients after RFA (6/61) versus 25 % of patients after TACE (12/47), p = 0.03.\n\nConsequently, the rate of treatment failure (primary treatment failure and LTP) was significantly higher after TACE (42.6%) than after RFA (9.8%), p < 0.001 (Figure 2).\n\nFigure 2 Cumulative incidence of treatment failure after radiofrequency ablation and transarterial chemoembolization\nAccording to tumor size, < 2cm; 2-3cm and 3.1-5cm, treatment failure rates for RFA and TACE were respectively, 12.5% (1/8), 10.7% (3/28) and 8% (2/25) versus 50% (4/8), 32% (9/28) and 52% (13/25).\n\nIn uni and multivariate analysis (Table 2), supra selective TACE was the only predictive factor of treatment failure, with hazard ratio (95% CI): 5.573 (2.281 -13.62), P < 0.001.\n\nTable 2 Predictive factor of treatment failure (primary treatment failure and local tumor progression)\nVariable\tUnivariate analysis\tMultivariate analysis\t\n\tP\tHazard ratio (95%CI)\tP\tHazard ratio (95%CI)\t\nAge (years)\t0.503\t0.988 (0.955-1.022)\t\t\t\nSex (Male) (%)\t0.151\t0.578 (0.273-1.218)\t\t\t\nBMI\t0.391\t0.968 (0.899-1.042)\t\t\t\nPlatelet count (<100G/L)\t0.517\t1.268 (0.618-2.602)\t\t\t\nNon-Viral hepatitis\t0.227\t1.357 (0.827-2.228)\t\t\t\nAFP>100 ng/ml\t0.250\t1.605 (0.716-3.598)\t\t\t\nHCC>3cm\t0.306\t1.453 (0.710-2.974)\t\t\t\nMultiple nodules\t0.542\t1.272 (0.586-2.760)\t\t\t\nTACE (vs\nRFA)\t<0.001\t5.573 (2.281 -13.62)\t<0.001\t5.573 (2.281 -13.62)\t\nAbbreviations: BMI= Body Mass Index; ALT= Alanine Amino Transferase; AFP= Alpha-Foeto-protein; HCC= HepatoCellular Carcinoma; RFA= Radiofrequency ablation; TACE= transarterial chemoembolization.\n\nPathological examination of initially treated tumors performed on explanted livers showed a mean necrosis percentage of 96% (range: 80-100) after RFA versus 61.4% (range: 20-100) after TACE (p = 0.008). In RFA group with explanted liver examination (n = 8), six patients showed complete tumor necrosis, 1 tumor necrosis equal to 90% and one 80%. In TACE group with explanted liver pathological examination (n = 7), only one patient showed complete tumor necrosis, one equal to 80%, two 70%, one 50%, one 40% and one 20%.\n\nOverall survival\n4-years overall survival for RFA and TACE groups were respectively 54.1% - versus 31.5%, with a mean and median overall survival of 4.6 years (95% CI: 3.6-5.5) and 4.9 years (95% CI: 3.6-6.3) in RFA group versus 3.7 years (95% CI: 12.8-4.5) and 2.4 years (1.7-3.1) in TACE group, p = 0.042 (Figure 3A).\n\nFigure 3 A. overall survival comparison between radiofrequency ablation and trans-arterial chemoembolization; B. Progression-free survival comparison between radiofrequency ablation and trans-arterial chemoembolization\nThe factors used to predict overall survival are summarized in Table 3. In univariate analysis, primary treatment failure (p < 0.001), TACE (p = 0.045), multiple nodules (p = 0.019) and serum AFP > 100ng/ml (p = 0.049) were significantly associated with overall survival. In multivariate analysis with the Cox proportional hazards model, primary treatment failure (Hazard Ratio [95% CI]: 4.163 [2.088-8.298]; p < 0.001) and multiple nodules (2.257 [1.261-4.039]; p = 0.006) were found to be independent predictive factor associated with overall survival.\n\nTable 3 Univariate and multivariate cox analysis for factors associated with overall survival for hepatocellular carcinoma patients treated by radiofrequency ablation (RFA) or transarterial chemoembolization (TACE) (n = 122)\nVariable\tUnivariate analysis\tMultivariate analysis\t\n\tP\tHazard ratio (95%CI)\tP\tHazard ratio (95%CI)\t\nAge (years)\t0.922\t0.998 (0.973-1.024)\t\t\t\nSex (Male) (%)\t0.727\t0.891 (0.468-1.696)\t\t\t\nBMI\t0.097\t0.952 (0.899-1.008)\t\t\t\nPlatelet count (<100G/L)\t0.119\t1.537 (0.895 -2.640)\t\t\t\nNon-Viral hepatitis\t0.527\t1.122 (0.656-2.274)\t\t\t\nAFP>100 ng/ml\t0.049\t1.799 (1.00 -3.230)\t\t\t\nHCC>3cm\t0.641\t1.138 (0.660-1.963)\t\t\t\nMultiple nodules\t0.019\t1.987 (1.122-3.519)\t0.006\t2.257 (1.261-4.039)\t\nPrimary treatment failure\t<0.001\t3.641 (1.853-7.154)\t<0.001\t4.163 (2.088-8.298)\t\nTACE (vs\nRFA)\t0.045\t1.746 (1.012-3.012)\t\t\t\nAbbreviations: BMI= Body Mass Index; ALT= Alanine Amino Transferase; AFP= Alpha-Foeto-protein; HCC= HepatoCellular Carcinoma; RFA= Radiofrequency ablation; TACE= transarterial chemoembolization.\n\nTreatments complications\nTwo major adverse events occurred after TACE: One treatment-related death in a 79 year-old cirrhotic patient with Alzheimer disease. He died twenty-eight days after TACE due to lung infection without liver failure. The other major complication was a liver failure requiring a prolonged hospitalization > 48 hours. In RFA group the major adverse event was abscess developed on ablation site, in the Couinaud segment 2. The rates of adverse event did not differ between the two groups (p = 1, by Fisher exact test).\n\nProgression-free survival (local or intra-hepatic distant recurrence)\nThe 4-years progression-free survival for RFA and TACE groups were respectively 29.7% versus 3% (Figure 3B) with a mean and median progression-free survival of 2.5 years (95% CI: 1.8, 3.1) and 1.4 years (95% CI: 0.601, 2.7) in RFA group versus 1.4 years (95% CI: 1.1-1.7) and 0.95 years (0.6-1.3) in TACE group, p = 0.009.\n\nFactors associated with progression-free survival are summarized in Table 4. In univariate analysis, primary treatment failure (p < 0.001) and TACE (p = 0.011) were significantly associated with progression-free survival. In multivariate analysis with the Cox proportional hazards model, primary treatment failure was the only predictive factor associated with progression-free survival, Hazard Ratio: 3.976 (95% CI: 2.175-7.267), p < 0.001. Nineteen patients (31%) in RFA group and 27 patients (44%) in TACE group experienced recurrence beyond Milan criteria: 5 secondary to tumor size (3 after RFA and 2 after TACE); 22 secondary to intra-liver multifocal recurrences (7 in RFA and 15 in TACE); 8 secondary to infiltrative HCC (6 in RFA group and 2 in TACE group); 7 secondary to intra-vascular tumoral extension (1 after RFA and 6 after TACE); 3 secondary to lung (n = 1), adrenal gland (n = 1) or lymph node (n = 1) metastasis (one after RFA and 2 after TACE) and one due to intra-ductal recurrence (1 after RFA and none after TACE).\n\nTable 4 Univariate and multivariate cox analysis for predictive factor of HCC recurrence\nVariable\tUnivariate analysis\tMultivariate analysis\t\n\tP\tHazard ratio (95%CI)\tP\tHazard ratio (95%CI)\t\nAge (years)\t0.110\t0.983 (0.63-1.003)\t\t\t\nSex (Male) (%)\t0.944\t0.981 (0.583-1.650)\t\t\t\nBMI\t0.720\t0.992 (0.950-1.036)\t\t\t\nPlatelet count (<100G/L)\t0.232\t1.304 (0.843-2.016)\t\t\t\nNon-Viral hepatitis\t0.227\t1.357 (0.827-2.228)\t\t\t\nAFP>100 ng/ml\t0.100\t1.521 (0.911-2.539)\t\t\t\nHCC>3cm\t0.707\t1.008 (0.709-1.657)\t\t\t\nMultiple nodules\t0.171\t1.385 (0.869-2.209)\t\t\t\nPrimary treatment failure\t<0.001\t3.976 (2.175-7.267)\t<0.001\t3.976 (2.175-7.267)\t\nTACE (vs\nRFA)\t0.011\t1.753 (1.138-2.701)\t\t\t\nAbbreviations: BMI= Body Mass Index; ALT= Alanine Amino Transferase; AFP= Alpha-Foeto-protein; HCC= HepatoCellular Carcinoma; RFA= Radiofrequency ablation; TACE= transarterial chemoembolization\n\nDISCUSSION\nIn this study, we investigated the local tumor control and survival benefits of RFA and TACE with a coarsened exact matching method. It provided a perfect matching for tumor size and serum AFP strata. When RFA cannot be performed under US guidance due to inconspicuous nodule, TACE appears like an attractive treatment alternative especially for HCC≤5cm, if cone-beam CT, CT-Scan or imaging fusion guidance are not available. However the rate of primary treatment failure (failing to achieve complete response) following TACE reached 23% in our cohort and 25% in Kim et al study [14] that is significantly higher than RFA (no primary treatment failure), p < 0.001. Beyond primary treatment failure, RFA can produce supra centimeter safety margin that limit the local recurrence rate [20, 21]. At odds supra-selective cTACE does not seems able to produce safety margin [22] due to the lack of portal vein embolization [23] that lead to a high local recurrence rate (25% in our study) despite primary treatment success. So treatment failure rates reached 42.6% after TACE versus 9.8% after RFA (p < 0.001). LTP and primary treatment failure are both predictive factor of poor outcome [24] as illustrated by the multivariate cox model selecting primary treatment failure as the main prognostic factor of OS (HR: 4.163) and PFS (HR: 3.976). Despite a high mean tumor size (3cm in each group) with 41% of patients with tumor > 3cm, we did not observed an increase of treatment failure using RFA for HCC > 3cm (around 10%) while Kim et al [15] and Cartier et al [19] reported a LTP rate > 70% for medium size HCC using Monopolar RFA. This excellent local tumor control for 3.1-5 cm HCC is explained by using multipolar devices that offer a larger and more homogeneous necrotic area [16, 17, 25–27] than monopolar devices even using overlapping technic [28]. Several authors [15, 29] tested the combination of monopolar RFA with TACE for HCC < or = 5 cm. Compared with RFA alone, improvement of LTP have been reported only for tumor > or = 3 cm in diameter. This strategy could be also interesting for tumor inconspicuous at unenhanced imaging (US or CT).\n\nThe 4-years overall survival after RFA and TACE were similar to previous publication studying western cirrhotic patients [30, 31] but at odds to previous eastern studies [12, 14], RFA offered a better OS than supra-selective TACE for HCC≤5cm (P = 0.042). The better OS and PFS provided by RFA compared to TACE could be explained par the lower rate of treatment failure but also by the higher rate of complete pathological tumor necrosis provided by RFA. Indeed on the explanted liver pathological examination we found that 6/8 (75%) tumor treated by RFA were completely necrosis while only 1/7 (14.2%) tumor treated by TACE showed complete necrosis. Allard et al [32] emphasized a clear benefice of a pathological tumor necrosis higher than 90% after TACE on survival after liver transplantation or liver resection. On the same line, Seror et al [17] published that pathological complete necrosis is achieved in more than 90% of cases using no touch multibipolar RFA while the rate of pathological complete necrosis is around 60% after TACE [33]. Moreover, recently drug-eluted beads TACE (DEB-TACE) appears as the main alternative to Lipiodol-TACE with a better pharmacological profile but without translation in better tumor response or survival in multicentric propective trials [34, 35].\n\nConsidering the better local tumor control leading to better OS and PFS offered by RFA compared to TACE, RFA should be the standard treatment used as first-line. In case of inconspicuous nodule, TACE should be considered, only when the tumor still unnameable to RFA using advanced technologies for ablation like multibipolar RFA and or for imaging guidance like CT, US fused with CT or MRI or Cone-Beam CT or guidance Indeed Cone-Beam CT since using these techniques 100% primary treatment success has been reported in preliminary reports [6, 7].\n\nNevertheless, our study has several limitations. The main limitation is the retrospective design although we used coarsened exact matching to avoid selection bias and none patient was lost to follow-up at 5 years. In our study, HCC treated by TACE were mostly inconspicuous on US and or in challenging location for electrode placement. Although this characteristic in our knowledge has never been associated with more aggressive natural tumor grow pattern, it is possible that in that circumstance the trickier radiofrequency needle placement even assisted with advanced imaging-guidance, leads to a higher rate of local tumor progression compared to easier radiofrequency treatment.\n\nNo systematic pre-treatment tumor biopsies are performed so tumor differentiations are not known, and cannot be included in matching model.\n\nDespite a high complete response rate (77%), supra-selective TACE is associated with a higher treatment failure (local tumor progression and primary treatment failure) and lower overall survival than RFA using mainly multipolar device. In case of inconspicuous nodule≤5cm, all efforts have to be made using proper technologies (ablation and guidance) to perform RFA rather than TACE.\n\nPATIENTS AND METHODS\nThe study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki and was approved by the institution's human research committee. Informed consent was not necessary for this retrospective analysis of our data.\n\nPatients\nPatients’ data were collected from a prospectively maintained and computerized database recording: age, sex, cirrhosis etiology, Child score, Platelet count, serum α-fetoprotein level (AFP), number and size of HCC, treatment, results of pathological radiological and pathological examinations. We included all consecutive cirrhotic, Ecog-0 and child-Pugh A patients with single HCC ≤ 5cm or ≤ three nodules ≤3 cm unsuitable for surgery, without extrahepatic metastasis (early-stage HCC), treated by first line RFA or supraselective TACE from January 2004 to December 2013 according the decision of local tumor boards. Additional criteria were: (i) Child-Pugh A; (ii) no other cancer. Exclusion criteria were: (i) Child-Pugh B; (ii) lost-to-follow-up before the first imaging control; (iii) combined treatment (RFA plus TACE or RFA plus surgery); (iv) treated by microwaves ablation; (v) ill-defined tumor. Then patients were matched in two groups according to treatment type: (i) RFA; (ii) TACE according to demographic data, surrogate marker of cirrhosis severity, serum AFP and tumor characteristics.\n\nDiagnosis of HCC\nAll patients were cirrhotic. Cirrhosis was histologically proven for 55 patients (45%), and based on liver stiffness, imaging and blood sample analysis for the 67 remaining patients (55%). Non-invasive criteria of the European Association for the Study of the Liver (EASL) were used to diagnose HCC in cirrhotic patients [1]. Diagnosis was performed on multiphase liver MRI or CT-Scan. Nodule was diagnosed as HCC if it was hypervascular in the arterial phase with washout in the portal venous or delayed phases (n = 83, 68%). Tumor biopsies with pathologic confirmation were performed for patients who did not meet the non-invasive diagnostic criteria (n = 39, 32%).\n\nRadiofrequency ablation\nAll RFA procedures were performed percutaneously under general anaesthesia. Real-time ultrasound (US) with a 4-MHz probe was chosen as guidance modality for all patients. Five senior interventional radiologists (at least five years of experience) performed RFA using one of the following devices: monopolar expandable Boston LeVeen ™ needles (RF 3000 Boston Scientific Corporate®), or multipolar internally cooled-tip CelonProSurge™ (CelonPOWER System OLYMPUS Medical®) (available in our center since 2006) [18]. The device was chosen based on the operator's expertise, the tumour shape, size, location and vascular proximity. Operators used multipolar device for ≥ 3cm and in case of vascular proximity. The thermal ablation was performed according to the manufacturer's instructions. Real-time procedure control of RFA was performed with ultrasound examination.\n\nTACE procedure\nThe same interventional radiologist performing RFA have performed supraselective TACE (at least five years experience). Portal vein permeability was checked by ultrasound examination before TACE. The transfemoral approach was carried out under local anaesthesia using 4-Fr angiographic catheters. The coeliac and hepatic arteries were catheterized with Cobra or Simmons 4-Fr (Terumo); next segmental and subsegmental tumor feeding arteries was catheterized using micro-catheter PROGREAT (Terumo) 2.8-Fr. An emulsion of 10ml iodized oil (Lipiodol; Andre Guerbet, France) and doxorubicin hydrochloride (50mg in 10 ml) was infused through the feeder vessels. Then embolization was performed using a mixture of gelatin sponge particles and contrast material until reaching a stasis flux.\n\nTreatment choice\nTreatments were decided upon in a multidisciplinary team meeting and the treatment option was chosen based on guidelines [1]. For early-stage HCC unsuitable for surgery, RFA was the first-line treatment. Before that protective manoeuvre as hydrodiscection and/or advanced guidance technologies as fusion US-CT or MR became routinely used or available in our center we preferably chose TACE for inconspicuous nodule on US or nodule with “at risk location” (near gallbladder, bile duct or gastro-intestinal tract). In case of local tumor progression, if HCC was seen on US examination RFA was the first treatment choice, if not TACE was performed.\n\nPatient follow up\nOncologic follow-up was performed with MRI (or CT-scan in case of contra-indication of MRI) at one month and then each three months for the liver and by chest CT-scan every six months. For TACE, the one-month follow-up consisted in an association of liver MRI and Thoracoabdominal unhanced-CT-scan to evaluate the tumor iodized oil labeling.\n\nStudy endpoint\nTreatment failure\nThe main endpoint of the study was to compare treatment failure rates defined as primary treatment failure or local tumor progression during follow-up [19]. Primary treatment failure was defined as failing to achieve complete treatment response according to mRECIST after up to two TACE or RFA. Local tumor progression (LTP) described by the appearance of tumor foci at the edge of the ablation zone, after at least one contrast-enhanced follow-up study has documented adequate ablation and an absence of viable tissue in the target tumor by using imaging criteria. This term applies regardless of when tumor foci were discovered either early or late in the course of imaging follow-up [36].\n\nSurvival\nSecondary endpoints were to compare: (i) overall survival defined as time to last follow-up evaluation or death (patients with liver transplantation were censored at the date of transplantation) measured from the date of treatment; (ii) Progression-Free survival defines as the time interval between initial treatment and radiological progression (local or intra-hepatic distant recurrence).\n\nComplications\nPost-treatment morbi-mortality was collected and perioperative mortality was defined as death within 30 days of treatment. Morbidity was stratified as recommended by the Society of Interventional Radiology [37].\n\nStatistical analysis\nTo control selection bias and provide a more accurate matching on prognosis factor than using only propensity score we used one-to-one coarsened exact matching (CEM). Briefly, The idea of CEM is coarsen each variable into substantively meaningful groups on then to perform exact match on these coarsened data [38]. CEM was performed using three variables: Tumor size (categorized as < 20mm; 20-30mm and > 30mm); Serum AFP (categorized as < 10ng/ml; 10-100ng/ml and > 100ng/ml); and a propensity score variable including: age, sex, BMI, tumor number, platelet count and cirrhosis etiology. The propensity score variable was categorized with a caliper of 0.2. Tumor size and serum AFP were included separately in CEM to achieve exact matching on them because they are the main prognostic factors of survival and recurrence [24, 27, 30].\n\nData are expressed as mean (±standard deviation) or median (1st-3rd quartiles) and compared using either the two-sample t-test or the Mann-Whitney test, according to data distribution. Percentages were compared using the Chi-2 test or Fisher's exact test. Survival without treatment failure and overall survival were computed by the Kaplan-Meier method and compared by the log-rank test. To identify factors associated with treatment failure; we first performed univariate analysis using univariate Cox regression. Variables with p < 0.1 were then introduced in a multivariate Cox Model and hazard ratios (HR) and corresponding 95% confidence intervals (CI) reported. Patients with primary treatment failure were censored at the date of the second treatment session. Two-sided statistical tests were used for all analyses. A p-value < 0.05 was considered as significant. Statistical analyses were performed with Stata 13.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflicts of interest.\n\nFINANCIAL SUPPORT\n\nNo financial support was received for this study.\n\nAbbreviations and acronyms\nHCCHepatocellular carcinoma\n\nSRsurgery resection\n\nRFAradiofrequency ablation\n\nTACEtransarterial chemoembolization\n\nCRcomplete response\n\nLTPlocal tumor progression\n\nCEMCoarsened exact matching\n==== Refs\nREFERENCES\n1 European Association For The Study Of The Liver, European Organisation For Research And Treatment Of Cancer EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma J Hepatol 2012 56 908 43 10.1016/j.jhep.2011.12.001 22424438 \n2 Kim JE Kim YS Rhim H Lim HK Lee MW Choi D Shin SW Cho SK Outcomes of patients with hepatocellular carcinoma referred for percutaneous radiofrequency ablation at a tertiary center: analysis focused on the feasibility with the use of ultrasonography guidance Eur J Radiol 2011 79 e80 84 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"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(19)",
"journal": "Oncotarget",
"keywords": "carcinoma, hepatocellular; chemoembolization, therapeutic; radiofrequency ablation",
"medline_ta": "Oncotarget",
"mesh_terms": "D000368:Aged; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular; D017115:Catheter Ablation; D016461:Chemoembolization, Therapeutic; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D012008:Recurrence; D017211:Treatment Failure; D016896:Treatment Outcome; D047368:Tumor Burden",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "32190-32200",
"pmc": null,
"pmid": "27793027",
"pubdate": "2017-05-09",
"publication_types": "D016428:Journal Article",
"references": "26414644;26365503;27010381;26455721;21512046;24757660;16628706;21445671;21514757;27422750;25646884;15333339;21351114;18483229;27156743;24937669;24475823;19559998;20672352;24147489;20410393;21506244;23921081;24927329;24935276;19557416;24529547;19731239;17377182;11566672;26074360;23332890;22424438;25373799;24520944",
"title": "Transarterial chemoembolization for early stage hepatocellular carcinoma decrease local tumor control and overall survival compared to radiofrequency ablation.",
"title_normalized": "transarterial chemoembolization for early stage hepatocellular carcinoma decrease local tumor control and overall survival compared to radiofrequency ablation"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1043218",
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"occurcountry": "FR",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": "3",
... |
{
"abstract": "The misuse of nootropics-any substance that may alter, improve, or augment cognitive performance, mainly through the stimulation or inhibition of certain neurotransmitters-may potentially be dangerous and deleterious to the human brain, and certain individuals with a history of mental or substance use disorders might be particularly vulnerable to their adverse effects. We describe four cases of probable nootropic-induced psychiatric adverse effects to illustrate this theory. To the best of our knowledge this has not been previously reported in the formal medical literature. We briefly describe the most common classes of nootropics, including their postulated or proven methods of actions, their desired effects, and their adverse side effects, and provide a brief discussion of the cases. Our objective is to raise awareness among physicians in general and psychiatrists and addiction specialists in particular of the potentially dangerous phenomenon of unsupervised nootropic use among young adults who may be especially vulnerable to nootropics' negative effects.",
"affiliations": "Dr. Talih is an assistant professor and Dr. Ajaltouni is a research fellow at the American University of Beirut Medical Center Department of Psychiatry.;Dr. Talih is an assistant professor and Dr. Ajaltouni is a research fellow at the American University of Beirut Medical Center Department of Psychiatry.",
"authors": "Talih|Farid|F|;Ajaltouni|Jean|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2158-8333",
"issue": "12(11-12)",
"journal": "Innovations in clinical neuroscience",
"keywords": "Nootropics; cognitive enhancers; psychiatric adverse effects; substance abuse; substance misuse; supplements",
"medline_ta": "Innov Clin Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101549695",
"other_id": null,
"pages": "21-5",
"pmc": null,
"pmid": "27222762",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "7639963;24532997;21484242;23881879;12417966;19536360;8234409;22514795;11145001;19663523;24950234;10088135;7954803;12006732;10224305;19151103;10217926;8734838;15121488;20043005;17119538;20163115;17504103",
"title": "Probable Nootropicinduced Psychiatric Adverse Effects: A Series of Four Cases.",
"title_normalized": "probable nootropicinduced psychiatric adverse effects a series of four cases"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0080828",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
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{
"abstract": "OBJECTIVE\nPatients with malignant lung cancer often develop a solitary pulmonary nodule after treatment of the initial cancer. In those cases, it is difficult to distinguish primary lung cancer (PLC) from lung metastasis. Therefore, both local therapy for a single lung lesions and systemic therapy for micrometastases are needed. This retrospective study aimed to evaluate the safety and tolerability of concurrent stereotactic body radiation therapy (SBRT) and chemotherapy in patients with metachronous PLC.\n\n\nMETHODS\nWe reviewed the records of 10 patients with metachronous PLC treated with SBRT and concurrent chemotherapy with curative intent from 2007 to 2013. The delivered radiation dose was 48 Gy in four fractions.\n\n\nRESULTS\nAll patients received SBRT with concurrent chemotherapy on schedule. Complete response rate was 90%. Safety profile of this treatment was compatible with that of traditional chemoradiotherapy.\n\n\nCONCLUSIONS\nOur study showed good feasibility and safety for SBRT with concurrent chemoradiotherapy.",
"affiliations": "Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan jumpeinr2tfm3@fbri.org.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Radiation Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.;Division of Radiation Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan Department of Radiation Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Division of Integrated Oncology, Institute of Biomedical Research and Innovation, Kobe, Japan.",
"authors": "Takeshita|Jumpei|J|;Masago|Katsuhiro|K|;Kato|Ryoji|R|;Otsuka|Kyoko|K|;Okuda|Chiyuki|C|;Hata|Akito|A|;Kaji|Reiko|R|;Fujita|Shiro|S|;Takayama|Kenji|K|;Kokubo|Masaki|M|;Katakami|Nobuyuki|N|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(5)",
"journal": "Anticancer research",
"keywords": "Non-small cell lung cancer; inoperable; metachronous; platinum doublets; stage I",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D016634:Radiosurgery",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "3103-7",
"pmc": null,
"pmid": "25964602",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A new strategy for metachronous primary lung cancer: stereotactic body radiation therapy with concurrent chemotherapy.",
"title_normalized": "a new strategy for metachronous primary lung cancer stereotactic body radiation therapy with concurrent chemotherapy"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2015INT000678",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "A 30-year-old lady treated with capecitabine for primary colon adenocarcinoma developed liver lesions suspicious for metastasis. Liver biopsies showed sinusoidal dilatation thought to be secondary to capecitabine. This case highlights the importance of differentiating between benign and malignant liver lesions during cancer surveillance preventing unnecessary liver resections for benign disease.",
"affiliations": "Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.;Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.;Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.;Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.;Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.;Department of General Surgery Whittington Health Magdala Avenue London N19 5NF UK.",
"authors": "Groom|Katherine|K|;Penna|Marta|M|;Arul|Dhili|D|;Steward|Michael|M|;Leonard|Pauline|P|;Wilson|Jonathan|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.539",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.539CCR3539Case ReportCase ReportsCapecitabine‐related liver lesions: sinusoidal dilatation mimicking liver metastasis K. Groom et al.Groom Katherine \n1\nPenna Marta \n1\nArul Dhili \n1\nSteward Michael \n1\nLeonard Pauline \n1\nWilson Jonathan \n1\n1 Department of General SurgeryWhittington HealthMagdala AvenueLondonN19 5NFUK* Correspondence\n\nJonathan Wilson, Department of General Surgery, Whittington Health, Magdala Avenue, London N19 5NF, UK. Tel: (+44) 020 7288 5406; Fax: 0207 288 5538; E‐mail: jonathan.wilson2@nhs.net\n21 4 2016 6 2016 4 6 10.1111/ccr3.2016.4.issue-6545 548 21 1 2015 01 2 2015 15 2 2015 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nA 30‐year‐old lady treated with capecitabine for primary colon adenocarcinoma developed liver lesions suspicious for metastasis. Liver biopsies showed sinusoidal dilatation thought to be secondary to capecitabine. This case highlights the importance of differentiating between benign and malignant liver lesions during cancer surveillance preventing unnecessary liver resections for benign disease.\n\nCapecitabinecolonic adenocarcinomaliver lesionssinusoidal dilatation source-schema-version-number2.0component-idccr3539cover-dateJune 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.1 mode:remove_FC converted:06.07.2016Consent: The patient has given their informed consent for the case report to be published.\n==== Body\nIntroduction\nCapecitabine (trade name Xeloda) is an orally administered chemotherapeutic drug used in cancer treatment. It is most commonly administered in the treatment of colorectal and breast cancer as both a neo‐adjuvant and adjuvant agent, as well as in metastatic disease, either as a single agent or in combination with other agents. It is also used in gastric and esophageal cancers. Capecitabine is a prodrug that is converted to 5‐fluorouracil (5‐FU) in the body, which then irreversibly inhibits thymidylate synthesis, interrupting its role in DNA synthesis. The conversion into 5‐FU preferentially occurs in tumor cells but also takes place in the liver by a three‐step enzymatic cascade. Capecitabine has been associated with mild liver damage most notably causing hepatic steatosis and has more recently been reported to have a possible association with sinusoidal obstruction syndrome (SOS) 1. Other drugs containing 5‐FU and oxaliplatin are known to cause veno‐occlusive hepatic injury as well as fatty change in the liver. The recognition and awareness of such adverse effects is important when managing patients taking these chemotherapeutic agents, and more documentation in the literature is required.\n\nCase Presentation\nA 30‐year‐old lady presented with a 7‐month history of intermittent rectal bleeding. This was initially associated with constipation and perianal pain. She noticed bright red blood both separate to and coating the stool. She denied any weight loss or abdominal pain. She was otherwise fit and well with no other significant past medical history. With regard to her family history, her mother suffered from irritable bowel syndrome and had a benign polyp removed in her 40s. Her maternal and paternal grandparents both had lung cancer while her maternal grandmother had gallbladder cancer. She did not take any regular medications and had no known drug allergies. She was a non‐smoker and drank 10–14 units of alcohol per week.\n\nOn examination, her abdomen was soft and nontender with no palpable masses or organomegaly. Digital rectal examination and rigid sigmoidoscopy were unremarkable. Unexpectedly, a flexible sigmoidoscopy showed a malignant looking sessile polyp in the lower rectum. Pelvic MRI scan showed thickening in the midrectum arising 7 cm from the anal verge with no extramural venous invasion and a threatened, but not invaded, circumferential resection margin anteriorly. Radiological staging on MRI and CT was T3 N0 M0 and histological biopsies confirmed a moderately differentiated adenocarcinoma.\n\nThe patient commenced a long course of neoadjuvant chemoradiotherapy using capecitabine as the radiosensitizing chemotherapeutic agent. While taking capecitabine, the patient reported episodes of angina‐type chest pain, which resolved on completion of the chemotherapy course and did not require any cardiac treatment. A MRI scan following the neoadjuvant therapy showed a good response with the tumor being downstaged to T2. She proceeded to a laparoscopic ultra low anterior resection with defunctioning loop ileostomy. Histological analysis of the resected specimen showed complete pathological response, pT0 pN0 (0/20), EMV negative, R0.\n\nA surveillance CT scan was performed at 3 months which identified four new subcapsular wedge‐shaped liver lesions suspicious for metastatic liver disease (Fig. 1).\n\nFigure 1 Axial multidetector computer tomography demonstrating low attenuation lesion within the subcapsular aspect of the left lobe (arrow).\n\nThese lesions were confirmed on Primovist MRI scanning as four new foci of low T1 signal within the liver, none of which were of high T2 signal and no hepatic steatosis. Post Primovist contrast, there was minimal arterial enhancement and no rim enhancement; the lesions were low signal on the delayed hepatobiliary phase (Fig. 3A).\n\nA subsequent PET–CT scan showed no FDG avid liver lesions and no extrahepatic disease. There was doubt on the etiology of these new liver lesions as they did not demonstrate the typical characteristics of metastasis. They were not visible on ultrasound but it was agreed via MDT that a CT‐guided core biopsy of the most accessible lesion should be performed. Histological examination revealed sinusoidal dilatation only with no other specific findings and no metastatic tumor (Fig. 2).\n\nFigure 2 Liver biopsy specimen showing sinusoidal dilatation with no evidence of malignancy.\n\nLiver function tests remained normal throughout the course of treatment and surveillance. The multidisciplinary team meeting opinion was that there was insufficient evidence for metastatic disease and therefore a close surveillance policy was adopted.\n\nA repeat Primovist MRI scan 2 months later showed the same peripheral wedge‐shaped areas of reduced T1 signal. They appeared more peripheral and more clearly defined than previously with no new areas of abnormality demonstrated and no enhancing lesions. Five months following the first postoperative scan, a third MRI scan was repeated and showed partial resolution of the four lesions in keeping with a benign etiology (Fig. 3B). Carcinoembryonic antigen levels were normal throughout.\n\nFigure 3 (A) Axial T1‐weighted Primovist MRI in the delayed hepatobiliary phase with low signal lesion corresponding to lesion on CT. (B) Axial T1‐weighted Primovist MRI in the delayed hepatobiliary phase with partial resolution of lesion at 5 months.\n\nDiscussion\nChemotherapy‐associated hepatotoxicity in cancer patients is a key area of ongoing research. It is especially important given the essential need to differentiate benign lesions from malignant liver metastases. Studies so far have reported associations between 5‐fluorouracil and hepatic steatosis, and irinotecan‐associated steatohepatitis 2. Morris‐Stiff et al. 3 found that 50% of liver resections following irinotecan‐ and oxaliplatin‐based regimes had hepatic steatosis and 20% had SOS. Sinusoidal obstruction syndrome following oxaliplatin does not appear to increase the risk of perioperative death, whereas irinotecan‐associated steatohepatitis can increase both morbidity and mortality posthepatectomy by reducing the hepatic reserve, thus leading to liver failure 2. More recently, Chin et al. 4 published a case report on capecitabine‐induced hepatic steatosis in a patient with stage III colon cancer treated with adjuvant chemotherapy.\n\nCapecitabine, known commercially as Xeloda, is a relatively new agent approved by the FDA in 2001. It is an orally administered chemotherapeutic drug used most commonly in the treatment of colorectal and breast cancer in both localized and metastatic disease. Capecitabine is converted to 5‐flurouracil preferentially in tumor cells but also in the liver by a three‐step enzymatic cascade, where it irreversibly inhibits thymidylate synthesis, involved in DNA synthesis. Phase I and II clinical trials showed that a regimen consisting of oral capecitabine in combination with radiotherapy is an active and well‐tolerated regimen with similar efficacy to the infusional 5‐FU/radiotherapy regimen as demonstrated by the National Surgical Adjuvant Breast and Bowel Project R‐04 trial and the German Margit trials. Although capecitabine has demonstrated substantial benefits as neoadjuvant treatment in locally advanced rectal disease 5, metastatic colorectal cancer, and metastatic breast cancer 6, it remains a fairly toxic drug with a number of side effects; some of which are still underreported, including the association with SOS.\n\nSinusoidal obstruction syndrome, also referred to as toxic sinusoidal injury, veno‐occlusive disease, or “blue liver syndrome”, is a commonly recognized vascular pattern of drug‐induced liver injury, frequently associated with oxaliplatin‐based chemotherapy. Kakar et al. 7 analyzed liver biopsies from 51 patients with sinusoidal dilatation. 66.7% of these cases had confirmed venous outflow impairment. For the 17 other cases; vascular causes included nodular regenerative hyperplasia, portal vein thrombosis, congenital absence of the portal vein, and sickle cell anemia. In three more patients, sinusoidal dilatation was identified postsurgery (gastric bypass, cholecystectomy, and splenectomy). In our patient, the most likely cause for sinusoidal dilatation was as a result of the long course of chemoradiotherapy using capecitabine. Capecitabine is a precursor to 5‐fluorouracil, which has already been documented to cause sinusoidal dilatation; hence, the association is plausible. Further, a study by Klinger et al. 1 also reported a likely association between capecitabine and SOS. However, the patient in Klinger's case report also received oxaliplatin and bevacizumab as well as capecitabine, and had to confirm liver metastasis prior to receiving chemotherapy. The differential diagnosis in our case is that of sinusoidal dilatation induced by surgery. However, there are no documented cases or evidence in the literature of vascular processes in the liver following colorectal cancer resections, nor have we identified such a problem in all our previous colorectal surveillance patients.\n\nPrimovist MR imaging is used preferentially in most hospitals for detecting colorectal liver metastases. Gadoxetic acid, Primovist, a liver‐specific contrast agent directed at hepatocytes 8, was approved by the FDA in 2004. It is understood to be superior to diffusion‐weighted MRI and multidetector CT scanning in detecting liver metastases. Bluemke et al. showed that there was a 2–15% more accurate classification of benign and malignant lesions compared with CT images of the same patients. They also showed a lower rate of false positives with Primovist MRI imaging 9. Hammerstingl et al. 8 showed a higher rate of detection of smaller hepatic lesions and distinctly lower false‐positive results. In our patient, Primovist MRI imaging was used to assess the hepatic lesions identified on the 3‐month surveillance CT scan, and for the follow‐up interval imaging.\n\nIt is important to keep an open mind when assessing new liver lesions during the surveillance period postcolorectal cancer treatment. Potential side effects of chemotherapeutic agents should always be considered especially when they can induce liver lesions that can mimic metastatic liver disease. Our case also highlights the important role of regular multidisciplinary team discussions with joint hepatobiliary involvement, interval imaging, and histological opinion of any suspicious lesions. This multidisciplinary approach helped to make a confident diagnosis and avoid unnecessary surgery. While it is important not to delay potentially curative treatment for resectable liver metastases, we need to be aware of other causes of liver lesions including veno‐occlusive injury by chemotherapeutic agents that are likely to reveal their benign nature with close surveillance and close interval scanning.\n\nFurthermore, ongoing research to evaluate the short‐ and long‐term side effects of capecitabine are needed. As Primovist is a relatively new contrast agent, it is important to be aware of rare complications that could mimic disease.\n\nConflict of Interest\nThe authors declare that there is no conflict of interests regarding the publication of this article.\n==== Refs\nReferences\n1 \n\nKlinger , M. \n, \nD. \nTamandl \n, \nS. \nEipeldauer \n, \nS. \nHacker \n, \nB. \nHerberger \n, \nK. \nKaczirek \n et al. 2010 \nBevacizumab improves pathological response of colorectal cancer liver metastases treated with XELOX/FOLFOX . Ann. Surg. Oncol. \n17 :2059 –2065 .20177795 \n2 \n\nZorzi , D. \n, \nA. \nLaurent \n, \nT. M. \nPawlik \n, \nG. Y. \nLauwers \n, \nJ. N. \nVauthey \n, and \nE. L. \nAbdalla \n. 2007 \nChemotherapy‐associated hepatotoxicity and surgery for colorectal liver metastases . Br. J. Surg. \n94 :274 –286 .17315288 \n3 \n\nMorris‐Stiff , G. \n, \nY. M. \nTan \n, and \nJ. N. \nVauthey \n. 2008 \nHepatic complications following preoperative chemotherapy with oxaliplatin or irinotecan for hepatic colorectal metastases . Eur. J. Surg. Oncol. \n34 :609 –614 .17764887 \n4 \n\nChin , S. N. \n, \nT. K. \nKim \n, and \nL. L. \nSiu \n. 2010 \nHepatic steatosis secondary to capecitabine: a case report . J. Med. Case Rep. \n4 :227 –229 .24576340 \n5 \n\nXiao , L. \n, \nY. \nGao \n, and \nM. \nLiu \n. 2014 \nAdvances in new chemotherapeutic drugs for preoperative chemoradiation of locally advanced rectal cancer . Chin. J. Gastrointest. Surg. \n17 :93 –97 .\n6 \n\nWalko , C. M. \n, and \nC. \nLindley \n. 2005 \nCapecitabine: a review . Clin. Ther. \n27 :23 –44 .15763604 \n7 \n\nKakar , S. \n, \nP. S. \nKamath \n, and \nL. J. \nBurgart \n. 2004 \nSinusoidal dilatation and congestion in liver biopsy; is it always due to venous obstruction? \nArch. Pathol. Lab. Med. \n128 :901 –904 .15270610 \n8 \n\nHammerstingl , R. \n, \nA. \nHuppertz \n, \nJ. \nBreuer \n, \nT. \nBalzer \n, \nA. \nBlakeborough \n, \nR. \nCarter \n et al. 2007 \nDiagnostic efficacy of gadoxetic acid (Primovist)‐enhanced MRI and spiral CT for a therapeutic strategy: comparison with intraoperative and histopathologic findings in focal liver lesions . Eur. Radiol. \n18 :457 –467 .18058107 \n9 \n\nBluemke , D. A. \n, \nD. \nSahani \n, \nM. \nAmendola \n, \nT. \nBalzer \n, \nJ. \nBreuer \n, \nJ. J. \nBrown \n et al. 2005 \nEfficacy and safety of MR imaging with liver specific contrast agent . Radiology \n237 :89 –98 .16126918\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "4(6)",
"journal": "Clinical case reports",
"keywords": "Capecitabine; colonic adenocarcinoma; liver lesions; sinusoidal dilatation",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "545-8",
"pmc": null,
"pmid": "27398193",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": "17315288;15270610;17764887;15763604;24576340;24519058;18058107;20177795;16126918",
"title": "Capecitabine-related liver lesions: sinusoidal dilatation mimicking liver metastasis.",
"title_normalized": "capecitabine related liver lesions sinusoidal dilatation mimicking liver metastasis"
} | [
{
"companynumb": "GB-MYLANLABS-2016M1027897",
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"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
... |
{
"abstract": "Heart failure is a rare condition in the paediatric population, associated with high morbidity and mortality. When medical therapy is no longer sufficient, mechanical circulatory support such as a ventricular assist device can be used to bridge these children to transplant or recovery. Coagulation-related complications such as thrombi, embolism and bleeding events represent the greatest challenge in paediatric patients on mechanical support. We aimed to describe the outcomes and coagulation-related complications in this patient population at our institution.\n\n\n\nA total of 20 patients with either Berlin Heart EXCOR® or HeartWare® implantation were reviewed in this retrospective study. Study endpoints were survival to heart transplant, weaning due to recovery or death. Thrombotic events were defined as thrombus formation in the device or in the patient, or cardioembolic strokes. Bleeding events were defined as events requiring interventional surgery or transfusion of red blood cells.\n\n\n\nThe aetiology of heart failure included cardiomyopathy (n = 12), end-stage congenital heart disease (n = 6) and myocarditis (n = 2). Of the 20 patients, 12 were bridged to transplant, 7 recovered and could be weaned and 1 died. The median duration of mechanical support was 84 days (range: 20-524 days). At least one major or minor bleeding event occurred in 45% of the patients. Thrombotic events occurred 21 times in 10 patients. Four of the patients (20%) had no bleeding or thromboembolic event.\n\n\n\nIn all, 95% of the patients were successfully bridged to transplant or recovery. Bleeding events and thrombotic events were common.",
"affiliations": "Department of Paediatric Anaesthesiology and Intensive Care, Queen Silvia Children's Hospital, Gothenburg, Sweden.;Department of Paediatric Anaesthesiology and Intensive Care, Queen Silvia Children's Hospital, Gothenburg, Sweden.;Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.;Department of Cardiothoracic Surgery, Sahlgrenska University Hospital, Gothenburg, Sweden.;Paediatric Heart Centre, Queen Silvia Children's Hospital, Gothenburg, Sweden.;Department of Paediatric Anaesthesiology and Intensive Care, Queen Silvia Children's Hospital, Gothenburg, Sweden.",
"authors": "Romlin|Birgitta|B|0000-0002-8187-9760;Dahlin|Anna|A|;Hallhagen|Stefan|S|;Björk|Kerstin|K|;Wåhlander|Håkan|H|;Söderlund|Fredrik|F|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/aas.13804",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5172",
"issue": "65(6)",
"journal": "Acta anaesthesiologica Scandinavica",
"keywords": "coagulation; paediatric; ventricular assist devices",
"medline_ta": "Acta Anaesthesiol Scand",
"mesh_terms": "D002648:Child; D006333:Heart Failure; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0370270",
"other_id": null,
"pages": "785-791",
"pmc": null,
"pmid": "33616235",
"pubdate": "2021-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical course and outcome after treatment with ventricular assist devices in paediatric patients: A single-centre experience.",
"title_normalized": "clinical course and outcome after treatment with ventricular assist devices in paediatric patients a single centre experience"
} | [
{
"companynumb": "SE-Fresenius Kabi-FK202205056",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "4",... |
{
"abstract": "Rapid drug desensitization (RDD) induces a temporary tolerance to chemotherapeutics that induce hypersensitivity reactions (HSRs).\n\n\n\nOur objective is to report our experience with RDD to platins, taxanes, etoposide, doxorubicin, and irinotecan.\n\n\n\nThe study was conducted as a retrospective chart review of patients with symptoms of HSRs to chemotherapeutics. HSRs were classified as grade I, II, or III, based on their severity. Skin prick/intradermal tests were performed with implicated chemotherapeutics. A 12-step RDD protocol was used.\n\n\n\nThe study consisted of 38 women and 3 men (mean age 53.3 ± 11.6 years). Patients had ovarian (n = 13, 31.8%), breast (n = 10, 24.4%), colon (n = 7, 17%), lung (n = 4, 9.8%), and other cancers (n = 7; endometrial sarcoma, testicular cancer, uterine cancer, ampulla of Vater tumor, choledochal tumor, peritonitis carcinomatosa, and Merkel cell carcinoma, n = 1, respectively). Twenty-two patients experienced HSRs to platins, 15 to taxanes, and 4 to other chemotherapeutics (doxorubicin, irinotecan, and etoposide). A total of 122 RDDs (47 to platins, 52 to taxanes, 23 to other chemotherapeutics) were performed. In 25 (61%) patients no reactions occurred during RDD, but breakthrough reactions developed in 16 patients (39%) with platins (n = 11), taxanes (n = 3), doxorubicin (n = 1), and irinotecan (n = 1). RDD procedures could not be completed in only 2 patients with grade II breakthrough reactions to carboplatin and oxaliplatin.\n\n\n\nIn our experience, 98.3% of 122 RDDs were completed. We found that RDD was safe and effective in this the largest series of RDD with chemotherapeutics in our country.",
"affiliations": "Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey.;Department of Chest Disease, Division of Allergy and Clinical Immunology, Ankara University School of Medicine, Ankara, Turkey, bavbek@medicine.ankara.edu.tr.",
"authors": "Kendirlinan|Reşat|R|;Gümüşburun|Reyhan|R|;Çerçi|Pamir|P|;Özbek|Emre|E|;Altıner|Seda|S|;Çelebi Sözener|Zeynep|Z|;Soyyiğit|Şadan|Ş|;Aydın|Ömür|Ö|;Bavbek|Sevim|S|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000496745",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-2438",
"issue": "179(2)",
"journal": "International archives of allergy and immunology",
"keywords": "Chemotherapeutics; Hypersensitivity reactions; Rapid drug desensitization",
"medline_ta": "Int Arch Allergy Immunol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D003888:Desensitization, Immunologic; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012882:Skin Tests; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9211652",
"other_id": null,
"pages": "114-122",
"pmc": null,
"pmid": "30893688",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rapid Drug Desensitization with Chemotherapeutics (Platins, Taxanes, and Others): A Single-Center Retrospective Study.",
"title_normalized": "rapid drug desensitization with chemotherapeutics platins taxanes and others a single center retrospective study"
} | [
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"companynumb": "TR-TEVA-2019-TR-1073610",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"actiondrug": "1",
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"activesubstancename": "DOCETAXEL"
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"abstract": "Refractory angina pectoris (AP) significantly impairs quality of life in patients with chronic coronary syndrome. Several minimally invasive methods (coronary sinus reducer, cell therapy, laser or shockwave revascularization, and spinal cord stimulation) or non-invasive methods (external counterpulzation) have been studied. However, their routine clinical use has not been widely implemented. Surgical or endoscopic sympathectomy is feasible for permanently relieving angina, but is often contraindicated due to the extent of complications associated with it. Neuromodulation by anaesthetic blockade of the left-sided stellate ganglion (SG) has been shown to relieve angina for days or weeks. To provide a long-term anti-anginal effect, novel pharmacological (phenol-based) or radiofrequency ablation techniques have been individually used to permanently destroy sympathetic pathways.\nWe describe a first-in-man use of stereotactic radiosurgical SG ablation using a linear accelerator (CyberKnife) in a heart failure patient after myocardial infarction with chronic refractory AP. Repeated anaesthetic SG blockade in this patient resulted in a significant, but only short-term, clinical improvement. The left, and subsequently the right, SG was ablated by targeted irradiation. During the 1-year follow-up, the patient remained without angina. We did not observe any clinically relevant early or late complications. Atrial fibrillation that developed 2 months after the second procedure was deemed to be associated with a natural progression of co-existing heart failure.\nWe conclude that stereotactic radiosurgical SG ablation has the potential to become a minimally invasive and low-risk procedure to treat refractory angina patients. However, this procedure needs to be evaluated in larger patient populations.",
"affiliations": "Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.;Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.;Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.;Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.;Department of Oncology, University Hospital Ostrava, 17. listopadu 5, Ostrava 708 00, Czechia.;Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.;Department of Oncology, University Hospital Ostrava, 17. listopadu 5, Ostrava 708 00, Czechia.;Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia.",
"authors": "Hudec|Miroslav|M|https://orcid.org/0000-0002-4613-7016;Jiravsky|Otakar|O|https://orcid.org/0000-0001-9334-5734;Spacek|Radim|R|https://orcid.org/0000-0003-4176-0885;Neuwirth|Radek|R|https://orcid.org/0000-0002-6925-5509;Knybel|Lukas|L|https://orcid.org/0000-0002-2461-6606;Sknouril|Libor|L|https://orcid.org/0000-0001-9190-2007;Cvek|Jakub|J|https://orcid.org/0000-0003-1579-1792;Miklik|Roman|R|https://orcid.org/0000-0001-6873-0729",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/ehjcr/ytab184",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n10.1093/ehjcr/ytab184\nytab184\nGrand Round\nAcademicSubjects/MED00200\nChronic refractory angina pectoris treated by bilateral stereotactic radiosurgical stellate ganglion ablation: first-in-man case report\nhttps://orcid.org/0000-0002-4613-7016\nHudec Miroslav 12\nhttps://orcid.org/0000-0001-9334-5734\nJiravsky Otakar 12\nhttps://orcid.org/0000-0003-4176-0885\nSpacek Radim 1\nhttps://orcid.org/0000-0002-6925-5509\nNeuwirth Radek 12\nhttps://orcid.org/0000-0002-2461-6606\nKnybel Lukas 3\nhttps://orcid.org/0000-0001-9190-2007\nSknouril Libor 1\nhttps://orcid.org/0000-0003-1579-1792\nCvek Jakub 3\nhttps://orcid.org/0000-0001-6873-0729\nMiklik Roman 1\n1 Department of Cardiology, Nemocnice Agel Trinec-Podlesi, Konska 453, Trinec 739 61, Czechia\n2 Faculty of Medicine, Masaryk University, Kamenice 735/5, Brno 625 00, Czechia\n3 Department of Oncology, University Hospital Ostrava, 17. listopadu 5, Ostrava 708 00, Czechia\nVrachatis Dimitrios A Handling Editor\nAsad Zain Ul Abideen Editor\nLittle Callum Editor\nMukherjee Rahul Editor\nChakir Mariame Editor\nCorresponding author. Tel: +420 777618514, Email: romanmiklik@yahoo.com\n8 2021\n31 8 2021\n31 8 2021\n5 8 ytab18423 11 2020\n17 12 2020\n16 4 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits 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.com\n\nAbstract\n\nBackground\n\nRefractory angina pectoris (AP) significantly impairs quality of life in patients with chronic coronary syndrome. Several minimally invasive methods (coronary sinus reducer, cell therapy, laser or shockwave revascularization, and spinal cord stimulation) or non-invasive methods (external counterpulzation) have been studied. However, their routine clinical use has not been widely implemented. Surgical or endoscopic sympathectomy is feasible for permanently relieving angina, but is often contraindicated due to the extent of complications associated with it. Neuromodulation by anaesthetic blockade of the left-sided stellate ganglion (SG) has been shown to relieve angina for days or weeks. To provide a long-term anti-anginal effect, novel pharmacological (phenol-based) or radiofrequency ablation techniques have been individually used to permanently destroy sympathetic pathways.\n\nCase summary\n\nWe describe a first-in-man use of stereotactic radiosurgical SG ablation using a linear accelerator (CyberKnife) in a heart failure patient after myocardial infarction with chronic refractory AP. Repeated anaesthetic SG blockade in this patient resulted in a significant, but only short-term, clinical improvement. The left, and subsequently the right, SG was ablated by targeted irradiation. During the 1-year follow-up, the patient remained without angina. We did not observe any clinically relevant early or late complications. Atrial fibrillation that developed 2 months after the second procedure was deemed to be associated with a natural progression of co-existing heart failure.\n\nDiscussion\n\nWe conclude that stereotactic radiosurgical SG ablation has the potential to become a minimally invasive and low-risk procedure to treat refractory angina patients. However, this procedure needs to be evaluated in larger patient populations.\n\nUpper thoracic sympathetic system\nStellate ganglion blockade\nRefractory angina\nStereotactic radiosurgery\nCase report\n==== Body\npmcLearning points\n\nStereotactic radiosurgery of the left stellate ganglion (SG) is a technically feasible, well-tolerated, and clinically effective method to meliorate anginal symptoms in a patient with refractory angina pectoris. It can be applied as an outpatient procedure.\n\nTemporary anaesthetic blockade of the SG can be used to verify the treatment effect of unilateral radiosurgical ablation. Bilateral ablation may be required as the right-sided SG may also be involved in ischaemic cardiac pain perception.\n\nPrimary specialities involved other than cardiology\n\nAnaesthesiology, radiation oncology.\n\nIntroduction\n\nRefractory angina pectoris (AP) is defined as chest pain caused by coronary insufficiency that cannot be controlled despite the maximal coronary revascularization using percutaneous coronary intervention (PCI) or aorto-coronary bypass graft (CABG), together with optimal medical therapy that includes a combination of anti-ischaemic drugs. The symptoms need to last for at least 3 months, and evidence of reversible myocardial ischaemia is usually required to confirm the diagnosis.1,2 The estimated incidence of new cases of refractory AP in Europe is between 30 000 and 50 000 cases per year.3 Given improvements in interventional techniques and overall survivability of coronary heart disease, these numbers are set to rise.2 New techniques have been developed and individually applied to relieve angina, neuromodulation being one of them. One of the targets of interest are sympathetic stellate (cervicothoracic) ganglia (SGs) that are situated at the level of C7 vertebrae. These ganglia originate from the sympathetic afferent cardiac fibres and transmit signals from the heart atria and ventricles to the upper thoracic spinal cord and eventually to the pain centres of the brain. The majority of sympathetic pathways coalesce in the left-sided ganglion. Given this observation, left-sided SG anaesthetic blockade has been proposed and demonstrated to be effective for the treatment of arrhythmic storms and refractory angina as part of holistic care.4–6 The therapeutic effect of this approach is temporary, lasting from days to weeks, and repeated applications are often required.\n\nThe involvement of the right SG in left ventricle innervation is less understood and somewhat controversial. A case series described a positive effect of cervicothoracic sympathectomy with bilateral removal of both SGs in order to mitigate pro-arrhythmic neural signalling within the ganglia or myocardium. The left-sided, and eventually the right-sided, denervation was performed as the former was not clinically effective.7 The additive effect of the right-sided denervation on the decrease of malignant arrhythmia occurrence and mortality was demonstrated in a multicentre study.8 To the best of our knowledge, there are no published data about affecting the right SG in terms of ischaemic pain modulation. Nevertheless, experimental data confirming the right SG involvement in myocardial innervation9 and clinical data suggesting safety and a positive effect of right-sided denervation in patients with arrhythmias may serve as a rationale to target the right SG to mitigate ischaemic pain.\n\nAt Trinec-Podlesi Hospital, we have been practising anaesthetic puncture blockades of the left SG since 2016 in patients with electrical storm,5 and in 2018 we expanded the indication to those with refractory angina.\n\nThis report presents a case of a patient who had been suffering from refractory angina. After several attempts to relieve pain by anaesthetic puncture blockades of SGs, the first-in-man stereotactic radiosurgical ablation of the left SG was performed, and, eventually, of the right SG to provide long-term pain relief and improve his quality of life.\n\nTimeline\n\nYear 1987—age 33\tInferolateral wall myocardial infarction: 2× venous aorto-coronary bypass graft (CABG) [left anterior descending artery (LAD) and D1]\t\nYear 1996—age 42\tSymptomatic angina pectoris: 3× venous CABG [LAD, obtuse marginal, and posterior descending artery (PDA)]\t\nYear 1999—age 45\tBradycardia: pacemaker implantation\t\nYear 2005—age 51\tCoronary angiography: all CABGs occluded but CABG–PDA, diffuse coronary disease, conservative approach\t\nYear 2016—age 62\tCoronary angiography: same findings as in 2005, conservative approach\t\nYear 2018—age 64\n\n 11 October\n\n 12 October\n\n 13 December\n\n\tPreventive biventricular internal cardioverter-defibrillator implantation\n\nAnaesthetic left stellate ganglion (SG) blockade: short-term clinical effect\n\nLeft SG stereotactic radiosurgical ablation\n\n\t\nYear 2019—age 65\n\n 25 June\n\n 8 October\n\n 29 October\n\n 18 November\n\n\tAnaesthetic left SG blockade: no clinical effect\n\nAnaesthetic right SG blockade: short-term clinical effect\n\nAnaesthetic right SG blockade: short-term clinical effect\n\nRight SG stereotactic radiosurgical ablation\n\n\t\nYear 2020—age 66\n\n 23 January\n\n 31 January\n\n 22 May\n\n 8 June\n\n\tAtrial fibrillation diagnosed\n\nElectrical cardioversion: sinus rhythm restored\n\nRecurrence of atrial fibrillation\n\nElectrical cardioversion: not effective\n\n\t\nBold formatting—milestones of the case report.\t\n\nCase presentation\n\nPatient's history\n\nThe patient is a male born in 1954, obese (body mass index 36.84 kg/m2), with positive family history of myocardial infarction (MI), and a heavy smoker who suffered inferolateral wall MI at the age of 33. Venous CABGs to the left anterior descending artery (LAD) and its first diagonal branch (D1) were performed in 1987 (at the age of 33 years) to treat the patient. Then, in 1996, he underwent a reoperation—three venous CABGs to LAD, the left obtuse marginal (OM1), and the right posterior descending artery (PDA) due to recurrence of exertional angina. In 1999, a permanent pacemaker was implanted for bradycardia. Due to rapidly progressive angina in 2005, another coronary angiography was performed demonstrating just one venous graft (CABG–PDA). The other CABGs were occluded and the native coronary arteries were diffusely diseased. The Heart team recommended a conservative approach. The patient was followed at a different cardiac centre and his treating cardiologist consulted with a heart transplant centre regarding the case. However, he was rejected due to extra-cardiac comorbidities (peripheral artery disease, according to available documentation).\n\nIn August 2016, the patient was referred to our centre for re-coronarography for resting angina (CCS Class IV). The findings were unchanged and a conservative approach was recommended as the only possible treatment option (Figure 1 and Videos 1 and 2). In November 2016, the patient was examined one more time at the transplant centre, and spiroergometry was performed. The result verified ischaemic origin of the chest pain and a very low exercise tolerance. The values were as follows: maximal tolerated load of 88 W (0.8 W/kg), maximal heart rate of 104/min while pacemaker stimulated, VO2 max of 10.6 mL/kg/min, O2 saturation of 99% throughout the test, and ventricular extrasystoles on electrocardiogram (ECG) during maximal load. The test was terminated due to anginal pain with a need of two sublingual nitrate applications.\n\nFigure 1 Major coronary angiography findings. All aorto-coronary bypass grafts are occluded, except for aorto-coronary bypass graft–posterior descending artery. (A) Native left coronary artery. Pink arrow—chronic total occlusion of left anterior descending artery; blue arrows—diffuse disease and distal occlusion of circumflex artery. (B) Native right coronary artery. Pink arrow—chronic total occlusion of the proximal segment. (C) Venous aorto-coronary bypass graft–posterior descending artery. Pink arrows—collaterals to left anterior descending artery; blue arrows—left anterior descending artery; yellow arrow—collaterals to obtuse marginal; green arrow—peripheral obtuse marginal.\n\nIn 2017, apart from suffering from ischaemic heart disease with low left ventricular ejection fraction of 30%, hypertension, and hyperlipidaemia, he was also re-evaluated for previously diagnosed peripheral artery disease. Significant stenoses of femoral and tibial arteries and asymptomatic right internal carotid artery occlusion were found. No intervention was indicated and conservative pharmacological therapy was chosen.\n\nLeft stellate ganglion blockade\n\nDue to the left ventricular dysfunction and 100% pacemaker dependency, cardiac resynchronization therapy (CRT) was indicated and a biventricular cardioverter-defibrillator was implanted on 11 October 2018. During this hospitalization, the patient complained of severe refractory angina despite the maximal pharmacotherapy (bisoprolol 10 mg daily, nitrate, molsidomine, and trimetazidine). He reported emergency nitrate spray use of 20–40 times a day.\n\nGiven the severity of anginal symptoms, ultrasound-guided anaesthetic blockade of the left SG was performed on 12 October 2018 (Figure 2 and Video 3). The technique was described previously.10 After application of 6 mL of 0.5% bupivacaine, temporary Horner’s syndrome and a slight left shoulder girdle paresis were observed, both resolving within 24 h. The patient was discharged 3 days after the procedure. At the ambulatory follow-up visit 31 days later, the patient reported complete resolution of AP for the initial 5 days. He then became symptomatic again. His angina rapidly graduated and reached the same level of severity within 14 days. Nevertheless, the patient's responsiveness to therapy was verified. As ergometry was highly positive in this patient already in 2016, there was no need to repeat non-invasive stress testing to confirm ischaemic origin of the chest pain and place the patient at risk for malignant arrhythmias or heart failure symptom worsening, or to perform invasive functional testing (e.g. fractional flow reserve) of the last patent artery, i.e. CABG to PDA. This graft did not have a stenosis of >50%, and diffuse atherosclerosis of the distal right coronary artery was not suitable for revascularization. As no other treatment option mentioned in the guidelines1 was available in the Czech Republic (one site had experience with radiofrequency SG ablation, but it was not manageable for logistical reasons) and surgical upper thoracic sympathectomy was contraindicated due to comorbidities, the case was discussed with an oncologist (J.C., co-author) experienced in radiosurgical techniques. The aim was to reach a longer-term anti-anginal effect. After mutual agreement, we opted for SG modulation by irradiation using a linear accelerator (CyberKnife).\n\nFigure 2 Ultrasound-guided left stellate ganglion anaesthetic blockade. (A) Patient positioning and introduction of puncture needle. (B) Ultrasound image of landmark structures and needle approaching left stellate ganglion. AC, internal carotid artery; VJ, internal jugular vein; yellow arrows—puncture needle reaching left stellate ganglion; pink arrow—left stellate ganglion.\n\nLeft stellate ganglion ablation\n\nThe highly symptomatic patient at this time agreed to undergo the first-in-man stereotactic radiosurgical procedure in order to modulate the left SG sympathetic activity and possibly relieve limiting anginal symptoms. After signing an informed consent, a fiducial marker (a golden particle) was implanted into the left SG area under the ultrasound guidance to mark the position of SG for computed tomography (CT) imaging (Supplementary material online, Figure S1). After fixating the patient in a thermoplastic mask on 10 December 2018, the CT scan was performed and images were stored for subsequent offline analysis. The target volume and surrounding vital structures were identified based on a frame-by-frame analysis, and a 3D topographical reconstruction was created (Figures 3A and B and 4). No contrast agent was necessary. The clinical target volume included the left SG. CT imaging of immobile neck structures reached sub-millimetre accuracy. Thus, no safety margin was added and the planned target volume of 0.4 mL matched the clinical target volume. The Multiplan system (Accuray, Sunnyvale, CA, USA) was used to calculate the appropriate radiation dose for 6 MeV of high-frequency photons (Figure 5). To deliver the dose, the CyberKnife system (version 10.5, Accuray) and XsightSpine tracking technology were used due to the close proximity of the target to the cervical spine. XsightSpine tracking allows to control patient position (translation and rotation) according to spine structures. This methodology has been described in detail previously11 and reaches sub-millimetre accuracy.12 Detailed description of radiotherapy can be found in Table 1 (left). The dose was maximized according to the size of the targeted volume based on the oncologist's experience with one-time ablation deliveries to treat trigeminal neuralgias. The procedure was carried out as outpatient without any periprocedural complications on 13 December 2018 (Figure 6). The patient experienced a mild headache that disappeared within 24 h. No early or late complications were observed. Neuron-specific enolase—a marker of a neuronal damage—was not increased.\n\nFigure 3 Delineation of stellate ganglion (red, centralized in the images) and organs at risk (oesophagus, arteries, veins, spine, and neck muscles) before ablation therapy using computed tomography imaging. Left-sided structures in transverse (A) and sagittal (B) planes and right-sided structures in transverse (C) and sagittal (D) planes.\n\nFigure 4 Computed tomography imaging of the left stellate ganglion—3D reconstruction.\n\nFigure 5 Dose distribution and dose-volume histograms (bottom pictures) for left stellate ganglion ablation (A) and right stellate ganglion ablation (B). Each colour represents the dose level in % relative to maximum dose. Thick orange line represents prescription dose of 40 Gy (minimum acceptable dose in target). Integral dose-volume histograms show percentage fraction of a given structure volume receiving a minimum dose.\n\nFigure 6 Visualization of treatment beams delivering dose to left stellate ganglion (using CyberKnife).\n\nTable 1 Left and right stellate ganglion radiosurgical ablation details\n\nPlanned target volume:\tLeft stellate ganglion, C7 level\tRight stellate ganglion, C7 level\t\nTechnique\tX/6, non-isocentric, non-coplanar, 109 fields\tX/6, non-isocentric, non-coplanar, 88 fields\t\nDevice\tCyberknife—stereotactic radiosurgery with online image guidance—Xsight Spine tracking\tCyberknife—stereotactic radiosurgery with online image guidance—Xsight Spine tracking\t\nDose prescription\t40 Gy/1 Fr at 78% isodose (Dmax 51.3 Gy)\t40 Gy/1 Fr at 77% of isodose (Dmax 51.9 Gy)\t\nProcedure date\t13 December 2018\t18 November 2019\t\nProcedure duration\t57 min\t49 min\t\nDose to the critical organs\tSpine Dmax 1.32 Gy, pharyngeal muscles Dmean 1.96 Gy\tSpine Dmax 4.36 Gy, carotid artery Dmean 1.94 Gy, oesophagus Dmean 2.26 Gy\t\nDmax (Gy), maximum dose applied (Gray); Dmean, mean dose applied (Gray).\n\nDuring the next 3–4 months, the patient reported a significant overall improvement of his condition. He used nitrates 10–20 times a day, which was a 50% reduction compared to previous usage. He was able to manage his family, child, house, and garden. Based on this improvement, he applied for a job and eventually started working as a security guard. However, he had to quit the job 2 months later (6 months in total after irradiation), as he became progressively symptomatic again. In order to verify the possible residual involvement of the left SG, an anaesthetic blockade was performed again. This was carried out on 25 June 2019, resulting in temporary Horner’s syndrome. There was no change in anginal symptomatology after this procedure. Given the fact that this procedure had always been effective before the left-sided stereotactic irradiation, it was clear evidence of the complete elimination of the left SG function.\n\nRight stellate ganglion ablation\n\nDespite the fact that cardiac sympathetic innervation is predominantly mediated by left-sided pathways, the involvement of the right-sided sympathetic chain must be considered, and its blockade might have beneficial clinical effects.9 Thus, it was decided to challenge the patient's response to the right SG blockade on 8 October 2019, which was again followed by temporary Horner’s syndrome. The patient was free of anginal symptoms and dyspnoea remained his only limitation for the period of 1 week. One more anaesthetic blockade of the right SG was performed on 29 October 2019 with the same result. This was sufficient proof that the right SG pathways were involved in ischaemic cardiac pain perception. With the patient's signed consent, we proceeded to irradiate the right SG. Due to good ultrasound visibility and well-understood topographical anatomy of the right SG area, a CT scan was performed without the need for a prior introduction of the fiducial marker. After precise mapping of the landing zone (Figure 3C and D), the stereotactic irradiation was performed on 18 November 2019 as an outpatient procedure (Table 1, right). No early or late procedure-related complications were observed or reported by the patient.\n\nFollow-up\n\nThe patient needed his nitrate 5–15 times a day for the first 10 days after the right SG ablation. At the 2-month visit he reported a complete resolution of angina, but complained of worsening dyspnoea and overall performance of basic daily activities. Atrial fibrillation with normal ventricular response was newly detected on ECG, without new valvular or structural changes on echocardiography. NT-proBNP level increased from a previous value of 400 ng/L (taken in a stable condition after the right SG ablation) to 1221 ng/L. An anticoagulant was introduced and after transoesophageal echocardiography excluding intracardiac thrombosis, the patient underwent a successful electrical cardioversion.13 At the next follow-up visit 2 months later, the patient reported relief from dyspnoea and non-specific nitrate non-responsive chest pain. NT-proBNP decreased to 769 ng/L. At the visit on 22 May 2020 (later than expected due to Covid-19 pandemic), recurrence of atrial fibrillation was found, and the patient reported New York Heart Association (NYHA) III dyspnoea with no anginal symptoms. The NT-proBNP level increased to 979 ng/L. A new attempt to restore sinus rhythm by electrical cardioversion failed this time. The patient was recommended to undergo radiofrequency ablation of atrial fibrillation. With his consent he was placed on the waiting list. The patient has been prescribed amiodarone as a rhythm control strategy, in addition to a chronic dose of bisoprolol at 10 mg/day that has been left unchanged since 2016. Another cardioversion was planned but never occurred due to Covid-19-related restrictions. Neither did the intended ablation procedure of atrial fibrillation. There is no solution in sight as the patient was hospitalized in November 2020 with suspected infective endocarditis on the CRT electrode system to be further managed. The latest NT-proBNP level reached 1687 ng/L. The patient is currently dyspnoeic NYHA III without anginal symptoms.\n\nDiscussion\n\nDespite all of the improvements in technical aspects of PCI and CABG, there are still patients in whom effective revascularization cannot be achieved. The latest anti-anginal, ischaemia-modulating drugs (e.g. ivabradine, ranolazine) are not able to completely eliminate AP. For this reason there is a considerable effort to develop new methods to mitigate anginal symptoms. Various procedures have been tested. One of them is thoracic epidural anaesthesia, which has been proven effective but cannot be used in everyday practice due to frequent complications.14 Another method is transmyocardial laser revascularization, in which the risk outweighs the possible treatment benefit.15 The so-called external counterpulzation has been proven effective and safe. It is applied for 1 h a day, 35 h in total.16 Implantation of a special stent to the coronary sinus (coronary sinus reducer) is one of the invasive procedures that causes a certain degree of coronary sinus stenosis and thus increases the pressure gradient in coronary vessels. This leads to redistribution of blood flow from the less ischaemic epicardium to the more ischaemic endocardium.17 The application of autologous CD 34+ cells that stimulate neoangiogenesis also seems to be beneficial for refractory angina patients. A pooled analysis of three randomized trials confirmed improvements in exercise capacity, frequency of angina, and mortality reduction.18\n\nNeuromodulation is probably the most ambitious and widely investigated topic of interest. Spinal cord neurostimulation is one of the currently approved methods the efficacy of which has been proven in clinical studies.19 This method, as well as external counterpulzation and coronary sinus reducer, have a IIb (level of evidence B) recommendation in the current Guidelines of European Society of Cardiology.1\n\nNeuromodulation also focuses on affecting the upper thoracic sympathetic system, of which SGs are components. Their anaesthetic blockade, particularly of the left SG, is used for many indications, for example, in a malignant storm.5,6 The effect of anaesthetic left SG blockade on AP recurrence was demonstrated many years ago.4 However, a double-blind clinical study showed that the effect on anginal symptoms might be due to mechanical compression caused by the applied volume rather than by anaesthetic properties of the solution.20 Several studies aimed to destroy SG permanently using minimally invasive techniques, such as injection of phenol21 or radiofrequency energy.22 Video-assisted upper thoracic sympathectomy is a currently used surgical method of choice to eliminate adverse effects of cervical and upper thoracic sympathetic pathways.23 However, this procedure is often contraindicated in patients with comorbidities due to the extent of complications that may arise.\n\nThe present case report described an option for refractory AP treatment using stereotactic radiosurgery. It is a minimally invasive procedure that is currently used in patients with brain tumours, arteriovenous malformations, and neuralgias. Contrary to applied surgical methods, CT-guided radiosurgery targeting structures of the neck has a very low incidence of acute (within 3 months), late, and very late complications. The radiation dose affecting the oesophagus is minimized and is far below the permitted limits to cause severe toxicity, such as necrosis or rupture. Nevertheless, acute focal mucositis of the oesophagus caused by scattered radiation may occur, usually manifested by cough and painful swallowing with a good clinical response to local antiseptics. Horner's syndrome caused by cervical sympathetic neuritis is a very rare acute complication. An occurrence of acute local dermatitis, the typical complication after radiotherapy in oncological patients, cannot be expected to be clinically relevant due to a very low dose of radiation. Late complications include focal necrosis of the adjacent longus colli muscle (most likely asymptomatic), oesophageal fibrosis (very unlikely as the doses of radiation are incomparably lower than those used in radiation oncology), or accelerated atherosclerosis in adjacent major arteries caused by scattered radiation that may potentiate endothelial changes. Finally, carcinogenesis resulting from radiation exposure may theoretically be a very late complication of radiosurgery, but is very unlikely due to very small target volumes. Given the justifications above and to the best of our knowledge, this is the first time this method was used in a patient with refractory angina, as concomitant comorbidities excluded the patient from other available therapies. Our approach required a precise knowledge of the upper thoracic sympathetic chain topography, verification of SG involvement, a positive response to neuromodulation (anaesthetic blockade), and interdisciplinary cooperation with a radiation oncologist and anaesthesiologists.\n\nWhen an irradiation strategy is being planned, the factors of irradiated area, target volume, safety margin, and dose determination are of utmost importance. In the present case, a dose of 40 Gy was applied for safety reasons in order not to exceed a maximum dose for organs at risk, especially the oesophagus in case of contralateral radiosurgery. The repeated anaesthetic blockade had no additional effect on angina, thus confirming that 40 Gy was an appropriate dose. According to our experience arising from this case, unilateral SG ablation might not be sufficiently effective as both left- and right-sided sympathetic chains are involved in the sensory component of AP. Moreover, a higher dose of 60–70 Gy that is usually used in the treatment of trigeminal neuralgia might be needed.24 It is also important to look for a clear endpoint of a successfully performed procedure because the patient's reported degree of anginal symptoms can be subjective. In this regard, heart rate variability, phase angle shift, and neuroECG are being investigated.25 The rationale for SG modulation/ablation can extend and be used to treat different parts of the sympathetic nervous system and secondarily impact the function of innervated tissues and organs.\n\nConclusion\n\nThis is the very first case report of stereotactic radiosurgery for bilateral SG ablation in a patient with refractory AP receiving optimal medical therapy and with no option for coronary revascularization. The method was found to be technically feasible, well tolerated by the patient, and clinically effective to ameliorate anginal symptoms. It can also be applied as an outpatient procedure. More studies are needed to justify its routine use in a refractory angina setting. The rationale for SG modulation/ablation by irradiation can also be applied to different sympathetic pathways.\n\nLead author biography\n\nMiroslav Hudec, MD, graduated at Masaryk University Brno, Czechia, in 2002. Having completed his internal medicine and general cardiology residency, he has been focusing on interventional cardiology. Presently, he works as a cardiology consultant and performs both coronary and non-coronary interventions (Mitraclips, LAAO, PTSMA, PFO/ASD closures, PVL closures). He started a PhD program in 2019.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSupplementary Material\n\nytab184_Supplementary_Data Click here for additional data file.\n\nAcknowledgements\n\nWe wish to thank the personnel of the Agel Trinec-Podlesi Hospital who helped co-ordinate the patient's procedures and follow-up visits, and Jan Chovancik, MD, for his great tips and tricks. We also thank our friend Adela Clausen, MD, an anaesthesiologist of Czech origin, for language and style editing.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n==== Refs\nReferences\n\n1 KnuutiJ, WijnsW, SarasteA, CapodannoD, BarbatoE, Funck-BrentanoC et al 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. The Task Force for the diagnosis and management of chronic coronary syndromes of the European Society of Cardiology (ESC). Eur Heart J 2020;41 :407–477.31504439\n2 ChengK, SainsburyP, FisherM, de SilvaR. Management of refractory angina pectoris. Eur Cardiol 2016;11 :69–76.30310450\n3 MannheimerC. The problem of chronic refractory angina. Report from the ESC Joint Study Group on the Treatment of Refractory Angina. Eur Heart J 2002;23 :355–370.11846493\n4 MooreR, GrovesD, HammondC, LeachA, ChesterMR. Temporary sympathectomy in the treatment of chronic refractory angina. J Pain Symptom Manage 2005;30 :183–191.16125034\n5 JiravskyO, SpacekR, ChovancikJ, SzmekB, NeuwirthR, HrosovaM et al P4609 The use of stellate ganglion block in the management of electrical storm reduces VA burden by 92% and completely excludes the need for general anesthesia. Eur Heart J 2019;40 (Suppl 1 ):19.\n6 MengL, TsengC-H, ShivkumarK, AjijolaO. Efficacy of stellate ganglion blockade in managing electrical storm: a systematic review. JACC Clin Electrophysiol 2017;3 :942–949.29270467\n7 AjijolaOA, LelloucheN, BourkeT, TungR, AhnS, MahajanA et al Bilateral cardiac sympathetic denervation for the management of electrical storm. J Am Coll Cardiol 2012;59 :91–92.22192676\n8 VaseghiM, BarwadP, Malavassi CorralesFJ, TandriH, MathuriaN, ShahR et al Cardiac sympathetic denervation for refractory ventricular arrhythmias. J Am Coll Cardiol 2017;69 :3070–3080.28641796\n9 VaseghiM, ZhouW, ShiJ, AjijolaOA, HadayaJ, ShivkumarK et al Sympathetic innervation of the anterior left ventricular wall by the right and left stellate ganglia. Heart Rhythm 2012;9 :1303–1309.22465457\n10 GhaiA, KaushikT, WadheraR, WadheraS. Stellate ganglion blockade-techniques and modalities. Acta Anaesthesiol Belg 2016;67 :1–5.27363208\n11 FuD, KuduvalliG, MaurerC, AllisionJ, AdlerJ. 3D target localization using 2D local displacements of skeletal structures in orthogonal X-ray images for image-guided spinal radiosurgery. Int J CARS 2006;1 :198–200.\n12 HoAK, FuD, CotrutzC, HancockSL, ChangSD, GibbsIC et al A study of the accuracy of cyberknife spinal radiosurgery using skeletal structure tracking. Neurosurgery 2007;60 :147–156.\n13 HindricksG, PotparaT, DagresN, ArbeloE, BaxJJ, Blomström-LundqvistC et al 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J 2020;42 :373–498.\n14 Gramling-BabbP, MillerMJ, ReevesST, RoyRC, ZileMR. Treatment of medically and surgically refractory angina pectoris with high thoracic epidural analgesia: initial clinical experience. Am Heart J 1997;133 :648–655.9200392\n15 BrionesE, LacalleJR, Marin-LeonI, RuedaJ-R. Transmyocardial laser revascularization versus medical therapy for refractory angina. Cochrane Database Syst Rev 2015;2 :CD003712.\n16 AroraRR, ChouTM, JainD, FleishmanB, CrawfordL, McKiernanT et al Effects of enhanced external counterpulsation on health-related quality of life continue 12 months after treatment: a substudy of the multicenter study of enhanced external counterpulsation. J Investig Med 2002;50 :25–32.\n17 BanaiS, Ben MuvharS, ParikhKH, MedinaA, SievertH, SethA et al Coronary sinus reducer stent for the treatment of chronic refractory angina pectoris: a prospective, open-label, multicenter, safety feasibility first-in-man study. J Am Coll Cardiol 2007;49 :1783–1789.17466229\n18 HenryTD, LosordoDW, TraverseJH, SchatzRA, JolicoeurEM, SchaerGL et al Autologous CD34+ cell therapy improves exercise capacity, angina frequency and reduces mortality in no-option refractory angina: a patient-level pooled analysis of randomized double-blinded trials. Eur Heart J 2018;39 :2208–2216.29315376\n19 ZipesDP, SvorkdalN, BermanD, Boortz-MarxR, HenryT, LermanA et al Spinal cord stimulation therapy for patients with refractory angina who are not candidates for revascularization. Neuromodulation 2012;15 :550–558.22494013\n20 DenbyC, GrovesDG, EleuteriA, TsangHK, LeachA, HammondC et al Temporary sympathectomy in chronic refractory angina: a randomised, double-blind, placebo-controlled trial. Br J Pain 2015;9 :142–148.26516570\n21 RaczGB, HolubecJT. Stellate ganglion phenol neurolysis. In: RaczGB, ed. Techniques of Neurolysis. New York: 133 © Springer Science+Business Media; 1989.p133–144.\n22 KastlerA, AubryS, SailleyN, MichalakisD, SilimanG, GoryG et al CT-guided stellate ganglion blockade vs. radiofrequency neurolysis in the management of refractory type I complex regional pain syndrome of the upper limb. Eur Radiol 2013;23 :1316–1322.23138389\n23 StriteskyM, DobiasM, DemesR, SemradM, PoliachovaE, CermakT et al Endoscopic thoracic sympathectomy—its effect in the treatment of refractory angina pectoris. Interact CardioVasc Thorac Surg 2006;5 :464–468.17670622\n24 TuleascaC, RégisJ, SahgalA, SallesAD, HayashiM, MaL et al Stereotactic radiosurgery for trigeminal neuralgia: a systematic review: international stereotactic radiosurgery society practice guidelines. J Neurosurg 2019;130 :733–757.\n25 DoytchinovaA, HasselJL, YuanY, LinH, YinD, AdamsD et al Simultaneous noninvasive recording of skin sympathetic nerve activity and electrocardiogram. Heart Rhythm 2017;14 :25–33.27670627\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2514-2119",
"issue": "5(8)",
"journal": "European heart journal. Case reports",
"keywords": "Case report; Refractory angina; Stellate ganglion blockade; Stereotactic radiosurgery; Upper thoracic sympathetic system",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
"other_id": null,
"pages": "ytab184",
"pmc": null,
"pmid": "34514297",
"pubdate": "2021-08",
"publication_types": "D002363:Case Reports",
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"title": "Chronic refractory angina pectoris treated by bilateral stereotactic radiosurgical stellate ganglion ablation: first-in-man case report.",
"title_normalized": "chronic refractory angina pectoris treated by bilateral stereotactic radiosurgical stellate ganglion ablation first in man case report"
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"companynumb": "CZ-MYLANLABS-2021M1087566",
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"abstract": "We report a newborn with asymmetric crying face and other anomalies whose mother had taken isotretinoin during the first month of pregnancy. We hypothesize that asymmetric crying face is a finding of retinoic acid embryopathy and results from the intrauterine effects of retinoic acid on the development of the depressor anguli oris muscle or the mandibular branch of the facial nerve.",
"affiliations": "Division of Neonatology, Faculty of Medicine, Erciyes University, KayseriDivision of Pediatric Cardiology, Department of Pediatrics, Faculty of Medicine, Erciyes University, KayseriDepartment of Medical Genetics, Faculty of Medicine, Erciyes University, Kayseri, Turkey.",
"authors": "Sarici|Dilek|D|;Akin|Mustafa Ali|MA|;Kurtoglu|Selim|S|;Uzum|Kazim|K|;Kiraz|Aslihan|A|",
"chemical_list": "D003879:Dermatologic Agents; D015474:Isotretinoin",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1525-1470.2012.01743.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "30(6)",
"journal": "Pediatric dermatology",
"keywords": null,
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000152:Acne Vulgaris; D003448:Crying; D003879:Dermatologic Agents; D004423:Ear; D005146:Facial Asymmetry; D005152:Facial Muscles; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D015474:Isotretinoin; D011247:Pregnancy",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "e289-90",
"pmc": null,
"pmid": "22612313",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Asymmetric crying face in a newborn with isotretinoin embryopathy.",
"title_normalized": "asymmetric crying face in a newborn with isotretinoin embryopathy"
} | [
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"companynumb": "TR-RANBAXY-2013R1-75952",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstance": {
"activesubstancename": "ISOTRETINOIN"
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{
"abstract": "OBJECTIVE\nANCA-associated vasculitis (AAV) is characterized by a chronic relapsing course. Rituximab (RTX) is an effective maintenance treatment; however, the long-term outcomes after its discontinuation are unclear. The aim of this study was to explore the long-term outcomes of AAV patients treated with repeat-dose RTX maintenance therapy.\n\n\nMETHODS\nAAV patients receiving a RTX treatment protocol consisting of an induction and maintenance phase were included. For initial remission induction, RTX was dosed at 1 g every 2 weeks or 375 mg/m(2) weekly for 4 consecutive weeks and for remission maintenance at 1 g every 6 months for 24 months. At the first RTX administration, ongoing immunosuppressives were withdrawn.\n\n\nRESULTS\nSixty-nine patients were identified, 67 of whom were failing other therapies. Nine relapsed during the RTX treatment protocol; however, all 69 were in remission at the end of the maintenance phase on a median prednisolone dose of 2.5 mg/day and 9% were receiving additional immunosuppression. During subsequent observation, 28 patients relapsed a median of 34.4 months after the last RTX infusion. Risk factors for relapse were PR3-associated disease (P = 0.039), B cell return within 12 months of the last RTX infusion (P = 0.0038) and switch from ANCA negativity to positivity (P = 0.0046). Two patients died and two developed severe hypogammaglobulinaemia.\n\n\nCONCLUSIONS\nThis study supports the efficacy and safety of a fixed-interval RTX maintenance regimen in relapsing/refractory AAV. Relapses after discontinuation of maintenance therapy did occur, but at a lower rate than after a single RTX induction course. PR3-associated disease, the switch from ANCA negative to positive and the return of B cells within 12 months of the last RTX administration were risk factors for further relapse.",
"affiliations": "Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK federico.alberici@gmail.com.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.;Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK Department of Medicine, University of Cambridge School of Clinical Medicine, Vasculitis and Lupus Service, Addenbrooke's Hospital, Cambridge, UK, Department of Clinical and Experimental Medicine, University of Parma, Italy and Cambridge Institute for Medical Research, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.",
"authors": "Alberici|Federico|F|;Smith|Rona M|RM|;Jones|Rachel B|RB|;Roberts|Darren M|DM|;Willcocks|Lisa C|LC|;Chaudhry|Afzal|A|;Smith|Kenneth G C|KG|;Jayne|David R W|DR|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D000069283:Rituximab; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.1093/rheumatology/keu452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1462-0324",
"issue": "54(7)",
"journal": "Rheumatology (Oxford, England)",
"keywords": "B cells; anti-neutrophil cytoplasm antibody; biologic therapies; granulomatosis with polyangiitis; maintenance treatment; microscopic polyangiitis; vasculitis",
"medline_ta": "Rheumatology (Oxford)",
"mesh_terms": "D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D058846:Antibodies, Monoclonal, Murine-Derived; D018501:Antirheumatic Agents; D015331:Cohort Studies; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007166:Immunosuppressive Agents; D015994:Incidence; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D012008:Recurrence; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100883501",
"other_id": null,
"pages": "1153-60",
"pmc": null,
"pmid": "25477054",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "3657876;22729997;15634903;16447239;16286784;16901958;8129773;24243925;20647199;22730028;24126571;12840090;11200865;17804455;18055469;18586761;19109574;18413444;18713783;20647198;21937757;23293123;22962314;23902481;22734797;22808956;22368231;21953279;24626432",
"title": "Long-term follow-up of patients who received repeat-dose rituximab as maintenance therapy for ANCA-associated vasculitis.",
"title_normalized": "long term follow up of patients who received repeat dose rituximab as maintenance therapy for anca associated vasculitis"
} | [
{
"companynumb": "GB-ROCHE-1611143",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROCORTISONE"
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"drugadditional": null,
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{
"abstract": "Pseudomonas fluorescens (P. fluorescens) and Pseudomonas putida (P. putida) are uncommon causes of skin and soft tissue infections (SSTIs). They are rarely associated with bacteremia and fatality. When presenting with sepsis/shock, patients are usually immunocompromised. Our case highlights the importance of early recognition, source control and antimicrobial choice.\nWe present a case of an immunocompetent 57 year old female who presented with rapidly progressive septic shock in the setting of P. fluorescens/putida bacteremia. The patient continued to deteriorate despite empiric antimicrobial coverage and aggressive source control.\nP. putida and P. fluorescens are gram negative bacillus bacteria that are ubiquitous in soil and water however have been reported as an opportunistic human pathogen capable of causing nosocomial infection especially in immunocompromised patients. Patients with bacteremia and shock should initially be covered with broad antimicrobial coverage for gram positive, gram negative as well as gas producing organisms and deescalate based on cultures and sensitivities. Along with antibiotics, aggressive source control is found to be the key to successful treatment in these patients.\nOur case highlights an immunocompetent patient with rapid progressive sepsis and associated multisystem organ failure. We emphasize the importance of early recognition in these patients and treatment with appropriate antimicrobial therapy followed by source control.",
"affiliations": "Department of Internal Medicine. Grand Strand Medical Center, Myrtle Beach, SC, USA.;Department of Internal Medicine. Grand Strand Medical Center, Myrtle Beach, SC, USA.;Department of Internal Medicine. Grand Strand Medical Center, Myrtle Beach, SC, USA.",
"authors": "Singh|Pratishtha|P|;Montano|Andreas|A|;Bostick|Adam|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.amsu.2021.102845",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)00795-0\n10.1016/j.amsu.2021.102845\n102845\nCase Report\nRapid severe sepsis from Pseudomonas fluorescens/putida bacteremia due to skin and soft tissue infection – A case report\nSingh Pratishtha Pratishtha.Singh@hcahealthcare.com\n∗\nMontano Andreas\nBostick Adam\nDepartment of Internal Medicine. Grand Strand Medical Center, Myrtle Beach, SC, USA\n∗ Corresponding author. Pratishtha.Singh@hcahealthcare.com\n08 9 2021\n10 2021\n08 9 2021\n70 1028456 8 2021\n7 9 2021\n7 9 2021\n© 2021 The Authors\n2021\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/).\nIntroduction\n\nPseudomonas fluorescens (P. fluorescens) and Pseudomonas putida (P. putida) are uncommon causes of skin and soft tissue infections (SSTIs). They are rarely associated with bacteremia and fatality. When presenting with sepsis/shock, patients are usually immunocompromised. Our case highlights the importance of early recognition, source control and antimicrobial choice.\n\nCase presentation\n\nWe present a case of an immunocompetent 57 year old female who presented with rapidly progressive septic shock in the setting of P. fluorescens/putida bacteremia. The patient continued to deteriorate despite empiric antimicrobial coverage and aggressive source control.\n\nClinical discussion\n\nP. putida and P. fluorescens are gram negative bacillus bacteria that are ubiquitous in soil and water however have been reported as an opportunistic human pathogen capable of causing nosocomial infection especially in immunocompromised patients. Patients with bacteremia and shock should initially be covered with broad antimicrobial coverage for gram positive, gram negative as well as gas producing organisms and deescalate based on cultures and sensitivities. Along with antibiotics, aggressive source control is found to be the key to successful treatment in these patients.\n\nConclusion\n\nOur case highlights an immunocompetent patient with rapid progressive sepsis and associated multisystem organ failure. We emphasize the importance of early recognition in these patients and treatment with appropriate antimicrobial therapy followed by source control.\n\nHighlights\n\n• Pseudomonas fluorescens and Pseudomonas putida are uncommon causes of skin and soft tissue infections.\n\n• These organisms are rarely associated with bacteremia and fatality.\n\n• When presenting with sepsis/shock, patients are usually immunocompromised or have comorbidities that lead to a blunted immune response.\n\n• When diagnosed early, treatment with appropriate antibiotics and source control leads to improved outcomes. However, patients with multisystem organ failure tend to have a poor prognosis.\n\nKeywords\n\nSkin and soft tissue infection\nSeptic shock\nPseudomonas putida\nPseudomonas fluorescens\nBacteremia\nNecrotizing fasciitis\n==== Body\npmc1 Introduction\n\nPseudomonas fluorescens (P. fluorescens) and Pseudomonas putida (P. putida) are uncommon causes of skin and soft tissue infections (SSTIs). Both are gram-negative bacillus related to P. aeruginosa and are found throughout the natural environment. Several case reports in the literature are notable for bacteremia however virulence is low and fatality is rare. A majority of the patients affected by the above mentioned are noted to be in an immunocompromised state or have comorbidities that lead to a blunted immune response [1].\n\n2 Case report\n\nA 57 year old female with no pertinent family history and a past medical history of hypertension (on amlodipine), hyperlipidemia (on atorvastatin), irritable bowel syndrome and gastroesophageal reflux disease (on famotidine) initially presented to the emergency department (ED) with complaints of right lateral ankle pain. She had reported an ankle injury 12 hours prior to presentation in her condominium non-salt water pool. Within eight hours of the injury, she developed significant pain, noted swelling on the lateral aspect and presented to the ED for further evaluation. Physical exam of the right lower extremity was notable for swelling with a 2 cm round ecchymotic lesion, limited to the lateral ankle, with limited range of motion secondary to pain, intact pulses and no other skin findings. A right leg and ankle x-ray revealed lateral malleolar edema without acute osseous findings (Fig. 1, Fig. 2). The patient was discharged home after supportive care.Fig. 1 Initial X-ray Right leg: (2 views) with evidence of soft tissue swelling, without any noticeable fractures or osseous findings.\n\nFig. 1\n\nFig. 2 Initial X-ray Right leg: (2 views) with evidence of soft tissue swelling, without any noticeable fractures or osseous findings.\n\nFig. 2\n\nSix hours after discharge from her initial ED visit, the patient and her husband noticed worsening swelling of her right lower extremity. The previously noticed ecchymotic lesion started to expand and become more painful. The patient then developed shortness of breath and emergency medical services were contacted. The patient had a cardiac arrest due to hypoxic respiratory failure enroute to the hospital and was intubated in the field. Upon her subsequent evaluation in the ED, her vital signs were significant for hypotension 85/57 mmHg, sinus tachycardia to 115 bpm, and she was mechanically ventilated. Her physical exam was notable for an extensive hemorrhagic lesion with associated bullous formation extending from the right foot lateral surface up to the right knee (Fig. 3).Fig. 3 Right lower extremity 24 hours after initial injury with evidence of extensive hemorrhagic extension from the ankle to knee.\n\nFig. 3\n\nInitial laboratory findings showed a white blood cell count of 3.3 K/mm3 (3.7–10.1), hemoglobin of 8.9 gm/dL (11.6–15.4), mean corpuscular volume of 112.8 fL (80–100), platelet count of 36 K/mm3 (156–352). Her chemistry was significant for potassium 5.1 mmol/L (3.5–5.1), carbon dioxide 11 mmol/L (22–32), anion gap 33 mEq/L (3–11), creatinine 2.9 mg/dL (0.7–1.5), lactic acid 21.4 mmol/L (0.7–2.1), total bilirubin 1.7 mg/dL (0.1–1.1), aspartate transaminase 327 U/L (15–46), alanine transaminase 164 U/L (13–69), troponin of 0.110 ng/mL (0.0–0.034). Her coagulation studies revealed an elevated prothrombin time of 25.9 seconds (9.8–13.9), international normalized ratio of 2.25, fibrinogen 318 mg/dL (224–424) and a d-dimer 5200 ng/mL (0–500). Her creatinine kinase levels were noted to be at 3197 U/L (range 30–170). Her arterial blood gas findings were consistent with a metabolic acidosis with pH 6.69, pCO2 69.1 mmHg, HCO3 8.3 mmol/L (obtained on 100% fraction of inspired oxygen on mechanical ventilator). Her chest x-ray showed clear lungs with an endotracheal tube in place. A head computed tomography (CT) showed a small volume left inferior sylvian fissure subarachnoid hemorrhage. A chest CT angiography did not show evidence of pulmonary embolism.\n\nThe patient was admitted to the intensive care unit for workup and treatment of septic shock. Intravenous fluids with 0.9% normal saline was initiated. Blood cultures were obtained prior to initiation of intravenous antibiotics and general surgery was emergently consulted for evaluation of necrotizing fasciitis. She was initiated on empiric coverage with intravenous vancomycin (15mg/kg every 8 hours), meropenem (1 gm every 8 hours) and clindamycin (600mg every 8 hours) for necrotizing fasciitis coverage. A bedside fasciotomy of her right lower extremity (RLE) was performed followed by a bedside below the knee guillotine amputation for aggressive source control given her clinical deterioration. Tissue cultures were obtained and sent for bacterial, fungal and acid fast bacillus. A second set of blood cultures were obtained after amputation. The patient continued to have progression of her acidosis and nephrology was consulted for initiation of continuous renal replacement therapy (CRRT).\n\nUnfortunately, her clinical status continued to deteriorate with worsening acidosis, requiring multiple pressors, and the patient shortly expired despite aggressive resuscitative efforts on the second hospital day due to multisystem organ failure. On the second day, blood cultures and tissue cultures grew P. fluorescens and P. putida. Both organisms were sensitive to piperacillin/tazobactam, gentamicin, tobramycin and meropenem.\n\n3 Discussion\n\nP. putida and P. fluorescens are gram negative bacillus bacteria that are ubiquitous in soil and water however have been reported as an opportunistic human pathogen capable of causing nosocomial infection especially in immunocompromised patients. Clinical data on both organisms is lacking owing to the rarity and relatively low virulence rate [2]. A series of case reports by Yang et al. described P. putida related infections and only 5% were SSTIs of which 80% were associated with trauma [3]. In 2017, Nishimura et al. identified three case reports of P. fluorescens infections related to contaminated infusions and an immunocompromised oncology patient [4]. Both P. fluorescens and P. putida rarely result in bacteremia, shock or mortality hence risk factors for all patients should be identified. Immunosuppression, contaminated blood product infusions or catheter related bloodstream infections as the most common cause of infections with these isolates [3]. Pseudobacteremia secondary to contamination of blood cultures during venipuncture, in the preparation of culture media, or during laboratory processing of the culture has been reported and should be considered. Blood cultures should be repeated to establish a true blood stream infection [5].\n\nWhen presenting with bacteremia and associated shock, signs and symptoms related to organ hypoperfusion should be identified. These include but are not limited to tachycardia, dyspnea, restlessness, diaphoresis, metabolic acidosis, hypotension, oliguria, and cool, clammy skin. Signs of end organ dysfunction should be evaluated. Progressive shock can lead to irreversible organ damage, multiorgan failure (MOF), and death. During this stage, anuria and acute renal failure develop, acidemia further depresses cardiac output, and hypotension becomes severe and recalcitrant to therapy [6]. Diagnosis can be made with blood cultures and tissue samples from the suspected source of SSTI. Other laboratory work should include a complete blood count, comprehensive metabolic panel, lactic acid levels, an arterial blood gas as well as other labs indicated based on patients presenting symptoms.\n\nPatients with bacteremia and shock should initially be covered with broad antimicrobial coverage for gram positive, gram negative as well as gas producing organisms and deescalate based on cultures and sensitivities. A study by von Graevenitz et al. looked at patients with positive cultures for P. putida and P. fluorescens which showed sensitivity of the two species to polymyxin colistin, aminoglycosides, tetracycline, higher generation cephalosporins, piperacillin/tazobactam and carbapenems [2]. However, there have been studies that show multi drug resistant species to carbapenems exist [2]. Along with antibiotics, aggressive source control was found to be the key to successful treatment in these patients [7]. Our patient underwent a bedside fasciotomy followed by an above the knee amputation. For worsening acidemia combined with acute renal failure nephrology was consulted and CRRT was initiated.\n\nAlthough there is lacking data, literature identifies two lethal cases of bacteremia from P. fluorescens and P. putida. Both patients were noted to be immunocompromised or have various other comorbidities [1,4]. When diagnosed early, treatment with appropriate antibiotics and source control leads to improved outcomes. However, patients with multisystem organ failure tend to have a poor prognosis. Despite aggressive source control and broad antimicrobial coverage, our patient expired due to the severity of her illness and associated multisystem organ failure.\n\n4 Conclusion\n\nP. fluorescens and P. putida are uncommon causes SSTIs rarely resulting in bacteremia and fatality. Very few cases have been reported and most respond well to appropriate antimicrobial therapy. A few lethal cases have been identified however patients were reported to be immunocompromised. Our case above highlights an immunocompetent patient with rapid progressive sepsis and associated multisystem organ failure. We emphasize the importance of early recognition in these patients and treatment with appropriate antimicrobial therapy followed by source control.\n\nAuthor contributions\n\nAll authors contributed to this manuscript. P. Singh is the article guarantor.\n\nFinancial disclosure\n\nNone to report.\n\nInformed written consent was obtained for this case report.\n\nAnnals of medicine and surgery\n\nThe following information is required for submission. Please note that failure to respond to these questions/statements will mean your submission will be returned. If you have nothing to declare in any of these categories then this should be stated.\n\nPlease state any conflicts of interest\n\nAll authors must disclose any financial and personal relationships with other people or organisations that could inappropriately influence (bias) their work. Examples of potential conflicts of interest include employment, consultancies, stock ownership, honoraria, paid expert testimony, patent applications/registrations, and grants or other funding.\n\nThe authors declare no conflict of interest.\n\nPlease state any sources of funding for your research\n\nAll sources of funding should be declared as an acknowledgement at the end of the text. Authors should declare the role of study sponsors, if any, in the collection, analysis and interpretation of data; in the writing of the manuscript; and in the decision to submit the manuscript for publication. If the study sponsors had no such involvement, the authors should so state.\n\nThis study has not received any funding.\n\nEthical approval\n\nResearch studies involving patients require ethical approval. Please state whether approval has been given, name the relevant ethics committee and the state the reference number for their judgement.\n\nThis study was approved by Ethics Committee.\n\nConsent\n\nStudies on patients or volunteers require ethics committee approval and fully informed written consent which should be documented in the paper.\n\nAuthors must obtain written and signed consent to publish a case report from the patient (or, where applicable, the patient's guardian or next of kin) prior to submission. We ask Authors to confirm as part of the submission process that such consent has been obtained, and the manuscript must include a statement to this effect in a consent section at the end of the manuscript, as follows: “Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request”.\n\nPatients have a right to privacy. Patients’ and volunteers' names, initials, or hospital numbers should not be used. Images of patients or volunteers should not be used unless the information is essential for scientific purposes and explicit permission has been given as part of the consent. If such consent is made subject to any conditions, the Editor in Chief must be made aware of all such conditions.\n\nEven where consent has been given, identifying details should be omitted if they are not essential. If identifying characteristics are altered to protect anonymity, such as in genetic pedigrees, authors should provide assurance that alterations do not distort scientific meaning and editors should so note.\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\n\nPlease specify the contribution of each author to the paper, e.g. study concept or design, data collection, data analysis or interpretation, writing the paper, others, who have contributed in other ways should be listed as contributors.Study concept or design – PS, AM\n\nData collection – PS, AM\n\nData interpretation – PS, AM\n\nLiterature review – PS\n\nDrafting of the paper – PS, AM\n\nEditing of the paper – PS, AM, AB\n\nRegistration of research studies\n\nIn accordance with the Declaration of Helsinki 2013, all research involving human participants has to be registered in a publicly accessible database. Please enter the name of the registry and the unique identifying number (UIN) of your study.\n\nYou can register any type of research at http://www.researchregistry.com to obtain your UIN if you have not already registered. This is mandatory for human studies only. Trials and certain observational research can also be registered elsewhere such as: ClinicalTrials.gov or ISRCTN or numerous other registries.1. Name of the registry: Not Applicable\n\n2. Unique Identifying number or registration ID: N/A\n\n3. Hyperlink to your specific registration (must be publicly accessible and will be checked): N/A\n\nGuarantor\n\nThe Guarantor is the one or more people who accept full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.\n\nPratishtha Singh, M.D.\n==== Refs\nReferences\n\n1 Thomas B.S. Okamoto K. Bankowski M.J. Seto T.B. A lethal case of Pseudomonas putida bacteremia due to soft tissue infection Infect. Dis. Clin. Pract. 21 3 2013 147 213 10.1097/IPC.0b013e318276956b\n2 Kim S.E. Park S.H. Park H.B. Nosocomial Pseudomonas putida bacteremia: high rates of carbapenem resistance and mortality Chonnam Med J 48 2 2012 91 95 10.4068/cmj.2012.48.2.91 22977749\n3 Yang C.H. Young T. Peng M.Y. Clinical spectrum of Pseudomonas putida infection J. Formos. Med. Assoc. 95 1996 754 761 8961672\n4 Nishimura T. Hattori K. Inoue A. Bacteremia or pseudobacteremia? Review of Pseudomonas fluorescens infections World J Emerg Med 8 2 2017 151 154 10.5847/wjem.j.1920-8642.2017.02.013 28458762\n5 Whyte A. Lafong C. Malone J. Golda B.P. Contaminated lithium heparin bottles as a source of pseudobacteremia J. Hosp. Infect. 42 4 1999 342 343 10467550\n6 Singer M. Deutschman C.S. Seymour C.W. The third international consensus definitions for sepsis and septic shock (Sepsis-3) J. Am. Med. Assoc. 315 2016 801\n7 Duong Tram-Anh Silva Taran McKillion Patrick A second reported fatal case of Pseudomonas putida septicemia from soft tissue infection Crit. Care Med. 47 1 2019 289 10.1097/01.ccm.0000551369.47016.e9\n\n",
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"journal": "Annals of medicine and surgery (2012)",
"keywords": "Bacteremia; Necrotizing fasciitis; Pseudomonas fluorescens; Pseudomonas putida; Septic shock; Skin and soft tissue infection",
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"title": "Rapid severe sepsis from Pseudomonas fluorescens/putida bacteremia due to skin and soft tissue infection - A case report.",
"title_normalized": "rapid severe sepsis from pseudomonas fluorescens putida bacteremia due to skin and soft tissue infection a case report"
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"abstract": "Castleman disease is a rare lymphoproliferative disorder with 2 distinctly defined clinical forms. While multicentric Castleman disease (UCD) poses a potential therapeutic challenge, unicentric variant has historically been considered curable with surgical resection. Hence, little is known to guide management of patients with UCD, refractory to surgical resection and combination chemotherapy. We present a case of a patient, negative for HIV and HHV-8, who had an unsuccessful surgical intervention and no response to radiotherapy and chemotherapy. He had severe paraneoplastic pemphigus and was treated with tocilizumab, an anti-interleukin-6 receptor monoclonal antibody that has demonstrated good response rates in multicentric Castleman disease but demonstrated no clinical response despite 2 months of treatment. Our report is the first to describe a lack of response to tocilizumab in the rare setting of refractory UCD and discuss potential for distinct disease biology.",
"affiliations": "Department of Haematology, University Hospitals of Bristol NHS Trust, Bristol, UK.;Department of Haematology, University Hospitals of Bristol NHS Trust, Bristol, UK.;Division of Otolaryngology and Head and Neck Surgery, John Hopkins School of Medicine, Baltimore, MD, USA.;Department of Haematology, University Hospitals of Bristol NHS Trust, Bristol, UK.;Department of Cellular Pathology, University Hospitals Bristol NHS Trust, Bristol, UK.;Department of Dermatology, University Hospitals of Bristol NHS Trust, Bristol, UK.;Department of Oral Medicine, University Hospitals of Bristol NHS Trust, Bristol, UK.;Department of Radiology, University Hospitals of Bristol NHS Trust, Bristol, UK.;Department of Haematology, University Hospitals of Bristol NHS Trust, Bristol, UK.",
"authors": "Abid|Muhammad Bilal|MB|http://orcid.org/0000-0002-1128-0445;Peck|Rachel|R|;Abid|Muhammad Abbas|MA|;Al-Sakkaf|Wesam|W|http://orcid.org/0000-0002-2901-7979;Zhang|Yuening|Y|;Dunnill|Giles S|GS|;Staines|Konrad|K|;Sequeiros|Iara-Maria|IM|;Lowry|Lisa|L|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; C502936:tocilizumab",
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"issue": "36(1)",
"journal": "Hematological oncology",
"keywords": "IL-6; cytokine storm; tocilizumab; unicentric Castleman disease (UCD)",
"medline_ta": "Hematol Oncol",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D005871:Castleman Disease; D006801:Humans; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8307268",
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"publication_types": "D002363:Case Reports",
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"title": "Is tocilizumab a potential therapeutic option for refractory unicentric Castleman disease?",
"title_normalized": "is tocilizumab a potential therapeutic option for refractory unicentric castleman disease"
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"abstract": "Vasopressin has gained wide support as an adjunct vasopressor in patients with septic shock. This agent exerts its vasoconstriction effects through smooth muscle V1 receptors and also has antidiuretic activity via renal V2 receptors. This interaction with the renal V2 receptors results in the integration of aquaporin 2 channels in the apical membrane of the renal collecting duct leading to free water reabsorption. Thus, water intoxication with subsequent hyponatremia, although rare, is a potentially serious side effect of exogenous vasopressin administration. We present 2 patients who developed hyponatremia within hours of initiation of vasopressin infusion. Extensive diuresis followed its discontinuation with subsequent normalization of serum sodium. One of the patients required the use of hypertonic saline for more rapid normalization of serum sodium due to concerns for potential seizure activity. A review of the literature relevant to the incidence of vasopressin-induced hyponatremia is provided as well as discussion on additional factors relevant to septic shock that should be considered when determining the relative risk of hyponatremia in patients receiving vasopressin.",
"affiliations": "Department of Pharmacy Practice, Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, TX, USA msalazar@pharmacy.tamhsc.edu.;Department of Pharmacy, St. Luke's Hospital, Houston, TX, USA.;Department of Medicine, Universidad Anahuac México Norte, State of México, México.;Kidney Associates, PLLC, Houston, TX, USA Department of Medicine, Division of Nephrology, Baylor College of Medicine, Houston, TX, USA Department of Medicine, Division of Nephrology, University of Texas Medical Branch, Galveston, TX, USA Department of Medicine, Division of Nephrology, The Methodist Hospital Weil-Cornell Medical Center, Houston, TX, USA.;Critical Care Services, University General Hospital, Houston, TX, USA Department of Acute and Continuing Care, The University of Texas Health Science Center at Houston, Houston, TX, USA Department of Medicine, University of Texas Medical Branch, Galveston, TX, USA.",
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"keywords": "antidiuresis; hyponatremia; vasodilatory shock; vasopressin; vasopressors",
"medline_ta": "J Intensive Care Med",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D004231:Diuresis; D005260:Female; D006801:Humans; D007010:Hyponatremia; D008297:Male; D017483:Receptors, Vasopressin; D012772:Shock, Septic; D012964:Sodium; D014662:Vasoconstrictor Agents; D014667:Vasopressins; D014869:Water Intoxication; D055815:Young Adult",
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"title": "Exogenous Vasopressin-Induced Hyponatremia in Patients With Vasodilatory Shock: Two Case Reports and Literature Review.",
"title_normalized": "exogenous vasopressin induced hyponatremia in patients with vasodilatory shock two case reports and literature review"
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"abstract": "Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients.\n\n\n\nA retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019.\n\n\n\nWe found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective.\n\n\n\nBCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.",
"affiliations": "Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. adeeb@hadassah.org.il.;Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Garvan Institute of Medical Research, Sydney, Australia.;Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Pediatric Infectious Diseases Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Allergy & Clinical Immunology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Allergy & Clinical Immunology Unit, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Department for Rheumatology and Clinical Immunology and Center for Chronic Immunodeficiency (CCI), Medical Center, University of Freiburg, Faculty of Medicine, Freiburg im Breisgau, Germany.;Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.;Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.",
"authors": "NaserEddin|Adeeb|A|;Dinur-Schejter|Yael|Y|0000-0003-3332-2391;Shadur|Bella|B|;Zaidman|Irina|I|;Even-Or|Ehud|E|;Averbuch|Diana|D|;Shamriz|Oded|O|;Tal|Yuval|Y|;Shaag|Avraham|A|;Warnatz|Klaus|K|;Elpeleg|Orly|O|;Stepensky|Polina|P|",
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"doi": "10.1007/s10875-020-00892-6",
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"issue": "41(1)",
"journal": "Journal of clinical immunology",
"keywords": "BCG vaccination; hematopoietic stem cell transplantation; immune reconstitution inflammatory syndrome; primary immune deficiency; severe combined immunodeficiency",
"medline_ta": "J Clin Immunol",
"mesh_terms": null,
"nlm_unique_id": "8102137",
"other_id": null,
"pages": "147-162",
"pmc": null,
"pmid": "33111199",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19164935;24679470;16421800;24722620;32006723;22430715;20030825;22248828;31123910;21057261;26936803;29226302;22664165;4153799;26769277;23157280;31081274;23692601;22110512;18044052;1915499;12105777;32377975;16712611;10886754;8733714;10359912;21184155;26121110;23389499;23680261;25011356;19025493;24804000;19483618;23324760;18992930;21690625;19606456;21879238;29609965;19952057",
"title": "Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation.",
"title_normalized": "bacillus calmette guerin bcg vaccine associated complications in immunodeficient patients following stem cell transplantation"
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"abstract": "BACKGROUND Acanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant. CASE REPORT We report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation. CONCLUSIONS We report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.",
"affiliations": "Department of Hematology, St. James's Hospital, Dublin, Ireland.;Department of Histopathology, Beaumont Hospital, Dublin, Ireland.;Department of Radiology, St. James's Hospital, Dublin, Ireland.;Department of Microbiology, St. James's Hospital, Dublin, Ireland.;Department of Radiology, St. James's Hospital, Dublin, Ireland.;Department of Rehabilitation Medicine, St. James's Hospital, Dublin, Ireland.;Department of Neurology, St. James's Hospital, Dublin, Ireland.;Department of Endocrinology, St. James's Hospital, Dublin, Ireland.;Department of Hematology, Waterford University Hospital, Waterford, Ireland.;Department of Radiology, St. James's Hospital, Dublin, Ireland.;Hospital for Tropical Diseases, University College London, London, United Kingdom.;Department of Microbiology, St. James's Hospital, Dublin, Ireland.;Department of Histopathology, Beaumont Hospital, Dublin, Ireland.;Department of Hematology, St. James's Hospital, Dublin, Ireland.",
"authors": "Keane|Niamh A|NA|;Lane|Louise Marie|LM|;Canniff|Emma|E|;Hare|Daniel|D|;Doran|Simon|S|;Wallace|Eugene|E|;Hutchinson|Siobhan|S|;Healy|Marie-Louise|ML|;Hennessy|Brian|B|;Meaney|Jim|J|;Chiodini|Peter|P|;O'Connell|Brian|B|;Beausang|Alan|A|;Vandenberghe|Elisabeth|E|",
"chemical_list": "D000981:Antiprotozoal Agents",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.923219",
"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\n32603318\n10.12659/AJCR.923219\n923219\nArticles\nA Surviving Case of Acanthamoeba Granulomatous Amebic Encephalitis in a Hematopoietic Stem Cell Transplant Recipient\nKeane Niamh A. DEF1 Lane Louise Marie C2 Canniff Emma BC3 Hare Daniel D4 Doran Simon BD3 Wallace Eugene E5 Hutchinson Siobhan B6 Healy Marie-Louise E7 Hennessy Brian BC8 Meaney Jim D3 Chiodini Peter D9 O’Connell Brian D4 Beausang Alan CD2 Vandenberghe Elisabeth EF1 \n1 Department of Hematology, St. James’s Hospital, Dublin, Ireland\n\n2 Department of Histopathology, Beaumont Hospital, Dublin, Ireland\n\n3 Department of Radiology, St. James’s Hospital, Dublin, Ireland\n\n4 Department of Microbiology, St. James’s Hospital, Dublin, Ireland\n\n5 Department of Rehabilitation Medicine, St. James’s Hospital, Dublin, Ireland\n\n6 Department of Neurology, St. James’s Hospital, Dublin, Ireland\n\n7 Department of Endocrinology, St. James’s Hospital, Dublin, Ireland\n\n8 Department of Hematology, Waterford University Hospital, Waterford, Ireland\n\n9 Hospital for Tropical Diseases, University College London, London, U.K.\nCorresponding Author: Elisabeth Vandenberghe, e-mail: evandenberghe@stjames.ieAuthors’ 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 \n30 6 2020 \n21 e923219-1 e923219-6\n02 2 2020 18 3 2020 26 5 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 32-year-old\n\nFinal Diagnosis: Granulomatous amebic encephalitis\n\nSymptoms: —\n\nMedication:—\n\nClinical Procedure: —\n\nSpecialty: —\n\nObjective:\nChallenging differential diagnosis\n\nBackground:\nAcanthamoeba are free-living amoebae with potential to infect immunocompromised hosts. The mortality rate of granulomatous amebic encephalitis (GAE) due to Acanthamoeba exceeds 90% and there are currently no reports of survival of this infection in recipients of hematopoietic stem cell transplant.\n\nCase Report:\nWe report herein the case of a 32-year-old man presenting to our service with abrupt neurological deterioration and seizures 5 months after allogeneic stem cell transplantation for Hodgkin lymphoma. Clinical and imaging findings were non-specific at presentation. Multiple circumscribed, heterogenous, mass-like lesions were identified on MRI. Brain biopsy was performed and revealed multiple cysts and trophozoites suggesting a diagnosis of granulomatous amebic encephalitis. PCR testing confirmed Acanthamoeba. Treatment with miltefosine, metronidazole, azithromycin, fluconazole, pentamidine isethionate, and co-trimoxazole was instituted and the patient survived and shows continued improvement with intensive rehabilitation.\n\nConclusions:\nWe report the first successful outcome in this setting. The diagnosis would have been missed on cerebrospinal fluid analysis alone, but was rapidly made by histological analysis of brain biopsy. This diagnostically challenging infection is likely under-recognized. Early brain biopsy and commencement of a prolonged miltefosine-containing anti-ameba regimen can be curative.\n\nMeSH Keywords:\nAcanthamoebaAmoebaCentral Nervous System Protozoal InfectionsHematopoietic Stem Cell Transplantation\n==== Body\nBackground\nGranulomatous amebic encephalitis is a rare central nervous system infection that is usually rapidly fatal [1,2]. Symptoms are myriad, and reflect the area of brain infected. Typically, the onset of symptoms is insidious until overwhelming infection results in rapid severe neurological decline, including seizures, altered levels of consciousness, coma, and death. Diagnosis is challenging due to the non-specific clinical presentation and radiological features. Brain biopsy is generally required for diagnosis, with cerebrospinal fluid analysis and culture yielding false-negative results in the majority of cases [2]. The optimal treatment for this infection has not been described. Herein, we report a case in which diagnosis was promptly made by early brain biopsy and a prolonged combination anti-amebic treatment approach was instituted with successful outcome.\n\nCase Report\nA 32-year-old male engineer presented 5 months after allogeneic hematopoietic stem cell transplant for chemotherapy-refractory Hodgkin lymphoma with a 4-day history of headache, difficulty finding words, and unable to read back cell phone texts which he had just completed. Collateral history confirmed he had driven through a red light he did not notice, and noted episodes of staring with speech arrest. Neurological examination confirmed anomic aphasia with compensatory circumlocution, and alexia without agraphia (unable to read despite retaining the ability to write). Visual field testing revealed right homonymous superior quadrantanopia.\n\nHe was diagnosed 2 years prior to this presentation with stage IVB classical Hodgkin lymphoma and international prognostic score (IPS) of 5. Interim positron emission tomography (PET) following 2 cycles of Adriamycin, Bleomycin, Vinblastine, and Dacarbazine (ABVD) chemotherapy was Deauville score 4, and treatment was intensified to the dose-escalated Bleomycin Etoposide Adriamycin Cyclophosphamide Oncovin Procarbazine Prednisolone (BEACOPP) regimen for 2 cycles, resulting in a persistent Deauville 4 score. The patient received salvage therapy with Brentuximab vedotin and Ifosfamide Carboplatin Etoposide (ICE) for 3 cycles, achieving a complete remission (Deauville score 1) which was consolidated with a matched unrelated allograft using Carmustine/BCNU Etoposide Cytarabine Melphalan (BEAM) and Alemtuzumab conditioning. He engrafted on day 12 and his post-transplant course was complicated by steroid-responsive grade 3 skin graft versus host disease. The patient was PET-negative and a 100% total and CD3 donor chimera on day 100.\n\nAt the time of this acute neurological presentation on day 160, he remained profoundly immunosuppressed. His medication consisted of valaciclovir 500 mg once daily, atovaquone 750 mg twice daily, phenoxymethylpenicillin 333 mg twice daily, prednisolone 10 mg once daily (for skin graft versus host disease), and ciclosporin 50mg twice daily. He reported adherence to all medications. His absolute lymphocyte count was 0.1×109/L with absolute CD4+ T cell count 51×106/L.\n\nMRI brain revealed multiple circumscribed heterogenous mass-like lesions in the left occipital and right frontal lobes, with further areas of edema in the splenium of the corpus callosum and left temporal lobe, which correlated with his alexia without agraphia and right superior quadrantanopia, respectively (Figure 1A). Cerebrospinal fluid (CSF) analysis revealed elevated white cell count of 42/mm3 (reference 0–5 WBC/mm3) and elevated protein 1.49 mg/dL (reference 0.15–0.45g/L) (Table 1). CSF microscopy was negative. The patient was rapidly deteriorating neurologically, and electroencephalogram was not possible, but an urgent brain biopsy was performed. The histological features were consistent with GAE, with Acanthamoeba spp. favored as the most likely causative organism based on morphological grounds (Figure 2), in the context of immunosuppression and due to the presence of intra-axial mass lesions. CSF PCR was negative for Acanthamoeba, Naegleria, and Balamuthia, but PCR of brain tissue was positive for Acanthamoeba species.\n\nThe Acanthamoeba trophozoites and cysts noted on brain biopsy led to a change in treatment from initial empiric antimicrobial cover to fluconazole 12 mg/kg once daily po, pent-amidine isethionate 4 mg/kg 4 times daily iv, metronidazole 500 mg 3 times daily iv, azithromycin 250 mg once daily po, co-trimoxazole 5 mg/kg twice daily IV, and miltefosine 50 mg 3 times daily po.\n\nThe patient deteriorated abruptly on day 9 of admission (day 5 of anti-amoebic therapy). Episodes of speech arrest became more frequent and he became disoriented to place and time. On day 8 of admission, serum sodium had been 139 mEq/L (139 mmol/L) (reference range 136–145 mEq/L, 136–145 mmol/L). On the evening of day 9, this fell to 129 mEq/L (129 mmol/L) in tandem with worsening symptomatology. Eslicarbazepine 400 mg qd and clobazam 5 mg bid anticonvulsant therapy was added, but on day 10, the patient had a generalized tonic-clonic seizure associated with a precipitous fall in serum sodium to 110 mmol/L. He was treated with hypertonic (3%) saline with temporary omission of other infusions, including pentamidine isethionate, given its potential to aggravate hyponatremia. Repeat MRI brain revealed significantly worsened vasogenic edema with resultant mass effect (Figure 1B). Risk of transforaminal herniation was deemed to be high based on the imaging, and dexamethasone 8 mg tid IV was instituted to ameliorate edema. Clinical and laboratory parameters were consistent with Syndrome of Inappropriate Anti-Diuretic Hormone secretion (SIADH) as a cause of this abrupt severe hyponatremia – the onset was 9 days after brain biopsy; serum osmolarity was 280 mmol/kg and urinary osmolarity and sodium were both inappropriately high at 556 mmol/kg and 178 mmol/L, respectively. The patient responded to hypertonic saline, with normalization of serum sodium and correction of both urinary osmolarity and sodium over the course of 11 days.\n\nIn total, our patient was hospitalized for 53 days. Increasing nausea limited tolerance of the anti-amebic regimen and in total he completed 21 days of pentamidine isethionate, 28 days of co-trimoxazole and azithromycin, 60 days of metronidazole, 120 days of fluconazole, and 150 days of miltefosine. Maintenance therapy of miltefosine 50 mg 3 times weekly was planned but discontinued because of gastrointestinal intolerance. CSF re-analysis on day 40 indicated normalization of cell count and protein. Repeat MRI at this time showed persistent decreased gyral enhancement, widespread edema, and areas of parenchymal necrosis. Repeat imaging on day 140 demonstrated resolution of edema and ex-vacuo dilatation of the posterior horn of the left lateral ventricle with surrounding gliosis, consistent with the natural history of treated necrotic areas (Figure 1C).\n\nPersistent language deficits, including anomic aphasia and alexia, on discharge from hospital reflected left temporoparietal and callosal injuries. He underwent an outpatient neuro-rehabilitation program, with significant improvement in attention and recall. At 12 months after presentation, he is performing well in language and reading, with minor residual difficulty in naming low-frequency items, but improved fluency and fewer word-finding pauses. He displays excellent procedural memory for complex skills learned previously including engine repair, which he has resumed as a hobby. Our patient shows ongoing improvement and remains in complete remission 1 year after transplant for Hodgkin lymphoma.\n\nDiscussion\nGranulomatous amoebic encephalitis (GAE) is a rare central nervous system infection caused by free-living amoebae and is associated with a high mortality rate. Three genera of pathogenic free-living amoebae are known to infect human hosts: Acanthamoeba spp., Balamuthia mandrillaris, and Naegleria fowleri [1,2]. Only the former 2 genera cause GAE and have 2 distinct life-cycle stages – the infectious trophozoite and dormant cyst stages [1,2]. Although Acanthamoeba are found ubiquitously in the environment, there are fewer than 50 reported cases of acanthamebic GAE in the literature, although it is likely that the true incidence is underestimated due to a failure to recognize and diagnose the infection. At the time of writing, we are aware of only 10 reported cases of acanthamebic GAE in patients after hematopoietic stem cell transplant [3–11]. In each of these cases, the infection proved fatal, and in 8 of the 10 cases the diagnosis was established only following histologic examination of autopsy specimens [3–9].\n\nThe source of the Acanthamoeba infection was not obvious in the case reported herein. Our patient previously used disposal contact lenses for correction of myopia but ceased using them prior to undergoing hematopoietic stem cell transplantation and had no symptoms or signs of keratitis. Acanthamoeba spp. are thought to enter the host via the lower respiratory tract or olfactory epithelium and spread hematogenously to the central nervous system [2] and this is the most likely mode of infection in our patient. The amoebae induce an inflammatory response and adhere to endothelial cells in the microvasculature via mannose binding protein to disrupt tight junctions and permeate the blood brain barrier [12,13]. Acanthamoeba spp. also produce proteases and toxins that damage tight junctions, connective tissue, and neurons [1,14]. The onset of clinical symptoms is insidious. Typical features include headache, nausea, irritability, and low-grade fever. Other clinical features depend on the area of brain affected, with a literature review indicating that the frontal and temporal lobes are the most commonly affected areas in Acanthamoeba GAE [15]. GAE is progressive, resulting in seizures, raised intracranial pressure, altered mental status, coma, and death. Diagnosis is challenging, with culture or isolation of Acanthamoeba from CSF of affected individuals proving difficult [2] and, in this case, had biopsy not been performed, the diagnosis would have been missed based on CSF analysis alone.\n\nThe optimal approach to the management of Acanthamoeba GAE is unknown. Drugs with in vitro activity that have resulted in successful outcomes for a small number of patients include rifampicin, azole anti-fungal drugs, pentamidine isethionate, sulfadiazine, flucytosine, azithromycin, caspofungin, and miltefosine. The Center for Disease Control and Prevention recommend a combination approach with miltefosine, pent-amidine isethionate, and fluconazole. Miltefosine is an alkyl-phosphocholine drug that was initially developed as an anti-cancer drug but found a niche in the treatment of parasitic infections, in particular leishmaniasis [16]. Later, in vitro activity against Acanthamoeba was observed [17]. The mechanism of activity is thought to be the disruption of lipid-dependent cell signalling pathways in the parasite cell membrane. The introduction of miltefosine-containing combinations for the treatment of acanthamebic GAE is thought to have improved survival, at least in immunocompetent patients [18,19] and a case of successful treatment of a heart transplant recipient is reported [20]. In general, miltefosine is well tolerated, with manageable gastrointestinal symptoms constituting the chief adverse effect reported. As yet, there has been no clear guidance regarding the optimal duration of therapy, but continued treatment until radiological evidence of the absence of active disease and a normal CSF examination is advisable. It is likely that, as in our patient’s case, several months of treatment will be required to secure a successful outcome.\n\nOur patient is the first reported case of survival following acanthamebic GAE in the setting of profound immunosuppression after hematopoietic stem cell transplantation. Prompt biopsy and institution of an appropriate miltefosine-containing regimen led to a successful outcome following a prolonged treatment course and intensive rehabilitation.\n\nConclusions\nThis case illustrates the importance of early brain biopsy in a profoundly immunosuppressed patient with unexplained neurological deterioration, as the diagnosis would not have been made if relying on CSF analysis alone. Granulomatous amebic encephalitis is a rapidly fatal infection that is likely under-recognized. Early recognition and prompt institution of appropriate miltefosine-containing anti-amebic regimen can secure a successful outcome, even in profoundly immunosup-pressed patients.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Imaging studies. (A) FLAIR images at presentation. Note circumscribed heterogenous 4-cm mass-like lesion in the left occipital lobe (arrows). Note also a 15-mm lesion with similar single characteristics within the medial right frontal lobe (arrow). Further areas of edema are present in the splenium of the corpus callosum and temporal lobe on the left, which correlate with the patient’s alexia without agraphia and right superior quadrantanopia, respectively. FLAIR images are shown. T1, T2, diffusion, and contrast-enhanced imaging modes revealed partial restricted diffusion and enhancement, but these abnormalities are more marked on FLAIR images. (B) FLAIR images following biopsy. Ten days later, there was significant deterioration with extension of the edema into the left temporal lobe and a mild mass effect (arrows). A more circumscribed focus of high signal intensity within the center of the lesion represents hematoma following biopsy. The right frontal lesion is unchanged. (C) FLAIR images at day 140. Follow-up scan 5 months later demonstrates resolution of the edema on the left, with significant dilatation of the posterior horn of the left lateral ventricle, consistent with ex-vacuo dilatation (asterisks). The high signal intensity within the left temporal lobe, which continues around the dilated posterior horn, is well-demarcated and is consistent with gliosis (arrows).\n\nFigure 2. Histopathology. (A) Low-power magnification H&E photomicrographs of brain histology. Fragments of grey and white matter showing perivascular and parenchymal chronic inflammation, composed of lymphocytes, macrophages, and microglial cells. Rare multinucleated giant cells are seen (H&E ×10 objective). (B) Low-power magnification H&E photomicrographs of brain histology. Several variably sized aggregates of microglial cells forming microglial nodules are seen (H&E ×10 objective). (C) High-power magnification H&E photomicrographs of brain histology. Multiple rounded organisms are seen. The majority have a well-defined capsule with abundant granular/vacuolated cytoplasm, a round nucleus, and prominent central karyosome, consistent with amoebic trophozoites (blue arrows). Smaller ones have dark nuclei with a wrinkled and rather refractile outer capsule, consistent with amoebic cysts (red arrows) (H&E ×40 objective).\n\nTable 1. Cerebrospinal fluid (CSF) analysis.\n\n\tParameter\tResult\t\nPeripheral blood\tWhite cell count (cells/mm3)\t2.3\t\nNeutrophils (cells/mm3/%)\t2/87%\t\nLymphocytes (cells/mm3/%)\t<0.1/4%\t\nGlucose (mg/dL)\t162\t\nProtein (g/dL)\t5\t\nCerebrospinal fluid\tWhite cell count (cells/mm3)\t42\t\nNeutrophils (cells/mm3/%)\t1/3%\t\nLymphocytes (cells/mm3/%)\t37/88%\t\nCD8 (cells/mm3/%)\t32/88%\t\nCD4 (cells/mm3/%)\t2/6%\t\nNK (cells/mm3/%)\t3/7%\t\nGlucose (mg/dL)\t72\t\nProtein (mg/dL)\t149\t\nMicrobiology CSF results\tBacterial culture\tNegative\t\nTB GeneXpert\tNegative\t\nViral PCR*\tNegative\t\nToxoplasma gondii PCR\tNegative\t\nMicrosporidia PCR\tNegative\t\nPCR for Acanthamoeba, Balamuthia, Naegleria\tNegative\t\n* PCR of CSF for HSV1, HSV2, EBV, CMV, VZV, JCV, HHV6 and enterovirus were all negative.\n==== Refs\nReferences:\n1. Siddiqui R Khan NA Biology and pathogenesis of Acanthamoeba Parasit Vectors 2012 5 6 22229971 \n2. Schuster FL Visvesvara GS Opportunistic amoebae: Challenges in prophylaxis and treatment Drug Resist Updat 2004 7 1 41 51 15072770 \n3. Anderlini P Przepiorka D Luna M Acanthamoeba meningoencephalitis after bone marrow transplantation Bone Marrow Transplant 1994 14 3 459 61 7994273 \n4. Feingold JM Abraham J Bilgrami S Acanthamoeba meningoencephalitis following autologous peripheral stem cell transplantation Bone Marrow Transplant 1998 22 3 297 300 9720747 \n5. Castellano-Sanchez A Popp AC Nolte FS Acanthamoeba castellani encephalitis following partially mismatched related donor peripheral stem cell transplantation Transpl Infect Dis 2003 5 4 191 94 14987204 \n6. Peman J Jarque I Frasquet J Unexpected postmortem diagnosis of Acanthamoeba meningoencephalitis following allogeneic peripheral blood stem cell transplantation Am J Transplant 2008 8 7 1562 66 18510635 \n7. Akpek G Uslu A Huebner T Granulomatous amebic encephalitis: An under-recognized cause of infectious mortality after hematopoietic stem cell transplantation Transpl Infect Dis 2011 13 4 366 73 21338461 \n8. Doan N Rozansky G Nguyen HS Granulomatous amebic encephalitis following hematopoietic stem cell transplantation Surg Neurol Int 2015 6 Suppl. 18 S459 62 26539322 \n9. Coven SL Song E Steward S Acanthamoeba granulomatous amoebic encephalitis after pediatric hematopoietic stem cell transplant Pediatr Transplant 2017 21 8 e13060 \n10. Kaul DR Lowe L Visvesvara GS Acanthamoeba infection in a patient with chronic graft-versus-host disease occurring during treatment with voriconazole Transpl Infect Dis 2008 10 6 437 41 18713138 \n11. Abd H Saeed A Jalal S Bekassy AN Sandstrom G Ante mortem diagnosis of amoebic encephalitis in a haematopoietic stem cell transplanted patient Scand J Infect Dis 2009 41 8 619 22 19479635 \n12. Alsam S Kim KS Stins M Acanthamoeba interactions with human brain microvascular endothelial cells Microb Pathog 2003 35 6 235 41 14580387 \n13. Khan NA Siddiqui R Acanthamoeba affects the integrity of human brain microvascular endothelial cells and degrades the tight junction proteins Int J Parasitol 2009 39 14 1611 16 19580812 \n14. Sissons J Alsam S Goldsworthy G Identification and properties of proteases from an Acanthamoeba isolate capable of producing granulomatous encephalitis BMC Microbiol 2006 6 42 16672059 \n15. Ong TYY Khan NA Siddiqui R Brain-eating amoebae: Predilection sites in the brain and disease outcome J Clin Microbiol 2017 55 7 1989 97 28404683 \n16. Dorlo TP Balasegaram M Beijnen JH de Vries PJ Miltefosine: A review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis J Antimicrob Chemother 2012 67 11 2576 97 22833634 \n17. Schuster FL Guglielmo BJ Visvesvara GS In-vitro activity of miltefosine and voriconazole on clinical isolates of free-living amebas: Balamuthia mandrillaris , Acanthamoeba spp., and Naegleria fowleri J Eukaryot Microbiol 2006 53 2 121 26 16579814 \n18. Aichelburg AC Walochnik J Assadian O Successful treatment of disseminated Acanthamoeba sp. infection with miltefosine Emerg Infect Dis 2008 14 11 1743 46 18976559 \n19. Webster D Umar I Kolyvas G Treatment of granulomatous amoebic encephalitis with voriconazole and miltefosine in an immunocompetent soldier Am J Trop Med Hyg 2012 87 4 715 18 22869634 \n20. Brondfield MN Reid MJ Rutishauser RL Disseminated Acanthamoeba infection in a heart transplant recipient treated successfully with a miltefo-sine-containing regimen: Case report and review of the literature Transpl Infect Dis 2017 19 2 e12661\n\n",
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"mesh_terms": "D000328:Adult; D000562:Amebiasis; D000981:Antiprotozoal Agents; D001921:Brain; D004359:Drug Therapy, Combination; D006099:Granuloma; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D000069544:Infectious Encephalitis; D008279:Magnetic Resonance Imaging; D008297:Male; D066027:Transplant Recipients",
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"title": "A Surviving Case of Acanthamoeba Granulomatous Amebic Encephalitis in a Hematopoietic Stem Cell Transplant Recipient.",
"title_normalized": "a surviving case of acanthamoeba granulomatous amebic encephalitis in a hematopoietic stem cell transplant recipient"
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"abstract": "Leukemias are the most frequent malignant neoplasms in childhood; acute lymphoblastic leukemia (ALL) is the most frequent. The addition of intrathecal methotrexate to chemotherapy regimens has been beneficial in preventing relapse to the central nervous system and avoiding the use of radiation therapy. Due to its mechanism of action, by inhibiting the enzyme dihydrofolate reductase, when it is used systemically, it has multiple expected adverse effects such as mucositis, myelosuppression and it has also been observed after intrathecal administration or high intravenous doses, acute, subacute neurotoxicity where stroke like syndrome is found. We present an 11-year-old patient diagnosed with T-ALL, who manifested after 8 days of intrathecal administration of methotrexate, faciobrachial hemiparesis and acute onset expression aphasia. The diagnosis of subacute encephalopathy reversible by methotrexate was reached by excluding other Encefalopatía subaguda reversible por metotrexato: notificación de un caso pediátrico Methotrexate-induced stroke-like syndrome: A pediatric case report more frequent pathologies and the typical evolution, with spontaneously ad integrum resolution of the symptoms.",
"affiliations": "Unidad 6 de Clínica Pediátrica, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Argentina.;Unidad 6 de Clínica Pediátrica, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Argentina.;Unidad 6 de Clínica Pediátrica, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Argentina.;Unidad 6 de Clínica Pediátrica, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Argentina. flor.palmieri@gmail.com.;Unidad 6 de Clínica Pediátrica, Hospital de Niños Ricardo Gutiérrez, Ciudad Autónoma de Buenos Aires, Argentina.",
"authors": "Marin|Florencia|F|;Astorquizaga|Lucía|L|;Font|Daniela|D|;Palmieri|Florencia|F|;Cheistwer|Ariel|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D008727:Methotrexate",
"country": "Argentina",
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"doi": "10.5546/aap.2021.e550",
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"issue": "119(5)",
"journal": "Archivos argentinos de pediatria",
"keywords": "lymphoblastic leukemia; methotrexate; stroke",
"medline_ta": "Arch Argent Pediatr",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002648:Child; D006801:Humans; D008727:Methotrexate; D020258:Neurotoxicity Syndromes; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D020521:Stroke",
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"pubdate": "2021-10",
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"title": "Methotrexate-induced stroke-like syndrome: A pediatric case report.",
"title_normalized": "methotrexate induced stroke like syndrome a pediatric case report"
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"drugadditional": "1... |
{
"abstract": "BACKGROUND\nWe compared the efficacy of two different taxanes, docetaxel and paclitaxel, given either weekly or every 3 weeks, in the adjuvant treatment of breast cancer.\n\n\nMETHODS\nWe enrolled 4950 women with axillary lymph node-positive or high-risk, lymph node-negative breast cancer. After randomization, all patients first received 4 cycles of intravenous doxorubicin and cyclophosphamide at 3-week intervals and were then assigned to intravenous paclitaxel or docetaxel given at 3-week intervals for 4 cycles or at 1-week intervals for 12 cycles. The primary end point was disease-free survival.\n\n\nRESULTS\nAs compared with patients receiving standard therapy (paclitaxel every 3 weeks), the odds ratio for disease-free survival was 1.27 among those receiving weekly paclitaxel (P=0.006), 1.23 among those receiving docetaxel every 3 weeks (P=0.02), and 1.09 among those receiving weekly docetaxel (P=0.29) (with an odds ratio >1 favoring the groups receiving experimental therapy). As compared with standard therapy, weekly paclitaxel was also associated with improved survival (odds ratio, 1.32; P=0.01). An exploratory analysis of a subgroup of patients whose tumors expressed no human epidermal growth factor receptor type 2 protein found similar improvements in disease-free and overall survival with weekly paclitaxel treatment, regardless of hormone-receptor expression. Grade 2, 3, or 4 neuropathy was more frequent with weekly paclitaxel than with paclitaxel every 3 weeks (27% vs. 20%).\n\n\nCONCLUSIONS\nWeekly paclitaxel after standard adjuvant chemotherapy with doxorubicin and cyclophosphamide improves disease-free and overall survival in women with breast cancer. (ClinicalTrials.gov number, NCT00004125 [ClinicalTrials.gov].).",
"affiliations": "Eastern Cooperative Oncology Group, Philadelphia, USA. jsparano@montefiore.org",
"authors": "Sparano|Joseph A|JA|;Wang|Molin|M|;Martino|Silvana|S|;Jones|Vicky|V|;Perez|Edith A|EA|;Saphner|Tom|T|;Wolff|Antonio C|AC|;Sledge|George W|GW|;Wood|William C|WC|;Davidson|Nancy E|NE|",
"chemical_list": "D000972:Antineoplastic Agents, Phytogenic; D011987:Receptors, Steroid; D043823:Taxoids; D000077143:Docetaxel; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa0707056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "358(16)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D017239:Paclitaxel; D011987:Receptors, Steroid; D043823:Taxoids",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "1663-71",
"pmc": null,
"pmid": "18420499",
"pubdate": "2008-04-17",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "12637460;15930421;12668651;16110015;15894097;16609087;15897552;17928597;17007996;17513820;11899388",
"title": "Weekly paclitaxel in the adjuvant treatment of breast cancer.",
"title_normalized": "weekly paclitaxel in the adjuvant treatment of breast cancer"
} | [
{
"companynumb": "US-JNJFOC-20130607253",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Dermatofibrosarcoma protuberans (DFSP) is an uncommon cutaneous sarcoma with high recurrence rate. Radical surgery is the treatment of choice, although in cosmetically-sensitive areas such as the head and neck, this option is often not pursued. Electrochemotherapy (ECT) is a minimal invasive anti-tumor modality which is increasingly being used to treat skin metastases from different malignancies. A 31-year-old woman presented with subcutaneous local multirecurring DFSP located at the proximal end of the left eyebrow. ECT was offered as a palliative treatment to avoid radical disfiguring surgery. Two days following ECT, the patient was discharged in good general health. Partial tumor regression was appreciable at two months' follow-up by ultrasound and magnetic resonance imaging. At six months, residual fibrotic tissue was observed; at three years, no evidence of the tumour was detected. In our case, ECT achieved good local tumor control with excellent cosmetic results, preserving the patient's quality of life.",
"affiliations": "Department of Plastic and Reconstructive Surgery, San Gallicano, Dermatologic Institute for Research and Care, Rome, Italy bonadies.antonio@gmail.com.;Radiology and Diagnostic Imaging Unit, San Gallicano Dermatologic Institute for Research and Care, Rome, Italy.;Radiology and Diagnostic Imaging Unit, San Gallicano Dermatologic Institute for Research and Care, Rome, Italy.;Radiology and Diagnostic Imaging Unit, Regina Elena Cancer Institute, Rome, Italy.;Dermatopathological Laboratory, San Gallicano, Dermatologic Institute for Research and Care, Rome, Italy.;Department of Plastic and Reconstructive Surgery, San Gallicano, Dermatologic Institute for Research and Care, Rome, Italy.",
"authors": "Bonadies|Antonio|A|;Elia|Fulvia|F|;Solivetti|Francesco Maria|FM|;Vidiri|Antonello|A|;Muscardin|Luca|L|;Bucher|Stefania|S|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "35(11)",
"journal": "Anticancer research",
"keywords": "Dermatofibrosarcoma protuberans; electrochemotherapy; ocular area; quality of life",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000328:Adult; D018223:Dermatofibrosarcoma; D053672:Electrochemotherapy; D005260:Female; D006801:Humans; D009364:Neoplasm Recurrence, Local; D009916:Orbital Diseases; D011379:Prognosis; D011788:Quality of Life; D012878:Skin Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6121-6",
"pmc": null,
"pmid": "26504038",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electrochemotherapy of a Multirecurrent Dermatofibrosarcoma Protuberans of the Orbital Margin: A Case Report.",
"title_normalized": "electrochemotherapy of a multirecurrent dermatofibrosarcoma protuberans of the orbital margin a case report"
} | [
{
"companynumb": "IT-FRESENIUS KABI-FK201506761",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": ... |
{
"abstract": "A patient under medication for depression underwent orthopedic surgery for osteoarthritis of the knee four times. For the second surgery, general anesthesia was induced with propofol, remifentanil, and rocuronium. Immediately after induction, she developed severe hypotension that was resistant to vasopressors. The hypotension likely resulted from the effect of psychotropic drugs, including levomepromazine, olanzapine, and clomipramine, which she had been receiving for a long time. Although her blood pressure recovered, the surgery was cancelled. We performed spinal anesthesia for the subsequent surgery to minimize interactions between anesthetic and psychotropic agents. A continuous infusion of the local anesthetic bupivacaine through a epidural catheter was started during the surgery. Although her general condition was stable during surgery, she developed hypotension after returning to the ward. We suspected an interaction with the psychotropic agents, and thus stopped infusion of the local anesthetic, after which, her blood pressure gradually increased. The first and fourth surgeries were performed uneventfully under spinal anesthesia. This case suggests that anesthesiologists should pay special attention to the interaction between anesthetic and psychotropic agents during anesthesia. Further, psychotropic drug withdrawal before surgery should be considered, if possible. Moreover, vasopressin may be utilized to treat catecholamine-resistant hypotension.",
"affiliations": null,
"authors": "Sakamoto|Shinya|S|;Hasegawa|Yoshiharu|Y|;Takata|Kosuke|K|;Ueno|Masayuki|M|;Takazawa|Tomonori|T|;Saito|Shigeru|S|",
"chemical_list": "D000779:Anesthetics, Local; D000928:Antidepressive Agents; D010880:Piperidines; D000077208:Remifentanil; D002045:Bupivacaine; D015742:Propofol",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "64(11)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000767:Anesthesia, Epidural; D000768:Anesthesia, General; D000772:Anesthesia, Local; D000775:Anesthesia, Spinal; D000779:Anesthetics, Local; D000928:Antidepressive Agents; D001794:Blood Pressure; D002045:Bupivacaine; D005260:Female; D006801:Humans; D007022:Hypotension; D008875:Middle Aged; D010880:Piperidines; D015742:Propofol; D000077208:Remifentanil",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "1198-202",
"pmc": null,
"pmid": "26689075",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abnormal Low Blood Pressure after Induction of General Anesthesia in a Patient on Medication for Depression.",
"title_normalized": "abnormal low blood pressure after induction of general anesthesia in a patient on medication for depression"
} | [
{
"companynumb": "JP-WATSON-2015-28067",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
"... |
{
"abstract": "Growing teratoma syndrome (GTS) consists of germ cell tumors that grow following chemotherapy despite complete eradication of the malignant cells. They can metastasize to any site, particularly the retroperitoneum, mediastinum and cervical region. It typically affects young adults and adolescents. Here we describe the youngest case reported in a 4-year-old girl with an ovarian mixed germ cell tumor who underwent an oophorectomy. Her tumor markers normalized by the end of her chemotherapeutic treatment; however, she developed a retroperitoneal mass that was subsequently resected. Histopathology revealed a mature teratoma, consisting of a GTS. We stress the need for early recognition and treatment of GTS to avoid the subsequent morbidity and mortality associated with it. Although GTS has an excellent prognosis when completely resected, it is essential that the patient be regularly followed-up with serum tumor markers and imaging.",
"affiliations": "Department of Pediatric Surgery, Hotel-Dieu de France University Hospital, Beirut, Lebanon.;Department of Pediatric Surgery, Hotel-Dieu de France University Hospital, Beirut, Lebanon. Electronic address: eddyriachy@gmail.com.;Department of Pediatric Surgery, Hotel-Dieu de France University Hospital, Beirut, Lebanon.;Department of Pediatric Surgery, Hotel-Dieu de France University Hospital, Beirut, Lebanon.;Department of Pathology, Hotel-Dieu de France University Hospital, Beirut, Lebanon.;Department of Pathology, Hotel-Dieu de France University Hospital, Beirut, Lebanon.",
"authors": "Daher|Paul|P|;Riachy|Edward|E|;Khoury|Antoine|A|;Raffoul|Lara|L|;Ghorra|Claude|C|;Rehayem|Caline|C|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2014.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "28(1)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Chemotherapy; Germ Cell Tumor; Growing Teratoma Syndrome; Ovary; Recurrence; Tumor Markers",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D014408:Biomarkers, Tumor; D002675:Child, Preschool; D005260:Female; D006801:Humans; D010051:Ovarian Neoplasms; D010052:Ovariectomy; D011379:Prognosis; D013577:Syndrome; D013724:Teratoma",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "e5-e7",
"pmc": null,
"pmid": "25256881",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Growing teratoma syndrome: first case report in a 4-year-old girl.",
"title_normalized": "growing teratoma syndrome first case report in a 4 year old girl"
} | [
{
"companynumb": "LB-HQ SPECIALTY-LB-2016INT000211",
"fulfillexpeditecriteria": "1",
"occurcountry": "LB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,... |
{
"abstract": "We assessed the outcomes of intravenous thrombolysis (IVT) in acute ischemic stroke (AIS) patients on dual antiplatelet therapy prior to stroke onset.\n\n\n\nWe analyzed prospectively collected data from the Safe Implementation of Treatments in Stroke (SITS) International Stroke Thrombolysis Register on consecutive IVT-treated AIS patients during a 7-year period (2010-2017). In propensity score matched groups of patients with dual antiplatelet pretreatment and no antiplatelet pretreatment, we compared: (1) symptomatic intracerebral hemorrhage (SICH), according to SITS Monitoring Study (MOST), European Cooperative Acute Stroke Study (ECASS) II, and National Institute of Neurological Disorders and Stroke (NINDS) definitions; (2) 3-month mortality; (3) 3-month favorable functional outcome (FFO; modified Rankin Scale [mRS] scores = 0-1); (4) 3-month functional independence (FI; mRS scores = 0-2); and (5) distribution of the 3-month mRS scores. Dual antiplatelet pretreatment was defined as all possible combinations among aspirin, clopidogrel, dipyridamole, and any other antiplatelet.\n\n\n\nPropensity score matching resulted in 2 groups of 1,043 patients each, balanced for all baseline characteristics. In the propensity score matched analysis, the 2 groups had comparable (p > 0.017 using Bonferroni correction for multiple comparisons) SICH rates according to SITS-MOST (2.9% vs 1.5%, 95% confidence interval [CI] = -0.03 to -0.01), ECASS II (5.2% vs 4.4%, 95% CI = -0.03 to 0.01), and NINDS (7.7% vs 6.6%, 95% CI = -0.03 to 0.01) definitions. No differences in the 3-month mortality (17.9% vs 16.6%, 95% CI = -0.05 to 0.02), FFO (45.6% vs 46.0%, 95% CI = -0.04 to 0.05), FI (59.2% vs 60.7%, 95% CI = -0.03 to 0.06), or distribution in 3-month mRS scores (2 [1-4] vs 2 [0-4], 95% CI = -0.29 to 0.09) were documented between the 2 groups.\n\n\n\nGiven that patients on dual antiplatelet pretreatment have similar SICH, 3-month mortality rates, and functional outcomes compared to patients with no antiplatelet pretreatment, dual antiplatelet pretreatment history should not be used as a reason to withhold IVT in otherwise eligible AIS patients. Ann Neurol 2018;83:89-97.",
"affiliations": "Second Department of Neurology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Second Department of Neurology, Attikon University Hospital, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece.;Department of Primary Education, University of Ioannina, Ioannina, Greece.;Department of Neurology, Faculty of Medicine, P. J. Šafárik University, Košice, Slovakia.;Second Department of Neurology, Institute of Psychiatry and Neurology, Warsaw, Poland.;Division of Applied Medicine, University of Aberdeen, Foresterhill, United Kingdom.;Department of Neurology, Helsinki University Central Hospital, Helsinki, Finland.;Department of Neurology, Karolinska University Hospital, Stockholm, Sweden.",
"authors": "Tsivgoulis|Georgios|G|;Katsanos|Aristeidis H|AH|;Mavridis|Dimitris|D|;Gdovinova|Zuzana|Z|;Karliński|Michał|M|0000-0001-6728-2020;Macleod|Mary Joan|MJ|;Strbian|Daniel|D|;Ahmed|Niaz|N|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1002/ana.25269",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-5134",
"issue": "84(1)",
"journal": "Annals of neurology",
"keywords": null,
"medline_ta": "Ann Neurol",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D012189:Retrospective Studies; D012720:Severity of Illness Index; D020521:Stroke; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "7707449",
"other_id": null,
"pages": "89-97",
"pmc": null,
"pmid": "30048012",
"pubdate": "2018-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Intravenous Thrombolysis for Ischemic Stroke Patients on Dual Antiplatelets.",
"title_normalized": "intravenous thrombolysis for ischemic stroke patients on dual antiplatelets"
} | [
{
"companynumb": "GR-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-041673",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPYRIDAMOLE"
},
... |
{
"abstract": "Treating bipolar chondral lesions in the tibiofemoral (TF) compartment with cartilage repair procedures is challenging, and a suitable treatment remains unclear.\n\n\n\nTo evaluate clinical outcomes after autologous chondrocyte implantation (ACI) for the treatment of bipolar chondral lesions in the TF compartment.\n\n\n\nCase series; Level of evidence, 4.\n\n\n\nWe evaluated 57 patients who underwent ACI for the treatment of symptomatic bipolar chondral lesions in the TF compartment by a single surgeon between October 1995 and June 2014. One patient did not return for follow-up. Thus, 56 patients (58 knees) were included with a minimum of 2 years' follow-up. A mean of 3.1 lesions per knee were treated, representing a mean total surface area of 16.1 cm2 (range, 3.2-44.5 cm2) per knee. Bipolar lesions were present in the medial compartment (32 knees) and in the lateral compartment (26 knees). Patients were evaluated with the modified Cincinnati Knee Rating Scale, visual analog scale for pain, Western Ontario and McMaster Universities Osteoarthritis Index, and Short Form-36. Patients also answered questions regarding self-rated knee function and satisfaction with the procedure. Standard radiographs were evaluated with the Kellgren-Lawrence grading system.\n\n\n\nThe survival rate was 80% at 5 years and 76% at 10 years. A significantly better survival rate was found in patients with the use of a collagen membrane than periosteum (97% vs 61% at 5 years, respectively; P = .0014). Of 46 knees with retained grafts, all functional scores significantly improved postoperatively, with a very high satisfaction rate (91%) at a mean of 8.3 ± 5.1 years (range, 2-20 years) after ACI. At last follow-up, 24 of 46 successful knees were radiographically assessed (mean, 5.5 ± 4.0 years [range, 2.0-18.7 years]) and showed no significant osteoarthritis progression ( P = .3173). Outcomes for 12 patients were considered as failures at a mean of 4.1 years. Of these, 9 patients were converted to partial or total knee arthroplasty at a mean of 4.4 years. Two patients underwent revision ACI at 5 and 17 months. The other 1 patient did not require revision surgery.\n\n\n\nOur study showed that ACI for the treatment of bipolar chondral lesions in the TF compartment provided successful clinical outcomes in patients with retained grafts and possibly prevented or delayed osteoarthritis progression at midterm to long-term follow-up. A collagen membrane is more encouraging than periosteum for bipolar lesions in the TF compartment. While addressing the predisposing factors affecting cartilage repair, ACI could be an adequate salvage procedure for bipolar chondral lesions in the TF compartment for the relatively young arthritic patient who wishes to avoid arthroplasty.",
"affiliations": "Cartilage Repair Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Cartilage Repair Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Cartilage Repair Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Cartilage Repair Center, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.",
"authors": "Ogura|Takahiro|T|;Bryant|Tim|T|;Mosier|Brian A|BA|;Minas|Tom|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/0363546518756977",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0363-5465",
"issue": "46(6)",
"journal": "The American journal of sports medicine",
"keywords": "articular; autologous chondrocyte implantation; bipolar/“kissing” lesions; cartilage; repair; tibiofemoral compartment",
"medline_ta": "Am J Sports Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019645:Arthroplasty, Replacement, Knee; D002358:Cartilage, Articular; D019902:Chondrocytes; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007718:Knee Injuries; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D012086:Reoperation; D014182:Transplantation, Autologous; D064232:Visual Analog Scale; D055815:Young Adult",
"nlm_unique_id": "7609541",
"other_id": null,
"pages": "1371-1381",
"pmc": null,
"pmid": "29533678",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Autologous Chondrocyte Implantation for Bipolar Chondral Lesions in the Tibiofemoral Compartment.",
"title_normalized": "autologous chondrocyte implantation for bipolar chondral lesions in the tibiofemoral compartment"
} | [
{
"companynumb": "US-VERICEL CORPORATION-VCEL-2018-000059",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AUTOLOGOUS CULTURED CHONDROCYTES"
},
... |
{
"abstract": "Non-small cell lung cancer is still diagnosed at late stage due to the lack of early symptoms and methods of diagnostic prevention. In the past ten years several targeted therapies have been introduced or explored. Tyrosine kinase inhibitors and immunotherapy are currently considered the most effective and safe therapies in comparison to the non-specific cytotoxic agents. Regarding tyrosine kinase inhibitors the adverse effects have been fully explored, however; on the other hand for immunotherapy there are still several issues to be clarified. We report a rare case of a patient with lung cancer adenocarcinoma who developed vitiligo throughout his body after nivolumab administration.",
"affiliations": "Pulmonary-Oncology Department, \"Theageneio\" Anticancer Hospital, Thessaloniki, Greece.;Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.;Pulmonary-Oncology Department, \"Theageneio\" Anticancer Hospital, Thessaloniki, Greece.;Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.;Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.;Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.;Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greece.;Surgery Department, \"Interbalkan\" European Medical Center, Thessaloniki, Greece.;Second Pulmonary Clinic, \"Sotiria\" Chest Diseases Hospital, Athens, Greece.;Pathology Department, \"G. Papanikolaou\" General Hospital, Thessaloniki, Greece.;Private Pathology Center \"Microdiagnostics\", Thessaloniki, Greece.;Private Scientigraphy Department, \"Bioiatriki\", Thessaloniki, Greece.;Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, China.;Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, \"Hof'' Clinics, University of Erlangen, Hof, Germany.",
"authors": "Zarogoulidis|Paul|P|;Huang|Haidong|H|;Tsiouda|Theodora|T|;Sardeli|Chrysa|C|;Trakada|Georgia|G|;Veletza|Lemonia|L|;Kallianos|Anastasios|A|;Kosmidis|Christoforos|C|;Rapti|Aggeliki|A|;Papaemmanouil|Liana|L|;Hatzibougias|Dimitrios|D|;Drougas|Dimitrios|D|;Bai|Chong|C|;Hohenforst-Schmidt|Wolfgang|W|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.rmcr.2017.10.006",
"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(17)30312-X10.1016/j.rmcr.2017.10.006Case ReportImmunotherapy “Shock” with vitiligo due to nivolumab administration as third line therapy in lung adenocarcinoma Zarogoulidis Paul pzarog@hotmail.coma∗Huang Haidong bTsiouda Theodora aSardeli Chrysa cTrakada Georgia dVeletza Lemonia dKallianos Anastasios dKosmidis Christoforos eRapti Aggeliki fPapaemmanouil Liana gHatzibougias Dimitrios hDrougas Dimitrios iBai Chong bHohenforst-Schmidt Wolfgang ja Pulmonary-Oncology Department, “Theageneio” Anticancer Hospital, Thessaloniki, Greeceb Department of Respiratory and Critical Care Medicine, Changhai Hospital, Second Military Medical University, Shanghai, Chinac Department of Pharmacology & Clinical Pharmacology, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greeced Division of Pulmonology, Department of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Alexandra Hospital, Athens, Greecee Surgery Department, “Interbalkan” European Medical Center, Thessaloniki, Greecef Second Pulmonary Clinic, “Sotiria” Chest Diseases Hospital, Athens, Greeceg Pathology Department, “G. Papanikolaou” General Hospital, Thessaloniki, Greeceh Private Pathology Center “Microdiagnostics”, Thessaloniki, Greecei Private Scientigraphy Department, “Bioiatriki”, Thessaloniki, Greecej Sana Clinic Group Franken, Department of Cardiology/Pulmonology/Intensive Care/Nephrology, “Hof’’ Clinics, University of Erlangen, Hof, Germany∗ Corresponding author. pzarog@hotmail.com26 10 2017 2017 26 10 2017 22 283 286 24 9 2017 17 10 2017 25 10 2017 © 2017 The Authors. Published by Elsevier Ltd.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Non-small cell lung cancer is still diagnosed at late stage due to the lack of early symptoms and methods of diagnostic prevention. In the past ten years several targeted therapies have been introduced or explored. Tyrosine kinase inhibitors and immunotherapy are currently considered the most effective and safe therapies in comparison to the non-specific cytotoxic agents. Regarding tyrosine kinase inhibitors the adverse effects have been fully explored, however; on the other hand for immunotherapy there are still several issues to be clarified. We report a rare case of a patient with lung cancer adenocarcinoma who developed vitiligo throughout his body after nivolumab administration.\n\nKeywords\nNSCLCNivolumabEBUSAdenocarcinoma\n==== Body\n1 Introduction\nLung cancer is still diagnosed at a late stage due to the fact that there are no early symptoms. Usually most of the patients have a persistent cough which they attribute to their smoking habit. Most patients visit their doctor if they observe hemoptysis or their cough changes character. Unfortunately until now we do not have an effective prevention algorithm. During the last decade tyrosine kinase inhibitors (TKIs) and immunotherapy (nivolumab and pembrolizumab) have entered our everyday clinical practice. The TKIs are based on the expression of the epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) [1], [2], [3]. On the other hand in order to administer immunotherapy (pembrolizumab) as first line we need programmed death-ligand 1 (PD-L1) expression >50% and for second line PD-L1 >2% (pembrolizumab) [4]. Regarding nivolumab we can administer as second line indifferent of the PD-L1 expression as second line [5], [6]. Current guidelines indicate that additional molecular pathways such as; proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Proto-oncogene tyrosine-protein kinase ROS-1 (ROS-1) have to be investigated upon diagnosis for adenocarcinoma and in squamous cell carcinoma, however; for now these two additional pathways are not obligatory for squamous cell carcinoma as it is with PD-L1 expression [7], [8], [9], [10]. In the case of EGFR positive patients and disease relapse we can investigate for the T790M mutation and administer osimertinib [11], while in the case of ALK positive patients upon disease relapse we can use ceritinib [12]. In any case tissue biopsy is the best material to investigate mutations and again re-biopsy should be performed when necessary [13], [14], [15].\n\n2 Case\nA 65 year old patient was diagnosed with convex probe endobronchial ultrasound endoscopy (EBUS) from a right lower lobe mass (Fig. 1, Fig. 2, Fig. 3). Positron emission computed tomography (PET-CT) revealed bone metastasis and the patient was investigated for epidermal growth factor (EGFR) expression and anaplastic lymphoma konase (ALK) expression. Both unfortunately were not identified and therefore a chemotherapy doublet of carbo AUC-6 and pemetrexed was administered. The patient received 6 cycles in total and remained under observation for 4 months where disease relapse was observed in the primary lesion and it was decided to receive carbo AUC-6 and gemcitabine. He received in total 6 cycles and remained under observation for 3 months where disease relapse was observed with liver metastasis. Programmed death-ligand 1 (PD-L1), along with proto-oncogene B-Raf and v-Raf murine sarcoma viral oncogene homolog B (BRAF) and Proto-oncogene tyrosine-protein kinase ROS-1 (ROS-1) were investigated. PD-L1 was observed to be 10% with Dako PD-L1 IHC 22C3 pharmDx kit, while BRAF and ROS-1 expression were negative. Based on these findings and the performance status of the patient (PS-1), it was decided that he received nivolumab. After 4 days from the administration skin scabs were observed. During the next 30 days vitiligo was observed throughout the body of the patient after healing of the skin scabs (Fig. 4). The patient did not receive any more nivolumab administration, and he receives methylprednisolone 16mg daily and he will be under close follow up for the next 30 days, where a decision will be made based on his clinical status whether he will continue or change his treatment.Fig. 1 PET-CT slice presenting the mass in the right lower lobe with pleural effusion.\n\nFig. 1Fig. 2 Figure from the ultrasound source EUB-6500HV presenting the mass during the biopsy procedure (figure by Paul Zarogoulidis).\n\nFig. 2Fig. 3 Biopsy sample from the mass with a 22G Mediglobe® needle (first biopsy 3 to follow during the procedure).\n\nFig. 3Fig. 4 Patient after 6 cycles of nivolumab; white arrow: area with melatonine, yellow arrow: area with melatonine, red arrow: area with melatonine (right hand), blue arrow: area with vitiligo (right hand). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)\n\nFig. 4\n\n3 Discussion\nNon-specific cytotoxic agents have severe side effects and in some cases life threatening [16]. Therefore alternative treatments such as; targeted therapies were welcomed. Tkis are considered targeted treatments with mild side effects most commonly observed are a diarrhea, skin rash and in very rare cases pneumonitis. In the case of adverse effects the dose has to be decreased, however; there have been cases where the drug admnistration had to be stopped [17], [18]. Immunotherapy on the other hand if it is administered based on the percentage of PD-L1 expression, then it could be considered again as a targeted treatment [6]. Immunotherapy treatment is an efficient alternative to those patients that cannot receive tki treatment and their performance status does not allow non-specific cytotoxic agents. However; for immunotherapy to be a successful therapy the immunological status plays a crucial role. Several factors are responsible for the adverse effects of immunotherapy, these could be summarised to the virus or vaccines that a patient had be exposed and to whether or not there is an underlying or undiagnosed systematic disease [19], [20]. To our knowledge the patient that we presented did have a systematic underlying disease and the development of vitiligo was due to the nivolumab administration. The PD-L1, BRAF and ROS-1 molecular pathways were investigated later on his treatment period due to the fact that they were not in the treatment guidelines as they are now. Vitiligo has been previously reported in patients with melanoma receiving immunotherapy [21].\n\nConflict of interest\nNone to Declare.\n\nAcknowledgments\nBiopsy was performed by Dr. Paul Zarogoulidis and his equipment (EBUS), “Saint Luke” Private Hospital, Thessaloniki, Greece.\n==== Refs\nReferences\n1 Domvri K. Zarogoulidis P. Darwiche K. Browning R.F. Li Q. Turner J.F. Kioumis I. Spyratos D. Porpodis K. Papaiwannou A. Tsiouda T. Freitag L. Zarogoulidis K. Molecular targeted drugs and biomarkers in NSCLC, the evolving role of individualized therapy J. Cancer 4 9 2013 736 754 24312144 \n2 Zarogoulidis K. Zarogoulidis P. Darwiche K. Boutsikou E. Machairiotis N. Tsakiridis K. Katsikogiannis N. Kougioumtzi I. Karapantzos I. Huang H. Spyratos D. Treatment of non-small cell lung cancer (NSCLC) J. Thorac. Dis. 5 Suppl 4 2013 S389 S396 24102012 \n3 Domvri K. Darwiche K. Zarogoulidis P. Zarogoulidis K. Following the crumbs: from tissue samples, to pharmacogenomics, to NSCLC therapy Transl. Lung Cancer Res. 2 4 2013 256 258 25806240 \n4 Garon E.B. Rizvi N.A. Hui R. Leighl N. Balmanoukian A.S. Eder J.P. Patnaik A. Aggarwal C. Gubens M. Horn L. Carcereny E. Ahn M.J. Felip E. Lee J.S. Hellmann M.D. Hamid O. Goldman J.W. Soria J.C. Dolled-Filhart M. Rutledge R.Z. Zhang J. Lunceford J.K. Rangwala R. Lubiniecki G.M. Roach C. Emancipator K. Gandhi L. Investigators K. Pembrolizumab for the treatment of non-small-cell lung cancer N. Engl. J. Med. 372 21 2015 2018 2028 25891174 \n5 Hahn A.W. Gill D.M. Agarwal N. Maughan B.L. PD-1 checkpoint inhibition: toxicities and management Urol. Oncol. 2017 \n6 Sheng Z. Zhu X. Sun Y. Zhang Y. The efficacy of anti-PD-1/PD-L1 therapy and its comparison with EGFR-TKIs for advanced non-small-cell lung cancer Oncotarget 8 34 2017 57826 57835 28915714 \n7 Planchard D. Smit E.F. Groen H.J.M. Mazieres J. Besse B. Helland A. Giannone V. D'Amelio A.M. Jr. Zhang P. Mookerjee B. Johnson B.E. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial Lancet. Oncol. 2017 \n8 Dugay F. Llamas-Gutierrez F. Gournay M. Medane S. Mazet F. Chiforeanu D.C. Becker E. Lamy R. Lena H. Rioux-Leclercq N. Belaud-Rotureau M.A. Cabillic F. Clinicopathological characteristics of ROS1- and RET-rearranged NSCLC in caucasian patients: data from a cohort of 713 non-squamous NSCLC lacking KRAS/EGFR/HER2/BRAF/PIK3CA/ALK alterations Oncotarget 8 32 2017 53336 53351 28881815 \n9 Li S.M. Chen C.H. Chen Y.W. Yen Y.C. Fang W.T. Tsai F.Y. Chang J.L. Shen Y.Y. Huang S.F. Chuu C.P. Chang I.S. Hsiung C.A. Jiang S.S. Upregulation of CISD2 augments ROS homeostasis and contributes to tumorigenesis and poor prognosis of lung adenocarcinoma Sci. Rep. 7 1 2017 11893 28928421 \n10 Dai X. Guo G. Zou P. Cui R. Chen W. Chen X. Yin C. He W. Vinothkumar R. Yang F. Zhang X. Liang G. (S)-crizotinib induces apoptosis in human non-small cell lung cancer cells by activating ROS independent of MTH1 J. Exp. Clin. Cancer Res. CR 36 1 2017 120 28882182 \n11 Santarpia M. Liguori A. Karachaliou N. Gonzalez-Cao M. Daffina M.G. D'Aveni A. Marabello G. Altavilla G. Rosell R. Osimertinib in the treatment of non-small-cell lung cancer: design, development and place in therapy Lung Cancer 8 2017 109 125 28860885 \n12 De Pas T. Pala L. Catania C. Conforti F. Molecular and clinical features of second-generation anaplastic lymphoma kinase inhibitors ceritinib Future Oncol. 2017 \n13 Zarogoulidis P. Rapti A. Sardeli C. Chinelis P. Athanasiadou A. Paraskevaidou K. Kallianos A. Veletza L. Trakada G. Hohenforst-Schmidt W. Huang H. Re-biopsy after relapse of targeted therapy. T790M after epidermal growth factor mutation, where and why based on a case series Respir. Med. Case Rep. 21 2017 171 175 28616379 \n14 Zarogoulidis P. Gaga M. Huang H. Darwiche K. Rapti A. Hohenforst-Schmidt W. Tissue is the issue and tissue competition. Re-biopsy for mutation T790: where and why? Clin. Transl. Med. 6 1 2017 6 28101783 \n15 Zarogoulidis P. Huang H. Bai C. Kosmidis C. Trakada G. Veletza L. Tsiouda T. Barbetakis N. Paliouras D. Athanasiou E. Hatzibougias D. Kallianos A. Panagiotopoulos N. Papaemmanouil L. Hohenforst-Schmidt W. Endobronchial ultrasound convex probe for lymphoma, sarcoidosis, lung cancer and other thoracic entities. A case series Respir. Med. Case Rep. 22 2017 187 196 28879075 \n16 Hu L.Y. Mi W.L. Wu G.C. Wang Y.Q. Mao-Ying Q.L. Prevention and treatment for chemotherapy-induced peripheral neuropathy: therapies based on CIPN mechanisms Curr. Neuropharmacol. 2017 \n17 Kimura K. Takayanagi R. Fukushima T. Yamada Y. Theoretical method for evaluation of therapeutic effects and adverse effects of epidermal growth factor receptor tyrosine kinase inhibitors in clinical treatment Med. Oncol. 34 10 2017 178 28887613 \n18 Zarogoulidis P. Chinelis P. Athanasiadou A. Porpodis K. Kallianos A. Rapti A. Trakada G. Velentza L. Huang H. Tsiouda T. Hohenforst-Schmidt W. \"Liquid elbows\" due to afatinib administration Respir. Med. Case Rep. 22 2017 64 66 28702338 \n19 Zarogoulidis P. Athanasiou E. Tsiouda T. Hatzibougias D. Huang H. Bai C. Trakada G. Veletza L. Kallianos A. Kosmidis C. Barbetakis N. Paliouras D. Rapti A. Drougas D. Hohenforst-Schmidt W. Immunotherapy \"Shock\" a case series of PD-L1 100% and pembrolizumab first-line treatment Respir. Med. Case Rep. 22 2017 197 202 28879076 \n20 Zarogoulidis P. Chinelis P. Athanasiadou A. Tsiouda T. Trakada G. Kallianos A. Veletza L. Hatzibougias D. Mihalopoulou E. Goupou E. Kosmidis C. Sardeli C. Huang H. Hohenforst-Schmidt W. Possible adverse effects of immunotherapy in non-small cell lung cancer; treatment and follow-up of three cases Respir. Med. Case Rep. 22 2017 101 105 28752057 \n21 Teulings H.E. Limpens J. Jansen S.N. Zwinderman A.H. Reitsma J.B. Spuls P.I. Luiten R.M. Vitiligo-like depigmentation in patients with stage III-IV melanoma receiving immunotherapy and its association with survival: a systematic review and meta-analysis J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 33 7 2015 773 781\n\n",
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"title": "Immunotherapy \"Shock\" with vitiligo due to nivolumab administration as third line therapy in lung adenocarcinoma.",
"title_normalized": "immunotherapy shock with vitiligo due to nivolumab administration as third line therapy in lung adenocarcinoma"
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"abstract": "Tumor lysis syndrome is a serious and sometimes lethal complication of cancer treatment that is comprised of a set of metabolic disturbances along with clinical manifestations. Initiating chemotherapy in bulky, rapidly proliferating tumors causes rapid cell turnover that in turn releases metabolites into circulation that give rise to metabolic derangements that can be dangerous. This syndrome is usually seen in high-grade hematological malignancies. Less commonly, tumor lysis syndrome can present in solid tumors and even rarely in genitourinary tumors. In this report, the authors describe a specific case of tumor lysis syndrome in a patient with metastatic prostate cancer following treatment with docetaxel.",
"affiliations": "Maimonides Medical Center, Brooklyn, NY, USA.;Maimonides Medical Center, Brooklyn, NY, USA.",
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"title": "Rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel.",
"title_normalized": "rare incidence of tumor lysis syndrome in metastatic prostate cancer following treatment with docetaxel"
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"abstract": "Ramsay-Hunt syndrome presents with a vesicular eruption in the ear canal or oral cavity associated with ipsilateral peripheral facial paralysis. The cause is reactivation of the herpes zoster virus in the geniculate ganglion. It is the second most frequent cause of non-traumatic peripheral facial paralysis. Acupuncture is a medical procedure endorsed by the WHO with a wide range of indications. It consists of the application of very fine needles in certain points of the body to relieve pain and relieve certain diseases. We present a case of a young woman with unilateral facial paralysis as part of Ramsay Hunt syndrome. She received conventional treatment with acyclovir, analgesics, corticosteroids and eye protection measures 48 h after the onset of symptoms. At three weeks, due to the lack of improvement of the facial paralysis, manual acupuncture was started along with electroacupuncture, plum blossom hammer for facial stimulation and Chinese herbal medicine. An almost complete improvement was obtained at 14 weeks since the onset of the condition. Acupuncture and related techniques may be an effective intervention for this type of condition, and are associated with very few adverse effects.",
"affiliations": "Medical Director Energimed, MD Acupuncturist at Woman Dexeus Hospital, Spain. Electronic address: isagiralt@gmail.com.;MD Acupuncturist and Anesthesiologist Energimed and at Woman Dexeus Hospital, Spain.;MD Acupuncturist at Energimed, Spain.;MD Family and Community Medicine and Acupuncturist at Energimed, Spain.;MD Rheumatology/Sports Medicine, Acupuncturist at Instituto Traumatologia, Hospital Quiron, Barcelona and at Energimed, Spain.",
"authors": "Giralt Sampedro|I|I|;Carvajal|G|G|;García-Janeras|A|A|;Fabà|A|A|;Nishishinya Aquino|M B|MB|",
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"title": "A severe case of Ramsay Hunt Syndrome treated with acupuncture and related techniques.",
"title_normalized": "a severe case of ramsay hunt syndrome treated with acupuncture and related techniques"
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"abstract": "The novel coronavirus disease 2019 (COVID-19) is associated with increased risk of thromboembolic events, but the extent and duration of this hypercoagulable state remain unknown. We describe the first case report of renal allograft infarction in a 46-year-old kidney-pancreas transplant recipient with no prior history of thromboembolism, who presented 26 days after diagnosis of COVID-19. At the time of renal infarct, he was COVID-19 symptom free and repeat test for SARS-CoV-2 was negative. This case report suggests that a hypercoagulable state may persist even after resolution of COVID-19. Further studies are required to determine thromboprophylaxis indications and duration in solid organ transplant recipients with COVID-19.",
"affiliations": "Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.;Division of Nephrology, Department of Medicine, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada.",
"authors": "Xu|Jieqing J|JJ|;Samaha|Daniel|D|;Mondhe|Suhas|S|;Massicotte-Azarniouch|David|D|;Knoll|Gregory|G|;Ruzicka|Marcel|M|0000-0002-0317-073X",
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"keywords": "clinical research/practice; infection and infectious agents - viral; kidney transplantation/ nephrology; thrombosis and thromboembolism",
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"mesh_terms": "D000086382:COVID-19; D006801:Humans; D007238:Infarction; D007668:Kidney; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D016035:Pancreas Transplantation; D058873:Pandemics; D014057:Tomography, X-Ray Computed; D066027:Transplant Recipients; D014463:Ultrasonography",
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"title": "Renal infarct in a COVID-19-positive kidney-pancreas transplant recipient.",
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"abstract": "Oral direct factor Xa inhibitors, collectively referred to as direct oral anticoagulants, are not recommended for breastfeeding women due to insufficient data about the transfer of these drugs into breast milk. In this study, we serially measured rivaroxaban concentrations in the breast milk of one nursing mother who was at high risk of deep vein thrombosis and evaluated the health of her breastfed infant. Breast milk rivaroxaban concentrations were measured 3 months after delivery by a validated liquid chromatography-tandem mass spectrometry method. Breast milk samples were collected sequentially after 15 mg of oral rivaroxaban administration after ethical approval and informed consent. Case report: A 38-year-old female diagnosed with the antiphospholipid syndrome had received rivaroxaban after delivery. The infant was partially breastfed until the age of 18 months. The mean minimum and maximum rivaroxaban concentrations in breast milk were 9.73 ng/mL before each dose and 53.9 ng/mL at 6 hours after each dose, respectively. The mean daily infant dose was 0.0034 mg/kg and the mean relative infant dose (RID) via breast milk was 1.79%. The RIDs of rivaroxaban did not exceed 10% of the maternal dose, suggesting that exposure of rivaroxaban via breastfed is seldom clinically relevant for the infant. A pediatric assessment of the infant found no detectable drug-related adverse effects. Further studies are needed to elucidate how breastfeeding infants are impacted by exposure to rivaroxaban.",
"affiliations": "Pharmaceutical Department, National Center for Child Health and Development, Tokyo, Japan.;Division of Maternal Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.;National Center for Child Health and Development, Japan Drug Information Institute in Pregnancy, Tokyo, Japan.;Pharmaceutical Department, National Center for Child Health and Development, Tokyo, Japan.;Pharmaceutical Department, National Center for Child Health and Development, Tokyo, Japan.;Division of Maternal Medicine, Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Tokyo, Japan.",
"authors": "Saito|Jumpei|J|;Kaneko|Kayoko|K|;Yakuwa|Naho|N|;Kawasaki|Hiroyo|H|;Yamatani|Akimasa|A|;Murashima|Atsuko|A|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
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"title": "Rivaroxaban Concentration in Breast Milk During Breastfeeding: A Case Study.",
"title_normalized": "rivaroxaban concentration in breast milk during breastfeeding a case study"
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"abstract": "Lincomycin-resistant Clostridium sporogenes obtained from the stools of a patient with lincomycin-associated pseudomembranous colitis produced a heat-stable cytotoxin in low titre when grown in chopped meat medium. Vancomycin eradicated this strain and all other clostridia, and controlled the symptoms. When diarrhea recurred 7 days after treatment with vancomycin was stopped, clostridia including C. sporogenes and C. difficile were again isolated. The C. difficile produced a heat-labile cytotoxin in high titre that was unaffected by growth in various media and induced colitis in hamsters. Treatment with vancomycin, to which all the clostridia were sensitive, eradicated both toxic species and controlled the diarrhea. Antibiotic-induced pseudomembranous colitis may be associated with more than one species of toxin-producing clostridia. Vancomycin therapy should be continued for 10 days or more in patients with severe disease to eradicate the responsible organism.",
"affiliations": null,
"authors": "Marrie|T J|TJ|;Faulkner|R S|RS|;Badley|B W|BW|;Hartlen|M R|MR|;Comeau|S A|SA|;Miller|H R|HR|",
"chemical_list": "D014640:Vancomycin; D008034:Lincomycin",
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"mesh_terms": "D000368:Aged; D000818:Animals; D003013:Clostridium; D003015:Clostridium Infections; D006224:Cricetinae; D046508:Culture Techniques; D048909:Diabetes Complications; D004352:Drug Resistance, Microbial; D004761:Enterocolitis, Pseudomembranous; D005243:Feces; D005260:Female; D006801:Humans; D007871:Leg Ulcer; D008034:Lincomycin; D014640:Vancomycin",
"nlm_unique_id": "0414110",
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"pubdate": "1978-11-04",
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"references": "75383;73011;320848;630301;625309;915343;892381;861560;48610;4412460",
"title": "Pseudomembranous colitis: isolation of two species of cytotoxic clostridia and successful treatment with vancomycin.",
"title_normalized": "pseudomembranous colitis isolation of two species of cytotoxic clostridia and successful treatment with vancomycin"
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"abstract": "Nerve damage may occur in the pharyngolaryngeal region during general anesthesia. The most frequently injured nerves are the hypoglossal, lingual and recurrent laryngeal. These injuries may arise in association with several factors, such as laryngoscopy, endotracheal intubation and tube insertion, cuff pressure, mask ventilation, the triple airway maneuver, the oropharyngeal airway, manner of intubation tube insertion, head and neck position and aspiration. Nerve injuries in this region may take the form of an isolated single nerve or of paresis of two nerves together in the form of hypoglossal and recurrent laryngeal nerve palsy (Tapia's syndrome). However, combined injury of the lingual and hypoglossal nerves following intubation anesthesia is a much rarer condition. The risk of this damage can be reduced with precautionary measures. We describe a case of combined unilateral nervus hypoglossus and nervus lingualis paresis developing after intubation anesthesia.",
"affiliations": "Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey. Electronic address: hulyaulusoy.md@gmail.com.;Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.;Department of Anesthesiology and Critical Care, Faculty of Medicine, Karadeniz Technical University, Trabzon, Turkey.",
"authors": "Ulusoy|Hulya|H|;Besir|Ahmet|A|;Cekic|Bahanur|B|;Kosucu|Muge|M|;Geze|Sukran|S|",
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"issue": "64(2)",
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"keywords": "Hypoglossal paralysis; Intubation anesthesia; Lingual paralysis",
"medline_ta": "Braz J Anesthesiol",
"mesh_terms": "D000328:Adult; D000768:Anesthesia, General; D005260:Female; D006801:Humans; D061228:Hypoglossal Nerve Injuries; D007442:Intubation, Intratracheal; D061222:Lingual Nerve Injuries; D010291:Paresis",
"nlm_unique_id": "101624623",
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"title": "Transient unilateral combined paresis of the hypoglossal nerve and lingual nerve following intubation anesthesia.",
"title_normalized": "transient unilateral combined paresis of the hypoglossal nerve and lingual nerve following intubation anesthesia"
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"abstract": "A 73-year-old man developed diplopia after the administration of pembrolizumab for lung adenocarcinoma. He had ptosis and external ophthalmoplegia without general muscle weakness. Serum CK levels were elevated. Although autoantibodies to acetylcholine receptor and muscle-specific kinase, the edrophonium test, and the repetitive nerve stimulation test were all negative, anti-titin autoantibody was positive, leading to the diagnosis of myasthenia gravis (MG). Muscle pathology showed necrotizing myopathy with tubular aggregates. Unlike previously reported cases of pembrolizumab-associated MG, the present case showed ocular MG. This is the first case of pembrolizumab-associated MG with anti-titin antibody, as well as the first case with tubular aggregates.",
"affiliations": "Department of Neurology, The Jikei University Kashiwa Hospital, Japan.;Department of Neurology, The Jikei University Kashiwa Hospital, Japan.;Department of Respiratory Medicine, The Jikei University Kashiwa Hospital, Japan.;Department of Respiratory Medicine, The Jikei University Kashiwa Hospital, Japan.;Department of Respiratory Medicine, The Jikei University Kashiwa Hospital, Japan.;Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Japan.;Department of Neurology, The Keio University School of Medicine, Japan.;Department of Neurology, The Kyorin University Hospital, Japan.;Department of Neurology, The Jikei University Kashiwa Hospital, Japan.",
"authors": "Onda|Asako|A|;Miyagawa|Shinji|S|;Takahashi|Naoko|N|;Gochi|Mina|M|;Takagi|Masamichi|M|;Nishino|Ichizo|I|;Suzuki|Shigeaki|S|;Oishi|Chizuko|C|;Yaguchi|Hiroshi|H|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001323:Autoantibodies; D015415:Biomarkers; D064211:Connectin; C577285:TTN protein, human; C582435:pembrolizumab",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3071331310.2169/internalmedicine.1956-18Case ReportPembrolizumab-induced Ocular Myasthenia Gravis with Anti-titin Antibody and Necrotizing Myopathy Onda Asako 1Miyagawa Shinji 1Takahashi Naoko 2Gochi Mina 2Takagi Masamichi 2Nishino Ichizo 3Suzuki Shigeaki 4Oishi Chizuko 5Yaguchi Hiroshi 1\n1 Department of Neurology, The Jikei University Kashiwa Hospital, Japan\n2 Department of Respiratory Medicine, The Jikei University Kashiwa Hospital, Japan\n3 Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Japan\n4 Department of Neurology, The Keio University School of Medicine, Japan\n5 Department of Neurology, The Kyorin University Hospital, JapanCorrespondence to Dr. Asako Onda, a.onda@jikei.ac.jp\n\n1 2 2019 1 6 2019 58 11 1635 1638 10 8 2018 4 11 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 73-year-old man developed diplopia after the administration of pembrolizumab for lung adenocarcinoma. He had ptosis and external ophthalmoplegia without general muscle weakness. Serum CK levels were elevated. Although autoantibodies to acetylcholine receptor and muscle-specific kinase, the edrophonium test, and the repetitive nerve stimulation test were all negative, anti-titin autoantibody was positive, leading to the diagnosis of myasthenia gravis (MG). Muscle pathology showed necrotizing myopathy with tubular aggregates. Unlike previously reported cases of pembrolizumab-associated MG, the present case showed ocular MG. This is the first case of pembrolizumab-associated MG with anti-titin antibody, as well as the first case with tubular aggregates. \n\npembrolizumabocular myasthenia gravisanti-titin antibodynecrotizing myopathytubular aggregates\n==== Body\nIntroduction\nPembrolizumab is an anti-programmed cell death 1 (PD-1) monoclonal antibody that is used for therapy against lung cancer. Increasing evidence suggests that it can cause myasthenia gravis (MG) and necrotizing myopathy, although the detailed clinicopathological features are still unclear (1).\n\nCase Report\nA 73-year-old man with hypertension and mitral valve regurgitation with no relevant family history of neuromuscular disorders was found to have a lung nodule on a regular medical checkup in 2016. Subsequently, a diagnosis of lung adenocarcinoma with brain and bone metastases was made by pulmonologists. The tumor proportion score of the programmed cell death-ligand 1 (PD-L1) expression was 85%, so he was started on pembrolizumab in July 2017 (day 1). On day 23, he was found to have diplopia, and his CK level had increased from 55 to 600 U/L. He was admitted to our hospital on day 30 with stable vital signs.\n\nOn a physical examination, he had diplopia and ptosis in the left eye with daily fluctuation. He had no easy fatigability or weakness in the limbs and trunk. On laboratory testing, his creatine kinase (CK) level was 7,311 U/L, aldolase 16.5 IU/L, aspartate aminotransferase (AST) 172 U/L, alanine aminotransferase (ALT) 74 U/L, lactate dehydrogenase (LDH) 631 U/L, creatinine 1.17 mg/dL, C-reactive protein (CRP) 0.68 mg/dL, erythrocyte sedimentation rate (ESR) 34 mm/h, and D-dimer 1.4 μg/mL. His thyroid function was within the normal range [thyroid stimulating hormone (TSH) 1.75 μIU/mL, FT3 2.61 pg/mL, FT4 1.05 ng/dL]. Rheumatoid factor, antinuclear antibody, anti-double stranded DNA (dsDNA) antibody, anti-ribonucleoprotein (RNP) antibody, anti-histidyl transfer RNA synthetase (Jo-1) antibody, anti-aminoacyl transfer RNA synthetase (ARS) antibody, anti-mitochondrial M2 (M2) antibody, anti-signal recognition particle (SRP) antibody, and anti-3-hydroxy-3-methylglutary-coenzyme A reductase (HMGCR) antibody were all negative. Anti-acetylcholine receptor (AChR) antibody, anti-muscle-specific kinase (MuSK) antibody, and anti-voltage-gated potassium channel Kv1.4 antibody were also negative, but anti-titin antibody was positive, leading to the diagnosis of MG, although both the repetitive nerve stimulation test (right accessory nerve, axillary nerve, median nerve, and ulnar nerve) and the edrophonium test were negative. The ice pack test was not evaluated.\n\nArterial blood gas analyses and spirometry showed no evidence of respiratory insufficiency. Echocardiography showed a good ejection fraction (70%) and no myocarditis.On electromyography of the right deltoid, biceps brachii, and iliopsoas, fibrillation potentials were seen only in the biceps muscle. Low-amplitude and short-duration motor unit potentials were recorded in all muscles, indicating myogenic changes. Magnetic resonance imaging of the thigh muscles showed no evidence of myopathy. A muscle biopsy from the left biceps brachii showed scattered necrotic and regenerating muscle fibers with minimal reactive mononuclear cell infiltration (Fig. 1A, B). Tubular aggregates were seen in some fibers (Fig. 1C, D). On immunohistochemistry, major histocompatibility complex (MHC)-I was mildly expressed in fibers in some areas (Fig. 1E), and membrane attack complex (MAC) was deposited on the sarcolemma of some non-necrotic fibers, in addition to the cytoplasm of necrotic fibers (Fig. 1F).\n\nFigure 1. Pathological features of necrotizing myopathy. A, B: Hematoxylin and Eosin staining demonstrates necrosis and regeneration of muscle fibers and necrotizing myopathy with inflammatory cell infiltration only around necrotic fibers. A: scale bar 100 μm, B: scale bar 50 μm. C: Gomori trichrome staining, D: dihydronicotinamide adenine dinucleotide (NADH) staining. Tubular aggregates can be seen. C, D: scale bar 20 μm. E: Major histocompatibility complex (MHC)-I staining demonstrates light staining of muscle fibers. Scale bar 100 μm. F: Membrane attack complex (MAC) staining demonstrates the deposition of necrotic fibers, with light deposition of non-necrotic fibers. Scale bar 50 μm.\n\nBased on the above results, a diagnosis of ocular MG (Myasthenia Gravis Foundation of America I) with anti-titin antibody and necrotizing myopathy with tubular aggregates was made. The Quantitative MG score was 6 points (ptosis and diplopia: 3 and 3 points, respectively). The patient was given an ascending-dose regimen of prednisolone that increased by 5 mg every 5 days to a total of 20 mg. He initially had exacerbation of ptosis and opthalmoplegia with diplopia. The CK level showed a trend toward reduction, but it remained high. Therefore, steroid pulse therapy (methylprednisolone 1 g/day 3 times) was given. The CK level then normalized promptly, and his symptoms improved gradually. All abnormal neurological findings disappeared four months after the start of steroid therapy (Fig. 2).\n\nFigure 2. Clinical course. The patient showed elevation of CK to 600 U/L at 23 days after and 7,311 U/L at 30 days after the administration of pembrolizumab, at which point he became aware of diplopia and ptosis. Various investigations were negative, and myasthenia gravis was diagnosed based on his symptoms that co-existed with myopathy. A left biceps muscle biopsy was performed. The patient received an ascending-dose regimen of prednisolone that increased by 5 mg every 5 days to a total of 20 mg. After steroid therapy, he developed exacerbations of ptosis and diplopia, and extraocular muscle weakness appeared. This was considered initial worsening. The CK level showed a trend toward reduction, but it remained high, so steroid pulse therapy (methylprednisolone 1 g/day 3 times) was given. The CK level then decreased to the normal range, and his symptoms improved. After four months, ptosis disappeared, and extraocular muscle weakness improved.\n\nDiscussion\nImmunotherapy is a recently established treatment method for lung cancer. Representative agents include antibodies targeting immune checkpoints, such as PD-1, PD-L1, and cytotoxic T-lymphocyte associated antigen-4 (CTLA-4). Pembrolizumab and nivolumab are anti-PD-1 monoclonal antibodies. These agents connect with PD-1 expressed on activated T cells and exert their anticancer activity by eliminating the suppression of activated T cells (1). These immune checkpoint inhibitors are reported to cause immune-related adverse events (irAEs), including MG and myopathy (2), although the pathomechanism is still unclear.\n\nAlthough the previously reported cases of anti-PD-1 monoclonal antibody-associated MG (anti-PD-1-associated MG) showed a relatively severe generalized type (3), the present case showed ocular MG without generalized symptoms. There have been four cases of anti-PD-1-associated MG that presented with the ocular type (Table) (3-5). Even if patients show ocular MG, there is the possibility of general inflammation, such as the elevation of the serum CK level and myopathy on electromyography and a muscle biopsy.\n\nTable. Cases of Ocular-type Anti-PD-1-associated MG.\n\nCase/age (y)/sex\tCancer\tPD-1\tOnset\tDiplopia/\nptosis\tAChR/\nMuSK/titin\tCK U/L\tTreatment\tOutcome\tReference number\t\n1/65/M\tNSCLC\tNivolumab\t25 days\t+/+\t-/-/ND\tND\tChEI\tCR\t4\t\n2/81/M\tMelanoma\tPembrolizumab\t58 days\t+/+\t-/ND/ND\tND\tPRED\tCR\t5\t\n3/74/F\tMelanoma\tNivolumab\t28 days\t+/+\t4.0/ND/ND\t654\tChEI, PRED\tPR\t3\t\n4/57/M\tNSCLC\tNivolumab\t58 days\t+/-\t0.5/ND/ND\t57\tChEI, PRED\tMM\t3\t\n5/73/M\tNSCLC\tPembrolizumab\t23 days\t+/+\t-/-/+\t7,311\tPRED\tCR\tPresent\t\nNSCLC: non-small-cell lung cancer, ChEI: cholinesterase inhibitor, PRED: prednisolone, CR: complete response, MM: minimal manifestation, PR: partial response, N/D: no data, Onset: the time between the appearance of MG symptoms and the administration of anti-PD-1 monoclonal antibody\n\nThere are some cases of co-existing anti-striated muscle antibody (anti-titin, anti-ryanodine, anti-Kv1.4 antibody) and anti-AChR antibody in idiopathic MG with myopathy and myocarditis (6). In the present case, anti-AChR antibody was negative, but anti-titin antibody was positive. Apparently, anti-striated muscle antibody was positive in previously reported cases of anti-PD-1-associated MG (7-9), but the details were not described. To our knowledge, this is the first case of anti-PD-1-associated MG with anti-titin antibody. In idiopathic MG, 80% of patients have anti-AChR antibody, and 10% have anti-MuSK antibody (10). In anti-PD-1-associated MG, however, the positive rate for anti-AChR antibody differs widely, from 20% (9) to 73% (11). Anti-MuSK antibody has never been reported in a case of anti-PD-1-associated MG.\n\nThere have been several cases of anti-PD-1 monoclonal antibody-associated myopathy in which a muscle biopsy was performed. The reported pathological changes have varied, including necrotizing myopathy, nonspecific myopathy, and myopathy with complement-mediated microvasculopathy (2,9). Serum CK is not elevated in all cases, but it is elevated in patients with necrotizing myopathy, as in the present case. This is the first case of anti-PD-1 monoclonal-antibody-associated myopathy that showed tubular aggregates on muscle pathology. Tubular aggregates are found in cases of periodic paralysis, congenital myasthenia, and myopathy due to abnormal store-operated Ca2+ channels (12), but the present case had neither clinical manifestations nor a family history suggesting any of these conditions. The relationship between tubular aggregates and anti-PD-1 monoclonal antibody therefore remains unclear.\n\nConclusion\nWe herein report a case of anti-PD-1-associated MG. Unlike other cases with anti-PD-1-associated MG, the present case showed ocular MG without limb or trunk weakness, although the serum CK level was high, and necrotic and regenerating fibers were seen in the muscle. Interestingly, anti-titin antibody was positive, and tubular aggregates were seen on muscle pathology, although the associations of these findings with PD-1 are still unclear. Similar cases will need to be accumulated in order to better understand this relationship.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nMiyauchi E , Inoue A \nImmune checkpoint therapy for non-small-cell lung cancer . Gan To Kagaku Ryoho \n43 : 666 -671 , 2016 (in Japanese, Abstract in English).27306803 \n2. \nKao JC , Liao B , Markovic SN , et al \nNeurological complications associated with anti-programmed death 1 (PD-1) antibodies . JAMA Neurol \n74 : 1216 -1222 , 2017 .28873125 \n3. \nSuzuki S , Ishikawa N , Konoeda F , et al \nNivolumab-related myasthenia gravis with myositis and myocarditis in Japan . Neurology \n89 : 1127 -1134 , 2017 .28821685 \n4. \nPolat P , Donofrio PD \nMyasthenia gravis induced by nivolumab therapy in a patient with non-small-cell lung cancer . Muscle Nerve \n54 : 507 , 2016 .\n5. \nNguyen BH , Kuo J , Budiman A , Christie H , Ali S \nTwo cases of clinical myasthenia gravis associated with pembrolizumab use in responding melanoma patients . Melanoma Res \n27 : 152 -154 , 2017 .27776019 \n6. \nSuzuki S , Utsugisawa K , Nagane Y , Suzuki N \nThree types of striational antibodies in myasthenia gravis . Autoimmune Dis , 2011 (Epub ahead of print).\n7. \nBilen MA , Subudhi SK , Gao J , Tannir NM , Tu SM , Sharma P \nAcute rhabdomyolysis with severe polymyositis following ipilimumab-nivolumab treatment in a cancer patient with elevated anti-striated muscle antibody . J Immunother Cancer \n4 : 36 , 2016 .27330809 \n8. \nNorwood TG , Westbrook BC , Johnson DB , et al \nSmoldering myocarditis following immune checkpoint blockade . J Immunother Cancer \n5 : 91 , 2017 .29157297 \n9. \nLiewluck T , Kao JC , Mauermann ML \nPD-1 inhibitor-associated myopathies: emerging immune-mediated myopathies . J Immunother \n41 : 208 -211 , 2018 .29200081 \n10. \nHurst RL , Gooch CL \nMuscle-specific receptor tyrosine kinase (MuSK) myasthenia gravis . Curr Neurol Neurosci Rep \n16 : 61 , 2016 .27170368 \n11. \nGonzalez NL , Puwanant A , Lu A , Marks SM , Živković SA \nMyasthenia triggered by immune checkpoint inhibitors: new case and literature review . Neuromuscul Disord \n27 : 266 -268 , 2017 .28109638 \n12. \nKim NR , Suh YL \nTubular aggregate myopathy: a case report . J Korean Med Sci \n18 : 135 -140 , 2003 .12589105\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "58(11)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "anti-titin antibody; necrotizing myopathy; ocular myasthenia gravis; pembrolizumab; tubular aggregates",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000074322:Antineoplastic Agents, Immunological; D001323:Autoantibodies; D015415:Biomarkers; D001763:Blepharoptosis; D064211:Connectin; D004172:Diplopia; D006801:Humans; D008297:Male; D009135:Muscular Diseases; D009157:Myasthenia Gravis; D009886:Ophthalmoplegia",
"nlm_unique_id": "9204241",
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"pages": "1635-1638",
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"references": "12589105;21785709;27121245;27170368;27306803;27330809;27776019;28109638;28821685;28873125;29157297;29200081",
"title": "Pembrolizumab-induced Ocular Myasthenia Gravis with Anti-titin Antibody and Necrotizing Myopathy.",
"title_normalized": "pembrolizumab induced ocular myasthenia gravis with anti titin antibody and necrotizing myopathy"
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"abstract": "Sorafenib is currently the gold standard therapy for palliative treatment of advanced hepatocellular carcinoma (HCC) in patients with compensated liver disease. There are few cases reported in literature describing patients with HCC achieving a complete remission (CR) due to Sorafenib therapy. We report the case of a 62-year old patient who obtained CR despite single, long drug discontinuation and kept it without any maintenance therapy. Furthermore, this is the first case describing the onset of a likely IgG4-related retroperitoneal fibrosis and cholangitis during Sorafenib administration. Further studies are required to define the predictors of a good response to Sorafenib and to codify a therapeutic maintenance regimen for patients who achieve CR.",
"affiliations": "Department of Medical and Surgical Science, Gastroenterology Unit, University of Bologna, Bologna, Italy. . impellizzerigiovanna@gmail.com.;Radiology Unit, Sant'Orsola Malpighi Hospital, Bologna, Italy. dr.matteo.renzulli@gmail.com.;Department of Medical and Surgical Science, Gastroenterology Unit, University of Bologna, Bologna, Italy. francesco.azzaroli@unibo.it.;Radiology Unit, Sant'Orsola Malpighi Hospital, Bologna, Italy. rita.golfieri@unibo.it.;Department of Medical and Surgical Science, Gastroenterology Unit, University of Bologna, Bologna, Italy. giuseppe.mazzella@unibo.it.;Department of Medical and Surgical Science, Gastroenterology Unit, University of Bologna, Bologna, Italy. giovannimarasco89@gmail.com.",
"authors": "Impellizzeri|Giovanna|G|;Renzulli|Matteo|M|;Azzaroli|Francesco|F|;Golfieri|Rita|R|;Mazzella|Giuseppe|G|;Marasco|Giovanni|G|",
"chemical_list": "D000970:Antineoplastic Agents; D007074:Immunoglobulin G; D000077157:Sorafenib",
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"issue": "30(1)",
"journal": "Journal of gastrointestinal and liver diseases : JGLD",
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"medline_ta": "J Gastrointestin Liver Dis",
"mesh_terms": "D000970:Antineoplastic Agents; D006528:Carcinoma, Hepatocellular; D006801:Humans; D007074:Immunoglobulin G; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias; D012074:Remission Induction; D000077157:Sorafenib",
"nlm_unique_id": "101272825",
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"title": "Complete Remission of Advanced Hepatocellular Carcinoma Treated with Sorafenib and Concomitant Appearance of IgG4- related Diseases. A Case Report.",
"title_normalized": "complete remission of advanced hepatocellular carcinoma treated with sorafenib and concomitant appearance of igg4 related diseases a case report"
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{
"abstract": "Collagenous sprue (CS) is a distinct clinicopathological disorder histologically defined by a thickened subepithelial band (Freeman, 2011). It is a rare condition which has been recently observed in a significant proportion of sprue-like enteropathy associated with olmesartan, a novel entity described by Rubio-Tapia et al. in 2012. CS is historically associated with a poor prognosis (Marthey et al., 2014). However, histological and clinical improvements have been described in most studies with concomitant usage of corticosteroids and/or gluten-free diet (Marthey et al., 2014). We report a unique case of olmesartan-induced collagenous sprue in a 79-year-old man that showed complete histological and clinical remission with the sole withdrawal of the incriminating drug. The literature on this topic is briefly reviewed.",
"affiliations": "Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Pathology Department, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Intensive Care Unit, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.;Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1.",
"authors": "Desruisseaux|Claudine|C|;Bensoussan|Michaël|M|;Désilets|Etienne|E|;Tran|Hanh-Khiem|HK|;Arcand|Robert|R|;Poirier|Germain|G|;Wisniewski|Andrew|A|;Manière|Thibaut|T|",
"chemical_list": "D000959:Antihypertensive Agents; D007093:Imidazoles; D013777:Tetrazoles; C437965:olmesartan",
"country": "Egypt",
"delete": false,
"doi": "10.1155/2016/4837270",
"fulltext": "\n==== Front\nCan J Gastroenterol HepatolCan J Gastroenterol HepatolCJGHCanadian Journal of Gastroenterology & Hepatology2291-27892291-2797Hindawi Publishing Corporation 10.1155/2016/4837270Images of the MonthAdding Water to the Mill: Olmesartan-Induced Collagenous Sprue—A Case Report and Brief Literature Review Desruisseaux Claudine \n1\n\n*\nBensoussan Michaël \n1\nDésilets Etienne \n1\nTran Hanh-Khiem \n1\nArcand Robert \n2\nPoirier Germain \n3\nWisniewski Andrew \n1\nManière Thibaut \n1\n1Gastroenterology Service, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H12Pathology Department, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H13Intensive Care Unit, Charles-LeMoyne Hospital, Sherbrooke University, Greenfield Park, QC, Canada J4V 2H1*Claudine Desruisseaux: claudine.desruisseaux@usherbrooke.caAcademic Editor: John Marshall\n\n2016 21 4 2016 2016 483727029 9 2015 29 3 2016 Copyright © 2016 Claudine Desruisseaux et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Collagenous sprue (CS) is a distinct clinicopathological disorder histologically defined by a thickened subepithelial band (Freeman, 2011). It is a rare condition which has been recently observed in a significant proportion of sprue-like enteropathy associated with olmesartan, a novel entity described by Rubio-Tapia et al. in 2012. CS is historically associated with a poor prognosis (Marthey et al., 2014). However, histological and clinical improvements have been described in most studies with concomitant usage of corticosteroids and/or gluten-free diet (Marthey et al., 2014). We report a unique case of olmesartan-induced collagenous sprue in a 79-year-old man that showed complete histological and clinical remission with the sole withdrawal of the incriminating drug. The literature on this topic is briefly reviewed.\n==== Body\n1. Case Presentation\nA 79-year-old man was referred to the emergency room for a three-week history of severe diarrhea. His past medical history was remarkable for chronic kidney disease with a baseline creatinine level of 170 μmol/L and hypertension. His medication was amlodipine 5 mg and olmesartan 40 mg daily started 3 years ago.\n\nThe patient had been experiencing worsening watery diarrhea, which had lately increased to as many as 10 episodes a day. He also reported diffuse abdominal pain, nausea, emesis, and a weight loss of 10 kg in 3 weeks.\n\nOn admission, the vital signs showed significant hypotension responding to volemic repletion. Antihypertensive medication was withheld. The physical examination showed mucosal dehydration and generalized abdomen tenderness without guarding. Laboratory investigations showed an acute renal failure associated with a metabolic acidosis (creatinine: 782 μmol/L; urea: 33 μmol/L; and bicarbonate: 9.9 mmol/L). The blood cells count, electrolytes, and albumin level were unremarkable.\n\nThe patient was admitted to the ICU and an alkaline fluid resuscitation with bicarbonate was able to prevent dialysis. The upper GI endoscopy was unremarkable except for a Mallory-Weiss tear and the ileocolonoscopy was normal. Biopsies were taken from the duodenum, terminal ileum, and colon. The duodenal and ileal histologic findings showed a collagenous sprue (CS) characterized by complete villous atrophy with increased intraepithelial lymphocytes and thickened collagen table (Figure 1). Colonic pathologic findings were negative. Stool analyses for infectious agents and tissue IgA transglutaminase antibodies were negative.\n\nGiven the histopathologic findings, olmesartan-induced enteropathy was suspected and the drug was withheld indefinitely. Within days, the patient noticed a slight improvement of the diarrhea. Two months later, the symptoms had subsided and repeat endoscopy with biopsies demonstrated a complete histologic remission of the CS (Figure 2).\n\n2. Discussion\nCS is a rare form of enteropathy that has been classically regarded as a complication of refractory celiac disease, an association that remains controversial [1]. In the past decade, a number of new causes of CS have been recognized: notably, the drug-induced form of enteropathy. In 2010, Rubio-Tapia et al. conducted one of the largest case series on CS to date and found that a significant proportion of the study cohort were taking olmesartan, an angiotensin II receptor antagonist commonly used for the management of hypertension [2]. Interestingly, the same group of authors later introduced sprue-like enteropathy associated with olmesartan, therefore broadening the differential diagnosis of seronegative villous atrophy enteropathy [3]. A warning related to the risk of sprue-like enteropathy has since been implemented for all olmesartan single and combination products.\n\nHistorically, it was often felt that the prognosis of patients presenting with CS was grim. However, complete histological resolution of olmesartan-induced CS has been demonstrated after the cessation of olmesartan but more often with concomitant use of corticosteroid and/or gluten-free diet, which may reveal itself to be a confusion factor pertaining to the clinical evolution [2, 3]. Very few series have documented both clinical and histological resolution with the sole withdrawal of olmesartan. In a recent national French study reporting 36 cases of olmesartan-induced enteropathy, complete recovery without being exposed to systemic steroids and/or immunosuppressants has been documented in only four cases [4].\n\nIndeed, since the recognition of olmesartan-associated enteropathy by Rubio-Tapia et al., our patient is the first reported case of olmesartan-induced CS in Canada that achieved complete clinical and histological resolution with sole withdrawal of the incriminating drug. This leads us to believe that this condition is likely to be underreported and that patients are exposed to unnecessary high dose corticosteroids treatments in attempt to treat this condition. Furthermore, considering the potential reversibility, we encourage physicians to be aware of this clinicopathological entity and include the latter in the differential diagnosis of seronegative villous atrophy with collagenous band thickening.\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nFigure 1 The ileal biopsies of the patient showed pathognomonic findings of collagenous sprue including villous atrophy with thickened collagen table (HPS, 10x).\n\nFigure 2 Normal ileal mucosa 4 months following cessation of olmesartan (HPS, 10x).\n==== Refs\n1 Freeman H. J. Collagenous sprue Canadian Journal of Gastroenterology 2011 25 4 189 192 10.1155/2011/821976 2-s2.0-80054702005 21523258 \n2 Rubio-Tapia A. Talley N. J. Gurudu S. R. Wu T.-T. Murray J. A. Gluten-free diet and steroid treatment are effective therapy for most patients with collagenous sprue Clinical Gastroenterology and Hepatology 2010 8 4 344.e3 349.e3 10.1016/j.cgh.2009.12.023 2-s2.0-77949626358 20060071 \n3 Rubio-Tapia A. Herman M. L. Ludvigsson J. F. Severe spruelike enteropathy associated with olmesartan Mayo Clinic Proceedings 2012 87 8 732 738 10.1016/j.mayocp.2012.06.003 2-s2.0-84866370242 22728033 \n4 Marthey L. Cadiot G. Seksik P. Olmesartan-associated enteropathy: results of a national survey Alimentary Pharmacology & Therapeutics 2014 40 9 1103 1109 10.1111/apt.12937 2-s2.0-84907981838 25199794\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2291-2789",
"issue": "2016()",
"journal": "Canadian journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Can J Gastroenterol Hepatol",
"mesh_terms": "D000368:Aged; D000959:Antihypertensive Agents; D064068:Collagenous Sprue; D003967:Diarrhea; D006801:Humans; D006973:Hypertension; D007093:Imidazoles; D008297:Male; D013777:Tetrazoles; D028761:Withholding Treatment",
"nlm_unique_id": "101623613",
"other_id": null,
"pages": "4837270",
"pmc": null,
"pmid": "27446843",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "20060071;21523258;22728033;25199794",
"title": "Adding Water to the Mill: Olmesartan-Induced Collagenous Sprue-A Case Report and Brief Literature Review.",
"title_normalized": "adding water to the mill olmesartan induced collagenous sprue a case report and brief literature review"
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"companynumb": "CA-PFIZER INC-2016314562",
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"abstract": "OBJECTIVE\nSome patients with multiple sclerosis (MS) can either present with or develop severe cognitive impairment during the course of their disease. However, the mechanisms underlying severe cognitive dysfunction in MS are not well understood.\n\n\nMETHODS\nWe report on a woman who was diagnosed as having MS at age 33 years and who after giving birth at age 37 years developed cognitive impairment with severe memory dysfunction as the leading symptom. Treatment with different immunotherapies, including cyclophosphamide and natalizumab, did not improve her cognitive deficits, necessitating admission to a nursing home at age 39 years. During a thorough reevaluation at age 43 years, analysis of current and stored cerebrospinal fluid and serum samples demonstrated an intrathecal synthesis of IgG antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor, that is, the characteristic laboratory finding of anti-N-methyl-D-aspartate receptor encephalitis. Although the patient initially stabilized under therapy with corticosteroids, plasma exchange, and mitoxantrone, severe cognitive impairment persisted and she eventually died from the sequelae of her disease.\n\n\nCONCLUSIONS\nThis report suggests that the occasional occurrence of severe cognitive impairment in patients with MS may, in some cases, be related to a superimposed antibody-mediated autoimmune encephalitis.",
"affiliations": "Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Psychiatry, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.;Department of Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany.",
"authors": "Fleischmann|Robert|R|;Prüss|Harald|H|;Rosche|Berit|B|;Bahnemann|Markus|M|;Gelderblom|Harald|H|;Deuschle|Katrin|K|;Harms|Lutz|L|;Kopp|Ute|U|;Ruprecht|Klemens|K|",
"chemical_list": "D000906:Antibodies; C409466:NR1 NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate",
"country": "United States",
"delete": false,
"doi": "10.1001/jamaneurol.2014.1817",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6149",
"issue": "72(1)",
"journal": "JAMA neurology",
"keywords": null,
"medline_ta": "JAMA Neurol",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D003072:Cognition Disorders; D005260:Female; D006801:Humans; D007278:Injections, Spinal; D008279:Magnetic Resonance Imaging; D009103:Multiple Sclerosis; D016194:Receptors, N-Methyl-D-Aspartate",
"nlm_unique_id": "101589536",
"other_id": null,
"pages": "96-9",
"pmc": null,
"pmid": "25384024",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Severe cognitive impairment associated with intrathecal antibodies to the NR1 subunit of the N-methyl-D-aspartate receptor in a patient with multiple sclerosis.",
"title_normalized": "severe cognitive impairment associated with intrathecal antibodies to the nr1 subunit of the n methyl d aspartate receptor in a patient with multiple sclerosis"
} | [
{
"companynumb": "DE-BIOGENIDEC-2014BI121979",
"fulfillexpeditecriteria": "1",
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"abstract": "OBJECTIVE\nTo report the results of a 104-week extension to a 52-week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin.\n\n\nMETHODS\nThis extension to a 52-week global, multicentre, parallel-group, active-controlled, double-blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1-6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5-91.3 mmol/mol [7.5%-10.5%]), and a body mass index of 20.0 to 45.0 kg/m2 , and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy.\n\n\nRESULTS\nOverall, 382 participants entered and 338 completed the 104-week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156-week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39-0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23-3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least-squares mean difference from GLIM+MET -4.89%, -0.41 L and -0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents.\n\n\nCONCLUSIONS\nOverall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.",
"affiliations": "National Research Institute, Los Angeles, California, USA.;AstraZeneca, Gaithersburg, Maryland, USA.;Kelly Services, Gaithersburg, Maryland, USA.;Antaros Medical AB, BioVenture Hub, Mölndal, Sweden.;Antaros Medical AB, BioVenture Hub, Mölndal, Sweden.;AstraZeneca, Gaithersburg, Maryland, USA.;Obesity and Endocrinology Research Group, Department of Cardiovascular and Metabolic Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK.",
"authors": "Frías|Juan P|JP|https://orcid.org/0000-0001-9486-1255;Maaske|Jill|J|;Suchower|Lisa|L|;Johansson|Lars|L|;Hockings|Paul D|PD|;Iqbal|Nayyar|N|;Wilding|John P H|JPH|https://orcid.org/0000-0003-2839-8404",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/dom.14548",
"fulltext": "\n==== Front\nDiabetes Obes Metab\nDiabetes Obes Metab\n10.1111/(ISSN)1463-1326\nDOM\nDiabetes, Obesity & Metabolism\n1462-8902\n1463-1326\nBlackwell Publishing Ltd Oxford, UK\n\n34514692\n10.1111/dom.14548\nDOM14548\nOriginal Article\nOriginal Articles\nLong‐term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104‐week extension to a 52‐week randomized, phase 3 study and liver fat MRI substudy\nFrías et al.\nFrías Juan P. MD https://orcid.org/0000-0001-9486-1255\n1 juan.frias@nritrials.com\n\nMaaske Jill MD 2\nSuchower Lisa MA 3\nJohansson Lars PhD 4\nHockings Paul D. PhD 4 5\nIqbal Nayyar MD 2\nWilding John P. H. DM https://orcid.org/0000-0003-2839-8404\n6\n1 National Research Institute Los Angeles California USA\n2 AstraZeneca Gaithersburg Maryland USA\n3 Kelly Services Gaithersburg Maryland USA\n4 Antaros Medical AB, BioVenture Hub Mölndal Sweden\n5 MedTech West Chalmers University of Technology Gothenburg Sweden\n6 Obesity and Endocrinology Research Group, Department of Cardiovascular and Metabolic Medicine Institute of Life Course and Medical Sciences, University of Liverpool Liverpool UK\n* Correspondence\nJuan P. Frías, MD, National Research Institute, 2010 Wilshire Blvd, Suite 302, Los Angeles, CA 90057, USA.\nEmail: juan.frias@nritrials.com\n\n28 9 2021\n1 2022\n24 1 10.1111/dom.v24.1 6171\n24 8 2021\n08 6 2021\n03 9 2021\n© 2021 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nAbstract\n\nAim\n\nTo report the results of a 104‐week extension to a 52‐week study in which dapagliflozin plus saxagliptin (DAPA+SAXA) improved glycaemic control, liver fat and metabolic variables compared with glimepiride (GLIM) in participants with type 2 diabetes (T2D) receiving background metformin.\n\nMaterials and methods\n\nThis extension to a 52‐week global, multicentre, parallel‐group, active‐controlled, double‐blind study (NCT02419612) continued randomized participants (1:1) on DAPA+SAXA (10/5 mg) plus placebo, or GLIM (1‐6 mg) plus placebo, once daily. Eligible participants were aged ≥18 years, had T2D (glycated haemoglobin [HbA1c] 58.5‐91.3 mmol/mol [7.5%‐10.5%]), and a body mass index of 20.0 to 45.0 kg/m2, and were receiving metformin (MET; ≥1500 mg/d). Key outcomes were: requirement for treatment intensification, based on HbA1c ≥53 mmol/mol (7%); achieving therapeutic glycaemic response; and changes in adipose tissue and liver fat on magnetic resonance imaging in a substudy.\n\nResults\n\nOverall, 382 participants entered and 338 completed the 104‐week extension period (MRI substudy, n = 82). The need for treatment intensification during the 156‐week period was lower for DAPA+SAXA+MET (37.0%) than GLIM+MET (55.6%; hazard ratio 0.52, 95% confidence interval [CI] 0.39‐0.68; P < 0.001). At week 156, 21.4% of DAPA+SAXA+MET versus 11.7% of GLIM+MET participants achieved therapeutic glycaemic response (HbA1c <53 mmol/mol; odds ratio 2.1, 95% CI 1.23‐3.42; P = 0.006). DAPA+SAXA+MET led to greater adjusted mean reductions from baseline in liver fat and visceral and subcutaneous adipose tissue volumes versus GLIM+MET at week 122 (least‐squares mean difference from GLIM+MET −4.89%, −0.41 L and −0.44 L, respectively; nominal P values ≤ 0.008). Safety was consistent with that of the monocomponents.\n\nConclusions\n\nOverall, glycaemic control, metabolic benefits and efficacy were better maintained with DAPA+SAXA+MET than with GLIM+MET in T2D.\n\ndapagliflozin\nDPP‐4 inhibitor\nliver\nphase III study\nsulphonylureas\ntype 2 diabetes\nAstraZeneca 10.13039/501100014091 source-schema-version-number2.0\ncover-dateJanuary 2022\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.1.7 mode:remove_FC converted:18.07.2022\nFrías JP , Maaske J , Suchower L , et al. Long‐term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104‐week extension to a 52‐week randomized, phase 3 study and liver fat MRI substudy. Diabetes Obes Metab. 2022;24 (1 ):61-71. doi:10.1111/dom.14548 34514692\n\nFunding information AstraZeneca\n\nThis article has an accompanied Plain Language Summary in the Supporting Information Data S1 .\n==== Body\npmc1 INTRODUCTION\n\nDespite the availability of multiple classes of glucose‐lowering drugs, the progressive nature of type 2 diabetes (T2D) makes maintenance of glycaemic control difficult. 1 Metformin (MET) is the preferred initial pharmacological treatment, with stepwise addition of glucose‐lowering drugs recommended if glycaemic targets are not acheived. 2 Because clinical inertia often leads to delays in achieving glycaemic goals, therapies that provide rapid control with durability over time are needed. Moreover, T2D is associated with nonalcoholic fatty liver disease (NAFLD) 3 ; therefore, assessing the effect of treatment on liver fat and other metabolic variables, in addition to glycaemic control, is of considerable interest.\n\nAmerican Diabetes Association (ADA) guidance advocates consideration of initial combination therapy for patients with significantly elevated glycated haemoglobin (HbA1c) levels (1.5%‐2% above target). 2 Sodium‐glucose cotransporter‐2 (SGLT2) inhibitors and dipeptidyl peptidase‐4 (DPP‐4) inhibitors are recommended as second‐line therapies for T2D management. 2 The ADA also recommends SGLT2 inhibitors irrespective of HbA1c levels in patients with established atherosclerotic cardiovascular disease, kidney disease or heart failure. 2 Dapagliflozin (DAPA), a selective SGLT2 inhibitor, reduces fasting plasma glucose (FPG) levels, HbA1c levels, systolic blood pressure (SBP) and body weight in patients with T2D. 4 Saxagliptin (SAXA), a selective DPP‐4 inhibitor, reduces HbA1c levels, with neutral effects on body weight. 4 Both drugs also have a low risk of causing hypoglycaemia, especially when compared with sulphonylureas. 4 The addition of DAPA in combination with SAXA to MET has been shown to have superior efficacy to that of either of the individual medications plus MET from 24 to 52 weeks of treatment. 5 , 6 , 7 , 8 , 9\n\nThe optimal pharmacological approach for achieving and maintaining glycaemic targets is currently unknown, but some evidence suggests that early intensive treatment with a combination of a DPP‐4 inhibitor and MET may be more beneficial than sequential addition of a DPP‐4 inhibitor when MET monotherapy fails to maintain glycaemic control. 10 However, more evidence is needed to help determine whether the durability of glycaemic response and metabolic benefits can be maintained over the long term. Add‐on therapy with a sulphonylurea can be considered for stepwise treatment intensification, particularly in patients for whom medication cost is a concern, although disadvantages include weight gain, increased risk of hypoglycaemia 11 and poor durability of glycaemic response. 12\n\nIn a 52‐week study, DAPA in combination with SAXA was previously evaluated as an add‐on to MET in comparison with the sulphonylurea glimepiride (GLIM) plus MET in participants with T2D inadequately controlled on MET monotherapy. 13 DAPA+SAXA+MET (compared with GLIM+MET) was associated with significantly greater adjusted mean reductions from baseline at week 52 in HbA1c (least‐squares [LS] mean change −1.35%, 95% confidence interval [CI] −1.49, −1.22 vs. −0.98%, 95% CI −1.12, −0.84), body weight and SBP, with 1.5 times greater odds of achieving a therapeutic glycaemic response of HbA1c <53.0 mmol/mol (7.0%) at 52 weeks, and with a lower proportion of participants requiring treatment intensification (addition of insulin or other glucose‐lowering drug for rescue therapy, or discontinuation for lack of glycaemic control – defined as an HbA1c level ≥ 53.0 mmol/mol [7.0%]) during the 52‐week treatment period. 13 A magnetic resonance imaging (MRI) substudy found greater adjusted mean decreases in liver fat and adipose tissue volumes from baseline at week 52 with DAPA+SAXA+MET versus GLIM+MET treatment. 14\n\nIn the present paper, we report the results of the 104‐week extension to the 52‐week study, as well as the 122‐week results of the MRI substudy.\n\n2 METHODS\n\n2.1 Study design and participants\n\nThis was a 52‐week, global, multicentre, randomized, parallel‐group, double‐blind, active‐controlled, phase 3b study, 13 , 14 with a site‐ and participant‐blinded 104‐week extension period (Figure S1). The study was conducted from August 2015 to September 2019 at 88 centres in 10 countries (United States, Hungary, Romania, Poland, Mexico, Russia, the Czech Republic, Sweden, Germany and the United Kingdom).\n\nEligible participants entered a 2‐week screening and a 2‐week lead‐in period. Men and women (aged ≥18 years) with T2D, HbA1c levels of 58.5 to 91.3 mmol/mol (7.5%‐10.5%; inclusive) and body mass index (BMI) of 20.0 to 45.0 kg/m2 (inclusive) at the enrolment visit, who were currently treated with MET and on a stable dose (≥1500 mg/d) for ≥8 weeks before enrolment, were eligible for inclusion. Additional inclusion/exclusion criteria information can be found in Appendix S1 and in the the 52‐week data publications. 13 , 14\n\n2.2 Ethics\n\nThe study followed regulatory requirements, including the sponsor's policy on bioethics, and was performed in accordance with the Declaration of Helsinki and the International Council for Harmonisation Good Clinical Practice guidelines. The local independent ethics committees/institutional review boards approved the final protocol and any amendments. All participants provided written informed consent prior to inclusion in the study and MRI substudy.\n\n2.3 Randomization and masking\n\nParticipants receiving MET were randomized in a 1:1 ratio to receive double‐blinded once‐daily DAPA 10 mg plus once‐daily SAXA 5 mg plus placebo or once‐daily titratable GLIM 1 to 6 mg (starting at 1 mg and titrated at 3‐week intervals up to week 12 to a maximum of 6 mg using stepwise doses of 2, 3, 4 and 6 mg) plus placebo. GLIM could be downtitrated in case of hypoglycaemia. Randomization, stratified by site, was performed via an interactive voice response system that assigned each participant a unique, sequential five‐digit number. Treatment with thiazolidinediones, glucagon‐like peptide‐1 receptor agonists, sulphonylureas and DPP‐4 inhibitors or SGLT2 inhibitors other than the investigational drugs was not allowed.\n\nParticipants were rescued for hyperglycaemia with open‐label insulin or, if not appropriate, other drugs except a DPP‐4 inhibitor, SGLT2 inhibitor or sulphonylurea. Up‐to‐week‐52 rescue criteria were based on FPG values, 13 whereas after‐week‐52 rescue was undertaken if the HbA1c level was >58.5 mmol/mol (7.5%).\n\n2.4 MRI substudy\n\nAs previously reported, 14 the MRI substudy included participants from the full study who had a BMI of 20.0 to 40.0 kg/m2 (inclusive) at enrolment, a maximum weight of 140 kg to accommodate MRI scanning and no other contraindications to MRI scanning.\n\nParticipants assigned to the MRI substudy had an ad hoc visit to the imaging site within 2 weeks prior to the randomization visit, within ±2 weeks of the week‐52 visit and within ±4 weeks of the week‐122 visit. Visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) volumes were assessed using abdominal MRI. Liver fat content was assessed using MRI‐estimated proton density fat fraction (PDFF).\n\n2.5 Study objectives and assessments\n\nSecondary endpoints for the overall 156‐week study were: time to treatment intensification during the 156‐week treatment period, and proportion of participants achieving a therapeutic glycaemic response at week 156.\n\nAll other objectives were exploratory and included mean changes from baseline in HbA1c, FPG, SBP, total body weight and serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels for all participants assessed at week 156. Other exploratory endpoints included the mean time spent at or below HbA1c 53.0 mmol/mol (7.0%) over 156 weeks, the proportion of participants achieving a therapeutic glycaemic response without any hypoglycaemia at week 156 and the proportion of participants achieving a therapeutic glycaemic response without any hypoglycaemia and without any weight gain at week 156. Participants rescued or discontinued prior to and participants with missing measurements at the specified timepoint were treated as nonresponders.\n\nIn the MRI substudy, endpoints included mean changes from baseline in liver fat percentage and SAT and VAT volumes at weeks 52 and 122. Post hoc analyses of mean changes from baseline for HbA1c, serum ALT and AST levels, body weight, and fibrosis‐4 (FIB‐4) scores were assessed over the 156‐week treatment period for this substudy.\n\n2.6 Statistical analyses\n\nSample size calculations and other statistical analysis details can be found in the 52‐week study and MRI substudy publications. 13 , 14\n\nEfficacy analyses during the 156‐week treatment period included two secondary endpoints (part of sequential statistical testing 13 ) and exploratory endpoints. Time to treatment intensification was tested before the proportion of participants achieving a therapeutic glycaemic response and was analysed using a Cox proportional hazards model and censored at 156 weeks if treatment intensification had not occurred by this timepoint. Participants rescued at the end of the treatment period were counted as having an event. The proportion of participants achieving a therapeutic glycaemic response at week 156 was analysed using logistic regression adjusting for baseline HbA1c. Participants rescued, discontinued prior to or with missed measurements at week 156 were considered as not achieving a glycaemic response (ie, nonresponders).\n\nExploratory change‐from‐baseline endpoints used a mixed model of repeated measures, which assumes that data are missing at random, including terms for treatment, baseline result, visit, treatment‐by‐visit interaction and baseline result‐by‐visit interaction, with no multiplicity adjustments and nominal P values presented. Efficacy results were summarized prior to rescue and treatment discontinuation (plus a tolerance window after the last dose). For HbA1c and body weight, assessments collected after initiation of rescue medication or collected >8 days after the last dose in the 156‐week treatment period were excluded from the analysis. For lipids and SBP, >4 days was used, whereas for FPG >1 day was used.\n\nTime spent at or below the HbA1c target (HbA1c ≤53 mmol/mol [7.0%]) over the 156‐week treatment period was calculated for each participant using linear interpolation and analysed using an analysis of covariance model including terms for treatment and baseline HbA1c.\n\nSafety data were summarized descriptively regardless of rescue medication (hypoglycaemic events summarized prior to rescue medication), and results >4 days after the last dose were excluded (30 days for serious adverse events [AEs] and liver function tests).\n\nStatistical analyses were performed with SAS version 9.4 (SAS Institute Inc.).\n\n3 RESULTS\n\nIn the main 52‐week study, 444 participants were randomized (443 received treatment) and 385 completed the double‐blind treatment period. 13 Overall, 382 participants entered the 104‐week long‐term extension period, of whom 338 completed the extension period and 318 completed treatment during the extension period (Figure S2). A total of 82 participants who gave consent to have MRI performed were included in the randomized MRI substudy (46 in the DAPA+SAXA+MET group and 36 in the GLIM+MET group).\n\nTreatment groups for the full study (Table 1) and the MRI substudy (Table S1) were proportionally well balanced with regard to demographics, participant characteristics and disease characteristics. Mean treatment compliance during the 156‐week treatment period was ~99% in both groups.\n\nTABLE 1 Demographics and baseline disease characteristics (randomized analysis set)\n\n\tDAPA+SAXA+MET (N = 227)\tGLIM+MET (N = 216)\tTotal (N = 443)\t\nAge, years\t56.1 (10.1)\t56.1 (9.2)\t56.1 (9.7)\t\nFemale, n (%)\t110 (48.5)\t115 (53.2)\t225 (50.8)\t\nWeight, kg\t91.0 (19.8)\t88.4 (17.1)\t89.7 (18.5)\t\nBMI, kg/m2\t32.4 (5.3)\t32.2 (5.1)\t32.3 (5.2)\t\nBMI group, n (%)\t\t\t\t\n<25 kg/m2\t13 (5.7)\t14 (6.5)\t27 (6.1)\t\n≥25 kg/m2\t214 (94.3)\t202 (93.5)\t416 (93.9)\t\n≥27 kg/m2\t191 (84.1)\t186 (86.1)\t377 (85.1)\t\n≥30 kg/m2\t145 (63.9)\t136 (63.0)\t281 (63.4)\t\nRace, n (%)\t\t\t\t\nWhite\t206 (90.7)\t196 (90.7)\t402 (90.7)\t\nBlack or African American\t4 (1.8)\t5 (2.3)\t9 (2.0)\t\nAmerican Indian or Alaska Native\t11 (4.8)\t10 (4.6)\t21 (4.7)\t\nOther a\t6 (2.6)\t5 (2.3)\t11 (2.5)\t\nRegion, n (%)\t\t\t\t\nNorth America\t57 (25.1)\t55 (25.5)\t112 (25.3)\t\nLatin America\t39 (17.2)\t37 (17.1)\t76 (17.2)\t\nEurope\t131 (57.7)\t124 (57.4)\t255 (57.6)\t\nDuration of T2D, years\t7.7 (6.4)\t7.9 (6.5)\t7.8 (6.4)\t\nHbA1c, %\t8.4 (0.8)\t8.5 (0.8)\t8.5 (0.8)\t\nFPG, mg/dL\t172.9 (41.5)\t176.5 (42.4)\t174.7 (41.9)\t\nNote: The randomized analysis set comprised all randomized participants who received ≥1 dose of the double‐blinded study drug during the 52‐week treatment period. Participants were included in the treatment group to which they were randomized at the start of the 52‐week treatment period. Data are mean (SD), unless otherwise indicated.\n\nAbbreviations: BMI, body mass index; DAPA, dapagliflozin; FPG, fasting plasma glucose; GLIM, glimepiride; HbA1c, glycated haemoglobin; MET, metformin; SAXA, saxagliptin; SD, standard deviation; T2D, type 2 diabetes.\n\na Includes Asian, Native Hawaiian or other Pacific Islander and Other.\n\n3.1 Full study\n\nThere were 84/227 participants (37.0%) in the DAPA+SAXA+MET group and 120/216 participants (55.6%) in the GLIM+MET group who required treatment intensification by week 156. Figure 1 shows a Kaplan‐Meier plot of the time to treatment intensification during the 156‐week treatment period. There was a 48% decreased risk of treatment intensification during the 156‐week treatment period for participants in the DAPA+SAXA+MET group compared with participants in the GLIM+MET group (hazard ratio 0.52 [95% CI 0.39, 0.68]; P < 0.001).\n\nFIGURE 1 Time to treatment intensification during the 156‐week treatment period, Kaplan‐Meier plot (randomized analysis set). Treatment intensification was defined as addition of insulin or other glucose‐lowering agents for rescue therapy or discontinuation for lack of glycaemic control. Time to treatment intensification was censored at 156 weeks if treatment intensification had not occurred by then. Participants rescued at week 156 were counted as having an event for the analysis. “|” and “0” denote a censored observation. DAPA, dapagliflozin; GLIM, glimepiride; MET, metformin; N, number of participants in the treatment group; r, number of participants at risk at that timepoint; SAXA, saxagliptin\n\nTable S2 shows the data for participants who were rescued during the 156‐week treatment period and the rescue medications taken. The most common rescue treatment was insulin (49 participants [21.6%] in the DAPA+SAXA+MET group and 71 participants [32.9%] in the GLIM+MET group).\n\nTable S3 shows the proportion of participants achieving a therapeutic glycaemic response (HbA1c <53.0 mmol/mol [7.0%]) at week 156. At week 156, 21.4% of participants in the DAPA+SAXA+MET group versus 11.7% of participants in the GLIM+MET group achieved a therapeutic glycaemic response (odds ratio 2.1 [95% CI 1.23, 3.42]; P = 0.006).\n\nFigure 2 presents the adjusted mean change from baseline in HbA1c through to week 156. Table S4 shows additional exploratory efficacy analysis results for the 156‐week treatment period. The proportion of participants in the DAPA+SAXA+MET group who achieved a therapeutic glycaemic response without any hypoglycaemia was 34.8% at week 52 13 and 16.7% at week 156; corresponding values for participants in the GLIM+MET group were 14.8% at week 52 and 3.2% at week 156.\n\nFIGURE 2 Adjusted mean change from baseline in glycated haemoglobin (HbA1c) up to week 156, prior to rescue and treatment discontinuation (randomized analysis set). Repeated measures analysis, least‐squares mean (95% confidence interval [CI]). Participants with nonmissing baseline assessment and ≥1 post‐baseline assessment were included in the analysis. (DAPA+SAXA+MET, 218; GLIM+MET, 212). Week 0 refers to the baseline value. Baseline is defined as participants in the randomized analysis set with nonmissing baseline assessment and ≥1 post‐baseline assessment. DAPA, dapagliflozin; GLIM, glimepiride; MET, metformin; N, number of participants in the treatment group; n, number of participants with observed result at a timepoint; SAXA, saxagliptin\n\nThe mean (standard deviation) duration of exposure throughout the 156‐week treatment period regardless of rescue was 902.0 (344.5) days in the DAPA+SAXA+MET group and 903.0 (338.5) days in the GLIM+MET group.\n\nTable 2 summarizes the AEs, hypoglycaemic events and urinary tract infection AEs of special interest during the 156‐week treatment period. None of the participants had any confirmed diabetic ketoacidosis AEs.\n\nTABLE 2 Selected AEs during the 156‐week treatment period (treated participants dataset)\n\n\tDAPA+SAXA+MET (N = 227)\tGLIM+MET (N = 216)\t\nRegardless of rescue\t\nTotal participants by AE category, a n (%)\t\t\t\n≥1 AE\t180 (79.3)\t179 (82.9)\t\n≥1 hypoglycaemic event b\t54 (23.8)\t120 (55.6)\t\n≥1 AE or hypoglycaemic event b\t188 (82.8)\t191 (88.4)\t\n≥1 AE causally related to IP\t41 (18.1)\t20 (9.3)\t\nAny AE with outcome of death\t1 (0.4)\t3 (1.4)\t\n≥1 SAE\t29 (12.8)\t24 (11.1)\t\n≥1 SAE causally related to IP\t3 (1.3)\t1 (0.5)\t\nSAE leading to discontinuation of IP\t2 (0.9)\t8 (3.7)\t\nAE leading to discontinuation of IP\t13 (5.7)\t13 (6.0)\t\nHypoglycaemia leading to discontinuation of IP\t1 (0.4)\t1 (0.5)\t\nUTI AEs of special interest c\t\t\t\nMen\t\t\t\nN\t117\t101\t\nParticipants with any AE of UTI, n (%)\t11 (9.4)\t7 (6.9)\t\nUTIs\t7 (6.0)\t7 (6.9)\t\nCystitis\t3 (2.6)\t0\t\nUrethritis\t1 (0.9)\t0\t\nWomen\t\t\t\nN\t110\t115\t\nParticipants with any AE of UTI, n (%)\t29 (26.4)\t17 (14.8)\t\nUTIs\t25 (22.7)\t14 (12.2)\t\nCystitis\t2 (1.8)\t4 (3.5)\t\nEscherichia UTIs\t1 (0.9)\t0\t\nUrogenital infection fungal\t1 (0.9)\t0\t\nPrior to rescue\t\nTotal participants with hypoglycaemic events, n (%)\t51 (22.5)\t103 (47.7)\t\nSevere hypoglycaemia\t0\t3 (1.4)\t\nDocumented symptomatic hypoglycaemia\t19 (8.4)\t53 (24.5)\t\nAsymptomatic hypoglycaemia\t39 (17.2)\t82 (38.0)\t\nProbable symptomatic hypoglycaemia\t4 (1.8)\t7 (3.2)\t\nRelative hypoglycaemia\t4 (1.8)\t9 (4.2)\t\nTotal number of hypoglycaemic events, n (%)\t275\t902\t\nSevere hypoglycaemia\t0\t5 (0.6)\t\nDocumented symptomatic hypoglycaemia\t65 (23.6)\t292 (32.4)\t\nAsymptomatic hypoglycaemia\t190 (69.1)\t581 (64.4)\t\nProbable symptomatic hypoglycaemia\t4 (1.5)\t12 (1.3)\t\nRelative hypoglycaemia\t11 (4.0)\t16 (1.8)\t\nNote: Safety was analysed according to the treated participants dataset, which comprised all participants who received ≥1 dose of the double‐blinded study drug during the 52‐week treatment period. Participants were included in the treatment group to which they were randomized, except if they received a different treatment for the entire course of participation in the treatment period. There were five events of hypoglycaemia episodes reported for the DAPA+SAXA+MET group, for which no symptoms or glucose level was recorded. Hypoglycaemic events were categorized using class of events following American Diabetes Association 2005 recommendations. 15 Percentages are based on the number of participants in the treated participants dataset, except for event level, where percentages are based on total events of hypoglycaemia.\n\nAbbreviations: AE, adverse event; DAPA, dapagliflozin; GLIM, glimepiride; IP, investigational product; MET, metformin; N, number of participants in the treatment group; SAE, serious adverse event; SAXA, saxagliptin; UTI, urinary tract infection.\n\na Participants with multiple events in the same category are counted only once in that category. Participants with events in more than one category are counted once in each of those categories.\n\nb Events recorded by the investigators are included in this category. All other categories exclude hypoglycaemic events not reported as SAEs.\n\nc AEs coded using the Medical Dictionary for Regulatory Activities version 22.0.\n\nA greater percentage of participants with any urinary tract infection AE were in the DAPA+SAXA+MET group (17.6%) than in the GLIM+MET group (11.1%), and such AEs were more common in women than in men, regardless of group. Table S5 shows the most common AEs reported with a frequency of ≥5% in either group.\n\n3.2 MRI substudy\n\nBaseline mean results for liver fat, VAT and SAT were similar for participants in the DAPA+SAXA+MET group (14.30%, 3.64 L and 4.71 L, respectively) compared with the GLIM+MET group (13.71%, 2.92 L and 4.14 L, respectively). At week 122, treatment with DAPA+SAXA+MET was associated with greater adjusted mean reductions from baseline in liver fat and VAT and SAT volumes (adjusting for baseline value) than treatment with GLIM+MET (LS mean difference from GLIM+MET −4.89%, −0.41 L and −0.44 L, respectively; nominal P values ≤ 0.008 [Figure 3A‐C]). The mean liver fat and VAT and SAT volumes at week 122 had relative reductions from baseline of 32%, 10% and 9%, respectively, in the DAPA+SAXA+MET group, determined as follows: (mean week‐122 result − mean baseline result)/mean baseline result. MRI results at week 122 were consistent with those at week 52. 14 Of the 35 participants in the DAPA+SAXA+MET group and the 24 participants in the GLIM+MET group with baseline and week‐52 liver fat results, 18 (51.4%) and six (25%), respectively, were considered responders at week 52 (ie, had relative liver fat reduction from baseline of at least 30% at week 52).\n\nFIGURE 3 Adjusted mean change from baseline at weeks 52 and 122 in (A) liver fat (proton density fat fraction [PDFF]), (B) visceral adipose tissue (VAT) volume, (C) subcutaneous adipose tissue (SAT) volume and (D) adjusted mean change from baseline at weeks 52 and 156 in total body weight (randomized analysis set for magnetic resonance imaging substudy). Nominal P value for difference versus glimepiride (GLIM) plus metformin (MET) in least‐squares mean change from baseline at weeks 52 (analysis of covariance [ANCOVA], except mixed model of repeated measures [MMRM] for total body weight) and 122 or 156 (MMRM), before rescue and treatment discontinuation, adjusting for baseline value. The mean liver fat and VAT and SAT volumes at week 122 had relative reductions from a baseline of 32%, 10% and 9%, respectively, in the dapagliflozin (DAPA)+ saxagliptin (SAXA)+MET group. The relative reductions are based on the unadjusted mean values at baseline and week 122. MMRM includes patients with both baseline value and ≥1 post‐baseline value for the variable. ANCOVA includes patients with both baseline and week 52 results for the variable. Δ, least‐squares mean difference from GLIM+MET; CI, confidence interval; n, number of patients included in the analysis\n\nMean baseline ALT and AST levels, respectively, were 27.2 and 20.5 U/L in the DAPA+SAXA+MET group, and 29.8 and 23.6 U/L in the GLIM+MET group (Table S1). LS mean body weight and mean ALT level reductions from baseline observed at week 52 (−4.50 kg [n = 46]; −5.55 U/L [n = 44]) were sustained to week 156 (−4.36 kg [n = 46]; −7.34 U/L [n = 41]) in the DAPA+SAXA+MET group. Participants in the DAPA+SAXA+MET group had greater adjusted mean decreases from baseline at weeks 52 and 156 in total body weight (Figure 3D) and at week 52 in HbA1c (Figure S3) compared with patients in the GLIM+MET group. Mean baseline FIB‐4 scores were <1.45 in both groups, indicative of an absence of advanced fibrosis, and mean FIB‐4 scores were consistent throughout 156 weeks. Mean changes from baseline in ALT and AST levels over 156 weeks for DAPA+SAXA+MET and GLIM+MET are shown in Figure S4.\n\nFigure S5 shows pre‐ and post‐treatment liver fat (PDFF) images from two patients (one patient from each group).\n\n4 DISCUSSION\n\nAt 156 weeks in this 104‐week extension to a 52‐week study, there were greater reductions in HbA1c, body weight and liver enzymes and greater maintenance of glycaemic control with DAPA+SAXA+MET than with GLIM+MET. Additionally, a higher adjusted mean weight gain from baseline at week 156 and a higher proportion of participants with hypoglycaemia during the 156‐week treatment period were observed in the GLIM+MET group than in the DAPA+SAXA+MET group.\n\nIn the MRI substudy, there were greater adjusted mean reductions from baseline in liver fat and adipose tissue volume at 122 weeks with DAPA+SAXA+MET than with GLIM+MET. These data provide evidence of the long‐term durability of treatment response in patients with T2D, showing that in addition to improving metabolic control, DAPA+SAXA+MET also reduces liver fat and associated markers of liver inflammation.\n\nMany patients with poorly controlled T2D have steatosis or some degree of steatohepatitis. 16 , 17 Our MRI substudy results showed that treatment with DAPA+SAXA+MET was associated with greater adjusted mean decreases in liver fat (with 32% relative reduction in means) and SAT and VAT volumes from baseline at week 122 compared with treatment with GLIM+MET. Results were consistent with decreases at week 52. Other studies support the reduction in liver fat content with DAPA that we observed. 18 , 19 A study on body fat content and distribution (whole body, SAT, VAT and liver) that addressed effects of DAPA in combination with exenatide is largely consistent with the present data, although numeric reductions in liver fat percent units were not statistically significant. 20\n\nThere is a strong association of NAFLD with T2D, and its presence increases the worsening of liver‐related complications as well as hepatic insulin resistance. 21 Given that approximately 70% of patients with T2D have NAFLD, 16 , 22 interventions that can mitigate the risk, halt the progression or lessen the impact of liver disease would be valuable additions to the treatment regimens of most patients with T2D. NAFLD sometimes involves elevated ALT levels. 23 At 156 weeks in both the MRI substudy and main study, there were greater mean decreases from baseline in ALT levels in the DAPA+SAXA+MET group versus the GLIM+MET group.\n\nOverall, our results demonstrate that DAPA+SAXA+MET offers several advantages over GLIM+MET because of greater overall glycaemic durability, HbA1c reduction, lower hypoglycaemia risk and improvement in metabolic profile as shown by weight loss and improvements in liver fat, adipose tissue volumes and liver enzyme levels over an extended time period.\n\nAlthough there are no clinical studies showing the impact of liver fat and adipose tissue volume reductions on long‐term metabolic health and clinical outcomes in patients with T2D, there is some clinical evidence suggesting that a reduction of >30% in liver fat at 72 weeks is associated with a statistically significant and clinically relevant histological response in patients with nonalcoholic steatohepatitis. 24 , 25 In a post hoc analysis of the present dataset for the MRI substudy, mean changes from baseline in HbA1c results were presented at several timepoints throughout the 156‐week treatment period by responders and “less responders” for each group, where a responder was defined as a participant who had a relative reduction in liver fat (PDFF %) from baseline at week 52 of ≥30% and “less responders” had a relative reduction of <30%, no change or a relative increase. These results did not suggest a prediction of long‐term glycaemic effects based on liver fat results (data not shown). Investigation of whether the improvements in indicators of liver health that we observed in the present study are associated with improvements in clinical outcomes would require larger and longer studies that are specifically designed to answer this question.\n\nIn a 4‐year study, DAPA added to MET showed greater durability of glycaemic control than glipizide plus MET treatment, with less hypoglycaemia and greater reductions in body weight and SBP. 12 Combining drugs with complementary mechanisms of action has been postulated to possibly maintain long‐term glycaemic control. 26 However, the results of the present study do not necessarily support that the combination per se of DAPA+SAXA+MET preserves β‐cell function to any greater extent than the individual drugs, only that it offers benefits over GLIM+MET. Further studies would be needed to explore this possibility. A rationale for early combination therapy with DAPA+SAXA+MET derives from complementary mechanisms of action involving insulin‐independent durable reductions in HbA1c, SBP and body weight with DAPA, glucose‐dependent insulin secretion with SAXA 4 and insulin sensitization with MET. 27 Although there are adherence benefits to monotherapy, 28 aggressive early intervention with a fixed‐dose combination 4 of DAPA and SAXA could improve adherence compared with administering these drugs separately.\n\nDurable glycaemic control is a cornerstone of long‐term T2D management. Our results demonstrate that more participants receiving DAPA+SAXA+MET were able to maintain durability of glycaemic response than those receiving GLIM+MET. In the short term, the difference between treatment groups in adjusted mean changes from baseline in HbA1c, particularly the increase between weeks 16 and 28 in the GLIM group, may have been attributable to hypoglycaemia and downtitration of GLIM. After week 28, the increases in adjusted mean changes from baseline in HbA1c appeared similar between the two study groups, which supports the progressive nature of T2D and the increased efficacy of the DAPA+SAXA combination versus GLIM. At week 156, DAPA+SAXA+MET was associated with greater mean reductions from baseline compared with GLIM+MET in HbA1c, body weight and serum liver enzyme levels.\n\nThe sudden increase in the number of participants in both treatment groups who required rescue therapy around week 56 was most likely protocol‐driven, related to the change from FPG to HbA1c results at week 52 determining whether rescue medication should be given (ie, the requirement for rescue being more easily met after week 52).\n\nOverall, the safety and tolerability profile of DAPA+SAXA+MET over 156 weeks was generally consistent with that observed over 52 weeks 13 and the established profiles of the individual components. 9 , 29\n\nThe present study has several limitations. Although this study included participants of different races, 90% and 100% of the population were White in the study and the MRI substudy, respectively. A more diverse ethnic mix and populations comprising the elderly and those vulnerable to hypoglycaemia remains to be explored. Furthermore, GLIM was uptitrated only during the initial 12 weeks of the study to achieve a stable and maximum dose, but some participants could have benefited from further uptitration during the study. Finally, almost 12% of the participants who entered the 104‐week extension period dropped out of the study and did not complete the extension period. Strengths of the study include the fact that it was long‐term (3 years), with double‐blinding that continued throughout the extension period, providing a comprehensive evaluation of liver fat and adipose tissue distribution over 122 weeks.\n\nIn conclusion, the present results indicate that glycaemic control and favourable metabolic benefits and efficacy are better maintained with DAPA+SAXA+MET compared with GLIM+MET in patients with T2D, with a safety profile consistent with that of the individual components.\n\nAUTHOR CONTRIBUTIONS\n\nJuan P. Frías was an investigator in the study and contributed to interpretation of the results. Jill Maaske and Lisa Suchower contributed to statistical analysis and interpretation of results. Lars Johansson contributed to study design, study conduct, data collection and data analysis. Paul D. Hockings contributed to study conduct, data collection and data analysis. Nayyar Iqbal contributed to study conception, study conduct and interpretation of results. John P. H. Wilding contributed to the interpretation of the results. Juan P. Frías is the guarantor of this work and, as such, had full access to all data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis. All authors contributed to critical review and revision of the manuscript and gave final approval of the version to be published.\n\nCONFLICTS OF INTEREST\n\nJ.P.F. reports research support from Akero, AbbVie, AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, Intercept, Janssen, Madrigal, Metacrine, Merck, NorthSea Therapeutics, Novartis, Novo Nordisk, Oramed, Pfizer, Poxel, Sanofi and Theracos; has served in advisory board and consulting roles for Akero, Altimmune, Axcella Health, Boehringer Ingelheim, Coherus Therapeutics, Echosens, 89bio, Eli Lilly, Gilead, Intercept, Merck, Novo Nordisk and Sanofi; and has served on Speaker Bureaus for Eli Lilly, Merck and Sanofi. L.S. is an employee of Kelly Services for AstraZeneca, a former employee of AstraZeneca and a stockholder in AstraZeneca, Merck and Express Scripts. J.M. is an employee of and stockholder in AstraZeneca. N.I. is an employee of AstraZeneca. P.D.H. reports a research contract with AstraZeneca. L.J. is an employee of and stockholder in Antaros Medical. J.P.H.W. reports grants, personal fees and institution consultancy fees from AstraZeneca and Novo Nordisk; personal fees and institution consultancy fees from Boehringer Ingelheim, Janssen, Napp and Mundipharma; grants and personal fees from Takeda; institution consultancy fees from Astellas, Rhythm Pharmaceuticals, Sanofi and Lilly; and personal fees from Merck outside the submitted work.\n\nPEER REVIEW\n\nThe peer review history for this article is available at https://publons.com/publon/10.1111/dom.14548.\n\nSupporting information\n\nData S1: Plain Language Summary\n\nClick here for additional data file.\n\nAppendix S1: Supporting information.\n\nClick here for additional data file.\n\nACKNOWLEDGMENTS\n\nAstraZeneca funded medical writing assistance provided by Steven Tresker and editorial assistance provided by Suchita Nath‐Sain, PhD, both of Cactus Life Sciences (part of Cactus Communications). Statistical expertise and support was provided by Dr John Monyak of AstraZeneca. This study was funded by AstraZeneca. The sponsor of the study was involved in study design, data collection, data review and data analysis and was responsible for gathering all data. The sponsor funded medical writing and editorial support. All authors had full access to the data in the study, critically reviewed and revised the manuscript and had final responsibility for the decision to submit for publication. The findings from this study were communicated in oral presentation form at the 78th Scientific Sessions of the American Diabetes Association in June 2018, and as a poster on the 122‐week MRI results that was presented at the American Association for the Study of Liver Diseases meeting in November 2020.\n\nDATA AVAILABILITY STATEMENT\n\nData underlying the findings described in this manuscript may be obtained in accordance with AstraZeneca's data sharing policy described at https://astrazenecagrouptrials.pharmacm.com/ST/Submission/Disclosure\n==== Refs\nREFERENCES\n\n1 Khunti K , Wolden ML , Thorsted BL , Andersen M , Davies MJ . Clinical inertia in people with type 2 diabetes: a retrospective cohort study of more than 80,000 people. Diabetes Care. 2013;36 (11 ):3411‐3417.23877982\n2 American Diabetes Association . 9. Pharmacologic approaches to glycemic treatment: standards of medical care in diabetes‐2020. Diabetes Care. 2020;43 (suppl 1 ):S98‐S110.31862752\n3 Chalasani N , Younossi Z , Lavine JE , et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67 (1 ):328‐357.28714183\n4 Yu H , Woo VC . Emerging use of combination therapies for the management of type 2 diabetes ‐ focus on saxagliptin and dapagliflozin. Diabetes Metab Syndr Obes. 2017;10 :317‐332.28769579\n5 Mathieu C , Herrera Marmolejo M , González González JG , et al. Efficacy and safety of triple therapy with dapagliflozin add‐on to saxagliptin plus metformin over 52 weeks in patients with type 2 diabetes. Diabetes Obes Metab. 2016;18 (11 ):1134‐1137.27385192\n6 Mathieu C , Ranetti AE , Li D , et al. Randomized, double‐blind, phase 3 trial of triple therapy with dapagliflozin add‐on to saxagliptin plus metformin in type 2 diabetes. Diabetes Care. 2015;38 (11 ):2009‐2017.26246458\n7 Matthaei S , Aggarwal N , Garcia‐Hernandez P , et al. One‐year efficacy and safety of saxagliptin add‐on in patients receiving dapagliflozin and metformin. Diabetes Obes Metab. 2016;18 (11 ):1128‐1133.27403645\n8 Matthaei S , Catrinoiu D , Celiński A , et al. Randomized, double‐blind trial of triple therapy with saxagliptin add‐on to dapagliflozin plus metformin in patients with type 2 diabetes. Diabetes Care. 2015;38 (11 ):2018‐2024.26324329\n9 Rosenstock J , Hansen L , Zee P , et al. Dual add‐on therapy in type 2 diabetes poorly controlled with metformin monotherapy: a randomized double‐blind trial of saxagliptin plus dapagliflozin addition versus single addition of saxagliptin or dapagliflozin to metformin. Diabetes Care. 2015;38 (3 ):376‐383.25352655\n10 Matthews DR , Paldánius PM , Proot P , Chiang Y , Stumvoll M , Del Prato S . VERIFY study group. Glycaemic durability of an early combination therapy with vildagliptin and metformin versus sequential metformin monotherapy in newly diagnosed type 2 diabetes (VERIFY): a 5‐year, multicentre, randomised, double‐blind trial. Lancet. 2019;394 (10208 ):1519‐1529.31542292\n11 Thulé PM , Umpierrez G . Sulfonylureas: a new look at old therapy. Curr Diab Rep. 2014;14 (4 ):473.24563333\n12 Del Prato S , Nauck M , Durán‐Garcia S , et al. Long‐term glycaemic response and tolerability of dapagliflozin versus a sulphonylurea as add‐on therapy to metformin in patients with type 2 diabetes: 4‐year data. Diabetes Obes Metab. 2015;17 (6 ):581‐590.25735400\n13 Frías JP , Gonzalez‐Galvez G , Johnsson E , et al. Efficacy and safety of dual add‐on therapy with dapagliflozin plus saxagliptin versus glimepiride in patients with poorly controlled type 2 diabetes on a stable dose of metformin: results from a 52‐week, randomized, active‐controlled trial. Diabetes Obes Metab. 2020;22 (7 ):1083‐1093.32052516\n14 Johansson L , Hockings PD , Johnsson E , et al. Dapagliflozin plus saxagliptin add‐on to metformin reduces liver fat and adipose tissue volume in patients with type 2 diabetes. Diabetes Obes Metab. 2020;22 (7 ):1094‐1101.32072735\n15 American Diabetes Association Workgroup on Hypoglycemia . Defining and reporting hypoglycemia in diabetes: a report from the American Diabetes Association Workgroup on Hypoglycemia. Diabetes Care. 2005;28 (5 ):1245‐1249.15855602\n16 Kwok R , Choi KC , Wong GL‐H , et al. Screening diabetic patients for non‐alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut. 2016;65 (8 ):1359‐1368.25873639\n17 Gastaldelli A , Cusi K . From NASH to diabetes and from diabetes to NASH: mechanisms and treatment options. JHEP Rep. 2019;1 (4 ):312‐328.32039382\n18 Eriksson JW , Lundkvist P , Jansson P‐A , et al. Effects of dapagliflozin and n‐3 carboxylic acids on non‐alcoholic fatty liver disease in people with type 2 diabetes: a double‐blind randomised placebo‐controlled study. Diabetologia. 2018;61 (9 ):1923‐1934.29971527\n19 Kurinami N , Sugiyama S , Yoshida A , et al. Dapagliflozin significantly reduced liver fat accumulation associated with a decrease in abdominal subcutaneous fat in patients with inadequately controlled type 2 diabetes mellitus. Diabetes Res Clin Pract. 2018;142 :254‐263.29859912\n20 Lundkvist P , Pereira MJ , Katsogiannos P , Sjöström CD , Johnsson E , Eriksson JW . Dapagliflozin once daily plus exenatide once weekly in obese adults without diabetes: sustained reductions in body weight, glycaemia and blood pressure over 1 year. Diabetes Obes Metab. 2017;19 :1276‐1288.28345814\n21 Glass LM , Hunt CM , Fuchs M , Su GL . Comorbidities and nonalcoholic fatty liver disease: the chicken, the egg, or both? Fed Pract. 2019;36 (2 ):64‐71.30867626\n22 Leite NC , Salles GF , Araujo ALE , Villela‐Nogueira CA , Cardoso CRL . Prevalence and associated factors of non‐alcoholic fatty liver disease in patients with type‐2 diabetes mellitus. Liver Int. 2009;29 (1 ):113‐119.18384521\n23 Yang H , Li D , Song X , et al. Joint associations of serum uric acid and ALT with NAFLD in elderly men and women: a Chinese cross‐sectional study. J Transl Med. 2018;16 (1 ):285.30333032\n24 Loomba R , Neuschwander‐Tetri BA , Sanyal A , et al. Multicenter validation of association between decline in MRI‐PDFF and histologic response in NASH. Hepatology. 2020;72 (4 ):1219‐1229.31965579\n25 Stine JG , Munaganuru N , Barnard A , et al. Change in MRI‐PDFF and histologic response in patients with nonalcoholic steatohepatitis: a systematic review and meta‐analysis. Clin Gastroenterol Hepatol. 2020. 10.1016/j.cgh.2020.08.061\n26 American Diabetes Association . Glycemic targets: standards of medical care in diabetes‐2020. Diabetes Care. 2020;43 (suppl 1 ):S66‐S76.31862749\n27 Giannarelli R , Aragona M , Coppelli A , Del Prato S . Reducing insulin resistance with metformin: the evidence today. Diabetes Metab. 2003;29 (4 pt 2 ):6S28‐6S35.14502098\n28 Dailey G , Kim MS , Lian JF . Patient compliance and persistence with antihyperglycemic drug regimens: evaluation of a Medicaid patient population with type 2 diabetes mellitus. Clin Ther. 2001;23 (8 ):1311‐1320.11558867\n29 Müller‐Wieland D , Kellerer M , Cypryk K , et al. Efficacy and safety of dapagliflozin or dapagliflozin plus saxagliptin versus glimepiride as add‐on to metformin in patients with type 2 diabetes. Diabetes Obes Metab. 2018;20 (11 ):2598‐2607.29947099\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1462-8902",
"issue": "24(1)",
"journal": "Diabetes, obesity & metabolism",
"keywords": "DPP-4 inhibitor; dapagliflozin; liver; phase III study; sulphonylureas; type 2 diabetes",
"medline_ta": "Diabetes Obes Metab",
"mesh_terms": null,
"nlm_unique_id": "100883645",
"other_id": null,
"pages": "61-71",
"pmc": null,
"pmid": "34514692",
"pubdate": "2022-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes: Results of a 104-week extension to a 52-week randomized, phase 3 study and liver fat MRI substudy.",
"title_normalized": "long term effects of dapagliflozin plus saxagliptin versus glimepiride on a background of metformin in patients with type 2 diabetes results of a 104 week extension to a 52 week randomized phase 3 study and liver fat mri substudy"
} | [
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"activesubstancename": "METFORMIN HYDROCHLORIDE"
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"abstract": "BACKGROUND\nChronic urticaria (CU) severely affects quality of life. If symptoms are not controlled by antihistamines, patients need immunomodulatory drugs. Recent studies show a tremendous effect of omalizumab, a monoclonal antibody against human IgE in refractory CU.\n\n\nMETHODS\nWe report on the use of omalizumab in four patients with CU. By reviewing medical files, we estimated the proportion of CU patients that are candidates for such treatment. We reviewed the literature to compare the dosing schedules and outcome measures used in different studies.\n\n\nRESULTS\nUp to 14% of CU patients referred to a tertiary center are candidates for omalizumab. Four of our CU were patients treated with doses of 150 mg/month or less, and all responded with nearly complete remission of symptoms. In the literature, 90% of patients respond to treatment, the response being obvious in days. Half of patients were able to stop all other medications, including antihistamines. More than half of patients responded well to doses of 150 mg of omalizumab every 4 to 8 weeks. In the majority of patients, the disease relapsed after discontinuation of omalizumab.\n\n\nCONCLUSIONS\nOmalizumab should be offered to patients with refractory CU. The duration of treatment is not known.",
"affiliations": "University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia. Corresponding author: mitja.kosnik@klinika-golnik.si.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.;University Clinic of Respiratory and Allergic Diseases, Golnik, Slovenia.",
"authors": "Košnik|Mitja|M|;Kopač|Peter|P|;Eržen|Renato|R|;Bajrović|Nissera|N|;Adamič|Katja|K|;Lalek|Nika|N|;Korošec|Peter|P|;Zidarn|Mihaela|M|",
"chemical_list": "D018926:Anti-Allergic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D000069444:Omalizumab",
"country": "Slovenia",
"delete": false,
"doi": "10.15570/actaapa.2014.14",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1318-4458",
"issue": "23(3)",
"journal": "Acta dermatovenerologica Alpina, Pannonica, et Adriatica",
"keywords": null,
"medline_ta": "Acta Dermatovenerol Alp Pannonica Adriat",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018926:Anti-Allergic Agents; D000888:Antibodies, Anti-Idiotypic; D061067:Antibodies, Monoclonal, Humanized; D002908:Chronic Disease; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D000069444:Omalizumab; D011788:Quality of Life; D016896:Treatment Outcome; D014581:Urticaria; D055815:Young Adult",
"nlm_unique_id": "9422563",
"other_id": null,
"pages": "57-61",
"pmc": null,
"pmid": "25242162",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Omalizumab in chronic urticaria: our experience and literature review.",
"title_normalized": "omalizumab in chronic urticaria our experience and literature review"
} | [
{
"companynumb": "PHHY2014SI134075",
"fulfillexpeditecriteria": "1",
"occurcountry": "SI",
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"activesubstancename": "MONTELUKAST SODIUM"
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{
"abstract": "BACKGROUND\nHypercalcemia has been observed in patients after liver transplantation. However, it is rare that the hypercalcemia induced disseminated tissue calcification and heart failure.\n\n\nMETHODS\nWe report a rare case of heart failure caused by disseminated metastatic tissue calcification that involved extensive progressive myocardial calcification after liver transplantation. A 20-year-old man with end-stage liver disease due to biliary atresia underwent ABO-incompatible living donor liver transplantation. After successful transplantation, he suffered from antibody-mediated rejection. Subsequently, ABO-matched cadaveric liver retransplantation was successfully performed. Hypercalcemia developed gradually following the second transplantation. His serum calcium level increased to 18.3 mg/dL with sudden onset of ventricular tachycardia. Although he was resuscitated with a cardiopulmonary support device, he died of heart and liver failure. Histopathologic examination revealed systemic disseminated metastatic tissue calcification, including massive myocardial calcification.\n\n\nCONCLUSIONS\nProgressive worsening of hypercalcemia resulted in disseminated metastatic tissue calcification and massive metastatic myocardial calcification, which led to heart failure after liver transplantation. Because hypercalcemia after liver transplantation can cause fatal tissue calcification, early intervention for hypercalcemia should be considered.",
"affiliations": "Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan. Electronic address: ueno@pedsurg.med.osaka-u.ac.jp.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatrics, Osaka University, Postgraduate School of Medicine, Osaka, Japan.;Department of Pediatric Surgery, Osaka University, Postgraduate School of Medicine, Osaka, Japan.",
"authors": "Deguchi|K|K|;Ueno|T|T|;Matsuura|R|R|;Yamanaka|H|H|;Nara|K|K|;Uehara|S|S|;Tazuke|Y|Y|;Bessho|K|K|;Okuyama|H|H|",
"chemical_list": "D002118:Calcium",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "48(1)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D001656:Biliary Atresia; D001787:Blood Group Incompatibility; D002114:Calcinosis; D002118:Calcium; D009202:Cardiomyopathies; D017809:Fatal Outcome; D006084:Graft Rejection; D006333:Heart Failure; D006801:Humans; D006934:Hypercalcemia; D008099:Liver; D017093:Liver Failure; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D012086:Reoperation; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "251-4",
"pmc": null,
"pmid": "26915877",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Disseminated Metastatic Tissue Calcification After Orthotopic Liver Transplantation: A Case Report.",
"title_normalized": "disseminated metastatic tissue calcification after orthotopic liver transplantation a case report"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1017113",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
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"drugadditional": null,
... |
{
"abstract": "Parkinsonism is a rare complication of non-germinomatous germ cell tumors (NGGCTs) arising from the pineal region.\nWe describe a 23-year-old man who presented with Parinaud syndrome, fatigue, and hypersomnia that were caused by a pineal region NGGCT with yolk sac component and an initial α-fetoprotein (AFP) of 1011.0 ng/ml. MRI revealed that the tumor was causing 10 mm of midline shift and compressing the cerebral aqueduct, the left thalamus, and the midbrain. Obstructive hydrocephalus was relieved by ventriculoperitoneal shunting. Six cycles of induction chemotherapy with ifosfamide, carboplatin, and etoposide reduced tumor size and decreased AFP levels in both serum and cerebrospinal fluid. Following the first cycle, the patient developed asymmetric, bilateral Parkinsonism consisting of bradykinesia, bradyphrenia, facial hypomimia, drooling, and dysphagia. Levodopa, amantadine, and methylphenidate were administered and resulted in symptom improvement. Second look neurosurgery revealed residual yolk sac tumor and a second induction regimen of gemcitabine, paclitaxel, and oxaliplatin was administered for rising AFP. The patient eventually received an autologous bone marrow transplant using a regimen of high-dose carboplatin, thiotepa, and etoposide with concomitant colony-stimulating factor and romiplostim support followed by consolidative proton craniospinal radiotherapy. Posttreatment head MRI showed that no evidence of tumor growth and serum AFP was within normal limits. His Parkinsonism eventually resolved and he was weaned off all dopaminergic drugs.\nBilateral Parkinsonism from NGGCT in this patient is probably caused by pressure on nigrostriatal tracts, substantia nigra, or both. The Parkinsonian symptoms can be reversed by aggressive treatment of the tumor and administration of dopaminergic drugs.",
"affiliations": "Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.;Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.;Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.;Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States.;Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.;Department of Neurosurgery, Columbia Presbyterian Medical Center, New York, United States.;Department of Radiation Oncology, Beth Israel Deaconess Medical Center, United States.;Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States.;Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.",
"authors": "Cole|Sydni M|SM|;Sarangi|Sasmit|S|;Einstein|David|D|;McMasters|Malgorzata|M|;Alterman|Ron|R|;Bruce|Jeffrey|J|;Hertan|Lauren|L|;Shih|Helen A|HA|;Wong|Eric T|ET|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.25259/SNI_595_2020",
"fulltext": "\n==== Front\nSurg Neurol Int\nSurg Neurol Int\nSurgical Neurology International\n2229-5097\n2152-7806\nScientific Scholar USA\n\n10.25259/SNI_595_2020\n10.25259/SNI_595_2020\nCase Report\nParkinsonism reversed from treatment of pineal non-germinomatous germ cell tumor\nCole Sydni M. 1smcole@bidmc.harvard.edu\n\nSarangi Sasmit 1sasmit.sarangi@Lifespan.org\n\nEinstein David 2deinstei@bidmc.harvard.edu\n\nMcMasters Malgorzata 3mmcmasters@mgh.harvard.edu\n\nAlterman Ron 4ralterma@bidmc.harvard.edu\n\nBruce Jeffrey 5jnb2@cumc.columbia.edu\n\nHertan Lauren 6lhertan@bidmc.harvard.edu\n\nShih Helen A. 7hshih@mgh.harvard.edu\n\nWong Eric T. 1ewong@bidmc.harvard.edu\n\n1 Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.\n2 Department of Hematology/Oncology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.\n3 Department of Hematology/Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States.\n4 Department of Neurosurgery, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States.\n5 Department of Neurosurgery, Columbia Presbyterian Medical Center, New York, United States.\n6 Department of Radiation Oncology, Beth Israel Deaconess Medical Center, United States.\n7 Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts, United States.\n* Corresponding author: Sydni M. Cole, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States. smcole@bidmc.harvard.edu\n2021\n25 5 2021\n12 23731 8 2020\n08 4 2021\nCopyright: © 2021 Surgical Neurology International\n2021\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-Share Alike 4.0 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.\nBackground:\n\nParkinsonism is a rare complication of non-germinomatous germ cell tumors (NGGCTs) arising from the pineal region.\n\nCase Description:\n\nWe describe a 23-year-old man who presented with Parinaud syndrome, fatigue, and hypersomnia that were caused by a pineal region NGGCT with yolk sac component and an initial α-fetoprotein (AFP) of 1011.0 ng/ml. MRI revealed that the tumor was causing 10 mm of midline shift and compressing the cerebral aqueduct, the left thalamus, and the midbrain. Obstructive hydrocephalus was relieved by ventriculoperitoneal shunting. Six cycles of induction chemotherapy with ifosfamide, carboplatin, and etoposide reduced tumor size and decreased AFP levels in both serum and cerebrospinal fluid. Following the first cycle, the patient developed asymmetric, bilateral Parkinsonism consisting of bradykinesia, bradyphrenia, facial hypomimia, drooling, and dysphagia. Levodopa, amantadine, and methylphenidate were administered and resulted in symptom improvement. Second look neurosurgery revealed residual yolk sac tumor and a second induction regimen of gemcitabine, paclitaxel, and oxaliplatin was administered for rising AFP. The patient eventually received an autologous bone marrow transplant using a regimen of high-dose carboplatin, thiotepa, and etoposide with concomitant colony-stimulating factor and romiplostim support followed by consolidative proton craniospinal radiotherapy. Posttreatment head MRI showed that no evidence of tumor growth and serum AFP was within normal limits. His Parkinsonism eventually resolved and he was weaned off all dopaminergic drugs.\n\nConclusion:\n\nBilateral Parkinsonism from NGGCT in this patient is probably caused by pressure on nigrostriatal tracts, substantia nigra, or both. The Parkinsonian symptoms can be reversed by aggressive treatment of the tumor and administration of dopaminergic drugs.\n\nGerm cell tumor\nParkinsonism\nPineal region tumor\n==== Body\nINTRODUCTION\n\nParkinsonism is a rare complication of germinomas and non-germinatous germ cell tumors (NGGCTs) arising from the pineal region. These pineal region tumors could directly cause this phenomenon by rostral-caudal extension and compression of the substantia nigra pars compacta in the midbrain and projections in the nigrostriatal tract to the dorsal stratum.[3] A more common etiology is likely from hydrocephalus caused by compression of the cerebral aqueduct and subsequent enlargement of the third ventricle, presumably stretching the nigrostriatal and nigropallidal tracts.[13] Hydrocephalus-induced Parkinsonism has been well-described and it is potentially reversible by relief of fluid pressure from the ventricular system.[11] Regardless, resection of the pineal region tumor is an important intervention to reverse this type of Parkinsonism.\n\nNGGCTs are sub-classified as “secretory” and “nonsecretory” based on the measurable α-fetoprotein (AFP) and β-human chorionic gonadotropin tumor markers in the cerebrospinal fluid, serum, or both.[4,9] Typical presenting symptoms include obstructive hydrocephalus and Parinaud’s syndrome, which are potentially reversible when timely intervention is administered.[4] In this case report, we describe a patient with AFP-secreting NGGCT who presented with asymmetric, bilateral Parkinsonism that was reversed by combined modality treatments consisting of tumor resection, cerebrospinal fluid shunting, multiple cytotoxic chemotherapies, and consolidative proton radiotherapy. Videos of the patient’s Parkinsonian state and recovery are also presented.\n\nCASE PRESENTATION\n\nA 23-year-old Caucasian man with history of idiopathic hepatic abscess complicated by portal vein thrombosis developed headache, blurry vision, fatigue, and hypersomnia up to 14 hours of sleep daily. Initial neurologic examination was notable for Parinaud’s syndrome characterized by sluggish pupils, bilateral end-gaze nystagmus, and impaired upgaze. Gadolinium-enhanced head MRI revealed a pineal region mass causing 10 mm of midline shift and compressing the cerebral aqueduct, the left thalamus, and the midbrain [Figure 1], requiring an immediate ventriculoperitoneal shunt for treatment of obstructive hydrocephalus. The patient also had thrombocytopenia caused by platelet sequestration from an enlarged spleen secondary to portal vein hypertension. He was supported with romiplostim and platelet transfusion. Tissue was eventually obtained from a stereotaxic biopsy and the diagnosis was NGGCT with yolk sac component, but without embryonal tissue, choriocarcinoma, or teratoma. The tumor grew quickly and nearly doubled in size in 3 weeks [Figure 2]. He was treated with induction ifosfamide, carboplatin, and etoposide for 6 cycles resulting in partial reduction of the tumor. His serum and cerebrospinal fluid AFP dropped from a high of 1011.0 to 3.6 ng/ml and 677.9 to 0.6 ng/ml, respectively. Before initiation of cytotoxic chemotherapy, the tumor had an increase in size from 34 × 28 × 23 mm to 48 × 32 × 37 mm, but decreased after induction to 24 × 18 × 23 mm.\n\nFigure 1: Initial presentation of non-germinatous germ cell tumor causing obstructive hydrocephalus. Gadolinium-enhanced T1-weighted head MRI in the axial (a), coronal (c), and sagittal (d) axes performed at presentation showed a pineal region tumor compressing the tectum and causing obstructive hydrocephalus. The FLAIR image in the axial plane (b) revealed some edema in the midbrain.\n\nFigure 2: Rapid growth of non-germinatous germ cell tumor displacing the left substantia nigra and rostral-caudal fibers from midbrain. Gadolinium-enhanced T1-weighted head MRI in the axial (a), coronal (e), and sagittal (f) axes performed before initiation of treatment showed a heterogeneously enhancing mass arising from the pineal region and measuring 34 × 28 × 23 mm. It caused 10 mm of midline shift and extended anteriorly into the left thalamus. The tumor extended caudally into the midbrain on the left exerted pressure medially and anteriorly (c). Diffusion tensor imaging showed that the rostral-caudal fibers (blue color) from the midbrain were displaced anteriorly and laterally on the left and laterally on the right at the pineal (b) and midbrain (d) levels.\n\nThe patient’s bilateral Parkinsonism developed after the first dose of induction carboplatin and etoposide, consisting of bradykinesia, bradyphrenia, facial hypomimia, drooling, and dysphagia requiring a gastric tube for feeding. The right side of his body was more severely affected than the left [Video 1]. His Parinaud’s syndrome and diffuse hyperreflexia also persisted during this time. Levodopa, amantadine, and methylphenidate were administered and titrated to maximal symptom improvement [Video 2]. When the tumor size was reduced by induction chemotherapies, the patient became less Parkinsonian and required fewer medications. Intensive physical and occupational therapies also helped improve his mobility.\n\nVideo 1: Shuffling gait and bradykinesia from asymmetric Parkinsonism. This video was obtained after 1 cycle of induction ifosfamide, carboplatin, and etoposide.\n\nVideo 2: Marked bradykinesia in upper extremities from asymmetric Parkinsonism. This video was obtained after 6 cycles of induction ifosfamide, carboplatin, and etoposide. The nongerminatous germ cell tumor was only partially reduced in size.\n\nHis Parkinsonism improved further after second-look neurosurgery, which achieved near total cytoreduction [Figure 3] and revealed residual yolk sac tumor. During recovery, his AFP began to rise again to a high of 134.6 ng/ml. He received a second induction regimen of gemcitabine, paclitaxel, and oxaliplatin followed by apheresis collection of CD34+ stem cells. An autologous transplant was performed using conditioning high-dose carboplatin, thiotepa, and etoposide with concomitant colony-stimulating factor and romiplostim to support his granulocytes and platelets, respectively. His stem cells engrafted promptly in the marrow on posttransplant day 13, enabling him to discontinue growth factor support. His posttransplant head MRI showed no evidence of tumor growth and his serum AFP was within normal limits. He later received consolidative proton beam radiotherapy on posttransplant day 48 for 6 weeks to the craniospinal space. He was completely weaned off all dopaminergic drugs 5 months after his second-look surgery.\n\nFigure 3: Second-look neurosurgical resection achieved additional cytoreduction. Gadolinium-enhanced T1-weighted head MRI obtained 1 day after surgery in the axial (a), coronal (c), and sagittal (d) axes, as well as T2-weighted image in the axial plane (b), demonstrated tumor cytoreduction and relief of compression on the tectum and the midbrain.\n\nThe patient remains in remission 2 years after transplant. At the time of this case report, the patient is able to perform all activities of daily living. He is able to participate in sporting activities such as jogging [Video 3], waterskiing [Video 4], and snowboarding. Consent was obtained from the patient to share videos of his Parkinsonism and subsequent recovery.\n\nVideo 3: Resumption of activities of daily living. The patient remains healthy and was able to jog 9 months after completion of bone marrow transplant and consolidative craniospinal proton beam radiotherapy. He is able to perform all activities of daily living.\n\nVideo 4: Resumption of swimming and water sports. This video was obtained 2 months after bone marrow transplant and consolidative craniospinal proton beam radiotherapy. He was able to participate in sports such as waterskiing (video) and snowboarding (not shown).\n\nDISCUSSION\n\nCentral nervous system germ cell tumors are rare, with an incidence of 0.10/100,000 in the United States[5] and belong to a spectrum of extragonadal germ cell malignancies. They are heterogeneous in histologies and are classified according to the revised 2016 WHO classification as germinomas and NGGCTs. Compared to germinomas, NGGCTs tend to be more aggressive and carry a poorer prognosis due to their resistance to treatment with chemotherapy and radiation, and there are no efficacy data for targeted agents or immunotherapies.[1,8] Therefore, combined modality cytotoxic chemotherapies, bone marrow transplant, and consolidative craniospinal radiotherapy are still the standard treatments.[1,6,10]\n\nThe presenting symptoms of intracranial germ cell tumors are related to their location in the midline near the pineal and suprasellar regions.[7] For tumors arising near the vicinity of the pineal gland, as in our patient, initial symptoms are often those of obstructive hydrocephalus, such as headache, vomiting, and papilledema, as well as symptoms of Parinaud syndrome from compression of the tectum.\n\nDysfunction of the left substantia nigra, nigrostriatal tracts, and subsequent decreased dopaminergic input to the respective striatum is most likely the cause of our patient’s bilateral Parkinsonism. It is important to note that his motor manifestations were asymmetric and his right side was more severely affected than the left, consistent with a contralateral (left-sided) nigrostriatal localization. The pretreatment diffusion tensor imaging (DTI) revealed that the rostral-caudal fibers from the midbrain were displaced anteriorly and laterally by the portion of NGGCT located in the left thalamus [Figure 1b]. Some of these fibers could be nigrostriatal tracts. Zhang et al.[14] performed DTI studies on patients suffering from Parkinson’s disease and found that signals from the nigrostriatal and nigropallidal tracts were decreased in quantity compared to controls. In our patient, the more severe displacement of the nigrostriatal fibers and/or direct mass effect on the left midbrain and left substantia nigra by the tumor are likely responsible for our patient’s asymmetric Parkinsonism.[2] There could have been additional contributions from evolving ventricular dilation on the right-sided nigrostriatal fibers; however, the asymmetry of the presentation would suggest that direct tumor-related effects on the left midbrain and thalamus were the predominant inciting factor.\n\nLevodopa treatment improved our patient’s secondary Parkinsonism. Using positron emission tomography, Racette et al.[11] demonstrated reduced uptake of 18F dopa in the caudate and anterior putamen of a patient suffering from hydrocephalus-induced Parkinsonism. Reversal of the decreased dopaminergic input is most likely the reason behind the improvements observed in the motor functions of our patient after treatment with levodopa and, to a lesser extent, with methylphenidate and amantadine. Ultimately, the treatment needed to reverse the Parkinsonism is chemotherapy to rapidly reduce tumor size and provide relief of substantia nigra and nigrostriatal fiber compression directly by the tumor, indirectly from the dilated third ventricle, or both.\n\nOur patient’s Parkinsonism appeared after his first dose of chemotherapy. We suspect that this is related to the cytotoxic effects of the chemotherapeutic agents. Cytotoxic chemotherapy can cause abrupt tumor swelling as cells undergo apoptosis, which may have precipitated the onset of the patient’s Parkinsonism. With ongoing chemotherapy, he began to have an improvement in his Parkinsonism and this improved substantially after second-look surgery. We speculate that in his case, surgery was able to relieve pressure on the substantia nigra and nigrostriatal fibers to a greater extent than chemotherapy. This patient’s younger age and motivation to participate in rehabilitation also aided his recovery, which resulted in his ability to perform all activities of daily living and participate in sports.\n\nThere are other case reports that describe Parkinsonism associated with pineal masses.[3,12] Both speculate Parkinsonism as associated with compression relating to dysfunction of the nigro-striatal-pallidal system. To the best of our knowledge, there are no published case reports that include videos demonstrating the Parkinsonism associated with pineal gland tumors. The striking improvement in symptoms can be best appreciated by video and offers an example to future clinicians regarding the degree of recovery that is possible.\n\nCONCLUSION\n\nThis case illustrates that aggressive treatments can reverse Parkinsonism from NGGCT, improve disease control, and restore overall quality of life. While poor functional status can be considered as a negative outcome predictor in brain tumors, this should be interpreted in the overall neurological context of the patient and can be potentially reversible.\n\nAcknowledgment\n\nWe would like to thank Jonathan L Finlay, MB, ChB, FRCP from the Nationwide Children’s Hospital and The Ohio State University College of Medicine for his expertise and advice.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nVideos available on:\n\nwww.surgicalneurologyint.com\n\nHow to cite this article: Cole SM, Sarangi S, Einstein D, McMasters M, Alterman R, Bruce J, et al. Parkinsonism reversed from treatment of pineal non-germinomatous germ cell tumor. Surg Neurol Int 2021;12:237.\n==== Refs\nREFERENCES\n\n1 Calaminus G Frappaz D Kortmann RD Krefeld B Saran F Pietsch T Outcome of patients with intracranial nongerminomatous germ cell tumors-lessons from the SIOP-CNSGCT-96 trial Neuro Oncol 2017 19 1661 72 29048505\n2 Curran T Lang AE Parkinsonian syndromes associated with hydrocephalus: Case reports, a review of the literature, and pathophysiological hypotheses Mov Disord 1994 9 508 20 7990846\n3 Dolendo MC Lin TP Tat OH Chong QT Timothy LK Parkinsonism as an unusual presenting symptom of pineal gland teratoma Pediatr Neurol 2003 28 310 2 12849888\n4 Fetcko K Dey M Primary central nervous system germ cell tumors: A review and update Med Res Arch 2018 6 1719 30271875\n5 Gittleman H Cioffi G Vecchione-Koval T Ostrom QT Kruchko C Osorio DS Descriptive epidemiology of germ cell tumors of the central nervous system diagnosed in the United States from 2006 to 2015 J Neurooncol 2019 143 251 60 31025275\n6 Goldman S Bouffet E Fisher PG Allen JC Robertson PL Chuba PJ Phase II trial assessing the ability of neoadjuvant chemotherapy with or without second-look surgery to eliminate measurable disease for nongerminomatous germ cell tumors: A children‘s oncology group study J Clin Oncol 2015 33 2464 71 26101244\n7 Jennings MT Gelman R Hochberg F Intracranial germ-cell tumors: Natural history and pathogenesis J Neurosurg 1985 63 155 67 2991485\n8 Lo AC Hodgson D Dang J Tyldesley S Bouffet E Bartels U Intracranial germ cell tumors in adolescents and young adults: A 40-year multi-institutional review of outcomes Int J Radiat Oncol Biol Phys 2020 106 269 78 31654785\n9 McCarthy BJ Shibui S Kayama T Miyaoka E Narita Y Murakami M Primary CNS germ cell tumors in Japan and the United States: An analysis of 4 tumor registries Neuro Oncol 2012 14 1194 200 22869621\n10 Mokhtech M Rotondo RL Bradley JA Sandler ES Nanda R Logie N Early outcomes and patterns of failure following proton therapy for nonmetastatic intracranial nongerminomatous germ cell tumors Pediatr Blood Cancer 2018 65 e26997 29380526\n11 Racette BA Esper GJ Antenor J Black KJ Burkey A Moerlein SM Pathophysiology of parkinsonism due to hydrocephalus J Neurol Neurosurg Psychiatry 2004 75 1617 9 15489399\n12 Vhora S Kobayashi S Okudera H Pineal cavernous angioma presenting with Parkinsonism J Clin Neurosci 2001 8 263 6 11386804\n13 Wakai S Nakamura K Niizaki K Nagai M Nishizawa T Yokoyama S Meningioma of the anterior third ventricle presenting with parkinsonism Surg Neurol 1984 21 88 92 6689817\n14 Zhang Y Wu IW Buckley S Coffey CS Foster E Mendick S Diffusion tensor imaging of the nigrostriatal fibers in Parkinson‘s disease Mov Disord 2015 30 1229 36 25920732\n\n",
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"journal": "Surgical neurology international",
"keywords": "Germ cell tumor; Parkinsonism; Pineal region tumor",
"medline_ta": "Surg Neurol Int",
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"pages": "237",
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"pubdate": "2021",
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"references": "22869621;31025275;31654785;11386804;6689817;26101244;29048505;2991485;7990846;25920732;15489399;29380526;12849888;30271875",
"title": "Parkinsonism reversed from treatment of pineal non-germinomatous germ cell tumor.",
"title_normalized": "parkinsonism reversed from treatment of pineal non germinomatous germ cell tumor"
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"abstract": "Latex responds for most allergic reactions in children, and repeated exposure to the agent is the main cause of sensitization. We report the case of a child allergic to latex who developed anaphylaxis during kidney transplantation performed in a latex-free environment. After immediate treatment with epinephrine the patient gradually improved. Subsequent investigation revealed that kidney harvesting was performed without latex allergy precautions, suggesting graft contamination by the antigen. We conclude that, for preventing this type of anaphylaxis, it is essential to implement latex-free procedures during donor organ harvesting.",
"affiliations": "Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil; Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Belo Horizonte, MG, Brazil. Electronic address: fernandesmagda@yahoo.com.br.;Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.;Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.;Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil.;Hospital Governador Israel Pinheiro (IPSEMG), Belo Horizonte, MG, Brazil.",
"authors": "Fernandes|Magda Lourenço|ML|;Pessoa|Daniel Werneck|DW|;Del'Asta|Isadora|I|;Oliveira|Mirella Pereira|MP|;Moreira|Lúcio Lourenço|LL|",
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"fulltext": "\n==== Front\nBraz J Anesthesiol\nBraz J Anesthesiol\nBrazilian Journal of Anesthesiology\n0104-0014\n2352-2291\nElsevier\n\nS0104-0014(20)30213-X\n10.1016/j.bjane.2020.12.010\nCase Reports\nLatex anaphylaxis in a recipient child during kidney transplant performed in a latex-free environment: case report☆\nFernandes Magda Lourenço fernandesmagda@yahoo.com.br\nab*\nPessoa Daniel Werneck a\nDel’Asta Isadora a\nOliveira Mirella Pereira a\nMoreira Lúcio Lourenço c\na Santa Casa de Belo Horizonte, Belo Horizonte, MG, Brazil\nb Universidade Federal de Minas Gerais (UFMG), Hospital das Clínicas, Belo Horizonte, MG, Brazil\nc Hospital Governador Israel Pinheiro (IPSEMG), Belo Horizonte, MG, Brazil\n⁎ Corresponding author. fernandesmagda@yahoo.com.br\n28 12 2020\nJan-Feb 2021\n28 12 2020\n71 1 7678\n2 10 2019\n18 10 2020\n© 2020 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda.\n2020\nSociedade Brasileira de Anestesiologia\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/).\nLatex responds for most allergic reactions in children, and repeated exposure to the agent is the main cause of sensitization. We report the case of a child allergic to latex who developed anaphylaxis during kidney transplantation performed in a latex-free environment. After immediate treatment with epinephrine the patient gradually improved. Subsequent investigation revealed that kidney harvesting was performed without latex allergy precautions, suggesting graft contamination by the antigen. We conclude that, for preventing this type of anaphylaxis, it is essential to implement latex-free procedures during donor organ harvesting.\n\nKeywords\n\nHypersensitivity to latex\nAnaphylaxis\nKidney transplantation\nOrgan donor\nCase report\n==== Body\npmcIntroduction and objectives\n\nLatex represents the leading cause of anaphylaxis in the pediatric population, and repeated exposure to latex products is the main cause of sensitization to this antigen.1 Therefore a past medical history with multiple procedures, such as of patients with urological malformations, is more prone to present this condition. Latex sensitization refers to the presence of circulating IgE antibodies against latex, while allergy refers to any immune-mediated reaction to latex.2 In sensitized patients, a latex-free environment is mandatory at all steps of perioperative management. Even though it seems obvious that for patients being submitted to transplant surgery, this tenet should also be extended to the donor, there is little information highlighting the importance of this routine, which now and then is overlooked. The present report aims to discuss the management of a kidney transplant recipient with a past medical history of latex allergy and the implications for donor management considering this aspect.\n\nCase report\n\nThe patient was a male, eight-year old, 28 kg, with chronic renal failure secondary to obstructive nephropathy due to posterior urethral valve with bilateral vesicoureteral reflux. Past medical history revealed continuing moderate bronchial asthma, several urinary tract surgical procedures, and during a previous surgery, an episode of severe allergic latex-related reaction as revealed by a positive test performed at the time. The child was admitted to our hospital to be submitted to a deceased-donor kidney transplant. The operating room was prepared abiding latex allergy precautions. The patient was monitored with electrocardiography, capnography and gas analyzer, pulse oximetry, invasive arterial pressure, and central venous pressure. Then, 1 g of cefazolin was administered, and anesthetic induction was performed with 75 μg of fentanyl, 4.2 mg of cisatracurium and sevoflurane. Anesthesia was maintained with sevoflurane inhalation and no other anesthetic or adjuvant drug was administered. Anesthesia progressed with patient showing no respiratory changes and with hemodynamic stability, with mean blood pressure kept around 75 mmHg, and heart rate around 90 beats per minute just to the beginning of the kidney graft implant. During vascular anastomosis, a low dose of norepinephrine (0.05 μg-1. kg-1. min-1) was initiated to ensure higher blood pressure levels during graft reperfusion. Roughly five minutes after transplanted kidney reperfusion, the patient developed severe bronchospasm, low peripheral oxygen saturation, rhonchi and wheezing on pulmonary auscultation, tachycardia and hypotension. The dose of norepinephrine was increased, with no response. Then, administration of 200 μg bolus of epinephrine started, with partial respiratory improvement and increase in blood pressure, therefore a continuous infusion of epinephrine (0.2 to 0.6 μg-1 kg-1. min-1) was maintained. The patient persisted with moderate bronchospasm and 30 mg of ketamine was associated. Then he underwent gradual clinical improvement, and, at the end of the surgery, was referred to the intensive care center intubated, sedated, receiving continuous infusion of epinephrine (0.4 μg-1 kg-1 min-1), with no diuresis. The patient remained hemodynamically dependent of epinephrine support, and infusion discontinuation was possible only after 48 hours. He presented progressive clinical improvement and hemodynamic stability. A new laboratory test for latex specific IgE was performed on the first postoperative day and showed high levels (8.2 kUA.L-1). The patient began to present diuresis from the third postoperative day, with gradual improvement in renal function. He was extubated on the seventh postoperative day and was discharged three days later. Serum creatinine reached levels of 0.78 mg.dL-1 in the third month after surgery. After more than one-year regular follow-up at our hospital, the patient remains with adequate renal function. The child`s guardian signed a consent form agreeing with the anonymous case report.\n\nDiscussion\n\nAlthough rare, latex reaction can lead to death even when properly managed. It is crucial to implement preventive measures for such events. Nonetheless, adopting a latex-free environment, the key recommendation for managing sensitized patients, was not enough to avert the severe anaphylaxis reported here.\n\nThe diagnosis of anaphylaxis is mostly clinical and based on the classic triad of cardiovascular collapse, wheezing and skin rash, but symptoms can vary from simple skin manifestations to cardiorespiratory arrest. If the causal agent has been administered intravenously, clinical signs start within 5 to 10 minutes, or within seconds in the most severe cases. On the other hand, when resulting from latex exposure, anaphylaxis usually starts later, as it follows a cutaneous-mucous contact.3 In the case reported, the patient presented hemodynamic and respiratory signs consistent with the diagnosis of anaphylaxis, and the reaction started immediately after reperfusion, suggesting more direct contact of the antigen with circulation than with a cutaneous-mucous surface. This information, associated with the fact that patient care was being performed in a latex-free environment, could pose a disadvantage to the hypothesis of latex as the causal agent. But examination into donor organ harvesting found lack of latex allergy precautions. Thus, the organ was contaminated by the antigen, which reached the circulation at the time of reperfusion. A similar event was described by Jacqmarcq et al.4 They reported an adult patient who developed anaphylactic shock during a kidney transplant performed in a latex-free environment and discussed contamination of the graft, which was removed without latex allergy precautions. Given the recipient population comprises a group of patients undergoing various medical procedures and frequent hospitalizations, we could infer that a considerable number of them is at higher risk of latex allergy. Conversely, there seems to be no special concern with this aspect in Brazil, as no investigation into latex allergy is routinely carried out for receptors. Likewise, there is no special regulation in the donor-recipient processes of management when a recipient has latex allergy. Therefore, based on the experience presented here and the discussion above, we suggest the implementation of a latex-free environment during the harvesting and handling of organs intended for transplantation. In addition, latex sensitization, using skin and serological tests, should be recommended for recipients. In the case of sensitized recipients, the professionals involved in the process need to be alerted to ensure that latex-free care is extended to the donor.\n\nIn the diagnostic investigation of anaphylactic reactions to latex, some laboratory tests are useful. The chief immune mechanism of anaphylaxis is mediated by specific IgE class antibodies, which results in mast cell and basophil activation, and in the rapid release of pre-formed mediators, such as tryptase and histamine. Thus, measuring IgE and the mediators can help confirm the diagnosis. Tryptase peaks in approximately 30 minutes, then gradually decreases. It has a half-life of two hours, which is the ideal time for its measurement, although it can persist for several hours, or even days, depending on the intensity of reaction. Histamine is not routinely measured because of its short half-life, and ideally should be collected from blood in the first minutes of the reaction, and from urine within 24 hours after reaction.2 In the case in question, the patient had a previous diagnosis of latex allergy and, due to the unavailability of other tests, only IgE specific for latex was measured. This test has high specificity, but low sensitivity,2 which certainly represented a limiting factor for diagnosis confirmation and, therefore, in the implications of the case.\n\nThus, it is important to highlight the differential diagnoses that were considered. The first, allergy to other drugs. This suspicion was considered unlikely, given that no drugs, including antibiotics and muscle relaxants, were administered in the moments preceding the reaction. Asthma attack would be another hypothesis; however, bronchospasm was not seen during anesthesia until that moment, and the symptoms of the patient were not only respiratory. Finally, the most relevant differential diagnosis would be post-reperfusion syndrome. This is classically characterized by bradycardia, hypotension and increased cardiac filling pressures. Criteria for its diagnosis include reduction in blood pressure to values less than 30% from baseline, with a minimum duration of one minute, occurring within the first five minutes after reperfusion.5 Although such hemodynamic instability was observed, other cardiovascular changes were also observed, such as tachycardia and bronchospasm, which favor the diagnosis of latex allergy more. Moreover, post-reperfusion syndrome during kidney transplant is rare, estimated at 4%.5\n\nIn the treatment of anaphylaxis, fast intervention is essential for a favorable outcome. Epinephrine is the recommended drug because it has inotropic and chronotropic effects. It also prevents or reduces mucosal edema, promotes bronchodilation, and suppresses the release of mast cell and basophil mediators. Intravenous doses of 5 to 10 μg.kg-1 are recommended in cases of mild to moderate hypotension, titrated according to results. Larger doses or continuous infusion (0.1 to 1.0 μg-1 kg-1 min-1) may be required in the face of cardiovascular collapse.1, 2 In the case reported, high doses were necessary and the infusion had to be maintained for 48 hours, period of time for likely elimination of the causal antigen.\n\nConclusion\n\nSpecial care is requested when managing donor/recipient regarding latex-related risks. The correct approach seeks to avert allergic reactions during surgery, including anaphylaxis, to improve outcomes. As to the recipient, it is essential to identify individuals sensitized to implement latex-free care. As for the donor, we recommend routine harvesting and handling of organs intended for transplant in a latex-free environment.\n\nConflicts of interest\n\nThe authors declare no conflicts of interest.\n\n☆ Institution: Santa Casa de Belo Horizonte.\n==== Refs\nReferences\n\n1 Provinciael S. Saldien V. Hans G. Vercauteren M. Perioperative allergy and anaphylaxis in children: a review Acta Anaesth Belg. 69 2018 13 24\n2 Hepner D.L. Castells M.C. Latex allergy: an update Anesth Analg. 96 2003 1219 1229 12651689\n3 Hepner D.L. Castells M.C. Anaphylaxis during the perioperative period Anesth Analg. 97 2003 1381 1395 14570656\n4 Jacqmarcq O. Karila C. Carli P. Latex-induced anaphylactic shock following graft reperfusion during renal transplantation Ann Fr Anesth Reanim. 24 2005 547 550 15904735\n5 Bruhl S.R. Vetteth S. Rees M. Grubb B.P. Khouri S.J. Post-reperfusion syndrome during renal transplantation: a retrospective study Int J Med Sci. 9 2012 391 396 22859898\n\n",
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"issue": "71(1)",
"journal": "Brazilian journal of anesthesiology (Elsevier)",
"keywords": "Anaphylaxis; Case report; Hypersensitivity to latex; Kidney transplantation; Organ donor",
"medline_ta": "Braz J Anesthesiol",
"mesh_terms": "D000707:Anaphylaxis; D002648:Child; D004837:Epinephrine; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D020315:Latex Hypersensitivity",
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"title": "Latex anaphylaxis in a recipient child during kidney transplant performed in a latex-free environment: case report.",
"title_normalized": "latex anaphylaxis in a recipient child during kidney transplant performed in a latex free environment case report"
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"abstract": "In this report we describe a 53-year-old woman with advanced non-small cell lung cancer, treated with pemetrexed and cisplatin combination therapy, followed by pemetrexed monotherapy. The patient developed severe muscle spasms at least twice, shortly after administration of pemetrexed monotherapy. A possible explanation for this observation is that in combination with cisplatin therapy, the patient was hyperhydrated before administration to promote renal excretion and reduce toxicity. Pemetrexed is also renally excreted, which supports the finding that toxicity did not occur when the patient was hyperhydrated. After discontinuation of pemetrexed the symptoms did not reoccur. All aspects of this case point to a possible relationship between pemetrexed and an adverse drug reaction (ADR). We conclude that muscle spasms are a rare, but possibly dose-related ADR of pemetrexed-based therapy.",
"affiliations": "ZANOB Pharmacy Jeroen Bosch Hospital, 5203 DK 's-Hertogenbosch, 3406, The Netherlands.;Netherlands Pharmacovigilance Centre - Lareb, 's-Hertogenbosch, The Netherlands.;Department of Pulmonary Diseases, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands.;ZANOB Pharmacy Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands Utrecht Institute for Pharmaceutical Sciences, Division of Pharmacoepidemiology & Clinical Pharmacology, Utrecht University, Utrecht, The Netherlands.",
"authors": "de Rouw|Hendrika J A|HJ|;Jessurun|Naomi T|NT|;Masen-Poos|Lucie J P|LJ|;Derijks|Hieronymus J|HJ|",
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"keywords": "adverse drug reaction; muscle spasms; non-small cell lung cancer; pemetrexed",
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"title": "Muscle spasms: an unexpected adverse drug reaction of pemetrexed?",
"title_normalized": "muscle spasms an unexpected adverse drug reaction of pemetrexed"
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{
"abstract": "BACKGROUND\nAlendronate may relate to the incidence of cancers, especially esophageal and colon cancer. But the results are inconsistent in different studies.\n\n\nOBJECTIVE\nTo quantify the association between the use of alendronate and the occurrence of different types of cancer.\n\n\nMETHODS\nWe searched Embase, Pubmed, CENTRAL, SIGLE and clinicaltrials.gov, up to 2014 June.\n\n\nMETHODS\nCohort studies reporting association between alendronate or bisphosphonate therapy including alendronate in patients with osteoporosis and risk of cancer were selected by two authors.\n\n\nMETHODS\nTwo authors independently extracted the data. The Chi-square test and the I-square test were used for testing heterogeneity between studies.\n\n\nRESULTS\nEight cohort studies were included in the meta-analysis. Meta-analysis result manifested that alendronate significantly increased the incidence of lung cancer (HR 1.23, 95%CI 1.03 to 1.47, P value = 0.03), nevertheless, there was no significant difference after we excluded either Lee's 2012 study (HR 1.17, 95%CI 0.95 to 1.44, P value = 0.13) or Chiang's 2012 study (HR 1.47, 95%CI 1 to 2.17, P value = 0.05). For the incidence of colorectal cancer, no significant difference occurred (HR 0.91, 95%CI 0.74 to 1.13, P value = 0.39), but there was a positive relationship when we used fixed model (HR 0.85, 95%CI 0.78 to 0.93, P value = 0.004). For the incidence of liver cancer, there was no significant difference (HR 1.36, 95%CI 0.9 to 2.04, P value = 0.14), however, the result changed after we excluded Chiang's 2012 study (HR 1.69, 95%CI 1.03 to 2.77, P value = 0.04). There was no significant difference in other types of cancer.\n\n\nCONCLUSIONS\nBased on current evidences, alendronate therapy may be associated with a high risk of lung cancer, may with an excess risk of liver cancer, a low risk of colorectal and no related risk of other cancers.",
"affiliations": "Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.;Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.;Department of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People's Republic of China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People's Republic of China.;Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.;Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.;Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.;Internal Medicine of Traditional Chinese Medicine Department, Jing 'an District Central Hospital of Shanghai, NO. 259, Xikang Road, 200040, Shanghai, People's Republic of China.;Comprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, People's Republic of China.;Department of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People's Republic of China.",
"authors": "Chen|Ling-Xiao|LX|;Ning|Guang-Zhi|GZ|;Zhou|Zhi-Rui|ZR|;Li|Yu-Lin|YL|;Zhang|Di|D|;Wu|Qiu-Li|QL|;Zhang|Tian-Song|TS|;Cheng|Lei|L|;Feng|Shi-Qing|SQ|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "United States",
"delete": false,
"doi": "10.1371/journal.pone.0123080",
"fulltext": "\n==== Front\nPLoS OnePLoS ONEplosplosonePLoS ONE1932-6203Public Library of Science San Francisco, CA USA 2588130410.1371/journal.pone.0123080PONE-D-14-50708Research ArticleThe Carcinogenicity of Alendronate in Patients with Osteoporosis: Evidence from Cohort Studies The Carcinogenicity of AlendronateChen Ling-Xiao \n1\nNing Guang-Zhi \n1\nZhou Zhi-Rui \n2\n\n3\nLi Yu-Lin \n1\nZhang Di \n1\nWu Qiu-Li \n1\nZhang Tian-Song \n4\nCheng Lei \n5\nFeng Shi-Qing \n1\n*\n1 \nDepartment of Orthopaedics, Tianjin Medical University General Hospital, 154 Anshan Road, Heping District, Tianjin, 300052, People’s Republic of China\n\n2 \nDepartment of Radiation Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032, People’s Republic of China\n\n3 \nDepartment of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, People’s Republic of China\n\n4 \nInternal Medicine of Traditional Chinese Medicine Department, Jing 'an District Central Hospital of Shanghai, NO. 259, Xikang Road, 200040, Shanghai, People’s Republic of China\n\n5 \nComprehensive Cancer Center of Drum-Tower Hospital, Medical School of Nanjing University, Clinical Cancer Institute of Nanjing University, 321 Zhongshan Road, Nanjing, 210008, People’s Republic of China\nGoel Ajay Academic Editor\nBaylor University Medical Center, UNITED STATES\nCompeting Interests: The authors have declared that no competing interests exist.\n\nConceived and designed the experiments: LXC SQF. Performed the experiments: LXC GZN. Analyzed the data: ZRZ YLL. Contributed reagents/materials/analysis tools: DZ QLW TSZ LC. Wrote the paper: LXC.\n\n* E-mail: fengsq321@gmail.com16 4 2015 2015 10 4 e012308019 11 2014 27 2 2015 © 2015 Chen et al2015Chen et alThis is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.Context\nAlendronate may relate to the incidence of cancers, especially esophageal and colon cancer. But the results are inconsistent in different studies.\n\nObjective\nTo quantify the association between the use of alendronate and the occurrence of different types of cancer.\n\nData Sources\nWe searched Embase, Pubmed, CENTRAL, SIGLE and clinicaltrials.gov, up to 2014 June.\n\nStudy Selection\nCohort studies reporting association between alendronate or bisphosphonate therapy including alendronate in patients with osteoporosis and risk of cancer were selected by two authors.\n\nData Extraction\nTwo authors independently extracted the data. The Chi-square test and the I-square test were used for testing heterogeneity between studies.\n\nData Synthesis\nEight cohort studies were included in the meta-analysis. Meta-analysis result manifested that alendronate significantly increased the incidence of lung cancer (HR 1.23, 95%CI 1.03 to 1.47, P value = 0.03), nevertheless, there was no significant difference after we excluded either Lee’s 2012 study (HR 1.17, 95%CI 0.95 to 1.44, P value = 0.13) or Chiang’s 2012 study (HR 1.47, 95%CI 1 to 2.17, P value = 0.05). For the incidence of colorectal cancer, no significant difference occurred (HR 0.91, 95%CI 0.74 to 1.13, P value = 0.39), but there was a positive relationship when we used fixed model (HR 0.85, 95%CI 0.78 to 0.93, P value = 0.004). For the incidence of liver cancer, there was no significant difference (HR 1.36, 95%CI 0.9 to 2.04, P value = 0.14), however, the result changed after we excluded Chiang’s 2012 study (HR 1.69, 95%CI 1.03 to 2.77, P value = 0.04). There was no significant difference in other types of cancer.\n\nConclusion\nBased on current evidences, alendronate therapy may be associated with a high risk of lung cancer, may with an excess risk of liver cancer, a low risk of colorectal and no related risk of other cancers.\n\nThe authors have no support or funding to report. Data AvailabilityAll relevant data are within the paper and its Supporting Information files.Data Availability\nAll relevant data are within the paper and its Supporting Information files.\n==== Body\nIntroduction\nBecause of its effectiveness and low cost, alendronate is recommended as the first-line drug in the treatment of osteoporosis in postmenopausal women, older men and patients with glucocorticoid-induced osteoporosis [1–3]. In addition, it is used in the secondary prevention of osteoporotic fractures in postmenopausal women [4]. Alendronate has the ability to inhibit the activity of osteoclasts and decrease the bone turnover rate. However, its use is associated with the potential risks of upper gastrointestinal bleeding or ulcers and rare cases of cancer.\n\nIn recent years, several researchers have reported that the use of bisphosphonates (including alendronate) is related to the incidence of cancers, especially esophageal and colon cancers. However, the results are inconsistent. For example, some studies have shown that bisphosphonate use is associated with a high risk of the occurrence of esophageal cancer [5, 6], but no significant differences in the increasing risk was observed in other research [7, 8]. Another paradox is that although one study indicated that alendronate significantly reduced the incidence of colon cancer [9]; another study reported that low doses of alendronate significantly increased the incidence of colon cancer, while the results were reversed at high doses [5]; however, other studies have shown that there was no significant difference.\n\nThe relationship between the usage of alendronate and the incidence of cancers is important for guiding patients in the selection of osteoporosis treatments. Therefore, we performed this meta-analysis and systematic review of cohort studies to quantify the association between the use of alendronate and the occurrence of different types of cancer.\n\nMethods\nCriteria for considering studies\nThe studies were considered to be acceptable for inclusion in this article if they met the following criteria: (1) Participants: patients with osteoporosis; (2) Interventions and comparisons: alendronate or bisphosphonate therapy, including alendronate vs control groups; (3) Outcomes: the incidence of cancer (all-cause cancer, colorectal cancer, gastric cancer, esophageal cancer, liver cancer, pancreatic cancer, lung cancer, breast cancer, cervical cancer, bladder cancer, kidney cancer, oral cancer, ovarian cancer, endometrial cancer, prostate cancer, lymphoma, bile duct cancer and small intestine cancer); and (4) Study design: cohort studies.\n\nTrials were excluded if they (1) were abstracts, letters, or proceedings of meetings; (2) had repeated data or did not report outcomes of interest; (3) did not supply sufficient data about alendronate; or (4) were case-control studies.\n\nSearch strategy and study selection\nA Meta-analysis of Observational Studies in Epidemiology (MOOSE) [10] was used to perform this systematic review. We searched Embase (from 1974 to June 2014), PubMed (From 1966 to June 2014), the Cochrane Central Register of Controlled Trials (CENTRAL), SIGLE (System for Information on Grey Literature in Europe) and clinicaltrials.gov. Keywords and MeSH terms including “colorectal cancer”, “gastric cancer”, “esophagus cancer”, “liver cancer”, “pancreas cancer”, “lung cancer”, “breast cancer”, “cervical cancer”, “bladder cancer”, “kidney cancer”, “oral cancer”, “ovary cancer”, “endometrial cancer”, “prostate cancer”, “lymphoma”, “bile duct cancer”, “small intestine cancer”, “bisphosphonate”, “alendronate”, “osteoporosis”, “cohort” and “follow-up studies” were used in the search strategy. We also reviewed the reference list of each of the included studies for any relevant papers that had been omitted from the search.\n\nTwo authors independently performed the selections based on the title and abstract. Any disagreement between the two authors was resolved by a discussion. If there was no consensus, a third reviewer (Feng) was consulted. If two or more studies used the data from the same cohort, we included the newest and most detailed study.\n\nData extraction and quality assessment\nInformation about the study, country, sex, sample size, age, duration of follow-up, covariates in the adjusted model, measure of associations, categories of dosage and types of cancer were extracted for each included study. One of the authors entered the data into RevMan 5.3, after which another author checked all of the values. We used the Newcastle-Ottawa Scale (NOS) for assessing the quality of the studies included by the two authors. The scale, which has a total score of up to nine, includes three categories (selection, comparability and outcome) and eight entries (representativeness of the exposed cohort, selection of the nonexposed cohort, ascertainment of exposure, demonstration that outcome of interest was not present at start of study, comparability of cohorts on the basis of the design or analysis, assessment of outcome, was follow-up long enough for outcomes to occur and adequacy of follow-up of cohorts).\n\nStatistical methods\nWe made meta-analyses using Stata software (version 12.0, StataCorp, College Station, TX). Hazard ratios (HR) and 95% confidence intervals (CI) were used as a measure of the incidence of the cancers. The term DDD was used to indicate the defined daily dose, which has been proposed by WHO as a statistical measure of drug consumption. For alendronate, the value of the DDD was 10 mg. The Chi-square test and the I-square test were used to test the heterogeneity between the studies. If heterogeneity was not present (P>0.10, I2<50%), a fixed-effect model was adopted for the analysis; otherwise, the random-effect model was employed. Additionally, I2 was used to evaluate the heterogeneity (an I2 of more than 50% was considered to be high heterogeneity and an I2 of less than 25% was considered to be no heterogeneity[11]). If the I2 was more than 50%, sensitivity analyses were used to investigate the origin of the heterogeneity. The funnel plot was used to identify a possible publication bias if the number of studies was larger than 10.\n\nThere was no protocol.\n\nResults\nStudy Identification and selection\nThe PRISMA flow diagram of the selection of the studies is depicted in Fig 1. The search was performed on June 8th, 2014, and 237 records were identified in the primary search and 4 records were identified from other sources. After the removal of 126 duplicate references, 115 records were screened. Twelve of the publications were eligible for inclusion, and the others were not selected for various reasons (e.g., studies without a control group or publications not related to the incidence of cancer). A total of 8 studies were included in the qualitative synthesis, and the data on these studies were included in the meta-analysis [5, 9, 12–17]. Four of the studies were excluded because the available data on alendronate could not be extracted [6–8, 18].\n\n10.1371/journal.pone.0123080.g001Fig 1 PRISMA flow diagram for study identification and inclusion.\nStudy characteristics\n\nTable 1 provides a summary of the studies included in the review. The duration of the follow-up ranged from 2.8 years to 12 years. Five of the studies included women, and the other studies included both men and women. Four studies were conducted in Denmark, two in Taiwan, one in the UK and one in the USA. The dates of publication were between 2010 and 2013. Three of the studies that included men and women had been adjusted for gender. Five of the studies were adjusted for age, and in two studies, no adjustment was made because all of the participants were the same age. Four of the studies were adjusted for NSAID prescriptions, four for alcohol consumption, two for proton pump inhibitor (PPI) use, two for the amount of prednisolone administered, two for the Charlson index and two for BMI. Other adjust factors included known ulcerative colitis, known Crohn’s disease, known coeliac disease, smoking, Barretts esophagus, working or not, married or not, income above vs. below median (112,000 DKK/year), gastric surgery before, education, irradiation, chemotherapy, physical activity, estrogen-only use, estrogen-progestin use, history of endoscopy, history of mammography, total calcium intake, total vitamin D intake, and 5-year hip fracture probability and they were referred only one time.\n\n10.1371/journal.pone.0123080.t001Table 1 Characteristics of studies included in meta-analysis.\nStudy\tCountry\tSex\tSample size\tAge Years\nb\n\n\tFollow-up Years\nb\n\n\tNOS\tTypes of cancer\t\nAbrahamsen 2012\na\n\n\tDenmark\tW\t153030\t71.9 (10)\t3.5 (1–11)\t6\t1–3\t\nCardwell 2010\tUK\tM/W\t81369(py)\t70 (11.4)\t4.5(2.6)/4.4(2.6)\t8\t1–2\t\nChiang 2012\tTaiwan\tW\t27603\t73.4 (8.4)/73.5 (8.4)\t4.3(2.5)/4.9(2.6)\t6\t1–8\t\nLee 2012\tTaiwan\tM/W\t21918\tNot mentioned\t2.92/3.04\t7\t1–7\t\nVestergaard (A) 2011\tDenmark\tM/W\t215142\t70.5 (11.4)\t2.8\t6\t1、3–4、8\t\nPassarelli 2013\tUSA\tW\t102219(py)\t63.1 (7.2)/67.2 (6.4)\t12\t8\t3\t\nVestergaard(B) 2011\tDenmark\tW\t306494\t71.7 (10.7)\tNot mentioned\t6\t6\t\nW: women, M: man, py: person years, NOS: Newcastle-Ottawa Scale, 1: Esophageal, 2: gastric, 3: colorectal, 4: liver, 5: lung, 6: breast, 7: cervical, 8: pancreatic.\n\nFor age and follow up, the left of the oblique line represents alendronate group and the right represents control group.\n\n\naPazianas 2012 is the other publication of the study.\n\n\nb For years, the numbers in the parenthesis represent standard deviation or range.\n\nThe average score of the studies’ quality was 6.7, and all of the studies had a score greater than 6. Two studies were regarded as having mild selection bias [15, 16]. Two of the studies were considered as having moderate comparability because they were only adjusted for two factors [13, 14]. Four included studies were judged as having mild outcome bias [5, 14–16].\n\nIncidence of lung cancer\nThe incidence of lung cancer was investigated in two studies, with a total of 49521 participants and 609 cancer patients. The pooled estimate of the two studies [13, 14] indicated that the incidence of lung cancer significantly increased in the alendronate groups in comparison with the control groups (HR 1.23, 95%CI 1.03 to 1.47, P value = 0.03, I2 = 4%) (Fig 2).\n\n10.1371/journal.pone.0123080.g002Fig 2 Forest plot of the incidence of lung cancer.\nLee et al. [13] reported that there was a strong positive relationship between the use of alendronate and the incidence of lung cancer (HR 3.07, 95%CI 1.97 to 4.76, P value<0.001) when the dosage was ≥1.0 g/per year. There was no significant difference in the other dosage amounts.\n\nIncidence of all-cause cancer\nThe pooled estimate of four studies [13–15, 17] indicated that there was no significant difference in the incidence of all-cause cancer between the alendronate groups and the control groups (HR 0.94, 95%CI 0.78 to 1.12, P value = 0.48, I2 = 73%) (S1 Fig).\n\nLee et al. [13] indicated that there was a strong positive relationship between the use of alendronate and the incidence of all-cause cancer (HR 1.69, 95%CI 1.39 to 2.04, P value<0.001) when the dosage was ≥1.0 g/per year. However, Abrahamsen et al. [15] showed that the use of alendronate significantly decreased the incidence of all-cause cancer (HR 0.44, 95%CI 0.27 to 0.69) when the number of prescriptions were ≥10. There was no significant difference for the other types of dosages.\n\nIncidence of colorectal cancer\nThe pooled estimate of five studies [5, 9, 12–14] indicated that there was no significant difference in the incidence of colorectal cancer (HR 0.91, 95%CI 0.74 to 1.13, P value = 0.39, I2 = 80%) (S2 Fig).\n\nVestergaard et al. [5] showed that the use of alendronate significantly increased the incidence of colorectal cancer at a low daily dosage (DDD≤0.66, HR 1.44, 95%CI 1.08 to 1.93) and at a medium daily dosage (DDD = 0.67–0.99, HR 1.49, 95%CI 1.08 to 2.04); however, alendronate significantly decreased the incidence of colorectal cancer at high dosages (DDD≥1, HR 0.3, 95%CI 0.14 to 0.63). Vestergaard et al. [5] also reported that the use of alendronate significantly increased the incidence of colorectal cancer when the accumulated dose was ≤365 DDD (HR 1.49, 95%CI 1.07 to 2.06). There was no significant difference in the other types of dosages.\n\nIncidence of gastric cancer\nThe pooled estimate of four studies [5, 13–15] indicated that there was no significant difference in the incidence of gastric cancer (HR 0.86, 95%CI 0.67 to 1.10, P value = 0.22, I2 = 24%) (S3 Fig).\n\nVestergaard et al. [5] reported that the use of alendronate significantly increased the incidence of gastric cancer when the accumulated dose ranged from 366 DDD to 730 DDD (HR 3.11, 95%CI 1.03 to 9.34). There was no significant difference in the other types of dosages.\n\nIncidence of esophagus cancer\nThe pooled estimate of five studies [5, 13–15, 17] indicated that there was no significant difference in the incidence of esophageal cancer (HR 1.07, 95%CI 0.7 to 1.64, P value = 0.75, I2 = 52%) (S4 Fig).\n\nVestergaard et al. [5] showed that the use of alendronate significantly increased the incidence of esophageal cancer at a low dosage (DDD≤0.66, HR 3.19, 95%CI 1.4 to 7.29). Moreover, Vestergaard et al. [5] reported that the use of alendronate significantly increased the incidence of esophageal cancer when the accumulated dose was ≤365 DDD (HR 4.45, 95%CI 1.93 to 10.3). There was no significant difference in the other types of dosages.\n\nIncidence of liver cancer\nThe incidence of liver cancer was investigated in three studies [5, 13, 14], with a total of 264663 participants and 529 cancer patients. The pooled estimate of the three studies indicated that there was no significant difference in the incidence of liver cancer (HR 1.36, 95%CI 0.9 to 2.04, P value = 0.14, I2 = 65%) (S5 Fig).\n\nLee et al. [13] indicated that there was a positive relationship between the use of alendronate and the incidence of liver cancer (HR 1.94, 95%CI 1.16 to 3.24, P value<0.05) when the dosage was ≥1.0 g/per year. In addition, Vestergaard et al. [5] showed that the use of alendronate significantly increased the incidence of liver cancer at a low dosage (DDD≤0.66, HR 4.13, 95%CI 1.66 to 10.3). Vestergaard et al. [5] reported that the use of alendronate significantly increased the incidence of liver cancer when the accumulated dose was ≤365 DDD (HR 5.53, 95%CI 2.13 to 14.3). There was no significant difference in the other types of dosages.\n\nIncidence of pancreas cancer\nThe pooled estimate of two studies [5, 14] indicated that there was no significant difference in the incidence of pancreatic cancer between the alendronate groups and the control groups (HR 1.11, 95%CI 0.78 to 1.59, P value = 0.56, I2 = 7%) (S6 Fig).\n\nVestergaard et al. [5] reported that the use of alendronate significantly increased the incidence of pancreatic cancer when the accumulated dose was ≤365 DDD (HR 5.53, 95%CI 2.13 to 14.3) and ranged from 366 DDD to 730 DDD (HR 2.82, 95%CI 1.25 to 6.35). There was no significant difference in the other types of dosages.\n\nIncidence of breast cancer\nThe pooled estimate of three studies [5, 13, 14] indicated that there was no significant difference in the incidence of breast cancer (HR 0.92, 95%CI 0.82 to 1.02, P value = 0.12, I2 = 0%) (S7 Fig).\n\nVestergaard et al. [16] indicated that alendronate significantly reduced the incidence of breast cancer when the treatment time ranged from 1.1 years to 5 years (HR 0.84, 95%CI 0.72 to 0.98, P value<0.05), with no significant effect when the treatment time was more than five years or less than one year. There was no significant difference in the other types of dosages.\n\nIncidence of cervical cancer\nThe pooled estimate of two studies [13, 14] indicated that there was no significant difference in the incidence of cervical cancer (HR 0.79, 95%CI 0.52 to 1.18, P value = 0.24, I2 = 27%) (S8 Fig). There was no significant difference in any of the types of dosages.\n\nIncidence of bladder and kidney cancer\nThe pooled estimate of two studies [13, 14] indicated that there was no significant difference in the incidence of bladder and kidney cancer (HR 0.98, 95%CI 0.69 to 1.40, P value = 0.92, I2 = 46%) (S9 Fig). There was no significant difference in any of the types of dosages.\n\nOther cancers\nLee 2012\nThere was no significant difference between the alendronate group and the control group in the incidence of oral cancer (HR 0.4, 95%CI 0.09 to 1.74), ovarian cancer (HR 0.58, 95%CI 0.07 to 4.93), endometrial cancer (HR 1.79, 95%CI 0.43 to 7.49), prostate cancer (HR 1.83, 95%CI 0.92 to 4.65), lymphoma (HR 2.34, 95%CI 0.93 to 5.94) or other cancers (HR 1.03, 95%CI 0.73 to 1.45).\n\nThere was a positive relationship between the two groups in the incidence of prostate cancer (HR 3.25, 95%CI 1.43 to 7.36, P value<0.01) and lymphoma (HR 4.37, 95%CI 1.49 to 12.8, P value<0.01) when the dosage was ≥1.0 g/per year. There was no significant difference in the other types of dosages.\n\nVestergaard 2011\nThere was no significant difference between the alendronate group and the control group in the incidence of bile duct cancer (HR 1.88, 95%CI 0.76 to 4.68) or small intestine cancer (HR 2.19, 95%CI 0.46 to 10.4).\n\nThe use of alendronate significantly increased the incidence of bile duct cancer (HR 3.11, 95%CI 1.03 to 9.34) and cancer of the small intestine (HR 10.5, 95%CI 1.75 to 63.2) when the accumulated dose ranged from 366 DDD to 730 DDD. There was no significant difference in the other types of dosages.\n\nSensitivity analyses and publication bias\nOverall, most of the outcomes were stable. For the incidence of colorectal cancer, there was a positive relationship when we used a fixed model (HR 0.85, 95%CI 0.78 to 0.93, P value = 0.004). For the incidence of liver cancer, the result changed after we excluded Chiang’s 2012 study (HR 1.69, 95%CI 1.03 to 2.77, P value = 0.04). The details of the sensitivity analyses are shown in S1 Table. We were unable to perform a funnel plot because the number of included studies was less than 10.\n\nDiscussion\nSummary of main results\nThis article shows the positive relationship between the use of alendronate and lung cancer. The sensitivity analyses indicate that there may be a positive relationship between the use of alendronate and colorectal or liver cancer. There was no significant difference between the alendronate group and the control group in the incidence of other cancers.\n\nAgreements and disagreements in the current literature\nFor esophageal cancer, our study results are consistent with the previous meta-analyses. Two previous meta-analyses, including cohort and case-control studies, showed that alendronate was not significantly associated with the incidence of esophageal cancer [19, 20]. Moreover, one case-control study that was conducted in Taiwan [21] reported a negative result (Odds Risk 0.61, 95%CI 0.21 to 1.75), and one nested case-control study conducted in the UK [22] indicated the same result in the data from the QResearch primary care database (Adjusted Odds Risk 0.91, 95%CI 0.73 to 1.14, P value = 0.4), the data from Clinical the Practice Research Datalink (CPRD) (Adjusted Odds Risk 1.03, 95%CI 0.83 to 1.28, P value = 0.8) and in the combined data (Adjusted Odds Risk 0.97, 95%CI 0.83 to 1.13, P value = 0.7).\n\nFor gastric cancer, there was no significant association between alendronate and gastric cancer in the two case-control studies, the data of which were obtained from the UK’s primary care electronic health records (CPRD)[22, 23]. Our results are agreed with the results from the CPRD. However, the result from the QResearch primary care database showed a positive relationship (Adjusted Odds Risk 1.47, 95%CI 1.11 to 1.95, P value = 0.008). Because the baseline characteristics of the CPRD and QResearch were almost the same, the difference between the CPRD and QResearch may be coincidental.\n\nFor colorectal cancer, one UK study [22] reported data from the QResearch primary care database (Adjusted Odds Risk 1.1, 95%CI 0.98 to 1.22, P value = 0.1), data from the Clinical Practice Research Datalink (CPRD) (Adjusted Odds Risk 1.1, 95%CI 0.98 to 1.22, P value = 0.1) and combined data (Adjusted Odds Risk 1.1, 95%CI 1.01 to 1.19, P value = 0.02). However, it was not significant at the 1% level. Our results basically support these results. Conversely, one meta-analysis that contained three case-control studies and one cohort study showed that oral bisphosphonates were associated with a reduced risk of colorectal cancer (Adjusted Odds Risk 0.87, 95%CI 0.78 to 0.97) [24]. Another meta-analysis containing six population-based observational studies also indicated the reduced risk for colorectal cancer (Adjusted Odds Risk 0.85, 95%CI 0.74 to 0.98) [25]. However, the two meta-analyses included two or more types of bisphosphonates that were not able to be separated. As a result, we could not exclude the possibility that other bisphosphonates and not the alendronate contributed to the positive association.\n\nFor breast cancer, there is an inconsistency among our study results and other researches. A meta-analysis that contained two cohort studies and two case-control studies indicated that the use of bisphosphonates, including alendronate, significantly decreased the incidence of breast cancer when compared with nonusage (Risk Ratio 1.24, 95%CI 0.74 to 0.98) [26]. However, a randomized controlled study showed that there was no significant difference between the alendronate group and the placebo group (HR 1.24, 95%CI 0.84 to 1.83) [27]. Our results agreed with the results from the randomized controlled study. The positive result in a previous meta-analysis might be attributed to the two following causes: 1. one of the cohort studies contained many types of bisphosphonates, of which etidronate and not alendronate had a positive effect; 2. the result of the case-control studies may have benefited the treatment group.\n\nFor lung cancer, a vitro study by Lin et al. [28] found that alendronate could selectively inhibit the proliferation of lung cancer cells. No other related studies were searched. However, our results showed that there was a positive relationship between the use of alendronate and the incidence of lung cancer. The mechanism is unclear now and relevant researchers should pay attention to it.\n\nFor the other types of cancer, this is the first attempt to integrate the available data and draw conclusions.\n\nStrengths and weaknesses\nThe strengths of this paper are (1) we used a comprehensive search strategy to minimize the possibilities of publication bias; (2) sensitivity analyses were conducted to investigate the origin of the high heterogeneity; and (3) the total sample size was large and the duration of the follow-up was sufficient.\n\nHowever, the results of this article should be interpreted with some limitations. First, the observational studies had some unmeasured confounding factors. Second, two of the included studies were adjusted only for age and sex, which may have overestimated the incidence of cancer because there was a positive relationship between some of the other factors (i.e., smoking and alcohol) and the incidence of cancer. Third, the geographical location of the included studies (only four countries, all of which were located in North America, Europe and East Asia) was limited, which reduces the available scope of our research. Fourth, there were differences in the categories of the dosages, resulting in our inability to integrate them and determine whether there was a dose-response reaction or not. Fifth, for lung cancer, two related studies were conducted in Taiwan, and the duration of the study time was almost the same. As we could not exclude that a possible overlap existed in the included patients, we conducted a sensitivity analysis to test the robustness of the result (S1 Table.). The result changed and showed no significant difference after excluding either Lee’s 2012 study (HR 1.17, 95%CI 0.95 to 1.44, P value = 0.13) or Chiang’s 2012 study (HR 1.47, 95%CI 1 to 2.17, P value = 0.05). From this information, we concluded that it was not a stable result and should be carefully interpreted.\n\nConclusion\nThis meta-analysis provides evidence that the use of alendronate may be associated with a high risk of occurrence of lung cancer, may increase the incidence of liver cancer and may decrease the incidence of colorectal cancer. There may be no relationship between the use of alendronate and the incidence of other cancers. Future studies should focus on the dose-response and the duration of the treatment time with alendronate and the incidence of the cancers, especially lung cancer, liver cancer and colorectal cancer. Additional high-quality RCTs are needed to estimate the carcinogenicity of alendronate.\n\nSupporting Information\nS1 Fig Forest plot of the incidence of all-cause cancer.\n(EPS)\n\nClick here for additional data file.\n\n S2 Fig Forest plot of the incidence of colorectal cancer.\n(EPS)\n\nClick here for additional data file.\n\n S3 Fig Forest plot of the incidence of gastric cancer.\n(EPS)\n\nClick here for additional data file.\n\n S4 Fig Forest plot of the incidence of esophagus cancer.\n(EPS)\n\nClick here for additional data file.\n\n S5 Fig Forest plot of the incidence of liver cancer.\n(EPS)\n\nClick here for additional data file.\n\n S6 Fig Forest plot of the incidence of pancreas cancer.\n(EPS)\n\nClick here for additional data file.\n\n S7 Fig Forest plot of the incidence of breast cancer.\n(EPS)\n\nClick here for additional data file.\n\n S8 Fig Forest plot of the incidence of cervical cancer.\n(EPS)\n\nClick here for additional data file.\n\n S9 Fig Forest plot of the incidence of bladder and kidney cancer.\n(EPS)\n\nClick here for additional data file.\n\n S1 File PRISMA Checklist for this meta-analysis.\n(DOC)\n\nClick here for additional data file.\n\n S1 Table Sensitivity analyses.\n(DOCX)\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \nMazzantini M , Di Munno O . Glucocorticoid-induced osteoporosis: 2013 update . Reumatismo . 2014 ;66 (2 ):144 –52 . 10.4081/reumatismo.2014.787 \n25069496 \n2 \nKhan SN , Craig L , Wild R . Osteoporosis: therapeutic guidelines. Guidelines for practice management of osteoporosis . Clinical obstetrics and gynecology . 2013 ;56 (4 ):694 –702 . 10.1097/01.grf.0000437016.19989.61 \n24177062 \n3 \nCompston J , Bowring C , Cooper A , Cooper C , Davies C , Francis R , et al\nDiagnosis and management of osteoporosis in postmenopausal women and older men in the UK: National Osteoporosis Guideline Group (NOGG) update 2013 . Maturitas . 2013 ;75 (4 ):392 –6 . 10.1016/j.maturitas.2013.05.013 \n23810490 \n4 \nWells GA , Cranney A , Peterson J , Boucher M , Shea B , Robinson V , et al\nAlendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women . The Cochrane database of systematic reviews . 2008 (1 ):Cd001155 .18253985 \n5 \nVestergaard P . Occurrence of gastrointestinal cancer in users of bisphosphonates and other antiresorptive drugs against osteoporosis . Calcified tissue international . 2011 ;89 (6 ):434 –41 . 10.1007/s00223-011-9539-4 \n22002678 \n6 \nGreen J , Czanner G , Reeves G , Watson J , Wise L , Beral V . Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort . BMJ (Clinical research ed) . 2010 ;341 :c4444 \n10.1136/bmj.c4444 \n20813820 \n7 \nHo YF , Lin JT , Wu CY . Oral bisphosphonates and risk of esophageal cancer: a dose-intensity analysis in a nationwide population . Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology . 2012 ;21 (6 ):993 –5 .\n8 \nNguyen DM , Schwartz J , Richardson P , El-Serag HB . Oral bisphosphonate prescriptions and the risk of esophageal adenocarcinoma in patients with Barrett's esophagus . Digestive diseases and sciences . 2010 ;55 (12 ):3404 –7 . 10.1007/s10620-010-1198-1 \n20397052 \n9 \nPazianas M , Abrahamsen B , Eiken PA , Eastell R , Russell RG . Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate—Danish National Register Based Cohort Study . Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA . 2012 ;23 (11 ):2693 –701 .\n10 \nStroup DF , Berlin JA , Morton SC , Olkin I , Williamson GD , Rennie D , et al\nMeta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group . JAMA: the journal of the American Medical Association . 2000 ;283 (15 ):2008 –12 .10789670 \n11 \nGS . HJ . Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011] . The Cochrane Collaborationk , Available from wwwcochrane-handbookorg. 2011 .\n12 \nPassarelli MN , Newcomb PA , LaCroix AZ , Lane DS , Ho GY , Chlebowski RT . Oral bisphosphonate use and colorectal cancer incidence in the Women's Health Initiative . Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research . 2013 ;28 (9 ):2043 –8 .\n13 \nLee WY , Sun LM , Lin MC , Liang JA , Chang SN , Sung FC , et al\nA higher dosage of oral alendronate will increase the subsequent cancer risk of osteoporosis patients in Taiwan: a population-based cohort study . PloS one . 2012 ;7 (12 ):e53032 \n10.1371/journal.pone.0053032 \n23300854 \n14 \nChiang CH , Huang CC , Chan WL , Huang PH , Chen TJ , Chung CM , et al\nOral alendronate use and risk of cancer in postmenopausal women with osteoporosis: A nationwide study . Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research . 2012 ;27 (9 ):1951 –8 .\n15 \nAbrahamsen B , Pazianas M , Eiken P , Russell RG , Eastell R . Esophageal and gastric cancer incidence and mortality in alendronate users . Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research . 2012 ;27 (3 ):679 –86 .\n16 \nVestergaard P , Fischer L , Mele M , Mosekilde L , Christiansen P . Use of bisphosphonates and risk of breast cancer . Calcified tissue international . 2011 ;88 (4 ):255 –62 . 10.1007/s00223-011-9463-7 \n21253712 \n17 \nCardwell CR , Abnet CC , Cantwell MM , Murray LJ . Exposure to oral bisphosphonates and risk of esophageal cancer . JAMA: the journal of the American Medical Association . 2010 ;304 (6 ):657 –63 . 10.1001/jama.2010.1098 \n20699457 \n18 \nChlebowski RT , Chen Z , Cauley JA , Anderson G , Rodabough RJ , McTiernan A , et al\nOral bisphosphonate use and breast cancer incidence in postmenopausal women . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2010 ;28 (22 ):3582 –90 . 10.1200/JCO.2010.28.2095 \n20567009 \n19 \nSun K , Liu JM , Sun HX , Lu N , Ning G . Bisphosphonate treatment and risk of esophageal cancer: a meta-analysis of observational studies . Osteoporosis international: a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA . 2013 ;24 (1 ):279 –86 .\n20 \nAndrici J , Tio M , Eslick GD . Meta-analysis: oral bisphosphonates and the risk of oesophageal cancer . Alimentary pharmacology & therapeutics . 2012 ;36 (8 ):708 –16 .22966908 \n21 \nChen YM , Chen DY , Chen LK , Tsai YW , Chang LC , Huang WF , et al\nAlendronate and risk of esophageal cancer: a nationwide population-based study in Taiwan . Journal of the American Geriatrics Society . 2011 ;59 (12 ):2379 –81 . 10.1111/j.1532-5415.2011.03693.x \n22188086 \n22 \nVinogradova Y , Coupland C , Hippisley-Cox J . Exposure to bisphosphonates and risk of gastrointestinal cancers: series of nested case-control studies with QResearch and CPRD data . BMJ (Clinical research ed) . 2013 ;346 :f114 \n10.1136/bmj.f114 \n23325866 \n23 \nWright E , Schofield PT , Seed P , Molokhia M . Bisphosphonates and risk of upper gastrointestinal cancer—a case control study using the General Practice Research Database (GPRD) . PloS one . 2012 ;7 (10 ):e47616 \n10.1371/journal.pone.0047616 \n23112825 \n24 \nThosani N , Thosani SN , Kumar S , Nugent Z , Jimenez C , Singh H , et al\nReduced risk of colorectal cancer with use of oral bisphosphonates: a systematic review and meta-analysis . Journal of clinical oncology: official journal of the American Society of Clinical Oncology . 2013 ;31 (5 ):623 –30 .23269990 \n25 \nSingh S , Singh AG , Murad MH , Limburg PJ . Bisphosphonates are associated with reduced risk of colorectal cancer: a systematic review and meta-analysis . Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association . 2013 ;11 (3 ):232 –9.e1 .23220165 \n26 \nLiu Y , Zhao S , Chen W , Hu F , Zhu L , Zhang Q , et al\nBisphosphonate use and the risk of breast cancer: a meta-analysis of published literature . Clinical breast cancer . 2012 ;12 (4 ):276 –81 . 10.1016/j.clbc.2012.04.003 \n22622199 \n27 Hue TF, Cummings SR, Cauley JA, Bauer DC, Ensrud KE, Barrett-Connor E, et al. Effect of Bisphosphonate Use on Risk of Postmenopausal Breast Cancer: Results From the Randomized Clinical Trials of Alendronate and Zoledronic Acid. JAMA internal medicine. 2014.\n28 \nLin X , Yu H , Tan C , Chen B , Wang T , Wang B . [Effects of bisphosphonates on proliferation of lung cancer cells in vitro ]. Zhongguo fei ai za zhi = Chinese journal of lung cancer . 2005 ;8 (6 ):510 –3 . 10.3779/j.issn.1009-3419.2005.06.05 \n21208538\n\n",
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"mesh_terms": "D019386:Alendronate; D050071:Bone Density Conservation Agents; D015331:Cohort Studies; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D008113:Liver Neoplasms; D008175:Lung Neoplasms; D009369:Neoplasms; D010024:Osteoporosis; D017594:Publication Bias; D013274:Stomach Neoplasms",
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"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review",
"references": "20397052;23300854;22622199;24177062;23052941;20813820;23519920;22188086;23220165;21208538;23325866;22490321;22532232;10789670;20567009;22002678;23112825;25111880;22966908;20699457;23810490;22113985;25069496;23269990;22392160;18253985;21253712",
"title": "The carcinogenicity of alendronate in patients with osteoporosis: evidence from cohort studies.",
"title_normalized": "the carcinogenicity of alendronate in patients with osteoporosis evidence from cohort studies"
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"abstract": "Fulminant viral myocarditis (FVM) is a rare cause of cardiogenic shock associated with high morbidity and mortality rates. An inappropriately activated immune system results in severe myocardial inflammation. Acute immunosuppressive therapy for FVM therefore gained in popularity and was described in numerous retrospective studies.\nWe conducted an extensive review of the literature and compared it with our single-centre retrospective review of all cases of FVM from 2009-2019 to evaluate the possible effect of acute immunosuppression with intravenous immunoglobulins and/or high dose corticosteroids in patients with FVM.\nWe report on 17 patients with a mean age of 46 ± 15 years with a mean left ventricular ejection fraction (LVEF) of 15 ± 9% at admission. Fourteen (82%) of our patients had acute LVEF recovery to ≥ 45% after a mean time from immunosuppression of 74 ± 49 hours (3.1 days). Extracorporeal membrane oxygenation (ECMO) was required in 35% (6/17) of our patients for an average support of 126 ± 37 hours. Overall mortality was 12% (2/17). No patient needed a long-term left ventricular assist device or heart transplant. All surviving patients achieved complete long-term LVEF recovery.\nOur cohort of 17 severely ill patients received acute immunosuppressive therapy and showed a rapid LVEF recovery, short duration of ECMO support, and low mortality rate. Our suggested scheme of investigation and treatment is presented. These results bring more cases of successfully treated FVM with immunosuppression and ECMO to the literature, which might stimulate further prospective trials or a registry.",
"affiliations": "Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Infectious Disease, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Pathology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada.;Department of Cardiac Surgery, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiac Surgery, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.;Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada.",
"authors": "Turgeon|Pierre Yves|PY|;Massot|Montse|M|;Beaupré|Frédéric|F|;Belzile|David|D|;Beaudoin|Jonathan|J|;Bernier|Mathieu|M|;Bourgault|Christine|C|;Germain|Valérie|V|;Laliberté|Claudine|C|;Morin|Joëlle|J|;Gervais|Philippe|P|;Trahan|Sylvain|S|;Charbonneau|Éric|É|;Dagenais|François|F|;Sénéchal|Mario|M|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.cjco.2020.10.017",
"fulltext": "\n==== Front\nCJC Open\nCJC Open\nCJC Open\n2589-790X\nElsevier\n\nS2589-790X(20)30184-0\n10.1016/j.cjco.2020.10.017\nOriginal Article\nEffect of Acute Immunosuppression on Left Ventricular Recovery and Mortality in Fulminant Viral Myocarditis: A Case Series and Review of Literature\nTurgeon Pierre Yves MD a\nMassot Montse MD a\nBeaupré Frédéric MD a\nBelzile David MD a\nBeaudoin Jonathan MD a\nBernier Mathieu MD a\nBourgault Christine MD a\nGermain Valérie BScN a\nLaliberté Claudine BScN a\nMorin Joëlle MD a\nGervais Philippe MD b\nTrahan Sylvain MD c\nCharbonneau Éric MD d\nDagenais François MD d\nSénéchal Mario MD mario.senechal@criucpq.ulaval.ca\na∗\na Department of Cardiology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada\nb Department of Infectious Disease, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada\nc Department of Pathology, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Canada\nd Department of Cardiac Surgery, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada\n∗ Corresponding author: Dr Mario Sénéchal, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725, chemin Sainte-Foy, Québec, Québec G1V 4G5, Canada. Tel.: +1-418-656-8711. mario.senechal@criucpq.ulaval.ca\n11 11 2020\n3 2021\n11 11 2020\n3 3 292302\n17 9 2020\n30 10 2020\n© 2020 Canadian Cardiovascular Society. Published by Elsevier Inc.\n2020\nCanadian Cardiovascular Society\nThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nBackground\n\nFulminant viral myocarditis (FVM) is a rare cause of cardiogenic shock associated with high morbidity and mortality rates. An inappropriately activated immune system results in severe myocardial inflammation. Acute immunosuppressive therapy for FVM therefore gained in popularity and was described in numerous retrospective studies.\n\nMethods\n\nWe conducted an extensive review of the literature and compared it with our single-centre retrospective review of all cases of FVM from 2009-2019 to evaluate the possible effect of acute immunosuppression with intravenous immunoglobulins and/or high dose corticosteroids in patients with FVM.\n\nResults\n\nWe report on 17 patients with a mean age of 46 ± 15 years with a mean left ventricular ejection fraction (LVEF) of 15 ± 9% at admission. Fourteen (82%) of our patients had acute LVEF recovery to ≥ 45% after a mean time from immunosuppression of 74 ± 49 hours (3.1 days). Extracorporeal membrane oxygenation (ECMO) was required in 35% (6/17) of our patients for an average support of 126 ± 37 hours. Overall mortality was 12% (2/17). No patient needed a long-term left ventricular assist device or heart transplant. All surviving patients achieved complete long-term LVEF recovery.\n\nConclusions\n\nOur cohort of 17 severely ill patients received acute immunosuppressive therapy and showed a rapid LVEF recovery, short duration of ECMO support, and low mortality rate. Our suggested scheme of investigation and treatment is presented. These results bring more cases of successfully treated FVM with immunosuppression and ECMO to the literature, which might stimulate further prospective trials or a registry.\n\nRésumé\n\nContexte\n\nLa myocardite virale fulminante (MVF) est une cause rare de choc cardiogénique, un état associé à des taux élevés de morbidité et de mortalité. L’activation inappropriée du système immunitaire entraîne une inflammation grave du myocarde. Le recours à un traitement immunosuppresseur aigu en cas de MVF a donc gagné en popularité et a fait l’objet de nombreuses études rétrospectives.\n\nMéthodologie\n\nNous avons effectué une revue exhaustive de la littérature et comparé nos observations avec les résultats de notre examen rétrospectif de tous les cas de MVF traités dans un même centre entre 2009 et 2019, afin d’évaluer l’effet possible d’une immunosuppression aiguë par des immunoglobulines administrées par voie intraveineuse et/ou par une corticothérapie à forte dose chez les patients présentant une MVF.\n\nRésultats\n\nNous rapportons les cas de 17 patients dont l’âge moyen était de 46 ± 15 ans et qui avaient une fraction d’éjection ventriculaire gauche (FEVG) moyenne de 15 ± 9 % à l’admission. Chez 14 (82 %) d’entre eux, la FEVG aiguë s’est rétablie à une valeur ≥ 45 % dans les 74 ± 49 heures (3,1 jours) en moyenne après l’administration d’un traitement immunosuppresseur. Un soutien par oxygénation extracorporelle par membrane (ECMO) a dû être administré à 35 % (6/17) des patients, pendant 126 ± 37 heures en moyenne. Le taux global de mortalité s’établissait à 12 % (2/17). Aucun patient n’a eu besoin d’assistance ventriculaire gauche de façon prolongée ni d’une transplantation cardiaque. La FEVG a fini par se rétablir complètement chez tous les patients qui ont survécu.\n\nConclusions\n\nLes 17 patients gravement malades de notre cohorte qui ont reçu un traitement immunosuppresseur aigu ont vu leur FEVG se rétablir rapidement, n’ont eu besoin d’ECMO que pendant une courte période et ont affiché un faible taux de mortalité. Nous présentons notre algorithme d’investigation et de traitement. Nos résultats s’ajoutent à ceux d’autres études témoignant de l’efficacité du traitement de la MVF par immunosuppression et ECMO, ce qui pourrait stimuler la réalisation de nouveaux essais prospectifs ou l’établissement d’un registre.\n==== Body\nMyocarditis is an inflammation of the myocardium induced by multiple factors with the most common etiology being viral infection.1, 2, 3, 4, 5, 6 A broad spectrum of clinical presentations exists in acute myocarditis, ranging from mild subclinical to severe life-threatening disease.7 Acute myocarditis with significant hemodynamic compromise requiring pharmacological or mechanical circulatory support (MCS) after the recent onset of symptoms is classified as fulminant myocarditis.7,8\n\nFulminant viral myocarditis (FVM) is caused by severe lymphocytic myocardium infiltration in the context of a recent viral infection with severe local inflammation, an increase in systemic inflammatory mediators, and myonecrosis. Pathogenesis of acute and chronic viral myocarditis shares a common pathway of inappropriately activated immune system and a certain degree of inflammatory cell infiltrate after an initial viral insult to the myocardial cells.9 The key role of autoimmune response was shown in experimental models.4,10 However, immunosuppression failed to show consistent benefits in large studies on acute or chronic myocarditis but none of them included the fulminant presentation.11, 12, 13, 14, 15\n\nIn patients with FVM, mortality rates between 7% and 45% have been reported16, 17, 18, 19, 20 and a need for short-term MCS up to 60%.16,18 Because of the higher morbidity and mortality rates of FVM reported in recent literature compared with previous studies, immunosuppressive therapy gained in popularity and was described in numerous studies of varying methodological robustness.21, 22, 23, 24, 25, 26\n\nMethods\n\nThe objective of this study was to evaluate the effect of acute immunosuppression with intravenous immunoglobulins (IVIG) and/or high dose corticosteroids on myocardial recovery, use of MCS, and mortality in patients with FVM at our centre.\n\nA retrospective chart review was carried out for the complete cohort of patients with a diagnosis of acute myocarditis between January 2009 and December 2019 at Institut Universitaire de Cardiologie et Pneumologie de Québec (Quebec Heart and Lungs Institute). Clinical, laboratory, and echocardiography data were reviewed to identify only cases of FVM. The institutional ethical board approved the design of the study.\n\nDefinition of FVM\n\nPatients had the classical FVM presentation defined by a viral prodrome of less than 2 weeks and subsequent cardiogenic shock due to acute myocarditis with elevated troponin levels and left ventricular systolic dysfunction with left ventricular ejection fraction (LVEF) < 40%. Cardiogenic shock was defined by significant hypotension or signs of hypoperfusion requiring hemodynamic support.\n\nInclusion criteria\n\n• Adult patients aged ≥ 18 years.\n\n• Clinical diagnosis of acute myocarditis with ≤ 2 weeks of symptoms.\n\n• Evidence of active inflammation (fever, increased white blood cell count, elevated c-reactive protein, and/or sedimentation time).\n\n• Evidence of myocardial damage: elevated troponin level.\n\n• Hypotension (systolic blood pressure < 90 mm Hg or mean blood pressure < 65 mm Hg).\n\n• Need for hemodynamic support (pharmacological and/or mechanical) justified by objective clinical or laboratory signs of hypoperfusion: persistent oliguria (< 20 mL/h), hyperlactatemia (> 2 mmol/L), acute renal insufficiency (serum creatinine increase > 30 μmol/L or > 1.5 times baseline serum creatinine), hepatic dysfunction (> 3 times the upper limit of normal of transaminase level), altered level of consciousness, or cold extremities.\n\nExclusion criteria\n\n• Dilated left ventricle defined as a left ventricular end-diastolic dimension using 2-dimensional guided linear measurements > 52 mm in women and > 58 mm in men.27\n\n• Coronary atherosclerotic disease (any history of ischemic heart disease or known coronary obstruction ≥ 50% in at least 1 main artery).\n\n• Giant cell myocarditis or eosinophilic myocarditis.\n\n• Previous cardiomyopathy of any type.\n\n• Postpartum onset < 6 months.\n\n• Systemic inflammatory disease.\n\nPathology\n\nHistopathological confirmation of lymphocytic myocardial infiltrate was not mandatory for inclusion. In the patients for whom endomyocardial biopsy (EMB) was deemed necessary, revised Dallas criteria were used for histopathologic diagnosis.28,29 Only patients with definite active myocarditis were considered to have a positive biopsy.\n\nActive research of viral etiology using EMB polymerase chain reaction (PCR) analysis is not routine at our institution. However, PCR analysis for influenza and respiratory syncytial viruses was done in all patients. On a case-by-case basis, a more extensive search for specific viral etiology was done by the infectious disease specialist.\n\nEchocardiography\n\nPatients underwent transthoracic echocardiography performed using a GE Vivid E95 (GE Vingmed Ultrasound, Horten, Norway) or Philips iE33 (Philips, Eindhoven, Netherlands) system. Two principal investigators (P.Y.T., M.S.) reviewed and confirmed all measurements according to the American Society of Echocardiography’s guidelines on chamber quantification.27,30 LVEF was determined using Simpson’s biplane method of disks. Two-dimensional guided linear measurement in the parasternal long-axis view was used for diameter and thickness.\n\nCardiac magnetic resonance\n\nTwo different cardiac magnetic resonance (CMR) scanners were used during our study: the Philips Achieva 1.5T (Philips Medical Systems, Best, Netherlands) until the end of September 2016 and Siemens 3T MAGNETOM Skyra (Siemens Medical Solutions USA, Inc, Malvern, PA) since.\n\nDiagnostic CMR criteria for acute myocarditis were the Lake Louise Consensus Criteria defined by the presence of at least 2 of the following criteria: regional or global myocardial signal intensity increase in T2-weighted images, increased global myocardial early gadolinium enhancement ratio between myocardium and skeletal muscle in gadolinium-enhanced T1-weighted images, and nonischemic regional distribution in inversion recovery-prepared gadolinium-enhanced T1-weighted images (late gadolinium enhancement).31 Most recent mapping techniques were not available during the study because of the lack of local validation of these techniques for clinical use during the study period.\n\nClinical management\n\nClinical management was at the discretion of the treating physician with the support of advanced heart failure and intensive care specialists. Pharmacological hemodynamic support consisted of noradrenaline, adrenaline, and milrinone. Intra-aortic balloon pump, extracorporeal membrane oxygenation (ECMO), and left ventricular assist device (VAD) were readily available for all patients included in this study. All patients with persisting or deteriorating signs of hypoperfusion, or severe hemodynamic instability despite inotropic support were considered for MCS with ECMO. The usual dose of IVIG is 1 g per kilogram repeated every 24 hours for 3-5 doses. With a corresponding volume of 10 mL per gram given in slow perfusion of 12 hours, it represents a volume of 500-1200 mL per day depending on the patient’s weight. This volume load was proactively considered in the diuretic management to prevent and treat lung edema.\n\nResults\n\nSeventeen patients with FVM were included in our analysis (Fig. 1). We excluded 7 patients with confirmed giant-cell myocarditis and 6 patients with systemic inflammatory disease associated with autoimmune myocarditis.Figure 1 Flow chart of patient selection. FVM, fulminant viral myocarditis.\n\nAs shown in Table 1, 53% of our cohort were female and the mean age was 46 ± 15 years. The mean duration of the viral prodrome was 5 ± 3 days before FVM diagnosis. Patients had a mean LVEF at admission of 15 ± 9% and a left ventricular end-diastolic diameter of 47 ± 5 mm. All patients had at least mildly increased ventricular wall thickness with a mean of 12 ± 2 mm. Myocarditis diagnosis was confirmed by positive EMB (n = 6) and/or CMR (n = 8) in 12 of 17 patients. All patients who underwent EMB (n = 6) had histopathological criteria for definite active lymphocytic myocarditis. Of the 11 remaining patients without EMB, 5 had identified viral pathogens. Two patients underwent both diagnostic confirmation tests. For the remaining 5 patients without a confirmatory test, 3 had positive PCR for influenza and 2 patients needed ECMO before CMR or EMB could be done. Coronary angiograms were performed in 8 patients and all were normal. All patients required pharmacological hemodynamic support and 41% (7/17) needed MCS. Of these, 6 required ECMO after a mean time from FVM diagnosis of 28 ± 27 hours and for a mean duration of 126 ± 37 hours. Thirteen patients (76%) needed invasive mechanical ventilation for a mean duration of 168 ± 93 hours. Subgroup data associated with treatment and outcomes is presented in Supplemental Table S1.Table 1 Clinical characteristics and echocardiographic parameters\n\nPatient\tSex\tAge, years\tIdentified pathogen\tEMB\tCMR\tInitial LVEF, %\tLVEDD, mm\tLVESD, mm\tIVS thickness, mm\tLVPW thickness, mm\t\n1\tM\t48\t–\t+\t-\t20\t58\t43\t11\t11\t\n2\tF\t56\t–\t+\t-\t20\t45\t35\t11\t13\t\n3\tM\t44\t–\t+\t+\t10\t47\t35\t13\t15\t\n4\tF\t28\t–\t+\t+\t35\t52\t42\t12\t13\t\n5\tF\t37\t–\t+\t-\t5\t49\t44\t8\t10\t\n6\tM\t31\tRhinovirus\t-\t+\t30\t50\t40\t10\t12\t\n7\tM\t37\t–\t-\t+\t20\t54\t42\t13\t14\t\n8\tM\t63\t–\t-\t-\t5\t46\t37\t13\t12\t\n9\tF\t72\tInfluenza A\t-\t-\t10\t46\t37\t11\t10\t\n10\tF\t70\t–\t-\t+\t10\t49\t35\t15\t13\t\n11\tM\t37\t–\t-\t+\t25\t49\t40\t12\t12\t\n12\tF\t45\t–\t-\t+\t10\t45\t36\t9\t11\t\n13\tF\t60\tInfluenza B\t-\t-\t20\t37\t29\t15\t15\t\n14\tM\t58\tWN virus\t+\t-\t10\t47\t43\t12\t14\t\n15\tM\t27\t–\t-\t+\t15\t45\t38\t12\t10\t\n16\tF\t35\tInfluenza A\t-\t-\t5\t48\t41\t10\t10\t\n17\tF\t31\tHantavirus\t-\t-\t10\t37\t33\t11\t10\t\nSummary\t9∗\t46\t6\t6\t8\t15\t47\t38\t12\t12\t\n% or ± SD\t53%\t± 15\t35%\t35%\t47%\t± 9\t± 5\t± 4\t± 2\t± 2\t\n+, indicates patients that underwent the diagnostic exam. -, indicates patients who have not undergone the diagnostic exam.\n\nCMR, cardiac magnetic resonance; EMB, endomyocardial biopsy; IVS, interventricular septum; LVEDD, left ventricular end-diastolic diameter; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic diameter; LVPW, left ventricular posterior wall; WN, West Nile.\n\n∗ Indicates number of female patients.\n\nImmunosuppressive treatment consisted of combination therapy with IVIG and high-dose methylprednisolone in 59% of patients (n = 10), IVIG only in 35% (n = 6), and methylprednisolone only in 6% (n = 1). Treatment with IVIG and methylprednisolone was received after a mean time from onset of the cardiogenic shock of 29 and 22 hours, respectively. The mean cumulative dose for IVIG was 3.1 ± 1.0 g per kilogram and for methylprednisolone was 2955 ± 1150 mg.\n\nAs shown in Table 2, acute recovery as defined by LVEF ≥ 45% was achieved in 82% (14/17) of patients after an average time of 74 hours (3.1 days) after the first dose of immunosuppressive treatment. Five of 6 patients who required ECMO support demonstrated acute LVEF recovery after an average time of 99 hours (4.1 days) after diagnosis compared with 60 hours (2.5 days) for the non-ECMO patients. Figure 2 shows the LVEF evolution in the first week. The overall mean LVEF achieved at 14 days was 50%. All survivors achieved complete recovery between 1 and 10 months.Table 2 Hemodynamic support, immunosuppressive treatment, and acute and long-term left ventricular function recovery\n\nPatient\tMV duration, h\tIABP duration, h\tECMO duration, h\tTime from diagnosis to ECMO, h\tMethylprednisolone\tIVIG\tLVEF at admission, %\tTime from treatment to LVEF ≥ 45%, h\tMaximal LVEF\tMaximum long-term LVEF, %\t\nTotal dose, mg\tTime, h∗\tTotal dose, g/kg\tTime, h∗\tAt day 7, %\tAt day 14, %\t\n1\t226\t-\t-\t-\t-\t-\t2\t95\t20\t45\t50\t50\t50\t\n2\t359\t-\t-\t-\t2000\t46\t-\t-\t20\t20\t45\t60\t70\t\n3\t-\t69\t-\t-\t3000\t34\t3\t39\t10\t90\t45\t65\t65\t\n4\t62\t-\t-\t-\t3000\t5\t2\t17\t35\t7\t45\t65\t65\t\n5\t110\t-\t-\t-\t1500\t30\t3\t8\t5\t-\t20\t25\t50\t\n6\t66\t-\t-\t-\t3000\t4\t2\t6\t30\t84\t45\t45\t55\t\n7\t110\t-\t-\t-\t-\t-\t2\t13\t20\t156\t50\t50\t55\t\n8\t240\t-\t155\t5\t-\t-\t3\t134\t5\t47\t50\t50\t70\t\n9\t-\t-\t-\t-\t3000\t8\t3\t9\t10\t16\t50\t50\t60\t\n10†\t175\t-\t82\t55\t4000\t74\t4\t74\t10\t108\t35\t50\tDeath at day 11\t\n11\t-\t-\t-\t-\t1000\t14\t3\t12\t25\t44\t50\t50\t60\t\n12\t28\t-\t-\t-\t-\t-\t3\t13\t10\t-\t20\t20\t60\t\n13\t168\t-\t75\t6\t4000\t0\t4\t2\t20\t58\t55\t75\t75\t\n14†\t216\t-\t140\t67\t3000\t7\t5\t7\t10\t-\t20\t20\tDeath at day 9\t\n15\t-\t-\t-\t-\t-\t-\t3\t3\t15\t78\t55\t55\t60\t\n16\t265\t-\t148\t27\t-\t-\t2\t21\t5\t149\t40\t60\t60\t\n17\t158\t-\t156\t9\t5000\t18\t5\t16\t10\t133\t60\t65\t65\t\nMean\t168\t69\t126\t28\t2955\t22\t3,1\t29\t15\t74\t43\t50\t61\t\n± SD\t93\tN/A\t37\t27\t1150\t23\t1\t38\t9\t49\t12\t16\t7\t\nECMO, extracorporeal membrane oxygenation; IABP, intra-aortic balloon pump; IVIG, intravenous immunoglobulins; LVEF, left ventricular ejection fraction; MV, mechanical ventilation; N/A, not applicable.\n\n∗ indicates time between the fulminant viral myocarditis diagnosis criteria fulfilment and the specific treatment.\n\n† indicates decreased patient.\n\nFigure 2 Left ventricular ejection fraction (LVEF) evolution in the acute phase.\n\nThe mortality rate was 12% (2/17). One patient died of mesenteric ischemia after embolization of an intraventricular thrombus on day 11, 4 days after successful weaning of ECMO, and 2 days after the complete normalization of LVEF. The second patient developed rapid and refractory multiple organ failure despite ECMO support that led to death on day 9 of hospitalization. Atypical West Nile virus infection with very severe cardiac inflammation was identified at autopsy. No patient needed VAD or heart transplant (HTx). All surviving patients showed stabilization or improvement after complete weaning of pharmacological or mechanical support and were discharged from the hospital. This left ventricular function recovery was durable, as shown in a mean follow-up period of 4.1 years.\n\nAdverse effects associated with IVIG were reported in 2 patients. One patient suffered from self-limited aseptic meningitis with headaches that lasted < 48 hours. One patient developed immune hemolysis with direct Coombs test conversion. No adverse effect attributed to high-dose methylprednisolone was identified.\n\nSelected studies that have described outcomes in FVM patients with and without immunosuppressive therapy are presented in Tables 3 and 4.Table 3 Descriptive studies that have described morbidity and mortality in patients with fulminant myocarditis\n\nReference\tStudy years\tStudy type\tFulminant\tOverall mortality\tOverall MCS use\tIABP\tECMO or short-term VAD\tHTx or long-term VAD\t\nn\t%\tn\t%\tn\t%\tn\t%\tn\t%\tn\t%\t\nLieberman, et al.7\t1983-1988\tRetrospective, single-centre, n = 35\t4\t11\t1\t25\t0\t0\t0\t0\t0\t0\t0\t0\t\nMcCarthy et al.32\t1984-1997\tRetrospective, single-centre, n = 147\t15\t10\t1\t7\t2\t13\tn.s.\tn.s.\tn.s.\tn.s.\t0\t0\t\nLee et al.20\t1990-2004\tRetrospective, single-centre, n = 35\t11\t31\t5\t45\t7\t64\t5\t45\t2\t18\t0\t0\t\nFreixa et al.19\t2000-2007\tProspective, single-centre, n = 185\t15\t8\t4\t27\t8\t53\t3\t20\t5\t33\t2\t13\t\nAmmirati et al.18\t2001-2016\tRetrospective, 2 centres, n = 130∗\t34\t26\t4\t12\t21\t62\t19\t56\t15\t44\t1\t3\t\nXu et al.17\t2012-2016\tRetrospective, single-centre, n = 73\t73\t100\t10\t14\t20\t27\t20\t27\t0\t0\tn.s.\tn.s.\t\nSummary (available data)\t\tn = 605\t152\t25\t25\t16\t58\t38\t47\t31\t22\t14\t3\t2\t\nECMO, extracorporeal membrane oxygenation; HTx, heart transplantation; IABP, intra-aortic balloon pump; MCS, mechanical circulatory support; n.s., not significant; VAD, ventricular assist device.\n\n∗ Subgroup of patients with symptoms onset < 2 weeks. Overall mortality represents the mortality at discharge or 30 days.\n\nTable 4 Studies that have described outcomes in patients with fulminant myocarditis treated with acute immunosuppressive therapy\n\nReference\tStudy years\tStudy type\tFulminant\tImmunosuppression\tImmunosuppressive regimen\tOverall mortality\tMCS\t\nn\t%\tn\t%\tn\t%\tn\t%\t\nChau et al.56\t1995-2005\n\n\tRetrospective, single-centre, n = 8\t7\n\n\t88\t6\n\n\t86\tMethylprednisolone 10 mg/kg q 24 hours for 3 doses\t0\t0\t3\t43\t\nIVIG 1-2 g/kg divided in 2-3 daily doses\t\n4/7 Steroid only; 2/7 steroid with IVIG\t\nGoland et al.55\t1998-2004\n\n\tRetrospective, single-centre, n = 6\t6\n\n\t100\t6\n\n\t100\tIVIG 2 g/kg total dose\t0\t0\t0\t0\t\n1 g/kg q 24 hours for 2 doses (3/6)\t\n2 g/kg in 24-hour perfusion (2/6)\t\n400 mg/kg q 24 hours for 5 doses (1/6)\t\nManins et al.54\t2009\n\tRetrospective, single-centre, n = 5\t5\n\t100\t5\n\t100\tATG 10 mg/kg q 24 hours for 2-4 days\t0\t0\t3\t60\t\nAiming T-lymphocytes CD3 count < 100 × 106/L\t\nYu et al.53\t2001-2010\n\tRetrospective, single-centre, n = 58\t58\n\t100\t32\n\t55\tIVIG 400 mg/kg q 24 hours for 5 doses\n\t2\t6\t10\t31\t\nSummary\t\tn = 77\t76\t99\t49\t64\t\t2\t4\t16\t33\t\nOverall mortality represents acute mortality.\n\nATG, antithymocyte globulins; IVIG, intravenous immunoglobulins; MCS, mechanical circulatory support; q, every.\n\nDiscussion\n\nIn this cohort, immunosuppressive therapy with IVIG and/or high dose methylprednisolone was associated with rapid LVEF recovery, short duration of ECMO support, and low mortality rate. The results of our retrospective study suggest that acute immunosuppression might influence the natural evolution of FVM compared with the actual published literature, and therefore, may be considered in carefully selected patients with FVM in addition to proactive ECMO support when indicated.\n\nRecent literature clearly supports higher morbidity and mortality rates patients with fulminant myocarditis (FM) than what has been described earlier.16, 17, 18, 19, 20 Knowledge about FM has dramatically increased since Lieberman et al. described the first clinicopathologic classification of myocarditis on the basis of EMB and reported 4 cases of FM with a mortality rate of 25%.7 In 2000, McCarthy et al. suggested that FM has an excellent long-term prognosis of 93% transplantation-free survival at 11 years, compared with acute myocarditis in their retrospective cohort of 147 cases of which only 15 patients met FM criteria.32 Of those 15 patients, only 2 required left VAD. However, the study was subject to a selection bias because patients were included on the basis of their biopsy results. This could have led to the under-representation of the most severe cases of FM that often do not have the time to be confirmed with biopsy. A more recent large study confirmed the poor short-term prognosis of patients with FM with a rate of in-hospital death or heart transplantation of more than 25% compared with none in the nonfulminant myocarditis group.18 Moreover, the risk of long-term left ventricular dysfunction with LVEF < 55% was more than 3 times higher in the FM group (29% vs 9%).18 Therefore, therapies that promote left ventricular recovery and prevent irreversible myocardial damage are the mainstay in the approach to FVM.\n\nDiagnosis confirmation\n\nBecause complete imaging with CMR or pathologic evaluations with EMB is often limited in patients with rapidly deteriorating disease that needs advanced and invasive support, FVM is mainly a clinical diagnosis. It is well known that EMB might help guide a specific treatment depending on the histology results, which might have an effect on the outcomes.1 According to guidelines, it is a class I recommendation to perform EMB in all patients that correspond to FVM criteria as defined by new-onset heart failure of < 2 weeks’ duration associated with normal-sized left ventricle and hemodynamic compromise.33 However, because of its limited availability and invasive character, EMB might not be possible to perform in critically ill patients. 28\n\nUsing strict clinical criteria, we are confident that we only included patients with FVM. Moreover, we present cases of high-risk FVM that are usually under-represented in the biopsy-proven registries. This is illustrated with a 76% need for mechanical ventilation and a 41% use of MCS in our cohort. Accordingly, only 6 (35%) patients underwent EMB. All patients for whom we managed to identify a typical pathogen or who required prompt use of ECMO were not considered for this invasive technique. EMB for suspected FVM with a typical presentation is not routine because of the precarity of most patients. In accordance with our study, a larger study with severely ill patients requiring ECMO had a rate of EMB of < 30%.34\n\nCMR imaging has an increasingly important role in the diagnostic confirmation of acute myocarditis. The Lake Louise criteria as used in our study shows good diagnostic accuracy of > 80% in a recent meta-analysis.35 Newer advanced techniques, especially parametric mapping techniques combined with late gadolinium enhancement, have shown higher diagnostic accuracy > 90%, which fairly compares with EMB.35,36 Most recent expert recommendations place CMR as a key evaluation tool for patients with suspected myocarditis with the potential to avoid exposing patients to invasive procedures such as EMB. 37\n\nIn light of the previous considerations, we suggest that EMB should be done mostly in FVM patients with severe hemodynamic instability, atypical presentation, or to rule out giant-cell myocarditis. However, because a significant proportion of patients will need prompt MCS use, the diagnosis of FVM using strict clinical criteria has an important role. For stabilized patients or after acute recovery, CMR may be used to confirm the diagnosis.\n\nMortality\n\nOur experience from a high-volume tertiary centre with a reference population of > 2.5 million people is that FVM myocarditis presentation might have an improved prognosis in the contemporary era when treated aggressively with immunosuppression and MCS. Although the patients in our cohort were severely ill, as supported by a higher need for ECMO support, we report a lower mortality rate than the most important descriptive studies presented in Table 3.7,17, 18, 19, 20,32 The 2 patients who died in our study required ECMO. One died of refractory left ventricular dysfunction with severe multiple organ failure. The other patient died of a left ventricular thrombus embolization in the superior mesenteric artery after complete and rapid recovery of left ventricular function. None of our patients needed VAD or HTx.\n\nMCS\n\nECMO has a main role in the paradigm shift of the treatment approach for FVM. Aggressive hemodynamic support with ECMO leaves time for the reduction of the severe systemic inflammation that directly and reversibly alters myocardial systolic function. The most robust studies that evaluated ECMO in patients with fulminant myocarditis are presented in Supplemental Table S2.34,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 Those studies represent the sickest subgroups of fulminant myocarditis patients and suggest that at least a third of patients supported by ECMO will die of the disease.\n\nAmmirati et al. recently concluded that MCS or HTx should be considered early in hemodynamically unstable patients with acute myocarditis and efforts should be made to anticipate its necessity.18 It is now well recognized that most deaths occur early after the presentation, therefore proactive ECMO use is essential in patients with refractory cardiogenic shock as a bridge to recovery. Severe hypotension, systemic hypoperfusion, or refractory arrhythmias are the most frequent consequences that lead to advanced support.\n\nOur results suggest that the prompt use of MCS with ECMO might promote the rapid recovery of LVEF. Rapid ECMO installation (time from diagnosis to ECMO use of 28 hours) in combination with acute immunosuppressive treatment might explain the short mean duration of ECMO use in our cohort (126 hours) vs that in previously published studies (206 hours).\n\nImmunosuppressive treatment\n\nTable 4 shows the main studies on acute immunosuppressive therapy that we selected after an extensive review of the literature and only the studies with clear inclusion criteria for FVM were retained.53, 54, 55, 56 In summary, those studies suggest an estimated average mortality rate of < 5% in patients with fulminant myocarditis treated with aggressive immunosuppressive therapy. Of note, a total of 27 patients who did not receive immunosuppressive treatment were included in 2 of those studies.53,56 Seven patients died in this control group, suggesting a mortality rate of 26%.\n\nRecently, Huang et al. published a meta-analysis, mostly on the basis of pediatric studies, that suggests that IVIG therapy can reduce in-hospital mortality, promote left ventricular function recovery, and increase long-term survival in patients with fulminant myocarditis. 57\n\nMore than half of our patients received a high dose of methylprednisolone and all but 1 patient received IVIG within a mean time from hemodynamic instability of 22 and 29 hours, respectively. This reflects a rapid recognition of the disease that resulted in prompt targeted treatment, which could have contributed to the high rate of acute LVEF recovery.\n\nOn the basis of the previously cited studies and the results of our case series, early acute immunosuppressive therapy with IVIG and/or high dose methylprednisolone may be considered for selected patients with FVM.\n\nInflammation and cytokines: the rationale for immunosuppressive treatment\n\nMultiple pathophysiological hypotheses for FVM were described in recent years and the direct effect of cytokines on cardiomyocytes seems to play a major role in the rapid reversibility of the disease.58 Interleukin-1 and tumour necrosis factor α were shown to have a reversible negative inotropic effect, impaired β-adrenergic receptor function, and endothelial dysfunction.22,59,60 The rapid rise and fall of cytokine levels due to an inappropriately activated inflammatory cascade might explain the transient profound systolic dysfunction without left ventricular dilatation or necrosis. This hypothesis stresses the importance of aggressive MCS until recovery and explains why acute immunosuppression therapy might be beneficial in FVM.\n\nMoreover, it is well studied that cytokines contribute to the recruitment of lymphocytes, particularly T cells, and other inflammatory cells in the myocardium that ultimately maintain prolonged inflammation with subsequent risk of myonecrosis and fibrosis.4,22,54,61 A subclass of T cells, T regulatory cells, has beneficial anti-inflammatory properties by negative regulation of the immune response. B lymphocytes have a central role in the inappropriate humoral response to viral infection with the production of autoantibodies that target myocardium.62\n\nVarious immunosuppressive regimens were studied in the past decades, and their role in recent-onset idiopathic or inflammatory cardiomyopathy remains highly controversial.12,15,59,63, 64, 65 Of note, those large studies did not evaluate the specific treatment of fulminant myocarditis.\n\nFigure 3 illustrates the mechanisms of action of the most frequently used acute immunosuppressive treatments as described in clinical and fundamental laboratory studies.54,59, 60, 61,66, 67, 68, 69, 70, 71Figure 3 Mechanisms of immunosuppressive agents frequently used in fulminant myocarditis. +, mild effect. ++, moderate effect. +++, strong effect. -, no significant effect. ?, unknown effect. ATG, antithymocyte globulin; IL, interleukin; IVIG, intravenous immunoglobulins; TNF, tumour necrosis factor.\n\nProposed treatment scheme\n\nIn light of the previously described considerations, Supplemental Figure S1 represents our suggested treatment and investigation scheme for patients suspected to have FVM. Considering the potential adverse effects of immunosuppression, we strongly recommend that IVIG be given only after the administration of appropriate antibiotics in patients suspected to have concomitant bacterial infection or septic shock. High-dose methylprednisolone can also accentuate serious systemic infections, therefore we recommend that it should not be used in those patients. Our approach is more aggressive than what is suggested by a recent scientific statement on FVM by the American Heart Association, which was mainly on the basis of studies without a clear definition of fulminant myocarditis or inclusion of patients with acute and subacute presentations.72 However, we consider that our study stresses the importance of giving more attention to such a proactive algorithm before concluding that immunosuppressive treatment is ineffective. Nonetheless, we must emphasize that in patients without acute recovery and requiring prolonged inotropic or mechanical support, which is atypical for FVM, EMB should be done to eliminate alternate causes of myocarditis with specific treatments before considering heart transplantation or durable support.\n\nLimitations\n\nOur study presents the usual limitations of a small retrospective single-centre experience. However, a prospective study to evaluate acute immunosuppressive therapy in the setting of FVM would be difficult to realize, mainly because of the very low incidence of the disease and the likely reluctance to use a placebo. Because of the widespread use of immunosuppressive treatment for FVM in our centre in the past decade, we lack a control group that could have allowed us to confirm and quantify the benefits of immunosuppression. Therefore, we cannot draw firm conclusions about the efficacy of the suggested treatment regimen but our results are hypothesis-generating. Finally, the local aggressive weaning strategy could have played a role in the short duration of ECMO.\n\nConclusions\n\nOur cohort of 17 severely ill patients received acute immunosuppressive therapy and showed a rapid LVEF recovery, short duration of ECMO support, and low mortality rate. Our suggested scheme of investigation and treatment is presented. These results bring more cases of successfully treated FVM with immunosuppression in the literature, which might stimulate further prospective trials or a registry.\n\nAcknowledgements\n\nThe authors thank Jean François Turgeon for language editing and proofreading.\n\nFunding Sources\n\nDr Massot’s fellowship is supported by a research grant from the Fundación Alfonso Martín Escudero (Madrid, Spain).\n\nDisclosures\n\nThe authors have no conflicts of interest to disclose.\n\nSupplementary Material\n\nSupplemental Tables S1 and S2 and Supplemental Figure S1\n\nEthics Statement: The study protocol was approved by the IUCPQ institutional review board and ethical committees.\n\nSee page 300 for disclosure information.\n\nTo access the supplementary material accompanying this article, visit CJC Open at https://www.cjcopen.ca/ and at https://doi.org/10.1016/j.cjco.2020.10.017.\n==== Refs\nReferences\n\n1 Caforio A.L. Pankuweit S. Arbustini E. 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The Myocarditis Treatment Trial Investigators N Engl J Med 333 1995 269 275 7596370\n14 McNamara D.M. Rosenblum W.D. Janosko K.M. Intravenous immune globulin in the therapy of myocarditis and acute cardiomyopathy Circulation 95 1997 2476 2478 9184576\n15 McNamara D.M. Holubkov R. Starling R.C. Controlled trial of intravenous immune globulin in recent-onset dilated cardiomyopathy Circulation 103 2001 2254 2259 11342473\n16 Ammirati E. Veronese G. Brambatti M. Fulminant versus acute nonfulminant myocarditis in patients with left ventricular systolic dysfunction J Am Coll Cardiol 74 2019 299 311 31319912\n17 Xu M. Jiang T. Zhou Y. Yang X. Influence of echocardiographic measurements and renal impairments on the prognosis of fulminant myocarditis Medicine (Baltimore) 97 2018 e9812\n18 Ammirati E. Cipriani M. Lilliu M. Survival and left ventricular function changes in fulminant versus nonfulminant acute myocarditis Circulation 136 2017 529 545 28576783\n19 Freixa X. Sionis A. Castel A. Low troponin-I levels on admission are associated with worse prognosis in patients with fulminant myocarditis Transplant Proc 41 2009 2234 2236 19715884\n20 Lee C.H. Tsai W.C. Hsu C.H. Predictive factors of a fulminant course in acute myocarditis Int J Cardiol 109 2006 142 145 16574533\n21 Hu H. Ma F. Wei X. Fang Y. Coronavirus fulminant myocarditis saved with glucocorticoid and human immunoglobulin Eur Heart J 42 2021 206 32176300\n22 Abe S. Okura Y. Hoyano M. Plasma concentrations of cytokines and neurohumoral factors in a case of fulminant myocarditis successfully treated with intravenous immunoglobulin and percutaneous cardiopulmonary support Circ J 68 2004 1223 1226 15564712\n23 Segawa T. Arita Y. Akari T. Hasegawa S. Fulminant myocarditis BMJ Case Rep 2018 2018 bcr2017223973\n24 Nakashima H. Umeyama Y. Minami K. Successive immunosuppressive treatment of fulminant myocarditis that is refractory to mechanical circulatory support Am J Case Rep 14 2013 116 119 23826449\n25 Kato S. Morimoto S. Hiramitsu S. Successful high-dose intravenous immunoglobulin therapy for a patient with fulminant myocarditis Heart Vessels 22 2007 48 51 17285446\n26 Takeda Y. Yasuda S. Miyazaki S. High-dose immunoglobulin G therapy for fulminant myocarditis Jpn Circ J 62 1998 871 872 9856608\n27 Lang R.M. Badano L.P. Mor-Avi V. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging J Am Soc Echocardiogr 28 2015 1 39.e14 25559473\n28 Leone O. Veinot J.P. Angelini A. 2011 Consensus statement on endomyocardial biopsy from the Association for European Cardiovascular Pathology and the Society for Cardiovascular Pathology Cardiovasc Pathol 21 2012 245 274 22137237\n29 Aretz H.T. Billingham M.E. Edwards W.D. Myocarditis. A histopathologic definition and classification Am J Cardiovasc Pathol 1 1987 3 14 3455232\n30 Lang R.M. Bierig M. Devereux R.B. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology J Am Soc Echocardiogr 18 2005 1440 1463 16376782\n31 Friedrich M.G. Sechtem U. Schulz-Menger J. Cardiovascular magnetic resonance in myocarditis: a JACC white paper J Am Coll Cardiol 53 2009 1475 1487 19389557\n32 McCarthy R.E. 3rd Boehmer J.P. Hruban R.H. Long-term outcome of fulminant myocarditis as compared with acute (nonfulminant) myocarditis N Engl J Med 342 2000 690 695 10706898\n33 Cooper L.T. Baughman K.L. Feldman A.M. The role of endomyocardial biopsy in the management of cardiovascular disease: a scientific statement from the American Heart Association, the American College of Cardiology, and the European Society of Cardiology. Endorsed by the Heart Failure Society of America and the Heart Failure Association of the European Society of Cardiology J Am Coll Cardiol 50 2007 1914 1931 17980265\n34 Lorusso R. Centofanti P. Gelsomino S. Venoarterial extracorporeal membrane oxygenation for acute fulminant myocarditis in adult patients: a 5-year multi-institutional experience Ann Thorac Surg 101 2016 919 926 26518372\n35 Lagan J. Schmitt M. Miller C.A. Clinical applications of multi-parametric CMR in myocarditis and systemic inflammatory diseases Int J Cardiovasc Imaging 34 2018 35 54 28130644\n36 Kotanidis C.P. Bazmpani M.A. Haidich A.B. Diagnostic accuracy of cardiovascular magnetic resonance in acute myocarditis: a systematic review and meta-analysis JACC Cardiovasc Imaging 11 2018 1583 1590 29454761\n37 Ferreira V.M. Schulz-Menger J. Holmvang G. Cardiovascular magnetic resonance in nonischemic myocardial inflammation: expert recommendations J Am Coll Cardiol 72 2018 3158 3176 30545455\n38 Chong S.Z. Fang C.Y. Fang H.Y. Associations with the in-hospital survival following extracorporeal membrane oxygenation in adult acute fulminant myocarditis J Clin Med 7 2018 452\n39 Ting M. Wang C.H. Tsao C.I. Heart transplantation under mechanical circulatory support for acute fulminant myocarditis with cardiogenic shock: 10 years’ experience of a single center Transplant Proc 48 2016 951 955 27234777\n40 Diddle J.W. Almodovar M.C. Rajagopal S.K. Rycus P.T. Thiagarajan R.R. Extracorporeal membrane oxygenation for the support of adults with acute myocarditis Crit Care Med 43 2015 1016 1025 25738858\n41 Nakamura T. Ishida K. Taniguchi Y. Prognosis of patients with fulminant myocarditis managed by peripheral venoarterial extracorporeal membranous oxygenation support: a retrospective single-center study J Intensive Care 3 2015 5 25705430\n42 Ishida K. Wada H. Sakakura K. Long-term follow-up on cardiac function following fulminant myocarditis requiring percutaneous extracorporeal cardiopulmonary support Heart Vessels 28 2013 86 90 22203407\n43 Wu M.Y. Lee M.Y. Lin C.C. Resuscitation of non-postcardiotomy cardiogenic shock or cardiac arrest with extracorporeal life support: the role of bridging to intervention Resuscitation 83 2012 976 981 22269099\n44 Chung S.Y. Sheu J.J. Lin Y.J. Outcome of patients with profound cardiogenic shock after cardiopulmonary resuscitation and prompt extracorporeal membrane oxygenation support Circ J 76 2012 1385 1392 22447007\n45 Mirabel M. Luyt C.E. Leprince P. Outcomes, long-term quality of life, and psychologic assessment of fulminant myocarditis patients rescued by mechanical circulatory support Crit Care Med 39 2011 1029 1035 21336134\n46 Gariboldi V. Grisoli D. Tarmiz A. Mobile extracorporeal membrane oxygenation unit expands cardiac assist surgical programs Ann Thorac Surg 90 2010 1548 1552 20971261\n47 Chen Y.S. Yu H.Y. Huang S.C. Extracorporeal membrane oxygenation support can extend the duration of cardiopulmonary resuscitation Crit Care Med 36 2008 2529 2535 18679121\n48 Asaumi Y. Yasuda S. Morii I. Favourable clinical outcome in patients with cardiogenic shock due to fulminant myocarditis supported by percutaneous extracorporeal membrane oxygenation Eur Heart J 26 2005 2185 2192 16014643\n49 Maejima Y. Yasu T. Kubo N. Long-term prognosis of fulminant myocarditis rescued by percutaneous cardiopulmonary support device Circ J 68 2004 829 833 15329503\n50 Aoyama N. Izumi T. Hiramori K. National survey of fulminant myocarditis in Japan: therapeutic guidelines and long-term prognosis of using percutaneous cardiopulmonary support for fulminant myocarditis (special report from a scientific committee) Circ J 66 2002 133 144 11999637\n51 Kato S. Morimoto S. Hiramitsu S. Use of percutaneous cardiopulmonary support of patients with fulminant myocarditis and cardiogenic shock for improving prognosis Am J Cardiol 83 1999 623 625, a610 10073879\n52 Kawahito K. Murata S. Yasu T. Usefulness of extracorporeal membrane oxygenation for treatment of fulminant myocarditis and circulatory collapse Am J Cardiol 82 1998 910 911 9781978\n53 Yu D.Q. Wang Y. Ma G.Z. Intravenous immunoglobulin in the therapy of adult acute fulminant myocarditis: a retrospective study Exp Ther Med 7 2014 97 102 24348772\n54 Manins V. Parle N. Dembo L. O’Driscoll G. Anti-thymocyte globulin as an adjunct to treatment of fulminant lymphocytic myocarditis J Heart Lung Transplant 28 2009 1211 1214 19783163\n55 Goland S. Czer L.S.C. Siegel R.J. Intravenous immunoglobulin treatment for acute fulminant inflammatory cardiomyopathy: series of six patients and review of literature Can J Cardiol 24 2008 571 574 18612500\n56 Chau E.M. Chow W.H. Chiu C.S. Wang E. Treatment and outcome of biopsy-proven fulminant myocarditis in adults Int J Cardiol 110 2006 405 406 16297469\n57 Huang X. Sun Y. Su G. Li Y. Shuai X. Intravenous immunoglobulin therapy for acute myocarditis in children and adults Int Heart J 60 2019 359 365 30745539\n58 Liu P.P. Mason J.W. Advances in the understanding of myocarditis Circulation 104 2001 1076 1082 11524405\n59 Kishimoto C. Shioji K. Kinoshita M. Treatment of acute inflammatory cardiomyopathy with intravenous immunoglobulin ameliorates left ventricular function associated with suppression of inflammatory cytokines and decreased oxidative stress Int J Cardiol 91 2003 173 178 14559127\n60 Castellano G. Affuso F. Di Conza P. Fazio S. Myocarditis and dilated cardiomyopathy: possible connections and treatments J Cardiovasc Med (Hagerstown) 9 2008 666 671 18545064\n61 Kawai C. From myocarditis to cardiomyopathy: mechanisms of inflammation and cell death: learning from the past for the future Circulation 99 1999 1091 1100 10051305\n62 Kaya Z. Afanasyeva M. Wang Y. Contribution of the innate immune system to autoimmune myocarditis: a role for complement Nat Immunol 2 2001 739 745 11477411\n63 Mason J.W. Immunopathogenesis and treatment of myocarditis: the United States Myocarditis Treatment Trial J Card Fail 2 4 suppl 1996 S173 S177 8951576\n64 Jones S.R. Herskowitz A. Hutchins G.M. Baughman K.L. Effects of immunosuppressive therapy in biopsy-proved myocarditis and borderline myocarditis on left ventricular function Am J Cardiol 68 1991 370 376 1858678\n65 Parrillo J.E. Cunnion R.E. Epstein S.E. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy N Engl J Med 321 1989 1061 1068 2677721\n66 Chen H.S. Wang W. Wu S.N. Liu J.P. Corticosteroids for viral myocarditis Cochrane Database Syst Rev 10 2013 CD004471\n67 Kraaij M.D. van der Kooij S.W. Reinders M.E. Dexamethasone increases ROS production and T cell suppressive capacity by anti-inflammatory macrophages Mol Immunol 49 2011 549 557 22047959\n68 Robinson J.L. Hartling L. Crumley E. Vandermeer B. Klassen T.P. A systematic review of intravenous gamma globulin for therapy of acute myocarditis BMC Cardiovasc Disord 5 2005 12 15932639\n69 Takada H. Kishimoto C. Hiraoka Y. Therapy with immunoglobulin suppresses myocarditis in a murine coxsackievirus B3 model. Antiviral and anti-inflammatory effects Circulation 92 1995 1604 1611 7664447\n70 Maisch B. Pankuweit S. Standard and etiology-directed evidence-based therapies in myocarditis: state of the art and future perspectives Heart Fail Rev 18 2013 761 795 23225133\n71 Kishimoto C. Abelmann W.H. Monoclonal antibody therapy for prevention of acute coxsackievirus B3 myocarditis in mice Circulation 79 1989 1300 1308 2541943\n72 Kociol R.D. Cooper L.T. Fang J.C. Recognition and initial management of fulminant myocarditis: a scientific statement from the American Heart Association Circulation 141 2020 e69 92 31902242\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2589-790X",
"issue": "3(3)",
"journal": "CJC open",
"keywords": null,
"medline_ta": "CJC Open",
"mesh_terms": null,
"nlm_unique_id": "101763635",
"other_id": null,
"pages": "292-302",
"pmc": null,
"pmid": "33778446",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": "1858678;17980265;24136037;7664447;7596370;23824828;3455232;2541943;8989150;16574533;17707091;9184576;11524405;23830649;11999637;30745539;28130644;17575480;19783163;14559127;26518372;22047959;23826449;22203407;31319912;27234777;19389557;31902242;9191484;30463365;16476862;16297469;30545455;9781978;29367381;1960305;18612500;20971261;29384884;10073879;19715884;16376782;11477411;22137237;24348772;22361396;21336134;15564712;25738858;18679121;10051305;15932639;28572050;17285446;8951576;9856608;32176300;19556262;25705430;18545064;29454761;28576783;25559473;2677721;11342473;22269099;15329503;10706898;22447007;23225133;16014643;11070105",
"title": "Effect of Acute Immunosuppression on Left Ventricular Recovery and Mortality in Fulminant Viral Myocarditis: A Case Series and Review of Literature.",
"title_normalized": "effect of acute immunosuppression on left ventricular recovery and mortality in fulminant viral myocarditis a case series and review of literature"
} | [
{
"companynumb": "CA-BEH-2021128333",
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"actiondrug": "6",
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"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
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... |
{
"abstract": "BACKGROUND\nIgA nephropathy (IgAN) has been anecdotally reported in association with atypical hemolytic uremic syndrome (aHUS). The association likely portends poor renal outcome, and the possible relationship with complement overactivation has yet to be elucidated. We evaluated a series of IgAN patients with aHUS and reviewed the available literature.\n\n\nMETHODS\nAdult patients who received a diagnosis of IgAN and developed aHUS between January 2009 and December 2019 were included in this retrospective review.\n\n\nRESULTS\nWe identified six IgAN-aHUS patients, all of whom developed end-stage kidney disease. At aHUS presentation all patients had decreased serum C3 levels. Predisposing pathogenetic variants and risk haplotypes for aHUS in CFH gene heterozygosity were documented in four out of six patients. Anti-CFH antibodies were found to be negative in the five tested patients. In the literature we identified 21 case reports involving aHUS-IgAN and six retrospective studies evaluating the presence of TMA at the time of renal biopsy. Hypertension, severe proteinuria, reduced sC3 and a worse renal prognosis were the common features of most cases.\n\n\nCONCLUSIONS\nOur case series and literature review show that the onset of either aHUS or renal TMA in the course of IgAN are associated with very poor renal outcome. Activation of the alternative pathway revealed by consumption of serum C3 seems to play a major role. Our hypothesis is that the presence of a predisposing factor (e.g. dysregualtion of complement alternative pathway and/or other intrarenal precipitating factors) might be at the heart of aHUS-IgAN pathophysiology.",
"affiliations": "Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy. lmanenti1969@gmail.com.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.;UO Nefrologia e Dialisi, Azienda Ospedaliero Universitaria di Modena, Modena, Italy.;UO di Anatomia Patologica, Azienda Ospedaliero Universitaria di Parma, Parma, Italy.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.;UO Nefrologia e Dialisi, Azienda Unità Sanitaria Locale della Romagna, Rimini, Italy.;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy.;Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Ranica, Bergamo, Italy.;Dipartimento di Medicina e Chirurgia, Università di Parma e UO Nefrologia, Azienda Ospedaliero-Universitaria di Parma, Via Gramsci 14, 43126, Parma, Italy.",
"authors": "Manenti|Lucio|L|http://orcid.org/0000-0002-4144-2142;Rossi|Giovanni Maria|GM|;Pisani|Isabella|I|;Gentile|Micaela|M|;Fontana|Francesco|F|;Pilato|Francesco Paolo|FP|;Delsante|Marco|M|;Ricco|Federico|F|;Mignani|Renzo|R|;Mele|Caterina|C|;Bresin|Elena|E|;Fiaccadori|Enrico|E|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.1007/s40620-021-01189-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": null,
"journal": "Journal of nephrology",
"keywords": "Acute renal failure; Complement; End-stage-kidney disease; Genetic; Hemolytic uremic syndrome; Hypertension; IgA nephropathy; Thrombotic microangiopathy",
"medline_ta": "J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "9012268",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34757577",
"pubdate": "2021-11-10",
"publication_types": "D016428:Journal Article",
"references": "28341274;25694468;33570723;19846853;23787552;26895476;10411356;20595690;20734203;22892290;24875561;25458228;24290408;26564419;26937078;29043138;28743127;29241200;30102484;29619992;32870493;22052055;31103332;29698975;30936425;17176910;31865800;19096082;28542627;23320601;25599621;15609695;23134230",
"title": "IgA nephropathy and atypical hemolytic uremic syndrome: a case series and a literature review.",
"title_normalized": "iga nephropathy and atypical hemolytic uremic syndrome a case series and a literature review"
} | [
{
"companynumb": "IT-MYLANLABS-2022M1044826",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
... |
{
"abstract": "The purpose of this study was to establish the efficacy and toxicities of concurrent erlotinib and docetaxel with intensity-modulated radiotherapy (IMRT) for locally advanced head and neck squamous cell carcinoma (HNSCC).\n\n\n\nPatients received daily erlotinib for 2 weeks, followed by daily IMRT with concurrent weekly docetaxel and daily erlotinib, followed by daily erlotinib for up to 2 years. The primary objective was disease-free survival (DFS). Secondary objectives included overall survival (OS), patterns of failure, and toxicities. Forty-three patients were recruited for this study.\n\n\n\nWith a median follow-up of 48.7 months, the 3-year DFS, OS, locoregional failure-free survival, and distant metastasis-free survival was 69.5%, 81%, 82.4%, and 83.7%, respectively. The most common grade III/IV local toxicities were dysphagia, dermatitis, and mucositis. Patients with p16-positive tumors had significantly better outcomes.\n\n\n\nThe regimen is tolerable and effective. It is worthy of further investigation in selected patients and may be useful in patients who cannot tolerate cisplatin. © 2016 Wiley Periodicals, Inc. Head Neck 38: E1770-E1776, 2016.",
"affiliations": "Department of Radiation Oncology, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Radiation Oncology, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Otolaryngology - Head and Neck Surgery, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, Cleveland, Ohio.;Department of Internal Medicine (Medical Oncology), University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Otolaryngology - Head and Neck Surgery, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Otolaryngology - Head and Neck Surgery, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Pathology, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Internal Medicine (Medical Oncology), University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Radiation Oncology, University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.;Department of Internal Medicine (Medical Oncology), University Hospitals Case Medical Center, Seidman Cancer Hospital, Cleveland, Ohio.",
"authors": "Yao|Min|M|;Woods|Charles|C|;Lavertu|Pierre|P|;Fu|Pingfu|P|;Gibson|Michael|M|;Rezaee|Rod|R|;Zender|Chad|C|;Wasman|Jay|J|;Sharma|Neelesh|N|;Machtay|Mitchell|M|;Savvides|Panayiotis|P|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24313",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38 Suppl 1()",
"journal": "Head & neck",
"keywords": "chemoradiation; docetaxel; erlotinib; head and neck cancer; radiation",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D059248:Chemoradiotherapy; D002945:Cisplatin; D018572:Disease-Free Survival; D000077143:Docetaxel; D000069347:Erlotinib Hydrochloride; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D050397:Radiotherapy, Intensity-Modulated; D043823:Taxoids",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E1770-6",
"pmc": null,
"pmid": "26918562",
"pubdate": "2016-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "25154822;25559415;23460709;22253412;21969503;21952273;20530316;19897418;19787782;19446902;18784101;18056187;17827454;17538162;17236972;16467544;15234052;14657228;14645636;25002723;10768432;12108901;10679658;24954745;25596660",
"title": "Phase II study of erlotinib and docetaxel with concurrent intensity-modulated radiotherapy in locally advanced head and neck squamous cell carcinoma.",
"title_normalized": "phase ii study of erlotinib and docetaxel with concurrent intensity modulated radiotherapy in locally advanced head and neck squamous cell carcinoma"
} | [
{
"companynumb": "US-ASTELLAS-2016US012798",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERLOTINIB"
},
"drugadditional": null,
... |
{
"abstract": "Piezo1, encoded by the gene PIEZO1, is an erythrocytic cellular membrane mechanoactivated cation channel. Mutations have been implicated in erythrocyte volume disorders (EVDs)-especially hereditary xerocytosis (HX)/dehydrated stomatocytosis (DHS). We identified three patients, all with novel PIEZO1 mutations, but only one displaying the HX/DHS phenotype. Retrospective review of three cases. Osmotic gradient red cell deformability (Osmoscan) was assessed via the Technicon Ektacytometer. Red cell band 3 content was estimated using Eosin-5'-Maleimide staining. Patient 1 was evaluated for polycythemia. Osmoscans suggested mild spherocytosis; a novel PIEZO1 mutation (p.Thr1589Ile, exon 35) was identified, causing mild erythrocytosis without hemolytic anemia. Patient 2 was evaluated for macrocytosis/reticulocytosis, normal-to-high hemoglobin, and indirect hyperbilirubinemia. Osmoscans suggested increased cellular hydration; a second novel PIEZO1 mutation (p.Arg1728Cys, exon 37) was identified, resulting in overhydrated stomatocytosis with well-compensated hemolysis. Patient 3 was evaluated for indirect hyperbilirubinemia only. Osmoscans suggested dehydrated stomatocytosis (DHS, xerocytosis); a third novel PIEZO1 mutation (p.Arg2279Cys, exon 47) was identified. All three patients' blood smears demonstrated stomatocytes and spherocytes. EVDs may be underdiagnosed due to the lack of \"expected\" anemia in a hemolytic disorder; two of three patients had high hemoglobin and red cell counts and one had high normal values for both parameters and the presence of stomatocytes/dehydrated cells lead to identification of causative PIEZO1 mutations. PIEZO1-associated EVDs may be more common than previously suspected and should be included in the diagnostic algorithms for mild erythrocytosis/unexplained jaundice.",
"affiliations": "Division of Pediatric Hematology and Oncology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Detroit , Michigan , USA.;Division of Pediatric Hematology and Oncology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Detroit , Michigan , USA.;Fulgent Diagnostics , Temple City , California , USA.;Division of Pediatric Hematology and Oncology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Detroit , Michigan , USA.;Division of Pediatric Hematology and Oncology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Detroit , Michigan , USA.;Division of Pediatric Hematology and Oncology, Carman and Ann Adams Department of Pediatrics, Children's Hospital of Michigan , Detroit , Michigan , USA.",
"authors": "Knight|Tristan|T|http://orcid.org/0000-0002-7828-1522;Zaidi|Ahmar Urooj|AU|;Wu|Shengnan|S|;Gadgeel|Manisha|M|;Buck|Steven|S|;Ravindranath|Yaddanapudi|Y|",
"chemical_list": "D007473:Ion Channels; C515204:PIEZO1 protein, human",
"country": "England",
"delete": false,
"doi": "10.1080/08880018.2019.1637984",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0888-0018",
"issue": "36(5)",
"journal": "Pediatric hematology and oncology",
"keywords": "Erythrocyte membrane; PIEZO1; erythrocyte volume disorders; erythrocytosis; hemolytic anemia; osmotic gradient ektacytometry; stomatocytosis; xerocytosis",
"medline_ta": "Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D019943:Amino Acid Substitution; D000745:Anemia, Hemolytic, Congenital; D004911:Erythrocyte Volume; D005091:Exons; D006801:Humans; D015160:Hydrops Fetalis; D007473:Ion Channels; D008297:Male; D020125:Mutation, Missense; D011086:Polycythemia; D013103:Spherocytosis, Hereditary",
"nlm_unique_id": "8700164",
"other_id": null,
"pages": "317-326",
"pmc": null,
"pmid": "31298594",
"pubdate": "2019-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mild erythrocytosis as a presenting manifestation of PIEZO1 associated erythrocyte volume disorders.",
"title_normalized": "mild erythrocytosis as a presenting manifestation of piezo1 associated erythrocyte volume disorders"
} | [
{
"companynumb": "US-OTSUKA-2019_033212",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Immune checkpoint inhibitors can enhance the antitumor activity of the immune system by mainly promoting CD8+ T lymphocyte immune function. However, they can also induce immune-related adverse events, especially skin toxicity. Some studies found that patients with autoimmune or inflammatory disease are susceptible to immune checkpoint inhibitors and were associated with a significantly increased risk of immune-related adverse events. In our present report, we described a newly diagnosed non-small-cell lung cancer patient who suffered from focal vitiligo for approximately ten years and was treated with the anti-programmed cell death-1 receptor antibody camrelizumab (SHR-1210), which accelerated the aggravation of depigmentation of the skin over the whole body in just half a year.",
"affiliations": "Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Dermatological Department, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Thoracic Surgery Department, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.;Cancer Center, The First Hospital of Jilin University, Changchun, Jilin 130021, China.",
"authors": "Xu|Yinghui|Y|;Cai|Yangyang|Y|;Zu|Jianjiao|J|;Wang|Xu|X|;Wang|Yizhuo|Y|;Sun|Chao|C|;Guo|Ye|Y|;Shao|Guoguang|G|;Yang|Zhiguang|Z|;Qiu|Shi|S|;Ma|Kewei|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000082082:Immune Checkpoint Inhibitors; D061026:Programmed Cell Death 1 Receptor; C000631724:camrelizumab",
"country": "England",
"delete": false,
"doi": "10.2217/imt-2019-0090",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1750-743X",
"issue": "12(3)",
"journal": "Immunotherapy",
"keywords": "AE; NSCLC; PD-1; adverse event; camrelizumab; non-small-cell lung cancer; vitiligo",
"medline_ta": "Immunotherapy",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002289:Carcinoma, Non-Small-Cell Lung; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008175:Lung Neoplasms; D008875:Middle Aged; D061026:Programmed Cell Death 1 Receptor; D012008:Recurrence; D014820:Vitiligo",
"nlm_unique_id": "101485158",
"other_id": null,
"pages": "175-181",
"pmc": null,
"pmid": "32064977",
"pubdate": "2020-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Aggravation of depigmentation for a non-small-cell lung cancer patient with pre-existing vitiligo using anti-programmed cell death-1 therapy: case report.",
"title_normalized": "aggravation of depigmentation for a non small cell lung cancer patient with pre existing vitiligo using anti programmed cell death 1 therapy case report"
} | [
{
"companynumb": "CN-EAGLE PHARMACEUTICALS, INC.-CN-2020EAG000124",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CAMRELIZUMAB"
},
"druga... |
{
"abstract": "Ganciclovir (GCV)-resistant cytomegalovirus (CMV) infection is a common problem among solid organ transplant (SOT) recipients without prior CMV immunity (CMV D+/R-). GCV-resistant CMV represents a particular challenge for CMV management. Letermovir is a recently licensed antiviral agent for primary CMV prophylaxis in allogenic hematopoietic stem cell transplant (HSCT) recipients. Given the favorable safety profile and its oral bioavailability letermovir may be considered a valuable off-label option for secondary prophylaxis of GCV-resistant CMV in SOT recipients. Here, we describe our experience with letermovir as secondary prophylaxis for GCV-resistant CMV in two renal transplant recipients and review the literature in regard of previously published cases. Letermovir resistance emerged after a few months of secondary prophylaxis in the two renal transplant recipients. In both cases, the previously described UL56 C325Y letermovir resistance mutation was detected. In vitro studies of letermovir suggest a relatively low genetic barrier to resistance. Therefore, caution is warranted when using letermovir as secondary prophylaxis for GCV-resistant CMV infection.",
"affiliations": "Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Nephrology, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Nephrology, Bern University Hospital, University of Bern, Bern, Switzerland.;Institute for Infectious Diseases, University of Bern, Bern, Switzerland.;Institute for Infectious Diseases, University of Bern, Bern, Switzerland.;Infectious Diseases Service, Department of Medicine, University Hospital and University of Lausanne, Lausanne, Switzerland.;Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.;Department of Infectious Diseases, Bern University Hospital, University of Bern, Bern, Switzerland.",
"authors": "Hofmann|Eveline|E|;Sidler|Daniel|D|;Dahdal|Suzan|S|;Bittel|Pascal|P|;Suter-Riniker|Franziska|F|;Manuel|Oriol|O|https://orcid.org/0000-0001-7607-0943;Walti|Laura N|LN|;Hirzel|Cédric|C|https://orcid.org/0000-0002-7870-912X",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D011799:Quinazolines; C000588473:letermovir; D015774:Ganciclovir",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "human cytomegalovirus infection (CMV); letermovir resistance; secondary CMV prophylaxis; solid organ transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000085:Acetates; D000998:Antiviral Agents; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D024882:Drug Resistance, Viral; D015774:Ganciclovir; D006801:Humans; D016377:Organ Transplantation; D011799:Quinazolines; D066027:Transplant Recipients",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13515",
"pmc": null,
"pmid": "33210830",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection: A case series and review of the literature.",
"title_normalized": "emergence of letermovir resistance in solid organ transplant recipients with ganciclovir resistant cytomegalovirus infection a case series and review of the literature"
} | [
{
"companynumb": "CH-MLMSERVICE-20210914-3097790-2",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "1"... |
{
"abstract": "A diabetic patient who was misdiagnosed as rheumatoid arthritis because of complicated musculoskeletal manifestations of diabetes is reported here. A 57 year old woman had been on sulphasalazine treatment with a diagnosis of rheumatoid arthritis for 3 years but failed to respond. Her past medical history disclosed that she had been using metformin due to diabetes mellitus for 8 years. On physical examination there was no evidence of arthritis. Her clinical picture was compatible with diffuse idiopathic skeletal hyperostosis (DISH), shoulder periarthritis, carpal tunnel syndrome, limited joint mobility of diabetes and furthermore myalgia due to metformin induced by hypovitaminosis D. Finally rheumatoid arthritis was excluded and a diagnosis of diabetes mellitus originated diffuse musculoskeletal system involvement was made. Diabetic musculoskeletal complications are common and sometimes cause clinical dilemmas. This case is also important for highlighting the contribution of low vitamin D status to the clinical status.",
"affiliations": "Ankara Physical Medicine and Rehabilitation Training and Research Hospital.;Ankara Physical Medicine and Rehabilitation Training and Research Hospital.;Ankara Physical Medicine and Rehabilitation Training and Research Hospital.;Ankara Physical Medicine and Rehabilitation Training and Research Hospital.",
"authors": "Tasoglu|Ozlem|O|;Dogan-Aslan|Meryem|M|;Yenigun|Didem|D|;Ozgirgin|Nese|N|",
"chemical_list": null,
"country": "Portugal",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-464X",
"issue": "40(1)",
"journal": "Acta reumatologica portuguesa",
"keywords": null,
"medline_ta": "Acta Reumatol Port",
"mesh_terms": "D001172:Arthritis, Rheumatoid; D048909:Diabetes Complications; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D008875:Middle Aged; D009140:Musculoskeletal Diseases",
"nlm_unique_id": "0431702",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "24880140",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A challenging case of diffuse diabetic musculoskeletal system involvement: diagnostic confusion with rheumatoid arthritis.",
"title_normalized": "a challenging case of diffuse diabetic musculoskeletal system involvement diagnostic confusion with rheumatoid arthritis"
} | [
{
"companynumb": "TR-INVENTIA-000157",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nAtypical antipsychotics, increasingly used in children and adolescents, modulate brain dopamine. Iron plays a critical role in dopaminergic signaling. Therefore, we explored whether body iron status is related to psychiatric symptom severity, treatment response, and tolerability following extended antipsychotic therapy.\n\n\nMETHODS\nBetween November 2005 and August 2009, medically healthy 7-17-year-old risperidone-treated participants enrolled in a cross-sectional study examining the long-term safety of this antipsychotic. Anthropometric measurements were obtained. Psychiatric symptom severity and dietary intake were assessed. Serum ferritin, transferrin receptor, and prolactin concentrations were measured. Linear multivariable regression analysis tested the association among body iron, symptom severity, the dose of risperidone and psychostimulants, and serum prolactin concentration.\n\n\nRESULTS\nThe sample consisted of 115 patients (87% males) with a mean (±SD) age of 11.6 (±2.8) years. The majority had externalizing disorders, and they had taken risperidone for 2.4 (±1.7) years. Body iron was low, with 45% having iron depletion and 14% having iron deficiency. Iron status was inversely associated with weight gain during risperidone treatment and with interleukin-6. Body iron was neither associated with psychiatric symptom severity nor with the daily dose of risperidone and psychostimulants. It was, however, inversely associated with prolactin concentration, which was nearly 50% higher in the iron-deficient group.\n\n\nCONCLUSIONS\nIron depletion and deficiency are prevalent in children and adolescents chronically treated with risperidone. Iron deficiency accentuates the antipsychotic-induced elevation in prolactin. Future studies should confirm this finding and investigate the potential benefit of iron supplementation in antipsychotic-treated patients.",
"affiliations": "Department of Psychiatry, University of Iowa, Iowa City, Iowa 52242, USA. chadi-calarge@uiowa.edu",
"authors": "Calarge|Chadi Albert|CA|;Ziegler|Ekhard E|EE|",
"chemical_list": "D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D015850:Interleukin-6; D011388:Prolactin; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1089/cap.2012.0046",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1044-5463",
"issue": "23(2)",
"journal": "Journal of child and adolescent psychopharmacology",
"keywords": null,
"medline_ta": "J Child Adolesc Psychopharmacol",
"mesh_terms": "D000293:Adolescent; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D002648:Child; D003430:Cross-Sectional Studies; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D015850:Interleukin-6; D000090463:Iron Deficiencies; D016014:Linear Models; D008297:Male; D001523:Mental Disorders; D015999:Multivariate Analysis; D015995:Prevalence; D011388:Prolactin; D018967:Risperidone; D012720:Severity of Illness Index; D013997:Time Factors; D015430:Weight Gain",
"nlm_unique_id": "9105358",
"other_id": null,
"pages": "101-9",
"pmc": null,
"pmid": "23480322",
"pubdate": "2013-03",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "20655955;15583094;12704220;18534235;9771341;11053528;19850683;19907144;20415603;19297460;10742372;20331935;18054688;16966351;19339912;8094018;12219063;17101454;15909765;10638065;12521995;21462109;11509198;2391604;20200263;19364288;19861668;19858761;2872066;18164140;9405575;21486167;18279203;20855045;12449285;16061790;9435670;14997175;21186968;22575541;11773541;11160596;20978274;7524105",
"title": "Iron deficiency in pediatric patients in long-term risperidone treatment.",
"title_normalized": "iron deficiency in pediatric patients in long term risperidone treatment"
} | [
{
"companynumb": "US-JNJFOC-20130317091",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "To evaluate whether use of comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) influences the retention of tumor necrosis factor inhibitors (TNFi) in patients with spondyloarthritis (SpA).\n\n\n\nPatients with SpA from the Rheumatic Diseases Portuguese Register who started treatment with their first TNFi between 2001 and 2014 were included in this study. Cox regression analysis was used to estimate the effect of comedication with csDMARDs on TNFi retention in 2 types of models: a model in which baseline (time-fixed) variables were included, and a second model incorporating time-varying variables, including sociodemographic features, measures of disease activity, measures of physical function, and cotreatment with other drugs (nonsteroidal antiinflammatory drugs and oral steroids). To control for possible confounding by indication, the effect of csDMARD comedication on TNFi retention was also tested after adjustment for the treatment propensity score.\n\n\n\nIn total, 954 patients were included in the study, of whom 289 (30.3%) discontinued treatment with their first TNFi after a median follow-up time of 2.5 years (range 0.08-13 years). Inefficacy was the most common reason for TNFi discontinuation (55.7% of patients). In the multivariable analyses, comedication with csDMARDs had no measurable effect on TNFi retention, neither in the baseline model (hazard ratio [HR] 0.83, 95% confidence interval [95% CI] 0.59-1.16) nor during follow-up in the model adjusted for time-varying covariates (HR 1.07, 95% CI 0.68-1.68). The effect of csDMARD comedication remained nonsignificant after propensity score adjustment.\n\n\n\nComedication with csDMARDs does not prolong TNFi retention in patients with SpA in clinical practice, suggesting that there is no benefit conferred by the concomitant use of these drugs.",
"affiliations": "Universidade Nova de Lisboa, Lisbon, Portugal, and Leiden University Medical Center, Leiden, The Netherlands. alexsepriano@gmail.com.;Universidade Nova de Lisboa, Lisbon, Portugal, and Leiden University Medical Center, Leiden, The Netherlands.;Leiden University Medical Center, Leiden, The Netherlands.;Lisbon Academic Medical Center, Lisbon, Portugal.;Centro Hospitalar São João, Porto, Portugal.;Instituto Português de Reumatologia, Lisbon, Portugal.;Hospital Garcia de Orta, Almada, Portugal.;Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Unidade Local de Saúde do Alto Minho, Ponte de Lima, Portugal.;Unidade Local de Saúde do Alto Minho, Ponte de Lima, Portugal.;Hospital Infante D. Pedro, Aveiro, Portugal.;Hospital Infante D. Pedro, Aveiro, Portugal.;Hospital de Faro, Faro, Portugal.;Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Hospital Garcia de Orta, Almada, Portugal.;Instituto Português de Reumatologia, Lisbon, Portugal.;Centro Hospitalar São João, Porto, Portugal.;Lisbon Academic Medical Center and Instituto de Medicina Molecular, Lisbon, Portugal.;Lisbon Academic Medical Center and Instituto de Medicina Molecular, Lisbon, Portugal.;Universidade Nova de Lisboa and Hospital de Egas Moniz-CHLO, Lisbon, Portugal.;Universidade Nova de Lisboa and Hospital de Egas Moniz-CHLO, Lisbon, Portugal.;Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands, and Atrium Medical Center, Heerlen, The Netherlands.",
"authors": "Sepriano|A|A|;Ramiro|S|S|;van der Heijde|D|D|;Ávila-Ribeiro|P|P|;Fonseca|R|R|;Borges|J|J|;Teixeira|L|L|;Carvalho|P D|PD|;Cerqueira|M|M|;Neves|J|J|;Meirinhos|T|T|;Barcelos|A|A|;Sequeira|G|G|;Salvador|M J|MJ|;Canas da Silva|J|J|;Santos|H|H|;Bernardes|M|M|;Vieira-Sousa|E|E|;Canhão|H|H|;Branco|J C|JC|;Pimentel-Santos|F|F|;Landewé|R|R|",
"chemical_list": "D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D014409:Tumor Necrosis Factor-alpha; D002097:C-Reactive Protein; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": "10.1002/art.39772",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "68(11)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D001799:Blood Sedimentation; D002097:C-Reactive Protein; D015331:Cohort Studies; D000069340:Deprescriptions; D004359:Drug Therapy, Combination; D000068800:Etanercept; D005260:Female; D006801:Humans; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D010147:Pain Measurement; D011446:Prospective Studies; D025241:Spondylarthritis; D025242:Spondylarthropathies; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "2671-2679",
"pmc": null,
"pmid": "27273894",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of Comedication With Conventional Synthetic Disease-Modifying Antirheumatic Drugs on Retention of Tumor Necrosis Factor Inhibitors in Patients With Spondyloarthritis: A Prospective Cohort Study.",
"title_normalized": "effect of comedication with conventional synthetic disease modifying antirheumatic drugs on retention of tumor necrosis factor inhibitors in patients with spondyloarthritis a prospective cohort study"
} | [
{
"companynumb": "PT-JNJFOC-20161126728",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GOLIMUMAB"
},
"drugadditional": null,
"... |
{
"abstract": "Subdural contrast effusion secondary to endovascular treatment is exceptionally rare and might be mistaken as subdural hematoma because of similar hyperattenuation on computer tomography. The authors present the case of a 13-month-old girl with a history of increased head circumference and developmental retardation. Cerebral digital subtraction angiography showed a high-flow pial arteriovenous fistula fed by multiple arteries on the right cerebellar surface, with occlusion of the right sigmoid sinus and severe stenosis of the left sigmoid sinus. Staged endovascular treatments were performed to eliminate the fistula. Follow-up head computer tomography scans performed 3 h after both procedures demonstrated typical high-density subdural effusion with computer tomography attenuation value similar to hemorrhage. These effusions did not aggravate the condition and disappeared spontaneously 32 h after the first treatment and 29 h after the second, respectively.",
"affiliations": "Department of Neurosurgery, 455994Capital Medical University Sanbo Brain Hospital, Beijing, China.;Department of Neurosurgery, 455994Capital Medical University Sanbo Brain Hospital, Beijing, China.;Department of Neurosurgery, 455994Capital Medical University Sanbo Brain Hospital, Beijing, China.;Department of Neurosurgery, 455994Capital Medical University Sanbo Brain Hospital, Beijing, China.",
"authors": "Yan|Wen-Tao|WT|;Li|Xiu-Zhen|XZ|;Yan|Chang-Xiang|CX|;Liu|Jia-Chun|JC|https://orcid.org/0000-0003-3239-5804",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1591019920938965",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1591-0199",
"issue": "27(1)",
"journal": "Interventional neuroradiology : journal of peritherapeutic neuroradiology, surgical procedures and related neurosciences",
"keywords": "Subdural effusion; arteriovenous fistula; contrast media; extravasation of diagnostic and therapeutic materials",
"medline_ta": "Interv Neuroradiol",
"mesh_terms": "D001164:Arteriovenous Fistula; D002533:Cerebral Angiography; D002648:Child; D004621:Embolization, Therapeutic; D057510:Endovascular Procedures; D005260:Female; D006801:Humans; D007223:Infant; D013353:Subdural Effusion",
"nlm_unique_id": "9602695",
"other_id": null,
"pages": "31-36",
"pmc": null,
"pmid": "32611214",
"pubdate": "2021-02",
"publication_types": "D016428:Journal Article",
"references": "28059677;26382645;29203309;25909569;18433495;25160131;27493234;27896904;31506726;1528455;28352965;6351570;20351515;30627297;28798216",
"title": "Typical subdural contrast effusion secondary to endovascular treatment of a pediatric pial arteriovenous fistula.",
"title_normalized": "typical subdural contrast effusion secondary to endovascular treatment of a pediatric pial arteriovenous fistula"
} | [
{
"companynumb": "CN-BAYER-2021-116449",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": null... |
{
"abstract": "BACKGROUND\nCancer-related stroke has been regarded as an emerging subtype of ischemic event. Acute treatment for this subtype may include the antiplatelet agents, anticoagulants, or endovascular intervention.\nA 63-year-old woman with sudden-onset right hemiparesis and conscious change was sent to our emergency department. The patient had underlying sigmoid adenocarcinoma and received chemotherapy FOLFIRI (FOL, folinic acid; F, fluorouracil; and IRI, irinotecan) with targeted therapy cetuximab following lower anterior resection since the diagnosis was made.\nBrain magnetic resonance angiography revealed a filling defect in left carotid bulb, and neurosonography showed a thick atherosclerotic plaque (size 4.9 mm) in the left internal carotid artery on day 5 after the onset of stroke.\n\n\nMETHODS\nDuring the first three hours after onset, administration of IV tissue plasminogen activator did not resolve the thrombus. Dabigatran (110 mg bid) started on day 7.\n\n\nRESULTS\nThe atherosclerotic plaque dissolved on day 24. The patient recovered her muscle strength but still had nonfluent speech in mild extent.\n\n\nCONCLUSIONS\nThrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy. Dabigatran, an oral anticoagulant, had a benefit for this subtype of ischemic stroke among patients with cancer.",
"affiliations": "School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City.;Division of Hematology and Oncology, Department of Medicine, Taipei Municipal Wangfang Hospital.;School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City.",
"authors": "Wu|Bo-Chang|BC|;Hu|Ming-Hung|MH|;Wang|Vinchi|V|",
"chemical_list": "D000991:Antithrombins; D010959:Tissue Plasminogen Activator; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000021922",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-02323\n10.1097/MD.0000000000021922\n21922\n5300\nResearch Article\nClinical Case Report\nThe resolution of carotid arterial thrombus by oral anticoagulation after IV thrombolysis for chemotherapy-induced stroke\nA case reportWu Bo-Chang MDa Hu Ming-Hung MDbc Wang Vinchi MD, PhDade∗ Saranathan. Maya a School of Medicine, College of Medicine, Fu-Jen Catholic University, New Taipei City\nb Division of Hematology and Oncology, Department of Medicine, Taipei Municipal Wangfang Hospital\nc Taipei Cancer Center, Taipei Medical University, Taipei\nd Department of Neurology, Cardinal Tien Hospital\ne Medical Quality Management Center, Cardinal Tien Hospital, New Taipei City, Taiwan.\n∗ Correspondence: Vinchi Wang, Department of Neurology, Cardinal Tien Hospital, 362, Zhongzheng Road, Xindian District, New Taipei City 231, Taiwan (e-mail: vwneur@yahoo.com.tw).\n28 8 2020 \n28 8 2020 \n99 35 e2192213 3 2020 1 7 2020 28 7 2020 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nCancer-related stroke has been regarded as an emerging subtype of ischemic event. Acute treatment for this subtype may include the antiplatelet agents, anticoagulants, or endovascular intervention.\n\nPatient concerns:\nA 63-year-old woman with sudden-onset right hemiparesis and conscious change was sent to our emergency department. The patient had underlying sigmoid adenocarcinoma and received chemotherapy FOLFIRI (FOL, folinic acid; F, fluorouracil; and IRI, irinotecan) with targeted therapy cetuximab following lower anterior resection since the diagnosis was made.\n\nDiagnoses:\nBrain magnetic resonance angiography revealed a filling defect in left carotid bulb, and neurosonography showed a thick atherosclerotic plaque (size 4.9 mm) in the left internal carotid artery on day 5 after the onset of stroke.\n\nInterventions:\nDuring the first three hours after onset, administration of IV tissue plasminogen activator did not resolve the thrombus. Dabigatran (110 mg bid) started on day 7.\n\nOutcomes:\nThe atherosclerotic plaque dissolved on day 24. The patient recovered her muscle strength but still had nonfluent speech in mild extent.\n\nLessons:\nThrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy. Dabigatran, an oral anticoagulant, had a benefit for this subtype of ischemic stroke among patients with cancer.\n\nKeywords\narterial thromboembolismdabigatranthrombolysistissue plasminogen activatorOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nStroke may be a critical complication among patients with cancer, regardless of venous occlusion or arterial ischemia. It has been regarded as the most common cause of complex disability and the 3rd most common cause of death in Taiwan,[1] and is still ranked the 2nd leading cause of death worldwide, despite the decline in the United States in the past decade.[2] It is already known that early reperfusion therapy for acute ischemic stroke after administration by tissue plasminogen activator (tPA) has a better prognosis and is the mainstay of treatment for those without contraindications.\n\nCancer-related stroke has been regarded as an emerging subtype of ischemic event.[3] Here, we report the case of a 63-year-old female patient with cancer with acute cerebral arterial embolism, in which the thrombus in the carotid bulb did not dissolve after tPA but did so later after dabigatran. There have been several case reports describing thrombus resolution after dabigatran, which acts as an anticoagulant by directly inhibiting thrombin.[4–6] We will discuss some interesting issues regarding the pathogenesis and pharmacologic effects.\n\n2 Case presentation\nA 63-year-old woman presented to our emergency department with sudden-onset right hemiparesis and consciousness change. The patient got a diagnosis of sigmoid adenocarcinoma (pT3N1aM1, p-stage IV) 4 months before this stroke, and she had been on chemotherapy FOLFIRI (FOL, folinic acid; F, fluorouracil; and IRI, irinotecan) with targeting agent cetuximab as systemic therapy after lower anterior resection. Her last FOLFIRI chemotherapy (5th cycle) with cetuximab had been administered 4 days prior.\n\nSudden conscious change and fall took place 1 hour before arrival at our emergency room. Upon arrival, she was alert, normal vital signs, and the neurologic examination revealed right-sided limb weakness with speech problems. She exhibited nonfluent speech output, incorrect naming, word substitution, but intact repetition, fair comprehension, and obedience on secondary commands. The initial National Institute of Health Stroke Scale scored 6 out of 42. Brain computed tomography excluded intracranial hemorrhage, and then IV bolus of tPA (35 mg, 0.7 mg/kg) was administered soon. Mechanical thrombectomy was deferred because of her weak physical condition after the recent chemotherapy course. Echocardiography did not reveal any intracardiac thrombus. Brain magnetic resonance imaging showed acute infarction in left middle cerebral artery territory, mainly involving left insula and parietal lobe, and magnetic resonance angiography revealed a vague plaque image in left internal carotid artery (ICA) of the neck and occlusion of the Sylvian and cortical M3 segment of left middle cerebral artery (Fig. 1). Coagulation studies showed normal partial thrombin time, prothrombin time, fibrinogen, and antithrombin III, but elevated D-Dimer 1152 μg/mL. All other laboratory studies were within normal limits, including tumor marker CEA 1.19 ng/mL and CA-199 11.92 IU/mL. Her motor aphasia persisted, but her weakness improved during her stay in the ICU on the 2nd day.\n\nFigure 1 A filling defect (arrow) in left carotid bulb region by magnetic resonance angiography.\n\nOn day 5 after the onset of stroke, neurosonography revealed a thick atherosclerotic plaque in left carotid bulb (Fig. 2). On day 7, she started dabigatran (110 mg twice daily) due to suspicion of cerebral embolism possibly caused by ICA plaque rupture. The plaque image by the follow-up neurosonography still existed on day 10, but disappeared on day 24 (Fig. 3), that is, 17 days after the use of dabigatran. During these 17 days, dabigatran was the only treatment administered. The patient left the hospital with mild motor dysphasia but no motor weakness. After discharge, the patient was on dabigatran for 3 months, and then aspirin to prevent thrombus formation. Besides, she continued oral chemotherapy Tegafur (5-FU) and remained stable for the following 18 months. There was no new episode of stroke during the follow-up period.\n\nFigure 2 A thick thrombus (49 mm in size) in left carotid bulb on day 5 by neurosonography.\n\nFigure 3 The thrombus dissolved on day 24 by the follow-up neurosonography.\n\n3 Discussion\nWe cast interest on this case because of the finding of atheroma by magnetic resonance angiography and neurosonography, and of the atheroma resolving after the use of dabigatran. Someone may question clinical issues about this case, including why the intravenous thrombolysis by tPA failed but later atheroma resolved by dabigatran; why the atheroma formed in the artery rather than vein; and whether the atheroma formation caused by cancer itself or by chemotherapy.\n\nThe tPA, a serine protease found on the endothelial lining of blood vessels, binds to fibrin and facilitates plasminogen conversion to plasmin, which then breaks down the thrombus.[7] The efficacy of recanalization by tPA may be related to the location and burden of the thrombus, as the thrombus in the proximal ICA is more resistant to tPA than distal ones.[8] In our case, we also postulate that tPA did have some subtle effect on the thrombus that made the latter medication – dabigatran resolve this atheroma efficiently. There have been several reports of similar resolution of intravascular and intracardiac thrombi by dabigatran. Kaku reported a case of intracardiac thrombus resolution after anticoagulation therapy with dabigatran (150 mg twice daily).[4] Nagamoto et al reported an example that dabigatran (110 mg twice daily) resolved a left ventricular thrombus.[5] Akiyama et al described the thrombolytic action of dabigatran (110 mg twice daily) on an ICA thrombus.[6] Kaku and Nagamoto et al reported cases with the resolution of intracardiac thrombi, whereas Akiyama et al reported a carotid thrombus. The intracardiac thrombus dissolved completely in 21 and 27 days in Kaku's and Nagamoto's cases, respectively (Table 1). The patient in the report by Akiyama et al took irregular dosing of dabigatran 110 mg bid for approximately 3 years. A carotid thrombus was incidentally found by the neck vessel sonographic examination performed for cancer staging, without mentioning the thrombus size. Regular use of dabigatran began in that case, and the carotid thrombus disappeared in 16 days. There are some similarities between our and Akiyama's cases, including the thrombus location (both were within ICA near carotid bulb), the dose of dabigatran (both were 110 mg twice daily), and history of cancer (stage III esophageal carcinoma in Akiyama's patient and stage IV colorectal carcinoma in ours). All of the above case reports did not mention the use of tPA for their patients. Dabigatran was the only treatment for the thrombus.\n\nTable 1 Thrombus resolution after dabigatran use, listing the thrombus location, dabigatran doses, and total treatment days of dabigatran before the thrombus disappearance first noted in our and previous reports.\n\nDabigatran, a direct oral anticoagulant, directly binds to thrombin. Without the activation of thrombin, the drug blocks the transformation of fibrinogen into fibrin, resulting in no new thrombus formation.[9] Besides its primary action of anticoagulation, its contribution to thrombolysis is postulated to be the inhibition of thrombus extension, which in turn causes unstable fibrin networks to be broken down by plasmin.[10]\n\nThrombi can be classified as white or red thrombi based on their macroscopic appearance and predominant color. Several different descriptions of red and white thrombi have been published. Koupenova et al described white thrombus as a platelet-rich thrombus formed in arteries, and red thrombus as a fibrin- and erythrocyte-rich thrombus formed in veins due to different velocities in arteries and veins.[11] In contrast, there are few reports of fibrin-rich thrombosis in arteries.[12,13] According to Quadros et al, white thrombi have a higher percentage of fibrin but a lower percentage of erythrocytes than red thrombi.[14] White thrombi are smaller and mainly composed of fibrin. Maekawa et al reported that cardioembolic thrombi have a higher percentage of fibrin and fewer erythrocytes than noncardioembolic thrombi.[15] Therefore, white thrombi may be either platelet rich or fibrin rich, whereas red thrombi contain erythrocytes.\n\nWe did not obtain the thrombus sample for pathologic diagnosis from this patient. Nevertheless, based on the fact that the thrombus disappeared after dabigatran administration, we thought that a fibrin- and erythrocyte-rich red thrombus was more likely than a platelet-rich white one in our case. According to Maekawa et al, a higher percentage of erythrocytes was more common in a noncardioembolic thrombus,[15] which was consistent with the left ICA thrombus in our case. Dabigatran would resolve the plaque indirectly by limiting the extension of the existing thrombus, making it easier to be removed by plasmin.\n\nAnother interesting issue is whether chemotherapy or cancer itself caused thrombus formation. Navi et al compared the incidences of arterial thromboembolisms (ATEs) (such as stroke and myocardial infarction) in patients with cancer at different sites and among those with advanced stages.[16] It is known that the risk of ATEs is higher in lung, colorectal, and gastric cancers. Advanced stages further increase the risk, and the risk of ischemic stroke is highest within the first 6 months after the diagnosis of cancer. The cumulative incidences of myocardial infarction and ischemic stroke since the diagnosis of colorectal cancer have been reported. Six-month hazard ratios of myocardial and cerebral ischemia among newly diagnosed patients with cancer were estimated to be 2.9 and 1.9, respectively.[16] It seems that intensive chemotherapy after diagnosis might be associated with this increased risk, as in our case.\n\nThe multifactorial pathogenesis of ATEs in cancers may include individual cardiovascular risks, comorbidities, immobilization, primary cancer location, and treatment by chemotherapy or radiotherapy.[17] Cancer can activate platelets, increase expression of procoagulants, and suppress fibrinolytic activity.[18–20] Activation of these procoagulant factors can take place during the apoptosis of tumor cells induced by chemotherapy or radiation.[17] Both chemotherapy and radiotherapy cause endothelium damage, which induces the activation of platelets and the coagulation cascade. In addition, a reduction in fibrinolysis is involved in tumor growth and metastasis. Furthermore, 5-fluorouracil, a pyrimidine analogue used in the treatment of colorectal cancer, may cause direct endothelial damage leading to platelet and coagulation cascade activation.[17]\n\nIn this patient with colorectal cancer, it was unlikely that the stroke was the result of metastasis or arterial invasion of tumor growth based on the evidence that dabigatran resolved the thrombus. Both cancer itself and chemotherapy give rise to a hypercoagulable state; therefore, it is difficult to say which one induced the thrombus. However, we figured that chemotherapy was the primary factor in thrombus formation because the onset of stroke was within a short period after the chemotherapy courses. We did not perform IA thrombectomy for this patient. If we did, the content of thrombus by pathologic analysis, platelet- or fibrin-rich, would cast more interest in the pathogenesis of the thrombus.\n\nThus, in our case, we hypothesized a “two-step” mechanism in this cancer-related stroke. First, the cancer made an environment with higher procoagulants predisposing the patient to thrombus formation. Second, on the following adjuvant chemotherapy, accelerated thrombus formation by damaging the endothelium and inducing the coagulation cascade occurred. Given that our patient developed stroke after several cycles of chemotherapy, the diagnosis of chemotherapy-induced stroke was reasonable as these events occurred chronologically. We also observed the thrombus resolution effect of dabigatran, which could be explained as stated in this article. In this stroke patient with colon cancer, thrombus formed in a “two-step” mechanism, which was later resolved by an oral anticoagulant. Oral anticoagulation had benefit for this subtype of ischemic stroke. Thrombolytic and anticoagulant medications in this patient suggested the thrombus formation with fibrin-rich content which may be attributable to both cancer and chemotherapy.\n\nAcknowledgment\nThe authors thank Editage-Taiwan (#VIANG_4) for providing this editing service.\n\nAuthor contributions\nBo-Chang Wu: review of the medical history; literature search; manuscript drafting.\n\nMing-Hung Hu: cancer history review; consultation of medication effects.\n\nVinchi Wang: stroke patient care; draft review and discussion; literature search.\n\nAbbreviations: ATE = arterial thromboembolism, ICA = internal carotid artery, tPA = tissue plasminogen activator.\n\nHow to cite this article: Wu BC, Hu MH, Wang V. The resolution of carotid arterial thrombus by oral anticoagulation after IV thrombolysis for chemotherapy-induced stroke: A case report. Medicine. 2020;99:35(e21922).\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors have no funding and conflicts of interest to disclose.\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Hsieh FI Chiou HY \nStroke: morbidity, risk factors, and care in taiwan\n. J Stroke \n2014 ;16 :59 64\n.24949310 \n[2] Guzik A Bushnell C \nStroke epidemiology and risk factor management\n. Continuum (Minneap Minn) \n2017 ;23 :15 39\n.28157742 \n[3] Bang OY Chung JW Lee MJ \nCancer-related stroke: an emerging subtype of ischemic stroke with unique pathomechanisms\n. J Stroke \n2020 ;22 :1 0\n.32027788 \n[4] Kaku B \nIntra-cardiac thrombus resolution after anti-coagulation therapy with dabigatran in a patient with mid-ventricular obstructive hypertrophic cardiomyopathy: a case report\n. J Med Case Rep \n2013 ;7 :238 .24103078 \n[5] Nagamoto Y Shiomi T Matsuura T \nResolution of a left ventricular thrombus by the thrombolytic action of dabigatran\n. Heart Vessels \n2014 ;29 :560 2\n.24005764 \n[6] Akiyama H Hoshino M Shimizu T \nResolution of internal carotid arterial thrombus by the thrombolytic action of dabigatran: a first case report\n. Medicine (Baltimore) \n2016 ;95 :e3215 .27057852 \n[7] Bivard A Lin L Parsonsb MW \nReview of stroke thrombolytics\n. J Stroke \n2013 ;15 :90 8\n.24324944 \n[8] del Zoppo GJ Poeck K Pessin MS \nRecombinant tissue plasminogen activator in acute thrombotic and embolic stroke\n. Ann Neurol \n1992 ;32 :78 86\n.1642475 \n[9] Hoffman M \nRemodeling the blood coagulation cascade\n. J Thromb Thrombolysis \n2003 ;16 :17 20\n.14760207 \n[10] Kato T Yasaka M Yabuki T \nTwo-week administration of rivaroxaban resolved left atrial thrombus\n. J Cardiol Cases \n2014 ;10 :238 40\n.30534252 \n[11] Koupenova M Kehrel BE Corkrey HA \nThrombosis and platelets: an update\n. Eur Heart J \n2017 ;38 :785 91\n.28039338 \n[12] Uchida Y Uchida Y Sakurai T \nCharacterization of coronary fibrin thrombus in patients with acute coronary syndrome using dye-staining angioscopy\n. Arterioscler Thromb Vasc Biol \n2011 ;31 :1452 60\n.21415387 \n[13] Niesten JM van der Schaaf IC van Dam L \nHistopathologic composition of cerebral thrombi of acute stroke patients is correlated with stroke subtype and thrombus attenuation\n. PLoS One \n2014 ;9 :e88882 .24523944 \n[14] Quadros AS Cambruzzi E Sebben J \nRed versus white thrombi in patients with ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention: clinical and angiographic outcomes\n. Am Heart J \n2012 ;164 :553 60\n.23067914 \n[15] Maekawa K Shibata M Nakajima H \nErythrocyte-rich thrombus is associated with reduced number of maneuvers and procedure time in patients with acute ischemic stroke undergoing mechanical thrombectomy\n. Cerebrovasc Dis Extra \n2018 ;8 :39 49\n.29402828 \n[16] Navi BB Reiner AS Kamel H \nRisk of arterial thromboembolism in patients with cancer\n. J Am Coll Cardiol \n2017 ;70 :926 38\n.28818202 \n[17] Canale ML Bisceglia I Lestuzzi C \nArterial thrombosis in cancer: spotlight on the neglected vessels\n. Anticancer Res \n2019 ;39 :4619 25\n.31519559 \n[18] Aronson D Brenner B \nArterial thrombosis and cancer\n. Thromb Res \n2018 ;164 : Suppl 1 : S23 8\n.29703480 \n[19] Falanga A Marchetti M Russo L \nThe mechanisms of cancer-associated thrombosis\n. Thromb Res \n2015 ;135 : Suppl 1 : S8 11\n.25903541 \n[20] Franco AT Corken A Ware J \nPlatelets at the interface of thrombosis, inflammation, and cancer\n. Blood \n2015 ;126 :582 8\n.26109205\n\n",
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"mesh_terms": "D000230:Adenocarcinoma; D000284:Administration, Oral; D000971:Antineoplastic Combined Chemotherapy Protocols; D000991:Antithrombins; D002341:Carotid Artery Thrombosis; D002343:Carotid Artery, Internal; D000069604:Dabigatran; D005260:Female; D006801:Humans; D020244:Infarction, Middle Cerebral Artery; D018810:Magnetic Resonance Angiography; D008875:Middle Aged; D058226:Plaque, Atherosclerotic; D012811:Sigmoid Neoplasms; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator",
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"pubdate": "2020-08-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "The resolution of carotid arterial thrombus by oral anticoagulation after IV thrombolysis for chemotherapy-induced stroke: A case report.",
"title_normalized": "the resolution of carotid arterial thrombus by oral anticoagulation after iv thrombolysis for chemotherapy induced stroke a case report"
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"abstract": "A case of Strongyloides stercoralis hyperinfection in a patient with dermatomyositis and diabetes mellitus is herein reported. The case was a 60-year-old female admitted due to watery diarrhea and unconsciousness. She had a 10-year history of chronic immunosuppressive therapy including methotrexate and prednisolone for dermatomyositis. Stool parasitological examination revealed numerous rhabditiform larvae of threadworm \"S. stercoralis.\" Larva in stool sample was characterized by sequencing of mitochondrial DNA. After treatment with ivermectin, the patient recovered without evidence of S. stercoralis in follow-up stool samples. In endemic areas, stool examination for detection of S. stercoralis should be performed on a regular basis for all patients receiving immunosuppressive therapy, as early detection and treatment are necessary to minimize complications of severe strongyloidiasis.",
"affiliations": "Department of Medical Parasitology and Mycology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran.;Emergency Department of Emam Reza Hospital, Qom Medical Center, Social Security Organization, Qom, Iran.;Department of Medical Parasitology and Mycology, Amol Faculty of Paramedics, Mazandaran University of Medical Sciences, Sari, Iran.;Center for Research of Endemic Parasites of Iran, Tehran University of Medical Sciences; Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.;Center for Research of Endemic Parasites of Iran, Tehran University of Medical Sciences; Department of Medical Parasitology and Mycology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Sharifdini|Meysam|M|;Hesari|Aniseh|A|;Mahdavi|Seif Ali|SA|;Alipour|Akram|A|;Kia|Eshrat Beigom|EB|",
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"keywords": "Dermatomyositis; Strongyloides stercoralis; diabetes mellitus; immunosuppression; strongyloidiasis hyperinfection; threadworm",
"medline_ta": "Indian J Pathol Microbiol",
"mesh_terms": "D000818:Animals; D000893:Anti-Inflammatory Agents; D003882:Dermatomyositis; D003920:Diabetes Mellitus; D005243:Feces; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007814:Larva; D008727:Methotrexate; D008875:Middle Aged; D011239:Prednisolone; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014474:Unconsciousness",
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"title": "Strongyloides stercoralis hyperinfection in an unconscious diabetic patient with dermatomyositis.",
"title_normalized": "strongyloides stercoralis hyperinfection in an unconscious diabetic patient with dermatomyositis"
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"abstract": "OBJECTIVE\nSince the 1970s, the use of metamizole is controversial due to the risk of agranulocytosis. The aim of this study was to analyze individual case safety reports (ICSRs) of metamizole-associated hematological adverse drug reactions (ADRs).\n\n\nMETHODS\nInternational and Swiss metamizole-associated ICSR concerning selected hematological ADR were retrieved from VigiBase™, the World Health Organization Global Database of ICSR, and the Swiss Pharmacovigilance Database. We evaluated demographic data, co-medication, drug administration information, dose and duration of metamizole treatment, as well as the latency time of ADR, their course, and severity. The subgroup analysis of Swiss reports allowed us to analyze cases with fatal outcome more in depth and to estimate a rough minimal incidence rate.\n\n\nRESULTS\nA total of 1417 international and 77 Swiss reports were analyzed. Around 52 % of the international and 33 % of the Swiss metamizole-associated hematological ADR occurred within a latency time of ≤7 days. More women were affected. The annual number of hematological reports and those with fatal outcome increased over the last years parallel to metamizole sales figures. In Switzerland, the minimal incidence rate of agranulocytosis was 0.46-1.63 cases per million person-days of use (2006-2012). Female sex, old age, pancytopenia, and co-medication with methotrexate were striking characteristics of the seven Swiss fatal cases.\n\n\nCONCLUSIONS\nMetamizole-associated hematological ADR remain frequently reported. This is underscored by increasing annual reporting rates, which mainly reflect growing metamizole use. Early detection of myelotoxicity and avoidance of other myelotoxic substances such as methotrexate are important measures for preventing fatalities.",
"affiliations": "Division of Clinical Pharmacology and Toxicology, University Hospital, Hebelstrasse 2, 4031, Basel, Switzerland.",
"authors": "Blaser|Lea S|LS|;Tramonti|Alexandra|A|;Egger|Pascal|P|;Haschke|Manuel|M|;Krähenbühl|Stephan|S|;Rätz Bravo|Alexandra E|AE|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004177:Dipyrone",
"country": "Germany",
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"issue": "71(2)",
"journal": "European journal of clinical pharmacology",
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"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000894:Anti-Inflammatory Agents, Non-Steroidal; D002648:Child; D002675:Child, Preschool; D004177:Dipyrone; D005260:Female; D006402:Hematologic Diseases; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D013557:Switzerland; D014944:World Health Organization; D055815:Young Adult",
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"references": "10215599;10493111;16689555;22172309;12136373;15330129;18043241;12449518;8515788;17435173;19999607;12051124;3747087;4723818;10086830;15073823;17470834;15580488;10030310;17435797;12812006;15851637",
"title": "Hematological safety of metamizole: retrospective analysis of WHO and Swiss spontaneous safety reports.",
"title_normalized": "hematological safety of metamizole retrospective analysis of who and swiss spontaneous safety reports"
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{
"abstract": "BACKGROUND\nDirect-acting antivirals are new drugs for chronic hepatitis C treatment. They are usually safe and well tolerated, but can sometimes cause serious adverse effects and there is no consensus on how to treat or prevent them. We described a case of hand-foot syndrome due to hepatitis C virus interferon-free therapy.\n\n\nMETHODS\nWe report the case of a 49-year-old man with compensated liver cirrhosis due to chronic hepatitis C genotype 1, treatment-naïve, who started viral treatment with sofosbuvir, simeprevir and ribavirin for 12 weeks.\n\n\nRESULTS\nAt the sixth week of treatment he had anemia, requiring a lower dose of ribavirin. At the tenth week, he had erythematous, pruritic, scaly and flaky lesions on hands and feet, which showed a partial response to oral antihistamines and topical corticosteroids. It was not necessary to discontinue antiviral treatment, but in the first week after the end of treatment, there was worsening of injuries, including signs of secondary infection, that required hospitalization, antibiotics and oral corticosteroid, with progressive improvement. Biopsy of the lesions was consistent with pharmacodermia. The patient had sustained a virological response, despite the side effect. He had a history of pharmacodermia one year ago attributed to the use of topiramate, responsive to oral corticosteroid.\n\n\nCONCLUSIONS\nInterferon-free therapies can rarely lead to severe adverse reactions, such as skin lesions. Patients receiving ribavirin combinations and those who had a history of pharmacodermia or skin disease may be more susceptible. There is no consensus on how to prevent skin reactions in these patients.",
"affiliations": "Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Dermatology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Dermatology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.;Department of Gastroenterology, School of Medical Sciences, University of Campinas (UNICAMP), Campinas, SP, Brasil.",
"authors": "Cunha-Silva|Marlone|M|http://orcid.org/0000-0002-4424-6606;Mazo|Daniel|D|;Arrelaro|Raquel|R|;Vaz|Nayana|N|;Rabello|Marcello|M|;Lopes|Tirzah|T|;Corrêa|Bárbara|B|;Torino|Ana Beatriz|AB|;Cintra|Maria|M|;Lorena|Sonia|S|;Sevá-Pereira|Tiago|T|;Almeida|Jazon|J|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D007372:Interferons; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1806-9282.64.05.415",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0104-4230",
"issue": "64(5)",
"journal": "Revista da Associacao Medica Brasileira (1992)",
"keywords": null,
"medline_ta": "Rev Assoc Med Bras (1992)",
"mesh_terms": "D000998:Antiviral Agents; D060831:Hand-Foot Syndrome; D006526:Hepatitis C; D006801:Humans; D007372:Interferons; D008297:Male; D008875:Middle Aged; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "9308586",
"other_id": null,
"pages": "415-419",
"pmc": null,
"pmid": "30304139",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hand-foot syndrome due to hepatitis C therapy.",
"title_normalized": "hand foot syndrome due to hepatitis c therapy"
} | [
{
"companynumb": "BR-KADMON PHARMACEUTICALS, LLC-KAD201810-000677",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIMEPREVIR"
},
"drugadd... |
{
"abstract": "Gilles de la Tourette's syndrome is a combined vocal and multiple motor tic disorder. Here, we present a case of Tourette's syndrome who attended our psychiatric causality with severe depression and suicidal ideation. On reviewing follow-up records of 23 years, we come to know about the academic decline and nicotine dependence in the early childhood. He also developed co-morbid obsessive compulsive disorder (OCD) along with severe depression. He was agitated and self-injurious. We diagnosed him as Gilles de la Tourette's syndrome with co-morbid OCD, depression, nicotine dependence. The patient was treated with haloperidol, sertraline, and clonidine when he developed mixed switch that necessitated us to stop sertraline. Hence, he was treated with a mood stabilizer and he remitted. Here, we want to show how Tourette's syndrome can take a longer course with different co-morbidities in a single person's life. As per our knowledge, such presentation is relatively rare in Indian literature.",
"affiliations": "Department of Psychiatry, Govt. T. D. Medical College, Alappuzha, Kerala, India.;Department of Psychiatry, Govt. T. D. Medical College, Alappuzha, Kerala, India.;Department of Psychiatry, Govt. T. D. Medical College, Alappuzha, Kerala, India.",
"authors": "Das|Soumitra|S|;Kartha|Arjun|A|;Purushothaman|Sumesh Thoppil|ST|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4103/0253-7176.183084",
"fulltext": "\n==== Front\nIndian J Psychol MedIndian J Psychol MedIJPsyMIndian Journal of Psychological Medicine0253-71760975-1564Medknow Publications & Media Pvt Ltd India IJPsyM-38-26310.4103/0253-7176.183084Case ReportLong-term Follow-up of a Case of Gilles de la Tourette's syndrome Das Soumitra Kartha Arjun Purushothaman Sumesh Thoppil Department of Psychiatry, Govt. T. D. Medical College, Alappuzha, Kerala, IndiaAddress for correspondence: Dr. Soumitra Das C/420, PG Hostel, Medical College Hospital, Vandanam, Alappuzha - 688 005, Kerala, India. E-mail: soumitratdmc@gmail.comMay-Jun 2016 38 3 263 265 Copyright: © Indian Journal of Psychological Medicine2016This is an open access article distributed under the terms of the Creative Commons Attribution NonCommercial ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non commercially, as long as the author is credited and the new creations are licensed under the identical terms.Gilles de la Tourette's syndrome is a combined vocal and multiple motor tic disorder. Here, we present a case of Tourette's syndrome who attended our psychiatric causality with severe depression and suicidal ideation. On reviewing follow-up records of 23 years, we come to know about the academic decline and nicotine dependence in the early childhood. He also developed co-morbid obsessive compulsive disorder (OCD) along with severe depression. He was agitated and self-injurious. We diagnosed him as Gilles de la Tourette's syndrome with co-morbid OCD, depression, nicotine dependence. The patient was treated with haloperidol, sertraline, and clonidine when he developed mixed switch that necessitated us to stop sertraline. Hence, he was treated with a mood stabilizer and he remitted. Here, we want to show how Tourette's syndrome can take a longer course with different co-morbidities in a single person's life. As per our knowledge, such presentation is relatively rare in Indian literature.\n\nCo-morbiditiescourseticsTourette's syndromes\n==== Body\nINTRODUCTION\nTourette's syndrome is characterized by multiple motor tics like eye blinking or shoulder shrugging and one or more vocal tics such as sniffing or snorting, although these need not have occurred concurrently. The disorder may present with common co-morbidities such as attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), self-injurious behavior (SIB), personality disorders, anxiety, depression, and other less common like oppositional defiant disorder, conduct disorder, learning disorder, rage, autism, etc.[1] There is hypotheses such as super sensitivity of postsynaptic dopamine receptors, dopamine hyperinnervation, abnormal presynaptic function or an excessive phasic release of dopamine as etiological factors.[2]\n\nCASE REPORT\nA 37-year-old married male auto driver sixth standard drop out attended psychiatric causality service with involuntary jerky side to side movement of the head, face, protruding of tongue, and production of abusive words. The onset of illness was during class six when the patient developed repeated eyelids elevation with looking toward the right side of his head and blowing his hair. After 3 months, he developed rapid and recurrent involuntary jerky up and down movement of the head, followed by front and back movement of the neck along with whistling sound suggesting of the motor as well as vocal tics. He was consulted with a neurologist as he refused to go to school due to bullying by schoolmates. He was investigated and diagnosed as Tourette's syndrome. There after he was under treatment for 19 years with haloperidol 5 mg daily with regular follow-up from neurologist. He was improved except eyelid tics. Meanwhile, he started using oral nicotine to control the protruding movement of the tongue. Gradually, he started taking almost 20 packets of oral nicotine (Hans, a local nicotine product) per day. He developed nicotine dependence and oral ulcer. He stopped taking drugs 4 years ago without any advice. He contributed the discontinuation due to sedation and started using alternative medicines (acupuncture). He stopped all types of treatment 9 months ago due to the financial crisis. His facial tics reappeared after 15 days of discontinuation. He started showing SIB and created multiple big ulcers on hand. Furthermore, he started suffering from ruminative thoughts about upcoming duties. For the last 4 months, he developed depressive symptoms like low mood, fatigability, decreased talk, decreased sleep, hopelessness, and death wishes. Furthermore, he stopped going to work for the last 2 months. At present, 2 days ago, he experienced auditory and visual hallucination of threatening and commanding type followed by relapse of motor tics with forceful forward movement of neck associated throat clearing sound, protruding out the tongue such as snake, tightly closing eyes, lip smacking, facial twitching, and also sniffing sound by mouth. His family member also noticed aggressive behavior as if he would beat them. He also occasionally uttered abusing words on provocation. We rated the patient's symptoms and quality of life with different scales, such as:\n\n\nTotal Yale Global Tic Severity Scale: 86 (0–100) (total tic severity: 36 + impairment: 50).\n\nModified Rush Videotape Rating Scale: 12/20.\n\nYale-Brown Obsessive Compulsive Scale, total score: 24.\n\nHamilton Depression Rating Scale, total score: 20.\n\nThe World Health Organization quality of life —BREF: 49.\n\n\n\n\nWe diagnosed him Tourette's syndrome with co-morbid depressive disorder, OCD, nicotine dependence, SIB. We started him on haloperidol 5 mg along with clonidine 50 mcg/day with close supervision and follow-up. After 1 month while on same medicines his tics were subsided but his depressive symptoms were worsened. It necessitated us to start sertraline 50 mg/day with reduction of haloperidol to 2.5 mg. However, after 2 weeks patient developed mixed affective state with both manic and depressive symptoms. We stopped sertraline and started him on valproate 600 mg/day with quetiapine 100 mg at night along with the continuation of haloperidol 2.5 mg and clonidine 50 mcg/day. At present, the patient is well maintained on the same drugs, and there is only occasional tics that patient can control by habit reversal techniques. Presently, there are no depressive or manic symptoms. He started going to his job without any difficulty.\n\nDISCUSSION\nDiagnosis of Tourette's syndrome is often missed due to confusion with manneristic motor behavior. Here in our case, disorder started at 14 years of age which is a common age of onset. Gradually, it leaded to academic decline and drop out from school due to inattention as a part of ADHD and milder form of OCD which are highly genetically correlated with Tourette's syndrome but often under diagnosed in pediatric age group.[3] The patient developed nicotine dependence that was related to motor tics of the tongue. Orth et al. described that, a single dose of nicotine, at serum nicotine levels similar to those seen after smoking a single cigarette, adjust electrophysiological measures of the excitability of circuit within the motor cortex to normal levels in Tourette's syndrome and reduces tics.[4] The patient developed SIB that has a direct relation with OCD, hostility, and tics severity. Tourette's syndrome plus at least one other psychiatric morbidity have a fourfold increased risk of SIB. Later patient also developed OCD and depression. OCD is intimately related with Tourette's syndrome, percentage varying from 11% to 80%. According to some authors, OCD is a different phonotypical expression of Tourette's syndrome. Lifetime risk of depression in Tourette's syndrome is 10%, which is multifactorial like genetic, psychological stressor due to chronic disabling disease, or lack of support.[56] Depression also may be due to direct co-morbidity of OCD, which is quite understandable in this case. Patient also had suicidal ideation and hopelessness which created a crisis situation for family members.\n\nOur case reflects that Tourette's syndrome often takes a complex progressive course even with treatment. Comorbidities are often disabling even more than primary disorder. Comorbities like SIB, nicotine dependence are less studied in India. Our case throws light on the need for early diagnosis, education, assessment and proper management, especially in growing children.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Cavanna AE Servo S Monaco F Robertson MM The behavioral spectrum of Gilles de la Tourette syndrome J Neuropsychiatry Clin Neurosci 2009 21 13 23 19359447 \n2 Singer HS Current issues in Tourette syndrome Mov Disord 2000 15 1051 63 11104186 \n3 Grados MA Mathews CA Tourette syndrome association international consortium for genetics. Latent class analysis of Gilles de la Tourette syndrome using comorbidities: Clinical and genetic implications Biol Psychiatry 2008 64 219 25 18359008 \n4 Orth M Amann B Robertson MM Rothwell JC Excitability of motor cortex inhibitory circuits in Tourette syndrome before and after single dose nicotine Brain 2005 128 Pt 6 1292 300 15774505 \n5 Kadesjö B Gillberg C Tourette's disorder: Epidemiology and comorbidity in primary school children J Am Acad Child Adolesc Psychiatry 2000 39 548 55 10802971 \n6 Robertson MM Tourette syndrome, associated conditions and the complexities of treatment Brain J Neurol 2000 123 Pt 3 425 62\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7176",
"issue": "38(3)",
"journal": "Indian journal of psychological medicine",
"keywords": "Co-morbidities; Tourette's syndromes; course; tics",
"medline_ta": "Indian J Psychol Med",
"mesh_terms": null,
"nlm_unique_id": "7910727",
"other_id": null,
"pages": "263-5",
"pmc": null,
"pmid": "27335527",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "15774505;10802971;11104186;19359447;10686169;18359008",
"title": "Long-term Follow-up of a Case of Gilles de la Tourette's syndrome.",
"title_normalized": "long term follow up of a case of gilles de la tourette s syndrome"
} | [
{
"companynumb": "IN-ACCORD-042168",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "HALOPERIDOL"
},
"drugadditional": "1",
"drug... |
{
"abstract": "Zonisamide is a sulfonamide drug used primarily for the treatment of partial seizures in adults. We describe the case of a 15-year-old woman with a mood disorder who survived without complications after ingestion of an estimated 7.5 g of zonisamide. To the best of our knowledge, there are 4 case reports of individuals with intentional ingestion of more than 4 g of zonisamide as a single agent. Our patient developed coma and hypotension 4 hours after ingestion and was treated with a catecholamine infusion, endotracheal intubation, and mechanical ventilation. She had mild electrocardiographic abnormalities and fully recovered after 4 days. This report contributes to the understanding of acute zonisamide poisoning.",
"affiliations": null,
"authors": "McStay|Charlayne|C|;Pierce|Richard|R|;Riley|Carley|C|",
"chemical_list": "D000927:Anticonvulsants; D002395:Catecholamines; D007555:Isoxazoles; D000078305:Zonisamide",
"country": "United States",
"delete": false,
"doi": "10.1097/PEC.0000000000000854",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-5161",
"issue": "34(2)",
"journal": "Pediatric emergency care",
"keywords": null,
"medline_ta": "Pediatr Emerg Care",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D002395:Catecholamines; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007442:Intubation, Intratracheal; D007555:Isoxazoles; D019964:Mood Disorders; D012121:Respiration, Artificial; D013406:Suicide, Attempted; D000078305:Zonisamide",
"nlm_unique_id": "8507560",
"other_id": null,
"pages": "e30-e31",
"pmc": null,
"pmid": "27749631",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Complete Recovery After Acute Zonisamide Overdose in an Adolescent Female.",
"title_normalized": "complete recovery after acute zonisamide overdose in an adolescent female"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2018GMK033013",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZONISAMIDE"
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{
"abstract": "Lyell's syndrome or toxic epidermal necrolysis (TEN) is a life threatening complication mostly caused by medications, characterized by desquamative lesions of the skin and mucous membranes with 30 percent or more epidermal involvement along with mucus membrane. We report a rare case of toxic epidermal necrolysis following administration of docetaxel, a semi-synthetic taxane. A female diagnosed as having metastatic breast carcinoma received chemotherapy in form of docetaxel after being exposed to adjuvant chemotherapy, developed severe involvement of skin and mucus membrane. Diagnosis of TEN was made and she was managed with steroids, antibiotics, intravenous fluids and antiseptic dressings. Common toxicities reported with this drug include myelosuppression, alopecia, nail damage, erythema multiforme major and neuropathy. We believe this is the first case report of Lyell's syndrome following docetaxel. Main aim of this case is to make physicians aware of the severe skin reactions with docetaxel, measures to avoid them, early recognition and prompt treatment.",
"affiliations": "Department of Internal Medicine, Sher-i-Kashmir Institute of Medical Sciences, Soura, Jammu and Kashmir, India.",
"authors": "Arshad|Faheem|F|;Bhat|Tahir Saleem|TS|;Lone|Abdul Rashid|AR|",
"chemical_list": "D000970:Antineoplastic Agents; D043823:Taxoids; D000077143:Docetaxel",
"country": "India",
"delete": false,
"doi": "10.4103/0973-1482.136025",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1998-4138",
"issue": "10(3)",
"journal": "Journal of cancer research and therapeutics",
"keywords": null,
"medline_ta": "J Cancer Res Ther",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D000077143:Docetaxel; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008875:Middle Aged; D012867:Skin; D013262:Stevens-Johnson Syndrome; D043823:Taxoids",
"nlm_unique_id": "101249598",
"other_id": null,
"pages": "742-4",
"pmc": null,
"pmid": "25313773",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Docetaxel induced Lyell's syndrome: a rare life threatening cause of dermatitis medicamentosas.",
"title_normalized": "docetaxel induced lyell s syndrome a rare life threatening cause of dermatitis medicamentosas"
} | [
{
"companynumb": "PHHY2015IN013581",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
"dr... |
{
"abstract": "BACKGROUND\nThe use of corticosteroids in Kawasaki disease (KD) is still controversial. The aim of this study was to investigate the safety and effectiveness of modified methylprednisolone (mPSL) regimen as an initial treatment for refractory KD.\n\n\nMETHODS\nThis is a real-world observational study. We identified refractory KD with a self-developed scoring system. Patients were divided into the intravenous immunoglobulin (IVIG) + mPSL group and the IVIG group. Clinical outcomes and changes in coronary arteries after the treatment during a 12-week period were observed. Propensity-score matching was used to analyze those patients with similar baseline characteristics.\n\n\nRESULTS\nOf a total of 168 patients, 104 patients were assigned into the IVIG group and 64 patients into the IVIG + mPSL group. The therapeutic response rate of the IVIG + mPSL group was significantly higher than that of the IVIG group (98.4 vs 76.0%, P < 0.05). The IVIG + mPSL group had a shorter duration of fever and a higher rate of C-reactive protein decline than the IVIG group (1.17 ± 0.64 vs 1.81 ± 1.16 days; 88.1 vs 83.5%; P < 0.05). The luminal diameter and Z-score of the left circumflex coronary artery (LCX) were significantly smaller and lower in the IVIG + mPSL group than that in the IVIG group at weeks 2 and 12.\n\n\nCONCLUSIONS\nModified mPSL regimen has minimal side effects. It might improve the initial response to IVIG and decrease the dilation of LCX for refractory KD.\n\n\nCONCLUSIONS\nModified mPSL regimen (2-4 mg/kg/day, divided into 2-3 doses for 3-5 days, then 1 mg/kg/day, once a day for 3-5 days, then oral prednisone was tapered over 3-5 weeks in 5-7 days steps) as an intensive initial treatment can decrease LCX dilation in high-risk IVIG-resistant KD patients. Our self-developed scoring system has been proven validated and can be used to identify high-risk IVIG-resistant KD patients in North China. The present study provides an alternative therapeutic regimen for high-risk refractory KD patients.",
"affiliations": "Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China. lxhmaggie@126.com.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.;Department of Cardiology, Children's Hospital Capital Institute of Pediatrics, Beijing, China.",
"authors": "Zhang|Mingming|M|;Zheng|Yang|Y|;Li|Xiaohui|X|;Yang|Shuai|S|;Shi|Lin|L|;Li|Aijie|A|;Liu|Yang|Y|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1038/s41390-021-01576-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-3998",
"issue": null,
"journal": "Pediatric research",
"keywords": null,
"medline_ta": "Pediatr Res",
"mesh_terms": null,
"nlm_unique_id": "0100714",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34021270",
"pubdate": "2021-05-21",
"publication_types": "D016428:Journal Article",
"references": "28129459;440805",
"title": "Refractory Kawasaki disease: modified methylprednisolone regimen decreases coronary artery dilatation.",
"title_normalized": "refractory kawasaki disease modified methylprednisolone regimen decreases coronary artery dilatation"
} | [
{
"companynumb": "CN-TAKEDA-2021TUS034372",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HUMAN IMMUNOGLOBULIN G"
},
"drugadditional": "3... |
{
"abstract": "Inhibitor development poses a significant challenge in the management of hemophilia because once an inhibitor is present, bleeding episodes can no longer be treated with standard clotting factor replacement therapy. Consequently, patients with inhibitors are at increased risk for difficult-to-control bleeding and complications, particularly arthropathy and physical disability. Three clinical trials in patients with inhibitors have demonstrated that prophylaxis with a bypassing agent reduces joint and other types of bleeding and improves health-related quality of life compared with on-demand bypassing therapy. In hemophilia patients without inhibitors, the initiation of prophylaxis with factor (F) VIII or FIX prior to the onset of recurrent hemarthroses can prevent the development of joint disease. Whether this is also true for bypassing agent prophylaxis remains to be determined.",
"affiliations": "Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center, New Orleans, LA; and.;Louisiana Center for Bleeding and Clotting Disorders, Tulane University Medical Center, New Orleans, LA; and.;Washington Center for Bleeding Disorders, Bloodworks Northwest, Seattle, WA.",
"authors": "Leissinger|Cindy A|CA|;Singleton|Tammuella|T|;Kruse-Jarres|Rebecca|R|",
"chemical_list": "D001323:Autoantibodies; D001779:Blood Coagulation Factors; D011994:Recombinant Proteins; D005169:Factor VIII",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2014-10-551952",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "126(2)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D001323:Autoantibodies; D001779:Blood Coagulation Factors; D002648:Child; D005169:Factor VIII; D006395:Hemarthrosis; D006467:Hemophilia A; D006470:Hemorrhage; D006801:Humans; D008297:Male; D011788:Quality of Life; D011994:Recombinant Proteins",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "153-9",
"pmc": null,
"pmid": "25827834",
"pubdate": "2015-07-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "How I use bypassing therapy for prophylaxis in patients with hemophilia A and inhibitors.",
"title_normalized": "how i use bypassing therapy for prophylaxis in patients with hemophilia a and inhibitors"
} | [
{
"companynumb": "US-BAYER-2015-398988",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ANTIHEMOPHILIC FACTOR, HUMAN RECOMBINANT"
},
"dru... |
{
"abstract": "Amantadine use has been temporally associated with bilateral corneal edema in a series of cases; however, its pathophysiological mechanisms have yet to be elucidated. We sought to rule out subclinical Fuchs dystrophy as a contributor, characterize its pattern of corneal edema, and describe the long-term outcome of concurrent topical steroids while resuming amantadine.\nAfter a 44-year-old woman presented with new acute onset bilateral corneal edema, amantadine was discontinued, with clinical improvement. However, neurological decompensation required restarting amantadine, which she did concurrently with topical loteprednol. To determine whether subclinical Fuchs dystrophy might be present, triplet-primed polymerase chain reaction was conducted to measure copy number of the CTG18.1 trinucleotide repeat in TCF4. Specular microscopy and Scheimpflug imaging were conducted and followed for 32 months to assess for resolution and stability. Literature review was conducted to assess for consistency of the clinical phenotype.\nCorneal edema resolved clinically 4 weeks after discontinuation of amantadine. Serial Scheimpflug imaging demonstrated resolution of posterior and central corneal edema and specular microscopy revealed intracellular opacities with loss of endothelial cell density. Despite resuming amantadine, Scheimpflug imaging and specular microscopy measurements remained stable at 32 months. Triplet-primed PCR of CTG18.1 in TCF4 revealed no trinucleotide repeat expansion.\nAmantadine-associated corneal edema is characteristically posterior and central and appears unlikely to represent early or subclinical decompensation of Fuchs dystrophy. We describe the unique outcome of continued corneal clearance after restarting amantadine concurrently with steroids, a pattern that has persisted over 32 months to date.",
"affiliations": "Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.edu.;Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.edu.;Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.edu.;Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.edu.;Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.edu.",
"authors": "Hessen|Michelle M|MM|;Vahedi|Sina|S|;Khoo|Chloe T|CT|;Vakili|Gelareh|G|;Eghrari|Allen O|AO|",
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"doi": "10.2147/OPTH.S166384",
"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolClinical OphthalmologyClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove Medical Press 10.2147/OPTH.S166384opth-12-1367Original ResearchClinical and genetic investigation of amantadine-associated corneal edema Hessen Michelle M Vahedi Sina Khoo Chloe T Vakili Gelareh Eghrari Allen O Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA, allen@jhmi.eduCorrespondence: Allen O Eghrari, Division of Cornea, Cataract, & External Diseases, The Wilmer Eye Institute, Johns Hopkins University School of Medicine, 600 N Wolfe Street, Woods 375, Baltimore, Maryland 21287, USA, Tel +1 410 955 5490, Fax +1 410 614 9172, Email allen@jhmi.edu2018 06 8 2018 12 1367 1371 © 2018 Hessen et al. This work is published and licensed by Dove Medical Press Limited2018The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.Purpose\nAmantadine use has been temporally associated with bilateral corneal edema in a series of cases; however, its pathophysiological mechanisms have yet to be elucidated. We sought to rule out subclinical Fuchs dystrophy as a contributor, characterize its pattern of corneal edema, and describe the long-term outcome of concurrent topical steroids while resuming amantadine.\n\nPatient and methods\nAfter a 44-year-old woman presented with new acute onset bilateral corneal edema, amantadine was discontinued, with clinical improvement. However, neurological decompensation required restarting amantadine, which she did concurrently with topical loteprednol. To determine whether subclinical Fuchs dystrophy might be present, triplet-primed polymerase chain reaction was conducted to measure copy number of the CTG18.1 trinucleotide repeat in TCF4. Specular microscopy and Scheimpflug imaging were conducted and followed for 32 months to assess for resolution and stability. Literature review was conducted to assess for consistency of the clinical phenotype.\n\nResults\nCorneal edema resolved clinically 4 weeks after discontinuation of amantadine. Serial Scheimpflug imaging demonstrated resolution of posterior and central corneal edema and specular microscopy revealed intracellular opacities with loss of endothelial cell density. Despite resuming amantadine, Scheimpflug imaging and specular microscopy measurements remained stable at 32 months. Triplet-primed PCR of CTG18.1 in TCF4 revealed no trinucleotide repeat expansion.\n\nConclusions\nAmantadine-associated corneal edema is characteristically posterior and central and appears unlikely to represent early or subclinical decompensation of Fuchs dystrophy. We describe the unique outcome of continued corneal clearance after restarting amantadine concurrently with steroids, a pattern that has persisted over 32 months to date.\n\nKeywords\namantadinecorneacorneal edemacorneal endotheliumFuchs dystrophyScheimpflug imaging\n==== Body\nIntroduction\nAmantadine is an antiviral and antiparkinsonian drug associated with rare episodes of bilateral corneal edema, which often resolves upon cessation of the medication.1 Endothelial cell loss may require corneal transplantation even after discontinuation of amantadine.2 Although cases have been temporally associated with amantadine and its cessation, national data suggest a higher frequency of new diagnoses of Fuchs dystrophy among individuals starting amantadine therapy.3 To date, the causes of corneal edema are unclear; therefore, we sought to investigate the clinical and genetic features associated with amantadine-associated edema in a 44-year-old woman who presented with bilateral corneal edema.\n\nPatient and methods\nA 44-year-old female presented with decreased vision in both eyes over the course of 2 weeks, at which time she only utilized topical loteprednol 0.5% twice daily in both eyes for blepharitis. She also took amantadine 400 mg daily by mouth for over 3 years in the setting of ataxic cerebral palsy and associated neurological complications. Best corrected visual acuity at baseline was measured four months prior to presentation at 20/25 in both eyes (oculus uterque [OU]).\n\nAt the time of presentation, visual acuity was 20/125 in the right eye (oculus dextrus [OD]) and 20/60 in the left eye (oculus sinister [OS]). Pentacam Scheimpflug imaging (OCULUS Optikgeräte GmbH, Weztlar, Germany) was conducted which revealed pachymetry of 927 microns OD and 641 microns OS. Central corneal edema with Descemet folds, as visible in Figure 1, was exhibited without anterior chamber cell, in the right eye greater than the left. The patient had no known history of Fuchs dystrophy, viral prodrome or infection. Amantadine toxicity was considered and a discussion was held with her neurologist regarding discontinuation of the medication. However, given her need for amantadine, she was reluctant to discontinue the medication until an alternative treatment was identified. She returned 3 weeks later with worsening of vision to 20/125 OU, and pachymetry of 946 microns OD and 598 microns OS.\n\nGiven the disease progression, she discontinued amantadine and returned to the clinic 1 week later (Week 4 since presentation), with continued progression of edema. Visual acuity was 20/250 OD and 20/150 OS. She was monitored with serial visits, improving at Week 6 to 20/70 OD and 20/50 OS.\n\nAt 2 months (Week 8), her corneal edema had resolved and visual acuity returned to 20/30 OU, with pachymetry of 585 microns OD and 550 microns OS. Specular microscopy of both eyes with a machine unable to conduct flex-center analysis revealed severe endothelial cell loss, greater in the right eye, which subjectively appeared stable over time through subsequent analyses able to provide quantitative estimates (Figure 2).\n\nAt 6 months (Week 24), she returned for a follow-up appointment with worsening of her neurological state. Therefore, she resumed amantadine at a lower dose of 300 mg by mouth daily, divided into 200 mg in the morning and 100 mg in the evening. She maintained use of topical loteprednol 0.5% twice daily in both eyes. Her visual acuity remained stable subjectively and improved objectively to 20/25 OU. Pachymetry was stable in the right eye at 586 microns and continued to improve in the left eye at 523 microns.\n\nAt month 12 (Week 48), the patient returned for repeat specular microscopy, which revealed endothelial cell counts of 609 cells/mm2 OD and 1,387 cells/mm2 OS. In light of a guttate appearance to her cornea, she enrolled in a longitudinal study of Fuchs dystrophy for which she provided a blood sample and we sequenced the CTG18.1 trinucleotide repeat in TCF4 using methods we have previously described.1 She was found not to bear the implicated repeat expansion. She continued oral amantadine, and due to changes in insurance coverage, began topical fluorometholone 0.1% twice daily in place of topical loteprednol 0.5%.\n\nAt 18 months, the patient underwent repeat specular microscopy, which continued to be stable at 627 and 1,309 cells/mm2 in the right and left eyes, respectively, and 649 and 1,186 cells/mm2 at 2.7 years, despite continuing amantadine 300 mg daily. Images were analyzed with the flex center method. Visual acuity remained stable at 20/30 bilaterally, with no corneal edema present. She remains on topical fluorometholone twice daily in both eyes.\n\nTable 1 delineates the progression and resolution of her corneal edema based on visual acuity, pachymetry and specular microscopy readings. Table 2 summarizes the patterns of corneal edema described in all known cases in the literature, revealing central corneal edema as a characteristic pattern present in a slight majority of cases at time of diagnosis. Written informed consent was provided by the patient to publish case details and accompanying images. The Institutional Research Board at Johns Hopkins University School of Medicine waived the need for approval for reporting a single case.\n\nDiscussion\nAmantadine was first approved in 1966 for influenza prophylaxis and 3 years later, was discovered to address symptoms of Parkinson’s disease. It has weak N-methyl-D-aspartate (NMDA)-type glutamate receptor antagonist and anticholinergic properties, and both increase dopamine release and block dopamine reuptake. Its antiviral properties are related to an unrelated, separate effect on the M2 proton channel, a homotetramer located in viral envelopes of influenza viruses which modulates local pH levels to promote intracellular viral functions.\n\nWhile its most common adverse effects are associated with central nervous system function, including anxiety, agitation, and modulation of pre-existing epileptic or psychiatric symptoms, corneal edema is uncommon, at 0.27% in a 2-year study among veterans;3 in a post-surveillance study of over 13,137 patients receiving amantadine over 2 years, 36 were newly diagnosed with either corneal edema or Fuchs dystrophy. It is notable that 73% of known cases (16 of 22) have occurred in females (Table 2), a predominance that is also seen in Fuchs dystrophy. It is unclear whether similar pathways may contribute to such disparity, as endothelial cell death appears to occur in both diseases.20 We demonstrate here that in this case, amantadine-associated corneal edema is independent of a common genetic change prevalent in approximately two-thirds of individuals diagnosed with Fuchs dystrophy. Moreover, the resolution of edema does not support a diagnosis of Fuchs dystrophy, which progressively worsens over time. Nevertheless, more cases and similar analyses will be needed to better elucidate an association or lack thereof.\n\nThe pathophysiological mechanisms of transient edema in such cases are poorly understood; however, based on specular microscopy and histopathologic findings, endothelial cell death appears to be induced or accelerated.8 In this study, we compared the temporal progression and resolution of corneal edema in two affected eyes with all reported instances of amantadine-associated corneal edema in the literature (Table 2) and identify characteristic patterns of edema. First, corneal edema often appears centrally and, in some cases, progresses to diffuse edema. Second, cases may be asymmetrically bilateral, a process captured with bilateral imaging.\n\nGiven the need in some cases for corneal transplantation,10 early identification and cessation of amantadine will be helpful to maximize the likelihood of achieving corneal clarity. However, in instances where amantadine cannot be discontinued, as no alternative therapy is available, we describe the possibility that resuming amantadine with steroids may have assisted to maintain corneal endothelial cell density. Our findings support prior reports that demonstrated partial responses to topical and intravenous corticosteroids.10 The relationship with long-term amantadine dosing is unclear; it may be that amantadine toxicity is not related to the cumulative dose, but rather potentially an alternative mechanism, such as rapid increase to a toxic level at a given point in time. In a nationwide cohort study in Taiwan of patients with Parkinson disease, a hazard ratio of 1.79 for corneal edema with amantadine use increased to 2.05 for those with a moderate dose (2,000–4,000 mg) and 2.84 for those with a high dose (>4,000 mg).21\n\nConclusion\nLong-term outcomes of amantadine toxicity are unknown. We include here follow-up data for 32 months, the longest such interval to our knowledge. In contrast to patients whose edema returned following repeat challenge with amantadine,3 this case revealed that it may be possible to tolerate a dose if necessary without development of further corneal edema. However, a single case does not equate to a recommendation, and outcomes from additional cases will be beneficial to understanding the likelihood of such benefit.\n\nAcknowledgments\nFinancial support was received from: NIH K12 EY015025-10 (AOE), NIH L30 EY024746 (AOE).\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nFigure 1 Serial Scheimpflug imaging of amantadine-associated corneal edema. At initial diagnosis, edema was noted to be central in distribution, worse in the right eye (A) than the left (B). After cessation, corneal edema resolved. Despite the necessity of resuming amantadine, the patient has continued to maintain corneal clarity with concurrent steroids, with resolution of edema in both right (C) and left (D) eyes, more than 2 years after initial presentation.\n\nAbbreviations: OD, oculus dextrus; OS, oculus sinister.\n\nFigure 2 Specular microscopy reveals marked endothelial cell loss. Concurrent with the asymmetry of corneal edema at presentation, the right eye (A) demonstrates worse polymegethism than the left (B). Dark opacities, which may represent toxic byproducts, debris or pigment, provide a guttate-like appearance with slit-lamp biomicroscopy. The area is 0.1 mm2.\n\nTable 1 Progression and resolution of the patient’s corneal edema based on visual acuity, pachymetry and specular microscopy. Although amantadine was resumed, the patient has maintained visual acuity, central corneal thickness and endothelial cell density over a 140-week period\n\nDate (week)\tVisual acuity\n\tPachymetry (microns)\n\tSpecular microscopy (cells/mm2)\n\t\nOD\tOS\tOD\tOS\tOD\tOS\t\nWeek 1\t20/125\t20/60\t927\t641\t\t\t\nWeek 3*\t20/125\t20/125\t946\t598\t\t\t\nWeek 4\t20/250\t20/150\t\t\t\t\t\nWeek 6\t20/70\t20/50\t\t\t\t\t\nWeek 8\t20/30\t20/30\t585\t550\tMarked endothelial cell loss (subjective analysis)\tMarked endothelial cell loss, less than right eye (subjective analysis)\t\nWeek 24\t20/25\t20/25\t586\t523\t\t\t\nWeek 48\t20/30\t20/40\t\t\t609\t1,387\t\nWeek 81\t20/40\t20/50\t541\t516\t627\t1,309\t\nWeek 110\t20/30\t20/30\t560\t536\t726\t1,138\t\nWeek 140\t20/30\t20/30\t563\t563\t649\t1,186\t\nNote:\n\n* Amantadine was discontinued at week 3.\n\nAbbreviations: OD, oculus dexter; OS, oculus sinister; OU, oculus uterque.\n\nTable 2 Review of 22 cases of amantadine-associated corneal edema. Notably, 12 out of 22 cases of corneal edema described are central in distribution, suggesting a characteristic pattern that may progress into diffuse edema over time. Moreover, many cases are severely thickened, approaching or exceeding 1,000 microns in thickness\n\n#\tGender\tAge\tPachymetry OD\tPachymetry OS\tDistribution of edema in photographs\tLength of amantadine therapy\t\n111\tFemale\t63\t661\t651\tCentral\t7 months\t\n218\tFemale\t64\t677\t756\tCentral epithelial bullae\t2 years\t\n316\tFemale\t16\tUnknown\tUnknown\tCentral\t6 months\t\n42\tFemale\t77\t1,000+\t1,000+\tDiffuse\t25 days\t\n54\tFemale\t61\t810\t780\tCentral\t6 years\t\n618\tFemale\t45\t867\t700\tCentral\t17 months\t\n77\tFemale\t68\t871\t746\tNo picture\t2 years\t\n812\tFemale\t40\tUnable to acquire\tUnable to acquire\tDiffuse\tUnknown\t\n96\tFemale\t39\t940\t802\tCentral folds, diffuse edema\t8 months\t\n1014\tMale\t43\t954\t828\tDiffuse\t4 months\t\n1110\tFemale\t55\t688\t687\tDiffuse\t6 years\t\n1210\tMale\t57\t838\t1,000\tCentral\t2 months\t\n1310\tFemale\t44\tUnknown\tUnknown\tDiffuse\t3 months\t\n1415\tFemale\t12\t851\t886\tNo picture\t6 months\t\n1515\tFemale\t55\t930\t934\tCentral\tSeveral years\t\n1619\tFemale\t52\tUnknown\tUnknown\tConfined to the central two-thirds\t6.5 years\t\n175\tFemale\t74\tUnknown\tUnknown\tNo picture\t8 years\t\n1813\tMale\t61\tUnknown\tUnknown\tCentral\t8 months\t\n199\tMale\t14\t973\t950\tNo picture\t<1 year\t\n2017\tMale\t46\t803\t911\tCentral\t3 years\t\n211\tMale\t12\t917\t937\tNo picture\t6 months\t\n22 (this study)\tFemale\t44\t946\t598\tCentral\t7 years\t\nAbbreviations: OD, oculus dexter; OS, oculus sinister.\n==== Refs\nReferences\n1 Beran M Okyere B Vova J Amantadine-induced corneal edema in a pediatric neuro-oncology patient: a case report PM R 2018 S1934 S1482 18 30126 30126 \n2 Hood CT Langston RH Schoenfield LR Amantadine-associated corneal edema treated with descemet’s stripping automated endothelial keratoplasty Ophthalm Surg Lasers Imaging 2010 41 Online 1 4 Available from: https://www.ncbi.nlm.nih.gov/pubmed/21158374 Accessed July 10, 2018 \n3 French DD Margo CE Postmarketing surveillance of corneal edema, Fuchs dystrophy, and amantadine use in the Veterans Health Administration Cornea 2007 26 1087 1089 17893540 \n4 Deogaonkar M Wilson K Vitek J Amantadine induced reversible corneal edema J Clin Neurosci 2011 18 298 299 21163653 \n5 Dubow JS Rezak M Berman AA Reversible corneal edema associated with amantadine use: an unrecognized problem Move Disord 2008 23 2096 2097 \n6 Esquenazi S Bilateral reversible corneal edema associated with amantadine use J Ocul Pharmacol Therapeut 2009 25 567 570 \n7 Ghaffariyeh A Honarpisheh N Amantadine-associated corneal edema Parkinsonism Relat Disord 2010 16 427 20350832 \n8 Hotehama A Mimura T Usui T Sudden onset of amantadine-induced reversible bilateral corneal edema in an elderly patient: case report and literature review Japan J Ophthalmol 2011 55 71 74 Available from: https://link.springer.com/article/10.1007%2Fs10384-010-0888-8 Accessed July 10, 2018 21331699 \n9 Hughes B Feiz V Flynn SB Brodsky MC Reversible amantadine-induced corneal edema in an adolescent Cornea 2004 23 823 824 Available from: https://journals.lww.com/corneajrnl/Fulltext/2004/11000/Reversible_Amantadine_Induced_Corneal_Edema_in_an.12.aspx Accessed July 10, 2018 15502485 \n10 Jeng BH Galor A Lee MS Amantadine-associated corneal edema potentially irreversible even after cessation of the medication Ophthalmology 2008 115 1540 1544 18501429 \n11 Kim YE Yun JY Yang HJ Amantadine induced corneal edema in a patient with primary progressive freezing of gait J Mov Disord 2013 6 34 36 24868424 \n12 Koenig SB McDermott ML Simons KB Nonimmunologic graft failure after Descemet’s Stripping Automated Endothelial Keratoplasty (DSAEK) for presumed amantadine-induced corneal edema Eye Contact Lens 2009 35 209 211 19516146 \n13 Kubo S Iwatake A Ebihara N Murakami A Hattori N Visual impairment in Parkinson’s disease treated with amantadine: case report and review of the literature Parkinsonism Rel Disord 2008 14 166 169 \n14 Park CY Chuck RS Sudden bilateral corneal oedema in a patient with Parkinson’s disease Acta Ophthalmolog 2011 89 198 199 \n15 Pond A Lee MS Hardten DR Harrison AR Krachmer JH Toxic corneal oedema associated with amantadine use Br J Ophthalmol 2009 93 413 \n16 Santiago-Caban LA Rivera E Lopez-Beauchamp V Bilateral corneal edema secondary to amantadine in the pediatric population: a case report Bol Asoc Med Puerto Rico 2012 104 69 76 \n17 Yang Y Teja S Baig K Bilateral corneal edema associated with amantadine CMAJ 2015 187 1155 1158 25991839 \n18 Avendano-Cantos EM Celis-Sanchez J Mesa-Varona D Gálvez-Martínez J López-Arroquia E González del Valle F Toxicidad corneal por amantadina [Corneal toxicity due to amantadine] Arch Sociedad Espanola Oftalmol 2012 87 290 293 Spanish \n19 Chang KC Kim MK Wee WR Lee JH Corneal endothelial dysfunction associated with amantadine toxicity Cornea 2008 27 1182 1185 19034138 \n20 Jurkunas UV Bitar MS Funaki T Azizi B Evidence of oxidative stress in the pathogenesis of fuchs endothelial corneal dystrophy Am J Pathol 2010 177 2278 2289 20847286 \n21 Lee PY Tu HP Lin CP Amantadine use as a risk factor for corneal edema: a nationwide cohort study in Taiwan Am J Ophthalmol 2016 171 122 129 27594137\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "12()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "Fuchs dystrophy; Scheimpflug imaging; amantadine; cornea; corneal edema; corneal endothelium",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "1367-1371",
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"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": "29550414;19516146;20350832;19604157;20028266;22788084;21331699;25991839;21163653;20847286;21158374;15502485;27594137;17893540;18785231;17509924;24868424;19034138;18501429;19244027",
"title": "Clinical and genetic investigation of amantadine-associated corneal edema.",
"title_normalized": "clinical and genetic investigation of amantadine associated corneal edema"
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"companynumb": "US-TEVA-2019-US-997323",
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"abstract": "HIV-associated progressive encephalopathy of childhood is characterized by impaired brain growth, decline in cognitive and neurobehavioral performances, and progressive motoric dysfunction The diagnosis is based on neurological examination, neuropsychological assessment and cerebral CT or MR imaging. While the importance of early use of antiretroviral combination therapy has been emphasized, limited data exist as to the effect of protease inhibitors in children with HIV-associated encephalopathy. We describe the effect of 3-drug antiretroviral combination therapy, including the protease inhibitor nelfinavir, in a 7-y-old girl with vertically acquired HIV infection and late onset progressive encephalopathy.",
"affiliations": "Department of Paediatrics, Copenhagen University Hospital Hvidovre, Denmark.",
"authors": "Rosenfeldt|V|V|;Valerius|N H|NH|;Paerregaard|A|A|",
"chemical_list": "D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D018894:Reverse Transcriptase Inhibitors; D019888:Nelfinavir",
"country": "England",
"delete": false,
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"issue": "32(5)",
"journal": "Scandinavian journal of infectious diseases",
"keywords": null,
"medline_ta": "Scand J Infect Dis",
"mesh_terms": "D015526:AIDS Dementia Complex; D019380:Anti-HIV Agents; D023241:Antiretroviral Therapy, Highly Active; D002648:Child; D005260:Female; D017320:HIV Protease Inhibitors; D006801:Humans; D019888:Nelfinavir; D018894:Reverse Transcriptase Inhibitors; D016896:Treatment Outcome",
"nlm_unique_id": "0215333",
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"pages": "571-4",
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"pubdate": "2000",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Regression of HIV-associated progressive encephalopathy of childhood during HAART.",
"title_normalized": "regression of hiv associated progressive encephalopathy of childhood during haart"
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"companynumb": "DK-PFIZER INC-1343-13221",
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"abstract": "Renal toxicity is a common side effect during tenofovir (TDF)-use in HIV-infected, but not necessarily HBV-infected, patients. Nevertheless, little is known regarding TDF-use on renal impairment during HIV-HBV coinfection. We aimed to evaluate the progression and determinants of renal impairment in coinfected patients undergoing TDF.\n\n\n\nA total of 175 coinfected patients initiating TDF-containing antiretroviral therapy were prospectively followed. Estimated glomerular filtration rates (eGFR) were calculated at baseline and every 6-12 months. Determinants of eGRF change from baseline (ΔeGFR) were evaluated using mixed-effect linear regression and progression towards renal impairment using proportional-hazards regression.\n\n\n\nAt baseline, average eGFR was 96.7 ml/min per 1.73m2 (95% CI 93.8, 99.6). During a median 58.3 months (IQR 33.7-92.1) of treatment, eGFR decreased a monthly average of -0.14 ml/min per 1.73m2 (95% CI -0.16, -0.12). Significantly faster ΔeGFR was associated with baseline eGFR>90 (P=0.002), male gender (P=0.04), previous AIDS-defining illness at baseline (P=0.03), baseline liver cirrhosis (P=0.03) and concomitant protease inhibitor use (P=0.005). Between respective baseline and end of follow-up visits, the proportion of patients with renal impairment increased: normal function, 65.7% to 53.1%; mild impairment, 32.6% to 40.0%; moderate impairment, 1.7% to 6.9%. Higher age (P=0.01) and previous AIDS-defining illness (P=0.02) at baseline were independent risk-factors for developing impairment, while undetectable HBV DNA on-treatment was protective (P=0.006). Five (2.9%) patients permanently discontinued TDF after a renal event.\n\n\n\nSevere HIV-related and HBV-related morbidity negatively affects renal function in coinfected patients undergoing long-term TDF. Although most patients only developed mild/moderate impairment, close renal monitoring is warranted for this particular population.",
"affiliations": "INSERM, UMR_S1136, Institut Pierre Louis d'Epidémiologie et de Santé Publique, Paris, France.;Centre de Recherche sur le Cancer de Lyon, Equipes 15 et 16, INSERM, Unité 1052, CNRS, UMR 5286, Lyon, France.;Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Louis, AP-HP, Paris, France.;Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.;Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.;INSERM, UMR_S 1155, Paris, France.;Service des Maladies Infectieuses et Tropicales, Hôpital Saint-Antoine, AP-HP, Paris, France.",
"authors": "Boyd|Anders|A|;Miailhes|Patrick|P|;Lascoux-Combe|Caroline|C|;Rougier|Hayette|H|;Girard|Pierre-Marie|PM|;Plaisier|Emmanuelle|E|;Lacombe|Karine|K|",
"chemical_list": "D019380:Anti-HIV Agents; D000068698:Tenofovir",
"country": "England",
"delete": false,
"doi": "10.3851/IMP3076",
"fulltext": null,
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"issn_linking": "1359-6535",
"issue": "22(1)",
"journal": "Antiviral therapy",
"keywords": null,
"medline_ta": "Antivir Ther",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D015331:Cohort Studies; D060085:Coinfection; D018450:Disease Progression; D005260:Female; D005919:Glomerular Filtration Rate; D015658:HIV Infections; D015497:HIV-1; D019694:Hepatitis B, Chronic; D006801:Humans; D007668:Kidney; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D051437:Renal Insufficiency; D012307:Risk Factors; D000068698:Tenofovir",
"nlm_unique_id": "9815705",
"other_id": null,
"pages": "31-42",
"pmc": null,
"pmid": "27553871",
"pubdate": "2017",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Renal outcomes after up to 8 years of tenofovir exposure in HIV-HBV-coinfected patients.",
"title_normalized": "renal outcomes after up to 8 years of tenofovir exposure in hiv hbv coinfected patients"
} | [
{
"companynumb": "FR-GILEAD-2017-0264119",
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"abstract": "BACKGROUND\nA 30-year-old man presented with intellectual disability associated with epilepsy. The epilepsy was initially treated with sodium valproate and since he was 28 years-old with lamotrigine. With the addition of lamotrigine, a pattern of Brugada syndrome appeared on the electrocardiogram. The family history was positive for epilepsy from the motheŕs side, who had never been treated with lamotrigine.\n\n\nOBJECTIVE\nDetermine the genetic cause of the intellectual disability, epilepsy and Brugada syndrome of the patient and try to establish a possible correlation between the genetic background and the Brugada syndrome pattern under lamotrigine treatment.\n\n\nMETHODS\nA standard karyotype, array comparative genomic hybridization and two different NGS panels have done to the index case to identify the genetic causes of the intellectual disability, epilepsy and Brugada syndrome pattern.\n\n\nRESULTS\nGenetic analyses in the family identified a de novo duplication of 1.3 Mb in 8p21.3 as well as two novel heterozygous rare variants in SCN9A and AKAP9 genes, both inherited from the mother.\n\n\nCONCLUSIONS\nWe hypothesize that in this family the SCN9A variant was responsible for the epileptic syndrome. In addition, given that SCN9A is lightly expressed in the heart tissue, we postulate that this SCN9A variant, alone or in combination with AKAP9 variant, might be responsible for the Brugada pattern when challenged by lamotrigine.",
"affiliations": "Neurology and Stroke Unit Divison, Circolo Hospital ASST Settelaghi University of Insubria Varese, Italy.;Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.;Institute of Public Health, Section of Legal Medicine, Catholic University, Rome, Italy.;Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain.;Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, \"G. Gaslini\" Institute, Genova, Italy.;Neurology and Stroke Unit Divison, Circolo Hospital ASST Settelaghi University of Insubria Varese, Italy.;Neurology and Stroke Unit Divison, Circolo Hospital ASST Settelaghi University of Insubria Varese, Italy.;Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain.;Neurology and Stroke Unit Divison, Circolo Hospital ASST Settelaghi University of Insubria Varese, Italy.;Cardiovascular Genetics Center, University of Girona-IDIBGI, Girona, Spain; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain; Medical Science Department, School of Medicine, University of Girona, Girona, Spain; Cardiology Service, Hospital JosepTrueta, University of Girona, Girona, Spain. Electronic address: rbrugada@idibgi.org.",
"authors": "Banfi|P|P|;Coll|M|M|;Oliva|A|A|;Alcalde|M|M|;Striano|P|P|;Mauri|M|M|;Princiotta|L|L|;Campuzano|O|O|;Versino|M|M|;Brugada|R|R|",
"chemical_list": "D000927:Anticonvulsants; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human; D000077213:Lamotrigine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gene.2020.144847",
"fulltext": null,
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"issn_linking": "0378-1119",
"issue": "754()",
"journal": "Gene",
"keywords": "Brugada syndrome; Epilepsy; Lamotrigine; SCN9A",
"medline_ta": "Gene",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D053840:Brugada Syndrome; D004827:Epilepsy; D020440:Gene Duplication; D006801:Humans; D000077213:Lamotrigine; D008297:Male; D062556:NAV1.7 Voltage-Gated Sodium Channel",
"nlm_unique_id": "7706761",
"other_id": null,
"pages": "144847",
"pmc": null,
"pmid": "32531456",
"pubdate": "2020-09-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Lamotrigine induced Brugada-pattern in a patient with genetic epilepsy associated with a novel variant in SCN9A.",
"title_normalized": "lamotrigine induced brugada pattern in a patient with genetic epilepsy associated with a novel variant in scn9a"
} | [
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"abstract": "There are limited data on the surgical management of localized and residual diseases in patients with stage IV non-small-cell lung cancer that was treated with nivolumab. Herein, we present two patients who underwent salvage thoracoscopic resection for residual diseases (left lower lobectomy and paratracheal lymph node resection, respectively) after chemotherapy and immunotherapy for stage IV adenocarcinoma. The indications, intraoperative findings, and histopathological findings are discussed in this report.",
"affiliations": "Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.;Department of Pulmonary Medicine, Kyoto University, Kyoto, Japan.;Department of Diagnostic Pathology, Kyoto University, Kyoto, Japan.;Department of Thoracic Surgery, Kyoto University, Kyoto, Japan.",
"authors": "Hamaji|Masatsugu|M|https://orcid.org/0000-0002-9808-8260;Ozasa|Hiroaki|H|;Yoshizawa|Akihiko|A|;Date|Hiroshi|H|",
"chemical_list": "D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1177/0218492320919477",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0218-4923",
"issue": "28(4)",
"journal": "Asian cardiovascular & thoracic annals",
"keywords": "Adenocarcinoma; antineoplastic agents; carcinoma; lung neoplasms; nivolumab; non-small-cell lung; pneumonectomy",
"medline_ta": "Asian Cardiovasc Thorac Ann",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000368:Aged; D000074322:Antineoplastic Agents, Immunological; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008197:Lymph Node Excision; D008297:Male; D009367:Neoplasm Staging; D000077594:Nivolumab; D011013:Pneumonectomy; D016879:Salvage Therapy; D020775:Thoracic Surgery, Video-Assisted; D016896:Treatment Outcome",
"nlm_unique_id": "9503417",
"other_id": null,
"pages": "216-218",
"pmc": null,
"pmid": "32276540",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Salvage thoracoscopic resection after nivolumab for stage IV.",
"title_normalized": "salvage thoracoscopic resection after nivolumab for stage iv"
} | [
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"companynumb": "JP-BRISTOL-MYERS SQUIBB COMPANY-BMS-2020-062116",
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"abstract": "Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.",
"affiliations": "Infectious Diseases/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Dermatology and Venereology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Dermatology and Venereology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Rheumatology/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.;Clinical Immunology and Transfusion Medicine/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden.",
"authors": "Sjöwall|Johanna|J|;Xirotagaros|Georgios|G|;Anderson|Chris D|CD|;Sjöwall|Christopher|C|;Dahle|Charlotte|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2021.645298",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295 Frontiers Media S.A. \n\n10.3389/fneur.2021.645298\nNeurology\nCase Report\nCase Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab\nSjöwall Johanna 1* Xirotagaros Georgios 2 Anderson Chris D. 2 Sjöwall Christopher 3 Dahle Charlotte 4 1Infectious Diseases/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n2Dermatology and Venereology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n3Rheumatology/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\n4Clinical Immunology and Transfusion Medicine/Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden\nEdited by: Luigi Lavorgna, University of Campania Luigi Vanvitelli, Italy\n\nReviewed by: Yoshiro Ohara, Kanazawa Medical University, Japan; Miriam Laura Fichtner, Yale Medicine, United States\n\n*Correspondence: Johanna Sjöwall johanna.sjowall@liu.seThis article was submitted to Multiple Sclerosis and Neuroimmunology, a section of the journal Frontiers in Neurology\n\n\n12 2 2021 \n2021 \n12 64529822 12 2020 25 1 2021 Copyright © 2021 Sjöwall, Xirotagaros, Anderson, Sjöwall and Dahle.2021Sjöwall, Xirotagaros, Anderson, Sjöwall and DahleThis 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.Borrelia-specific antibodies in serum did not contribute to the diagnosis of Borrelia arthritis or Borrelia-associated dermatitis in a young woman with ongoing treatment with rituximab due to multiple sclerosis. The diagnosis was confirmed by the detection of Borrelia-DNA in a skin punch biopsy. The patient history did not reveal any tick exposure. She had suffered for several months from fluctuating pain and swelling of the right knee as well as skin involvement with redness and oedema around the ankle of the same leg. Monoarthritis was confirmed by a rheumatologist. Knee puncture was performed but the synovial fluid was only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were found. Borrelia serology in blood revealed borderline levels of immunoglobulin (Ig)M and IgG, respectively. Treatment with doxycycline resulted in resolution of the joint and skin manifestations within a month. This case highlights that Borrelia-specific antibody levels cannot be reliably interpreted in patients who have received B-cell depleting therapy. Under these circumstances, detection of the bacterial genome in different body fluids, such as in the skin, can be a useful complement to the diagnosis of Lyme disease. In this young female, the diagnosis would certainly have been further delayed without the detection of Borrelia-DNA in the skin.\n\nLyme diseaseBorrelia-DNAarthritisdermatitisrituximabBorrelia serology\n==== Body\nIntroduction\nAn atypical clinical presentation and absence of an adequate immune response to infections are common phenomena in patients with primary immunodeficiency disorders (PID) (1) and multiple sclerosis (MS) (2), as well as in subjects receiving immunosuppressive agents (3). Furthermore, several immune modulating therapies may have similar effects, but this is less well-recognized among physicians lacking deeper knowledge of the impact of the immune system on the pathogenesis and the clinical manifestations of different infectious diseases. As immunomodulating therapies (IMT) are now widely used for a variety of autoimmune and inflammatory diseases, specialists of many different disciplines may need to treat patients using this group of drugs. For instance, patients with MS are often diagnosed and started on treatment at young age and continue for years or decades (4). These circumstances emphasize the importance of physicians being aware of atypical reactions regarding both clinical symptoms and laboratory test results obscuring infections among these patients. This case illustrates that an ongoing infection can easily be overlooked or misinterpreted due to a weak serological response during treatment with a B-cell depleting drug.\n\nCase Presentation\nThis case illustrates a 20-year-old female diagnosed with MS at the age of 17. She was initially treated with tocilizumab as neuromyelitis optica was suspected due to bilateral optical neuritis and the presence of spinal cord lesions. However, antibodies against aquaporin-4 and myelin oligodendrocyte glycoprotein were not detected and the magnetic resonance imaging (MRI) of the brain and spinal cord as well as cerebrospinal fluid (CSF) findings were supportive of MS. Apart from persistent bilateral severely reduced visual acuity she had no other signs of neurological dysfunction. She had previously been in good health and had no family history of PID, or other systemic inflammatory diseases.\n\nEighteen months prior to the episode of arthritis and skin symptoms reported here, she was started on off-label treatment with rituximab (RTX). RTX is the most frequently used immunomodulatory drug for MS in Sweden according to the Swedish MS registry (5). Initially, she received 1,000 mg of RTX followed by 500–1,000 mg every 6th month, resulting in depletion of circulating B-cells (<0.001 ×109/L). During this period, there were no signs of neuroinflammatory activity of MS.\n\nClinical Episode\nA rheumatologist confirmed the diagnosis of monoarthritis. The right knee had typical signs of inflammation with rubor, tumor, and calor accompanied by a discretely reduced range of motion. The general status was good without fever. The lower right leg was diffusely swollen and two circular erythematous areas around the ankle were seen (Figures 1A,B). A dermatologist interpreted the skin symptoms as possible panniculitis with atypical erythema nodosum as a potential alternative diagnosis. There were no other clinical or laboratory findings of sarcoidosis.\n\nFigure 1 Periarticular swelling of the right leg and ankle. The skin is slightly atrophic adjacent to the two erythematous circular areas seen on the lateral side. The blood vessels appear prominently over the apical part of the foot; a common phenomenon in late cutaneous borreliosis (A). The right knee, calf, and ankle are swollen, without a distinct erythema. Fifteen to twenty degrees deficit in knee extension was observed. Note the dark discoloration of the medial and apical parts of the foot, typically seen in patients with late cutaneous borreliosis (B).\n\nTimeline\nTreatment with RTX had been ongoing for approximately one and a half year prior to the onset of arthritis and the cutaneous symptoms had been present for at least 6 months prior to the diagnosis. The last dose of RTX was given 1.5 months before the onset of symptoms related to Lyme disease.\n\nDiagnostic Assessments\nAspiration of synovial fluid resulted in a limited volume, only sufficient for microscopic examination of crystals. Neither monosodium urate crystals nor calcium pyrophosphate crystals were detected in the joint fluid. Duplex ultrasonography of the lower leg showed no signs of deep vein thrombosis and there were no laboratory signs of systemic inflammation. Serological analysis performed 5 months after the last dose of RTX showed borderline levels of immunoglobulin (Ig)M and IgG antibodies against recombinant Borrelia antigens (Liason®, Borrelia IgM detecting OspC and VlsE; Borrelia IgG detecting VlsE). The results were interpreted to be of uncertain clinical significance. Laboratory results are detailed in Table 1.\n\nTable 1 Laboratory findings in blood.\n\nAnalyte\tResults\tReference interval\t\nHemoglobin\t151\t117–153 g/L\t\nLeukocyte count\t7.2\t3.5–8.8 ×109/L\t\nLymphocyte count\t1.3\t1.1–4.8 ×109/L\t\nB-cells\t<0.001\t0.075–0.53 ×109/L\t\nPlatelet count\t283\t160–390 ×109/L\t\nErythrocyte sedimentation rate (ESR)\t2\t<21 mm/h\t\nP-C-reactive protein (CRP)\t<5\t<10 mg/L\t\nS-Creatinine kinase\t1.5\t<3.6 μkat/L\t\nP-Alanine transaminase\t0.35\t<0.76 μkat/L\t\nP-Creatinine\t81\t45–90 μmol/L\t\nP-Urate\t209\t155–350 μmol/L\t\nS-Angiotensin converting enzyme\t0.51\t<1.1 μkat/L\t\nAnti-cyclic citrullinated peptide antibody (IgG)\t1\t<7 U/L\t\nBorrelia antibody (IgM)\t38.6\t<30 AU/mL\t\nBorrelia antibody (IgG)\t16.6\t<10 AU/mL\t\nAU, arbitrary units; P-, analysis in plasma; S-, analysis in serum; U, units.\n\nDespite the vague antibody results, there were an enduring clinical suspicion of Borrelia infection. Skin biopsies from one of the erythematous areas at the ankle were performed. Standard histopathology showed mild non-specific inflammation. Borrelia-DNA was detected in the biopsy analyzed by polymerase chain reaction (PCR). The method amplifies a 116 base-pair long fragment of the 16S rRNA gene. In addition, a lumbar puncture was done, and CSF was analyzed without presence of intrathecal Borrelia-specific antibodies or elevated levels of the B-cell chemokine CXCL13. Thus, the final diagnosis was Borrelia associated dermatitis and arthritis (Lyme disease).\n\nTherapeutic Intervention\nPrior to the diagnosis of Lyme disease, the patient was prescribed topical steroids for the skin manifestations and the joint symptoms were managed with paracetamol. Once the diagnosis of Lyme disease was confirmed, doxycycline 200 mg once daily for 3 weeks was prescribed. The knee and skin symptoms dissipated during the following month.\n\nFollow-Up and Outcome\nAt the last follow-up 1 year after the antibiotic treatment had been ended, there was still minor swelling of the lower leg but no signs of arthritis or dermatitis. An MRI of the lower leg showed mild oedema in musculus soleus and gastrocnemius. Creatinine kinase in plasma was within normal reference.\n\nDiscussion\nIMT in general, and particularly B-cell depleting therapies, may be associated with an increased risk of infections (2, 6, 7). Serological screening for IgG against several infectious agents is therefore routinely performed prior to initiation of IMT and vaccination should be considered when immunity is not detected. However, the fact that IMT can have an impact on the clinical picture and serological response to infectious agents is less well recognized among physicians outside the field of immunology and infectious diseases. B-cell depleting therapies are widely used in MS as well as in many other autoimmune diseases, often with a dramatic anti-inflammatory effect and symptom relief (6). In chronic inflammatory diseases like MS, the treatment is often continued for many years and results in undetectable or very low numbers of circulating B-cells. Although RTX, compared to other disease modifying drugs in MS, has been shown to be associated with an increased risk for serious infections it is widely used due its marked effect on the disease activity and disease progression (4). Another side effect is weak and non-protective responses to vaccinations, as long as the circulating B-cells are very low (8, 9).\n\nIn the patient described here, Borrelia caused late skin and joint manifestations that did not raise the clinical suspicion of Lyme disease, until the weak serological response was received. Still, the antibody results were interpreted to be of dubious significance. The correct diagnosis was not made until Borrelia-DNA was detected in the skin biopsy. This is consistent with previous and more recent findings of improved diagnostic accuracy using detection of the Borrelia genome in the skin of patients with acrodermatitis chronica atrophicans, the late cutaneous manifestation of borreliosis (10, 11). In addition, our case clearly illustrates that, during treatment with B-cell depleting therapies, infections may give rise to an atypical clinical picture as well as a weak serological response to specific pathogens. Awareness of these circumstances should be highlighted to clinicians serving patients on IMT.\n\nPatient Perspective\nThe patient had suffered from knee pain and painful skin erythema for several months before the correct diagnosis was identified. She had been in contact with the primary health care several times before the correct diagnosis was made. Despite the fact that she was treated with IMT, her symptoms were initially interpreted as “non-specific findings of uncertain origin.”\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patient provided her written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable image or data included in this article.\n\nAuthor Contributions\nJS, CS, and CD had full access to all of the data and takes responsibility for the integrity, accuracy and interpretation of the data. All authors contributed to the article and approved the submitted version. All authors were involved in drafting the manuscript or revising it critically for important intellectual content and all authors approved the final version to be published.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1. Lewandowicz-Uszynska A Pasternak G Swierkot J Bogunia-Kubik K . Primary immunodeficiencies: diseases of children and adults - a review\n. Adv Exp Med Biol. (2020 ) 1289 :37 –54\n. 10.1007/5584_2020_556 \n2. Persson R Lee S Ulcickas Yood M Wagner Usn Mc CM Minton N Niemcryk S . Infections in patients diagnosed with multiple sclerosis: a multi-database study\n. Mult Scler Relat Disord. (2020 ) 41 :101982 . 10.1016/j.msard.2020.101982 32070858 \n3. Celius EG . Infections in patients with multiple sclerosis: Implications for disease-modifying therapy\n. Acta Neurol Scand. (2017 ) 136 (Suppl 201 ):34 –6\n. 10.1111/ane.12835 29068490 \n4. Piehl F . A changing treatment landscape for multiple sclerosis: challenges and opportunities\n. J Intern Med. (2014 ) 275 :364 –81\n. 10.1111/joim.12204 24444084 \n5. Hillert J Stawiarz L . The Swedish MS registry - clinical support tool and scientific resource\n. Acta Neurol Scand. (2015 ) 132 :11 –9\n. 10.1111/ane.12425 26046553 \n6. Parodis I Stockfelt M Sjowall C . B cell therapy in systemic lupus erythematosus: from rationale to clinical practice\n. Front Med (Lausanne). (2020 ) 7 :316 . 10.3389/fmed.2020.00316 32754605 \n7. Luna G Alping P Burman J Fink K Fogdell-Hahn A Gunnarsson M . Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies\n. JAMA Neurol. (2020 ) 77 :184 –91\n. 10.1001/jamaneurol.2019.3365 31589278 \n8. Adler S Krivine A Weix J Rozenberg F Launay O Huesler J . Protective effect of A/H1N1 vaccination inimmune-mediated disease–a prospectively controlled vaccination study\n. Rheumatology (Oxford). (2012 ) 51 :695 –700\n. 10.1093/rheumatology/ker389 22171015 \n9. Crnkic Kapetanovic M Saxne T Jonsson G Truedsson L Geborek P . Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis\n. Arthritis Res Ther. (2013 ) 15 :R171 . 10.1186/ar4358 24286269 \n10. von Stedingk LV Olsson I Hanson HS Asbrink E Hovmark A . Polymerase chain reaction for detection of Borrelia burgdorferi DNA in skin lesions of early and late Lyme borreliosis\n. Eur J Clin Microbiol Infect Dis. (1995 ) 14 :1 –5\n. 10.1007/BF02112610 7729446 \n11. Lenormand C Jaulhac B Debarbieux S Dupin N Granel-Brocard F Adamski H . Expanding the clinicopathological spectrum of late cutaneous Lyme borreliosis (acrodermatitis chronica atrophicans [ACA]): a prospective study of 20 culture- and/or polymerase chain reaction (PCR)-documented cases\n. J Am Acad Dermatol. (2016 ) 74 :685 –92\n. 10.1016/j.jaad.2015.10.046 26781226\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2295",
"issue": "12()",
"journal": "Frontiers in neurology",
"keywords": "Borrelia serology; Borrelia-DNA; Lyme disease; arthritis; dermatitis; rituximab",
"medline_ta": "Front Neurol",
"mesh_terms": null,
"nlm_unique_id": "101546899",
"other_id": null,
"pages": "645298",
"pmc": null,
"pmid": "33643217",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "29068490;26046553;22171015;24444084;26781226;32070858;32754605;7729446;24286269;31589278;32803731",
"title": "Case Report: Borrelia-DNA Revealed the Cause of Arthritis and Dermatitis During Treatment With Rituximab.",
"title_normalized": "case report borrelia dna revealed the cause of arthritis and dermatitis during treatment with rituximab"
} | [
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{
"abstract": "BACKGROUND\nChildren with Hodgkin lymphoma (HL) have excellent survival rates in high-income countries, but there are minimal outcome data in South African patients. Differing approaches to treatment are used in centres across South Africa, and the South African Children's Cancer Study Group (SACCSG) embarked on a programme to audit outcomes to improve survival rates.\n\n\nMETHODS\nA multicentre study was conducted to analyse outcomes and prognostic factors of children with HL in South Africa. Ten dedicated South African paediatric oncology units participated in a retrospective data review. All patients with HL treated consecutively between January 2000 and December 2010 were included. Kaplan-Meier curves and Cox regression model were employed to determine survival rates and prognostic factors.\n\n\nRESULTS\nTwo hundred and ninety-four patients were eligible for inclusion. The median age at presentation was 9.6 years (range 2.9-18.8); 55.4% of the patients presented with Stage III and IV disease and 9.9% were human immunodeficiency virus (HIV) positive. First-line therapy consisted of adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) in 158 patients, vincristine, procarbazine/etoposide, prednisone and doxorubicin in 97 and adriamycin, bleomycin, vincristine and dacarbazine-chlorambucil, vinblastine, prednisone and procarbazine in 23 patients. The 5-year overall survival (OS) was 79% (95% confidence interval 73-84%). Multivariate analysis demonstrated that HIV infection (P = 0.018) and Ann Arbor Stage III and IV disease (P = 0.006) conferred a poor prognosis, while treatment with ABVD was associated with higher survival rates (P = 0.028).\n\n\nCONCLUSIONS\nOS rates are encouraging for a middle-income country, although economic disparities continue to impact negatively on outcomes. Study results will form the basis for the development of national protocol and continued advocacy to rectify disparities.",
"affiliations": "Faculty of Health Sciences, University of the Witwatersrand, Charlotte Maxeke Johannesburg Academic Hospital, Johannesburg, South Africa.;Division of Epidemiology and Biostatistics, School of Public Health, University of the Witwatersrand, Johannesburg, South Africa.;Faculty of Health Sciences, University of the Witwatersrand, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa.;Faculty of Economics, University of Cape Town, Cape Town, South Africa.;Faculty of Health Sciences, University of Pretoria, Steve Biko Academic Hospital, Pretoria, South Africa.;Faculty of Health Sciences, University of the Free State, Universitas Hospital, Bloemfontein, South Africa.;Faculty of Health Sciences, University of Kwazulu-Natal, Inkosi Albert Luthuli Hospital, Durban, South Africa.;South African Medical Research Council, Parow, South Africa.;Faculty of Health Sciences, University of Stellenbosch, Tygerberg Hospital, Tygerberg, South Africa.;Divison of Paediatric Haemetology and Oncology, Frere Hospital, East London, South Africa.;Divison of Paediatric Haemetology and Oncology, Polokwane-Mankweng Hospital Complex, Polokwane, South Africa.;Netcare Parklands Hospital, Durban, South Africa.;Faculty of Health Sciences, University of Cape Town, Red Cross War Memorial Children's Hospital, Cape Town, South Africa.",
"authors": "Geel|Jennifer A|JA|;Chirwa|Tobias C|TC|;Rowe|Biance|B|;Eyal|Katherine C|KC|;Omar|Fareed|F|;Stones|David K|DK|;Goga|Yasmin|Y|;Stefan|D Cristina|DC|;van Zyl|Anel|A|;Van Emmenes|Barry|B|;Wedi|Oloko|O|;Vaithilingum|Manickavallie|M|;Hendricks|Marc G|MG|;|||",
"chemical_list": "D001761:Bleomycin; D014747:Vinblastine; D003606:Dacarbazine; D004317:Doxorubicin",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(10)",
"journal": "Pediatric blood & cancer",
"keywords": "Hodgkin disease; SACCSG; South Africa; prognostic indicators",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D002648:Child; D002675:Child, Preschool; D003606:Dacarbazine; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D013019:South Africa; D015996:Survival Rate; D014747:Vinblastine",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28383768",
"pubdate": "2017-10",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Treatment outcomes of children with Hodgkin lymphoma between 2000 and 2010: First report by the South African Children's Cancer Study Group.",
"title_normalized": "treatment outcomes of children with hodgkin lymphoma between 2000 and 2010 first report by the south african children s cancer study group"
} | [
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"companynumb": "ZA-JNJFOC-20171033040",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
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{
"abstract": "This is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.",
"affiliations": "Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France.;Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France.;Department of Haematology, Brest University Hospital, Brest, France.;Department of Haematology, Brest University Hospital, Brest, France.;Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France.;Medical Intensive Care, Brest University Hospital, Brest, France.;Laboratory of Haematology, Brest University Hospital, Brest, France.;Laboratory of Haematology, Brest University Hospital, Brest, France.;Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France.;Department of Biochemistry and Pharmaco-Toxicology, Martinique University Hospital, Fort-de-France, France.",
"authors": "Galakhoff|Nicolas|N|;Leven|Cyril|C|;Eveillard|Jean-Richard|JR|;Tempescul|Adrian|A|;Kerspern|Hélène|H|;Aubron|Cécile|C|;Buors|Caroline|C|;Lippert|Éric|É|;Carré|Jean-Luc|JL|;Padelli|Maël|M|",
"chemical_list": "D000970:Antineoplastic Agents; D007073:Immunoglobulin E; D000069286:Bortezomib; D003907:Dexamethasone",
"country": "Croatia",
"delete": false,
"doi": "10.11613/BM.2020.010801",
"fulltext": "\n==== Front\nBiochem Med (Zagreb)\nBiochem Med (Zagreb)\nBM\nBiochemia Medica\n1330-0962\n1846-7482\nCroatian Society of Medical Biochemistry and Laboratory Medicine\n\nbm-30-1-010801\n10.11613/BM.2020.010801\nCase Reports\nA case of IgE myeloma transformed into IgE-producing plasma cell leukaemia\nGalakhoff Nicolas 1\nLeven Cyril 1\nEveillard Jean-Richard 2\nTempescul Adrian 2\nKerspern Hélène 1\nAubron Cécile 3\nBuors Caroline 4\nLippert Éric 45\nCarré Jean-Luc 1\nPadelli Maël *6\n1 Department of Biochemistry and Pharmaco-Toxicology, Brest University Hospital, Brest, France\n2 Department of Haematology, Brest University Hospital, Brest, France\n3 Medical Intensive Care, Brest University Hospital, Brest, France\n4 Laboratory of Haematology, Brest University Hospital, Brest, France\n5 Université de Brest, INSERM, EFS, UMR 1078, GGB, Brest, France\n6 Department of Biochemistry and Pharmaco-Toxicology, Martinique University Hospital, Fort-de-France, France\n* Corresponding author: mael.padelli@chu-martinique.fr\n15 12 2019\n15 2 2020\n30 1 01080108 4 2019\n07 10 2019\nCroatian Society of Medical Biochemistry and Laboratory Medicine.\n2019\nCroatian Society of Medical Biochemistry\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nThis is a case report of a challenging diagnosis of IgE monoclonal gammopathy of undetermined significance, which transformed into myeloma, then transformed into IgE-producing plasma cell leukaemia in a 71-year-old male who was followed in Brest, France, from 2015 to 2019. The IgE-producing variant is the rarest sub-type of multiple myeloma, and plasma cell leukaemia is considered to be the rarest and the most aggressive of human monoclonal gammopathies. In November 2015, hypogammaglobulinemia was detected during a systematic check-up. A kappa light chain monoclonal gammopathy was first diagnosed due to an increase of the free kappa/lambda light chains ratio. No monoclonal immunoglobulin was detected by either serum protein electrophoresis (Capillarys 2, Sebia, Issy-les-Moulineaux, France) or immunofixation (Hydrasys 2, Sebia, Issy-les-Moulineaux, France). In June 2018, a blood smear led to the diagnosis of plasma cell leukaemia. A monoclonal peak was detected and identified as IgE-kappa. Analysis of an archival sample taken three years earlier, revealed the presence of a monoclonal IgE, which had been missed at diagnosis. Chemotherapy with bortezomib and dexamethasone was introduced. The patient survived 10 months after the diagnosis of leukaemia. This case shows that an abnormal free light chain ratio should be considered as a possible marker of IgE monoclonal gammopathy even in the absence of a solitary light chain revealed by immunofixation. In addition, the use of an undiluted serum may increase the sensitivity of the immunofixation for the detection of IgE monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer.\n\nKeywords:\n\nimmunofixation\nimmunoglobulin E\nmonoclonal gammopathy of undetermined significance\nmultiple myeloma\nplasma cell leukaemia\n==== Body\nIntroduction\n\nMultiple myeloma (MM) is a haematological malignancy characterized by the clonal proliferation of plasma cells in the bone marrow leading to overproduction of a monoclonal immunoglobulin (1). It constitutes 1% of all cancers and over 10% of all haematological malignancies (2). The plasma cells of monoclonal gammopathy of undetermined significance (MGUS) are immunoglobulin producing premalignant precursor tumours of MM that are stable and not associated with the presence of the secondary clinical manifestations including skeletal lytic lesions, anaemia, immunodeficiency, renal failure and hypercalcemia (3). They are derived from long-lived, post-germinal center B cells, which are activated B cells differentiated into plasma blasts that typically migrate back to the bone marrow where they become terminally differentiated long-lived plasma cells. Monoclonal gammopathy of undetermined significance is present in about 4% of Caucasians over the age of 50, with a 1% average annual risk of progression to malignant MM (4). The IgE-producing variant is the rarest sub-type of MM accounting for less than 0.1% of MM cases (5). About 60 cases have been described in the literature so far highlighting that IgE MM seems to have the poorest outcomes among heavy chain subtypes of MM with a mean survival time of 16 months versus 30 months for non IgE MM (6).\n\nPlasma cell leukaemia (PCL) is considered to be the rarest of human monoclonal gammopathy, accounting for 0.04 cases per 100,000 persons per year in Europe and also the most aggressive (7). It can either develop de novo (primary PCL) or evolve as a late-stage complication of MM (secondary PCL, sPCL) occurring in less than 1% of MM cases (8). Plasma cell leukaemia is a serious MM complication defined by the presence of > 2000/mm3 plasma cells in the peripheral blood or > 20% of the total white blood cell count (9). The median overall survival of 1 to 2 months (10, 11). Secondary PCL is characterized by a multistep accumulation of adverse biological features in patients with advanced relapsed and/or refractory MM (12). Unlike MM cells, PCL cells are poorly dependent on the bone marrow microenvironment for their growth and survival. The neoplastic plasma cells are more prone to enter the blood stream due to changes in expression of adhesion molecules, chemokine receptors, and the presence of molecular aberration promoting tumour growth outside the bone marrow, inhibition of apoptosis, and escape from immune surveillance (13).\n\nThe diagnosis of monoclonal gammopathy (MG) requires the laboratory’s great vigilance, especially when a heavy chain D or E is involved. The International Myeloma Working Group provides guidelines that recommend performing serum protein electrophoresis (SPE), serum quantitation of free light chains (FLC) and serum immunofixation electrophoresis (IFE) testing for IgA, IgG, IgM, kappa and lambda light chains in the screening of MG (14, 15). When an isolated light chain monoclonal band is detected in IFE, IgD and IgE IFE must be performed to distinguish a light chain MG and an IgD or IgE MG. On the other hand, when the FLC quantitation detects an imbalance in light chain production no guidelines, to our knowledge, propose to perform IgD and IgE IFE.\n\nThe aim of this case report was to illustrate that an abnormal serum FLC result can reveal IgE monoclonal gammopathy even when no light chain monoclonal bands are detected in IFE. We report here a challenging diagnosis of IgE MGUS transformed into MM transformed into IgE-producing sPCL.\n\nCase report\n\nIn November 2015, a 71-year-old male was referred to the haematology department of Brest University Hospital (France) after the systematic discovery of hypogammaglobulinemia. A time line summarizing patient follow-up from 2015 to 2019 is presented in Figure 1. His past medical history was confined to high blood pressure, gastroesophageal reflux, inguinal hernia surgery, and an uninvestigated mild renal impairment. He was under antihypertension treatment by nebivolol and indapamide. At the time of haematological consultation, the patient was asymptomatic and the physical examination was unremarkable. Laboratory testing (Table 1), showed an elevated serum creatinine concentration of 131 µmol/L corresponding to a glomerular filtration rate of 47 mL/min estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and an elevated serum β2-microglobulin of 2.85 mg/L (16). There was no hypercalcaemia, no hyperproteinaemia and the blood count showed no particularity. The SPE performed by capillary electrophoresis with a Capillarys 2 instrument (Sebia, Issy-les-Moulineaux, France) showed important hypogammaglobulinemia of 4.8 g/L but no monoclonal component. Serum IFE performed in agarose gel with a Hydrasys 2 instrument (Sebia, Issy-les-Moulineaux, France) using IgG, IgA, IgM, kappa and lambda antisera provided no evidence of monoclonal protein band. The IgD and IgE antisera had not been tested due to the absence of monoclonal light chain in the IFE. Serum FLC quantification performed with a BN ProSpec instrument (Siemens, Erlangen, Germany) showed an excess of free kappa light chains (FKLC) of 163 mg/L, 6 mg/L of free lambda light chains (FLLC), and an increased FKLC/FLLC ratio of 27.2. The research of Bence-Jones proteinuria was not performed at that time. No bone lesion was observed by standard X-ray imaging and the disease was classified as light-chain MGUS. No treatment was deemed to be indicated at the time and a regular follow-up was scheduled.\n\nFigure 1 Time line summarizing the relevant patient data and diagnoses. IFE - immunofixation electrophoresis performed with Hydrasys 2. IgE - Immunoglobulin E; MGUS - Monoclonal gammopathy of undetermined significance; sPCL - Secondary plasma cell leukaemia.\n\nTable 1 Laboratory results\n\nParameter, unit\tResults\n(November 2015)\tResults\n(June 2018)\tResults\n(November 2018)\tReference interval\t\nRed blood cells, x1012/L\t4.73\t3.09\t3.03\t4.50 – 6.50\t\nHaemoglobin, g/L\t130\t101\t106\t130 – 170\t\nHaematocrit, L/L\t0.392\t0.292\t0.307\t0.400 – 0.540\t\nMCV, fL\t82.9\t94.5\t101.3\t82.0 – 98.0\t\nMCH, pg\t27.5\t32.7\t35\t> 27.0\t\nMCHC, g/L\t332\t346\t345\t315 – 365\t\nPlatelets, x109/L\t217\t79\t184\t150 – 400\t\nLeukocytes, x109/L\t7.5\t80.3\t3.1\t4.0 – 10.0\t\nNeutrophils, x109/L\t5.90\t10.44\t1.56\t1.50 – 7.00\t\nLymphocytes, x109/L\t1.31\t1.21\t0.52\t1.50 – 4.00\t\nMonocytes, x109/L\t0.22\t4.02\t0.93\t0.20 – 1.00\t\nEosinophils, x109/L\t0.00\t0.80\t0.03\t0.00 – 0.50\t\nBasophiles, x109/L\t0.04\t0.00\t0.05\t0.00 – 0.20\t\nAlbumin, g/L\t43.5\t35.5\t35.9\t40.2 – 47.6\t\nα1, g/L\t2.7\t5.3\t4.7\t2.1 – 3.5\t\nα2, g/L\t6.0\t6.4\t7.2\t5.1 – 8.5\t\nβ1, g/L\t4.0\t2.9\t3.1\t3.4 – 5.2\t\nβ2, g/L\t2.2\t3.0\t2.0\t2.3 – 4.7\t\nγ, g/L\t4.8\t4.6\t1.9\t8 – 13.5\t\nPeak, g/L\tabsence\t3.4\tabsence\tNA\t\nParameter, unit\tResults\n(November 2015)\tResults\n(June 2018)\tResults\n(November 2018)\tReference interval\t\nImmunofixation\tabsence\tMonoclonal IgE-Kappa\tMonoclonal IgE-Kappa\tNA\t\nImmunoglobulin G, g/L\t5.3\t2.2\t1.2\t6.1 – 13.0\t\nImmunoglobulin A, g/L\t0.760\t0.180\t0.310\t0.400 – 3.50\t\nImmunoglobulin M, g/L\t0.28\t< 0.20\t0.86\t0.50 – 3.0\t\nFKLC, g/L\t163\t516\t3.8\t3.3 – 19.4\t\nFLLC, g/L\t6\t2.6\t1.4\t5.7 – 26.3\t\nFKLC/FLLC ratio\t27.2\t200.8\t2.8\t0.26 – 1.65\t\nCreatinine, µmol/L\t131\t741\t119\t55 – 96\t\nUrea, mmol/L\t7.4\t26.1\t9.7\t2.5 – 7.5\t\nTotal protein, g/L\t63.2\t57.7\t55\t57.0 – 82.0\t\nCalcium, mmol/L\t2.36\t3.42\t2.31\t2.08 – 2.65\t\nBeta2-microglobulin, mg/L\t2.85\t69.9\t5.06\t1.09 – 2.53\t\nLD, U/L\t361\t1051\t603\t208 – 378\t\nNA – not available. FKLC – Free kappa light chains. FLLC – Free lambda light chains. LD – Lactate dehydrogenase. MCH – Mean cell haemoglobin. MCHC – Mean cell haemoglobin concentration. MCV – Mean cell volume.\t\n\nIn October 2016, the patient was asymptomatic at the follow-up consultation. The concentration of FKLC increased to 289 mg/L, with a FKLC/FLLC ratio of 28.7. The SPE showed hypogammaglobulinemia of 4.2 g/L without monoclonal component. A slightly haemodiluted bone marrow aspiration analysis showed poor bone marrow reserve with an excess of plasma cells (5.5%). No bone marrow biopsy was performed due to the refusal of the patient. Plasma cells fluorescence in-situ hybridization (FISH) study demonstrated cytogenetic abnormalities including an immunoglobulin heavy locus (also known as IGH) rearrangement in 88% of the nuclei and three copies of cyclin-dependent kinases regulatory subunit 1 (CKS1B), a chromosome 1q marker, in 46% of the nuclei analysed. The patient was diagnosed with light-chain MM stage II according to the revised International Staging System for Myeloma classification (17). Due to the low production of monoclonal component and the absence of symptoms, a regular follow-up was scheduled without additional treatment.\n\nIn June 2018, the patient remained asymptomatic, but a systematic follow-up laboratory testing (Table 1) showed an acute renal failure with a glomerular filtration rate of 6 mL/min estimated by the CKD-EPI equation, hyperkalaemia of 6.1 mmol/L, hypercalcemia of 3.42 mmol/L, anaemia with haemoglobin of 101 g/L and extreme leucocytosis of 80.3 x109/L. He was then admitted to intensive care for renal failure management. The blood smear performed with Sysmex SP1000-I (Sysmex Corporation, Kobe, Japan) showed 74% of plasma cells (Figure 2) which displayed a typical myeloma immunophenotype (CD38+, CD138+, CD28+, CD56+) analysed by flow cytometry Navios (Beckman Coulter, Fullerton, CA, USA). The SPE revealed for the first time a monoclonal peak in the gamma region, quantified at 3.4 g/L. The IFE using IgG, IgA, IgM, kappa and lambda antisera provided evidence of a slight monoclonal band for the kappa light chain. Further testing was carried out with IgE, IgD, kappa and free kappa-chain antisera. This second IFE exhibited a slight but distinct band for IgE and kappa light chain revealing for the first time the presence of an IgE-kappa monoclonal protein. Urinary immunofixation performed by Hydrasys 2 (Sebia) detected no Bence-Jones protein. A retrospective IFE was then performed using IgD, IgE, kappa and lambda antisera with the November 2015 patient’s frozen serum sample and revealed a slight distinct monoclonal band in the IgE (Figure 3). Interestingly, only testing pure serum, but not the 1:3 dilution recommended by the manufacturer, revealed the abnormal IFE pattern (18). The patient was diagnosed with IgE-producing plasma cells leukaemia secondary to an IgE-kappa MM. The patient had all the criteria of poor prognosis: PCL was secondary to MM, age ≥ 60 years, platelet count ≤ 100 x109/L and peripheral blood plasma cell count ≥ 20 x109/L (19). The decision was made to start treatment.\n\nFigure 2 Blood smear from June 2018 showing the presence of circulating plasma cells.\n\nFigure 3 Immunofixation electrophoresis performed in June 2018 with a November 2015 frozen serum sample of the patient revealing a distinct slight band in IgE while using undiluted serum (E*). D - IgD migration profile; E* - IgE migration profile; ELP - reference profile of total protein electrophoretic migration; Kli - Kappa free light chain migration profile; Te - Negative control track.\n\nThe patient received intravenous Pamidronate (60 mg/day) and adapted hydration to correct hypercalcemia. A renal replacement therapy resulted in a decrease of plasma potassium to 3.6 mmol/L, calcium to 1.95 mmol/L and creatinine to 342 µmol/L. As recommended, chemotherapy with the proteasome inhibitor bortezomib (1.3 mg/m2, twice a week) and dexamethasone (0.5 mg/kg, twice a week) was introduced (patient weight: 65 kg), decreasing the white-blood cell to 13.8 x109/L after one week (20). The patient was discharged to the nephrology ward four days later to monitor the renal failure and to complete the first cycle of chemotherapy with bortezomib and dexamethasone.\n\nA few days later, the patient was transferred to the haematology ward to receive the second and third chemotherapy cycles: bortezomib (1.3 mg/m2, twice a week), cyclophosphamide (300 mg/m2/week) and dexamethasone (40 mg/week); and the fourth chemotherapy cycle: bortezomib (1.3 mg/m2, twice a week), doxorubicin (36 mg/m2) and dexamethasone (40 mg/week). At the end of the four chemotherapy cycles in November 2018, laboratory results showed a leukocyte count of 3.1 x109/L without circulating plasma cells. Serum protein electrophoresis showed complete disappearance of the monoclonal peak in the gamma-globulin region but IFE still detected the IgE-kappa monoclonal component. Free kappa light chains and FLLC were 3.8 and 1.4 mg/L, respectively, with a FKLC/FLLC ratio of 2.75. Due to an alteration of the general state and the development of peripheral neuropathy secondary to chemotherapy, the patient was admitted to a follow-up and rehabilitative care unit for palliative care and no further chemotherapy was performed. An informed consent form for the publication of a case report was signed by the patient during his last hospitalization in February 2019. He died in March 2019, 10 months after the diagnosis of sPCL.\n\nDiscussion\n\nThis case report presents a very rare case of a 71-year-old male with IgE MGUS transforming into MM transforming to an IgE-producing sPCL. To our best knowledge, only 7 cases of IgE-producing sPCL have been described in the literature (21).\n\nThe detection and the identification of monoclonal immunoglobulin are cornerstones in the diagnosis of monoclonal gammopathy highlighting the role of the laboratory practitioner in the management of MM patients. The SPE in combination with serum FLC assay and IFE yields high sensitivity in the context of screening for MM and related plasma cell disorders (14, 15). When a monoclonal peak consists only of light chains, an IFE specific for IgD and IgE is required (5, 22, 23). In our case, the recommended screening procedure to detect monoclonal gammopathies had been applied. The SPE and the IFE tests for monoclonal IgG, IgM, IgA and light chains kappa and lambda had not shown any abnormality that did not lead to suspect IgD and IgE gammopathies. In contrast, the increased serum FKLC and FLLC ratio supported the presence of a monoclonal gammopathy. Then, a faulty diagnosis of light chain MGUS was made in November 2015. To our knowledge, no guidelines specify whether an abnormal FLC test should lead to the detection of IgD and IgE monoclonal gammopathy in the absence of an isolated light chain (22). In our case, an IgD and IgE IFE could have rectified the diagnosis to an IgE-Kappa MGUS as early as 2015. Interestingly, the 1:3 serum dilutions for IFE recommended by the manufacturer did not detect the production of IgE monoclonal immunoglobulin while IFE performed without prior dilution showed clear bands in IgE. Thus, the 1:3 dilution seems to decrease the sensitivity of the IFE compared to the non-diluted test. On the one hand, the manufacturer indicates that this dilution reduces the risk of non-specific fixation, but on the other hand, the use of a control track without anti-serum allows the presence of these non-specific fixations to be detected. A similar report was made by Bossuyt et al., who observed a case of light chain disease missed by IFE with Hydrasys when the sample was diluted 1:3, but not when the sample was analysed undiluted (23).\n\nSerum protein electrophoresis quality controls were performed before each series with the Sebia normal control serum (PN 4785) and after each series with the Sebia hypergamma control serum (PN 4787). Quality controls for IFE (IT/IF control PN 4788) were performed once a week. No quality control of IgD and IgE immunofixation has been performed. No standard has been used. Dilutions of sera before immunofixation were 1:6 for IgG and 1:3 for IgA, IgM; IgD, IgE, FKLC and FLLC excepted with the 2015 sample performed retrospectively in June 2018 without diluting IgD and IgE.\n\nThe absence of urinary immunofixation at the time of screening followed the recommendations of the International Myeloma Working Group: “In the context of screening, the serum FLC assay in combination with serum protein electrophoresis and immunofixation yields high sensitivity, and negates the need for 24h urine studies for diagnoses other than light chain amyloidosis” (14). To our knowledge, no guidelines require urinary immunofixation in the presence of a single FLC abnormality. According to Kyle RA and Rajkumar, the search for Bence-Jones proteinuria is only necessary during follow-up (15). Nevertheless, it appears in retrospect that it would have been useful to perform urinary immunofixation at the time of diagnosis.\n\nFrench legislation requires that samples be stored frozen as soon as tumour markers have been tested for further analysis if necessary. In this case, the sample used for the measurement of β2-microglobulin in 2015 was stored at - 20°C and used in 2018 to perform the IFE. The literature on the storage stability of immunoglobulins is quite poor and no data are available to our knowledge on IgE stability. Glislefoss et al. did not observe any significant difference in IgG measurement before and after 25 years of storage at - 25°C (24). However, this alone cannot guarantee that immunofixation as a whole has retained all the initial characteristics 3 years later.\n\nIn a recent literature review of 63 IgE MM cases, Hejl et al. observed that IgE MM has a more aggressive clinical course than others MM subtypes (5). However, IgE monoclonal gammopathies do not necessarily imply malignant evolution and benign courses are indeed possible (5, 25, 26). The IgE MM patients mean age at the time of diagnosis was 68 years (range: 28 – 87 years) with a male predominance (sex ratio M/F: 1.26). Approximately 45% of patients had anaemia, 27% had renal failure, 17% had hypercalcemia and β2-microglobulin was > 3 mg/L in 63% of cases. The IgE migrated predominantly in the gamma region and were associated with a kappa light chain in 63% of cases. Bone lesions were present in 56% of cases. The authors pointed out that the characteristics of IgE MM are very similar to those of other MM types with the exception of a poorer prognosis. The patient described herein had similar epidemiological characteristics but had no anaemia, no hypercalcemia, and no bone lesions at the time of MM diagnosis.\n\nSecondary PCL is a rare late-stage complication of relapsed/refractory myeloma (27). Patients with sPCL were generally about 60 years old and they frequently had anaemia, thrombocytopenia and bone lesions (28). Multiple myeloma cells and sPCL cells are known to secrete inflammatory cytokines like tumour necrosis factor alpha, interleukin-1 beta and interleukin-6 that enhance osteoclast proliferation and activity while inhibiting osteoblast bone formation (29). In addition, the expansion of sPCL cells deregulates the bone compartment. These explained the patient’s hypercalcemia at the time of sPCL diagnosis resulting in acute renal failure due to extracellular dehydration. The patient developed IgE-producing sPCL 31 months after the initial diagnosis of MGUS. This corresponds to the median time reported by Jurczyszyn et al. to develop sPCL from MM (30). A strong association between IgE MM and sPCL has been suggested by Hejl et al. in his review: 7 of the 63 IgE MM patients reported have developed a sPCL (5). However, this statement should be viewed with caution. On the one hand, the review was not a systematic review of the literature, and on the other hand, drawing epidemiological conclusions from case series necessarily expose the reader to the risk of publication bias. A systematic study of the IgE MM patient population would be necessary to obtain more reliable data.\n\nAlthough Avet-Loiseau et al. reported the translocation t (11, 14) as the hallmark feature of IgE myeloma and t (11, 14)(q13;q32) was associated with PCL, these cytogenetic abnormalities were not observed at either the MM or sPCL stages in the case of our patient (31).\n\nThe International Myeloma Working Group provides recommendations for primary PCL treatment (26).To our knowledge, there is no standardized recommendation for the management of sPCL. Induction therapy needs to be promptly initiated and has high clinical activity leading to rapid disease control in an effort to minimize the risk of early death (32). A recent study showed an improvement in prognosis through treatment with bortezomib-containing regimens which was the treatment chosen for the patient (11). As in MM, treatments with thalidomide and lenalidomide are likely to have some effect on sPCL (33). The survival is still poor, and few patients achieve remission for more than 1 year.\n\nSeveral limitations to the conclusions of this case report must be considered. This is a rare case not chosen from representative population samples, so we cannot generate information on rates, incidences or prevalence. This case report could strengthen the hypothesis that the IgE myeloma subtype may expose the patient to an increased risk of developing aggressive leukaemia compared to other subtypes but this generalization must be taken with caution.\n\nConclusion\n\nIgE myeloma is the rarest subtype of myeloma and it has probably the worst prognosis. The medical laboratory plays an important role in the proper diagnosis and quality of management of MM patients. This case revealed that an abnormal FLC ratio should be considered as a warning signal suggesting the possibility of IgD or IgE myeloma even in the absence of a solitary light chain in IFE. In addition, the use of an undiluted serum could increase the sensitivity of the immunofixation for the detection of IgE and IgD monoclonal gammopathies compared to the 1:3 dilution recommended by the manufacturer. Further investigation is warranted to evaluate the diagnostic strategy of systematically testing IgD and IgE with IFE in the presence of an abnormal FLC ratio.\n\nPotential conflict of interest: None declared.\n==== Refs\nReferences\n\n1 Rajkumar SV Dimopoulos MA Palumbo A Blade J Merlini G Mateos M-V International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014;15 :e538–48. 10.1016/S1470-2045(14)70442-5 25439696\n2 Kyle RA Gertz MA Witzig TE Lust JA Lacy MQ Dispenzieri A Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78 :21–33. 10.4065/78.1.21 12528874\n3 Zingone A Kuehl M Pathogenesis of monoclonal gammopathy of undetermined significance (MGUS) and progression to multiple myeloma. Semin Hematol. 2011;48 :4–12. 10.1053/j.seminhematol.2010.11.003 21232653\n4 Dispenzieri A Katzmann JA Kyle RA Larson DR Melton LJ Colby CL Prevalence and risk of progression of light-chain monoclonal gammopathy of undetermined significance: a retrospective population-based cohort study. Lancet. 2010;375 :1721–8. 10.1016/S0140-6736(10)60482-5 20472173\n5 Hejl C Mestiri R Carmoi T Bugier S Chianea D Renard C IgE monoclonal gammopathy: A case report and literature review. Clin Biochem. 2018;51 :103–9. 10.1016/j.clinbiochem.2017.09.015 28941591\n6 Macro M André I Comby E Chèze S Chapon F Ballet JJ IgE multiple myeloma. Leuk Lymphoma. 1999;32 :597–603. 10.3109/10428199909058419 10048434\n7 Sant M Allemani C Tereanu C De Angelis R Capocaccia R Visser O Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood. 2010;116 :3724–34. 10.1182/blood-2010-05-282632 20664057\n8 International Myeloma Working Group Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121 :749–57. 10.1046/j.1365-2141.2003.04355.x 12780789\n9 Jiménez-Zepeda VH Domínguez VJ Plasma cell leukemia: a rare condition. Ann Hematol. 2006;85 :263–7. 10.1007/s00277-005-0054-4 16416115\n10 Cha CH Park CJ Huh JR Chi HS Suh CW Kang YK Significantly better prognosis for patients with primary plasma cell leukemia than for patients with secondary plasma cell leukemia. Acta Haematol. 2007;118 :178–82. 10.1159/000109470 17934254\n11 Katodritou E Terpos E Kelaidi C Kotsopoulou M Delimpasi S Kyrtsonis M-C Treatment with bortezomib-based regimens improves overall response and predicts for survival in patients with primary or secondary plasma cell leukemia: Analysis of the Greek myeloma study group. Am J Hematol. 2014;89 :145–50. 10.1002/ajh.23600 24123068\n12 Mina R D’Agostino M Cerrato C Gay F Palumbo A Plasma cell leukemia: update on biology and therapy. Leuk Lymphoma. 2017;58 :1538–47. 10.1080/10428194.2016.1250263 27819179\n13 van de Donk NW Lokhorst HM Anderson KC Richardson PG How I treat plasma cell leukemia. Blood. 2012;120 :2376–89. 10.1182/blood-2012-05-408682 22837533\n14 Dispenzieri A Kyle R Merlini G Miguel JS Ludwig H Hajek R International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23 :215–24. 10.1038/leu.2008.307 19020545\n15 Kyle RA Rajkumar SV Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23 :3–9. 10.1038/leu.2008.291 18971951\n16 Matsushita K Mahmoodi BK Woodward M Emberson JR Jafar TH Jee SH Comparison of risk prediction using the CKD-EPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA. 2012;307 :1941–51. 10.1001/jama.2012.3954 22570462\n17 Palumbo A Avet-Loiseau H Oliva S Lokhorst HM Goldschmidt H Rosinol L Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015;33 :2863–9. 10.1200/JCO.2015.61.2267 26240224\n18 Sebia Instructions. Available at: http://www.ilexmedical.com/files/Sebia%20inserts/HYDRAGEL__IF_DM_Hydrasis.pdf Accessed July 9th 2019.\n19 Jurczyszyn A Radocha J Davil J Fiala MA Gozzeti A Grzsko N Prognostic indicators in primary plasma cell leukaemia: a multicentre retrospective study of 117 patients. Br J Haematol. 2018;180 :831–9. 10.1111/bjh.15092 29315478\n20 D’Arena G Valentini CG Pietrantuono G Guariglia R Martorelli MC Mansueto G Frontline chemotherapy with bortezomib-containing combinations improves response rate and survival in primary plasma cell leukemia: a retrospective study from GIMEMA Multiple Myeloma Working Party. Ann Oncol. 2012;23 :1499–502. 10.1093/annonc/mdr480 22039089\n21 Talamo G Castellani W Dolloff NG Prozone effect of serum IgE levels in a case of plasma cell leukemia. J Hematol Oncol. 2010;3 :32. 10.1186/1756-8722-3-32 20828419\n22 Altinier S Barberio G Varagnolo M Zaninotto M Furlan A Caberlotto L An IgE multiple myeloma: contradictory findings in clinical laboratory testing. Clin Chim Acta. 2013;425 :114–6. 10.1016/j.cca.2013.07.006 23872298\n23 Bossuyt X Bogaerts A Schiettekatte G Blanckaert N Serum protein electrophoresis and immunofixation by a semiautomated electrophoresis system. Clin Chem. 1998;44 :944–9.9590366\n24 Gislefoss RE Grimsrud TK Mørkrid L Stability of selected serum proteins after long-term storage in the Janus Serum Bank. Clin Chem Lab Med. 2009;47 :596–603. 10.1515/CCLM.2009.121 19290843\n25 Caldini A Balboni F Parronchi P Scoccianti S Biagioli T Terreni A A rare condition: IgE type monoclonal gammopathy of undetermined significance. Clin Chem Lab Med. 2014;52 :e183–5. 10.1515/cclm-2014-0182 24791823\n26 Ludwig H Vormittag W “Benign” monoclonal IgE gammopathy. BMJ. 1980;281 :539–40. 10.1136/bmj.281.6239.539 7427360\n27 Fernández de Larrea C Kyle RA Durie BGM Ludwig H Usmani S Vesole DH Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013;27 :780–91. 10.1038/leu.2012.336 23288300\n28 Pandey S Kyle RA Unusual myelomas: a review of IgD and IgE variants. Oncology (Williston Park). 2013;27 :798–803.24133829\n29 Panaroni C Yee AJ Raje NS Myeloma and bone disease. Curr Osteoporos Rep. 2017;15 :483–98. 10.1007/s11914-017-0397-5 28861842\n30 Jurczyszyn A Castillo JJ Avivi I Czepiel J Davila J Vij R Secondary plasma cell leukemia: a multicenter retrospective study of 101 patients. Leuk Lymphoma. 2019;60 :118–23. 10.1080/10428194.2018.1473574 29965787\n31 Avet-Loiseau H Garand R Lodé L Harousseau J-L Bataille R Intergroupe Francophone du Myélome. Translocation t(11;14)(q13;q32) is the hallmark of IgM, IgE, and nonsecretory multiple myeloma variants. Blood. 2003;101 :1570–1. 10.1182/blood-2002-08-2436 12393502\n32 Gundesen MT Lund T Moeller HEH Abildgaard N Plasma cell leukemia: definition, presentation and treatment. Curr Oncol Rep. 2019;21 :8. 10.1007/s11912-019-0754-x 30689121\n33 Jimenez-Zepeda VH Reece DE Trudel S Chen C Tiedemann R Kukreti V Lenalidomide (Revlimid), bortezomib (Velcade) and dexamethasone for the treatment of secondary plasma cell leukemia. Leuk Lymphoma. 2015;56 :232–5. 10.3109/10428194.2014.893304 24884320\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1330-0962",
"issue": "30(1)",
"journal": "Biochemia medica",
"keywords": "immunofixation; immunoglobulin E; monoclonal gammopathy of undetermined significance; multiple myeloma; plasma cell leukaemia",
"medline_ta": "Biochem Med (Zagreb)",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D000069286:Bortezomib; D003907:Dexamethasone; D006801:Humans; D007073:Immunoglobulin E; D007952:Leukemia, Plasma Cell; D008297:Male; D010265:Paraproteinemias; D010950:Plasma Cells",
"nlm_unique_id": "9610305",
"other_id": null,
"pages": "010801",
"pmc": null,
"pmid": "31839726",
"pubdate": "2020-02-15",
"publication_types": "D002363:Case Reports",
"references": "29965787;24791823;12528874;28941591;21232653;24133829;20828419;18971951;12393502;24123068;25439696;12780789;23872298;23288300;19290843;29315478;16416115;9590366;7427360;22570462;24884320;17934254;10048434;19020545;20664057;30689121;22837533;27819179;28861842;20472173;26240224;22039089",
"title": "A case of IgE myeloma transformed into IgE-producing plasma cell leukaemia.",
"title_normalized": "a case of ige myeloma transformed into ige producing plasma cell leukaemia"
} | [
{
"companynumb": "FR-PFIZER INC-2020010080",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Immunosuppressive drugs are the milestone of treatment of autoimmune diseases, but they can lead to serious complications, including hepatitis B virus reactivation in HBV carriers as well as in patients with occult HBV infection (OBI). A 36-year-old man with OBI was diagnosed with pemphigus vulgaris. He was prescribed prednisolone and his hepatitis B surface antigen turned positive. Viral replication was successfully controlled by lamivudine and adefovir. Mycophenolate mofetil and intravenous immunoglobulin were not effective in controlling the pemphigus vulgaris. The patient received rituximab 500 mg weekly for four weeks and went into remission without any adverse effect. He safely received another course of rituximab after a relapse one year later. In conclusion, testing for hepatitis B core antibody should be considered mandatory, in addition to HBsAg, for the screening of pemphigus patients to detect rare cases of OBI before starting therapy. Furthermore, rituximab may in some cases be safely used in HBV carriers using antivirals concomitantly.",
"affiliations": "Autoimmune Bullous Diseases Research Center, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Tavakolpour|Soheil|S|;Soori|Tahereh|T|;Noormohammadpour|Pedram|P|;Balighi|Kamran|K|;Mahmoudi|Hamidreza|H|;Daneshpazhooh|Maryam|M|",
"chemical_list": "D018951:Antigens, CD20; D000998:Antiviral Agents; D005938:Glucocorticoids; D006514:Hepatitis B Surface Antigens; D007155:Immunologic Factors; D000069283:Rituximab; D011239:Prednisolone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "23(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000328:Adult; D018951:Antigens, CD20; D000998:Antiviral Agents; D004359:Drug Therapy, Combination; D005938:Glucocorticoids; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006801:Humans; D016867:Immunocompromised Host; D007155:Immunologic Factors; D008297:Male; D010392:Pemphigus; D011239:Prednisolone; D012008:Recurrence; D012074:Remission Induction; D000069283:Rituximab",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28633752",
"pubdate": "2017-06-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab administration in a patient with pemphigus vulgaris following reactivation of occult hepatitis B virus infection.",
"title_normalized": "rituximab administration in a patient with pemphigus vulgaris following reactivation of occult hepatitis b virus infection"
} | [
{
"companynumb": "IR-ALKEM LABORATORIES LIMITED-IR-ALKEM-2018-00085",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"dru... |
{
"abstract": "BACKGROUND\nEctopic pregnancy is the most common cause of mortality during the first trimester of pregnancy, and intrauterine ectopic pregnancies show significantly higher morbidity and mortality than extrauterine ones. Despite being less invasive, safety and effectiveness of the hysteroscopic treatment are still unclear. Moreover, such approach is not standardized. We aimed to evaluate safety and effectiveness of hysteroscopic intact removal of angular or cesarean section scar pregnancies, defining a novel and markedly less invasive hysteroscopic technique with a 5-mm Bettocchi hysteroscope or a 3.5-mm Versascope hysteroscope.\n\n\nMETHODS\nMedical records and video archives were reviewed for all the patients with angular or caesarean scar pregnancies treated with hysteroscopic intact removal technique from January 2000 to December 2018 at our Department. Success and complication rates were assessed.\n\n\nRESULTS\nFour patients with angular (n = 1) or cesarean scar pregnancy (n = 3) met inclusion criteria. Case #1 was treated with bipolar resectoscope, cases #2 and #3 with 5-mm Bettocchi hysteroscope, and case #4 with 3.5-mm Versascope hysteroscope. Cases #2-4 did not require cervical dilatation. Before hysteroscopic treatment, cases #2-4 underwent unsuccessful medical therapy with multiple-dose methotrexate. Hysteroscopic treatment success rate was 100%, while complication rate was 0%. All patients were treated with a novel technique: hysteroscopic intact removal of angular or cesarean scar pregnancies. Such technique was described step-by-step.\n\n\nCONCLUSIONS\nHysteroscopic treatment of angular and cesarean scar pregnancies may be a safe and effective minimally invasive option. The novel technique of hysteroscopic intact removal technique may allow a markedly less invasive approach.",
"affiliations": "Gynecology and Obstetrics Unit, Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi (SA), Italy, antmollo66@gmail.com.;Gynecology and Obstetrics Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy.;Anatomic Pathology Unit, Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy.;Gynecology and Obstetrics Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy.;Anatomic Pathology Unit, Department of Advanced Biomedical Sciences, School of Medicine, University of Naples Federico II, Naples, Italy.;Department of Public Health, School of Medicine, University of Naples Federico II, Naples, Italy.;Gynecology and Obstetrics Unit, Department of Neuroscience, Reproductive Sciences and Dentistry, School of Medicine, University of Naples Federico II, Naples, Italy.;Gynecology and Obstetrics Unit, Department of Medicine, Surgery and Dentistry \"Scuola Medica Salernitana\", University of Salerno, Baronissi (SA), Italy.",
"authors": "Mollo|Antonio|A|;Battagliese|Alessandra|A|;Mascolo|Massimo|M|;Raffone|Antonio|A|;Travaglino|Antonio|A|;D'Armiento|Maria|M|;Insabato|Luigi|L|;Zullo|Fulvio|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000510510",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0378-7346",
"issue": "86(1-2)",
"journal": "Gynecologic and obstetric investigation",
"keywords": "Conservative; Ectopic; Extrauterine; Fertility sparing; Intrauterine",
"medline_ta": "Gynecol Obstet Invest",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D002921:Cicatrix; D005260:Female; D006801:Humans; D015907:Hysteroscopy; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011271:Pregnancy, Ectopic; D016896:Treatment Outcome",
"nlm_unique_id": "7900587",
"other_id": null,
"pages": "55-62",
"pmc": null,
"pmid": "33302286",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Hysteroscopic Intact Removal of Angular and Caesarean Scar Pregnancy: A Novel and Markedly Less Invasive Surgical Treatment.",
"title_normalized": "hysteroscopic intact removal of angular and caesarean scar pregnancy a novel and markedly less invasive surgical treatment"
} | [
{
"companynumb": "IT-MYLANLABS-2021M1044697",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "FOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Thyroid storm is a rare, but critical, illness that can lead to multiorgan failure and carries a high death rate. The following case series describes two adult men with Graves' disease who presented in thyroid storm and either failed or could not tolerate conventional medical management. However, both patients responded well to plasmapheresis, which resulted in clinical and biochemical stabilisation of their disease processes. The treatment option of plasmapheresis should be considered as a stabilising measure, especially when patients have failed or cannot tolerate conventional therapy. Plasmapheresis leads to amelioration of symptoms and a significant decline in thyroid hormone levels, providing a window to treat definitively with thyroidectomy.",
"affiliations": "Department of Medicine/Endocrinology, Baylor College of Medicine, Houston, Texas, USA.",
"authors": "Carhill|Aubrey|A|;Gutierrez|Absalon|A|;Lakhia|Ronak|R|;Nalini|Ramaswami|R|",
"chemical_list": "D013963:Thyroid Hormones",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2012()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D006111:Graves Disease; D006801:Humans; D008297:Male; D010956:Plasmapheresis; D013958:Thyroid Crisis; D013963:Thyroid Hormones; D013965:Thyroidectomy",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23087271",
"pubdate": "2012-10-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10988222;1117982;4390923;7212477;3671132;6438222;10599633;20439250;20146655;10563748;20568098;7700289;10204591;19506329;5536311;4639754;15111206;4542105;8784067;4634489;63848;7808090;7668312;20248293;5412484;15853819;12699596;8325286;20420590;15805713;22107688;8435884;6407376;19484727;17127140;17394188;17308209;10391824",
"title": "Surviving the storm: two cases of thyroid storm successfully treated with plasmapheresis.",
"title_normalized": "surviving the storm two cases of thyroid storm successfully treated with plasmapheresis"
} | [
{
"companynumb": "US-PFIZER INC-2015033209",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Palbociclib, a CDK4/6 inhibitor, is found to be an effective therapeutic drug in the treatment of estrogen receptor positive (ER+)metastatic breast cancer. In this report, we describe a case of rapid progression of life-threatening multiple bone metastases of breast cancer treated with a combination of fulvestrant and palbociclib. The patient, a 58-year-old postmenopausal woman, was diagnosed with left breast cancer at the age of 43 years and underwent breast-conserving surgery. After the completion of postoperative adjuvant endocrine therapy and radiotherapy, the patient was placed on regular follow-up. Eleven years after the surgery, multiple bone metastases and multiple lymph node metastases occurred, and the patient was treated with letrozole as first-line therapy for recurrent breast cancer. Although she continued to receive this treatment for 2 years and 10 months, her general condition worsened due to the occurrence of new liver metastases and the rapid progression of existing metastatic lesions. Thus, she was sent to an emergency room. Marked hypercalcemia and a severe decrease in erythrocyte and platelet counts were observed, which could be the cause of her worsening general condition. Her performance status(PS)was 4, and palliative treatment was also considered. However, she received treatment for hypercalcemia and red blood cell transfusion; as a result, she recovered to the PS 2 where she could begin chemotherapy. Then, she began a treatment consisting of a combination of fulvestrant and palbociclib as a second-line treatment for the recurrence. The patient responded well to the treatment, and her general condition improved to PS 1. She has since maintained a good quality of life for 2 years and 11 months without serious adverse events. In conclusion, the combination of fulvestrant and palbociclib has a low risk of serious adverse events and is a worthwhile treatment for rapidly progressing, life-threatening multiple bone metastases of breast cancer.",
"affiliations": "Dept. of Breast Oncology, Tokyo Kyosai Hospital.",
"authors": "Nakamura|Asuka|A|;Shigekawa|Takashi|T|;Asakawa|Hideki|H|;Park|Keiichi|K|;Baba|Noriyuki|N|",
"chemical_list": "D010879:Piperazines; D011725:Pyridines; D011960:Receptors, Estrogen; D000077267:Fulvestrant; D018719:Receptor, ErbB-2; C500026:palbociclib",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(10)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010879:Piperazines; D011725:Pyridines; D011788:Quality of Life; D018719:Receptor, ErbB-2; D011960:Receptors, Estrogen",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1251-1254",
"pmc": null,
"pmid": "34657057",
"pubdate": "2021-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful Treatment of Estrogen Receptor Positive, HER2 Negative Breast Cancer with Life-Threatening Multiple Bone Metastases Using the Combination of Fulvestrant and Palbociclib-A Case Report.",
"title_normalized": "successful treatment of estrogen receptor positive her2 negative breast cancer with life threatening multiple bone metastases using the combination of fulvestrant and palbociclib a case report"
} | [
{
"companynumb": "JP-NOVARTISPH-NVSJ2022JP002577",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LETROZOLE"
},
"drugadditional": null,
... |
{
"abstract": "In epithelial ovarian carcinoma, very late (more than 20 years) recurrence is an unusual event. In patients experiencing such a recurrence, the effectiveness of platinum/taxane chemotherapy has been questioned. A 54-year old woman presented with paraaortic node swelling that appeared 25 years after treatment of stage I epithelial ovarian carcinoma. She underwent a partial resection of the nodes and histologic examination showed high-grade serous carcinoma. She received paclitaxel and carboplatin chemotherapy and a partial response was initially observed on imaging studies; however, serum cancer antigen125 levels increased thereafter. She received radiation therapy to the paraaortic nodal disease with doses of 45 Gy and achieved a complete response. She was disease-free more than eight years after the detection of recurrence. In conclusion, radiation therapy may be an effective treatment option in patients with very late recurrence of epithelial ovarian carcinoma refractory to platinum/taxane chemotherapy.",
"affiliations": "Department of Gynecology, Kameda Medical Center, Kamogawa, Japan. otsuka.isao@kameda.jp.;Department of Radiology, Kameda Medical Center, Kamogawa, Japan.",
"authors": "Otsuka|Isao|I|;Shoji|Kazufusa|K|",
"chemical_list": "D000970:Antineoplastic Agents; D016190:Carboplatin; D017239:Paclitaxel",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13115",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "42(11)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "late recurrence; ovarian cancer; paraaortic-node; radiation",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D000077216:Carcinoma, Ovarian Epithelial; D005260:Female; D006801:Humans; D008223:Lymphoma; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D017239:Paclitaxel; D012074:Remission Induction; D016896:Treatment Outcome",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "1609-1612",
"pmc": null,
"pmid": "27641229",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Paraaortic node recurrence 25 years after removal of epithelial ovarian carcinoma.",
"title_normalized": "paraaortic node recurrence 25 years after removal of epithelial ovarian carcinoma"
} | [
{
"companynumb": "JP-CIPLA LTD.-2016JP21222",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Nivolumab plus ipilimumab (nivo/ipi) is an approved therapy for patients with intermediate-risk or poor-risk metastatic renal cell carcinoma (mRCC). Clinical factors that guide the selection of this regimen for patients with mRCC are urgently needed. We retrospectively analyzed medical records of patients with mRCC who were hospitalized at MD Anderson Cancer Center because of cancer-related symptoms and received their first cycle of nivo/ipi in the inpatient setting. Clinical parameters, including demographics, histology, clinical history, response, and survival, were collected. The 4-month survival probability, progression-free survival (PFS), and overall survival (OS) were calculated using Kaplan-Meier methods. Between November 2017 and 21 June 2020 patients were identified that fit the search: 19 patients (91%) had poor-risk disease based on the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score; 17 patients (81%) had ≥4 risk factors; and 9 patients (43%) had sarcomatoid features on histology. Shortness of breath (28%) and abdominal pain (19%) were the two most common reasons for hospitalization. Partial response was achieved in 14% (3/21) of patients. Median PFS for all patients was 1.7 months (95% CI 0-3.9); median OS for all patients was 1.7 months (95% CI 0-4.2); and the 4-month survival probability was 36% (95% CI 25%-47%). In this retrospective study, patients with intermediate-risk or poor-risk mRCC who are hospitalized at a large tertiary referral center for cancer-related symptoms derive limited clinical benefit from nivo/ipi when started in the inpatient setting. Alternative, more effective systemic therapies should be considered for these patients.",
"affiliations": "Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Internal Medicine, University of Texas Houston, McGovern Medical School, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Genitourinary Medical Oncology, Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Alhalabi|Omar|O|0000-0002-9658-2206;Hasanov|Elshad|E|0000-0002-7195-0842;Wilson|Nathaniel R|NR|;Araujo|John|J|;Wang|Jianbo|J|;Campbell|Matthew T|MT|;Goswami|Sangeeta|S|;Shah|Amishi Y|AY|;Gao|Jianjun|J|;Msaouel|Pavlos|P|;Tannir|Nizar M|NM|0000-0001-5559-8060",
"chemical_list": "D000074324:Ipilimumab; D000077594:Nivolumab",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.33560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "149(2)",
"journal": "International journal of cancer",
"keywords": null,
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002292:Carcinoma, Renal Cell; D023381:Endpoint Determination; D005260:Female; D006760:Hospitalization; D006801:Humans; D000074324:Ipilimumab; D007680:Kidney Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000077594:Nivolumab; D012189:Retrospective Studies; D016019:Survival Analysis; D062606:Tertiary Care Centers; D016896:Treatment Outcome",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "387-393",
"pmc": null,
"pmid": "33739450",
"pubdate": "2021-07-15",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Outcomes of patients with intermediate-risk or poor-risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease: The MD Anderson Cancer Center experience.",
"title_normalized": "outcomes of patients with intermediate risk or poor risk metastatic renal cell carcinoma who received their first cycle of nivolumab and ipilimumab in the hospital because of symptomatic disease the md anderson cancer center experience"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-036072",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "NIVOLUMAB"
},
"drugaddi... |
{
"abstract": "The development of new drugs for treatment of HIV has increased the efficacy and the quality of life together with decreased unwanted side-effect for people living with HIV. The integrase inhibitor dolutegravir has in short time become part of the first-line treatment in many countries, but is not a recommended first-line drug in pregnancy. As there are few publications of dolutegravir use during pregnancy, we found it valuable to analyze the Stockholm pregnancy cohort. A retrospective analysis of all pregnant women and their infants exposed to dolutegravir at Karolinska University Hospital, 2014-August 2017. Information about maternal health, treatment, pregnancy, and child outcome were collected. Thirty-six women with singleton pregnancies were included. Four early spontaneous abortions occurred. One late termination was performed and one was lost to follow-up. Fourteen were on dolutegravir before and 22 started during pregnancy. Eighteen delivered by caesarean section, three of them because of HIV RNA > 50 copies/mL. The preeclampsia rate and the maternal liver function were normal. One infant was delivered in GW 34 on maternal indication and the rest in full term. No gross malformations were noted. All infants received antiretroviral prophylaxis and have tested negative on follow-up. No increased maternal or infant morbidity was detected in this retrospective study of dolutegravir during pregnancy. This is so far one of the largest observational studies of dolutegravir treatment during pregnancy, but the number is indeed small, and further studies are needed to evaluate the safety and efficacy.",
"affiliations": "Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden. Riikka.bornhede@sll.se.;Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.;Department of Medicine, Huddinge, Unit of Infectious Diseases and Dermatology, Karolinska Institute, and Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden.;Department of Obstetrics and Gynecology, Karolinska University Hospital, Stockholm, Sweden.;Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institute, Stockholm, Sweden.",
"authors": "Bornhede|Riikka|R|http://orcid.org/0000-0001-5614-5098;Soeria-Atmadja|Sandra|S|;Westling|Katarina|K|;Pettersson|Karin|K|;Navér|Lars|L|",
"chemical_list": "D019380:Anti-HIV Agents; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10096-018-3195-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0934-9723",
"issue": "37(3)",
"journal": "European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology",
"keywords": null,
"medline_ta": "Eur J Clin Microbiol Infect Dis",
"mesh_terms": "D019380:Anti-HIV Agents; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D008111:Liver Function Tests; D008297:Male; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011256:Pregnancy Outcome; D011728:Pyridones; D012189:Retrospective Studies; D013548:Sweden; D019562:Viral Load",
"nlm_unique_id": "8804297",
"other_id": null,
"pages": "495-500",
"pmc": null,
"pmid": "29396773",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "8774277;26185421;24754479;25350958;26379069;28905222;26538508;18019878;25845873;27404185;15166829;23101466;26372490;27128333;28748198",
"title": "Dolutegravir in pregnancy-effects on HIV-positive women and their infants.",
"title_normalized": "dolutegravir in pregnancy effects on hiv positive women and their infants"
} | [
{
"companynumb": "SE-MYLANLABS-2018M1058225",
"fulfillexpeditecriteria": "1",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITONAVIR"
},
"drugadditional": null,
... |
{
"abstract": "Rare cases of clonally related histiocytic sarcoma (HS) following B-lymphoblastic leukemia/lymphoma (B-ALL/LBL) have been reported to date.\n\n\n\nWe present a patient with HS, which appeared as a breast mass 12 months after the initial diagnosis of B-ALL.\n\n\n\nBoth HS and the B-ALL shared IGH-MYC and IGK gene rearrangements. Next-generation sequencing and whole-exome sequencing (WES) studies detected 35 common mutations, as well as mutations unique to B-ALL (16) and HS (15), including BRAF D594G. The patient achieved complete remission of B-ALL, but HS failed to respond to many cycles of intensive chemotherapy regimens. A partial response was achieved with sorafenib, a BRAF-targeted therapy.\n\n\n\nTo our knowledge, this is the first study to demonstrate by WES that clonally related B-ALL and HS arise through divergent evolution from a common precursor. We present our findings together with a discussion of the previously reported cases of HS in patients with B-ALL.",
"affiliations": "Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Medicine, Weill Cornell Medicine/NewYork-Presbyterian Hospital, New York, NY.;Departments of Pathology and Laboratory Medicine/NewYork-Presbyterian Hospital, New York, NY.",
"authors": "Geyer|Julia T|JT|;Yigit|Nuri|N|;Miyaguchi|Ayako|A|;Cheng|Shuhua|S|;Casano|Joseph|J|;Mathew|Susan|S|;Desai|Pinkal|P|;Gergis|Usama|U|;Tam|Wayne|W|",
"chemical_list": "D016271:Proto-Oncogene Proteins c-myc",
"country": "England",
"delete": false,
"doi": "10.1093/ajcp/aqz056",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9173",
"issue": "152(4)",
"journal": "American journal of clinical pathology",
"keywords": "\n BRAF D594G; \n IGH-MYC fusion; B-ALL; Clonally related neoplasms; Histiocytic sarcoma; Sorafenib; Whole-exome sequencing",
"medline_ta": "Am J Clin Pathol",
"mesh_terms": "D001943:Breast Neoplasms; D005260:Female; D015321:Gene Rearrangement; D059014:High-Throughput Nucleotide Sequencing; D054747:Histiocytic Sarcoma; D006801:Humans; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D016271:Proto-Oncogene Proteins c-myc",
"nlm_unique_id": "0370470",
"other_id": null,
"pages": "486-494",
"pmc": null,
"pmid": "31172191",
"pubdate": "2019-09-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Histiocytic Sarcoma Following B-Lymphoblastic Leukemia/Lymphoma.",
"title_normalized": "histiocytic sarcoma following b lymphoblastic leukemia lymphoma"
} | [
{
"companynumb": "US-CELGENEUS-USA-20191011877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOXORUBICIN"
},
"drugadditional": null,
... |
{
"abstract": "To investigate differences in palivizumab prescription rates between Dutch paediatricians, and the role of parent counselling in this practice variation.\n\n\n\nA retrospective chart review of premature infants <32 weeks of gestation, aged less than six months at the start of the winter season, born between January 2012 and July 2014, in three secondary hospital-based paediatric practices in the Netherlands.\n\n\n\nWe included 208 patients, 133 (64%) of whom received palivizumab. Prescription rates varied considerably between the three hospitals: 8% (6/64), 89% (32/36) and 99% (97/98). A noticeable difference in the way parents were counselled about palivizumab was the use of the number needed to treat (NNT). In the hospital with the lowest prescription rate (8%), an NNT of 20 to prevent one hospitalisation was explicitly discussed with parents. Bronchiolitis-related hospital admissions occurred in 11.3% of patients receiving palivizumab compared to 20.0% in nonimmunised infants (p = 0.086).\n\n\n\nConsiderable practice variation exists among Dutch paediatricians regarding palivizumab prescription rates. The counselling method seems to play an important role. Presenting palivizumab prophylaxis as a preference-sensitive decision, combined with the explicit use and explanation of an NNT, leads many parents to refrain from respiratory syncytial virus immunisation.",
"affiliations": "Department of Paediatrics, Isala, Zwolle, The Netherlands.;Department of Paediatrics, Martini Hospital, Groningen, The Netherlands.;Department of Paediatrics, Deventer Hospital, Deventer, The Netherlands.;Department of Paediatrics, Isala, Zwolle, The Netherlands.;Department of Paediatrics, Isala, Zwolle, The Netherlands.",
"authors": "Kooiman|L M P|LMP|0000-0002-8067-8385;Kamps|A W A|AWA|;Dassel|A C M|ACM|;Brand|P L P|PLP|;Bekhof|J|J|",
"chemical_list": "D000998:Antiviral Agents; D000069455:Palivizumab",
"country": "Norway",
"delete": false,
"doi": "10.1111/apa.14689",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0803-5253",
"issue": "108(7)",
"journal": "Acta paediatrica (Oslo, Norway : 1992)",
"keywords": "Bronchiolitis; Counselling; Number needed to treat; Palivizumab",
"medline_ta": "Acta Paediatr",
"mesh_terms": "D000998:Antiviral Agents; D001990:Bronchiolitis, Viral; D003376:Counseling; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007234:Infant, Premature; D009426:Netherlands; D000069455:Palivizumab; D010290:Parents; D010343:Patient Admission; D010372:Pediatrics; D010818:Practice Patterns, Physicians'; D012189:Retrospective Studies",
"nlm_unique_id": "9205968",
"other_id": null,
"pages": "1345-1349",
"pmc": null,
"pmid": "30536910",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Practice variation among Dutch paediatricians in palivizumab prescription rates: the importance of parental counselling approach.",
"title_normalized": "practice variation among dutch paediatricians in palivizumab prescription rates the importance of parental counselling approach"
} | [
{
"companynumb": "NL-BIOVITRUM-2020NL5762",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PALIVIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Two patients with systemic lupus erythematosus who developed progressive multifocal leukoencephalopathy (PML) are described. Although the time of PML onset could not be determined with certainty, it probably developed after steroid-induced immunosuppression. However, high-dose corticosteroids appeared to produce transient amelioration in the neurologic disorder. We suggest that PML is an important addition to the list of conditions to be considered in the differential diagnosis when a patient with systemic lupus erythematosus develops neurologic abnormalities.",
"affiliations": null,
"authors": "Newton|P|P|;Aldridge|R D|RD|;Lessells|A M|AM|;Best|P V|PV|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/art.1780290305",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-3591",
"issue": "29(3)",
"journal": "Arthritis and rheumatism",
"keywords": null,
"medline_ta": "Arthritis Rheum",
"mesh_terms": "D000328:Adult; D001921:Brain; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008180:Lupus Erythematosus, Systemic; D008854:Microscopy, Electron; D008875:Middle Aged",
"nlm_unique_id": "0370605",
"other_id": null,
"pages": "337-43",
"pmc": null,
"pmid": "3964312",
"pubdate": "1986-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Progressive multifocal leukoencephalopathy complicating systemic lupus erythematosus.",
"title_normalized": "progressive multifocal leukoencephalopathy complicating systemic lupus erythematosus"
} | [
{
"companynumb": "GB-PFIZER INC-2021576405",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "To report a case of intravitreal methotrexate treatment and fluocinolone acetonide (Retisert®) implantation in a patient with Vogt-Koyanagi-Harada syndrome (VKH).\nA 34-year-old male was referred for worsening vision and bilateral panuveitis consistent with VKH. He was treated with prednisone, mycophenolate mofetil, prednisolone acetate eye drops, and injections of triamcinolone and adalimumab. He failed to improve with these therapies and developed multiple adverse effects, including hepatotoxicity, severe eye pain, cataracts, and cystoid macular edema. We treated him with intravitreal methotrexate injections in both eyes, which rapidly improved his eye pain, inflammation, and vision. He subsequently underwent fluocinolone acetonide (Retisert®) implantation, cataract extraction with intraocular lens insertion, and Ahmed tube placement for long-term intraocular pressure control. His vision improved from hand motions to 20/30, intraocular pressure remained stable at 17, there was complete resolution of his panuveitis and uveitic macular edema, and his systemic medications were able to be discontinued.\n/Importance: This case demonstrates intravitreal methotrexate may successfully treat intraocular inflammation, pain, and macular edema in VKH. Excellent long-term vision and reduction of adverse effects of systemic medications were also achieved with subsequent fluocinolone acetonide implantation. Combining these two targeted therapies may be an effective strategy in treating VKH in patients who have severe pain and cannot tolerate systemic therapy.",
"affiliations": "Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.;Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA.",
"authors": "Park|Jong G|JG|;Callaway|Natalia F|NF|;Ludwig|Cassie A|CA|;Mahajan|Vinit B|VB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2020.100859",
"fulltext": "\n==== Front\nAm J Ophthalmol Case Rep\nAm J Ophthalmol Case Rep\nAmerican Journal of Ophthalmology Case Reports\n2451-9936 Elsevier \n\nS2451-9936(20)30174-2\n10.1016/j.ajoc.2020.100859\n100859\nCase Report\nIntravitreal methotrexate and fluocinolone acetonide implantation for Vogt-Koyanagi-Harada uveitis\nPark Jong G. a Callaway Natalia F. a Ludwig Cassie A. a Mahajan Vinit B. vinit.mahajan@stanford.eduab∗ a Department of Ophthalmology, Byers Eye Institute, Stanford University, Palo Alto, CA, USA\nb Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA\n∗ Corresponding author. Byers Eye Institute, Department of Ophthalmology, Stanford University, Palo Alto, CA, 94304, USA. vinit.mahajan@stanford.edu\n02 8 2020 \n9 2020 \n02 8 2020 \n19 10085929 7 2019 14 6 2020 26 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/).Purpose\nTo report a case of intravitreal methotrexate treatment and fluocinolone acetonide (Retisert®) implantation in a patient with Vogt-Koyanagi-Harada syndrome (VKH).\n\nObservations\nA 34-year-old male was referred for worsening vision and bilateral panuveitis consistent with VKH. He was treated with prednisone, mycophenolate mofetil, prednisolone acetate eye drops, and injections of triamcinolone and adalimumab. He failed to improve with these therapies and developed multiple adverse effects, including hepatotoxicity, severe eye pain, cataracts, and cystoid macular edema. We treated him with intravitreal methotrexate injections in both eyes, which rapidly improved his eye pain, inflammation, and vision. He subsequently underwent fluocinolone acetonide (Retisert®) implantation, cataract extraction with intraocular lens insertion, and Ahmed tube placement for long-term intraocular pressure control. His vision improved from hand motions to 20/30, intraocular pressure remained stable at 17, there was complete resolution of his panuveitis and uveitic macular edema, and his systemic medications were able to be discontinued.\n\nConclusions\n/Importance: This case demonstrates intravitreal methotrexate may successfully treat intraocular inflammation, pain, and macular edema in VKH. Excellent long-term vision and reduction of adverse effects of systemic medications were also achieved with subsequent fluocinolone acetonide implantation. Combining these two targeted therapies may be an effective strategy in treating VKH in patients who have severe pain and cannot tolerate systemic therapy.\n\nKeywords\nIntravitreal methotrexateFluocinolone acetonide implantRetisert®Vogt-koyanagi-harada syndrome\n==== Body\n1 Introduction\nVogt-Koyanagi-Harada (VKH) syndrome is an inflammatory disease characterized by bilateral granulomatous panuveitis. Although the exact etiology is not known, VKH can occur after a virus trigger in the presence of an HLA-DRB1*0405 allele, and can lead to a Th1 lymphocyte-mediated attack on melanocytes in the eye, inner ear, meninges, skin and hair.1 The acute uveitic stage is typically treated with systemic corticosteroid therapy with or without immunomodulatory agents.2, 3, 4, 5 Patients who develop severe side effects from systemic therapy can be very challenging to manage. Targeted intraocular treatment may be an underutilized strategy in these patients.\n\nIntravitreal methotrexate is one potential treatment option. Methotrexate is an antimetabolite that competitively inhibits dihydrofolate reductase. It induces immunosuppression through the inhibition of leukocyte differentiation and was utilized as one of the first curative therapies for metastatic cancer. Methotrexate was proposed for use in leukemia in 1950, shortly after Sidney Farber demonstrated that aminopterin, a chemical analogue of folic acid, could induce remission in acute lymphoblastic leukemia.6,7 It was first used intravitreally for intraocular lymphoma in 1995.8 Today intravitreal methotrexate is used most commonly for intraocular lymphoma, but it has more recently shown promise in uveitis as well.9,10 In a large retrospective cohort study, Gangaputra et al. found methotrexate to be well tolerated by most patients and to be an effective corticosteroid-sparing agent for several types of uveitis.11\n\nHere we present a case of intravitreal methotrexate to treat panuveitis in a patient with VKH, and subsequent fluocinolone acetonide (Retisert®) implantation resulting in vision improvement and symptom control.\n\n2 Methods\nRetrospective case report. The study protocol was approved by the Institutional Review Board for Human Subjects Research at Stanford University. Wide angle fundus and fluorescein angiography photos were obtained with the Optos imaging system. Optical coherence tomography photos were obtained with the Zeiss Cirrus OCT imaging system. Intravitreal methotrexate injections were given at 400 μg/0.1 mL through the pars plana using sterile technique with application of betadine and use of lid speculum. The fluocinolone acetonide (Retisert®) device was implanted as previously described.12 Briefly, a limbal peritomy was performed to expose the inferotemporal quadrant. A double-armed 8–0 prolene suture was passed through the hole in the strut of the implant. A scleral incision was made with a keratome blade 3.5 mm from the limbus and 4.0 mm in length. The implant was then placed with the drug tablet anteriorly into the vitreous cavity. To secure the implant, each arm of the 8–0 Prolene suture was placed through the inner scleral wound at half-depth and tied in a 3-1-1 fashion.\n\n2.1 Case report\nA 34-year-old Hispanic male was referred for one year of worsening vision in both eyes secondary to panuveitis. At presentation to our clinic, his vision was hand motions (HM) OD and 20/100 OS. There was no relative afferent pupillary defect, the intraocular pressure (IOP) was 13 OD, 18 OS. The right eye had 2+ injection, numerous medium sized keratic precipitates (KP), anterior chamber had 4+ cell and 3+ flare, posterior synechiae, 2+ posterior subcapsular cataract (PSC), 3+ vitreous cell, a hyperemic optic disc, cystoid macular edema (CME), and scattered peripheral yellow nodules (Fig 1A,C). The left eye had a few KP, trace cell and flare, trace PSC, 1+ vitreous cell, optic disk edema, and scattered peripheral yellow nodules (Fig. 1B). B-scan ultrasonography showed choroidal thickening (Fig. 1D). Fluorescein angiography demonstrated multifocal leakage, hyperfluorescent staining of peripheral nodules, and late optic disc leakage (Fig. 1E and F). Samples from the patient's blood, aqueous and vitreous were tested. Complete blood count, basic metabolic profile, erythrocyte sedimentation rate, rapid plasma reagin, fluorescent treponemal antibody absorption, quantiferon, lyme antibody, and angiotensin converting enzyme were unremarkable. Vitreous fluid yielded rare polymorphonuclear neutrophils and no organisms, and chest x-ray was normal. After exclusion of infectious, neoplastic, and other inflammatory etiologies, the patient was diagnosed with Vogt-Koyanagi-Harada (VKH) syndrome.Fig. 1 34-year-old male with Vogt-Koyanagi-Harada syndrome. A-B) Wide field fundus photos with 3+ vitreous cells and hyperemic disc OD, and scattered peripheral yellow nodules OU. C) Optical coherence tomography of the macula with extensive cystic macular edema OD. D) B-scan ultrasonography showing diffuse choroidal thickening without posterior scleritis. E-F) Fluorescein angiography demonstrating diffuse multifocal areas of leakage, staining of peripheral nodules, and late optic disc leakage OU. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)\n\nFig. 1\n\nAt presentation, the patient was taking prednisone 25 mg daily, mycophenolate mofetil 500 mg twice daily, and prednisolone acetate 1% three times daily in both eyes. The side effects of the steroids were becoming intolerable for the patient, and included hip necrosis and difficulty sleeping. He had developed hepatotoxicity with elevated liver function test enzymes from the mycophenolate. He had also previously received two injections of sub-tenon's triamcinolone acetate as well as six treatments of subcutaneous adalimumab. Despite this treatment, he suffered from constant and severe eye pain, recurrent inflammation, and worsening vision with cystoid macular edema and cataracts.\n\nGiven the complex and worsening clinical course, the decision was made to first treat the right eye with 400 μg/0.1 mL intravitreal methotrexate. He reported that the intravitreal methotrexate was immediately effective for his pain and inflammation. The patient's vision improved from HM to 20/400 OD within 1 week, and 20/150 after 4 weeks, with improvement of the CME. The decision was made to perform surgery for cataract extraction and intravitreal fluocinolone acetonide (Retisert®) implantation (Fig. 2A and B). He had a subsequent surgery for Ahmed tube placement and a second vitrectomy for a mild non-clearing vitreous hemorrhage. His symptoms improved dramatically, and 6 months after surgery, his right eye vision stabilized to 20/30, IOP 17, with resolution of the panuveitis and macular edema (Fig. 2C).Fig. 2 Surgical management with postoperative improvement in visual acuity. A-B) Cataract extraction, intraocular lens placement, and fluocinolone acetonide (Retisert®) implantation. C-D) Postoperative optical coherence tomography showing resolution of cystoid macular edema in both eyes after intravitreal methotrexate injections and intravitreal fluocinolone acetonide (Retisert®) implants.\n\nFig. 2\n\nDuring the postoperative course of his right eye, the patient developed worsening vision and CME in the left eye. He received an injection of intravitreal methotrexate OS, which resulted in reduced vitreous cells and mild improvement of the CME. He was taken to the operating room 3 months later for repeat intravitreal methotrexate, pars plana vitrectomy, and fluocinolone acetonide (Retisert®) implantation in his left eye. His postoperative course was unremarkable, and 2 months after surgery in his left eye, his vision had improved to 20/30, IOP 21, and there was no intraocular inflammation or macular edema (Fig. 2D).\n\n3 Discussion\nVogt-Koyanagi-Harada syndrome can be very difficult to manage in patients who have failed systemic therapy and who develop severe side effects from treatment. Most cases of VKH are treated with oral corticosteroids alone or in combination with immunomodulatory agents. Our patient was initially treated with such a regimen, including prednisone, mycophenolate mofetil, and adalimumab. Although all of these agents have been shown to be effective in treating VKH,4,13 our patient did not respond to these combined therapies. His uveitis was not controlled, and he was developing severe side effects, including worsening eye pain, cataract, cystoid macular edema, and liver toxicity. Given this challenging clinical course, we did not pursue further systemic therapy which could lead to worsening adverse effects. We instead decided to offer more aggressive local therapy with intravitreal methotrexate and fluocinolone acetonide implantation.\n\nIntravitreal methotrexate was first used in the eye to treat intraocular lymphoma,14 and was subsequently demonstrated to be effective in patients with non-infectious uveitis and uveitic cystoid macular edema.10 In VKH, systemic methotrexate has resulted in some success when combined with systemic corticosteroids.15 However, the use of intravitreal methotrexate in VKH has not been previously reported, and, to our knowledge, this may be the first case of intravitreal methotrexate therapy in a patient with VKH.\n\nIn our patient, intravitreal methotrexate was successful in rapidly improving his eye pain, visual acuity, and macular edema within 1–2 weeks in his more severely affected right eye. Intravitreal methotrexate was not given in his left eye until he developed CME months after the initial therapy in his right eye. The intravitreal methotrexate rapidly resolved the CME, consistent with previous findings that demonstrated efficacy in treating uveitic CME.10 The methotrexate injections were well tolerated without any further systemic side effects. Importantly, the resolution of the panuveitis and macular edema facilitated the placement of the fluocinolone acetonide implant, which would have been challenging given the severity of the patient's active intraocular inflammation.\n\nFluocinolone acetonide intravitreal implants, which can deliver intravitreal corticosteroid for up to 30 months, have been used to treat VKH but with mixed results.16,17 The main adverse outcomes are increased intraocular pressure and cataract formation. Anticipating these complications is important. In our patient, we performed the steroid implantation in conjunction with cataract extraction and Ahmed tube placement. Our results were positive, and 6 months after surgery, the patient's visual acuity improved from HM to 20/30, with stable IOP and complete resolution of the panuveitis and macular edema. Given such a positive outcome, it is possible that combining intravitreal methotrexate with fluocinolone acetonide implants may increase the efficacy of the steroid. However, further studies are needed to determine if these two therapies act on synergistic anti-inflammatory pathways.\n\n4 Conclusions\nVogt-Koyanagi-Harada syndrome can be a challenging condition to manage with systemic therapy alone, especially in patients who develop intolerable side effects. Localized treatment with intravitreal methotrexate can be effective in controlling intraocular inflammation, and fluocinolone acetonide implantation with appropriate measures for intraocular pressure control can result in excellent long-term visual outcomes.\n\nPatient consent\nThis report does not contain any information that could lead to the identification of the patients.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for Authorship.\n\nFunding\nVBM is supported by NIH grants [R01EY031952, R01EY026877, R01EY024665, R01EY025225, P30EY026877], Research to Prevent Blindness (RPB), New York, NY, and the Stanford ChEM-H Testing Molecular Hypotheses in Human Subjects Seed Grant.\n\nCRediT authorship contribution statement\nJong G. Park: Supervision, Conceptualization, Funding acquisition, Formal analysis, Writing - original draft, Writing - review & editing. Natalia F. Callaway: Supervision, Conceptualization, Funding acquisition, Formal analysis, Writing - original draft, Writing - review & editing. Cassie A. Ludwig: Supervision, Conceptualization, Funding acquisition, Formal analysis. Vinit B. Mahajan: Supervision, Conceptualization, Funding acquisition, Formal analysis, Writing - original draft, Writing - review & editing.\n\nDeclaration of competing interest\nNone reported.\n\nAcknowledgements\nThe authors would like to acknowledge Dr. Kuldev Singh who performed the Ahmed tube surgery.\n==== Refs\nReferences\n1 Lavezzo M.M. Sakata V.M. Morita C. Vogt-Koyanagi-Harada disease: review of a rare autoimmune disease targeting antigens of melanocytes Orphanet J Rare Dis 11 2016 29 10.1186/s13023-016-0412-4 27008848 \n2 Cuchacovich M. Solanes F. Díaz G. Comparison of the clinical efficacy of two different immunosuppressive regimens in patients with chronic vogt-koyanagi-harada disease Ocul Immunol Inflamm 18 3 2010 200 207 10.3109/09273941003587541 20482399 \n3 Tomkins-Netzer O. Lightman S. Drye L. Outcome of treatment of uveitic macular edema: the multicenter uveitis steroid treatment trial 2-year results Ophthalmology 122 11 2015 2351 2359 10.1016/j.ophtha.2015.07.036 26359188 \n4 Abu El-Asrar A.M. Hemachandran S. Al-Mezaine H.S. Kangave D. Al-Muammar A.M. The outcomes of mycophenolate mofetil therapy combined with systemic corticosteroids in acute uveitis associated with Vogt-Koyanagi-Harada disease Acta Ophthalmol 90 8 2012 e603 608 10.1111/j.1755-3768.2012.02498.x 22971163 \n5 Yamanaka E. Ohguro N. Yamamoto S. Nakagawa Y. Imoto Y. Tano Y. Evaluation of pulse corticosteroid therapy for vogt-koyanagi-harada disease assessed by optical coherence tomography Am J Ophthalmol 134 3 2002 454 456 10.1016/s0002-9394(02)01575-1 12208266 \n6 Meyer L.M. Miller F.R. Rowen M.J. Bock G. Rutzky J. Treatment of acute leukemia with amethopterin (4-amino, 10-methyl pteroyl glutamic acid) Acta Haematol 4 3 1950 157 167 10.1159/000203749 14777272 \n7 Farber S. Diamond L.K. Temporary remissions in acute leukemia in children produced by folic acid antagonist, 4-aminopteroyl-glutamic acid N Engl J Med 238 23 1948 787 793 10.1056/NEJM194806032382301 18860765 \n8 de Smet M. Stark-Vancs V. Kohler D. Ruddel M. Wittes R. Nussenblatt R. Intravitreal chemotherapy for intraocular lymphoma unresponsive to conventional therapeutic modalities Ophthalmology 102 161 1995 \n9 Taylor S.R.J. Habot-Wilner Z. Pacheco P. Lightman S. Intravitreal methotrexate in uveitis Ophthalmology 119 4 2012 878 879 10.1016/j.ophtha.2011.12.015 \n10 Taylor S.R.J. Habot-Wilner Z. Pacheco P. Lightman S.L. Intraocular methotrexate in the treatment of uveitis and uveitic cystoid macular edema Ophthalmology 116 4 2009 797 801 10.1016/j.ophtha.2008.10.033 19344827 \n11 Gangaputra S. Newcomb C.W. Liesegang T.L. Methotrexate for ocular inflammatory diseases Ophthalmology 116 11 2009 10.1016/j.ophtha.2009.04.020 2188-2198.e1 \n12 Mahajan V.B. Gehrs K.M. Goldstein D.A. Fischer D.H. Lopez J.S. Folk J.C. Management of sympathetic ophthalmia with the fluocinolone acetonide implant Ophthalmology 116 3 2009 10.1016/j.ophtha.2008.10.024 552-557.e1 \n13 Couto C. Schlaen A. Frick M. Adalimumab treatment in patients with vogt-koyanagi-harada disease Ocul Immunol Inflamm 26 3 2018 485 489 10.1080/09273948.2016.1236969 27775450 \n14 Fishburne B.C. Wilson D.J. Rosenbaum J.T. Neuwelt E.A. Intravitreal methotrexate as an adjunctive treatment of intraocular lymphoma Arch Ophthalmol Chic Ill 115 9 1960 1152 1156 1997 \n15 Shen E. Rathinam S.R. Babu M. Outcomes of vogt-koyanagi-harada disease: a subanalysis from a randomized clinical trial of antimetabolite therapies Am J Ophthalmol 168 2016 279 286 10.1016/j.ajo.2016.06.004 27296490 \n16 Khalifa Y. Loh A.R. Acharya N.R. Fluocinolone acetonide intravitreal implants in Vogt-Koyanagi-Harada disease Ocul Immunol Inflamm 17 6 2009 431 433 10.3109/09273940903267936 20001265 \n17 Heo J.W. Cho B.-J. Goldstein D.A. Sepah Y.J. Do D.V. Nguyen Q.D. Fluocinolone acetonide implant for vogt-koyanagi-harada disease: three-year outcomes of efficacy and safety Retina Phila Pa 36 11 2016 2124 2131 10.1097/IAE.0000000000001094\n\n",
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"journal": "American journal of ophthalmology case reports",
"keywords": "Fluocinolone acetonide implant; Intravitreal methotrexate; Retisert®; Vogt-koyanagi-harada syndrome",
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"title": "Intravitreal methotrexate and fluocinolone acetonide implantation for Vogt-Koyanagi-Harada uveitis.",
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"abstract": "Quetiapine is occasionally associated with cardiovascular adverse effects such as QTc prolongation. QTc prolongation is a side effect that requires monitoring in order to avoid more serious cardiac complications. One particular understudied area is the potential for antipsychotics to elicit electroconduction abnormalities in patients with Wolff-Parkinson-White (WPW) Syndrome. In the present report, we describe a case of quetiapine overdose in a patient with WPW.",
"affiliations": "Department of Psychiatry, Lehigh Valley Health Network, 2545 Schoenersville road, Bethlehem PA 18017, USA.;Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA.;Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA.;Department of Psychiatry, Thomas Jefferson University, Philadelphia, PA, USA.;Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA.;Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA.",
"authors": "Chen|Michael|M|;Gomaa|Hassaan|H|;Cortez-Resendiz|Alonso|A|;Martin|Christopher|C|;Francis|Andrew|A|;Bellon|Alfredo|A|https://orcid.org/0000-0003-2669-084X",
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"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X 2090-6838 Hindawi \n\n10.1155/2020/6633385\nCase Report\nQuetiapine and Wolff-Parkinson-White Syndrome\nChen Michael \n1\n Gomaa Hassaan \n2\n Cortez-Resendiz Alonso \n2\n Martin Christopher \n3\n Francis Andrew \n2\n https://orcid.org/0000-0003-2669-084XBellon Alfredo alfredobellon@yahoo.com\n2\n\n4\n \n1Department of Psychiatry, Lehigh Valley Health Network, 2545 Schoenersville road, Bethlehem PA 18017, USA\n\n2Department of Psychiatry and Behavioral Health, Penn State Hershey Medical Center, 500 University Drive P.O. Box 850. Mail Code R130. Hershey, PA 17033-0850, USA\n\n3Department of Psychiatry, Thomas Jefferson University, Philadelphia, PA, USA\n\n4Department of Pharmacology, Penn State College of Medicine, Penn State Hershey Medical Center, Hershey, PA, USA\nAcademic Editor: Erik J nsson\n\n\n2020 \n11 12 2020 \n2020 66333854 11 2020 29 11 2020 6 12 2020 Copyright © 2020 Michael Chen et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Quetiapine is occasionally associated with cardiovascular adverse effects such as QTc prolongation. QTc prolongation is a side effect that requires monitoring in order to avoid more serious cardiac complications. One particular understudied area is the potential for antipsychotics to elicit electroconduction abnormalities in patients with Wolff-Parkinson-White (WPW) Syndrome. In the present report, we describe a case of quetiapine overdose in a patient with WPW.\n\nPenn State IRBSTUDY00008872\n==== Body\n1. Introduction\nWolff-Parkinson-White (WPW) Syndrome is a cardiac condition deviation characterized by an accessory pathway that bypasses the atrioventricular (AV) node resulting in abnormally fast ventricular contractions. Specific electrocardiogram (EKG) findings of WPW include delta wave, widened QRS complex (>110 ms), shortened PR interval (<120 ms), and inverted T waves [1]. Although generally asymptomatic [2], the most common clinical symptom is “palpitations of the heart [3].” In rare, severe cases, WPW has been linked to Torsades de pointes and sudden cardiac death [4]. While the pathophysiology of WPW is well established and studied, the effects of antipsychotics on patients with WPW remain unknown.\n\nOther cardiac consequences of antipsychotic medications have been well characterized, including QTc prolongation [5]. Specifically, quetiapine is well known to have QTc prolonging effects and has been linked to dangerous conditions such as Torsades de pointes [6]. However, the potential effects of quetiapine on patients with WPW have not been described. Therefore, here, we report the consequences of a quetiapine overdose in a patient with WPW.\n\n2. Case Report\nA 30-year-old female with a past medical history significant for WPW and a psychiatric history of major depressive disorder, posttraumatic stress disorder, borderline personality disorder, and several suicide attempts presented to the Emergency Department (ED) with complaints of decreased energy, swollen lymph nodes, weight loss (approximately 13.5 kg), and mild abdominal pain. Subsequent interviews revealed that while waiting for the results of her evaluation, the patient overdosed on 1200 mg of trazodone, 1200 mg of quetiapine, and 900 mg of venlafaxine, as a suicide attempt. Two hours postoverdose, the patient began to exhibit a prolonged QTc interval of 486 ms which contrasted with her QTc baseline of 445 ms (Figure 1). Of note, no delta wave was appreciated in the EKG. Her PR interval was 160 ms at baseline and 146 ms 2 hrs after (Table 1). Baseline blood pressure was noted at 114/70, but 2 hours postoverdose, the patient developed hypotension of 86/45 mmHg. In addition, the patient complained of palpitations with a heart rate ranging from 83 to 97. All psychiatric medications were discontinued, and intravenous fluids were provided. Forty-eight hours after discontinuation of her medication, the patient's EKG normalized including her QTc interval (QT/QTc of 414/434) (Figure 1), and her PR interval was at 160 ms (Table 1). At this point, the patient was medically cleared and transferred to our inpatient unit.\n\nOn the inpatient unit, the patient was slowly reintroduced to her psychiatric medications. On day 1, the patient was started on quetiapine 100 mg at bedtime, trazodone 100 mg at bedtime, and venlafaxine 150 mg in the morning. This was gradually raised to a maximum dose of quetiapine100 mg in am and 300 mg at bedtime. Venlafaxine was increased to 225 mg daily and trazodone remained at 100 mg at bedtime. Apart from mild sedation, the patient reported no symptoms or side effects from medications such as sensation of rapid, fluttering, or pounding heartbeats (palpitations); dizziness or lightheadedness; or shortness of breath. The patient was discharged after 11 days of inpatient psychiatric treatment.\n\nAfter discharge, maintenance treatment consisted of 300 mg of quetiapine, 100 mg of trazodone, and 225 mg of venlafaxine. A year later, the patient was seen in the ED for chest palpitations, pain, and dizziness. Her initial EKG was significant for heart rate of 109 beats per minute, QTc of 450 ms, and PR interval of 160 ms. Twenty-four hours later her EKG showed a QTc interval of 457 ms, PR interval of 170 ms, and heart rate of 89 bpm (Figure 1). Of note, delta waves were not appreciated on either EKG. Initially, the patient was worked up for chest pain via 3 sets of troponins, EKG, and stress test. All test results came back negative. Her symptoms resolved within 24 hours with no changes in medication, and the patient was discharged without further issues.\n\n3. Discussion\nIn recent years, special consideration has been placed on the QTc prolonging side effects of various psychotropic medications, particularly, typical antipsychotics such as haloperidol [7], droperidol [8], and atypical antipsychotics such as olanzapine, ziprasidone, and risperidone [9]. But very little is known about the effects antipsychotics may have on patients with WPW. We have recently reviewed all published information currently available [10], which mostly comes from case reports, some providing conflicting results. For example, olanzapine has been shown to have varying levels of safety in WPW patients. In one case a dosage of 5 mg/day was shown to cause QTc prolongation from 390 to 466 ms [11]. In another case, a dosage of 7.5 mg/day was shown to have no effect on QTc intervals [12]. On the other hand, data on risperidone is more consistent. In two separate cases, risperidone at 1 mg BID induced palpitations, QTc prolongation, shortened PR intervals, and induction of a delta wave on EKG [9, 13]. To our knowledge, there is no published data on the effects of quetiapine on WPW.\n\nQuetiapine is a dibenzothiazepine derivative that is FDA-approved to treat schizophrenia and bipolar disorder. Compared to typical antipsychotics, quetiapine is unique in that it has transient antagonist effects on dopamine 2 receptors and, as a result, lower risk for extrapyramidal symptoms [14]. At the same time, when compared to typical antipsychotics, quetiapine has an affinity for muscarinic receptors resulting in anticholinergic side effects such as orthostatic hypotension and transient sedation [15].\n\nThe general medical effects of quetiapine overdose have been documented in several previous case studies. Most overdose cases result in exaggeration of the anticholinergic side effects including tachycardia, hypotension, and sedation. However, several other symptoms have been documented in severe overdoses. One report in a 26-year-old woman who ingested over 10,000 mg of quetiapine, resulted in rapid deterioration of mental status and required intubation [16]. Another case was a 19-year-old man who ingested 9,600 mg of quetiapine, leading to QTc prolongation [17]. A third publication described a 31-year-old female who ingested 2,000 mg of quetiapine and then became comatose requiring intubation. QTc prolongation was also observed [5].\n\nIn our case, our patient had an overdose of 1,200 mg that resulted in typical anticholinergic side effects of hypotension and sedation. Initially, the patient presented with concerning symptoms of QTc prolongation. However, despite having an extra electrical pathway, the patient did not develop any further cardiac complications such as arrhythmia. In fact, discontinuation of quetiapine led to recovery within 48 hours. Furthermore, after reintroduction of quetiapine to therapeutic levels, the patient did not present any clinical symptoms associated with WPW such as palpitations or shortness of breath. The only symptoms that the patient expressed were mild fatigue, which can be attributed to the anticholinergic effects of quetiapine and mild QTc prolongation. Of note, the side effect of fatigue resolved after slightly lowering her quetiapine dose. Her QT interval also returned to baseline.\n\nMost importantly, the patient was discharged on a therapeutic dose of quetiapine with no cardiac complications. This was confirmed upon reevaluation 1 year after discharge in which the patient initially reported some symptoms that could be related to WPW. While the patient did report palpitations, the EKG demonstrated a QTc interval similar to baseline. A repeat EKG 24 hours later remained at baseline. Thus, it is evident that 1 year of therapeutic dosage of quetiapine did not affect the patient's WPW.\n\nIt also has to be considered that the patient was concomitantly taking trazodone and venlafaxine. While some studies have shown a slight increase in QTc interval with trazodone [18] and venlafaxine [19], this side effect is less frequently observed than when quetiapine is administered. The combination of quetiapine with trazodone, especially considering that the patient overdosed on 2000 mg of trazodone, could have elicited significant QTc prolongation and even Torsades. Serious cardiac arrhythmias have been documented in cases of trazodone and venlafaxine overdose or when combined with other QTc prolonging medications [20].\n\nIn conclusion, to our knowledge, this is the first case reporting the potential effects of quetiapine, trazodone, and venlafaxine in an individual with WPW, and no serious cardiac complications were encountered even after a year of follow-up. But these medications cannot be considered entirely safe for patients with WPW until further research is developed on this topic.\n\nAcknowledgments\nThe authors would like to thank the Ling and Esther Tan Early Career Professorship endowment given to AB. This case was reviewed by the Penn State IRB, and it was deemed exempt (STUDY00008872).\n\nData Availability\nAll data used for this work is included in the manuscript.\n\nConflicts of Interest\nThe authors have no conflict of interest related to this manuscript.\n\nFigure 1 Effects of quetiapine on QTc on a patient with Wolff-Parkinson-White (WPW) Syndrome. This graph represents changes in the QTc interval expressed in milliseconds at various points in time including at baseline, 2, 24, and 48 hours postoverdose and then finally a year after.\n\nTable 1 EKG parameters at baseline and several time points after quetiapine overdose.\n\n\tQT\tQTc\tPR interval\tPulse\t\nBaseline\t358 ms\t445 ms\t160 ms\t93 BPM\t\n2-hour postintoxication\t416 ms\t486 ms\t146 ms\t82 BPM\t\n24-hour postintoxication\t404 ms\t472 ms\t180 ms\t82 BPM\t\n48-hour postintoxication\t414 ms\t434 ms\t160 ms\t66 BPM\t\n1-year postintoxication\t344 ms\t450 ms\t170 ms\t89 BPM\n==== Refs\n1 Rao A. L. Salerno J. C. Asif I. M. Drezner J. A. Evaluation and management of wolff-Parkinson-white in athletes Sports Health: A Multidisciplinary Approach 2014 6 4 326 332 10.1177/1941738113509059 2-s2.0-84902965879 24982705 \n2 Cohen M. I. Triedman J. K. Cannon B. C. PACES/HRS Expert Consensus Statement on the Management of the Asymptomatic Young Patient with a Wolff-Parkinson-White (WPW, Ventricular Preexcitation) Electrocardiographic Pattern. Heart Rhythm 2012 9 6 1006 1024 10.1016/j.hrthm.2012.03.050 2-s2.0-84861471157 22579340 \n3 Chiu S.-N. Wang J.-K. Wu M.-H. Cardiac conduction disturbance detected in a pediatric population The Journal of Pediatrics 2008 152 1 85 89 10.1016/j.jpeds.2007.05.044 2-s2.0-37249087842 18154906 \n4 Finocchiaro G. Papadakis M. Behr E. R. Sharma S. Sheppard M. Sudden cardiac death in pre-excitation and Wolff-Parkinson-White Journal of the American College of Cardiology 2017 69 12 1644 1645 10.1016/j.jacc.2017.01.023 2-s2.0-85015611749 28335848 \n5 Vieweg W. V. R. New generation antipsychotic drugs and QTc interval prolongation The Primary Care Companion to The Journal of Clinical Psychiatry 2003 5 5 205 215 10.4088/PCC.v05n0504 15213787 \n6 Hasnain M. Vieweg W. V. Howland R. H. Quetiapine, QTc interval prolongation, and torsade de pointes: a review of case reports Therapeutic Advances in Psychopharmacology 2014 4 3 130 138 10.1177/2045125313510194 2-s2.0-84998090344 25057346 \n7 Zou D. Shao Y. Qin Z. Death due to fulminant neuroleptic malignant syndrome induced by low doses of haloperidol: a rare case Journal of Forensic and Legal Medicine 2014 24 12 14 10.1016/j.jflm.2014.02.011 2-s2.0-84896964692 24794843 \n8 Ostinelli E. G. Brooke-Powney M. J. Li X. Adams C. E. Haloperidol for psychosis-induced aggression or agitation (rapid tranquillisation) Cochrane Database of Systematic Reviews 2017 7 7, article CD009377 10.1002/14651858.cd009377.pub3 2-s2.0-85026462887 \n9 Imran T. F. Niazi O. T. Amin R. Mazza V. Klapholz M. Risperidone unmasking an accessory pathway International Journal of Cardiology 2015 187 488 490 10.1016/j.ijcard.2015.03.419 2-s2.0-84929311689 25863733 \n10 Nutting S. Martin C. Prensner R. Francis A. Bellon A. Antipsychotics for patients with Wolff-Parkinson-White Syndrome Clinical Schizophrenia & Related Psychoses 2019 aop 10.3371/CSRP.SNCM.121218 \n11 Czekalla J. Beasley C. M. Dellva M. A. Berg P. H. Grundy S. Analysis of the QTc interval during olanzapine treatment of patients with schizophrenia and related psychosis The Journal of Clinical Psychiatry 2001 62 3 191 198 10.4088/JCP.v62n0310 2-s2.0-0035062824 11305706 \n12 Salsano E. Giovagnoli A. R. Morandi L. Mitochondrial dementia: a sporadic case of progressive cognitive and behavioral decline with hearing loss due to the rare m.3291T>C MELAS mutation Journal of the Neurological Sciences 2011 300 1-2 165 168 10.1016/j.jns.2010.09.022 2-s2.0-78650515513 20943236 \n13 Bon F. Constant E. L. Goethals P. Neu D. Absence of cardiac side effects during treatment of Schirophrenia with risperidone in a patient with wolff-Parkinson-white syndrome The Primary Care Companion to The Journal of Clinical Psychiatry 2007 9 3 p. 235 10.4088/PCC.v09n0311d \n14 Farah A. Atypicality of atypical antipsychotics The Primary Care Companion to The Journal of Clinical Psychiatry 2005 7 6 268 274 10.4088/PCC.v07n0602 16498489 \n15 Chew M. L. Mulsant B. H. Pollock B. G. A model of anticholinergic activity of atypical antipsychotic medications Schizophrenia Research 2006 88 1-3 63 72 10.1016/j.schres.2006.07.011 2-s2.0-33750628479 16928430 \n16 Harmon T. J. Benitez J. G. Krenzelok E. P. Cortes-Belen E. Loss of consciousness from acute quetiapine overdosage Journal of Toxicology. Clinical Toxicology 1998 36 6 599 602 10.3109/15563659809028056 2-s2.0-0031656218 9776965 \n17 Hustey F. M. Acute quetiapine poisoning The Journal of Emergency Medicine 1999 17 6 995 997 10.1016/S0736-4679(99)00128-6 2-s2.0-0032705044 10595886 \n18 Soe K. K. Lee M. Y. Arrhythmias in severe trazodone overdose American Journal of Case Reports 2019 20 1949 1955 10.12659/AJCR.919833 31879415 \n19 Hefner G. Hahn M. Hohner M. Roll S. Klimke A. Hiemke C. QTc time correlates with amitriptyline and venlafaxine serum levels in elderly psychiatric inpatients Pharmacopsychiatry 2019 52 1 38 43 10.1055/s-0044-102009 2-s2.0-85042360205 29466824 \n20 Wenzel-Seifert K. Wittmann M. Haen E. QTc prolongation by psychotropic drugs and the risk of torsade de pointes Deutsches Ärzteblatt International 2011 108 41 687 693 10.3238/arztebl.2011.0687 2-s2.0-82155164409 22114630\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6838",
"issue": "2020()",
"journal": "Case reports in psychiatry",
"keywords": null,
"medline_ta": "Case Rep Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101583308",
"other_id": null,
"pages": "6633385",
"pmc": null,
"pmid": "33381342",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "18154906;22579340;24794843;24982705;10595886;22114630;11305706;25057346;9776965;28335848;16928430;17632661;25863733;31879415;20943236;16498489;30649911;28758203;29466824;15213787",
"title": "Quetiapine and Wolff-Parkinson-White Syndrome.",
"title_normalized": "quetiapine and wolff parkinson white syndrome"
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"abstract": "Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012-2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8-50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4-4.5) and 42×109/L (interquartile range, 11-100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.",
"affiliations": "Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France etienne.lengline@aphp.fr.;Department of Hematology, Hôpital Emile Muller - CH de Mulhouse, France.;Department of Hematology, Nantes University Hospital, France.;Service d'Hematologie Clinique et de Therapie Cellulaire, CHU, Universite d'Auvergne, Clermont-Ferrand, France.;Service d'Hématologie Clinique et Thérapie Cellulaire, CHU de Limoges, France.;Department of Hematology, Besançon University Hospital, France.;Department of Hematology, Centre hospital-ier de Lens, France.;Department of Hematology and Oncology, CH Augustin Morvan, Brest, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.;Department of Hematology 1G, Centre Hospitalier Lyon Sud, Pierre Benite, France.;Department of Hematology, CH Victor Dupouy, Argenteuil, France.;Department of Hematology, French Reference Center for Thrombotic Microangiopathies, Saint Antoine University Hospital, Paris, France.;Department of Hematology, Hôpital Privé Médipole de Savoie, Challes les Eaux, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.;Bone Marrow Transplant Unit Clinical Hematology, Hopital La Miletrie, Poitiers University Hospital, France.;Department of Internal Medicine, Clinical Immunology, Hôpital Huriez Lille University Hospital, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.;Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital - AP-HP, Paris, France.",
"authors": "Lengline|Etienne|E|;Drenou|Bernard|B|;Peterlin|Pierre|P|;Tournilhac|Olivier|O|;Abraham|Julie|J|;Berceanu|Ana|A|;Dupriez|Brigitte|B|;Guillerm|Gaelle|G|;Raffoux|Emmanuel|E|;de Fontbrune|Flore Sicre|FS|;Ades|Lionel|L|;Balsat|Marie|M|;Chaoui|Driss|D|;Coppo|Paul|P|;Corm|Selim|S|;Leblanc|Thierry|T|;Maillard|Natacha|N|;Terriou|Louis|L|;Socié|Gerard|G|;de Latour|Regis Peffault|RP|",
"chemical_list": "D000961:Antilymphocyte Serum; D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; C520809:eltrombopag",
"country": "Italy",
"delete": false,
"doi": "10.3324/haematol.2017.176339",
"fulltext": "\n==== Front\nHaematologicaHaematologicahaematolHaematologicaHaematologica0390-60781592-8721Ferrata Storti Foundation 2917025210.3324/haematol.2017.1763391030212ArticleBone Marrow FailureNationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia Lengline Etienne 1Drenou Bernard 2Peterlin Pierre 3Tournilhac Olivier 4Abraham Julie 5Berceanu Ana 6Dupriez Brigitte 7Guillerm Gaelle 8Raffoux Emmanuel 1de Fontbrune Flore Sicre 1Ades Lionel 1Balsat Marie 9Chaoui Driss 10Coppo Paul 11Corm Selim 12Leblanc Thierry 113Maillard Natacha 14Terriou Louis 15Socié Gerard 116*de Latour Regis Peffault 1*\n1 Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital – AP-HP, Paris, France\n2 Department of Hematology, Hôpital Emile Muller - CH de Mulhouse, France\n3 Department of Hematology, Nantes University Hospital, France\n4 Service d’Hematologie Clinique et de Therapie Cellulaire, CHU, Universite d’Auvergne, Clermont-Ferrand, France\n5 Service d’Hématologie Clinique et Thérapie Cellulaire, CHU de Limoges, France\n6 Department of Hematology, Besançon University Hospital, France\n7 Department of Hematology, Centre hospital-ier de Lens, France\n8 Department of Hematology and Oncology, CH Augustin Morvan, Brest, France\n9 Department of Hematology 1G, Centre Hospitalier Lyon Sud, Pierre Benite, France\n10 Department of Hematology, CH Victor Dupouy, Argenteuil, France\n11 Department of Hematology, French Reference Center for Thrombotic Microangiopathies, Saint Antoine University Hospital, Paris, France\n12 Department of Hematology, Hôpital Privé Médipole de Savoie, Challes les Eaux, France\n13 Department of Pediatric Hematology, Robert-Debré University Hospital, Paris, France\n14 Bone Marrow Transplant Unit Clinical Hematology, Hopital La Miletrie, Poitiers University Hospital, France\n15 Department of Internal Medicine, Clinical Immunology, Hôpital Huriez Lille University Hospital, France\n16 University Paris Denis Diderot & INSERM UMR 1160, FranceCorrespondence: etienne.lengline@aphp.fr* GS and RPL contributed equally to this work.\n\n2 2018 23 11 2017 103 2 212 220 12 7 2017 15 11 2017 Copyright© 2018 Ferrata Storti Foundation2018Material published in Haematologica is covered by copyright. All rights are reserved to the Ferrata Storti Foundation. Use of published material is allowed under the following terms and conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode. Copies of published material are allowed for personal or internal use. Sharing published material for non-commercial purposes is subject to the following conditions:https://creativecommons.org/licenses/by-nc/4.0/legalcode, sect. 3. Reproducing and sharing published material for commercial purposes is not allowed without permission in writing from the publisher.Few therapeutic options are available for patients with aplastic anemia who are ineligible for transplantation or refractory to immunosuppressive therapy. Eltrombopag was recently shown to produce trilineage responses in refractory patients. However, the effects of real-life use of this drug remain unknown. This retrospective study (2012–2016) was conducted by the French Reference Center for Aplastic Anemia on patients with relapsed/refractory aplastic anemia, and patients ineligible for antithymocyte globulin or transplantation, who received eltrombopag for at least 2 months. Forty-six patients with aplastic anemia were given eltrombopag without prior antithymocyte globulin treatment (n=11) or after antithymocyte globulin administration (n=35) in a relapsed/refractory setting. Eltrombopag (median daily dose 150 mg) was introduced 17 months (range, 8–50) after the diagnosis of aplastic anemia. At last followup, 49% were still receiving treatment, 9% had stopped due to a robust response, 2% due to toxicity and 40% due to eltrombopag failure. Before eltrombopag treatment, all patients received regular transfusions. The overall rates of red blood cell and platelet transfusion independence were 7%, 33%, 46% and 46% at 1, 3, 6 months and last follow-up. Responses were slower to develop in antithymocyte treatment-naïve patients. In patients achieving transfusion independence, hemoglobin concentration and platelet counts improved by 3 g/dL (interquartile range, 1.4–4.5) and 42×109/L (interquartile range, 11–100), respectively. Response in at least one lineage (according to National Institutes of Health criteria) was observed in 64% of antithymocyte treatment-naïve and 74% of relapsed/refractory patients, while trilineage improvement was observed in 27% and 34%, respectively. We found high rates of hematologic improvement and transfusion independence in refractory aplastic anemia patients but also in patients ineligible for antithymocyte globulin receiving first-line treatment. In conclusion, elderly patients unfit for antithymocyte globulin therapy may benefit from eltrombopag.\n==== Body\nIntroduction\nAplastic anemia (AA) is caused by the destruction of hematopoietic stem cells, leading to pancytopenia. Rapid front-line bone marrow transplantation with an HLA-identical sibling donor can lead to excellent outcomes.1–4 However, most patients cannot undergo such a procedure because of the absence of a sibling donor or because of their age and/or co-morbidities. Immunosuppressive therapy with horse antithymocyte globulin (ATG) plus cyclosporine A (CsA) is considered to be the standard treatment in this situation, producing an overall hematologic response rate of 60–70%.5–7 Nevertheless, few therapeutic options are currently open to patients with AA who fail to achieve a hematologic response or those who relapse after this therapy and are ineligible for allogeneic stem cell transplantation. Moreover, in elderly patients who cannot receive ATG, the chance of obtaining a hematologic response with CsA alone is low.8,9 In these latter cases, complications including infections,10 bleeding and anemia may occur and lead to significantly poorer quality of life, recurrent transfusions, hospital admissions, secondary hemochromatosis, and death.\n\nIt has recently been reported that eltrombopag, a non-peptide thrombopoietin mimetic oral drug which binds to the transmembrane domain of the MPL receptor, can induce trilineage response in patients with refractory AA.11 In a single center phase 2 trial, hematologic improvement was obtained in 17 out of 43 patients who had previously failed to benefit from one or several courses of ATG.12\n\nHowever, the effects of real-life use of this drug remain largely unknown, as the risks and benefits have not yet been independently assessed, while data for five patients achieving a robust response to eltrombopag may yet be updated.12 In France, physicians have access to eltrombopag through a compassionate use program. We used this program to assess the indications for and the safety and efficacy of eltrombopag in a large number of AA patients in France who received eltrombopag in the case of refractory AA, but also as a first-line treatment for patients considered unfit to receive ATG.\n\nMethods\nIdentifying cases\nThis retrospective study (2012–2016) was conducted in 15 centers. A survey to identify patients receiving eltrombopag in France in the setting of AA was created on behalf of the French Reference Center for Aplastic Anemia. For the purposes of this study, we screened files for all patients referred to the center, and sent three waves of e-mails to more than 100 specialized physicians (Online Supplementary Material). The study was conducted in accordance with the Declaration of Helsinki. The institutional review board of the national AA center approved the study, and anonymous data collection was declared to the appropriate authorities. In accordance with French law, written informed consent was not required for this retrospective, non-interventional study, as patients had provided a non-opposition statement.\n\nPopulation\nPatients with a diagnosis of AA confirmed by a bone marrow biopsy, irrespective of their age or the primary etiology, were eligible for inclusion if they received at least 2 months of treatment with eltrombopag, regardless of their indication for treatment. Patients who received eltrombopag in a relapsed or refractory setting (defined by occurring at least 6 months after initial ATG treatment) were considered to be relapsed/refractory, irrespective of the number of previous ATG courses. Unfit patients who had not received at least one course of ATG before eltrombopag were considered to be receiving first-line treatment, even if they had previously been administered CsA as a stand-alone therapy.\n\nPatients with moderate AA requiring blood transfusion less frequently than every 4 weeks were not included. Furthermore, prior diagnoses of myelodysplastic syndrome, acute leukemia or immune thrombocytopenia were considered to be exclusion criteria. Patients who received eltrombopag in the setting of thrombocytopenia after stem cell transplantation were also excluded.\n\nProcedures and definitions\nThe minimal initial diagnostic panel for AA required for this study consisted of a complete blood count, a bone marrow biopsy, bone marrow karyotype analysis and assessment of a paroxysmal nocturnal hemoglobinuria (PNH) clone (Online Supplementary Methods)\n\nGiven the retrospective nature of this study, dose adaptations for adverse events or insufficient responses were not formally defined. However, the recommendations of the reference center were shared with all centers once eltrombopag was approved for treatment in France (July 1, 2012). Centers were therefore advised to start treatment at the dose of 75 mg/day for 2 weeks and then increase the dose to 150 mg/day if no clinical or biological adverse events occurred.5,11 In the absence of any hematologic response or adverse event, some clinicians used higher doses, of up to 225 mg/day, after 3 months. When eltrombopag was used with rabbit ATG, the eltrombopag was started on day 15 after the ATG treatment.\n\nHematologic improvements were assessed using the National Institutes of Health (NIH) response criteria. Thus, a platelet response was defined by a platelet count increase of 20×109/L above baseline, or stable platelet counts with transfusion independence for at least 8 weeks; an erythroid lineage response was defined by a hemoglobin increase of >1.5 g/dL or a reduction in >4 units of transfused red blood cells (RBC) for 8 consecutive weeks; and a leukocyte response was defined as an absolute neutrophil increase of 100% or an absolute neutrophil count increase >0.5×109/L.12 A robust response was defined as platelets >50×109/L, hemoglobin >10 g/dL, and neutrophils >1×109/L for longer than 8 weeks without transfusion support.12 Not achieving at least one NIH criterion during eltrombopag treatment was considered to be treatment failure.\n\nStatistical analysis\nThe data were recorded as percentages for discrete variables and medians with interquartile ranges (IQR) for continuous variables. A Fisher exact test and Wilcoxon non-parametric rank sum test were used, respectively, to compare these two types of variables. Follow-up and survival were reported since the start of eltrombopag treatment. Kaplan-Meier plots were constructed to estimate overall survival. All statistical tests were two-sided, with P values ≤0.05 indicating statistical significance. Statistical analyses were performed using R 2.14.0 (http://www.R-project.org/) packages.\n\nResults\nPatients\nForty-six patients were identified for this study. We separated the subjects into two different cohorts according to the rationale for having initiated eltrombopag treatment and principal clinical situations.\n\nEleven ATG-naïve patients (cohort A) were given eltrombopag because they were considered ineligible for ATG treatment. For nine of these patients, the reason for ATG ineligibility was their age of over 65 years. One patient had dyskeratosis congenita with severe portal hypertension and hepatic dysfunction, while another, a 48-year old woman, had severe ischemic myocardial disease, complicated by a post-anoxia encephalopathy. Of these 11 patients, five had previously failed to benefit from treatment with CsA alone, four had been treated with androgens, while two further ATG-naïve patients had received eltrombopag as first-line therapy.\n\nThirty-five patients (cohort B) received eltrombopag in the setting of refractory or relapsed disease, defined by the persistence or reappearance of transfusion dependency or a neutrophil count <0.5×109/L at least 6 months after treatment with ATG. The first ATG treatment used was horse ATG in 66% of cases and rabbit ATG in the other 33%. Thirty percent of these patients had initially responded before relapsing, and 70% were primary refractory to this treatment. Not all patients were candidates for allogeneic stem cell transplantation at the time of eltrombopag initiation, either because of the lack of a suitable donor and/or age or comorbidities. The median age was 53 years old (IQR, 26–63) and 48% of patients had already received one cycle of ATG. Thirty-seven percent had previously received two cycles, including eight patients with primary refractory disease who were given eltrombopag in combination with the second course of ATG (eltrombopag was started between day 15 and day 45 after the rabbit ATG). The remaining 11% of patients in this cohort received three cycles of ATG prior to eltrombopag.\n\nTable 1 shows the main characteristics of the patients divided into the two cohorts described above. At the time of AA diagnosis, a PNH clone was detected in 37% of all patients. One patient in each cohort was found to have germinal mutations consistent with dyskeratosis congenita, including a patient with no extra-hematologic phenotype who received one ATG course prior to genetic testing.\n\nTable 1. Main baseline characteristics of the patients divided by cohort (A and B).\n\nEltrombopag treatment\nCohort A\nThe median time from the diagnosis of AA to the start of eltrombopag treatment was 7 months (IQR, 3–33). The patients received eltrombopag for a median of 5 months (range, 3–20). The median eltrombopag dose prescribed was 150 mg once a day, and CsA was associated with eltrombopag in two patients (18%) from this cohort.\n\nCohort B\nThe median time from the diagnosis of AA to starting eltrombopag treatment was 23 months (IQR, 9–50). Overall, these patients received eltrombopag for a median of 6 months (range, 2–39). Those who had a hematologic response received treatment for a median of 8 months (IQR, 5–18), compared with 5 months (IQR, 4–6) in cases of treatment failure. The median eltrombopag dose prescribed was 150 mg once a day, and CsA was associated with eltrombopag in 20 patients (57%) from this cohort.\n\nHematologic evolution and transfusion dependency\nBefore starting eltrombopag treatment, all patients in both cohorts were transfusion-dependent. In cohort A (n=11), all patients were RBC transfusion-dependent, requiring a median number of three packed RBC units (IQR, 2–4) per month, and ten of the 11 patients were dependent on platelet transfusions, being given a median number of two units (IQR, 1.5–3.5) of platelet concentrates (0.5×1011× kg) per month. In cohort B, 34/35 patients were RBC transfusion-dependent, requiring a median number of four packed RBC units (IQR, 2–4) per month, and 33/35 patients were dependent on platelet transfusions, being given a median number of three units (IQR, 2–4) of platelet concentrates (0.5×1011× kg) per month.\n\nFigure 1 shows the kinetics and proportions of patients achieving transfusion independence (RBC and platelets) in both cohorts. At last follow up, we confirmed transfusion independence (both RBC and platelets) in 36% and 49% of cohort A and B patients, respectively. It is worth noting that patients treated with eltrombopag first-line seemed to respond more slowly, with no responders during the first 3 months of treatment, compared with 44% in cohort B (P=0.02). In patients achieving transfusion independence, the increased hemoglobin level was 5 g/dL (IQR, 3.3–6) and 2.75 g/dL (IQR, 1.15–4.03) in cohorts A and B, respectively (P=0.3). Neutrophil and platelet counts also improved significantly in both cohorts (Table 2).\n\nFigure 1. Rate (percentage) of transfusion independence before and after eltrombopag treatment by cohort and blood product type.\n\nTable 2. Trilineage hematologic improvement after eltrombopag therapy.\n\nHematologic improvements were also assessed for each lineage using NIH criteria (Figure 2). According to these criteria, a response was observed in at least one lineage in 64% and 74% of cohorts A and B, respectively, including trilineage responses in 27% and 34% of cohorts A and B, respectively. Furthermore, a robust hematologic response12 was observed in three patients from cohort A and seven patients from cohort B.\n\nFigure 2. Hematologic responses for each cell lineage in accordance with National Institutes of Health criteria.\n\nAmong the patients with refractory AA, the median eltrombopag dose in responders (i.e., patients who had a response in at least one lineage according to NIH criteria) was 150 mg/day (IQR, 100–150), which was not different from that in non-responders. In cohort A patients, the median eltrombopag dose in responders was 150 mg/day (IQR, 131–162), which was not different from that in non-responders. Hematologic responses were observed in two out of four and three out of three patients whose daily eltrombopag dose was increased above 150 mg, to a maximum of 300 mg/day, in refractory patients and patients treated with eltrombopag first-line, respectively.\n\nAt last follow-up, 22 patients (49%) were still receiving eltrombopag treatment, four (9%) eventually stopped after gradual tapering due to a robust hematologic response, one (2%) due to limited toxicity, and 18 (40%) due to eltrombopag failure. There were no significant differences in these proportions between the two cohorts. The four patients who were weaned off eltrombopag all remained in hematologic response 27, 24, 12 and 7 months after eltrombopag withdrawal.\n\nWe also conducted a separate analysis on the eight patients with primary refractory AA who received eltrombopag in combination with a second course of ATG and CsA. These patients were 49.2 years old (IQR, 33.8–55.5) and received eltrombopag at a median of 21 days after rabbit ATG therapy (having all previously received horse ATG). Remarkably, all eight patients achieved transfusion independence (7/8 at 3 months), despite the fact that they had received a median of three packed RBC units/month and three platelet units/month before treatment. At 6 months, the median hemoglobin level was 11 g/dL, the median platelet count 85×109/L, and the median neutrophil count 1.6×109/L.\n\nIn cohort B, four patients with a median age of 25 years (IQR, 19–37) underwent hematopoietic stem cell transplantation with an alternative donor (2 HLA mismatched donors and 2 cord blood transplants) at a median time of 8 months (IQR, 6–11) after eltrombopag failure. One patient eventually died of Epstein-Barr virus-associated post-transplant lymphoproliferative disease 4 months after cord blood transplantation. The other patients were alive at last follow-up, more than 2 years after transplantation. No patient in the first-line cohort was considered for hematopoietic stem cell transplantation.\n\nOf particular note, neither of the two patients with dyskeratosis congenita experienced a hematologic response.\n\nFinally, we failed to identify any baseline factor associated with the occurrence of transfusion independence or hematologic improvement in this cohort.\n\nSafety analysis and clonal evolution\nWe retrospectively recorded potential toxicities of treatment among patients who received eltrombopag. The median follow-up after starting eltrombopag was 9 and 13 months for cohorts A and B, respectively. Table 3 reports the adverse events recorded in both cohorts. Most of the events were related to bone marrow dysfunction, with infections (mainly febrile neutropenia) and hemorrhages reported in a total of 13 and six patients, respectively. Thirteen patients developed elevated transaminase levels (grade 1, n=9; grade 2, n=2; grade 3, n=2) between 1.5 and 8 times the upper limit of normal without hepatic dysfunction, and one patient developed grade 2 hyperbilirubinemia. One patient had grade 2 insomnia, and one patient developed a localized lung cancer that required surgery. No thrombotic events or thrombocytosis (maximum platelet count: 250×109/L) were observed in either cohort. Among patients who had their PNH clone size evaluated after eltrombopag treatment, we found a non-statistically significant increase in size in 45%, which is consistent with the natural history of refractory AA. There was no statistically significant difference between responders and non-responders (43% versus 50%; P=NS).\n\nTable 3. Adverse events and outcomes by treatment cohort during the follow-up observation time.\n\nThe median follow-up was 9 months (IQR, 5–15) in cohort A and 13 months (IQR, 7.5–26) in cohort B. We recorded six deaths, all of which occurred in non-responding patients. Deaths were caused by cerebral hemorrhage in two thrombocytopenic patients and acute myeloid leukemia in one patient: another patient had a sudden death, probably caused by a pulmonary embolism occurring 6 months after eltrombopag had been discontinued, one patient died of septic shock, and one died following a cord blood transplant.\n\nWhile 42 (91%) of patients had a bone marrow karyotype analysis at a median of 95 days before eltrombopag was introduced, only 12 patients (26% of the whole study population) had a subsequent karyotype analysis after eltrombopag had been started, to evaluate the risk of clonal evolution, despite an overall exposure to eltrombopag of 428 patient-months. The post-treatment karyotype analysis was conducted at a median of 14 months (IQR, 2–22) after eltrombopag had been started. Trisomy 8 was identified in one patient during eltrombopag treatment, with no myelodysplastic marrow morphology, but this abnormality had already been present at the time of diagnosis of the AA. The two patients with monosomy 7 before starting eltrombopag treatment did not undergo new karyotype analysis after treatment initiation (1 had a complete response with no evolution after 2 years of follow-up, while the other developed acute myeloid leukemia and eventually died). Online Supplementary Table S1 provides details of all karyotype analyses performed on the entire study population.\n\nDiscussion\nRecently, eltrombopag has been reported to induce clinically significant increases in blood counts and/or decreases in transfusion requirements in 40% of patients with refractory AA, and some of these patients achieved multi-lineage responses.11,12 However, to date, little use has been made of this drug in refractory AA patients, with available prospective data for 43 patients from the NIH12 and data from another single center study that included ten patients from China.13 On behalf of the French Reference Center for Aplastic Anemia, we retrospectively collected data on all patients who received eltrombopag between 2012 and 2016. Forty-six patients were identified who had been given eltrombopag for relapsed/refractory AA after ATG treatment (n=35) or as first-line therapy (n=11). We confirmed the overall efficacy of eltrombopag which pro duced a 46% rate of red blood cell and platelet transfusion independence. Hematologic improvement in more than one lineage, according to NIH criteria, was observed in 74% of relapsed/refractory patients but also in 64% of ATG-naïve patients, while trilineage improvement was observed in 27% and 34%, respectively.\n\nTable 4. Summary of bone marrow karyotype analysis before and after eltrombopag treatment.\n\nThe standard treatment for patients who do not have an HLA–identical sibling donor is the association of horse ATG plus CsA, although 30% show primary refractoriness to this treatment,4,7,14 and 30% of initial responders relapse after this first therapy. In this situation, transplantation from a well-matched unrelated donor may be considered in younger patients (under 30 years of age) in the first year after the diagnosis of AA,15 while results with mismatched unrelated donors are currently not as favorable.4 A significant number of patients overall will therefore be considered to be refractory and possibly exposed to infectious complications and intensive transfusion support, mainly complicated by hemosiderosis and alloimmunization.1 Until recently, the standard second-line treatment for patients without a histocompatible donor was a second course of immunosuppression using rabbit, horse or anti-CD52 antibodies, which produces an overall response rate of 30%.7,16 This latter treatment requires extensive hospitalization and careful, close follow-up because of initial worsening of transfusion requirements and induced immune deficiency arising from T-cell depletion.6 Eltrombopag is an oral thrombopoietin mimetic that is easy to use in an outpatient context. In this study, we confirmed an overall hematologic response of 71%, with almost half of these responders achieving trilineage improvement. The only alternative, in this situation, would be androgens such as oxymetholone, which were used to treat AA before the emergence of ATG plus CsA, and are, in fact, still used to treat certain patients with constitutional AA in a relapsed/refractory setting. However, data available regarding idiopathic AA are very scarce, especially in relapsed/refractory patients.17 Furthermore, side effects are commonplace after prolonged exposure to androgens.8 In our experience, eltrombopag was very well tolerated, with mild hepatic dysfunction in only one patient who stopped taking the drug because of a rise in transaminase levels. On the whole, our experience has led us to prefer the use of eltrombopag in this situation.\n\nAs already mentioned, 11 patients were given eltrombopag as first-line treatment alone (n=9) or in association with CsA (n=2). These patients were not eligible for conventional ATG plus CsA treatment because of their age (median 74 years, versus 53 years for patients with refrac tory) or comorbidities (notably kidney dysfunction, which precludes the use of CsA). In this subgroup, we observed a 40% rate of hematologic improvement and transfusion independence at 6 months, with no excess of mortality compared to that of younger patients. In this particular population, treatment options are limited most of the time and include growth factors, transfusion support and antibiotics. While requiring confirmation through prospective control trials, eltrombopag alone might be a reasonable option in these specific patients. Of note, in this group, responses seemed to be slower, as no response was observed during the first 3 months of treatment. Eltrombopag should not, therefore, be discontinued too early in this specific setting, and we propose a treatment algorithm based on the findings of this study in Figure 3.\n\nFigure 3. French guidelines for the use of eltrombopag in patients with aplastic anemia (2017). (a) All patients should be screened at diagnosis for (i) an inherited bone marrow failure regardless of their family history and clinical findings, (ii) clonal evolution. (b) Data for children and in the literature are insufficient at present to do anything more than generate hypotheses, and should not be applied in patients < 18 years old. (c) Patients with aplastic anemia are considered to be eligible for transplantation as a second-line treatment in case of refractory status after first-line immunosuppressive therapy, excellent health status and (i) if a matched sibling donor is available (for patients who have been offered immunosuppressive therapy first line because of age > 40 years) or (ii) if a matched unrelated donor is available for patients aged 30 years and under. Regarding the age limits, stated cutoff ages are recommendations and are therefore open to debate in accordance with institution and patient specificities. (d) For refractory patients, a careful reassessment of the diagnosis – to exclude a clonal evolution such as myelodysplastic syndrome or constitutional bone marrow failure – is mandatory. (d) In patients over 65–70 years old or patients with severe comorbidities (cardiac and/or renal failure), the use of ATG may be responsible for inadequate toxicity. (e) Rabbit antithymoglobulin: 3.75 mg/kg continuous intravenous administration over 12 h from day 1 to day 5, Cyclosporine A: 5 mg/kg/d from day 1 in order to achieve residual dosage of between 200 and 400 ng/mL. Start the treatment orally. Cyclosporine should not be withdrawn prematurely before 6 months unless toxicity grade >2 occurs. Eltrombopag 75 mg per day for 2 weeks, and thereafter increased to 150 mg per day from day 14 and as soon as transaminases < 2 times upper limit of normal (ULN) and bilirubin < 1,5 ULN for a minimum of 3 months. Eltrombopag should be interrupted in case of transaminases > 3N. (f) Eltrombopag should be initiated at 75 mg per day for 2 weeks in a fasting patient and thereafter increased to 150 mg per day if no clinical or biological toxicity is identified. The dosage should be halved for subjects of fully (both parents) East Asian heritage (i.e. Japanese, Chinese, Taiwanese and Korean) because plasma eltrombopag AUC(0-τ) concentrations have been found to be approximately 80% higher in healthy Japanese subjects than in non-Japanese healthy subjects (predominantly Caucasian). (g) The starting date for evaluation is the first day at 150 mg. In patients not responding at 150 mg per day, the dosage may be carefully increased, up to 225 mg per day. These patients should be monitored closely for adverse events (abdominal pain, diarrhea, cataract). (h) A robust response is considered for patients with Hemoglobin>10g/dL, neutrophils 1×109/L and platelets more than 50×109/L. HSCT: hematopoietic stem cell transplantation; ATG: anti-thymocyte globulins; hATG: horse anti-thymocyte globulins; rATG: rabbit anti-thymocyte globulins; CSA: cyclosporin A; ELT: eltrombopag; resp: responders; BM: bone marrow; BMF: bone marrow failure.\n\nRegarding refractory patients, our results are in line with those published previously.11,12 Initial studies defined the optimal dose of eltrombopag as 150 mg/day for hematologic response at 3 to 4 months.11,12 In this compassionate use program, we recommended that French centers using eltrombopag in 35 relapsed/refractory patients took into account the published NIH studies.11,12 Following this treatment plan, 43% of patients responded at 3 months and 50% at 6 months, which illustrates that the optimal time to appreciate the efficacy of this treatment is about 6 months overall. Of note, only three out of 21 evaluated patients responded to the higher dose of eltrombopag of 225 mg/day, illustrating the minimal benefit of increasing dosage in Caucasian patients. Importantly, four patients fulfilled the criteria for robust response;12 in these patients eltrombopag was then tapered and discontinued after a median of 14 months. All four patients then maintained stable blood counts, with a median medication-free follow-up of 18 months. Of particular note, two patients were also included in our study because of genetically proven dyskeratosis congenita with no response.\n\nThe mechanism by which eltrombopag acts in the setting of bone marrow failure remains largely unclear. Among the nine patients in our study who received eltrombopag alone as a first-line treatment because they were ineligible for standard treatment, five responded of whom three had a trilineage response. This suggests that abrogation of immune attack may not be necessary for a response to eltrombopag in patients with idiopathic AA, which is in line with reported observed responses to eltrombopag in patients with moderate AA not previously treated with immunosuppression.12 It is thus likely that eltrombopag acts directly to stimulate the proliferation of small numbers of residual stem-progenitor cells in patients with AA. However, outstanding results published very recently regarding responses in treatment-naïve AA patients in a phase 2 trial investigating the association of ATG plus CsA plus eltrombopag18 highlighted the benefit of decreasing the intensity of the immune attack to improve responses to eltrombopag. Two ongoing prospective phase 3 trials have randomized the addition of eltrombopag to standard therapy (Figure 3). The RACE study is comparing horse ATG plus CsA with or without eltrombopag as front-line therapy for patients with severe AA (EudraCT: 2014-000363-40), while the EMAA study is comparing the use of CsA with or without eltrombopag as front-line therapy for patients with moderate AA (EudraCT: 2014-000147-19).\n\nWe did not identify any predictors of response in our study. However, higher reticulocyte counts in refractory patients,12 as well as longer telomere length and younger age in treatment-naïve patients18 have been reported to be associated with better responses, although these factors are also a reflection of the stem cell pool. Collectively, this suggests that a critical mass of stem cells is required for bone marrow recovery, and that this is better if the immune response has been abated. While the exact role of eltrombopag in AA is still being investigated, enough evidence exists to suggest that it directly stimulates hematopoietic stem and progenitor cells, which could theoretically affect the emergence of abnormal clones, as has already been retrospectively reported with the use of hematopoietic growth factor in AA.19,20 In two prospective studies examining both refractory12 and treatment-naïve patients,18 no evidence of a higher rate of clonal evolution was identified after comparison with historical controls treated in the same institution. Unfortunately, patients in our study were not examined serially, so any potential clonal evolution of karyotypic aberrations could not be extensively and systematically defined. Regarding the potential risk of clonal evolution associated with the use of eltrombopag alone, randomized studies with careful serial evaluation of clonal evolution, including karyotype, fluorescence in situ hybridization analysis and molecular studies, will enable the risks associated with eltrombopag in this setting to be assessed more accurately. We detected a non-significant increase in the size of the PNH clone after eltrombopag treatment, especially in patients who had already received immunosuppressive therapy. There are no data in the literature suggestimg a similar finding with eltrombopag; indeed, no firm conclusions can be drawn from this observation.\n\nOur work has both strengths and limitations. The latter are mostly due to its retrospective nature and limited numbers of patients. The strengths include the systematic enrollment of all AA patients who received eltrombopag in France between 2012 and 2016 through the French Reference Center for Aplastic Anemia. This provides a clear picture of our current practice for refractory patients but also on first-line monotherapy for patients who are not eligible for standard immunosuppression.\n\nIn conclusion, eltrombopag has shown convincing efficacy in the majority of refractory AA patients both in this analysis and in previously published studies.11,12 We also confirmed that eltrombopag was able to restore trilineage hematopoiesis in half of the responders. Responses were identified up to 6 months after treatment with an overall acceptable toxicity profile. This report, based on real-life clinical practice, also provides three novel findings that require further investigation: (i) eltrombopag monotherapy may benefit older patients considered to be unfit for ATG; (ii) in patients with a first relapse or who are refractory after one cycle of ATG, high response rates may be achieved with eltrombopag when combined with a second course of ATG plus CsA treatment; and (iii) the optimal dose of eltrombopag merits further investigation, as it would appear that some patients might respond to a dose higher than 150 mg/day. In brief, the encouraging overall results now need to be confirmed through prospective controlled trials.\n\nSupplementary Material\nLengline et al. Supplementary Appendix\n Disclosures and Contributions\n Acknowledgments\nThe authors would like to thank Dr Antonio Risitano for constructive intellectual input and advice and Mr David Williams for editorial assistance.\n\nCheck the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/2/212\n==== Refs\nReferences\n1. Marsh JCW Kulasekararaj AG \nManagement of the refractory aplastic anemia patient: what are the options? \nBlood . 2013 ;122 (22 ):3561 –3567 .24052548 \n2. Bacigalupo A Hows J Gluckman E \nBone marrow transplantation (BMT) versus immunosuppression for the treatment of severe aplastic anaemia (SAA): a report of the EBMT* SAA Working Party . Br J Haematol . 1988 ;70 (2 ):177 –182 .3056497 \n3. Yoshida N Kobayashi R Yabe H \nFirst-line treatment for severe aplastic anemia in children: bone marrow transplantation from a matched family donor versus immunosuppressive therapy . Haematologica . 2014 ;99 (12 ):1784 –1791 .25193958 \n4. Peffault de Latour R \nTransplantation for bone marrow failure: current issues . Hematology Am Soc Hematol Educ Program . 2016 ;2016 (1 ):90 –98 .27913467 \n5. Scheinberg P Nunez O Weinstein B \nHorse versus rabbit antithymocyte globulin in acquired aplastic anemia . N Engl J Med . 2011 ;365 (5 ):430 –438 .21812672 \n6. Young NS \nPathophysiologic mechanisms in acquired aplastic anemia . Hematology Am Soc Hematol Educ Program . 2006 ;72 –77 .17124043 \n7. Scheinberg P \nAplastic anemia: therapeutic updates in immunosuppression and transplantation . ASH Education Program Book \n2012 ;2012 (1 ):292 –300 .\n8. Scheinberg P Young NS \nHow I treat acquired aplastic anemia . Blood . 2012 ;120 (6 ):1185 –1196 .22517900 \n9. Marsh J Schrezenmeier H Marin P \nProspective randomized multicenter study comparing cyclosporin alone versus the combination of antithymocyte globulin and cyclosporin for treatment of patients with nonsevere aplastic anemia: a report from the European Blood and Marrow Transplant (EBMT) Severe Aplastic Anaemia Working Party . Blood . 1999 ;93 (7 ):2191 –2195 .10090926 \n10. Torres HA Bodey GP Rolston KVI Kantarjian HM Raad II Kontoyiannis DP \nInfections in patients with aplastic anemia: experience at a tertiary care cancer center . Cancer . 2003 ;98 (1 ):86 –93 .12833460 \n11. Olnes MJ Scheinberg P Calvo KR \nEltrombopag and improved hematopoiesis in refractory aplastic anemia . N Engl J Med . 2012 ;367 (1 ):11 –19 .22762314 \n12. Desmond R Townsley DM Dumitriu B \nEltrombopag restores trilineage hematopoiesis in refractory severe aplastic anemia that can be sustained on discontinuation of drug . Blood . 2014 ;123 (12 ):1818 –1825 .24345753 \n13. Gill H Leung GMK Lopes D Kwong Y-L \nThe thrombopoietin mimetics eltrombopag and romiplostim in the treatment of refractory aplastic anaemia . Br J Haematol . 2017 ;176 (6 ):991 –994 .27097929 \n14. Young NS Calado RT Scheinberg P \nCurrent concepts in the pathophysiology and treatment of aplastic anemia . Blood . 2006 ;108 (8 ):2509 –2519 .16778145 \n15. Devillier R Dalle J-H Kulasekararaj A \nUnrelated alternative donor transplantation for severe acquired aplastic anemia: a study from the French Society of Bone Marrow Transplantation and Cell Therapies and the EBMT Severe Aplastic Anemia Working Party . Haematologica . 2016 ;101 (7 ):884 –890 .27056924 \n16. Scheinberg P Nunez O Weinstein B Scheinberg P Wu CO Young NS \nActivity of alemtuzumab monotherapy in treatment-naive, relapsed, and refractory severe acquired aplastic anemia . Blood . 2012 ;119 (2 ):345 –354 .22067384 \n17. Chuhjo T Yamazaki H Omine M Nakao S \nDanazol therapy for aplastic anemia refractory to immunosuppressive therapy . Am J Hematol . 2008 ;83 (5 ):387 –389 .18161784 \n18. Townsley DM Scheinberg P Winkler T \nEltrombopag added to standard immunosuppression for aplastic anemia . N Engl J Med . 2017 ;376 (16 ):1540 –1550 .28423296 \n19. Kojima S Ohara A Tsuchida M \nRisk factors for evolution of acquired aplastic anemia into myelodysplastic syndrome and acute myeloid leukemia after immunosuppressive therapy in children . Blood . 2002 ;100 (3 ):786 –790 .12130487 \n20. Socie G Mary J-Y Schrezenmeier H \nGranulocyte-stimulating factor and severe aplastic anemia: a survey by the European Group for Blood and Marrow Transplantation (EBMT) . Blood . 2007 ;109 (7 ):2794 –2796 .17110459\n\n",
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"issue": "103(2)",
"journal": "Haematologica",
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"mesh_terms": "D000368:Aged; D000741:Anemia, Aplastic; D000961:Antilymphocyte Serum; D000971:Antineoplastic Combined Chemotherapy Protocols; D001565:Benzoates; D005260:Female; D005602:France; D006801:Humans; D006834:Hydrazines; D008297:Male; D008875:Middle Aged; D011720:Pyrazoles; D012189:Retrospective Studies; D016879:Salvage Therapy; D011795:Surveys and Questionnaires; D016896:Treatment Outcome",
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"title": "Nationwide survey on the use of eltrombopag in patients with severe aplastic anemia: a report on behalf of the French Reference Center for Aplastic Anemia.",
"title_normalized": "nationwide survey on the use of eltrombopag in patients with severe aplastic anemia a report on behalf of the french reference center for aplastic anemia"
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"activesubstancename": "ELTROMBOPAG"
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"abstract": "Inherited thrombocytopenias correspond to a group of hereditary disorders characterized by a reduced platelet count, platelet dysfunction, and a family history of thrombocytopenia. It is commonly associated with mucocutaneous bleeding. Thrombocytopenia results from mutations in genes involved in megakaryocyte differentiation, platelet formation, and clearance. Here we report on a patient presenting with severe syndromic inherited thrombocytopenia manifesting as spontaneous mucocutaneous bleeds, requiring frequent platelet transfusions. Thrombocytopenia was explained by the presence of 4 mutations in 3 hematopoietic transcription factor genes: FLI1, RUNX1, and ETV6. The patient was successfully treated with high-dose eltrombopag at 150 mg/day, an orally available non-peptide thrombopoietin receptor agonist. Since the start of treatment 23 months ago, the manifestations of bleeding have resolved, and no platelet transfusions or corticosteroids have been required. The patient has no clinical or laboratory evidence of myeloid malignancy so far.",
"affiliations": "Unite d'Hemostase Clinique, Hopital Cardiologique Louis Pradel, Lyon, France.;Service de Medecine Interne, Centre Hospitalier Pierre Oudot, Bourgoin-Jallieu, France.;Service d'Hématologie, Centre Hospitalier Lyon Sud, Pierre-Bénite, France.;Assistance Publique Hôpitaux de Paris, Service d'Hématologie Biologique, CRPP, Hôpital Armand Trousseau, Paris, France.;Assistance Publique Hôpitaux de Paris, Service d'Hématologie Biologique, CRPP, Hôpital Armand Trousseau, Paris, France.;Laboratoire d'Hemostase, Groupement Hospitalier Est, CHU de Lyon, Lyon, France.;Unite d'Hemostase Clinique, Hopital Cardiologique Louis Pradel, Lyon, France, ydargaud@univ-lyon1.fr.",
"authors": "Abdelmoumen|Karim|K|;Fabre|Marc|M|;Ducastelle-Lepretre|Sophie|S|;Favier|Remi|R|;Ballerini|Paola|P|;Bordet|Jean Claude|JC|;Dargaud|Yesim|Y|",
"chemical_list": "D001565:Benzoates; D050676:Core Binding Factor Alpha 2 Subunit; C087043:ETS translocation variant 6 protein; D006834:Hydrazines; D050783:Proto-Oncogene Proteins c-ets; D011720:Pyrazoles; C493728:RUNX1 protein, human; D012097:Repressor Proteins; C520809:eltrombopag",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000509922",
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"issue": "144(3)",
"journal": "Acta haematologica",
"keywords": "ETV6; Eltrombopag; FLI1; Inherited thrombocytopenia; RUNX1",
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D001565:Benzoates; D001772:Blood Cell Count; D001792:Blood Platelets; D050676:Core Binding Factor Alpha 2 Subunit; D005260:Female; D006579:Heterozygote; D006801:Humans; D006834:Hydrazines; D010375:Pedigree; D050783:Proto-Oncogene Proteins c-ets; D011720:Pyrazoles; D012097:Repressor Proteins; D012720:Severity of Illness Index; D013921:Thrombocytopenia",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "308-313",
"pmc": null,
"pmid": "32987389",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Eltrombopag for the Treatment of Severe Inherited Thrombocytopenia.",
"title_normalized": "eltrombopag for the treatment of severe inherited thrombocytopenia"
} | [
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"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-317629",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PREDNISONE"
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{
"abstract": "A preterm infant with zone 1 aggressive posterior retinopathy of prematurity developed infectious endophthalmitis after intravitreal injection of ranibizumab. Urgent empirical intravitreal therapy with vancomycin, ceftazidime, and dexamethasone along with intravenous therapy with amikacin and meropenem helped in early resolution. Vascularization/activity of disease subsided on follow-up, media cleared, and laser photocoagulation was completed. Later the disease reactivated, developed vitreous membranes and central retinal traction, for which 25-gauge lens-sparing vitrectomy was performed. Emergent treatment helped in salvaging the eye from both aggressive ROP disease and devastating endophthalmitis. Rationale approach to such a case is being discussed.",
"affiliations": "Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.;Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.;Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.;Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Chandra|Parijat|P|;Kumawat|Devesh|D|;Tewari|Ruchir|R|;Azimeera|Suresh|S|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D042461:Vascular Endothelial Growth Factor A; D000069579:Ranibizumab",
"country": "India",
"delete": false,
"doi": "10.4103/ijo.IJO_884_17",
"fulltext": "\n==== Front\nIndian J OphthalmolIndian J OphthalmolIJOIndian Journal of Ophthalmology0301-47381998-3689Wolters Kluwer - Medknow India 31124535IJO-67-96710.4103/ijo.IJO_884_17Case ReportsPost-Ranibizumab injection endophthalmitis in aggressive posterior retinopathy of prematurity Chandra Parijat Kumawat Devesh Tewari Ruchir Azimeera Suresh Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, New Delhi, IndiaCorrespondence to: Dr. Parijat Chandra, Room No. 373, Third Floor, Dr. Rajendra Prasad Centre for Ophthalmic Sciences, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029, India. E-mail: parijatchandra@gmail.com6 2019 67 6 967 969 04 10 2017 29 11 2017 Copyright: © 2019 Indian Journal of Ophthalmology2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.A preterm infant with zone 1 aggressive posterior retinopathy of prematurity developed infectious endophthalmitis after intravitreal injection of ranibizumab. Urgent empirical intravitreal therapy with vancomycin, ceftazidime, and dexamethasone along with intravenous therapy with amikacin and meropenem helped in early resolution. Vascularization/activity of disease subsided on follow-up, media cleared, and laser photocoagulation was completed. Later the disease reactivated, developed vitreous membranes and central retinal traction, for which 25-gauge lens-sparing vitrectomy was performed. Emergent treatment helped in salvaging the eye from both aggressive ROP disease and devastating endophthalmitis. Rationale approach to such a case is being discussed.\n\nEndophthalmitisranibizumabretinopathy of prematurityvascular endothelial growth factor\n==== Body\nThe use of anti-vascular endothelial growth factor (VEGF) agents is an emerging treatment for retinopathy of prematurity (ROP). Bevacizumab eliminates the angiogenic threat of ROP (BEAT-ROP) study has shown the benefits of intravitreal use of these agents in Stage 3+ disease in zone 1 and 2.[1] Thereafter, the off-label use of these agents has widely increased in ROP.\n\nInfectious endophthalmitis is the most devastating complication of intravitreal anti-VEGF injections.[2] To the best of our knowledge, only a single report exists on infectious endophthalmitis after anti-VEGF injection in ROP, which described the early clinical characteristics and benefit of early intravitreal antibiotic injection.[3] We here report the course of disease in a case of post-ranibizumab injection endophthalmitis in aggressive posterior ROP (APROP) disease and discuss the management approach.\n\nCase Report\nA male infant born at 31 weeks with birth weight of 1350 g was diagnosed elsewhere with zone 1 APROP in both eyes at 4 weeks of life (postconceptional age [PCA] 35 weeks). As per referral records, intravitreal injection of ranibizumab (0.25 mg) was given in the left eye in operation theater (OT) under sedation with strict aseptic precautions. At day 4 after injection, conjunctival congestion, hypopyon, and vitritis were noted in the left eye suggestive of infectious endophthalmitis. Empirically intravitreal injection of vancomycin (0.5 mg), ceftazidime (1 mg), and dexamethasone (200 μg) was given in the left eye (all half of the adult dosage). A dry vitreous tap was noted before intravitreal injection. Intravenous meropenem (40 mg BD) and amikacin (15 mg BD) were also started after sending sample for blood culture. Later, blood culture for bacterial sepsis turned out to be sterile. Intravitreal injection of ranibizumab (0.25 mg) was given in the right eye under similar OT conditions at 36 weeks’ PCA (after 5 days of starting endophthalmitis treatment) followed by partial laser photocoagulation. Thereafter, the child was shifted to our center for further management.\n\nIn between, the child was brought once to our center on day 6 after injection for the second opinion, when fundus imaging revealed signs suggestive of resolving endophthalmitis in the left eye [Fig. 1a]. At 37 weeks’ PCA, we observed that the right eye had zone 1 APROP with decreasing plus disease with mild central traction with laser scars [Fig. 2a]. The left eye had clear anterior chamber, resolving vitritis, and zone 1 disease with mild central traction. Intravenous antibiotics were continued for a total of 10 days. The media cleared well and laser photocoagulation was completed in both eyes in two sittings. On follow-up (42 weeks), the neovascularization regressed in both eyes with persistent low central traction [Figs. 1b and b]. At 48 weeks, reactivation of disease with sudden worsening of central tractional retinal detachment (TRD) was noted in the left eye [Fig. 1c]. After obtaining informed consent from the parents, 25-gauge lens-sparing vitrectomy was performed in the left eye at 49 weeks’ PCA. The vitreous membranes were removed and central traction over the disc was relieved. Since surgery was performed 14 weeks after starting treatment of endophthalmitis, vitreous sample was not sent for microbiological analysis. Six weeks after surgery, the left eye had regressed disease with clear media and sequelae in the form of puckered posterior retina [Fig. 1d].\n\nFigure 1 Course of disease in the left eye of an infant with aggressive posterior retinopathy of prematurity who developed infectious endophthalmitis after intravitreal ranibizumab injection. (a) Fundus photograph shows signs of resolving endophthalmitis/vitritis at day 6 after injection (35 weeks). (b) At 42 weeks following laser photocoagulation, media had cleared with resolved neovascularization with minimal central retinal traction. (c) At 48 weeks, retinopathy of prematurity reactivated with severe worsening of central vitreoretinal traction. (d) Post lens-sparing vitrectomy (55 weeks), retinal traction had reduced in height with resolving preretinal hemorrhage and central macular pucker\n\nFigure 2 (a) At 37 weeks, the right eye shows zone 1 aggressive posterior retinopathy of prematurity with severe plus disease and avascular loops. (b) At 42 weeks, neovascularization had regressed following complete laser photocoagulation with minimal central retinal traction\n\nDiscussion\nAntiangiogenic therapy has numerous advantages over laser treatment in active ROP.[1] However, safety is the reason for exercising caution when considering the use of intravitreal anti-VEGFs in infants with ROP. Major studies have not reported any cases of endophthalmitis related to the intraocular injection in ROP.[14]\n\nEndophthalmitis in infancy poses many challenges such as lack of obvious clinical features, delayed presentation, difficulty in differentiating between infectious and sterile inflammation, possibility of initial misdiagnosis as metastatic endophthalmitis, and need for multiple examinations under anesthesia.\n\nEndophthalmitis in infancy particularly in ROP should be managed with inpatient treatment. Definite intravitreal and intravenous antibiotic therapy is not known for exogenous endophthalmitis in neonates. However, given the safety profile and outcomes in studies on endogenous endophthalmitis in infants,[567] standard empirical intravitreal therapy (preferably a combination of vancomycin with ceftazidime or amikacin) should be given at earliest after taking vitreous tap for culture sensitivity testing. Wang and Xiang used one-third of adult dosage in their case based on the approximation that a premature infant's eye is one-third of the volume of an adult eye.[3] Similar to Ranibizumab dosage, half of the adult dosage was used in our case (0.5 mg vancomycin, 1 mg ceftazidime, and 200 μg dexamethasone).\n\nIntravenous therapy with broad antimicrobial coverage should also be started after taking vitreous sample. Meropenem, amikacin, or piperacillin-tazobactam seem to be the ideal empirical systemic therapy with higher vitreous penetration as per the studies in infants.[57] Vitrectomy is usually reserved in cases of endophthalmitis in infants because of significantly higher risk of ocular complications and anesthesia-related morbidity and mortality. However, endophthalmitis in ROP warrants early surgery if not responding with medical management.\n\nThe presence of endophthalmitis affects the follow-up management of ROP. The media haze due to vitritis/vitreous membranes may hamper visualization of retina making evaluation of plus disease and stage of disease difficult. The response to anti-VEGF therapy cannot be evaluated well in such cases. Furthermore, rescue laser which is often needed as adjuvant treatment in advancing APROP may be difficult to perform.\n\nLate disease reactivation is not uncommon after initial quiescence following intravitreal anti-VEGF injection in ROP.[189] This usually occurs due to persistent avascular peripheral retina. However, surprisingly in our case, reactivation occurred despite adequate laser, leading to rapidly progressive tractional retinal detachment which necessitated urgent surgery, although the endophthalmitis had resolved well initially. Possibly altered inflammatory milieu due to endophthalmitis may have adversely affected the disease progression.\n\nConclusion\nAfter injecting anti-VEGF drugs in ROP, close monitoring for signs of endophthalmitis and disease reactivation is essential and such cases should be managed aggressively.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Mintz-Hittner HA Kennedy KA Chuang AZ BEAT-ROP Cooperative Group Efficacy of intravitreal bevacizumab for stage 3+retinopathy of prematurity N Engl J Med 2011 364 603 15 21323540 \n2 McCannel CA Meta-analysis of endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents: Causative organisms and possible prevention strategies Retina 2011 31 654 61 21330939 \n3 Wang J Xiang D Early clinical characteristics of bacterial endophthalmitis in retinopathy of prematurity after intravitreal bevacizumab injection: A case report Exp Ther Med 2017 13 3563 6 28588680 \n4 Nicoară SD Nascutzy C Cristian C Irimescu I Ştefănuţ AC Zaharie G Outcomes and prognostic factors of intravitreal bevacizumab monotherapy in zone I stage 3+ and aggressive posterior retinopathy of prematurity J Ophthalmol 2015 2015 102582 26491545 \n5 Basu S Kumar A Kapoor K Bagri NK Chandra A Neonatal endogenous endophthalmitis: A report of six cases Pediatrics 2013 131 e1292 7 23478867 \n6 Sparks JR Recchia FM Weitkamp JH Endogenous group B streptococcal endophthalmitis in a preterm infant J Perinatol 2007 27 392 4 17522689 \n7 Lohrer R Belohradsky BH Bacterial endophthalmitis in neonates Eur J Pediatr 1987 146 354 9 3308466 \n8 Snyder LL Garcia-Gonzalez JM Shapiro MJ Blair MP Very late reactivation of retinopathy of prematurity after monotherapy with intravitreal bevacizumab Ophthalmic Surg Lasers Imaging Retina 2016 47 280 3 26985803 \n9 Hajrasouliha AR Garcia-Gonzales JM Shapiro MJ Yoon H Blair MP Reactivation of retinopathy of prematurity three years after treatment with bevacizumab Ophthalmic Surg Lasers Imaging Retina 2017 48 255 9 28297039\n\n",
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"issue": "67(6)",
"journal": "Indian journal of ophthalmology",
"keywords": "Endophthalmitis; ranibizumab; retinopathy of prematurity; vascular endothelial growth factor",
"medline_ta": "Indian J Ophthalmol",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000900:Anti-Bacterial Agents; D009877:Endophthalmitis; D005500:Follow-Up Studies; D006801:Humans; D007231:Infant, Newborn; D007275:Injections, Intravenous; D058449:Intravitreal Injections; D008297:Male; D000069579:Ranibizumab; D012178:Retinopathy of Prematurity; D042461:Vascular Endothelial Growth Factor A",
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"title": "Post-Ranibizumab injection endophthalmitis in aggressive posterior retinopathy of prematurity.",
"title_normalized": "post ranibizumab injection endophthalmitis in aggressive posterior retinopathy of prematurity"
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"abstract": "Class Ic antiarrhythmic agents flecainide and propafenone are amongst the drugs most frequently prescribed to control atrial arrhythmias, in particular atrial fibrillation (AF). Despite being cited in some guidelines as a warning when using 1c antiarrhythmic agents, atrial flutter (AFl) with 1:1 atrioventricular conduction is rare in adults, with only small series reported in the literature, mainly including patients having 1:1 AFl during physical activity, and often associated with a predisposing factor, namely a dual AV nodal conduction pathway. We describe here a rare case of 1:1 AFl induced by flecainide, developing whilst the patients was resting in bed, in a 56 year old man who presented to the local Emergency Department (ED) complaining for palpitations due to acute-onset AF. After ED discharge, the patient was then evaluated in the Arrhythmologic Clinic of the Cardiology Department, and channellopaties were excluded. This case report should raise alertness in emergency physicians about this serious and potentially fatal side effect of flecainide, when using this drug for pharmacological cardioversion of AF.",
"affiliations": "Emergency Department, Academic Hospital of Parma, Parma, Italy.;Emergency Department, Academic Hospital of Parma, Parma, Italy.;Emergency Department, Academic Hospital of Parma, Parma, Italy. Electronic address: gcervellin@ao.pr.it.",
"authors": "Comelli|Ivan|I|;Pigna|Federica|F|;Cervellin|Gianfranco|G|",
"chemical_list": "D005424:Flecainide",
"country": "United States",
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"doi": "10.1016/j.ajem.2018.07.040",
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"issn_linking": "0735-6757",
"issue": "36(11)",
"journal": "The American journal of emergency medicine",
"keywords": "1:1 atrial flutter; 1c-dependent atrial flutter; Atrial fibrillation; Atrial flutter; Flecainide",
"medline_ta": "Am J Emerg Med",
"mesh_terms": "D001281:Atrial Fibrillation; D001282:Atrial Flutter; D004562:Electrocardiography; D004636:Emergency Service, Hospital; D005424:Flecainide; D006801:Humans; D007275:Injections, Intravenous; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8309942",
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"pages": "2131.e3-2131.e5",
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"pmid": "30033133",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "1:1 atrial flutter induced by flecainide, whilst the patient was at rest.",
"title_normalized": "1 1 atrial flutter induced by flecainide whilst the patient was at rest"
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"abstract": "BACKGROUND\nIn addition to its role in cell adhesion and gene expression in the canonical Wingless/integrated Wnt signaling pathway, β-catenin also regulates genes that underlie the transmission of nerve impulses. Mutations of CTNNB1 (β-catenin) have recently been described in patients with a wide range of neurodevelopmental disorders (intellectual disability, microcephaly and other syndromic features). We for the first time associate CTNNB1 mutation with hyperekplexia identifying it as an additional candidate for consideration in patients with startle syndrome.\n\n\nMETHODS\nWe describe an 11 year old male Polish patient with a de novo nonsense mutation in CTNNB1 who in addition to the major features of CTNNB1-related syndrome including intellectual disability and microcephaly, exhibited hyperekplexia and apraxia of upward gaze. The patient became symptomatic at the age of 20 months exhibiting delayed speech and psychomotor development. Social and emotional development was normal but mild hyperactivity was noted. Episodic falls when startled by noise or touch were observed from the age of 8.5 years, progressively increasing but never with loss of consciousness. Targeted gene panel next generation sequencing (NGS) and patient-parents trio analysis revealed a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 identifying a novel association of β-catenin with hyperekplexia.\n\n\nCONCLUSIONS\nWe report for the first time a clear association of mutation in CTNNB1 with an atypical syndromic heperekplexia expanding the phenotype of CTNNB1-related syndrome. Consequently CTNNB1 should be added to the growing list of genes to be considered as a cause of startle disease or syndromic hyperekplexia.",
"affiliations": "Chair and Department of Child Neurology, Poznan University of Medical Sciences, Poznan, Poland.;Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland. bstronka@gmail.com.;Poznan University of Medical Sciences, Poznan, Poland.;Poznan University of Medical Sciences, Poznan, Poland.;Chair and Department of Child Neurology, Poznan University of Medical Sciences, Poznan, Poland.;Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608, Poznań, Poland.;Department of Genetics, King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia.",
"authors": "Winczewska-Wiktor|Anna|A|;Badura-Stronka|Magdalena|M|;Monies-Nowicka|Anna|A|;Nowicki|Michal Maciej|MM|;Steinborn|Barbara|B|;Latos-Bieleńska|Anna|A|;Monies|Dorota|D|",
"chemical_list": "C495270:CTNNB1 protein, human; D018389:Codon, Nonsense; D051176:beta Catenin",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-016-0554-y",
"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 55410.1186/s12883-016-0554-yCase ReportA de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report Winczewska-Wiktor Anna awwiktor@ump.edu.pl Badura-Stronka Magdalena +48607566527bstronka@gmail.com Monies-Nowicka Anna aniamonies@gmail.com Nowicki Michal Maciej mmnowickimd@gmail.com Steinborn Barbara bstein@ump.edu.pl Latos-Bieleńska Anna alatos@ump.edu.pl Monies Dorota dmonies@kfshrc.edu.sa Chair and Department of Child Neurology, Poznan University of Medical Sciences, Poznan, Poland Chair and Department of Medical Genetics, Poznan University of Medical Sciences, ul. Rokietnicka 8, 60-608 Poznań, Poland Poznan University of Medical Sciences, Poznan, Poland Department of Genetics, King Faisal Hospital and Research Centre, Riyadh, Saudi Arabia 12 3 2016 12 3 2016 2016 16 3530 9 2015 26 2 2016 © Winczewska-Wiktor et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nIn addition to its role in cell adhesion and gene expression in the canonical Wingless/integrated Wnt signaling pathway, β-catenin also regulates genes that underlie the transmission of nerve impulses. Mutations of CTNNB1 (β-catenin) have recently been described in patients with a wide range of neurodevelopmental disorders (intellectual disability, microcephaly and other syndromic features). We for the first time associate CTNNB1 mutation with hyperekplexia identifying it as an additional candidate for consideration in patients with startle syndrome.\n\nCase presentation\nWe describe an 11 year old male Polish patient with a de novo nonsense mutation in CTNNB1 who in addition to the major features of CTNNB1-related syndrome including intellectual disability and microcephaly, exhibited hyperekplexia and apraxia of upward gaze. The patient became symptomatic at the age of 20 months exhibiting delayed speech and psychomotor development. Social and emotional development was normal but mild hyperactivity was noted. Episodic falls when startled by noise or touch were observed from the age of 8.5 years, progressively increasing but never with loss of consciousness. Targeted gene panel next generation sequencing (NGS) and patient-parents trio analysis revealed a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 identifying a novel association of β-catenin with hyperekplexia.\n\nConclusion\nWe report for the first time a clear association of mutation in CTNNB1 with an atypical syndromic heperekplexia expanding the phenotype of CTNNB1-related syndrome. Consequently CTNNB1 should be added to the growing list of genes to be considered as a cause of startle disease or syndromic hyperekplexia.\n\nKeywords\nβ-cateninHyperekplexiaMicrocephalyIntellectual disabilityissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nA novel dominant intellectual disability (ID) syndrome caused by β-catenin gene (CTNNB1) haploinsufficiency was recently identified [1]. Mutations in CTNNB1 (chr3: 41,194,837-41,260,096) are responsible for a wide spectrum of neurodevelopmental disorders. The phenotypes of all 21 patients with CTNNB1 mutations reported to date in four different studies are broad and consistently include several major features: ID and motor delay with different degrees of severity, speech impairment, behavioral anomalies, spastic paraplegia, microcephaly and overlapping facial features [1–4]. In addition, variable clinical findings may involve brain MRI abnormalities (corpus callosum thinning and enlarged ventricles) and spinal anomalies (syringomyelia or tethered cord) [2]. We report a case of an 11-year-old boy with a de novo nonsense mutation in CTNNB1 who presented with mild ID, ataxia, spastic paraplegia, mild microcephaly and dysmorphic features. Notably our patient exhibited hyperekplexia and apraxia of upward gaze, features which to date have not been described in patients with mutations of CTNNB1.Table 1 Clinical findings in patients with mutation in the N-terminal of β-catenin. * Previously published patients [2], n.e. not examined, n.r. not recorded\n\n\tOur Patient\tPatient 5*\tPatient 10*\tPatient 13*\t\n\nGender\n\tM\tF\tF\tM\t\n\nGestational weeks\n\t39\t40\t40\t39\t\n\nApgar scores\n\t10\t9/10/10\tn.r.\t10/10\t\n\nBirth weight [g]\n\t2900\t3450\t3300\t3160\t\n\nBirth length [cm]\n\t53\t51\t50.8\t49\t\n\nAge at last examination [y]\n\t11\t5 7/12\t4\t5 6/12\t\n\nHeight [cm]\n\t150\t108\t104.5\t112\t\n\nWeight [kg]\n\t46\t15\t14.15\t17.2\t\n\nBMI [kg/m2]\n\t20.4\t12.9\t13.0\t13.7\t\n\nOFC [cm]\n\t51\t47.3\t46\t48.5\t\n\nMicrocephaly\n\t+\t+\t+\t+\t\n\nCroniofacial dysmorphism\n\t\t\t\t\n\nbroad nasal tip\n\t+\t+\t+\t(+)\t\n\nsmall alae nasi\n\t+\t+\t+\t-\t\n\nlong and/or flat philtrum\n\t−/+\t+/+\t+/+\t−/+\t\n\nthin upper lip vermillion\n\t+\t+\t+\t+\t\nDevelopmental and neurological abnormalities\t\t\n\nTruncal hypotonia\n\t+\t+\t+\t+\t\nPeripheral hypertonia/spasticity\t+\t+\natactic gait\t+\t+\nlegs > arms\t\nMotor delay\nCrowling (months)\nFree walking\tmoderate\tsevere\tmoderate\tmoderate\t\ndid not crawl\t24\t12\t25\t\n3 years\tnot yet, walking frame\t4 years, falls a lot\tnot yet, walking frame\t\nSpeech impairment\tmoderate, unclear speech\tsevere, few words (30–34), sign language\tspeech apraxia, ~50 words\tshort sentences at 6 years\t\nBasic speech comprehension\t+\t+\t+\t+\ngood\t\nIntellectual disability\t+\t+\t+\t+ (no formal test available)\t\n\nRegression\n\t+ speech\t?\t-\t-\t\n\nBehavioral characteristics\n\ttemper tantrums/crying, friendly personality, aggression, frustration, anxiety, sleep disturbances, stereotypic movements\tsleep disturbances, stereotypic movements, autoagression\tnormal\tnormal, friendly, sensitive to loud noises\t\n\nSeizures\n\t-\t-\t-\t-\t\n\nEEG\n\tduring episodes diffused fast background activity\tnormal\tnormal\tn.e.\t\n\nBrain MRI\n\tarachnoid cyst, enlarged Sylvius sulcus\tnormal\tbasically normal\tnormal\t\n\nHearing loss\n\t-\t-\t-\t-\t\n\nVision\n\thyperopia, astigmatism, strabismus\thyperopia, intermittent strabismus\tnormal\tstrabismus\t\n\nOthers\n\t\t\n\nInternal abnormalities\n\t-\t-\t-\t-\t\n\nFrequent infections\n\t-\t-\t-\t+ (infancy)\t\n\nMiscellaneous\n\tginecomastia, inverted nipples\t-\tfeeding difficulties\t-\t\n\nHands\n\tslender and long fingers\tthin fingers, short distal phalanges\tnormal\tclinodactyly V, hand and feet\t\n\nFeet\n\tsandal gap, long toes\tflat feet\tnormal\tpes equines\t\n\n\nCase Presentation\nThe study was approved by an ethics committee of Poznan University of Medical Sciences, Poland. Parents provided written informed consent according to the Declaration of Helsinki for publication of clinical information. The index case, a male patient was born at term as the first child to healthy, young, non-consanguineous Caucasian parents. Family history was negative for the presence of neurological disorders. He weighed 2900 g, with a good Apgar score. After a normal neonatal period, delayed psychomotor and speech development was evident (at 20 months of age he was unable to walk unassisted and was able to speak only a few words). His social and emotional development was within normal range but hyperactivity was observed. No focal lesions were visualized in 1.5 T MRI; notably in cortex, thalami, midbrain and medulla, except for a 12–13 mm in diameter arachnoid cyst in the posterior fossa and an enlarged Sylvian fissure. An EEG recording showed mild slowing of background activity. The parents had noticed episodic falls since the age 8.5 years. The episodes were provoked by noise, touch or rapid movement in the neighbourhood. Sudden loss in muscle tonus of lower limbs was observed, together with an increase in axial muscle tonus. It led to a rapid flexion in knees and hips provoking a fall. The boy has never had any head injury while falling, due probably to the extension position of his trunk. Episodes were short, lasting a second or two, without loss of consciousness. The boy was able to lift up by himself very quickly directly afterwards and was able to recall the entire episode. This sequence was highly repetitive. A progressive increase in the frequency of falls was noticed. Neurological examination between episodes indicated a left hemiparesis with positive Babinski sign and mild dysarthria. EEG during episodes showed diffused fast background activity, typical for hyperekplexia. In the interictal EEG no epileptiform discharges were observed. Levetiracetam was introduced with good clinical response however the drug was withdrawn because of behavioral disturbances (aggression, tendency to cry). Brivaricetam was introduced instead and the effect was similar to Levetiracetam with fewer side effects. During the last examination at the age of 11 years problems with speech were shown to have increased and coordination problems appeared. In addition to episodes of hyperekplexia, he presents with mild ID, ataxia, truncal hypotonia, bilateral spastic paraplegia, dysarthria and apraxia of upward gaze. He needs support to walk. Ophthalmic examination showed astigmatism and hyperopia with a normal fundus of the eye. Periodical horizontal nystagmus is present but vision evoked potentials are normal. The boy has height and weight within normal ranges, he is mildly dysmorphic (asymmetric face, right frontal hair upsweep, hypotelorism, deep set eyes, strabismus, diastema, small teeth, short philtrum, thin upper lip vermillion, prominent columella, broad nasal tip, small alae nasi, hypoplastic upper crus of the inner helix), has long slender fingers and toes, mild scoliosis, gynecomastia, inverted nipples and microcephaly. He is generally a friendly child, rather anxious, avoiding eye contact, with episodes of frustration. Verbal aggression, crying and sleep disturbances have been also observed (Table 1).\n\nThe patient was followed by neuropediatrics and based upon symptoms including ataxia with progressive pyramidal syndrome, combined with supranuclear vertical gaze palsy, Niemann-Pick type C disease was assumed initially. However, sequencing of the entire coding and flanking regions of NPC1 and NPC2 failed to identify any pathogenic mutations. We further analyzed the index case using a NGS gene panel (targeted resequencing) that included 758 OMIM genes (including GLRA1, GLRB and SLCA) associated with neurological disorders (genomebiology.com/content/supplementary/s13059-015-0693-2-s4.xls). Genes were amplified and a library constructed using an AmpliSeq HiFi mix, proprietary primers and library kit (Thermo Fisher, Carlsband, CA, USA) followed by sequencing on the Ion Proton platform following the manufacturer’s protocol (Thermo Fisher, Carlsband, CA, USA). Sequences were mapped to hg19 and variants were called and annotated using the ion torrent pipeline (Thermo Fisher, Carlsband, CA, USA). Sequencing identified 2985 variants relative to hg19. By excluding previously reported variants (present in RefSeq, OMIM, Genbank, dbSNP, 1000 genomes, in-house database) and only focusing on non-synonymous, splicing, frameshift, indel and nonsense variants we decreased the number to 10 heterozygous changes each in a different gene (Fig. 1A). All changes were validated by Sanger sequencing of the index case and parents. Nine changes were inherited with the only other variant being confirmed as a heterozygous de novo nonsense mutation in exon 3 of CTNNB1 (NM_001098209): c.C232T; p.Q78X (Fig. 1B).Fig. 1 Filtering strategy used for identification of a causative mutation using trio analysis and NGS-gene panel (a). DNA electrophoregram with the c.C232T; p.Q78X mutation in exon 3 of CTNNB1 (b)\n\n\n\nConclusions\nIn this study we present an 11 year old boy in which we detected a de novo nonsense mutation in β-catenin (CTNNB1). Mutations of CTNNB1 were recently reported to be associated with a rare ID syndrome with consistent clinical features including significant motor delay with hypotonia of the trunk, progressive distal hypertonia/spasticity of the legs, speech impairment, behavioral anomalies, frequently microcephaly and overlapping dysmorphic facial features [1–4]. Our patient’s phenotype was consistent with, albeit generally milder than major signs of this entity. However, the boy also suffers from hyperekplexia and apraxia of upward gaze. These features have not been previously described in patients with a mutation of CTNNB1.\n\nHyperekplexia, or human startle disease, (OMIM#149400) is a rare, nonepileptic, paroxysmal neurogenetic disorder characterized by hypertonia and exaggerated persistent startle reflex to unexpected auditory, visual, and somatosensorial stimuli [5, 6]. The cluster of these symptoms is associated with failure of glycinergic synaptic transmission often resulting from mutations in genes encoding presynaptic and postsynaptic proteins [7]. Hyperekplexia results from mutations in GLRA1 and GLRB encoding the human glycine receptor and also the glycine transporter SLCA5 [8, 9]. Later, mutations in the proteins (GPHN and ARHGEF9) that cluster and localize the inhibitory glycine and GABA receptors were identified [10, 11]. However, patients with defects in these synaptic clustering proteins presented a disorder that had only a degree of phenotypic overlap with hyperexplexia. The genetic basis of hyperekplexia in a large proportion of cases remains to be discovered [12]. In our case the clinical diagnosis of hyperekplexia is based on the presence of its typical features: falls as a reaction to sudden stimuli, paroxysmal character, shortness and repetitiveness of episodes (that differenciate hyperekplexia from episodic falls and dyskinesias), no epileptiform EEG discharges during episode nor loss of conciousness (that are observed in atonic seizures), rapid recovery (that is never seen in cataplexy). However, the hyperekplexia in our patient lacks some of cardinal features of hyperekplexia such as rigidity during first year of life, general increase of muscle tonus during an episode and frequent head injuries. Presence of progressive neurologic impairment is also not typical for hyperekplexia. Therefore, we propose a diagnosis of atypical hyperekplexia for this patient`s neurological condition.\n\nβ-catenin (CTNNB1) belongs to the armadillo family of proteins responsible for regulation of gene expression in the canonical Wnt signaling pathway, in addition to their function in cell adhesion [13]. Wnt family secreted glycoproteins are highly conserved and modulate cell-cell communication in cellular processes including central nervous system development [14]. A central component of this pathway, β-catenin binds the TCF/LEF transcription factors that are involved in regulation of many genes [15]. In the thalamus, β-catenin regulates the expression of genes encoding proteins associated with excitation of neurons. In the mouse, it binds to Gabra 3 encoding the GABA receptor, and also to genes responsible for voltage and ligand-gated ion channels: Cacna1g and Kcna6. This indicates a role of β-catenin in the maintenance of neuronal excitability [13].\n\nDuring axonal developmental, the specification of the axon initial segment (AIS), characterized by a high density of voltage-gated Na+ and K+ channels, is critical in initiating and modulating action potentials [16]. These ion channels are tethered by ankyrinG (intracellular protein) to the membrane of the AIS and during this process, β-catenin is progressively accumulated at the AIS and is an essential component of this neuronal domain [17]. Its enrichment plays a role in dendritic morphogenesis, axonal growth and the maturation of AIS functions, modulating neuronal excitability and voltage-gated sodium channels [13, 18]. β-catenin knockdown decreases voltage-gated sodium currents at the AIS. The sodium current reduction is most likely due to diminished ankyrinG tethering at the AIS and the loss of AIS integrity when β-catenin is absent [17]. This molecular mechanism underlying neuronal action potential generation explains β-catenin involvement in disorders related to neuronal development and excitability [17].\n\nOur patient expresses hyperekplexia, a unique symptom that has not been seen among other reported CTNNB1 patients. Only in one other case (P14) a pronounced startle response on both auditory and visual stimuli provoking a breath holding spell was noted without a clear diagnosis of hyperekplexia [2]. Our patient has a de novo mutation in CTNNB1 (c.C232T; p.Q78X) which is localized in the N-terminal domain of β-catenin. Three other patients (P5, P10 and P13) described by Kuechler’s et al. also had mutations in the N-terminal helical domain [2]. This region contains a conserved short linear motif responsible for binding β-TrCPE3 ubiquitin ligase, but only when it is phosphorylated. Degradation of β-catenin is regulated by this N-terminal segment. When comparing the clinical findings for all four patients with mutation in the N-terminal of β-catenin, consistent phenotypic features emerge with exception of atypical hyperekplexia and impaired upward gaze unique to our case (Table 1). In some cases with CTNNB1 haploinsufficiency syndrome, there are patients with additional features not seen in others [4]. There is also, perhaps not surprisingly, inconsistency in the phenotype resulting from heterozygous loss-of-function mouse and human mutations, with phenotype in humans being much more severe [3]. This wide spectrum of clinical features in cases with CTNNB1 mutations may result from compensatory activity of other protein partners that can assume the role of β-catenin in its absence [3]. Plakoglobin for instance (also called γ-catenin) has a very similar structure and ligand binding capacity to β-catenin [19]. The data presented here provides new insight into the role of β-catenin in brain development and its association with neurodevelopmental disorders including hyperekplexia. CTNNB1 should be considered a candidate in patients with hyperekplexia in whom classical genetic mechanisms identified to date are negative.\n\nConsent\nWritten informed consent was obtained from the patient’s parents 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\nWntWingless/Integrated\n\nNGSNext Generation Sequencing\n\nCTNNB1β-catenin protein\n\nGABAγ-aminobutyric acid\n\nEEGElectroencephalogram\n\nTCF/LEFT-cell factor-1 (Tcf-1) and lymphoid enhancing factor-1 (Lef-1)\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nAWW, MBS, BS and ALB performed the medical assessment. AMN, MN and DM performed genetic analysis. AWW, MBS and DM drafted the manuscript with the help of all other authors. All authors read and approved the final manuscript.\n\nAcknowledgements\nThe authors would like to thank the patient and parents for their cooperation and consent in relation to this study\n==== Refs\nReferences\n1. de Ligt J Willemsen MH van Bon BW Kleefstra T Yntema HG Kroes T Diagnostic exome sequencing in persons with severe intellectual disability N Engl J Med 2012 367 20 1921 1929 10.1056/NEJMoa1206524 23033978 \n2. Kuechler A Willemsen MH Albrecht B Bacino CA Bartholomew DW van Bokhoven H De novo mutations in beta-catenin (CTNNB1) appear to be a frequent cause of intellectual disability: expanding the mutational and clinical spectrum Hum Genet 2015 134 1 97 109 10.1007/s00439-014-1498-1 25326669 \n3. Tucci V Kleefstra T Hardy A Heise I Maggi S Willemsen MH Dominant beta-catenin mutations cause intellectual disability with recognizable syndromic features J Clin Invest 2014 124 4 1468 1482 10.1172/JCI70372 24614104 \n4. Dubruc E Putoux A Labalme A Rougeot C Sanlaville D Edery P A new intellectual disability syndrome caused by CTNNB1 haploinsufficiency Am J Med Genet A 2014 164A 6 1571 1575 10.1002/ajmg.a.36484 24668549 \n5. Al-Futaisi AM Al-Kindi MN Al-Mawali AM Koul RL Al-Adawi S Al-Yahyaee SA Novel mutation of GLRA1 in Omani families with hyperekplexia and mild mental retardation Pediatr Neurol 2012 46 2 89 93 10.1016/j.pediatrneurol.2011.11.008 22264702 \n6. Bakker MJ van Dijk JG van den Maagdenberg AM Tijssen MA Startle syndromes Lancet Neurol 2006 5 6 513 524 10.1016/S1474-4422(06)70470-7 16713923 \n7. Thomas RH Chung SK Wood SE Cushion TD Drew CJ Hammond CL Genotype-phenotype correlations in hyperekplexia: apnoeas, learning difficulties and speech delay Brain 2013 136 Pt 10 3085 3095 10.1093/brain/awt207 24030948 \n8. Chung SK Bode A Cushion TD Thomas RH Hunt C Wood SE GLRB is the third major gene of effect in hyperekplexia Hum Mol Genet 2013 22 5 927 940 10.1093/hmg/dds498 23184146 \n9. Carta E Chung SK James VM Robinson A Gill JL Remy N Mutations in the GlyT2 gene (SLC6A5) are a second major cause of startle disease J Biol Chem 2012 287 34 28975 28985 10.1074/jbc.M112.372094 22700964 \n10. Rees MI Harvey K Ward H White JH Evans L Duguid IC Isoform heterogeneity of the human gephyrin gene (GPHN), binding domains to the glycine receptor, and mutation analysis in hyperekplexia J Biol Chem 2003 278 27 24688 24696 10.1074/jbc.M301070200 12684523 \n11. Harvey K Duguid IC Alldred MJ Beatty SE Ward H Keep NH The GDP-GTP exchange factor collybistin: an essential determinant of neuronal gephyrin clustering J Neurosci 2004 24 25 5816 5826 10.1523/JNEUROSCI.1184-04.2004 15215304 \n12. Bode A Lynch JW The impact of human hyperekplexia mutations on glycine receptor structure and function Mol Brain 2014 7 2 10.1186/1756-6606-7-2 24405574 \n13. Wisniewska MB Nagalski A Dabrowski M Misztal K Kuznicki J Novel beta-catenin target genes identified in thalamic neurons encode modulators of neuronal excitability BMC Genomics 2012 13 635 10.1186/1471-2164-13-635 23157480 \n14. Maguschak KA Ressler KJ The dynamic role of beta-catenin in synaptic plasticity Neuropharmacology 2012 62 1 78 88 10.1016/j.neuropharm.2011.08.032 21903109 \n15. Narasipura SD Henderson LJ Fu SW Chen L Kashanchi F Al-Harthi L Role of beta-catenin and TCF/LEF family members in transcriptional activity of HIV in astrocytes J Virol 2012 86 4 1911 1921 10.1128/JVI.06266-11 22156527 \n16. Kole MH Ilschner SU Kampa BM Williams SR Ruben PC Stuart GJ Action potential generation requires a high sodium channel density in the axon initial segment Nat Neurosci 2008 11 2 178 186 10.1038/nn2040 18204443 \n17. Tapia M Del Puerto A Puime A Sanchez-Ponce D Fronzaroli-Molinieres L Pallas-Bazarra N GSK3 and beta-catenin determines functional expression of sodium channels at the axon initial segment Cell Mol Life Sci 2013 70 1 105 120 10.1007/s00018-012-1059-5 22763697 \n18. Yu X Malenka RC Multiple functions for the cadherin/catenin complex during neuronal development Neuropharmacology 2004 47 5 779 786 10.1016/j.neuropharm.2004.07.031 15458849 \n19. Huelsken J Vogel R Brinkmann V Erdmann B Birchmeier C Birchmeier W Requirement for beta-catenin in anterior-posterior axis formation in mice J Cell Biol 2000 148 3 567 578 10.1083/jcb.148.3.567 10662781\n\n",
"fulltext_license": "CC BY",
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"issue": "16()",
"journal": "BMC neurology",
"keywords": "Hyperekplexia; Intellectual disability; Microcephaly; β-catenin",
"medline_ta": "BMC Neurol",
"mesh_terms": "D002648:Child; D018389:Codon, Nonsense; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008607:Intellectual Disability; D008297:Male; D008831:Microcephaly; D010641:Phenotype; D016750:Stiff-Person Syndrome; D051176:beta Catenin",
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"title": "A de novo CTNNB1 nonsense mutation associated with syndromic atypical hyperekplexia, microcephaly and intellectual disability: a case report.",
"title_normalized": "a de novo ctnnb1 nonsense mutation associated with syndromic atypical hyperekplexia microcephaly and intellectual disability a case report"
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"abstract": "BACKGROUND\nLittle is known about the toxicity of sildenafil overdose in the pediatric population. We present a case of prolonged priapism and tachycardia due to unintentional sildenafil overdose in a child.\n\n\nMETHODS\nA 19-month-old male ingested up to six 50 mg Viagra tablets 45 minutes prior to presentation at the emergency department. Initial vital signs included temperature 98.2 degrees F, blood pressure 90/58 mmHg, heart rate 140, respirations 20, and oxygen saturation of 100% on room air. The child weighed 10.4 kg. Physical exam revealed a happy, smiling, laughing toddler who was cooperative with all aspects of his exam. He had mild facial flushing and an erect penis which was normal in color and had a capillary refill of two seconds. Precordial palpation did not show evidence of increase dynamic force, his heart sounds were regular, and no ectopy was noted. His peripheral pulses were strong and regular in all four extremities. No gastrointestinal decontamination was performed. The patient was started on maintenance IV fluids and admitted to the pediatric floor for observation. The patient had a non-painful tumescent penis and mild tachycardia for about 24 hours post-ingestion. The child never had pain from the constant erection. Sildenafil concentration drawn approximately seven hours after ingestion was 3900 ng/ml (reporting limit 24 ng/ml) and N-desmethylsildenafil level was 1700 ng/ml (reporting limit 24 ng/ml).\n\n\nCONCLUSIONS\nThis case of pediatric sildenafil ingestion (up to 30 mg/kg) initially resulted in facial flushing and priapism. The child had asymptomatic tachycardia and prolonged priapism that persisted until hospital discharge approximately 24 hours after ingestion. The erection was non-painful and required no urologic intervention, most likely representing a high flow state. In this ingestion, only supportive care was required.",
"affiliations": "Toxikon Consortium, Chicago, Illinois, USA.",
"authors": "Wills|Brandon K|BK|;Albinson|Charlotte|C|;Wahl|Michael|M|;Clifton|Jack|J|",
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"mesh_terms": "D005483:Flushing; D006801:Humans; D007223:Infant; D008297:Male; D010879:Piperazines; D011041:Poisoning; D011317:Priapism; D011687:Purines; D000068677:Sildenafil Citrate; D013450:Sulfones; D013610:Tachycardia; D016896:Treatment Outcome; D014665:Vasodilator Agents",
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"references": null,
"title": "Sildenafil citrate ingestion and prolonged priapism and tachycardia in a pediatric patient.",
"title_normalized": "sildenafil citrate ingestion and prolonged priapism and tachycardia in a pediatric patient"
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"abstract": "BACKGROUND\nPrimary cardiac tumors are very rare, and angiosarcoma accounts for about 33% of all primary malignant cardiac tumors. Primary cardiac epithelioid angiosarcoma is a highly aggressive and difficult to diagnose tumor, with early systemic metastasis and poor prognosis.\nA 35-year-old Han male experienced sudden severe palpitation and moderate dyspnea. The patient received a whole body F-18 fluoro-deoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) scan, the scan showed a large mass in the right atrium (RA) and numerous pulmonary nodules in both lungs.\nThe patient was diagnosed as right atrial epithelioid angiosarcoma with multiple pulmonary metastasis by pulmonary biopsy through CT-guided percutaneous transthoracic fine needle aspiration.\n\n\nMETHODS\nThe patient received a cycle of chemotherapy with docetaxel and gemcitabine, followed by another cycle with epirubicin and ifosfamide.\n\n\nRESULTS\nThe chemotherapy was ineffective. After the two cycles, the bilateral pleural effusion steadily increased, the patient had severe dyspnea and palpitation, and died three weeks later, with an overall survival of 2.5 months.\n\n\nCONCLUSIONS\nPrimary angiosarcoma of heart is a very rare and aggressive disease, and its diagnosis and treatment are difficult. Most patients may have systemic metastasis at diagnosis, and have a very short survival without surgical resection. Hence, early diagnosis and surgical resection is extremely important to treat this disease.",
"affiliations": "Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.",
"authors": "Liu|Cuiwei|C|;Zhao|Yanxia|Y|;Yin|Zhongyuan|Z|;Hu|Ting|T|;Ren|Jinghua|J|;Wei|Jielin|J|;Xie|Linka|L|;Xiong|Jie|J|;Wu|Hongge|H|;Dai|Xiaofang|X|;Fei|Shihong|S|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30045289MD-D-18-0107410.1097/MD.0000000000011588115885700Research ArticleClinical Case ReportRight atrial epithelioid angiosarcoma with multiple pulmonary metastasis confirmed by multimodality imaging-guided pulmonary biopsy A case report and literature reviewLiu Cuiwei MDZhao Yanxia MDYin Zhongyuan MDHu Ting MDRen Jinghua MDWei Jielin BSXie Linka MDXiong Jie MDWu Hongge MDDai Xiaofang MDFei Shihong MM∗NA. Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.∗ Correspondence: Shihong Fei, Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China (e-mail: feishihongxiehe@163.com).7 2018 27 7 2018 97 30 e115884 4 2018 20 6 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nPrimary cardiac tumors are very rare, and angiosarcoma accounts for about 33% of all primary malignant cardiac tumors. Primary cardiac epithelioid angiosarcoma is a highly aggressive and difficult to diagnose tumor, with early systemic metastasis and poor prognosis.\n\nPatient concerns:\nA 35-year-old Han male experienced sudden severe palpitation and moderate dyspnea. The patient received a whole body F-18 fluoro-deoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) scan, the scan showed a large mass in the right atrium (RA) and numerous pulmonary nodules in both lungs.\n\nDiagnoses:\nThe patient was diagnosed as right atrial epithelioid angiosarcoma with multiple pulmonary metastasis by pulmonary biopsy through CT-guided percutaneous transthoracic fine needle aspiration.\n\nInterventions:\nThe patient received a cycle of chemotherapy with docetaxel and gemcitabine, followed by another cycle with epirubicin and ifosfamide.\n\nOutcomes:\nThe chemotherapy was ineffective. After the two cycles, the bilateral pleural effusion steadily increased, the patient had severe dyspnea and palpitation, and died three weeks later, with an overall survival of 2.5 months.\n\nLessons:\nPrimary angiosarcoma of heart is a very rare and aggressive disease, and its diagnosis and treatment are difficult. Most patients may have systemic metastasis at diagnosis, and have a very short survival without surgical resection. Hence, early diagnosis and surgical resection is extremely important to treat this disease.\n\nKeywords\natrial angiosarcomacase reportimaging-guided biopsypulmonary metastasisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nPrimary cardiac tumors are very rare, and detected in 0.002% to 0.33% of autopsy series.[1] Approximately 20% to 30% of all primary cardiac neoplasms are malignant, of which angiosarcoma is the most common. Primary cardiac angiosarcoma accounts for about 33% of all primary malignant cardiac tumors.[1,2] Angiosarcoma is typically localized in the right atrium, in about 74% of the patients.[3] It is a highly aggressive tumor with early systemic metastasis and poor prognosis. Diagnosis of this disease is difficult, and is often delayed due to lack of specific symptoms. Definitive diagnosis is based on the histopathological examination.[4] The therapy for cardiac epithelioid angiosarcoma remains controversial, with no standard treatment regimens.\n\nIn this study, we presented a rare case of right atrial mass and multiple pulmonary lesions, which was suspected to be malignant cardiac tumor with multiple lung metastasis. This case study highlights the difficulties in diagnosing and treating cardiac tumors.\n\n2 Case report\nA 35-year-old Han male experienced sudden severe palpitation and moderate dyspnea since November 2014. The symptoms lasted for approximately 1 to 5 minutes and were relieved by rest. The patient smoked for >10 years, but had no history of drinking, circulatory or respiratory diseases. In December 2014, the patient visited hospital nearby, a transthoracic echocardiogram (TTE) was performed, which showed severe pericardial effusion. After drainage, the patient's pericardial effusion was controlled, palpitation and dyspnea improved, but severe cough and occasional hemoptysis occurred. For evaluation of the disease, whole body F-18 fluoro-deoxyglucose positron emission tomography (18F-FDG PET)/computed tomography (CT) was performed, which confirmed a large mass (6 cm × 6.7 cm × 6.3 cm) in the right atrium (RA) with intense FDG uptake (SUVmax:22) and numerous pulmonary nodules in both lungs with FDG avid (SUVmax:7.2). The enlarged mediastinal and bilateral hilar nodes also had elevated FDG activity (SUVmax:4.5) (Fig. 1). For further diagnosis and treatment, the patient visited our Wuhan Union Hospital one week later, and cardiac magnetic resonance imaging (MRI) showed a heterogeneously enhanced hypodense mass in the inner wall of RA, which was suspected to be malignant cardiac tumor (Fig. 2). To confirm the diagnosis, we performed a chest CT scan (Fig. 3), and CT-guided percutaneous transthoracic fine needle aspiration biopsy of the pulmonary nodule. The pulmonary nodule was confirmed to be an epithelioid angiosarcoma probably originating from the heart (Fig. 4). The immunohistochemistry results were as follows: VIM(+), TTF-1(−), NapsinA(−), CK7(−), Ki67(LI:60%), PCK(−), Syn(−), cgA(−), CD56(−), LCA(−), CK8/18(−), Hepatocyte(−), Gly-3(−), CD34(+), CD31(+), SMA(−), ERG(+), Des(−), MyoD1(−), MyoGenin(−), and Calretinin(−).\n\nFigure 1 18-F-fluoro-deoxyglucose (FDG) contrast enhanced positron emission tomography/computed tomography (PET-CT) images. (A) Pulmonary nodules in both lungs and hilar nodes with elevated FDG activity. (B) A large mass (6 cm × 6.7 cm × 6.3 cm) in the right atrium (RA) with intense FDG uptake (SUVmax:22). (C) Whole body projection images showed intense FDG uptake in cardiac mass with multiple FDG avid metastases. 18F-FDG = F-18 fluoro-deoxyglucose, CT = computed tomography, PET = positron emission tomography, RA = right atrium.\n\nFigure 2 Cardiac magnetic resonance imaging (MRI) showed a mass in the inner wall of the right atrium. MRI = magnetic resonance imaging.\n\nFigure 3 Chest computed tomography (CT) scan. (A) a large mass (6 cm × 6.7 cm × 6.3 cm) in the right atrium (RA) and numerous pulmonary nodules in both lungs were seen by CT scan before therapy. (B) Some pulmonary nodules were enlarged and the bilateral pleural effusion increased after one cycle of chemotherapy. CT = computed tomography, RA = right atrium.\n\nFigure 4 Epithelioid angiosarcoma was identified by H&E and immunohistochemical staining. (A) H&E staining (×400). (B) High expression of CD 31 by immunohistochemical staining (×400). (C) High expression of ERG by immunohistochemical staining (×400). (D) High expression of VIM by immunohistochemical staining (×400).\n\nThe final diagnosis of this patient was right atrial epithelioid angiosarcoma with multiple pulmonary metastasis (stage IV), based on the imaging and biopsy results. The patient had no family history of this disease. Three days later, the patient started chemotherapy with docetaxel (75 mg/m2) and gemcitabine (900 mg/m2). After a cycle of this chemotherapy, the patient had grade 3 leucopenia, grade 2 thrombocytopenia, and slight nausea, the adverse reactions gradually decreased after corresponding supportive care. Three weeks after the first cycle of chemotherapy, the patient had severe cough, hemoptysis, aggravated dyspnea, and palpitation. Chest CT scan was repeated (Fig. 3) to evaluate the effectiveness of chemotherapy. The disease had progressed indicating that the chemotherapy had failed. Some pulmonary nodules were enlarged and the bilateral pleural effusion had increased. Then, we used epirubicin (30 mg/m2, d1–3) and ifosfamide (1500 mg/m2, d1–4) in the second cycle of chemotherapy. The patient had grade 4 leucopenia, grade 2 thrombocytopenia, severe anemia, and nausea after therapy, and this cycle of chemotherapy was also ineffective. The bilateral pleural effusion rapidly increased, the patient had severe dyspnea and palpitation, and died 3 weeks after the second cycle of chemotherapy, with an overall survival of 2.5 months.\n\n3 Discussion\nPrimary cardiac tumors are very rare, and fewer than one-third are malignant. The malignant tumors include angiosarcoma, lymphoma, fibrosarcoma, myosarcoma, and myxosarcoma, of which angiosarcoma is the most common with an extremely rare incidence of 0.0001%.[5] It typically occurs in middle-aged men, in the right atrium and pericardium.[6] Our patient was a 35-year-old male with a tumor in the right atrium.\n\nThe diagnosis of cardiac angiosarcoma is difficult because the symptoms associated with the disease are not specific. Common symptoms include palpitation, heart failure, chest pain, dyspnea, hemoptysis and congestive heart failure, or acute right heart failure secondary to pericardial tamponade.[7] Occasionally, an abrupt event may occur as the first clinical sign. Systemic symptoms occur in few cases and include night sweats, fever and weight loss.[8] Our patient presented with sudden severe palpitation and moderate dyspnea. Since the symptoms were nonspecific, he was initially misdiagnosed as coronary heart disease. Our patient had no systemic symptoms, which was in accordance with previous reports.\n\nDue to the location of the tumor and nonspecific symptoms, diagnosis is often delayed with an average time interval from presentation to the correct diagnosis of 3 years,[9] and >50% of these tumors have systemic metastases at the time of diagnosis. Most common metastasis sites include lung, liver, brain and bone, although metastasis to lymph nodes, pancreas, spleen, skin, mandible, adrenal glands and kidneys have also been reported.[9–11] Angiosarcoma has extensive infiltration and high degree of malignancy, and infiltration or direct extension into myocardium and pericardium is common. Our patient also had pericardial effusion and multiple pulmonary metastasis at the time of diagnosis, which were the most frequent sites of metastasis.\n\nGiven the specific properties of cardiac angiosarcoma, imaging examinations are critical in diagnosing this disease. Echocardiography is usually the first imaging modality for the diagnosis. The sensitivity and specificity of transthoracic and transesophageal for detection of cardiac masses are 93% and 97%, respectively.[12] Cardiac MRI has high specificity to identify pseudotumors, thrombi and lipomas, but cannot differentiate residual disease.[9,13] Whole body PET/CT also provides metabolic information of tumors and is particularly helpful to delineate the extent of tumor infiltration and assess the metastasis.[14] In some cases, the typical location of mass with infiltration is suggestive of angiosarcoma.[6,9] Cardiac MRI and PET/CT were performed in our patient, which showed a heterogeneously enhanced hypodense mass in the inner wall of right atrium with high grade FDG uptake and numerous pulmonary nodules with serious FDG avid, suggestive of malignant cardiac tumor with pulmonary metastasis.\n\nAlthough imaging examinations are important, the definitive diagnosis of cardiac angiosarcoma is based on histopathology.[15] Previously, the diagnosis of cardiac angiosarcoma was made by surgery or postmortem.[15] In addition, hemorrhagic pericardial fluid and cytologic examination of fluid were helpful for diagnosis.[16] However, histopathology based on tissue specimens is critical for clarifying the nature of a cardiac mass. In preceding decades, various methods were used to obtain tissue specimens in addition to thoracotomy. Transthoracic echocardiography or CT-guided biopsy and transesophageal echocardiography-guided transvenous endomyocardial biopsy of cardiac mass are less invasive as compared to thoracotomy, and are frequently used for diagnosis. However, transthoracic biopsy of a right atrial mass has a potential risk of cardiac rupture because the right atrial wall is thin.[8] Hence, patients may refuse the biopsy at the original site. In some rare cases, biopsy of metastatic nodules outside the heart was also performed for pathological evidence. Qiu and Zhang[17] diagnosed a case of primary cardiac angiosarcoma by multimodality imaging-guided liver biopsy. In our case, after careful consideration of the advantages and disadvantages of all available techniques, and the patient's refusal of biopsy or surgical treatment of the right atrial mass, we performed a biopsy of pulmonary nodule through CT-guided percutaneous transthoracic fine needle aspiration, which supported the diagnosis of primary cardiac epithelioid angiosarcoma with pulmonary metastasis. To the best of our knowledge, this is the first report on primary cardiac epithelioid angiosarcoma confirmed by pulmonary biopsy through CT-guided percutaneous transthoracic fine needle aspiration.\n\nCardiac angiosarcoma has a dismal prognosis because of highly aggressive malignancy with local invasion and a high incidence of systemic metastasis with a median survival ranging from 6 to 11 months.[18] Treatment of cardiac angiosarcoma is controversial due to the poor prognosis.[19] Surgical resection remains the first-line treatment of choice when no evidence of metastases exists and myocardial resection is reparative.[20] If the tumor is resectable, adjuvant therapies, including chemotherapy, radiotherapy and targeted therapy, can improve the chances of survival because of the high probability of metastasis.[21–24] Among the surgical therapeutic methods, heart transplantation has also been suggested, although many moral and social dilemmas exist.[25] The survival after surgery ranges from 2 to 55 months, with a median survival of 14 months.[18] In patients with incomplete surgical resection, chemotherapy and radiotherapy can also be selected. High doses of radiation could improve control of local tumor, but increases severe adverse events.[26]\n\nHowever, most patients have systemic metastasis at diagnosis, for which multi-modality treatment is favored. Thus, various combinations of surgery, chemotherapy, radiotherapy, and/or transplantation have been utilized, with varying results. The patients with systemic metastasis have a mean survival of 3.8 ± 2.5 months without surgical resection.[27] In our patient, the tumor involved the right atrium along with multiple pulmonary metastasis and pericardium infusion, so surgical resection was inappropriate, and hence we selected chemotherapy.\n\nChemotherapy for cardiac angiosarcoma is controversial, and there is no randomized trial of metastatic sarcomas with or without chemotherapy. For the majority of sarcomas, the most eligible agents are doxorubicin and ifosfamide cyclophosphamide, taxanes, vincristine, dactinomycin, etc.[25] Combination therapy with doxorubicin and ifosfamide was effective for the treatment of metastatic soft-tissue sarcoma, including angiosarcoma, regardless of origin.[28,29] Recent studies showed that docetaxel has similar efficacy for metastatic angiosarcomas.[26,30,31] Gemcitabine was also effective for treating advanced angiosarcoma.[29,32] Moreover, the successful administration of molecular targeted therapy in some tumors indicated that it may have possible therapeutic benefit in angiosarcoma as well.[33] The efficacy of antiangiogenic drugs, such as sorafenib, bevacizumab, and imatinib, have been demonstrated in some phase II trials for the treatment of advanced or metastatic angiosarcoma. Sorafenib had a better progression-free survival with 3.8 months, and the overall survival was 14.9 months, but the response rate was lower than standard cytotoxic agents.[34] Bevacizumab was also effective for sarcoma with 57% response rate,[33] but imatinib was ineffective.[35] Since our patient had hemoptysis, and given the adverse effects of anti-angiogenic drugs, we used chemotherapy without anti-angiogenic drugs. However, the first cycle of chemotherapy with docetaxel and gemcitabine, and the second cycle of chemotherapy with epirubicin and ifosfamide were both ineffective. After 2 cycles of chemotherapy, the bilateral pleural effusion rapidly increased, the patient had severe dyspnea and palpitation, and died 3 weeks later, with an overall survival of 2.5 months.\n\n4 Conclusion\nPrimary angiosarcoma of the heart is a very rare and aggressive disease, and its diagnosis and treatment are difficult. Most patients may have systemic metastasis at diagnosis, and have a very short survival without surgical resection. This is the first report on diagnosis of primary cardiac epithelioid angiosarcoma by pulmonary biopsy through CT-guided percutaneous transthoracic fine needle aspiration, but the prognosis of our patient was very poor. Hence, we need to improve the methods of diagnosis and therapy of this disease.\n\nAcknowledgments\nThe authors thank the family of this patient for providing the medical information.\n\nAuthor contributions\nConceptualization: Cuiwei Liu, Yanxia Zhao, Ting Hu, Jinghua Ren, Linka Xie, Jie Xiong, Hongge Wu, Xiaofang Dai, Shihong Fei.\n\nData curation: Cuiwei Liu, Zhongyuan Yin, Jinghua Ren, Jielin Wei, Shihong Fei.\n\nFormal analysis: Yanxia Zhao, Zhongyuan Yin, Jielin Wei, Jie Xiong, Shihong Fei.\n\nInvestigation: Cuiwei Liu, Yanxia Zhao, Ting Hu, Jielin Wei, Linka Xie, Jie Xiong, Xiaofang Dai.\n\nMethodology: Cuiwei Liu, Yanxia Zhao, Zhongyuan Yin, Ting Hu, Jinghua Ren, Jielin Wei, Linka Xie, Jie Xiong, Xiaofang Dai.\n\nProject administration: Cuiwei Liu, Linka Xie, Hongge Wu.\n\nResources: Hongge Wu.\n\nSoftware: Zhongyuan Yin, Hongge Wu.\n\nSupervision: Yanxia Zhao.\n\nValidation: Zhongyuan Yin, Ting Hu, Jinghua Ren, Linka Xie, Hongge Wu, Xiaofang Dai.\n\nVisualization: Ting Hu, Hongge Wu.\n\nWriting - original draft: Cuiwei Liu, Yanxia Zhao, Zhongyuan Yin, Ting Hu, Jinghua Ren, Jielin Wei, Linka Xie, Jie Xiong, Hongge Wu, Xiaofang Dai.\n\nWriting - review & editing: Cuiwei Liu, Yanxia Zhao, Zhongyuan Yin, Ting Hu, Jinghua Ren, Jielin Wei, Linka Xie, Jie Xiong, Hongge Wu, Xiaofang Dai, Shihong Fei.\n\nAbbreviations: 18F-FDG PET = F-18 fluoro-deoxyglucose positron emission tomography, CT = computed tomography, MRI = magnetic resonance imaging, RA = right atrium, TTE = transthoracic echocardiogram.\n\nThis study was supported by a grant from the National Natural Science Foundation of China (No. 81602189). The Ethics Committee of Tongji Medical College, Huazhong University of Science and Technology gave an approval for this study. The patient was dead, his family had agreed for publication of the case, and his wife had provided informed consent.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Silverman NA \nPrimary cardiac tumors . Ann Surg \n1980 ;191 :127–38 .7362282 \n[2] Janigan DT Husain A Robinson NA \nCardiac angiosarcomas. A review and a case report . Cancer \n1986 ;57 :852–9 .3510706 \n[3] Herrmann MA Shankerman RA Edwards WD \nPrimary cardiac angiosarcoma: a clinicopathologic study of six cases . J Thorac Cardiovasc Surg \n1992 ;103 :655–64 .1548908 \n[4] Mahajan A Rekhi B Laskar S \nPrimary pulmonary artery sarcoma masquerading as pulmonary thromboembolism: a rare diagnosis unveiled . Clin Sarcoma Res \n2017 ;7 :13.28680558 \n[5] Kodali D Seetharaman K \nPrimary cardiac angiosarcoma . Sarcoma \n2006 ;2006 :39130.17251657 \n[6] Dhull VS Sharma P Mukherjee A \n18F-FDG PET-CT for evaluation of cardiac angiosarcoma: a case report and review of literature . Mol Imaging Radionucl Ther \n2015 ;24 :32–6 .25800597 \n[7] Chalhoub E Mattar BI Shaheen W \nCardiac angiosarcoma presenting with tamponade . Intern Med \n2012 ;51 :2905–7 .23064565 \n[8] Bruce CJ \nCardiac tumours: diagnosis and management . Heart \n2011 ;97 :151–60 .21163893 \n[9] Jain A Simon S Elangovan I \n(18)F-fluoro-deoxyglucose positron emission tomography-computed tomography in initial assessment and diagnosis of right atrial angiosarcoma with widespread visceral metastases: A rare case report and review of the literature . Indian J Nucl Med \n2015 ;30 :51–4 .25589807 \n[10] Waness A Batoon AA Mirza I \nElusive cardiac angiosarcoma in a young pregnant female: rare presentation with fatal outcome . Cardiol Res \n2015 ;6 :292–6 .28197244 \n[11] Ramadhan A Willén H Thor A \nAngiosarcoma of the mandible: metastasis from a primary tumor of the right atrium of the heart . Case Rep Clin Med \n2013 ;02 :53–7 .\n[12] Chen YC \nLocalization of angiosarcoma by peri-operative transesophageal echocardiography . Int J Cardiovasc Imaging \n2017 ;33 :1749–51 .28593398 \n[13] Lindsey J Stacey RB \nCardiac magnetic resonance in cardiac angiosarcoma . Echocardiography \n2017 ;34 :1077–81 .28664548 \n[14] Taywade SK Damle NA Tripathi M \nUnusual presentation of rare cardiac tumor: the role of F-18-fluorodeoxyglucose positron emission tomographyc/computed tomography . Indian J Nucl Med \n2017 ;32 :157–8 .28533653 \n[15] Leduc C Jenkins SM Sukov WR \nCardiac angiosarcoma: histopathologic, immunohistochemical, and cytogenetic analysis of 10 cases . Hum Pathol \n2017 ;60 :199–207 .27818284 \n[16] Randall MB Geisinger KR \nAngiosarcoma of the heart: pericardial fluid cytology . Diagn Cytopathol \n1990 ;6 :58–62 .2323298 \n[17] Qiu ZX Zhang Q \nPrimary cardiac angiosarcoma confirmed by multimodality imaging guided liver biopsy . Int J Clin Exp Pathol \n2014 ;7 :1188–92 .24696736 \n[18] Antonuzzo L Rotella V Mazzoni F \nPrimary cardiac angiosarcoma: a fatal disease . Case Rep Med \n2009 ;2009 :591512.19724650 \n[19] Shanmugam G \nPrimary cardiac sarcoma . Eur J Cardio-thoracic Surg \n2006 ;29 :925–32 .\n[20] Fukunaga NM Kitai TMDP Imai YMDP \nThree-year survival in primary cardiac angiosarcoma . J Med Invest \n2017 ;64 :181–3 .28373620 \n[21] Wang M Fu G Jiang H \nMultimodality treatment for cardiac angiosarcoma . Int Med \n2014 ;53 :1949–53 .\n[22] Bellitti R Buonocore M De Rosa N \nPrimary cardiac angiosarcoma in a 25-year-old man: excision, adjuvant chemotherapy, and multikinase inhibitor therapy . Tex Heart Inst J \n2013 ;40 :186–8 .23678219 \n[23] Abu Saleh WK Ramlawi B Shapira OM \nImproved outcomes with the evolution of a neoadjuvant chemotherapy approach to right heart sarcoma . Ann Thorac Surg \n2017 ;104 :90–6 .28189277 \n[24] Schur S Hamacher R Brodowicz T \nPazopanib in primary cardiac angiosarcoma of the right atrium: a case report . Case Rep Oncol \n2016 ;9 :363–7 .27462238 \n[25] Batzios S Michalopoulos A Kaklamanis L \nAngiosarcoma of the heart: case report and review of the literature . Anticancer Res \n2006 ;26 :4837–42 .17214349 \n[26] Jang Y Kim J Shim JW \nPrimary cardiac angiosarcoma: a prolonged response to surgical resection followed by concurrent chemoradiotherapy with docetaxel . SpringerPlus \n2016 ;5 :648.27330914 \n[27] Patel SD Peterson A Bartczak A \nPrimary cardiac angiosarcoma—a review . Med Sci Monit \n2014 ;20 :103–9 .24452054 \n[28] Serrano C García Á Brana I \nAngiosarcoma of the ovary: is it always a lethal disease? \nJ Clin Oncol \n2010 ;28 :675–7 .19841329 \n[29] Yonezawa I Waki M Tamura Y \nGemcitabine-based regimen for primary ovarian angiosarcoma with MYC amplification . Curr Oncol \n2014 ;21 :e782–789 .25489268 \n[30] Penel N Italiano A Raycoquard I \nMetastatic angiosarcomas: doxorubicin-based regimens, weekly paclitaxel and metastasectomy significantly improve the outcome . Ann Oncol \n2012 ;23 :517.21566149 \n[31] Minichillo S Pantaleo MA Nannini M \nEfficacy of weekly docetaxel in locally advanced cardiac angiosarcoma . BMC Res Notes \n2015 ;8 :325.26223870 \n[32] Stacchiotti S Palassini E Sanfilippo R \nGemcitabine in advanced angiosarcoma: a retrospective case series analysis from the Italian Rare Cancer Network . Ann Oncol \n2012 ;23 :501–8 .21464156 \n[33] Agulnik M Yarber JL Okuno SH \nAn open-label, multicenter, phase II study of bevacizumab for the treatment of angiosarcoma and epithelioid hemangioendotheliomas . Ann Oncol \n2013 ;24 :257–63 .22910841 \n[34] Maki RG D’Adamo DR Keohan ML \nPhase II study of sorafenib in patients with metastatic or recurrent sarcomas . J Clin Oncol \n2009 ;7 :3133–40 .\n[35] RC JK W RG M \nPhase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model . J Clin Oncol \n2009 ;7 :3148–53 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0025-7974",
"issue": "97(30)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D001706:Biopsy; D004417:Dyspnea; D019788:Fluorodeoxyglucose F18; D006325:Heart Atria; D006338:Heart Neoplasms; D018323:Hemangioendothelioma, Epithelioid; D006394:Hemangiosarcoma; D006801:Humans; D008168:Lung; D008175:Lung Neoplasms; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e11588",
"pmc": null,
"pmid": "30045289",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "17214349;25589807;19451436;26223870;25800597;28593398;21566149;19451433;21163893;24452054;23064565;21464156;24696736;25489268;28373620;28533653;28680558;28664548;19724650;27330914;28189277;2323298;22910841;3510706;7362282;27818284;23678219;16675225;1548908;27462238;28197244;25175128;20823420;17251657",
"title": "Right atrial epithelioid angiosarcoma with multiple pulmonary metastasis confirmed by multimodality imaging-guided pulmonary biopsy: A case report and literature review.",
"title_normalized": "right atrial epithelioid angiosarcoma with multiple pulmonary metastasis confirmed by multimodality imaging guided pulmonary biopsy a case report and literature review"
} | [
{
"companynumb": "CN-MYLANLABS-2018M1062147",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Sulphasalazine, one of the 5-amino-salicylates, is widely used for the treatment of inflammatory bowel diseases and arthritis. Among the reported adverse effects are blood dyscrasias and hepatic failure. Peripheral neuropathy has been reported as a rare adverse drug reaction to sulphasalazine. Most reported patients developed symptoms several weeks after onset of treatment. We describe a patient with an axonal polyneuropathy that occurred after two years of treatment with sulphasalazine.",
"affiliations": "Department of Neurology and the Department of Rheumatology, V.U. University Medical Centre, Amsterdam, The Netherlands. m.liedorp@vumc.nl",
"authors": "Liedorp|M|M|;Voskuyl|A E|AE|;Van Oosten|B W|BW|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D012460:Sulfasalazine",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0392-856X",
"issue": "26(4)",
"journal": "Clinical and experimental rheumatology",
"keywords": null,
"medline_ta": "Clin Exp Rheumatol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes; D011115:Polyneuropathies; D025242:Spondylarthropathies; D012460:Sulfasalazine; D055815:Young Adult",
"nlm_unique_id": "8308521",
"other_id": null,
"pages": "671-2",
"pmc": null,
"pmid": "18799104",
"pubdate": "2008",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Axonal neuropathy with prolonged sulphasalazine use.",
"title_normalized": "axonal neuropathy with prolonged sulphasalazine use"
} | [
{
"companynumb": "NL-PFIZER INC-2008087308",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "1",
... |
{
"abstract": "The patients with hematologic malignancies and hematopoietic stem cell transplantation (HSCT) recipients are at high risk for invasive fungal diseases (IFDs) mainly due to the severe and prolonged neutropenia related to high-dose chemotherapy. Voriconazole prophylaxis is recommended for possible IFDs. Mucormycosis is a fulminant infection, which may occur after voriconazole prophylaxis for invasive aspergillosis in immunocompromised hosts. Here, we report mucormycosis after 4 months of voriconazole prophylaxis in a young patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure and discuss the clinical manifestation, imaging, laboratory findings and therapeutic regimens. Clinician's awareness of this entity and timely diagnosis using conventional and molecular methods are the promising approach for the management of this devastating infection.",
"affiliations": "Department of Internal Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: asharifpour_0209@yahoo.com.;Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: n.gholinejad.ghadi@gmail.com.;Antimicrobial Resistance Research Center, and Department of Infectious Diseases, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: roya31gh@yahoo.com.;Student Research Committee, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: zhrseifi@gmail.com.;Department of Medical Mycology, School of Medicine/Invasive Fungi Research Center (IFRC), Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: aghili70@yahoo.com.;Department of Internal Medicine, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: e.zaboli@mazums.ac.ir.;Department of Radiology, School of Medicine, Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: sian_abdi@yahoo.com.;Department of Medical Mycology, School of Medicine/Invasive Fungi Research Center (IFRC), Mazandaran University of Medical Sciences, Sari, Iran. Electronic address: shokohi.tahereh@gmial.com.",
"authors": "Sharifpour|A|A|;Gholinejad-Ghadi|N|N|;Ghasemian|R|R|;Seifi|Z|Z|;Aghili|S R|SR|;Zaboli|E|E|;Abdi|R|R|;Shokohi|T|T|",
"chemical_list": "D065819:Voriconazole",
"country": "France",
"delete": false,
"doi": "10.1016/j.mycmed.2018.05.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1156-5233",
"issue": "28(3)",
"journal": "Journal de mycologie medicale",
"keywords": "Acute lymphoblastic leukemia; Hematopoietic stem cell transplantation recipients; Invasive fungal disease; Mucormycosis; Prophylaxis; Voriconazole; Zygomycosis",
"medline_ta": "J Mycol Med",
"mesh_terms": "D000293:Adolescent; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009091:Mucormycosis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012008:Recurrence; D017211:Treatment Failure; D065819:Voriconazole",
"nlm_unique_id": "9425651",
"other_id": null,
"pages": "527-530",
"pmc": null,
"pmid": "29807852",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Voriconazole associated mucormycosis in a patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure: A case report.",
"title_normalized": "voriconazole associated mucormycosis in a patient with relapsed acute lymphoblastic leukemia and hematopoietic stem cell transplant failure a case report"
} | [
{
"companynumb": "IR-PRINSTON PHARMACEUTICAL INC.-2018PRN00317",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugaddi... |
{
"abstract": "Ethyl chloride spray, which is usually used to relieve pain after injuries, is increasingly being used as a sniffing alternative. The number of people using this is rising due to its easy availability, cost-effectiveness and legality. The high lipid solubility of ethyl chloride leads to a rapid absorption of it in the lungs. However, data on the biotransformation of ethyl chloride in humans are sparse. We present the case of a 53-year-old male who had been inhaling ethyl chloride up to 3 times a week since 25 years, and describe his symptoms and the circumstances of abuse. This should help raise awareness of this issue so that abuse can be recognized early and rapid action taken.",
"affiliations": "Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.;Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.;Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.;Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.;Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.;Psychiatrie LMU, Ludwig-Maximilians-Universität München Medizinische Fakultät, München, Germany.",
"authors": "Hager|Laura|L|0000-0002-4457-4706;Kamp|Felicia|F|;Proebstl|Lisa|L|;Behle|Nina|N|;Pogarell|Oliver|O|;Koller|Gabriele|G|",
"chemical_list": "D005018:Ethyl Chloride",
"country": "Germany",
"delete": false,
"doi": "10.1055/a-1483-9865",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0720-4299",
"issue": "89(7-08)",
"journal": "Fortschritte der Neurologie-Psychiatrie",
"keywords": null,
"medline_ta": "Fortschr Neurol Psychiatr",
"mesh_terms": "D005018:Ethyl Chloride; D006801:Humans; D058545:Inhalant Abuse; D008297:Male; D008875:Middle Aged; D010146:Pain; D010147:Pain Measurement",
"nlm_unique_id": "8103137",
"other_id": null,
"pages": "382-384",
"pmc": null,
"pmid": "34237782",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Inhalant Abuse of Ethyl Chloride Spray: A Case Report.",
"title_normalized": "inhalant abuse of ethyl chloride spray a case report"
} | [
{
"companynumb": "DE-TEVA-2021-DE-1977543",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BROMAZEPAM"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nStudy the therapeutic maintenance, efficacy and reasons for tocilizumab stop in daily practice.\n\n\nMETHODS\nA monocentric, retrospective study of patients treated for rheumatoid arthritis who received at least one TCZ infusion between January 2009 and December 2015. Therapeutic maintenance was evaluated using the Kaplan-Meier method. The efficacy of TCZ was measured by DAS28 and the EULAR response. Reasons for stopping and new treatment lines were also collected.\n\n\nRESULTS\nOf the 88 patients (83% women and 17% men) who were included, the mean age was 54±12.5 years. There were 75% positive rheumatoid factors and 76% positive anti-CCP. The mean duration of the follow-up was 31 months. TCZ was used as monotherapy in 24 patients (27%). Before the introduction of TCZ, the mean DAS28 was 5.07±1.32. The EULAR response at 1 year in patients still under treatment (n=63) was obtained in 59 (93.7%) patients, 46 good responders and 13 moderate responders. Therapeutic maintenance was 82.9%, 72.5%, 68.7% and 57.2%, respectively, at 12, 24, 36 and 54 months. Twenty-eight patients (32%) followed TCZ, 10 for adverse events and 14 for ineffectiveness. Abatacept was the main new therapeutic line.\n\n\nCONCLUSIONS\nThe therapeutic maintenance of TCZ in common practice over a long period of follow-up is similar to pivotal studies. Efficacy data are reassuring in the long-term.",
"affiliations": "Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France. Electronic address: clement.chopin51@gmail.com.;Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France.;Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France.;Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France.;Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France.;Service de rhumatologie, CHU de Reims, 45, rue Cognac-Jay, 51100 Reims, France.",
"authors": "Chopin|Clément|C|;Pauvele|Loïc|L|;Jaulerry|Sarah|S|;Brochot|Pascal|P|;Eschard|Jean-Paul|JP|;Salmon|Jean-Hugues|JH|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; C502936:tocilizumab",
"country": "France",
"delete": false,
"doi": "10.1016/j.therap.2017.08.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "73(3)",
"journal": "Therapie",
"keywords": "Maintenance thérapeutique; Polyarthrite rhumatoïde; Rheumatoid arthritis; Therapeutic maintenance; Tocilizumab; Traitement; Treatment",
"medline_ta": "Therapie",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D005260:Female; D006785:Hospitals, University; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "231-236",
"pmc": null,
"pmid": "29146040",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Effectiveness, therapeutic maintenance and reasons for stopping tocilizumab (TCZ): A retrospective and monocentric study in 88 patients followed for rheumatoid arthritis (RA) at the Reims university hospital.",
"title_normalized": "effectiveness therapeutic maintenance and reasons for stopping tocilizumab tcz a retrospective and monocentric study in 88 patients followed for rheumatoid arthritis ra at the reims university hospital"
} | [
{
"companynumb": "FR-ROCHE-2037393",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Direct antiviral therapies for chronic hepatitis C virus (HCV) infection have expanded treatment options for neglected patient populations, including elderly patients who are ineligible/intolerant to receive interferon (IFN)-based therapy.\n\n\n\nTo investigate the efficacy, tolerability and potential for drug-drug interactions (DDIs) of IFN-free treatment in patients aged ≥65 years in a large real-world cohort.\n\n\n\nA total of 541 patients were treated with different combinations of direct antiviral agents (DAAs: ledipasvir/sofosbuvir ±ribavirin; daclatasvir/sofosbuvir ±ribavirin; paritaprevir/ombitasvir ±dasabuvir ±ribavirin or simeprevir/sofosbuvir ±ribavirin in genotype 1/4, and daclatasvir/sofosbuvir ±ribavirin or sofosbuvir/ribavirin in genotype 2/3). Efficacy, safety and potential DDIs were analysed and compared between patients aged <65 years (n = 404) and patients aged ≥65 years (n = 137) of whom 41 patients were ≥75 years.\n\n\n\nSustained virological response rates were 98% and 91% in patients aged ≥65 years and <65 years, respectively. Elderly patients took significantly more concomitant medications (79% vs. 51%; P < 0.0001). The number of concomitant drugs per patient was highest in patients ≥65 years with cirrhosis (median, three per patient; range, 0-10). Based on the hep-druginteractions database, the proportion of predicted clinically significant DDIs was significantly higher in elderly patients (54% vs. 28%; P < 0.0001). The number of patients who experienced treatment-associated adverse events was similar between the two age groups (63% vs. 65%; P = n.s.).\n\n\n\nElderly patients are at increased risk for significant DDIs when treated with DAAs for chronic HCV infection. However, with careful pre-treatment assessment of concomitant medications, on-treatment monitoring or dose-modifications, significant DDIs and associated adverse events can be avoided.",
"affiliations": "Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany. Johannes.Vermehren@kgu.de.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.;Medizinische Klinik 1, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany.",
"authors": "Vermehren|J|J|;Peiffer|K-H|KH|;Welsch|C|C|;Grammatikos|G|G|;Welker|M-W|MW|;Weiler|N|N|;Zeuzem|S|S|;Welzel|T M|TM|;Sarrazin|C|C|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1111/apt.13769",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-2813",
"issue": "44(8)",
"journal": "Alimentary pharmacology & therapeutics",
"keywords": null,
"medline_ta": "Aliment Pharmacol Ther",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D004347:Drug Interactions; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "8707234",
"other_id": null,
"pages": "856-65",
"pmc": null,
"pmid": "27549000",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The efficacy and safety of direct acting antiviral treatment and clinical significance of drug-drug interactions in elderly patients with chronic hepatitis C virus infection.",
"title_normalized": "the efficacy and safety of direct acting antiviral treatment and clinical significance of drug drug interactions in elderly patients with chronic hepatitis c virus infection"
} | [
{
"companynumb": "DE-KADMON PHARMACEUTICALS, LLC-KAD201710-001186",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DASABUVIR\\OMBITASVIR\\PARITAPREVIR\\RITONA... |
{
"abstract": "An 86-year-old man was referred to our hospital with pulmonary tuberculosis developed during postoperative chemotherapy for gastric cancer. We initiated treatment with an anti-tuberculosis drug. Following confirmation of the effectiveness of this regimen, we combined the treatment with anti-cancer drugs. Tuberculosis treatment was completed without any drug interactions or serious side effects due to multidrug administration. For cancer patients who developed tuberculosis, combination treatment requires careful observation; however, it is a treatment option that can control both diseases.",
"affiliations": "Dept. of Gastroenterology Surgery, Hyogo-Chuo National Hospital.",
"authors": "Nakajima|Takahiro|T|;Fujikawa|Takeya|T|;Takagi|Yasuyuki|Y|;Shiroiwa|Hiroshi|H|;Fujiwara|Hidetoshi|H|",
"chemical_list": "D000970:Antineoplastic Agents; D000995:Antitubercular Agents",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "48(7)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000995:Antitubercular Agents; D006801:Humans; D008297:Male; D013274:Stomach Neoplasms; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "959-962",
"pmc": null,
"pmid": "34267036",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Concomitant Administration of Anti-Cancer Drug and Anti-Tuberculosis Drug for Pulmonary Tuberculosis Developed during Postoperative Chemotherapy for Gastric Cancer.",
"title_normalized": "a case of concomitant administration of anti cancer drug and anti tuberculosis drug for pulmonary tuberculosis developed during postoperative chemotherapy for gastric cancer"
} | [
{
"companynumb": "JP-CHUGAI-2021011440",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRASTUZUMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "OBJECTIVE\nTenofovir disoproxil fumarate (TDF) is recommended as first-line monotherapy for nucleos(t)ide (NA)-naïve chronic hepatitis B (CHB) patients and as a second-line rescue therapy for NA-experienced patients with a previous treatment failure. However, data regarding the efficacy of TDF monotherapy in patients with lamivudine resistance (LAM-R) successfully treated with LAM+adefovir (ADV) are limited. Herein, the efficacy and safety of switching from LAM+ADV to TDF monotherapy in clinical practice have been evaluated.\n\n\nMETHODS\nSixty LAM-R HBeAg-negative CHB patients treated with ADV add-on therapy and stable viral suppression, were switched to TDF monotherapy and prospectively evaluated for virological response, liver and renal function, and bone mineral density.\n\n\nRESULTS\nDuring a median period of 57 months of TDF monotherapy, all patients maintained a virological response, four of whom cleared HBsAg (6.6%) and discontinued treatment. Monitoring of renal function showed no case of the Fanconi syndrome, no significant alterations of median serum creatinine, eGFR and phosphate levels, although a reduction of TDF dosage was required in five patients (8.3%). Despite the stable virological suppression, five cirrhotic patients and one CHB patient developed hepatocellular carcinoma.\n\n\nCONCLUSIONS\nOur results demonstrate the efficacy of switching to TDF monotherapy in virologically suppressed CHB patients receiving long-term LAM+ADV therapy, with a low rate of adverse events.",
"affiliations": "Clinic of Infectious Diseases, University of Foggia, Italy.;Clinic of Infectious Diseases, University of Bari, Italy.;Clinic of Infectious Diseases, University of Bari, Italy.;Clinic of Infectious Diseases, University of Bari, Italy.;Clinic of Infectious Diseases, University of Foggia, Italy.;Clinic of Infectious Diseases, University of Bari, Italy.;Clinic of Infectious Diseases, University of Foggia, Italy. Electronic address: teresa.santantonio@unifg.it.",
"authors": "Fasano|Massimo|M|;Maggi|Paolo|P|;Leone|Armando|A|;Volpe|Anna|A|;Fiore|Jose Ramon|JR|;Angarano|Gioacchino|G|;Santantonio|Teresa Antonia|TA|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D019259:Lamivudine; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.dld.2017.01.140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8658",
"issue": "49(5)",
"journal": "Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver",
"keywords": "Antiviral therapy; Chronic hepatitis B; Nucleos(t)ide analogues; Tenofovir",
"medline_ta": "Dig Liver Dis",
"mesh_terms": "D000225:Adenine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D004359:Drug Therapy, Combination; D005260:Female; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D007558:Italy; D053208:Kaplan-Meier Estimate; D007677:Kidney Function Tests; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates; D000068698:Tenofovir; D017211:Treatment Failure",
"nlm_unique_id": "100958385",
"other_id": null,
"pages": "530-534",
"pmc": null,
"pmid": "28179096",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Long-term efficacy and safety of switching from lamivudine+adefovir to tenofovir disoproxil fumarate in virologically suppressed patients.",
"title_normalized": "long term efficacy and safety of switching from lamivudine adefovir to tenofovir disoproxil fumarate in virologically suppressed patients"
} | [
{
"companynumb": "IT-GLAXOSMITHKLINE-IT2017GSK025283",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": nul... |
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