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{
"abstract": "During the period January 2004 to April 2007, nine cases of breakthrough invasive aspergillosis occurred among 156 allogeneic haematopoietic stem cell transplant recipients receiving caspofungin therapy, mainly for empirical treatment of persisting fever. Voriconazole salvage therapy induced two complete responses. However, seven patients ultimately died a median of 5 weeks after diagnosis, including five patients with aspergillosis. This high incidence of breakthrough invasive aspergillosis in this patient population receiving caspofungin therapy warrants further investigation.",
"affiliations": "Hematology-Bone Marrow Transplant Unit, Saint-Louis Hospital, Université Paris VII, 1 avenue Claude Vellefaux, 75010 Paris, France.",
"authors": "Madureira|Adrienne|A|;Bergeron|Anne|A|;Lacroix|Claire|C|;Robin|Marie|M|;Rocha|Vanderson|V|;de Latour|Régis Peffault|RP|;Ferry|Christèle|C|;Devergie|Agnès|A|;Lapalu|Jordane|J|;Gluckmana|Eliane|E|;Socié|Gérard|G|;Ghannoum|Mahmoud|M|;Ribaud|Patricia|P|",
"chemical_list": "D000935:Antifungal Agents; D054714:Echinocandins; D055666:Lipopeptides; D011743:Pyrimidines; D014230:Triazoles; D000077336:Caspofungin; D065819:Voriconazole",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijantimicag.2007.07.026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0924-8579",
"issue": "30(6)",
"journal": "International journal of antimicrobial agents",
"keywords": null,
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000935:Antifungal Agents; D001228:Aspergillosis; D001230:Aspergillus; D000077336:Caspofungin; D025141:Drug Resistance, Fungal; D054714:Echinocandins; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D055666:Lipopeptides; D011743:Pyrimidines; D014184:Transplantation, Homologous; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "551-4",
"pmc": null,
"pmid": "18029149",
"pubdate": "2007-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Breakthrough invasive aspergillosis in allogeneic haematopoietic stem cell transplant recipients treated with caspofungin.",
"title_normalized": "breakthrough invasive aspergillosis in allogeneic haematopoietic stem cell transplant recipients treated with caspofungin"
} | [
{
"companynumb": "FR-PFIZER INC-2014322952",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this report was to describe a case with paracentral acute middle maculopathy after oral intake of sumatriptan.\n\n\nMETHODS\nCase presentation.\n\n\nRESULTS\nOne patient showed typical findings on fundoscopic examination and optical coherence tomography consistent with paracentral acute middle maculopathy following oral intake of sumatriptan.\n\n\nCONCLUSIONS\nSumatriptan may be a trigger for paracentral acute middle maculopathy.",
"affiliations": "Department of Ophthalmology, UZ Leuven, Leuven, Belgium.",
"authors": "E Zonnevylle|Kirsten|K|;Jacob|Julie|J|;Luyten|Steven|S|;Stanescu-Segall|Dinu|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000914",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": null,
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": null,
"nlm_unique_id": "101298744",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31425447",
"pubdate": "2019-08-13",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "PARACENTRAL ACUTE MIDDLE MACULOPATHY FOLLOWING ORAL INTAKE OF SUMATRIPTAN.",
"title_normalized": "paracentral acute middle maculopathy following oral intake of sumatriptan"
} | [
{
"companynumb": "BE-UPSHER-SMITH LABORATORIES, LLC-2019USL00799",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SUMATRIPTAN"
},
"drugadd... |
{
"abstract": "Bone-specific drugs (BSDs) increase the risk of osteonecrosis of the jaw (ONJ), but whether they increase the risk of osteonecrosis at other sites is not known. Two studies, a cohort study and a case-control study, were conducted using registry data on everyone who was residing in Sweden on December 31, 2005, and who was 50 years of age or older at the time (n = 3,523,912). In the cohort study, individuals prescribed a BSD during the period 2006-2017 (n = 217,387) were 1:1 matched with nonusers on birth year, sex, hip fracture status, and Swedish or foreign origin. In the case-control study, individuals diagnosed with osteonecrosis during 2006-2017 (n = 12,614) were 1:1 matched with individuals without a diagnosis of osteonecrosis on birth year, sex, and Swedish or foreign background. In the cohort study, osteonecrosis was diagnosed in 983 BSD users and 214 nonusers (adjusted hazard ratio [aHR] 4.02; 95% CI, 3.32-4.87), during a mean treatment time of 2.8 years. A similar association was observed in a subcohort where all individuals diagnosed with cancer (HR 4.82; 95% CI, 2.52-9.22). The greatest difference in incidence between BSD users and nonusers was observed in patients with a femoral neck fracture that was not treated with total hip arthroplasty or hemiarthroplasty (incidence rate difference, 77.8 cases per 10,000 person-years, p < .05). The risk of osteonecrosis was higher in users of denosumab (HR 1.93; 95% CI, 1.33-2.79) and users of zoledronic acid (HR 1.95; 95% CI, 1.31-2.91) than in users of other BSDs. The increased risk of osteonecrosis decreased after the end of therapy (p < .001 for time trend). The results were confirmed in the case-control study. In summary, use of BSDs, especially more potent BSDs, is associated with increased risk of osteonecrosis of sites other than the jaw. This increased risk decreases after the final dose of BSD. © 2020 American Society for Bone and Mineral Research.",
"affiliations": "Unit of Geriatric Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.;Unit of Geriatric Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.;Unit of Geriatric Medicine, Department of Community Medicine and Rehabilitation, Umeå University, Umeå, Sweden.;Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.;Section of Sustainable Health, Department of Public Health and Clinical Medicine, Umeå University, Umeå, Sweden.",
"authors": "Nordström|Peter|P|0000-0003-2924-508X;Bergman|Jonathan|J|0000-0003-1904-6140;Ballin|Marcel|M|;Björk|Sabine|S|;Nordström|Anna|A|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004364:Pharmaceutical Preparations",
"country": "United States",
"delete": false,
"doi": "10.1002/jbmr.4040",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-0431",
"issue": "35(9)",
"journal": "Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research",
"keywords": "BISPHOSPHONATES; HIP FRACTURE; OSTEONECROSIS",
"medline_ta": "J Bone Miner Res",
"mesh_terms": "D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D016022:Case-Control Studies; D015331:Cohort Studies; D004164:Diphosphonates; D006801:Humans; D010020:Osteonecrosis; D004364:Pharmaceutical Preparations; D012307:Risk Factors; D013548:Sweden",
"nlm_unique_id": "8610640",
"other_id": null,
"pages": "1703-1710",
"pmc": null,
"pmid": "32379370",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bone-Specific Drugs and Osteonecrosis of Sites Other Than the Jaw: A Nationwide Cohort Study.",
"title_normalized": "bone specific drugs and osteonecrosis of sites other than the jaw a nationwide cohort study"
} | [
{
"companynumb": "SE-AMGEN-SWESP2020077228",
"fulfillexpeditecriteria": "2",
"occurcountry": "SE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Rasmussen encephalitis is a rare, devastating condition, typically presenting in childhood. Cases of adult-onset Rasmussen have also been described, but the clinical picture is less defined, rendering final diagnosis difficult. We present a case of adult-onset Rasmussen encephalitis with dual pathology, associated with focal cortical dysplasia and encephalitis. We interpreted the Rasmussen encephalitis to be caused by severe and continuous epileptic activity due to focal cortical dysplasia. The best therapeutic approach for such cases remains unclear.",
"affiliations": "Department of Neurology.;Department of Anatomopathology.;Department of Nuclear Medecine, Cliniques universitaires Saint-Luc, Université Catholique de Louvain, Bruxelles.;Department of Neurology.;Department of Neurology, Centre Hospitalier Neurologique William Lennox, Ottignies, Belgium.;Department of Neurology.",
"authors": "Hohenbichler|Katharina|K|;Lelotte|Julie|J|;Lhommel|Renaud|R|;Tahry|Riëm El|RE|;Vrielynck|Pascal|P|;Santos|Susana Ferrao|SF|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2017.0947",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "19(4)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "adult-onset Rasmussen encephalitis; dual pathology; focal cortical dysplasia",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000293:Adolescent; D001921:Brain; D004569:Electroencephalography; D004660:Encephalitis; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D054220:Malformations of Cortical Development",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "476-480",
"pmc": null,
"pmid": "29258971",
"pubdate": "2017-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Adult-onset Rasmussen encephalitis associated with focal cortical dysplasia.",
"title_normalized": "adult onset rasmussen encephalitis associated with focal cortical dysplasia"
} | [
{
"companynumb": "DE-JNJFOC-20180303308",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Pimozide is a dopamine receptor antagonist indicated for the treatment of Tourette syndrome. Prior in vitro studies characterized N-dealkylation of pimozide to 1,3-dihydro-1-(4-piperidinyl)-2H-benzimidazol-2-one (DHPBI) via CYP3A4 and, to a lesser extent, CYP1A2 as the only notable routes of pimozide biotransformation. However, drug-drug interactions between pimozide and CYP2D6 inhibitors and CYP2D6 genotype-dependent effects have since been observed. To reconcile these incongruities between the prior in vitro and in vivo studies, we characterized two novel pimozide metabolites: 5-hydroxypimozide and 6-hydroxypimozide. Notably, 5-hydroxypimozide was the major metabolite produced by recombinant CYP2D6 (Km ∼82 nM, V max ∼0.78 pmol/min per picomoles), and DHPBI was the major metabolite produced by recombinant CYP3A4 (apparent Km ∼1300 nM, V max ∼2.6 pmol/min per picomoles). Kinetics in pooled human liver microsomes (HLMs) for the 5-hydroxylation (Km ∼2200 nM, V max ∼59 pmol/min per milligram) and N-dealkylation (Km ∼3900 nM, V max ∼600 pmol/min per milligram) reactions were also determined. Collectively, formation of DHPBI, 5-hydroxypimozide, and 6-hydroxypimozide accounted for 90% of pimozide depleted in incubations of NADPH-supplemented pooled HLMs. Studies conducted in HLMs isolated from individual donors with specific cytochrome P450 isoform protein abundances determined via mass spectrometry revealed that 5-hydroxypimozide (r 2 = 0.94) and 6-hydroxypimozide (r 2 = 0.86) formation rates were correlated with CYP2D6 abundance, whereas the DHPBI formation rate (r 2 = 0.98) was correlated with CYP3A4 abundance. Furthermore, the HLMs differed with respect to their capacity to form 5-hydroxypimozide relative to DHPBI. Collectively, these data confirm a role for CYP2D6 in pimozide clearance via 5-hydroxylation and provide an explanation for a lack of involvement when only DHPBI formation was monitored in prior in vitro studies. SIGNIFICANCE STATEMENT: Current CYP2D6 genotype-guided dosing information in the pimozide label is discordant with available knowledge regarding the primary biotransformation pathways. Herein, we characterize the CYP2D6-dependent biotransformation of pimozide to previously unidentified metabolites. In human liver microsomes, formation rates for the novel metabolites and a previously identified metabolite were determined to be a function of CYP2D6 and CYP3A4 content, respectively. These findings provide a mechanistic basis for observations of CYP2D6 genotype-dependent pimozide clearance in vivo.",
"affiliations": "Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri bchapron@cmh.edu.;Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri.;Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri.;Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri.;Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Department of Pediatrics, Children's Mercy Kansas City, Kansas City, Missouri.",
"authors": "Chapron|Brian D|BD|;Dinh|Jean C|JC|;Toren|Paul C|PC|;Gaedigk|Andrea|A|0000-0001-6968-1893;Leeder|J Steven|JS|",
"chemical_list": "D014150:Antipsychotic Agents; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D011994:Recombinant Proteins; D010868:Pimozide; D019389:Cytochrome P-450 CYP2D6; D051544:Cytochrome P-450 CYP3A; C510163:CYP3A4 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1124/dmd.120.000188",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-9556",
"issue": "48(11)",
"journal": "Drug metabolism and disposition: the biological fate of chemicals",
"keywords": null,
"medline_ta": "Drug Metab Dispos",
"mesh_terms": "D000328:Adult; D000368:Aged; D014150:Antipsychotic Agents; D001711:Biotransformation; D002648:Child; D019389:Cytochrome P-450 CYP2D6; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D051544:Cytochrome P-450 CYP3A; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008862:Microsomes, Liver; D008875:Middle Aged; D010868:Pimozide; D011994:Recombinant Proteins; D005879:Tourette Syndrome; D055815:Young Adult",
"nlm_unique_id": "9421550",
"other_id": null,
"pages": "1113-1120",
"pmc": null,
"pmid": "32847865",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "2665687;21732066;6146373;4566416;9951426;10831018;23295003;31647186;18043468;11584332;9580580;7961347;9304852;11910261;8448725;1242360;11876575;28833066;18940377;20947523;29602798;12109926;28074615;28686474;16154484;21188439;9247389;23059146;824116",
"title": "The Respective Roles of CYP3A4 and CYP2D6 in the Metabolism of Pimozide to Established and Novel Metabolites.",
"title_normalized": "the respective roles of cyp3a4 and cyp2d6 in the metabolism of pimozide to established and novel metabolites"
} | [
{
"companynumb": "US-OTSUKA-2021_020724",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe number of elderly patients with advanced non-small cell lung cancer (NSCLC) is increasing. Although several studies have suggested the benefit of chemotherapy with a platinum doublet for elderly patients with advanced NSCLC, this treatment is still controversial in this age group. To evaluate the efficacy and tolerability of combination chemotherapy with biweekly paclitaxel and carboplatin for elderly patients with advanced NSCLC, we conducted a multicenter, non-randomized, open label, phase II trial.\n\n\nMETHODS\nWe recruited patients aged ≥70 years with clinical stage IIIB and IV NSCLC and ECOG performance status (PS) of 0-2. Patients received paclitaxel (90 mg/m(2)) and carboplatin (AUC = 2.5) on day 1 and 15, every 4 weeks. The primary endpoint was overall response rate (ORR), and the secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety.\n\n\nRESULTS\nSixty-five patients (median age 79 years; range 70-87 years) were enrolled. Forty-nine patients were men, and 48 were stage IV. The PS was 0, 1, and 2 in 28, 33, and 4 patients, respectively. The histological type of NSCLC was non-squamous in 69.3 % and squamous cell carcinoma in 30.7 % of patients. The median number of treatment cycles was 3 (range 1-6). The response rate was 29.4 % (95 % CI 18.7-43.0), and the disease control rate was 78.0 % (95 % CI 64.8-87.2). Median PFS and OS were 3.8 months (95 % CI 1.9-5.3) and 17.3 months (95 % CI 10.4-25.1), respectively. The most common grade 3 or 4 toxicities were neutropenia (27 %), leukopenia (15 %), infection (10 %), and anemia (8 %).\n\n\nCONCLUSIONS\nThe combination of biweekly paclitaxel and carboplatin was effective and well tolerated in elderly patients with advanced NSCLC.",
"affiliations": "Division of Pulmonary Medicine, Department of Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan, ksoejima@cpnet.med.keio.ac.jp.",
"authors": "Soejima|Kenzo|K|;Naoki|Katsuhiko|K|;Ishioka|Kota|K|;Nakamura|Morio|M|;Nakatani|Michie|M|;Kawada|Ichiro|I|;Watanabe|Hideo|H|;Nakachi|Ichiro|I|;Yasuda|Hiroyuki|H|;Satomi|Ryosuke|R|;Nakayama|Sohei|S|;Yoda|Satoshi|S|;Ikemura|Sinnosuke|S|;Terai|Hideki|H|;Sato|Takashi|T|;Ohgino|Keiko|K|;Arai|Daisuke|D|;Tani|Tetsuo|T|;Kuroda|Aoi|A|;Nishino|Makoto|M|;Betsuyaku|Tomoko|T|",
"chemical_list": "D016190:Carboplatin; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-014-2673-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "75(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009367:Neoplasm Staging; D017239:Paclitaxel; D015996:Survival Rate; D016896:Treatment Outcome",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "513-9",
"pmc": null,
"pmid": "25563719",
"pubdate": "2015-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A phase II study of biweekly paclitaxel and carboplatin in elderly patients with advanced non-small cell lung cancer.",
"title_normalized": "a phase ii study of biweekly paclitaxel and carboplatin in elderly patients with advanced non small cell lung cancer"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP02087",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Overexpression of human epidermal growth factor receptor 2 (HER2) is associated with aggressive disease and poor prognosis. Traditional HER2-targeted agents can improve clinical outcome and have played an essential role in therapy. Pyrotinib is a newly irreversible tyrosine kinase inhibitor (TKI) that is well developed for the treatment of HER2-positive advanced breast tumors.\nA 37-year-old postpartum female was presented at a local hospital and was diagnosed with HER2-positive stage IIIB (cT4N1M0) invasive micropapillary adenocarcinoma in the left breast with left axillary metastatic lymph nodes. The patient failed to respond to two cycles of the doxorubicin plus cyclophosphamide (AC) regimen but achieved clinical partial response (cPR) after 4 cycles of the combination of pyrotinib, trastuzumab, paclitaxel and cisplatin (PTPC) regimen according to radiologic assessments. Then, she underwent left-side modified radical mastectomy (MRM) and achieved pathologic complete response (pCR), as confirmed by postoperative pathology. The patient held on receiving 2 cycles of the targeted therapy plus chemotherapy with trastuzumab, paclitaxel plus cisplatin (TPC) and adjuvant radiation therapy but continued to receive targeted therapy with trastuzumab and pertuzumab during the 1-year follow-up period. There has been no clinical evidence of disease progression so far.\nBreast cancer overexpressing HER2 is a malignant tumor responsible for many cancer-related deaths. The combination of pyrotinib plus other targeted chemotherapy can dramatically improve the outcome of locally advanced disease.",
"affiliations": "Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.;Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, People's Republic of China.;Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.;Department of Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, People's Republic of China.;Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People's Republic of China.",
"authors": "He|Lina|L|0000-0001-7919-7958;Zhang|Fengchun|F|;Ma|Yue|Y|;Zuo|Li|L|;Xu|Yingchun|Y|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/OTT.S252117",
"fulltext": "\n==== Front\nOnco Targets Ther\nOnco Targets Ther\nott\nott\nOncoTargets and therapy\n1178-6930 Dove \n\n252117\n10.2147/OTT.S252117\nCase Report\nPathological Complete Response from Pyrotinib Combined with Trastuzumab, Paclitaxel and Cisplatin in a Postpartum Woman with HER2-Positive Locally Advanced Breast Cancer: A Case Report\nHe et alHe et alhttp://orcid.org/0000-0001-7919-7958He Lina 1* Zhang Fengchun 2* Ma Yue 1* Zuo Li 3 Xu Yingchun 1 1 Department of Oncology, Renji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China\n2 Department of Oncology, Suzhou Kowloon Hospital, Shanghai Jiaotong University School of Medicine, Suzhou, People’s Republic of China\n3 Department of Oncology, Fudan University Shanghai Cancer Center, Minhang Branch, Shanghai, People’s Republic of China\nCorrespondence: Li Zuo; Yingchun Xu Email zuohuang2005@163.com; xiaoxu2384@163.com* These authors contributed equally to this work\n\n\n27 8 2020 \n2020 \n13 8749 8756\n04 3 2020 06 8 2020 © 2020 He et al.2020He et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background\nOverexpression of human epidermal growth factor receptor 2 (HER2) is associated with aggressive disease and poor prognosis. Traditional HER2-targeted agents can improve clinical outcome and have played an essential role in therapy. Pyrotinib is a newly irreversible tyrosine kinase inhibitor (TKI) that is well developed for the treatment of HER2-positive advanced breast tumors.\n\nCase Presentation\nA 37-year-old postpartum female was presented at a local hospital and was diagnosed with HER2-positive stage IIIB (cT4N1M0) invasive micropapillary adenocarcinoma in the left breast with left axillary metastatic lymph nodes. The patient failed to respond to two cycles of the doxorubicin plus cyclophosphamide (AC) regimen but achieved clinical partial response (cPR) after 4 cycles of the combination of pyrotinib, trastuzumab, paclitaxel and cisplatin (PTPC) regimen according to radiologic assessments. Then, she underwent left-side modified radical mastectomy (MRM) and achieved pathologic complete response (pCR), as confirmed by postoperative pathology. The patient held on receiving 2 cycles of the targeted therapy plus chemotherapy with trastuzumab, paclitaxel plus cisplatin (TPC) and adjuvant radiation therapy but continued to receive targeted therapy with trastuzumab and pertuzumab during the 1-year follow-up period. There has been no clinical evidence of disease progression so far.\n\nConclusion\nBreast cancer overexpressing HER2 is a malignant tumor responsible for many cancer-related deaths. The combination of pyrotinib plus other targeted chemotherapy can dramatically improve the outcome of locally advanced disease.\n\nKeywords\npyrotiniblocally advanced breast canceranti-HER2 targeted therapy\n==== Body\nBackground\nBreast cancer, a heterogeneous phenotypically diverse disease, is composed of four biologic subtypes that have distinct behaviors and responses to therapy. Overexpression of human epidermal growth factor receptor 2 (HER2) has been reported in 15% to 20% of breast cancer patients and is associated with aggressive biological behavior, short time to recurrence, and poor prognosis.1 There has been a significant improvement in relapse-free survival of HER2-positive disease, supporting the efficacy of anti-HER2 agents.2 However, the reduced but persistent peak of early recurrence in estrogen receptor (ER)-negative/HER2-positive disease signals the need for new treatment strategies, including dual HER2 blockade.\n\nPyrotinib is a new irreversible, pan-ErbB receptor tyrosine kinase inhibitor that is well developed for the treatment of HER2-positive advanced breast tumors. In a Phase I clinical trial, pyrotinib was well tolerated and demonstrated promising antitumor activity in patients with HER2-positive metastatic breast cancer—the overall response rate was 50.0%, the clinical benefit rate (complete response + partial response + stable disease ≥24 weeks) was 61.1%, and the median progression-free survival was 35.4 weeks.3 Moreover, pyrotinib plus capecitabine significantly prolonged median progression-free survival (PFS) versus lapatinib plus capecitabine (18.1 vs 7.0 months) in patients with advanced or metastatic breast cancer previously treated with anthracycline or taxane chemotherapy according to the Phase II study, and the ongoing Phase III trial is to validate the superiority of pyrotinib plus capecitabine.4,5 With regard to pyrotinib-related adverse events, common side effects include diarrhea, nausea, oral ulceration, leukopenia and others.3 Grade 3 diarrhea was a dose-limiting toxicity.3 The maximum tolerated dose was established as 400 mg, and the minimum dosage of pyrotinib is 240 mg once daily.6\n\nPyrotinib is still in clinical trials, and recently, many studies have been performed with great efforts to evaluate the clinical efficacy of pyrotinib combined with other chemotherapies in neoadjuvant or adjuvant settings. Here, we present a case of a HER2-positive locally advanced breast tumor in a postpartum woman responding excellently to the combination of pyrotinib, trastuzumab, paclitaxel and cisplatin (PTPC) as neoadjuvant therapy with no response to prior doxorubicin plus cyclophosphamide (AC) chemotherapy.\n\nCase Presentation\nOur patient, a 37-year-old postpartum female, presented to the Tianjin Tumor Hospital in China. Her B-ultrasonography results showed a left breast mass with the largest measuring up to 8 * 7cm in size and with left axillary multiple lymph node metastasis (BI-RADS 5). The pathology of the left breast by core needle biopsy revealed invasive micropapillary adenocarcinoma with the following results: estrogen receptor (ER) (<1%), progesterone receptor (PR) (<1%), HER-2 (3+), and Ki-67 (25%); moreover, the fine needle axillary lymph node biopsy samples confirmed metastatic and poorly differentiated adenocarcinoma with the following findings: ER (<1%), PR (<1%), HER-2 (3+) and Ki-67 (25%). The patient had undergone chemotherapy with an AC regimen (liposomal doxorubicin 40 mg on day 1 + cyclophosphamide 800 mg on day 1, q3w) for two cycles. However, no obvious reduction in breast mass was observed, and she felt pain in the left breast. Then, she presented to Shanghai Renji Hospital. Physical examination showed 9.0cm mass in left breast with diffuse edema and erythema in skin and several fixed and matted enlarged lymph nodes in the left axilla. The chest CT showed internal nodular foci in the left breast and multiple enlarged lymph nodes in the left armpit. Mammography found a diffusely increased density of the left mammary gland with local distortion and fine sand-like calcification (BI-RADS.6) (Figure 1). Breast MRI was carried out and showed a widely abnormal signal (with the largest measuring up to 8.7cm) and skin thickening in the left breast (BI-RADS.6), left nipple depression, fat pad edema in the subcutaneous and anterior areas of the pectoralis major muscle, and enlargement of the left axillary lymph node (Figure 2, Figure 3A). Therefore, the clinical stage was designated IIIB (cT4N1M0). Moreover, vacuum-assisted breast biopsy and fine needle aspiration of left axillary lymph node were performed for the patient. The pathology indicated infiltrating carcinoma with ER (-), PR (-), HER2 (2+) and Ki67 (10%). The HER2 fluorescence in situ hybridization test was positive, and the HER2/CEP17 ratio was 4.5. Then the patient started to receive neoadjuvant chemotherapy (pyrotinib 400 mg once daily + weekly trastuzumab (first 4 mg/kg, then 2 mg/kg) + paclitaxel (120 mg (80 mg/m2) on days 1, 8, 15, and 22, q28d) + cisplatin (40 mg (25 mg/m2) on days 1, 8, and 15, q28d)) (PTPC). She experienced grade 3 diarrhea and grade 2 neutropenia, and the dosage of pyrotinib was reduced to 320 mg and then 240 mg once daily for diarrhea. After 2 cycles, breast MRI showed a significant reduction in the lesion size in the left breast (with the largest measuring up to 0.7cm) (Figure 3B) and a visibly reduced size of the lymph node in the left armpit, which was evaluated as clinical partial response (cPR) by efficacy assessment according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST1.1). After 4 cycles, the breast MRI results showed close to a clinical complete response (cCR) (Figure 3C). The most frequent tolerated adverse events were grade 2 neutropenia and grade 2 diarrhea, which were observed in the patient but were not mitigated with further dose reduction. Modified radical mastectomy of the left breast was performed. The specimen suggested hyperplasia of the breast interstitial fibrous tissue with a few infiltrating inflammatory cells and no tumor tissue residue. The tissues from the nipple, dissected surface, lymph nodes, fibrous adipose tissue, and the left axillary lymph node were negative for disease. The postoperative pathology revealed pathological complete remission (pCR). The patient held on receiving 2 cycles of the targeted therapy plus chemotherapy with TPC, but adjuvant radiation therapy and HER2-targeted therapy with trastuzumab were administered in the neoadjuvant setting, and pertuzumab was administered over the 1-year follow-up duration. There has been no clinical evidence of disease progression so far. The disease-free survival is currently 8 months.Figure 1 Mammography presentations (2019.02.14).\n\nNotes: Mammography shows that bilateral breast was asymmetrical, and the density of the left breast was abnormal with focal architectural distortion and fine sand-like calcification (BI-RADS.6). (A) right craniocaudal (RCC), (B) left craniocaudal (LCC), (C) right mediolateral oblique (RMLO), and (D) left mediolateral oblique (LMLO).Figure 2 Breast MRI (2019.02.13).\n\nNotes: The time-intensity curve (TIC) shows a platform-type or outflow-type curve, and the Apparent Diffusion Coefficient (ADC) value was approximately 0.95*10 −3 mm2/s, suggesting a malignant tumor (BI-RADS.6).Figure 3 Breast MRI imaging.\n\nNotes: (A) MRI presents with a left breast mass (8.7cm in diameter) which was apparently intensified before treatment. (B) The imaging was scanned after 2-cycle treatment with PTPC (the combination of pyrotinib, trastuzumab, paclitaxel and cisplatin). It shows us a significant decrease in lesion size (0.7cm in diameter) and visibly reduced lymph node size in the left armpit, which was evaluated as a clinical partial response (cPR). (C) After 4-cycle treatment with PTPC, the imaging results were similar to those seen in the right breast on the imaging, suggesting a response close to a clinical complete response (cCR).\n\nDiscussion\nBreast cancer is the most common malignant tumor in the Chinese female population, accounts for approximately 15% of female cancers, and has high morbidity and mortality. The gene that encodes HER2 (ERBB2, formerly known as neu) is amplified and overexpressed in approximately 20% of newly diagnosed breast cancers and is associated with aggressive disease, lymph node or vascular metastasis and poor survival. HER2 belongs to the human epidermal receptor family, which contains three other receptors, EGFR (also known as HER1), HER3 and HER4, that are known to bind to at least 11 peptide ligands; this binding results in homodimerization and heterodimerization among these receptors and subsequent downstream tyrosine kinase signaling cascades. These signaling cascades stimulate subsequent cell proliferation, migration, invasion and survival, all of which are hallmarks of cancer. HER2 has no known ligand but is a preferred dimerization partner of the other three receptors.7 Over the past two decades, multiple HER2-targeted therapies, including trastuzumab, pertuzumab, lapatinib, neratinib and the antibody–drug conjugate trastuzumab emtansine (T-DM1), have dramatically changed the clinical outcomes of patients with HER2-positive breast cancer in neoadjuvant, adjuvant and metastatic settings. Trastuzumab, pertuzumab, and T-DM1 bind to the extracellular domain of HER2. Trastuzumab and pertuzumab either alter normal tyrosine kinase signaling or induce antibody-dependent complement-mediated cytotoxicity (ADCC). Trastuzumab emtansine is internalized, and the chemotherapeutic agent is enzymatically cleaved, which leads to cytotoxic cell death.8 The tyrosine kinase inhibitors lapatinib and neratinib cross the cell membrane and inhibit intracellular tyrosine kinase domain activities.9 Despite the improvement in survival thanks to the first HER2-targeted agent trastuzumab, unclear mechanisms of resistance occur in approximately 70% of patients within one year.1 The continuous development of anti-HER2 therapies such as lapatinib, pertuzumab, and T-DM1 has improved the outcomes of patients with HER2-positive breast cancer, but efficacy is still limited in different settings. Lapatinib is considered one of the key agents used in combination with capecitabine or trastuzumab in managing metastatic HER2-positive breast cancer that fails treatment with trastuzumab (as reported in NCT00078572).10 Lapatinib has been tested as a second-line therapy in patients with advanced HER2-positive breast cancer but failed in the early adjuvant setting (reported in the ALTTO trial) and the advanced first-line therapy setting (reported in the COMPLETE trial) in clinical trials. Neratinib is only indicated and approved for use in the extended adjuvant setting (as reported in the ExteNET trial) and has not been shown to be effective in the neoadjuvant and first-line therapy settings according to the I-SPY2 and NefERT-T trials, respectively.11 Nevertheless, pertuzumab has demonstrated survival benefits for patients with metastatic HER2-positive breast cancer in first-line therapy settings according to CLEOPATRA study and has also been studied in the neoadjuvant setting and adjuvant setting (APHINITY trial); the addition of pertuzumab to trastuzumab and docetaxel improved pCR rates from 29% to 45.8% for early-stage HER2-positive breast cancer (as reported in the NeoSphere trial). It reminded us of the relatively higher pCR rates (51.3%) of additional lapatinib to trastuzumab in NeoALLTO study; therefore, additional agents need to be developed further to improve the current results and overcome resistance, and the optimal combination of targeted drugs in different treatment settings is still uncertain.\n\nPyrotinib is an oral, irreversible dual pan-ErbB TKI developed as an antitumor agent for patients with HER2-positive advanced solid tumors, including breast cancer, by Jiangsu Hengrui Pharmaceutical.1 The 3-cyanoquinoline derivative pyrotinib has activity against epidermal growth factor receptor (EGFR)/HER1, HER2, and HER4, inhibits HER2-driven tumor growth and HER2-mediated downstream signaling, and blocks tumor cells in the G1 phase of the cell cycle.12 Pyrotinib induces potent inhibition of tyrosine kinase activity.12 Compared with the reversible TKI lapatinib, pyrotinib forms a conjugated double-bond and is permanently bound to the ATP-binding site, making its actions irreversible and more effective.12 In contrast to the irreversible TKI neratinib, pyrotinib has higher bioavailability and stronger efficacy.12 In the pharmacokinetic experiments of rats, the absorption of pyrotinib is three times that of neratinib; and it has a higher AUC value and relatively low side effects.12 Though in animal studies, the inhibition rates of pyrotinib and neratinib in breast cancer and lung cancer were similar. Until now, there is no report or trial to verify efficacy in the clinic of pyrotinib in comparison with neratinib. Moreover, pyrotinib is highly effective in trastuzumab-resistant patients, which has been confirmed by the superior median PFS for pyrotinib in combination with capecitabine versus placebo (11.1 months vs 4.1 months) in women with HER2-positive metastatic breast cancer who previously received taxane and trastuzumab therapy (as reported at ASCO; the PHENIX trial).13 In August 2018, pyrotinib received its first global conditional approval in China for use in combination with capecitabine for the treatment of HER2-positive, advanced or metastatic breast cancer in patients previously treated with anthracycline or taxane chemotherapy.4 Pyrotinib plus capecitabine yielded a statistically significant better overall response rate and progression-free survival (PFS) than lapatinib plus capecitabine in women with HER2-positive metastatic breast cancer previously treated with taxanes, anthracyclines, and/or trastuzumab in a randomized, open-label, active comparator-controlled, multicenter phase II trial (NCT02422199).14 The overall response rate was 78.5% in the pyrotinib group and 57.1% in the lapatinib group, representing a statistically significant objective response rate (ORR) increase of 21.3% with pyrotinib versus lapatinib. The median progression-free survival (PFS) was 18.1 months with pyrotinib and 7.0 months with lapatinib. Furthermore, the median PFS was longer with pyrotinib than lapatinib regardless of prior trastuzumab treatment.14 Based on its superior tolerability and efficacy, pyrotinib was newly added as a Level II recommendation for anti-HER2 second-line rescue treatment in place of trastuzumab for patients with HER2-positive advanced or metastatic breast cancer in the 2019 Chinese Society of Clinical Oncology breast cancer guidelines.\n\nThe NeoALTTO trial is a neoadjuvant, multicenter, randomized phase III trial in which patients with HER2-positive early breast cancer were randomly assigned to receive lapatinib 1500 mg/day, trastuzumab, or the combination of lapatinib 1000 mg/day and trastuzumab for 6 weeks followed by the addition of paclitaxel for 12 weeks before surgery. Lapatinib was shown to significantly improve the pCR rate, and the combination group had nearly double the pCR rate compared with the other two groups.15 As such, we wondered if pyrotinib is better than lapatinib in the metastatic setting,16 is it effective as a neoadjuvant treatment in combination with trastuzumab? In previous data in neoadjuvant settings, a paclitaxel plus cisplatin (PC) regimen combined with trastuzumab was proven to have a high pCR rate.17 Therefore, the antitumor activities of the combination of dual HER2-targeted agents (trastuzumab plus pyrotinib) and the PC regimen in the neoadjuvant setting may be promising. In our case, the patient failed to respond to the AC regimen but achieved cCR after receiving only 4 cycles of pyrotinib with trastuzumab, paclitaxel and cisplatin according to radiologic assessments. She achieved pCR as confirmed by postoperative pathology. Further exploration of efficacy and toxicities with PTPC in neoadjuvant setting in breast cancer is ongoing (NCT03947242) (Table 1). Recently, a one-arm exploratory clinical study was designed to test pyrotinib combined with albumin paclitaxel and trastuzumab for Her2-positive early or locally advanced breast cancer with the aim of assessing efficacy and safety and exploring the efficacy of tumor-associated molecular markers such as residual cancer burden (RCB) scores and tumor-infiltrating lymphocyte (TIL) proportions for predicting pyrotinib treatment efficacy (NCT04152057). Intriguingly, the biomarker analysis of previous trials suggested that PIK3CA and TP53 mutation status in ctDNA in tumor tissues correlated with response and even PFS.3,18-20 Interestingly, our patient had the PIK3CA H1047R mutation, but the value of the detection of biomarkers in the adjuvant setting still needs to be proven.Table 1 The Ongoing Clinical Trials of Pyrotinib in HER2 Breast Cancer Treatment\n\nStudy Phase\tRegistration Number\tTrial Arm\tCondition\tSubjects\tStatus\tLocation\t\nII\tNCT03910712\tPyrotinib +Trastuzumab +Aromatase inhibitor vs Trastuzumab + Aromatase inhibitor\tHER2-positive Breast Cancer; Hormone Receptor Positive Metastatic Breast Cancer\t250\tNot yet recruiting\tPeking Union Medical College Hospital, China\t\nII\tNCT03847818\tPyrotinib + Trastuzumab + Docetaxel + Carboplatin vs Trastuzumab + Docetaxel + Carboplatin\tHER2-positive Breast Cancer\t268\tNot yet recruiting\tShandong University, China\t\nII\tNCT04033172\tPyrotinib + Fulvestrant\tHER2-positive Breast Cancer\t40\tRecruiting\tChinese Academy of Medical Sciences, China\t\nII\tNCT03933982\tPyrotinib + Vinorelbine\tBreast Cancer; Brain Metastases\t30\tRecruiting\tChinese Academy of Medical Sciences, China\t\nII\tNCT04126525\tPyrotinib\tBreast Cancer Female\t52\tRecruiting\tRenji Hospital, China\t\nII\tNCT04001621\tPyrotinib + capecitabine\tMetastatic Breast Cancer\t100\tRecruiting\tFudan University, China\t\nIII\tNCT03980054\tPyrotinib vs Placebo\tBreast Cancer\t1192\tNot yet recruiting\tJiangsu HengRui Medicine Co., Ltd. China\t\nIII\tNCT03863223\tPyrotinib + Trastuzumab + Docetaxel vs Placebo+ Trastuzumab+ Docetaxel\tMetastatic Breast Cancer\t590\tRecruiting\tJiangsu HengRui Medicine Co., Ltd. China\t\nIII\tChiCTR1900022293\tEpirubicin + cyclophosphamide + pyrotinib + trastuzumab vs Epirubicin + cyclophosphamide + trastuzumab\tStage I to III HER2-positive breast cancer\t210\tNot yet recruiting\tFirst Affiliated Hospital of Army Medical University, China\t\nIV\tChiCTR1900020670\tPyrotinib + standard treatment\tHER2-positive brain metastatic breast cancer\t48\tNot yet recruiting\tAffiliated Cancer Hospital of Harbin Medical University, China\t\nIV\tChiCTR1900021819\tPyrotinib\tHER2-positive locally advanced breast cancer\t1000\tNot yet recruiting\tJiangsu Cancer Hospital, China\t\n\n\n\nIn one study, pyrotinib had a manageable toxicity profile in patients with HER2-positive metastatic breast cancer.14 The common treatment-emergent adverse events (TEAEs) of any grade (occurring in ≥20% of patients and with a numerically higher incidence in the pyrotinib plus capecitabine group than the lapatinib plus capecitabine group) were diarrhea, hand-foot syndrome, vomiting, leukopenia, neutropenia, and others. Diarrhea is the most common adverse effect observed with tyrosine kinase inhibitors targeting EGFR/HER2.3,21 In a randomized phase II trial, grade 3 diarrhea occurred mostly during the first treatment cycle, with 50% of instances occurring on days 2 to 15 after starting treatment. Diarrhea was generally reversible with symptomatic treatment (eg, loperamide or montmorillonite) or by suspending or decreasing the dose of pyrotinib. It is recommended that pyrotinib should be permanently discontinued when grade 4 diarrhea occurs.14 The grade 3 TEAE that inevitably occurred in our patient was diarrhea. Luckily, this symptom was quickly relieved by dose reduction.\n\nThere are many clinical trials underway to further confirm the efficacy of pyrotinib combined with trastuzumab and/or other chemotherapy agents in different settings, such as in the neoadjuvant, adjuvant, and rescue therapy settings and even in the management of brain-metastatic HER2-positive breast cancer (Table 1).\n\nConclusion\nPyrotinib is a newly developed agent, what we could learn from this case is that our case further strengthens the evidence of the efficacy of pyrotinib combined with trastuzumab and other chemotherapy agents in patients with HER2-positive advanced breast cancer in the neoadjuvant setting, but the potential side effects of the combination treatment should be highly concerned, and fully discussed with the patients in clinical practice. Pyrotinib combined with trastuzumab may present a new potential treatment option for the dual anti HER2 targeted therapy in the future; however, its efficacy and safety need further investigation in randomized Phase 3 study.\n\nAcknowledgments\nThe authors would like to thank the patient for giving consent and for providing the detailed information of this case.\n\nAbbreviations\nADC, apparent diffusion coefficient; ADCC, antibody-dependent complement-mediated cytotoxicity; cCR, clinical complete response; cPR, clinical partial response; EGFR, epidermal growth factor receptor; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; ORR, objective response rate; OS, overall survival; pCR, pathologic complete response; PFS, progression-free survival; PR, progesterone receptor; RCB, residual cancer burden; RR, recurrence rate; T-DM1, antibody–drug conjugate trastuzumab emtansine; TEAEs, treatment-emergent adverse events; TILS, tumor infiltrating lymphocytes; TKI, tyrosine kinase inhibitor.\n\nEthics Approval and Consent to Participate\nThis study has been approved by Ethics Committee of Renji Hospital of Shanghai Jiaotong University School of Medicine and the patient has signed an informed consent.\n\nConsent for Publication\nThe patient was informed that the information published may potentially compromise anonymity. Publication was consented by the patient. Written informed consent was obtained from the case patient for publication of this report and any accompanying images.\n\nDisclosure\nAll authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Slamon \nDJ , Clark \nGM , Wong \nSG , et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene\n. Science . 1987 ;235 :177 –182\n. doi:10.1126/science.3798106 3798106 \n2. Cossetti \nRJ , Tyldesley \nSK , Speers \nCH , Zheng \nY , Gelmon \nKA . Comparison of breast cancer recurrence and outcome patterns between patients treated from 1986 to 1992 and from 2004 to 2008\n. J Clin Oncol . 2015 ;33 (1 ):65 –73\n.25422485 \n3. Ma \nF , Li \nQ , Chen \nS , et al. Phase I study and biomarker analysis of pyrotinib, a novel irreversible pan-erbb receptor tyrosine kinase inhibitor, in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer\n. J Clin Oncol . 2017 ;35 (27 ):3105 –3112\n. doi:10.1200/JCO.2016.69.6179 28498781 \n4. De Leon \nJ \nChina approves Hengrui breast cancer drug on phase II data\n; 2018 \nAvailable from : https://www.biocentury.com/bc-extra/company-news/2018-08-22/china-approveshengrui-breast-cancer-drug-phase-ii-data. Accessed 9 25 , 2018.\n5. Blair \nHA . Pyrotinib: first global approval\n. Drugs . 2018 .\n6. State Food and Drug Administration . Pyrotinib maleate tablets: prescribing information\n; 2018 \nAvailable from : http://202.96.26.102. Accessed 9 25 , 2018.\n7. Hayes \nDF . HER2 and breast cancer – a phenomenal success story\n. N Engl J Med . 2019 ;381 (13 ):1284 –1286\n. doi:10.1056/NEJMcibr1909386 31502769 \n8. Barok \nM , Tanner \nM , Koninki \nK , et al. Trastuzumab-DM1 causes tumour growth inhibition by mitotic catastrophe in trastuzumab-resistant breast cancer cells in vivo\n. Breast Cancer Res . 2011 ;13 :R46 . doi:10.1186/bcr2868 21510863 \n9. Traxler \nP . Tyrosine kinases as targets in cancer therapy-successes and failures\n. Expert Opin Ther Targets . 2003 ;7 (2 ):215 –234\n. doi:10.1517/14728222.7.2.215 12667099 \n10. Geyer \nCE , Forster \nJ , Lindquist \nD , et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer\n. N Engl J Med . 2006 ;355 (26 ):2733 –2743\n. doi:10.1056/NEJMoa064320 17192538 \n11. Martin \nM , Holmes \nFA , Ejlertsen \nB , et al.Neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): 5-year analysis of a randomised, double-blind, placebo-controlled, phase 3 trial\n. Lancet Oncol . 2017 :S1470204517307179 \n12. Li \nX , Yang \nC , Wan \nH , et al. Discovery and development of pyrotinib: a novel irreversible EGFR/HER2 dual tyrosine kinase inhibitor with favorable safety profiles for the treatment of breast cancer\n. Eur J Pharm Sci . 2017 ;110 :51 –61\n.28115222 \n13. Jiang \nZ , Yan \nM , Hu \nX , et al. Pyrotinib combined with capecitabine in women with HER2+ metastatic breast cancer previously treated with trastuzumab and taxanes: a randomized phase III study\n. J Clin Oncol . 2019 ;37 (12 ):1001 . doi:10.1200/JCO.18.00938 30817249 \n14. Ma \nF , Ouyang \nQ , Li \nW , et al. Pyrotinib or lapatinib combined with capecitabine in HER2-positive metastatic breast cancer with prior taxanes, anthracyclines, and/or trastuzumab: a randomized, phase II study\n. J Clin Oncol . 2019 ;37 (29 ):2610 –2619\n. doi:10.1200/JCO.19.00108 31430226 \n15. de Azambuja \nE , Holmes \nAP , Piccart-Gebhart \nM , et al. Lapatinib with trastuzumab for HER2-positive early breast cancer (NeoALTTO): survival outcomes of a randomised, open-label, multicentre, phase 3 trial and their association with pathological complete response\n. Lancet Oncol . 2014 ;15 (10 ):1137 –1146\n. doi:10.1016/S1470-2045(14)70320-1 25130998 \n16. Gourd \nE . Pyrotinib versus lapatinib in HER2-positive breast cancer\n. Lancet Oncol . 2019 ;20 (10 ):e562 . doi:10.1016/S1470-2045(19)30568-6 31477452 \n17. Zhou \nL , Xu \nS , Yin \nW , et al. Paclitaxel and cisplatin as neoadjuvant chemotherapy with locally advanced breast cancer: a prospective, single arm, phase II study\n. Oncotarget . 2017 ;8 (45 ):79305 –79314\n. doi:10.18632/oncotarget.17954 29108309 \n18. Gourd \nE . Pyrotinib shows activity in metastatic breast cancer\n. Lancet Oncol . 2017 ;18 (11 ):e643 . doi:10.1016/S1470-2045(17)30755-6 28943217 \n19. Li \nQ , Guan \nX , Chen \nS , et al. Safety, efficacy, and biomarker analysis of pyrotinib in combination with capecitabine in HER2-positive metastatic breast cancer patients: a phase I clinical trial\n. Clin Cancer Res . 2019 ;25 (17 ):5212 –5220\n. doi:10.1158/1078-0432.CCR-18-4173 31138588 \n20. Ma \nF , Guan \nY , Yi \nZ , et al. Assessing tumor heterogeneity using ctDNA to predict and monitor therapeutic response in metastatic breast cancer\n. Int J Cancer . 2019 . doi:10.1002/ijc.32536 \n21. Chan \nA . Neratinib in HER-2-positive breast cancer: results to date and clinical usefulness\n. Ther Adv Med Oncol . 2016 ;8 (5 ):339 –350\n. doi:10.1177/1758834016656494 27583026\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6930",
"issue": "13()",
"journal": "OncoTargets and therapy",
"keywords": "anti-HER2 targeted therapy; locally advanced breast cancer; pyrotinib",
"medline_ta": "Onco Targets Ther",
"mesh_terms": null,
"nlm_unique_id": "101514322",
"other_id": null,
"pages": "8749-8756",
"pmc": null,
"pmid": "32943881",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "12667099;29146401;25130998;31138588;25422485;31502769;17192538;30341682;28498781;27583026;29108309;28115222;3798106;28943217;31430226;31241775;31477452;21510863",
"title": "Pathological Complete Response from Pyrotinib Combined with Trastuzumab, Paclitaxel and Cisplatin in a Postpartum Woman with HER2-Positive Locally Advanced Breast Cancer: A Case Report.",
"title_normalized": "pathological complete response from pyrotinib combined with trastuzumab paclitaxel and cisplatin in a postpartum woman with her2 positive locally advanced breast cancer a case report"
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"fulfillexpeditecriteria": "1",
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"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
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"abstract": "Saccharomyces cerevisiae, known as baker's yeast, is also used as a probiotic agent to treat gastroenteritis by modulating the endogenous flora and immune system. However, since there have been increasing reports of fungemia due to S.cerevisiae and its subspecies S.boulardii, it is recommended that probiotics should be cautiously used in immunosuppressed patients, people with underlying diseases and low-birth weight babies. To emphasize this phenomenon, in this report, a case of S.cerevisiae fungemia developed in a patient given probiotic treatment for antibiotic-associated diarrhea, was presented. An 88-year-old female patient was admitted to our hospital with left hip pain, hypotension, and confusion. Her medical history included hypertension, chronic renal failure, left knee replacement surgery, and recurrent urinary tract infections due to neurogenic bladder. She was transferred to the intensive care unit with the diagnosis of urosepsis. After obtaining blood and urine samples for culture, empirical meropenem (2 x 500 mg) and linezolid (1 x 600 mg) treatment were administered. A central venous catheter (CVC) was inserted and after one day of inotropic support, her hemodynamic parameters were stabilized. The urine culture obtained on admission yielded extended-spectrum beta-lactamase-producing Klebsiella pneumoniae and Escherichia coli. Urine culture was repeated after three days and no bacteria were isolated. On the 4th day of admission she developed diarrhea. Toxin A/B tests for Clostridium difficile were negative. To relieve diarrhea, S.boulardii (Reflor 250 mg capsules, Sanofi Aventis, Turkey) was administered twice a day, without opening capsules. Two days later, her C-reactive protein (CRP) level increased from 23.2 mg/L to 100 mg/L without fever. Her blood culture taken from the CVC yielded S.cerevisiae. Linezolid and meropenem therapies were stopped on the 13th and 14th days, respectively, while prophylactic fluconazole therapy was replaced with caspofungin 1 x 50 mg on the fifth day. After seven days of therapy CRP and serum creatinine levels decreased to 9.1 mg/L and 1.2 mg/dl, respectively; and she was discharged from the hospital with improvement. The probiotic capsules were used unopen, thus, it was proposed that S.cerevisiae fungemia originated from translocation from the intestinal mucosa. Since it was not possible to investigate the molecular genetics of the strain isolated from the blood culture and the strain present in the probiotic, a definite conclusion about the origin of the strain could not be reached. It was thought that old age and underlying disease of the patient were the related predisposing factors for S.cerevisiae fungemia. This case emphasized that clinicians should be cautious in case of probiotic application even though in encapsulated form, even in immunocompetent patients with a history of long-term hospital stay and use of broad-spectrum antimicrobials since there may be a risk of S.cerevisiae fungemia development.",
"affiliations": "Yeditepe University Faculty of Medicine, Department of Nephrology, İstanbul, Turkey. zeren@yeditepe.edu.tr.",
"authors": "Eren|Zehra|Z|;Gurol|Yeşim|Y|;Sonmezoglu|Meral|M|;Eren|Hatice Seyma|HS|;Celik|Gülden|G|;Kantarci|Gülçin|G|",
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"journal": "Mikrobiyoloji bulteni",
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"mesh_terms": "D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D015984:Causality; D003967:Diarrhea; D005260:Female; D016469:Fungemia; D006801:Humans; D019936:Probiotics; D012441:Saccharomyces cerevisiae",
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"title": "Saccharomyces cerevisiae fungemia in an elderly patient following probiotic treatment.",
"title_normalized": "saccharomyces cerevisiae fungemia in an elderly patient following probiotic treatment"
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"abstract": "BACKGROUND\nAdolescents with psychoses usually have full recovery from their first psychotic episode, but the first relapse often arises within 2 years of the first episode. Cannabis-related psychoses are difficult to distinguish from schizophrenic psychoses. Here, we describe a particularly severe clinical case, with a first psychotic episode occurring after heavy cannabis smoking, an atypically long symptom-free duration, and a subsequent non-substance-related episode.\n\n\nMETHODS\nA 17-year-old male adolescent of Middle-East origin presented with delusions and hallucinations after extensive cannabis smoking. His first psychotic episode, with paranoid delusions and hallucinations, progressed into severe catatonic symptoms. His symptoms were treated with electroconvulsive therapy and risperidone and he was transferred to a residential substance abuse treatment center. He remained drug-free and non-psychotic for 3.5 years. Given the temporal association with extensive cannabis use, and his full remission of symptoms lasting several years, a cannabis-induced psychosis-though atypically extended-could be suspected. However, after 3.5 years without psychiatric care, and in a drug-free state, our patient again presented with positive psychotic symptoms, possibly induced by a period of severe psychosocial stress.\n\n\nCONCLUSIONS\nWe here discuss whether a primary schizophrenic episode possibly induced by cannabis can increase the risk of subsequent non-drug-related schizophrenic episodes.",
"affiliations": "Department of Clinical Sciences Lund, Division of Psychiatry, Lund University, Malmö Addiction Centre, Södra Förstadsgatan 35, Malmö, S-205 02, Sweden. anders_c.hakansson@med.lu.se.;Department of Clinical Sciences Lund, Division of Child & Adolescent Psychiatry, Lund University, Malmö, Sweden. bjorn_axel.johansson@med.lu.se.",
"authors": "Håkansson|Anders|A|;Johansson|Björn Axel|BA|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 67810.1186/s13256-015-0678-5Case ReportAtypical course in severe catatonic schizophrenia in a cannabis-dependent male adolescent: a case report Håkansson Anders +46 46 175596anders_c.hakansson@med.lu.se Johansson Björn Axel bjorn_axel.johansson@med.lu.se Department of Clinical Sciences Lund, Division of Psychiatry, Lund University, Malmö Addiction Centre, Södra Förstadsgatan 35, Malmö, S-205 02 Sweden Department of Clinical Sciences Lund, Division of Child & Adolescent Psychiatry, Lund University, Malmö, Sweden Office for Healthcare ‘Sund’, Child & Adolescent Psychiatry, Regional Inpatient Care, Emergency Unit, Malmö, Sweden 21 9 2015 21 9 2015 2015 9 20023 12 2014 18 8 2015 © Håkansson and Johansson. 2015\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.Introduction\nAdolescents with psychoses usually have full recovery from their first psychotic episode, but the first relapse often arises within 2 years of the first episode. Cannabis-related psychoses are difficult to distinguish from schizophrenic psychoses. Here, we describe a particularly severe clinical case, with a first psychotic episode occurring after heavy cannabis smoking, an atypically long symptom-free duration, and a subsequent non-substance-related episode.\n\nCase presentation\nA 17-year-old male adolescent of Middle-East origin presented with delusions and hallucinations after extensive cannabis smoking. His first psychotic episode, with paranoid delusions and hallucinations, progressed into severe catatonic symptoms. His symptoms were treated with electroconvulsive therapy and risperidone and he was transferred to a residential substance abuse treatment center. He remained drug-free and non-psychotic for 3.5 years. Given the temporal association with extensive cannabis use, and his full remission of symptoms lasting several years, a cannabis-induced psychosis—though atypically extended—could be suspected. However, after 3.5 years without psychiatric care, and in a drug-free state, our patient again presented with positive psychotic symptoms, possibly induced by a period of severe psychosocial stress.\n\nConclusion\nWe here discuss whether a primary schizophrenic episode possibly induced by cannabis can increase the risk of subsequent non-drug-related schizophrenic episodes.\n\nissue-copyright-statement© The Author(s) 2015\n==== Body\nIntroduction\nAdolescent schizophrenia, in comparison to the adult-onset forms, is associated with an increased family history of schizophrenia; male predominance; more premorbid anomalies in speech, psychomotor, and social development; intelligence below average; insidious onset; fewer systematic delusions and hallucinations [1–3]; and more negative symptoms such as flattened affects and bizarre behavior [1]. It can present with enuresis and incontinence during psychosis [4]. The distinction between adolescent schizophrenia and other diagnoses, such as affective psychosis, may be difficult [1]. Adolescents with schizophrenia usually make a full recovery after the first psychotic episode, but after 6 months of psychosis, the prognosis for full recovery is poor [1]. The first relapse often arises within 2 years of the end of the first episode [5–7]. Several potential predictors of relapse have been discussed, including rearing problems in the family, ethnicity, migrant status, urban upbringing [8], treatment discontinuation [7], social adjustment, and poor adaptation to school [6].\n\nAn acute and usually transient psychosis, including a confusional condition with delusions or hallucinations, has been associated with prolonged cannabis intoxication [9, 10]. Cannabis-related psychoses may be difficult to distinguish from schizophrenic psychoses [11], but may be partly distinguishable [12, 13] by a shorter duration than schizophrenic episodes (typically from hours to a few weeks) and, typically, an onset after intense cannabis smoking. Patients generally remain non-psychotic in the absence of drug relapse [13, 14].\n\nHere, we describe a severe clinical case of catatonic schizophrenia in a male adolescent with a history of substantial cannabis smoking, and with an atypically long period of remission between the first and second psychotic episodes. Our aim in presenting this case is to demonstrate the diagnostic challenge in cannabis-induced psychosis vis-à-vis schizophrenia, and to demonstrate the atypical course of a patient with a psychotic disorder but with a particularly long symptom-free period between his first and second psychotic episodes. We also highlight the discussion about whether cannabis might potentially increase the risk of subsequent non-cannabis-related psychotic episodes.\n\nCase presentation\nSix years ago, a 17-year old adolescent male of Middle-East origin was brought to our emergency room at the Department of Child & Adolescent Psychiatry, Malmö, Sweden, by his mother and stepfather. Over the previous weeks, he had reported being observed by authorities and criminal gangs. He talked to himself, felt that TV broadcasts referred to his mother, and had aggressive outbursts.\n\nOur patient lived with his mother, stepfather, and a 15-year-old brother. He had no family history of psychiatric disease. His psychomotor development had been normal. After his parents’ divorce, our patient moved from a Middle-Eastern country to Sweden with his mother and brother. He started to use illicit drugs before age 13. Contacts with social authorities and a regional addiction center were established.\n\nIn our emergency room, our patient’s mother reported that he had been smoking cannabis daily for 4 years, up to 3g per day. For the past 2 years, he had also misused tramadol, taking 200–1,000mg daily. He had tried lysergic acid diethylamide, cocaine, hallucinogenic mushrooms, ecstasy, inhalants, and different analgesics. For the 3 weeks preceding the emergency room visit, he had abstained from cannabis and tramadol after being enrolled in a youth service program related to a conviction for robbery and cannabis possession. Five days prior to admission, he still screened positive for tetrahydrocannabinol (THC). Upon examination, our patient was mute, reacted inappropriately, and presented a depressed mood. A urine toxicology test was negative for THC and other substances. After evaluation, he returned home with a short-term prescription of one antipsychotic medication in a very low dose (levomepromazine, 10mg at night, for 2 consecutive days) and alimemazine (20mg as needed, for 2 days), and with a short-term outpatient appointment.\n\nSix days later, still with pronounced ideas of reference, he was voluntarily admitted to the Addiction Centre of our hospital. A urine toxicology test was still negative. After 4 days of inpatient care with persistent delusions, he was transferred to the Department of Child & Adolescent Psychiatry. He reported feelings of being observed by staff and by perceived cameras in street lights, and he laughed without obvious reason. Results from a blood screen, computed tomography of his brain, and an electroencephalogram (EEG) were normal. Our patient’s delusions and hallucinations gradually diminished. After 10 days of inpatient care without specific psychopharmacological treatment, he communicated almost adequately and was discharged to a residential addiction treatment center.\n\nOne week after his arrival at the treatment institution, our patient’s behavior was again altered. He was assessed at the local Department of Child & Adolescent Psychiatry, where he isolated himself, and presented bizarre body postures and inappropriate laughs. A urine toxicology test was negative for THC and other drugs. His arm appeared to be paralyzed and he collected saliva in his mouth. After consultation with pediatric expertise, he was transferred back to the Department of Child & Adolescent Psychiatry in his hometown, after receiving an intramuscular injection of 10mg of olanzapine.\n\nUpon arrival, he was mute and sat completely still, eyes closed, with saliva running down his chin. He also presented with urine and fecal incontinence, and with asymmetric convulsions in his arms and legs. His blood pressure (130/60mmHg) and heart rate (80 beats per minute) were normal. Results of an EEG and magnetic resonance imaging (MRI) of his brain were normal. A pediatric neurologist did not find signs of physical illness. Possible differential diagnoses included substance-induced psychosis, depressive stupor, catatonic schizophrenia and neuroleptic malignant syndrome (NMS). A nasogastric tube was introduced for nutrition. He received 20mg of diazepam daily. Electroconvulsive therapy (ECT) was initiated along with risperidone, initially 1mg per day. During the next 5 weeks, he received ECT 12 times with bilateral stimulation. Risperidone was gradually increased to 3mg per day. After the seventh ECT treatment, he opened his eyes and started to communicate with his hands. After the eighth ECT, the nasogastric tube was withdrawn and the diazepam dose was reduced by half. Occasionally he talked about the mafia, laughed inappropriately, and expressed doubts about his medication. After the ninth ECT, the risperidone dose was increased to 4mg per day, and our patient gradually improved. Colleagues from the outpatient Psychosis Team confirmed the preliminary diagnosis of catatonic schizophrenia. Our patient fulfilled diagnostic criteria of catatonic schizophrenia according to the International Classification of Diseases 10th Revision (ICD-10 [15]), including the general schizophrenia criterion (criterion A), at least four out of seven cluster B criteria (criteria number 1, 3, 4, and 5), and the C criterion excluding another factor likely to cause catatonic behavior. Thus, he was diagnosed with catatonic schizophrenia (F20.2) and cannabis dependence (F12.2) upon discharge from inpatient treatment, with a prompt appointment with the Psychosis Team.\n\nDuring the first few weeks after discharge, our patient relapsed into tramadol and cannabis abuse. Paranoid delusions and hallucinations re-appeared, and 4 months after discharge he was re-hospitalized. Symptoms improved and he was successfully discharged to another residential addiction treatment institution.\n\nFive years ago, having been abstinent from illicit drugs for almost 4 months, our patient started work. The follow-up contact with the Psychosis Team was limited to occasional telephone appointments and finally ceased. Our patient met and moved in with a girlfriend. He started formal training to become a nursing assistant, and maintained good relationships with his girlfriend and friends.\n\nTwo years ago, our patient started to feel stressed; his girlfriend’s parents expressed doubts about his employment, and he worked and studied at the same time. He started to be absent from classes and suffered from insomnia and weight loss. When his girlfriend traveled, he became suspicious, developed delusions about being poisoned, and changed to vegetarian food. When his girlfriend returned home, he was irritable and expressed ideas of references related to TV broadcasts.\n\nOur patient started to spend time with his mother, who reported that he occasionally presented bizarre postures and screamed without reason. On one occasion, he also behaved aggressively towards his mother, and held a knife against his own neck. He was transported by the police to the psychiatric emergency room, where he presented with bizarre facial expressions, inappropriate laughs, paranoid and bizarre delusions, and aggressive and disrupted behavior. Results from a urine toxicology test were negative. He was admitted for compulsory psychiatric treatment, including temporary physical restraint and acute intramuscular treatment with zuclopenthixol. Subsequently, his medication was changed to risperidone in doses increasing to 6mg per day per os. Our patient’s mother was opposed to the medication. After two weeks of inpatient treatment he was discharged in a somewhat improved condition.\n\nOwing to anxiety and sleeping problems, our patient returned to the psychiatric emergency unit on several occasions after discharge. He was prescribed levomepromazine without significant effect. One week after discharge, he was brought to hospital after an overdose with a prescribed medication, reportedly levomepromazine. He denied any suicidal intent and his urine toxicology screen was negative. Our patient was again hospitalized for compulsory psychiatric treatment. He was paranoid and dysphoric. Again, his mother was opposed to pharmacological treatment. After 5 days he was discharged with a prescription for risperidone, 25mg weekly, to be administered via the intramuscular route by the Psychosis Team.\n\nDuring the next 4 months, he was seen by a senior consultant at the Psychosis Team on five occasions. Initially he presented with a somewhat dysphoric mood, and inadequate smiles were reported. He was continuously opposed to the medication, and requested a change from injections to oral medication. He started treatment with risperidone, 2mg daily per os. At follow-up, 1 year ago, he reported taking his medication and felt well.\n\nDiscussion\nDifferential diagnoses\nOur experience with this case illustrates that adolescent schizophrenia can be challenging to classify in individuals with a history of smoking cannabis. The onset was acute with delusions and hallucinations, supporting a cannabis-related or possibly affective psychosis. Owing to the clinical picture, our patient was diagnosed with schizophrenia despite a history of heavy cannabis abuse. A catatonic subtype was determined given the motor immobility, extreme negativism and mutism, and bizarre postures and facial expressions [15]. NMS was ruled out because changes in his level of consciousness, muscular rigidity (bizarre body postures), and autonomic instability (urine incontinence and salivation) began before therapeutic doses of antipsychotic medication were prescribed. The absence of leukocytosis, hyperthermia, and tachycardia along with a normal EEG supports other diagnostic alternatives [16]. After 3.5 years of social adjustment without psychiatric treatment, our patient’s first psychotic episode was more likely to be classified as cannabis-induced, despite the atypically pronounced duration and severity of that first episode [13, 14]. However, after relapsing into pronounced psychotic symptoms without any signs of substance abuse, he was re-diagnosed with catatonic schizophrenia.\n\nThe temporal association of our patient’s first psychotic episode with heavy cannabis use clearly raises questions about a potential role of cannabis in psychotic disorders. There is a relatively large amount of literature describing the association between cannabis and acute and chronic psychosis [9–14, 17–19]. Here, the onset of our patient’s psychosis was acute rather than insidious, typically suggesting a cannabis-induced psychosis rather than schizophrenia, and although results of his urine toxicology had returned to normal after 3 weeks of social authority supervision, the temporal association with heavy cannabis consumption was confirmed by our patient’s family.\n\nThe acute onset with positive symptoms, along with a nearly full remission after 10 days of inpatient care, could have pointed towards an affective psychosis [4]. However, our patient presented no signs of elevated mood. Depressive stupor was considered; our patient presented with depressive symptoms, possibly mood-congruent delusions, and he was clearly improved by ECT, but severe psychotic symptoms including motor and vegetative symptoms clearly dominated the clinical picture, and an affective diagnosis was rejected in favor of catatonic schizophrenia [20, 21]. Normal blood test results, an MRI of his brain, an EEG, and consultation with pediatric expertise ruled out neurodegenerative psychosis. Thus, after an initial interpretation of the symptoms as manifestations of a cannabis-induced psychosis, a primary catatonic schizophrenia appeared a considerably more likely explanation. While an entirely substance-related etiology was ruled out, we cannot exclude that cannabis played a significant role in the onset of the first episode, and that it may even have predisposed our patient to a subsequent psychotic episode, potentially precipitated by a stressful situation. Although the literature is not conclusive in this area, it cannot be ruled out that heavy cannabis abuse can be a predictor of later psychosis [18].\n\nProximal stressors\nOur experience in this case suggests that adolescent schizophrenic episodes in the same patient may potentially be elicited by different stressors, for example, cannabis smoking [17–19] and psychological stress [22, 23], and cause almost the same clinical presentation. This case illustrates the potential role of proximal risk factors for the development of schizophrenic episodes [17–19, 22, 23]. Our patient had no known heredity predisposition for schizophrenia, but was vulnerable in other aspects, including stressful life events. He was brought up in a war-torn country, his parents were divorced, and he became a migrant with an urban up-bringing at the age of 12 years. Soon after arriving in Sweden he became socially marginalized and failed academically. It cannot be excluded that these circumstances, together with heavy cannabis smoking, contributed to his illness [8, 17, 18].\n\nRelapse prevention\nAn asymptomatic duration of 3.5 years of social adjustment, without medication and psychiatric services, is uncommon after the first severe schizophrenic episode [5–7], making the clinical course of the present case unusual. Continued contact with the Psychosis Team probably would have reduced the risk for relapse [1, 23]. The change from a hazardous lifestyle with heavy cannabis smoking to a drug-free state with social adaption was not enough for our patient to maintain health. With increased social adjustment, our patient might have experienced a feeling of false safety, making him end the outpatient contact with the Psychosis Team. This case emphasizes the importance of educating a patient and their parents, especially in cases where there is hesitation about treatment, because compliance is likely to be fundamental in the control of symptoms [1, 24]. Our patient’s mother was critical to the pharmacological treatment, and this may have contributed to the short treatment period and re-hospitalization one week after discharge [25]. Pharmacological treatment is crucial for recovery [7], and more psycho-educational efforts could have been made in the communication with our patient and his parents, and potentially could have improved compliance with treatment [1]. Finally, this case demonstrates the importance of maintaining at least a sparse outpatient contact after a first psychotic episode, although this may be challenging in patients who are currently not presenting subjective symptoms of disease [1, 6, 24].\n\nConclusions\nDiagnostic classification of adolescents with psychotic symptoms can be challenging. Here, an assumingly cannabis-induced psychotic episode was followed by a 3.5-year symptom-free period in absence of drugs, but pronounced psychotic symptoms re-appeared in the absence of drugs. We highlight the question of whether a primary psychosis induced by cannabis can increase the risk of subsequent non-drug-related psychoses.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nECTelectroconvulsive therapy\n\nEEGelectroencephalogram\n\nMRImagnetic resonance imaging\n\nNMSneuroleptic malignant syndrome\n\nTHCtetrahydrocannabinol\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\n\nBoth AH and BAJ have treated the patient in the different clinical settings. The two authors have equally contributed to the analyses and to the writing of the paper. Both authors reviewed and approved the final and submitted version of the manuscript.\n\nAcknowledgements\nThe authors are grateful to Dr Erland Schubert for comments on the manuscript, and to secretaries of the local psychiatric facilities who helped in the collection of relevant hospital records. The present work was carried out without specific funding, and expenses including working hours were financed only by the employers of the authors, that is, the regional psychiatric hospital facilities.\n==== Refs\nReferences\n1. Hollis C Adolescent schizophrenia Adv Psych Treatm Royal Coll Psychiatrists. 2000 6 83 92 10.1192/apt.6.2.83 \n2. Werry JS McClellan JM Chard L Childhood and adolescent schizophrenic, bipolar, and schizoaffective disorders: a clinical and outcome study J Am Acad Child Adol Psychiatry. 1991 30 457 65 10.1097/00004583-199105000-00017 \n3. McClellan JM Werry JS Ham M A follow-up study of early onset psychosis: comparison between outcome diagnoses of schizophrenia, mood disorders, and personality disorders J Autism Dev Disord. 1993 23 243 62 10.1007/BF01046218 8331046 \n4. Hollis C Developmental precursors of child- and adolescent-onset schizophrenia and affective psychoses: diagnostic specificity and continuity with symptom dimensions Br J Psychiatry. 2003 182 37 44 10.1192/bjp.182.1.37 12509316 \n5. Wiersma D Nienhuis FJ Slooff CJ Giel R Natural course of schizophrenic disorders: a 15-year followup of a Dutch incidence cohort Schiz Bull. 1998 24 75 85 10.1093/oxfordjournals.schbul.a033315 \n6. Robinson D Woerner MG Alvir JMA Bilder R Goldman R Geisler S Predictors of relapse following response from a first episode of schizophrenia or schizoaffective disorder Arch Gen Psychiatry. 1999 56 241 7 10.1001/archpsyc.56.3.241 10078501 \n7. Emsley R Chiliza B Asmal L Harvey BH The nature of relapse in schizophrenia BMC Psychiatry. 2013 13 50 10.1186/1471-244X-13-50 23394123 \n8. Mäki P Veijola J Jones PB Murray GK Koponen H Tienari P Predictors of schizophrenia - a review Br Med Bull 2005 73-74 1 15 10.1093/bmb/ldh046 15947217 \n9. Thacore VR Shukla SR Cannabis psychosis and paranoid schizophrenia Arch Gen Psychiatry. 1976 33 383 6 10.1001/archpsyc.1976.01770030081012 1259526 \n10. Hall W Cannabis and psychosis Drug Alc Rev. 1998 17 433 44 10.1080/09595239800187271 \n11. McGuire PK Jones P Harvey I Cannabis and acute psychosis Schiz Res. 1994 13 161 7 10.1016/0920-9964(94)90097-3 \n12. Núnez LA Gurpegui M Cannabis-induced psychosis: a cross-sectional comparison with acute schizophrenia Acta Psych Scand. 2002 105 173 8 10.1034/j.1600-0447.2002.1o079.x \n13. Basu D Malhotra A Bhagat A Varma VK Cannabis psychosis and acute schizophrenia: a case-control study from India Eur Addict Res. 1999 5 71 3 10.1159/000018968 10394036 \n14. Talbott JA Teague JW Marihuana psychosis: acute toxic psychosis associated with the use of cannabis derivatives JAMA. 1969 210 299 302 10.1001/jama.1969.03160280039006 5394365 \n15. World Health Organization International statistical classification of diseases and related health problems, 10th revision 1990 Geneva WHO \n16. Strawn JR Keck PE Caroff SN Neuroleptic malignant syndrome Am J Psychiatry. 2007 164 870 6 10.1176/ajp.2007.164.6.870 17541044 \n17. Arseneault L Cannon M Witton J Murray RM Causal association between cannabis and psychosis: examination of the evidence Br J Psychiatry. 2004 184 110 7 10.1192/bjp.184.2.110 14754822 \n18. Moore TH Zammit S Lingford-Hughes A Barnes TR Jones PB Burke M Cannabis use and risk of psychotic or affective mental health outcomes: a systematic review Lancet. 2007 370 319 28 10.1016/S0140-6736(07)61162-3 17662880 \n19. Kuepper R van Os J Lieb R Wittchen HU Höfler M Henquet C Continued cannabis use and risk of incidence and persistence of psychotic symptoms: 10 year follow-up cohort study BMJ. 2011 342 d738 10.1136/bmj.d738 21363868 \n20. Cohen D Flament M Dubos P-F Basquin M Case series: catatonic syndrome in young people J Am Academy Child Adol Psych. 1999 38 1040 6 10.1097/00004583-199908000-00021 \n21. Dhossche DM, Wilson X, Wachtel X. Catatonia in childhood and adolescence: implications for the DSM-5. Primary Psychiatry. 2013. http://primarypsychiatry.com/catatonia-in-childhood-and-adolescence-implications-for-the-dsm-5/. Accessed 22 June 2015.\n22. Kavanagh DJ Recent developments in expressed emotion and schizophrenia Br J Psychiatry. 1992 160 601 20 10.1192/bjp.160.5.601 1591571 \n23. Bebbington P Kuipers L The predictive utility of expressed emotion in schizophrenia: an aggregate analysis Psychol Med. 1994 24 707 18 10.1017/S0033291700027860 7991753 \n24. McWilliams S Hill S Mannion N Fetherston A Kinsella A O’Callaghan E Schizophrenia: a five-year follow-up of patient outcome following psycho-education for caregivers Eur Psychiatry. 2012 27 56 61 10.1016/j.eurpsy.2010.08.012 21982177 \n25. Alvarez-Jimenez M Priede A Hetrick SE Bendall S Killackey E Parker AG Risk factors for relapse following treatment for first episode psychosis: a systematic review and meta-analysis of longitudinal studies Schizophr Res. 2012 139 116 28 10.1016/j.schres.2012.05.007 22658527\n\n",
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"abstract": "BACKGROUND\nInvasive fungal infections are a life-threatening complication of cancer treatments, especially in hemato-oncological patients. Mucormycosis is the third leading cause of invasive fungal infections after Aspergillus and Candida infections. The first clinical symptoms are usually non-specific, which can lead to a late diagnosis and delayed therapy.\n\n\nOBJECTIVE\nThe objective of this report is to summarize data in the literature about mucormycosis and to present a case report of a patient with acute lymphoblastic leukemia, who developed this infection at our center. Risk factors for the development of mucormycosis, clinical symptoms, radiology, laboratory results, and outcome were retrospectively evaluated.\n\n\nMETHODS\nWe describe a 6-years-old female patient with acute lymphoblastic leukemia. During the induction phase of therapy, the patient developed febrile neutropenia and did not respond to therapy with a combination of antibiotics and supportive treatment. Pansinusitis and orbitocellulitis developed. Examination of the biological material revealed that the etiological agent was a Rhizopus sp. The patient was treated with a combination of antimycotic drugs, but the infection disseminated to the central nervous system. She underwent radical surgical resection of the affected tissue. At this time, she is still under treatment with antimycotic and oncology agents, but is in remission of the main diagnosis and in good clinical condition.\n\n\nCONCLUSIONS\nMucormycosis is an invasive fungal infection with high morbidity and mortality. Early diagnosis and initiation of effective therapy using a combination of amphotericin B administration and surgery are necessary to obtain a favorable outcome. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.",
"affiliations": null,
"authors": "Bačová|Eva|E|;Chovanec|Filip|F|;Makohusová|Miroslava|M|;Hederová|Stanislava|S|;Mikesková|Martina|M|;Hrašková|Andrea|A|;Rudinský|Bruno|B|;Plank|Lukáš|L|;Volfová|Pavlína|P|;Kolenová|Alexandra|A|",
"chemical_list": "D000935:Antifungal Agents; D000970:Antineoplastic Agents; D000666:Amphotericin B",
"country": "Czech Republic",
"delete": false,
"doi": "10.14735/amko2020138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0862-495X",
"issue": "33(2)",
"journal": "Klinicka onkologie : casopis Ceske a Slovenske onkologicke spolecnosti",
"keywords": "Rhizopus; acute leukemia; mucormycosis",
"medline_ta": "Klin Onkol",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D000970:Antineoplastic Agents; D002490:Central Nervous System; D002648:Child; D005260:Female; D006801:Humans; D009091:Mucormycosis; D054517:Orbital Cellulitis; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D012233:Rhizopus; D012852:Sinusitis",
"nlm_unique_id": "9425213",
"other_id": null,
"pages": "138-144",
"pmc": null,
"pmid": "32303134",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Invasive Rhino-Orbito-Cerebral Mucormycosis in Pediatric Patient with Acute Leukemia.",
"title_normalized": "invasive rhino orbito cerebral mucormycosis in pediatric patient with acute leukemia"
} | [
{
"companynumb": "SK-TEVA-2020-SK-1229350",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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"drugadditional": "1",
... |
{
"abstract": "Purpose: To investigate the use of letermovir 480 mg daily for the treatment of cytomegalovirus (CMV)-associated uveitis (AU).Methods: Retrospective case series of CMV-AU patients on letermovir.Results: Six eyes of five patients (mean age 54 years) were included. Mean follow-up time was 10 months. Four patients had CMV anterior uveitis and one patient had bilateral CMV retinitis. All were treated initially with valganciclovir 900 mg twice daily. Transition to letermovir was due to cytopenias (n = 3), transaminitis (n = 1), and persistent inflammation on valganciclovir (n = 1). At the initiation of letermovir, mean visual acuity (VA) was 0.35 logMAR and IOP was 14 mmHg. One of the six eyes had a recurrence of anterior uveitis due to self-discontinuation of letermovir. No adverse events were observed. At last follow-up, no patients had active inflammation. Mean VA was 0.08 logMAR and IOP was 9 mmHg.Conclusion: Letermovir may be an alternative treatment for CMV-AU in patients with persistent inflammation or side effects on valganciclovir.",
"affiliations": "F.I. Proctor Foundation, University of California, San Francisco, California, USA.;F.I. Proctor Foundation, University of California, San Francisco, California, USA.;Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia, USA.;F.I. Proctor Foundation, University of California, San Francisco, California, USA.;F.I. Proctor Foundation, University of California, San Francisco, California, USA.",
"authors": "Tsui|Edmund|E|https://orcid.org/0000-0001-7532-9191;Gonzales|John A|JA|https://orcid.org/0000-0003-0558-9793;Shantha|Jessica G|JG|;Acharya|Nisha|N|;Doan|Thuy|T|https://orcid.org/0000-0003-2733-8370",
"chemical_list": "D000085:Acetates; D000998:Antiviral Agents; D004279:DNA, Viral; D011799:Quinazolines; C000588473:letermovir",
"country": "England",
"delete": false,
"doi": "10.1080/09273948.2019.1662062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0927-3948",
"issue": "29(1)",
"journal": "Ocular immunology and inflammation",
"keywords": "Letermovir; cytomegalovirus; retinitis; uveitis; valganiciclovir",
"medline_ta": "Ocul Immunol Inflamm",
"mesh_terms": "D000085:Acetates; D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D001082:Aqueous Humor; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D015828:Eye Infections, Viral; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D011799:Quinazolines; D012189:Retrospective Studies; D014605:Uveitis; D014792:Visual Acuity",
"nlm_unique_id": "9312169",
"other_id": null,
"pages": "169-174",
"pmc": null,
"pmid": "31638841",
"pubdate": "2021-01-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Letermovir for the Management of Cytomegalovirus-associated Uveitis.",
"title_normalized": "letermovir for the management of cytomegalovirus associated uveitis"
} | [
{
"companynumb": "US-DRREDDYS-LIT/USA/21/0137274",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FOSCARNET"
},
"drugadditional": null,
... |
{
"abstract": "Male breast cancer occurs rarely, comprising <1% of breast cancers. Due to the low incidence of male breast cancer, clinical trials of this disease are lacking. Therefore, therapeutic strategies utilized in the management of female breast cancer are often applied to male patients with breast cancer. Specifically, clinical outcomes using CDK 4/6 inhibitors require further investigation in male patients. To the best of our knowledge, the present report presents the first known case of a male patient treated with second line Abemaciclib, Lupron and Fulvestrant, producing complete remission. To the best of our knowledge this is also the first report of complete remission in a male breast cancer patient with a regimen utilizing a CDK 4/6 inhibitor.",
"affiliations": "Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USA.;Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USA.;Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USA.;Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USA.;Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USA.",
"authors": "Hansra|Damien|D|;Jackson|Shirelle|S|;Sequeira|Judy|J|;Vazirani|Rajendra|R|;Alvarez|Ricardo|R|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2019.1955",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2019.1955MCO-0-0-1955ArticlesMale patient with metastatic stage IV breast cancer achieves complete remission on second line Abemaciclib, Fulvestrant and Leuprolide: A case report Hansra Damien Jackson Shirelle Sequeira Judy Vazirani Rajendra Alvarez Ricardo Cancer Treatment Centers of America, Breast Cancer Institute, Atlanta, GA 30265, USACorrespondence to: Dr Damien Hansra, Cancer Treatment Centers of America, Breast Cancer Institute, 600 Celebrate Life Parkway, Newnan, Atlanta, GA 30265, USA damien.hansra@ctca-hope.com2 2020 29 11 2019 29 11 2019 12 2 120 125 28 4 2019 08 10 2019 Copyright: © Hansra et al.2019This is an open access article distributed 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.Male breast cancer occurs rarely, comprising <1% of breast cancers. Due to the low incidence of male breast cancer, clinical trials of this disease are lacking. Therefore, therapeutic strategies utilized in the management of female breast cancer are often applied to male patients with breast cancer. Specifically, clinical outcomes using CDK 4/6 inhibitors require further investigation in male patients. To the best of our knowledge, the present report presents the first known case of a male patient treated with second line Abemaciclib, Lupron and Fulvestrant, producing complete remission. To the best of our knowledge this is also the first report of complete remission in a male breast cancer patient with a regimen utilizing a CDK 4/6 inhibitor.\n\nmale breast cancerCDK 4/6 inhibitorfulvestrantabemaciclibmetastatic disease\n==== Body\nIntroduction\nMale breast cancer is a rare entity that shares many overlapping features with female breast cancer (1). Although female breast cancer has been extensively studied, far less is known about male breast cancer. As with women, the incidence of breast cancer in men increases with age and males are typically diagnosed 5 to 10 years later than females (2-8). Furthermore, the incidence of male breast cancer seems to be increasing (9). Family history of breast cancer appears to play an important role in the development of male breast cancer (10). For example, men with a family history of breast cancer in a female or male relative have two to three times the risk of developing breast cancer themselves (11-13). BRCA2 mutations are well described as causal factors for male breast cancer. Multiple studies have demonstrated that 4-15% of men with breast cancer carry deleterious BRCA2 mutations (14-16). BRCA1 mutations are less commonly seen with <5% of male breast cancer patients harboring the mutation (14,16-18). Other genes have also been implicated in male breast cancer risk including mutations in PTEN tumor suppressor gene (Cowden syndrome), TP53 (Li-Fraumeni syndrome), PALB2, and mismatch repair genes (Lynch syndrome) (19-21). Other risk factors for male breast cancer include androgen/estrogen imbalance and environmental exposures (10). Histologically, 85-90% of males present with invasive ductal carcinomas (22,23). Since males lack acini and lobules in the normal male breast lobular carcinoma is rare in male breast cancer (9,24). Other histologic variants are rare but have been observed (25). Over 80% of male breast cancer is hormone positive with some series showing estrogen (ER) positivity as high as 99% (10,23). Rates of human epidermal growth factor receptor (HER2) overexpression in male breast cancer have been variable in different studies ranging from 2 to 45% (26-30). Cardoso et al (23) conducted immunohistochemistry evaluations of male breast cancer patients and found 42% luminal A-like, 42% luminal B-like, 8.7% HER2 positive, and 0.3% triple negative expression amog male breast cancer patients.\n\nProspective randomized trials in the treatment of male breast cancer are lacking due to the rarity of this entity. Furthermore, little data exists on the activity of CDK 4/6 inhibitors in the treatment of hormone positive metastatic breast cancer in male patients. In this report we describe the first known case of a male patient treated with second line Abemaciclib, Lupron, and Fulvestrant producing a dramatic and durable complete remission. This is the first known case of a male achieving complete remission on a CDK 4/6 inhibitor.\n\nCase report\nWe present a case of a 39 year old male with no past medical history who initially palpated a mass in his left breast in March 2015. A diagnostic mammogram and left breast ultrasound showed an irregular mass measuring 9x7x7 mm in the outer left breast at 3 o'clock suspicious for malignancy. In March 2015 he underwent left mastectomy with pathology demonstrating grade II infiltrating ductal carcinoma, 1.6 cm tumor with extensive lymphovascular invasion, five of five lymph nodes positively involved, and margins negative. The invasive component was estrogen receptor 58% positive, progesterone receptor 7% positive, human epidermal growth factor receptor 1+ not overexpressed/negative (Fig. 1). Of note, a computed tomography scan (CT) of the chest abdomen pelvis and a bone scan were performed and negative for metastatic disease. The patient was staged as pT1cN2aMx stage IIIA. He was treated with adjuvant chemotherapy with Adriamycin and Cyclophosphamide followed by Paclitaxel then radiation therapy to the chest wall and regional lymphatics (left supraclavicular fossa 5,000 cGy, left chest wall 5,000 cGy, left scar boost 1,000 cGy) ending December 2015. In December 2015 the patient was started on Tamoxifen 20 mg orally daily and was doing well until a restaging MRI in April 2017 identified a solitary metastatic lesion to the sternum. No biopsy was performed at this time. He received palliative radiation (4,000 cGy) to the sternal lesion which was completed in June 2017. A follow-up CT chest abdomen and pelvis October 2017 showed numerous bilateral pulmonary nodules suspicious for metastatic disease. His local team switched him to Anastrazole in June 2017. Patient presented for initial consultation to our facility October 2017 where a biopsy to confirm metastatic disease and to obtain genomic information was requested. Patient underwent video assisted thoracoscopy and wedge resection of two pulmonary nodules in left upper and lower lobes November 2017. Pathology was consistent with metastatic adenocarcinoma compatible with breast primary (Fig. 2). Genomic testing on the lung biopsy specimen revealed PIK3CA amplification, GATA 3 mutation, stable microsatellites, and a low tumor mutational burden. Genetic testing revealed absence of deleterious mutations for the BRCA1 or BRCA2 genes. In November 2017 a baseline 18F-fluorodeoxyglucose-positron emission tomography computed tomography (FDG-PET CT) was performed post wedge resection showing metastatic disease to subcarinal lymph node, left hilum, and osseous metastatic disease involving the 5th cervical vertebral body, 2nd lumbar vertebral body, the ninth right rib (Fig. 3). Baseline labs: CA 15-3 was 45.2 U/ml (0.0-35.0 U/ml), CA 27.29 was 60 U/ml (<38 U/ml), complete blood count with white blood cell (wbc) count 5.2 K/µl, hemoglobin 17.2 g/dl, platelet count 134 K/µl (150-450 K/µl), absolute neutrophil 2.15 K/µl, complete metabolic panel was normal except for elevated aspartate aminotransferase (AST) 69 U/l (17-59 U/l), alanine aminotransferase 135 U/l (21-72 U/l), and testosterone level 1,240 ng/dl (132-813.0 ng/dl).\n\nThe patient was initiated on Abemaciclib 150 mg orally twice daily, Fulvestrant 500 mg intramuscular injection days 1, 15, 29 then monthly there after, and Leuprolide 7.5 mg intramuscular injections every month in November 2017. Additionally, he was given Denosumab 120 mg subcutaneously every month for prevention of skeletal related events. The patient tolerated treatment well with grade 1 fatigue, grade 1 hot flashes, grade 3 diarrhea mitigated by Loperamide and resolved. Testosterone levels appropriately suppressed <50 ng/dl. Patient also had transient grade 2 thrombocytopenia which resolved spontaneously and persistent grade 2 neutropenia. Follow-up PET CT February 2018 showed resolution of the hypermetabolic osseous metastatic foci with sclerosis at prior locations also there was resolution of the previously described abnormal metabolic activity in the left hilar and subcarinal mediastinal regions. Patient's subsequent PET CT imaging every 3 months remained negative with last PET CT June 2019. Patients tumor markers normalized in December 2017 with episodic mild flare up in CA 27.29. Last tumor markers over past 10 months remained negative June 2019. Patient is clinically asymptomatic and developed a grade 3 neutropenia in October 2018 requiring dose reduction of Abemaciclib to 100 mg po BID. So far the patient remains in a durable complete remission for 18 months on this treatment regimen.\n\nDiscussion\nDue to the rarity of male breast cancer, treatment approaches used for female breast cancer patients in the metastatic setting are often applied to males with metastatic breast cancer. Given that most males with metastatic breast cancer are hormone positive, hormonal therapy is often the first approach in the absence of visceral crisis (31). Tamoxifen is considered standard of care frontline therapy for males with metastatic disease (32,33). Luteinizing hormones-releasing hormone agonists with or without anti-androgens have been shown to be effective in male breast cancer (34-36). Aromatase inhibitors have shown clinical activity in male breast cancer with increased clinical benefit observed with the addition of a GnRH analogue (37). Data regarding the role of Fulvestrant are limited. One pooled analysis of 23 male patients receiving Fulvestrant in the first, second, or third line setting reported a partial response rate of 26% and an additional 48% had stable disease (38). Resistance to hormonal therapy in the metastatic setting is common and most patients will eventually experience progression of disease (39). Research into the mechanisms of resistance to endocrine therapy had shed light on cell cycle regulation, particularly the cyclin-dependent kinases (CDKs). The CDKs play an important role in regulating cell-cycle progression (40).\n\nThe cyclin-dependent kinases, CDK4 and CDK6, are responsible for regulating the cell cycle by initiating the transition of cells through the G1 restriction point (41). A common feature in human cancers is the dysregulation and aberrant activation of CDK4 and 6 therefore promoting cell cycle progression (42,43). Inhibition of CDK4 and CDK6 seems like a rational therapeutic target to prevent the progression of tumor cells through the G1 restriction point. Various preclinical studies have been conducted and support CDK4 and CDK6 as potential tumor targets (22,44-46). Subsequently three CDK4/6 inhibitors have been approved for use in patients with metastatic breast cancer in the first or second line setting: Palbociclib (PD-0332991; Pfizer), Ribociclib (LEE011; Novartis), and Abemaciclib (LY2835219; Lilly). Palbociclib was the first FDA approved CDK 4/6 inhibitor in combination with Letrozole as initial therapy for postmenopausal women with advanced hormone positive, HER2 negative metastatic breast cancer based on the results from the phase II PALOMA-I clinical trial (47). In PALOMA-I, patients who received Palbociclib and Letrozole experienced a roughly doubling of the progression free survival compared to treatment with Letrozole alone (47). These results were later confirmed in the randomized phase III study PALOMA-II (48). In the second line setting, Palbociclib was paired with Fulvestrant vs. Fulvestrant alone in patients with metastatic hormone positive HER2 negative breast cancer who had progressed on prior endocrine therapy in the PALOMA III randomized phase III trial (49). The study also included pre and perimenopausal females who were required to take Goserelin (49). The combination of Palbociclib and Fulvestrant produced a significant 9.2 month progression free survival compared with 3.8 in the Fulvestrant and placebo arm (49). Abemaciclib is an inhibitor of CDK4 and CDK6 and in enzymatic assays is 14 times more potent against CDK4/cyclin D1 than CDK6/cyclin D3(50). Fujiwara et al (51) conducted a phase 1 study of single-agent Abemaciclib in Japanese patients with advanced metastatic solid tumors where 5/12 (41.6%) patients were males. They concluded that single agent Abemaciclib demonstrated antitumor activity as a single agent and had an acceptable safety profile (51). In another phase I study, Abemaciclib as a single agent demonstrated antitumor activity in patients with several cancers with an ORR of 26% in patients with hormone refractory hormone positive metastatic breast cancer (52). Based on the single agent activity observed with Abemaciclib, the phase II MONARCH 1 study was launched (53). In this open label phase II single arm trial, women with hormone positive HER2 negative metastatic breast cancer who had progressed on or after prior endocrine therapy and had 1 or 2 prior chemotherapy regimens in the metastatic setting were enrolled (53). In this study patients who received single agent administered on a continuous schedule had an overall response rate of 19.7% with a median progression free survival of 6 months (53). Based on the results of MONARCH-I, the U.S. Food and Drug Administration approved Abemaciclib to be used alone to treat women and men diagnosed with hormone positive HER2 negative metastatic breast cancer that has progressed after hormone therapy and prior chemotherapy in the metastatic setting. Abemaciclib was also studied in the randomized phase III trial MONARCH 2, where Abemaciclib and Fulvestrant vs. Abemaciclib and placebo were studied in patients with hormone positive HER2 negative metastatic breast cancer who had progressed on prior endocrine therapy (54). The combination of Abemaciclib and Fulvestrant yielded a significantly improved PFS of 16.4 months compared with 9.3 months in the Fulvestrant and Placebo arm (54). Data regarding treatment responses to CDK 4/6 inhibitors in males is extremely limited. The first reported response in males was demonstrated in 2016 by S. Sorcher where a male with metastatic breast cancer achieved a partial response to Palbocliclib and Letrozole in the fifth line setting (55). The second known report by Castrellon et al (56) demonstrated a case of a male with metastatic breast cancer to lung and bone who achieved partial response to CDK 4/6 therapy with Palbociclib and Fulvestrant. Here we report the first male patient with metastatic breast cancer to achieve complete remission on a CDK 4/6 inhibitor. Given the lack of randomized controlled trials in male breast cancer treatment decisions are often extrapolated from data derived from female breast cancer trials. The standard of care for females with metastatic hormone positive HER2 negative metastatic breast cancer who progress on endocrine therapy is treatment with CDK 4/6 inhibitor with Fulvestrant. Our patient was treated as per MONARCH-II protocol given the significant benefit of the addition of Abemaciclib to Fulvestrant compared with Fulvestrant alone (54). Furthermore, Abemaciclib is the only CDK 4/6 inhibitor with an FDA approval in males and it has been previously studied in male cancer patients (51,52). It should be noted however among the three FDA approved CDK 4/6 inhibitors (Abemaciclib, Palbociclib, Ribociclib) no head to head trials have been performed therefore no superior agent has been identified in cancer patients. The relative favorable side effect profile and response seen in this patient utilizing the combination of Fulvestrant, Abemaciclib and Lupron seems encouraging and further reports of CDK4/6 drug combinations may show responses. Identification of predictive biomarkers of response to CDK inhibitors represents one of the most important clinical areas of interest as CDK inhibitors have become the accepted first line treatment in metastatic hormone receptor positive HER2 negative breast cancer. Despite the excellent clinical advancement afforded by CDK inhibition a significant percent (20%) of patients will not respond to CDK inhibition. Therefore identification of predictive biomarkers of response to CDK inhibition is prudent. Studies are slowly emerging in this field. Gong et al (57) analyzed the sensitivity of 560 cell lines to the selective CDK4/6 inhibitor abemaciclib and they found that cell lines with genomic features of D-cyclin activating features are particularly sensitive. Clinically however no reproducible predictive biomarker has emerged. For example in a phase II study using Palbociclib as a single agent in advanced breast cancer assessed progression free survival and Rb expression, KI-67, p16 loss, and CCND1 amplification. In this study there was no association between these biomarkers and response to therapy (58). Several studies are ongoing to elucidate potential predictive biomarkers. If more clinicopathologic and predicitive biomarker data could be accumulated on CDK 4/6 drug combinations in males with metastatic hormone positive male breast cancer this would help facilitate clinicians in selecting optimal therapeutic algorithms for individual males with breast cancer.\n\nAcknowledgements\nNot applicable.\n\nFunding\nNo funding was received.\n\nAvailability of data and materials\nAll data generated or analyzed during the present study are included in this published article.\n\nAuthors' contributions\nDH provided clinical management for the patient and developed their treatment protocol. DH also conceived the present study, wrote the manuscript, reviewed the treatment of stage IV male breast cancer and CDK 4/6 inhibitors for use in breast cancer, and supervised the study. SJ clinically treated the patient, and partially wrote and revised the manuscript. JS assembled pathological images and partially wrote the manuscript. RV assembled radiographic images and partially wrote the manuscript. RA wrote, critically revised and approved the manuscript, and developed the treatment protocol. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe present case report was reviewed and approved by the Ethics Committee of the Cancer Treatment Centers of America.\n\nPatient consent for publication\nThe patient verbalized consent for the publication of their information in a medical journal, which was documented in the medical record of the patient.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Invasive ductal carcinoma. (A) A combination of tubules and solid ribbons are observed under a 4X objective (final magnification, x40). (B) Under a 20X objective, nuclear pleomorphism is demonstrated, with one case of mitosis (final magnification, x200). The overall grade was determined to be 2/3.\n\nFigure 2. Invasive ductal carcinoma obtained via lung wedge resection conducted in 2017. The tumor fills 4/5 of the photographed field and exhibits tumor replacing lung tissue, with central fibrosis surrounded by nests and tumor glands. Lung parenchyma is observed in the upper left and upper right corner (final magnification, x100).\n\nFigure 3. Baseline PET CT scans. (A) Sagittal view demonstrating metastatic disease to the 5th vertebral body of the cervical spine. (B) Post treatment PET CT demonstrating resolution of FDG activity involving the 5th vertebral body of the cervical spine with overlying sclerosis.\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A Cancer Statistics, 2017 CA Cancer J Clin 67 7 30 2017 10.3322/caac.21387 28055103 \n2 Anderson WF Althuis MD Brinton LA Devesa SS Is male breast cancer similar or different than female breast cancer? Breast Cancer Res Treat 83 77 86 2004 10.1023/B:BREA.0000010701.08825.2d 14997057 \n3 Thomas DB Breast cancer in men Epidemiol Rev 15 220 231 1993 10.1093/oxfordjournals.epirev.a036108 8405206 \n4 O'Malley CD Prehn AW Shema SJ Glaser SL Racial/ethnic differences in survival rates in a population-based series of men with breast carcinoma Cancer 94 2836 2843 2002 10.1002/cncr.10521 12115370 \n5 Giordano SH Buzdar AU Hortobagyi GN Breast cancer in men Ann Intern Med 137 678 687 2002 10.7326/0003-4819-137-8-200210150-00013 12379069 \n6 Cutuli B Lacroze M Dilhuydy JM Velten M De Lafontan B Marchal C Resbeut M Graic Y Campana F Moncho-Bernier V Male breast cancer: Results of the treatments and prognostic factors in 397 cases Eur J Cancer 31A 1960 1964 1995 10.1016/0959-8049(95)00366-5 8562148 \n7 Mabuchi K Bross DS Kessler II Risk factors for male breast cancer J Natl Cancer Inst 74 371 375 1985 3856050 \n8 Nahleh ZA Srikantiah R Safa M Jazieh AR Muhleman A Komrokji R Male breast cancer in the veterans affairs population: A comparative analysis Cancer 109 1471 1477 2007 10.1002/cncr.22589 17342768 \n9 Giordano SH Cohen DS Buzdar AU Perkins G Hortobagyi GN Breast carcinoma in men: A population-based study Cancer 101 51 57 2004 10.1002/cncr.20312 15221988 \n10 Ferzoco RM Ruddy KJ The epidemiology of male breast cancer Curr Oncol Rep 18 1 2016 10.1007/s11912-015-0487-4 26694922 \n11 Ewertz M Holmberg L Tretli S Pedersen BV Kristensen A Risk factors for male breast cancer-a case-control study from scandinavia Acta Oncol 40 467 471 2001 10.1080/028418601750288181 11504305 \n12 Rosenblatt KA Thomas DB McTiernan A Austin MA Stalsberg H Stemhagen A Thompson WD Curnen MG Satariano W Austin DF Breast cancer in men: Aspects of familial aggregation J Natl Cancer Inst 83 849 854 1991 10.1093/jnci/83.12.849 2061945 \n13 Casagrande JT Hanisch R Pike MC Ross RK Brown JB Henderson BE A case-control study of male breast cancer Cancer Res 48 1326 1330 1988 3342411 \n14 Basham VM Lipscombe JM Ward JM Gayther SA Ponder BA Easton DF Pharoah PD BRCA1 and BRCA2 mutations in a population-based study of male breast cancer Breast Cancer Res BCR 4 R2 2002 10.1186/bcr419 11879560 \n15 Couch FJ Farid LM DeShano ML Tavtigian SV Calzone K Campeau L Peng Y Bogden B Chen Q Neuhausen S BRCA2 germline mutations in male breast cancer cases and breast cancer families Nat Genet 13 123 125 1996 10.1038/ng0596-123 8673091 \n16 Friedman LS Gayther SA Kurosaki T Gordon D Noble B Casey G Ponder BA Anton-Culver H Mutation analysis of BRCA1 and BRCA2 in a male breast cancer population Am J Hum Genet 60 313 319 1997 9012404 \n17 Ottini L Masala G D'Amico C Mancini B Saieva C Aceto G Gestri D Vezzosi V Falchetti M De Marco M BRCA1 and BRCA2 mutation status and tumor characteristics in male breast cancer: A population-based study in italy Cancer Res 63 342 347 2003 12543786 \n18 Sverdlov RS Barshack I Bar Sade RB Baruch RG Hirsh-Yehezkel G Dagan E Feinmesser M Figer A Friedman E Genetic analyses of male breast cancer in israel Genet Test 4 313 327 2000 10.1089/10906570050501579 11142766 \n19 Ding YC Steele L Kuan CJ Greilac S Neuhausen SL Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States Breast Cancer Res Treat 126 771 778 2011 10.1007/s10549-010-1195-2 20927582 \n20 Silvestri V Rizzolo P Zanna I Falchetti M Masala G Bianchi S Papi L Giannini G Palli D Ottini L PALB2 mutations in male breast cancer: A population-based study in central italy Breast Cancer Res Treat 122 299 301 2010 10.1007/s10549-010-0797-z 20180015 \n21 Boyd J Rhei E Federici MG Borgen PI Watson P Franklin B Karr B Lynch J Lemon SJ Lynch HT Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome Breast Cancer Res Treat 53 87 91 1999 10.1023/a:1006030116357 10206076 \n22 Fry DW Harvey PJ Keller PR Elliott WL Meade M Trachet E Albassam M Zheng X Leopold WR Pryer NK Toogood PL Specific inhibition of cyclin-dependent kinase 4/6 by PD 0332991 and associated antitumor activity in human tumor xenografts Mol Cancer Ther 3 1427 1438 2004 15542782 \n23 Cardoso F Bartlett JMS Slaets L van Deurzen CHM van Leeuwen-Stok E Porter P Linderholm B Hedenfalk I Schröder C Martens J Characterization of male breast cancer: Results of the EORTC 10085/TBCRC/BIG/NABCG international male breast cancer program Ann Oncol 29 405 417 2018 10.1093/annonc/mdx651 29092024 \n24 Cardoso F Costa A Senkus E Aapro M André F Barrios CH Bergh J Bhattacharyya G Biganzoli L Cardoso MJ 3rd ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 3) Ann Oncol 28 16 23 2017 10.1093/annonc/mdw544 28177437 \n25 Sharif MA Mamoon N Arif A Khadim MT Histological and immuno-histochemical study of male breast carcinoma in northern Pakistan J Pak Med Assoc 59 67 71 2009 19260565 \n26 Fox SB Rogers S Day CA Underwood JC Oestrogen receptor and epidermal growth factor receptor expression in male breast carcinoma J Pathol 166 13 18 1992 10.1002/path.1711660104 1538271 \n27 Arslan UY Oksüzoğlu B Ozdemir N Aksoy S Alkış N Gök A Kaplan MA Gümüş M Berk V Uncu D Outcome of non-metastatic male breast cancer: 118 patients Med Oncol 29 554 560 2012 10.1007/s12032-011-9978-9 21573973 \n28 Moore J Friedman MI Gansler T Gramlich TL Derose PB Hunt D Cohen C Prognostic indicators in male breast carcinoma Breast J 4 261 269 1998 10.1046/j.1524-4741.1998.440261.x 21223446 \n29 Leach IH Ellis IO Elston CW C-erb-B-2 expression in male breast carcinoma J Clin Pathol 45 942 1992 10.1136/jcp.45.10.942-c 1430274 \n30 Willsher PC Leach IH Ellis IO Bell JA Elston CW Bourke JB Blamey RW Robertson JF Male breast cancer: Pathological and immunohistochemical features Anticancer Res 17 2335 2338 1997 9245247 \n31 Giordano SH A review of the diagnosis and management of male breast cancer Oncologist 10 471 479 2005 10.1634/theoncologist.10-7-471 16079314 \n32 Gradishar WJ Anderson BO Balassanian R Blair SL Burstein HJ Cyr A Elias AD Farrar WB Forero A Giordano SH Invasive breast cancer version 1.2016, NCCN clinical practice guidelines in oncology J Natl Compr Canc Netw 14 324 354 2016 10.6004/jnccn.2016.0037 26957618 \n33 White J Kearins O Dodwell D Horgan K Hanby AM Speirs V Male breast carcinoma: Increased awareness needed Breast Cancer Res 13 219 2011 \n34 Labrie F Dupont A Belanger A Lacourcière Y Béland L Cusan L Lachance R Complete response to combination therapy with an LHRH agonist and flutamide in metastatic male breast cancer: A case report Clin Invest Med 13 275 278 1990 2276222 \n35 Lopez M Natali M Di Lauro L Vici P Pignatti F Carpano S Combined treatment with buserelin and cyproterone acetate in metastatic male breast cancer Cancer 72 502 505 1993 10.1002/1097-0142(19930715)72:2<502::aid-cncr2820720228>3.0.co;2-1 8319180 \n36 Doberauer C Niederle N Schmidt CG Advanced male breast cancer treatment with the LH-RH analogue buserelin alone or in combination with the antiandrogen flutamide Cancer 62 474 478 1988 10.1002/1097-0142(19880801)62:3<474::aid-cncr2820620305>3.0.co;2-2 3134119 \n37 Zagouri F Sergentanis TN Azim HA Jr Chrysikos D Dimopoulos MA Psaltopoulou T Aromatase inhibitors in male breast cancer: A pooled analysis Breast Cancer Res Treat 151 141 147 2015 10.1007/s10549-015-3356-9 25850534 \n38 Zagouri F Sergentanis TN Chrysikos D Dimopoulos MA Psaltopoulou T Fulvestrant and male breast cancer: A pooled analysis Breast Cancer Res Treat 149 269 275 2015 10.1007/s10549-014-3240-z 25519043 \n39 Lumachi F Luisetto G Basso SM Camozzi V Endocrine therapy of breast cancer Curr Med Chem 18 513 522 2011 10.2174/092986711794480177 21143113 \n40 Finn RS Aleshin A Slamon DJ Targeting the cyclin-dependent kinases (CDK) 4/6 in estrogen receptor-positive breast cancers Breast Cancer Res 18 17 2016 10.1186/s13058-015-0661-5 26857361 \n41 Lundberg AS Weinberg RA Functional inactivation of the retinoblastoma protein requires sequential modification by at least two distinct cyclin-cdk complexes Mol Cell Biol 18 753 761 1998 10.1128/mcb.18.2.753 9447971 \n42 Malumbres M Cyclin-dependent kinases Genome Biol 15 122 2014 10.1186/gb4184 25180339 \n43 Gelbert LM Cai S Lin X Sanchez-Martinez C Del Prado M Lallena MJ Torres R Ajamie RT Wishart GN Flack RS Preclinical characterization of the CDK4/6 inhibitor LY2835219: In vivo cell cycle-dependent/independent anti-tumor activities alone/in combination with gemcitabine Invest New Drugs 32 825 837 2014 10.1007/s10637-014-0120-7 24919854 \n44 Puyol M Martin A Dubus P Mulero F Pizcueta P Khan G Guerra C Santamaria D Barbacid M A synthetic lethal interaction between K-Ras oncogenes and Cdk4 unveils a therapeutic strategy for non-small cell lung carcinoma Cancer Cell 18 63 73 2010 10.1016/j.ccr.2010.05.025 20609353 \n45 Baker SJ Reddy EP CDK4: A key player in the cell cycle, development, and cancer Genes Cancer 3 658 669 2012 10.1177/1947601913478972 23634254 \n46 Dean JL McClendon AK Hickey TE Butler LM Tilley WD Witkiewicz AK Knudsen ES Therapeutic response to CDK4/6 inhibition in breast cancer defined by ex vivo analysis of human tumors Cell Cycle 11 2756 2761 2012 10.4161/cc.21195 22767154 \n47 Finn RS Crown JP Lang I Boer K Bondarenko IM Kulyk SO Ettl J Patel R Pinter T Schmidt M The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomized phase 2 study Lancet Oncol 16 25 35 2015 10.1016/S1470-2045(14)71159-3 25524798 \n48 Finn RS Martin M Rugo HS Jones SE Im SA Gelmon KA Harbeck N Lipatov ON Walshe JM Walshe JM PALOMA-2: Primary results from a phase III trial of palbociclib (P) with letrozole (L) compared with letrozole alone in postmenopausal women with ER+ /HER2-advanced breast cancer J Clin Oncol May 11, 2017 (Epub ahead of print). doi: 10.1200/JCO.2016.34.15_suppl.507 10.1200/JCO.2016.34.15_suppl.507 \n49 Turner NC Ro J Andre F Loi S Verma S Harbeck HI Loibl S Bartlett CH Zhang K and Giorgetti C PALOMA3: A double-blind, phase III trial of fulvestrant with or without palbociclib in pre- and post-menopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer that progressed on prior endocrine therapy J Clin Oncol Jan 31, 2017 (Epub ahead of print). doi: 10.1200/jco.2015.33.18_suppl.lba502 10.1056/NEJMoa1505270 26030518 \n50 Lallena MJ Boehnke K Torres R Hermoso A Amat J Calsina B De Dios A Buchanan S Du J Beckmann RP In-vitro characterization of Abemaciclib pharmacology in ER+ breast cancer cell lines Presented at Proceedings of the 106th Annual Meeting of the American Association for Cancer Research (AACR) Congress. (abstract 3101) 2015 doi: 10.1158/1538-7445.AM2015-3101 10.1158/1538-7445.AM2015-3101 \n51 Fujiwara Y Tamura K Kondo S Tanabe Y Iwasa S Shimomura A Kitano S Ogasawara K Turner PK Mori J Phase 1 study of abemaciclib, an inhibitor of CDK 4 and 6, as single agent for Japanese patients with advanced cancer Cancer Chemother Pharmacol 78 281 288 2016 10.1007/s00280-016-3085-8 27312735 \n52 Patnaik A Tolaney SM Tolcher AW Goldman JW Gandhi L Papadopoulos KP Beeram M Rasco DW Hilton JF Nasir A Efficacy and safety of abemaciclib, an inhibitor of CDK4 and CDK6, for patients with breast cancer, non-small cell lung cancer, and other solid tumors Cancer Discov 6 740 753 2016 10.1158/2159-8290.CD-16-0095 27217383 \n53 Dickler MN Tolaney SM Rugo HS Cortés J Diéras V Patt D Wildiers H Hudis CA O'Shaughnessy J Zamora E MONARCH 1, a phase II study of abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+ /HER2- metastatic breast cancer Clin Cancer Res 23 5218 5224 2018 10.1158/1078-0432.CCR-18-3193 30385657 \n54 Sledge GW Jr Toi M Neven P Sohn J Inoue K Pivot X Burdaeva O Okera M Masuda N Kaufman PA Monarch 2: Abemaciclib in combination with fulvestrant in women with HR+ /HER2- advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 1 2875 2884 2017 10.1200/JCO.2017.73.7585 28580882 \n55 Sorscher S A first case of male breast cancer responding to combined aromatase inhibitor/palbociclib therapy Int J Cancer Clin Res Oct 19, 2016 (Epub ahead of print) 10.23937/2378-3419/3/5/1069 \n56 Castrellon AB Nguyen SM Milillo Naraine AM Velez M Raez LE Initial response to therapy with fulvestrant and cyclin-dependent kinase 4/6 inhibitor in a male with stage IV breast cancer Mathews J Cancer Sci Mar 1, 2017 (Epub ahead of print) \n57 Gong X Litchfield LM Webster Y Chio LC Wong SS Stewart TR Dowless M Dempsey J Zeng Y Torres R Genomic aberrations that activate D-type cyclins are associated with enhanced sensitivity to the CDK4 and CDK6 inhibitor abemaciclib Cancer Cell 32 761 776 2017 10.1016/j.ccell.2017.11.006 29232554 \n58 DeMichele A Clark AS Tan KS Heitjan DF Gramlich K Gallagher M Lal P Feldman M Zhang P Colameco C CDK 4/6 inhibitor palbociclib (PD0332991) in Rb+ advanced breast cancer: Phase II activity, safety, and predictive biomarker assessment Clin Cancer Res 21 995 1001 2015 10.1158/1078-0432.CCR-14-2258 25501126\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-9450",
"issue": "12(2)",
"journal": "Molecular and clinical oncology",
"keywords": "CDK 4/6 inhibitor; abemaciclib; fulvestrant; male breast cancer; metastatic disease",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "120-125",
"pmc": null,
"pmid": "31929882",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "1538271;27312735;23634254;19260565;25180339;8405206;21143113;22767154;29092024;28580882;15221988;20180015;28177437;9245247;9447971;20609353;10206076;20927582;21223446;11142766;8673091;2061945;25524798;1430274;12543786;9012404;28533223;27217383;22017761;24919854;12115370;29232554;26694922;25850534;3342411;21573973;26957618;14997057;3134119;15542782;8562148;25519043;25501126;3856050;11879560;12379069;2276222;11504305;28055103;17342768;16079314;8319180;26857361",
"title": "Male patient with metastatic stage IV breast cancer achieves complete remission on second line Abemaciclib, Fulvestrant and Leuprolide: A case report.",
"title_normalized": "male patient with metastatic stage iv breast cancer achieves complete remission on second line abemaciclib fulvestrant and leuprolide a case report"
} | [
{
"companynumb": "US-AMGEN-USASP2020117922",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FULVESTRANT"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlthough buprenorphine therapy has proved to be successful in opioid maintenance treatments, the drug is also widely abused in many countries by intravenous injection or sniffing (\"snorting\"). In Finland, buprenorphine is the most important abused opioid causing fatal poisonings.\n\n\nOBJECTIVE\nTo evaluate the drug and alcohol findings as well as the cause and manner of death in all buprenorphine-related post-mortem cases for the age group 14-44 years in Finland from 2000 to 2008.\n\n\nMETHODS\nThis was a retrospective analysis of data on opioid-associated deaths in the Finnish comprehensive postmortem toxicology database based on medico-legal autopsies, case background information and laboratory analyses.\n\n\nRESULTS\nBuprenorphine was found in 29% of all 1,363 opioid-positive cases, and buprenorphine poisoning was the cause of death in 182 cases out of 391 buprenorphine-positive cases (47%). In these fatal poisonings, the blood buprenorphine/norbuprenorphine concentration ratio was significantly higher than in cases with other causes of death. The manner of death in buprenorphine poisonings that were almost exclusively accidental differed significantly from other buprenorphine-related cases, which also involved diseases and suicides. Death was immediate in 10% of fatal buprenorphine poisonings, was delayed, during sleep, in 52%, and followed an unknown course of events in 38%. In immediate poisonings, the median blood buprenorphine concentration (3.0 μg/l) was significantly higher than that in delayed poisonings (1.2 μg/l). In most buprenorphine poisonings (92%), no opioids other than buprenorphine were involved, but benzodiazepines and alcohol were found in 82 and 58% of cases, respectively. The median concentrations of opioids and benzodiazepines in buprenorphine poisonings were in the therapeutic range. Only one fatal poisoning was found in which neither alcohol nor drugs other than buprenorphine were found.\n\n\nCONCLUSIONS\nA fatal buprenorphine poisoning is typically accidental, and the average victim is a 27-year-old male addict. Circumstantial and environmental factors seem to be crucial in determining the outcome of the poisoning.",
"affiliations": "Department of Forensic Medicine, University of Helsinki, Hjelt Institute, PO Box 40, Kytösuontie 11, Helsinki, 00014, Finland.",
"authors": "Häkkinen|Margareeta|M|;Launiainen|Terhi|T|;Vuori|Erkki|E|;Ojanperä|Ilkka|I|",
"chemical_list": "D000701:Analgesics, Opioid; D002492:Central Nervous System Depressants; D001569:Benzodiazepines; D000431:Ethanol; D002047:Buprenorphine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00228-011-1122-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-6970",
"issue": "68(3)",
"journal": "European journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Eur J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000701:Analgesics, Opioid; D001569:Benzodiazepines; D002047:Buprenorphine; D002423:Cause of Death; D002492:Central Nervous System Depressants; D000431:Ethanol; D005260:Female; D005387:Finland; D006801:Humans; D008297:Male; D055815:Young Adult",
"nlm_unique_id": "1256165",
"other_id": null,
"pages": "301-9",
"pmc": null,
"pmid": "21927835",
"pubdate": "2012-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "12233958;12493578;1943071;215096;15966752;14588010;12820745;12705964;10654569;6829887;17286641;9698298;2850923;945347;409449;16521169;18584194;4795079;21306845;17624687;17686941;2850212;409448;19232849;7438685;11137276;21036495;9788517;8988577;7352279;15265095;11516889;21355939;6149907;7293215;7853163;21047194;9926544;16879940;15943948;16289615;20132123;20554411;10707430;20369247;6139041",
"title": "Benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning.",
"title_normalized": "benzodiazepines and alcohol are associated with cases of fatal buprenorphine poisoning"
} | [
{
"companynumb": "FI-MYLANLABS-2017M1064648",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMalignancy and diabetes mellitus (DM) cause significant morbidity and mortality after heart transplantation (HTx). Metformin, one of the most commonly used anti-diabetic drugs worldwide, has also been shown to exhibit anti-tumor activity. We therefore investigated the association between metformin therapy and malignancy after HTx.\n\n\nMETHODS\nThe study population comprised 237 patients who underwent HTx between 1991 and 2016 and were prospectively followed-up. Clinical data were recorded on prospectively designed forms. The primary outcome was any cancer recorded during 15 years of follow-up. Treatment with metformin and the development of DM after HTx were assessed as time-dependent factors in the analyses.\n\n\nRESULTS\nOf the 237 study patients, 85 (36%) had diabetes. Of the DM patients, 48 (56%) were treated with metformin. Kaplan-Meier survival analysis showed that, at 15 years after HTx, malignancy rate was 4% for DM patients treated with metformin, 62% for those who did not receive metformin and 27% for non-DM patients (log-rank test, p < 0.0001). Consistently, multivariate analysis showed that for DM patients, metformin therapy was independently associated with a significant 90% reduction (hazard ratio = 0.10; 95% confidence interval 0.02 to 0.40; p = 0.001) in the risk of the development of a malignancy. DM patients who were treated with metformin had a markedly lower risk (65%; p = 0.001) for the development of a malignancy or death after HTx as compared with non-DM patients.\n\n\nCONCLUSIONS\nOur findings suggest that metformin therapy is independently associated with a significant reduction in the risk of malignancy after HTx.",
"affiliations": "The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: Yael.Peled-Potashnik@sheba.health.gov.il.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Cardiology Department, Loyola University Medical Center, Maywood, Illinois, USA.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;Clalit Health Services, Central Region, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel.;Israeli Association for Cardiovascular Trials, The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; Israeli Association for Cardiovascular Trials, The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel.;The Olga and Lev Leviev Heart Center, Sheba Medical Center, Ramat Gan, Israel; Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Peled|Yael|Y|;Lavee|Jacob|J|;Raichlin|Eugenia|E|;Katz|Moshe|M|;Arad|Michael|M|;Kassif|Yigal|Y|;Peled|Amir|A|;Asher|Elad|E|;Elian|Dan|D|;Har-Zahav|Yedael|Y|;Shlomo|Nir|N|;Freimark|Dov|D|;Goldenberg|Ilan|I|;Klempfner|Robert|R|",
"chemical_list": "D007004:Hypoglycemic Agents; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.healun.2017.06.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1053-2498",
"issue": "36(12)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "diabetes mellitus; heart transplantation; malignancy; metformin; reduction",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": "D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D005544:Forecasting; D016027:Heart Transplantation; D006801:Humans; D007004:Hypoglycemic Agents; D007557:Israel; D008297:Male; D008687:Metformin; D008875:Middle Aged; D009017:Morbidity; D009369:Neoplasms; D011446:Prospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "1350-1357",
"pmc": null,
"pmid": "28736111",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Metformin therapy reduces the risk of malignancy after heart transplantation.",
"title_normalized": "metformin therapy reduces the risk of malignancy after heart transplantation"
} | [
{
"companynumb": "PHHY2017IL178765",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "The Lennox-Gastaut Syndrome (LGS) is a childhood epileptic encephalopathy. Incidence: 1/1.000.000/year, prevalence: 15/100.000. LGS covers 5-10% of epileptic patients and 1-2% of childhood epilepsies. Also referred to as cryptogenic or symptomatic generalized epilepsy. LGS is characterized by: multiple seizures (atypical absences, axial tonic seizures and sudden atonic or myoclonic falls), diffuse slow cryptic EEG waves when awake (<3 Hz), fast rhythmic peaks (10 Hz) during sleep, mental retardation and personality disorders. The LGS is not responding to treatment. Some new drugs have proven to be effective in controlling the disease (Felbamate, Lamotrigine, Topiramate, Levetiracetam). The mortality rate is about 5%; only rarely death is due to epilepsy, which is usually caused by stroke or epileptic episodes. Here we describe the case of a 45-year-old female patient with LGS, severe hypokalemia, mental retardation and focal seizures. Normal renal function: creatinine 0.9 mg/dl, urea 26 mg/dl, creatinine clearance 96 ml/min, serum potassium levels to the minimum: 3.5 mEq/L. This level of potassium, however, had been achieved with the assumption of 8 oral tablets/day of potassium chloride. Osmotic diuresis, use of diuretics, Bartter, Gitelman (normal urinary calcium and magnesium) and pseudo-Bartter syndromes were all excluded whereas aldosteronism was found. Our findings lead to hypokalemia related to assumption of topiramate and hyperaldosteronism. Reduction in drug intake was not effective due to the increased seizures, so the drug was maintained, along with potassium supplementation. In conclusion, the patient has been diagnosed with hypokalemia and iatrogenic hyperaldosteronism, rare in our outpatient practice.",
"affiliations": null,
"authors": "Tattoli|Fabio|F|;Falconi|Daniela|D|;De Prisco|Ornella|O|;Gherzi|Maurizio|M|;Marazzi|Federico|F|;Marengo|Marita|M|;Serra|Ilaria|I|;Tamagnone|Michela|M|;Formica|Marco|M|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0393-5590",
"issue": "32(3)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": null,
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D005260:Female; D006801:Humans; D007008:Hypokalemia; D065768:Lennox Gastaut Syndrome; D008875:Middle Aged",
"nlm_unique_id": "9426434",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26093133",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypokalemia in Lennox-Gastaut syndrome.",
"title_normalized": "hypokalemia in lennox gastaut syndrome"
} | [
{
"companynumb": "IT-JNJFOC-20150619030",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "Primitive neuroectodermal tumours (PNET) that arise in the urinary bladder are an extremely rare occurrence. Very few cases have been reported so far in the literature1-13 and we report another case here in a 31-year-old-female. The patient presented with polyuria, gross hematuria, followed by development of anuria, and was discovered to have a 9.4 cm mass arising in the posterolateral aspect of the bladder. Histologically, the tumour showed small, round, blue cells. Further analysis using break-apart fluorescent in situ hybridization (FISH) revealed non-random chromosomal translocations of the ews gene suggestive of Ewing sarcoma (ES)/PNET. The patient completed seven cycles of neoadjuvant chemotherapy, which significantly reduced the size of the lesion. Due to the location of the lesion, surgical resection of the entire bladder and urethra with use of a continent cutaneous reservoir was performed. Here, the management of a 31-year-old female with ES/PNET arising from the bladder is reported.",
"affiliations": "Michael G. DeGroote School of Medicine, McMaster University, Hamilton, ON, Canada.;Division of Urology, McMaster University, Hamilton, ON, Canada.",
"authors": "Lam|Cameron J|CJ|;Shayegan|Bobby|B|",
"chemical_list": null,
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"title": "Complete resection of a primitive neuroectodermal tumour arising in the bladder of a 31-year-old female after neoadjuvant chemotherapy.",
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"abstract": "Intravenous levetiracetam has been approved for use as an antiepileptic drug, as well as in cases of status epilepticus. There are few reports that detail the clinical data and outcomes associated with this antiepileptic drug, particularly in patients with renal impairment. This was a retrospective analytical study conducted at Khon Kaen University's Srinagarind Hospital in Thailand. The study period was between January 1, 2010 and December 31, 2014. The inclusion criteria were that patents were over 15 years old, had renal impairment, and had received intravenous levetiracetam treatment. The main clinical outcomes were seizure control and mortality. Clinical outcomes were compared between those with and without status epilepticus. Mortality of patients with status epilepticus were compared in terms of seizure control and order of intravenous levetiracetam treatment. During the study period, there were 247 patients who met the study criteria. The average age of the patients was 58 years with nearly equal sex distribution. Of those, 90 patients (36.4%) had GRFs of less than 15 mL/min/1.73 m2 and 60 patients (24.3%) received intravenous LEVE due to status epilepticus. The seizure control rates in the status epilepticus and non-status epilepticus groups were 36.7% and 88.7%, respectively (P<0.001). The mortality rate did not differ significantly between the two groups (33.3% vs 27.8%; P=0.418). There was no significant overall difference in mortality rate between seizure-controlled and seizure-uncontrolled patients in the status epilepticus group. In the convulsive status epilepticus group, variations in terms of treatment order of intravenous levetiracetam and seizure control resulted in no significant difference in mortality rates (P=0.311). No major side effects were detected in any patients after the intravenous levetiracetam treatment. In conclusion, intravenous levetiracetam treatment was effective and safe in patients with renal impairment.",
"affiliations": "Cinical Pharmacy Division, Faculty of Pharmaceutical Sciences, Khon Kaen University.;Cinical Pharmacy Division, Faculty of Pharmaceutical Sciences, Khon Kaen University.;Cinical Pharmacy Division, Faculty of Pharmaceutical Sciences, Khon Kaen University.;Department of Medicine, Faculty of Medicine, Khon Kaen University, Thailand.;Integrated Epilepsy Research Group, Khon Kaen University.",
"authors": "Lapmag|Anyamanee|A|;Lertsinudom|Sunee|S|;Chaiyakam|Aporanee|A|;Sawanyawisuth|Kittisak|K|;Tiamkao|Somsak|S|;|||",
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"fulltext": "\n==== Front\nNeurol IntNINeurology International2035-83852035-8377PAGEPress Publications, Pavia, Italy 10.4081/ni.2018.7469ArticleClinical outcomes of intravenous levetiracetam treatment in patients with renal impairment Lapmag Anyamanee 12Lertsinudom Sunee 123Chaiyakam Aporanee 12Sawanyawisuth Kittisak 4Tiamkao Somsak 34Group on behalf of Integrated Epilepsy Research University Khon Kaen 1 Cinical Pharmacy Division, Faculty of Pharmaceutical Sciences, Khon Kaen University2 The College of Pharmacotherapy of Thailand, Pharmacy Council, Bangkok3 Integrated Epilepsy Research Group, Khon Kaen University4 Department of Medicine, Faculty of Medicine, Khon Kaen University, ThailandDepartment of Medicine, Faculty of Medicine, Khon Kaen University, 40002, Khon Kaen, Thailand. somtia@kku.ac.thContributions: the authors contributed equally.\n\nConflict of interest: the authors declare no potential conflict of interest.\n\n25 9 2018 05 9 2018 10 3 746928 10 2017 25 1 2018 09 3 2018 ©Copyright A. Lapmag et al., 20182018Licensee PAGEPress, ItalyThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Intravenous levetiracetam has been approved for use as an antiepileptic drug, as well as in cases of status epilepticus. There are few reports that detail the clinical data and outcomes associated with this antiepileptic drug, particularly in patients with renal impairment. This was a retrospective analytical study conducted at Khon Kaen University’s Srinagarind Hospital in Thailand. The study period was between January 1, 2010 and December 31, 2014. The inclusion criteria were that patents were over 15 years old, had renal impairment, and had received intravenous levetiracetam treatment. The main clinical outcomes were seizure control and mortality. Clinical outcomes were compared between those with and without status epilepticus. Mortality of patients with status epilepticus were compared in terms of seizure control and order of intravenous levetiracetam treatment. During the study period, there were 247 patients who met the study criteria. The average age of the patients was 58 years with nearly equal sex distribution. Of those, 90 patients (36.4%) had GRFs of less than 15 mL/min/1.73 m2 and 60 patients (24.3%) received intravenous LEVE due to status epilepticus. The seizure control rates in the status epilepticus and non-status epilepticus groups were 36.7% and 88.7%, respectively (P<0.001). The mortality rate did not differ significantly between the two groups (33.3% vs 27.8%; P=0.418). There was no significant overall difference in mortality rate between seizure-controlled and seizure-uncontrolled patients in the status epilepticus group. In the convulsive status epilepticus group, variations in terms of treatment order of intravenous levetiracetam and seizure control resulted in no significant difference in mortality rates (P=0.311). No major side effects were detected in any patients after the intravenous levetiracetam treatment. In conclusion, intravenous levetiracetam treatment was effective and safe in patients with renal impairment.\n\nKey words\nstatus epilepticusdosemortalityFunding: none.\n==== Body\nIntroduction\nEpilepsy is a common disease in clinical practice. There were at least 70 million people worldwide suffered from epilepsy in 2010.1 Untreated or uncontrolled epilepsy may lead to several serious conditions or complications including status epilepticus. The administration of antiepileptic drugs is the main method used in the treatment of epilepsy, and is aimed at to controlling seizures, avoiding side effects, and maintaining a good quality of life.2 Currently, there are at least 155 antiepileptic products registered in Hong Kong, including new antiepileptic drugs such as levetiracetam and zonisamide.3 The International League Against Epilepsy (ILAE) reported that further clinical studies are required to evaluate the relevant overall outcomes associated with antiepileptic drugs.4\n\nIntravenous levetiracetam has been approved for use as an antiepileptic drug, as well as in cases of status epilepticus.5 Although it is effective, the dosage for patients with renal impairment should be reduced.6 Since levetiracetam clearance via kidney is 66% in patients with renal impairment, its half-life may last for 25 hours.7 Additionally, body clearance decreases by 50% in patients with an estimated glomerular filtration rate of 30-50 mL/min.6 Despite the widespread use of intravenous levetiracetam, there are few reports that detail the clinical data and outcomes associated with this antiepileptic drug, particularly in patients with renal impairment. This study aimed to evaluate the clinical use of intravenous levetiracetam in patients with renal impairment.\n\nMaterials and Methods\nThis was a retrospective analytical study conducted at Khon Kaen University’s Srinagarind Hospital in Thailand. The study period was between January 1, 2010 and December 31, 2014. The inclusion criteria were that patents were over 15 years old, had renal impairment, and had received intravenous levetiracetam treatment. The definition of renal impairment was based on creatinine clearance using the Cockcroft- Gault formula adjusted by skin surface area.8 The study protocol was approved by the ethic committee in human research, Khon Kaen University (HE591031).\n\nMedical records of all eligible patients were reviewed. Baseline characteristics, estimated glomerular filtration rate (GFR, mL/min), indications for intravenous levetiracetam treatment, details regarding intravenous levetiracetam treatment, and clinical outcomes were recorded. The main clinical outcomes were seizure control and mortality. The definitions for clinical terms were as follows: antiepileptic drug treatment order in cases of status epilepticus was determined after initial benzodiazepine treatment; seizure control indicated that seizures were under control and there were no recurrent seizures within 24 hours after treatment with intravenous levetiracetam; and death meant in-hospital mortality regardless of cause.\n\nStatistical analysis. Data of all eligible patients were analyzed using descriptive statistics. Baseline clinical data and treatment with intravenous levetiracetam are presented as mean (SD) or number (percentage). Clinical outcomes were compared between those with and without status epilepticus using a Chi-square test, while mortality of patients with status epilepticus were compared in terms of seizure control and order of intravenous levetiracetam treatment using a Fisher’s Exact test. Statistical significance was defined as a P value less than 0.05. All statistical analysis was performed using STATA software version 10.1 (College Station, Texas, USA) and SPSS program version 16 (Chicago, Illinois, USA).\n\nResults\nDuring the study period, there were 247 patients who met the study criteria. The average age of the patients was 58 years with nearly equal sex distribution. Of those, 90 patients (36.4%) had GRFs of less than 15 mL/min/1.73 m2 and 60 patients (24.3%) received intravenous levetiracetam due to status epilepticus. Intravenous levetiracetam was administered as the first-line antiepileptic drug in 165 patients (66.8%) and was given at a dose between 1-2 gm/day in 226 patients (91.5%). There were 44 patients who received intravenous levetiracetam without dose adjustment for renal impairment, but 97.7% were given a dose that was within treatment dosage range (Table 1). The average expense per patient was 13,072 Baht (373.5 USD) which was due to the cost of intravenous levetiracetam, at 10,165 Baht (290.4 USD).\n\nThe seizure control rates in the status epilepticus and non-status epilepticus groups were 36.7% and 88.7%, respectively (P<0.001). The mortality rate did not differ significantly between the two groups (33.3% vs 27.8%; P value 0.418). The most common cause of death in both groups was sepsis (44 patients) as shown in Table 2. There was no significant overall difference in mortality rate between seizure-controlled and seizure-uncontrolled patients in the status epilepticus group (Table 3). In the status epilepticus group, variations in terms of treatment order of intravenous levetiracetam and seizure control resulted in no significant difference in mortality rates, as shown in table 3 (P value 0.311). No major side effects were detected in any patients after the intravenous levetiracetam treatment.\n\nDiscussion and Conclusions\nLevetiracetam is a broad-spectrum antiepileptic drug and is approved as adjunctive therapy for focal-onset seizures, myoclonic seizure, juvenile myoclonic epilepsy, and primary generalized tonicclonic seizures in patients six years of age and older.9,10 The benefit of levetiracetam is its low drug interaction due to independent metabolism via the cytochrome P450 system. 11 However, in patients with renal impairment, dose adjustment is required.12\n\nIn this study, the most common indication for intravenous levetiracetam treatment was non-status epilepticus (119 patients or 48.2%), followed by status epilepticus (60 patients or 24.3%). There were 23 patients (9.3%) who received intravenous levetiracetam due to perioperative brain surgery prophylaxis. A previous study showed that intravenous levetiracetam reduced the rate of postoperative seizure in brain surgery from 15-20% to 7.3%.13 Most patients received the appropriate dose for renal impairment (203 patients; 82.2%). Although 44 patients received an inappropriate dose, the drug levels were within therapeutic range for 43 patients (97.7%), as shown in Table 1. These findings may imply that intravenous levetiracetam may have a rather wide therapeutic range in renal impairment. Intravenous levetiracetam was prescribed as the first-line treatment at the highest ratio (66.8%) due to low drug interaction.11\n\nIntravenous levetiracetam was more effective in terms of seizure control in the non-status epilepticus group than in the status epilepticus group (88.7% vs 36.7%). In this study, intravenous levetiracetam had a lower seizure-control rate than it did in a previous study.14 A study conducted by Oman found that intravenous levetiracetam had a seizure-control rate of 82% in 22 status epilepticus patients. In our previous study, the seizure-control rate of intravenous levetiracetamin cases of status epilepticus was lower than that of sodium valproate (47.06%) but higher than phenytoin (21.62%).15 These findings may be explained by differences in study population. Both previous studies were conducted in normal adults, but this study was performed in patients with renal impairment. This may indicate that intravenous levetiracetam may have lower efficacy in this setting. Note that mortality rates did not differ between status epilepticus and non-status epilepticus patients.\n\nThe overall mortality rate for the 60 patients with status epilepticus in the seizures-controlled group did not differ from that of the seizures-uncontrolled group (36.4% vs 31.6%), as shown in Table 3. Additionally, the order of intravenous levetiracetam did not affect the overall mortality rate (P value 0.311). As previously reported, factors associated with mortality in status epilepticus are varied, but the types of antiepilptic drugs administered is not among them.15-18 The mortality rates in status epilepticus patients treated with phenytoin and sodium valproate were 29.73% and 11.76%, respectively (P value 0.189).15 Older age or early treatment may be associated with status epilepticus mortality.16-18 Further studies may be needed to confirm the results of this study in terms of order of intravenous levetiracetam treatment on mortality in status epilepticus patients.\n\nThere are some limitations to this study. First, mortality in this study was not specifically due to seizure and was recorded as inhospital mortality. No long-term mortality rates were recorded. Additionally, definition of seizure control in this study implied only 24 hours after seizure cessation. Second, there was no correlation data with regard to the level of renal impairment and treatment outcomes. Third, some data were missing due to the retrospective nature of the medical record reviews. Most patients in this study (91.5%) received intravenous levetiracetam treatment between 1000-1999 mg/day despite almost equal of CKD level distribution (Table 1). These findings occurred because the recommended dose for those with GFR less than 50 is between 500-1500 mg/day (Table 4).19 Finally, as mentioned earlier, predictors for mortality and seizure control were not studied.\n\nIn conclusion, intravenous levetiracetam treatment was effective in patients with renal impairment.\n\nTable 1. Baseline characteristics and treatment of patients with renal impairment who received intravenous levetiracetam (n=247).\n\nFactors\tValues\t\nMean age (SD), years\t58.0 (18.8)\t\nMale sex\t120 (48.6)\t\nGlomerular filtration rate (GFR), mL/min/1.73 m2\t\t\n 45-59\t63 (25.5)\t\n 30-44\t33 (13.4)\t\n 15-29\t61 (24.7)\t\n <15\t90 (36.4)\t\nIndications\t\t\n Status epilepticus\t60 (24.3)\t\n Non-status epilepticus\t187 (75.7)\t\n Naïve to levetiracetam\t119 (48.2)\t\n Currently on levetiracetam\t19 (7.7)\t\n Pre-operative prophylaxis\t23 (9.3)\t\n Others\t26 (10.5)\t\nDose, mg/d\t\t\n 500-999\t17 (6.9)\t\n 1000-1999\t226 (91.5)\t\n 2000-3000\t4 (1.6)\t\n Inappropriate dose by GFR\t44 (17.8)\t\n Dose within therapeutic range\t43 (97.7)\t\nTreatment order\t\t\n First-line\t165 (66.8)\t\n Second-line\t64 (25.9)\t\n Third-line\t15 (6.1)\t\n Fourth-line\t3 (1.2)\t\nMean (SD) numbers of levetiracetam vials/patient\t25.2 (24.6)\t\nMean (SD) of levetiracetam treatment, days\t8.6 (11.3)\t\nTable 2. Clinical outcomes of patients with renal impairment who received intravenous levetiracetam (n=247) categorized by status epilepticus.\n\nOutcomes\tStatus epilepticus (n=60)\tNon- status epilepticus (n=187)\tP value\t\nSeizure controlled\t22 (36.7)\t166 (88.7)\t< 0.001\t\nDeath\t20 (33.3)\t52 (27.8)\t0.418\t\n Sepsis\t14\t30\t\t\n Gastric perforation/UGIB\t2\t1\t\t\n Severe metabolic disturbance\t2\t7\t\t\n Respiratory failure\t1\t4\t\t\n Sudden cardiac arrest/shock\t1\t8\t\t\n Hypovolemic shock\t0\t1\t\t\n Liver failure\t0\t1\t\t\nData presented as number (percentage); UGBI: upper gastrointestinal bleeding.\n\nTable 3. Mortality of status epilepticus patients with renal impairment who received intravenous levetiracetam (n=60) categorized by treatment order of intravenous levetiracetam and seizure control (P=0.311).\n\nOrder of intravenous levetiracetam\tSeizures controlled (n=22)\tSeizures uncontrolled\tTotal\t\n\tDied\t(n=22) Survived\tTotal\tDied\t(n=38) Survived\tTotal\t\t\nFirst line\t4\t9\t13\t8\t10\t18\t31\t\nSecond line\t4\t1\t5\t3\t10\t13\t18\t\nThird line\t0\t4\t4\t0\t4\t4\t8\t\nFourth line\t0\t0\t0\t1\t2\t3\t3\t\nTotal\t8\t14\t22\t12\t26\t38\t60\t\nTable 4. Doses of intravenous levetiracetam renal impairment.\n\nGlomerular filtration rate (mL/min/1.73m2)\tDoses (mg)\tTotal doses (mg)/day\t\n50-80\t500-1,000 q 12 h\t1000-2000\t\n30-50\t250-750 mg q 12 h\t500-1500\t\n< 30\t250-500 mg q 12 h\t500-1000\n==== Refs\nReferences\n1. Ngugi AK Bottomley C Kleinschmidt I \nEstimation of the burden of active and life-time epilepsy: a metaanalytic approach . Epilepsia \n2010 ;51 :883 -90 .20067507 \n2. Schachter SC \nAdvances in the assessment of refractory epilepsy . Epilepsia \n1993 ;34 :S24 -30 .8339713 \n3. Fong JK Chan EL Leung H \nAn update of the Hong Kong Epilepsy Guideline: consensus statement on the use of antiepileptic drugs in Hong Kong . Hong Kong Med J \n2017 ;23 :74 -88 .28184017 \n4. Glauser T Ben-Menachem E Bourgeois B \nUpdated ILAE evidence review of antiepileptic drug efficacy and effectiveness as initial monotherapy for epileptic seizures and syndromes . Epilepsia \n2013 ;54 :551 -63 .23350722 \n5. Trinka E Dobesberger J. \nNew treatment options in status epilepticus: a critical review on intravenous levetiracetam . Ther Adv Neurol Disord \n2009 ;2 :79 -91 .21180643 \n6. Radtke RA \nPharmacokinetics of levetiracetam . Epilepsia \n2001 ;42 :24 -71 .\n7. Wright C Downing J Mungall D \nClinical pharmacology and pharmacokinetics of levetiracetam . Front Neurol \n2013 ;4 :192 .24363651 \n8. [No authors listed] \nChapter 1: Definition and classification of CKD . Kidney Int Suppl \n2013 ;3 :19 -62 .\n9. Delanty N Jones J Tonner F. \nAdjunctive levetiracetam in children, adolescents, and adults with primary generalized seizures: open-label, noncomparative, multicenter, long-term follow-up study . Epilepsia \n2012 ;53 : 111 -9 .22050371 \n10. Mbizvo GK Dixon P Hutton JL Marson AG \nLevetiracetam add-on for drug-resistant focal epilepsy: an updated Cochrane Review . Cochrane Database Syst Rev \n2012 ;9 :CD001901 .\n11. Otoul C De Smedt H Stockis A. \nLack of pharmacokinetic interaction of levetiracetam on carbamazepine, valproic acid, topiramate, and lamotrigine in children with epilepsy . Epilepsia \n2007 ;48 :2111 -5 .17651416 \n12. Yamamoto J Toublanc N Kumagai Y Stockis A. \nLevetiracetam pharmacokinetics in Japanese subjects with renal impairment . Clin Drug Invest \n2014 ;34 :819 -28 .\n13. Gokhale S Khan SA Agrawal A Friedman AH McDonagh DL \nLevetiracetam seizure prophylaxis in craniotomy patients at high risk for postoperative seizures . Asian J Neurosurg \n2013 ;8 :169 -73 .24550999 \n14. Gujjar AR Nandhagopal R Jacob PC \nIntravenous levetiracetam vs phenytoin for status epilepticus and cluster seizures: A prospective, randomized study . Seizure \n2017 ;49 :8 -12 .28528211 \n15. Tiamkao S Sawanyawisuth K Chancharoen A. \nThe efficacy of intravenous sodium valproate and phenytoin as the first-line treatment in status epilepticus: a comparison study . BMC Neurol \n2013 ;13 :98 .23889906 \n16. Kantanen AM Reinikainen M Parviainen I Kälviäinen R. \nLong-term outcome of refractory status epilepticus in adults: A retrospective population- based study . Epilepsy Res \n2017 ;133 :13 -21 .28402834 \n17. Tiamkao S Pranboon S Thepsuthammarat K Sawanyawisuth K. \nStatus epilepticus in the elderly patients: A national data study in Thailand . J Neurol Sci \n2017 ;372 :501 -5 .27842985 \n18. Moghaddasi M Joodat R Ataei E. \nEvaluation of Shortterm Mortality of Status Epilepticus and Its Risk Factors . J Epilepsy Res \n2015 ;5 :13 -6 .26157668 \n19. French J \nUse of levetiracetam in special populations . Epilepsia \n2001 ;42 :40 -3 .11564125\n\n",
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"title": "Clinical outcomes of intravenous levetiracetam treatment in patients with renal impairment.",
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"abstract": "To describe international normalized ratio (INR) trends and warfarin dosage adjustments required for four veterans who were receiving warfarin therapy and started treatment for hepatitis C virus (HCV) with ledipasvir/sofosbuvir with or without ribavirin.\n\n\n\nCase series.\n\n\n\nPharmacist-led anticoagulation clinic in a Veterans Affairs Health Care System.\n\n\n\nFour patients aged 59-66 years who were receiving warfarin and had stable, therapeutic INRs and started ledipasvir/sofosbuvir therapy with or without ribavirin for HCV infection.\n\n\n\nAll four patients developed subtherapeutic INRs after the addition of ledipasvir/sofosbuvir with or without ribavirin. An increase in weekly warfarin dose ranging from 14-67% was required, with changes in warfarin doses starting 2-3 weeks after ledipasvir/sofosbuvir initiation. Two patients required dose reductions after HCV treatment completion, whereas the other two did not. Use of the Drug Interaction Probability Scale indicated that the interaction between warfarin and ledipasvir/sofosbuvir was doubtful (score of 1 [two patients]) or possible (score of 4 [two patients]). The mechanism of this interaction is unknown but may be related to improvements in hepatic function during HCV treatment.\n\n\n\nTo our knowledge, this is the first case series describing a possible drug interaction between warfarin and ledipasvir/sofosbuvir (with or without ribavirin). Close monitoring is warranted when ledipasvir/sofosbuvir is initiated in patients receiving anticoagulation therapy with warfarin, especially those with evidence of cirrhosis prior to treatment. This is particularly important in the first month after starting treatment and the first month after completion. Failure to monitor and achieve therapeutic INR after HCV therapy completion may have the potential to result in adverse outcomes.",
"affiliations": "Pharmacy Department, Durham Veterans Affairs Health Care System, Durham, North Carolina.;Pharmacy Department, Durham Veterans Affairs Health Care System, Durham, North Carolina.;Pharmacy Department, Durham Veterans Affairs Health Care System, Durham, North Carolina.;Pharmacy Department, Durham Veterans Affairs Health Care System, Durham, North Carolina.;Pharmacy Department, Durham Veterans Affairs Health Care System, Durham, North Carolina.",
"authors": "Britnell|Sara R|SR|;Willets|Amy E|AE|;Vanderman|Adam J|AJ|;Woodard|Catherine L|CL|;Britt|Rachel B|RB|0000-0003-4303-7316",
"chemical_list": "D000925:Anticoagulants; D000998:Antiviral Agents; D001562:Benzimidazoles; D005449:Fluorenes; C000595958:ledipasvir, sofosbuvir drug combination; D012254:Ribavirin; D014859:Warfarin; D014542:Uridine Monophosphate; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1845",
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"issue": "36(11)",
"journal": "Pharmacotherapy",
"keywords": "chronic; drug interactions; hepatitis C; ledipasvir; ribavirin; sofosbuvir; veterans; warfarin",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000368:Aged; D000925:Anticoagulants; D000998:Antiviral Agents; D001562:Benzimidazoles; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005449:Fluorenes; D019698:Hepatitis C, Chronic; D006801:Humans; D019934:International Normalized Ratio; D008297:Male; D008875:Middle Aged; D010593:Pharmaceutical Services; D010595:Pharmacists; D012254:Ribavirin; D000069474:Sofosbuvir; D016896:Treatment Outcome; D014542:Uridine Monophosphate; D014728:Veterans; D014859:Warfarin",
"nlm_unique_id": "8111305",
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"pages": "1173-1179",
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"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Influence of Successful Chronic Hepatitis C Virus Treatment with Ledipasvir/Sofosbuvir on Warfarin Dosing Requirements in Four Veterans.",
"title_normalized": "influence of successful chronic hepatitis c virus treatment with ledipasvir sofosbuvir on warfarin dosing requirements in four veterans"
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"druga... |
{
"abstract": "OBJECTIVE\nTo improve the understanding of pulmonary mucormycosis by analyzing the clinical manifestations, imaging features, diagnosis, treatment and prognosis of this disease.\n\n\nMETHODS\nThe clinical data of eight patients diagnosed as pulmonary mucormycosis by histopathologic examination were retrospectively analyzed.\n\n\nRESULTS\nEight patients included six males and two females with age from 36 days to 66 years. Underlying conditions covered diabetes (n = 4), renal transplantation (n = 3), premature (n = 1) and long-term corticosteroid treatment in two cases. Imaging manifestations revealed multiple irregular lumps or nodules in three cases, multiple cavities with thick wall in three cases, diffuse lung infiltrate in one case and lung opacities in one case. The diagnoses of seven patients were confirmed by percutaneous needle lung biopsy and the remaining one was diagnosed with fiberoptic bronchoscopy biopsy. Surgery combined with amphotericin B liposome (60 mg/d for three weeks) was applied to one patient who was cured with no recurrence after a 22 month follow-up. Three cases were given amphotericin B liposome (a newborn with 7mg/d for 62 days, the other two 60 mg/d for 31 days and 70 mg/d for 71 days respectively). All had achieved marked response with follow up from 8 to 29 months, but one patient relapsed and died of recurrent lung mucormycosis. The other three patients were treated with itraconazole 400-200 mg/d from 21 days to 1 year with duration of follow up from 1 month to 20 months. One patient was not evaluable due to missing. Two patients relapsed and one died.\n\n\nCONCLUSIONS\nPulmonary mucormycosis is difficult to diagnose and treat with a high mortality. Percutaneous transthoracic lung biopsy is a useful diagnostic method. Amphotericin B liposome or itraconazole may be active against mucus. Early control of causes is essential to improve the prognosis and reduce the recurrence in patients with pulmonary mucormycosis.",
"affiliations": "Respiratory and Critical Care Medicine, Fuzhou General Hospital of Nanjing Military Command, Fuzhou 350025, China. Email: laiguoxiang2007@163.com.",
"authors": "Xu|Liyu|L|;Bao|Yuwang|Y|;Wang|Shibiao|S|;Liu|Deling|D|;Yu|Yinghao|Y|;Liu|Daoming|D|;Lai|Guoxiang|G|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0578-1426",
"issue": "53(3)",
"journal": "Zhonghua nei ke za zhi",
"keywords": null,
"medline_ta": "Zhonghua Nei Ke Za Zhi",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D055815:Young Adult",
"nlm_unique_id": "16210490R",
"other_id": null,
"pages": "206-9",
"pmc": null,
"pmid": "24767209",
"pubdate": "2014-03",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A clinical analysis of eight proven cases of pulmonary mucormycosis.",
"title_normalized": "a clinical analysis of eight proven cases of pulmonary mucormycosis"
} | [
{
"companynumb": "CN-PFIZER INC-2015317011",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "Patients with refractory ascites that develops >3 months after allogenic stem cell transplantation typically have a poor prognosis. We present the case of a 61-year-old man who developed refractory massive ascites approximately 3 months after cord blood transplantation (CBT) and showed complete and spontaneous remission from ascites after 18 months. The patient complained of severe bloating and needed weekly paracentesis to manage the fluid levels. Laboratory tests indicated that the ascites was caused by liver fibrosis. After the patient underwent Keisuke-Matsusaki cell-free and concentrated ascites reinfusion therapy (KM-CART), we were able to decrease the frequency of paracentesis treatments. We planned a transjugular liver biopsy, but the patient contracted pneumocystis pneumonia before the procedure could be performed. Although the pneumonia improved, the ascites worsened again. However, weekly paracentesis spontaneously stopped the progression of ascites and eventually resolved it completely, resulting in the patient's survival.",
"affiliations": "Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.;Division of Hematology, Department of Internal Medicine, National Defense Medical College.",
"authors": "Kawamura|Toshikuni|T|;Teramoto|Masahiro|M|;Sone|Takehiro|T|;Takada|Kohei|K|;Ogata|Hiraku|H|;Saito|Keita|K|;Izumi|Takuya|T|;Okada|Yosuke|Y|;Tachi|Noriaki|N|;Kobayashi|Shinichi|S|;Kimura|Fumihiko|F|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.62.20",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "62(1)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Ascites; Concentrated ascites reinfusion therapy (CART); Cord blood transplantation (CBT)",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D001201:Ascites; D036101:Cord Blood Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008103:Liver Cirrhosis; D008297:Male; D008875:Middle Aged; D019152:Paracentesis",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "20-24",
"pmc": null,
"pmid": "33551420",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia.",
"title_normalized": "spontaneous resolution of refractory ascites in the late phase after cord blood transplantation in acute myeloid leukemia"
} | [
{
"companynumb": "JP-OTSUKA-2021_005247",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUSULFAN"
},
"drugadditional": null,
"d... |
{
"abstract": "Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation. We report a patient with chronic kidney disease who had deterioration of renal function due to combination of risk factors like hypothyroidism and interaction of amlodipine and clopidogrel with statins.",
"affiliations": "Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India.",
"authors": "Ram|R|R|;Swarnalatha|G|G|;Ramesh|V|V|;Rao|K Nageswar|KN|;Dakshinamurty|K V|KV|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0971-4065.111853",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-23-21110.4103/0971-4065.111853Case ReportRhabdomyolysis induced acute renal failure secondary to statins Ram R. Swarnalatha G. Ramesh V. Rao K. Nageswar 1Dakshinamurty K. V. Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India1 Department of Orthopaedics, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, IndiaAddress for correspondence: Dr. Rapur Ram, Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, India. E-mail: ram_5_1999@yahoo.comMay-Jun 2013 23 3 211 213 Copyright: © Indian Journal of Nephrology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation. We report a patient with chronic kidney disease who had deterioration of renal function due to combination of risk factors like hypothyroidism and interaction of amlodipine and clopidogrel with statins.\n\nAcute renal failureamlodipineclopidogrelhypothyroidismrhabdomyolysisstatins\n==== Body\nIntroduction\nRhabdomyolysis is characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation. The spectrum of the syndrome ranges from asymptomatic serum muscle enzymes elevation to life-threatening extreme enzyme elevations, electrolyte imbalances, and acute renal failure. We report an elderly lady with a combination of risk factors who developed rhabdomyolytic acute renal failure.\n\nCase Report\nA 65-year-old lady was suffering from type 2 diabetes for the past 30 years, hypertension for the past 20 years, and coronary heart disease for the past 10 years. She was diagnosed chronic kidney disease about 6 months ago. Her serum creatinine was stable at 2.0 mg/dL. The medications included clopidogrel 75 mg/day, amlodipine 10 mg/day, frusemide 40 mg bds, and insulin. A week before presenting to us, a cardiologist had added atorvastatin 10 mg/day to her prescription. She presented to us with complaints of severe generalized myalgia, difficulty in assuming upright posture from sitting position, and difficulty in walking of 1 week duration. She also complained of swelling of feet, face, nausea, loss of appetite and noticed decreased urine output, and reddish discoloration to urine for the last 3 days. There was no fever, history of trauma, viral exanthem, severe exercise, seizure, uncontrolled blood glucose, and use of herbal medication preceding the illness. On examination, she was well-built and well-nourished, and had pedal edema and facial puffiness. There was no icterus, no clubbing, and no lymphadenopathy. She was afebrile with pulse rate of 60 beats per min and blood pressure of 160/90 mm Hg. Neurological examination showed 2/5 power in all four limbs, absent deep tendon reflexes, and muscle tenderness with no sensory involvement. Examination of cardiovascular, respiratory, and gastrointestinal systems was unremarkable. The investigations are presented in Table 1.\n\nTable 1 Investigations\n\nUrinalysis showed glucose 2+, ketone bodies negative, blood positive, red blood cells nil, and white blood cells 1-2/hpf. Her hemoglobin was 11.4 g/dL, total leukocyte count 18, 300 per mm3, platelet count 5.0 lakh per mm3, ESR 20 mm after 1 h, electrocardiogram showed tall peaked and widened T waves with proximal limb steeper than distal limb, and the chest radiograph was normal. Ultrasound abdomen showed right kidney 9.3 × 3.7 cm and left kidney 9.2 × 3.2 cm. The urine and blood cultures were sterile, HIV, HBsAg, anti-HCV antibodies, anti-HAV IgM, and anti-HEV IgM were negative.\n\nPatient was initiated on hemodialysis. Myalagia, reddish discoloration to urine, deterioration of renal function, elevated SGOT, creatinine kinase, and increased urine myoglobin led to the diagnosis of rhabdomyolysis. Atorvastatin was stopped. Levothyroxine replacement was initiated at a dose of 50 μg/day, increased after 15 days to 100 μg/day. The following three risk factors for the onset of rhabdomyolysis were identified: Use of statin, undiagnosed hypothyroidism, and co-administration of amlodipine and clopidogrel. Amlodipine and clopidogrel were also withheld. Frusemide was stopped as she had hypokalemia before the onset of illness which was again a risk factor for rhabdomyolysis. After seven sessions of hemodialysis the urine output improved and serum creatinine stabilized at 3.2 mg/dL. Creatine kinase and SGOT levels returned to normal. She regained power in all limbs. Deep tendon reflexes appeared again.\n\nDiscussion\nIn randomized controlled trials, statin myopathy incidence is about 1.5–5.0%.[12] However, it is difficult to directly compare the incidence of statin myopathy in clinical trials with real world clinical practice given the inconsistent definitions. The common risk factors for the development of a statin-induced myopathy include high dosages, increasing age, female sex, renal and hepatic insufficiency, diabetes mellitus and concomitant therapy with fibrates, cyclosporine, macrolide antibiotics, warfarin, and digoxin.[3]\n\nIndividual statins differ in their risk of inducing rhabdomyolysis, with some patients developing this syndrome when switching from one statin to another. Other patients developed rhabdomyolysis when exposed to any statin. It is probable that genetic factors play a role in the pathogenesis of this syndrome. The temporal relation between statin therapy and the onset or resolution of myopathy is not fully defined. A retrospective study of 45 patients with statin myopathy at a tertiary center revealed a mean therapy duration of 6.3 months before symptom onset and a mean duration of 2.3 months for symptom resolution after discontinuation of statin therapy.[4] Patients in PRIMO study developed muscle symptoms after a median of 1 month after initiation of statin therapy, ranging up to 12 months after initiation.[5]\n\nThe combinations of risk factors present in this patient were not widely reported.[6] Hypothyroidism was reported as a predictor of statin-associated myopathy (OR 1.71; CI, 1.10-2.65) in PRIMO study.[5] Hypothyroidism could itself be a risk factor for renal impairment. The likely mechanisms of renal impairment in hypothyroidism are the reduction in glomerular filtration rate due to the lower cardiac output and renal blood flow,[7] thyroxine may mediate tubular secretion of creatinine,[8] hypothyroidism may increase creatinine release from muscle,[9] and rhabdomyolysis.[10]\n\nAmlodipine, atorvastatin, and clopidogrel are metabolized by hepatic CYP450 3A4. It is possible for two different substrates of the same metabolizing enzyme to compete for catalytic sites on the same enzyme; through competitive inhibition, one substrate may gain access to these sites whereas the other is excluded. This process results in metabolism of the drug that successfully accesses the catalytic sites of the enzyme, whereas the excluded drug is metabolized at a significantly slower rate.[1112] In the present patient there were three drugs which might have competed for the hepatic CYP450 3A4 enzyme. The metabolism of atorvastatin might have been slowed.\n\nThe present patient provided a caution that hypothyroidism and interaction with other drugs should be considered when patients were going to be initiated on statins.\n\nSource of Support: Nil\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Bays H Statin safety: An overview and assessment of the data - 2005 Am J Cardiol 2006 97 6C 26 \n2 Law M Rudnicka AR Statin safety: A systematic review Am J Cardiol 2006 97 52C 60 \n3 Thompson PD Clarkson P Karas RH Statin-associated myopathy JAMA 2003 289 1681 90 12672737 \n4 Hansen KE Hildebrand JP Ferguson EE Stein JH Outcomes in 45 patients with statin-associated myopathy Arch Intern Med 2005 165 2671 6 16344427 \n5 Bruckert E Hayem G Dejager S Yau C Bégaud B Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients - The PRIMO study Cardiovasc Drugs Ther 2005 19 403 14 16453090 \n6 Kursat S Alici T Colak HB A case of rhabdomyolysis induced acute renal failure secondary to statin-fibrate-derivative combination and occult hypothyroidism Clin Nephrol 2005 64 391 3 16312269 \n7 Katz AI Emmanouel DS Lindheimer MD Thyroid hormone and the kidney Nephron 1975 15 223 49 1101087 \n8 den Hollander JG Wulkan RW Mantel MJ Berghout A Correlation between severity of thyroid function and renal dysfunction Clin Endocrinol 2005 62 423 7 \n9 Kuhlback B Creatine and creatinine metabolism in thyrotoxicosis and hypothyroidism; a clinical study Acta Med Scand Suppl 1957 331 1 70 13508118 \n10 Altay M Duranay M Ceri M Rhabdomyolysis due to hypothyroidism Nephrol Dial Transplant 2005 20 847 8 15716291 \n11 Horn JR Hansten PD Do statins inhibit clopidogrel’s antiplatelet activity? Pharm Times 2003 Last accessed 2012 May 22 10 1 2 Available from: www.http://hanstenandhorn.com/hh-article10-03.pdf \n12 Burton JR Burton I Pearson GJ Clopidogrel-precipitated rhabdomyolysis in a stable heart transplant patient Ann Pharmacother 2007 41 133 7 17200431\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "23(3)",
"journal": "Indian journal of nephrology",
"keywords": "Acute renal failure; amlodipine; clopidogrel; hypothyroidism; rhabdomyolysis; statins",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "211-3",
"pmc": null,
"pmid": "23814421",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports",
"references": "12672737;16581330;16344427;16312269;13508118;17200431;15716291;1101087;16581329;16453090;15807872",
"title": "Rhabdomyolysis induced acute renal failure secondary to statins.",
"title_normalized": "rhabdomyolysis induced acute renal failure secondary to statins"
} | [
{
"companynumb": "PHHY2013IN073736",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN NOS"
},
"drugadditional": null,
"dru... |
{
"abstract": "Treatment of refractory Evans syndrome (ES) remains a challenge in hematology practice. Due to rarity of this condition, evidence-based approaches are limited and often treatment choices stem from small case series or anecdotal experiences. There is mounting evidence that some patients have genetic defects that could be targeted with promising preliminary results. Here, we describe three very refractory pediatric ES cases treated on bortezomib without adverse effects. Two of the three patients had dramatic and long-lasting recovery that started following the initial doses of the drug. Clinical trials to assess the role of bortezomib in ES treatment are warranted.",
"affiliations": "Division of Hematology/Oncology, Children's Hospital of Michigan.;Division of Hematology/Oncology, Children's Hospital of Michigan.;Division of Hematology/Oncology, Children's Hospital of Michigan.;Division of Hematology/Oncology, Children's Hospital of Michigan Department of Pediatrics, Barbara Ann Karmanos Cancer Center, Children's Hospital of Michigan, Central Michigan University College of Medicine.;Division of Hematology/Oncology, Children's Hospital of Michigan Department of Pediatrics, Barbara Ann Karmanos Cancer Center, Children's Hospital of Michigan, Central Michigan University College of Medicine.",
"authors": "Beydoun|Serina B|SB|0000-0003-1130-0941;Persaud|Yogindra|Y|0000-0001-8266-9434;Lafferty|Jennifer|J|;Callaghan|Michael U|MU|0000-0001-8742-0275;Savaşan|Süreyya|S|0000-0001-7138-3027",
"chemical_list": "D000970:Antineoplastic Agents; D013256:Steroids; D000069286:Bortezomib",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28725",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(12)",
"journal": "Pediatric blood & cancer",
"keywords": "Evans syndrome; bortezomib; children; recovery; steroid-refractory",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000744:Anemia, Hemolytic, Autoimmune; D000970:Antineoplastic Agents; D000069286:Bortezomib; D002648:Child; D004351:Drug Resistance; D006801:Humans; D007223:Infant; D008297:Male; D011379:Prognosis; D013256:Steroids; D013921:Thrombocytopenia",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28725",
"pmc": null,
"pmid": "32969165",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bortezomib treatment of steroid-refractory Evans syndrome in children.",
"title_normalized": "bortezomib treatment of steroid refractory evans syndrome in children"
} | [
{
"companynumb": "US-AMGEN-USASP2020199266",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ELTROMBOPAG"
},
"drugadditional": null,
... |
{
"abstract": "Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing's signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing's syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli.",
"affiliations": "Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan, tanaka.sho@nihon-u.ac.jp.;Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, Japan.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan, tanaka.sho@nihon-u.ac.jp.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan, tanaka.sho@nihon-u.ac.jp.;Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan, tanaka.sho@nihon-u.ac.jp.",
"authors": "Tanaka|Sho|S|;Fujishiro|Midori|M|;Nakamura|Yoshihiro|Y|;Hatanaka|Yoshinari|Y|;Abe|Masanori|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/TCRM.S196171",
"fulltext": "\n==== Front\nTher Clin Risk ManagTher Clin Risk ManagTherapeutics and Clinical Risk ManagementTherapeutics and Clinical Risk Management1176-63361178-203XDove Medical Press 10.2147/TCRM.S196171tcrm-15-337Case ReportRetention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy Tanaka Sho 1Fujishiro Midori 2Nakamura Yoshihiro 1Hatanaka Yoshinari 1Abe Masanori 1\n1 Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, Tokyo, Japan, tanaka.sho@nihon-u.ac.jp\n2 Division of Diabetes and Metabolic Diseases, Nihon University School of Medicine, Tokyo, JapanCorrespondence: Sho Tanaka, Division of Nephrology, Hypertension and Endocrinology, Department of Internal Medicine, Nihon University School of Medicine, 30-1 Kamicho, Oyaguchi, Itabashi-ku, Tokyo 173-8610, Japan, Tel +81 33 972 8111, Fax +81 33 972 8311, Email tanaka.sho@nihon-u.ac.jp2019 27 2 2019 15 337 342 © 2019 Tanaka et al. This work is published and licensed by Dove Medical Press Limited2019The 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.Aberrant cortisol secretion responses after exogenous stimuli such as upright posture, eating a mixed meal or receiving agents influencing aberrant G-protein-coupled receptors in adrenal glands, are often observed in patients with bilateral macronodular adrenal hyperplasia (BMAH). However, little is known about whether this aberrant response is retained after unilateral adrenalectomy. Here, we describe a 61-year-old postmenopausal Japanese woman with unsatisfactorily controlled hypertension who was referred to us for further investigation due to her pre-obesity characteristics (body mass index 28.4 kg/m2). Cushing’s signs and serum cortisol at 16.2 µg/dL with undetectable adrenocorticotropic hormone indicated adrenal Cushing’s syndrome. Adrenal imaging revealed bilaterally enlarged adrenal glands with 131-I adosterol uptake; hence, BMAH was diagnosed. Preoperatively, in vivo screening for aberrant adrenal receptors revealed an aberrant response of cortisol secretion on metoclopramide challenge. The patient underwent unilateral adrenalectomy; thereafter, glucocorticoid replacement therapy was reduced to hydrocortisone 15 mg/day at postoperative day 6. Fasting morning serum cortisol level measured at postoperative day 8 was 2.96 µg/dL, suggesting adrenal insufficiency. However, following metoclopramide administration serum cortisol level rose to 19.7 µg/dL, indicating potential efficient adrenal function. Aberrant cortisol secretory capacity was thus preserved in BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Caution should be exercised when assessing the hypothalamus-pituitary-adrenal axis, because in this patient, a high cortisol level did not guarantee appropriate adrenal function when the patient was challenged by exogenous stimuli.\n\nKeywords\nadrenal glandsCushing’s syndromeglucocorticoidshydrocortisonemetoclopramidereceptorsG-protein-coupled\n==== Body\nIntroduction\nBilateral macronodular adrenal hyperplasia (BMAH) is a subtype of adrenal Cushing’s syndrome, and is characterized by bilaterally enlarged adrenal glands consisting of non-pigmented macronodules. The molecular mechanisms of cortisol secretion in BMAH, which does not depend on circulating adrenocorticotropic hormone (ACTH) released by the pituitary gland, have become clear in the last two decades. It is widely recognized that cAMP signaling evoked by activation of aberrant G-protein-coupled receptors (GPCRs) in adrenal glands largely contributes to steroid genesis.1 Clinically, this is confirmed by aberrant responses of serum cortisol level on challenge by endogenous stimuli such as upright posture, eating a mixed meal or exposure to certain chemicals.1 Previous investigations have demonstrated that metoclopramide, an agent frequently used for alleviating gastrointestinal symptoms, stimulates adrenal serotonin type 4 receptors in some cases of BMAH, leading to excess cortisol in vivo and in vitro.2–8 There are several different treatment modalities for patients with BMAH, including unilateral adrenalectomy.9 In patients who underwent this operation, assessing residual cortisol secretion capacity is clinically important in order to avoid unnecessary steroid replacement therapy while reducing the risk of adrenal insufficiency or crisis. While more than 20 cases of BMAH with aberrant responses against metoclopramide have been reported in the literature, the impact of metoclopramide on cortisol secretion from the remaining adrenal gland in patients after unilateral adrenalectomy remains unknown.2,3,5,7,8 Herein, we report a Japanese woman with BMAH in whom aberrant serum cortisol levels on metoclopramide use were seen despite adrenal insufficiency after surgery.\n\nCase description\nA 61-year-old postmenopausal Japanese woman was referred to us for further investigation of her pre-obese state. She had had hypertension, dyslipidemia and osteoporosis for 10 years. Hypertension was treated with telmisartan 80 mg/day, and amlodipine 7.5 mg/day but was not satisfactorily controlled. Home-monitored blood pressure level remained 130–160/70– 90 mmHg. Her family history included hypertension in an elderly sister but was otherwise unremarkable. The patient habitually smoked a pack of cigarettes per day and consumed 30 g alcohol daily.\n\nOn physical examination, pre-obesity was observed: height 147 cm, weight 61.3 kg and BMI 28.4 kg/m2. Additionally, centripetal obesity, facial plethora, skin atrophy with easy bruising, proximal lower limb weakness and mild moon face were apparent. Randomly measured serum cortisol at 16.2 µg/dL (reference range, 6.24–18.0) with undetectable ACTH at <2 pg/mL (reference range, 7.2–63.3) indicated adrenal Cushing’s syndrome. Computed tomography and single photon emission computed tomography using 131-I adosterol revealed bilateral nodules in the adrenal glands. Maximum nodule size in the left-side gland was 34 mm with strong uptake, and 31 mm with relatively weak uptake in the right-side gland (Figure 1). Circadian variation of serum cortisol and ACTH levels was abnormal; Cortisol levels were11.2, 11.4, 14.5 and 10.8 µg/dL at 0.00am, 6.00am, 0.00pm and 6.00pm, respectively, and ACTH was undetectable throughout the day. Urinary free cortisol excretion was high at 380 µg/day (reference range, 11.2–80.3). Reduction of serum cortisol level was not seen in overnight dexamethasone suppression tests; morning serum cortisol levels following 1 or 8 mg dexamethasone administration were 11.3 and 15.3 µg/dL, respectively. Responses of serum cortisol after eating a mixed meal, on intravenously administered glucagon 1 mg, or orally administered metoclopramide 10 mg were investigated. Additionally, responses against ACTH and gonadotropin-releasing hormone (GnRH) were assessed using intravenous synacthen 250 µg and gonadorelin 0.1 mg, respectively. Responses on transitioning to an upright posture could not be investigated due to the patient’s refusal because of knee pain and lower limb muscle weakness. Results are shown in Figure 2. Serum cortisol levels increased only in response to ACTH and metoclopramide administration. The increased cortisol level following metoclopramide administration was 239% from a baseline of 11.2 to a peak of 26.8 µg/dL. Based on the above data, the patient was diagnosed as having BMAH and underwent left adrenalectomy. Surgery was successful, and the dose of postoperative glucocorticoid replacement therapy was uneventfully reduced to hydrocortisone 15 mg/day (10 mg after breakfast and 5 mg after dinner) at day 6. On the morning of postoperative day 8, prior to use of hydrocortisone in the morning, the fasting serum cortisol response against oral metoclopramide 10 mg was investigated once again. A baseline morning cortisol level of 2.96 µg/dL strongly suggested adrenal insufficiency, but the peak level following administration of metoclopramide was at 19.7 µg/dL (representing an increase of 666%, Figure 3).On receiving hydrocortisone 15 mg/day, the patient showed no signs of adrenal insufficiency thereafter, and was therefore uneventfully discharged at postoperative day 10.\n\nSerum cortisol levels prior to hydrocortisone in the morning were monitored on an outpatient basis on postoperative day 72 and 109, when the patient was receiving hydrocortisone 12.5 mg/day (10 mg after breakfast and 2.5 mg after dinner). Markedly decreased morning serum cortisol levels were repeatedly confirmed, and adrenal insufficiency was strongly suggested even at day 109; thus, steroid coverage could not be withdrawn (Figure 4). Undetectable ACTH at, 2 pg/mL was sustained throughout the observation period, which also suggested an unrestored hypothalamus-pituitary-adrenal (HPA) axis. Meanwhile, the patient’s weight was successfully reduced to 53.0 kg with a BMI of 24.5 kg/m2, and hypertension is currently controlled at 120–140/70–90 mmHg with amlodipine 5 mg/day alone.\n\nDiscussion\nBMAH is a rare subtype of adrenal Cushing’s syndrome, and genetic involvement is suggested because of bilateral involvement and reports of familial cases. A major genetic characteristic is the presence of inactivating mutations of ARMC5, a potential tumor suppressor gene; biallelic alterations consisting of an additive pathogenic somatic mutation and a germline mutation inactivating ARMC5 result in nodule formation in the adrenal glands of BMAH patients.10 Clinically, Cushing’s syndrome of BMAH type is characterized by marked bilateral enlargement of the adrenal glands and aberrant cortisol secretion responses on challenge with exogenous stimuli.1 Previously, several investigators reported that this aberrant response is associated with an upright posture, eating a mixed meal, ACTH, GnRH, thyrotropin-releasing hormone, glucagon, vasopressin and serotonin type 4 receptor agonists including metoclopramide which was first described by Lacroix et al in 1999.2–8 The present case we describe here is a patient with BMAH associated with an aberrant response of cortisol secretion on metoclopramide challenge. Clinical profiles such as age, nodule sizes and urinary cortisol excretion in the present case seem similar to the previously reported BMAH cases with aberrant responses to metoclopramide administration (Table 1).2,3,5,7,8 However, this patient highlights two clinically important issues. First, metoclopramide-stimulated aberrant cortisol secretion responses by the remaining adrenal gland are retained even under conditions of adrenal insufficiency in the early postoperative period. Second, the impact of metoclopramide use in such cases has a substantial ability to conceal adrenal insufficiency as assessed by morning, or randomly timed, serum cortisol level determinations.\n\nIn the present case, adrenal insufficiency after left adrenalectomy was apparent, and did not recover over the observation period; thus, morning serum cortisol levels were 2.96, 4.13 and 2.12 µg/dL on postoperative day 8, 72 and 109. This is sufficiently low to predict adrenal insufficiency because a recent retrospective cohort study reported that morning serum cortisol level was correlated with peak serum cortisol level on an insulin hypoglycemia test, with morning cortisol level below 4 µg/dL or above 17 µg/dL being highly predictive of insufficient and sufficient adrenal function, respectively.11 Furthermore, another retrospective cohort study reported an association between randomly sampled serum cortisol levels and the results of ACTH testing. In that study, a cortisol level below 5.1 µg/dL predicted a 30 minutes serum cortisol level below 20 µg/dL during the ACTH test, indicating insufficient adrenal function, with 100% specificity and 35% sensitivity.12 In contrast, a value exceeding .15.2 µg/dL guaranteed a 30 minutes value exceeding 20 µg/dL during the ACTH test, indicating adequate adrenal function.12 Therefore, it seems highly likely that our patient had adrenal insufficiency sustained until at least postoperative day 109.\n\nThe postoperative course of adrenal function observed in this present case is not a chance event, because a previous retrospective study reported that postoperative adrenal insufficiency following unilateral adrenalectomy in BMAH patients was observed in 40% of patients (6 of 15 enrolled).13 The report also remarked that adrenal insufficiency and the following latent adrenal insufficiency persisted for two years or more.13 It was also mentioned that the 250 µg synacthen test was unreliable for diagnosis of adrenal insufficiency in such situations because the cortisol secretory response to a challenge of 250 µg synacthen could occur even under conditions of adrenal insufficiency after surgery.13 Similarly, this present case indicates that the remaining gland still did have substantial cortisol secretory capacity when stimulated via an aberrant GPCRs, even though the patient was ordinarily adrenal-insufficient.\n\nThe 666% increase in the serum cortisol level following metoclopramide stimulation observed after surgery is of interest. Although the baseline serum cortisol level of 2.96 µg/dL was strongly suggestive of adrenal insufficiency, the peak value of 19.7 µg/dL would indicate sufficient adrenal function when measured either in the morning or randomly.11,12 In the clinical setting, morning or random serum cortisol measurement is frequently used to assess HPA axis functionality because it is easy to perform. However, the marked fluctuation of serum cortisol level observed in this present case suggests that external stimuli associated with aberrant cortisol secretion can conceal underlying adrenal insufficiency and mislead clinicians assessing the HPA axis after unilateral adrenalectomy in BMAH patients. Because metoclopramide is frequently used, also after surgery, caution is required to avoid the risk of inappropriate withdrawal of steroid coverage. Moreover, habitual use of metoclopramide might suppress the hypothalamus and pituitary via negative feedback due to cortisol excess, and lead to delayed recovery of the HPA axis. Similarly, this risk should be considered in all patients with BMAH receiving unilateral adrenalectomy, because not only metoclopramide but also upright posture or eating a mixed meal, always happening in daily life, were also reported to induce cortisol secretion.3,7,8 To conclude, detailed surveillance of aberrant cortisol secretion responses on challenge with exogenous stimuli influencing aberrant GPCRs is clinically important in BMAH patients.\n\nThis report has certain limitations. First, it is an observational case report of a single patient, and there are several unavailable data, such as results of a vasopressin test, a postoperative synacthen test and postoperative urinary free cortisol excretion. Further cases with fully-assessed pre- and postoperative aberrant responses to exogeneous stimuli must be accumulated to assess cortisol secretory capacity after surgery in BMAH. Second, cortisol levels following metoclopramide stimulation after surgery were possibly modified by hydrocortisone use, despite the small doses applied (15 mg/day), so underestimates cannot be excluded.\n\nConclusion\nThe aberrant cortisol secretion response after exogenous stimulation influencing aberrant G-protein-coupled receptors was found to be retained in a patient with BMAH, even in a state of adrenal insufficiency after unilateral adrenalectomy. Thus, a high serum cortisol level when the patient receives such exogenous stimuli does not guarantee efficient adrenal function. Caution is thus required for assessing the actual status of the HPA axis.\n\nEthics and consent for publication\nThe patient described in this study provided permission to publish data and accompanying images, and written informed consent was obtained. A formal ethical review by an institutional review board was not required because this is a case report.\n\nAcknowledgments\nThis report was not funded by any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAuthor contributions\n\nST designed the study, contributed to collect, analyze and interpret data, and wrote the initial draft of the manuscript. MF contributed to interpret the data, and assisted in the preparation of the manuscript. All authors contributed to data analysis, drafting and revising the article, gave final approval of the version to be published, and agree to be accountable for all aspects of the work.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n\nAbbreviations\nACTHadrenocorticotropic hormone\n\nBMAHbilateral macronodular hyperplasia\n\nBMIbody mass index\n\nGnRHgonadotropin-releasing hormone\n\nGPCRsG-protein-coupled receptors\n\nHPAhypothalamus-pituitary-adrenal\n\nFigure 1 Imaging of adrenal glands.\n\nNotes: The arrows indicate the nodule in the right (yellow) and left (red) adrenal gland. (A) Image of CT. (B) Merged image of CT and 131-I adosterol SPECT. (C) Image of 131-I adosterol SPECT.\n\nAbbreviations: CT, computed tomography; SPECT, single photon emission computed tomography.\n\nFigure 2 Aberrant responses of cortisol secretion preoperatively.\n\nNotes: Vertical axis indicates serum cortisol level. Horizontal axis indicates time course after exogenous stimuli.\n\nAbbreviations: ACTH, adrenocorticotropic hormone; GnRH, gonadotropin-releasing hormone.\n\nFigure 3 Cortisol secretion on metoclopramide challenge at postoperative day 8.\n\nNotes: Vertical axis indicates serum cortisol level. Horizontal axis indicates time course after metoclopramide administration. Numerical values are also shown with trajectory.\n\nFigure 4 Time course of morning serum cortisol before and after left adrenalectomy.\n\nNotes: Vertical axis indicates morning serum cortisol level. Horizontal axis indicates time course before and after left adrenalectomy (week 0). Three data points collected before surgery, and data collected at postoperative days 8, 72 and 109 are shown. Regimen of steroid coverage at day 8 was hydrocortisone 15 mg/day (10 and 5 mg after breakfast and dinner, respectively). Regimen of steroid coverage at days 72 and 109 was hydrocortisone 12.5 mg/day, 10 and 2.5 mg after breakfast and dinner, respectively. Numerical values are also shown with trajectory.\n\nTable 1 Review of BMAH cases with paradoxical cortisol secretion response on metoclopramide challenge\n\nCase\tAuthor\tSex\tAge (years)\tBMI (kg/m2)\tFunction\tMaleifestation\tNodule size (mm)\n\tU-Cor (µg/day)\tDegree of increase (%)\t\nRight\tLeft\t\n\n\t\n1\tLibé R\tMale\t53\t31.2\tCS\tCushing’s sign\t35\t45\t293\t133\t\n2\t\tFemale\t34\t30.0\tCS\tCushing’s sign\t45\t30\t373\t180\t\n3\t\tFemale\t70\t25.0\tCS\tIncidentaloma\t50\t30\t122\t204\t\n4\t\tFemale\t45\t21.3\tSCS\tIncidentaloma\t60\t30\t44\t438\t\n5\t\tFemale\t37\t30.5\tSCS\tIncidentaloma\t33\t15\t26\t185\t\n6\t\tMale\t59\t25.6\tSCS\tHypertension\t30\t60\t31\t426\t\n7\t\tFemale\t66\t27.8\tSCS\tIncidentaloma\t14\t30\t29\t209\t\n8\t\tFemale\t35\t27.4\tSCS\tIncidentaloma\t26\t27\t18\t180\t\n9\t\tFemale\t67\t28.6\tSCS\tIncidentaloma\t14\t40\t56\t209\t\n10\t\tFemale\t54\t28.2\tSCS\tIncidentaloma\t18\t44\t36\t137\t\n11\t\tFemale\t53\t26.7\tSCS\tIncidentaloma\t35\t27\t83\t310\t\n12\t\tMale\t74\t23.3\tSCS\tIncidentaloma\t20\t25\t85\t160\t\n13\t\tMale\t51\t20.6\tSCS\tIncidentaloma\t27\t40\t63\t206\t\n14\t\tMale\t52\t27.0\tSCS\tIncidentaloma\t55\t46\t50\t138\t\n15\t\tMale\t51\t24.0\tSCS\tIncidentaloma\t40\t37\t47\t183\t\n16\t\tFemale\t43\t22.3\tSCS\tIncidentaloma\t45\t15\t46\t154\t\n17\t\tFemale\t55\t33.6\tSCS\tHypertension\t30\t24\t26\t183\t\n\n\t\n18\tBourdeau I\tFemale\t51\tNA\tSCS\tHypertension, weight gain\t44\t50\tNA\t145\t\n19\t\tMale\t61\tNA\tSCS\tNA\t61\t73\tNA\t191\t\n20\t\tMale\t53\t25.3\tSCS\tHypertension\t35\t40\tNA\t300\t\n\n\t\n21\tVezzosi D\tFemale\t56\tNA\tCS\tHypertension, Centripetal obesity, facial plethora, dorsal fat pad supraclavicular fat pad, glucose intolerance, mild hirsutism\tNA\tNA\t34\t270\t\n22\t\tFemale\t54\tNA\tCS\tHypertension, centripetal obesity, facial plethora, easy bruising, diabetes mellitus\tNA\tNA\t50\t301\t\n\n\t\n23\tFeelders RA\tFemale\t60\t24.4\tCS\tCentripetal obesity, facial plethora, muscle weakness, easy bruising depression, skin atrophy\t35\t50\t199–228 326–652\t289 195\t\n24\t\tFemale\t40\t32.8\tCS\tHypertension, centripetal obesity, facial plethora, weight gain, muscle weakness, easy bruising, dorsal fat pad, supraclavicular fat pad, depression\t50\t30\t\t\t\n\n\t\n25\tLacroix A\tFemale\t63\t28.9\tCS\tHypertension, weight gain, muscle weakness, numbness, hot flushes, decrease in concentration and memory\t40\t40\t279\t257\t\nNote: Clinical features of cases with BMAH reported to be associated with paradoxical response of cortisol secretion on metoclopramide challenge are shown together with the percentage increase of cortisol level.\n\nAbbreviations: BMAH, bilateral macronodular adrenal hyperplasia; BMI, body mass index; CS, Cushing’s syndrome; NA, not applicable; SCS, subclinical Cushing’s syndrome; U-Cor, urinary cortisol excretion.\n==== Refs\nReferences\n1 El Ghorayeb N Bourdeau I Lacroix A Multiple aberrant hormone receptors in Cushing’s syndrome Eur J Endocrinol 2015 173 4 M45 M60 25971648 \n2 Lacroix A Hamet P Boutin JM Leuprolide acetate therapy in luteinizing hormone – dependent Cushing’s syndrome N Engl J Med 1999 341 21 1577 1581 10564687 \n3 Bourdeau I D’Amour P Hamet P Boutin JM Lacroix A Aberrant membrane hormone receptors in incidentally discovered bilateral macronodular adrenal hyperplasia with subclinical Cushing’s syndrome J Clin Endocrinol Metab 2001 86 11 5534 5540 11701732 \n4 Cartier D Lihrmann I Parmentier F Overexpression of serotonin4 receptors in cisapride-responsive adrenocorticotropin-independent bilateral macronodular adrenal hyperplasia causing Cushing’s syndrome J Clin Endocrinol Metab 2003 88 1 248 254 12519861 \n5 Feelders RA Lamberts SW Hofland LJ Luteinizing hormone (LH)-responsive Cushing’s syndrome: the demonstration of LH receptor messenger ribonucleic acid in hyperplastic adrenal cells, which respond to chorionic gonadotropin and serotonin agonists in vitro J Clin Endocrinol Metab 2003 88 1 230 237 12519858 \n6 Louiset E Contesse V Groussin L Expression of serotonin7 receptor and coupling of ectopic receptors to protein kinase A and ionic currents in adrenocorticotropin-independent macronodular adrenal hyperplasia causing Cushing’s syndrome J Clin Endocrinol Metab 2006 91 11 4578 4586 16954157 \n7 Vezzosi D Cartier D Régnier C Familial adrenocorticotropin-independent macronodular adrenal hyperplasia with aberrant serotonin and vasopressin adrenal receptors Eur J Endocrinol 2007 156 1 21 31 17218722 \n8 Libé R Coste J Guignat L Aberrant cortisol regulations in bilateral macronodular adrenal hyperplasia: a frequent finding in a prospective study of 32 patients with overt or subclinical Cushing’s syndrome Eur J Endocrinol 2010 163 1 129 138 20378721 \n9 Lacroix A ACTH-independent macronodular adrenal hyperplasia Best Pract Res Clin Endocrinol Metab 2009 23 2 245 259 19500767 \n10 Assié G Libé R Espiard S Armc5 mutations in macronodular adrenal hyperplasia with Cushing’s syndrome N Engl J Med 2013 369 22 2105 2114 24283224 \n11 Erturk E Jaffe CA Barkan AL Evaluation of the integrity of the hypothalamic-pituitary-adrenal axis by insulin hypoglycemia test J Clin Endocrinol Metab 1998 83 7 2350 2354 9661607 \n12 Kadiyala R Kamath C Baglioni P Geen J Okosieme OE Can a random serum cortisol reduce the need for short synacthen tests in acute medical admissions? Ann Clin Biochem 2010 47 Pt 4 378 380 20488874 \n13 Debillon E Velayoudom-Cephise FL Salenave S Unilateral adrenalectomy as a first-line treatment of Cushing’s syndrome in patients with primary bilateral macronodular adrenal hyperplasia J Clin Endocrinol Metab 2015 100 12 4417 4424 26451908\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1176-6336",
"issue": "15()",
"journal": "Therapeutics and clinical risk management",
"keywords": "Cushing’s syndrome; G-protein-coupled; adrenal glands; glucocorticoids; hydrocortisone; metoclopramide; receptors",
"medline_ta": "Ther Clin Risk Manag",
"mesh_terms": null,
"nlm_unique_id": "101253281",
"other_id": null,
"pages": "337-342",
"pmc": null,
"pmid": "30880999",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
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"title": "Retention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy.",
"title_normalized": "retention of aberrant cortisol secretion in a patient with bilateral macronodular adrenal hyperplasia after unilateral adrenalectomy"
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"activesubstancename": "AMLODIPINE BESYLATE"
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... |
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"abstract": "A 62-year-old patient was admitted with an acute unprovoked portal vein thrombosis with splenic and mesenteric extension. His progress was complicated by progressive small bowel ischaemia and increasing clot burden despite systemic anticoagulation. This case report describes the use of catheter-directed thrombolysis via a transjugular intrahepatic portosystemic shunt, with the disease and its treatment complicated by a ruptured iatrogenic pseudoaneurysm, abdominal compartment syndrome and small bowel infarction necessitating extensive small bowel resection.",
"affiliations": "Department of Surgery, Westmead Hospital, Westmead, New South Wales, Australia andy.chen@health.nsw.gov.au.;Department of Surgery, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Radiology, Westmead Hospital, Westmead, New South Wales, Australia.;Department of Surgery, Westmead Hospital, Westmead, New South Wales, Australia.",
"authors": "Chen|Andy Ze Lin|AZL|http://orcid.org/0000-0003-2857-4033;Allaway|Matthew George Roy|MGR|;Al-Asady|Rafid|R|;Richardson|Arthur|A|",
"chemical_list": null,
"country": "England",
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"doi": "10.1136/bcr-2020-234282",
"fulltext": null,
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"issn_linking": "1757-790X",
"issue": "13(6)",
"journal": "BMJ case reports",
"keywords": "gastrointestinal surgery; interventional radiology; portal vein",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000208:Acute Disease; D006801:Humans; D008642:Mesenteric Veins; D008875:Middle Aged; D011169:Portal Vein; D019168:Portasystemic Shunt, Transjugular Intrahepatic; D013162:Splenic Vein; D015912:Thrombolytic Therapy; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32565434",
"pubdate": "2020-06-21",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of acute extensive portal vein thrombosis: the complexity and morbidity.",
"title_normalized": "management of acute extensive portal vein thrombosis the complexity and morbidity"
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"companynumb": "AU-FRESENIUS KABI-FK202007775",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
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"activesubstancename": "HEPARIN SODIUM"
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{
"abstract": "OBJECTIVE\nTo assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.\n\n\nMETHODS\nPregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.\n\n\nRESULTS\nThe incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6-4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1-2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6-6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73-4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69-6.98], p = 0.183).\n\n\nCONCLUSIONS\nThis observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.",
"affiliations": "Department of Pharmacy, Toranomon Hospital, Minato-ku, Tokyo, Japan.;Department of Pharmacy, Toranomon Hospital, Minato-ku, Tokyo, Japan.;Department of Obstetrics and Gynecology, Toranomon Hospital, Minato-ku, Tokyo, Japan.;Department of Obstetrics and Gynecology, Toranomon Hospital, Minato-ku, Tokyo, Japan.;Department of Biostatistics, M&D Data Science Center, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo, Japan.;The Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.;Human Health Sciences, Kyoto University Graduate School of Medicine, Sakyo-ku, Tokyo, Japan.;Department of Pharmacy, Yokohama Minami Kyousai Hospital, Yokohama, Kanagawa, Japan.;Center of Maternal-Fetal, Neonatal and Reproductive Medicine, National Center for Child Health and Development, Setagaya-ku, Tokyo, Japan.;Department of Pharmacy, Toranomon Hospital, Minato-ku, Tokyo, Japan.",
"authors": "Hishinuma|Kayoko|K|https://orcid.org/0000-0003-1916-3726;Yamane|Ritsuko|R|;Yokoo|Ikuko|I|;Arimoto|Takahide|T|;Takahashi|Kunihiko|K|;Goto|Mikako|M|;Saito|Yoshiyuki|Y|;Nakajima|Ken|K|;Murashima|Atsuko|A|;Hayashi|Masahiro|M|",
"chemical_list": "D004294:Domperidone; D008787:Metoclopramide",
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.14709",
"fulltext": "\n==== Front\nJ Obstet Gynaecol Res\nJ Obstet Gynaecol Res\n10.1111/(ISSN)1447-0756\nJOG\nThe Journal of Obstetrics and Gynaecology Research\n1341-8076\n1447-0756\nJohn Wiley & Sons Australia, Ltd Kyoto, Japan\n\n33631840\n10.1111/jog.14709\nJOG14709\nOriginal Article\nOriginal Articles\nPregnancy outcome after first trimester exposure to domperidone—An observational cohort study\nSafety of domperidone use in pregnancy\nHishinuma et al.\nHishinuma Kayoko https://orcid.org/0000-0003-1916-3726\n1 kayo_h0413@hotmail.co.jp\n\nYamane Ritsuko 1\nYokoo Ikuko 2\nArimoto Takahide 2\nTakahashi Kunihiko 3\nGoto Mikako 4\nSaito Yoshiyuki 5\nNakajima Ken 6\nMurashima Atsuko 7\nHayashi Masahiro 1\n1 Department of Pharmacy Toranomon Hospital Minato‐ku Tokyo Japan\n2 Department of Obstetrics and Gynecology Toranomon Hospital Minato‐ku Tokyo Japan\n3 Department of Biostatistics, M&D Data Science Center Tokyo Medical and Dental University Bunkyo‐ku Tokyo Japan\n4 The Japan Drug Information Institute in Pregnancy National Center for Child Health and Development Setagaya‐ku Tokyo Japan\n5 Human Health Sciences Kyoto University Graduate School of Medicine Sakyo‐ku Tokyo Japan\n6 Department of Pharmacy Yokohama Minami Kyousai Hospital Yokohama Kanagawa Japan\n7 Center of Maternal‐Fetal, Neonatal and Reproductive Medicine National Center for Child Health and Development Setagaya‐ku Tokyo Japan\n* Correspondence: Kayoko Hishinuma, Toranomon Hospital, Department of Pharmacy, 2‐2‐2, Toranomon, Minato‐ku, Tokyo 105‐8470, Japan.\nEmail: kayo_h0413@hotmail.co.jp\n\n25 2 2021\n5 2021\n47 5 10.1111/jog.v47.5 17041710\n02 12 2020\n12 5 2020\n29 1 2021\n© 2021 The Authors. Journal of Obstetrics and Gynaecology Research published by John Wiley & Sons Australia, Ltd on behalf of Japan Society of Obstetrics and Gynecology\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nAim\n\nTo assess the teratogenic risk of domperidone by comparing the incidence of major malformation with domperidone to a control.\n\nMethods\n\nPregnancy outcome data were obtained for women at two Japanese facilities that provide counseling on drug use during pregnancy between April 1988 and December 2017. The incidence of major malformation was calculated among infants born to women taking domperidone (n = 519), nonteratogenic drugs (control, n = 1673), or metoclopramide (reference, n = 241) during the first trimester of pregnancy. Using the control group as reference, the crude odds ratio (OR) of the incidence of major malformation in the domperidone and metoclopramide groups was calculated using univariable logistic regression analysis. Adjusted OR was also calculated using multivariable logistic regression analysis adjusted for various other factors.\n\nResults\n\nThe incidence of major malformation was 2.9% (14/485, 95% confidence interval [CI]: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group. The adjusted multivariable logistic regression analysis showed no significant difference in incidence between the control and domperidone groups (adjusted OR: 1.86 [95%CI: 0.73–4.70], p = 0.191) or between the control and metoclopramide groups (adjusted OR: 2.20 [95%CI: 0.69–6.98], p = 0.183).\n\nConclusions\n\nThis observational cohort study showed that domperidone exposure during the first trimester was not associated with increased risk of major malformation in infants. These results may help alleviate the anxiety of patients who took domperidone during pregnancy.\n\ndomperidone\nfirst trimester\nobservational cohort study\npregnancy outcomes\nteratogenicity\nResearch and Development 10.13039/100006190 source-schema-version-number2.0\ncover-dateMay 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:01.07.2021\n==== Body\nIntroduction\n\nDomperidone is an antidopaminergic benzimidazolone compound first synthesized by Janssen Pharmaceutica (Belgium) in 1974. Originally approved in Belgium in 1978, it has since been approved in over 100 countries, including in Japan in 1982. In Japan, domperidone has been widely used for the treatment of gastrointestinal symptoms such as nausea, vomiting, and anorexia.\n\nIn a study of domperidone administration during organogenesis in rats, skeletal and visceral malformations were observed in fetuses following an oral dose of 200 mg/kg or an intraperitoneal dose of ≥15 mg/kg. These observed malformations in rats occurred at approximately 300 times the daily oral dose for humans based on body weight. Due to these results, the package insert for domperidone in Japan states that it is contraindicated for use in pregnant women or women suspected of being pregnant.\n\nIn some cases, however, domperidone is prescribed for gastrointestinal symptoms such as nausea and vomiting to women who do not yet know they are pregnant due to the pregnancy being unplanned. In such cases, patients often become anxious when they find out they are pregnant and learn that domperidone is contraindicated.\n\nDomperidone and metoclopramide are commonly used as antiemetic drugs in general clinical practice in Japan. Large‐scale epidemiological studies have shown that metoclopramide does not increase the risk of malformation 1 , 2 . On the other hand, teratogenic risk with domperidone has been reported in only a few small‐scale, cohort studies. A report by JS Choi et al. investigated 120 pregnancies treated with domperidone in the first trimester and concluded that domperidone is unlikely to be a major human teratogen 3 . Also, in an abstract, J Cottin et al. compared 124 pregnancies exposed to domperidone during organogenesis with those exposed to other antiemetics or nonteratogenic drugs 4 . There was no significant difference between the three groups in the incidence of major congenital malformations, but the authors commented that the small sample size was a limitation. A report on drug use during pregnancy in the French population stated that about 13% of all pregnant women were using domperidone 5 . Although the teratogenic risk of domperidone was not analyzed in that survey, it suggests that the drug is widely used by pregnant women in some countries.\n\nIn the present study, we evaluated the teratogenic risk of domperidone exposure during the first trimester. This is based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy.\n\nMethods\n\nSubjects\n\nThis study included women who consulted the Counseling Clinic for “Pregnancy and Medicine” of Toranomon Hospital or the Japan Drug Information Institute in Pregnancy of National Center for Child Health and Development regarding the safety of drugs during pregnancy. Pregnancy outcome data were extracted from the clinical databases of these facilities.\n\nThe inclusion criteria were pregnant women who consented to the study and with known pregnancy outcomes who took domperidone (domperidone group), or control drugs (control group) in the first trimester. Among these, women who used domperidone in combination with metoclopramide were excluded from the study. First trimester exposure was defined as drug use between the 28th and 97th days (4th week to 13th week of pregnancy) after the last menstrual period. Experts discussed and selected control drugs considered to be nonteratogenic, referring the report by F. Habermann et al. 6 Control drugs included acetaminophen, antihistamines that were reported in previous studies to have no increased risk of teratogenicity, anti‐infectives like penicillins and cephalosporins, histamine H2‐receptor (H2) blockers, digestive enzyme preparations, and topical drugs (e.g., eye drops, ointment, or cream). Metoclopramide is a similar drug and is expected to be used for the same diseases. In addition, it has been commonly used as an antiemetic drug in pregnant women. Therefore, although statistical comparison with the domperidone group was not performed, patients who took metoclopramide were defined as the reference group.\n\nData collection\n\nFor Toranomon Hospital, women who consulted the Counseling Clinic for “Pregnancy and Medicine” during pregnancy between April 1988 and December 2016 were included in the study. People who wished to make a counseling appointment were first required by the clinic to complete a pre‐appointment questionnaire regarding information such as the names and dosages of drugs taken during pregnancy and expected delivery date, and to return it by mail. At the time of counseling, subjects were interviewed to confirm their expected delivery dates and to obtain other information, including previous medical history, pregnancy and reproductive history, alcohol use, smoking, and family history. We asked patients who provided informed consent for study participation to complete a study questionnaire regarding pregnancy outcomes and any abnormalities during delivery, as well as sex, length, and weight at birth, and any abnormalities of the neonate, and to submit it by mail. If patients provided unclear answers about pregnancy outcomes, an obstetrician contacted their attending physician to obtain clarification. Information on pregnancy outcomes was collected about 1 month after delivery, and the survey was considered complete when this information was obtained.\n\nAt the National Center for Child Health and Development, women in pregnancy who sought consultation the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017 were included in the study. The Japan Drug Information Institute in Pregnancy was established under a program of the Ministry of Health Labour and Welfare in October 2005. People who wished to make a counseling appointment were required to complete a pre‐appointment questionnaire and to return it by mail. The pre‐appointment questions were on age, use of drugs during pregnancy, history of present illness, previous medical history, experience of pregnancy, reproductive history, alcohol use, smoking, and intake of folic acid. Approximately a month after their expected delivery date, patients who provided informed consent for participation in the study were sent a postcard‐type questionnaire on pregnancy outcomes and the 1‐month checkup results of their infants. In cases where pregnancy outcomes were unclear, research assistants, doctors or pharmacists contacted the women's attending obstetricians to confirm their pregnancy outcome by telephone. The survey was concluded when information on pregnancy outcomes had been obtained.\n\nPrimary endpoint and statistical analysis\n\nThe primary endpoint of this study was the incidence of major malformation. To assess the teratogenic risk of domperidone, we compared the incidence of major malformation in the domperidone group with the control group. Major malformations were defined according to the European Surveillance of Congenital Anomalies (EUROCAT) 7 . In cases of congenital abnormalities not included in EUROCAT, a specialist in congenital abnormalities provided diagnoses. Two of the authors concluded that congenital abnormalities could be defined either as surficial malformations or as those requiring surgical treatment. Finally, two independent specialists confirmed the diagnoses.\n\nThe incidence of major malformation was analyzed in liveborn, single‐birth infants, and was calculated by dividing the number of liveborn singletons with congenital malformation by the number of all liveborn singletons analyzed in each group. This incidence was compared between the domperidone and control groups. Using the control group as the reference of odds ratio (ORs), the crude ORs of the incidence of major malformations in the domperidone group were calculated using univariable logistic regression analysis. In addition, adjusted ORs were calculated using multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling. Similarly, the crude and adjusted ORs of the incidence of major malformations in the metoclopramide group were calculated. In a subgroup analysis, adjusted ORs were calculated for each facility. The significance level of the test was 5%.\n\nEthics statement\n\nThis study was approved by the Ethics Committee of National Center for Child Health and Development and that of Toranomon Hospital. It was conducted according to the Declaration of Helsinki, and informed consent was obtained from all participants. Information collected from questionnaires was entered into the database and de‐identified by an information administrator. Therefore, the investigators were unable to identify individuals based on the analysis data.\n\nResults\n\nPatient characteristics\n\nAt Toranomon Hospital, 12 074 women consulted the Counseling Clinic for “Pregnancy and Medicine” between April 1988 and December 2016. Of these, 1422 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. At National Center for Child Health and Development, 12 971 women consulted the Japan Drug Information Institute in Pregnancy between October 2005 and December 2017. Of these, 1011 who met the inclusion criteria and did not meet the exclusion criteria were included in the analysis. In total, the number of participants was 519 in the domperidone group, 1673 in the control group, and 241 in the metoclopramide group (Figure 1).\n\nFigure 1 Flowchart\n\nThe median age of the subjects at the time of counseling was 30 years in all groups and the groups showed no difference in age distribution. There were no notable differences between groups in either alcohol use or smoking habits, as shown in Table 1.\n\nTable 1 Patient characteristics\n\n\tDomperidone group\tControl group\tMetoclopramide group\t\nn\t519\t1673\t241\t\nAge (year), n (%)\t\t\t\t\n50% [25%, 75%]\t30 [26, 33]\t30 [27, 34]\t30 [27, 34]\t\n≦24\t79 (15.2)\t160 (9.6)\t30 (12.4)\t\n25–29\t170 (32.8)\t548 (32.8)\t81 (33.6)\t\n30–34\t167 (32.2)\t628 (37.5)\t83 (34.4)\t\n35–39\t84 (16.2)\t288 (17.2)\t40 (16.6)\t\n40≦\t18 (3.5)\t46 (2.7)\t6 (2.5)\t\nNA\t1 (0.2)\t3 (0.2)\t1 (0.4)\t\nAlcohol, n (%)\t\t\t\t\nNo use\t292 (56.3)\t861 (51.5)\t125 (51.9)\t\nStop before pregnancy\t7 (1.3)\t45 (2.7)\t13 (5.4)\t\nStop after pregnancy\t84 (16.2)\t305 (18.2)\t48 (19.9)\t\nOngoing\t3 (0.6)\t16 (1.0)\t5 (2.1)\t\nUnknown stop time\t75 (14.5)\t250 (14.9)\t28 (11.6)\t\nNA\t58 (11.2)\t196 (11.7)\t22 (9.1)\t\nSmoking, n (%)\t\t\t\t\nNo habit\t390 (75.1)\t1244 (74.4)\t176 (73.0)\t\nStop before pregnancy\t9 (1.7)\t36 (2.2)\t10 (4.1)\t\nStop after pregnancy\t25 (4.8)\t56 (3.3)\t16 (6.6)\t\nOngoing\t16 (3.1)\t59 (3.5)\t10 (4.1)\t\nUnknown stop time\t32 (6.2)\t122 (7.3)\t13 (5.4)\t\nNA\t47 (9.1)\t156 (9.3)\t16 (6.6)\t\nAbbreviation: NA, not available.\n\nDelivery outcomes and incidence of major malformations\n\nDelivery outcomes were aggregated for all subjects. The percentage of liveborn infants was 94.0% (488 cases) in the domperidone group, 93.8% (1570 cases) in the control group, and 94.2% (227 cases) in the metoclopramide group. There were no notable differences in the incidences of stillbirth, miscarriage or abortion between the three groups (Table 2).\n\nTable 2 Pregnancy outcomes\n\n\tDomperidone group\tControl group\tMetoclopramide group\t\nn\t519\t1673\t241\t\nOutcome, n (%)\t\nLive birth\t488 (94.0)\t1570 (93.8)\t227 (94.2)\t\nStillbirth a\t3 (0.6)\t7 (0.4)\t0 (0.0)\t\nMiscarriage\t18 (3.5)\t80 (4.8)\t8 (3.3)\t\nAbortion\t10 (1.9)\t15 (0.9)\t6 (2.5)\t\nOther\t0 (0.0)\t1 b (0.1)\t0 (0.0)\t\nNumber of infant, n (%)\t\n1\t506 (97.5)\t1627 (97.3)\t234 (97.1)\t\n2≦\t1 (0.2)\t9 (0.5)\t3 (1.2)\t\nNA\t12 (2.3)\t37 (2.2)\t4 (1.7)\t\nAbbreviation: NA, not available.\n\na Fetal death after 22 weeks gestation was defined as stillbirth.\n\nb Ectopic pregnancy.\n\nMajor malformations in liveborn, single‐birth infants occurred in 14 cases in the domperidone group, 27 in the control group, and 8 in the metoclopramide group (Table 3). There was no pattern of malformation types between the three groups.\n\nTable 3 Risk of major malformation\n\n\tMajor malformation\t95%CI\tCrude OR (95%CI)\tp‐Value a\tAdjusted OR b (95%CI)\tp‐Value a\t\nNo\tYes\t\nControl group (n = 1554)\t1527\t27 c (1.7%)\t(1.1–2.5)\t1\t‐\t1\t‐\t\nDomperidone group (n = 485)\t471\t14 d (2.9%)\t(1.6–4.8)\t1.68 (0.87–3.23)\t0.119\t1.86 (0.73–4.70)\t0.191\t\nMetoclopramide group (n = 224)\t216\t8 e (3.6%)\t(1.6–6.9)\t2.09 (0.94–4.67)\t0.071\t2.20 (0.69–6.98)\t0.183\t\nRisk of major malformation was analyzed in liveborn, single‐birth infants.\n\nAbbreviations: CI, confidence interval; OR, odds ratio.\n\na Significance level p < 0.05, *<0.05.\n\nb Adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling.\n\nc Ventricular septal defect (6); ventricular and atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); peripheral pulmonary stenosis (1); endocardial cushion defect (1); complete transposition of great arteries (1); double outlet right ventricle (1); esophageal atresia (1); cleft lip (1); diastasis recti (1); adhesion of scrotum and penis (1); hydronephrosis (2); imperforate anus (1); talipes varus (1); polydactyly (3); a combination of coarctation of the aorta and ventricular septal defect (1); a combination of single ventricle and pulmonary stenosis (1); a combination of ventricular septal defect, pulmonary stenosis and syndactyly (1).\n\nd Ventricular septal defect (5); ventricular and atrial septal defect (1); atrial septal defect (1); tetralogy of Fallot (1); pulmonary stenosis (1); cleft lip and palate (1); double vagina (1); hydroureteropathy (1); hydronephrosis (1); a combination of duodenal obstruction, heart disease, upper aortic malposition and pulmonary artery occlusion (1).\n\ne Ventricular septal defect (1); endocardial cushion defect (1); myelomeningocele (1); lissencephaly (1); hypospadias (1); talipes varus (1); polydactyly (1); scalp defect (1).\n\nRisk of major malformation\n\nThe incidence of major malformation in liveborn, single‐birth infants (95% confidence interval [CI]) was 2.9% (14/485, 95%CI: 1.6–4.8) in the domperidone group, 1.7% (27/1554, 95%CI: 1.1–2.5) in the control group, and 3.6% (8/224, 95%CI: 1.6–6.9) in the metoclopramide group.\n\nUnivariable logistic regression analysis showed no significant difference in the incidence of major malformation between the domperidone and control groups (OR: 1.68 [95% CI: 0.87–3.23], p = 0.119). Additionally, multivariable logistic regression analysis adjusted for alcohol intake, smoking, maternal age, use of concomitant drugs other than the control drugs during the first trimester of pregnancy, facility, and the year of counseling also showed no significant difference in the incidence of major malformation between the domperidone and control groups (adjusted OR: 1.86 [95% CI: 0.73–4.70], p = 0.191) (Table 3). Similar results were obtained when comparing the metoclopramide and control groups (OR: 2.09 [95% CI: 0.94–4.67], p = 0.071; adjusted OR: 2.20 [95% CI: 0.69–6.98], p = 0.183).\n\nSubgroup analysis\n\nFor the cases at Toranomon Hospital, the adjusted OR (95%CI) of the incidence of major malformation was 2.54 (95%CI: 0.68–9.46, p = 0.164) in the domperidone group and 2.54 (95%CI: 0.47–13.82, p = 0.282) in the metoclopramide group, indicating no significant difference for either group compared with the control group.\n\nFor the cases at National Center for Child Health and Development, the adjusted OR (95%CI) of the incidence of major malformation was 1.45 (95%CI: 0.38–5.54, p = 0.583) in the domperidone group and 2.06 (95%CI: 0.43–9.98, p = 0.370) in the metoclopramide group, again indicating no significant difference for either group compared with the control group (Supporting Information, Table SS1).\n\nWe also compared the adjusted OR of risk of major malformations by the year of counseling (Table SS2). To rule out the year of counseling as a possible confounding factor, we compared the first half of the data from Toranomon Hospital (1988–2004), to the second half (2005–2016) (adjusted OR: 0.79 [95%CI: 0.26–2.39], p = 0.680) and to the data from the National Center for Child Health and Development (2005–2017) (adjusted OR: 1.34 [95%CI: 0.69–2.60], p = 0.381), and found no significant differences in the adjusted OR.\n\nDiscussion\n\nAlthough there are prior reports 3 , 4 of domperidone administered to pregnant women, those studies lacked sufficient detection power to ensure that domperidone exposure is not harmful to the fetus. Therefore, no information has been available to ensure the safety of using domperidone in pregnant women.\n\nIn this study, the 485 patients who received domperidone during the first trimester of pregnancy showed no increase in the incidence of major malformation compared with patients in the control group, who received drugs that are considered to have no teratogenicity. In addition, no difference was found in the results of a sensitivity analysis that assessed teratogenic risk by excluding patients who used teratogenic drugs defined by the clinical guidelines for gynecology and obstetrics 8 .\n\nThis study enrolled pregnant women who consulted at Toranomon Hospital or the National Center for Child Health and Development. We therefore performed a subgroup analysis to determine if there were any discrepancies in results between the facilities. There were no such differences, and the incidence of major malformation in the domperidone group did not higher than that in the control group at neither facility.\n\nThis study analyzed participants who received counseling at Toranomon Hospital after April 1988 and at National Center for Child Health and Development after October 2005. The use of imaging modalities to detect visceral malformations began in 1997. Therefore, it is presumed that since then it has been possible to detect even minor malformations, such as inconsequential heart defects. However, there was no significant difference in the incidence of major malformation at Toranomon Hospital between 1988 to 2004 and 2005 to 2016. Also, the data from National Center for Child Health and Development (2005–2017) yielded similar results as those from Toranomon Hospital (1988–2004). Thus, the timing of counseling is unlikely to be associated with the detection rate of malformation.\n\nThe package insert for domperidone states that it is contraindicated for use in pregnant women and in women suspected of being pregnant, due to teratogenicity observed in reproductive toxicity studies. This has led to the problem of pregnant women becoming anxious when they discover they have taken domperidone before finding out they were pregnant.\n\nThis observational cohort study was based on highly precise data about drug use by pregnant women, derived from interviews conducted by healthcare professionals at medical facilities that provide counseling on drug use during pregnancy. It showed that the risk of major malformation was not increased in women who received domperidone during pregnancy. However, it should be noted that a limitation of the study is that women could cancel their counseling if they had a miscarriage or abortion beforehand, resulting in underreported miscarriage or abortion cases.\n\nIn future counseling, this information is clinically very useful because it can reduce or eliminate the anxiety of patients who have taken domperidone during pregnancy. The Japanese clinical guidelines for obstetrics and gynecology (obstetrics portion) list domperidone as one of the “drugs that may be used by women in early pregnancy without having a clinically significant adverse effect on the fetus, even though the package inserts state that they are contraindicated in pregnant women.” 8 The results of this study support this statement in the guidelines.\n\nConflict of interest\n\nAtsuko Murashima received lecture fees from Chugai Pharmaceutical Co.Ltd and Astellas Pharma Inc.\n\nSupporting information\n\nTable S1 Subgroup analysis by the facility\n\nClick here for additional data file.\n\nTable S2 Subgroup analysis by the year of counseling\n\nClick here for additional data file.\n\nAcknowledgments\n\nThis work was supported by a Research Program from the Japanese Agency for Medical Research and Development under Grant Number JP19mk0101086h0003, awarded to A.M. The authors would like to thank Dr. Kenjiro Kosaki and Dr. Rika Kosaki for their great advice in diagnosing congenital malformations and we would like to thank Mariko Takagai for her administrative assistance. They are also grateful to women who donated their clinical information and for colleagues worked as a member of Japan Teratology Information Services Network.\n==== Refs\nReferences\n\n1 Matok I , Gorodischer R , Koren G , Sheiner E , Wiznitzer A , Levy A . The safety of metoclopramide use in the first trimester of pregnancy. N Engl J Med. 2009;360 :2528–35.19516033\n2 Pasternak B , Svanström H , Mølgaard‐Nielsen D , Melbye M , Hviid A . Metoclopramide in pregnancy and risk of major congenital malformations and fetal death. JAMA. 2013;310 (15 ):1601–11.24129464\n3 Choi JS , Han JY , Ahn HK , Ryu HM , Kim MY , Yang JH , et al. Fetal and neonatal outcomes in women taking domperidone during pregnancy. J Obstet Gynaecol. 2013;33 :160–2.23445139\n4 Cottin J , Beghin D , Jonville‐Bera AP , et al. First trimester exposure to domperidone: a comparative prospective study of exposed infants. Reprod Toxicol. 2015;57 :217.\n5 Bérard A , Abbas‐Chorfa F , Kassai B , Vial T , Nguyen KA , Sheehy O , et al. The French pregnancy cohort: medication use during pregnancy in the French population. PLoS One. 2019;14 (7 ):e0219095.31314794\n6 Habermann F , Fritzsche J , Fuhlbrück F , Wacker E , Allignol A , Weber‐Schoendorfer C , et al. Atypical antipsychotic drugs and pregnancy outcome a prospective, cohort study. J Clin Psychopharmacol. 2013;33 (4 ):453–62.23764684\n7 EUROCAT Guide 1.4 and Reference Documents (Last update version 15/11/2019). Available from https://eu‐rd‐platform.jrc.ec.europa.eu/sites/default/files/JRC‐EUROCAT‐Full‐Guide‐1.4‐version‐15‐Nov‐2019.pdf\n8 Japan Society of obstetrics and gynecology, Japan Gynecologist Association (eds) The clinical guidelines for gynecology and obstetrics (obstetrics portion) 2017. Tokyo: Japan Society of obstetrics and gynecology; 2017.\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "47(5)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "domperidone; first trimester; observational cohort study; pregnancy outcomes; teratogenicity",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D015331:Cohort Studies; D004294:Domperidone; D005260:Female; D006801:Humans; D008787:Metoclopramide; D011247:Pregnancy; D011256:Pregnancy Outcome; D011261:Pregnancy Trimester, First",
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"pages": "1704-1710",
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"pmid": "33631840",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "19516033;24129464;23445139;23764684;31314794",
"title": "Pregnancy outcome after first trimester exposure to domperidone-An observational cohort study.",
"title_normalized": "pregnancy outcome after first trimester exposure to domperidone an observational cohort study"
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"companynumb": "JP-AMNEAL PHARMACEUTICALS-2021-AMRX-00903",
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"abstract": "The present study reports on the experience at Jiangxi Provincial People's Hospital (Nanchang, China) with liver transplantation in adults using pediatric donor livers, including indications, technique and results. A total of three cases of liver transplantation performed between April 2008 and May 2016 were retrospectively reviewed. Liver procurement and trimming, recipient selection, surgical tips, prevention and treatment of small-for-size syndrome, selection of immunosuppressive regimens, prevention and treatment of vascular complications and anticoagulant therapy were discussed. The three pediatric donors were 8, 8 and 10 years old. The three recipients were confirmed to have primary liver cancer. In recipient 1 (female; age, 39 years), jaundice persisted in the recipient after the liver transplantation. A reduced dose of FK506 was then given to gradually decrease the total bilirubin level to the normal range. Recipient 1 recovered and was discharged from hospital; however, the patient died of liver cancer recurrence and bone metastasis 6 years post-transplantation. In recipient 2 (male; age, 56 years), the recipient experienced sudden abdominal distension on postoperative day 7. The patient's clotting time was prolonged and the transaminase level was sharply increased, peaking on day 9. The patient was suspected of having small-for-size syndrome and was treated symptomatically. The patient experienced a significant improvement in symptoms on postoperative day 13 and regular postoperative follow-ups were performed until now and the patient is now in remission. In recipient 3 (male; age, 48 years), the recipient recovered well and the liver function returned to normal on postoperative day 3. The patient was discharged from hospital and has been in remission thus far. Adult liver transplantations from pediatric donors are feasible treatments. Systematic donor and recipient assessments, sound surgical skills and optimal postoperative treatments are essential for success in the transplantation of livers from pediatric donors into adult recipients. Considering the condition of the donor liver, the selection of recipients and appropriate surgical methods are particularly important in these cases.",
"affiliations": "Department of Transplantation, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330000, P.R. China.;Secretarial Section, Jiangxi Provincial Cultural and Sports Management Center for the Disablede, Nanchang, Jiangxi 330000, P.R. China.;Department of Transplantation, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330000, P.R. China.;Department of Transplantation, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330000, P.R. China.",
"authors": "Ding|Limin|L|;Deng|Lishan|L|;Li|Xinchang|X|;Xu|Zhidan|Z|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/etm.2020.9155",
"fulltext": "\n==== Front\nExp Ther Med\nExp Ther Med\nETM\nExperimental and Therapeutic Medicine\n1792-0981 1792-1015 D.A. Spandidos \n\n10.3892/etm.2020.9155\nETM-0-0-09155\nArticles\nAdult liver transplantation using pediatric donor livers after cardiac or brain death: A report of three cases\nDing Limin 1 Deng Lishan 2 Li Xinchang 1 Xu Zhidan 1 1 Department of Transplantation, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, Nanchang, Jiangxi 330000, P.R. China\n2 Secretarial Section, Jiangxi Provincial Cultural and Sports Management Center for the Disablede, Nanchang, Jiangxi 330000, P.R. China\nCorrespondence to: Dr Zhidan Xu, Department of Transplantation, Jiangxi Provincial People's Hospital Affiliated to Nanchang University, 152 Aiguo Road, Nanchang, Jiangxi 330000, P.R. China xuzhidan1970@163.com\n11 2020 \n31 8 2020 \n31 8 2020 \n20 5 2725 8 2019 01 5 2020 Copyright: © Ding et al.2020This is an open access article distributed 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.The present study reports on the experience at Jiangxi Provincial People's Hospital (Nanchang, China) with liver transplantation in adults using pediatric donor livers, including indications, technique and results. A total of three cases of liver transplantation performed between April 2008 and May 2016 were retrospectively reviewed. Liver procurement and trimming, recipient selection, surgical tips, prevention and treatment of small-for-size syndrome, selection of immunosuppressive regimens, prevention and treatment of vascular complications and anticoagulant therapy were discussed. The three pediatric donors were 8, 8 and 10 years old. The three recipients were confirmed to have primary liver cancer. In recipient 1 (female; age, 39 years), jaundice persisted in the recipient after the liver transplantation. A reduced dose of FK506 was then given to gradually decrease the total bilirubin level to the normal range. Recipient 1 recovered and was discharged from hospital; however, the patient died of liver cancer recurrence and bone metastasis 6 years post-transplantation. In recipient 2 (male; age, 56 years), the recipient experienced sudden abdominal distension on postoperative day 7. The patient's clotting time was prolonged and the transaminase level was sharply increased, peaking on day 9. The patient was suspected of having small-for-size syndrome and was treated symptomatically. The patient experienced a significant improvement in symptoms on postoperative day 13 and regular postoperative follow-ups were performed until now and the patient is now in remission. In recipient 3 (male; age, 48 years), the recipient recovered well and the liver function returned to normal on postoperative day 3. The patient was discharged from hospital and has been in remission thus far. Adult liver transplantations from pediatric donors are feasible treatments. Systematic donor and recipient assessments, sound surgical skills and optimal postoperative treatments are essential for success in the transplantation of livers from pediatric donors into adult recipients. Considering the condition of the donor liver, the selection of recipients and appropriate surgical methods are particularly important in these cases.\n\nliver transplantationorgan donationpediatric liver donorspostoperative complications\n==== Body\nIntroduction\nLiver transplantation is widely accepted as an effective therapy for patients with end-stage liver disease (1). In the past, donor organs in China were mainly transplanted from relatives and deceased patients. With improvements in China's legal system, the use of deceased patients as donors was banned in 2015 (2,3). As a consequence, there has been a severe shortage of organ donors (4). Organ transplantation from living relative donors has become the last resort; however, it is not advocated (4). After lengthy discussions and developments within the organ transplant branch of the Chinese medical association (5), donation after citizen's death (DCD) became the major source of organs for transplantation in 2015(3). Pediatric DCDs account for a certain proportion of the total DCD donors (6). It is at times difficult to find matching child recipients for the organs of older-aged normally developed child donors (6). Therefore, liver transplantations in adults using pediatric donor livers have been performed to improve organ utilization (7-18). This has broadened the source of liver donors for transplantation in adults and certainly alleviated any shortages (7,8). Selection of optimal recipients and appropriate surgical methods based on the condition of the donor liver (including donor liver volume, caliber difference between donor and recipient vessels, and the spatial location of the donor liver in the abdominal cavity of recipients, are crucial for successful liver transplantation in adults using pediatric donor livers (16-18). At present, pediatric donation in China is still in its infancy (9-15). The DCD donation process was implemented in the hospital of the current study during its initial development as a pilot project. In April 2008, a preliminary experience was obtained at the hospital with the first case of an adult liver transplantation using a pediatric donor liver (case 1 of the present study). Another two transplantations wherein child donors provided organs for liver transplantation in adults were performed in November 2015 (case 2) and May 2016 (case 3). In the present study, these three cases of adult liver transplantation using pediatric liver DCDs were discussed. The relevant points and challenges discussed include liver procurement and trimming, recipient selection, surgical tips, prevention and treatment of small-for-size syndrome (SFSS), selection of immunosuppressive regimens, prevention and treatment of vascular complications and anticoagulant therapy.\n\nMaterials and methods\n\nPatients\nThe study was approved by the Ethics Committee of Jiangxi Provincial People's Hospital (Nanchang, China). Informed consent was obtained from the legal guardians of donors for use of their tissues and publication of associated data. Informed consent was obtained from the recipients for receiving pediatric donor tissue and publication of their data.\n\nPediatric donor data\nAdult liver transplantations using pediatric donor livers were successfully performed in three cases at Jiangxi Provincial People's Hospital (Nanchang, China) between April 2008 and May 2016. A total of 3 pediatric donors (male, 2; female, 1; mean age, 8.67 years; age range, 8-10 years, mean body mass index, 15.12±3.31 kg/m2) were recruited between April 2008 and May 2016. Using the China Classification for Organ Donation (5), one donor was designated China Category I (organ donation consistent with international standards for donation following brain death) and the other two donors were designated China Category III (organ donation following brain death awaiting cardiac death). Of the three pediatric donors, one had died of a brain tumor and two had died of brain trauma. Age, sex and relevant laboratory indexes, including total bilirubin (TBIL), direct bilirubin (DBIL), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, warm ischemia time, cold ischemic time and quality of the donor liver, were evaluated. All of these parameters were within normal limits (Table I). Following trimming, the graft/recipient weight ratio (GRWR) was 1.07-1.39% and the graft volume/recipient standard liver volume ratio (GV/SLV) was 65.14-69.54%.\n\nClinical data of liver transplant recipients and postoperative medications\nA total of 3 liver recipients (male, 2; female, 1; mean age, 47.67 years; age range, 39-56 years) who were confirmed to have primary liver cancer were recruited between April 2008 and May 2016. The liver functions were graded as Child-Pugh A in two patients and Child-Pugh B in one patient (19). Two recipients underwent orthotopic liver transplantation and one underwent piggyback liver transplantation (Table II). Post-operatively, an immunosuppressive regimen consisting of mycophenolate mofetil and tacrolimus was scheduled for the recipients with primary hepatocellular carcinoma. Anti-HBV treatment was administered orally in the form of anti-HBV drugs. If necessary, anti-HBV drugs were recommended in combination with two antiviral drugs. Hepatitis B immunoglobulin was administered during the hospitalization. Post-operative anticoagulant therapies, including low molecular weight heparin sodium and aspirin, were administered according to the recipients' liver blood flow monitored by color Doppler ultrasound and associated coagulation function indicators.\n\nResults\nIn the case of recipient 1, postoperative jaundice worsened during the course of the hospital stay following transplantation. On the 3rd postoperative day, TBIL, DBIL, ALT and AST levels were up to 178, 93.9, 84.1 µmol/l, 153 and 267 IU/l, respectively, but the recipient had no chills or fever and no liver pain, and the T-tube drainage prevented bile leakage. Recipient 1 was considered to suffer from FK506 toxicity as the FK506 blood concentration was 12.66 ng/ml and there was no evidence of rejection. After reducing the FK506 dose, the TBIL level gradually decreased and the bile drainage volume gradually increased to 300-500 ml per day. Recipient 1 was discharged around postoperative day 40. The T-tube was clamped at 2 postoperative months and cholangiography was performed after 3 months of continuous clamping of the T-tube. The cholangiography results indicated normal biliary tract outflow, with no signs of obstruction and the T-tube was removed. Postoperative chemotherapy with 5-fluorouracil and calcium folinate was administered only once, as the white blood cell count was low after chemotherapy. In 2011, recipient 1 died of liver cancer recurrence and bone metastasis.\n\nIn the case of recipient 2, on the 7th postoperative day, the patient suddenly developed abdominal distension, prolongation of the clotting time and a sudden and dramatic rise in transaminase levels, which peaked on the 9th postoperative day. The TBIL, DBIL, ALT and AST levels were 89.8 µmol/l, 5,698 and 3,705 IU/l, respectively (Table III). The results of CT angiography revealed multiple low-density lesions in the liver and a weakly developed hepatic artery (Figs. 1 and 2). Recipient 2 was diagnosed with avascular necrosis of the liver and the following measures were taken: Withdrawal or reduction of the dosages of the drugs considered to have caused the liver damage, adjustment of the dosage of the immunosuppressive agents, increasing the administration of antibacterial drugs and initiation of somatostatin and terlipressin to improve the blood supply to the liver. Thereafter, the clinical symptoms of recipient 2 improved significantly on the 13th postoperative day. He experienced a gradual recovery of his liver function and was then discharged from hospital. As of now, recipient 2 remains in remission and is subjected to regular follow-ups.\n\nRecipient 3 recovered well after the liver transplantation and his liver function returned to normal on the 3rd postoperative day. Since his discharge from hospital, the patient has been in remission and is subjected to regular follow-ups.\n\nDiscussion\nIn the present study, three cases of adult liver transplantation using pediatric donor livers achieved good clinical results. Pediatric donor livers have abundant blood vessels, little connective tissue, incomplete liver parenchyma, strong regenerative capacity and are unlikely to develop cirrhosis (20). Hepatocytes are basically mature at the age of 8 years (6) and there is still space for postoperative donor liver growth (9). Increased attention should be paid to the harvesting and trimming of the donor liver, the choice of recipients and the prevention and management of postoperative complications.\n\nRegarding the procurement of donor livers, it should be observed during organ harvesting that the blood vessels and biliary tract in the livers of the pediatric donors, particularly those of underweight children, are thin (9,16-18). Therefore, a modified no. 10 suction tube may be used to achieve better perfusion instead of using a modified Foley catheter, which is generally used for adult abdominal aortae. The donor livers from underweight children are not necessarily mature and, therefore, the perfusion fluid should be maintained at a moderate level so to prevent excessive pressure that may cause liver sinus injury (10). Furthermore, the perfusion amount for pediatric donors is lower than that for adult donors (9). Care must be taken to avoid overperfusion while still ensuring adequate donor perfusion (16). In the present study, during the harvesting of the donor liver, the perfusion height for the pediatric donor was 10-20 cm lower than that for the adult donor and the perfusion amount for the pediatric donor was 1/2 to 2/3 of that of the adult donor to reduce perfusion damage to the donor liver.\n\nDuring the trimming of the donor livers, the pediatric donor liver used in adult liver transplantation should be strictly assessed to avoid small-for-size donor livers (21-24). The small-sized pediatric liver grafts may easily shift in the abdominal cavity, causing the blood vessels and biliary tract to be distorted (21-24). Therefore, during trimming of donor livers, a part of the sacral ligament may be retained to fix the donor liver after surgery. As the wall of the inferior vena cava in the pediatric liver is thinner, the surrounding tissue does not require to be completely separated (21). Otherwise, blood oozing may easily occur during and after surgery (21). The hepatic artery in the pediatric liver is slender and complete trimming is not required (22). This reduces the probability of vascular embolism caused by intimal injury during manipulation (22,23). Special trimming of the common bile duct is not generally required, which may be severed directly at the edge of the pancreas to avoid interruption of the blood supply (24).\n\nRegarding the choice of recipients, patients with tumors as the primary disease and those with lower body weights are considered to be the optimal recipients in adult liver transplantation using pediatric donor livers (11,16-18). Patients who have had >1 episode of gastrointestinal bleeding, multiple previous surgeries and/or severe portal hypertension are not considered ideal candidates for pediatric liver transplantations (11). In the present study, the body masses of recipients 1, 2 and 3 were all under 60 kg and their primary disease was primary liver cancer. Preoperative liver function was graded as Child-Pugh A in two cases and Child-Pugh B in one case. Therefore, the postoperative incidence of SFSS was effectively reduced. In addition, the donor GV/SLV may be used as a selection criterion to assess the size matching between the liver graft and the recipient. GV may be measured by CT or directly by the water displacement method. SLV may be measured using the following formula: SLV (ml)=706.2x body surface area (BSA, m2) + 2.4(25), BSA of pediatric donor (m2)=0.0061x body height (BH, cm) + 0.0128x body weight (BW, kg)-0.1529 and BSA of adult recipient (m2)=0.00659x BH (cm) + 0.0126x BW (kg) -0.1603(4). The GRWR may be calculated according to the conversion of weight to volume by the conversion factor of 1.19 ml/g (26). The currently accepted standard is that GV/SLV should be >40% (27) and GRWR should not be <0.8-1% (28). In the present study, the GV/SLV was 65.14-69.54% and the GRWR was 1.07-1.39%.\n\nOrthotopic or piggyback adult liver transplantations from pediatric donors may be advantageous (9,16-18). The choice of orthotopic liver transplantation falls in line with the physiological requirements of the human body (9,16-18). Therefore, considering the relatively small size of the pediatric donor liver, the first porta hepatis (portal vein, hepatic artery and the common bile duct) should be isolated carefully to preserve the adequate length and the blood supply of the biliary tract. Since the adult recipient has a larger abdominal cavity relative to the child donor, orthotopic liver transplantations are relatively better with respect to fixation of the donor liver and they impart a lower risk of vascular complications such as outflow obstruction (9). The use of piggyback liver transplantations may avoid vena cava stenosis caused by the differences in the vena cava diameters and reduce the surgical complications caused by the blood vessel mismatches in the donor liver (29). During liver trimming, the donor hepatic artery may be trimmed using vascular loops for anastomosis in order to solve the mismatch with the caliber of the hepatic artery (11,21-24). For the anastomosis of the common bile duct between the donor and recipient, continuous anastomosis of the posterior wall and intermittent anastomosis of the anterior wall have been adopted (11). Furthermore, a T-tube may be placed to guide the drainage if a significant difference exists in the calibers of the common bile ducts of the donor and the recipient (30). When entering the blood vessels, controlling the blood pressure is necessary to reduce damage to the donor liver (9). In the present study, orthotopic liver transplantation was performed in two cases as there were no significant differences in the vena cava calibers between the recipients and donors. The ligaments of the donor livers and the abdominal drainage tubes with balloons placed around the livers were used in all three cases to fix the liver grafts in the abdominal cavities (Fig. 3) . This effectively reduced the blood vessel and biliary tract distortions caused by position changes in the transplanted livers.\n\nSFSS prevention is key in adult liver transplantations using pediatric donor livers (31,32). The mechanism underlying SFSS is that excessive perfusion of the portal vein causes mechanical injury to the hepatic sinus and portal vein endothelial cells, destruction of the space of Disse, as well as flaky necrosis of liver tissues (17,33). During liver transplantation in an adult using a pediatric donor liver, effective control of the blood flow in the portal vein may significantly reduce the risk of SFSS in adult recipients (34-37). To reduce postoperative portal venous pressure, intraoperative ligation of the splenic artery or splenectomy may be considered and a postoperative intravenous infusion of somatostatin or terlipressin may also be administered according to the unique situation of the patient (38-40). In the present study, on the 7th postoperative day, recipient 2 experienced sudden abdominal distension, developed a prolongation of the clotting time and exhibited a sudden and marked rise in the level of transaminase that peaked on the 9th postoperative day. Postoperative TBIL, DBIL, ALT and AST levels in recipient 2 were 89.8 µmol/l, 5,698 and 3,705 IU/l, respectively. CT angiography revealed multiple low-density lesions in the liver and a weakly developed hepatic artery. Recipient 2 was thus diagnosed with avascular necrosis of the liver, in line with the manifestations of SFSS. Somatostatin and terlipressin were administered to improve the blood supply in the liver. On the 13th postoperative day, the patient's clinical symptoms improved significantly. The patient exhibited a gradual improvement in liver function and was then discharged from hospital. These observations indicate that the ability of pediatric donor liver cells to regenerate is stronger than that of adults; transplant liver function and postoperative growth are issues of concern in adult liver transplantations using pediatric donors (41). Postoperative administration of terlipressin effectively alleviates high portal venous pressure, reduces hepatic blood flow and eases the mechanical damage to the liver sinuses. The early rise in portal venous pressure is specifically controlled to avoid dual injury from excessive perfusion and ischemia-reperfusion (42). This postoperative treatment provides a novel method for effective prevention and treatment of SFSS after liver transplantation (42,43). Terlipressin administration should not be prolonged. Close monitoring of the patient's vital signs and routine color Doppler ultrasound of the transplanted liver are necessary to reduce the incidence of portal vein thrombosis and bradycardia.\n\nThe use of immunosuppressive agents is key to prevent rejection after liver transplantation. Tacrolimus is mainly metabolized via the cytochrome P450 system in the liver and small intestine and is then excreted via the biliary tract (44-47). The use of immunosuppressive agents after liver transplantation in an adult using a pediatric donor liver cannot be generalized. Considering the smaller size of the donor liver in case 1, the ability of the donor liver to metabolize the immunosuppressive agents was less effective than that of the adult liver and therefore, the FK506 blood concentration was maintained at a lower level than the standard value. Combined with the results from cases 2 and 3 in the present study and the results of previous studies (48-50), it was indicated that pediatric donor livers have higher clearance rates for tacrolimus and therefore, the dose of tacrolimus for pediatric donors should be 2-4 times that of adult donors to achieve the same concentration. This is inconsistent with the conclusion obtained in case 1 of the present study. Therefore, individualization of tacrolimus dosing is required after liver transplantation in an adult using a pediatric donor liver (51,52).\n\nRegarding the prevention and treatment of vascular complications and anticoagulation therapy, vascular complications associated with liver transplantation in adults using a pediatric donor liver are mainly triggered by blood vessel volume mismatches between donors and recipients (10). Furthermore, high portal perfusion pressures may easily cause reactive contractions of hepatic arterioles, which reduces the arterial blood flow and may potentially cause the formation of a thrombus (9,16-18). Anticoagulant therapy is given according to blood flow monitoring on color Doppler ultrasound and laboratory indicators (8). In the present study, early postoperative administration of low molecular weight heparin, warfarin and aspirin anticoagulation was initiated to prevent hepatic artery thrombosis. The anticoagulant drugs were adjusted or stopped in accordance with the follow-up results from 3-6 months postoperatively.\n\nIn conclusion, the present study suggested that liver transplantations in adults using pediatric donor livers are feasible. Systematic donor and recipient assessments, sound surgical skills and optimal postoperative management are essential for success in adult liver transplantations using pediatric donor livers. Adult liver transplantations using pediatric donor livers can widen the pool of liver donors for adult transplantation and certainly alleviate the source shortage. Considering the condition of the donor liver, selection of recipients and appropriate surgical methods are particularly important for adult liver transplantations using pediatric donor livers.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe current work was supported by grants from Key R&D Project of Scientific and Technical Supporting Program of Jiangxi Province (grant no. 20161BBG70121) and the Science and Technology Planning Project of Health and Family Planning Commission of Jiangxi Province (grant no. 20181006).\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors' contributions\nLDi designed the study, analyzed and interpreted data and wrote the manuscript. LDe and XL collected, analyzed and interpreted data. ZX designed the study and critically revised the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe current study was approved by the Ethics Committee of Jiangxi Provincial People's Hospital (Nanchang, China). Written informed consent was obtained from the legal guardians of donors for use of their tissues and publication of associated data. Written informed consent was obtained from the recipients for receiving pediatric donor tissue and publication of their data.\n\nPatient consent for publication\nNot applicable.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1 Multiple low-density lesions are visible on CT angiography in recipient 2.\n\nFigure 2 CT angiography in recipient 2 reveals that the hepatic artery was weakly developed on the 9th postoperative day. Images from the left to right are the coronal image and two angles of a three-dimensional reconstruction image.\n\nFigure 3 The abdominal drainage tubes with balloons. The internal diameter and length of the tube was 7.3 mm and 39 cm, respectively.\n\nTable I Clinical data of the pediatric liver donors and liver grafts.\n\nDonor no.\tDonation classification (China category)\tPrimary disease\tAge (years)\tSex\tTBIL (µmol/l)\tDBIL (µmol/l)\tAST (IU/l)\tALT (IU/l)\tCREA (µmol/l)\tWarm ischemia time (min)\tCold ischemia time (h)\tHarvested liver mass (g)\t\n1\tI\tBrain tumor\t 8\tMale\t22.4\t12.5\t43\t35\t76\t2\t4.2\t641\t\n2\tIII\tBrain trauma\t 8\tFemale\t19.6\t11.6\t36\t27\t43\t5\t4.5\t550\t\n3\tIII\tBrain trauma\t10\tMale\t16.3\t9.3\t45\t38\t86\t6\t5.0\t545\t\nTBIL, total bilirubin (normal range, 3.4-20.5 µmol/l); DBIL, direct bilirubin (normal range, 0-7.00 µmol/l); AST, aspartate aminotransferase (normal range,15-40 IU/l); ALT, alanine aminotransferase (normal range, 9-50 IU/l); CREA, creatinine (normal range, 44-115 µmol/l).\n\nTable II Clinical data of adult liver transplant recipients of pediatric donor livers.\n\nRecipient no.\tPrimary disease\tAge (years)\tSex\tBody height (cm)\tBody weight (kg)\tLiver function grading\tAnhepatic time (min)\tSurgical mode\tOperation time (h)\t\n1\tPrimary liver cancer\t39\tFemale\t156\t46\tChild B\t49\tOrthotopic\t6.1\t\n2\tPrimary liver cancer\t56\tMale\t160\t49\tChild A\t53\tPiggyback\t5.2\t\n3\tPrimary liver cancer\t48\tMale\t162\t51\tChild A\t58\tOrthotopic\t4.5\t\nTable III Clinical data of recipient 2 following surgery.\n\nNumber of days after surgery\tTBIL (µmol/l)\tDBIL (µmol/l)\tAST (U/l)\tALT (U/l)\tPT (sec)\tAPTT (sec)\tINR\tBlood ammonia (µmol /l)\tDepth of ascites in sitting position monitored by color Doppler ultrasound (cm)\t\n 1\t23.2\t16.5\t659\t516\t17.5\t82.6\t1.56\t121.9\t3.4\t\n 3\t80.3\t65.1\t316\t266\t15.2\t45.9\t1.34\t61.2\t2.2\t\n 5\t44.8\t26.9\t64\t182\t13.3\t34.8\t1.16\t75.4\t2.0\t\n 7\t42.5\t23.3\t3,431\t4,588\t21.0\t36.3\t1.89\t108.5\t4.2\t\n 9\t89.8\t54.2\t3,705\t5,698\t31.2\t52.1\t2.89\t146.0\t8.7\t\n11\t86.1\t50.2\t1,853\t5,135\t20.9\t39.4\t1.88\t125.7\t5.2\t\n13\t66.1\t46.1\t85I\t1,027\t19.2\t38.8\t1.72\t89.2\t4.8\t\n15\t45.9\t30.5\t43\t443\t16.5\t43.4\t1.46\t44.6\t3.3\t\nTBIL, total bilirubin; DBIL, direct bilirubin; AST, aspartate aminotransferase; ALT, alanine aminotransferase; PT, prothrombin time; APTT, activated partial thromboplastin time; INR, international normalized ratio.\n==== Refs\nReferences\n1 Chen ZH New sight after a quarter century: A long Chinese way to tackle the organ shortage in the era of worldwide organ crises Zhonghua Yizhi Zazhi Diziban 4 265 272 2010 \n2 Zhang L Zeng L Gao X Wang H Zhu Y Transformation of organ donation in China Transpl Int 28 410 415 2015 10.1111/tri.12467 25267538 \n3 Zhang GY Liao T Fu XB Li QF Organ transplantation in China: Concerns remain Lancet 385 854 855 2015 10.1016/S0140-6736(15)60485-8 25773095 \n4 Yan LN: Modern Liver Transplantation. 1st edition. Beijing, Military science publishing house, pp292-306, 2004. \n5 Organ Transplantation Branch of the Chinese Medical Association. National guidelines for donation after cardiac death in China (2nd edition). Zhonghua Qiguanyizhi Zazhi 32: 756-758, 2011. \n6 Shen XM: Clinical Pediatrics. 1st edition. People's Medical Publishing House, Beijing, pp1010-1011, 2005. \n7 Werner MJM van Leeuwen OB de Jong IEM Bodewes FAJA Fujiyoshi M Luhker OC Scheenstra R de Vries Y de Kleine RHJ Porte RJ First report of successful transplantation of a pediatric donor liver graft after hypothermic machine perfusion Pediatr Transplant 23 e13362 2019 10.1111/petr.13362 30801955 \n8 Croome KP Lee DD Burns JM Saucedo-Crespo H Perry DK Nguyen JH Taner CB Mayo Clinic Collaborative in Transplant Research and Outcomes: Outcomes of liver transplantation with liver grafts from pediatric donors used in adult recipients Liver Transpl 22 1099 1106 2016 10.1002/lt.24466 27145067 \n9 He XS Ju WQ Guo ZY Wu LW Tai Q Han M Wang DP Zhu XF Huang JF First case of pediatric donor liver for adult liver transplantation in China Zhonghua Waike Zazhi 48 1597 1598 2010 \n10 Shi J Luo WF Ding LM Xu ZD Wang YG Li XC Luo LB Long CM Clinical analysis of liver transplant from a child of brain death to an adult Zhonghua Gandan Waike Zazhi 17 359 363 2011 \n11 Wei L Zhu ZJ Dong C Gao W Yang T Sun LY Qu W Rao W Sun XY Shen ZY Use of liver graft from pediatric donor of donation after cardiac death in adult recipient (report of one case) Zhongguo Puwai Jichu Yu Linchuang Zazhi 19 490 492 2012 \n12 Huang XL Li GQ Mu XX Qin JJ Zhou S Li MY Pang XX Tan SB and Sun PC Preliminary experience of pediatric donor liver and advanced marginal donor liver in adult liver transplantation Nanjing Yike Daxue Xuebao (Ziranban) 36 193 196 209 2016 \n13 Lan C Song JL Yan LN Yang JY Wen TF Li B Xu MQ Pediatric donor to adult recipients in donation after cardiac death liver transplantation: A single-center experience Transplant Proc 49 1383 1387 2017 10.1016/j.transproceed.2017.01.088 28736011 \n14 Ju W Li C Zhang C Ko DS Wang D Han M Schroder PM Wang X Jiao X Wu L Outcome of the use of paediatric donor livers in adult recipients: A single Chinese Centre experience Clin Res Hepatol Gastroenterol 43 148 154 2019 10.1016/j.clinre.2018.08.018 30318357 \n15 Li JJ, Zu CH, Li SP, Gao W, Shen ZY and Cai JZ: Effect of graft size matching on pediatric living-donor liver transplantation at a single center. Clin Transplant: 32, 2018. doi: 10.1111/ctr.13160. \n16 Yasutomi M Harmsmen S Innocenti F DeSouza N Krom RA Outcome of the use of pediatric donor livers in adult recipients Liver Transpl 7 38 40 2001 10.1053/jlts.2001.18482 11150420 \n17 Emre S Soejima Y Altaca G Facciuto M Fishbein TM Sheiner PA Schwartz ME Miller CM Safety and risk of using pediatric donor livers in adult liver transplantation Liver Transpl 7 41 7 2001 10.1053/jlts.2001.20940 11150421 \n18 Zhang R Zhu ZJ Sun LY Wei L Qu W Outcomes of liver transplantation using pediatric deceased donor livers: A single-center analysis of 102 donors Chin Med J (Engl) 131 677 683 2018 10.4103/0366-6999.226901 29521290 \n19 Pugh RN Murray-Lyon IM Dawson JL Pietroni MC Williams R Transection of the oesophagus for bleeding oesophageal varices Br J Surg 60 646 649 1973 10.1002/bjs.1800600817 4541913 \n20 Shore PM Huang R Roy L Darnell C Grein H Robertson T Thompson L Potential for liver and kidney donation after circulatory death in infants and children Pediatrics 128 e631 e638 2011 10.1542/peds.2010-3319 21859917 \n21 Gu L Fang H Li F Zhang S Shen C Han L Impact of hepatic arterial hemodynamics in predicting early hepatic arterial thrombosis in pediatric recipients younger than three yr after living donor liver transplantation Pediatr Transplant 19 273 278 2015 10.1111/petr.12444 25693722 \n22 Ackermann O Branchereau S Franchi-Abella S Pariente D Chevret L Debray D Jacquemin E Gauthier F Hill C Bernard O The long-term outcome of hepatic artery thrombosis after liver transplantation in children: Role of urgent revascularization Am J Transplant 12 1496 503 2012 10.1111/j.1600-6143.2011.03984.x 22390346 \n23 Gu LH Fang H Li FH Li P Zhu CX Zhu JJ Zhang SJ Prediction of early hepatic artery thrombosis by intraoperative color Doppler ultrasound in pediatric segmental liver transplantation Clin Transplant 26 571 576 2012 10.1111/j.1399-0012.2011.01580.x 22324884 \n24 Guo WZ Zhang JK Cao SL Wang ZH Wen PH Shi XY Yang H Chen CQ Zhang SJ Experience of pediatric organ procurement and bench surgery from donation after citizen's death Shiyong Qiguan Yizhi Dianzi Zazhi 5 11 14 2017 \n25 Urata K Hashikura Y Ikegami T Terada M Kawasaki S Standard liver volume in adults Transplant Proc 32 2093 2094 2000 10.1016/s0041-1345(00)01583-9 11120082 \n26 Chan SC Liu CL Lo CM Lam BK Lee EW Wong Y Fan ST Estimating liver weight of adults by body weight and gender World J Gastroenterol 12 2217 2222 2006 10.3748/wjg.v12.i4.2217 16610024 \n27 Shimada M Ijichi H Yonemura Y Harada N Shiotani S Ninomiya M Yoshizumi T Soejima Y Suehiro T Maehara Y Is graft size a major risk factor in living-donor adult liver transplantation? Trans Int 17 310 316 2004 10.1007/s00147-004-0720-9 15221124 \n28 Lee HH Joh JW Lee KW Kim SJ Lee DS Park JH Choi SH Heo JS Hyon WS Kwak MS Lee SK Small-for-size graft in adult living-donor liver transplantation Transplant Proc 36 2274 2276 2004 10.1016/j.transproceed.2004.09.004 15561216 \n29 Tannuri U Mello ES Carnevale FC Santos MM Gibelli NE Ayoub AA Maksoud-Filho JG Velhote MC Silva MM Pinho ML Hepatic venous reconstruction in pediatric living-related donor liver transplantation-experience of a single center Pediatr Transplant 9 293 298 2005 10.1111/j.1399-3046.2005.00306.x 15910383 \n30 Yang DS Chen JJ Lu Q Huang ZY Yang GD Complicated bile duct stricture and its surgical treatment Zhonghua Gandan Waike Zazhi 9 73 75 2003 \n31 Tanaka K Ogura Y ‘Small-for-size graft’ and ‘small-for-size syndrome’ in living donor liver transplantation Yonsei Med J 45 1089 1094 2004 15627301 \n32 Marcos A Right lobe living donor liver transplantation: A review Liver Transpl 6 3 20 2000 10.1002/lt.500060117 10648573 \n33 Adam R Castaing D Bismuth H Transplantation of small donor livers in adult recipients Transplant Proc 25 1105 1106 1993 8442057 \n34 Gondolesi GE Florman S Matsumoto C Huang R Fishbein TM Sheiner PA Schwartz ME Emre S Thung S Shapiro R Miller CM Venous hemodynamics in living donor right lobe liver transplantation Liver Transpl 8 809 813 2002 10.1053/jlts.2002.33690 12200783 \n35 Man K Lo CM Ng IO Wong YC Qin LF Fan ST Wong J Liver transplantation in rats using small-for-size grafts: A study of hemodynamic and morphological changes Arch Surg 136 280 285 2001 10.1001/archsurg.136.3.280 11231846 \n36 Hill MJ Hughes M Jie T Cohen M Lake J Payne WD Humar A Graft weight/recipient weight ratio: How well does it predict outcome after partial liver transplants? Liver Transpl 15 1056 1062 2009 10.1002/lt.21846 19718640 \n37 Campos BD Botha JF Strategies to optimize donor safety with smaller grafts for adult-to-adult living donor liver transplantation Curr Opin Organ Transplant 17 230 234 2012 10.1097/MOT.0b013e32835365b2 22569511 \n38 Zhang YH Zhang R Xu J Clinical observation for hemodynamic changes of children DCD donor liver in adult recipients during early stage Shiyong Qiguan Yizhi Dianzi Zazhi 5 359 362 2017 \n39 Mack DR Traystman MD Colombo JL Sammut PH Kaufman SS Vanderhoof JA Antonson DL Markin RS Shaw BW Jr Langnas AN Clinical denouement and mutation analysis of patients with cystic fibrosis undergoing liver transplantation for biliary cirrhosis J Pediatr 127 881 887 1995 10.1016/s0022-3476(95)70022-6 8523183 \n40 Noble-Jamieson G Valente J Barnes ND Friend PJ Jamieson NV Rasmussen A Calne RY Liver transplantation for hepatic cirrhosis in cystic fibrosis Arch Dis Child 71 349 52 1994 10.1136/adc.71.4.349 7979532 \n41 Song YW Zhu ZJ Sun LY Wei L Qu W Zeng ZG Liu Y Clinical study on growth and development of children after liver transplantation Qiguan Yizhi 235 239 2015 \n42 Li LB Chen YM Zhang SN Gao Y Ren G Zhang CP Xiong G Ma J Combination of terlipressin and FK409 for protection against small-for-size syndrome in living donor liver transplantation Zhongwai Jiankang Wenzhai 25 27 2014 \n43 Mo LQ Yuan BL Xiao Y Xiao LC Xu KQ Huang WQ Effects of terlipressin on hemodynamics and renal function in cirrhotic patients undergoing orthotopic liver transplantation Shiyong Yixue Zazhi 23 2461 2463 2007 \n44 Fung JJ Starzl TE FK506 in solid organ transplantation Ther Drug Monit 17 592 595 1995 10.1097/00007691-199512000-00008 8588226 \n45 Spada M Corno V Colledan M Segalin A Lucianetti A Torre G Riva S Sonzogni A Petz W Gridelli B Rejection and tacrolimus conversion therapy in paediatric liver transplantation Transpl Int 13 (Suppl 1) S341 S344 2000 10.1007/s001470050357 11112028 \n46 van Hooff JP Christiaans MH Use of tacrolimus in renal transplantation Transplant Proc 31 3298 3299 1999 10.1016/s0041-1345(99)00732-0 10616483 \n47 Crespo-Leiro MG Tacrolimus in heart transplantation Transplant Proc 35 1981 1983 2003 10.1016/s0041-1345(03)00566-9 12962869 \n48 Yan LZ Chen L Wang LJ Lu YX Metabolic differences between tacrolimus in adult and child carcasses and living donor liver transplant recipients Wujing Houqin Xueyuan Xuebao (Yixueban) 23 578 582 2014 \n49 Neuhaus P Blumhardt G Bechstein WO Platz KP Jonas S Mueller AR Langrehr JM Lohmann R Schattenfroh N Knoop M Comparison of FK506- and cyclosporine-based immunosuppression in primary orthotopic liver transplantation. A single center experience Transplantation 59 31 40 1995 10.1097/00007890-199501150-00007 7530868 \n50 Flanagan WM Corthésy B Bram RJ Crabtree GR Nuclear association of a T-cell transcription factor blocked by FK-506 and cyclosporin A Nature 352 803 807 1991 10.1038/352803a0 1715516 \n51 Ameyaw MM Regateiro F Li T Liu X Tariq M Mobarek A Thornton N Folayan GO Githang'a J Indalo A MDR1 pharmacogenetics: Frequency of the C3435T mutation in exon 26 is significantly influenced by ethnicity Pharmacogenetics 11 217 221 2001 10.1097/00008571-200104000-00005 11337937 \n52 Jain A Venkataramanan R Sharma R Kwong T Orloff M Abt P Kashyap R Tsoulfas G Batzold P Williamson M Bozorgzadeh A Pharmacokinetics of tacrolimus in living donor liver transplant and deceased donor liver transplant recipients Transplantation 85 554 560 2008 10.1097/TP.0b013e3181642c95 18347534\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1792-0981",
"issue": "20(5)",
"journal": "Experimental and therapeutic medicine",
"keywords": "liver transplantation; organ donation; pediatric liver donors; postoperative complications",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "27",
"pmc": null,
"pmid": "32952618",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": "25693722;8523183;8442057;28736011;7979532;30318357;11150420;12200783;11112028;11337937;27145067;7530868;1715516;10616483;16610024;19718640;12962869;15221124;29521290;25773089;21859917;15561216;10648573;22569511;29154411;4541913;11150421;11231846;15910383;18347534;15627301;30801955;22390346;22324884;11120082;8588226;25267538",
"title": "Adult liver transplantation using pediatric donor livers after cardiac or brain death: A report of three cases.",
"title_normalized": "adult liver transplantation using pediatric donor livers after cardiac or brain death a report of three cases"
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"abstract": "The most frequent ocular manifestation of acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis (CMVR). This infection is reportedly inversely proportional to the CD4 counts. Usually CMVR develops once the CD4 counts fall below 50/mm3. Our case report documents an AIDS patient who developed CMVR despite CD4 counts being persistently >200/mm3. The patient was self-administering dehydroepiandrosterone, high dose Vitamin C, testosterone and hydrocortisone. This case report describes a unique case of pharmacologically induced elevated CD4 counts, which however, did not prevent the development of CMVR in the patient.",
"affiliations": "Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia.;Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia.;Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia.;Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia.;Department of Ophthalmology, University Malaya, Kuala Lumpur, Malaysia.",
"authors": "Keat|Gan Yuen|GY|;Ahmad|Syed Shoeb|SS|;Subramaniam|Suresh|S|;Ghani|Shuaibah Abdul|SA|;Samsudin|Amir|A|",
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"fulltext": "\n==== Front\nIndian J Sex Transm Dis AIDS\nIJSTD\nIndian Journal of Sexually Transmitted Diseases and AIDS\n2589-0557 2589-0565 Wolters Kluwer - Medknow India \n\nIJSTD-41-119\n10.4103/ijstd.IJSTD_90_15\nCase Reports\nCytomegalovirus retinitis associated with high CD4 counts and DHEA abuse\nKeat Gan Yuen Ahmad Syed Shoeb Subramaniam Suresh Ghani Shuaibah Abdul Samsudin Amir 1 Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, Malaysia\n1 Department of Ophthalmology, University Malaya, Kuala Lumpur, Malaysia\nAddress for correspondence: Dr. Syed Shoeb Ahmad, Department of Ophthalmology, Queen Elizabeth Hospital, Kota Kinabalu, 88586, Malaysia. E-mail: syedshoebahmad@yahoo.com\nJan-Jun 2020 \n18 6 2020 \n41 1 119 122\n21 8 2015 30 8 2016 03 12 2019 Copyright: © 2020 Indian Journal of Sexually Transmitted Diseases and AIDS2020This 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.The most frequent ocular manifestation of acquired immunodeficiency syndrome (AIDS) is cytomegalovirus retinitis (CMVR). This infection is reportedly inversely proportional to the CD4 counts. Usually CMVR develops once the CD4 counts fall below 50/mm3. Our case report documents an AIDS patient who developed CMVR despite CD4 counts being persistently >200/mm3. The patient was self-administering dehydroepiandrosterone, high dose Vitamin C, testosterone and hydrocortisone. This case report describes a unique case of pharmacologically induced elevated CD4 counts, which however, did not prevent the development of CMVR in the patient.\n\nCytomegalovirus retinitisdehydroepiandrosteroneganciclovir\n==== Body\nINTRODUCTION\nIndividuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) are at increased risk for developing cytomegalovirus retinitis (CMVR). This risk is inversely proportional to the CD4 counts.\n\nHere, we present this case report of an HIV-positive individual who obtained access to anabolic steroids and high-dose Vitamin C, leading to an elevated CD4 count. However, despite his high CD4 count, the patient developed CMVR in both eyes. This case report is being presented to highlight the possible role of supplemental medication in elevating the CD4 count and yet keep the patient susceptible to develop CMVR.\n\nCASE REPORT\nA young homosexual male presented to our clinic with complaints of sudden onset of progressive blurring of vision in both eyes. A year earlier, he was diagnosed as HIV-positive individual, but did not seek any treatment. However, since then, until the time of presentation, he had been injecting intravenous dehydroepiandrosterone (DHEA), testosterone, and Vitamin C on his own. He also took high-dose multivitamins and minerals orally.\n\nOn his first visit to our clinic, his best-corrected visual acuity (BCVA) was 6/60 (right eye) and 6/48 (left eye). The anterior segments in both eyes were normal. Ophthalmoscopy showed +2 vitreous cells in both eyes. There were large areas of dense white opacification, exudates, vasculitis, and scattered preretinal hemorrhages in both eyes [Figures 1 and 2]. General examination showed an alert and oriented individual. His blood pressure was 160/90 mmHg. There were generalized scabies and an intergluteal ulcer present. He also had right-sided hemiparesis, requiring him to seek assistance for ambulation.\n\nFigure 1 Ophthalmoscopic picture of the right eye at first presentation\n\nFigure 2 Ophthalmoscopic picture of the left eye at first presentation\n\nInvestigations for other systemic infections were negative. Initial CD4 counts were 267/mm3 (38%), and CD8 counts were 267/mm3 (38%). A magnetic resonance imaging of the brain showed a hematoma in the left basal ganglia.\n\nA clinical diagnosis of bilateral CMVR was made. He was given intravitreal ganciclovir injections 2 mg/0.1 ml in each eye immediately. Subsequently, he was referred to the infectious disease department of our hospital. There, he was started on intravenous ganciclovir 350 mg twice daily for two weeks, along with tablet Bactrim (trimethoprim/sulfamethoxazole) and permethrin cream for scabies. He was also given topical miconazole cream for the intergluteal ulcer.\n\nAfter 2 weeks of antibiotic therapy, he was started on highly active antiretroviral therapy (HAART) with efavirenz and tenofovir. The patient received intravitreal ganciclovir 2 mg/0.1 ml twice weekly in each eye for 5 weeks. The vitritis and retinitis progressively resolved with treatment. At the completion of therapy, the patient had BCVA of 6/12 (right eye) and 6/20 (left eye) [Figures 3 and 4].\n\nFigure 3 Ophthalmoscopic appearance of right eye following treatment\n\nFigure 4 Ophthalmoscopic appearance of left eye following treatment\n\nDISCUSSION\nCMVR is the most common ocular manifestation of AIDS. With the introduction of HAART, there has been an 80% decline in the incidence of this condition.[1] Most case reports have noted CMVR occurring with CD4 counts below 50/mm3. There are only occasional case reports of patients developing CMVR with CD4 counts above 250/mm3.[23] In our patient, the CD4 counts were consistently >200/mm3, and the patient developed features of CMVR before initiating HAART, thus excluding the possibility of immune-recovery uveitis.[4] CD4 counts are assumed to be surrogate markers for the level of immune dysfunction.[3] They are useful for screening patients at higher risk of CMVR. However, CD4 counts may hide subtle abnormalities in function and immune systems.[3] Apart from HIV, a number of other factors could possibly increase the susceptibility of this patient to CMVR. These include known risk factors such as unprotected homosexual behavior and self-administered intravenous injections.[5]\n\nClinically, CMVR can occur as indolent or fulminant forms. This ranges from mild granular opacification to large dense areas of retinitis, vasculitis, and vitritis. The diagnosis of CMVR is usually clinical, based on the characteristic posterior segment changes. Aqueous or vitreous tap can be done for polymerase chain reaction (PCR) analysis. However, PCR analysis has poor sensitivity and specificity, so clinical examination and history are more important. Most cases of CMVR respond well to ganciclovir, valganciclovir, foscarnet, or cidofovir. Untreated, the patient may become blind from extensive retinal involvement, retinal detachment, or consecutive optic atrophy. In our case, intravitreal and intravenous ganciclovir were sufficient to produce clinical resolution of the condition.\n\nThe role of supplemental therapies abused by our patient in modifying the clinical features is conjectural. He was on intravenous, high-dose DHEA, hydrocortisone, testosterone, and Vitamin C for nearly 2 years before being seen by us. These supplements can modulate the clinical features of CMVR. DHEA is a steroid hormone synthesized in large quantities by the adrenal gland. However, its physiologic role remains unclear. In animals, DHEA was found to increase interleukin-2, which may help to guard against acute viral illness.[6] It is reported that low DHEA levels can lead to increased risk of disease progression in HIV-positive individuals. There is evidence that the DHEA levels correlate directly with the CD4 counts.[789] A preliminary open-labeled trial reported positive results on the effect of DHEA on mood and fatigue.[10] Studies have also demonstrated the immunomodulatory properties of DHEA. In HIV-positive patients, it inhibits the expression of HIV1 in latently infected cells.[11] However, there are no long-term clinical trials which support the use of DHEA therapy to alter the disease outcome in HIV-infected patients. Estradiol, testosterone, the steroid hormone precursor dehydroepiandrosterone-sulfate (DHEA-S), and progesterone are major immunoregulatory steroid hormones. DHEA-S is of special importance, as it is converted by the immune system to specific bioactive steroids that are required for normal immune function. HIV-positive individuals commonly have androgen deficiency. Low testosterone concentrations are associated with lower CD4 count, advanced stage of illness, medication use, and weight loss. Specific therapies recommended for HIV-associated wasting with low CD4 counts include testosterone replacement and other anabolic steroids. This also probably explains the lack of cachexia and elevated CD4 counts in our patient.[12]\n\nIn conclusion, the possibility of CMVR should not be excluded based on CD4 counts alone. The occurrence of the disease in our patient despite his high CD4 counts could probably be correlated to the self-administered supplemental hormonal therapy. Fortunately, potentially sight-threatening complications of CMVR were prevented by the prompt initiation of appropriate treatment in this case.\n\nWHAT IS NEW?\n\nCMVR in HIV-positive patients usually develops in those with CD4 counts below 50/mm3. In our patient, CMVR occurred even though CD4 counts were consistently above 200/mm3. Thus, CMVR should not be overlooked based on CD4 counts alone.\n\nThe occurrence of CMVR in our patient, despite the high CD4 counts, could be correlated to the self-administered supplemental hormonal therapy.\n\nThis case report highlights the role of high-dose DHEA, hydrocortisone, testosterone, and Vitamin C in modulating the systemic and ocular features of HIV and secondary infections such as CMV.\n\nThere are no long-term clinical trials supporting the use of DHEA therapy to alter disease outcome in HIV-infected patients. However, this case report points to a possible role of this agent in modulating HIV and related secondary infections.\n\n\n\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Whitcup SM Fortin E Nussenblatt RB Polis MA Muccioli C Belfort R Jr Therapeutic effect of combination antiretroviral therapy on cytomegalovirus retinitis JAMA 1997 277 1519 20 9153364 \n2 Fairley I Waugh MA Cytomegalovirus retinitis in a healthy antiretroviral naive HIV positive male with a CD4 count of 277/mm3 Genitourin Med 1996 72 446 7 9038648 \n3 Ang BC Teoh SC Case report of cytomegalovirus retinitis in an HIV-positive patient with a CD4-count nadir of 254 cells per μl Eye (Lond) 2012 26 1153 4 22595905 \n4 Pertel P Hirschtick R Phair J Chmiel J Poggensee L Murphy R Risk of developing cytomegalovirus retinitis in persons infected with the human immunodeficiency virus J Acquir Immune Defic Syndr 1992 5 1069 74 1357151 \n5 Dhillon B Maclean H Eddyshaw D Cheong I Flegg P Brettle R Cytomegalovirus retinitis and AIDS in Edinburgh Int J STD AIDS 1993 4 339 41 8305575 \n6 Johnson MD Bebb RA Sirrs SM Uses of DHEA in aging and other disease states Ageing Res Rev 2002 1 29 41 12039447 \n7 Centurelli MA Abate MA The role of dehydroepiandrosterone in AIDS Ann Pharmacother 1997 31 639 42 9161664 \n8 Christeff N Gherbi N Mammes O Dalle MT Gharakhanian S Lortholary O Serum cortisol and DHEA concentrations during HIV infection Psychoneuroendocrinology 1997 22 Suppl 1 S11 8 9264142 \n9 Rabkin JG Ferrando SJ Wagner GJ Rabkin R DHEA treatment for HIV + patients: Effects on mood, androgenic and anabolic parameters Psychoneuroendocrinology 2000 25 53 68 10633535 \n10 Berczi I Szentivanyi A editors Immunodeficiency The Immune-Neuroendocrine Circuitry – History and Progress. Neuroimmune Biology 2003 3 Amsterdam Elsevier Science BV 221 70 \n11 Abrams DI Shade SB Couey P McCune JM Lo J Bacchetti P Dehydroepiandrosterone (DHEA) effects on HIV replication and host immunity: A randomized placebo-controlled study AIDS Res Hum Retroviruses 2007 23 77 85 17263636 \n12 Mylonakis E Koutkia P Grinspoon S Diagnosis and treatment of androgen deficiency in human immunodeficiency virus-infected men and women Clin Infect Dis 2001 33 857 64 11512091\n\n",
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"issn_linking": "2589-0557",
"issue": "41(1)",
"journal": "Indian journal of sexually transmitted diseases and AIDS",
"keywords": "Cytomegalovirus retinitis; dehydroepiandrosterone; ganciclovir",
"medline_ta": "Indian J Sex Transm Dis AIDS",
"mesh_terms": null,
"nlm_unique_id": "101730896",
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"pages": "119-122",
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"pmid": "33062999",
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"title": "Cytomegalovirus retinitis associated with high CD4 counts and DHEA abuse.",
"title_normalized": "cytomegalovirus retinitis associated with high cd4 counts and dhea abuse"
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"companynumb": "MY-BAUSCH-BL-2021-026763",
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"abstract": "The abrupt development of multiple melanocytic nevi has been described in association with many conditions, including human immunodeficiency virus infection. We report three cases of eruptive nevi in men with human immunodeficiency virus type 1 infection. One patient developed this phenomenon during the stage of acquired immunodeficiency syndrome. The other two patients had human immunodeficiency virus infection recently diagnosed and presented to our clinic reporting the development of multiple melanocytic nevi after starting highly active antiretroviral treatment, with improvement of their immunity. To our knowledge, this is the first report of eruptive melanocytic nevi as a possible consequence of the immune reconstitution inflammatory syndrome.",
"affiliations": "Clinica Universitaria de Dermatologia de Lisboa, Centro Hospitalar Lisboa Norte, EPE (CHLN) - Lisbon. pedro.mi.garrido@gmail.com.",
"authors": "Garrido|P M|PM|;Borges-Costa|J|J|",
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"issue": "24(6)",
"journal": "Dermatology online journal",
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"medline_ta": "Dermatol Online J",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008875:Middle Aged; D009508:Nevus, Pigmented; D012878:Skin Neoplasms; D055815:Young Adult",
"nlm_unique_id": "9610776",
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"pmid": "30142721",
"pubdate": "2018-06-15",
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"title": "Eruptive melanocytic nevi in HIV infected patients: report of three cases.",
"title_normalized": "eruptive melanocytic nevi in hiv infected patients report of three cases"
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"abstract": "OBJECTIVE\nCerebellar atrophy has been noted in patients with phenytoin exposure. This finding has been attributed by some investigators to seizures, but by others to phenytoin. Previous studies included patients with mental retardation and convulsive seizures. We undertook a study in a group of nonretarded patients with partial epilepsy to better elucidate the cause of the cerebellar atrophy.\n\n\nMETHODS\nCase control study.\n\n\nMETHODS\nReferral population from an epilepsy center.\n\n\nMETHODS\nThirty-six patients with partial epilepsy and long-term phenytoin exposure were selected from a consecutive sample of admissions to an epilepsy center. Patients with histories of ethanol abuse, perinatal distress, anoxia, status epilepticus, or neurodegenerative disorders were excluded. Age- and sex-matched controls were selected from a pool of healthy volunteers and patients who had undergone magnetic resonance imaging for complaints of headache and dizziness.\n\n\nMETHODS\nAll patients and controls underwent magnetic resonance imaging.\n\n\nMETHODS\nDegree of cerebellar atrophy.\n\n\nRESULTS\nThe magnetic resonance imaging scans were reviewed in a blind fashion. A rating was assigned to each scan based on the degree of cerebellar atrophy. Cerebellar atrophy was significantly more pronounced in patients than in controls. No correlation was found between cerebellar atrophy and variables reflective of seizure severity or degree of phenytoin exposure.\n\n\nCONCLUSIONS\nCerebellar atrophy may be seen in phenytoin-exposed patients with epilepsy in the absence of generalized tonic-clonic seizures or preexistent brain damage. Whether it is the phenytoin or the seizures that play the primary etiologic role remains unanswered. These factors may be synergistic.",
"affiliations": "Department of Neurology, Long Island Jewish Medical Center, New Hyde Park, NY.",
"authors": "Ney|G C|GC|;Lantos|G|G|;Barr|W B|WB|;Schaul|N|N|",
"chemical_list": "D010672:Phenytoin",
"country": "United States",
"delete": false,
"doi": "10.1001/archneur.1994.00540200043014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-9942",
"issue": "51(8)",
"journal": "Archives of neurology",
"keywords": null,
"medline_ta": "Arch Neurol",
"mesh_terms": "D000328:Adult; D001284:Atrophy; D002531:Cerebellum; D004827:Epilepsy; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010672:Phenytoin",
"nlm_unique_id": "0372436",
"other_id": null,
"pages": "767-71",
"pmc": null,
"pmid": "8042924",
"pubdate": "1994-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cerebellar atrophy in patients with long-term phenytoin exposure and epilepsy.",
"title_normalized": "cerebellar atrophy in patients with long term phenytoin exposure and epilepsy"
} | [
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"companynumb": "US-PFIZER INC-2015102355",
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"activesubstancename": "PHENYTOIN"
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"abstract": "A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.",
"affiliations": "Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, Japan.",
"authors": "Inoue|Kayo|K|;Tsubamoto|Hiroshi|H|;Ueda|Tomoko|T|;Tajima|Chihiro|C|;Nakagomi|Nami|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.gore.2020.100563",
"fulltext": "\n==== Front\nGynecol Oncol Rep\nGynecol Oncol Rep\nGynecologic Oncology Reports\n2352-5789 Elsevier \n\nS2352-5789(20)30029-1\n10.1016/j.gore.2020.100563\n100563\nCase Report\nRecurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report\nInoue Kayo inouekayomana51713@yahoo.co.jpa⁎ Tsubamoto Hiroshi a Ueda Tomoko a Tajima Chihiro a Nakagomi Nami b a Department of Obstetrics and Gynecology, Hyogo College of Medicine, Japan\nb Department of Surgical Pathology, Hyogo College of Medicine, Japan\n⁎ Corresponding author. inouekayomana51713@yahoo.co.jp\n05 4 2020 \n5 2020 \n05 4 2020 \n32 10056324 1 2020 17 3 2020 21 3 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma.\n\n• Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation.\n\n• Olaparib is a possible treatment option for uterine serous carcinomas with BRCA2 mutations.\n\n\n\nA germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.\n\nKeywords\nOlaparibUterine serous carcinomaGermline BRCA2 mutation\n==== Body\n1 Introduction\nCase report\n\nA 57-year-old, Japanese woman (gravida 2) presented to our hospital with postmenopausal vaginal bleeding. She had no past medical or family history, and had a body mass index of 25.7 kg/m2. Endometrial biopsy revealed the presence of a serous carcinoma. Pelvic magnetic resonance imaging (MRI) revealed a tumor invading the cervix and lower uterine segment (Fig. 1-A). 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) / computed tomography (CT) findings suggested a tumor in the lower uterine segment and multiple metastases to the pelvic lymph nodes. Complete cytoreduction was achieved by total abdominal hysterectomy, bilateral salpingo-oophorectomy, omentectomy, and retroperitoneal lymphadenectomy. The final pathologic diagnosis was uterine serous carcinoma stage IIIC1, according to the International Federation of Gynecology and Obstetrics (FIGO) staging for uterine cancer (2008). The tumor was 5 cm in diameter located in the lower uterine segment. There was no lymphovascular invasion, and less than half the myometrium appeared to have been invaded (Fig. 2, Fig. 3). Metastases were found in the right ovary, pelvic lymph nodes, and the peritoneum of the Douglas pouch. The tumor in the right ovary was microscopic, and the tumor in the uterus and right ovary showed positivity for immunohistochemical staining of WT-1 (Fig. 2). There were no findings indicative of malignancy in the right fallopian tube and left adnexa.Fig. 1 A: Magnetic resonance image (T2 image) acquired before the primary surgery. The tumor was located in the lower uterine segment and cervix. B: 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET)/ computed tomography (CT) performed after first-line chemotherapy for the diagnosis of recurrence. Peritoneal dissemination in multiple sites, and strong accumulation of FDG in the lesions under the right diaphragm and in the greater omentum and parietal peritoneum can be observed. C: FDG-PET/CT after two cycles of second-line chemotherapy showing a significant reduction in peritoneal dissemination and decreased accumulation of FDG. D and E: Enhanced CT performed 11 months after olaparib initiation showing peritoneal dissemination in the abdominal wall and small bowel obstruction. The arrow in panel D indicates the lesion seen in panel C; this lesion became slightly larger after 11-month treatment with olaparib. The arrow in panel E shows one of the new peritoneal dissemination lesions.\n\nFig. 2 A: Macroscopic findings of the uterus and adnexa obtained from the primary surgery. The uterus and cervix were cut through the midline and a parallel axis. The tumor was 5 cm in diameter and was located in the lower uterine segment. The arrows show the normal-sized and macroscopically normal ovaries. B and C: Loupe view of the right ovary shows 4 × 5 mm and 1 × 1 tumors. B: Hematoxylin and eosin (H&E) staining. C: Immunohistochemical staining of WT-1. The tumors show positivity for WT-1. D and E: Tumor in the uterus. D: H&E staining. E: Tumor cells are positive for WT-1.\n\nFig. 3 Histological findings of the uterus: hematoxylin and eosin staining (A, B, and C) and immunohistochemical staining for p53 (D). A: Tumor cells were observed mainly in the surface of the endometrium. B: Papillary growth of tumor cells with high-grade cellular and nuclear atypia. C: Coexistence of tumor cells on the left and residual non-neoplastic atrophic glands on the right; these findings suggest that tumors developed from the non-neoplastic atrophic endometrial glands and grew replacing the non-neoplastic glands. D: Serous carcinoma with strong and diffuse positivity for p53, and non-neoplastic endometrial glands negative for p53. These findings are consistent with high-grade serous carcinoma of the uterus origin.\n\n\n\nThe patient underwent six cycles of adjuvant chemotherapy with paclitaxel, carboplatin, and bevacizumab. She remained disease-free for 10 months after the completion of chemotherapy, at which point she complained of upper abdominal pain. FDG-PET/CT findings suggested tumor recurrence in the peritoneum under the right diaphragm and the greater omentum (Fig. 1-B). A multi-gene panel examination of the tumor obtained from the primary surgery was performed via next-generation sequencing. The results revealed a BRCA2 loss-of-function mutation (p.l1859fs, c.5576_5579delTTAA). After the patient and family members underwent genetic counseling, germline testing was conducted, and the same mutation was detected in the patient’s germline cells.\n\nWhile waiting for the above-mentioned genetic test results, the patient underwent second-line chemotherapy with doxorubicin and cisplatin. After two cycles of chemotherapy, the patient’s serum CA125 level decreased from 397 to 201 IU/mL. FDG-PET/CT revealed a significant reduction in peritoneal dissemination and decreased maximum standardized uptake (SUVmax from 10.1 to 3.4) in the recurrent tumors (Fig. 1-C). The recurrent tumors were found to be platinum sensitive, but chemotherapy was halted due to ileus that occurred each time after cisplatin administration and for which hospitalization was required.\n\nDue to limited therapeutic options and the somatic and germline BRCA2 mutations, olaparib was considered as a candidate for treatment. A multidisciplinary team conference was held, and institutional review board approval was granted. Informed consent was obtained from the patient and her family, and off-label use of olaparib was chosen as the treatment plan, though the treatment was not covered by medical insurance. Olaparib was administered orally (300 mg twice daily, a total daily dose of 600 mg). The patient was relieved of the abdominal pain after being treated with olaparib for 3 months, and her serum CA125 level decreased to 26.6 IU/mL. However, she also experienced anemia, which is an adverse effect of olaparib; thus, intermittent cessations and several rounds of blood transfusion were required. The dosage of olaparib was reduced to two daily doses of 200 mg (for a total daily dose of 400 mg). Subsequently, the patient’s appetite recovered, and she became free of pain. Olaparib was administered for another 8 months, during which the patient remained asymptomatic. The patient developed bowel obstruction during taking olaparib, thus olaparib was discontinued. The placement of an ileus tube was ineffective in treating bowel obstruction. Enhanced CT showed pelvic peritoneal dissemination without masses or ascites (Fig. 1-D and E). The patient decided to discontinue olaparib and other anticancer treatments. The patient has since been receiving total parenteral nutrition and supportive care at home; at the time of writing this report, the patient has been alive at home for two months with disease.\n\nWritten informed consent to report the case was obtained from the patient.\n\n2 Discussion\nHere, we report two new insights from a case of uterine serous carcinoma. First, a BRCA2 pathogenic variant was secondarily identified via genomic sequencing of uterine serous carcinoma. Second, we report the long-term clinical response of a patient treated with olaparib for 11 months. Considering that there are limited standard chemotherapeutic options for recurrent endometrial cancer, and hormonal therapy is not effective for uterine serous carcinoma, our patient underwent tumor DNA sequencing to identify possible targeted treatments. The results of the somatic tumor panel led to a secondary finding of a germline BRCA2 mutation. The patient had no family or medical history of cancer, and the BRCA2 mutation was unexpected.\n\nIt remains unclear whether mutations in BRCA1 and BRCA2 are associated with increased risks for endometrial cancer, and especially uterine serous carcinoma. A case-controlled study found no differences in risks of endometrial cancer between individuals with and without BRCA1/2 mutations (Segev et al., 2015). In contrast, studies show that patients with BRCA1 mutations undergoing risk-reducing salpingo-oophorectomy have increased risks of uterine serous carcinoma (Shu et al., 2016, Saule et al., 2018).\n\nConversely, the frequency of BRCA1/2 mutations has been reported to be higher among patients with uterine serous carcinoma than among those with all histologic types of endometrial cancer. A different study reported that among unselected 381 endometrial cancer patients who underwent cancer panel testing, 26 had serous carcinoma, and among them BRCA2 mutations were found in one patient with uterine serous carcinoma. A BRCA1 mutation was found in one of 289 patients with endometrioid carcinoma (Ring et al., 2016). A meta-analysis demonstrated three out of 207 Caucasian women with uterine serous carcinoma had germline BRCA1/2 mutations (Jonge et al., 2017). Accordingly, it is estimated that 1–3% of uterine serous carcinomas are associated with BRCA1/2 mutations.\n\nOlaparib, the first poly (ADP-Ribose) polymerase (PARP) inhibitor, was approved by the Food and Drug Administration for the treatment of recurrent platinum-sensitive ovarian cancer with germline or somatic pathogenic BRCA1/2 mutations and also for patients with germline BRCA-positive, HER2-negatvie metastatic breast cancer. The efficacy of olaparib for the treatment of patients with metastatic pancreatic cancer with BRCA1/2 mutations was demonstrated in a randomized-controlled trial (Golan et al., 2019). Olaparib also showed positive phase III results in metastatic prostate cancer treatment.\n\nThe efficacy of olaparib in endometrial cancer patients with germline BRCA1/2 mutations remains unknown. To our knowledge, there has only been one case report showing a durable response (more than 15 months) to olaparib treatment in a patient with recurrent grade 1 endometrioid carcinoma with a germline BRCA2 mutation and a different somatic BRCA2 mutation (Gockley et al., 2018). This case report was the first to show a 11-month clinical response to olaparib in a patient with uterine serous carcinoma with a germline pathogenic BRCA2 variant.\n\nIt also remains unclear whether uterine serous carcinoma is a manifestation of homologous recombination deficiency (HRD). Previous work has suggested that HRD and sensitivity to PARP inhibitors were tied to BRCA-associated cancer types in patients with BRCA1/2 mutations (Jonsson et al., 2019). Jonge et al. showed HRD occurs in high-grade, non-endometrioid endometrial cancers (serous carcinoma and carcinosarcoma) and is related with pathogenic BRCA1 variants or high somatic copy-number losses of HR genes. In their study, 24% (n = 6) of endometrial cancers were HR deficient, with either serous carcinoma or carcinosarcoma with a serous component, and two of them had pathogenic BRCA1 variants (Jonge et al., 2019a). In addition, Jonge et al. also reported that, among 40 endometrial cancer patients with germline BRCA1/2 mutations, there were six with uterine serous carcinoma (3 BRCA1 and 3 BRCA2 mutations), five of whom were positive for loss of heterozygosity of the BRCA1/2 wild-type allele (3 BRCA1 and 2 BRCA2 mutations). They thus suggested that endometrial carcinoma might be a form of germline BRCA-associated hereditary breast and ovarian cancer (Jonge et al., 2019b).\n\nAlthough the frequency of germline BRCA1/2 mutations in patients with uterine serous carcinoma may not be high, olaparib could be an efficient treatment strategy for uterine serous carcinoma in cases involving HRD or germline BRCA1/2 mutations. Finally, screening for germline BRCA1/2 mutations may be worthwhile.\n\nIn summary, olaparib provided 11-month progression free survival for the patient in our case report. Our report suggests that uterine serous carcinoma may be a BRCA-associated cancer. Germline or tumor DNA testing for pathogenic BRCA1/2 mutations in patients with uterine serous carcinoma might be beneficial, and olaparib could be a potential treatment option in patients with a germline pathogenic BRCA2 variant.\n\n3 Conclusion\nOlaparib could be a promising candidate for the treatment of uterine serous carcinoma associated with germline BRCA2 mutations.\n\nAuthor contributions\n\nKayo Inoue drafted the article, Hisroshi Tsubamoto supervised, Tomoko Ueda and Chihiro Tajima collected information, and Nami Nakagomi drafted the pathological information and selected the figures. All authors read and approved the final article.\n\nStatement of informed consent\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\nDeclaration of Competing Interest\nThe authors declared that there is no conflict of interest.\n==== Refs\nReferences\nSegev Y. Rosen B. Lubinski J. Gronwald J. Lynch H.T. Moller Fam P. Cancer Risk factors for endometrial cancer among women with a BRCA1 or BRCA2 mutation: A case control study 14 3 2015 383 391 25838159 \nShu C.A. Pike M.C. Jotwani A.R. Friebel T.M. Soslow R.A. Levine D.A. JAMA oncol uterine cancer after risk-reducing salpingo-oophorectomy Without Hysterectomy in Women With BRCA Mutations 2 11 2016 1434 1440 \nSaule Claire Mouret-Fourme Emmanuelle Briaux Adrien Becette Véronique Rouzier Roman Houdayer Claude Stoppa-Lyonnet Dominique Risk of serous endometrial carcinoma in women with pathogenic BRCA1/2 variant after risk-reducing salpingo-oophorectomy J. Natl Cancer Inst. 110 2 2018 213 215 \nRing K.L. Bruegl A.S. Allen B.A. Elkin E.P. Singh N. Hartman A.R. Germline multi-gene hereditary cancer panel testing in an unselected endometrial cancer cohort. Mod. Pathol. 29 11 2016 1381 1389 27443514 \nde Jonge M.M. Mooyaart A.L. Vreeswijk M.P. de Kroon C.D. van Wezel T. van Asperen C.J. Cancer Eur J Linking uterine serous carcinoma to BRCA1/2-associated cancer syndrome: a meta-analysis and case report Eur. J. Cancer 72 2017 215 225 28049106 \nGolan T. Hammel P. Reni M. Van Cutsem E. Macarulla T. Hall M.J. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N. Engl. J. Med. 381 4 2019 317 327 31157963 \nJonsson P. Bandlamudi C. Cheng M.L. Srinivasan P. Chavan S.S. Friedman N.D. Tumour lineage shapes BRCA-mediated phenotypes. Nature 571 7766 2019 576 579 31292550 \nGockley A.A. Kolin D.L. Awtrey C.S. Lindeman N.I. Matulonis U.A. Durable response in a woman with recurrent low-grade endometrioid endometrial cancer and a germline BRCA2 mutation treated with a PARP inhibitor Konstantinopoulos PA Gynecol Oncol. 150 2 2018 219 226 29937315 \nde Jonge M.M. Auguste A. van Wijk L.M. Schouten P.C. Meijers M. Ter Haar N.T. Frequent homologous recombination deficiency in high-grade endometrial carcinomas Clin. Cancer Res. 25 3 2019 1087 1097 30413523 \nde Jonge MM, Litterhouse LL, de KroonCD, Vreeswijk MPG, Segal JP, Puranik R, et al. Clin. Cancer Res. Germline BRCA-Associated Endometrial Carcinoma Is a Distinct Clinicopathologic Entity. 2019; 25(24):7517-7526.\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2352-5789",
"issue": "32()",
"journal": "Gynecologic oncology reports",
"keywords": "Germline BRCA2 mutation; Olaparib; Uterine serous carcinoma",
"medline_ta": "Gynecol Oncol Rep",
"mesh_terms": null,
"nlm_unique_id": "101652231",
"other_id": null,
"pages": "100563",
"pmc": null,
"pmid": "32300630",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "28049106;27443514;29937315;31292550;27367496;31157963;28954295;30413523;31492746;25838159",
"title": "Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report.",
"title_normalized": "recurrent uterine serous carcinoma with a germline pathogenic brca2 variant treated using olaparib a case report"
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"companynumb": "JP-ACCORD-192532",
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"abstract": "BACKGROUND\nVarious molecular-targeted therapeutic agents that inhibit cytokines and immune checkpoints are used in clinical practice. Some of these biologics that control immunity, such as anti-interleukin-17, anti-programmed cell death protein-1, and anti-cytotoxic T-lymphocyte-associated protein antibodies, affect intestinal immune homeostasis and cause intestinal inflammation. Development of enteritis due to dupilumab (an anti-IL-4Ralpha monoclonal antibody) therapy is not yet reported in the literature.\n\n\nMETHODS\nA 17-year-old man was administered an injection of dupilumab and continued to receive it for refractory atopic dermatitis. After 3 months of initiating dupilumab therapy, he developed intermittent abdominal pain, tenesmus, and had diarrhea. Colonoscopy examination showed decreased vascularity, mild friability, and erythema in the cecum, part of the ascending colon, sigmoid colon, and rectum without any pathogenic bacteria. Histological examination revealed moderate mixed inflammatory cell infiltration, cryptitis, destruction of the crypt, decreased goblet cells, mucosal erosions, and edema. He was diagnosed with UC and was prescribed oral mesalazine (4800 mg/day) treatment. Within a month of the treatment, his diarrhea improved and the frequency of defecation decreased.\n\n\nCONCLUSIONS\nThis is a first report that dupilumab mimicked ulcerative colitis. Careful monitoring for adverse effects with the onset of an intestinal inflammation will be recommended after dupilumab administration.",
"affiliations": "Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, 0108543, Japan. yosuke.shimodaira@med.akita-u.ac.jp.;Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, 0108543, Japan.;Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita, 0108543, Japan.",
"authors": "Shimodaira|Yosuke|Y|http://orcid.org/0000-0003-0314-9196;Takahashi|So|S|;Iijima|Katsunori|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C582203:dupilumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-021-01803-8",
"fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X\nBioMed Central London\n\n1803\n10.1186/s12876-021-01803-8\nCase Report\nAnti-IL-4Ralpha monoclonal antibody dupilumab mimics ulcerative colitis: a case report\nhttp://orcid.org/0000-0003-0314-9196\nShimodaira Yosuke yosuke.shimodaira@med.akita-u.ac.jp\n\nTakahashi So\nIijima Katsunori\ngrid.251924.9 0000 0001 0725 8504 Department of Gastroenterology and Neurology, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita City, Akita 0108543 Japan\n8 5 2021\n8 5 2021\n2021\n21 20712 2 2021\n3 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.\nBackground\n\nVarious molecular-targeted therapeutic agents that inhibit cytokines and immune checkpoints are used in clinical practice. Some of these biologics that control immunity, such as anti-interleukin-17, anti-programmed cell death protein-1, and anti-cytotoxic T-lymphocyte-associated protein antibodies, affect intestinal immune homeostasis and cause intestinal inflammation. Development of enteritis due to dupilumab (an anti-IL-4Ralpha monoclonal antibody) therapy is not yet reported in the literature.\n\nCase presentation\n\nA 17-year-old man was administered an injection of dupilumab and continued to receive it for refractory atopic dermatitis. After 3 months of initiating dupilumab therapy, he developed intermittent abdominal pain, tenesmus, and had diarrhea. Colonoscopy examination showed decreased vascularity, mild friability, and erythema in the cecum, part of the ascending colon, sigmoid colon, and rectum without any pathogenic bacteria. Histological examination revealed moderate mixed inflammatory cell infiltration, cryptitis, destruction of the crypt, decreased goblet cells, mucosal erosions, and edema. He was diagnosed with UC and was prescribed oral mesalazine (4800 mg/day) treatment. Within a month of the treatment, his diarrhea improved and the frequency of defecation decreased.\n\nConclusions\n\nThis is a first report that dupilumab mimicked ulcerative colitis. Careful monitoring for adverse effects with the onset of an intestinal inflammation will be recommended after dupilumab administration.\n\nKeywords\n\nDupilumab\nIL-4Ralpha\nUlcerative colitis\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nMolecular-targeted therapeutic agents are innovative therapeutic agents used in several fields, such as cancer and immune diseases, that effectively act on specific molecules and in turn inhibit disease pathways [1, 2]. Various therapeutic agents that inhibit cytokines and immune checkpoints are used in clinical practice. However, some of these biologics that control immunity, such as anti-interleukin (IL)-17, anti-programmed cell death protein-1, and anti-cytotoxic T-lymphocyte-associated protein antibodies, affect intestinal immune homeostasis and mimic ulcerative colitis (UC) [3–5].\n\nIntestinal immunity is mediated through cell signaling, and the immune system is tightly regulated even when exposed to foreign substances, such as intestinal microorganisms and dietary antigens. UC is a chronic intestinal inflammation caused by intestinal immune response dysregulation. It has been reported that TH2 cytokines are predominant in the intestinal mucosa in UC [6]; however, no amelioration of UC was observed after blocking the expression of TH2 cytokines in clinical trials [7, 8]. In addition, the development of enteritis due to dupilumab (an anti-IL-4Ralpha monoclonal antibody) therapy is not yet well understood.\n\nAn anti-IL-12/23p40 antibody has been used clinically as a cytokine-targeted therapy for UC [9]. However, it has been pointed out that while IL-23 regulates the differentiation function of TH17, and the inhibition of IL-17 conversely produces an inflammatory state that mimics UC [4]. Thus, the regulation of intestinal immunity in UC is complex and remains to be elucidated.\n\nHere, we report a case in which dupilumab, an anti-IL-4Ralpha monoclonal antibody, mimics UC, an inflammatory bowel disease.\n\nCase presentation\n\nA 17-year-old man with a height of 168 cm and a weight of 70 kg presented to our dermatology department for the treatment of atopic dermatitis. He had a history of pediatric asthma and attention-deficit hyperactivity disorder and also allergies to house dust and pollen. Furthermore, his father had a medical history of UC. He had been treated with topical and oral therapy for refractory atopic dermatitis at a local clinic. Due to his refractory condition, he was administered an injection of dupilumab 600 mg and continued to receive it 300 mg every two weeks without any adverse events. After the administration of three doses, the skin rash on his back and trunk had almost disappeared. However, after 3 months of initiating dupilumab therapy, he developed intermittent abdominal pain, tenesmus, and had diarrhea seven times a day. Therefore, he was treated with polycarbophil calcium and lactomin for suspected irritable bowel syndrome but did not show any signs of improvement. He was referred to our department and underwent colonoscopy. The examination showed decreased vascularity, mild friability, and erythema in the cecum, part of the ascending colon, sigmoid colon, and rectum (Fig. 1a). No pathogenic bacteria were identified in the stool culture, and Clostridioides difficile toxin was also not detected. Blood tests showed no elevation of white blood cells, C reactive protein, or erythrocyte sedimentation rate, and there were no signs of anemia. Histological examination revealed moderate mixed inflammatory cell infiltration, cryptitis, destruction of the crypt, decreased goblet cells, mucosal erosions, and edema (Fig. 1b). Based on these findings, he was diagnosed with UC and was prescribed oral mesalazine (4800 mg/day) treatment. Within a month of the treatment, his diarrhea improved and the frequency of defecation decreased to three times a day. His atopic dermatitis continued to improve and dupilumab therapy was continued without any interruption for 1 year.Fig. 1 a Endoscopic image of rectum is shown. b Mucosal tissue was biopsied in sigmoid colon and histological examination with hematoxylin and eosin staining is shown with a scale bar\n\nDiscussion and conclusions\n\nWe encountered a case where the administration of an IL-4Ralpha monoclonal antibody resulted in an inflammatory state mimicking UC. The endoscopic and histopathological findings closely resembled those of UC, leading to a UC diagnosis. The medical history of UC of his father suggested that he might have been genetically predisposed to develop UC, and it was assumed that chronic inflammation had developed due to inflammation triggers that caused immunological changes.\n\nThere have been various reports on the involvement of cytokines in UC. Many reports on effector cytokines have indicated that UC is a TH2 dominant disease [6, 10]. Dupilumab inhibits IL-4 and IL-13 signaling through IL-4Ralpha/IL-4RgammaC receptor dimer and IL-4Ralpha/IL-13Ralpha1 receptor dimer respectively and has been indicated for TH2-mediated allergic diseases with type 2 inflammation, such as atopic dermatitis and bronchial asthma [11]. There are two IL-13 receptor subtypes, IL-13Ralpha1 that forms a dimer with IL-4Ralpha, whereas IL-13Ralpha2 does not [12]. Therefore, dupilumab does not block IL-13Ralpha2 signaling. Although the function of IL-13Ralpha2 is yet unclear, the mucosal expression of IL-13Ralpha2 is found to affect the treatment of Crohn’s disease, which is another type of chronic inflammatory bowel disease [13]. It can be hypothesized that IL-13Ralpha2-mediated signaling plays an important role in the manifestation of an inflammatory state mimicking UC in this case. A previous study has reported the involvement of IL-17 in the development of UC, and the blocking of IL-17 expression causes an inflammatory condition mimicking UC [4], although anti-IL-12/23p40 antibodies which affects TH17 maintenance and function improve ulcerative colitis [9]. More than 200 disease susceptibility genes have been identified in UC. Although the odds ratio was not large for each gene, environmental factors were thought to play a crucial role in their development. In individuals with a genetic predisposition resulting in an altered intestinal immunity, IL-17 antibodies may influence the development of chronic intestinal inflammation. Actually, dupilumab downregulated mRNA expression of IL-17 but not that of IL-12/23p40 in atopic dermatitis [14]. The molecular signaling pathway interaction between IL-4Ralpha inhibition and TH17 is still needed to elucidated.\n\nIn this case, dupilumab was administered to treat refractory atopic dermatitis. A previous report indicated the association between atopic dermatitis and UC [15], and the fact that they are both TH2-dominant inflammations. Both these diseases may have a common risk factor as barrier dysfunction is involved in their pathology. UC is characterized by marked infiltration of eosinophils; however, no specific allergens have been identified. An abnormal immune response to intestinal bacteria has been suggested to be one of the causes of UC.\n\nOf note, four patients were reported to have developed UC as an adverse event as per the post-marketing surveillance of dupilumab for bronchial asthma and atopic dermatitis conducted in Japan [16]. However, there have been no detailed reports on the onset of UC due to IL-4Ralpha antibodies. Although this case was mild, the development of an inflammatory state mimicking UC after administration of dupilumab was worthy of being reported. On this basis, careful monitoring for adverse effects is recommended after dupilumab administration so as the onset of an inflammatory state mimicking UC.\n\nAbbreviations\n\nUC Ulcerative colitis\n\nIL Interleukin\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nYS drafted the manuscript. ST and KI participated in the manuscript preparation. All authors approved the final manuscript.\n\nFunding\n\nNo funding was received.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nEthical approval was obtained from the Ethics Committee of Akita University Graduate School of Medicine (Approved Number: 2621).\n\nConsent for publication\n\nThe written consent to publish the personal and clinical details (including figures) of the participant was obtained from the patient and his parent.\n\nCompeting interests\n\nAuthors declare that they have no competing interests.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Weinstein IB Joe AK Mechanisms of disease: oncogene addiction–a rationale for molecular targeting in cancer therapy Nat Clin Pract Oncol 2006 3 8 448 457 10.1038/ncponc0558 16894390\n2. Bradley JR TNF-mediated inflammatory disease J Pathol 2008 214 2 149 160 10.1002/path.2287 18161752\n3. Beck KE Blansfield JA Tran KQ Feldman AL Hughes MS Royal RE Kammula US Topalian SL Sherry RM Kleiner D Enterocolitis in patients with cancer after antibody blockade of cytotoxic T-lymphocyte-associated antigen 4 J Clin Oncol 2006 24 15 2283 2289 10.1200/JCO.2005.04.5716 16710025\n4. Philipose J Ahmed M Idiculla PS Mulrooney SM Gumaste VV Severe de novo ulcerative colitis following ixekizumab therapy Case Rep Gastroenterol 2018 12 3 617 621 10.1159/000493922 30483039\n5. Yoshino K Nakayama T Ito A Sato E Kitano S Severe colitis after PD-1 blockade with nivolumab in advanced melanoma patients: potential role of Th1-dominant immune response in immune-related adverse events: two case reports BMC Cancer 2019 19 1 1019 10.1186/s12885-019-6138-7 31664934\n6. Heller F Florian P Bojarski C Richter J Christ M Hillenbrand B Mankertz J Gitter AH Bürgel N Fromm M Interleukin-13 is the key effector Th2 cytokine in ulcerative colitis that affects epithelial tight junctions, apoptosis, and cell restitution Gastroenterology 2005 129 2 550 564 10.1016/j.gastro.2005.05.002 16083712\n7. Danese S Rudziński J Brandt W Dupas JL Peyrin-Biroulet L Bouhnik Y Kleczkowski D Uebel P Lukas M Knutsson M Tralokinumab for moderate-to-severe UC: a randomised, double-blind, placebo-controlled, phase IIa study Gut 2015 64 2 243 249 10.1136/gutjnl-2014-308004 25304132\n8. Reinisch W Panés J Khurana S Toth G Hua F Comer GM Hinz M Page K O'Toole M Moorehead TM Anrukinzumab, an anti-interleukin 13 monoclonal antibody, in active UC: efficacy and safety from a phase IIa randomised multicentre study Gut 2015 64 6 894 900 10.1136/gutjnl-2014-308337 25567115\n9. Sands BE Sandborn WJ Panaccione R O'Brien CD Zhang H Johanns J Adedokun OJ Li K Peyrin-Biroulet L Van Assche G Ustekinumab as induction and maintenance therapy for ulcerative colitis N Engl J Med 2019 381 13 1201 1214 10.1056/NEJMoa1900750 31553833\n10. Li J Ueno A Fort Gasia M Luider J Wang T Hirota C Jijon HB Deane M Tom M Chan R Profiles of Lamina Propria T helper cell subsets discriminate between ulcerative colitis and Crohn's disease Inflamm Bowel Dis 2016 22 8 1779 1792 10.1097/MIB.0000000000000811 27243594\n11. Beck LA Thaçi D Hamilton JD Graham NM Bieber T Rocklin R Ming JE Ren H Kao R Simpson E Dupilumab treatment in adults with moderate-to-severe atopic dermatitis N Engl J Med 2014 371 2 130 139 10.1056/NEJMoa1314768 25006719\n12. Hoving JC Targeting IL-13 as a host-directed therapy against ulcerative colitis Front Cell Infect Microbiol 2018 8 395 10.3389/fcimb.2018.00395 30460209\n13. Verstockt B Verstockt S Creyns B Tops S Van Assche G Gils A Ceuppens JL Vermeire S Ferrante M Breynaert C Mucosal IL13RA2 expression predicts nonresponse to anti-TNF therapy in Crohn's disease Aliment Pharmacol Ther 2019 49 5 572 581 10.1111/apt.15126 30663072\n14. Guttman-Yassky E Bissonnette R Ungar B Suárez-Fariñas M Ardeleanu M Esaki H Suprun M Estrada Y Xu H Peng X Dupilumab progressively improves systemic and cutaneous abnormalities in patients with atopic dermatitis J Allergy Clin Immunol 2019 143 1 155 172 10.1016/j.jaci.2018.08.022 30194992\n15. Niwa Y Sumi H Akamatsu H An association between ulcerative colitis and atopic dermatitis, diseases of impaired superficial barriers J Investig Dermatol 2004 123 5 999 1000 10.1111/j.0022-202X.2004.23462.x 15482492\n16. Pharmaceuticals and Medical Devices Agency (Japanese). https://www.info.pmda.go.jp/fsearchnew/jsp/menu_fukusayou_base.jsp. Search with the word of dupilumab and ulcerative colitis in Japanese. Accessed 15 Jan 2021.\n\n",
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"title": "Anti-IL-4Ralpha monoclonal antibody dupilumab mimics ulcerative colitis: a case report.",
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"abstract": "Despite the compelling preclinical rationale of evaluating the genetically engineered heparin derivative, necuparanib, combined with standard therapy in metastatic pancreas adenocarcinoma, the results were ultimately disappointing.Safety was documented, although dose escalation was limited by the number of subcutaneous injections, the potential for skin toxicity (cellulitis), and low-level anticoagulant effect. Nonetheless, the hypothesis of targeting prothrombotic pathways in pancreas adenocarcinoma remains compelling.\n\n\n\nNecuparanib is derived from unfractionated heparin and engineered for reduced anticoagulant activity while preserving known heparin-associated antitumor properties. This trial assessed the safety, pharmacokinetics (PK), pharmacodynamics, and initial efficacy of necuparanib combined with gemcitabine ± nab-paclitaxel in patients with metastatic pancreatic cancer.\n\n\n\nPatients received escalating daily subcutaneous doses of necuparanib plus 1,000 mg/m2 gemcitabine (days 1, 8, 15, and every 28 days). The protocol was amended to include 125 mg/m2 nab-paclitaxel after two cohorts (following release of the phase III MPACT data). The necuparanib starting dose was 0.5 mg/kg, with escalation via a modified 3 + 3 design until the maximum tolerated dose (MTD) was determined.\n\n\n\nThirty-nine patients were enrolled into seven cohorts (necuparanib 0.5, 1 mg/kg + gemcitabine; necuparanib 1, 2, 4, 6, and 5 mg/kg + nab-paclitaxel + gemcitabine). The most common adverse events were anemia (56%), fatigue (51%), neutropenia (51%), leukopenia (41%), and thrombocytopenia (41%). No deaths and two serious adverse events were potentially related to necuparanib. Measurable levels of necuparanib were seen starting at the 2 mg/kg dose. Of 24 patients who received at least one dose of necuparanib + nab-paclitaxel + gemcitabine, 9 (38%) achieved a partial response and 6 (25%) achieved stable disease (63% disease control rate). Given a cellulitis event and mild activated partial thromboplastin time increases at 6 mg/kg, the 5 mg/kg dose was considered the MTD and selected for further assessment in phase II.\n\n\n\nAcceptable safety and encouraging signals of activity in patients with metastatic pancreatic cancer receiving necuparanib, nab-paclitaxel, and gemcitabine were demonstrated.",
"affiliations": "Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, New York, USA oreillye@mskcc.org.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, New York, USA.;Memorial Sloan Kettering Cancer Center, Department of Medicine, New York, New York, USA.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Novella Clinical, Morrisville, North Carolina, USA.;Massachusetts General Hospital, Department of Medicine, Boston, Massachusetts, USA.;Momenta Pharmaceuticals, Cambridge, Massachusetts, USA.;Massachusetts General Hospital, Department of Medicine, Boston, Massachusetts, USA.",
"authors": "O'Reilly|Eileen M|EM|;Roach|James|J|;Miller|Paul|P|;Yu|Kenneth H|KH|;Tjan|Catherine|C|;Rosano|Molly|M|;Krause|Silva|S|;Avery|William|W|;Wolf|Julie|J|;Flaherty|Keith|K|;Nix|Darrell|D|;Ryan|David P|DP|",
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"title": "Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Necuparanib Combined with Nab-Paclitaxel and Gemcitabine in Patients with Metastatic Pancreatic Cancer: Phase I Results.",
"title_normalized": "safety pharmacokinetics pharmacodynamics and antitumor activity of necuparanib combined with nab paclitaxel and gemcitabine in patients with metastatic pancreatic cancer phase i results"
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"abstract": "The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground-glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected.",
"affiliations": "Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan.;Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan.;Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan.;Division of Respiratory Medicine, Chiba Cancer Center, Chiba, Japan.",
"authors": "Ashinuma|Hironori|H|https://orcid.org/0000-0002-5277-5233;Mizuno|Satoko|S|;Yoshida|Yasushi|Y|;Shingyoji|Masato|M|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2019/4836404Case ReportA Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer https://orcid.org/0000-0002-5277-5233Ashinuma Hironori hashinuma@chiba-cc.jpMizuno Satoko Yoshida Yasushi Shingyoji Masato Division of Respiratory Medicine, Chiba Cancer Center, Chiba, JapanAcademic Editor: Jose I. Mayordomo\n\n2019 26 12 2019 2019 483640411 6 2019 14 12 2019 Copyright © 2019 Hironori Ashinuma et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.The management of grade 1 checkpoint inhibitor pneumonitis (CIP) is to withhold immune checkpoint inhibitors; however, the natural history of this condition is unknown. We herein report the case of a woman with squamous cell lung cancer who was a long-term survivor after CIP. After 4 rounds of treatment with nivolumab, a chest CT revealed a reticular pattern and ground-glass attenuation with shrinkage of the primary nodule. Nivolumab treatment was withheld without the administration of steroids. Although she remained asymptomatic, subsequent images revealed an increasing interstitial shadow until 2 months after the stop of nivolumab treatment. Thereafter, the interstitial shadow began to improve spontaneously without steroid treatment. Moreover, although the patient has not received additional therapy, disease control of lung cancer has been obtained within a follow-up period of more than 3 years. Although the exacerbation of CIP may appear on images for several months, asymptomatic cases can be followed without the administration of steroids. If the tumor had already responded prior to the onset of CIP, a favorable long-term prognosis can be expected.\n==== Body\n1. Introduction\nImmune checkpoint inhibitors (ICIs) have been widely used for the treatment of non-small-cell lung cancer, but attention to immune-related adverse events (irAEs) including serious events, such as pneumonitis, is necessary. The incidence of checkpoint inhibitor pneumonitis (CIP) has been reported to be between 3% and 5% in clinical settings, but a higher frequency of 19% was reported in a single retrospective study [1].\n\nLong-term results after ICI treatment have been reported [2], but data on the natural history and prognosis of patients with CIP remain inadequate. We herein report a patient with squamous cell lung cancer who developed CIP; the patient's condition improved after the discontinuation of nivolumab treatment only, and disease control has been achieved for more than 3 years without treatment.\n\n2. Case Presentation\nA 64-year-old woman with a smoking history of 40 pack-years was admitted to our neurological surgery ward complaining of a headache and aphasia. A brain magnetic resonance imaging (MRI) examination revealed a 30 mm mass in the left-anterior lobe, and a chest computed tomography (CT) examination revealed a 30 mm mass in the left upper lobe with metastasis to the left hilar lymph nodes. A brain metastasis from lung cancer was suspected. A craniotomy was performed, and the presence of a squamous cell carcinoma that was negative for epidermal growth factor receptor mutation or anaplastic lymphoma kinase fusion was confirmed. Because we were unable to perform immunohistochemistry for programmed cell death 1 (PD-L1) at that time, the PD-L1 status was unknown. After the addition of localized radiation (50 Gy/25 fractions) to the excised site of the brain, she was treated with carboplatin and S-1 and achieved a partial response. After 7 months, the lung mass had increased in size. She was treated with docetaxel (DOC) monotherapy and achieved a stable disease condition. After 7 cycles of DOC, however, the lung mass began to increase in size once again.\n\nTreatment with nivolumab (3 mg/kg, every 2 weeks) was next initiated. On the first day of 5 cycles of nivolumab, a chest CT examination revealed a reticular pattern and ground-glass attenuation with a shrinking lung mass in the left upper lobe (Figures 1(b) and 2(b)). She had no symptoms at that time. She was afebrile, and her oxygen saturation on room air was 96%, which was the same as previous measurements. Her white blood count was 5900 cells/μL, and her C-reactive protein level was 0.33 mg/dL. Other blood tests were almost normal except for a sialylated carbohydrate antigen Krebs von den Lungen-6 (KL-6) level of 606 U/mL (normal range: 500 U/mL or less) and a pulmonary surfactant protein-D (SP-D) level of 195 ng/mL (normal range: 110 ng/mL or less). Although a bronchoalveolar lavage fluid test and additional tests were not performed, she was clinically diagnosed as having grade 1 CIP. Treatment with nivolumab was discontinued, and a repeat chest X-ray and CT were performed. Although she remained asymptomatic, her chest X-ray and CT images revealed an increasing interstitial shadow similar in appearance to that of a cryptogenic organizing pneumonia pattern until 2 months after the discontinuation of nivolumab (Figures 1(c)–1(f) and 2(c)). Her KL-6 level increased to a maximum of 1300 U/mL at 2 months, and her SP-D level increased to a maximum of 302 ng/mL after one month. However, three months thereafter, the interstitial shadow began to disappear on the chest X-ray and CT images (Figures 1(g) and 2(d)), despite a lack of prednisone treatment. The KL-6 and SP-D levels also began to decrease gradually. After 6 months, almost all the interstitial shadow had disappeared and the lung mass was continuing to shrink in size (Figures 1(h) and 2(e)). Although she has not been treated with additional therapy, the lung mass has continued to shrink and no new lesions have appeared for more than 3 years.\n\n3. Discussion\nHere, we report a case depicting the natural history of grade 1 CIP in which disease control has been achieved for more than two and a half years without any therapy and after only 4 rounds of nivolumab administration.\n\nIn a meta-analysis, the overall incidence of CIP was 2.7% for all-grade [3]. The onset of CIP ranges from 9 days to 27.4 months [4]. Guidelines [5] for the management of grade 1 CIP recommend withholding immune checkpoint inhibitors (ICIs). If no improvement is seen, the patient should then be treated as if they have grade 2 CIP. However, the natural history of grade 1 CIP is unclear. Because of concerns over possible deterioration, steroid therapy is often administered early during the disease course. In a retrospective study where 39 out of 205 patients had CIP, all the patients with CIP received high-dose steroids [1]. Ricciuti et al. reported that patients receiving ≥10 mg of prednisone at baseline had worse outcomes than those receiving 0 to <10 mg of prednisone [6]. In a small study of melanoma patients who had ipilimumab-induced hypophysitis, patients who received a high dose of glucocorticoids had reduced survival than those who received a low dose of glucocorticoids [7]. Therefore, it is better to avoid using steroids in unnecessary cases. Predicting which cases will improve and which cases will deteriorate is difficult. In the present case, the radiological findings continued to worsen until 3 months after onset, despite a lack of clinical symptoms, and then improved spontaneously. A similar case has been previously reported [8]. In this previous report, the patient was diagnosed as having suspected interstitial pneumonia (IP) and was followed up without treatment; the IP subsequently resolved spontaneously 3 months after onset. Although details of the patient's clinical course were not provided, an improvement in grade 1 CIP generally requires several months. However, careful follow-up is still necessary. In the presently reported case, the main reason why the patient was followed without treatment was that she remained asymptomatic, despite a worsening in her radiographic findings. However, it should be noted that a fatal case of a patient who was diagnosed as having grade 1 pneumonitis but who did not initially receive steroids has also been reported [8]. Recently, Park et al. reported that the CIP patients who never needed to receive steroids had a later onset from initiation of ICIs (mean 37.48 weeks vs. 25.45 weeks), more prior lines of chemotherapy (median 2.5 vs. 1.0 lines), higher proportion of current/ex-smokers (83.3% vs. 50.0%), and fewer other accompanying irAEs (50% vs. 75%) [4]. In the present case, onset from initiation of ICIs was 8 weeks, prior lines of chemotherapy were 2 lines, ex-smoker, and no other accompanying irAEs.\n\nAlthough irAEs can be lethal, the development of irAEs has been reported to be associated with a survival benefit in patients with non-small-cell lung cancer (NSCLC) [9, 10]. This survival benefit also applies to patients with pneumonitis. Fujimoto et al. reported that lung cancer patients who were treated with ICIs and developed CIP ultimately achieved higher response rates and longer progression-free survival periods than those who did not develop CIP (37% vs. 18% and 5.8 vs. 2.1 months, respectively) in a multicenter retrospective study [11]. Our presently reported case has also had a very good survival period. On the other hand, another retrospective study has shown that pneumonitis associated with cytotoxic chemotherapy or targeted therapy has an adverse impact on survival [12], which seems like a reasonable association. Therefore, the good prognosis of patients who develop pneumonitis might be specific to treatment with ICIs.\n\nWhether the readministration of ICIs should be undertaken following recovery from an irAE remains unknown. In the presently reported case, the patient has not been retreated with nivolumab because of concerns over pneumonitis relapse and the absence of tumor regrowth. Santini et al. reported that among patients with early objective responses prior to serious irAE, the outcomes were similar regardless of whether they were retreated [13]. In cases like ours, it may be reasonable to withdraw readministration.\n\nA limitation of this case is that we diagnosed the patient as having CIP based only on images and the clinical course. However, very little is known about the pathological findings for CIP in lung biopsy specimens, and the utility of bronchoscopy in establishing a diagnosis of CIP is unknown [14]. Although infectious diseases are an important differential diagnosis, there were no findings suggestive of an infectious disease, and the spontaneous improvement makes an infectious disease unlikely.\n\n4. Conclusions\nThis case was able to be followed up without the steroid treatment as the patient remained asymptomatic (grade 1) though the imaging studies were initially exacerbated. This case showed response to nivolumab at the time of CIP onset, and no relapse has been observed for about 3 years without any additional anticancer treatment including readministration of nivolumab.\n\nAcknowledgments\nWriting assistance was provided by the International Medical Information Center, Translation Section. This service and article processing charges were paid for by internal funding.\n\nConflicts of Interest\nHironori Ashinuma received honorarium from Ono Pharmaceutical and Bristol-Myers Squibb. Masato Shingyoji received honorarium from Ono Pharmaceutical.\n\nFigure 1 Changes in chest X-ray images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 week after the onset of CIP (c), 2 weeks after the onset of CIP (d), 1 month after the onset of CIP (e), 2 months after the onset of CIP (f), 3 months after the onset of CIP (g), and 6 months after the onset of CIP (h). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis.\n\nFigure 2 Changes in chest computed tomography images. Before treatment with nivolumab (a), at the onset of CIP (b), 1 month after the onset of CIP (c), 3 months after the onset of CIP (d), and 6 months after the onset of CIP (e). The relapsed lung tumor is indicated by the arrows. CIP: checkpoint inhibitor pneumonitis.\n==== Refs\n1 Suresh K. Voong K. R. Shankar B. Pneumonitis in non-small cell lung cancer patients receiving immune checkpoint immunotherapy: incidence and risk factors Journal of Thoracic Oncology 2018 13 12 1930 1939 10.1016/j.jtho.2018.08.2035 2-s2.0-85055109588 30267842 \n2 Gettinger S. Horn L. Jackman D. Five-year follow-up of Nivolumab in previously treated advanced non-small-cell lung cancer: results from the CA209-003 study Journal of Clinical Oncology 17, 2018 36 17 1675 1684 10.1200/JCO.2017.77.0412 2-s2.0-85046686545 29570421 \n3 Nishino M. Giobbie-Hurder A. Hatabu H. Ramaiya N. H. Hodi F. S. Incidence of programmed cell death 1 inhibitor-related pneumonitis in patients with advanced cancer: a systematic review and meta-analysis JAMA Oncology 2016 2 12 1607 1616 10.1001/jamaoncol.2016.2453 2-s2.0-85013156149 27540850 \n4 Park C. Keam B. Yoon S. H. Clinical insights on outcomes of corticosteroid administration in immune checkpoint inhibitor-induced pneumonitis by retrospective case series analysis ESMO Open 2019 4 6, article e000575 10.1136/esmoopen-2019-000575 31803501 \n5 Brahmer J. R. Lacchetti C. Schneider B. J. Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American Society of Clinical Oncology clinical practice guideline Journal of Clinical Oncology 2018 36 17 1714 1768 10.1200/JCO.2017.77.6385 2-s2.0-85048283183 29442540 \n6 Ricciuti B. Dahlberg S. E. Adeni A. Sholl L. M. Nishino M. Awad M. M. Immune checkpoint inhibitor outcomes for patients with non-small-cell lung cancer receiving baseline corticosteroids for palliative versus nonpalliative indications Journal of Clinical Oncology 22, 2019 37 22 1927 1934 10.1200/JCO.19.00189 2-s2.0-85069668648 31206316 \n7 Faje A. T. Lawrence D. Flaherty K. High-dose glucocorticoids for the treatment of ipilimumab-induced hypophysitis is associated with reduced survival in patients with melanoma Cancer 18, 2018 124 18 3706 3714 10.1002/cncr.31629 2-s2.0-85050564478 29975414 \n8 Kato T. Masuda N. Nakanishi Y. Nivolumab-induced interstitial lung disease analysis of two phase II studies patients with recurrent or advanced non-small-cell lung cancer Lung Cancer 2017 104 111 118 10.1016/j.lungcan.2016.12.016 2-s2.0-85007494884 28212992 \n9 Haratani K. Hayashi H. Chiba Y. Association of immune-related adverse events with nivolumab efficacy in non-small-cell lung cancer JAMA Oncology 2018 4 3 374 378 10.1001/jamaoncol.2017.2925 2-s2.0-85046022431 28975219 \n10 Teraoka S. Fujimoto D. Morimoto T. Early immune-related adverse events and association with outcome in advanced non-small cell lung cancer patients treated with nivolumab: a prospective cohort study Journal of Thoracic Oncology 2017 12 12 1798 1805 10.1016/j.jtho.2017.08.022 2-s2.0-85032215673 28939128 \n11 Fujimoto D. Yoshioka H. Kataoka Y. Efficacy and safety of nivolumab in previously treated patients with non-small cell lung cancer: a multicenter retrospective cohort study Lung Cancer 2018 119 14 20 10.1016/j.lungcan.2018.02.017 2-s2.0-85042803014 29656747 \n12 Fujimoto D. Kato R. Morimoto T. Characteristics and prognostic impact of pneumonitis during systemic anti-cancer therapy in patients with advanced non-small-cell lung cancer PLoS One 2016 11 12, article e0168465 10.1371/journal.pone.0168465 2-s2.0-85007283965 28006019 \n13 Santini F. C. Rizvi H. Plodkowski A. J. Safety and efficacy of re-treating with immunotherapy after immune-related adverse events in patients with NSCLC Cancer Immunology Research 2018 6 9 1093 1099 10.1158/2326-6066.CIR-17-0755 2-s2.0-85052869570 29991499 \n14 Suresh K. Naidoo J. Lin C. T. Danoff S. Immune checkpoint immunotherapy for non-small cell lung cancer: benefits and pulmonary toxicities Chest 2018 154 6 1416 1423 10.1016/j.chest.2018.08.1048 2-s2.0-85055756124 30189190\n\n",
"fulltext_license": "CC BY",
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"title": "A Case of Long-Term Survival after Checkpoint Inhibitor Pneumonitis in a Patient with Squamous Cell Lung Cancer.",
"title_normalized": "a case of long term survival after checkpoint inhibitor pneumonitis in a patient with squamous cell lung cancer"
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"abstract": "Adult Attention Deficit Disorder is increasingly diagnosed and treated. Psychostimulant medications, such as methylphenidate, are commonly prescribed for this condition, but the long-term safety of such medications in an adult population is unknown at present. Because these medications are closely related to amphetamines, it is expected that toxic side effects would be similar. We present the case of a 27-year-old man who suffered an acute myocardial infarction due to coronary vasospasm related to use of methylphenidate complicated by concomitant use of pseudoephedrine.",
"affiliations": "Division of Cardiovascular Services, University of Mississippi Medical Center, Jackson, Mississippi 39216, USA.",
"authors": "Thompson|Jan|J|;Thompson|James R|JR|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
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"title": "Acute myocardial infarction related to methylphenidate for adult attention deficit disorder.",
"title_normalized": "acute myocardial infarction related to methylphenidate for adult attention deficit disorder"
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"abstract": "Chordomas are rare malignant bone tumours with a predilection for the axial skeleton, especially the sacrum and skull base. Median survival in patients with metastatic disease is usually dismal. Treatment is challenging due to the propensity for local recurrence, metastatic disease as well as lack of clear consensus regarding the optimal management. Our case report highlights two cases of sacral chordoma with locally recurrent and widespread metastatic disease, stable on molecular targeted therapy.",
"affiliations": "Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.;Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.;Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.;Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.;Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.;Brigham and Women's Hospital/Dana Farber Cancer institute/ Harvard Medical School - Radiology Boston, Massachusetts, USA.",
"authors": "Rohatgi|Saurabh|S|;Ramaiya|Nikhil H|NH|;Jagannathan|Jyothi P|JP|;Howard|Stephanie A|SA|;Shinagare|Atul B|AB|;Krajewski|Katherine M|KM|",
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"issue": "47(2)",
"journal": "The Eurasian journal of medicine",
"keywords": "Chordoma; Kordoma; imatinib; metastasis; metastaz; positron emission tomography; pozitron emisyon tomografi",
"medline_ta": "Eurasian J Med",
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"title": "Metastatic Chordoma: Report of the Two Cases and Review of the Literature.",
"title_normalized": "metastatic chordoma report of the two cases and review of the literature"
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"abstract": "Femoral artery thrombosis is a rare complication of intramuscular (IM) injection in children. A 12-month-old boy presented with right lower limb ischemia and digital gangrene 3 days after an injection of ceftriaxone administered to his medial aspect of the right thigh. Successful thrombolysis and partial limb salvage was possible with enoxaparin despite a late presentation. Unnecessary and unsafe IM injection in community practice might lead to such devastating outcome which should be avoided.",
"affiliations": "Department of Pediatric Medicine, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, West Bengal, India.;Department of Pediatric Medicine, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, West Bengal, India.;Department of Pediatric Medicine, NRS Medical College, Kolkata, West Bengal, India.;Department of Pediatric Medicine, Medical College, Kolkata, West Bengal, India.",
"authors": "Sarkar|Sumantra|S|;Misra|Sarbani|S|;Nandi|Madhumita|M|;Mondal|Rakesh|R|",
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"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Medknow Publications & Media Pvt Ltd India JFMPC-6-68010.4103/2249-4863.222058Case ReportA misplaced intramuscular injection and limb-threatening ischemia Sarkar Sumantra 1Misra Sarbani 1Nandi Madhumita 2Mondal Rakesh 31 Department of Pediatric Medicine, Institute of Post Graduate Medical Education and Research and SSKM Hospital, Kolkata, West Bengal, India2 Department of Pediatric Medicine, NRS Medical College, Kolkata, West Bengal, India3 Department of Pediatric Medicine, Medical College, Kolkata, West Bengal, IndiaAddress for correspondence: Dr. Sumantra Sarkar, Flat No. B/1, Jibantaru Apartment, North Jagtala, Maheshtala, Kolkata - 700 141, West Bengal, India. E-mail: sumantra.com@gmail.comJul-Sep 2017 6 3 680 682 Copyright: © 2017 Journal of Family Medicine and Primary Care2017This 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.Femoral artery thrombosis is a rare complication of intramuscular (IM) injection in children. A 12-month-old boy presented with right lower limb ischemia and digital gangrene 3 days after an injection of ceftriaxone administered to his medial aspect of the right thigh. Successful thrombolysis and partial limb salvage was possible with enoxaparin despite a late presentation. Unnecessary and unsafe IM injection in community practice might lead to such devastating outcome which should be avoided.\n\nGangreneinjectionintramuscularthrombolysis\n==== Body\nIntroduction\nIntramuscular (IM) injection is a common practice among the rural practitioners and in primary health-care settings. Femoral artery thrombosis is an unusual complication after IM injection which might lead to a serious complication like limb gangrene.[1234] Here, we report a case of a 12-month-old boy, presented with ischemic limb and digital gangrene 3 days after a misplaced IM injection of ceftriaxone by a local practitioner.\n\nCase Report\nA 12-month-old, previously well infant presented with blackish discoloration of toes and part of the right foot for last 3 days. It had developed 12 h after an IM ceftriaxone injection given for fever and respiratory infection by a local practitioner. Parents confirmed that the injection was administered over the medial aspect of right mid-thigh. Few hours after the injection, the right lower limb of the baby became cold along with progressive discoloration of the foot starting from the right second toe. Consequently, the whole of the right leg became tender and limp.\n\nHis history was insignificant. His birth, developmental, immunization, and family histories were noncontributory.\n\nOn examination, baby was irritable and apprehensive. His right lower limb was motionless like a log of wood [Figure 1]. It was cold, and tender to touch. Pulsations were absent in femoral, popliteal and arteria dorsalis pedis. The part of the foot distal to the base of the metatarsals was blackish indicative of gangrenous change with indistinct line of demarcation. No local skin change was noted at the injection site. Color Doppler of arterial system of right lower limb revealed a large thrombus obstructing the femoral artery lumen. Subcutaneous enoxaparin was started immediately at a dose of 1 mg/kg. An opinion from vascular surgeon was sought for thrombectomy. However, the child improved considerably in next 24 h requiring no surgical intervention. The limb became warm and nontender concurrent with return of all pulses. Doppler revealed a patchy and partial thrombosis.\n\nFigure 1 Ischemic and motionless right limb with gangrenous changes\n\nMeanwhile, the investigations revealed no abnormality in the hemogram. Liver function test, electrolytes, urea, creatinine, and lipid profile were within normal limits. Studies on venous system of the right leg, renal vasculature, and echocardiography were normal.\n\nEnoxaparin was continued for next 2 weeks and switched to oral acenocoumarol for another 1 week. Initial prothrombin time (PT) was 12.0 (control 11.6), INR was 1.03 and activated PT (APTT) was27.0 s (control 28.0). PT and APTT were repeated several times to titrate the dose of acenocoumarol. Anti-factor Xa assay for monitoring enoxaparin therapy was not possible due to lack of facility. Repeat Doppler after 2 weeks revealed no thrombus. The gangrenous area gradually receded distally and area of superficial healing was evident [Figure 2]. Ultimately, the limb could be salvaged at the expense of the digits only which required a surgical amputation later [Figure 3].\n\nFigure 2 Gangrenous digits and healing areas after 2 weeks\n\nFigure 3 Salvaged right lower limb with amputated digits\n\nAntithrombotic workup for detecting underlying primary disease was carried out later revealed lupus anticoagulant (LA) was normal with LA ratio was 1.15 (reference range: 0.8–1.2), Protein C was 86.3% (reference range: 70–140%), Protein S was 89% (reference range: 60–150%), antithrombin C was 113% (reference range: 75–125), activated Protein C resistance (Factor V Leiden) normalized ratio was within normal limit. Homocysteine level in the blood and urine was normal.\n\nDiscussion\nFemoral artery thrombosis in children following IM injection is extremely rare. Although drugs such as penicillin, promethazine, Vitamin B complexes, diclofenac had been implicated in a few instances, extensive search of literature could not reveal ceftriaxone as an offender.[1234] Authors presume that it was an inadvertent intra-arterial or periarterial injection which could be possible in case of administration to the medial aspect of the thigh. Postinjection ischemic gangrene may result from direct vascular injury, perivascular inflammation or vasoconstriction from the unintentional intra-arterial injection.[45] Arterial embolization phenomenon along with intense vasospasm could be other hypothesis.[6]\n\nThrombolytic agents are increasingly being used in last decades, but there is no consensus in indications, dose, mode of delivery, or duration of therapy.[7] In children tissue plasminogen activator (tPA) is the agent of choice. Experience with other thrombolytics like streptokinase or urokinase are minimal due to lack of controlled, prospective studies.[8] The cost and a late presentation preclude the use of tPA in our case. Enoxaparin, as an antithrombotic agent, is recommended treatment option by American College of Chest Physicians and successful thrombolysis with this drug has been demonstrated in a few cases.[910] The drug exerts its fibrinolytic activity through stimulation of endothelial release of tPA and increases tissue factor pathway inhibitor release, which inhibits coagulation activity.[10] In our patient, we found rapid return of pulse in the affected limb just 24 h after starting of enoxaparin along with improvement of Doppler findings. The distal part of the limb including the digits could not be salvaged probably because there could be underlying necrotic changes already and more tissue damage well before the treatment began.\n\nThe idea of presenting the case is to make aware regarding the devastating complication of unsafe injection practice. Unnecessary IM administration of antibiotics without proper technique is quite common in rural and suburban community practice which must be avoided. Second, in a resource-poor infrastructure, enoxaparin could be a useful option for thrombolysis even when there is a late presentation with a limb-threatening ischemia.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Talbert JL Haslam RH Haller JA Jr Gangrene of the foot following intramuscular injection in the lateral thigh: A case report with recommendations for prevention J Pediatr 1967 70 110 4 6016791 \n2 Ozel A Yavuz H Erkul I Gangrene after penicillin injection (a case report) Turk J Pediatr 1995 37 67 71 7732611 \n3 Ghosh D Saha S Das S Konar H Limb gangrene following intramuscular injection of long acting penicillin Journal of Indian Association of Pediatric Surgeons 2002 7 92 5 \n4 Hajong R Upper limb gangrene following intramuscular diclofenac: A rare side effect J Surg Case Rep 2013 2013 pii: Rjs039 \n5 Kim SK Kim TH Lee KC Nicolau syndrome after intramuscular injection: 3 cases Arch Plast Surg 2012 39 249 52 22783535 \n6 Sengupta S Gangrene following intra-arterial injection of procaine penicillin Aust N Z J Med 1976 6 71 3 1065306 \n7 Yee DL Chan AK Williams S Goldenberg NA Massicotte MP Raffini LJ Varied opinions on thrombolysis for venous thromboembolism in infants and children: Findings from a survey of pediatric hematology-oncology specialists Pediatr Blood Cancer 2009 53 960 6 19544387 \n8 Williams MD Thrombolysis in children Br J Haematol 2010 148 26 36 19807732 \n9 Monagle P Chan AK Goldenberg NA Ichord RN Journeycake JM Nowak-Göttl U Antithrombotic therapy in neonates and children: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines Chest 2012 141 2 Suppl e737S 801S 22315277 \n10 Wiegand G Icheva V Schöning M Hofbeck M Successful thrombolysis following enoxaparin therapy in two pediatric patients with congenital heart disease presenting with intracardiac and cerebral thrombosis Thromb J 2014 12 19 25278813\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2249-4863",
"issue": "6(3)",
"journal": "Journal of family medicine and primary care",
"keywords": "Gangrene; injection; intramuscular; thrombolysis",
"medline_ta": "J Family Med Prim Care",
"mesh_terms": null,
"nlm_unique_id": "101610082",
"other_id": null,
"pages": "680-682",
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"pubdate": "2017",
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"title": "A misplaced intramuscular injection and limb-threatening ischemia.",
"title_normalized": "a misplaced intramuscular injection and limb threatening ischemia"
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"abstract": "Metastases of differentiated thyroid cancer (DTC) in sites different from lungs and bone are unusual (UM); their impact in management and prognosis remains unknown. Our aim was to evaluate the prevalence of UM, to describe their characteristics and to analyze their impact in disease outcome and mortality.\n\n\n\nWe retrospectively reviewed the file records from 8 different centers. Those patients with DTC and UM were included. UM were diagnosed by: (i) biopsy/cytology and/or (ii) radioiodine (RAI) uptake associated to elevated thyroglobulin (Tg) levels and/or c) presence of one or more structural lesion/s with 18-FDG uptake in the PET/CT scan and elevated Tg levels.\n\n\n\nThirty-six (0.9%) out of a total of 3982 DTC patients were diagnosed with UM; 75% had papillary histology. The most frequent localization was central nervous system (CNS, 31%). UM were metachronous in 75%, symptomatic in 55.6% and fulfilled RAI-refractoriness criteria in 77.8% of cases. Metastatic lesions in lung/bone and/or locoregional disease were present in 34 cases (94.4%). Diagnosis of UM changed the therapeutic approach in 72.2% of patients. After a median follow up of 13 months, 21 (58.3%) patients died from DTC related causes. In 8 of them CNS progression was the immediate cause of death.\n\n\n\nPrevalence of UM was low; they were frequently metachronic and RAI-refractory. Although UM were found in patients with widespread disease, their diagnosis usually led to changes in therapy. UM were associated with poor prognosis and high frequency of disease-specific mortality.",
"affiliations": "Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina. anabelazunino@gmail.com.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.;Thyroid Department of Sociedad Argentina de Endocrinología y Metabolismo, Díaz Vélez 3889 (C1200AAF), Ciudad Autónoma de Buenos Aires, Argentina.",
"authors": "Zunino|Anabela|A|0000-0002-6082-7670;Pitoia|Fabián|F|0000-0002-2742-7085;Faure|Eduardo|E|0000-0003-1974-1485;Reyes|Adriana|A|;Sala|Mónica|M|;Sklate|Rosana|R|;Ilera|Verónica|V|0000-0003-1724-9390;Califano|Inés|I|0000-0002-7450-5832;|||",
"chemical_list": "D007457:Iodine Radioisotopes",
"country": "United States",
"delete": false,
"doi": "10.1007/s12020-019-01991-0",
"fulltext": null,
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"issn_linking": "1355-008X",
"issue": "65(3)",
"journal": "Endocrine",
"keywords": "Advanced thyroid cancer; Distant metastases; Radioiodine refractory; Thyroid carcinoma; Unusual metastases",
"medline_ta": "Endocrine",
"mesh_terms": "D000328:Adult; D000368:Aged; D001859:Bone Neoplasms; D002291:Carcinoma, Papillary; D016543:Central Nervous System Neoplasms; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000072078:Positron Emission Tomography Computed Tomography; D011379:Prognosis; D012189:Retrospective Studies; D013964:Thyroid Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "9434444",
"other_id": null,
"pages": "630-636",
"pmc": null,
"pmid": "31327159",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "27548104;26476828;25162180;29694635;23607000;25785333;26793559;16684830;10566647;26462967;23734630;27856495;24795243;16303836;23607002;29102432;19436230;29947184;22827579;27530124;28704099;15947102;20156922;26662609;20392874;24999689;25192681;29387239;28699989;26307020;19779325",
"title": "Unusual metastases from differentiated thyroid carcinoma: analysis of 36 cases.",
"title_normalized": "unusual metastases from differentiated thyroid carcinoma analysis of 36 cases"
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"abstract": "OBJECTIVE\nTo investigate risk factors, imaging characteristics, and treatment responses of cystoid macular edema (CME) after rhegmatogenous retinal detachment (RRD) repair.\n\n\nMETHODS\nConsecutive, retrospective case-control series of patients who underwent pars plana vitrectomy (PPV) and/or scleral buckling (SB) for RRD, with at least six months of follow-up. Clinical and surgical parameters of patients with and without CME (nCME), based on spectral-domain optical coherence tomography (OCT), were compared.\n\n\nRESULTS\nOf 99 eyes enrolled, 25 had CME while 74 had nCME. Patients with CME underwent greater numbers of surgeries (P < 0.0001). After adjusting for number of surgeries, macula-off RRD (P = 0.06), proliferative vitreoretinopathy (PVR) (P = 0.09), surgical approach (PPV and/or SB, P = 0.21), and tamponade type (P = 0.10) were not statistically significant, although they all achieved significance on univariate analysis (P = 0.001 or less). Intraoperative retinectomy (P = 0.009) and postoperative pseudophakia or aphakia (P = 0.008) were more frequent in the CME group, even after adjustment. Characteristics of cCME on OCT included diffuse distribution, confluent cysts, and absence of subretinal fluid or intraretinal hyperreflective foci. Macular thickness improved significantly with intravitreal triamcinolone (P = 0.016), but not with anti-vascular endothelial growth factor agents (P = 0.828) or dexamethasone implant (P = 0.125). After adjusting for number of surgeries and macular detachment, final visual acuities remained significantly lower in the CME vs nCME group (P = 0.012).\n\n\nCONCLUSIONS\nRisk factors of CME include complex retinal detachment repairs requiring multiple surgeries, and pseudophakic or aphakic lens status. Although this cCME was associated with poor therapeutic response, corticosteroids were the most effective studied treatments.",
"affiliations": "Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095-7002, USA.;Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095-7002, USA.;Ophthalmology Department, Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, Milan, Italy.;Tufts Medical Center/New England Eye Center, Ophthalmic Consultants of Boston, Boston, MA, USA.;Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095-7002, USA.;Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA, 90095-7002, USA. hubschman@jsei.ucla.edu.",
"authors": "Pole|Cameron|C|;Chehaibou|Ismael|I|;Govetto|Andrea|A|;Garrity|Sean|S|;Schwartz|Steven D|SD|;Hubschman|Jean-Pierre|JP|http://orcid.org/0000-0002-8631-3467",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40942-020-00254-9",
"fulltext": "\n==== Front\nInt J Retina Vitreous\nInt J Retina Vitreous\nInternational Journal of Retina and Vitreous\n2056-9920 BioMed Central London \n\n254\n10.1186/s40942-020-00254-9\nOriginal Article\nMacular edema after rhegmatogenous retinal detachment repair: risk factors, OCT analysis, and treatment responses\nPole Cameron 1 Chehaibou Ismael 12 Govetto Andrea 3 Garrity Sean 4 Schwartz Steven D. 1 http://orcid.org/0000-0002-8631-3467Hubschman Jean-Pierre hubschman@jsei.ucla.edu 1 1 grid.19006.3e0000 0000 9632 6718Retina Division, Stein Eye Institute, University of California Los Angeles, 100 Stein Plaza, Los Angeles, CA 90095-7002 USA \n2 grid.508487.60000 0004 7885 7602Ophthalmology Department, AP-HP, Hôpital Lariboisière, Université de Paris, 75010 Paris, France \n3 grid.507997.50000 0004 5984 6051Ophthalmology Department, Fatebenefratelli-Oftalmico Hospital, ASST-Fatebenefratelli-Sacco, Milan, Italy \n4 grid.477682.8Tufts Medical Center/New England Eye Center, Ophthalmic Consultants of Boston, Boston, MA USA \n25 1 2021 \n25 1 2021 \n2021 \n7 928 5 2020 28 10 2020 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Purpose\nTo investigate risk factors, imaging characteristics, and treatment responses of cystoid macular edema (CME) after rhegmatogenous retinal detachment (RRD) repair.\n\nMethods\nConsecutive, retrospective case–control series of patients who underwent pars plana vitrectomy (PPV) and/or scleral buckling (SB) for RRD, with at least six months of follow-up. Clinical and surgical parameters of patients with and without CME (nCME), based on spectral-domain optical coherence tomography (OCT), were compared.\n\nResults\nOf 99 eyes enrolled, 25 had CME while 74 had nCME. Patients with CME underwent greater numbers of surgeries (P < 0.0001). After adjusting for number of surgeries, macula-off RRD (P = 0.06), proliferative vitreoretinopathy (PVR) (P = 0.09), surgical approach (PPV and/or SB, P = 0.21), and tamponade type (P = 0.10) were not statistically significant, although they all achieved significance on univariate analysis (P = 0.001 or less). Intraoperative retinectomy (P = 0.009) and postoperative pseudophakia or aphakia (P = 0.008) were more frequent in the CME group, even after adjustment. Characteristics of cCME on OCT included diffuse distribution, confluent cysts, and absence of subretinal fluid or intraretinal hyperreflective foci. Macular thickness improved significantly with intravitreal triamcinolone (P = 0.016), but not with anti-vascular endothelial growth factor agents (P = 0.828) or dexamethasone implant (P = 0.125). After adjusting for number of surgeries and macular detachment, final visual acuities remained significantly lower in the CME vs nCME group (P = 0.012).\n\nConclusion\nRisk factors of CME include complex retinal detachment repairs requiring multiple surgeries, and pseudophakic or aphakic lens status. Although this cCME was associated with poor therapeutic response, corticosteroids were the most effective studied treatments.\n\nKeywords\nIntravitreal injectionMacular edemaRetinal detachmentSpectral-domain optical coherence tomographyVitrectomyCorticosteroidshttp://dx.doi.org/10.13039/100001818Research to Prevent Blindnesshttp://dx.doi.org/10.13039/100008340UCLA Health SystemCTSI Grant Number UL1TR001881issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nCystoid macular edema (CME) is a common retinal condition characterized by macular thickening with intra-retinal fluid accumulation, often accompanied by decreased visual acuity (VA) [1]. It may develop as a complication of a wide spectrum of retinal diseases including diabetic retinopathy (DR), uveitis, exudative age-related macular degeneration (AMD), retinal vein occlusion (RVO), and genetic syndromes such as retinitis pigmentosa (RP) [2].\n\nAlthough the pathophysiology of CME is multifactorial, breakdown of the inner blood retinal barrier is a common endpoint in most cases [1]. Current theories suggest subclinical inflammation as responsible for post-rhegmatogenous retinal detachment (RRD) CME [3]. While progressive leakage may be outlined with fluorescein angiography (FA) as the gold-standard for CME diagnosis, optical coherence tomography (OCT) is currently the most common imaging modality in the diagnosis and characterization of CME, as it is non-invasive and provides high resolution cross-sectional imaging of retinal anatomy [4], allowing easier and more frequent follow-up,\n\nRhegmatogenous retinal detachment is characterized by progressive accumulation of subretinal fluid due to retinal breaks. Although surgical repairs, including scleral buckle (SB) and pars plana vitrectomy (PPV), are effective surgical treatments, some cases with successful reattachment may have poor visual outcomes related to postoperative CME development [5, 6], which may persist for years in a minority of patients [7]. Retrospective and observational studies using FA and OCT have shown rates of post-vitrectomy CME varying from 5.5% after PPV for symptomatic floaters to 40% after complicated detachment repairs [6, 8, 9]. Treatments for CME primarily target inflammatory and pro-angiogenic mediators, but standard therapies such as anti-vascular endothelial growth factor (anti-VEGF) therapies may be ineffective for post-RRD CME [9, 10].\n\nThere is little data on post-RRD CME risk factors, rates, and anatomical characteristics [3, 5, 11]. Therefore, this observational study was designed to compare a consecutive case series of eyes with versus without post-RRD CME, with the aim to determine its risk factors and describe its clinical characteristics and therapeutic outcomes.\n\nMethods\nThis was a retrospective, observational study approved by the medical center’s institutional review board, University of California Los Angeles Office of Human Research Protection (IRB#16-000574). This study adhered to the tenets of the Declaration of Helsinki and the rules of the Health Insurance Portability and Accountability Act of 1996.\n\nElectronic health records (EHR) from a large academic referral center (Stein Eye Institute at UCLA) were reviewed. Current Procedural Terminology (CPT) coding records of surgical procedures from January 2015 to December 2017 were queried.\n\nPopulation\nAll candidates underwent SB, PPV, or combined procedures for RRD, performed by two experienced vitreoretinal surgeons (JPH and SDS), with at least 6 months of follow up after surgery. Records were evaluated through July 2018.\n\nExclusion criteria were severe ocular trauma, uveitis, DR, endophthalmitis, RVO, myopic retinoschisis, or advanced dry or wet AMD.\n\nSpectral Domain-OCT Analysis\nAll patients diagnosed with CME were examined with eye-tracked OCT. All OCTs were acquired with the Spectralis® (Heidelberg Engineering GmbH, Heidelberg, Germany) and RS-3000 (Nidek® Inc, San Jose, CA) devices. All CME was analyzed with Spectralis® OCTs consisting of 19 horizontal B-scans and manually adjusted for foveal centration. All OCT scans were carefully reviewed independently by two graders (CP, JPH) on the Heidelberg Eye Explorer software (Version 1.10.0.0).\n\nA diagnosis of CME was noted if intraretinal hyporeflective spaces were noted in the inner nuclear layer (INL) and/or outer plexiform layer (OPL). Retinal thickness measurements were not used for CME diagnosis, as eyes had varying levels of atrophy.\n\nEyes were classified as having postoperative transient CME (tCME), chronic CME (cCME), or no CME (nCME). Both tCME and cCME were included as all CME (aCME) for statistical analysis. Postoperative tCME was defined as CME seen on OCT within 6 months of the final RRD, lasting less than 6months, and resolving using topical treatment. Postoperative cCME was defined as CME seen on two OCTs at least 6 months apart, based on previous reports [12].\n\nRecorded characteristics of cCME on OCTs included presence of subretinal fluid, layers of CME involvement, presence of intraretinal hyperreflective foci, and integrity of outer retinal layers. Efficacy of anti-VEGF, triamcinolone acetonide (TA), or dexamethasone implant (Ozurdex®, Allergan Inc, Irvine, California) (DEX) injections were assessed after 4–6 weeks, if OCT was available. To determine treatment effect, pre- and post-injection OCTs were analyzed for central subfield thicknesses (CST) and inner macular volumes, comprised of the central five areas of the standard early treatment for diabetic retinopathy study (ETDRS) subfields [13].\n\nClinical charts analysis\nPreoperative RRD parameters, intraoperative and post-operative data were collected. Glaucoma was counted if the patient carried this diagnose from a glaucoma specialist. Visual acuity was measured on a Snellen chart and converted to logarithm of the minimum angle of resolution (LogMAR) values for statistical analysis. Count fingers and hand motions vision were recorded as 1.98 and 2.28 LogMAR, respectively, based on previous studies using the Freiburg Visual Acuity Test [14]. Type of cCME treatment and number of intravitreal injections were included.\n\nStatistical analysis\nQualitative values were listed as ratios and percentages while quantitative values were presented as mean ± standard deviation (SD). Qualitative variables were compared using the Fisher exact test. To compare continuous data between two groups, a Mann–Whitney U test was used. The Wilcoxon signed rank test was used to analyze changes in CST and inner retinal volume. The Kruskal–Wallis test was used to compare pre-injection OCT parameters between groups. The Shapiro–Wilk test assessed the normality of variable distribution. Covariate adjusted differences between CME groups were assessed using regression modeling (i.e. logistic, linear, and multinomial) using the number of surgeries as the covariate. Final visual acuity (logMAR) was log transformed in multivariable analyses and used the additional covariate of macula on/off. All statistics were performed in Stata SE 15.1 (StataCorp LP, College Station, TX). A P value of less than 0.05 was considered statistically significant. Denominators of ratios were less than the total number of eyes in the category if eyes could not be included in analyses due to missing or incomplete records.\n\nResults\nPopulation\nA flowchart of population selection is shown in Fig. 1. A total of 508 surgical records were retrieved using CPT codes from January 2015 to December 2017. Of these, 133 eyes undergoing RRD repair met inclusion and exclusion criteria. Of these, 34 had less than 6 months of follow-up. The remaining 99 eyes of 97 patients were included for analysis. Of these, 20 patients (20%) had cCME, 5 (5%) had tCME, and 74 (75%) had nCME. Our primary analyses examine tCME and cCME as a single group, all CME (aCME), in comparison to nCME due to the small sample size for tCME. Descriptive statistics for all three groups can be found in the Additional file 1: Table S1.Fig. 1 Flowchart of patient selection process. ICD-9: International Classification of Disease, 9th edition. CPT Current Procedural Terminology, CME Cystoid Macular Edema\n\n\n\nCME risk factors\nDemographic and surgical data are summarized by CME group in Table 1. There was no difference in age at last surgery between patients in the aCME group (64.1 ± 11.6 years) versus patients in the nCME group (56.7 ± 18.0 years, P = 0.092). There was no significant difference in gender (P = 0.093), glaucoma status (P = 0.258), or length of follow-up (P = 0.869). Among those with glaucoma, there was no difference in the rates of topical prostaglandin analogs, other topical medications, or glaucoma surgery between groups (P = 0.992).Table 1 Demographics, baseline characteristics, and surgical data of patients with aCME and nCME\n\n\taCME\tnCME\tP value\tAdjusted P value1\t\nDemographic data\t\n Number of eyes\t25 (25%)\t74 (75%)\t\t\t\n Follow-up (months)\t21.4 ± 12.1\t20.4 ± 10.8\t0.87\t\t\n Sex, Female\t8 (32%)\t38 (34%)\t0.09\t\t\n Age (years)\t64.1 ± 11.6\t56.7 ± 18.0\t0.09\t\t\nClinical data\t\n Right eye\t11 (44%)\t40 (54%)\t0.38\t\t\n Glaucoma\t4 (16%)\t6 (8%)\t0.26\t\t\n Lens status\t\t\t< 0.001\t0.008\t\n Phakic\t1 (4%)\t44 (60%)\t\t\t\n Pseudophakic\t14 (56%)\t28 (38%)\t\t\t\n Aphakic\t10 (40%)\t2 (3%)\t\t\t\nMacula offa\t20/24 (83%)\t31/70 (44%)\t0.001\t0.06\t\nPVR Stage Ca\t15/24 (63%)\t5/74 (7%)\t< 0.001\t0.09\t\nFinal VA (LogMAR)\t0.85 ± 0.80\t0.20 ± 0.30\t< 0.001\t0.012b\t\nERM\t18 (72%)\t28 (38%)\t0.005\t\t\nSurgical details\t\n Number of surgeries\t3.5 ± 1.8\t1.4 ± 0.9\t< 0.001\t\t\n Multiple PPV\t21 (84%)\t17 (23%)\t< 0.001\t–c\t\n Referred after surgery elsewhere\t12 (48%)\t5 (7%)\t< 0.001\t0.31\t\n Number of surgery outside\t1 ± 1.3\t0.095 ± 0.4\t< 0.001\t\t\n Type of surgery\t\t\t< 0.001\t0.21\t\n SB\t1 (4%)\t25 (34%)\t\t\t\n PPV\t7 (28%)\t28 (38%)\t\t\t\n PPV + SB\t17 (68%)\t21 (28%)\t\t\t\nTamponade agent\t\t\t< 0.001\t0.10\t\n None/Air\t1 (4%)\t24 (32%)\t\t\t\n Gas (SF6 or C3F8)\t8 (32%)\t46 (62%)\t\t\t\nSilicone oil\t16 (64%)\t4 (5%)\t\t\t\nCryotherapya\t4/24 (17%)\t30/73 (41%)\t0.047\t0.036\t\nRetinectomy\t9 (36%)\t4 (5%)\t< 0.001\t0.009\t\nPFCLa\t18/23 (78%)\t35/47 (75%)\t0.73\t0.38\t\naCME all (chronic + transient) cystoid macular edema, nCME no cystoid macular edema, PVR proliferative vitreoretinopathy, VA visual acuity, LogMAR (logarithm of the minimum angle of resolution), PPV pars-plana vitrectomy, ERM epiretinal membrane, SB scleral buckle, PFCL perfluorocarbon liquid\n\naDenominators are provided if the number is less than the total number of eyes in the category due to missing or incomplete data\n\nbFinal VA adjusted P value from a model with covariates for total number of surgeries and Macula on/off\n\ncAdjusted model not possible due to collinearity of Multiple PPV with number of surgeries (i.e. those with Multiple PPV had greater than 2 surgeries, while those with no PPV had fewer)\n\n1P-value for difference after adjustment for total number of surgeries\n\n\n\nEyes in the aCME group underwent a significantly greater number of retinal surgeries (3.5 ± 1.8) compared with eyes in the nCME group (1.4 ± 1.9) (P < 0.001). Due to the high collinearity between CME status and number of surgeries, multivariate analysis using this as a covariate was performed. Final lens status differed significantly between groups after adjustment (P = 0.008), with only one eye in the aCME group remaining phakic. A higher rate of aCME eyes had a macula-off retinal detachment (20/24, 83%), compared with nCME eyes (31/70, 44%, P = 0.001). Proliferative vitreoretinopathy (PVR) stage C was more frequent in the aCME group (15/24, 63%) versus the nCME group (5/74, 7%), P < 0.0001. However, both macula-off status (P = 0.06) and presence of PVR C (P = 0.09) lost statistical significance after adjustment for the total number of surgeries performed. Surgical approaches were statistically different between the aCME and nCME groups: primary SB in 1/25 (4%) aCME eyes vs. 25/74 (34%) nCME eyes, PPV in 7/25 (28%) aCME eyes vs. 28/74 (38%) nCME eyes, and combined SB + PPV in 17/25 (68%) aCME eyes vs. 21/74 (28%) nCME eyes (P <0.0001). However, these differences in the surgical approach were not reliably different after adjustment for the number of surgeries. Rates of retinectomy were higher in the aCME group than the nCME group after adjustment (9/25, 36% vs 4/74, 5%, P = 0.009). Rates of cryotherapy were higher in the nCME group (30/74, 41%) than aCME group (4/24, 17%), even after adjustment (P = 0.036). Unadjusted differences in tamponade agent between groups were statistically significant (P < 0.0001). Notably, 16 out of 25 (64%) aCME eyes received silicone oil (SO) at least once, while only 4 out of 74 (5%) of nCME eyes did. However, tamponade differences were no long significant after covariate adjustment. There was no difference in the use of perfluorocarbon liquid (PFCL) (P = 0.728).\n\nAt last examination, VA was significantly lower in aCME group (0.85 ± 0.80 LogMAR) than in nCME group (0.20 ± 0.30 LogMAR), P < 0.0001. When adjusting for the number of surgeries and macular detachment, the marginal estimates for between group differences in LogMAR were attenuated (aCME = 0.55 vs nCME = 0.26), though still statistically significant (P = 0.012).\n\nTwo patients had non-simultaneous RRDs in each eye. One patient was 23 years of age at the time of both surgeries and underwent SB with cryotherapy in each eye for inferior chronic RRD, without CME development. The other patient was 83 at the time of final surgery in both eyes, had initial surgeries performed elsewhere, had multiple PPVs in both eyes, and received SO in both eyes, and this patient developed cCME in both eye.\n\nOCT characteristics of cCME\nEyes in the cCME group (n = 20) shared particular qualities on OCT (Fig. 2). All eyes had diffuse CME involving the four macular quadrants. The CME always involved the fovea but had variable extent into peripheral macula and was often asymmetric. Cysts were uniformly present in the INL and OPL, with occasional ganglion cell layer involvement. Florid CME often assumed a retinoschitic appearance. With time, cysts coalesced into larger confluent cavities with irregular, polygonal shapes. These cysts often spanned within the same retinal layer and across adjacent layers. Temporary resolution of these cysts after treatment disclosed disorganization and variable atrophy of the retinal layers in areas of cyst confluency. If CME recurred after treatment, it typically recurred in the same distribution of the macula.Fig. 2 Spectral-domain optical coherence tomography and infrared image elevation overlays of two different patients with chronic cystoid macular edema post-rhegmatogenous retinal detachment. The scan in Row A demonstrates schisis-like changes. The scan in Row B demonstrates confluent cystic cavities spanning retinal layers that developed over two years. In both scans, note diffuse, asymmetric distribution of retinal cysts crossing the horizontal raphe, involvement of inner and outer retinal layers, absence of subretinal fluid, and relative preservation of outer retinal bands subjacent to retinal edema\n\n\n\nOuter retinal layer integrity was heterogeneous. On the first OCT with CME after the final RRD repair, ellipsoid zone (EZ) disruption was seen in 18 eyes (90%), external limiting membrane (ELM) disruption in 14 eyes (80%), and retinal pigment epithelial (RPE) disruption in 11 eyes (55%). Remarkably, there was no case with subretinal fluid (SRF), and no case of intraretinal hyperreflective foci or hemorrhage.\n\nAn epiretinal membrane (ERM) was detectable on OCT during the post-operative follow-up period in 17/20 (85%) cCME eyes, 2/5 (40%) tCME eyes, and 28/74 (38%) of nCME eyes (P = 0.005). Evidence of traction on OCT, such as inner retinal wrinkling or ectopic inner foveal layers, was appreciable in only 4 of the 17 cCME eyes with ERM. However, the severity of CME was out of proportion to the ERM changes in all but one of these four eyes.\n\nCME Treatments\nAll patients with tCME (n = 5) and cCME (n = 20) received topical medications. Intravitreal injections and surgical interventions were administered according to physician discretion. All patients received corticosteroid drops, non-steroidal anti-inflammatory agent (NSAID) drop, or a combination of both for at least two months after the diagnosis of CME. If the CME failed to respond, patients thereafter received intravitreal injections of anti-VEGF (bevacizumab, ranibizumab, aflibercept), or steroids (triamcinolone acetate (TA), and/or dexamethasone intravitreal implant (DEX)).\n\nThe five patients (25%) with tCME had permanent resolution of CME with drops. Table 2 summarizes intravitreal treatments and anatomical responses of cCME. Five patients received at least one bevacizumab (Avastin®, Genentech Inc., San Francisco, CA, USA) injection, and one of these patients also received aflibercept (Eylea®, Regeneron Inc., Tarrytown, NY, USA) injections. In cCME eyes, there was a significant CST (P = 0.016, Wilcoxon signed rank test) and volume (P = 0.016) decrease after TA. (P = 0.125) (Fig. 3). There was no difference in pre-injection CST or volume between groups (P = 0.397, P = 0.457). There was no significant change in CST or volume with anti-VEGF treatment (P =0.915, P = 0.828) or DEX (P = 0.434, P = 0.125). No patient developed elevated intraocular pressure (IOP) after intravitreal injection requiring treatment. One patient developed sterile endophthalmitis after her seventh TA injection that spontaneously resolved without sequelae. A PPV for an ERM was performed in 9/16 cCME eyes with OCT evidence of ERM, with full resolution of the CME in only one eye.Table 2 Treatments for chronic cystoid macular edema (cCME) and anatomical responses on spectral-domain optical coherence tomography\n\nType of treatment\tAnti-VEGF\tTA\tDEX\t\t\nNumber of eyes\t5\t7\t4\t\t\nNumber of Injections (Median; [Range])\t2.5, 1-14\t2.0, 1-10\t2.5, 1-7\t\t\nCST pre-injection (μm)\t401 ± 84.9\t481 ± 104\t397 ± 57.0\tP = 0.397\t\nCST post-injection (μm)\t393 ± 106\t402 ± 102\t355 ± 80.4\t\t\nPercent CST change (μm)\t− 1.44 ± 17.1, P = 0.915\t− 15.6 ± 16.6, P = 0.016\t− 11.0 ± 10.7, P = 0.434\t\t\nInner macular volume pre-injection (mm3)\t2.81 ± 0.43\t3.18 ± 0.56\t3.12 ± 0.80\tP = 0.457\t\nInner macular volume post-injection (mm3)\t2.74 ± 0.53\t2.72 ± 0.53\t2.66 ± 0.486\t\t\nPercent (%) inner macular volume change (mm3)\t−2.49 ± 12.35, P = 0.828\t−13.9 ± 10.8, P = 0.016\t−10.7 ± 25.7, P = 0.125\t\t\nValues are listed as averages with standard deviations\n\nVEGF vascular endothelial growth factor, TA triamcinolone acetate, DEX dexamethasone implant, CST central subfield thickness\n\nFig. 3 Spectral-domain optical coherence tomography (OCT) images of chronic cystoid macular edema (CME) post-rhegmatogenous retinal detachment (RRD) repair of the left eye, with dates and visual acuities (VA). Panel A: OCT prior to dexamethasone implant (DEX) injection. Panel B: OCT 1 month after DEX injection, showing resolution of CME but retinal layer atrophy. Modest VA improvement was noted. Panel C: OCT four months after injection, showing recurrence of CME in a similar distribution and slight decrease in VA\n\n\n\nDiscussion\nChronic CME after retinal detachment repair remains a challenging complication. In this paper, the risk factors for post-RRD CME, its OCT characteristics, and treatments outcomes are described.\n\nChronic post-RRD CME is thought to be pathophysiologically distinct from other etiologies of CME [3]. Among CME etiologies such as uveitis, RVO, and DME, many of the cytokines and damaged tissue responses are shared [1, 2, 15]. Certain CME etiologies, however, may have unique pathophysiologic mechanisms despite phenotypic similarities [16]. Entities with a significant pro-angiogenic component, such as exudative AMD, may respond to anti-VEGF agents, while those with a broad inflammatory component, such as uveitic CME or Irvine-Gass syndrome, may respond better to anti-inflammatory drugs [12].\n\nWhile some studies found no risk factor differences for CME rates [5, 17], some series have, on univariate analyses, reported increased rates in pseudophakic [18] and aphakic eyes [6], older patients, more extensive RRD, and a history of a detached macula. In the present study, lens status was significantly different between groups, with increased pseudophakia and aphakia in aCME eyes. Unicameral communication in vitrectomized eyes modifies circulation of inflammatory cytokines, as animal studies have noted changes in oxygen and antioxidant gradients [19]. Higher rates of pseudophakia/aphakia in the aCME group may be related either to the actual lens surgery or to the complexity of the vitreo-retinal surgeries requiring lens extraction. As a substantial proportion of eyes with complicated RRD will be made pseudophakic or aphakic, anticipating CME in complex cases can have prognostic implications.\n\nEyes with CME had a greater number of surgeries, higher rates of PVR grade C and retinectomy, and higher rates of SO use. Many studies have shown increased inflammation and CME with more complicated ocular surgeries and inflammatory risk factors [3, 11, 20]. Re-detachments are frequently associated with PVR formation and warrant additional surgeries, both of which can increase intraocular inflammation and possible risk for CME [21]. Retinectomy is helpful when PVR membranes are not amenable to mechanical peeling, and therefore retinectomy likely indicates severe pathology rather than directly causing CME.\n\nMacular detachment was associated with a higher risk of CME, which is in line with prior papers [18]. Of note, previous studies have noted outer nuclear layer CME on OCT of the detached macula [22, 23]. Although the retinal hydration theory, implicated in macular hole edema formation [24], may contribute to post-RRD CME, the presence of leakage on FA suggests dynamic fluid movements as opposed to static, non-leaking cysts. Moreover, absence of SRF after RD repair would theoretically lead to rapid elimination of intraretinal fluid by normal pumping mechanisms. Although such studies for macular detachment and CME development have not been explored [18, 25], permanent damage to retinal cellular elements while detached may lead to persistent dysfunction and contribute to CME.\n\nThere was a significant difference in surgical approaches between groups, with higher rates of combined SB and PPV in aCME eyes. This is not surprising, given that scleral buckles are often combined with PPV for complex or recurrent detachments to support the vitreous base and/or areas of retinal pathology. However, there was significantly more cryotherapy in the nCME group. Cryotherapy at our institution is only used during primary scleral buckling, usually for limited and uncomplicated detachments in phakic patients. While data comparing CME rates between PPV and SB are scant, the correlation between more complicated detachments and CME is consistent [3, 11, 18].\n\nAfter adjusting for the number of surgeries, type of surgery (P = 0.21), macular detachment (P = 0.06), PVR Grade C (P = 0.09) and tamponade type (P = 0.10) lost statistical significance. This may be related to the limited sample size, as there remained a trend towards significance. Moreover, these factors are clinically related to the number of surgeries and surgical failure. The interplay of inflammation among these factors requires more formal study.\n\nCharacteristics of CME on OCT can be useful diagnostic clues, and post-RRD cCME displays distinguishing OCT features (Fig. 2). Previous studies have examined OCTs of various conditions associated with CME and noted distinctive findings [13]. These findings could then be used to diagnose conditions accurately as well as account for variability in VA [26]. Post-RRD cCME shares features of uveitic CME, such as diffuse macular distribution, inner and outer layer cysts, and absence of hyperreflective foci. This contrasts to post-RRD tCME, which is much less severe, more central and fleeting, and may be a variant of pseudophakic CME.\n\nThe presence of ERM is common after RRD and may confound CME diagnosis [16]. Although there was a significant difference between groups in the presence of ERM on OCT, there was resolution of CME in only one eye after ERM peeling, suggesting that traction plays a small role in most cases of post-RRD CME. Therefore, there should be high suspicion for post-RRD cCME in any patient status-post RRD repair that has severe, diffuse CME without SRF in the absence of other typical inflammatory or tractional signs.\n\nThe RPE has a well-studied role in pumping syneretic vitreous fluid through the retina and into the choroidal space [1]. Active fluid transport regulation by the RPE and Muller cells along with maintenance of tight junctional proteins are thought to mitigate CME accumulation [1, 2, 15], and dysfunction of these cells causes an imbalance of fluid inflow and egress. Previous papers examining CME OCT findings note varying SRF rates, from 5% in uveitic CME up to 100% in central RVO-associated CME [1, 4, 13, 27]. Therefore, the absence of SRF in cCME suggests a grossly functioning RPE and outer retinal barrier.\n\nIntravitreal corticosteroids were more effective than intravitreal anti-VEGF or topical medications for cCME in our series. Recent investigations have shown success with intravitreal corticosteroids for chronic post-RRD CME [16, 25]. Thanos et al. found favorable responses to DEX all eyes, but in all cases CME recurred after 3 months. This aligns with pharmacokinetic studies showing a dual-phase response of high dexamethasone concentrations for the first 2 months after delivery followed by a precipitous decrease during the third month [28]. Experimental studies have demonstrated a reduced half-life of anti-VEGF agents and triamcinolone acetate in vitrectomized eyes compared with non-vitrectomized eyes [28, 29], but similar clearances between eyes with DEX. Statistically significance for anatomical improvement was not reached for DEX in our series, likely due to the small number of eyes. Moreover, aphakia has been suggested to cause increased unicameral circulation of inflammatory cytokines [6, 30], but aphakia precludes the use of DEX. One randomized controlled trial evaluating PPV with SO for RRD with grade C PVR found a significant decrease in CME occurrence at 6 months post-operatively in those with intraoperative DEX [31]. Corticosteroids have been shown to modulate a number of cytokines secreted by retinal cells, such as tumor necrosis factor-α, interleukins-1β, 6, and 8, as well as induce expression of occludin, ZO-1, and claudin-5 [1, 16, 31]. Steroids also modulate expression of aquaporin, predominantly expressed in end-feet of Müller cells and astrocytes. Corticosteroids may therefore stabilize the BRB and encourage resolution of CME, accounting for the increased efficacy of corticosteroids over anti-VEGF agents. Nevertheless, disadvantages of TA and DEX include accelerated cataract formation and risk of increased IOP; however, most patients with cCME will require cataract extraction, and no patient in our series required treatment for ocular hypertension.\n\nAverage final visit VA was significantly worse in the aCME group even after adjusting for macula-off status and number of surgeries. Reports on recalcitrant CME after PPV for RRD, despite anatomic improvement, found only short-term visual acuity gains [16, 25].\n\nIrvine-Gass syndrome (IGS) is another potential diagnosis in these cases. We did not regularly perform FA or optic disc evaluations to check for optic nerve head leakage during the course of follow up. However, IGS is not described after PPV and has been described as a potential treatment option in many cases [32]. Therefore, IGS would have likely responded to topical treatments, steroid injections, or PPV. The OCT appearance of IGS is also less diffuse, more foveocentric, and may be associated with SRF, as opposed to characteristics noted with post-RRD cCME.\n\nOur paper has a relatively large sample size of post-RRD CME, long-term patient records and follow up, and variety of treatments. Despite this, our study has several limitations. The retrospective analysis precluded standardized imaging and treatment protocols. Significant loss to follow-up likely led to underreporting of chronic post-RRD CME and an inability to accurately determine incidence. The high percentage of CME likely relates to inclusion of eyes that had initial RRD repairs prior to the inclusion period and multiple referrals for complex cases. We were unable to determine after which surgery CME appeared due to inconsistent timing and absence of OCT acquisition between surgeries, or missing outside records. A small number of eyes received anti-VEGF injections, and greater numbers may show CME improvement. A larger, prospective study evaluating complex macular surgeries is warranted.\n\nIn conclusion, cCME after RRD is a complex entity with interconnected risk factors. A high index of suspicion based on risk factor and imaging characteristics can allow anticipation of cCME development and early treatment. Currently, corticosteroids have the most evidence of treatment success, and prompt intervention may provide better functional and structural outcomes.\n\nSupplementary information\n\nAdditional file 1: Table S1. Descriptive statistics for all three groups, as explained in results population section.\n\n \n\nAbbreviations\nCMECystoid macular edema\n\ntCMETransient CME\n\ncCMEChronic CME\n\naCMEAll CME\n\nDRDiabetic retinopathy\n\nAMDAge-related macular degeneration\n\nRVORetinal vein occlusion\n\nRPRetinitis pigmentosa\n\nRRDRhegmatogenous retinal detachment\n\nFAFluorescein angiography\n\nOCTOptical coherence tomography\n\nSBScleral buckle\n\nPPVPars plana vitrectomy\n\nVEGFVascular endothelial growth factor\n\nEHRElectronic health records\n\nCPTCurrent procedural terminology\n\nTATriamcinolone acetonide\n\nDEXDexamethasone intravitreal implant\n\nCSTCentral subfield thickness\n\nETDRSEarly treatment for diabetic retinopathy study\n\nSDStandard deviation\n\nPVRProliferative vitreoretinopathy\n\nPFCLPerfluorocarbon liquid\n\nINLInner nuclear layer\n\nOPLOuter plexiform layer\n\nEZEllipsoid zone\n\nELMExternal limiting membrane\n\nERMEpiretinal membrane\n\nRPERetinal pigment epithelium\n\nSRFSubretinal fluid\n\nNSAIDNon-steroidal anti-inflammatory drug\n\nIOPIntraocular pressure\n\nSOSilicone oil\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s40942-020-00254-9.\n\nAcknowledgements\nThe authors would like to thank Nicholas J. Jackson, PhD, for his statistical assistance and valuable review of the manuscript.\n\nAuthors’ contributions\nAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by CP, IC, AG, SG, SDS, and JPH. The first draft of the manuscript was written by CP, and all authors commented on draft versions of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nThe research described was supported by NIH/National Center for Advancing Translational Science (NCATS) UCLA CTSI Grant Number UL1TR001881, and by an unrestricted grant from Research to Prevent Blindness.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nEthics approval and consent to participate\nThis research study was conducted retrospectively from data obtained for clinical purposes. An IRB official waiver of ethical approval was granted from the IRB of the University of California Los Angeles Office of Human Research Protection (IRB#16-000574).\n\nConsent for publication\nNot applicable.\n\nCompeting interests\nAll authors certify that they have no affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this manuscript.\n==== Refs\nReferences\n1. Daruich A Matet A Moulin A Mechanisms of macular edema: beyond the surface Prog Retin Eye Res 2018 63 20 68 10.1016/j.preteyeres.2017.10.006 29126927 \n2. Spaide RF Retinal vascular cystoid macular edema: review and new Theory Retina 2016 36 10 1823 1842 10.1097/IAE.0000000000001158 27328171 \n3. Romano V Angi M Scotti F Inflammation and macular oedema after pars plana vitrectomy Mediators Inflamm 2013 2013 971758 24288446 \n4. Catier A Tadayoni R Paques M Characterization of macular edema from various etiologies by optical coherence tomography Am J Ophthalmol 2005 140 2 200 206 10.1016/j.ajo.2005.02.053 15992752 \n5. Bonnet M Prognosis of cystoid macular edema after retinal detachment repair Graefes Arch Clin Exp Ophthalmol 1986 224 1 13 17 10.1007/BF02144125 3943728 \n6. Meredith TA Reeser FH Topping TM Cystoid macular edema after retinal detachment surgery Ophthalmology 1980 87 11 1090 1095 10.1016/S0161-6420(80)35114-2 7243204 \n7. Bonnet M Payan X Long-term prognosis of cystoid macular edema after microsurgery of rhegmatogenous retinal detachment J Fr Ophtalmol 1993 16 4 259 263 8326107 \n8. de Nie KF Crama N Tilanus MA Pars plana vitrectomy for disturbing primary vitreous floaters: clinical outcome and patient satisfaction Graefes Arch Clin Exp Ophthalmol 2013 251 5 1373 1382 10.1007/s00417-012-2205-3 23250478 \n9. Miyake K Miyake Y Maekubo K Incidence of cystoid macular edema after retinal detachment surgery and the use of topical indomethacin Am J Ophthalmol 1983 95 4 451 456 10.1016/0002-9394(83)90264-7 6340512 \n10. Benson SE Ratclliffe S Van Raders P A randomized comparison of parecoxib/valdecoxib and placebo for the prevention of cystoid macular edema after scleral buckling surgery Retina 2009 29 3 387 394 10.1097/IAE.0b013e318192f4d8 19092729 \n11. Lai TT Huang JS Yeh PT Incidence and risk factors for cystoid macular edema following scleral buckling Eye 2017 31 4 566 571 10.1038/eye.2016.264 27935601 \n12. Rossetti L Chaudhuri J Dickersin K Medical prophylaxis and treatment of cystoid macular edema after cataract surgery. The results of a meta-analysis Ophthalmology 1998 105 3 397 405 10.1016/S0161-6420(98)93018-4 9499767 \n13. Munk MR Sacu S Huf W Differential diagnosis of macular edema of different pathophysiologic origins by spectral domain optical coherence tomography Retina 2014 34 11 2218 2232 10.1097/IAE.0000000000000228 25011028 \n14. Schulze-Bonsel K Feltgen N Burau H Visual acuities “hand motion” and “counting fingers” can be quantified with the freiburg visual acuity test Invest Ophthalmol Vis Sci 2006 47 3 1236 1240 10.1167/iovs.05-0981 16505064 \n15. Augustin A Loewenstein A Kuppermann BD Macular edema. General pathophysiology Dev Ophthalmol 2010 47 10 26 10.1159/000320071 20703041 \n16. Thanos A Todorich B Yonekawa Y Dexamethasone intravitreal implant for the treatment of recalcitrant macular edema after rhegmatogenous retinal detachment repair Retina 2018 38 6 1084 1090 10.1097/IAE.0000000000001720 28622270 \n17. Yang JY, Kim HK, Kim SH, et al. Incidence and Risk Factors of Cystoid Macular Edema after Vitrectomy with Silicone Oil Tamponade for Retinal Detachment. Korean J Ophthalmol. 2017.\n18. Tunc M Lahey JM Kearney JJ Cystoid macular oedema following pneumatic retinopexy vs scleral buckling Eye 2007 21 6 831 834 10.1038/sj.eye.6702431 16710429 \n19. Siegfried CJ Shui YB Tian B Effects of vitrectomy and lensectomy on older rhesus macaques: oxygen distribution, antioxidant status, and aqueous humor dynamics Invest Ophthalmol Vis Sci 2017 58 10 4003 4014 10.1167/iovs.17-21890 28800647 \n20. Kiss CG Richter-Muksch S Sacu S Anatomy and function of the macula after surgery for retinal detachment complicated by proliferative vitreoretinopathy Am J Ophthalmol 2007 144 6 872 877 10.1016/j.ajo.2007.08.001 17937924 \n21. Pastor JC Rojas J Pastor-Idoate S Proliferative vitreoretinopathy: a new concept of disease pathogenesis and practical consequences Prog Retin Eye Res 2016 51 125 155 10.1016/j.preteyeres.2015.07.005 26209346 \n22. Nakanishi H Hangai M Unoki N Spectral-domain optical coherence tomography imaging of the detached macula in rhegmatogenous retinal detachment Retina 2009 29 2 232 242 10.1097/IAE.0b013e31818bcd30 18997641 \n23. Lee SY Joe SG Kim JG Optical coherence tomography evaluation of detached macula from rhegmatogenous retinal detachment and central serous chorioretinopathy Am J Ophthalmol 2008 145 6 1071 1076 10.1016/j.ajo.2008.01.031 18374302 \n24. Gaudric A Haouchine B Massin P Macular hole formation: new data provided by optical coherence tomography JAMA Ophthalmology 1999 117 6 744 751 \n25. Alam MR Arcinue CA Mendoza NB Recalcitrant cystoid macular edema after pars plana vitrectomy Retina 2016 36 7 1244 1251 10.1097/IAE.0000000000000892 26655611 \n26. Gharbiya M Grandinetti F Scavella V Correlation between spectral-domain optical coherence tomography findings and visual outcome after primary rhegmatogenous retinal detachment repair Retina 2012 32 1 43 53 10.1097/IAE.0b013e3182180114 21778929 \n27. Kim BY Smith SD Kaiser PK Optical coherence tomographic patterns of diabetic macular edema Am J Ophthalmol 2006 142 3 405 412 10.1016/j.ajo.2006.04.023 16935584 \n28. Edington M Connolly J Chong NV Pharmacokinetics of intravitreal anti-VEGF drugs in vitrectomized versus non-vitrectomized eyes Expert Opin Drug Metab Toxicol 2017 13 12 1217 1224 10.1080/17425255.2017.1404987 29134820 \n29. Chin HS Park TS Moon YS Difference in clearance of intravitreal triamcinolone acetonide between vitrectomized and nonvitrectomized eyes Retina 2005 25 5 556 560 10.1097/00006982-200507000-00002 16077349 \n30. Lobes LA Jr Grand MG Incidence of cystoid macular edema following scleral buckling procedure Arch Ophthalmol 1980 98 7 1230 1232 10.1001/archopht.1980.01020040082010 7396774 \n31. Banerjee PJ Quartilho A Bunce C Slow-release dexamethasone in proliferative vitreoretinopathy: a prospective. Randomized Controlled Clinical Trial Ophthalmology 2017 124 6 757 767 10.1016/j.ophtha.2017.01.021 28237428 \n32. Guo S Patel S Baumrind B Management of pseudophakic cystoid macular edema Surv Ophthalmol 2015 60 2 123 137 10.1016/j.survophthal.2014.08.005 25438734\n\n",
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"issue": "7(1)",
"journal": "International journal of retina and vitreous",
"keywords": "Corticosteroids; Intravitreal injection; Macular edema; Retinal detachment; Spectral-domain optical coherence tomography; Vitrectomy",
"medline_ta": "Int J Retina Vitreous",
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"references": "16935584;26655611;25011028;23250478;28800647;7243204;19092729;25438734;10369584;20703041;3943728;6340512;28237428;29134820;28622270;8326107;15992752;7396774;18997641;24288446;29022299;16505064;21778929;29126927;27328171;16710429;9499767;26209346;27935601;17937924;18374302;16077349",
"title": "Macular edema after rhegmatogenous retinal detachment repair: risk factors, OCT analysis, and treatment responses.",
"title_normalized": "macular edema after rhegmatogenous retinal detachment repair risk factors oct analysis and treatment responses"
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"abstract": "BACKGROUND\nFanconi-Bickel syndrome (FBS) is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene, which encodes glucose transporter protein 2 (GLUT2).\n\n\nMETHODS\nWe report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly, jaundice, liver transaminase elevation, fasting hypoglycemia, hyperglycosuria, proteinuria, hypophosphatemia, rickets, and growth retardation. After prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, while she still had aggravating hepatomegaly and severe hyperglycosuria. Then, whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents, which was predicted to change alanine 139 to valine (p.A139Vfs*3), indicating a diagnosis of FBS. During the follow-up, the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch. Her weight increased to normal range at 3 years old without hepatomegaly. However, she still had short stature. Although there was heterogeneity between phenotype and genotype, Chinese children had typical clinical manifestations. No hot spot mutation or association between severity and mutations was found, but nonsense and missense mutations were more common. Data of long-term follow-up were rare, leading to insufficient assessment of the prognosis in Chinese children.\n\n\nCONCLUSIONS\nFBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients' quality of life and decrease mortality.",
"affiliations": "Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China. xionglijing1985@qq.com.;Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China.;Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China.;Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China.;Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China.",
"authors": "Xiong|Li-Jing|LJ|;Jiang|Mao-Ling|ML|;Du|Li-Na|LN|;Yuan|Lan|L|;Xie|Xiao-Li|XL|",
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"doi": "10.12998/wjcc.v8.i21.5467",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960 Baishideng Publishing Group Inc \n\n33269285\njWJCC.v8.i21.pg5467\n10.12998/wjcc.v8.i21.5467\nCase Report\nFanconi-Bickel syndrome in an infant with cytomegalovirus infection: A case report and review of the literature\nXiong Li-Jing Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China. xionglijing1985@qq.com\n Jiang Mao-Ling Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China\n Du Li-Na Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China\n Yuan Lan Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China\n Xie Xiao-Li Department of Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu 610091, Sichuan Province, China\n Author contributions: Xiong LJ, Jiang ML, and Du LN were the patient’s doctors for diagnosis, treatment, and follow-up; Xiong LJ reviewed the literature and contributed to manuscript drafting; Yuan L interpreted the results of testing and findings; Xie XL performed the disease consultation and was responsible for the revision of the manuscript; all authors declared no conflicts of interest and issued final approval for the version to be submitted.\n\nCorresponding author: Li-Jing Xiong, MD, Attending Doctor, Gastroenterology, Hepatology and Nutrition, Chengdu Women's and Children's Central Hospital, School of Medicine, University of Electronic Science and Technology of China, No. 1617 Riyue Avenue, Chengdu 610091, Sichuan Province, China. xionglijing1985@qq.com\n\n\n6 11 2020 \n6 11 2020 \n8 21 5467 5473\n26 5 2020 16 9 2020 26 9 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nFanconi–Bickel syndrome (FBS) is a rare autosomal recessive disorder caused by mutation of the SLC2A2 gene, which encodes glucose transporter protein 2 (GLUT2). \n\nCASE SUMMARY\nWe report a 7-mo-old girl with cytomegalovirus infection presenting hepatomegaly, jaundice, liver transaminase elevation, fasting hypoglycemia, hyperglycosuria, proteinuria, hypophosphatemia, rickets, and growth retardation. After prescription of ganciclovir, the levels of bilirubin and alanine aminotransferase decreased to normal, while she still had aggravating hepatomegaly and severe hyperglycosuria. Then, whole exome sequencing was conducted and revealed a homozygous c.416delC mutation in exon 4 of SLC2A2 inherited from her parents, which was predicted to change alanine 139 to valine (p.A139Vfs*3), indicating a diagnosis of FBS. During the follow-up, the entire laboratory test returned to normal with extra supplement of vitamin D and corn starch. Her weight increased to normal range at 3 years old without hepatomegaly. However, she still had short stature. Although there was heterogeneity between phenotype and genotype, Chinese children had typical clinical manifestations. No hot spot mutation or association between severity and mutations was found, but nonsense and missense mutations were more common. Data of long-term follow-up were rare, leading to insufficient assessment of the prognosis in Chinese children. \n\nCONCLUSION\nFBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients’ quality of life and decrease mortality.\n\nFanconi–Bickel syndromeGlucose transporter protein 2Case reportChildrenChinese\n==== Body\nCore Tip: Fanconi–Bickel syndrome (FBS) is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients’ quality of life and decrease mortality.\n\nINTRODUCTION\nFanconi–Bickel syndrome (FBS), also known as glycogen storage disease type XI (OMIM227810), is a rare, autosomal recessive disorder first described by Fanconi and Bickel in 1949[1]. FBS is caused by mutations in the SLC2A2 gene, which encodes glucose transporter protein 2 (GLUT2). GLUT2 is a member of the facilitative glucose transporter family and is expressed in liver cells, renal tubular epithelial cells, pancreatic β cells, and the intestinal mucosal epithelium. Mutations that alter the structure or structural dynamics of GLUT2 impair glucose transportation, leading to hepato-renal glycogen accumulation[2]. Generally, impaired glucose liver homeostasis and proximal renal tubular dysfunction are mainly present in FBS children. Clinical manifestations of FBS include hepatomegaly, glucose intolerance, fasting hypoglycemia, hyperglycosuria, proteinuria, hypophosphatemia, rickets, and growth retardation. To date, there have been more than 40 different SLC2A2 mutations reported in FBS patients across the world[3-12]. Due to the rarity of FBS, some patients may be misdiagnosed, especially if symptoms overlap those of other diseases. Here, we report a rare case of an infant with cytomegalovirus (CMV) infection that was identified with a mutation of the SLC2A2 gene and diagnosed with FBS. \n\nCASE PRESENTATION\nChief complaints\nA 7 mo-old girl presented obvious abdominal distension for more than 2 mo. \n\nHistory of present illness\nTwo months ago, her parents found that this female infant presented aggravating abdominal distension and jaundice. She had normal milk ingestion and the color of the stool was normal. She failed to gain weight after 5 mo of age, while the motor development was normal referring to the age. \n\nPersonal and family history\nThe infant was born at full term and appeared healthy at birth, weighing 3.2 kg. She was fed a combination of breast milk and cow milk formula. Her brother was healthy with no symptoms. No family history of relevant diseases was reported.\n\nPhysical examination\nThe patient was found to have moderate jaundice and hepatomegaly with the liver palpable 5 cm below the costal margin (Figure 1). Her weight was 5.0 kg (< -2SD) and height was 54 cm (< -3SD) at examination.\n\nFigure 1 A 7 mo-old girl presenting with obvious abdominal distension with moderate jaundice.\n\nLaboratory examinations\nLaboratory tests showed elevated serum liver transaminase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (γ-GT), and alpha-fetoprotein, moderate hyperbilirubinemia (direct bilirubin 68%), fasting hypoglycemia (2.01 mmol/L), and hypophosphatemia. A routine urine test revealed proteinuria (+) and hyperglycosuria (+++ to ++++), with a 24 h urinary protein excretion of 0.415 g. CMV infection was identified by CMV-IgM (> 140 U/mL) and positive urine and serum CMV-DNA (1.2 × 105 copies/mL). Other laboratory tests were normal, including microbiology and ceruloplasmin. Hearing test was normal.\n\nImaging examinations\nContrast-enhanced computed tomography confirmed the presence of hepatomegaly and decreased liver density. There was no evidence of morphological abnormality in the kidney or other organs. \n\nMULTIDISCIPLINARY EXPERT CONSULTATION\nThe infant was initially diagnosed with CMV infection and given a 2-wk course of ganciclovir, combined with a diet of milk without lactose and high in medium-chain triglycerides. Two weeks later, bilirubin and ALT levels decreased to normal. However, the patient still had aggravating hepatomegaly and severe hyperglycosuria. Sine congenital or hereditary liver diseases were suspected, whole exome sequencing was conducted. \n\nFINAL DIAGNOSIS\nWhole exome sequencing revealed a homozygous c.416delC mutation in exon 4 of SLC2A2, which was predicted to change alanine 139 to valine (p.A139Vfs*3), indicating a diagnosis of FBS. Both parents were also found to be heterozygous for the same mutation. \n\nTREATMENT\nThe infant was supplied with corn starch besides the formula and extra vitamin D. \n\nOUTCOME AND FOLLOW-UP\nDuring the follow-up, all the laboratory test results maintained normal after one year of standard treatment. Her weight had increased to 12 kg (Z score: -2 to -1) and her liver was no longer enlarged. However, she still had short stature, with a height of 83 cm (Z score: < -2). \n\nDISCUSSION\nIn this study, we report the case of an infant with CMV infection diagnosed with FBS. We made the diagnosis of CMV infection by elevated CMV specific IgM, and CMV-DNA in serum and urine by PCR. However, since we tested for CMV after 21 d and the hearing test was normal, we regarded that the virus was acquired postnatally. Initially, we attributed the signs and symptoms to the CMV infection as sequelae, and used ganciclovir. Although the levels of bilirubin and alanine aminotransferase decreased to normal after antivirus treatment, she still had aggravating hepatomegaly and severe hyperglycosuria. Perinatally, CMV infection acquired from infected mother is a common situation in Chinese infants (CMV maternal seroprevalence is 96.2%)[13], while FBS is a rare metabolic disease worldwide. We proposed that hereditary metabolic diseases such as FBS ought to be considered in cases where initial therapy to treat CMV infection did not completely alleviate symptoms, or where there were other symptoms that could not be explained by CMV infection entirely. \n\nIn our case, proteinuria and hyperglycosuria were found in this 7-mo-old infant. Although there were some overlap symptoms with GSD-I like hepatomegaly and hypoglycemia, the previous cases reported by Riva S and Bahíllo-Curieses MP suggested that FBS might be taken into consideration if infants present with polyuria, glycosuria, and hyperglucemia[14,15]. Therefore, the results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. \n\nThe most straightforward and accurate method to diagnose FBS is the sequencing of SLC2A2 gene. Santer et al[14] reported 33 different SLC2A2 mutations (9 missense, 7 nonsense, 10 frameshift, and 7 splice-site) detected in 49 FBS patients. The prevalence of SLC2A2 mutations is relatively low in most populations, and no mutation hot spots have been reported[16]. A liver biopsy also provides additional information for understanding this rare disease, but it is not definitive proof of FBS. Therefore, biopsies are typically performed only for unusual cases of FBS involving severe acute acidosis[17] or hepatocellular carcinoma[18]. \n\nVarious SLC2A2 mutations identified including missense, nonsense, insertion, deletions, splice site, and frame-shift indels have been reported in cases around the world. Previous studies reported that FBS patients with a homozygous p.R310X mutation had failure to thrive and a doll-like face and/or hepatomegaly[19]. However, diverse clinical presentations and progressions were observed even in patients with same mutation[20]. The association between phenotype and phenotype heterogeneity was controversial. Therefore, the disease severity was considered to be affected primarily by patient growth pattern, maximal electrolyte replacement, and skeletal and renal complications. Recently, Enogieru et al[21] conducted a comprehensive analysis including functional assays and structural analysis of 17 mutations to characterize the pathogenesis of SLCA2 variants in FBS. They found that GLUT2 variants could affect substrate-binding, steric hindrance, or overall transporter structure. However, only half of the mutant transporters expressed on the plasma membrane had no function, while the majority of SLC2A2 missense mutations were associated with normal glucose uptake. \n\nGenerally, the majority of FBS patients with mild symptoms have a good prognosis after treatment with standard therapy of supplementation with electrolytes, vitamin D, and corn starch. Poor clinical outcomes and complications including bone fractures, hepatocelluar carcinoma, liver failure, and death were reported rarely in patients with delayed diagnosis and treatment[18,22,23]. Although patients exhibited catch-up growth with nutrition supported, some case series reported that there was still some impact on linear growth[24]. Recently, a study suggested the intensive nutritional intervention including nocturnal enteral nutrition and uncooked cornstarch was able to rescue growth failure with final growth parameters into the normal range[25]. Follow-up compliance and hospitalization also play a role in FBS prognosis. One study reported that a female FBS patient who was followed for at least 20 years became pregnant at 31 years of age and delivered a healthy boy, despite having reduced adult height, osteopenia, and other clinical problems[26]. This demonstrates the importance of long-term follow-up to deepen our understanding of this rare metabolic disorder and improve quality of life in affected children and their families. Little is known about epidemiological features of FBS children in China. The first two pediatric FBS cases were reported in 2011[7]. To date, there have been nine cases of FBS associated with various SLC2A2 mutations reported in China, including our case[27-31] (Table 1). Seven patients were female, and one was male, suggesting that FBS might be more prevalent in females in China. The onset age of diagnosis ranged from 1-18 mo, with no adolescent cases. The majority of reported patients showed typical clinical features of FBS including hepatomegaly (100%), hypophosphatemic ricket (100%), failure to thrive, fasting hypoglycemia, postprandial hyperglycemia (100%), glucosuria (100%), and proteinuria (100%). All the cases were diagnosed through gene sequencing analysis. Except that one case was confirmed to have de novo mutation, all other patients inherited the FBS mutation from parents. No Chinese families with multiple familial FBS cases have been reported. All Chinese FBS patients had similar clinical manifestations, and there was no association found between clinical severity and mutations. Although no hot spot mutation was found, nonsense and missense mutations were more common than other types of mutations. Long-term follow-up data were rare in China, leading to insufficient assessment of the prognosis in Chinese children. Although symptoms were improved with appropriate treatment, one case was reported to be dead due to severe diarrhea and surgery, which may have been associated with a severe acid-base disturbance[28].\n\nTable 1 Fanconi-Bickel syndrome cases in China with different glucose transporter protein 2 mutations\n\n\nPatient\n\n\t\nAge (mo)\n\n\t\nGender\n\n\t\nPatient\n\n\t\nMutation in mother\n\n\t\nMutation in father\n\n\t\nMutation type\n\n\t\n\nMutation\n\n\t\nAmino acid change\n\n\t\n1[27]\t12\tFemale\tc.1068+5G>C\tNot stated\tC.1068 + 5G>C\tUnknown\tSplice-site\t\n2[27]\t9\tFemale\tc.1194T>A\tp.Tyr398X\tUnknown\tUnknown\tNonsense\t\n3[27]\t17\tFemale\tc.380C>A\tp.Ala127Asp\tNone\tc.380C>A\tMissense\t\nc.970dupT\tp.324TyrfsX392\tNone\tNone\tRepeat (de novo)\t\n4[28]\tNot stated\tNot stated\tc.380insTC\tNot stated\tNone\tc.380insTC\tUnknown\t\nc.1313insT\tNot stated\tc.1313insT\tNone\t\n5[29]\t12\tFemale\tc.682C>T\tp.Arg228X\tc.682C > T\tNone\tNonsense\t\nc.1185 >A\tp.Trp395X\tNone\tc.1185G>A\t\n6[29]\t11\tMale\tc.196G>A\tp.Glu66X\tNone\tUnknown\tNonsense\t\nc.1117delA\tp.Met373X\tc.1117delA\t\n7[30]\t1\tFemale\tc.609T>A\tp.Ser203Arg\tc.609T > A\tc.609T>A\tMissense\t\n8\t6\tFemale\tc.416delC\tp.A139Vfs*3\tc.416delC\tc.416delC\tFrameshift\t\n9[31]\t18\tFemale\tc.1134_1137del\tp.V378fs\tc.1134_1137del\t-\tFrameshift\t\nc.2T>C\tp.M1T\t-\tc.2T>C\tMissense\t\nCONCLUSION\nIn conclusion, FBS is a rare genetic metabolic disease causing impaired glucose liver homeostasis and proximal renal tubular dysfunction. Results of urine and blood testing suggesting abnormal glucose metabolism could be the clues for FBS in neonates and infants. Genetic sequencing is indispensable for diagnosis. Since the diversity of disease severity, early identification and long-term follow-up could help improve patients’ quality of life and decrease mortality.\n\nInformed consent statement: Informed written consent was obtained from patient’s parents for publication of this report and any testing results. \n\nConflict-of-interest statement: The authors declare that they have no conflict of interest to disclose. \n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist, and the manuscript was prepared and revised according to the CARE Checklist.\n\nManuscript source: Unsolicited manuscript\n\nCorresponding Author's Membership in Professional Societies: Group of Pediatric Gastroenterology, Society of Pediatrics, Chinese Medical Association; and Group of Pediatric Digestive Endoscopy, Chinese Medical Doctor Association.\n\nPeer-review started: May 26, 2020\n\nFirst decision: September 14, 2020\n\nArticle in press: September 26, 2020\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): 0\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Gonzalez-Granado L S-Editor: Zhang H L-Editor: Wang TQ P-Editor: Liu JH\n==== Refs\n1 Fanconi G Bickel H [Chronic aminoaciduria (amino acid diabetes or nephrotic-glucosuric dwarfism) in glycogen storage and cystine disease] Helv Paediatr Acta 1949 4 359 396 15397919 \n2 Santer R Schneppenheim R Dombrowski A Götze H Steinmann B Schaub J Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome Nat Genet 1997 17 324 326 9354798 \n3 Mohandas Nair K Sakamoto O Jagadeesh S Nampoothiri S Fanconi-Bickel syndrome Indian J Pediatr 2012 79 112 114 21327337 \n4 Sakamoto O Ogawa E Ohura T Igarashi Y Matsubara Y Narisawa K Iinuma K Mutation analysis of the GLUT2 gene in patients with Fanconi-Bickel syndrome Pediatr Res 2000 48 586 589 11044475 \n5 Al-Haggar M Sakamoto O Shaltout A El-Hawary A Wahba Y Abdel-Hadi D Fanconi Bickel Syndrome: Novel Mutations in GLUT 2 Gene Causing a Distinguished Form of Renal Tubular Acidosis in Two Unrelated Egyptian Families Case Rep Nephrol 2011 2011 754369 24533196 \n6 Abbasi F Azizi F Javaheri M Mosallanejad A Ebrahim-Habibi A Ghafouri-Fard S Segregation of a novel homozygous 6 nucleotide deletion in GLUT2 gene in a Fanconi-Bickel syndrome family Gene 2015 557 103 105 25523092 \n7 Su Z Du ML Chen HS Chen QL Yu CS Mal HM Two cases of Fanconi-Bickel syndrome: first report from China with novel mutations of SLC2A2 gene J Pediatr Endocrinol Metab 2011 24 749 753 22145468 \n8 Al-Haggar M Fanconi-Bickel syndrome as an example of marked allelic heterogeneity World J Nephrol 2012 1 63 68 24175243 \n9 Kehar M Bijarnia S Ellard S Houghton J Saxena R Verma IC Wadhwa N Fanconi-Bickel syndrome - mutation in SLC2A2 gene Indian J Pediatr 2014 81 1237 1239 24912437 \n10 Şeker-Yılmaz B Kör D Bulut FD Yüksel B Karabay-Bayazıt A Topaloğlu AK Ceylaner G Önenli-Mungan N Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations Turk J Pediatr 2017 59 434 441 29624224 \n11 Shah R Rao S Parikh R Sophia T Khalid H Fanconi Bickel Syndrome with Hypercalciuria due to GLUT 2 Mutation Indian Pediatr 2016 53 829 830 27771652 \n12 Amita M Srivastava P Mandal K De S Phadke SR Fanconi-Bickel Syndrome: Another Novel Mutation in SLC2A2 Indian J Pediatr 2017 84 236 237 27738794 \n13 Wang S Wang T Zhang W Liu X Wang X Wang H He X Zhang S Xu S Yu Y Jia X Wang M Xu A Ma W Amin MM Bialek SR Dollard SC Wang C Cohort study on maternal cytomegalovirus seroprevalence and prevalence and clinical manifestations of congenital infection in China Medicine (Baltimore) 2017 96 e6007 28151899 \n14 Riva S Ghisalberti C Parini R Furlan F Bettinelli A Somaschini M The Fanconi-Bickel syndrome: a case of neonatal onset J Perinatol 2004 24 322 323 15116130 \n15 Bahíllo-Curieses MP Garrote-Molpeceres R Miñambres-Rodríguez M Del Real-Llorente MR Tobar-Mideros C Rellán-Rodríguez S Glycosuria and hyperglycemia in the neonatal period as the first clinical sign of Fanconi-Bickel syndrome Pediatr Diabetes 2018 19 180 183 28493372 \n16 Santer R Groth S Kinner M Dombrowski A Berry GT Brodehl J Leonard JV Moses S Norgren S Skovby F Schneppenheim R Steinmann B Schaub J The mutation spectrum of the facilitative glucose transporter gene SLC2A2 (GLUT2) in patients with Fanconi-Bickel syndrome Hum Genet 2002 110 21 29 11810292 \n17 Mihout F Devuyst O Bensman A Brocheriou I Ridel C Wagner CA Mohebbi N Boffa JJ Plaisier E Ronco P Acute metabolic acidosis in a GLUT2-deficient patient with Fanconi-Bickel syndrome: new pathophysiology insights Nephrol Dial Transplant 2014 29 Suppl 4 iv113 iv116 25165176 \n18 Pogoriler J O'Neill AF Voss SD Shamberger RC Perez-Atayde AR Hepatocellular Carcinoma in Fanconi-Bickel Syndrome Pediatr Dev Pathol 2018 21 84 90 28382841 \n19 Fridman E Zeharia A Markus-Eidlitz T Haimi Cohen Y Phenotypic variability in patients with fanconi-bickel syndrome with identical mutations JIMD Rep 2015 15 95 104 24718840 \n20 Dweikat IM Alawneh IS Bahar SF Sultan MI Fanconi-Bickel syndrome in two Palestinian children: marked phenotypic variability with identical mutation BMC Res Notes 2016 9 387 27487919 \n21 Enogieru OJ Ung PMU Yee SW Schlessinger A Giacomini KM Functional and structural analysis of rare SLC2A2 variants associated with Fanconi-Bickel syndrome and metabolic traits Hum Mutat 2019 40 983 995 30950137 \n22 Berry GT Baker L Kaplan FS Witzleben CL Diabetes-like renal glomerular disease in Fanconi-Bickel syndrome Pediatr Nephrol 1995 9 287 291 7632512 \n23 Karamizadeh Z Saki F Imanieh MH Zahmatkeshan M Fardaee M A new mutation of Fanconi-Bickel syndrome with liver failure and pseudotumour cerebri J Genet 2012 91 359 361 23271022 \n24 Lee PJ Van't Hoff WG Leonard JV Catch-up growth in Fanconi-Bickel syndrome with uncooked cornstarch J Inherit Metab Dis 1995 18 153 156 7564233 \n25 Pennisi A Maranda B Benoist JF Baudouin V Rigal O Pichard S Santer R Romana Lepri F Novelli A Ogier de Baulny H Dionisi-Vici C Schiff M Nocturnal enteral nutrition is therapeutic for growth failure in Fanconi-Bickel syndrome J Inherit Metab Dis 2020 43 540 548 31816104 \n26 Pena L Charrow J Fanconi-Bickel syndrome: report of life history and successful pregnancy in an affected patient Am J Med Genet A 2011 155A 415 417 21271664 \n27 Wang W Wei M Song HM Qiu ZQ Zhang LJ Li Z Tang XY [SLC2A2 gene analysis in three Chinese children with Fanconi-Bickel syndrome] Zhongguo Dang Dai Er Ke Za Zhi 2015 17 362 366 25919556 \n28 Dai YE Liu QQ Shi X Gu W Ni SN Case report of Fanconi-Bickel syndrome and its clinical feature. Annual Congress of Pediatric Society; Zhejiang, China. 2012: 408 \n29 Su Z Li YH Du ML Ma HM Zheng PM Clinical characteristics of children with fanconi-bickel syndrome J Sun Yat-Sen Univ (Med Sci) 2011 32 557 560 \n30 Zhao ZH Luo FH Shen SX Zhi DJ Ye R Lu Z Xi L Cheng RQ Zheng ZQ Zhang MY Li XJ Chen LQ A case of glycogen storage disease XI presented neonate onset diabetes mellitus. 16th National Congress of Chinese Medical Association, Diabetes Society; Zhejiang, China. 2012: 172-173 \n31 Shi PP Wang M Dou WJ [Fanconi-Bickel syndrome with SLC2A2 gene mutation in a child] Zhonghua Er Ke Za Zhi 2018 56 65 66 29343004\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "8(21)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Children; Chinese; Fanconi–Bickel syndrome; Glucose transporter protein 2",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "5467-5473",
"pmc": null,
"pmid": "33269285",
"pubdate": "2020-11-06",
"publication_types": "D002363:Case Reports",
"references": "15116130;7632512;25165176;29624224;31816104;24912437;27738794;15397919;25523092;28382841;24533196;29343004;28151899;27771652;27487919;7564233;9354798;21271664;28493372;25919556;23271022;11044475;30950137;24718840;22145468;21327337;24175243;11810292",
"title": "Fanconi-Bickel syndrome in an infant with cytomegalovirus infection: A case report and review of the literature.",
"title_normalized": "fanconi bickel syndrome in an infant with cytomegalovirus infection a case report and review of the literature"
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"abstract": "The most common osseous metastatic regions for colorectal cancer are the lumbar and sacral vertebrae and the pelvis. There are few reported cases of isolated solitary tibial metastasis, and simultaneous bilateral solitary tibial metastases in colorectal cancer are even rarer. A 62-year-old female patient was admitted to our inpatient clinic 3 years after receiving initial chemotherapy for a rectosigmoid adenocarcinoma with liver metastasis. The patient complained of left leg pain. Radiographs and magnetic resonance imaging revealed a 3- × 3-cm mass in the right proximal tibia and a 2- × 7-cm mass in the middle third of the left tibia; both were highly suggestive of bone metastases. Bilateral tibial metastases were confirmed after tumor excision and prophylactic open reduction and internal fixation. The postoperative course was relatively uneventful. Colorectal cancer with bone metastases is uncommon, and most metastases are found at a single site in an extremity. We believe this is the first published case of simultaneous bilateral tibial metastases in a patient with colorectal cancer.",
"affiliations": "Department of Orthopedic Surgery, 46608Far Eastern Memorial Hospital, Far Eastern Memorial Hospital, New Taipei City.;Department of Orthopedic Surgery, 46608Far Eastern Memorial Hospital, Far Eastern Memorial Hospital, New Taipei City.",
"authors": "Hsu|Ta Li|TL|https://orcid.org/0000-0002-3662-4910;Wu|Karl|K|https://orcid.org/0000-0003-2193-3451",
"chemical_list": null,
"country": "England",
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"doi": "10.1177/03000605211027773",
"fulltext": "\n==== Front\nJ Int Med Res\nJ Int Med Res\nIMR\nspimr\nThe Journal of International Medical Research\n0300-0605\n1473-2300\nSAGE Publications Sage UK: London, England\n\n34308691\n10.1177/03000605211027773\n10.1177_03000605211027773\nCase Reports\nColorectal cancer with first known case of simultaneous bilateral tibial metastases\nhttps://orcid.org/0000-0002-3662-4910\nHsu Ta Li\nhttps://orcid.org/0000-0003-2193-3451\nWu Karl\nDepartment of Orthopedic Surgery, 46608 Far Eastern Memorial Hospital , Far Eastern Memorial Hospital, New Taipei City\nKarl Wu, Department of Orthopaedic Surgery, Far Eastern Memorial Hospital, No. 21, Sec. 2, Nanya S. Rd., Banciao Dist., New Taipei City 220. Email: kevinwooo@gmail.com\n25 7 2021\n7 2021\n49 7 0300060521102777326 2 2021\n4 6 2021\n© The Author(s) 2021\n2021\nSAGE Publications\nhttps://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nThe most common osseous metastatic regions for colorectal cancer are the lumbar and sacral vertebrae and the pelvis. There are few reported cases of isolated solitary tibial metastasis, and simultaneous bilateral solitary tibial metastases in colorectal cancer are even rarer. A 62-year-old female patient was admitted to our inpatient clinic 3 years after receiving initial chemotherapy for a rectosigmoid adenocarcinoma with liver metastasis. The patient complained of left leg pain. Radiographs and magnetic resonance imaging revealed a 3- × 3-cm mass in the right proximal tibia and a 2- × 7-cm mass in the middle third of the left tibia; both were highly suggestive of bone metastases. Bilateral tibial metastases were confirmed after tumor excision and prophylactic open reduction and internal fixation. The postoperative course was relatively uneventful. Colorectal cancer with bone metastases is uncommon, and most metastases are found at a single site in an extremity. We believe this is the first published case of simultaneous bilateral tibial metastases in a patient with colorectal cancer.\n\nColorectal carcinoma\nosseous metastasis\nBatson's plexus\nbone scan\ntibia\nchemotherapy\ntypesetterts2\n==== Body\nIntroduction\n\nColorectal cancer is a major public health burden and the third leading cause of cancer-associated deaths worldwide. 1 Organs, such as the liver and lungs, are the most common sites of distant metastases. Patients with bone metastases have a poor prognosis, with a median survival of <10 months.2,3 The incidence of osseous metastases from colorectal cancer is reportedly between 4.7% and 10.9% in clinical cases. In autopsy case series, incidence rates of 10.7% to 23.7% were observed.1,2,4–7\n\nConsidering the anatomical proximity of the colon to the paravertebral venous plexuses, the most common bone metastatic regions are the lumbar and sacral vertebrae, and the pelvis. 4 There are few reported cases of isolated solitary tibial metastasis,2,4,7 and simultaneous bilateral solitary tibial metastases in colorectal cancer are even rarer. To the best of our knowledge, this patient is the first reported case of simultaneous bilateral solitary tibial metastases of colorectal cancer.\n\nCase report\n\nIn April 2015, a 62-year-old woman was admitted to our inpatient clinic with a suspected rectosigmoid adenocarcinoma with liver metastasis. The patient underwent low-anterior resection and liver tumor resection. Pathological examination confirmed pT4bN2bM1a, stage IVa cancer, and 12 cycles of Avastin-FOLFIRI adjuvant chemotherapy (bevacizumab, leucovorin-calcium, fluorouracil, irinotecan hydrochloride) were administered, followed by the leucovorin, fluorouracil and oxaliplatin (FOLFOX) 7 regimen for tumor recurrence 1 month later. The patient tolerated chemotherapy well and was asymptomatic until July 2018, when she came to our clinic with a chief complaint of left leg pain that was aggravated by standing or walking. Mild limited range of motion owing to dull pain was also reported. No traumatic event was mentioned. Radiography showed cortical erosion with periosteal reaction in the left tibial shaft, which was highly suggestive of tumor involvement (Figure 1).\n\nFigure 1. Preoperative radiographs. The left tibial shaft has cortical erosion with periosteal reaction (1.5 × 6 cm) (white arrow). (a) anterior-posterior view; (b) lateral view.\n\nMagnetic resonance imaging of the legs illustrated a 3- × 3-cm mass located in the right proximal tibia and a 2- × 7-cm mass in the middle third of the left tibia; both were highly suggestive of bone metastases (Figure 2). Although preoperative positron emission tomography-computed tomography (PET-CT) was ordered, the examination was not completed because of the patient’s concern about the amount of radiation and because her health insurance did not totally cover the examination fee. The preoperative Eastern Cooperative Oncology Group (ECOG) performance status was grade one, and estimated survival was approximately 8 months in unselected patients after diagnosis of bone metastases in colorectal cancer, with a 5.7% 5-year survival rate. 8 , 9 Therefore, the main concern was intolerable pain under the maximum pain medication dose. Owing to the relatively high risk of sustaining a pathological fracture according to Mirels’ scoring system, 10 prophylactic internal fixation was indicated and performed.\n\nFigure 2. Bilateral lower limb magnetic resonance imaging. (a) T1-weighted turbo spin echo image showing a 3- × 3-cm mass located in the right proximal tibia and a 2- × 7-cm mass in the left middle third of the tibia; both masses were highly suspicious for bone metastases (white arrow). (b) Right leg T2-weighted short-tau inversion recovery (STIR) image showing a tumor-like lesion in the proximal tibial bone marrow (white arrow). (c) Left leg T2 STIR image showing a tumor-like lesion in the tibial shaft bone marrow (white arrow).\n\nThe right leg tumor was surgically excised, and bone curettage was performed, with 95% alcohol irrigation. The bone defect was then grafted with bone cement. The right tibia was fixed with a lateral buttress plate, and the left tibia was fixed with an intramedullary nail (the right and left tibia were operated separately) (Figure 3). Whole-body technetium 99m bone scans were performed 3 weeks after the operation and showed uptake signals around the coccyx and bilateral tibia mixed with postoperative changes (Figure 4).\n\nFigure 3. Postoperative radiographs. We performed tumor excision accompanied by 95% alcohol irrigation and prophylactic internal fixation with a lateral buttress plate (8H6S) in the right tibia (a, b) and a prophylactic intramedullary nail in the left tibia (c, d) (the right and left tibia were operated separately).\n\nFigure 4. Whole-body bone technetium 99 m scans. Postoperative technetium 99 m scans showing uptake signals around the coccyx and bilateral tibia (black arrows). (a) anterior view; (b) posterior view.\n\nThe postoperative course was relatively uneventful, with right leg splinting and ambulation with partial weight-bearing. The preoperative left leg pain subsided, and the patient underwent early active range of motion exercises after immobilization with a left long leg splint for 3 weeks. Further adjuvant radiotherapy was scheduled. Pathology reports for both legs indicated metastatic adenocarcinoma of colorectal origin. The bilateral tibial pathological results are presented in Figure 5.\n\nFigure 5. Right tibial pathological and immunohistochemical analysis of the biopsy specimen. (a) Microscopically, the sections show metastatic carcinoma composed of hyperchromatic columnar cells with intracellular mucin infiltrating the bone marrow spaces in a complex glandular pattern (scale bar: 100 mm). (b) Immunohistochemically, the neoplastic cells stained positive for cytokeratin (CK)20, and negative for CK7, estrogen receptor (ER), and thyroid transcription factor-1 (TTF-1) (scale bar: 100 mm). (c) Left tibia pathological and immunohistochemical analysis of the biopsy specimen. Microscopically, metastatic adenocarcinoma in a glandular pattern and focal mucin production are seen (scale bar: 100 mm).\n\nDiscussion\n\nBone metastases occur frequently in patients with breast, prostate, multiple myeloma, and lung cancer. Osseous metastases are much less frequent in colorectal cancer cases. 4 Colorectal cancer commonly metastasizes to the liver (>70%), lungs (20%–30%), and peritoneum. In contrast, bone metastasis is uncommon (4.7%–10.9% in clinical cases) and often indicates advanced disease with a poor prognosis (5-year survival rate <5%). 11 Pathologic detection of signet-ring cells appears to be associated with a high incidence of bone metastases. 12\n\nThe first reported case of solitary tibial metastasis in a patient with colon cancer was published by Kose in 2009. 4 One study by Kanthan et al., 13 using bone scans and plain radiography, retrospectively reviewed 5352 cases of primary colorectal carcinoma and found a very low incidence (1.1%) of isolated solitary skeletal metastases.\n\nMetastatic colorectal cancer is usually osteolytic or mixed osteolytic/osteoblastic. 14 The tumor may be deposited on cortical or cancellous bone. 3 Clinically, in the early stages, patients are sometimes asymptomatic. However, bone metastases can lead to widespread symptoms, such as pain (usually unrelieved with nonsteroidal anti-inflammatory drugs), 15 nerve compression, and even pathological fractures. The most commonly involved metastatic bony sites are the spine (65%), hip/pelvis (34%), long bones (26%), and other sites (17%).11,16 A valveless drainage system of veins named Batson's plexus is thought to be the most likely route of skeletal seeding because of the connection between the spinal veins around the lumbar region and the iliofemoral venous system. 17 Interestingly, irinotecan or oxaliplatin exposure during treatment is thought to be associated with an increased incidence of osseous metastases. 12 Some authors believe that the increasing incidence associated with irinotecan or oxaliplatin exposure was correlated with the improved survival rate of patients who received irinotecan or oxaliplatin for metastatic colorectal carcinoma treatement. 4 Additionally, improved radiological and PET scan equipment were considered important for increased early detection. 3 In our case, the patient had received several cycles of irinotecan therapy.\n\nBone scan is considered the most effective method for early detection of occult osseous metastases 1 because some bone metastases are asymptomatic in the early stages. In a retrospective study, Santini et al., 2 reported an average duration of 11 months between making a diagnosis of primary colorectal cancer and detecting osseous metastases.\n\nOur case is classified as metachronous bone metastasis because bone metastasis was detected 3 years after the initial diagnosis of colorectal cancer. Owing to a poor 5-year prognosis and survival of approximately 8 months in unselected patients after a diagnosis of bone metastases in colorectal cancer, 9 our case stresses relieving intolerable pain and providing a return to bilateral lower limb function to support daily activities and improve quality of life, as first considerations.\n\nPreoperative potential bone reconstruction strategies for the middle tibial shaft include bone allograft transplantation and a custom prosthesis. Bone allograft transplantation may be considered if the lesion site has marked unreducible cortical destruction resulting in unstable bridging length by plating or nailing intraoperatively. A custom prosthesis can be considered if a pathological fracture extends to the joint line and the fracture is non-reducible after tumor excision. Our patient underwent plating and interlocking nail after tumor excision because the bone defect was controlled, with no shortening or rotation deformity after tumor excision. Unfortunately, the patient died owing to multiorgan failure without bilateral tibial bone pain complaints 1.5 years after the operation.\n\nColorectal cancer with bone metastasis is uncommon (4.7%), and most cases are found at a single site in an extremity. Simultaneous bilateral tibial metastases, as presented in our case, are extremely rare. Early detection of bone metastases significantly improves prognosis; thus, routine bone scan screening is suggested in patients with advanced colorectal cancer.\n\nSupplemental Material\n\nsj-pdf-1-imr-10.1177_03000605211027773 - Supplemental material for Colorectal cancer with first known case of simultaneous bilateral tibial metastases\n\nClick here for additional data file.\n\nSupplemental material, sj-pdf-1-imr-10.1177_03000605211027773 for Colorectal cancer with first known case of simultaneous bilateral tibial metastases by Ta Li Hsu and Karl Wu in Journal of International Medical Research\n\nAcknowledgment\n\nWe greatly thank all the members of FEMH Orthopaedic Department of Surgery.\n\nEthics statement: The Research Ethics Review Committee of the Far Eastern Memorial Hospital waives the requirement for ethical approval of case reports. We obtained verbal informed consent from the patient, and she confirmed that she understood that her diagnosis, data, and treatment course were being collected for publication. Additionally, we completely deidentified all patient details, and this case report conforms to the CARE guidelines. 17 Written informed consent was obtained from the patient for the publication of this case report and the associated images.\n\nAvailability of data and materials: All data associated with the case are presented in the manuscript.\n\nDeclaration of conflicting interest: The authors declare that there is no conflict of interest.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iDs: Ta Li Hsu https://orcid.org/0000-0002-3662-4910\n\nKarl Wu https://orcid.org/0000-0003-2193-3451\n==== Refs\nReferences\n\n1 Rodrigues J Ramani A Mitta N , et al . A rare case of colon cancer with metastases to the bone with review of the literature. Internet J Oncol 2012; 8 : 1–5.\n2 Santini D Tampellini M Vincenzi B , et al . Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study. Ann Oncol 2012; 23 : 2072–2077.22219016\n3 Assi R Mukherji D Haydar A , et al . Metastatic colorectal cancer presenting with bone marrow metastasis: a case series and review of literature. J Gastrointest Oncol 2016; 7 : 284–297.27034798\n4 Kose F Sakalli H Sezer A , et al . Colon adenocarcinoma and solitary tibia metastasis: rare entity. J Gastrointest Cancer 2008; 39 : 146–148.19241183\n5 Katoh M Unakami M Hara M , et al . Bone metastasis from colorectal cancer in autopsy cases. J Gastroenterol 1995; 30 : 615–618.8574333\n6 Vatandoust S Price TJ Karapetis CS. Colorectal cancer: metastases to a single organ. World J Gastroenterol 2015; 21 : 11767–11776.26557001\n7 Alnajjar A Kumar Mohanty A. Solitary bone metastasis to the tibia from colorectal cancer- a case report. Int J Cancer Ther Oncol 2014; 2 : 02045.\n8 Baek SJ Hur H Min BS , et al . The characteristics of bone metastasis in patients with colorectal cancer: a long-term report from a single institution. World J Surg 2015; 40 : 982–986.\n9 Christensen TD Jensen SG Larsen FO , et al . Systematic review: incidence, risk factors, survival and treatment of bone metastases from colorectal cancer. J Bone Oncol 2018; 13 : 97–105.30591863\n10 Mirels H. Metastatic disease in long bones: a proposed scoring system for diagnosing impending pathologic fractures. 1989. Clin Orthop Relat Res 2003; 415 : S4–S13.\n11 Kawamura H Yamaguchi T Yano Y , et al . Characteristics and prognostic factors of bone metastasis in patients with colorectal cancer. Dis Colon Rectum 2018; 61 : 673–678.29722726\n12 Sundermeyer ML Meropol NJ Rogatko A , et al . Changing patterns of bone and brain metastases in patients with colorectal cancer. Clin Colorectal Cancer 2005; 5 : 108–113.16098251\n13 Kanthan R Loewy J Kanthan SC. Skeletal metastases in colorectal carcinomas: a Saskatchewan profile. Dis Colon Rectum 1999; 42 : 1592–1597.10613479\n14 Pakos EE Gartzonikas DN Tsekeris PG , et al . Solitary tibial osteolytic lesion. Case Rep Med 2009; 2009 : 352085.19718252\n15 Zihua Z. Retrospective study of predictors of bone metastasis in colorectal cancer patients. J Bone Oncol 2017; 9 : 25–28.29234589\n16 Libson E Bloom RA Husband JE , et al . Metastatic tumours of bones of the hand and foot. Skeletal Radiol 1987; 16 : 387–392.3306939\n17 Gagnier JJ Kienle G Altman DG , et al ; CARE Group. The CARE guidelines: consensus-based clinical case reporting guideline development. Headache. 2013 Nov-Dec; 53 (10 ): 1541-–1547.24266334\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0300-0605",
"issue": "49(7)",
"journal": "The Journal of international medical research",
"keywords": "Batson's plexus; Colorectal carcinoma; bone scan; chemotherapy; osseous metastasis; tibia",
"medline_ta": "J Int Med Res",
"mesh_terms": "D000230:Adenocarcinoma; D001859:Bone Neoplasms; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D012004:Rectal Neoplasms; D013977:Tibia",
"nlm_unique_id": "0346411",
"other_id": null,
"pages": "3000605211027773",
"pmc": null,
"pmid": "34308691",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "22219016;8574333;19241183;26557001;19718252;27034798;3306939;30591863;29234589;16098251;26541868;29722726;10613479;24266334;14600587",
"title": "Colorectal cancer with first known case of simultaneous bilateral tibial metastases.",
"title_normalized": "colorectal cancer with first known case of simultaneous bilateral tibial metastases"
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"abstract": "BACKGROUND\nAcyclovir (ACV)-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, an ACV metabolite, and is often reported in patients with renal dysfunction. We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral administration of valacyclovir (VACV) and review literature of previous ACV-associated encephalopathy cases.\nAn 88-year-old man was diagnosed with herpes zoster. VACV (3000 mg/day) treatment was initiated. Serum creatinine (Cr) level was 0.80 mg/dL. However, irritability, memory impairment, and decreased responsiveness occurred after 3 days. The Cr level was 6.76 mg/dL on admission.\n\n\nMETHODS\nHe was diagnosed with ACV-associated encephalopathy with acute kidney injury.\n\n\nMETHODS\nVACV was discontinued, hemodialysis was initiated on the day of admission, and then the signs and symptoms improved approximately 72 hours after the admission.\n\n\nCONCLUSIONS\nWorsening of renal function and encephalopathy should be a focus when using VACV or ACV, regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary during VACV treatment.",
"affiliations": "Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba.;Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba.",
"authors": "Kenzaka|Tsuneaki|T|0000-0002-3120-6605;Sugimoto|Kazuma|K|;Goda|Ken|K|;Akita|Hozuka|H|",
"chemical_list": "D000998:Antiviral Agents; D006147:Guanine; D003404:Creatinine; D000077483:Valacyclovir; C035400:9-carboxymethoxymethylguanine",
"country": "United States",
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"doi": "10.1097/MD.0000000000026147",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974\n1536-5964\nLippincott Williams & Wilkins Hagerstown, MD\n\n34032768\nMD-D-21-01167\n10.1097/MD.0000000000026147\n26147\n4900\nResearch Article\nClinical Case Report\nAcute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function\nA case report and literature review\nKenzaka Tsuneaki MD, PhD ab∗\nSugimoto Kazuma MD a\nGoda Ken MD ab\nAkita Hozuka MD, PhD a\nSaranathan. Maya\na Department of Internal Medicine, Hyogo Prefectural Tamba Medical Center, Tamba\nb Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, Kobe, Japan.\n∗ Correspondence: Tsuneaki Kenzaka, Division of Community Medicine and Career Development, Kobe University Graduate School of Medicine, 2-1-5, Arata-cho, Hyogo-ku, Kobe 652-0032, Hyogo, Japan (e-mail: smile.kenzaka@jichi.ac.jp).\n28 5 2021\n28 5 2021\n100 21 e2614711 2 2021\n29 4 2021\n11 5 2021\nCopyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This 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/4.0\n\nAbstract\n\nIntroduction:\n\nAcyclovir (ACV)-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, an ACV metabolite, and is often reported in patients with renal dysfunction. We report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral administration of valacyclovir (VACV) and review literature of previous ACV-associated encephalopathy cases.\n\nPatient concerns:\n\nAn 88-year-old man was diagnosed with herpes zoster. VACV (3000 mg/day) treatment was initiated. Serum creatinine (Cr) level was 0.80 mg/dL. However, irritability, memory impairment, and decreased responsiveness occurred after 3 days. The Cr level was 6.76 mg/dL on admission.\n\nDiagnosis:\n\nHe was diagnosed with ACV-associated encephalopathy with acute kidney injury.\n\nInterventions:\n\nVACV was discontinued, hemodialysis was initiated on the day of admission, and then the signs and symptoms improved approximately 72 hours after the admission.\n\nConclusion:\n\nWorsening of renal function and encephalopathy should be a focus when using VACV or ACV, regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary during VACV treatment.\n\nKeywords\n\nacute kidney injury\nacyclovir neurotoxicity\ncase report\nherpes zoster\nvalacyclovir\nOPEN-ACCESSTRUE\n==== Body\n1 Introduction\n\nAcyclovir (ACV) associated encephalopathy is a very rare case induced by ACV and valacyclovir (VACV), a prodrug of ACV.[1] Rashiq et al reported that several neuropsychiatric symptoms, such as consciousness disturbance, tremor, and myoclonus, usually occur within 2 days of administering VACV.[1] Hallucination frequently occurs in addition to consciousness disturbance and involuntary movements.[1–3] However, headache, fever, convulsions, and focal symptoms are rare.[2] Abnormalities in cerebrospinal fluid examinations or head computed tomography (CT)/magnetic resonance imaging are generally not observed, and symptoms disappear 48 to 72 hours after discontinuing ACV. However, dialysis may be necessary.[4]\n\nACV-associated encephalopathy is related to an increase in plasma levels of 9-carboxymethoxymethylguanine, a metabolite of ACV, and is often reported in patients with renal dysfunction.[5] However, there are few reports of the onset of ACV-associated encephalopathy in patients in whom renal dysfunction was not indicated.[4] Here, we report a case of ACV-associated encephalopathy with the rapid progression of renal dysfunction after oral VACV administration, although serum creatinine (Cr) levels were normal. In addition, we report a review of previous ACV-associated encephalopathy cases.\n\n2 Case report\n\nAn 88-year-old man who could independently perform activities of daily living visited the hospital with a primary complaint of consciousness disturbance. The patient had a history of radical resection for prostate cancer (T1c N0 M0, stage I). His history of varicella-zoster infection was unknown. A painful vesicular eruption appeared in the right axilla 8 days before admission, and he visited a nearby clinic the following day. The Cr level was 0.80 mg/dL. He was consequently diagnosed with herpes zoster. Thus, VACV administration (3000 mg/d) was initiated. Pregabalin (75 mg/d) and mecobalamin (1500 μg/d) were also administered for analgesic purposes without the concomitant use of nonsteroidal anti-inflammatory drugs. The patient experienced pain that led to reduced food intake and dehydration. He urinated about 4 times daily. Also, irritability, memory impairment, and decreased responsiveness occurred after 3 days, and the patient was admitted to our hospital for emergency treatment due to exacerbated symptoms.\n\nPhysical findings on admission were as follows: E3V3M6 on the Glasgow Coma Scale, body temperature of 35°C, blood pressure of 110/60 mm Hg, pulse rate of 60 beats/min, respiratory rate of 20 breaths/min, and oxygen saturation level of 96% (room air). The patient had xerostomia. Herpes zoster scarring on the right upper limb (TH-1/TH-2 areas) was noted in the extremities. Furthermore, examination of meningeal irritation symptoms showed no neck stiffness, negative Kernig sign, and negative Brudzinski sign. The diameter/light reflex of the pupils was 2+/2+. Myoclonus was observed with no clear paralysis. Hematologic examination results were as follows: white blood cell, 6530/μL; C-reactive protein, 1.07 mg/dL; blood urea nitrogen, 58.4 mg/dL; Cr, 6.76 mg/dL; and blood glucose, 91 mg/dL (Table 1). The urine sediment showed muddy brown casts of epithelial cells, indicating acute tubular necrosis. Cerebrospinal fluid test results revealed an initial pressure of 13 cm H2O, cell count of 71/μL (mononuclear cell count, 70/μL), protein level of 147 mg/dL, and glucose level of 48 mg/dL (Table 2). However, blood, urine, and cerebrospinal fluid cultures were negative.\n\nTable 1 Laboratory data on admission.\n\nParameter\tRecorded value\tStandard value\t\nWhite blood cell count\t6530/μL\t4500–7500/μL\t\nNeutrophils\t68%\t42%–74%\t\nHemoglobin\t11.7 g/dL\t11.3–15.2 g/dL\t\nHematocrit\t34.2%\t36%–45%\t\nPlatelet count\t17.0 × 104/μL\t13–35 × 104/μL\t\nInternational normalized ratio\t0.93\t0.80–1.20\t\nActivated partial thromboplastin time\t23.3 s\t26.9–38.1 s\t\nFibrin degradation products\t10.4 μg/mL\t2.0–8.0 μg/mL\t\nC-reactive protein\t1.07 mg/dL\t<0.14 mg/dL\t\nEstimated glomerular filtration rate\t6.6\t\t\nTotal protein\t6.6 g/dL\t6.9–8.4 g/dL\t\nAlbumin\t3.5 g/dL\t3.9–5.1 g/dL\t\nTotal bilirubin\t0.3 mg/dL\t0.2–1.2 mg/dL\t\nAspartate aminotransferase\t25 U/L\t11–30 U/L\t\nAlanine aminotransferase\t8 U/L\t4–30 U/L\t\nLactate dehydrogenase\t227 U/L\t109–216 U/L\t\nCreatine phosphokinase\t252 U/L\t40–150 U/L\t\nBlood urea nitrogen\t58.4 mg/dL\t8–20 mg/dL\t\nCreatinine\t6.76 mg/dL\t0.63–1.03 mg/dL\t\nSodium\t130 mEq/L\t136–148 mEq/L\t\nPotassium\t6.4 mEq/L\t3.6–5.0 mEq/L\t\nGlucose\t91 mg/dL\t70–109 mg/dL\t\nHemoglobin A1c\t5.4%\t<6.5%\t\nThyroid-stimulating hormone\t3.022 IU/mL\t0.541–4.261 μIU/mL\t\nFree thyroxine\t0.9 ng/dL\t0.72–1.51 ng/dL\t\nAmmonia\t35 g/dL\t12–66 g/dL\t\nACV\t34.6 g/mL\t\t\npH\t7.359\t7.350–7.450\t\nPartial pressure of arterial carbon dioxide\t37.3 mm Hg\t35–45 mm Hg\t\nPartial pressure of arterial oxygen\t88.6 mm Hg\t80–100 mm Hg\t\nBicarbonate\t21.6 mEq/L\t22–26 mEq/L\t\nLactate\t1.26 mmol/L\t<2.0 mmol/L\t\n\nTable 2 Results of cerebrospinal fluid tests on admission.\n\nParameter\tRecorded value\tStandard value\t\nCell count\t71/μL\t0–5/μL\t\nMononuclear count\t70/μL\t\t\nPolynuclear count\t1/μL\t\t\nTotal protein\t147 mg/dL\t10–40 mg/dL\t\nGlucose\t48 mg/dL\t50–75 mg/dL\t\nLactate dehydrogenase\t39 IU/L\t0–25 IU/L\t\nCreatine phosphokinase\t3 IU/L\t<6 IU/L\t\nHSV DNA PCR\tNegative\t\t\nVZV DNA PCR\tNegative\t\t\n\nThe hemodynamics were maintained, but ultrasound showed that the inferior vena cava collapsed, suggesting dehydration. Abdominal CT revealed no obstruction, and postrenal renal failure was ruled out. The maximum diameter of the kidney was 62 mm on the right and 65 mm on the left, and there was no prominent renal swelling. However, urinary retention of about 250 mL in the bladder was observed. Moreover, head magnetic resonance imaging did not reveal any findings suggestive of encephalitis.\n\nTable 3 shows the comparison of ACV-associated encephalopathy and varicella zoster virus encephalitis.[6,7] Our elderly patient had taken VACV for a sufficient period and was thus suspected to have ACV-associated encephalopathy based on the absence of fever, stiff neck, and headache, and normal imaging findings. The clinical course is shown in Fig. 1. VACV was discontinued, hemodialysis was initiated from the day of admission to day 3, and then the signs and symptoms improved approximately 72 hours after the admission. The Glasgow Coma Scale score was 14 points, and hemodialysis was discontinued on hospital day 4. The plasma concentration of ACV level at the time of examination, which was discovered later, was markedly elevated (34.6 μg/mL), and results of polymerase chain reaction analysis of the cerebrospinal fluid were negative for herpes simplex virus and varicella zoster virus DNA. The plasma concentration of ACV level was <0.5 μg/mL (normal range <2.0) when the consciousness level became normal on day 10 of hospitalization. Negative blood, urine, and cerebrospinal fluid cultures ruled out bacterial consciousness disorder. Furthermore, the consciousness level did not improve immediately after the dialysis on day 1; however, it improved after the dialysis was performed for 3 days. Therefore, the consciousness disorder due to uremia was ruled out. Thus, a definitive diagnosis of ACV-associated encephalopathy was made based on the patient's course. The increase in cell count in the cerebrospinal fluid could have been due to the effects of ACV-associated encephalopathy, although this finding was atypical.\n\nTable 3 Differences between acyclovir-associated encephalopathy and varicella zoster virus encephalitis.\n\n\tACV-associated encephalopathy\tVZV encephalitis\t\nRisk factors\tACVElderlyNSAIDs\tImmunocompromisedCranial nerve dermatomePresence of cutaneous dissemination\t\nSymptoms\tRarely meningismus·fever·headache\tMeningismus·fever·headache\t\nCerebrospinal fluid\tNormal\tLymphocyte domination\t\nImaging studies\tNormal\tAbnormal (50%)\t\nTreatment\tACV discontinuedDialysis\tACV\t\nPrognosis\tImprove (within 48–72 h)\tMortality 0%–25%(Normal immunity)\t\n\nFigure 1 Clinical course.\n\nSubsequently, ambulatory discharge was possible on hospital day 35 without any sequelae.\n\n2.1 Search strategy\n\nThe terms “acyclovir neurotoxicity” or “acyclovir encephalopathy” were searched in the MEDLINE database. Fifty-one cases have existed in the literature since 1988. Among those 51 cases, 35 reported acyclovir neurotoxicity when limited to the English and Japanese literature.\n\n3 Discussion\n\nWe report a case of ACV-associated encephalopathy with rapid progression of renal dysfunction after oral VACV administration despite normal serum Cr levels (0.80 mg/dL). The patient experienced pain that led to reduced food intake and dehydration. Moreover, the use of VACV, which has a high oral bioavailability and a long plasma half-life, caused renal dysfunction, leading to ACV-associated encephalopathy. Furthermore, as shown in Table 4, ACV-associated encephalopathy may occur even under normal renal function or prophylactic administration of antiviral drugs. ACV-associated encephalopathy is commonly observed in patients with impaired renal function but may develop even when renal function is normal.[1]\n\nTable 4 A summary of the literature review on ACV-associated encephalopathy cases.\n\nCase\tAuthor\tReference number\tAge\tSex\tCause\tMedication (dosing period, days)\tTotal dosing period (days)\tDosage (mg/day)\tComorbidity\tSerum acyclovir measurement\tDialysis treatment for underlying disease\tNormal Creatinine (mg/dL)\tOnset Creatinine (mg/dL)\tConcomitant drug\t\n1\tUmoru GO et al\t[9]\t57\tMan\tHerpes Zoster\tOral ACV (4)\t4\t4000 mg/d\themodialysis, type2 diabetes mellitus, hypertension, hyperlipidemia, coronary artery disease, congestive heart failure, shingles, and multiple incision and drainage procedures for bilateral recurrent abscesses in his thighs\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n2\tKawabe Matsukawa M et al\t[10]\t77\tMan\tHerpes Zoster\tOral ACV (2)\t2\t800 mg/d\tAngina after stenting, Hyperuricemia, Dyslipidemia, hypertension\tNo\tCAPD\t9∼10\t12.58\tUnknown\t\n3\tBełz A et al\t[11]\t86\tUnknown\tHerpetic simplex keratitis\tOral VACV (4)\t4\t800 mg/d\tchronic heart failure Class IINYHA (ejection fraction 40%), moderate mixed aortic valve disease, mild mitral and tricuspid insufficiency, paroxysmal atrial fibrillation, and type 2 diabetes mellitus\tNo\tHD\tUnknown\t8.48\tUnknown\t\n4\tIkuta K et al\t[12]\t27\tMan\tHerpes simplex virus–1\tintravenous ACV (6)→intravenous ACV (12)\t18\t30 mg/kg/d (6 days)→15 mg/kg/d\tHepatitis A infection, Hepatitis B infection\tYes\tNone\t1.4\tNone\tNone\t\n5\tPatel J et al\t[13]\t63\tMan\tHerpes Zoster\tOral ACV (5)\t5\t4000 mg/d\tAbscesses in his thighs\tNo\tNone\t1\t1.2\tUnknown\t\n6\tSadjadi SA et al\t[14]\t80\tMan\tHerpes Zoster\tintravenous ACV(2)→oral ACV(1)\t3\t5 mg/kg/d→200 mg/ds\tHypertension, congestive heart failure and end stage renal disease\tYes\tCAPD\tNone\tNone\tUnknown\t\n7\tGorlitsky BR et al\t[15]\t60\tMan\tHerpes simplex virus–2\tOral VACV (4)\t4\t800 mg/d\thypertensive nephrosclerosis and diabetes\tYes\tHD\tNone\t9.73\tUnknown\t\n8\tWatson WA et al\t[16]\t62\tMan\tHerpes Zoster\tOral VACV (14)→intravenous ACV (2)→intravenous ACV (6)\t16\tUnknown→Unknown→24.2 mg/kg\tGoodpasture syndrome complicated by end-stage renal disease requiring a living donor kidney transplant 11 years prior to presentation, chronic allograft glomerulopathy, and a recent diagnosis of collagenous colitis.\tNo\tNone\t1.2\t2.5\tUnknown\t\n9\tThind GS et al\t[17]\t82\tMan\tHerpes Zoster\tOral VACV (5)→intravenous ACV (6)\t11\t3000 mg/d→5 mg/kg\ttype 2 diabetes mellitus, a history of coronary artery disease, chronic atrial fibrillation, gastro-esophageal reflux disease and gout\tNo\tHD\tNone\tNone\tNone\t\n10\tChowdhury MA et al\t[5]\t69\tWoman\tHerpes simplex virus\tIntravenous ACV (1.5)\t1.5\t1500 mg/d\thypertension, diabetes, chronic obstructive pulmonary disease, and end-stage renal disease on hemodialysis was admitted with a diagnosis of pneumonia and right breast cellulitis\tYes\tHD\tNone\tNone\tNone\t\n11\tSacchetti D et al\t[4]\t69\tWoman\tHerpes zoster\tOral ACV (2)→intravenous ACV (1)→intravenous ACV (2)\t5\t800 mg/d→1500 mg/d→550 mg/d\tuncontrolled diabetes and asthma\tNo\tNone\tUnknown\t3.94\tNSAIDs\t\n12\tAdair JC et al\t[3]\t70\tWoman\tHerpes zoster\tOral ACV (2)\t2\t1400 mg/d\tGranulomatosis with polyangiitis\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n13\tAdair JC et al\t[3]\t64\tWoman\tHerpes simplex virus\tOral ACV (2)\t2\t600 mg/d\themolytic uremic syndrome\tNo\tHD\t8.8\tNone\tUnknown\t\n14\tTomori K et al\t[18]\t30\tWoman\tHerpes simplex virus\tintravenous ACV (2)\t2\t1000 mg/d\tNone\tNo\tNone\tUnknown\tUnknown\tUnknown\t\n15\tItoh M et al\t[19]\t7\tWoman\tHerpes simplex virus\tOral ACV (2)\t2\t1000 mg/d\tNone\tNo\tNone\tUnknown\t0.3\tUnknown\t\n16\tGómez Campderá FJ et al\t[20]\t59\tWoman\tHerpes zoster\tOral ACV (7)\t7\t200 mg/d\tsecondary to chronic interstitial nephropathy.\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n17\tHoskote SS et al\t[21]\t52\tMan\tHerpes zoster\tOral VACV (7)→oral ACV (2)→intravenous ACV (6)\t15\t3000 mg/d→1000 mg/d→600 mg/d\thypertension, diastolic congestive heart failure, end-stage renal disease on hemodialysis 3 times a week, hemorrhagic stroke\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n18\tSagawa N et al\t[22]\t83\tMan\tHerpes zoster\tOral VACV (5)\t5\t3000 mg/d\ttype 2 diabetes mellitus\tYes\tNone\t0.8\t5.11\tNSAIDs\t\n19\tStrong DK et al\t[23]\t5\tWoman\tEpstein-Barr virus-induced lymphoproliferative disease\tIntravenous ACV (2)→intravenous ACV (12)\t14\t920 mg/m2/d→460 mg/m2 3 times wk\tcadaveric renal transplant for end-stage renal failure due to cystinosis\tYes\tNone\tUnknown\tUnknown\tUnknown\t\n20\tBlohm ME et al\t[24]\t12\tWoman\tPrevention\tIntravenous ACV (8)→intravenous ACV (18)\t26\t30 mg/kg→20 mg/kg\tCML\tYes\tNone\t0.8\t1.7\tUnknown\t\n21\tPeces R et al\t[25]\t44\tMan\tHerpes zoster\tOral ACV (2)\t2\t4800 mg/d\tUnknown\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n22\tMesar I et al\t[26]\t78\tWoman\tHerpes zoster\tOral ACV (2)\t2\t4000 mg/d\tEndemic nephropathy, arterial hypertension, cardiovascular disease\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n23\tMesar I et al\t[26]\t61\tMan\tHerpes zoster\tACV (Unknown)\tUnknown\tUnknown\tExtracapillary glomerulonephritis, arterial hypertension\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n24\tMesar I et al\t[26]\t72\tWoman\tHerpes zoster\tOral VACV (4)\t3\t1600 mg/d\trenal amyloidosis, arterial hypertension, hypothyroidism\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n25\tAsahi T et al\t[2]\t78\tWoman\tHerpes zoster\tOral VACV (5)\t5\t3000 mg/d\tAlzheimer's disease\tNo\tNone\tUnknown\t3.2\tUnknown\t\n26\tAsahi T et al\t[2]\t73\tMan\tHerpes zoster\tOral ACV (2)\t2\t3000 mg/d\tchronic renal failure\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n27\tHussein MM et al\t[27]\t51\tMan\tAnti-CMV prophylaxis\tOral GCV (5)\t5\t1.25 mg/d every 48 h\tend-stage renal disease of uncertain etiology, diabetes mellitus\tNo\tHD\tUnknown\t10.45\tUnknown\t\n28\tYang HH et al\t[28]\t70\tMan\tHerpes zoster\tIntravenous ACV (1.5)\t1.5\t500 mg/d\trectal cancer status post-colostomy and end-stage renal disease\tYes\tHD\t5.7\t6.2\tUnknown\t\n29\tChevret L et al\t[29]\t0.5\tWoman\tPrevention\tIntravenous ACV (2)→intravenous ACV (1)\t3\t250 mg/m2→750 mg/m2\tAcute liver failure, related to neonatal enterovirus infection, occurred within a few days after birth, liver transplantation at 6 months of age\tYes\tNone\tUnknown\tUnknown\tUnknown\t\n30\tPeyrière H et al\t[30]\t13\tMan\tPrevention\tIntravenous GCV (14)+VGCV(Unknown)→oral ACV(2)→oral VGCV(Unknown)\t16\tUnknown→450 mg/d (every 2 d)→600 mg/d→450 mg/d (twice weekly)\tacute lymphoblastic leukemia\tYes\tNone\tUnknown\tUnknown\tUnknown\t\n31\tRajan GR et al\t[31]\t73\tMan\tHerpes simplex labialis\tIntravenous ACV (2)\t2\t400 mg/d\tamiodarone pulmonary toxicity, coronary artery bypass grafting, chronic atrial fibrillation, non-sustained ventricular tachycardia, and congestive heart failure\tYes\tNone\tUnknown\tUnknown\tUnknown\t\n32\tBeales P et al\t[32]\t51\tMan\tHerpes zoster\tOral ACV (1.5)\t1.5\t1600 mg/d\tend-stage renal failure due to IgA nephropathy, poor blood pressure control\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n33\tBeales P et al\t[32]\t56\tWoman\tHerpes zoster\tOral ACV (9)\t9\t1600 mg\tend-stage renal failure of uncertain cause, tuberculosis, lumbar osteomyelitis, and recurrent continuous ambulatory peritoneal dialysis peritonitis\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n34\tKrieble BF et al\t[33]\t77\tWoman\tHerpes zoster\tIntravenous ACV (2)\t2\t3000 mg/d\tNone\tYes\tNone\t1.09\t4.46\tNone\t\n35\tDavenport A et al\t[34]\t72\tWoman\tHerpes zoster\tOral ACV (1)→intravenous ACV (1)→intravenous+oral ACV (1)\t1\t800 mg/d→4 mg/kg/d→4 mg/kg/d+800 mg/d\tend-stage renal failure due to chronic pyelonephritis\tYes\tCAPD\tUnknown\tUnknown\tUnknown\t\n36\tDavenport A et al\t[34]\t41\tMan\tViral pneumonia\tOral ACV (5)\t5\t1600 mg/d\tend-stage renal failure secondary to focal glomerular sclerosis\tYes\tCAPD\tUnknown\tUnknown\tUnknown\t\n37\tMacDiarmaid-Gordon AR et al\t[35]\t62\tMan\tHerpes zoster\tOral ACV(Unknown)\tUnknown\t2000 mg/d\tNone\tNo\tCAPD\tUnknown\tUnknown\tUnknown\t\n38\tMacDiarmaid-Gordon AR et al\t[35]\t47\tMan\tHerpes zoster\tOral ACV (3)\t3\t4000 mg/d\tUnknown\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n39\tMacDiarmaid-Gordon AR et al\t[35]\t30\tMan\tHerpes zoster\tOral ACV (3)→oral ACV (5)\t8\t2000 mg/d→1000 mg/d\tGranulomatosis with polyangiitis\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n40\tMacDiarmaid-Gordon AR et al\t[35]\t56\tMan\tHerpes zoster\tOral ACV (9.2)\t9\t2000 mg/d\tUnknown\tYes\tHD\tUnknown\tUnknown\tUnknown\t\n41\tSwan SK et al\t[36]\t76\tWoman\tHerpes zoster\tOral ACV (4)\t4\t1000 mg/d\tUnknown\tNo\tHD\tUnknown\tUnknown\tUnknown\t\n42\tFeldman S et al\t[37]\t17\tWoman\tHerpes simplex virus\tIntravenous ACV (2)\t2\t4000 mg/d\tmetastatic ovarian germ cell tumor\tYes\tNone\t1.5\tUnknown\tUnknown\t\n43\tSugimoto K et al\t[38]\t70\tMan\tPrevention\tOral VACV (36)\t36\t500 mg three times a wk\tmultiple myeloma\tNo\tNone\t8.78\t7.71\tNone\t\n\nTwo mechanisms of ACV-induced acute kidney injury exist. One is renal dysfunction due to dehydration and the use of nonsteroidal anti-inflammatory drugs, as well as tubular obstruction due to ACV itself,[5] and the other is renal dysfunction caused by a direct mechanism of ACV aldehyde.[6] The serum ACV level increases due to dysuria when renal dysfunction occurs, which further exacerbates renal dysfunction and causes ACV-associated encephalopathy.[8] Elderly people are prone to dehydration and potentially impaired renal function. The aforementioned mechanism causes acute renal damage and a tendency for the onset of ACV-associated encephalopathy. Moreover, VACV is a prodrug of ACV and has better gastrointestinal absorption than ACV. Consequently, the oral bioavailability of ACV is 10% to 20% (54.2% for VACV), and its serum half-life is approximately 5 times longer. Hence, VACV is simpler to administer than ACV because the number of doses is smaller and characteristically tends to result in increased serum levels.[1]\n\nIn total, 43 cases of ACV-associated encephalopathy have been reported in 35 studies. A summary of the literature review is presented in Table 4. The age range of the patients with ACV-associated encephalopathy was from 0.5 to 88 years (mean age, 55.0 years; median age, 62 years). Among the patients, 24 (55.8%) were aged ≥60 years, and 6 (13.9%) were aged ≤18 years. The sex ratio was almost equal (18 females and 24 males [55.8]; 1 unknown). ACV-associated encephalopathy occurred following the treatment of herpes zoster in 27 cases (62.7%), treatment of herpetic simplex in nine cases (20.9%), and for the purpose of suppressing the onset of virus associated with chemotherapy in 5 cases (11.6%).\n\nACV-associated encephalopathy occurred in 24 patients (55.8%) using oral medication only. The administered antiviral agent was ACV in 37 cases (86.0%). The duration of antiviral administration was known in 40 patients, and the time of onset was 1 to 36 days (median, 4 days). Moreover, an NSAID was concomitantly used in only 2 patients (4.7%).\n\nMany patients had an underlying disease, especially 27 dialysis patients (62.7%; 22 undergoing hemodialysis and 5 undergoing peritoneal dialysis). However, 4 patients (9.3%) had no underlying disease, and the presence of the underlying disease was unknown in 4 patients (9.3%).\n\nSerum ACV concentration was measured in 21 of 43 cases (48.8%). The serum concentration of 9-carboxymethoxymethylguanine was measured in only 1 case (case 28). VACV is a prodrug of ACV, which becomes ACV in the blood; thus, there were no cases with VACV concentration measurement.\n\nFor many patients, the precritical serum Cr levels were unknown, and in 2 patients (4.7%), the levels were <1.0 mg/dL. Moreover, serum Cr levels at the time of onset were often unknown. The serum Cr level at the time of onset, when known, was elevated except in 1 patient, a 7-year-old child (0.3 mg/dL).\n\nIn conclusion, based on our case findings, it is important to focus on the worsening of renal function and encephalopathy when using VACV or ACV regardless of age and original renal function. Acute kidney injury and ACV-associated encephalopathy may particularly occur in the elderly even when renal function is normal. Therefore, regular monitoring of renal function and consciousness is necessary.\n\nAuthor contributions\n\nConceptualization: Tsuneaki Kenzaka.\n\nData curation: Tsuneaki Kenzaka, Ken Goda.\n\nInvestigation: Kazuma Sugimoto, Ken Goda.\n\nSupervision: Hozuka Akita.\n\nWriting – original draft: Tsuneaki Kenzaka.\n\nWriting – review & editing: Kazuma Sugimoto, Ken Goda, Hozuka Akita.\n\nAbbreviations: ACV = acyclovir, VACV = valacyclovir.\n\nHow to cite this article: Kenzaka T, Sugimoto K, Goda K, Akita H. Acute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function: a case report and literature review. Medicine. 2021;100:21(e26147).\n\nEthics approval and consent to participate in this case report were waived.\n\nWritten informed consent was obtained from the patient for the publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nThe authors have no funding and conflicts of interests to disclose.\n\nAll data generated or analyzed during this study are included in this published article and its supplementary information files.\n\nACV = acyclovir.\n\nHSV = herpes simplex virus, PCR = polymerase chain reaction, VZV = varicella zoster virus.\n\nACV = acyclovir, VZV = varicella-zoster virus.\n\nThis table is an original table adapted from the following literature:\n\n[6] Kaewpoowat et al Infection. 2016; 44:337-45\n\n[7] Dworkin et al Clin Infect Dis. 2007;44 Suppl 1: S1-26.\n\nACV = acyclovir, VACV = valacyclovir, GCV = ganciclovir, VGCV = valganciclovir, HD = hemodialysis, CAPD = continuous ambulatory peritoneal dialysis.\n==== Refs\nReferences\n\n[1] Rashiq S Briewa L Mooney M . Distinguishing acyclovir neurotoxicity from encephalomyelitis. J Intern Med 1993;234 :507–11.8228796\n[2] Asahi T Tsutsui M Wakasugi M . Valacyclovir neurotoxicity: clinical experience and review of the literature. Eur J Neurol 2009;16 :457–60.19187258\n[3] Adair JC Gold M Bond RE . Acyclovir neurotoxicity: clinical experience and review of the literature. South Med J 1994;87 :1227–31.7973922\n[4] Sacchetti D Alawadhi A Albakour M . Herpes zoster encephalopathy or acyclovir neurotoxicity: a management dilemma. BMJ Case Rep 2014;2014 : bcr2013201941.\n[5] Chowdhury MA Derar N Hasan S . Acyclovir-induced neurotoxicity: a case report and review of literature. Am J Ther 2016;23 :e941–3.24942005\n[6] Kaewpoowat Q Salazar L Aguilera E . Herpes simplex and varicella zoster CNS infections: clinical presentations, treatments and outcomes. Infection 2016;44 :337–45.26680781\n[7] Dworkin RH Johnson RW Breuer J . Recommendations for the management of herpes zoster. Clin Infect Dis 2007;44 : Suppl 1 : S1–26.17143845\n[8] Gunness P Aleksa K Bend J . Acyclovir-induced nephrotoxicity: the role of the acyclovir aldehyde metabolite. Transl Res 2011;158 :290–301.22005269\n[9] Umoru GO Shah PJ Tariq F . A case report of neurotoxicity after prolonged doses of acyclovir in a patient with renal dysfunction. J Pharm Pract 2020;33 :217–21.30669921\n[10] Kawabe Matsukawa M Suzuki Y Ikuma D . Acyclovir encephalopathy in a peritoneal dialysis patient despite adjusting the dose of oral acyclovir: a case report. Rinsho Shinkeigaku 2019;59 :834–9.31761838\n[11] Bełz A Dębowska P Głogowska-Szeląg J . Acyclovir neurotoxicity in an elderly patient with end-stage renal failure. Am J Ther 2020;27 :e525–7.31794437\n[12] Ikuta K Roychoudhury P Xie H . Trillions and trillions: Herpes simplex virus-1 hepatitis in an immunocompetent adult. Open Forum Infect Dis 2019;6 :ofz465.31777756\n[13] Patel J Hayes B Bauler L . Neurologic acyclovir toxicity in the absence of kidney injury. J Emerg Med 2019;57 :e35–9.31171414\n[14] Sadjadi SA Regmi S Chau T . Acyclovir neurotoxicity in a peritoneal dialysis patient: report of a case and review of the pharmacokinetics of acyclovir. Am J Case Rep 2018;19 :1459 L-1462.30531673\n[15] Gorlitsky BR Herion JT . Sticking to the script: a curious case of confusion in an ESRD patient. Hemodial Int 2017;21 :E58–62.28067468\n[16] Watson WA Rhodes NJ Echenique I . Resolution of acyclovir-associated neurotoxicity with the aid of improved clearance estimates using a Bayesian approach: a case report and review of the literature. J Clin Pharm Ther 2017;42 :350–5.28370067\n[17] Thind GS Roach R . A case of acyclovir neurotoxicity presenting with atypical cerebrospinal fluid findings. BMJ Case Rep 2017;2017 : bcr-2017.\n[18] Tomori K Isozumi K Motohashi S . A young patient of acute encephalitis complicated with acyclovir encephalopathy without renal dysfunction. Rinsho Shinkeigaku 2003;43 :470–6.14658398\n[19] Itoh M Hayakawa K . A girl with transient psychological disturbance caused by orally administered acyclovir--differentiation between acyclovir neurotoxicity and herpes simplex encephalitis. No To Hattatsu 1998;30 :328–33.9695629\n[20] Gómez Campderá FJ Verde E Vozmediano MC . More about acyclovir neurotoxicity in patients on haemodialysis. Nephron 1998;78 :228–89.9496746\n[21] Hoskote SS Annapureddy N Ramesh AK . Valacyclovir and acyclovir neurotoxicity with status epilepticus. Am J Ther 2016;23 :e304–6.24368610\n[22] Sagawa N Tsurutani Y Nomura K . Acyclovir-induced neurotoxicity and acute kidney injury in an elderly diabetic patient treated with valacyclovir: report of a case. Nihon Ronen Igakkai Zasshi 2014;51 :581–5.25749332\n[23] Strong DK Hebert D . Acute acyclovir neurotoxicity in a hemodialyzed child. Pediatr Nephrol 1997;11 :741–3.9438656\n[24] Blohm ME Nurnberger W Aulich A . Reversible brain MRI changes in acyclovir neurotoxicity. Bone Marrow Transplant 1997;19 :1049–51.9169653\n[25] Peces R de la Torre M Alcázar R . Acyclovir-associated encephalopathy in haemodialysis. Nephrol Dial Transplant 1996;11 :752.\n[26] Mesar I Basić-Jukić N Hudolin T . Varicella zoster virus reactivation in hemodialysis patients: manifestations, treatment, complications and outcome. Acta Clin Croat 2011;50 :549–52.22649885\n[27] Hussein MM Mooij JM Al Malki N . Confusion and agitation after a recent kidney transplantation. Saudi J Kidney Dis Transpl 2008;19 :446–9.18445909\n[28] Yang HH Hsiao YP Shih HC . Acyclovir-induced neuropsychosis successfully recovered after immediate hemodialysis in an end-stage renal disease patient. Int J Dermatol 2007;46 :883–4.17651180\n[29] Chevret L Debray D Poulain C . Neurological toxicity of acyclovir: report of a case in a six-month-old liver transplant recipient. Pediatr Transplant 2006;10 :632–4.16857003\n[30] Peyrière H Jeziorsky E Jalabert A . Neurotoxicity related to valganciclovir in a child with impaired renal function: usefulness of therapeutic drug monitoring. Ann Pharmacother 2006;40 :143–6.16368917\n[31] Rajan GR Cobb JP Reiss CK . Acyclovir induced coma in the intensive care unit. Anaesth Intensive Care 2000;28 :305–7.10853214\n[32] Beales P Almond MK Kwan JT . Acyclovir neurotoxicity following oral therapy: prevention and treatment in patients on haemodialysis. Nephron 1994;66 :362–3.8190194\n[33] Krieble BF Rudy DW Glick MR . Case report: acyclovir neurotoxicity and nephrotoxicity-the role for hemodialysis. Am J Med Sci 1993;305 :36–9.8416680\n[34] Davenport A Goel S Mackenzie JC . Neurotoxicity of acyclovir in patients with end-stage renal failure treated with continuous ambulatory peritoneal dialysis. Am J Kidney Dis 1992;20 :647–9.1462997\n[35] MacDiarmaid-Gordon AR O’Connor M Beaman M . Neurotoxicity associated with oral acyclovir in patients undergoing dialysis. Nephron 1992;62 :280–3.1436338\n[36] Swan SK Bennett WM . Oral acyclovir and neurotoxicity. Ann Intern Med 1989;111 :188.\n[37] Feldman S Rodman J Gregory B . Excessive serum concentrations of acyclovir and neurotoxicity. J Infect Dis 1988;157 :385–8.3335815\n[38] Sugimoto K Kenzaka T Sugimoto R . Encephalopathy induced by preventive administration of acyclovir in a man with symptomatic multiple myeloma and renal dysfunction. Int J Gen Med 2021;14 :413–7.33603447\n\n",
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"mesh_terms": "D058186:Acute Kidney Injury; D000369:Aged, 80 and over; D000998:Antiviral Agents; D001927:Brain Diseases; D003404:Creatinine; D006147:Guanine; D006562:Herpes Zoster; D006801:Humans; D007668:Kidney; D008297:Male; D012016:Reference Values; D006435:Renal Dialysis; D000077483:Valacyclovir",
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"pubdate": "2021-05-28",
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"title": "Acute kidney injury and acyclovir-associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function: A case report and literature review.",
"title_normalized": "acute kidney injury and acyclovir associated encephalopathy after administration of valacyclovir in an elderly person with normal renal function a case report and literature review"
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"abstract": "We report a case of a 58-year-old woman with a true non secretory multiple myeloma of the producer type relapsing after many lines of therapy including the novel anti-myeloma drugs, which eventually relapsed as extramedullary liver plasmacytomas manifesting as a fatal acute cholestatic hepatitis. Due to the aggressiveness of this disease, new therapeutic modalities are necessary.",
"affiliations": "Serviço de Hematologia, Hospital Santo António dos Capuchos, 1169-050 Lisboa, Portugal. ronolosi@gmail.com",
"authors": "Lopes da Silva|Rodrigo|R|;Monteiro|Alexandra|A|;Veiga|Joana|J|",
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"medline_ta": "J Gastrointestin Liver Dis",
"mesh_terms": "D002779:Cholestasis; D005260:Female; D006505:Hepatitis; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D009101:Multiple Myeloma; D010954:Plasmacytoma; D012008:Recurrence",
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"title": "Non-secretory multiple myeloma relapsing as extramedullary liver plasmacytomas.",
"title_normalized": "non secretory multiple myeloma relapsing as extramedullary liver plasmacytomas"
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"abstract": "BACKGROUND\nA suicidal person with a do-not-resuscitate (DNR) order presents an ethical dilemma to the emergency physician. Many believe that suicide is an irrational action, and therefore, all suicide attempts must be treated. Others believe a DNR order should be respected even in the setting of a suicide attempt.\n\n\nMETHODS\nAn elderly woman with a known terminal illness presented to the emergency department after a suspected suicide attempt. She had a DNR order during her previous hospitalization. The emergency physician felt obligated to intubate the woman despite his recognition that she was terminally ill.\n\n\nCONCLUSIONS\nReasons to both honor and not honor a DNR order after a suicide attempt are reviewed.\n\n\nCONCLUSIONS\nNot all patients who attempt suicide are necessarily incapable of making a rational decision about their health care. In some cases it may be appropriate to withhold resuscitation attempts in suicidal patients who have a preexisting DNR order. Institutional policies are needed to provide guidance in this situation.",
"affiliations": "Meriter Hospital, Madison, Wisconsin.",
"authors": "Henman|Mary P|MP|",
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"journal": "The Journal of emergency medicine",
"keywords": "DNR order; ethics; hospital policy; prehospital DNR; suicide",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000369:Aged, 80 and over; D003657:Decision Making; D004636:Emergency Service, Hospital; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D009294:Narcotics; D010098:Oxycodone; D026684:Personal Autonomy; D016414:Resuscitation Orders; D059020:Suicidal Ideation; D017236:Suicide, Assisted",
"nlm_unique_id": "8412174",
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"pubdate": "2017-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Suicidal Patients with a Do-Not-Resuscitate Order.",
"title_normalized": "suicidal patients with a do not resuscitate order"
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"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
... |
{
"abstract": "A rapid LC-MS/MS method for the targeted screening of 132 NPS in hair is described. Drugs include cathinones and synthetic cannabinoids, as well as amphetamine-type stimulants, piperazines and other hallucinogenic compounds. This method utilizes hair pulverization in acidified methanol followed by analysis using liquid chromatography coupled with tandem MS. The limit of detection varied from 0.001 to 0.1ng/mg hair among the various analytes. The method was validated in terms of sensitivity, selectivity, repeatability and stability. The limit of reporting was set at 0.1ng/mg of hair. The method was successfully applied to 23 medico-legal cases where NPS were detected in blood or where NPS use was suspected. The identified NPS included acetyl fentanyl, 25C-NBOMe, MDPV, PB-22 and AB-FUBINACA, allowing hair to be used where historical or retrospective information on use of NPS is sought. This technique has proven to be efficient for the one step extraction from hair of different classes of NPS in routine toxicological investigations; from unstable and volatile compounds, such as most of the cathinones, to hydrophobic compounds such as synthetic cannabinoids.",
"affiliations": "Department of Forensic Medicine, Monash University, Australia; Laboratory of Forensic Medicine & Toxicology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece. Electronic address: vboumba@uoi.gr.;Department of Forensic Medicine, Monash University, Australia; Victorian Institute of Forensic Medicine, 65 Kavanagh St., Southbank, Victoria 3006, Australia.;Victorian Institute of Forensic Medicine, 65 Kavanagh St., Southbank, Victoria 3006, Australia.;Department of Forensic Medicine, Monash University, Australia; Victorian Institute of Forensic Medicine, 65 Kavanagh St., Southbank, Victoria 3006, Australia.;Department of Forensic Medicine, Monash University, Australia; Victorian Institute of Forensic Medicine, 65 Kavanagh St., Southbank, Victoria 3006, Australia.",
"authors": "Boumba|Vassiliki A|VA|;Di Rago|Matthew|M|;Peka|Melissa|M|;Drummer|Olaf H|OH|;Gerostamoulos|Dimitri|D|",
"chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs; D006851:Hydrochloric Acid; D000432:Methanol",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2017.08.031",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "279()",
"journal": "Forensic science international",
"keywords": "Acidic extraction; Hair; LC–MS/MS; Novel psychoactive substances (NPS); Screening",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D002853:Chromatography, Liquid; D006197:Hair; D006801:Humans; D006851:Hydrochloric Acid; D013287:Illicit Drugs; D057230:Limit of Detection; D000432:Methanol; D011619:Psychotropic Drugs; D015203:Reproducibility of Results; D015813:Substance Abuse Detection; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "192-202",
"pmc": null,
"pmid": "28910664",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The analysis of 132 novel psychoactive substances in human hair using a single step extraction by tandem LC/MS.",
"title_normalized": "the analysis of 132 novel psychoactive substances in human hair using a single step extraction by tandem lc ms"
} | [
{
"companynumb": "PHHY2017GR135009",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nThe National Psoriasis Foundation (NPF) published treat-to-target guidelines for psoriasis, yet their applicability in clinical practice remains unknown.\n\n\nOBJECTIVE\nTo estimate the proportion of psoriasis patients meeting the NPF's body surface area (BSA) 'target' (≤1%) and 'acceptable' (≤3%) response criteria and the cross-sectional associations of these criteria with patient-reported outcomes (PROs) in the Corrona Psoriasis Registry.\n\n\nMETHODS\nSeparately for three independent cross-sectional cohorts of patients at the (i) enrolment, (ii) 6-month and (iii) 12-month visits, we calculated the proportion of patients with BSA ≤1% and ≤3%. Furthermore, we calculated odds ratios estimating the risk of PROs associated with not meeting criteria in the 6-month cohort.\n\n\nRESULTS\nThe enrolment, 6- and 12-month cohorts included 2794, 1310 and 629 patients, respectively. At enrolment, 24% of patients had a BSA ≤ 1% and 41% a BSA ≤ 3%. In the 6-month cohort, 43%/64% had a BSA ≤ 1%/BSA ≤ 3%. In the 12-month cohort, 46%/69% of patients had a BSA ≤ 1%/BSA ≤ 3%. Patients not at target/acceptable criteria had higher odds for worse quality of life compared with those who were.\n\n\nCONCLUSIONS\nWhile most patients at 6- and 12-month visits were at the 'acceptable' response, less than half were at the 'target' response despite systemic therapy. There remain unmet needs to optimize psoriasis therapy and further validate current treat-to-target guidelines.",
"affiliations": "Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.;National Psoriasis Foundation, Portland, OR, USA.;Psoriasis Treatment Center of Central New Jersey, East Windsor, NJ, USA.;Evans Dermatology Partners, Austin, TX, USA.;DermAssociates, Silver Spring, MD, USA.;Corrona LLC, Waltham, MA, USA.;Corrona LLC, Waltham, MA, USA.;Corrona LLC, Waltham, MA, USA.;Corrona LLC, Waltham, MA, USA.;Eastern Virginia Medical School, Norfolk, VA, USA.",
"authors": "Merola|J F|JF|https://orcid.org/0000-0001-6514-4353;Perez Chada|L M|LM|https://orcid.org/0000-0001-7724-7309;Siegel|M|M|;Bagel|J|J|;Evans|C|C|;Lockshin|B|B|;Mason|M|M|;Guo|N|N|;McLean|R R|RR|;Greenberg|J D|JD|;Van Voorhees|A S|AS|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1111/jdv.16274",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0926-9959",
"issue": "34(9)",
"journal": "Journal of the European Academy of Dermatology and Venereology : JEADV",
"keywords": null,
"medline_ta": "J Eur Acad Dermatol Venereol",
"mesh_terms": "D003430:Cross-Sectional Studies; D006801:Humans; D000071066:Patient Reported Outcome Measures; D015995:Prevalence; D011565:Psoriasis; D011788:Quality of Life; D012042:Registries; D012720:Severity of Illness Index",
"nlm_unique_id": "9216037",
"other_id": null,
"pages": "2051-2058",
"pmc": null,
"pmid": "32027420",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The National Psoriasis Foundation psoriasis treatment targets in real-world patients: prevalence and association with patient-reported outcomes in the Corrona Psoriasis Registry.",
"title_normalized": "the national psoriasis foundation psoriasis treatment targets in real world patients prevalence and association with patient reported outcomes in the corrona psoriasis registry"
} | [
{
"companynumb": "US-AMGEN-USASP2020176410",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "APREMILAST"
},
"drugadditional": "3",
... |
{
"abstract": "A 67-year-old man presented with abdominal pain and fever. Many abdominal tumors were detected by enhanced computed tomography(CT). The largest tumor, measuring 20 cm, had perforated the ileum and formed an abscess. Emergency surgery was performed to remove multiple tumors in the peritoneal cavity as much as possible. Immunostaining showed c-kit and CD34 positivity, and the tumors were diagnosed as gastrointestinal stromal tumor(GIST). During postoperative imatinib therapy for the residual tumor, low-dose intermittent administration was required due to side effects, but the disease was controlled for over 91months. For advanced GIST with peritoneal dissemination, 200mg/day imatinib or intermittent administration after volume reduction surgery might be effective depending on the patient's general condition.",
"affiliations": "Division of Digestive Surgery, Dept. of Surgery, Kyoto Prefectural University of Medicine.",
"authors": "Nanishi|Kenji|K|;Taniguchi|Fumihiro|F|;Mizuno|Aya|A|;Furuke|Hirotaka|H|;Tanaka|Sachie|S|;Kumano|Tatsuya|T|;Komatsu|Shuhei|S|;Imura|Kenichiro|K|;Shimomura|Katsumi|K|;Ikeda|Jun|J|;Takashina|Kenichiro|K|;Shioaki|Yasuhiro|Y|;Ikeda|Eito|E|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "45(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000970:Antineoplastic Agents; D050110:Bariatric Surgery; D001549:Benzamides; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D010879:Piperazines; D011743:Pyrimidines",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2348-2350",
"pmc": null,
"pmid": "30692460",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of GIST with Extensive Peritoneal Dissemination Controlled over Long-Term by Low-Dose, Intermittent Administration of Imatinib after Weight Loss Surgery.",
"title_normalized": "a case of gist with extensive peritoneal dissemination controlled over long term by low dose intermittent administration of imatinib after weight loss surgery"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-209878",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
... |
{
"abstract": "Afatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.",
"affiliations": "Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Sendai Medical Association Hospital, Sendai 895-0005, Japan.;United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima 890-0065, Japan.;Department of Pharmacy, University of Miyazaki Hospital, Miyazaki 889-1692, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.;Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan.",
"authors": "Takahashi|Takayuki|T|;Terazono|Hideyuki|H|0000-0002-2657-4454;Suetsugu|Takayuki|T|;Sugawara|Hideki|H|;Arima|Junko|J|;Nitta|Mina|M|;Tanabe|Toru|T|;Okutsu|Kayu|K|;Ikeda|Ryuji|R|;Mizuno|Keiko|K|;Inoue|Hiromasa|H|0000-0001-8080-3812;Takeda|Yasuo|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3390/cancers13143425",
"fulltext": "\n==== Front\nCancers (Basel)\nCancers (Basel)\ncancers\nCancers\n2072-6694\nMDPI\n\n10.3390/cancers13143425\ncancers-13-03425\nArticle\nHigh-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction\nTakahashi Takayuki 1\nhttps://orcid.org/0000-0002-2657-4454\nTerazono Hideyuki 1*\nSuetsugu Takayuki 2\nSugawara Hideki 1\nArima Junko 1\nNitta Mina 1\nTanabe Toru 3\nOkutsu Kayu 4\nIkeda Ryuji 5\nMizuno Keiko 2\nhttps://orcid.org/0000-0001-8080-3812\nInoue Hiromasa 2\nTakeda Yasuo 1\nJono Hirofumi Academic Editor\n1 Department of Clinical Pharmacy and Pharmacology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; t-takah@m3.kufm.kagoshima-u.ac.jp (T.T.); suu@m2.kufm.kagoshima-u.ac.jp (H.S.); junko@m3.kufm.kagoshima-u.ac.jp (J.A.); ushiyama@m3.kufm.kagoshima-u.ac.jp (M.N.); takeda@m.kufm.kagoshima-u.ac.jp (Y.T.)\n2 Department of Pulmonary Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima 890-8520, Japan; taka3741@m2.kufm.kagoshima-u.ac.jp (T.S.); keim@m.kufm.kagoshima-u.ac.jp (K.M.); inoue@m2.kufm.kagoshima-u.ac.jp (H.I.)\n3 Sendai Medical Association Hospital, Sendai 895-0005, Japan; drug-info@sendaihp.jp\n4 United Graduate School of Agricultural Sciences, Kagoshima University, Kagoshima 890-0065, Japan; k8673711@kadai.jp\n5 Department of Pharmacy, University of Miyazaki Hospital, Miyazaki 889-1692, Japan; ryuji_ikeda@med.miyazaki-u.ac.jp\n* Correspondence: terazono@m.kufm.kagoshima-u.ac.jp; Tel.: +81-99-275-5543\n08 7 2021\n7 2021\n13 14 342522 5 2021\n02 7 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nSimple Summary\n\nAfatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). We examined the relationship between the trough plasma concentrations of afatinib and adverse effects, including diarrhea, rash, stomatitis and mucositis. The dose reduction of afatinib was associated with the trough plasma concentration of afatinib in this paper. As a result, we clarified that a higher trough plasma concentration induced adverse events, and there was a threshold to reduce the dosage or not. Monitoring plasma concentrations of afatinib is useful to predict the adverse effects of afatinib and to support quality of life in patients with EGFR-mutated advanced NSCLC.\n\nAbstract\n\nAfatinib is used to treat non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutation as a second-generation EGFR-tyrosine kinase inhibitor (TKI). Early prediction of adverse effects based on the pharmacokinetics of afatinib enables support for quality of life (QOL) in patients with no change in efficacy. We examined the pharmacokinetic relationship between trough plasma concentration and adverse effects and evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study. Twenty-four patients treated with afatinib were enrolled in this study. All blood samples were collected at the trough point, and plasma concentrations were measured using high-performance liquid chromatography–tandem mass spectrometry. Logistic regression analysis for the dose reduction of afatinib was performed, and the receiver operating characteristic (ROC) curve was plotted. Although all patients started afatinib at 40 mg/day, plasma concentrations were variable, and mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL in this study, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL, respectively. This variability was speculated to involve personal parameters such as laboratory data. However, no patient characteristics or laboratory data examined correlated with the trough plasma concentration of afatinib, except albumin. Albumin showed a weak correlation with plasma concentration (r = 0.60, p = 0.009). The trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047). The area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81. The cut-off value was 21.4 ng/mL. The sensitivity and specificity of the cut-off as a risk factor were 0.80 and 0.75. In summary, the trough plasma concentration of afatinib was associated with continued or reduced dosage because of the onset of several adverse effects, and a threshold was seen. Adverse effects not only lower QOL but also hinder continued treatment. Measuring plasma concentrations of afatinib appears valuable to predict adverse effects and continue effective therapy.\n\nafatinib\nepidermal growth factor receptor\ntyrosine kinase inhibitor\nnon-small-cell lung cancer\ntrough plasma concentration\nreceiver operating characteristic curve\n==== Body\n1. Introduction\n\nEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show robust efficacy for EGFR mutation-positive non-small-cell lung cancer (NSCLC). EGFR-TKIs have been used worldwide as a first-line treatment for patients in this setting [1].\n\nAfatinib is used for the treatment of NSCLC harboring EGFR mutation as a second-generation EGFR-TKI. Unlike the first generation of reversible EGFR-TKIs, including gefitinib and erlotinib, afatinib binds irreversibly to EGFR (ErbB1), ErbB2 (human epidermal growth factor receptor 2 (HER2)), and ErbB4 [2,3]. The prolongation of progression-free survival (PFS) and improvement of symptoms and quality of life (QOL) in EGFR mutation-positive NSCLC treated with afatinib have been shown in several clinical trials [4,5,6,7,8,9,10,11,12,13,14,15]. In a Japanese population, afatinib showed prolonged overall survival (OS) in a subgroup analysis of LUX-Lung 3 [16]. Although afatinib is likely to prove more effective for Japanese patients than for American or European patients according to this subgroup analysis, the frequency and severity of adverse effects, including diarrhea, rash, stomatitis, and mucositis, were worse in Japanese patients than in American or European patients. Over 75% of Japanese patients in the subgroup analysis experienced dose reduction because of the expression of adverse effects.\n\nSome studies have revealed the relationship between the frequency and severity of adverse effects and plasma concentration of afatinib. In a study with a combined analysis of Lux-Lung 3 and 6, higher trough concentration was shown to lead to dose reduction, whereas lower trough concentration led to dose escalation, and no difference in PFS was seen between patients with or without dose reduction [17]. Furthermore, a meta-analysis of population pharmacokinetics revealed some risk factors for a higher area under the curve (AUC) for afatinib [18]. That analysis reported female sex, lower creatinine clearance, higher Eastern Cooperative Oncology Group (ECOG) performance status (PS), alkaline phosphatase (ALP), lactate dehydrogenase (LDH), and total protein were factors associated with a higher AUC. Measuring the blood concentration of afatinib thus allows us to support QOL in patients without changing efficacy.\n\nMeasuring the trough plasma concentration is easier and more tolerable than determining the AUC. However, previous studies have only evaluated the effectiveness of afatinib according to the AUC. We therefore investigated the pharmacokinetic relationship between trough plasma concentration and adverse events. Furthermore, we evaluated the utility of measuring the trough plasma concentration of afatinib as the first EGFR-TKI treatment for NSCLC in a prospective multicenter study.\n\n2. Materials and Methods\n\n2.1. Subjects\n\nThe subjects in this study were patients who received afatinib (Giotrif® tablets; Japanese Boehringer Ingelheim Co., Tokyo, Japan) for NSCLC at five centers in Kagoshima, Japan: Kagoshima University Hospital; Kagoshima City Hospital; Minami Kyushu National Hospital; Sendai Medical Association Hospital; and Imakiire General Hospital, from October 2017 to March 2019.\n\nThe study protocol was approved by the Ethics Review Boards of Kagoshima University Hospital (Approval Number: 170258) and all other participating centers. All patients provided written informed consent for participation in this study. This study was performed in accordance with the Declaration of Helsinki.\n\n2.2. Administration of Afatinib and Blood Sampling\n\nThe attending physician started afatinib administration at 40 mg/day. All patients were administered afatinib between meals. Administration was discontinued when adverse effects greater than or equal to grade 3, as defined in Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, were observed. Moreover, when adverse effects were seen to recover to grade 1, the dosage was reduced by 10 mg/day, and afatinib administration was restarted.\n\nAll blood samples were collected at the trough point just before the next administration, and blood samples were collected at Days 8–14 from the beginning of afatinib at 40 mg/day.\n\n2.3. Chemicals and Reagents\n\nAfatinib was purchased from Toronto Research Chemicals (Toronto, Canada). Imatinib mesylate for use as the internal standard (IS) was purchased from LKT Laboratories (St. Louis, MO, USA). tert-Butyl methyl ether (TBME), ammonium formate, formic acid, and liquid chromatography–mass spectrometry (LC-MS)-grade acetonitrile were purchased from Wako (Osaka, Japan).\n\n2.4. Measuring Plasma Concentration of Afatinib in Patients\n\nCollected blood samples were centrifuged at 1300× g for 10 min at ambient temperature. We then collected and preserved the supernatant of blood samples from subjects at −80 °C until concentrations of afatinib in plasma were measured.\n\nThe sample extraction method reported in 2015 by Hayashi et al. [19] was slightly modified. In summary, internal standard (IS) (5 µL of 2 µM) was added to the collected plasma sample (250 µL) in a polypropylene tube. After mixing, TBME (1.5 mL) was added, and the tube was vortexed for 30 s then centrifuged at 2300× g for 10 min at ambient temperature. A sample of the supernatant (1.75 mL) was transferred to a glass tube and dried under nitrogen gas. A mobile phase (50 µL) was added to the dried sample containing glass tubes. After filtration through a 0.2 µm pore membrane filter (GL Chromatodisk; GL Science, Tokyo, Japan), samples were transferred to a 200 µL polypropylene autosampler vial, and a sample (10 µL) was injected onto the LC instrument for quantitative analysis using an autosampler operating at 4 °C.\n\nPlasma concentrations of afatinib were measured in patients using a high-performance LC-MS/MS system (AB SCIEX 3200QTRAP LC-MS/MS; SCIEX, Tokyo, Japan, and LC-20; Shimadzu, Kyoto, Japan). The mobile phase consisted of 2 nm of ammonium formate buffer (pH 4.1) and acetonitrile (65:35, v/v). Detection was carried out using multiple reaction monitoring. The lower limit of quantification was 1.67 ng/mL.\n\n2.5. Evaluation of Efficacy and Adverse Effects of Afatinib\n\nThe attending physician evaluated efficacy in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) and adverse effects in accordance with the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.\n\n2.6. Correlation between Trough Plasma Concentration and Patient Characteristics, Laboratory Data\n\nPatient characteristics and laboratory data of patients were collected from the database at Kagoshima University Hospital, Minami-Kyushu Hospital, and Sendai Medical Association Hospital. Spearman’s rank correlation test was conducted to confirm the correlation between trough plasma concentration, patient characteristics, and laboratory data.\n\n2.7. Logistic Regression Analysis for Dose Reduction of Afatinib\n\nThe relationship between trough plasma concentration and dose reduction of afatinib was analyzed by logistic regression analysis. Items showing significant differences were considered risk factors for the dose reduction of afatinib.\n\n2.8. ROC Curve\n\nWe plotted ROC curves to identify cut-off values of the trough plasma concentration of afatinib for dose reduction. The cut-off value was considered to be the maximum of the sum of sensitivity and specificity.\n\n2.9. Statistics\n\nDifferences were considered statistically significant at values of p < 0.05. Statistical analyses, including t-test, Spearman’s rank correlation test, logistic regression analysis, and ROC curve, were performed using JMP® Pro 15 (SAS Institute Inc., Cary, NC, USA).\n\n3. Results\n\n3.1. Patient Characteristics\n\nThe participants in this study comprised 24 NSCLC patients treated with afatinib. The characteristics of patients who experienced a dose reduction of afatinib are summarized in Table 1.\n\nThe median age was 67 years (range: 46–79 years), and half of the patients were female (n = 12). Twenty of the 24 patients experienced a dose reduction of afatinib in the study. From the physician’s judgment based on RECIST, all patients of the nonreduction group were judged as partial response (PR), while the reduction group had some variety: stable disease (SD), 5 patients; PR, 13; progressive disease (PD), 1 patient; and nonevaluated, 1. Two groups did not show significant differences (Fisher’s exact test p = 0.62).\n\n3.2. Histogram of Trough Plasma Concentration of Afatinib\n\nA histogram and boxplot of the trough plasma concentration of afatinib are shown in Figure 1, respectively. The mean and median trough plasma concentrations were 32.9 ng/mL and 32.5 ng/mL, respectively. Minimum and maximum trough plasma concentrations were 10.4 ng/mL and 72.7 ng/mL (Figure 2). The standard deviation (SD) was 16.1. The coefficient of variation (CV) was 48.9%, similar to a previous report [17].\n\n3.3. Associations between Trough Plasma Concentration, Patient Characteristics, and Laboratory Data\n\nSpearman’s rank correlation test was used to confirm patient characteristics or laboratory data correlating with the plasma concentration of afatinib (Figure 2). Serum albumin was the only factor found to correlate with the trough plasma concentration of afatinib (r = −0.5988, p = 0.0087, n = 22) (Figure 2l), although serum albumin was not examined in two patients. Other laboratory data, including height, body weight, body surface area, total protein, total bilirubin (T-bil), aspartate aminotransferase (AST), alanine aminotransferase (ALT), serum creatinine, estimated glomerular filtration rate (eGFR), and creatinine clearance, calculated by the Cockcroft–Gault equation, showed no correlation with the trough plasma concentration of afatinib. T-bil was not examined in one patient, and total protein was not examined in two patients.\n\n3.4. Trough Plasma Concentration of Afatinib and Logistic Regression Analysis between Continuous Dosage and Dose Reduction\n\nThe median trough plasma concentrations of afatinib identifying dose reduction and continuous dosage were 33.1 and 18.0 ng/mL, respectively (Figure 3a). Logistic regression analysis between dose reduction and trough plasma concentration of afatinib is shown in Table 2. The reasons for the dose reduction of afatinib were diarrhea (n = 15, 75% of the reduction group), mucositis oral (n = 2, 10% of the reduction group), rash (n = 2. 10% of the reduction group), and paronychia (n =1, 5% of the reduction group).\n\nThe trough plasma concentration of afatinib was significantly associated with the dose reduction of afatinib (p = 0.047).\n\n3.5. Receiver Operating Characteristic (ROC) Curves\n\nThe area under the ROC curve (AUC) for the trough plasma concentration of afatinib was 0.81, and the cut-off value for the trough plasma concentration of afatinib was 21.4 ng/mL (Table 2). The sensitivity and specificity of this cut-off were 0.80 and 0.75, as summarized in Table 2, and the ROC curve is shown in Figure 3b.\n\n4. Discussion\n\nA relationship between the dose reduction of afatinib and the high-trough plasma concentration of afatinib was found in Japanese patients receiving afatinib as the first EGFR-TKI. The rate of dose reduction of afatinib and inter-patient variability of the trough plasma concentration of afatinib were high. Measuring the trough plasma concentration of afatinib thus has the potential to predict the dose reduction of afatinib as a first-line treatment for EGFR mutation-positive NSCLC.\n\nIn the present study, a relationship between the dose reduction of afatinib and the trough plasma concentration of afatinib was found by logistic regression analysis. The mean trough plasma concentration of patients who experienced a dose reduction was about 1.7 times that of patients who did not experience a dose reduction. In addition, high inter-patient variability of the trough plasma concentration of afatinib was detected, with a CV of 48.94%. This result of variability was in agreement with previous studies in EGFR mutation-positive NSCLC [7,17,20]. Collectively, results from the present study indicate that the therapeutic drug monitoring of afatinib is important to predict dose reduction or the occurrence of adverse effects. In addition, the cut-off value for the trough plasma concentration of afatinib was 21.4 ng/mL in the present study. This value is similar to the mean trough plasma concentration of afatinib after dose adjustment in post hoc analyses of the LUX-Lung 3 and 6 trial [17] and a previous report of Japanese EGFR mutation-positive NSCLC [21]. In light of the results, a cut-off value of 21.4 ng/mL is useful for earlier prediction of the severe adverse effects such as diarrhea, oral mucositis, and rash. If we have this information, we can prepare the medication to avoid or relieve the adverse effects and follow continuous treatments.\n\nThe post hoc analyses of the LUX-Lung 3 and 6 trial also discussed efficacy [17]. Both studies examined whether PFS changed among patients who underwent dose reductions within 6 months and those who remained on afatinib ≥ 40 mg/day. The dose reduction of afatinib did not significantly change the estimated PFS (hazard ratios of LUX-Lung 3 and 6 were 1.25 (95% confidence interval (CI): 0.91–1.72; p = 0.175) and 1.00 (95%CI: 0.69–1.46; p = 0.982)), respectively. Furthermore, trough plasma concentrations of patients who remained on 40 mg/day compared to those who underwent dose reduction were 23.3 ng/mL and 22.8 ng/mL, respectively, in those studies. These results support our own findings and suggest that monitoring trough plasma concentration is effective for avoiding adverse effects and continuing effective therapy.\n\nSerum albumin was the only laboratory data to show a correlation with the trough plasma concentration of afatinib (r = −0.5988, p = 0.0087), with data from only two patients not examined. Serum albumin may thus offer an indicator of elevated exposure to afatinib. However, precisely predicting the plasma concentration of afatinib from our result is difficult. Dömötör et al. reported that human serum albumin and afatinib do not appear to show high affinity in the experimental data [22]. The difference between our data and the report is unclear. Further research targeted the relationship between serum afatinib concentration, and serum albumin is essential to predict dose reduction (=severe adverse effect).\n\nRecently, population pharmacokinetics of afatinib in Japanese patients, including those who underwent gefitinib or erlotinib treatments in the past, have shown that hepatic impairment is associated with afatinib pharmacokinetics, and trough plasma concentrations of afatinib on Day 8 were significantly higher in patients who experienced dose reduction or interruption than in those who did not [23]. However, hepatic function tests, including AST, ALT, and T-bil, were not correlated with the trough plasma concentration of afatinib. Moreover, a past study showed that hepatic impairment had no effect on afatinib excretion [24]. Further studies are thus needed to confirm the relationships between hepatic function and afatinib pharmacokinetics.\n\nAccording to the present study, serum creatine and creatinine clearance as calculated from the Cockcroft–Gault equation did not correlate with the trough plasma concentration of afatinib. However, from a previous report on the population pharmacokinetics of afatinib, the AUC was increased by 27.8% with creatinine clearance of 43 mL/min as calculated from the Cockcroft–Gault equation when compared with creatinine clearance of 79 mL/min [18], although afatinib is mainly (around 85.4%) excreted into feces as afatinib dimalate [25]. In addition, from a case series of Japanese patients, the estimated glomerular filtration rate (eGFR) was significantly lower in patients who experienced a dose reduction of afatinib than patients who did not [21]. Moreover, some reports have shown that other nonrenal elimination pathways were decreased in renal dysfunction [26,27]. The mechanism of the relationship between renal function and adverse effects or the dose reduction of afatinib is not fully understood. Further studies are thus needed to elucidate the reasons for the relationship between renal function and adverse effects or dose reduction of afatinib.\n\nRegarding other TKIs, some studies have indicated a relationship between the plasma concentration and adverse effects of TKIs. The steady-state trough plasma concentration of sunitinib is associated with fatigue and anorexia [28]. In addition, pazopanib, a multikinase inhibitor, shows relationships between steady-state trough plasma concentration and adverse effects, including hypertension, fatigue, and anorexia in renal cell carcinoma [29,30]. These results support the suggestion from the present results that measuring plasma concentrations of afatinib is valuable to predict adverse effects or dose reduction.\n\nAlthough the present study was a multicenter prospective study, the number of patients was small. This may have contributed to the lack of significant findings in this study. Therefore, it cannot have been ruled out that other factors may have an effect. Further study involving more samples needs to perform multivariate analysis. In the present study, a detailed analysis of concomitant medications was not conducted. Ritonavir has been shown to elevate the plasma concentration and AUC for afatinib [31]. Strong P-glycoprotein inhibitors including ritonavir, itraconazole, and verapamil hydrochloride, or inducers including rifampicin and carbamazepine, are thus likely to affect the plasma concentration of afatinib. As far as prescription records could be confirmed, no patients in this study were treated with strong P-glycoprotein inhibitors or inducers. In this study, the number of the nonreduction group was small because the patients we selected were firstly administered afatinib without previously being administered other TKIs to exclude the other effects. Therefore, this study just reflected the adverse effect of afatinib. The dosage for the patients was reduced from 40 mg to 30 or 20 mg in the LUX-Lung 3 clinical trial. In that study, the ratio of the nonreduction group was 46.7%. It is difficult to collect the patients; however, it is essential to increase the number of patients to resolve the limitation or strengthen the results of the study.\n\n5. Conclusions\n\nDose reduction of afatinib is associated with the trough plasma concentration of afatinib in patients with EGFR-mutated advanced NSCLC receiving afatinib as the first EGFR-TKI treatment. Measuring and monitoring the plasma concentration of afatinib thus appears valuable to predict adverse effects of afatinib and to support QOL in patients with EGFR-mutated advanced NSCLC.\n\nAcknowledgments\n\nWe would like to thank the Division of Instrumental Analysis Research Support Center for operating the LC-MS/MS system.\n\nAuthor Contributions\n\nConceptualization, T.T. (Takayuki Takahashi), H.T., T.S., H.S. and K.M.; methodology, K.O. and M.N.; formal analysis, T.T. (Takayuki Takahashi); investigation, T.T. (Takayuki Takahashi); resources, T.T. (Takayuki Takahashi); writing-original draft preparation, T.T. (Takayuki Takahashi); writing-review and editing, T.T. (Takayuki Takahashi), H.T., J.A., T.T. (Toru Tanabe), R.I., K.M., H.S., H.I. and Y.T.; Supervision, H.T. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research was funded by Taisho Pharmaceutical Co., Ltd.\n\nInstitutional Review Board Statement\n\nThe study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Review Boards of Kagoshima University Hospital (Approval Number: 170258, data of approval: 7/2/2018).\n\nInformed Consent Statement\n\nInformed consent was obtained from all subjects involved in the study.\n\nData Availability Statement\n\nThe data presented in this study are available on request from the corresponding author.\n\nConflicts of Interest\n\nThere are no conflict of interest.\n\nFigure 1 Histogram and boxplot of the trough plasma concentration of afatinib (n = 24).\n\nFigure 2 Correlation between the trough plasma concentration of afatinib and laboratory data (personal parameters, renal function, and hepatic function). The r- and p-values provided above each graph represent Spearman’s rank correlation and the p-value, respectively. (a) Age. (b) Body weight. (c) Body mass index. (d) Body surface area. (e) Serum creatinine. (f) Cockcroft–Gault equation. (g) Estimated glomerular filtration rate. (h) Aspartate aminotransferase. (i) Alanine aminotransferase. (j) Total bilirubin. (k) Total protein. (l) Albumin. (a–d) Correlations between trough plasma concentration and personal characteristics. (e–g) Correlations between trough plasma concentration and renal function. (h–l) Correlations between trough plasma concentration and hepatic function.\n\nFigure 3 Relationship between the trough plasma concentration of afatinib and continuous dose/dose reduction. (a) Boxplot of distribution for the trough plasma concentration of afatinib between continuous dosage and dose reduction. (b) Receiver operating characteristic curve for the trough plasma concentration of afatinib.\n\ncancers-13-03425-t001_Table 1 Table 1 Characteristics of patients in the study.\n\nAll Patients (n = 24)\t\nFemale, n (%)\t12 (50)\t\nAge, years, median (range)\t67 (46−79)\t\nHeight, cm, median (range)\t158.9 (145.2−177.8)\t\nBody weight, kg, median (range)\t57.4 (37.2−77.1)\t\nBody mass index, kg/m2, median (range)\t22.7 (15.27−28.49)\t\nBody surface area, m2, median (range)\t1.58 (1.30−1.84)\t\nEGFR mutation, n (%)\t\t\nExon 19del\t9 (37.5)\t\nL858R\t15 (62.5)\t\nECOG performance status, n (%)\t\t\n0\t12 (50)\t\n1\t12 (50)\t\nStage, n (%)\t\t\nPostoperative recurrence\t3 (12.5)\t\nIII B\t3 (12.5)\t\nIV\t18 (75)\t\nDose reduction of afatinib, n (%)\t\t\nReduction\t20 (83.3)\t\nNonreduction\t4 (16.7)\t\nECOG, Eastern Cooperative Oncology Group; EGFR, epidermal growth factor receptor.\n\ncancers-13-03425-t002_Table 2 Table 2 Logistic regression analysis for the dose reduction of afatinib and the parameters of the receiver operating characteristic (ROC) curve.\n\np-Value\tArea under the ROC Curve\tCut-off for Trough Plasma Concentration (ng/mL)\tSensitivity\tSpecificity\t\n0.0472\t0.8125\t21.4\t0.80\t0.75\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Gelatti A.C. Drilon A. Santini F.C. Optimizing the sequencing of tyrosine kinase inhibitors (TKIs) in epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) Lung Cancer 2019 137 113 122 10.1016/j.lungcan.2019.09.017 31568888\n2. Li D. Ambrogio L. Shimamura T. Kubo S.H. Takahashi M. Chirieac L.R. Padera R.F. Shapiro G.I. Baum A. Himmelsbach F. BIBW2992, an irreversible EGFR/HER2 inhibitor highly effective in preclinical lung cancer models Oncogene 2008 27 4702 4711 10.1038/onc.2008.109 18408761\n3. Solca F. Dahl G. Zoephel A. Bader G. Sanderson M. Klein C. Krämer O. Himmelsbach F. Haaksma E. Adolf G.R. Target Binding Properties and Cellular Activity of Afatinib (BIBW 2992), an Irreversible ErbB Family Blocker J. Pharmacol. Exp. Ther. 2012 343 342 350 10.1124/jpet.112.197756 22888144\n4. Miller V.A. Hirsh V. Cadranel J. Chen Y.-M. Park K. Kim S.-W. Zhou C. Su W.-C. Wang M. Sun Y. Afatinib versus placebo for patients with advanced, metastatic non-small-cell lung cancer after failure of erlotinib, gefitinib, or both, and one or two lines of chemotherapy (LUX-Lung 1): A phase 2b/3 randomised trial Lancet Oncol. 2012 13 528 538 10.1016/S1470-2045(12)70087-6 22452896\n5. Hirsh V. Cadranel J. Cong X.J. Fairclough D. Finnern H.W. Lorence R.M. Miller V.A. Palmer M. Yang J.C.-H. Symptom and Quality of Life Benefit of Afatinib in Advanced Non–Small-Cell Lung Cancer Patients Previously Treated with Erlotinib or Gefitinib: Results of a Randomized Phase IIb/III Trial (LUX-Lung 1) J. Thorac. Oncol. 2013 8 229 237 10.1097/JTO.0b013e3182773fce 23328549\n6. Yang J.C.-H. Shih J.-Y. Su W.-C. Hsia T.-C. Tsai C.-M. Ou S.-H.I. Yu C.-J. Chang G.-C. Ho C.-L. Sequist L.V. Afatinib for patients with lung adenocarcinoma and epidermal growth factor receptor mutations (LUX-Lung 2): A phase 2 trial Lancet Oncol. 2012 13 539 548 10.1016/S1470-2045(12)70086-4 22452895\n7. Sequist L.V. Yang J.C.-H. Yamamoto N. Obyrne K. Hirsh V. Mok T. Geater S.L. Orlov S. Tsai C.-M. Boyer M. Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations J. Clin. Oncol. 2013 31 3327 3334 10.1200/JCO.2012.44.2806 23816960\n8. Yang J.C.-H. Hirsh V. Schuler M. Yamamoto N. O’Byrne K.J. Mok T. Zazulina V. Shahidi M. Lungershausen J. Massey D. Symptom Control and Quality of Life in LUX-Lung 3: A Phase III Study of Afatinib or Cisplatin/Pemetrexed in Patients With Advanced Lung Adenocarcinoma With EGFR Mutations J. Clin. Oncol. 2013 31 3342 3350 10.1200/JCO.2012.46.1764 23816967\n9. Katakami N. Atagi S. Goto K. Hida T. Horai T. Inoue A. Ichinose Y. Koboyashi K. Takeda K. Kiura K. LUX-Lung 4: A Phase II Trial of Afatinib in Patients With Advanced Non–Small-Cell Lung Cancer Who Progressed During Prior Treatment With Erlotinib, Gefitinib, or Both J. Clin. Oncol. 2013 31 3335 3341 10.1200/JCO.2012.45.0981 23816963\n10. Schuler M. Yang J.C.-H. Park K. Kim J.-H. Bennouna J. Chen Y.-M. Chouaid C. De Marinis F. Feng J.-F. Grossi F. Afatinib beyond progression in patients with non-small-cell lung cancer following chemotherapy, erlotinib/gefitinib and afatinib: Phase III randomized LUX-Lung 5 trial Ann. Oncol. 2016 27 417 423 10.1093/annonc/mdv597 26646759\n11. Wu Y.-L. Zhou C. Hu C.-P. Feng J. Lu S. Huang Y. Li W. Hou M. Shi J.H. Lee K.Y. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): An open-label, randomised phase 3 trial Lancet Oncol. 2014 15 213 222 10.1016/S1470-2045(13)70604-1 24439929\n12. Geater S.L. Xu C.-R. Zhou C. Hu C.-P. Feng J. Lu S. Huang Y. Juliane L. Hou M. Shi J.H. Symptom and Quality of Life Improvement in LUX-Lung 6: An Open-Label Phase III Study of Afatinib Versus Cisplatin/Gemcitabine in Asian Patients With EGFR Mutation-Positive Advanced Non–small-cell Lung Cancer J. Thorac. Oncol. 2015 10 883 889 10.1097/JTO.0000000000000517 25933111\n13. Yang J.C.-H. Wu Y. Schuler M. Sebastian M. Popat S. Yamamoto N. Zhou C. Hu C.-P. O’Byrne K. Feng J. Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): Analysis of overall survival data from two randomised, phase 3 trials Lancet Oncol. 2015 16 141 151 10.1016/S1470-2045(14)71173-8 25589191\n14. Park K. Tan E.-H. O’Byrne K. Zhang L. Boyer M. Mok T. Hirsh V. Yang J.C.-H. Lee K.H. Lu S. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): A phase 2B, open-label, randomised controlled trial Lancet Oncol. 2016 17 577 589 10.1016/S1470-2045(16)30033-X 27083334\n15. Schuler M. Wu Y.-L. Hirsh V. O’Byrne K. Yamamoto N. Mok T. Popat S. Sequist L.V. Massey D. Zazulina V. First-Line Afatinib versus Chemotherapy in Patients with Non–Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases J. Thorac. Oncol. 2016 11 380 390 10.1016/j.jtho.2015.11.014 26823294\n16. Kato T. Yoshioka H. Okamoto I. Yokoyama A. Hida T. Seto T. Kiura K. Massey D. Seki Y. Yamamoto N. Afatinib versus cisplatin plus pemetrexed in Japanese patients with advanced non-small cell lung cancer harboring activatingEGFRmutations: Subgroup analysis of LUX-Lung 3 Cancer Sci. 2015 106 1202 1211 10.1111/cas.12723 26094656\n17. Yang J.C.-H. Sequist L.V. Zhou C. Schuler M. Geater S.L. Mok T. Hu C.-P. Yamamoto N. Feng J. O’Byrne K. Effect of dose adjustment on the safety and efficacy of afatinib for EGFR mutation-positive lung adenocarcinoma: Post hoc analyses of the randomized LUX-Lung 3 and 6 trials Ann. Oncol. 2016 27 2103 2110 10.1093/annonc/mdw322 27601237\n18. Freiwald M. Schmid U. Fleury A. Wind S. Stopfer P. Staab A. Population pharmacokinetics of afatinib, an irreversible ErbB family blocker, in patients with various solid tumors Cancer Chemother. Pharmacol. 2014 73 759 770 10.1007/s00280-014-2403-2 24522402\n19. Hayashi H. Kita Y. Iihara H. Yanase K. Ohno Y. Hirose C. Yamada M. Todoroki K. Kitaichi K. Minatoguchi S. Simultaneous and rapid determination of gefitinib, erlotinib and afatinib plasma levels using liquid chromatography/tandem mass spectrometry in patients with non-small-cell lung cancer Biomed. Chromatogr. 2016 30 1150 1154 10.1002/bmc.3642 26525154\n20. Murakami H. Tamura T. Takahashi T. Nokihara H. Naito T. Nakamura Y. Nishio K. Seki Y. Sarashina A. Shahidi M. Phase I study of continuous afatinib (BIBW 2992) in patients with advanced non-small cell lung cancer after prior chemotherapy/erlotinib/gefitinib (LUX-Lung 4) Cancer Chemother. Pharmacol. 2011 69 891 899 10.1007/s00280-011-1738-1 22071596\n21. Sato J. Morikawa N. Chiba R. Nihei S. Moriguchi S. Saito H. Yamauchi K. Kudo K. Case series on the association between blood levels and side effects of afatinib maleate Cancer Chemother. Pharmacol. 2017 80 545 553 10.1007/s00280-017-3378-6 28718011\n22. Dömötör O. Pelivan K. Borics A. Keppler B.K. Kowol C.R. Enyedy É.A. Comparative studies on the human serum albumin binding of the clinically approved EGFR inhibitors gefitinib, erlotinib, afatinib, osimertinib and the investigational inhibitor KP2187 J. Pharm. Biomed. Anal. 2018 154 321 331 10.1016/j.jpba.2018.03.011 29567575\n23. Nakao K. Kobuchi S. Marutani S. Iwazaki A. Tamiya A. Isa S. Okishio K. Kanazu M. Tamiya M. Hirashima T. Population pharmacokinetics of afatinib and exposure-safety relationships in Japanese patients with EGFR mutation-positive non-small cell lung cancer Sci. Rep. 2019 9 1 11 10.1038/s41598-019-54804-9 30626917\n24. Schnell D. Buschke S. Fuchs H. Gansser D. Goeldner R.-G. Uttenreuther-Fischer M. Stopfer P. Wind S. Petersen-Sylla M. Halabi A. Pharmacokinetics of afatinib in subjects with mild or moderate hepatic impairment Cancer Chemother. Pharmacol. 2014 74 267 275 10.1007/s00280-014-2484-y 24906422\n25. Stopfer P. Marzin K. Narjes H. Gansser D. Shahidi M. Uttereuther-Fischer M. Ebner T. Afatinib pharmacokinetics and metabolism after oral administration to healthy male volunteers Cancer Chemother. Pharmacol. 2012 69 1051 1061 10.1007/s00280-011-1803-9 22200729\n26. Nolin T.D. Naud J. Leblond F.A. Pichette V. Emerging Evidence of the Impact of Kidney Disease on Drug Metabolism and Transport Clin. Pharmacol. Ther. 2008 83 898 903 10.1038/clpt.2008.59 18388866\n27. Zhang Y. Zhang L. Abraham S. Apparaju S. Wu T.-C. Strong J.M. Xiao S. Atkinson A.J. Jr. Thummel K.E. Leeder J.S. Assessment of the Impact of Renal Impairment on Systemic Exposure of New Molecular Entities: Evaluation of Recent New Drug Applications Clin. Pharmacol. Ther. 2008 85 305 311 10.1038/clpt.2008.208 19020495\n28. Noda S. Otsuji T. Baba M. Yoshida T. Kageyama S. Okamoto K. Okada Y. Kawauchi A. Onishi H. Hira D. Assessment of Sunitinib-Induced Toxicities and Clinical Outcomes Based on Therapeutic Drug Monitoring of Sunitinib for Patients with Renal Cell Carcinoma Clin. Genitourin. Cancer 2015 13 350 358 10.1016/j.clgc.2015.01.007 25701374\n29. Suttle A.B. Ball H.A. Molimard M. Hutson T. Carpenter C.M. Rajagopalan D. Lin Y. Swann S.L. Amado R.G. Pandite L. Relationships between pazopanib exposure and clinical safety and efficacy in patients with advanced renal cell carcinoma Br. J. Cancer 2014 111 1909 1916 10.1038/bjc.2014.503 25349968\n30. Noda S. Yoshida T. Hira D. Murai R. Tomita K. Tsuru T. Kageyama S. Kawauchi A. Ikeda Y. Morita S.-Y. Exploratory Investigation of Target Pazopanib Concentration Range for Patients With Renal Cell Carcinoma Clin. Genitourin. Cancer 2019 17 e306 e313 10.1016/j.clgc.2018.12.001 30598361\n31. Wind S. Giessmann T. Jungnik A. Brand T. Marzin K. Bertulis J. Hocke J. Gansser D. Stopfer P. Pharmacokinetic Drug Interactions of Afatinib with Rifampicin and Ritonavir Clin. Drug Investig. 2014 34 173 182 10.1007/s40261-013-0161-2 24399452\n\n",
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"keywords": "afatinib; epidermal growth factor receptor; non-small-cell lung cancer; receiver operating characteristic curve; trough plasma concentration; tyrosine kinase inhibitor",
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"title": "High-Trough Plasma Concentration of Afatinib Is Associated with Dose Reduction.",
"title_normalized": "high trough plasma concentration of afatinib is associated with dose reduction"
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"abstract": "Mycetoma (or \"madura foot\") is characterized by deformation, cutaneous lesions, infection of tissues extending from the cutaneous layer to the underlying fascia, and an indolent course. A number of fungal or bacterial agents that are introduced through traumatic inoculation can be responsible for the disease, but Actinomadura madurae is among the most common agents of mycetoma occurring worldwide. We report a case of madura foot caused by A. madurae in an immunocompetent young Somali man who was admitted with a diagnosis of skin and soft tissue infection of the left foot with osteomyelitis. The present report emphasizes the importance of the knowledge of this infection, which is sporadic but problematic to treat and, above all, difficult to diagnose. Moreover, a multidisciplinary approach with involvement of an infectious diseases specialist with experience in tropical diseases and a microbiology unit performing rapid molecular diagnostic tests is required for early diagnosis and an optimal antibiotic therapy.",
"affiliations": "Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.;Department of Sciences for Health Promotion and Mother and Child care \"G. D'Alessandro\", University of Palermo, Palermo, Italy.",
"authors": "Fasciana|Teresa|T|;Colomba|Claudia|C|;Cervo|Adriana|A|;Di Carlo|Paola|P|;Scarlata|Francesco|F|;Mascarella|Chiara|C|;Giammanco|Anna|A|;Cascio|Antonio|A|",
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"issue": "26(2)",
"journal": "Le infezioni in medicina",
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"medline_ta": "Infez Med",
"mesh_terms": "D000076263:Communicable Diseases, Imported; D006801:Humans; D007558:Italy; D008297:Male; D008271:Mycetoma; D012998:Somalia; D055815:Young Adult",
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"pages": "167-170",
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"pmid": "29932092",
"pubdate": "2018-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Madura foot: an imported case of a non-common diagnosis.",
"title_normalized": "madura foot an imported case of a non common diagnosis"
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"abstract": "BACKGROUND\nHepatitis B infection is a significant worldwide health issue, predispose to the development of liver cirrhosis and hepatocellular carcinoma. Entecavir is a potent oral antiviral agent of high genetic barrier for the treatment of chronic hepatitis B infection. Cutaneous adverse reaction associated with entecavir has rarely been reported in literature. As our knowledge, this case was the first case reported on entecavir induced lichenoid drug eruption.\n\n\nMETHODS\n55 year old gentlemen presented with generalised pruritic erythematous rash on trunk and extremities. Six weeks prior to his consultation, antiviral agent entecavir was commenced for his chronic hepatitis B infection. Skin biopsy revealed acanthosis and focal lymphocytes with moderate perivascular lymphocyte infiltration. Skin condition recovered completely after caesation of offending drug and short course of oral corticosteroids.\n\n\nCONCLUSIONS\nThis case highlight the awareness of clinicians on the spectrum of cutaneous drug reaction related to entecavir therapy.",
"affiliations": "Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Kuala Lumpur, Malaysia.;Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Kuala Lumpur, Malaysia. wzhiqin@ppukm.ukm.edu.my.;Dermatology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Kuala Lumpur, Malaysia.;Department of Pathology, Hospital Pantai Kuala Lumpur, Jalan Bukit Pantai, Bangsar, 59100, Kuala Lumpur, Malaysia.",
"authors": "Cheong|Xiong Khee|XK|;Wong|Zhiqin|Z|;Nor|Norazirah Md|NM|;Lee|Bang Rom|BR|",
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"doi": "10.1186/s12876-020-01452-3",
"fulltext": "\n==== Front\nBMC Gastroenterol\nBMC Gastroenterol\nBMC Gastroenterology\n1471-230X BioMed Central London \n\n1452\n10.1186/s12876-020-01452-3\nCase Report\n“Black box warning” rash with entecavir - case report\nCheong Xiong Khee cheongxk@gmail.com 1 Wong Zhiqin wzhiqin@ppukm.ukm.edu.my 2 Nor Norazirah Md norazirah78@gmail.com 3 Lee Bang Rom leebangrom@yahoo.com 4 1 grid.412113.40000 0004 1937 1557Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia \n2 grid.412113.40000 0004 1937 1557Gastroenterology and Hepatology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia \n3 grid.412113.40000 0004 1937 1557Dermatology Unit, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Jalan Yaacob Latif, Bandar Tun Razak, 56000 Kuala Lumpur, Malaysia \n4 Department of Pathology, Hospital Pantai Kuala Lumpur, Jalan Bukit Pantai, Bangsar, 59100 Kuala Lumpur, Malaysia \n18 9 2020 \n18 9 2020 \n2020 \n20 30518 8 2020 13 9 2020 © The Author(s) 2020Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nHepatitis B infection is a significant worldwide health issue, predispose to the development of liver cirrhosis and hepatocellular carcinoma. Entecavir is a potent oral antiviral agent of high genetic barrier for the treatment of chronic hepatitis B infection. Cutaneous adverse reaction associated with entecavir has rarely been reported in literature. As our knowledge, this case was the first case reported on entecavir induced lichenoid drug eruption.\n\nCase presentation\n55 year old gentlemen presented with generalised pruritic erythematous rash on trunk and extremities. Six weeks prior to his consultation, antiviral agent entecavir was commenced for his chronic hepatitis B infection. Skin biopsy revealed acanthosis and focal lymphocytes with moderate perivascular lymphocyte infiltration. Skin condition recovered completely after caesation of offending drug and short course of oral corticosteroids.\n\nConclusion\nThis case highlight the awareness of clinicians on the spectrum of cutaneous drug reaction related to entecavir therapy.\n\nKeywords\nDrug eruptionEntecavirHepatitis Bissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nHepatitis B infection is a global health issue, contributing to approximately 887,000 deaths in 2015 due to hepatocellular carcinoma and liver cirrhosis [1, 2]. Entecavir is a nucleoside analogue reverse transcriptase inhibitor that is widely used in the treatment of chronic hepatitis B (HBV) infection. Adverse events associated with entecavir that commonly reported were headache, fatigue, myalgia, dizziness, nausea, raise alanine transaminase (ALT) and lactic acidosis. Cutaneous adverse reactions is a rare complication, only reported in few case reports. A case of lichenoid drug eruption associated with entecavir therapy has been described here for its rarity and unusual adverse effect.\n\nCase presentation\nA 55 years old gentlemen, background of chronic hepatitis B (treatment naïve), was referred for 2 weeks of generalised itchy erythematous rash. His other medical illnesses were ischemic heart disease, chronic kidney disease stage 3, diabetes mellitus and hypertension of which he has been on a stable medication for one year with no recent alteration of medications except for initiation of treatment for hepatitis B. Entecavir 0.5 mg once in 48 h was initiated 2 months ago in view of fibroscan revealed significant liver fibrosis with eGFR ranging between 30 and 49 mL/min/1.73m2. Four weeks after initiation of entecavir therapy, he developed multiple pruritic erythematous patches started on bilateral legs and gradually spread to lower thighs and trunk. The patient did not show other systemic symptoms. On examination, there was extensive erythematous patches with scaly edges involving the lower limbs and trunk. The face, palms and soles and the oral mucosa were spared (Fig. 1). There was no associated lymphadenopathy and other systemic examinations were normal. Laboratory investigations revealed normal leucocyte count (8.5 × 109/L) with elevated absolute eosinophils count of 1.0 × 109/L and raised C-reactive protein of 8.29 mg/dL (normal range ≤ 0.5). Liver function test was normal and renal profile similar with baseline, creatinine of 158 mmol/L.\nFig. 1 Pruritic erythematous patches with scaly on right lower limb\n\n\n\nSkin biopsy showed acanthosis and focal lymphocytes with dyskeratotic cells in the epidermis. There were moderate perivascular lymphocyte infiltration and occasional eosinophils at the dermis (Fig. 2a and b); no extravasation of red blood cell or vasculitic features noted. Skin patch or prick test was not performed for this patient. The patient was diagnosed with lichenoid drug eruption secondary to entecavir based on the clinical and histopathological findings.\nFig. 2 a & b: Mild acanthosis and focal parakeratosis in the epidermis. Lymphocytic inflammatory infiltrate at dermal interface and perivascular lymphocytic infiltration with occasional eosinophils at the dermis (Hematoxylin and eosin stain × 200 magnification)\n\n\n\nEntecavir was discontinued immediately. The patient was started on oral corticosteroids at dose of 30 mg/day oral prednisolone and topical emollients. The lesions improved remarkably after two weeks of caseation of entecavir and initiation of oral corticosteroid. Oral prednisolone was gradually tapering off the period of over two weeks. Two months later, he was started on Tenofovir Alanfenamide 25 mg once daily for his hepatitis B treatment, he tolerated well and no further adverse events reported.\n\nDiscussion and conclusions\nEntecavir is a potent oral antiviral agent that effectively controlled chronic hepatitis B infection in adult and children. It is a nucleoside analogue that highly selective inhibitor of DNA polymerase, with a high genetic barrier towards hepatitis B virus (HBV). Clinical trials have proven that entecavir is superior to lamivudine on the treatment of drug naïve chronic hepatitis B infection by histological improvement and reduction of serum HBV DNA level [3, 4]. The commonest adverse events reported were increased ALT, lactic acidosis, headache, fatigue, dizziness, nausea and peripheral neuropathy [4].\n\nThere were limited cases published on cutaneous adverse reactions caused by entecavir (Table 1). Skin manifestation were presented in various types; from immediate allergy skin reaction [5], maculopapular rash [6, 7], granulomatous [8], bullous type [9] to erythematous patches [10]. The time interval between exposure of entecavir and the onset of symptoms varies from 2 days to 6 months.\nTable 1 Summary on cases of drug eruption secondary to entecavir\n\nAuthor/Year\tAge\tSex\tClinical manifestations\tSites of lesions\tTime intervalH\tDLST (drug lymphocyte\nstimulation test)/skin patch/scratch test\tConfirmed by\nHistopathology\t\nSugiura K et al. 2009 [5]\t30\tMale\tAnaphylaxis\tButtock\t2 days\tScratch test positive\tNot done\t\nYamada S et al. 2011 [6]\t62\tMale\tMaculopapular rash\tTrunk & extremities\t7 days\tDLST positive\tNot done\t\nJimi Yoon et al. 2013 [8]\t65\tFemale\tGranulomatous\tForehead & face\t2 months\tPatch test negative\tYes\t\nMaiko Taura et al. 2014 [10]\t65\tMale\tErythematous plaque\tUpper limbs\t6 months\tDLST positive\tYes\t\nJeong Tae Kim et al. 2014 [7]\t45\tMale\tMaculopapular rash\tBack & extremities\t1 months\tNot done\tYes\t\nTemiz SA et al. 2018 [9]\t50\tFemale\tBullous eruption\tLower limb\t7 days\tNot done\tYes\t\nOur case 2020\t55\tMale\tLichenoid erythematous patch\tTrunk & extremities\t6 weeks\tNot done\tYes\t\nH time interval between drug exposure and onset of symptom\n\n\n\nThe recognition of the causative agent could be problematic if patient is taking more than one medication simultaneously. Skin biopsy is a useful diagnostic tool to rule out other differential diagnosis that mimic drug eruption.\n\nTo our knowledge, there were total of six cases that had been reported so far; this case is the seventh (Table 1). Our patient presented as generalised lichenoid erythematous patches, which was different from other reported cases. The diagnosis of entecavir associated drug eruption in this case was made based on the history of no recent exposure to other drugs and supported by the histopathology findings. Resolution of skin lesions upon discontinuation of the offending drug also favours the diagnosis.\n\nAlthough the mechanism of action of entecavir still remains unclear, it is thought that the reduction in regulatory or helper T cells during entecavir treatment, might play a role on the development of drug eruption [11]. Besides that, the chemical structure of entecavir is similar to other nucleoside analogue antiviral agents such as lobucavir, acyclovir and ganciclovir; possibly inducing the same pattern of immunologic responses that triggered hypersensitivity skin reaction [5].\n\nIt is interesting to note that all seven cases (including our case) arise from the Asian population. The association of HLA allele and occurrence of drug eruption due to entecavir is yet to be determined. We postulate that genetic predisposition could have contribute to the hypersensitivity reaction towards entecavir.\n\nThe mainstay of treatment of drug eruption is discontinuation of the causative agent. Topical corticosteroids ointment and emollients can be use as adjunctive therapy. Systemic corticosteroids should be considered in severe or extensive cutaneous eruptions.\n\nThis case highlighted the possibility and the spectrum of cutaneous drug reaction related to entecavir. Awareness on the spectrum of cutaneous reaction and its duration of onset are important among clinician prescribing etecavir.\n\nAbbreviations\nALTAlanine transaminase\n\nHBVHepatitis B virus\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nNone to declare.\n\nAuthors’ contributions\nXKC did the literature reviews and prepared the manuscript. ZW, NMN involved in correction of the manuscript. XKC, ZW, NMN, BHL were involved in the diagnosis and management of the patient. All the authors approved the manuscript.\n\nFunding\nThe authors did not receive any funding for this research.\n\nAvailability of data and materials\nThe authors declare that all data concerning this case report are provided within the manuscript.\n\nEthics approval and consent to participate\nOur institution does not require ethics approval for case reports.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Bray F Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 10.3322/caac.21492 30207593 \n2. Maucort-Boulch D Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide Int J Cancer 2018 142 12 2471 2477 10.1002/ijc.31280 29388206 \n3. Lai CL Entecavir is superior to lamivudine in reducing hepatitis B virus DNA in patients with chronic hepatitis B infection Gastroenterology 2002 123 6 1831 1838 10.1053/gast.2002.37058 12454840 \n4. Chang T-T A comparison of Entecavir and lamivudine for HBeAg-positive chronic hepatitis B N Engl J Med 2006 354 10 1001 1010 10.1056/NEJMoa051285 16525137 \n5. Sugiura K Immediate allergy, drug-induced eruption, by entecavir J Eur Acad Dermatol Venereol 2009 23 4 487 489 10.1111/j.1468-3083.2008.02932.x 18721215 \n6. Yamada S Sawada Y Nakamura M Maculopapular-type drug eruption caused by entecavir Eur J Dermatol 2011 21 4 635 636 10.1684/ejd.2011.1411 21697053 \n7. Kim J, et al. Delayed hypersensitivity reaction resulting in maculopapular-type eruption due to entecavir in the treatment of chronic hepatitis B. World J Gastroenterol. 2014;20:15931–6.\n8. Yoon J, Park D, Kim C. A granulomatous drug eruption induced by entecavir. Ann Dermatol. 2013;25(4):493–5.\n9. Temiz SA, et al. A case of entecavir-associated bullous fixed drug eruption and a review of literature. Turk J Gastroenterol. 2019;30(3):299–302.\n10. Taura M, et al. Drug eruption due to entecavir: A case report and mini-review. Allergol Int. 2016:65.\n11. Zhang J-Y Decreased ratio of Treg cells to Th17 cells correlates with HBV DNA suppression in chronic hepatitis B patients undergoing Entecavir treatment PLoS One 2010 5 11 e13869 10.1371/journal.pone.0013869 21079784\n\n",
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"mesh_terms": "D000998:Antiviral Agents; D005076:Exanthema; D006147:Guanine; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008113:Liver Neoplasms; D008875:Middle Aged; D016896:Treatment Outcome",
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"abstract": "OBJECTIVE\nThe prognosis of hepatocellular carcinoma (HCC) patients treated with transcatheter arterial chemoembolization (TACE) is still poor. We aimed to evaluate the impact of TACE combined with radiofrequency ablation (TACE+RFA) on the prognosis of HCC patients using decision-tree analysis after propensity score matching.\n\n\nMETHODS\nThis was a retrospective study. We enrolled 420 patients with HCC treated with TACE alone (n = 311) or TACE+RFA (n = 109) between 1998 and 2016 (median age, 72 years; male / female, 272/148; Barcelona Clinic Liver Cancer (BCLC) stage A / B, 215/205). The prognosis of patients who underwent TACE+RFA was compared to patients who underwent TACE alone after propensity score matching. Decision-tree analysis was used to investigate the profile for prognosis of the patients.\n\n\nRESULTS\nAfter propensity score matching, there was no significant difference in age, sex, BCLC stage, or albumin-bilirubin (ALBI) score between both groups. The survival rate of the TACE+RFA group was significantly higher than the TACE alone group (median survival time [MST] 57.9 months vs. 33.1 months, P < 0.001). In a stratification analysis according to BCLC stage, the overall survival rate of the TACE+RFA group was significantly higher than the TACE alone group in BCLC stage A and B (MST 57.9 and 50.7 months vs. 39.8 and 24.5 months [P = 0.007 and 0.001], respectively). Decision-tree analysis showed that TACE+RFA was the third distinguishable factor for survival in patients with α-fetoprotein level >7 ng/mL and ALBI <-2.08.\n\n\nCONCLUSIONS\nDecision-tree analysis after propensity score matching showed that TACE+RFA could prolong the survival of HCC patients compared to TACE alone.",
"affiliations": "Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Clinical Research Center, Yokokura Hospital, Miyama, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Center for Comprehensive Community Medicine, Faculty of Medicine, Saga University, Saga, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.;Department of Surgery, Yokokura Hospital, Miyama, Japan.;Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan.",
"authors": "Shimose|Shigeo|S|;Tanaka|Masatoshi|M|;Iwamoto|Hideki|H|;Niizeki|Takashi|T|;Shirono|Tomotake|T|;Aino|Hajime|H|;Noda|Yu|Y|;Kamachi|Naoki|N|;Okamura|Shusuke|S|;Nakano|Masahito|M|;Kuromatsu|Ryoko|R|;Kawaguchi|Takumi|T|https://orcid.org/0000-0002-7064-4325;Kawaguchi|Atsushi|A|;Koga|Hironori|H|;Yokokura|Yoshinori|Y|;Torimura|Takuji|T|",
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"keywords": "HCC treatment; advanced HCC; exploratory data analysis; hepatoma",
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"title": "Prognostic impact of transcatheter arterial chemoembolization (TACE) combined with radiofrequency ablation in patients with unresectable hepatocellular carcinoma: Comparison with TACE alone using decision-tree analysis after propensity score matching.",
"title_normalized": "prognostic impact of transcatheter arterial chemoembolization tace combined with radiofrequency ablation in patients with unresectable hepatocellular carcinoma comparison with tace alone using decision tree analysis after propensity score matching"
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"abstract": "A case of acute oliguric renal failure following gentamicin and linocomycin therapy is described. Renal biopsy showed an acute interstitial nephritis. This was associated with high serum gentamicin levels and the later development of ototoxicity. Withdrawal of antibiotics and conservative measures was followed by rapid recovery of renal function. Attention is drawn to the association between gentamicin and lincomycin therapy and the development of an acute interstitial nephritis.",
"affiliations": null,
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"mesh_terms": "D000208:Acute Disease; D000368:Aged; D005260:Female; D005839:Gentamicins; D006801:Humans; D007684:Kidney Tubules; D008034:Lincomycin; D009395:Nephritis, Interstitial",
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"title": "Acute interstitial nephritis associated with gentamicin and lincomycin therapy.",
"title_normalized": "acute interstitial nephritis associated with gentamicin and lincomycin therapy"
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"abstract": "BACKGROUND\nSodium valproate is widely used in the treatment of epilepsy in clinical practice. Most adverse reactions to sodium valproate are mild and reversible, while serious idiosyncratic side effects are becoming apparent, particularly hepatotoxicity. Herein, we report a case of fatal acute liver failure (ALF) with thrombotic microangiopathy (TMA) caused by treatment with sodium valproate in a patient following surgery for meningioma.\n\n\nMETHODS\nA 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue, severe jaundice accompanied by oliguria, soy sauce-colored urine, and ecchymosis. His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level, severe liver and kidney dysfunction, and disturbance of the coagulation system. He was diagnosed with drug-induced liver failure combined with TMA. After plasma exchange combined with hemoperfusion, pulse therapy with high-dose methylprednisolone, and blood transfusion, his liver function deteriorated, and finally, he died.\n\n\nCONCLUSIONS\nALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.",
"affiliations": "Department of Hepatobiliary Internal Medicine, The 900 Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China.;Department of Hepatobiliary Internal Medicine, The 900 Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China. 847614051@qq.com.;Department of Hepatobiliary Internal Medicine, The third affiliated people's hospital of FuJian University of traditional Chinese medicine, Fuzhou 350100, Fujian Province, China.;Department of Hepatobiliary Internal Medicine, The 900 Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China.",
"authors": "Mei|Xuan|X|;Wu|Hai-Cong|HC|;Ruan|Mei|M|;Cai|Li-Rong|LR|",
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"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i17.pg4310\n10.12998/wjcc.v9.i17.4310\nCase Report\nAcute liver failure with thrombotic microangiopathy due to sodium valproate toxicity: A case report\nMei X et al. Sodium valproate-induced ALF with TMA\nMei Xuan Department of Hepatobiliary Internal Medicine, The 900th Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China\n\nWu Hai-Cong Department of Hepatobiliary Internal Medicine, The 900th Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China. 847614051@qq.com\n\nRuan Mei Department of Hepatobiliary Internal Medicine, The third affiliated people's hospital of FuJian University of traditional Chinese medicine, Fuzhou 350100, Fujian Province, China\n\nCai Li-Rong Department of Hepatobiliary Internal Medicine, The 900th Hospital of PLA Joint Logistics Support Force, Fuzhou 350025, Fujian Province, China\n\nAuthor contributions: Mei X analyzed the data, reviewed the literature, and wrote the manuscript; Ruan M and Cai LR performed the diagnostic investigations and treatments, and collected the data; Wu HC followed the patient and reviewed and revised the manuscript; all authors have read and approved the final manuscript.\n\nCorresponding author: Hai-Cong Wu, MS, Attending Doctor, Department of Hepatobiliary Internal Medicine, The 900th Hospital of PLA Joint Logistics Support Force, No. 156 North of West Second Ring Road, Gulou District, Fuzhou 350025, Fujian Province, China. 847614051@qq.com\n\n16 6 2021\n16 6 2021\n9 17 43104317\n10 1 2021\n21 2 2021\n2 4 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/Licenses/by-nc/4.0/\nBACKGROUND\n\nSodium valproate is widely used in the treatment of epilepsy in clinical practice. Most adverse reactions to sodium valproate are mild and reversible, while serious idiosyncratic side effects are becoming apparent, particularly hepatotoxicity. Herein, we report a case of fatal acute liver failure (ALF) with thrombotic microangiopathy (TMA) caused by treatment with sodium valproate in a patient following surgery for meningioma.\n\nCASE SUMMARY\n\nA 42-year-old man who received antiepileptic treatment with sodium valproate after surgery for meningioma exhibited extreme fatigue, severe jaundice accompanied by oliguria, soy sauce-colored urine, and ecchymosis. His postoperative laboratory values indicated a rapid decreased platelet count and hemoglobin level, severe liver and kidney dysfunction, and disturbance of the coagulation system. He was diagnosed with drug-induced liver failure combined with TMA. After plasma exchange combined with hemoperfusion, pulse therapy with high-dose methylprednisolone, and blood transfusion, his liver function deteriorated, and finally, he died.\n\nCONCLUSION\n\nALF with TMA is a rare and fatal adverse reaction of sodium valproate which needs to be highly valued.\n\nSodium valproate\nDrug-induced liver injury\nThrombotic microangiopathy\nPlasma exchange\nOrgan transplantation\nCase report\n==== Body\nCore Tip: Sodium valproate is widely used in the treatment of epilepsy in clinical practice although it has potential hepatotoxicity. Herein, we report a case of fatal acute liver failure (ALF) with thrombotic microangiopathy (TMA) caused by sodium valproate treatment. A history of chronic hepatitis B virus infection or combination therapy with sodium valproate and carbapenem may increase the risk of ALF. The combination therapy of plasma exchange, glucocorticoid, and supportive therapy is essential for TMA. Organ transplantation at the early stage of the disease may be the first choice for critically ill patients. Our case report can facilitate further studies on the diagnosis and therapy of ALF with TMA.\n\nINTRODUCTION\n\nSodium valproate is one of the common fatty-acid antiepileptic drugs in the current daily clinical routine[1]. It is effective in the treatment of various types of epilepsy to different extents. With extensive application in the clinic, an increasing number of adverse reactions of sodium valproate have been reported[2,3]. Adverse reactions involve multiple organ systems, such as the hematological system, nervous system, and digestive system[4]. Sodium valproate has been the most common drug to induce liver injury among all antiepileptic drugs in recent years[5]. The proportion of patients with hepatic dysfunction caused by sodium valproate has been reported to be as high as 5%-10%[3]. Symptoms in most patients are temporary and reversible, while a minority can be fatal, and some patients can develop drug-induced thrombotic microangiopathy (DI-TMA)[6]. We report a case of sodium valproate-induced acute liver failure (ALF) with thrombotic microangiopathy (TMA), which has not been reported previously.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 42-year-old male was admitted to the Department of Hepatobiliary Internal Medicine 10 d following surgery for meningioma with fatigue and abdominal distension for 1 d.\n\nHistory of present illness\n\nTen days before admission to the Department of Hepatobiliary Internal Medicine, the patient underwent surgery for atypical meningioma (World Health Organization grade II) resection because of progressive deterioration of vision in the right eye for more than half a year and headache for more than one month. His preoperative hematological parameters were essentially normal: Hemoglobin (Hgb), 132 g/L (130-175 g/L); platelet (PLT) count 99 × 109/L (125-350 × 109/L); alanine aminotransferase (ALT), 34.7 U/L (7-50 U/L); aspartate aminotransferase (AST), 22.5 U/L (13-40 U/L); total bilirubin (TBIL), 12 µmol/L (< 21 mmol/L); direct bilirubin (DBIL), 2.7 µmol/L (< 5 mmol/L); indirect bilirubin (IBIL), 9.3 µmol/L (< 16 mmol/L); creatine kinase (CK), 86 U/L (26-174 U/L); lactate dehydrogenase (LDH), 226 U/L (109-245 U/L); serum creatinine (Scr), 94 µmol/L (53-115 mmol /L); prothrombin time (PT), 11.9 s (9.8-12.1s); international normalized ratio (INR), 1.05 (0.82-1.15); D-dimer (D-D), 0.14 mg/L (< 0.5 mg/L); fibrinogen (FIB), 2.48 g/L (2-4 g/L). Preoperative abdominal color Doppler ultrasound showed that his other organs were normal except a mildly coarse hepatic parenchymal echotexture. Cranial contrast-enhanced magnetic resonance imaging indicated the right sphenoid ridge meningioma (6.6 cm × 5.5 cm). After the surgery, sodium valproate 1.2 g per day was used to treat secondary epilepsy. On postoperative day 3, sodium valproate was increased to 1.6 g per day and was given for 7 d due to the exacerbation of secondary epilepsy. On postoperative day 5, the patient started to develop symptoms of cerebral edema with headaches and intermittent vomiting; therefore, methylprednisolone 1000 mg per day was given for 4 d (postoperative day 5 to day 8). During his surgical hospitalization, because of fever on postoperative day 1 and increased cerebrospinal fluid leukocytes on postoperative day 5, antibiotics were used for anti-infective therapy as follows: Ceftriaxone plus vancomycin (postoperative day 1 to day 4) and biapenem plus linezolid (postoperative day 5 to day 9). The major medications used in the patient during hospitalization are recorded in Figure 1.\n\nFigure 1 Major medications used in the patient during hospitalization. The dosage of the antibiotics are as follows: Ceftriaxone 2 g/q12h; vancomycin 1000 mg/q12h; biapenem 0.6 g/q12h; linezolid 600 mg/q12h.\n\nOn postoperative day 9, the patient began to experience restlessness and progressive abdominal distension. His hematological parameters were as follows: Hgb, 103 g/L; PLT count, 109 × 109/L; ALT, 5713.8 U/L; AST, 7329.5 U/L; TBIL, 71.7 µmol/L; DBIL, 33.6 µmol/L; IBIL, 38.1 µmol/L; CK, 3912 U/L; LDH, 7744 U/L; Scr, 80 µmol/L; PT, 18.3 s; INR, 1.63; and D-D, 10.63 mg/L. Then, he received treatment for liver protection, gastrointestinal motility promotion, and enema; however, he did not recover from aggravated abdominal distension and gradually developed sleepiness, fatigue, oliguria, soy sauce-colored urine, and jaundice. Therefore, sodium valproate was discontinued. and he was transferred to the Department of Hepatobiliary Internal Medicine for further treatment on postoperative day 10.\n\nHistory of past illness\n\nThe patient was diagnosed with hepatitis B surface antigen (HBsAg) positivity without antiviral treatment for 3 years due to continuous normal hepatic function, and hepatitis B virus (HBV) DNA was < 500 IU/mL (< 500 IU/mL) during periodic re-examinations.\n\nPersonal and family history\n\nThe patient did not have a history of smoking or alcoholism or a remarkable family medical history.\n\nPhysical examination\n\nThe patient was in a somnolent state with myoclonic jerks in the upper limbs. His skin and sclera were severely yellow. Bilateral petechia and ecchymosis were noted both in the lower limbs and near the injection and puncture sites. His abdomen was distended, with tympanic percussion sounds.\n\nLaboratory examinations\n\nOn postoperative day 10, the patient’s laboratory data showed that his Hgb was 61 g/L, hematocrit was 18.3% (40%-50%), PLT count was 56 × 109/L, D-D exceeded 35.2 mg/L, PT was 76.9 s, INR was 7.25, and FIB was 0.88 g/L. His reticulocyte percentage was up to 4.5% (0.5%-1.5%). Although the urinalysis revealed that his urine was positive for occult blood and urobilinogen, there were no fragmented erythrocytes on the peripheral blood smear. His ALT was 16144.0 U/L, AST exceeded 21000.0 U/L, CK was 4471.0 U/L, LDH was 21962.0 U/L, TBIL was 144.1 µmol/L, DBIL was 19.6 µmol/L, IBIL was 124.5 µmol/L, and Scr was 255.0 µmol/L. HBV DNA, ceruloplasmin, and autoimmune antibodies in his serum were all negative. The hematological indices of the patient during hospitalization are shown in Figure 2.\n\nFigure 2 Hematological indices of the patient during hospitalization. A: Serum aminotransferase; B: Serum bilirubin; C: Renal function; D: Serum myocardial enzymes; E: Coagulation function; F: Routine blood parameters. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; TBIL: Total bilirubin; DBIL: Direct bilirubin; IBIL: Indirect bilirubin; Scr: Serum creatinine; BUN: Blood urea nitrogen; LDH: Lactate dehydrogenase; CK: Creatine kinase; PT: Prothrombin time; INR: International Normalized Ratio; D-D: D-dimer; FIB: Fibrinogen; Hgb: Hemoglobin; PLT: Platelet; HCT: Hematocrit.\n\nImaging examinations\n\nThe morphology and density of the liver were normal on preoperative day 5. On postoperative day 9, geographical patterns of low-density shadow in the liver were demonstrated on computed tomography (CT), which suggested extensive hepatic necrosis. No noticeable abnormality was detected in the kidneys and spleen, but a small amount of pelvic and peritoneal effusions. The abdominal CT of the patient during hospitalization is shown in Figure 3.\n\nFigure 3 Abdominal computed tomography of the patient during hospitalization. A: On preoperative day 5, the morphology and density of the liver were normal; B: On postoperative day 9, the density of several parts of the liver was low.\n\nFINAL DIAGNOSIS\n\nThe patient was diagnosed with drug-induced liver injury (DILI) (hepatocellular type, acute, RUCAM score 6 (probable), level 5 severity of liver injury) complicated with TMA.\n\nTREATMENT\n\nThe patient was placed on the active waiting list for liver transplantation as soon as the diagnosis was made. Sequential plasma exchange (PE) with fresh frozen plasma and hemoperfusion were initiated immediately after admission. After the above therapy, the patient was still anuric, and continuous renal replacement therapy was performed. He underwent treatment with methylprednisolone 80 mg per day for 2 d on the basis of PE. Meanwhile, he was given human prothrombin complex and washed red blood cells to improve coagulation function and anemia. Polyene phosphatidylcholine, glutathione, ademetionine 1,4-butanedisulfonate, and ornithine aspartate were used to promote hepatic recovery.\n\nOUTCOME AND FOLLOW-UP\n\nAfter treatment, the patient’s hemolysis was controlled, the color of his separated plasma gradually changed from red-brown to dark yellow, and the hemoglobin level did not decline. However, he was still in a persistent anuric and coma state, and there were no suitable liver or kidney sources for transplantation. Finally, the patient died in the early morning of postoperative day 12.\n\nDISCUSSION\n\nOn the 9th postoperative day for meningioma, the patient developed ALF with extreme fatigue, severe jaundice, prolonged prothrombin time, and acute progressive hepatic coma. Although he was an HBsAg carrier, the HBV DNA in his serum was negative; thus, the possibility of liver injury caused by HBV reactivation can be excluded. In addition, the patient’s history suggested no trauma, exertion, hyperthermia, or infections, which are common causes for liver failure, and his symptoms did not include myalgia, which is typical in rhabdomyolysis. Although he was on several medications during hospital stay, the major adverse effects did not include rhabdomyolysis. Therefore, the liver failure was not considered to be associated with rhabdomyolysis. Because his alcoholism history and hematological indices of autoimmune diseases were negative, we finally considered his ALF to be attributed to the drug.\n\nSodium valproate, vancomycin, and linezolid are the common drugs associated with DILI[5,7,8]. Among all the adverse reactions of vancomycin, most are rapid onset, and renal injury occurs more frequently than liver injury[9]. Common adverse reactions of linezolid include myelotoxicity and peripheral and optic neuropathy[10]. Studies show that liver injury induced by linezolid usually occurs after two weeks of medication, with a mild elevation of transaminase[11]. The characteristics of our patient who developed severe liver dysfunction after using linezolid for only 5 d were inconsistent with those reported in the literature. Liver injury is one of the most often reported adverse effects of sodium valproate because sodium valproate is metabolized by glucuronidation and mitochondrial beta-oxidation in the liver[5]. ALF due to sodium valproate can still be encountered in the clinic[12]. The RUCAM scoring table is recognized as the primary DILI causality assessment tool[13]. The RUCAM score of this patient was 6 (probable) when we completed the causality assessment for sodium valproate. Thus, we considered that his liver injury was induced by sodium valproate.\n\nSodium valproate, as one of the most widely used broad-spectrum antiepileptic drugs, has been used as a first-line treatment in clinical practice[1]. It has the characteristics of high bioavailability, good tolerability, and remarkable efficacy except for a narrow therapeutic window[14]. A black box warning of severe hepatotoxicity with sodium valproate was published by the Food and Drug Administration[15]. The pathogenesis of the toxic effects of sodium valproate on the liver has not yet been fully elucidated. The obstacles of cytochrome P450 metabolism and β-oxidation in mitochondria are generally considered the major mechanisms of the hepatotoxicity of sodium valproate, while the former is an important factor for individual differences in liver injury. Studies have shown that risk factors for fatal liver failure caused by sodium valproate include age younger than 2 years, combination therapy with sodium valproate and other antiepileptic drugs, pregnancy, a history of liver diseases, and other neurological diseases[16,17]. It is controversial whether the liver injury induced by sodium valproate is related to the plasma concentration of sodium valproate. The research has shown that patients with high plasma concentrations of sodium valproate are more susceptible to liver injury than those with low plasma concentrations[18]. However, Ghozzi et al[19] supposed that liver injury is independent of the sodium valproate plasma concentration. However, there is currently no research on the correlation between HBV infection and liver injury induced by sodium valproate. Therefore, whether the fatal liver failure induced by sodium valproate in our patient is related to HBV infection needs further research.\n\nExcept for ALF, TMA should be considered in diagnosis. Generally, microangiopathic hemolytic anemia is a sine qua non for the diagnosis of TMA[20]. This patient exhibited anuria, hemoglobinuria, progressively decreased levels of hemoglobin and platelets, elevated proportion of reticulocytes, and significantly elevated bilirubin and D-D level during the early stage of his disease, which were consistent with the characteristics of TMA. However, no fragmented erythrocytes were observed on the peripheral blood smear either before or after PE. Cases of TMA without the presence of fragmented erythrocytes on the peripheral blood smear have been reported previously[21,22]. This patient responded to PE and methylprednisolone. Therefore, a diagnosis of TMA was suggested. As far as we are concerned, the presence of fragmented erythrocytes is essential for TMA diagnosis in most cases, but not all.\n\nTMA is defined as a clinical syndrome characterized by thrombocytopenia, hemolytic anemia, and multiple organ dysfunction[21]. The microthrombosis of capillaries and arterioles is the typical pathological feature of TMA. Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) are the two clinical presentation forms of TMA. TTP mostly involves the nervous system, while there is a preponderance of renal injury in HUS patients. The etiology of TMA is multifactorial, including genetic factors and acquired risk factors. DI-TMA is a type of acquired TMA that is caused by multiple drugs, such as antitumor agents, antiplatelet drugs, and oral contraceptives. Studies show that DI-TMA occurs via two main mechanisms: Immune-mediated reactions or dose-dependent toxicity[23]. TMA mediated by dose-dependent reactions has a slow, progressive onset, while immune-mediated TMA has a rapid onset[21]. Our patient can be classified as having immune-mediated DI-TMA.\n\nFor the patient, it was inferred that sodium valproate plus carbapenem antibiotics might increase the risk of hemolysis, which could cause TMA. However, the period of the combination was short. König et al[24] showed that sodium valproate altered the exposure of immunoglobulin receptor and fatty acid content in the erythrocyte membrane. Alteration of the membrane fluidity and receptor proteins on the membrane would facilitate immunoglobulin to destruct erythrocytes. The correlation between destruction of erythrocytes and plasma level of sodium valproate remains unclear. Carbapenem antibiotics can reduce the plasma level of sodium valproate by inhibiting multidrug resistance-associated proteins, which can efflux sodium valproate back to the plasma from erythrocytes and result in an increased erythrocyte distribution of sodium valproate[25]. Therefore, it would be of great significance to study the effects of interaction between carbapenem antibiotics and sodium valproate on hemolysis.\n\nIn summary, this is the first case report of ALF with TMA caused by sodium valproate, which is notable. However, there were some limitations to our study. Liver pathology was unavailable. Without results regarding ADAMTS13 activities or anti-ADAMTS13 antibodies, we found it difficult to distinguish between HUS and TTP in this patient. Establishing an animal model can facilitate further studies on pathogenesis and pathophysiological state.\n\nCONCLUSION\n\nALF with TMA, which has not been reported before, is a fatal complication caused by sodium valproate. It is a disease with sudden onset and rapid progression, which needs great attention. A history of chronic HBV infection or combination therapy with sodium valproate and carbapenem may increase the risk of ALF. The combination therapy of PE, hemoperfusion, glucocorticoid, and supportive therapy is essential for TMA. However, it is not effective for all. For critically ill patients, organ transplantation should be considered first.\n\nACKNOWLEDGEMENTS\n\nThe authors would like to thank all researchers and study participants for their contributions.\n\nInformed consent statement: Informed written consent was obtained from the patient’s family for publication of this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflicts of interest to report.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: January 10, 2021\n\nFirst decision: February 11, 2021\n\nArticle in press: April 2, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: China\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B, B, B\n\nGrade C (Good): C, C\n\nGrade D (Fair): D\n\nGrade E (Poor): E\n\nP-Reviewer: Abe Y, Fahrner R, Maslennikov R, Paramesh AS, Skok P S-Editor: Liu M L-Editor: Wang TQ P-Editor: Li JH\n==== Refs\n1 Hanaya R Arita K The New Antiepileptic Drugs: Their Neuropharmacology and Clinical Indications Neurol Med Chir (Tokyo) 2016 56 205 220 26935782\n2 Yamazaki S Watanabe T Sato S Yoshikawa H Outcome of renal proximal tubular dysfunction with Fanconi syndrome caused by sodium valproate Pediatr Int 2016 58 1023 1026 26896192\n3 Nanau RM Neuman MG Adverse drug reactions induced by valproic acid Clin Biochem 2013 46 1323 1338 23792104\n4 Romoli M Mazzocchetti P D'Alonzo R Siliquini S Rinaldi VE Verrotti A Calabresi P Costa C Valproic Acid and Epilepsy: From Molecular Mechanisms to Clinical Evidences Curr Neuropharmacol 2019 17 926 946 30592252\n5 Guo HL Jing X Sun JY Hu YH Xu ZJ Ni MM Chen F Lu XP Qiu JC Wang T Valproic Acid and the Liver Injury in Patients with Epilepsy: An Update Curr Pharm Des 2019 25 343 351 30931853\n6 Hebert SA Bohan TP Erikson CL Swinford RD Thrombotic microangiopathy associated with Valproic acid toxicity BMC Nephrol 2017 18 262 28774273\n7 Bruniera FR Ferreira FM Savioli LR Bacci MR Feder D Pereira EC Pedreira ML Peterlini MA Perazzo FF Azzalis LA Rosa PC Junqueira VB Sato MA Fonseca FL Endothelial, renal and hepatic variables in Wistar rats treated with Vancomycin An Acad Bras Cienc 2014 86 1963 1972 25590732\n8 De Bus L Depuydt P Libbrecht L Vandekerckhove L Nollet J Benoit D Vogelaers D Van Vlierberghe H Severe drug-induced liver injury associated with prolonged use of linezolid J Med Toxicol 2010 6 322 326 20358416\n9 Peng Y Li CY Yang ZL Shi W Adverse reactions of vancomycin in humans: A protocol for meta-analysis Medicine (Baltimore) 2020 99 e22376 32957416\n10 Vinh DC Rubinstein E Linezolid: a review of safety and tolerability J Infect 2009 59 Suppl 1 S59 S74 19766891\n11 Bayram N Düzgöl M Kara A Özdemir FM Devrim İ Linezolid-related adverse effects in clinical practice in children Arch Argent Pediatr 2017 115 470 475 28895694\n12 Bassett JT Rodriguez B Mulligan L Fontana RJ Acute liver failure in a military recruit treated with valproic acid and harboring a previously unrecognized POLG-1 mutation Epilepsy Behav Rep 2019 12 100342 31799506\n13 Danan G Teschke R RUCAM in Drug and Herb Induced Liver Injury: The Update Int J Mol Sci 2015 17 14\n14 Trinka E Höfler J Zerbs A Brigo F Efficacy and safety of intravenous valproate for status epilepticus: a systematic review CNS Drugs 2014 28 623 639 24806973\n15 U.S. National Library of Medcine. Valproic acid capsule drug label information, 2015 [cited 8 June 2020]. Datebase: DailyMed [Internet]. Available from: https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=c628829c-74de-485a-b6cb-42e1da894376\n16 Koenig SA Buesing D Longin E Oehring R Häussermann P Kluger G Lindmayer F Hanusch R Degen I Kuhn H Samii K Jungck A Brückner R Seitz R Boxtermann W Weber Y Knapp R Richard HH Weidner B Kasper JM Haensch CA Fitzek S Hartmann M Borusiak P Müller-Deile A Degenhardt V Korenke GC Hoppen T Specht U Gerstner T Valproic acid-induced hepatopathy: nine new fatalities in Germany from 1994 to 2003 Epilepsia 2006 47 2027 2031 17201699\n17 Schmid MM Freudenmann RW Keller F Connemann BJ Hiemke C Gahr M Kratzer W Fuchs M Schönfeldt-Lecuona C Non-fatal and fatal liver failure associated with valproic acid Pharmacopsychiatry 2013 46 63 68 22915484\n18 Schulpis KH Karikas GA Tjamouranis J Regoutas S Tsakiris S Low serum biotinidase activity in children with valproic acid monotherapy Epilepsia 2001 42 1359 1362 11737173\n19 Ghozzi H Hakim A Sahnoun Z Ben Mahmoud L Atheymen R Hammami S Zeghal K [Relationship between plasma concentrations of valproic acid and hepatotoxicity in patients receiving high doses] Rev Neurol (Paris) 2011 167 600 606 21492891\n20 George JN Nester CM Syndromes of thrombotic microangiopathy N Engl J Med 2014 371 654 666 25119611\n21 Wirtschafter E VanBeek C Linhares Y Bone marrow transplant-associated thrombotic microangiopathy without peripheral blood schistocytes: a case report and review of the literature Exp Hematol Oncol 2018 7 14 29977661\n22 Daram SR Philipneri M Puri N Bastani B Thrombotic thrombocytopenic purpura without schistocytes on the peripheral blood smear South Med J 2005 98 392 395 15813170\n23 Chatzikonstantinou T Gavriilaki M Anagnostopoulos A Gavriilaki E An Update in Drug-Induced Thrombotic Microangiopathy Front Med (Lausanne) 2020 7 212 32528969\n24 König SA Knolle J Friedewald S Koelfen W Longin E Lenz T Hannak D Effects of valproic acid, carbamazepine, and phenobarbitone on the fatty acid composition of erythrocyte membranes in children Epilepsia 2003 44 708 711 12752471\n25 Ogawa K Yumoto R Hamada N Nagai J Takano M Interaction of valproic acid and carbapenem antibiotics with multidrug resistance-associated proteins in rat erythrocyte membranes Epilepsy Res 2006 71 76 87 16806827\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(17)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Drug-induced liver injury; Organ transplantation; Plasma exchange; Sodium valproate; Thrombotic microangiopathy",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "4310-4317",
"pmc": null,
"pmid": "34141795",
"pubdate": "2021-06-16",
"publication_types": "D002363:Case Reports",
"references": "29977661;15813170;24806973;21492891;30931853;12752471;25119611;26712744;28774273;31799506;32528969;11737173;26896192;22915484;23792104;17201699;20358416;32957416;30592252;28895694;25590732;16806827;26935782;19766891",
"title": "Acute liver failure with thrombotic microangiopathy due to sodium valproate toxicity: A case report.",
"title_normalized": "acute liver failure with thrombotic microangiopathy due to sodium valproate toxicity a case report"
} | [
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"companynumb": "CN-PRA-000155",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nLevofloxacin and amiodarone are both known to prolong the QT interval. This study was conducted to estimate the risk of cardiac events in patients receiving concomitant levofloxacin and amiodarone.\n\n\nMETHODS\nThe study included patients who were admitted to a large academic community medical center from 1/2012 to 12/2015 and received both levofloxacin and amiodarone at some point during their hospitalization. Patients received concomitant or non-concomitant levofloxacin and amiodarone during hospitalization. The primary outcome was the occurrence of cardiac events during therapy. The secondary outcome was the proportion of patients with an electrocardiogram performed before and after initiation of therapy. Odds ratios for cardiac events were calculated using a multivariable logistic regression model with and without adjusting for the study variables. The concomitant group was further evaluated for predictors of the primary outcome using multivariable logistic regression.\n\n\nRESULTS\nThis study included 240 patients, 164 (68.3%) of whom received concomitant levofloxacin and amiodarone. Concomitant medication therapy was associated with a greater than six-fold increased risk of cardiac events after adjusting for the study variables (Odds Ratio=6.20; 95% Confidence Interval=1.34-28.62).\n\n\nCONCLUSIONS\nPatients receiving concomitant amiodarone and levofloxacin experienced a five-fold increase in cardiac events compared to patients given either medication alone.",
"affiliations": "Rutgers University School of Pharmacy, Piscataway, NJ, USA; RWJ Barnabas Health-Robert Wood Johnson University Hospital Somerset, Somerville, NJ, USA.;Rutgers University School of Pharmacy, Piscataway, NJ, USA; Chung-Ang University College of Pharmacy, Seoul, South Korea.;Rutgers University School of Pharmacy, Piscataway, NJ, USA; RWJ Barnabas Health-Robert Wood Johnson University Hospital Somerset, Somerville, NJ, USA.;Columbia University School of Public Health, New York, NY, USA.;Rutgers University School of Pharmacy, Piscataway, NJ, USA.;RWJ Barnabas Health-Robert Wood Johnson University Hospital Somerset, Somerville, NJ, USA.;Chung-Ang University College of Pharmacy, Seoul, South Korea.;Chung-Ang University College of Pharmacy, Seoul, South Korea.;Chung-Ang University College of Pharmacy, Seoul, South Korea. Electronic address: dongsuh75@gmail.com.",
"authors": "Brunetti|Luigi|L|;Lee|Seung-Mi|SM|;Nahass|Ronald G|RG|;Suh|David|D|;Miao|Benjamin|B|;Bucek|John|J|;Kim|Dongwon|D|;Kim|Ok-Kyu|OK|;Suh|Dong-Churl|DC|",
"chemical_list": "D064704:Levofloxacin; D000638:Amiodarone",
"country": "Canada",
"delete": false,
"doi": "10.1016/j.ijid.2018.10.017",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1201-9712",
"issue": "78()",
"journal": "International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases",
"keywords": "Amiodarone; Cardiac death; Cardiac risk; Levofloxacin; QT interval",
"medline_ta": "Int J Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000638:Amiodarone; D001145:Arrhythmias, Cardiac; D015992:Body Mass Index; D003643:Death; D004359:Drug Therapy, Combination; D004562:Electrocardiography; D005260:Female; D006760:Hospitalization; D006801:Humans; D064704:Levofloxacin; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012189:Retrospective Studies; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "9610933",
"other_id": null,
"pages": "50-56",
"pmc": null,
"pmid": "30385404",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The risk of cardiac events in patients who received concomitant levofloxacin and amiodarone.",
"title_normalized": "the risk of cardiac events in patients who received concomitant levofloxacin and amiodarone"
} | [
{
"companynumb": "US-PFIZER INC-2019047476",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
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"drugadditional": null,
... |
{
"abstract": "Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of non-small cell lung cancer (NSCLC). With the increasing use of ICIs, clinicians should be familiar with their immune-related adverse events, including sarcoid-like reactions, which have been associated with the use of ICIs in patients with cancer. Sarcoid-like reactions are caused by uncontrolled T helper 1-mediated immune responses resulting from ICIs, but their pathophysiology is not fully understood. Sarcoid-like reactions are often clinically important because they mimic metastases from treated cancer. According to previous reports, sarcoid-like reactions are typically observed in intrathoracic locations (lung and/or mediastinal lymph nodes) and the skin. In this study, we report an extremely rare case of extrathoracic sarcoid-like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. The laboratory data and computed tomography images suggested that infectious and autoimmune diseases were not considered to be the causative agents. Residual bone metastasis might have caused T helper 1-mediated immune responses by pembrolizumab, and contributed to sarcoid-like reactions in the right external iliac lymph node. Sarcoid-like reactions should be considered in the differential diagnosis of patients with lung cancer treated with ICIs who exhibit worsening extrathoracic lymph node swelling. Clinicians should be cautious not to mistake extrathoracic sarcoid-like reactions of the lymph nodes for progression of the treated disease.",
"affiliations": "Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Cancer Pathology Laboratory, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Urology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.",
"authors": "Takamori|Shinkichi|S|0000-0001-8175-6798;Furubayashi|Nobuki|N|;Taguchi|Kenichi|K|;Matsubara|Taichi|T|;Fujishita|Takatoshi|T|;Ito|Kensaku|K|;Yamaguchi|Masafumi|M|;Toyozawa|Ryo|R|;Seto|Takashi|T|0000-0002-2960-4364;Negishi|Takahito|T|;Nakamura|Motonobu|M|;Okamoto|Tatsuro|T|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1111/1759-7714.14011",
"fulltext": "\n==== Front\nThorac Cancer\nThorac Cancer\n10.1111/(ISSN)1759-7714\nTCA\nThoracic Cancer\n1759-7706\n1759-7714\nJohn Wiley & Sons Australia, Ltd Melbourne\n\n34002950\n10.1111/1759-7714.14011\nTCA14011\nCase Report\nCase Reports\nSarcoid‐like reaction of the extrathoracic lymph node in a patient with lung adenocarcinoma treated with pembrolizumab\nTakamori et al.\nTakamori Shinkichi https://orcid.org/0000-0001-8175-6798\n1 takamori@surg2.med.kyushu-u.ac.jp\n\nFurubayashi Nobuki 2\nTaguchi Kenichi 3\nMatsubara Taichi 1\nFujishita Takatoshi 1\nIto Kensaku 1\nYamaguchi Masafumi 1\nToyozawa Ryo 1\nSeto Takashi https://orcid.org/0000-0002-2960-4364\n1\nNegishi Takahito 2\nNakamura Motonobu 2\nOkamoto Tatsuro 1\n1 Department of Thoracic Oncology National Hospital Organization Kyushu Cancer Center Fukuoka Japan\n2 Department of Urology National Hospital Organization Kyushu Cancer Center Fukuoka Japan\n3 Cancer Pathology Laboratory National Hospital Organization Kyushu Cancer Center Fukuoka Japan\n* Correspondence\nShinkichi Takamori, Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, 3‐1‐1 Notame, Minami‐ku, Fukuoka 811‐1395, Japan.\nEmail: takamori@surg2.med.kyushu-u.ac.jp\n\n18 5 2021\n7 2021\n12 14 10.1111/tca.v12.14 21222125\n04 5 2021\n28 3 2021\n05 5 2021\n© 2021 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nImmune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of non‐small cell lung cancer (NSCLC). With the increasing use of ICIs, clinicians should be familiar with their immune‐related adverse events, including sarcoid‐like reactions, which have been associated with the use of ICIs in patients with cancer. Sarcoid‐like reactions are caused by uncontrolled T helper 1‐mediated immune responses resulting from ICIs, but their pathophysiology is not fully understood. Sarcoid‐like reactions are often clinically important because they mimic metastases from treated cancer. According to previous reports, sarcoid‐like reactions are typically observed in intrathoracic locations (lung and/or mediastinal lymph nodes) and the skin. In this study, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. The laboratory data and computed tomography images suggested that infectious and autoimmune diseases were not considered to be the causative agents. Residual bone metastasis might have caused T helper 1‐mediated immune responses by pembrolizumab, and contributed to sarcoid‐like reactions in the right external iliac lymph node. Sarcoid‐like reactions should be considered in the differential diagnosis of patients with lung cancer treated with ICIs who exhibit worsening extrathoracic lymph node swelling. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease.\n\nSarcoid‐like reactions are sometimes caused by immune checkpoint inhibitor through uncontrolled T helper 1‐mediated immune responses. Here, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease.\n\nlung adenocarcinoma\nlymph node metastasis\nprogrammed death‐ligand 1\nsarcoid reaction\nsource-schema-version-number2.0\ncover-dateJuly 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.4 mode:remove_FC converted:19.07.2021\nTakamori S , Furubayashi N , Taguchi K , et al. Sarcoid‐like reaction of the extrathoracic lymph node in a patient with lung adenocarcinoma treated with pembrolizumab. Thorac Cancer. 2021;12 :2122–2125. 10.1111/1759-7714.14011\n==== Body\nINTRODUCTION\n\nLung cancer is one of the most devastating neoplasms, and patient prognosis remains poor. 1 Immune checkpoint inhibitors (ICIs) targeting programmed death‐1 and programmed death‐ligand 1 have become the standard of care in the treatment of non‐small cell lung cancer (NSCLC). 2 , 3 , 4 , 5 With the increasing use of ICIs, clinicians should be familiar with their immune‐related adverse events such as sarcoid‐like reactions, which have been associated with the use of ICIs in patients with cancer. 6 Sarcoid‐like reactions are often clinically important because they mimic metastases from treated cancer. 6 According to previous reports, sarcoid‐like reactions are typically observed in the lungs, thoracic lymph nodes, and skin. 7 , 8 , 9 , 10 , 11 In this study, we report an extremely rare case of extrathoracic sarcoid‐like reaction of the lymph nodes following pembrolizumab administration mimicking oligometastasis from treated primary lung adenocarcinoma.\n\nCASE REPORT\n\nThe patient was a 62‐year‐old woman with a 38‐pack‐year smoking history. In May 2018, the patient experienced left upper limb weakness and back pain. Brain magnetic resonance imaging (MRI) revealed a tumor in the right frontal lobe of the brain. In July 2018, she underwent resection of the tumor in the right frontal lobe of the brain. The pathological diagnosis was metastasis from lung adenocarcinoma. Epidermal growth factor receptor (EGFR) status was wild‐type, and ≥95% of tumor cells expressed programmed death‐ligand 1 (22C3). Chest computed tomography (CT) revealed a mass in the right upper lobe of the lungs (maximum diameter: 5.6 cm) and swollen right hilar and mediastinal lymph nodes (Figure 1(a); cT3N2M1c [BRA, OSS], cStage IVB). Baseline abdominal CT showed no lymph node swelling (Figure 1(b)). Lumbar MRI revealed extensive bone metastasis of the spine into the spinal canal from the level of the eleventh thoracic spine to the first lumbar spine. In August 2018, the patient underwent palliative radiotherapy (30 Gy/10 fractions) for the bone metastasis of the spine because of her back pain. In October 2018, the patient completed two cycles of pembrolizumab (200 mg/bodyweight) and achieved a partial response (tumor shrinkage rate: 33.6%). Owing to an immune‐related adverse event (diarrhea; grade 2), pembrolizumab was discontinued. However, the effects of the drug had been monitored without any treatment for 1.25 years. In January 2020, CT revealed worsening of right external iliac lymph node swelling (Figure 1(c)). Positron emission tomography (PET) illustrated that the maximum standardized uptake value was 9.56 in the right external iliac lymph node (Figure 1(d)), and the accumulation of 18F fluorodeoxyglucose activity in the primary lesion and bone metastasis of the spine was negative. The laboratory data showed no inflammatory findings, and CT images showed no abnormal findings in the bilateral lung fields. Infectious diseases (i.e., bacteria, fungi, and tuberculosis) as well as autoimmune diseases were not considered to be the causative agents. The right external iliac lymph node was suspected to be a metastasis from the primary lung adenocarcinoma. The patient underwent surgical resection of the right external iliac lymph node because the right external iliac lymph node was considered a single metastatic lesion. The pathological diagnosis was sarcoid‐like reaction carrying no carcinoma cells (Figure 2). The patient has received no treatment, and she has visited our hospital with no recurrence for one year.\n\nFIGURE 1 (a) Chest computed tomography (CT) revealed a mass in the right upper lobe of the lungs. (b) Baseline abdominal CT showed no lymph node swelling. (c) Abdominal CT and (d) positron emission tomography (PET) images revealed worsening of the right external iliac lymph node swelling (yellow arrow) with the accumulation of 18F fluorodeoxyglucose activity\n\nFIGURE 2 (a) Surgically resected right external iliac lymph node showing nodular lesions of epithelioid granulomata (scale bar: 2.5 mm, H&E). (b, c) The lymph node comprised lymphocytes and multinucleated giant cells without foreign bodies (scale bar: [b] 250 μm, [c] 50 μm, H&E). H&E, hematoxylin and eosin\n\nDISCUSSION\n\nTo the best of our knowledge, this is the first report of a case of extrathoracic sarcoid‐like reaction of the lymph node following ICI administration in a patient with lung cancer. Regarding the underlying pathophysiology of sarcoid‐like reactions, uncontrolled T helper 1‐mediated immune responses caused by ICIs may contribute to their occurrence, but their pathophysiology is not fully understood. 12 Several previous articles have reported ICI‐associated sarcoid‐like reactions in patients with lung cancer, 7 , 8 , 9 , 10 , 11 and all of the reactions arose in intrathoracic locations (lung and/or mediastinal lymph nodes) and the skin. 6 In this case, metastatic tumors were observed in the bone metastases from the level of the eleventh thoracic spine to the first lumbar spine, which means that cancer cells existed in the extrathoracic lesion. According to the previous report, bone metastasis is an independent worse prognostic factor in NSCLC patients treated with ICIs. 13 Residual bone metastasis might have caused T helper 1‐mediated immune responses by pembrolizumab, and contributed to sarcoid‐like reactions in the right external iliac lymph node in this case. In our search of the previous literature, we identified only one case of extrathoracic sarcoid‐like reaction of the lymph nodes in a patient with melanoma who received nivolumab and ipilimumab. 14 In patients with lung cancer, extrathoracic sarcoid‐like reactions of the lymph nodes following ICI therapy are extremely rare. Nevertheless, sarcoid‐like reactions should be considered in the differential diagnosis of patients with lung cancer treated with ICIs who have developed 18F fluorodeoxyglucose‐avid extrathoracic lymph node swelling. Regarding a method to distinguish between a sarcoid‐like reaction and metastasis from cancer, a blood test investigating tumor DNA may be helpful in diagnosing whether or not the swelling lymph node is metastasis from cancer given that the residual cancer cells could be detected by circulating tumor DNA. 15 In conclusion, clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of a treated lung cancer.\n\nCONFLICT OF INTEREST\n\nAll authors declare no conflicts of interest in association with the present study.\n\nACKNOWLEDGMENTS\n\nWe thank Joe Barber Jr., PhD, from Edanz Group (https://en-author-services.edanz.com/ac) for editing a draft of this manuscript. The publication fee was funded by the Japanese Foundation for Multidisciplinary Treatment of Cancer.\n==== Refs\nREFERENCES\n\n1 Torre LA , Bray F , Siegel RL , Ferlay J , Lortet‐Tieulent J , Jemal A . Global cancer statistics, 2012. CA Cancer J Clin. 2015;65 :87–108.25651787\n2 Reck M , Rodriguez‐Abreu D , Robinson AG , Hui R , Csőszi T , Fülöp A , et al. Pembrolizumab versus chemotherapy for PD‐L1‐positive non‐small‐cell lung cancer. N Engl J Med. 2016;375 :1823–33.27718847\n3 Paz‐Ares L , Luft A , Vicente D , Tafreshi A , Gümüş M , Mazières J , et al. Pembrolizumab plus chemotherapy for squamous non‐small‐cell lung cancer. N Engl J Med. 2018;379 :2040–51.30280635\n4 Gandhi L , Rodriguez‐Abreu D , Gadgeel S , Esteban E , Felip E , de Angelis F , et al. Pembrolizumab plus chemotherapy in metastatic non‐small‐cell lung cancer. N Engl J Med. 2018;378 :2078–92.29658856\n5 Rittmeyer A , Barlesi F , Waterkamp D , Park K , Ciardiello F , von Pawel J , et al. Atezolizumab versus docetaxel in patients with previously treated non‐small‐cell lung cancer (OAK): a phase 3, open‐label, multicentre randomised controlled trial. Lancet. 2017;389 :255–65.27979383\n6 Gkiozos I , Kopitopoulou A , Kalkanis A , Vamvakaris IN , Judson MA , Syrigos KN . Sarcoidosis‐like reactions induced by checkpoint inhibitors. J Thorac Oncol. 2018;13 :1076–82.29763666\n7 Birnbaum MR , Ma MW , Fleisig S , Packer S , Amin BD , Jacobson M , et al. Nivolumab‐related cutaneous sarcoidosis in a patient with lung adenocarcinoma. JAAD Case Rep. 2017;3 :208–11.28443311\n8 Fakhri G , Akel R , Salem Z , Tawil A , Tfayli A . Pulmonary sarcoidosis activation following neoadjuvant Pembrolizumab plus chemotherapy combination therapy in a patient with non‐small cell lung cancer: a case report. Case Rep Oncol. 2017;10 :1070–5.29515398\n9 Lainez S , Tissot C , Cottier M , Vergnon JM . EBUS‐TBNA can distinguish Sarcoid‐like side effect of Nivolumab treatment from tumor progression in non‐small cell lung cancer. Respiration. 2017;94 :518–21.28910804\n10 Nishino M , Sholl LM , Awad MM , Hatabu H , Armand P , Hodi FS . Sarcoid‐like granulomatosis of the lung related to immune‐checkpoint inhibitors: distinct clinical and imaging features of a unique immune‐related adverse event. Cancer Immunol Res. 2018;6 :630–5.29622582\n11 Noguchi S , Kawachi H , Yoshida H , Fukao A , Terashita S , Ikeue T , et al. Sarcoid‐like granulomatosis induced by Nivolumab treatment in a lung cancer patient. Case Rep Oncol. 2018;11 :562–6.30186140\n12 Berthod G , Lazor R , Letovanec I , Romano E , Noirez L , Mazza Stalder J , et al. Pulmonary sarcoid‐like granulomatosis induced by ipilimumab. J Clin Oncol. 2012;30 :e156–9.22547608\n13 Li X , Wang L , Chen S , Zhou F , Zhao J , Zhao W , et al. Adverse impact of bone metastases on clinical outcomes of patients with advanced non‐small cell lung cancer treated with immune checkpoint inhibitors. Thorac Cancer. 2020;11 :2812–9.32779372\n14 Lomax AJ , McGuire HM , McNeil C , Choi CJ , Hersey P , Karikios D , et al. Immunotherapy‐induced sarcoidosis in patients with melanoma treated with PD‐1 checkpoint inhibitors: case series and immunophenotypic analysis. Int J Rheum Dis. 2017;20 :1277–85.28480561\n15 Moding EJ , Diehn M , Wakelee HA . Circulating tumor DNA testing in advanced non‐small cell lung cancer. Lung Cancer. 2018;119 :42–7.29656751\n\n",
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"keywords": "lung adenocarcinoma; lymph node metastasis; programmed death-ligand 1; sarcoid reaction",
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"title": "Sarcoid-like reaction of the extrathoracic lymph node in a patient with lung adenocarcinoma treated with pembrolizumab.",
"title_normalized": "sarcoid like reaction of the extrathoracic lymph node in a patient with lung adenocarcinoma treated with pembrolizumab"
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"abstract": "We described pregnancy outcomes in Crohn's disease (CD) patients enrolled in the TREAT Registry who received infliximab before, or during pregnancy and those not treated with infliximab or any biologic agent.\n\n\n\nIn the TREAT Registry (1999-2012), pregnancy outcomes were analyzed from maternal and paternal patients exposed to infliximab ≤365 days (gestational exposure), >365 days (pre-gestational exposure) of pregnancy outcome or without infliximab exposure (non-biologic exposed). \"Healthy infants\" were defined as those with no congenital abnormalities, neonatal complications (e.g., jaundice, prematurity, heart murmur, cortical vision/fine motor delay, cardiac failure, hemophilia, or torticollis), prolonged hospitalization, or those who received no special treatment. Disease activity and concomitant medications were also evaluated.\n\n\n\nOverall, 92.3% (324/351) of pregnancies had known outcomes. The majority of both maternal pregnancies (92.6, 91.2, and 87.8%) and partner outcomes (92.7, 93.8, and 91.7%) resulted in live births of healthy infants across gestational, pre-gestational, and non-biologic exposure groups, respectively. Among these, rates of neonatal complications were low for both maternal (6.2, 7.0, and 8.5%), and partner outcomes (4.9, 0, and 0%) in gestational, pre-gestational, and non-biologic exposure groups, respectively. Among maternal pregnancies, numerically higher rates of spontaneous abortions were observed for the gestational exposure group than for the pre-gestational or non-biologic exposed groups.\n\n\n\nThe clinical condition of infants born to women with gestational infliximab exposure was similar to those without exposure. Although a lower live birth rate was reported among infliximab-exposed women, these patients had more severe CD and were more likely to have been exposed to immunosuppressives.",
"affiliations": "Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.;Department of Medicine, Division of Gastroenterology, Hospital of the University of Pennsylvania, University of Pennsylvania School of Medicine, Philadelphia, PA, USA. Robarts Clinical Trials, Western University, London, ON, Canada. University of California, San Francisco, CA, USA. Atlanta Gastroenterology Specialists, Atlanta, GA, USA. Janssen Research & Development, LLC, Spring House, PA, USA. Formerly an employee of Janssen Scientific Affairs, LLC, Horsham, PA, USA. Janssen-Cilag Oy, Espoo, Finland. Formerly an employee of Janssen Biologics BV, Leiden, The Netherlands. Division of Gastroenterology, University of California San Diego, La Jolla, CA, USA. Department of Medicine, Section of Gastroenterology, University of Chicago Medical Center, Chicago, IL, USA. Some of the data in this article were presented at United European Gastroenterology Week 2013 in Berlin, Germany.",
"authors": "Lichtenstein|Gary R|GR|;Feagan|Brian G|BG|;Mahadevan|Uma|U|;Salzberg|Bruce A|BA|;Langholff|Wayne|W|;Morgan|James G|JG|;Safdi|Michael|M|;Nissinen|Riikka|R|;Taillard|François|F|;Sandborn|William J|WJ|;Cohen|Russell D|RD|",
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"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000328:Adult; D003424:Crohn Disease; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000069285:Infliximab; D008297:Male; D018811:Maternal Exposure; D008875:Middle Aged; D018812:Paternal Exposure; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D012042:Registries; D012720:Severity of Illness Index; D014409:Tumor Necrosis Factor-alpha; D055815:Young Adult",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1678-1688",
"pmc": null,
"pmid": "30022113",
"pubdate": "2018-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pregnancy Outcomes Reported During the 13-Year TREAT Registry: A Descriptive Report.",
"title_normalized": "pregnancy outcomes reported during the 13 year treat registry a descriptive report"
} | [
{
"companynumb": "PHHY2018US197461",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
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"abstract": "We describe the clinical course of one industrial technician occupationally exposed to nickel carbonyl (NiC).\n\n\n\nA 50-year-old male industrial technician presented with complaints of nausea, myalgia, and cough to a local clinic after suspected occupational exposure to nickel carbonyl. He has no history of lung disease or smoking. His initial urine nickel concentration was 692 ug/L. He had infiltrates on the initial chest X-ray (CXR) and an oxygen saturation (O2) of 97% on room air. The patient was started on disulfiram 1 g by mouth (PO), 500 mg six hours after the first dose, then 250 mg twice daily for five days with prednisone 60 mg by mouth for five days. He presented 48 hours later with worsening respiratory symptoms. His O2 saturation decreased to 85% despite two days of oral steroids, and he was admitted to a hospital. He received prednisone 60 mg/day PO, 4 L nasal O2, and disulfiram 500 mg twice daily. He was discharged on day 7 post-exposure with disulfiram and prednisone. Case discussions: NiC is a severe respiratory irritant. Disulfiram was used off-label and was based on an established company protocol.\n\n\n\nInhalation exposure to NiC resulted in a delayed respiratory dysfunction which responded to disulfiram treatment.",
"affiliations": "a Tennessee Poison Center , Nashville , TN , USA.;c Division of Emergency Medicine , University of Utah Hospital , Salt Lake City , UT , USA.;d Oregon Poison Center , Portland , OR , USA.;f Pharmacotherapy , Utah Poison Control Center , Salt Lake City , UT , USA.",
"authors": "Bowman|Nena|N|;Caravati|E Martin|EM|;Horowitz|B Zane|BZ|;Crouch|Barbara Insley|BI|",
"chemical_list": "D009942:Organometallic Compounds; D011239:Prednisolone; D004221:Disulfiram",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1355057",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(3)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Disulfiram; nickel carbonyl; pneumonitis",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D004221:Disulfiram; D006801:Humans; D019570:Inhalation Exposure; D008297:Male; D008875:Middle Aged; D016273:Occupational Exposure; D009942:Organometallic Compounds; D011014:Pneumonia; D011239:Prednisolone; D016896:Treatment Outcome",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "223-225",
"pmc": null,
"pmid": "28753074",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute pneumonitis associated with nickel carbonyl exposure in the workplace.",
"title_normalized": "acute pneumonitis associated with nickel carbonyl exposure in the workplace"
} | [
{
"companynumb": "US-MYLANLABS-2015M1033292",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMutations in PARK2 result in autosomal recessive young onset Parkinson's disease (YOPD). Although there have been a number of reports on the clinical characteristics of PARK2-related PD, there is limited information available on the associated neuropathologic changes.\n\n\nMETHODS\nWe describe the clinical and pathological characteristics of a Peruvian family with YOPD. The proband and one unaffected sibling were screened for PARK2 dosage and point mutations. One affected sibling had detailed neuropathologic examination.\n\n\nMETHODS\nInstituto Nacional de Ciencias Neurologicas (INCN) in Lima, Peru.\n\n\nRESULTS\nThe proband and two of her four siblings developed YOPD and both parents were unaffected. The clinical course has been characterized by akinetic-rigid parkinsonism predominantly affecting the lower limbs and dyskinesias. Analysis of PARK2 showed that the proband is compound heterozygous for a novel acceptor splice site mutation in intron 5 (IVS5-1G>A) and an exon 7 deletion. Neuropathologic assessment of an affected sibling revealed severe neuronal loss in the substantia nigra (SN) and loss of tyrosine hydroxylase immunopositive fibers in the striatum. No Lewy body pathology was observed using standard histology or immunohistochemistry for α-synuclein.\n\n\nCONCLUSIONS\nConsistent with most neuropathologic reports of patients with PARK2 mutations, we did not observe Lewy body inclusions, despite marked SN degeneration and severe dopaminergic denervation of the striatum. These data describe a novel splice site mutation and further extend the clinicopathological characterization of PARK2-associated PD.",
"affiliations": "Northern Pacific Global Health Research Fellows Training Consortium, Bethesda, MD, USA; Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, USA; Department of Neurology, University of Washington, Seattle, WA, USA.;Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Neuropathology Department, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Neurogenetics Research Center, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Movement Disorders Unit, Instituto Nacional de Ciencias Neurologicas, Lima, Peru.;Geriatric Research Education and Clinical Center, VA Puget Sound Health Care System, USA; Parkinson's Disease Research Education and Clinical Center, VA Puget Sound Health Care System, USA; Department of Neurology, University of Washington, Seattle, WA, USA.;Lou Ruvo Center for Brain Health, Neurological Institute, Cleveland Clinic, Cleveland, OH, USA. Electronic address: leverej@ccf.org.",
"authors": "Cornejo-Olivas|Mario R|MR|;Torres|Luis|L|;Mata|Ignacio F|IF|;Mazzetti|Pilar|P|;Rivas|Diana|D|;Cosentino|Carlos|C|;Inca-Martinez|Miguel|M|;Cuba|Juan M|JM|;Zabetian|Cyrus P|CP|;Leverenz|James B|JB|",
"chemical_list": "D044767:Ubiquitin-Protein Ligases; C111567:parkin protein",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1353-8020",
"issue": "21(5)",
"journal": "Parkinsonism & related disorders",
"keywords": "Familial parkinsonism; Mutations; Parkin; Pathology",
"medline_ta": "Parkinsonism Relat Disord",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D020734:Parkinsonian Disorders; D010375:Pedigree; D010568:Peru; D017354:Point Mutation; D044767:Ubiquitin-Protein Ligases",
"nlm_unique_id": "9513583",
"other_id": null,
"pages": "444-8",
"pmc": null,
"pmid": "25817512",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "19205068;12815654;18987353;18241240;1779131;15584030;11558785;14976155;23401296;12764050;12722931;9808334;18591091;12781588;19025984;17388944;20876472;16130111;19330201;11222808;18519021;15326242;15249681;14519684;16001409;23459986;11009195;9748052;12764051;10984666",
"title": "A Peruvian family with a novel PARK2 mutation: Clinical and pathological characteristics.",
"title_normalized": "a peruvian family with a novel park2 mutation clinical and pathological characteristics"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2016SP002147",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
},
... |
{
"abstract": "Abuse of and addiction to medication are a major public health issue which is evolving fast, in particular in countries like France, one of the largest consumers of medication in Europe. As a single source of information is not generally sufficient to measure a phenomenon as difficult to apprehend as medication-related addiction, as can be seen in the case of methylphenidate, it is essential to mobilise all the tools available, here surveillance programmes developed by the French CEIP Addiction vigilance network, such as suspicious prescriptions indicating possible abuse data (OSIAP) or observatory of illegal or misused psychoactive medications (OPPIDUM), as well as the health insurance databases, and health professional sentinel networks. The latest data available on methylphenidate abuse in France suggests a stabilisation of the phenomenon, which emerged in the Provence-Alpes-Côte-d'Azur (PACA) region in southern France. It also evidences its diffusion to other regions, so that the information needs to be widely relayed, and suggests that health professionals should exercise the greatest caution in the use of this substance, and should look for early signs of its misuse.",
"affiliations": "CEIP-Addictovigilance Paca Corse, Service de Pharmacologie Clinique & Pharmacovigilance, Aix Marseille Université, Institut de Neurosciences Timone, CNRS 7289, Marseille, France.;CEIP-Addictovigilance Paca Corse, Service de Pharmacologie Clinique & Pharmacovigilance, Aix Marseille Université, Institut de Neurosciences Timone, CNRS 7289, Marseille, France.;CEIP-Addictovigilance de Toulouse, Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine, Université de Toulouse III, Inserm, UMR1027, Toulouse, France.;CEIP-Addictovigilance Paca Corse, Service de Pharmacologie Clinique & Pharmacovigilance, Aix Marseille Université, Institut de Neurosciences Timone, CNRS 7289, Marseille, France.;CEIP-Addictovigilance de Toulouse, Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire, Faculté de Médecine, Université de Toulouse III, Inserm, UMR1027, Toulouse, France.",
"authors": "Micallef|Joëlle|J|;Frauger|Elisabeth|E|;Palmaro|Aurore|A|;Boucherie|Quentin|Q|;Lapeyre Mestre|Maryse|M|",
"chemical_list": "D000697:Central Nervous System Stimulants; D011619:Psychotropic Drugs; D008774:Methylphenidate",
"country": "France",
"delete": false,
"doi": "10.2515/therapie/2015013",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "70(2)",
"journal": "Therapie",
"keywords": null,
"medline_ta": "Therapie",
"mesh_terms": "D000697:Central Nervous System Stimulants; D016208:Databases, Factual; D005602:France; D006801:Humans; D008774:Methylphenidate; D060735:Pharmacovigilance; D011159:Population Surveillance; D063487:Prescription Drug Misuse; D011619:Psychotropic Drugs; D019966:Substance-Related Disorders",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "191-202",
"pmc": null,
"pmid": "25858575",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Example of an investigation of an \"emergent\" phenomenon in addiction vigilance: the case of methylphenidate.",
"title_normalized": "example of an investigation of an emergent phenomenon in addiction vigilance the case of methylphenidate"
} | [
{
"companynumb": "FR-JNJFOC-20150412870",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Background. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8 mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative.",
"affiliations": "Department of Internal Medicine, Conemaugh Memorial Medical Center Hospital, Johnstown, PA 15905, USA.",
"authors": "Alam|Mian Bilal|MB|;Kadoura|Amin|A|;Sathaiah|Magesh|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2012/953714",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2012/953714Case ReportA Fatal Case of Nafcillin-Induced Hepatotoxicity: A Case Report and the Literature Review Alam Mian Bilal \n1\n*Kadoura Amin \n1\nSathaiah Magesh \n2\n1Department of Internal Medicine, Conemaugh Memorial Medical Center Hospital, Johnstown, PA 15905, USA2Department of Surgery, University of Pittsburgh School of Medicine, and the University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA*Mian Bilal Alam: bilalalam1@yahoo.comAcademic Editor: Florian Thalhammer\n\n2012 11 7 2012 2012 95371413 1 2012 15 6 2012 15 6 2012 Copyright © 2012 Mian Bilal Alam et al.2012This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. Drug-induced hepatotoxicity (DIH) is quite common, and there are several recommendations for its treatment based upon its etiology. DIH may range from mild and subclinical to fulminant liver failure and death. Even though there is extensive list of drugs causing DIH, antibiotics, as a class of drugs, are the most common cause of DIH. Here, we present a fatal case of nafcillin-induced hepatotoxicity confirmed by liver biopsy, with total bilirubin peaking to 21.8 mg/dl and subsequent further extensive evaluation for hepatic injury turning out to be negative.\n==== Body\n1. Introduction\nNafcillin is a Narrow-spectrum beta-lactam antibiotic used to treat gram-positive staphylococcal infections except for methicillin resistant staphylococcal aureus (MRSA). It is usually a first-line drug for staphylococcal endocarditis in patients without artificial heart valves.It is widely distributed in various body fluids including bile, pleural, amniotic, and synovial fluids with poor CSF penetration but enhanced in meningitis. The mean plasma concentration of the drug was approximately 30 ug/mL at 5 minutes after injection. The serum half-life is 30–60 minutes after intravenous administration of the drug. It is 90% bound to albumin and primarily metabolized in the liver and undergoes enterohepatic circulation.\n\nNafcillin is a well-tolerated and a commonly prescribed drug for most staphylococcal infections. Adverse drug reactions to this drug range from mild gastrointestinal side effects to severe pseudomembranous colitis with superinfection to Clostridium difficile. Agranulocytosis, renal tubular damage, cases of acute interstitial nephritis [1], and acute tubular necrosis [2] have often been reported, but idiosyncratic liver injury with nafcillin is very rare [3]. Hence we report an irreversible fatal case of nafcillin-induced fatal hepatotoxicity with cholestatic jaundice.\n\n2. Case Report\nA 53-year-old white female with the past medical history of type II diabetes mellitus, hypertension, hyperlipidemia, depression, coronary artery disease after RCA stent, and peripheral vascular disease after bilateral stents to the common iliac arteries was transferred to our hospital after being diagnosed to have osteomyelitis of right great toe and methicillin-sensitive staphylococcus aureus bacteremia from an outside hospital. She was started on ertapenem for bacteremia before getting transferred to our hospital. The baseline laboratory values done on an outpatient evaluation basis just 10 days prior to the admission were WBC 12.5, hemoglobin 13.4, haematocrit 39, platelets 564, BUN 22, creatinine 1.5, glucose 222, sodium 138 meq/L, potassium 4.2 meq/L, chloride 101 meq/L, bicarbonate 25 meq/L, bilirubin total-0.3 mg/dL, bilirubin direct 0.1 mg/dL, alanine transaminase (ALT)-8 IU/L, aspartate transaminase (AST) 9 IU/L, alkaline phosphatase (ALP) 78 IU/L, direct albumin, 3.8 gm/dL, protein total 7.80 gm/dL, PT-10.2 s, INR 1.0, PTT 28 s, and sedimentation rate 72 h; blood culture showed no growth even after 5 days. On admission, physical examination findings were unremarkable except for her right great toe which was swollen and oozing; pedal pulses were not palpable. Laboratory showed an increase in leukocytes 16,300/uL; reference range (4500–8500), platelets 775 thousand/cu·mm reference (140–440), glucose 300 mg/dL (70–105), creatinine 2 mg/dL (0.6–1.1), low glomerular filtration rate (gfr) 26 mL/min, normal PT 16.4 s (9.0–12.0), PTT 42 s (25–35), and INR 1.6. Blood culture done two times showed no growth even after 5 days. X-ray right foot showed osteomyelitis of right great toe; ertapenem was discontinued and was started on nafcillin 12 gram/day. The day nafcillin started was considered as day 1. Surgery was done under general anesthesia on day 4 for the amputation of right great toe. Abdominal aortogram was performed on day 10 and was found to have mild narrowing at the level of tibioperoneal trunk with areas of stenosis the dorsalis pedis artery was occluded. The patient underwent right second toe amputation and percutaneous angioplasty for worsening of her osteomyelitis. On day 15, she was found to be jaundiced with mild disorientation; her liver function showed elevated total and direct bilirubin, alkaline phosphatase (ALP), and gamma glutamyl transpeptidase (GGTP) levels (bilirubin total (T)-9.6; direct (D)-7.3; ALP-388 IU/L; AST-67 IU/L; ALT-24 IU/L; GGTP-878 IU/L, with decreased creatinine clearance 30 mL/min/24 hr reference range (72–141 mL/min/24 hr). Pharmacy was consulted for drug-related hepatic injury, and nafcillin was discontinued immediately. A mild, transient drop in the levels of AST, ALT, ALP, and GGTP was noted immediately after stopping nafcillin. Further workup for hepatitis and jaundice was done to rule out other causes of hepatotoxicity. Workup included a negative direct coombs, and antibody screening, negative ANCA test for MPO and PR3 antibodies, rheumatoid factor, antismooth muscle antibody, antinuclear antibody, and HLA B27 were also negative. Levels of C3 and C4 complements were normal; liver-kidney microsomal antibody, alpha fetoprotein, and antithyroid peroxidase were also normal. Abdominal ultrasound showed a heterogenous appearance of liver parenchyma, and MRI abdomen was normal. The patient had an elevated GGTP, ALP, and bilirubin, mostly direct bilirubin (Figure 1) before being discharged to transitional care unit for rehabilitation.\n\nOn day 36, her jaundice worsened, and she was admitted at a liver transplant center for further evaluation. Her workup included elevated AST 152 IU/L, ALT 85 IU/L, ALP >1800 IU/L, GGT >1500 IU/L, and total bilirubin 11.5 mg/dL, repeat ultrasound abdomen showed no intra- and extrahepatic biliary obstruction; MRCP was unremarkable; liver biopsy showed diffuse hepatocanalicular cholestasis with focal centrizonal bile infarct, periportal hepatocellular swelling and mild nodular hyperplasia like changes. Diagnosis of cholestatic jaundice secondary to nafcillin was made and Ursodiol 10 mg/kg was started. There was no evidence of fulminant hepatic failure, coagulopathy, or encephalopathy. The patient was discharged to home. The patient was followed as an outpatient with regular blood tests for LFT. The GGTP and ALP both remained elevated >1500 IU/L.\n\nOn day 54, she was readmitted to the ER for abdominal pain and hematuria. Her workup revealed bilirubin (T-28.7 mg/dL, D-21.3 mg/dL), ALP >1884 IU/L, ALT 24 IU/L, ammonia 45 ug/dL (reference 31–123), creatinine 1.6, INR 5.4, PT 58.5, haemoglobin 7.5 gm/dL (reference 11.5–16.0), and haematocrit 21% (reference 37–47); urinalysis showed blood in urine, and blood culture remained negative. She was transfused two units of blood and was hemodynamically stabilized. She was monitored closely in the hospital. On day 84, she redeveloped an abdominal pain and was shifted to the liver transplant centre for further evaluation, where she went into respiratory arrest and succumbed to her underlying disease conditions.\n\n3. Discussion\nNafcillin in general is a safer semisynthetic penicillin antibiotic prescribed most commonly for methicillin-sensitive staphylococcal infections. It is primarily metabolized in liver and excreted unchanged in urine (30%) and predominantly in bile. The most frequently recognized side effect ranges from mild nausea and vomiting to occasional serious Clostridium difficile superinfection. Cases of acute interstitial nephritis [1] due to nafcillin and its drug interactions showing the evidence to induce cytochrome P-450 enzymes have been reported with warfarin and nifedipine [4]. The incidence of drug-induced hepatotoxicity [5] and occasionally cases of cholestatic jaundice has been reported with Nafcillin [6]. Although drug-induced cholestasis injury has been reported before, a case of fatal hepatic canalicular injury which never returned to baseline even after discontinuation of the offending drug incites a new warning. The exact mechanism for such toxicities is unclear, but previous reports of hepatic and renal dysfunction with Nafcillin administration greater than 9 g/24 hours [7] suggest an involvement of high-dose therapy as in this case for the treatment of chronic osteomyelitis. Here in this case, the patient had stage III kidney disease secondary to diabetic nephropathy reducing the clearance of Nafcillin and increasing the cholestatic liver injury.\n\nHer laboratory values were consistent with cholestatic jaundice with persistent elevation of ALP and GGTP until her last followup (Figure 1). Extensive workup to rule out other causes of hepatitis and cholestasis, including anti-nuclear antibodies and anti-Sm antibodies, turned out to be negative, ultrasound abdomen was normal, and MRCP was unremarkable. Liver biopsy was consistent with the picture of cholestatic liver injury either drug induced, stricturing, biliary obstruction, or sepsis; since the patient was not septic and blood cultures were negative, and MRCP was unremarkable leaving out with only choice of drug-induced hepatitis. Patient drug list was reviewed with pharmacy and was found to have Nafcillin as the only offending drug to cause cholestasis jaundice.\n\n4. Conclusion\nEven though nafcillin is a safer drug with fewer side effects, the chances of idiosyncratic drug injury have to be considered. When prescribing higher doses of >10 gram/day, it should be followed up with both renal and liver function tests after initiating such therapies.\n\nAuthors' Contributions\nM. B. Alam and M. Sathaiah were involved in the paper writing. A. Kadoura was involved in contribution of Figure 1.\n\nAcknowledgments\nThe authors like to acknowledge Dr. William Fink for his valuable suggestions and critical reading of the paper.\n\nFigure 1 Elevation of AST, ALT, GGTP, and ALP following nafcillin treatment (day 1 marked as dashed arrow). Undashed straight arrow marks the day of nafcillin withdrawal (day 15).\n==== Refs\n1 Hoppes T Prikis M Segal A Four cases of nafcillin-associated acute interstitial nephritis in one institution Nature Clinical Practice Nephrology 2007 3 8 456 461 2-s2.0-34547235467 \n2 Morin JP Fillastre JP Olier B Antibiotic nephrotoxicity Chemioterapia 1984 3 1 33 40 2-s2.0-0021325744 6100174 \n3 Presti ME Janney CG Neuschwander-Tetri BA Nafcillin-associated hepatotoxicity: report of a case and review of the literature Digestive Diseases and Sciences 1996 41 1 180 184 2-s2.0-0030024315 8565754 \n4 Lang CC Jamal SK Mohamed Z Mustafa MR Mustafa AM Lee TC Evidence of an interaction between nifedipine and nafcillin in humans British Journal of Clinical Pharmacology 2003 55 6 588 590 2-s2.0-0038804152 12814453 \n5 Presti ME Janney CG Neuschwander-Tetri BA Nafcillin-associated hepatotoxicity: report of a case and review of the literature Digestive Diseases and Sciences 1996 41 1 180 184 2-s2.0-0030024315 8565754 \n6 Mazuryk H Kastenberg D Rubin R Munoz SJ Cholestatic hepatitis associated with the use of nafcillin American Journal of Gastroenterology 1993 88 11 1960 1962 2-s2.0-0027367982 8237951 \n7 Lestico MR Vick KE Hetsko CM Hepatic and renal dysfunction following nafcillin administration Annals of Pharmacotherapy 1992 26 7-8 985 990 2-s2.0-0026681638 1504413\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2012()",
"journal": "Case reports in medicine",
"keywords": null,
"medline_ta": "Case Rep Med",
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"nlm_unique_id": "101512910",
"other_id": null,
"pages": "953714",
"pmc": null,
"pmid": "22844299",
"pubdate": "2012",
"publication_types": "D016428:Journal Article",
"references": "17653125;1504413;6100174;12814453;8565754;8237951",
"title": "A fatal case of nafcillin-induced hepatotoxicity: a case report and the literature review.",
"title_normalized": "a fatal case of nafcillin induced hepatotoxicity a case report and the literature review"
} | [
{
"companynumb": "BAXTER-2017BAX038784",
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NAFCILLIN\\NAFCILLIN SODIUM"
},
"drugadditional": ... |
{
"abstract": "Novel oral anticoagulants present challenges and uncertainties in the management of hemorrhagic emergencies. An 84-year-old man taking dabigatran presented with a subdural hematoma requiring neurosurgical intervention. Routine coagulation assays were prolonged at admission and following administration of Factor VIII Inhibitor Bypassing Activity (FEIBA). Thromboelastography (TEG(®)) was utilized to assess clot dynamics prior to placement of a subdural drain, which was safely inserted despite a prolonged thrombin time (TT). Exclusive reliance on the TT may delay necessary interventions. TEG(®) may be a valuable tool to investigate hemostasis in patients on dabigatran requiring emergent procedures.",
"affiliations": "Department of Pharmacy, Medical University of South Carolina, Charleston, SC, USA.",
"authors": "Neyens|Ron|R|;Bohm|Nicole|N|;Cearley|Madelyne|M|;Andrews|Charles|C|;Chalela|Julio|J|",
"chemical_list": "D000991:Antithrombins; D001562:Benzimidazoles; D015091:beta-Alanine; D000069604:Dabigatran",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11239-013-0933-9",
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"issn_linking": "0929-5305",
"issue": "37(2)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": null,
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000369:Aged, 80 and over; D000991:Antithrombins; D001562:Benzimidazoles; D000069604:Dabigatran; D003657:Decision Making; D006408:Hematoma, Subdural; D006801:Humans; D013916:Thrombelastography; D015091:beta-Alanine",
"nlm_unique_id": "9502018",
"other_id": null,
"pages": "80-3",
"pmc": null,
"pmid": "23666496",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19719819;20978992;2781460;20352166;20056441;18948035;22438031;22111735;23348428;17982317;22627883",
"title": "Dabigatran-associated subdural hemorrhage: using thromboelastography (TEG(®)) to guide decision-making.",
"title_normalized": "dabigatran associated subdural hemorrhage using thromboelastography teg to guide decision making"
} | [
{
"companynumb": "US-BAXTER-2014BAX066195",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "ANTI-INHIBITOR COAGULANT COMPLEX"
},
"drugaddit... |
{
"abstract": "In this case report, we present an evaluation of the distribution of postmortem concentrations of butyr-fentanyl in a fatality attributed principally to the drug. A man who had a history of intravenous drug abuse was found unresponsive on the bathroom floor of his home. Drug paraphernalia was located on the bathroom counter. Toxicology testing, which initially screened positive for fentanyl by enzyme-linked immunosorbent assay, subsequently confirmed butyr-fentanyl, which was then quantitated by gas chromatography-mass spectrometry-specific ion monitoring (GC-MS SIM) analysis following liquid-liquid extraction. The butyr-fentanyl peripheral blood concentration was quantitated at 58 ng/mL compared with the central blood concentration of 97 ng/mL. The liver concentration was 320 ng/g, the vitreous was 40 ng/mL, the urine was 670 ng/mL and the gastric contained 170 mg. Acetyl-fentanyl was also detected in all biological specimens tested. Peripheral blood concentration was quantitated at 38 ng/mL compared with the central blood concentration of 32 ng/mL. The liver concentration was 110 ng/g, the vitreous was 38 ng/mL, the urine was 540 ng/mL and the gastric contained <70 mg. The only other drug detected was a relatively low concentration of benzoylecgonine. The cause of death was certified as acute butyr-fentanyl, acetyl-fentanyl and cocaine intoxication, and the manner of death was certified as accident.",
"affiliations": "County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA iain.mcintyre@sdcounty.ca.gov.;County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.;County of San Diego Medical Examiner's Office, 5570 Overland Ave., Suite 101, San Diego, CA 92123, USA.",
"authors": "McIntyre|Iain M|IM|;Trochta|Amber|A|;Gary|Ray D|RD|;Wright|Jennifer|J|;Mena|Othon|O|",
"chemical_list": "D000701:Analgesics, Opioid; C000610976:butyrfentanyl; C005618:benzoylecgonine; C000594854:N-(1-phenethylpiperidin-4-yl)-N-phenylacetamide; D003042:Cocaine; D005283:Fentanyl",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bkv138",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "40(2)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D003042:Cocaine; D062787:Drug Overdose; D004797:Enzyme-Linked Immunosorbent Assay; D017809:Fatal Outcome; D005283:Fentanyl; D053593:Forensic Toxicology; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D059625:Liquid-Liquid Extraction; D008297:Male; D009293:Opioid-Related Disorders; D015819:Substance Abuse, Intravenous",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "162-6",
"pmc": null,
"pmid": "26683128",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An Acute Butyr-Fentanyl Fatality: A Case Report with Postmortem Concentrations.",
"title_normalized": "an acute butyr fentanyl fatality a case report with postmortem concentrations"
} | [
{
"companynumb": "US-ACTAVIS-2016-06754",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COCAINE"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nConcerns regarding the efficacy of daptomycin for methicillin-resistant Staphylococcus aureus (MRSA) bloodstream infections in patients with impaired renal function are reflected in a recent package insert change by the Food and Drug Administration (FDA). However, this decision was based on a small subgroup analysis and it is unclear if this is a true association.\n\n\nMETHODS\nWe conducted a retrospective cohort study of patients with MRSA bacteremia treated at a tertiary hospital from 2001 to 2011 and who received either vancomycin or daptomycin. We used propensity score and multivariable logistic regression to assess the outcome of treatment failure, via blinded adjudication, in daptomycin- vs vancomycin-treated subjects and the interaction with renal function.\n\n\nRESULTS\nOne hundred fifty patients were analyzed, 100 in the vancomycin arm and 50 in the daptomycin arm. The average age was 61 years, and 60% were men. Of patients treated with daptomycin or vancomycin, 29 (58%) and 51 (51%), respectively, had an estimated glomerular filtration rate (GFR) <50 mL/minute/1.73 m(2). Compared with vancomycin, the usage of daptomycin in patients was not significantly associated with treatment failure in patients with a GFR >50 mL/minute/1.73 m(2) (odds ratio [OR], 0.45; 95% confidence interval [CI], .11 -1.79), nor in patients with a GFR of <50 mL/minute/1.73 m(2) (OR, 0.46; 95% CI, .11 -1.94). There was no significant interaction between them (P = .54).\n\n\nCONCLUSIONS\nIn patients with MRSA bacteremia, daptomycin efficacy was not affected by GFR level and was similar to vancomycin's efficacy. Although our sample size was small, it was larger than than the one used by the FDA. However, smaller differences may be significant with a larger sample size.",
"affiliations": "Division of Geographic Medicine and Infectious Diseases, Tufts Medical Center and Tufts University School of Medicine.",
"authors": "Weston|Adam|A|;Golan|Yoav|Y|;Holcroft|Christina|C|;Snydman|David R|DR|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "58(11)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "bloodstream infection; daptomycin; methicillin-resistant Staphylococcus aureus (MRSA); renal failure; vancomycin",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D015331:Cohort Studies; D017576:Daptomycin; D005260:Female; D005919:Glomerular Filtration Rate; D006801:Humans; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D051437:Renal Insufficiency; D012189:Retrospective Studies; D013203:Staphylococcal Infections; D062606:Tertiary Care Centers; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "9203213",
"other_id": null,
"pages": "1533-9",
"pmc": null,
"pmid": "24642554",
"pubdate": "2014-06",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "22109947;21775337;22709685;22130283;19843483;23449272",
"title": "The efficacy of daptomycin versus vancomycin for methicillin-resistant Staphylococcus aureus bloodstream infection in patients with impaired renal function.",
"title_normalized": "the efficacy of daptomycin versus vancomycin for methicillin resistant staphylococcus aureus bloodstream infection in patients with impaired renal function"
} | [
{
"companynumb": "US-BAXTER-2015BAX006559",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "The treatment of ulcerative colitis is based on systemic corticosteroids, immunomodulators such as cyclosporine and azathioprine and TNF-α antagonists. Patients undergoing such immunosuppressive treatment are more susceptible for infectious pathogens. Here, we report the case of a patient with a 13-year history of ulcerative colitis, treated initially with systemic corticosteroids in combination with immunomodulators, and subsequently with infliximab. The patient presented with severe watery diarrhoea, abdominal cramps, weight loss and low-grade fever. Stool examinations for cytomegalovirus, bacteria and parasites were negative. Following detection of numerous oocytes of Isospora belli (IB) in direct smear preparations of the diarrhoeic stool samples, the patient was successfully treated with trimethoprim-sulfamethoxazole (co-trimoxazole).",
"affiliations": "Department of Internal Medicine, Krankenhaus Sachsenhausen, Frankfurt/Main, Germany. j.stein@em.uni-frankfurt.de",
"authors": "Stein|Juergen|J|;Tannich|Egbert|E|;Hartmann|Franz|F|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000069285:Infliximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001379:Azathioprine; D003093:Colitis, Ulcerative; D004359:Drug Therapy, Combination; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D021865:Isosporiasis; D008297:Male; D008875:Middle Aged; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23709557",
"pubdate": "2013-05-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12408672;17580223;3487730;8993857;16883348",
"title": "An unusual complication in ulcerative colitis during treatment with azathioprine and infliximab: Isospora belli as 'Casus belli'.",
"title_normalized": "an unusual complication in ulcerative colitis during treatment with azathioprine and infliximab isospora belli as casus belli"
} | [
{
"companynumb": "DE-SAMSUNG BIOEPIS-SB-2019-17336",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3"... |
{
"abstract": "Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare central nervous system neoplasm in which gliomatous tissue is diffusely identified in the subarachnoid space with no evidence of a primary intraparenchymal tumor. A 52-year-old man presented low back pain followed by sudden unconsciousness and had also cognitive dysfunction and meningeal sign. Examinations of cerebrospinal fluid (CSF) did not show malignant cells but increased protein and pleocytosis. Magnetic resonance (MR) imaging demonstrated diffuse leptomeningeal enhancement without any source of intraparenchymal lesion. Fluid-attenuated inversion recovery (FLAIR) also demonstrated individual diffuse high intensity area in the subarachnoid space. A biopsy disclosed wide spreading of anaplastic glial cells within the leptomeninges. He died 3 months later because of disease progression despite both radiotherapy and chemotherapy. Post-mortem examination identified PDLG and several neuropathological features of glioblastoma as well. Reviewing previous cases of PDLG instructs that this entity is rare, resembles meningitis in clinical pictures, usually occurs in a relatively younger population and has more progressive clinical course than the ordinary form of malignant gliomas.",
"affiliations": "Department of Neurosurgery, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, 390-8621, Japan. yomo@hsp.md.shinshu-u.ac.jp",
"authors": "Yomo|Shoji|S|;Tada|Tsuyoshi|T|;Hirayama|Shuichi|S|;Tachibana|Naoko|N|;Otani|Masako|M|;Tanaka|Yuichiro|Y|;Hongo|Kazuhiro|K|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s11060-006-9219-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-594X",
"issue": "81(2)",
"journal": "Journal of neuro-oncology",
"keywords": null,
"medline_ta": "J Neurooncol",
"mesh_terms": "D017809:Fatal Outcome; D005910:Glioma; D006801:Humans; D017116:Low Back Pain; D008279:Magnetic Resonance Imaging; D008297:Male; D008577:Meningeal Neoplasms; D008875:Middle Aged",
"nlm_unique_id": "8309335",
"other_id": null,
"pages": "209-16",
"pmc": null,
"pmid": "17031563",
"pubdate": "2007-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "9377304;9817460;3652562;10212927;3703199;11305449;7639122;11160482;10782164;1625019;11118261;7754854;7708153;2336982;15995830;4052890;10362329;9716625;10992815;14804124;12535360;16003541;9524095;12761643;8738401;14606585;11154809;8454762;8903081;8360714;10945815;15980977;8455062;1805932;2399813;7863170;7792477;11274832;8163998;3701447;11678426;15378329;7674024;12682758;11303666;4020450",
"title": "A case report and review of the literature.",
"title_normalized": "a case report and review of the literature"
} | [
{
"companynumb": "GB-ARBOR PHARMACEUTICALS, LLC-GB-2017ARB000005",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ERYTHROMYCIN"
},
"drugad... |
{
"abstract": "A 79-year-old male was admitted to the hospital for acute exacerbation of heart failure. The patient had history of atrial fibrillation and was planned for cardioversion. Preprocedure transesophageal echocardiogram (TEE) revealed a large multilobulated mobile thrombus in the left atrial appendage. The patient refused warfarin therapy and instead chose to take rivaroxaban. Upon outpatient follow-up, 3 months later, no visible thrombus was appreciated on repeat TEE. This case demonstrates successful resolution of left atrial and left atrial appendage thrombi with the use of rivaroxaban. At present time, limited data is available to support the use of rivaroxaban for treatment of intracardiac thrombi. This case highlights the need for further studies to investigate the outcomes and relative efficiency of use of direct oral anticoagulants (DOACs) in lysis of intracardiac thrombus. The benefits of DOACs compared to the standard of therapy could increase patient compliance, reduce length of stay, and improve treatment efficacy.",
"affiliations": "Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave., Chicago, IL 60657, USA.;Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave., Chicago, IL 60657, USA.;Department of Internal Medicine, Flushing Hospital Medical Center, 4500 Parsons Blvd, Flushing, NY 11355, USA.;Department of Cardiology, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave, Chicago, IL 60657, USA.",
"authors": "Gaznabi|Safwan|S|0000-0002-4439-3008;Abugroun|Ashraf|A|0000-0003-3824-9031;Mahbub|Hasan|H|;Campos|Enrique|E|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/6076923",
"fulltext": "\n==== Front\nCase Rep CardiolCase Rep CardiolCRICCase Reports in Cardiology2090-64042090-6412Hindawi 10.1155/2019/6076923Case ReportSuccessful Resolution of a Large Left Atrial and Left Atrial Appendage Thrombus with Rivaroxaban http://orcid.org/0000-0002-4439-3008Gaznabi Safwan sgaznabi@gmail.com\n1\nhttp://orcid.org/0000-0003-3824-9031Abugroun Ashraf \n1\nMahbub Hasan \n2\nCampos Enrique \n3\n\n1Department of Internal Medicine, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave., Chicago, IL 60657, USA\n2Department of Internal Medicine, Flushing Hospital Medical Center, 4500 Parsons Blvd, Flushing, NY 11355, USA\n3Department of Cardiology, Advocate Illinois Masonic Medical Center, 836 W Wellington Ave, Chicago, IL 60657, USAAcademic Editor: Aiden Abidov\n\n2019 9 4 2019 2019 607692316 11 2018 20 2 2019 Copyright © 2019 Safwan Gaznabi et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.A 79-year-old male was admitted to the hospital for acute exacerbation of heart failure. The patient had history of atrial fibrillation and was planned for cardioversion. Preprocedure transesophageal echocardiogram (TEE) revealed a large multilobulated mobile thrombus in the left atrial appendage. The patient refused warfarin therapy and instead chose to take rivaroxaban. Upon outpatient follow-up, 3 months later, no visible thrombus was appreciated on repeat TEE. This case demonstrates successful resolution of left atrial and left atrial appendage thrombi with the use of rivaroxaban. At present time, limited data is available to support the use of rivaroxaban for treatment of intracardiac thrombi. This case highlights the need for further studies to investigate the outcomes and relative efficiency of use of direct oral anticoagulants (DOACs) in lysis of intracardiac thrombus. The benefits of DOACs compared to the standard of therapy could increase patient compliance, reduce length of stay, and improve treatment efficacy.\n==== Body\n1. Introduction\nAtrial fibrillation is an ever-growing global problem, with an estimated 2.7-6.1 million affected in the United States and roughly 33.5 million affected worldwide [1]. Left atrial abnormalities, such as dilated left atrium and reduced left atrial and/or left atrial appendage blood flow, are independent risk factors for development of thromboembolism [2, 3]. In order to estimate the annual minimal risk of a thromboembolic event in these patients, we use the CHA2DS2-VASc scoring tool. Anticoagulation therapy helps to mitigate the risks of thromboembolic events and specifically in cases of nonvalvular atrial fibrillation (NVAF) [4, 5]. In cases of left atrial or left atrial appendage (LA/LAA) thrombus, current guidelines recommend vitamin K antagonist (VKA) therapy [6–10]. Here, we describe a successful resolution of left atrial and left atrial appendage thrombus with use of rivaroxaban.\n\n2. Case Report\nA 79-year-old male with past medical history of hypertension, atrial fibrillation (CHA2DS2-VASc score = 4, only on Aspirin), type 2 diabetes mellitus, and right lower extremity leiomyosarcoma with lymphedema of the affected limb treated with surgical resection and radiotherapy presented to the emergency department with exertional dyspnea, worsening of lower extremity edema, and weight gain. On arrival vitals shows blood pressure 140/95, heart rate 80, and SpO2 98. Physical examination was remarkable for irregular heartbeat, decreased bilateral lung sounds, and bilateral grade 3+ lower extremity edema up to the sacrum. Electrocardiogram (EKG) showed atrial fibrillation with new left bundle branch block (LBBB) (Figure 1). The laboratory workup was significant for brain natriuretic peptide (BNP) 2,233 pg/ml, troponin 0.38 ng/ml, and d-dimer 1.81 mg/l. Otherwise, he had normal basic metabolic panel (BMP) and complete blood count (CBC). Chest X-ray (CXR) and computed tomography (CT) of the chest showed cardiomegaly and moderate pleural effusion in bilateral lung fields (Figure 2).\n\nTransthoracic echocardiogram (TTE) showed left ventricular ejection fraction of 20% and severe global hypokinesis. Coronary angiogram revealed minimal coronary artery disease. The patient was diagnosed with nonischemic cardiomyopathy and was treated with lisinopril, metoprolol, spironolactone, diuretics, and enoxaparin. Despite medical management, he remained in atrial fibrillation for which he was scheduled for rhythm restoration with transesophageal echocardiogram- (TEE-) guided DC cardioversion (DCCV). TEE revealed a large multilobulated mobile thrombus in the left atrial appendage, and sessile irregular echogenic material attached to the wall of the left atrium was visualized (Figure 3(a)). Accordingly, cardioversion was aborted. The patient refused anticoagulation with Coumadin therapy and instead opted for rivaroxaban, aware of risks of possible anticoagulation failure or adverse events, as he would not be on standard of therapy. The patient was discharged with guideline-directed management for coronary artery disease and heart failure as well as rivaroxaban 20 mg daily. On subsequent outpatient follow-up three months later, repeat TEE showed no visible thrombus (Figure 3(b)). No evidence of clinical thromboembolic events was noted between initial and follow-up encounters.\n\n3. Discussion\nStandard of therapy for stroke prophylaxis in setting of LA/LAA/intracardiac thrombus in patients with NVAF is vitamin K antagonist (VKA) oral anticoagulation [6–10]; however, there is limited data regarding the use and clinical outcomes of direct thrombin inhibitors (DOACs) for diagnosed thrombus in LA/LAA. The ROCKET-AF trial evaluated the treatment of nonvalvular atrial fibrillation (NVAF) with the direct oral factor Xa inhibitor (rivaroxaban) compared with warfarin. Rivaroxaban was noninferior to warfarin in preventing stroke or systemic embolism in NVAF patients [11]. Among patients excluded were those with mitral valve stenosis, prosthetic valves, and left ventricular thrombus; however, there is no specific mention of inclusion or exclusion of LA/LAA thrombus. Investigators commented that patients in the warfarin group were in the therapeutic INR range, a mean of 55% of the time [11].\n\nAccording to the 2018 European Heart Rhythm Association Practical Guide on the use of nonvitamin K antagonist oral anticoagulants in patients with atrial fibrillation [12], in patients with atrial fibrilation ≥ 48-hour duration (or unknown) provided TEE negative for thrombi, the initiation of DOACs can be considered with at least a single DOAC dose ≥ 4 hours before electrical or pharmacological cardioversion. Otherwise, an alternative strategy would be initiating DOAC therapy for at least 3 weeks prior to cardioversion. After cardioversion, continuous oral anticoagulation is mandatory for at least another 4 weeks, irrespective of the CHA2DS2-VASc score [7]. One prospective open-label multicenter study by Lip et al. (X-TRA study) explored the use of vitamin K antagonist oral anticoagulation for the treatment of nonvalvular atrial fibrillation/flutter with documented LA/LAA thrombi on TEE [13]. This was based on the 2015 CLOT AF registry which with a total of 156 sample sizes in ITT population at 23 institutions among 7 European country [14] findings from the X-TRA showed that resolved or reduced thrombus after rivaroxaban treatment was evident and consistent with LA/LAA thrombus resolution with VKA therapy, suggesting that rivaroxaban maybe a potential treatment option for LA/LAA thrombi in patients with NVAF or atrial flutter [13].\n\nWarfarin inhibits the hepatic synthesis of the vitamin K-dependent coagulation factors by preventing extension of existing thrombi and de novo thrombosis [8]. Limitations for use of warfarin among cardiac patients who require anticoagulation therapy include a narrow therapeutic range, food and drug interactions, and unpredictable pharmacokinetics requiring regular and frequent International Normalized Ratio (INR) checks [15]. Failure of adequate anticoagulation can lead to progression of thromboembolism, hemorrhage, repeated hospital admissions, necessitation of more invasive procedures such as placement of a left atrial appendage closure device, increased cost burden, and increased risks of morbidity and mortality [9, 16, 17].\n\nRivaroxaban is approved for the reduction in risk of stroke for NVAF, primary and secondary venous thromboembolism (VTE) prophylaxes, and treatment of VTE; however, limited data and literature have been reported to establish the use or efficacy of DOACs on established left-sided intracardiac thrombus and its outcomes. This case demonstrates successful resolution of LA/LAA thrombi on DOAC therapy, specifically rivaroxaban. If enough clinical data supports DOAC relative efficacy in lysis of LA/LAA/intracardiac thrombus, the benefits of DOAC compared to the standard of therapy could increase patient compliance, reduce length of stay, and improve treatment efficacy.\n\n4. Conclusion\nAt present time, there is limited data on DOACs or factor Xa inhibitors in cases of diagnosed left atrial/left atrial appendage/intracardiac thrombi. Ideally, a well-designed randomized clinical trial to provide meaningful data and guidance as to the use of DOACs for such cases.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 EKG shows atrial fibrillation and LBBB.\n\nFigure 2 (a) CXR showed cardiomegaly with pulmonary congestion and bilateral pleural effusion. (b) CT chest with contrast showed moderately large bilateral pleural effusions, right greater than left, with cardiomegaly and reflux of IV contrast into the IVC, consistent with cardiogenic pulmonary vascular congestion.\n\nFigure 3 (a) The TEE transesophageal short axis view shows a large multilobulated mobile thrombus in the left atrial appendage. (b) TEE done 3 months later shows resolution of the thrombus.\n==== Refs\n1 Chugh S. S. Havmoeller R. Narayanan K. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study Circulation 2014 129 8 837 847 10.1161/CIRCULATIONAHA.113.005119 2-s2.0-84896723562 24345399 \n2 Brickner M. E. Friedman D. B. Cigarroa C. G. Grayburn P. A. Relation of thrombus in the left atrial appendage by transesophageal echocardiography to clinical risk factors for thrombus formation The American Journal of Cardiology 1994 74 4 391 393 10.1016/0002-9149(94)90409-X 2-s2.0-0027934757 8059703 \n3 Kamp O. Importance of left atrial appendage flow as a predictor of thromboembolic events in patients with atrial fibrillation European Heart Journal 1999 20 13 979 985 10.1053/euhj.1998.1453 2-s2.0-0033168887 10361051 \n4 Ruff C. T. Giugliano R. P. Braunwald E. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials The Lancet 2014 383 9921 955 962 10.1016/S0140-6736(13)62343-0 2-s2.0-84896117299 \n5 Salazar C. A. Aguila D. D. Cordova E. G. Direct thrombin inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with non-valvular atrial fibrillation Cochrane Database of Systematic Reviews 2014 3 10.1002/14651858.CD009893.pub2 2-s2.0-84907011613 \n6 Developed with the special contribution of the European Heart Rhythm Association (EHRA) Endorsed by the European Association for Cardio-Thoracic Surgery (EACTS) Authors/Task Force Members Guidelines for the management of atrial fibrillation: The Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC) European Heart Journal 2010 31 19 2369 2429 10.1093/eurheartj/ehq278 2-s2.0-77957699729 20802247 \n7 Kirchhof P. Benussi S. Kotecha D. 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS European Heart Journal 2016 37 38 2893 2962 10.1093/eurheartj/ehw210 2-s2.0-84994501747 27567408 \n8 Corrado G. Tadeo G. Beretta S. Atrial thrombi resolution after prolonged anticoagulation in patients with atrial fibrillation Chest 1999 115 1 140 143 10.1378/chest.115.1.140 2-s2.0-0032931641 9925075 \n9 Egolum U. O. Stover D. G. Lenihan D. Intracardiac thrombus: diagnosis, complications and management The American Journal of the Medical Sciences 2013 345 5 391 395 10.1097/MAJ.0b013e318272b0b0 2-s2.0-84876836756 23328835 \n10 Delewi R. Zijlstra F. Piek J. J. Left ventricular thrombus formation after acute myocardial infarction Heart 2012 98 23 1743 1749 10.1136/heartjnl-2012-301962 2-s2.0-84869209782 23151669 \n11 Patel M. R. Mahaffey K. W. Garg J. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation New England Journal of Medicine 2011 365 10 883 891 10.1056/NEJMoa1009638 2-s2.0-80052592404 21830957 \n12 Steffel J. Verhamme P. Potpara T. S. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation European Heart Journal 2018 39 16 1330 1393 10.1093/eurheartj/ehy136 2-s2.0-85046281325 29562325 \n13 Lip G. Y. Hammerstingl C. Marin F. Left atrial thrombus resolution in atrial fibrillation or flutter: results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF) American Heart Journal 2016 178 126 134 10.1016/j.ahj.2016.05.007 2-s2.0-84973324735 27502860 \n14 Lip G. Y. H. Hammerstingl C. Marin F. Rationale and design of a study exploring the efficacy of once-daily oral rivaroxaban (X-TRA) on the outcome of left atrial/left atrial appendage thrombus in nonvalvular atrial fibrillation or atrial flutter and a retrospective observational registry providing baseline data (CLOT-AF) American Heart Journal 2015 169 4 464 471.e2 10.1016/j.ahj.2014.12.020 2-s2.0-84927570044 25819852 \n15 Dobashi S. Fujino T. Ikeda T. Use of apixaban for an elderly patient with left atrial thrombus BMJ Case Reports 2014 2014 1, article bcr2014203870 10.1136/bcr-2014-203870 2-s2.0-84903593928 \n16 Agarwal S. Hachamovitch R. Menon V. Current trial-associated outcomes with warfarin in prevention of stroke in patients with nonvalvular atrial fibrillation: a meta-analysis Archives of Internal Medicine 2012 172 8 623 631 10.1001/archinternmed.2012.121 2-s2.0-84860372565 22450212 \n17 Mearns E. S. White C. M. Kohn C. G. Quality of vitamin K antagonist control and outcomes in atrial fibrillation patients: a meta-analysis and meta-regression Thrombosis Journal 2014 12 1 p. 14 10.1186/1477-9560-12-14 2-s2.0-84904133274\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6404",
"issue": "2019()",
"journal": "Case reports in cardiology",
"keywords": null,
"medline_ta": "Case Rep Cardiol",
"mesh_terms": null,
"nlm_unique_id": "101576452",
"other_id": null,
"pages": "6076923",
"pmc": null,
"pmid": "31093379",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10361051;20802247;21830957;22450212;23151669;23328835;24315724;24345399;24677203;24962484;25024644;25819852;27502860;27567408;29562325;8059703;9925075",
"title": "Successful Resolution of a Large Left Atrial and Left Atrial Appendage Thrombus with Rivaroxaban.",
"title_normalized": "successful resolution of a large left atrial and left atrial appendage thrombus with rivaroxaban"
} | [
{
"companynumb": "US-009507513-1909USA005112",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional"... |
{
"abstract": "We retrospectively evaluated the role of rituximab (R) in maintenance treatment after autologous stem cell transplantation performed in patients with relapsed follicular lymphoma. We compared the outcome of 67 follicular lymphoma (FL) patients according to the use of rituximab maintenance (RM) or not. All patients received rituximab plus chemotherapy before autologous stem-cell transplantation (ASCT). Patients received median of two lines of prior therapy. The RM schedule was one injection of rituximab every 3 months for 2 years. Median follow-up is 4.6 years. The 3-year progression-free survival (PFS) after ASCT was 86 % with RM vs. 46 % without (p = 0.0045). Median is not reached in the RM arm vs. 31 months in non-RM arm. The 3-year OS was 96 % with RM vs. 78 % without (p = 0.059). The present monocentric study shows that 2 years of RM after ASCT significantly increases response duration for non-naive rituximab relapsed FL patients compared with observation.",
"affiliations": "Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Epidemiology, University Hospital of Nantes, Nantes, France.;Department of Pathology, University Hospital of Nantes, Nantes, France.;Department of Pathology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, CHD de la Roche-Sur-Yon, La Roche-sur-Yon, France.;Department of Hematology, CH de Lorient, Lorient, France.;Centre Catherine de Sienne, Rezé, France.;Department of Hematology, CH de Vannes, Vannes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France.;Department of Hematology, University Hospital of Nantes, Nantes, France. steven.legouill@chu-nantes.fr.",
"authors": "Bourcier|J|J|;Gastinne|T|T|;Leux|C|C|;Moreau|A|A|;Bossard|C|C|;Mahé|B|B|;Blin|N|N|;Dubruille|V|V|;Touzeau|C|C|;Voldoire|M|M|;Guillaume|T|T|;Peterlin|P|P|;Gallas|P|P|;Garnier|A|A|;Maisonneuve|H|H|;Moreau|P|P|;Juge-Morineau|N|N|;Jardel|H|H|;Chevallier|P|P|;Moreau|P|P|;Le Gouill|S|S|",
"chemical_list": "D000069283:Rituximab",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-016-2705-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "95(8)",
"journal": "Annals of hematology",
"keywords": "Autologous stem cell transplantation; Follicular lymphoma; Relapse; Rituximab maintenance",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003131:Combined Modality Therapy; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D053208:Kaplan-Meier Estimate; D008224:Lymphoma, Follicular; D060046:Maintenance Chemotherapy; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009364:Neoplasm Recurrence, Local; D017063:Outcome Assessment, Health Care; D011184:Postoperative Period; D016016:Proportional Hazards Models; D012074:Remission Induction; D012189:Retrospective Studies; D000069283:Rituximab; D013997:Time Factors; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1287-93",
"pmc": null,
"pmid": "27297970",
"pubdate": "2016-08",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Rituximab maintenance after autologous stem cell transplantation prolongs response duration in non-naive rituximab follicular lymphoma patients: a single institution experience.",
"title_normalized": "rituximab maintenance after autologous stem cell transplantation prolongs response duration in non naive rituximab follicular lymphoma patients a single institution experience"
} | [
{
"companynumb": "FR-JNJFOC-20160927931",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": n... |
{
"abstract": "The incidence of anal squamous cell carcinoma has been increasing markedly in the past few decades. Currently, there is no validated treatment for advanced-stage anal squamous cell carcinoma. Therefore, we aimed to validate the clinical activity and safety of docetaxel, cisplatin, and fluorouracil (DCF) chemotherapy in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma.\n\n\n\nWe did a multicentre, single-arm, phase 2 study. We recruited patients from 25 academic hospitals, cancer research centres, and community hospitals in France who were aged 18 years or older with histologically confirmed anal squamous cell carcinoma, with metastatic disease or with unresectable local recurrence; an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; and with at least one evaluable lesion according to the Response Evaluation Criteria in Solid Tumors (version 1.1). Chemotherapy-naive patients received either six cycles of standard DCF (75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 and 750 mg/m2 per day of fluorouracil for 5 days, every 3 weeks) or eight cycles of modified DCF (40 mg/m2 docetaxel and 40 mg/m2 cisplatin on day 1 and 1200 mg/m2 per day of fluorouracil for 2 days, every 2 weeks), which were administered intravenously. The choice between the standard versus modified regimens was recommended based on, but not limited to, age (≤75 years vs >75 years) and ECOG performance status (0 vs 1). The primary endpoint was investigator-assessed progression-free survival at 12 months from the first DCF cycle; for the primary endpoint to be met, at least 11 (17%) of 66 enrolled patients had to be alive without disease progression at 12 months. Efficacy and safety analyses were done in a modified intention-to-treat population, defined as all patients who were evaluable for progression at 12 months who received at least one cycle of DCF. This trial is registered at ClinicalTrials.gov, number NCT02402842, and the final results are presented here.\n\n\n\nBetween Sept 17, 2014, and Dec 7, 2016, we enrolled 69 patients. Of these patients, three did not receive DCF. Of the 66 patients who received treatment, 36 received the standard DCF regimen and 30 received modified DCF. The primary endpoint was met: 31 (47%) of 66 patients were alive and progression free at 12 months. 22 (61%) of 36 patients who received the standard DCF regimen and 18 (60%) of 30 patients who received the modified DCF regimen had disease progression at data cutoff. 46 (70%) of 66 patients had at least one grade 3-4 adverse event (30 [83%] of 36 in the standard DCF regimen and 16 [53%] of 30 in the modified DCF regimen). The most common grade 3-4 adverse events were neutropenia (15 [23%]; eight [22%] for standard DCF vs seven [23%] for modified DCF), diarrhoea (12 [18%]; nine [25%] vs three [10%]), asthenia (ten [15%]; eight [22%] vs two [7%]), anaemia (ten [15%]; six [17%] vs four [13%]), lymphopenia (eight [12%]; three [8%] vs five [17%]), mucositis (seven [11%]; seven [19%] vs none), and vomiting (seven [11%]; five [14%] vs two [7%]). No grade 4 non-haematological adverse events and febrile neutropenia were observed with modified DCF, whereas three (8%) grade 4 non-haematological adverse events and five (14%) cases of febrile neutropenia were reported with standard DCF. 97 serious adverse events were reported (69 in patients who received the standard DCF regimen [61 drug-related] and 28 in those given the modified DCF regimen [14 drug-related]). No treatment-related deaths were recorded.\n\n\n\nCompared with standard DCF, modified DCF provided long-lasting response with good tolerability in patients with metastatic or unresectable locally recurrent anal squamous cell carcinoma with ECOG performance status of 0-1 in the first-line setting, and therefore could be considered as a new standard of care for these patients. Regarding the elevated risk of high-grade and serious adverse events and febrile neutropenia, standard DCF cannot be recommended in this situation.\n\n\n\nBesançon University Hospital and Ligue contre le cancer Grand-Est.",
"affiliations": "Department of Oncology, University Hospital of Besancon, Centre Hospitalier Universitaire de Besançon, Besançon, France; Department of Oncology and Radiotherapy, Hôpital Nord Franche Comté, Montbéliard, France; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France; Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France. Electronic address: chkim@chu-besancon.fr.;Medical Oncology Department, Centre Antoine-Lacassagne, Nice, France.;Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France; Department of Medical Oncology, Hôpital Saint Antoine, Assistance Publique Hôpitaux de Paris and Sorbonne Universités, Paris, France.;Department of Oncology, Institut du Cancer de Montpellier, Montpellier, France.;Department of Oncology, University Hospital of Besancon, Centre Hospitalier Universitaire de Besançon, Besançon, France; Department of Oncology and Radiotherapy, Hôpital Nord Franche Comté, Montbéliard, France; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France.;Department of Oncology, Centre Oscar Lambret, Lille, France.;Department of Oncology, Groupe Hospitalier Paris Saint-Joseph, Paris, France.;Department of Oncology, Hôpital Européen Georges-Pompidou, Paris, France.;Department of Oncology, Institut de Cancérologie de Lorraine, Nancy, France.;Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France; Department of Oncology, Centre Hospitalier Universitaire de Reims, Reims, France.;Department of Oncology, Hôpital Privé Jean Mermoz, Lyon, France.;Department of Oncology, Hôpital Privé des Peupliers, Paris, France.;Department of Oncology, Centre Georges-François Leclerc, Dijon, France.;Department of Oncology, Centre François Baclesse, Caen, France.;Department of Oncology, Centre Léon Bérard, Lyon, France.;Department of Oncology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Department of Oncology, Centre Hospitalier Lyon Sud, Lyon, France.;INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France.;Department of Oncology, Clinique Saint Vincent, Besançon, France.;Department of Oncology, University Hospital of Besancon, Centre Hospitalier Universitaire de Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France.;Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; French National Platform Quality of Life and Cancer, Besançon, France.;Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France.;Methodology and Quality of Life in Oncology Unit, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France.;Department of Oncology, Hôpital Européen Georges-Pompidou, Paris, France.;Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France; Department of Oncology, Centre Hospitalier Universitaire de Bordeaux, Bordeaux, France.;Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France; Department of Oncology, Institut Curie, Paris, France.;Department of Oncology, University Hospital of Besancon, Centre Hospitalier Universitaire de Besançon, Besançon, France; Department of Oncology and Radiotherapy, Hôpital Nord Franche Comté, Montbéliard, France; Clinical Investigational Center, CIC-1431, University Hospital of Besançon, Besançon, France; INSERM, Unit 1098, University of Bourgogne Franche-Comté, Besançon, France; Groupe Coopérateur Multidisciplinaire en Oncologie (GERCOR) Oncology Multidisciplinary Group, Paris, France; Fédération Francophone de Cancérologie Digestive (FFCD), Dijon, France.",
"authors": "Kim|Stefano|S|;François|Eric|E|;André|Thierry|T|;Samalin|Emmanuelle|E|;Jary|Marine|M|;El Hajbi|Farid|F|;Baba-Hamed|Nabil|N|;Pernot|Simon|S|;Kaminsky|Marie-Christine|MC|;Bouché|Olivier|O|;Desrame|Jérôme|J|;Zoubir|Mustapha|M|;Ghiringhelli|François|F|;Parzy|Aurélie|A|;De La Fouchardiere|Christelle|C|;Smith|Denis|D|;Deberne|Mélanie|M|;Spehner|Laurie|L|;Badet|Nicolas|N|;Adotevi|Olivier|O|;Anota|Amélie|A|;Meurisse|Aurélia|A|;Vernerey|Dewi|D|;Taieb|Julien|J|;Vendrely|Véronique|V|;Buecher|Bruno|B|;Borg|Christophe|C|",
"chemical_list": "D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(18)30321-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "19(8)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001005:Anus Neoplasms; D002294:Carcinoma, Squamous Cell; D002945:Cisplatin; D000077143:Docetaxel; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D000077982:Progression-Free Survival",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "1094-1106",
"pmc": null,
"pmid": "30042063",
"pubdate": "2018-08",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Docetaxel, cisplatin, and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma (Epitopes-HPV02): a multicentre, single-arm, phase 2 study.",
"title_normalized": "docetaxel cisplatin and fluorouracil chemotherapy for metastatic or unresectable locally recurrent anal squamous cell carcinoma epitopes hpv02 a multicentre single arm phase 2 study"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1093784",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nLike angiotensin converting enzyme (ACE) inhibitors angiotensin II (AT II)-receptor-antagonists may cause persistent or even lethal fetotoxic defects when used during the late second or third trimester. There are insufficient data on first-trimester exposure to these substances in terms of teratogenicity. The two databases of the Berlin Teratology Information Service (TIS) were evaluated for pregnancy outcome following exposure to AT II-receptor-antagonists. One database covers case reports on newborns with congenital abnormalities identified after birth, in which drug-effect associations can be evaluated retrospectively. The other enrolls women prospectively according to exposure to particular drugs during pregnancy, with follow-up of pregnancy outcome.\n\n\nMETHODS\nFive cases (four retrospective and one prospective) involving late-pregnancy use of AT II-receptor-antagonists were recently reported to us, each of which included one or more of the following abnormalities: oligohydramnios/anhydramnios, anuria, hypoplastic skull bones, limb contractions, lung hypoplasia, and neonatal death. Among 37 prospectively enrolled first-trimester-exposed pregnancies there were 30 live births including one with a major malformation (cleft palate). One pregnancy was electively terminated after exencephaly had been diagnosed.\n\n\nCONCLUSIONS\nAT II-receptor-antagonists may induce fetotoxic effects when used in the second and third trimesters. The available data on first-trimester use do not strongly support a teratogenic potential. AT II-receptor-antagonists should not be used by pregnant women. In case of inadvertent exposure, therapy should be changed to the known antihypertensives of choice (e.g., metoprolol, methyldopa, and hydralazine) and fetotoxic effects should be ruled out by ultrasound. Treatment with AT II-receptor-antagonists during early pregnancy is not in itself an indication for termination of a wanted pregnancy.",
"affiliations": "Fachbereich Embryonaltoxikologie (Department of Embryotoxicology), Berliner Betrieb für Zentrale Gesundheitliche Aufgaben, Berlin, Germany. schaefer@embryotox.de",
"authors": "Schaefer|Christof|C|",
"chemical_list": "D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000804:Angiotensin II",
"country": "United States",
"delete": false,
"doi": "10.1002/bdra.10081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-0752",
"issue": "67(8)",
"journal": "Birth defects research. Part A, Clinical and molecular teratology",
"keywords": null,
"medline_ta": "Birth Defects Res A Clin Mol Teratol",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000328:Adult; D000804:Angiotensin II; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D005260:Female; D005313:Fetal Death; D006801:Humans; D007223:Infant; D007226:Infant Mortality; D007231:Infant, Newborn; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "101155107",
"other_id": null,
"pages": "591-4",
"pmc": null,
"pmid": "14632309",
"pubdate": "2003-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity.",
"title_normalized": "angiotensin ii receptor antagonists further evidence of fetotoxicity but not teratogenicity"
} | [
{
"companynumb": "DE-MYLANLABS-2019M1044670",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "VALSARTAN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTreatment-resistant schizophrenia (TRS) is a condition characterized by intense symptom severity and poor response to different antipsychotic agents. The first therapeutic option in TRS is clozapine, but often high/medium doses are not tolerated. Adding an oral antipsychotic to low doses of clozapine is a promising strategy in the management of TRS. On the contrary, there are few data on combined clozapine/long-acting injectable (LAI) medications, and none on clozapine/LAI-aripiprazole.\n\n\nMETHODS\nA 21-year-old male schizophrenic patient, resistant to several oral and LAI medications, partially improved after clozapine 300 mg/d treatment. Unfortunately, he also reported excessive sedation and an episode of myoclonus, so clozapine was reduced to 150 mg/d, but no additional benefits were observed. Subsequently, LAI-aripiprazole (first 200 mg/mo, then 400 mg/mo) was added, and the patient's conditions dramatically improved over time. After 1 year of observation, symptoms reduction was 50% or greater, without significant adverse events.\n\n\nCONCLUSIONS\nClozapine use in TRS is often reduced or delayed due to the fear of serious adverse effects. Adding LAI-aripiprazole to low doses of clozapine may be a useful therapeutic option to obtain a good efficacy/tolerability balance.",
"affiliations": "*Department of Basic Medical Sciences, Neurosciences and Sense Organs, \"A. Moro\" University of Bari, Bari; †Department of Neuroscience, Imaging and Clinical Science, \"G. d' Annunzio\" University of Chieti; and ‡National Health Trust, Department of Mental Health, Chieti, Italy.",
"authors": "Sepede|Gianna|G|;Di Iorio|Giuseppe|G|;Spano|Maria Chiara|MC|;Lorusso|Marco|M|;Sarchione|Fabiola|F|;Santacroce|Rita|R|;Salerno|Rosa Maria|RM|;Di Giannantonio|Massimo|M|",
"chemical_list": "D000068180:Aripiprazole; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "39(6)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000068180:Aripiprazole; D003024:Clozapine; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D012559:Schizophrenia; D055815:Young Adult",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "322-324",
"pmc": null,
"pmid": "27764052",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Resistant Schizophrenia Successfully Treated With Clozapine/Long-acting Injectable Aripiprazole Combination.",
"title_normalized": "a case of resistant schizophrenia successfully treated with clozapine long acting injectable aripiprazole combination"
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"companynumb": "IT-MYLANLABS-2016M1050280",
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"activesubstancename": "RISPERIDONE"
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"abstract": "The aim of this study was to determine (1) whether ibuprofen treatment in very preterm infants causes an increase in the renal water channel aquaporin-2 (AQP2) activity in the collecting duct via prostaglandin synthesis inhibition and (2) whether AQP2 activity remains disturbed long after ibuprofen treatment has ended. This was a prospective study involving premature infants with a gestation age of 27-31 weeks who received treatment between December 2005 and August 2006 in a tertiary Neonatal Intensive Care Unit. Each ibuprofen-treated infant was matched to two controls. Renal glomerular and tubular function were evaluated weekly for 1 month, and urinary AQP2 was measured by immuno-dotting. In total, 166 longitudinal samples were analyzed in 36 infants. Median [interquartile range] gestational age and birthweight were 28 [27.0-29.5] weeks and 1160 [1041-1242] g, respectively. Perinatal factors were similar in both groups. Urine output was significantly decreased in the ibuprofen-treated infants during the treatment. The urinary AQP2 level decreased significantly from day 2 to day 7 in both groups and was similar thereafter for the first month of life in ibuprofen-treated and control groups. Based on our results, we conclude that ibuprofen-induced oligo-anuria is not associated with a change in AQP2 activity and that ibuprofen does not affect AQP2 activity during the first month of life in very preterm neonates.",
"affiliations": "Neonatal Department, Maternite Regionale Universitaire, 54042 Nancy, France.",
"authors": "Vieux|Rachel|R|;Zelenina|Marina|M|;Aperia|Anita|A|;Hascoët|Jean-Michel|JM|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D051399:Aquaporin 2; D007052:Ibuprofen",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00467-010-1487-0",
"fulltext": null,
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"issn_linking": "0931-041X",
"issue": "25(7)",
"journal": "Pediatric nephrology (Berlin, Germany)",
"keywords": null,
"medline_ta": "Pediatr Nephrol",
"mesh_terms": "D018712:Analgesics, Non-Narcotic; D051399:Aquaporin 2; D001724:Birth Weight; D005260:Female; D005865:Gestational Age; D005919:Glomerular Filtration Rate; D006801:Humans; D007052:Ibuprofen; D007231:Infant, Newborn; D007234:Infant, Premature; D007668:Kidney; D007674:Kidney Diseases; D007677:Kidney Function Tests; D008297:Male; D011446:Prospective Studies; D014555:Urination Disorders",
"nlm_unique_id": "8708728",
"other_id": null,
"pages": "1277-84",
"pmc": null,
"pmid": "20390303",
"pubdate": "2010-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15579502;7532304;11044478;10752764;16773405;7877873;9570029;16897006;18254020;12119536;8770174;8770180;10710543;9279181;6351537;7472835;7541941;3720168;19902266;11773613;860762;8032394;12537310;9335377;15811164;7018256;7359417;16902321;7015783;16113155;7931888;11768323;3588043;6524361;16869817",
"title": "The renal adverse effects of ibuprofen are not mediated by AQP2 water channels.",
"title_normalized": "the renal adverse effects of ibuprofen are not mediated by aqp2 water channels"
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"companynumb": "US-JNJFOC-20150219514",
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"abstract": "Hepatitis C virus (HCV)-HBV coinfection is a significant health problem with rapid progression of liver disease without precise diagnosis and treatment. We aimed in this study to identify if there were any role of HBV antiviral therapy in patients with HBV reactivation after direct-acting antiviral therapy in HCV-HBV coinfected patients.\nA prospective random study was carried out on 140 patients presenting with chronic HCV and chronic HBV coinfection. All patients had pretreatment HBeAg seroconversion, HBV DNA <2,000 IU/mL, normal liver enzymes, and F0/F1 hepatic fibrosis. They treated with sofosbuvir 400 mg and daklatasvir 60 mg once daily for 3 months. All patients underwent pretreatment hepatic fibrosis assessment using Fibro Scan and laboratory investigations: platelet count, liver-function tests, quantitative HCV PCR, HBsAg, HBc IgG, HBeAg, and HBeAb. All patients were followed up at 1, 3, 6, and 12 months from the start of HCV therapy.\nThe study enrolled 140 HCV-HBV coinfected patients: 55% were F0 and the rest F1. All our patients had negative HCV PCR at 1 month posttreatment and had achieved sustained virologic response with negative HCV PCR 3 months after treatment end. Four patients showed HBV reactivation with raised HBV DNA PCR and liver enzymes. Their mean age was 23.7±2.7 years, and three were male. Regarding patients with HBV reactivation, at 12 months posttreatment they showed significant decreases in liver enzymes, bilirubin, and INR, with increased platelet count (P=0.001), each with undetectable HBV PCR (P=0.001).\nHBV-HCV coinfected patients with no/mild hepatic fibrosis, HBeAg seroconversion, and HBV DNA <2,000 IU/mL can complete direct-acting antiviral therapy without HBV antiviral treatment with close monitoring.",
"affiliations": "Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Egypt.;Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Egypt.;Internal Medicine and Gastroenterology Department, Faculty of Medicine, Helwan University, Helwan, Egypt.;Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt.;Clinical Pathology Department, Faculty of Medicine, Sohag University, Sohag, Egypt.",
"authors": "Osman|Heba Ahmed|HA|0000-0001-6302-3443;Ghweil|Ali A|AA|;Sabry|Abeer Mm|AM|0000-0002-7028-7479;Mahdy|Reem E|RE|;Khodeary|Ashraf|A|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.2147/IDR.S215974",
"fulltext": "\n==== Front\nInfect Drug ResistInfect Drug ResistIDRidrInfection and Drug Resistance1178-6973Dove 21597410.2147/IDR.S215974Original ResearchManagement Of Patients With Hepatitis B Virus Reactivation Post–DAA Treatment Of Chronic Hepatitis C Virus Infection In HCV–HBV Coinfected Patients With Pretreatment HBeAg Seroconversion And Early Degree Of Hepatic Fibrosis Osman et alOsman et alhttp://orcid.org/0000-0001-6302-3443Osman Heba Ahmed 1Ghweil Ali A 1http://orcid.org/0000-0002-7028-7479Sabry Abeer MM 2Mahdy Reem E 3Khodeary Ashraf 41 Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Egypt2 Internal Medicine and Gastroenterology Department, Faculty of Medicine, Helwan University, Helwan, Egypt3 Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut, Egypt4 Clinical Pathology Department, Faculty of Medicine, Sohag University, Sohag, EgyptCorrespondence: Heba Ahmed Osman Lecturer of Tropical Medicine and Gastroenterology Department, Faculty of Medicine, South Valley University, Qena, Qena83523, EgyptTel +20 96 10 656 4745 Email drheba.saleh@med.svu.edu.eg30 9 2019 2019 12 3067 3073 16 5 2019 27 8 2019 © 2019 Osman et al.2019Osman et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Background and aim\nHepatitis C virus (HCV)–HBV coinfection is a significant health problem with rapid progression of liver disease without precise diagnosis and treatment. We aimed in this study to identify if there were any role of HBV antiviral therapy in patients with HBV reactivation after direct-acting antiviral therapy in HCV–HBV coinfected patients.\n\nMethods\nA prospective random study was carried out on 140 patients presenting with chronic HCV and chronic HBV coinfection. All patients had pretreatment HBeAg seroconversion, HBV DNA <2,000 IU/mL, normal liver enzymes, and F0/F1 hepatic fibrosis. They treated with sofosbuvir 400 mg and daklatasvir 60 mg once daily for 3 months. All patients underwent pretreatment hepatic fibrosis assessment using Fibro Scan and laboratory investigations: platelet count, liver-function tests, quantitative HCV PCR, HBsAg, HBc IgG, HBeAg, and HBeAb. All patients were followed up at 1, 3, 6, and 12 months from the start of HCV therapy.\n\nResults\nThe study enrolled 140 HCV–HBV coinfected patients: 55% were F0 and the rest F1. All our patients had negative HCV PCR at 1 month posttreatment and had achieved sustained virologic response with negative HCV PCR 3 months after treatment end. Four patients showed HBV reactivation with raised HBV DNA PCR and liver enzymes. Their mean age was 23.7±2.7 years, and three were male. Regarding patients with HBV reactivation, at 12 months posttreatment they showed significant decreases in liver enzymes, bilirubin, and INR, with increased platelet count (P=0.001), each with undetectable HBV PCR (P=0.001).\n\nConclusion\nHBV–HCV coinfected patients with no/mild hepatic fibrosis, HBeAg seroconversion, and HBV DNA <2,000 IU/mL can complete direct-acting antiviral therapy without HBV antiviral treatment with close monitoring.\n\nKeywords\nHBVHCVPCRDAAs\n==== Body\nIntroduction\nHepatitis B virus (HBV) infection is still a global health affair. Patients who progress to chronic HBV can early develop liver cirrhosis and hepatocellular carcinoma, with an accession risk of morbidity and mortality.1 HBV and HCV infections share the same transmission routes, so the presence of HBV coinfection in patients with HCV infection is frequent.2 The presence of HBV surface antigens in patient blood is known as overt HBV infection. However, in the absence of an HBsAg test, detection of HBV DNA is recognized as occult HBV infection, and is commonly found in patients with chronic HCV infection.3\n\nCoinfection with HBV and HCV is common in Southeast Asia and the Mediterranean.4 HBV–HCV coinfection is associated with higher incidence of cirrhosis, hepatic decompensation, and development of primary liver malignancy (hepatocellular carcinoma) compared with monoinfected individuals.5 The true prevalence of HBV–HCV coinfection is unknown.6 HBsAg-positive patients have been excluded from clinical trials during treatment of patients with chronic HCV with direct-acting antivirals (DAAs).7 This was confirmed by a different study wherein interaction between HBV and HCV in coinfected patients led to suppression of HBV replication.8,9 However, severe cases of chronic HBV reactivation after HCV clearance have been reported after DAA therapy, which led to US Food and Drug Administration concern about the risk of HBV reactivation with DAA therapy.10\n\nAim\nThe aim of this work was to identify if there was any role of HBV antiviral therapy following DAA treatment of chronic HCV infection in HBV reactivation in patients with pretreatment HBeAg seroconversion, HBV DNA <2,000 IU/mL, normal liver enzymes, and F0/F1 hepatic fibrosis.\n\nMethods\nThis prospective randomized study was carried out on 140 patients presenting with chronic HCV–HBV coinfection who had been referred to the outpatient clinic of the Tropical Medicine and Gastroenterology Department of Qena University Hospital. The study period was from August 1, 2016 to January 1, 2019. HBV PCR ≤2,000 IU/mL, normal liver enzymes, HBeAg seroconversion with formation of HBeAb before treatment, and F0/F1 hepatic fibrosis were the inclusion criteria. Patients with worse than F1 hepatic fibrosis, previous HBV antiviral treatment, absence of HBeAg seroconversion, had failed previous HCV therapy, and malignancy anywhere in the body, including hepatocellular\ncarcinoma and laboratory parameters of hepatic decompensation, pregnancy, autoimmune disease, and uncontrolled diabetes mellitus were excluded from the study.\n\nAll included patients were treated with sofosbuvir 400 mg and daklatasvir 60 mg once daily for 3 months following the Egyptian protocol for treatment of chronic HCV infection, which is based on the European\nAssociation for the Study of the Liver guidelines for treatment of HCV infection.11 All patients underwent pretreatment complete history taking, full clinical examination, and laboratory investigations, including liver-function tests, platelet count, prothrombin time, prothrombin concentration, and INR. Quantitate HCV PCR, HBsAg, HBc IgG, HBeAg and HBeAb were also assessed. Also, all patients underwent pretreatment hepatic fibrosis assessment using a FibroScan FS502. Hepatic scans were performed after overnight fasting. Liver stiffness correlate directly with wave velocity. FibroScan results were correlated with the METAVIR histological staging system. Cutoff values in our study were 5.4–6.9 kPa.12 All patients were followed up at 1 month, 3 months (end of HCV treatment), 6 months (to confirm HCV sustained virologic response), and 12 months (to confirm absence of HBV reactivation) from the start of HCV therapy.\n\nBlood Sampling\nVenous blood (8 mL) was collected from each patient under aseptic precautions and divided in four tubes: two tubes containing EDTA, one for platelet count used directly and the other for HBV DNA, HBc IgG, HBeAg, and HBeAb centrifuged, separated in sterile tubes, and frozen at −20°C until assay; a plain glass tube for liver-function tests, after clotting the tube being centrifuged at 3,000 rpm for 5 minutes at room temperature and then serum was separated to be used for estimation of liver function (including liver enzymes, albumin, and bilirubin); and a sodium citrate–containing tube for prothrombin time, prothrombin concentration, and INR.\n\nLaboratory Tests\nVenous blood (5 mL) was obtained from each subject in a plain tube, centrifuged, and then the serum separated for laboratory tests. Platelet counts were done with a Celtak hematology analyzer (Nihon Kohden. Liver-function tests (total and direct bilirubin, serum albumin, AST, and ALT) were done with a BT 1500 fully automated chemistry analyzer (Biotecnica). Prothrombin time, concentration, and INR were assessed using Thromborel S kits (Siemens) using a BE coagulator. HBV DNA, HBc IgG, HBeAg, and HBeAb were assessed with a StepOnePlus real-time PCR system (Thermo Fisher Scientific) using TaqMan PCR master mix (Thermo Fisher Scientific) after DNA extraction with a Qiagen kit and according to the manufacturer’s pamphlet. HCV PCR and HBsAg were measured with a MiniVidas fully automated immunoassay system (Biomérieux).\n\nStatistical Analysis\nData were analyzed using SPSS version 15.0. Quantitative data are expressed as means ± SD. Qualitative data are expressed as frequencies and percentages. Independent-sample t-tests were used when comparing two means, χ2 when comparing nonparametric data, and one-way ANOVA when comparing more than two means. Significance was established at P<0.05.\n\nEthical Considerations\nThe study protocol was approved by the Medical Ethics Committee of South Valley University, and the study was performed in accordance with clinical ethics guidelines, the Declaration of Helsinki, and rules of good clinical practice. All patients provided informed consent for participation in the study. No specific medical intervention was conducted specifically.\n\nResults\nThe study enrolled 140 patients coinfected with HCV–HBV. All patients had HBV PCR ≤2,000 IU/mL, normal pretreatment liver enzymes, and showed HBeAg seroconversion with development of HBeAb. In sum, 77 (55%) were F0 and 63 (45%) F1, mean age was 32.4±8.02 years, and 96 (68.6%) were male and 44 (31.4%) female. Four patients (2.86%, three male, mean age 23.7±2.7 years) showed HBV reactivation in the form of raised liver enzymes and HBV DNA PCR 1 month after DAA therapy (Table 1). On liver-function tests, all patients showed decreased mean ALT at 1 month, 3 months, 6 months, and 12 months post:treatment: 24.9± 14.2, 24.4±10.8, 23±8.2, and 13.2±3.5 U/L, respectively (P=0.001). Significant improvement in AST levels was also detected, reaching 13.7±3.5 U/L at 1 year posttherapy. (P=0.001). Bilirubin, INR, and platelet counts showed significant improvement at 1 year posttreatment (Table 2, Figures 1 and 2). Patients showed decreased mean HBV PCR levels: from 913.4±1,362.4 IU/mL (before treatment) to 760.8±379.02 IU/mL (6 months after starting treatment) and 396.1±124.8 IU/mL (12 months after starting treatment).Table 1 Demographic Data Of Studied Patients\n\n\tPatients (n=140)\t\nAge (years), mean ± SD)\t32.44±8.02\t\nSex, n (%)\t\t\n Male\t96 (68.6%)\t\n Female\t44 (31.4%)\t\nFibroScan, n ( %)\t\t\n F0\t77 (55%)\t\n F1\t63 (45%)\t\nHBV-reactivated patients (n=4)\t\nAge (years), mean ± SD\t23.75±2.75\t\nSex\t\t\n Male\t3 (75%)\t\n Female\t1 (25%)\t\n\nTable 2 Comparisons Of ALT, AST, And HBV PCR (Before Chronic Hepatitis C Virus Treatment, 1 Month, 3 Months, And 6 Months After Therapy)\n\n\tBefore\tAfter 1 Month\tAfter 3 Months (End Of Treatment)\tAfter 6 Months\tAfter 12 Months\tP-value\t\nPlatelets (103/µL), mean ± SD\t181.1±64.5\t201.5±59.7\t203.5±53.6\t210.5±52.7\t221.3±53.1\t0.001\t\nBilirubin (mg/dL), mean ± SD\t1.2±0.5\t1.2±0.3\t1.12±0.2\t1.01±0.1\t0.9±0.1\t0.001\t\nAST (U/L), mean ± SD\t23.3±8.3\t24.8±9.7\t25.4±10.5\t22.3±8.3\t13.7±3.5\t0.001\t\nALT (U/L), mean ± SD\t29.7±39.1\t24.9±14.2\t24.4±10.8\t23±8.2\t13.2±3.5\t0.001\t\nINR, ean ± SD\t1.3±0.11\t1.2±0.12\t1.05±0.1\t0.9±0.1\t0.9±0.1\t0.001\t\nHBV PCR (IU/mL), mean ± SD\t913.4±1,362.4\t1,395.4±2,619.3\t2,282.8±5,415.4\t760.8±379.02\t396.1±124.8\t0.049\t\nHBV-reactivated patients (n=4)\t\nPlatelets (103/µL), mean ± SD\t183±4.2\t183±2.9\t194.2±4.3\t196.3±2.2\t202.3±2.2\t0.001\t\nBilirubin (mg/dL), mean ± SD\t1.27±0.17\t1.4±0.08\t1.35±0.05\t1.01±0.01\t0.9±0.05\t0.001\t\nAST (U/L), mean ± SD\t29.7±2.2\t60.3±4.8\t71.5±5.8\t23.3±0.5\t11.5±3.3\t0.001\t\nALT (U/L), mean ± SD\t25.8±5.5\t68.5±5.1\t65.2±8.3\t11.8±4.9\t10.0±1.4\t0.001\t\nINR, mean ± SD\t1.2±0.12\t1.2±0.09\t1.1±0.05\t0.9±0.03\t0.8±0.02\t0.001\t\nHBV PCR (IU/mL), mean ± SD\t1,494±571\t10,184.5 ±1,857.2\t20,802±1,059.7\t666±148.6\t—\t0.001\t\nNotes:\nP<0.05 considered significant; P<0.001 considered highly significant.\n\n\nFigure 1 ALT in all included patients.\n\nFigure 2 HBV PCR in all included patients.\n\n\n\nFor liver-function tests in patients with HBV reactivation, AST levels before treatment and at 1 month, 3 months, 6 months, and 12 months after starting DAA therapywere 29.7±2.2, 60.3±4.8, 71.5±5.8, 23.3±0.5, and 11.5±3.3 U/L, respectively, with a significant decrease at 12 months posttreatment (P=0.001). ALT was 25.8±5.5, 68.5±5.1, 65.2±8.3, 11.8±4.9, and 10.0±1.4 U/L before treatment and at 1 month, 3 months, 6 months, and 1 year after DAA therapy, respectively, with significant improvement (P=0.001). Bilirubin and INR both showed significant 1-year posttreatment improvement (P=0.001). Quantitative HBV DNA PCR in patients with HBV reactivation during DAA therapy was raised at 1 month (10,184.5±1,857.2 IU/mL) and 3 months (20,802±1,059.7 IU/mL) after starting DAAs. HBV PCR then gradually decreased (without HBV antiviral therapy) until finally becoming undetectable 1 year posttherapy (6 months after the end of DAA therapy, P=0.001). At 1 year posttreatment, platelet counts showed significant increase: from 183±4.2×103/µL (before treatment) to 202.3±2.2×103/µL (1 year posttreatment; P=0.001; Table 2, Figures 3 and 4). All patients had negative HCV PCR at 1 month posttreatment, and all had achieved sustained virologic response with negative HCV PCR 3 months after the end of treatment.Figure 3 ALT in HBV reactivation patients.\n\nFigure 4 HBV PCR in hepatitis B reactivation patients.\n\n\n\nDiscussion\nThe reactivation of HBV means detection of de novo HBV DNA not previously detected, a 1–2 log IU/mL increase in serum HBV DNA, or lasty seroconversion in individuals with HBc Ab.13 Studies concerned with the reactivation of HBV after DAA treatment for HCV have given different results over the past few years. It is postulated that HCV infection suppresses HBV replication through many HCV core proteins, such as NS5Aa and NS2.14–19 This is why suppression of HCV by DAA is postulated to increase HBV replication. This was manifested in our data, where after 1 month of treatment there was marked elevation in HBV DNA.\n\nIn a cohort study on chronic HCV patients with positive HBsAg who underwent DAAs in Egypt, the risk of reactivation in the absence of HBV treatment was 28.6% (95% CI 15.6%–46.4%) and the risk of hepatitis in the patients who experienced reactivation 10.0% (95% CI 0.9%–57.8%). Also, the pooled risk of reactivation in HBsAg-negative anti-HBc-positive patients was negligible (0.1%, 95% CI 0–0.3%), irrespective of the presence of anti-HBs.20\n\nWe studied patients that were coinfected with HCV–HBV. All patients had HBV PCR <2,000 IU/mL and showed HBeAg seroconversion with development of HBeAb. From the 140 patients studied, only four showed HBV reactivation, representing 2.8% of the studied group. When we followed all patients after DAA therapy, there were significant decreases in liver enzymes and HBV DNA. This was similar to a study that showed a decrease in liver enzymes after treatment of HCV, but without the statistical significance found in our study. Also, that study counted on quantitative HbcAb to diagnose the condition, while we tested patients for seroconversion of HbeAg, but not quantitative HbcAb.21 It is known that the HBeAg seroconversion is associated with low levels of HBV DNA, with clinical improvement in liver disease in the majority of patients.22–25 This was the case in our patients, where a significant decrease was observed in liver enzymes that was associated with a decrease in HBV DNA.\n\nIn a meta-analysis, Chen et al compared the rate of reactivation in patients with chronic HBV versus those with occult infection. One of the results of the study was that HBV reactivation and hepatitis were less common among individuals with occult HBV infection.26 This was in concordance with our study. In another study investigating 848 individuals treated with DAAs, only eight patients showed detectable HBV DNA with titers <20 IU/mL at the end of treatment, and no HBV reactivation was observed in HBsAg-negative but anticore-positive patients.27\n\nHBV reactivation was manifested in our study by elevated liver enzymes and increasing HBV DNA in four patients. This rise had resolved at 6-month of follow up without adding antiviral treatment for HBV. This was the case in another study where elevated ALT was present in 18 patients during follow-up of 108 patients coinfected with HCV–HBV.28 In a 72-year-old woman, HBV reactivation was observed 4 weeks after the end of treatment with sofosbuvir and ribavirin with resolved HBV.29 This was similar to our study, where resolution of the four reactivated cases occurred with no treatment.\n\nIn our study, we conclude that patients with F0 or F1, HBeAg seroconversion, and HBV DNA <2,000 IU/mL can complete without treatment with close monitoring. Also, the risk of HBV reactivation is low in patients treated with DAAs. Being a prospective study with close monitoring of the patients gives strength to our work. Still, we need longer follow-up and larger samples.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. Bartholomeusz \nA , Locarnini \nSA . Antiviral drug resistance: clinical consequences and molecular aspects . Semin Liver Dis . 2006 ;26 (2 ):162 –170 . doi:10.1055/s-2006-939758 16673294 \n2. Chen \nLW , Chien \nRN , Yen \nCL , Chang \nJJ , Liu \nCJ , Lin \nCL . Therapeutic effects of pegylated interferon plus ribavirin in chronic hepatitis C patients with occult hepatitis B virus dual infection . J Gastroenterol Hepatol . 2010 ;25 (2 ):259 –263 . doi:10.1111/j.1440-1746.2009.06006.x 19817959 \n3. Mrani \nS , Chemin \nI , Menouar \nK , et al. Occult HBV infection may represent a major risk factor of nonresponse to antiviral therapy of chronic hepatitis C . J Med Virol . 2007 ;79 (8 ):1075 –1081 . doi:10.1002/jmv.20943 17596829 \n4. Crespo \nJ , Lozano \nJL , de la Cruz \nF , et al. Prevalence and significance of hepatitis C viremia in chronic active hepatitis B . Am J Gastroenterol . 1994 ;89 :1147 –1151 .8053425 \n5. Pol \nS , Haour \nG , Fontaine \nH , et al. The negative impact of HBV/HCV coinfection on cirrhosis and its consequences . Aliment Pharmacol Ther . 2017 ;46 :1054 –1060 . doi:10.1111/apt.14352 28994127 \n6. Tyson \nGL , Kramer \nJR , Duan \nZ , Davila \nJA , Richardson \nPA , El-Serag \nHB . Prevalence and predictors of hepatitis B virus co-infection in a United States cohort of hepatitis C virus-infected patient . Hepatology . 2013 ;58 :538 –545 . doi:10.1002/hep.26400 23505059 \n7. AASLD/IDSA . Recommendations for testing, managing and treating hepatitis C. Joint panel from the American Association of the Study of Liver Diseases and the Infectious Diseases Society of America . Available from: \nwww.Hcvguidelines.org/. Accessed 12 11 , 2017.\n8. Sagnelli \nE , Coppola \nN , Scolastico \nC , et al. Virologic and clinical expressions of reciprocal inhibitory effect of hepatitis B, C, and delta viruses in patients with chronic hepatitis . Hepatology . 2000 ;32 :1106 –1110 . doi:10.1053/jhep.2000.19288 11050062 \n9. Jardi \nR , Rodriguez \nF , Buti \nM , et al. Role of hepatitis B, C, and D viruses in dual and triple infection: influence of viral genotypes and hepatitis B precore and basal core promoter mutations on viral replicative interference . Hepatology . 2001 ;34 :404 –410 . doi:10.1053/jhep.2001.26511 11481626 \n10. Bersoff-Matcha \nSJ , Cao \nK , Jason \nM , et al. Hepatitis B virus reactivation associated with direct-acting antiviral therapy for chronic hepatitis C virus: a review of cases reported to the U.S. Food and Drug Administration; Adverse Event Reporting System . Ann Intern Med . 2017 ;166 :792 –798 . doi:10.7326/M17-0377 28437794 \n11. European Association for the Study of the Liver . EASL recommendations on treatment of hepatitis C 2015 . J Hepatol . 2015 ;63 :199 –236 . doi:10.1016/j.jhep.2015.03.025 25911336 \n12. Mostafa \nAA , El-Shewi \nME , Amin \nAM , Alibiary \nSHAA . Assessment of CD163 as a predictor of esophageal varices in patients with liver cirrhosis . N Y Sci J . 2016 ;9 :3747 .\n13. Gonzalez \nSA , Perrillo \nR . Hepatitis B virus reactivation in the setting of cancer chemotherapy and other immunosuppressive drug therapy . Clin Infect Dis . 2016 ;62 :S306 –S313 . doi:10.1093/cid/ciw043 27190320 \n14. Shih \nCM , Chen \nCM , Chen \nSY , Lee \nY . Modulation of the trans-suppression activity of hepatitis C virus core protein by phosphorylation . J Virol . 1995 ;69 :1160 –1171 \n[PMC free article] [PubMed] .7815494 \n15. Shih \nCM , Lo \nSJ , Miyamura \nT , Chen \nSY , Lee \nY . Suppression of hepatitis B virus expression and replication by hepatitis C virus core protein in HuH-7 cells . J Virol . 1993 ;67 :5823 –5832 \n[PMC free article] [PubMed] .8396658 \n16. Chen \nSY , Kao \nCF , Chen \nCM , et al. Mechanisms for inhibition of hepatitis B virus gene expression and replication by hepatitis C virus core protein . J Biol Chem . 2003 ;278 :591 –607 \n[PubMed] . doi:10.1074/jbc.M204241200 12401801 \n17. Schuttler \nCG , Fiedler \nN , Schmidt \nK , Repp \nR , Gerlich \nWH , Schaefer \nS . Suppression of hepatitis B virus enhancer 1 and 2 by hepatitis C virus core protein . J Hepatol . 2002 ;37 :855 –862 . doi:10.1016/S0168-8278(02)00296-9 12445429 \n18. Dumoulin \nFL , von Dem Bussche \nA , Li \nJ , et al. Hepatitis C virus NS2 protein inhibits gene expression from different cellular and viral promoters in hepatic and nonhepatic cell lines . Virology . 2003 ;305 :260 –266 \n[PubMed] . doi:10.1006/viro.2002.1769 12573571 \n19. Pan \nY , Wei \nW , Kang \nL , et al. NS5A protein of HCV enhances HBV replication and resistance to interferon response . Biochem Biophys Res Commun . 2007 ;359 :70 –75 . doi:10.1016/j.bbrc.2007.05.052 17532300 \n20. Kassas \nME , Shimakawa \nY , Ali-Eldin \nZ , et al. Risk of hepatitis B virus reactivation with direct-acting antivirals against hepatitis C virus: A cohort study from Egypt and meta-analysis of published data . Liver Int . 2018 ;38 :2159 –2169 . doi:10.1111/liv.13874 29738637 \n21. Bhatia \nM , Gupta \nE , Choudhary \nMC , Jindal \nA , Sarin \nSK . Evaluation of impact of occult hepatitis B infection in chronic HCV-infected patients: a retrospective cohort study . J Lab Physicians . 2018 ;10 (3 ):304 –308 . doi:10.4103/JLP.JLP_12_18 30078967 \n22. Hsu \nYS , Chien \nRN , Yeh \nCT , et al. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B . Hepatology . 2002 ;35 :1522 –1527 . doi:10.1053/jhep.2002.33638 12029639 \n23. Chu \nCM , Hung \nSJ , Lin \nJ , Tai \nDI , Liaw \nYF . Natural history of hepatitis B e antigen to antibody seroconversion in patients with normal serum aminotransferase levels . Am J Med . 2004 ;116 :829 –834 . doi:10.1016/j.amjmed.2003.12.040 15178498 \n24. Chu \nCM , Liaw \nYF . Chronic hepatitis B virus infection acquired in childhood: special emphasis on prognostic and therapeutic implication of delayed HBeAg seroconversion . J Viral Hepatol . 2007 ;14 :147 –152 . doi:10.1111/j.1365-2893.2006.00810.x \n25. Chu \nCM , Liaw \nYF . Predictive factors for reactivation of hepatitis B following hepatitis B e antigen seroconversion in chronic hepatitis B . Gastroenterology . 2007 ;133 :1458 –1465 . doi:10.1053/j.gastro.2007.08.039 17935720 \n26. Chen \nG , Wang \nC , Chen \nJ , et al. Hepatitis B reactivation in hepatitis B and C coinfected patients treated with antiviral agents: a systematic review and meta-analysis . Hepatology . 2017 ;66 :13 –26 . doi:10.1002/hep.29109 28195337 \n27. Mucke \nVT , Mucke \nMM , Peiffer \nKH , et al. No evidence of hepatitis B virus reactivation in patients with resolved infection treated with direct-acting antivirals for hepatitis C in a large real-world cohort . Aliment Pharmacol Ther . 2017 ;46 :432 –439 . doi:10.1111/apt.14177 28627791 \n28. Mücke \nMM , Mücke \nVT , Peiffer \nK-H , et al. Absence of HBV reactivation in patients with resolved HBV infection following DAA therapy for hepatitis C: a 1-year follow-up study . Open Forum Infect Dis . 2019 ;6 (1 ):1 –5 . doi:10.1093/ofid/ofy340 \n29. Odolini \nS , Lanza \nP , Angiola \nA , et al. Hepatitis B virus reactivation after effective sofosbuvir and ribavirin treatment in a patient with occult hepatitis B virus infection . New Microbiol . 2017 ;40 :218 –220 .28513813\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6973",
"issue": "12()",
"journal": "Infection and drug resistance",
"keywords": "DAAs; HBV; HCV; PCR",
"medline_ta": "Infect Drug Resist",
"mesh_terms": null,
"nlm_unique_id": "101550216",
"other_id": null,
"pages": "3067-3073",
"pmc": null,
"pmid": "31632097",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "30648130;28513813;29738637;17532300;19817959;30078967;17935720;28437794;28994127;17305879;16673294;28627791;12445429;8396658;11050062;12401801;25911336;27190320;12573571;28195337;12029639;23505059;17596829;11481626;8053425;7815494;15178498",
"title": "Management Of Patients With Hepatitis B Virus Reactivation Post-DAA Treatment Of Chronic Hepatitis C Virus Infection In HCV-HBV Coinfected Patients With Pretreatment HBeAg Seroconversion And Early Degree Of Hepatic Fibrosis.",
"title_normalized": "management of patients with hepatitis b virus reactivation post daa treatment of chronic hepatitis c virus infection in hcv hbv coinfected patients with pretreatment hbeag seroconversion and early degree of hepatic fibrosis"
} | [
{
"companynumb": "EG-GILEAD-2019-0434204",
"fulfillexpeditecriteria": "1",
"occurcountry": "EG",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DACLATASVIR"
},
"drugadditional": null,
... |
{
"abstract": "A healthy multiparous woman presented at 35 weeks and 4 days' gestation with threatened preterm labour on multiple occasions. An incidental finding of severe hypokalaemia (2.4 mmol/L) was detected on routine blood tests. The cause of this hypokalaemia was not initially obvious. It was eventually linked to overuse of over-the-counter antacids for pregnancy-associated heartburn. The patient was managed with parenteral and then oral electrolyte replacement which corrected a pH of 7.55, bicarbonate of 36.7 mEq/L and a base excess 13.1. In this case report we consider whether hypokalaemia could be linked to uterine irritability and threatened preterm labour, whether antacids were being abused in the context of an eating disorder and the importance of taking a full drug history.",
"affiliations": "Department of Obstetrics and Gynaecology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK kat.lattey@gmail.com.;Department of Obstetrics and Gynaecology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.;Department of Obstetrics and Gynaecology, Royal United Hospitals Bath NHS Foundation Trust, Bath, UK.",
"authors": "Lattey|Katherine|K|;Quinn|Sarah|S|;O'Brien|Katherine|K|",
"chemical_list": "D000863:Antacids; D004366:Nonprescription Drugs; D009853:Omeprazole; D011188:Potassium",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-236083",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(1)",
"journal": "BMJ case reports",
"keywords": "drug misuse (including addiction); gynaecology and fertility; obstetrics; pregnancy; unwanted effects / adverse reactions",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000863:Antacids; D015148:Cardiotocography; D062787:Drug Overdose; D005260:Female; D005764:Gastroesophageal Reflux; D006801:Humans; D007008:Hypokalemia; D033162:Incidental Findings; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D004366:Nonprescription Drugs; D009853:Omeprazole; D011188:Potassium; D011247:Pregnancy; D047928:Premature Birth",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33431440",
"pubdate": "2021-01-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Over-the-counter antacids linked to severe hypokalaemia in the context of threatened preterm labour.",
"title_normalized": "over the counter antacids linked to severe hypokalaemia in the context of threatened preterm labour"
} | [
{
"companynumb": "NVSC2021GB083969",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM"
},
"drugadditional": null,
"druga... |
{
"abstract": "OBJECTIVE\nFor patients with resected stage II-III non-small cell lung cancers (NSCLCs), adjuvant cisplatin-based chemotherapy improves survival over surgery alone. For cisplatin ineligible patients, there is no standard adjuvant option. We evaluated drug delivery and toxicity of docetaxel and vinorelbine in patients who could not receive cisplatin.\n\n\nMETHODS\nPatients with completely resected stage IB-III NSCLCs were treated with up to 4 cycles of docetaxel and vinorelbine at the recommended phase II dose. The primary endpoint was drug delivery compared to historical delivery of adjuvant cisplatin plus vinorelbine. Secondary endpoints were toxicity and feasibility.\n\n\nRESULTS\nTwenty-five patients were enrolled. Overall, 13/25 (52 %, 95 % CI 34-70) completed 4 cycles, and 19/25 (76 %, 95 % CI 60-87) completed ≥3 cycles. Twenty of 25 patients (80 %) experienced a Grade 3 or 4 adverse event.\n\n\nCONCLUSIONS\nDelivery of this dose and schedule of docetaxel and vinorelbine was difficult with a dose delivery comparable to cisplatin plus vinorelbine, and cisplatin plus docetaxel, used in this setting.",
"affiliations": "Thoracic Oncology Service, Division of Solid Tumor Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center, 300 E, 66th Street, New York, NY, 10065, USA, chaftj@mskcc.org.",
"authors": "Chaft|Jamie E|JE|;Rekhtman|Natasha|N|;Sima|Camelia S|CS|;Rusch|Valerie|V|;Kris|Mark G|MG|;Zakowski|Maureen|M|;Azzoli|Christopher G|CG|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D014747:Vinblastine; D000077235:Vinorelbine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-013-2263-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "72(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": null,
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D016503:Drug Delivery Systems; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D043823:Taxoids; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "931-4",
"pmc": null,
"pmid": "23975243",
"pubdate": "2013-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "15972865;11377599;10699893;15886314;10715307;19933916;17938425;12202657;18506026;15713522;14736927;17607120;16945766",
"title": "Phase II study of docetaxel and vinorelbine as adjuvant chemotherapy for resected non-small cell lung cancers.",
"title_normalized": "phase ii study of docetaxel and vinorelbine as adjuvant chemotherapy for resected non small cell lung cancers"
} | [
{
"companynumb": "US-AMGEN-USASP2020013257",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
... |
{
"abstract": "Splenic abscess is a rare disease that generally occurs in immunocompromised patients. It is difficult to distinguish between splenic abscesses and cysts using imaging studies, especially if they are asymptomatic. A 50-year-old asymptomatic man who had received steroid therapy for underlying rheumatoid arthritis was referred to a university hospital due to presence of several splenic cysts, with the largest being 3.5 cm in diameter. Percutaneous aspiration was performed, and fluid analysis showed cysts infected by extended-spectrum, beta-lactamase-producing Escherichia coli. The patient was treated with ertapenem for four weeks, and the lesion disappeared on follow-up imaging studies. Splenic abscess should be included as a differential diagnosis of splenic cystic lesions in immunocompromised patients.",
"affiliations": "Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea.;Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea.;Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea.;Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea.;Division of Gastroenterology, Department of Internal Medicine, Catholic Kwandong University, International St. Mary's Hospital, College of Medicine, Catholic Kwandong University, Incheon, Korea.",
"authors": "Hwang|Hyunjung|H|;Baeg|Myong Ki|MK|;Kim|Pumsoo|P|;Kim|Yu Jin|YJ|;Kang|Seok Hyung|SH|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.4166/kjg.2018.72.4.209",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1598-9992",
"issue": "72(4)",
"journal": "The Korean journal of gastroenterology = Taehan Sohwagi Hakhoe chi",
"keywords": "Arthritis, rheumatoid; Percutaneous drainage; Splenic abscess; Splenic cyst",
"medline_ta": "Korean J Gastroenterol",
"mesh_terms": "D018784:Abdominal Abscess; D003560:Cysts; D003937:Diagnosis, Differential; D004322:Drainage; D004926:Escherichia coli; D006801:Humans; D016867:Immunocompromised Host; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D013158:Splenic Diseases; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101189416",
"other_id": null,
"pages": "209-212",
"pmc": null,
"pmid": "30419646",
"pubdate": "2018-10-25",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Asymptomatic Splenic Cysts in an Immunocompromised Patient: Should They Be Investigated.",
"title_normalized": "asymptomatic splenic cysts in an immunocompromised patient should they be investigated"
} | [
{
"companynumb": "KR-TEVA-2019-KR-1077713",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HYDROXYCHLOROQUINE"
},
"drugadditional": "3",
... |
{
"abstract": "Recent studies support the use of bortezomib-based therapies in light chain amyloidosis (AL). We performed a retrospective analysis of the safety, efficacy and long-term survival (median follow-up 3 years) after bortezomib-based treatment in 28 consecutive patients with de novo AL deemed ineligible at initial presentation. The first 14 patients received bortezomib and dexamethasone (VD), and the second 14 patients received cyclophosphamide, bortezomib and dexamethasone (CVD; CyBorD). Both regimens were well tolerated with no treatment-related mortality. The overall hematological response (HR) rate was 93% in both the groups. Median time to response was shorter in the CVD group (39 days vs 96 days in the VD group; P=0.002). Hematological and organ responses induced with bortezomib-based therapy enabled 8 (33%) of initially transplant ineligible patients to undergo autologous hematopoietic stem cell transplantation (AHCT), including 4 patients with cardiac stage III or IV. Seven of the eight patients (88%) who underwent subsequent AHCT achieved sustained HR at a median of 33 months posttransplant. These data suggest that bortezomib-based induction followed by AHCT is a viable therapeutic strategy for transplant-ineligible AL. Larger, multicenter prospective trials are necessary to confirm our findings.",
"affiliations": "Department of Medicine, Division of Hematology and Oncology, Vanderbilt University Medical Center, Nashville, TN, USA.;Department of Biostatistics, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.;Department of Medicine, Medical College of Wisconsin, Milwaukee, WI, USA.",
"authors": "Cornell|R F|RF|;Zhong|X|X|;Arce-Lara|C|C|;Atallah|E|E|;Blust|L|L|;Drobyski|W R|WR|;Fenske|T S|TS|;Pasquini|M C|MC|;Rizzo|J D|JD|;Saber|W|W|;Hari|P N|PN|",
"chemical_list": "D000970:Antineoplastic Agents; D000069286:Bortezomib",
"country": "England",
"delete": false,
"doi": "10.1038/bmt.2015.73",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "50(7)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D000328:Adult; D000368:Aged; D000686:Amyloidosis; D000970:Antineoplastic Agents; D000069286:Bortezomib; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "914-7",
"pmc": null,
"pmid": "25915809",
"pubdate": "2015-07",
"publication_types": "D016428:Journal Article",
"references": "24859879;20085941;22475872;18519408;19644136;24650974;22331188;25111581;22331187;9920856;23541011;22489348;21562045",
"title": "Bortezomib-based induction for transplant ineligible AL amyloidosis and feasibility of later transplantation.",
"title_normalized": "bortezomib based induction for transplant ineligible al amyloidosis and feasibility of later transplantation"
} | [
{
"companynumb": "US-BAXTER-2015BAX041794",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "To report the successful closure of full-thickness macular hole (MH), using an office-based intravitreal gas injection, in two eyes having undergone prior pars plana vitrectomy (PPV).\nPatient 1 presented with acute loss of visual acuity to 20/300 in the left eye 5 months following PPV for fovea-off rhegmatogenous retinal detachment; MH was confirmed by examination and optical coherence tomography (OCT). 0.6 cc of 100% C3F8 gas was injected, with subsequent MH closure following one week of face-down positioning. Patient 2 presented with right eye visual acuity of 20/60 one month following PPV for optic nerve pit-associated maculopathy; MH was confirmed by examination and OCT. 0.85 cc of 100% C3F8 gas was injected in the office, with subsequent MH closure following one week of face-down positioning.\nMH management in previously vitrectomized eyes has traditionally been repeat PPV with internal limiting membrane peeling, fluid-air exchange, and expansile gas exchange. Intravitreal gas injection, in an office-based setting, is a viable clinical approach to close MH in some previously vitrectomized eyes.",
"affiliations": "Retina Consultants of Houston, Houston, TX, USA.;Retina Consultants of Houston, Houston, TX, USA.;Retina Consultants of Houston, Houston, TX, USA.;Retina Consultants of Houston, Houston, TX, USA.;Retina Consultants of Houston, Houston, TX, USA.",
"authors": "Apolinario|Michael A|MA|;Lampen|Shaun I R|SIR|;Wong|Tien P|TP|;Henry|Christopher R|CR|;Wykoff|Charles C|CC|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.ajoc.2019.100492",
"fulltext": "\n==== Front\nAm J Ophthalmol Case RepAm J Ophthalmol Case RepAmerican Journal of Ophthalmology Case Reports2451-9936Elsevier S2451-9936(18)30213-510.1016/j.ajoc.2019.100492100492Case ReportOffice-based intravitreal injection of expansile gas for management of macular hole in previously vitrectomized eyes Apolinario Michael A. abLampen Shaun I.R. aWong Tien P. acHenry Christopher R. acWykoff Charles C. ccwmd@houstonretina.comac∗a Retina Consultants of Houston, Houston, TX, USAb Texas A&M Health Science Center College of Medicine, College Station, TX, USAc Blanton Eye Institute, Houston Methodist Hospital & Weill Cornell Medical College, Houston, TX, USA∗ Corresponding author. 6560 Fannin Street, Suite 750, Houston, TX, 77030, USA. ccwmd@houstonretina.com05 7 2019 9 2019 05 7 2019 15 10049222 5 2018 7 11 2018 6 6 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Purpose\nTo report the successful closure of full-thickness macular hole (MH), using an office-based intravitreal gas injection, in two eyes having undergone prior pars plana vitrectomy (PPV).\n\nObservations\nPatient 1 presented with acute loss of visual acuity to 20/300 in the left eye 5 months following PPV for fovea-off rhegmatogenous retinal detachment; MH was confirmed by examination and optical coherence tomography (OCT). 0.6 cc of 100% C3F8 gas was injected, with subsequent MH closure following one week of face-down positioning. Patient 2 presented with right eye visual acuity of 20/60 one month following PPV for optic nerve pit-associated maculopathy; MH was confirmed by examination and OCT. 0.85 cc of 100% C3F8 gas was injected in the office, with subsequent MH closure following one week of face-down positioning.\n\nConclusions and importance\nMH management in previously vitrectomized eyes has traditionally been repeat PPV with internal limiting membrane peeling, fluid-air exchange, and expansile gas exchange. Intravitreal gas injection, in an office-based setting, is a viable clinical approach to close MH in some previously vitrectomized eyes.\n\nKeywords\nMacular holePars plana vitrectomyIntravitreal gas injection\n==== Body\n1 Introduction\nMacular hole (MH) is a well-recognized clinical entity whose formation is primarily attributed to vitreomacular traction, as originally described by J. Donald Gass in the pre-optical coherence tomography (OCT) era.1 Pioneered in the 1990s, a standard management approach includes pars plana vitrectomy (PPV), with or without peeling of the internal limiting membrane (ILM).2 However, MH can also occur in the absence of vitreous traction2 as evidenced by the development of MH in eyes having previously undergone PPV.3, 43,4 The current standard approach to managing MH following PPV is to repeat PPV with concurrent ILM peeling. In the current report, two cases of MH in previously vitrectomized eyes were successfully closed following an office-based intravitreal injection of expansile gas.\n\n2 Findings\n2.1 Case 1\nA 60-year-old male with type 2 diabetes mellitus receiving intravitreal anti-vascular endothelial growth factor (VEGF) injections for diabetic macular edema (DME) in the left eye developed acute onset photopsias and floaters six days following an intravitreal aflibercept injection. The patient was diagnosed with a fovea-involving rhegmatogenous retinal detachment (RRD) (Fig. 1A). Best prior visual acuity (VA) while receiving anti-VEGF injections was 20/25; VA at RRD diagnosis was 20/400. The patient underwent RRD repair with PPV and encircling scleral buckle placement one day following RRD diagnosis without concurrent ILM peeling. Due to persistent DME post-operatively, the patient resumed anti-VEGF intravitreal injections four months following RRD repair. One month after the first intravitreal anti-VEGF injection following RRD repair, corresponding to 5 months following RRD repair, the patient presented with acute onset scotoma centrally with VA of 20/300. Ophthalmoscopic examination and OCT imaging identified the presence of a full thickness MH (Fig. 1B). Office-based MH closure was attempted with injection of 0.6 cc of 100% C3F8 gas with concurrent anterior chamber paracentesis for normalization of intraocular pressure (IOP). Bubble expansion resulted in greater than 40% gas fill in the vitreous cavity. The patient was instructed to maintain face down positioning for one week. Evaluation 7 days following intravitreal gas injection demonstrated MH closure (Fig. 1C). Three weeks later he resumed anti-VEGF treatments, with subsequent gradual VA improving to 20/40 by 6 months post-MH closure (Fig. 1D).Fig. 1 Optical coherence tomography line-scans of Patient 1 at time of rhegmatogenous retinal detachment (RRD) diagnosis (A), at time of full thickness macular hole (MH) diagnosis measuring 53 μm in widest width five months following RRD repair (B), seven days post-0.6 cc 100% C3F8 gas intravitreal injection demonstrating MH closure (C), and six months post-successful MH closure (D).\n\nFig. 1\n\n2.2 Case 2\nAn otherwise healthy 19-year-old male presented with VA of 20/100 and distorted vision in his right eye. Examination revealed a prominent optic nerve pit with associated maculopathy involving intraretinal and subretinal fluid extending through the fovea (Fig. 2A). PPV was performed with concurrent ILM peeling, fluid-air exchange, and expansile gas exchange. One month following PPV with ILM peeling, VA had improved to 20/60, however, a new full thickness MH was identified on examination and OCT (Fig. 2B). Office-based MH closure was attempted with injection of 0.85 cc of 100% C3F8 gas with concurrent anterior chamber paracentesis for normalization of the IOP. Bubble expansion resulted in a greater than 80% gas fill in the vitreous cavity. The patient was instructed to maintain face down positioning for one week. OCT 8 weeks following intravitreal gas injection demonstrated MH closure with improvement of VA to 20/40 (Fig. 2C). Follow-up visit two years later demonstrated VA improvement to 20/30 (Fig. 2D).Fig. 2 Optical coherence tomography line-scans of Patient 2 at time of presentation with optic pit-associated maculopathy (A), at time of full thickness macular hole (MH) diagnosis measuring 763 μm in widest width one month following pars plana vitrectomy and internal limiting membrane peeling (B), one week post-0.85 cc 100% C3F8 gas intravitreal injection demonstrating MH closure (C), and two years post-successful MH closure (D).\n\nFig. 2\n\n3 Discussion\nSuccessful closure of MH with clinic-based intravitreal gas injection has been described for MH in non-vitrectomized eyes, especially in the setting of vitreomacular traction.8, 98,9 MH following PPV is an uncommon clinical entity and data related to its management are limited. Successful closure of MH in previously vitrectomized eyes has been reported with repeat PPV, simultaneous ILM peeling, fluid-air exchange, and expansile gas exchange.2,5, 6, 7 Compared to repeat PPV, office-based intravitreal gas injection has the advantage of being a readily performed procedure, possibly with lower risk of peri-operative complications.9,10 In the current manuscript, two cases of MH developing following PPV were successfully closed with clinic-based 100% C3F8 intravitreal gas injection with prescribed face down positioning for one week.\n\nThere are at least two notable differences between the current cases. First, one case underwent ILM peeling during the initial PPV and one did not. A previous analysis of 423 eyes having undergone PPV with ILM peeling reported that 2 eyes subsequently developed centrally located MH postoperatively; the authors postulated that ILM peeling may have resulted in Müller cell trauma, glial structural damage, and subsequent development of full-thickness MH.11 Second, the MH widest widths of the two current cases were remarkably different, at 53 and 763 μm. While MH closure can be achieved with or without ILM removal,11,12 it is still unclear precisely which patients may benefit from ILM removal. Similarly, the current series does not define which patients may, and which may not, achieve MH closure without returning to the operating room. Larger series are needed to better understand which patients may benefit from the less invasive procedure described in the current series and still achieve similar MH closure rates as could be achieved by returning to the operating room.\n\nPneumatic retinopexy for RRD repair typically involves injection of less than 0.6 cc of C3F8. Because C3F8 is expected to expand approximately 4-fold over 48–72 hours, injection of 1 cc C3F8 has been reported to cause severe IOP elevation.13 However, these reports focus on the experiences of eyes with formed vitreous where there may be limited volume for gas to expand. In comparison, within an eye that has undergone PPV, the aqueous filling the vitreous cavity can theoretically readily egress from the eye through the anterior chamber angle while the patient is in a prone position and the apex of the gas is at the macula.\n\n4 Conclusion\nThe current two cases illustrate the successful management of MH, which formed following PPV, with intravitreal injection of 100% C3F8 gas with one week of face down positioning. Office-based intravitreal gas injection may be a viable clinical approach to consider that may have advantages over repeat PPV.\n\nPatient consents\nConsent to publish the case series was not obtained due to an existing institutional review board approval for retrospective analyses. This report does not contain any personal information that could lead to the identification of the patient.\n\nInstitutional review board\nInstitutional review board approval (Houston Methodist Hospital) was obtained.\n\nAcknowledgements and disclosures\nThe data discussed in the current manuscript has not been presented at any meetings or conferences.\n\nFinancial support\nNo funding or grant support.\n\nAuthorship\nAll authors attest that they meet the current ICMJE criteria for authorship.\n\nAppendix A Supplementary data\nThe following is the Supplementary data to this article:Multimedia component 1\nMultimedia component 1 \n\nAcknowledgements\nNone.\n\nConflicts of interest\nAll authors have no financial disclosures: MAA, SIRL, TPW, CRH, CCW.\n\nAppendix A Supplementary data to this article can be found online at https://doi.org/10.1016/j.ajoc.2019.100492.\n==== Refs\nReferences\n1 Gass J.D.M. Reappraisal of biomicroscopic classification of stages of development of a macular hole Am J Ophthalmol 119 6 1995 752 759 7785690 \n2 Fabian I.D. Moisseiev E. Moisseiev J. Moroz I. Barak A. Alhalel A. Macular hole after vitrectomy for primary rhegmatogenous retinal detachment Retina 32 3 2012 511 519 21799463 \n3 Khurana R.N. Wykoff C.C. Bansal A.S. The association of epiretinal membrane with macular hole formation after rhegmatogenous retinal detachment repair Retina 37 6 2017 1073 1078 27632712 \n4 Schlenker M.B. Lam W.-C. Devenyi R.G. Kertes P.J. Understanding macular holes that develop after repair of retinal detachment Can J Ophthalmol 47 5 2012 435 441 23036545 \n5 Benzerroug M. Genevois O. Siahmed K. Nasser Z. Muraine M. Brasseur G. Results of surgery on macular holes that develop after rhegmatogenous retinal detachment Br J Ophthalmol 92 2 2008 217 219 18227202 \n6 Kumagai K. Ogino N. Furukawa M. Larson E. Uemura A. Surgical outcomes for patients who develop macular holes after pars plana vitrectomy Am J of Ophthalmol 145 6 2008 1077 1080 18378210 \n7 Moshfeghi A.A. Salam G.A. Deramo V.A. Management of macular holes that develop after retinal detachment repair Am J Ophthalmol 136 5 2003 895 899 14597042 \n8 Gupta B. Mchugh D. Pneumatic retinopexy for the management of impending macular hole: an optical coherence tomography study Int Ophthalmol 31 1 2010 23 24 20364432 \n9 Chen F.-T. Yeh P.-T. Lin C.-P. Chen M.-S. Yang C.-H. Yang C.-M. Intravitreal gas injection for macular hole with localized retinal detachment in highly myopic patients Acta Ophthalmol 89 2 2011 172 178 19832732 \n10 Chen T.-C. Yang C.-H. Yang C.-M. Intravitreal expansile gas in the treatment of early macular hole: reappraisal Ophthalmologica 228 3 2012 159 166 22688252 \n11 Rush R.B. Simunovic M.P. Aragon A.V. Ysasaga J.E. Postoperative macular hole formation after vitrectomy with internal limiting membrane peeling for the treatment of epiretinal membrane Retina 34 5 2014 890 896 24217702 \n12 Michalewska Z. Michalewski J. Adelman R.A. Nawrocki J. Inverted internal limiting membrane flap technique for large macular holes Ophthalmology 117 10 2010 2018 2025 20541263 \n13 Gedde S.J. Management of glaucoma after retinal detachment surgery Current Op in Ophthalmol 13 2 2002 103 109\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2451-9936",
"issue": "15()",
"journal": "American journal of ophthalmology case reports",
"keywords": "Intravitreal gas injection; Macular hole; Pars plana vitrectomy",
"medline_ta": "Am J Ophthalmol Case Rep",
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"pages": "100492",
"pmc": null,
"pmid": "31334383",
"pubdate": "2019-09",
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"title": "Office-based intravitreal injection of expansile gas for management of macular hole in previously vitrectomized eyes.",
"title_normalized": "office based intravitreal injection of expansile gas for management of macular hole in previously vitrectomized eyes"
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"abstract": "Donor cell leukemia (DCL) is an infrequent complication after allogeneic hematopoietic stem cell transplantation (HSCT). Its true incidence is difficult to assess, although improvements in chimerism studies contributed to a better diagnosis of DCL. We report two rare cases of donor cell-derived acute promyelocytic leukemia (APL). To our knowledge, only two cases have been described in the literature. Here, we report one male and one female patients with acute myeloid leukemia (AML), who developed an APL in donor cells after HSCT. The latency between HSCT and DCL was 279 and 43 months, respectively. Fluorescent in situ hybridation and chimerism monitoring analysis proved the donor origin of APL. Surprisingly, donor lymphocyte infusion provided a hematological response during 19 months in the female patient. The mechanisms associated with pathogenesis of DCL are unclear and seem to be multifactorial. Increasing worldwide allogeneic hematopoietic stem cell transplantation activity and potentially the age of donor could explain the increasing incidence of DCL in the future. It is highlighted that long-term follow up of recipients will allow to report all cases of DCL, to clarify the genetic landscape and factors which contribute to DCL, to understand the response to DLI.",
"affiliations": "Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Angers, France.;Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Laboratoire d'Hématologie, CHU d'Angers, Angers, France.;Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Angers, France.;Fédération Hospitalo-Universitaire 'Grand Ouest Against Leukemia' (FHU GOAL), Angers, France.",
"authors": "Bouvier|Anne|A|http://orcid.org/0000-0003-0140-5360;Ribourtout|Bénédicte|B|;François|Sylvie|S|;Orvain|Corentin|C|http://orcid.org/0000-0003-1849-0186;Paz|Damien Luque|DL|;Beucher|Annaëlle|A|;Guérard|Alexandre|A|;Guardiola|Philippe|P|;Ugo|Valérie|V|;Blanchet|Odile|O|;Geneviève|Franck|F|;Schmidt|Aline|A|;Hunault-Berger|Mathilde|M|",
"chemical_list": "D015415:Biomarkers",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.13143",
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"issn_linking": "0902-4441",
"issue": "101(4)",
"journal": "European journal of haematology",
"keywords": "acute myeloid leukemia; bone marrow transplantation",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D015415:Biomarkers; D001706:Biopsy; D001853:Bone Marrow; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D014019:Tissue Donors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "570-574",
"pmc": null,
"pmid": "30007088",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Donor cell-derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation.",
"title_normalized": "donor cell derived acute promyelocytic leukemia after allogeneic hematopoietic stem cell transplantation"
} | [
{
"companynumb": "PHHY2018FR091966",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
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"activesubstancename": "CYTARABINE"
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"abstract": "BACKGROUND Nocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients. CASE REPORT A 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated ß-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD. CONCLUSIONS Clarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.",
"affiliations": "Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Laboratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Laboratory Medicine, Yamagata University School of Medicine, Yamagata, Japan.;Department of Infectious Diseases, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Radiology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan.;Medical Mycology Research Center, Chiba University, Chiba, Japan.;Medical Mycology Research Center, Chiba University, Chiba, Japan.",
"authors": "Tajima|Katsushi|K|;Okuyama|Shuhei|S|;Terada|Taichi|T|;Akaneya|Daisuke|D|;Hori|Ryuichiro|R|;Abe|Shuichi|S|;Honma|Tsuguo|T|;Tsumanuma|Riko|R|;Omoto|Eijiro|E|;Ito|Junko|J|;Gonoi|Tohru|T|",
"chemical_list": "D012336:RNA, Ribosomal, 16S; D017291:Clarithromycin",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.931731",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923\nInternational Scientific Literature, Inc.\n\n34129542\n10.12659/AJCR.931731\n931731\nArticles\nClarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient\nTajima Katsushi ABCDEFG1\nOkuyama Shuhei B1\nTerada Taichi B1\nAkaneya Daisuke BC2\nHori Ryuichiro D3\nAbe Shuichi B4\nHonma Tsuguo D5\nTsumanuma Riko B1\nOmoto Eijiro B1\nIto Junko CD6\nGonoi Tohru CD6\n1 Department of Hematology, Yamagata Prefectural Central Hospital, Yamagata, Japan\n2 Department of Laboratory Medicine, Yamagata Prefectural Central Hospital, Yamagata, Japan\n3 Department of Laboratory Medicine, Yamagata University School of Medicine, Yamagata, Japan\n4 Department of Infectious Diseases, Yamagata Prefectural Central Hospital, Yamagata, Japan\n5 Department of Radiology, Yamagata Prefectural Central Hospital, Yamagata, Japan\n6 Medical Mycology Research Center, Chiba University, Chiba, Japan\nCorresponding Author: Katsushi Tajima, e-mail: katsushitajima@ypch.gr.jp\nAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nSource of support: This work was supported by a grant-in-aid for scientific research KAKENHI grant number 16K10376 (K Tajima) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan\n\n2021\n15 6 2021\n22 e931731-1e931731-5\n20 2 2021\n27 4 2021\n11 5 2021\n© Am J Case Rep, 2021\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)\nPatient: Male, 34-year-old\n\nFinal Diagnosis: Nocardia infection\n\nSymptoms: Chest pain\n\nMedication: —\n\nClinical Procedure: —\n\nSpecialty: Infectious Diseases\n\nObjective:\n\nRare disease\n\nBackground:\n\nNocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, who usually receive the prophylactic use of sulfamethoxazole/trimethoprim (ST) against Pneumocystis jiroveci. However, the ST prophylaxis, sensitive to Nocardia species, sometimes induces renal toxicities. Therefore, alternative prophylactic or therapeutic drugs are required for nocardiosis in HSCT patients.\n\nCase Report:\n\nA 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9; 22) received allogenic peripheral blood HSCT from a haplo-identical sibling donor. He developed graft versus host disease (GVHD) with grade II, and was treated with prednisolone and cyclosporine A with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, the prophylactic ST was ceased because of its renal toxicity. He developed a pulmonary nodular lesion with elevated β-D-glucan and Aspergillus galactomannan antigen. Repeated blood and sputum culture isolated no pathogens. Voriconazole treatment administered once improved these lesions and laboratory findings. One month later, he presented with right pleuritic chest pain and multiple ring-enhancing cavitation lesions along the ribs. A needle biopsy demonstrated Nocardia elegans, which is an extremely rare infection induced by Nocardia species, in the cavitation lesions, shown by 16S rRNA gene sequencing. He was started on doripenem and liposomal amphotericin B, and a subsequent treatment kept him free from Nocardia elegans infection, without any adverse effects, while continuing the cyclosporine A and prednisolone treatment for chronic GVHD.\n\nConclusions:\n\nClarithromycin has fewer adverse effects than ST. This case suggests that clarithromycin is an appropriate alternative and prophylactic therapy for patients with nocardiosis and ST toxicities.\n\nKeywords:\n\nClarithromycin\nHematopoietic Stem Cell Transplantation\nNocardia elegans\nTrimethoprim, Sulfamethoxazole Drug Combination\n==== Body\nBackground\n\nNocardia infections have rarely been reported in hematopoietic stem cell transplantation (HSCT) patients, although these patients have numerous risk factors for Nocardia infection, including lymphopenia and steroid therapy for graft versus host disease (GVHD) [1–4]. The low incidence in HSCT patients may be due to not only the routine prophylactic use of sulfamethoxazole/trim-ethoprim (ST) against Pneumocystis jiroveci, but also the difficult isolation and identification of the genus Nocardia by routine microbiological methods [4,5]]. However, HSCT patients cannot always be treated with ST prophylaxis and/or therapy because of its various toxicities, including renal impairment [6]. Therefore, novel methods to precisely and rapidly identify Nocardia species, and safer alternative agents to ST, are required for HSCT patients. In the present study, we demonstrate that N. elegans, which is extremely rare in nocardiosis, was precisely and rapidly identified in subcostal abscesses in an HSCT patient by molecular methods, including matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) and 16S rRNA gene sequencing [5]. The present patient, who was the first HSCT patient with nocardiosis by N. elegans, was safely treated with long-term oral clarithromycin as an alternative to ST.\n\nCase Report\n\nThe patient was a 34-year-old Japanese man with acute mixed phenotypic leukemia with t(9;22), which expressed myeloperoxidase and CD79a. He had no history of tobacco smoking, alcohol drinking, or substance abuse. After dasatinib and prednisolone chemotherapy, he achieved complete remission and subsequently underwent allogeneic peripheral blood HSCT from a haplo-identical female sibling donor, with a conditioning regimen comprising cyclophosphamide (60 mg/kg/day for 2 days) and busulfan (3.2 mg/kg/day for 4 days) in December 2015. The intersexual fluorescent in situ hybridization revealed complete chimerism on day 20.\n\nThe prophylactic treatment for acute GVHD comprised intravenous cyclosporine A (CyA) (3 mg/kg/day) and conventional short-term methotrexate. However, he developed acute stage 3 skin GVHD and stage 1 (grade II) gastrointestinal tract GVHD on day 22. He was initially treated with prednisolone (0.5 mg/kg) in addition to CyA, and the acute GVHD was relieved. However, upon tapering the prednisolone, he continued to have recurrent flares of GVHD, including the stage 3 skin and stage 3 gastrointestinal tract GVHD with diarrhea and weight loss and sicca syndrome. Finally, prednisolone (12.5 mg/day) and CyA (150 mg/day) were required, with concurrent ciprofloxacin, fluconazole, valacyclovir, and ST. However, renal impairment (creatinine, 1.83 mg/dL) occurred, and the prophylactic ST administration was ceased.\n\nOne month after the prednisolone treatment for chronic GVHD following acute GVHD on day 140, he developed a nodular lesion in segment 6 of the right lung (Figure 1A), and pleural effusion with elevated β-D-glucan (99.0 pg/mL: normal <20 pg/mL) and a positive reaction to Aspergillus galactomannan antigen. These findings suggested that he might have invasive pulmonary aspergillosis, although a bronchoalveolar lavage and biopsy were not performed. He was started on oral voriconazole, which suppressed the nodular lesions in the lung (Supplementary Figure 1). One month later, he presented with right pleuritic chest and back pain, non-productive cough, and fever without sputum. The laboratory findings were: hemoglobin level, 8.7 g/dL (13.7–16.8); white blood cell count, 15 000/ mm3 (3300–8600) (neutrophils, 90% (40–71); lymphocytes, 7% (27–46); platelet count, 19.2×104/mm3 (15.8–34.8); and C-reactive protein concentration, 11.3 mg/dL (0.0–0.14). The serum liver enzyme levels were: glutamic-oxaloacetic transaminase, 47 IU/L (10–42); glutamate pyruvic transaminase, 101 IU/L (13–30); alkaline phosphatase, 2553 IU/L (38–113); gamma glutamic transpeptidase, 1097 IU/L (13–54); total bilirubin, 1.4 mg/dL (0.4–1.5); serum creatinine, 1.22 mg/dL (0.65–1.07); immunoglobulin (Ig) G, 113 g/dL (861–1747); IgA, 7 mg/dL (93–393); and IgM, 37 mg/dL (33–183). Assays for β-D glucan, Candida antigen, Aspergillus galactomannan antigen, cryptococcal antigen, and cytomegalovirus pp65 antigenemia were all negative. Repeated blood cultures isolated no pathogens. A contrast-enhancing computed tomography (CT) scan revealed slight growth of the previous lung nodule (Figure 1B) and new multiple ring-enhancing cavitation lesions along the tenth to twelfth ribs with pleural effusion (Figure 1C, 1D). The initial images of these lesions suggested mucormycosis as a possible breakthrough infection, despite the voriconzole administration. A CT scan of the brain was normal.\n\nTo determine the precise cause of the cavitation lesions in the subcostal muscle, a percutaneous CT-guided needle aspiration biopsy was performed, and a white, viscous specimen was obtained. Microscopic observation of the specimen revealed beaded or branching rods that were positive for modified Ziehl-Neelsen and Gram-staining, suggesting abscesses induced by the genus Nocardia (Figure 1E). We analyzed the isolated colonies by Bruker Biotype MALDI-TOF MS; the score for N. nova was 1.84 and that for N. elegans was 1.61. Finally, the 16S rRNA gene sequencing identified the isolated colonies as N. elegans.\n\nThe patient was started on intravenous doripenem (0.25 g every 6 h) and liposomal amphotericin B (5 mg/kg), and oral ST (320/1600 mg/day) was reattempted. However, the oral ST treatment was discontinued due to renal function deteriorating again. The continuing doripenem and amphotericin B treatments halted the cavitation lesions in the subcostal muscle for 2 weeks, and gradually relieved all of his symptoms and improved his laboratory findings for 4 weeks. The isolated N. elegans strain was susceptible to ST, imipenem, amikacin, line-zolid, and clarithromycin, based on antimicrobial susceptibility tests (Table 1). Thus, the patient was started on the clarithromycin treatment, with the subsequent withdrawal of doripenem and amphotericin B. Six months later, he remains well and free of N. elegans infection, while continuing the clarithromycin, the same dose of CyA, and the prednisolone treatment for the limited chronic GVHD, without any adverse effects.\n\nDiscussion\n\nNocardiosis occurs in less than 3% of HSCT patients due to the routine prophylactic use of ST [1]. However, breakthrough nocardiosis in some HSCT patients receiving ST prophylaxis has recently been noted [4,7]. A previous report showed that 42% of the Nocardia isolates in the United States during 1995 to 2004 were resistant to ST [8]. However, in other studies, Nocardia isolates in Spain and Taiwan remained susceptible to\n\nST [9,10]. The susceptibility to ST may depend on geographical Nocardia species variations and the history of antimicrobial use. A recent report revealed that the onset of nocardiosis in HSCT patients was related to either receiving steroids or not receiving ST prophylaxis at the time of diagnosis [7]. Our patient received prednisolone for chronic GVHD and no ST prophylaxis, and in addition, he had low levels of immunoglobulins and persistent lymphopenia, which have been suggested to be risk factors for Nocardia development [4]. These combined risk factors might have induced his nocardiosis.\n\nIn selecting antibiotics, the precise and rapid identification of the Nocardia species is critical for physicians to provide the most appropriate therapies. Advanced molecular methods, such as 16S rRNA sequencing and MALDI-TOF MS analysis, are useful and valuable tools in clinical laboratories to identify the taxonomy of Nocardia species. In this case, the presence of N. elegans was precisely identified by a combination of microbiological and molecular analysis for the subcostal abscess by needle biopsy. Therefore, we emphasize that vigorous examinations, including CT-guided needle aspiration, should be considered even in HSCT patients who have a bleeding risk [5].\n\nIn this case, the MALDI-TOF-MS analysis initially suggested N. nova, and not N. elegans, as the cause of the abscess lesions. This mistake was corrected by the 16S rRNA gene sequencing. The present MALDI-TOF-MS system may be improved by upgrading the analysis system, including an updated database, especially considering the molecular similarities of the Nocardia species and the insufficient depth of the database, which lacked extremely rare species, including N. elegans [11].\n\nOnly 8 cases of nocardiosis induced by N. elegans have been reported [12]. This is the first report of N. elegans nocardiosis in an HSCT patient; thus, the clinical characteristics remain to be fully elucidated. However, half of the cases of N. elegans had pulmonary or connective tissue lesions[12]. The present patient also had these lesions. There are only a few reports of antibiotic susceptibility and therapeutic experiences in N. elegans nocardiosis [9,12,13]. These reports showed that in addition to ST, imipenem, meropenem, amikacin, minocycline, and clarithromycin are also active against N. elegans. ST has been the first-choice therapy in nocardiosis because of the sufficient tissue penetration with oral administration and the synergistic activities against nocardiosis in conjunction with other agents [3]. In the present patient, the antibiotic susceptibility of the isolated N. elegans was primary compatible with previous reports [8,10,14]. In our patient, treatment with oral clarithromycin maintained remission of his abscesses without any adverse effects [15,16]. In fact, clarithromycin has a higher concentration in connective tissue and better white blood cell penetration than in the plasma, and thus provides several other advantages in connective tissue lesions in terms of oral administration and fewer adverse effects that ST or injection agents. Therefore, we suggest that clarithromycin may be the most appropriate therapy, especially for nocardiosis caused by N. elegans. However, clarithromycin is also one of the drugs that inhibit drug metabolism in the liver, and the dose used should be monitored as it can lead to high levels of other concurrent medications utilizing the same pathway. There is a need for further studies to explore alternative prophylactic alternatives to ST.\n\nOur patient initially presented with a nodular lesion in the right lung, and the voriconazole treatment relieved the progression of this lesion and restored the levels of β-D-glucan and Aspergillus galactomannan antigen. These findings could not exclude the possibility that he might have had concurrent N. elegans nocardiosis and mycosis caused by unidentified fungal pathogens. Therefore, the surviving N. elegans might have directly extended to the subcostal muscle and formed abscesses from the primary nodular lesions. A previous study reported concurrent nocardiosis induced by N. nova and mucormycosis by the genus Rhizopus in an HSCT recipient, and emphasized that mucormycosis should still be suspected despite the use of prophylactic antifungal treatments [17]. However, the prevalence of nocardiosis and concomitant fungal infection remains unknown in HSCT patients. A recent report of a patient with disseminated nocardiosis caused by N. farcinica had elevated serum β-D-glucan, and suggested that the Nocardia genus may show cross-reactivity with the β-D-glucan assay [18], but this disagrees with our experience in the present case. The cross-reactivity with β-D-glucan may differ in each Nocardia species.\n\nConclusions\n\nWe precisely and rapidly identified N. elegans in the cavitation lesions in the subcostal muscle in an HSCT patient with GVHD and adverse effects from ST, using a combination of microbiological and molecular methods. Oral clarithromycin, as an alternative agent to ST, safely controlled the nocardiosis without any adverse effects for a long time. Oral clarithromycin treatment may be a promising alternative therapeutic agent, especially for some HSCT patients with GVHD and ST adverse effects.\n\nWe thank Harumi Matsumoto for her technical support.\n\nSupplementary Data\n\nSupplementary Figure 1. A chest CT scan revealed improvements of the nodular lesions in the lung.\n\nFigure 1. (A) A chest CT scan revealed a nodular lesion in the right lung (black arrow). (b)(c)(d) A CT scan revealed the previous lesion (B) (black arrow), (C) (white arrow), and ring-enhancing cavitation lesions in the subcostal muscle along with the ribs (D) (black arrows). (E) A microscopic analysis revealed beaded or branching rods (Gram staining).\n\nTable 1. Activities of antibiotics against Nocardia elegans in the current case.\n\nAntibiotics\tMIC (µg/ml)\tSusceptibility\t\nAMK\t<0.5\tS\t\nACV\t>32/16\tR\t\nCTRX\t16\tI\t\nCPFX\t>4\tR\t\nIPM\t<0.5\tS\t\nLZD\t<1\tS\t\nMINO\t2\tI\t\nST\t19/1\tS\t\nTOB\t16\tR\t\nCTX\t4\tS\t\nCFPM\t2\tS\t\nDOXY\t8\tR\t\nGM\t16\tR\t\nCAM\t<0.25\tS\t\nMIC – minimum inhibitory concentration; S – susceptible; I – intermediate; R – resistant; AMK – amikacin; ACV – potassium clavulanate; CTRX – ceftriaxone sodium; CPFX – ciprofloxacin hydrochloride; IPM – imipenem; LZD – linezolid; MINO – minocycline; ST – sulfamethoxazole/trimethoprim; TOB – tobramycin; CTX – cefotaxime; CFPM – cefepime dihydrochloride; DOXY – doxycycline hydrochloride; GM – gentamicin; CAM – clarithromycin.\n\nConflict of Interest\n\nNone.\n==== Refs\nReferences:\n\n1. Schuster MG Cleveland AA Dubberke ER Infections in hematopoietic cell transplant recipients: Results from the organ transplant infectionproject, a multicenter, prospective, cohort study. a multicenter, prospective, cohort study Open Forum Infect Dis 2017 4 2 ofx050 28491889\n2. Lebeaux D Morelon E Suarez F Nocardiosis in transplant recipients Eur J Clin Microbiol Infect Dis 2014 33 5 689 702 24272063\n3. Choucino C Goodman SA Greer JP Nocardial infections in bone marrow transplant recipients Clin Infect Dis 1996 23 5 1012 19 8922795\n4. Cattaneo C Antoniazzi F Caira M Nocardia spp infections among hematological patients: Results of a retrospective multicenter study Int J Infect Dis 2013 17 8 e610 14 23453714\n5. Ooi Y Shiba H Nagai K Lung Nocardia elegans infection diagnosed on matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) Intern Med 2014 53 18 2111 13 25224198\n6. Nishida R Mori Y Iwasaki H Pulmonary nocardiosis developed in a hematopoietic stem cell transplant recipient with bronchiolitis obliterans Intern Med 2010 49 14 1441 44 20647664\n7. Shannon K Pasikhova Y Ibekweh Q Nocardiosis following hematopoietic stem cell transplantation Transpl Infect Dis 2016 18 2 169 75 26809666\n8. Uhde KB Pathak S McCullum I Jr Antimicrobial-resistant nocardia isolates, United States, 1995–2004 Clin Infect Dis 2010 51 12 1445 48 21058914\n9. Lai CC Liu WL Ko WC Multicenter study in Taiwan of the in vitro activities of nemonoxacin, tigecycline, doripenem, and other antimicrobial agents against clinical isolates of various Nocardia species Antimicrob Agents Chemother 2011 55 5 2084 91 21343461\n10. Minero MV Marin M Cercenado E Nocardiosis at the turn of the century Medicine (Baltimore) 2009 88 4 250 61 19593231\n11. Pasciak M Dacko W Sikora J Creation of an in-house matrix-assisted laser desorption ionization-time of flight mass spectrometry corynebacterineae database overcomes difficulties in identification of Nocardia farcinica clinical isolates J Clin Microbiol 2015 53 8 2611 21 26041903\n12. Nakamura I Nagakura T Fujita H Nocardia elegans infection: A case report and literature review Int J Infect Dis 2017 54 15 17 27826114\n13. Masaki T Ohkusu K Ezaki T Miyamoto H Nocardia elegans infection involving purulent arthritis in humans J Infect Chemother 2012 18 3 386 89 21968966\n14. Lai CC Liu WL Ko WC Antimicrobial-resistant nocardia isolates, Taiwan, 1998–2009 Clin Infect Dis 2011 52 6 833 35 21367741\n15. Liapakis IE Light RW Pitiakoudis MS Penetration of clarithromycin in experimental pleural empyema model fluid Respiration 2005 72 3 296 300 15942299\n16. Yoshida H Furuta T [Tissue penetration properties of macrolide antibiotics – comparative tissue distribution of erythromycin-stearate, clarithromycin, roxithromycin and azithromycin in rats] Jpn J Antibiot 1999 52 7 497 503 [in Japanese] 10516929\n17. Lim MY Alker AP Califano S Concurrent disseminated nocardiosis and GI mucormycosis in a stem-cell transplantation recipient J Clin Oncol 2016 34 10 e84 86 25071136\n18. Sawai T Nakao T Yamaguchi S Detection of high serum levels of beta-D-Glucan in disseminated nocardial infection: A case report BMC Infect Dis 2017 17 1 272 28407752\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "22()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D017291:Clarithromycin; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D009615:Nocardia; D009617:Nocardia Infections; D012336:RNA, Ribosomal, 16S",
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"title": "Clarithromycin As an Alternative and Prophylactic Agent in a Hematopoietic Stem Cell Transplantation Patient.",
"title_normalized": "clarithromycin as an alternative and prophylactic agent in a hematopoietic stem cell transplantation patient"
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"abstract": "Posttransplant lymphoproliferative disorder (PTLD) occurs in 1% to 3% of adult renal transplant recipients (RTRs). PTLD has a heterogeneous presentation and is often associated with Epstein-Barr virus (EBV) and immunosuppression. We present a descriptive case series of 16 RTRs who demonstrate a variety of PTLD manifestations. Fifty-six percent received rabbit antithymocyte globulin induction, and 37.5% received basiliximab. Maintenance immunosuppression included glucocorticoids, tacrolimus, and mycophenolate mofetil. Median time from transplantation to PTLD diagnosis was 96.5 months. PTLD involved a single site in 44% of RTRs and multiple sites in 56%. PTLD was localized to the gastrointestinal tract in 9 RTRs, in lymph nodes in 9, central nervous system in 4, bone marrow in 3, skin in 3, lungs in 2, perinephric space in 2, mediastinum in 1, and native kidney in 1. PTLD was EBV positive in 8 RTRs, monomorphic/monoclonal in 14, and of B-cell lineage in 13. Three RTRs had T-cell PTLD. Immunosuppressive agents, except glucocorticoids, were discontinued at diagnosis. Treatment was chemotherapy either alone (in 14 RTRs) or in combination with radiation. Complete remission was achieved in 62.5% of RTRs. Renal dysfunction developed in 62.5% of RTRs, and 4 received dialysis. The overall mortality rate was 62.5%, with median time of death 6.5 months after diagnosis. PTLD that was EBV negative and had T-cell involvement presented with aggressive disease and a higher mortality. Clinicians should be aware of the various PTLD manifestations. Early diagnosis and a multidisciplinary approach to treatment is crucial for improved patient outcomes.",
"affiliations": "Wayne State University School of Medicine, Detroit, Michigan.;Kidney and Pancreas Transplant Program, Henry Ford Transplant Institute, Detroit, Michigan.;Kidney and Pancreas Transplant Program, Henry Ford Transplant Institute, Detroit, Michigan. Electronic address: Apatel2@hfhs.org.",
"authors": "Patil|Rujuta|R|;Prashar|Rohini|R|;Patel|Anita|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2021.04.020",
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"issn_linking": "0041-1345",
"issue": "53(5)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D020031:Epstein-Barr Virus Infections; D005260:Female; D004854:Herpesvirus 4, Human; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008223:Lymphoma; D008232:Lymphoproliferative Disorders; D008297:Male; D009173:Mycophenolic Acid; D011183:Postoperative Complications; D006435:Renal Dialysis; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "0243532",
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"pages": "1519-1527",
"pmc": null,
"pmid": "34134932",
"pubdate": "2021-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Heterogeneous Manifestations of Posttransplant Lymphoma in Renal Transplant Recipients: A Case Series.",
"title_normalized": "heterogeneous manifestations of posttransplant lymphoma in renal transplant recipients a case series"
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"abstract": "We report the cases of two women who began to experience urinary hesitancy and retention after starting treatment with sertraline for depression. Discontinuation of the drug resulted in complete symptom relief. Serotonergic neurons are involved at several levels in control of the lower urinary tract. Retention is apparently an uncommon complication of sertraline. Discontinuation should be considered for patients presenting with voiding difficulties.",
"affiliations": "Division of Female Pelvic Medicine and Reconstructive Surgery, Loyola Medical Center, 2160 South First Avenue, Maywood, IL 60153, USA. llowenstein@lumc.edu",
"authors": "Lowenstein|L|L|;Mueller|E R|ER|;Sharma|S|S|;FitzGerald|M P|MP|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"country": "England",
"delete": false,
"doi": "10.1007/s00192-006-0241-4",
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"issue": "18(7)",
"journal": "International urogynecology journal and pelvic floor dysfunction",
"keywords": null,
"medline_ta": "Int Urogynecol J Pelvic Floor Dysfunct",
"mesh_terms": "D000368:Aged; D005260:Female; D006801:Humans; D008875:Middle Aged; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D016055:Urinary Retention",
"nlm_unique_id": "9514583",
"other_id": null,
"pages": "827-9",
"pmc": null,
"pmid": "17089079",
"pubdate": "2007-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "14550831;9666094;2258379;8573661;16455184;12137933;14764128;16034945;7702445;15254599;2258378;14636079;9868574;11916537",
"title": "Urinary hesitancy and retention during treatment with sertraline.",
"title_normalized": "urinary hesitancy and retention during treatment with sertraline"
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"companynumb": "US-PFIZER INC-202101424839",
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"abstract": "Background: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. The most frequent symptoms are fatigue and cognitive dysfunction. We describe a patient suffering from Long COVID in whom adrenal involvement was highlighted. Methods: The patient described Long COVID symptoms that persist 3 months after the negativization of the molecular swab test. The main symptoms were weakness, brain fog, dizziness, and muscular and joint pain. All routine lab panels for inflammation, anemia, and thyroid and liver function were conducted. Moreover, salivary cortisol and DHEA-S determinations were used to compute the adrenal stress index (ASI). Results: All tests were negative, except the ASI that showed very low levels of free cortisol. The patient started hydrocortisone acetate supplementation. Conclusion: Long COVID symptoms could be explained by an adrenal involvement, due to a COVID-19 action on adrenal glands and by a iatrogenic side effect of high glucocorticoid therapy during the COVID-19 infection. Salivary cortisol determination is effective for establishing a correct recovery plan.",
"affiliations": "Unit of Internal Medicine, San Giovanni Bosco Hospital, ASL-NA1, Via Filippo Maria Briganti, 255, 80144 Napoli, Italy.;Medylab-Advanced Biochemistry, Viale Martiri di Nassiriya, 14, 81030 Lusciano, Italy.;Medylab-Advanced Biochemistry, Viale Martiri di Nassiriya, 14, 81030 Lusciano, Italy.",
"authors": "Salzano|Ciro|C|0000-0001-7966-7868;Saracino|Giovanna|G|;Cardillo|Giuseppe|G|0000-0001-6414-8475",
"chemical_list": "D019314:Dehydroepiandrosterone Sulfate; D006854:Hydrocortisone",
"country": "Switzerland",
"delete": false,
"doi": "10.3390/medicina57101087",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X\n1648-9144\nMDPI\n\n10.3390/medicina57101087\nmedicina-57-01087\nCase Report\nPossible Adrenal Involvement in Long COVID Syndrome\nhttps://orcid.org/0000-0001-7966-7868\nSalzano Ciro 1\nSaracino Giovanna 2\nhttps://orcid.org/0000-0001-6414-8475\nCardillo Giuseppe 2*\nCirocchi Roberto Academic Editor\n1 Unit of Internal Medicine, San Giovanni Bosco Hospital, ASL-NA1, Via Filippo Maria Briganti, 255, 80144 Napoli, Italy; cirosalzano89@gmail.com\n2 Medylab–Advanced Biochemistry, Viale Martiri di Nassiriya, 14, 81030 Lusciano, Italy; giovanna.saracino.83@gmail.com\n* Correspondence: giuseppe.cardillo.75@gmail.com\n11 10 2021\n10 2021\n57 10 108713 9 2021\n08 10 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nBackground: A significant number of patients with COVID-19 experience prolonged symptoms, known as Long COVID. The most frequent symptoms are fatigue and cognitive dysfunction. We describe a patient suffering from Long COVID in whom adrenal involvement was highlighted. Methods: The patient described Long COVID symptoms that persist 3 months after the negativization of the molecular swab test. The main symptoms were weakness, brain fog, dizziness, and muscular and joint pain. All routine lab panels for inflammation, anemia, and thyroid and liver function were conducted. Moreover, salivary cortisol and DHEA-S determinations were used to compute the adrenal stress index (ASI). Results: All tests were negative, except the ASI that showed very low levels of free cortisol. The patient started hydrocortisone acetate supplementation. Conclusion: Long COVID symptoms could be explained by an adrenal involvement, due to a COVID-19 action on adrenal glands and by a iatrogenic side effect of high glucocorticoid therapy during the COVID-19 infection. Salivary cortisol determination is effective for establishing a correct recovery plan.\n\nLong COVID\nsalivary cortisol and DHEA-S\nadrenal insufficiency\n==== Body\npmc1. Introduction\n\nDuring the outbreak of the COVID-19 pandemic, about 10% of patients reported a prolonged, multisystem involvement and significant disability symptoms persistent for more than 24 days after the diagnosis, known as Long COVID [1,2,3]. The most frequent symptoms are fatigue, headache, post-exertional malaise and cognitive dysfunction, and hair loss. Almost all patients reported symptoms relapses elicited by exercise, physical or mental activity, and stress [4,5]. Moreover, as described in several recent works [6,7,8,9], the Long COVID syndrome has a significant impact on the endocrine system. Many of the frequently reported symptoms [4,5], such as unusual tiredness and weakness, nausea, diarrhea, dizziness, and joint pain, overlap with adrenal insufficiency symptoms [10]. In this case report, we describe a patient with Long COVID syndrome for whom the involvement of the adrenal gland was first suspected and then confirmed by using the measurement of cortisol and DHEA-S on saliva specimens.\n\n2. Materials and Methods\n\nClinical history. A 38 years-old female, of 80-kg weight, 150-cm height, with one pregnancy completed in September 2015 with vaginal delivery, gall bladder surgically removed for cholelithiasis in December 2016, atopic dermatitis since birth, and apparent good state of health, developed COVID-19 symptoms 7 days after a voluntary quarantine started subsequent to a positive close contact. Disease started on 23 April 2021 with cephalalgia and pain localized along left lesser occipital nerve, cough, disgeusia, normal blood pressure, 40 °C body temperature, weakness, and positive walking test with saturation dropping from 97% to 92% SpO2. COVID-19 was confirmed by molecular swab test. Viral Genome sequencing to identify a variant was not performed. The patient was assisted at home with: oxygen on demand when saturation dropped under 95% SpO2, cefditoren 800 mg/day for 10 days, enoxaparin 16,000 U/day for 7 days then 8000 U/day for 7 days, dexamethasone 6 mg/day, famotidine 40 mg/day, KCl 600 mg/day for 14 days, vitamin D 50,000 U/day for 4 days then 10,000 U/day for 17 days, vitamin K2 0.1 mg/day for 21 days, vitamin C 3 g/day for 21 days, vitamin B12 0.05 mg/day for 21 days, zinc pidolate 12.5 mg/day for 21 days, quercetin 200 mg/days for 21 days, lactoferrin 200 mg/day for 21 days, and polidatina 160 mg/day for 21 days. After 3 days of high dosage dexamethasone, the patient developed psychosis: dosage was scaled down to 5 mg/day and lorazepam 2 mg/day for 3 days was added, then scaled down to 1 mg/day for another 4 days. Dexamethasone was scaled down by 1 mg/day each of the 3 days. A negative molecular swab test was obtained on 13 May 2021. During the recovery period, the patient complained of: severe weakness, muscles and joints pain, disgeusia, dizziness, brain fog, and depressed mood. Skin lesions and dischromic spots by atopic dermatitis were more numerous and severe than usual. Symptoms became worse (nausea and vomiting added) during study exam session in the first days of July 2021: the patient had full marks but her body was exhausted.\n\nMedical and Biochemical examination. The patient arrived at our observation facility in the middle of July 2021. Blood pressure and heart frequency were normal, and fair lower limb edema was observed. A negative six-minutes walking test and the lack of a cycle ergometer did not make us inclined to carry out other cardiopulmonary exercises test [11]. Complete blood count, reticulocytes, iron, ferritin, transferrin, total iron binding capacity, C-reactive protein, erythrocyte sedimentation rate, uric acid, AST, ALT, GGT, α2-macroglobulin, aptoglobin, D-dimer, fibrinogen, TSH, fT4, and fT3 tests were prescribed. Considering the psychosis during dexamethasone administration [4,5,12] and HPA axes’ suppression that can occur even for 3 years after glucocorticoid suspension [13,14], to assess free cortisol, unbound from cortisol binding globulin, we performed an adrenal stress index, measuring salivary cortisol and DHEA-S [15,16]. DHEA-S reference range was adjusted by age and sex. Cortisol and DHEA-S were measure by an ELISA test supplied by DiaMetra srl, Italy.\n\n3. Results\n\nTable 1 summarizes biochemical evaluation results. Anemia was excluded and iron depots were preserved. Moreover, white cell ratios and systemic inflammation index did not show an immune system involvement. Furthermore, recent data in the literature evidenced that patients with COVID-19 present lower fT4 levels compared to those without COVID-19 [6]. Moreover, thyroid and liver functions were normal; the aminotransferase ratio was quite positive due to the patient being overweight. Finally, inflammatory markers showed the presence of a low grade inflammation. Table 2 and Figure 1 (panels A and B) summarize salivary cortisol and DHEA-S results that show a selective cortisol pathway suppression, but not the DHEA-S pathway. The patient started treatment with hydrocortisone acetate 18.75 mg/day. After 1 week, the dosage was raised to 25 mg/day. The first observed effect was the edema reduction due to an increased urine excretion: this sign is due to aldosterone synthesis up-regulation. One month after the treatment started, the patient was still on hydrocortisone supplementation and symptoms were reduced, but still not resolved.\n\n4. Discussion\n\nThe most common causes compatible with the reported symptoms were anemia and hypothyroidism, but biochemical examinations excluded both. Nonetheless, following a closer examination of thyroid function, it was possible to observe that fT4 levels were close to the lower bound of the reference range. This clinical picture is often associated with high stress situations, and the patient demonstrated a reduction in thyroid function during the viral infection [4]. Hypocortisolism is described as the main hormonal disease diagnosed in patients with COVID-19 after three months of recovery and central adrenal insufficiency represents the most frequent hormonal affection described in patients with COVID-19 [4,5,7,8,9,10].\n\nFigure 1 panel C shows the phases of adrenal glands’ response to stress. In the normal condition, both cortisol and DHEA-S are within their reference ranges (the green rectangle). When adrenal glands must respond to an acute stress, they up-regulate the production of both hormones (the blue rectangle–stress adaption phase). If the stressor is not removed, we will observe the shunt of steroidogenesis: progesterone will be preferably converted into 17-OH-progesterone to sustain the cortisol synthesis (stealth of pregnenolone—pink rectangle); cortisol remains high, but DHEA-S is normal. In this phase, aldosterone synthesis is also affected. In the next phase, adrenal glands do not have sufficient material for androgen synthesis: cortisol is high, but DHEA-S is low (maladaption phase I—orange rectangle). In the next step, steroidogenesis starts to be ineffective: cortisol is normal and DHEA-S is low (maladaption phase II—goldenrod rectangle). Finally, steroidogenesis leads to adrenal insufficiency (exhaustion—red rectangle): both cortisol and DHEA-S are low. Occasionally, it is possible to observe a cortisol level that drops before DHEA-S (disadaption—brown rectangle) due to a selective cortisol suppression, or a constitutionally high DHEA-S (grey rectangle) due to hyper-androgenism (for example, females with Poly Cystic Ovarian Syndrome—PCOS).\n\nThe reported Long COVID symptoms [1,2,3,4,5] overlap with low cortisol symptoms [10]. A recent review reported that fatigue, myalgia, and arthralgia affect respectively 65%, 50.6%, and 54.7% of patients with Long COVID [5]. This may be due to HPA suppression induced by high dosage dexamethasone [4,12,13,14] and by COVID-19 free radical stress induced both by the virus and the immune system myeloperoxidase.\n\nFurthermore, recent studies evidenced that ACTH and SARS-CoV-2 express homology in specific amino acid sequences, hypothesizing that COVID-19 infection may favor cross-reacting antibody production that could inactivate endogenous ACTH and destroy ACTH-secreting cells [17]. Adrenal cortex impairment was also implicated in hypocortisolism following COVID-19 infection. In fact, ACE2 expression was described in the zona fasciculata and zona reticularis of the adrenal cortex, favoring the hypothesis of an adrenal tissue injury by COVID-19 that could affect glucocorticoid synthesis [18]. In regards to this, autopsy studies in patients with COVID-19 revealed the necrosis of adrenal cortical cells and identified the virus in the adrenal glands [9].\n\nExamination of total cortisol could not effectively highlight this condition, mainly in a female patient. In fact, estrogens induce liver synthesis of Cortisol Binding Globulin (CBG): this transport protein is not routinely dosed in laboratory and thus, free cortisol is not easily determined. Salivary cortisol bypasses this problem, because only free cortisol can pass the salivary barrier; CBG is too big to pass through that barrier. Hence, even if the blood total cortisol level is normal or close to a low range, the patient can experience adrenal insufficiency symptoms due to high CBG levels.\n\n5. Conclusions\n\nLong COVID symptoms may be due to free cortisol insufficiency, due to cortisol synthesis pathway suppression induced by dexamethasone and salivary cortisol is effective for showing this lack that can be masked by normal cortisol production and high CBG synthesis [16]. This study also gives information on how to approach a recovery therapeutic plan with hydrocortisone acetate and how follow-up with it.\n\nAuthor Contributions\n\nAll authors equally contributed to this manuscript. All authors have read and agreed to the published version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nEthical review and approval were waived for this study, because none experimental or invasive procedure were used, but only routinary laboratory examination.\n\nInformed Consent Statement\n\nPatient gave informed consent in accordance with the 1962 Helsinki declaration and its later amendments or comparable ethical standards to publish this paper.\n\nData Availability Statement\n\nAll data are reported in the paper.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nFigure 1 Adrenal Stress Index (ASI). (A) Circadian salivary cortisol; (B) circadian salivary DHEA-S; (C) ASI phase graph.\n\nmedicina-57-01087-t001_Table 1 Table 1 Biochemical data of the patient.\n\nComplete Blood Count\t\nAnalyte\tValue\tUnits\tReference Range\t\nRed blood cells (RBC)\t5.07\t1012 cells/L\t4.0–5.4\t\nHemoglobin (Hb)\t136\tg/L\t120–160\t\nHematocrit (Hct)\t42.2\t%\t35–48\t\nMCV\t83.2\tfL\t78–95\t\nMCH\t26.9\tpg\t26–33\t\nMCHC\t323\tg/L\t320–360\t\nRDW\t14.4\t%\t11.0–15.5\t\nReticulocytes\t1\t%\t0.5–2.5\t\nPlatelets (PLT)\t339\t109 cells/L\t130–400\t\nMPV\t7.6\tfL\t7.2–11.1\t\nPCT\t0.26\t%\t0.12–0.36\t\nPDW\t50.3\t%\t25.0–65.0\t\nWhite blood cells (WBC)\t9.28\t109 cells/L\t4.8–10.8\t\nNeutrophils\t5.94\t109 cells/L\t1.90–8.10\t\nLymphocytes\t2.63\t109 cells/L\t0.90–5.20\t\nMonocytes\t0.41\t109 cells/L\t0.16–1.20\t\nEosinophils\t0.19\t109 cells/L\t0.00–0.80\t\nBasophils\t0.03\t109 cells/L\t0.00–0.20\t\nLUC\t0.08\t109 cells/L\t0.00–0.40\t\nMonocytes to Lymphocytes Ratio (MLR)\t0.156\t\t0.105–0.403\t\nNeutrophils to Lymphocytes Ratio (NLR)\t2.3\t\t0.7–3.5\t\nPlatelets to Lymphocytes Ratio (PLR)\t128.9\t\t76.5–251.4\t\nSystemic Inflammation Index (SII)\t765.7\t109 cells/L\t158–1028\t\nIron metabolism\t\nIron\t21.3\tμmol/L\t5.0–30.4\t\nFerritin\t64.0\tμmol/L\t33.7–337.1\t\nTransferrin\t31.3\tμmol/L\t25.1–50.3\t\nTotal Iron Binding Capacity (TIBC)\t62.5\tμmol/L\t50.2–100.6\t\nUnsaturated Iron Binding Capacity (UIBC)\t41.2\tμmol/L\t21.0–84.0\t\nTransferrin saturation\t34.1\t%\t15–50\t\nThyroid Function\t\nTSH\t2.035\tmU/L\t0.45–4.5\t\nfT4\t11.58\tpmol/L\t10–22\t\nfT3\t5.01\tpmol/L\t2.8–6.5\t\nLiver Function\t\nFibrinogen\t3.9\tg/L\t1.5–4.5\t\nD-dimer\t349\tμg/L\t140–500\t\nAspartate Aminotransferase (AST)\t22\tU/L\t6–34\t\nAlanine Aminotransferase (ALT)\t13\tU/L\t7–35\t\nγ-Glutamyl transferase (GGT)\t11\tU/L\t7–38\t\nAST/ALT\t1.7\t\t≤1\t\nGGT/ALT\t0.8\t\t≤1\t\nAST to Platelets Ratio Index (APRI)\t0.2\t\t≤0.5\t\nInflammatory Markers\t\nα2-Macroglobulin\t2.1\tg/L\t1.3–3.0\t\nC-reactive protein (CRP)\t5.5\tmg/L\t≤10\t\nAptoglobin\t2.68\tg/L\t0.30–2.00\t\nErythrocyte sedimentation rate (ESR)\t38\tmm\t≤20\t\nUric acid\t2.97\tmmol/L\t≤1.78\t\n\nmedicina-57-01087-t002_Table 2 Table 2 Determination of circadian salivary cortisol and DHEA-S. In normal conditions, DHEA-S peak precedes cortisol peak, both induced by ACTH, and then its production is constant all day long. Thus, DHEA-S was measured only in the first and last points to ensure this condition is respected.\n\nSALIVARY CORTISOL\t\nHours\tng/mL\tnmol/L\tRange\t\n07:00–08:00\t0.68\t1.88\t13–24 nmol/L\t\n11:00–12:00\t0.77\t2.12\t5–10 nmol/L\t\n16:00–17:00\t0.59\t1.63\t3–8 nmol/L\t\n23:00–24:00\t0.44\t1.21\t1–4 nmol/L\t\nCortisol area\t27.3\t70–155 nmol/L/16 h\t\nSALIVARY DHEA-S\t\nHours\tng/mL\tnmol/L\tRange\t\n07:00–08:00\t7.15\t19.40\tSex: Female-Age: 38\t\n23:00–24:00\t8.18\t22.20\t\nMean\t20.80\t10.6–30.9 nmol/L\t\nDHEA-S area\t332.8\t169–495 nmol/L/16 h\t\nDHEA-S–CORTISOL AREAS RATIO\t\nRatio\tRange\t\n12.2\t1.1–7.1\t\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Davis H.E. Assaf G.S. McCorkell L. Wei H. Low R.J. Re’em Y. Redfield S. Austin J.P. Akrami A. Characterizing long COVID in an international cohort: 7 months of symptoms and their impact EClinicalMedicine 2021 10.1016/j.eclinm.2021.101019\n2. Ladds E. Rushforth A. Wieringa S. Taylor S. Rayner C. Husain L. Greenhalgh T. Persistent symptoms after Covid-19: Qualitative study of 114 “long Covid” patients and draft quality principles for services BMC Health Serv. Res. 2020 20 1144 10.1186/s12913-020-06001-y 33342437\n3. Mendelson M. Nel J. Blumberg L. Madhi S.A. Dryden M. Stevens W. Long-COVID: An evolving problem with an extensive impact S. Afr. Med. J. 2020 111 10 12 10.7196/SAMJ.2020.v111i11.15433 33403997\n4. Lopez-Leon S. Wegman-Ostrosky T. Perelma C. Sepulveda R. Rebolledo P.A. Cuapio A. Villapol S. More than 50 long-term effects of COVID-19: A systematic review and meta-analysis Sci. Rep. 2021 11 16144 10.1038/s41598-021-95565-8 34373540\n5. Martimbianco A.L.C. Pacheco R.L. Bagattini A.M. Riera R. Frequency, signs and symptoms, and criteria adopted for long COVID-19: A systematic review Int. J. Clin. Pract. 2021 e14357 10.1111/ijcp.14357 33977626\n6. Khoo B. Tan T. Clarke S.A. Mills E.G. Patel B. Modi M. Phylactou M. Eng P.C. Thurston L. Alexander E.C. Thyroid Function Before, During, and After COVID-19 J. Clin. Endocrinol. Metab. 2021 106 e803 e811 10.1210/clinem/dgaa830 33180932\n7. Pal R. Banerjee M. COVID-19 and the endocrine system: Exploring the unexplored J. Endocrinol. Investig. 2020 43 1027 1031 10.1007/s40618-020-01276-8 32361826\n8. Lisco G. De Tullio A. Stragapede A. Solimando A.G. Albanese F. Capobianco M. Giagulli V.A. Guastamacchia E. de Pergola G. Vacca A. COVID-19 and the Endocrine System: A Comprehensive Review on the Theme J. Clin. Med. 2021 10 2920 10.3390/jcm10132920 34209964\n9. Piticchio T. Le Moli R. Tumino D. Frasca F. Relationship between betacoronaviruses and the endocrine system: A new key to understand the COVID-19 pandemic—A comprehensive review J. Endocrinol. Investig. 2021 44 1553 1570 10.1007/s40618-020-01486-0 33583003\n10. Brender E. Lynm C. Glass R.M. JAMA patient page. Adrenal insufficiency JAMA 2005 294 2528 10.1001/jama.294.19.2528 16287965\n11. Naeije R. Caravita S. Phenotyping long COVID Eur. Respir. J. 2021 58 2101763 10.1183/13993003.01763-2021 34244323\n12. Kamin H.S. Kertes D.A. Cortisol and DHEA in development and psychopathology Horm. Behav. 2017 89 69 85 10.1016/j.yhbeh.2016.11.018 27979632\n13. Nicolaides N.C. Pavlaki A.N. Maria Alexandra M.A. Chrousos G.P. Glucocorticoid Therapy and Adrenal Suppression Endotext [Internet] Feingold K.R. Anawalt B. Boyce A. MDText.com, Inc. South Dartmouth, MA, USA 2000 Available online: https://www.ncbi.nlm.nih.gov/books/NBK279156/ (accessed on 19 October 2018)\n14. Broersen L.H. Pereira A.M. Jørgensen J.O. Dekkers O.M. Adrenal Insufficiency in Corticosteroids Use: Systematic Review and Meta-Analysis J. Clin. Endocrinol. Metab. 2015 100 2171 2180 10.1210/jc.2015-1218 25844620\n15. Inder W.J. Dimeski G. Russell A. Measurement of salivary cortisol in 2012–laboratory techniques and clinical indications Clin. Endocrinol. 2012 77 645 651 10.1111/j.1365-2265.2012.04508.x 22812714\n16. Langelaan M.L.P. Kisters J.M.H. Oosterwerff M.M. Boer A.K. Salivary cortisol in the diagnosis of adrenal insufficiency: Cost efficient and patient friendly Endocr. Connect. 2018 7 560 566 10.1530/EC-18-0085 29531158\n17. Wheatland R. Molecular mimicry of ACTH in SARS–implications for corticosteroid treatment and prophylaxis Med. Hypotheses 2004 63 855 862 10.1016/j.mehy.2004.04.009 15488660\n18. Mao Y. Xu B. Guan W. Xu D. Li F. Ren R. Zhu X. Gao Y. Jiang L. The Adrenal Cortex, an Underestimated Site of SARS-CoV-2 Infection Front. Endocrinol. (Lausanne) 2021 11 593179 10.3389/fendo.2020.593179 33488517\n\n",
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"title": "Possible Adrenal Involvement in Long COVID Syndrome.",
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"abstract": "We report a case of osteonecrosis in a patient treated with adjuvant chemotherapy for breast cancer. A 68-year-old woman presented with severe right hip pain. Seven months after completing a course of 6 cycles of adjuvant Cyclophosphamide, Methotrexate and 5-Fluorouracil with standard anti-emetic prophylaxis of Dexamethasone and Domperidone for a T2N0M0 breast cancer. Investigations revealed evidence of osteonecrosis of the right femoral head. Due to ongoing hip pain, she underwent an elective total hip replacement and her mobility has returned almost to normal. Osteonecrosis has been associated with corticosteroids and cytotoxic regimens which omit these agents. Osteonecrosis is a rare complication of cytotoxic therapy but with the increasing use of chemotherapy it should be considered in the differential diagnosis of joint pain in patients who have received anti-tumour therapies.",
"affiliations": "Department of Oncology, Western General Hospital, Edinburgh, UK.",
"authors": "Dawson|L K|LK|;Nussey|F|F|;Oliver|T B|TB|;Marks|R C|RC|;Leonard|R C|RC|",
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"title": "Osteonecrosis of the femoral head following adjuvant chemotherapy for breast cancer.",
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"abstract": "COVID-19 is characterized by a severe pulmonary disease due to severe acute respiratory syndrome (SARS)-CoV-2 infection. For clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression during the COVID-19 pandemic is a major topic. Pemphigus is a rare autoimmune blistering disease (AIBD) of the skin and mucous membranes caused by autoantibodies to desmosomal components, desmoglein 1 and 3. Among immunosuppressant therapies, rituximab (RTX) is considered a highly effective treatment with a favorable safety profile, but it induces a prolonged B-cell depletion that can lead to higher susceptibility to infections. For this reason, concerns about its use during the pandemic have been raised. We describe a case of a pemphigus patient in which RTX-induced B cell depletion led to the severe inflammatory phase, whereas corticosteroid treatment allowed a favorable outcome.",
"affiliations": "Molecular and Cell Biology Laboratory IDI-IRCCS, Rome, Italy.;Department of Infectious Diseases, Central Hospital of Bolzano, Bolzano, Italy.;Department of Infectious Diseases, Central Hospital of Bolzano, Bolzano, Italy.;Molecular and Cell Biology Laboratory IDI-IRCCS, Rome, Italy.;Molecular and Cell Biology Laboratory IDI-IRCCS, Rome, Italy.;Rare Diseases Unit, IDI-IRCCS, Rome, Italy.;Rare Diseases Unit, IDI-IRCCS, Rome, Italy.;Molecular and Cell Biology Laboratory IDI-IRCCS, Rome, Italy.",
"authors": "Sinagra|Jo Linda|JL|;Vedovelli|Claudio|C|;Binazzi|Raffaella|R|;Salemme|Adele|A|;Moro|Francesco|F|;Mazzanti|Cinzia|C|;Didona|Biagio|B|;Di Zenzo|Giovanni|G|",
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"fulltext": "\n==== Front\nFront Immunol\nFront Immunol\nFront. Immunol.\nFrontiers in Immunology\n1664-3224\nFrontiers Media S.A.\n\n10.3389/fimmu.2021.665522\nImmunology\nCase Report\nCase Report: Complete and Fast Recovery From Severe COVID-19 in a Pemphigus Patient Treated With Rituximab\nSinagra Jo Linda 1 *\n\nVedovelli Claudio 2\nBinazzi Raffaella 2\nSalemme Adele 1\nMoro Francesco 1\nMazzanti Cinzia 3\nDidona Biagio 3\nDi Zenzo Giovanni 1\n\n1 Molecular and Cell Biology Laboratory IDI-IRCCS, Rome, Italy\n2 Department of Infectious Diseases, Central Hospital of Bolzano, Bolzano, Italy\n3 Rare Diseases Unit, IDI-IRCCS, Rome, Italy\nEdited by: Takashi Hashimoto, Osaka City University, Japan\n\nReviewed by: Farzan Solimani, Charité – Universitätsmedizin Berlin, Germany; Jun Yamagami, Keio University Hospital, Japan; Khalaf Kridin, Rambam Health Care Campus, Israel\n\n*Correspondence: Jo Linda Sinagra, jlsinagra@hotmail.com\nThis article was submitted to Autoimmune and Autoinflammatory Disorders, a section of the journal Frontiers in Immunology\n\n16 4 2021\n2021\n16 4 2021\n12 66552208 2 2021\n29 3 2021\nCopyright © 2021 Sinagra, Vedovelli, Binazzi, Salemme, Moro, Mazzanti, Didona and Di Zenzo\n2021\nSinagra, Vedovelli, Binazzi, Salemme, Moro, Mazzanti, Didona and Di Zenzo\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nCOVID-19 is characterized by a severe pulmonary disease due to severe acute respiratory syndrome (SARS)-CoV-2 infection. For clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression during the COVID-19 pandemic is a major topic. Pemphigus is a rare autoimmune blistering disease (AIBD) of the skin and mucous membranes caused by autoantibodies to desmosomal components, desmoglein 1 and 3. Among immunosuppressant therapies, rituximab (RTX) is considered a highly effective treatment with a favorable safety profile, but it induces a prolonged B-cell depletion that can lead to higher susceptibility to infections. For this reason, concerns about its use during the pandemic have been raised. We describe a case of a pemphigus patient in which RTX-induced B cell depletion led to the severe inflammatory phase, whereas corticosteroid treatment allowed a favorable outcome.\n\npemphigus\nautoimmune blistering disease\nrituximab\nimmunosuppression\nCOVID-19\nB cell\n==== Body\nIntroduction\n\nThe novel coronavirus SARS-CoV-2 is the pathogenic agent responsible for COVID-19, a severe pulmonary disease, the dramatic worldwide outbreak of which led the WHO to announce a pandemic in March 2020 (1). Several aspects of COVID-19 epidemiology, transmission and morbidity in the general population are still unclear. Some mortality risk factors have been identified, such as older age, male sex and certain comorbidities (obesity, diabetes, heart disease, lung disease, kidney disease) (1, 2). There is some evidence that immunocompromised patients do not have a higher incidence or complications from COVID-19 than the general population (3–5). Despite this, for clinicians involved in the management of patients with chronic autoimmune diseases the risk linked to the conditions itself and to drug-induced immunosuppression is a major topic.\n\nPemphigus is an autoimmune blistering disease (AIBD) of the skin and mucous membranes in which autoantibodies targeting cell-cell adhesion molecules (desmoglein 1 and 3) induce blister formation. Standard pemphigus treatment includes corticosteroids and a variety of immunosuppressants (azathioprine, cyclophosphamide, mycophenolate) (6). Even if their use is not contraindicated during the pandemic, adjusting the dosage could be considered in patients with active COVID-19 infection (7). In this context the use of IV immunoglobulins appears to be of particular interest due to their role in immunity support and the absence of immunosuppressive effects (2, 8). Rituximab (RTX) an anti-CD20 monoclonal antibody that induces a prolonged B-cell depletion, is considered a highly effective treatment with a favorable safety profile and is included among the first line therapies for this disease (9–11). However, as it can lead to higher susceptibility to infections, concerns about its use during the pandemic have been raised (2). Some authors have suggested avoiding or temporarily postponing RTX during the pandemic due to the risk of SARS-CoV-2 infection (2, 12).\n\nFew studies have been published about the clinical course of COVID-19 in pemphigus patients treated with RTX, and none have been published on patients infected immediately after RTX treatment.\n\nWe describe a case of a pemphigus patient with RTX-induced B-cell depletion who contracted COVID-19 with a severe course and had a favorable clinical outcome.\n\nCase-Report\n\nWe contacted 31 pemphigus patients routinely followed-up in our hospital in Rome who received RTX in the 12 months preceding the COVID-19 pandemic. Among them, a 45-year-old woman (professional nurse, living in Northern Italy) confirmed having COVID-19.\n\nShe was affected by pemphigus foliaceous, as assessed by clinical examination and direct immunofluorescence microscopy ( Figure 1A ), from January 2019 and received a cycle of RTX (500 mg x 4 weekly infusions) in May 2019 reaching complete remission off-therapy in November 2019 ( Figure 2 ). Two months later, a relapse occurred; therefore, on January 23 2020, she received an additional 500 mg RTX infusion and started prednisone 50 mg/day. Disease control was reached two weeks after infusion, prednisone was gradually tapered to 5 mg and lesions completely resolved at the beginning of March when B cells were still depleted. By the 15th of March, she developed mild flu-like symptoms (fever up to 37.5°C, asthenia and some cough). She was treated with azithromycin 500 mg/day for 3 days without clinical improvement. On the 21st of March, a nasopharyngeal swab was performed, resulting in negative SARS-CoV-2 result. She was started on Co-amoxiclav 875/125 mg bid for 6 days. During antibiotic treatment she experienced hyposmia, ageusia, dry cough, nocturnal dyspnea and hyperpyrexia (up to 39.5 C). As symptoms persisted, on March 27 a second nasopharyngeal swab was performed, resulting in positivity for SARS-CoV-2 ( Figure 2 ). She was admitted to the Geriatric-COVID-19 Unit of the referral hospital in Bolzano-Bozen. At admission, the patient’s oxygen saturation was 94% on room air, ABG revealed pO2 61.9 mmHg, pCO2 34 mmHg, pO2(a)/FO2(l) 295 mmHg and pH 7.49. Laboratory tests showed lymphopenia (940 cells/µL, n.v. 1100-4500), slightly increased LDH (337 U/L, n.v. 123-230), increased CRP (11.03 mg/dl, n.v. < 0.05) and increased IL-6 (51.7 pg/ml, n.v. <7.0). The chest radiograph showed interstitial pneumonia with bilateral airspace opacities ( Figure 1B ). She was started on hydroxychloroquine (200 mg bid for 8 days), lopinavir/ritonavir (200/50 mg qd for 8 days) and enoxaparin 0.4 ml qd. Oxygen therapy (from 3 up to 8 l/min) was administered. Despite this, her fever persisted, dyspnea worsened and on April 1, she was transferred to the Infectious Diseases Unit of the same hospital. High flux oxygen therapy was given through a nonrebreather mask, intravenous methylprednisolone 80 mg qd was added and enoxaparin was increased to 0.4 ml bid, resulting in a sudden clinical improvement. Three days later, the patient was apyretic, her oxygen saturation improved to 98% with 4-6 liters of oxygen. Intravenous methylprednisolone was continued for 2 days and then gradually tapered to 16 mg per os. The patient’s conditions recovered. After two positive swabs, 18 days from admission a further nasopharyngeal swab was negative for SARS-CoV-2, so the patient was discharged continuing oral methylprednisolone 8 mg qd ( Figure 2 ). At present (February 2021), the patient is in good general condition and her pemphigus is in complete remission off-therapy. She had no pulmonary sequelae and reported no difficulties in returning to her everyday habits or work.\n\nFigure 1 Essential elements for pemphigus and COVID-19 diagnosis. (A) Intercellular deposition of IgG (arrow heads) by direct immunofluorescence microscopy; (B) Chest radiograph of pemphigus patient with COVID-19 showing interstitial pneumonia with bilateral airspace opacities.\n\nFigure 2 Timeline with relevant data from the episode of care.\n\nDiscussion\n\nPemphigus patients can have a higher risk of infection due to exposed lesions and immunosuppressive treatments. As it is a rare disease, at present few cases of COVID-19 in RTX-treated pemphigus patients have been reported (7, 13). To our knowledge this is the first detailed case of severe COVID-19 in a pemphigus patient treated with RTX shortly before infection with a complete B cell depletion.\n\nShahidi-Dadras et al. reported 5 COVID-19 cases in a cohort of 45 RTX treated pemphigus patients, none of whom had a severe course. All patients received RTX at least one year before infection, thus they did not have a severe reduction in B cell count (14). Uzuncakmak et al. reported only one case of COVID-19 among 48 pemphigus patients treated with RTX during the past five years. The patient received RTX seven months before COVID-19 and had a mild course (15). Recently, Mahmoudi et al. reported 21 COVID-19 cases from a cohort of patients with AIBDs. Thirteen of them received RTX in the previous six months, but no specific information was provided about the temporal distance of COVID-19 infections from RTX and B cell counts (13).\n\nCOVID-19 seems to primarily involve T lymphocytes (16). As reported by Chen and coworkers, the number of CD4+ and CD8+ T cells was markedly lower in severe cases of COVID-19 than in moderate cases. In contrast, neither the proportion nor the number of B cells was reduced in most patients (16). From a histopathological point of view, in lung biopsy, the infiltrated lymphocytes were mostly CD3-positive (17). In animal models, similar to other coronaviruses, after comparing T cell–deficient mice and B cell–deficient mice Zhao et al. found that T cells are able to survive and kill virus-infected cells in the infected lung (18), highlighting the role of T lymphocytes in the pathogenesis and outcome of SARS-CoV and MERS-CoV infection. Niu et al. found that IgM/IgG and IgA B cell responses were induced in the early phase of infection (19). IgA may migrate to the respiratory tract, the gastrointestinal tract, or other mucosal sites to play an early immune function in virus clearance. In this context, the reduction of the B cell and/or T cell repertoire and their function, such as that which occurs in older patients, could limit viral clearance and prolong the innate proinflammatory response (20, 21). In particular, in severe patients an excessive inflammatory response induced by neutrophils and monocytes leads to potentially fatal hypercytokinemia (22). Zhang and coworkers identified several genes upregulated in severe patients that are responsible for the recruitment of neutrophils that probably represent the main contributor to disease progression (23). These authors also demonstrated a downregulation of the type I interferon (IFN) response, especially in severe patients (23). This phenomenon could impair the first line of defense against viral infection exerted by IFNs and reduce their ability to limit the overactive inflammatory response leading the patient to a more severe course (23). In our patient, RTX-induced B cell depletion may have impaired the immune response, preventing a rapid virus clearance. Thereafter, as described in a subgroup of patients (24), an exaggerated immune response led to inflammatory-induced lung injury and worsening of the disease. The severe disease course of our 46-year-old female patient appears quite different from the reported general disease course for her sex and age-range (25). In fact, a correlation between COVID-19 disease severity and age and sex has been recently suggested, with older age and male sex being associated with more severe disease (25, 26). An Italian study on 1591 patients admitted to intensive care units showed that only 143/1591 (8.9%) were in the 41-50 age range, and they were predominantly males (27). Moreover, pulmonary involvement seems to be more severe and prolonged in patients over 60 years of age (28). However, when inflammatory-induced lung injury occurs, immunosuppressants, such as steroids, might be useful in suppressing inflammation. In this regard, a randomized trial from Oxford University (RECOVERY) investigated the role of several drugs (lopinavir-ritonavir, hydroxychloroquine, corticosteroids, azithromycin, convalescent plasma or tocilizumab) on mortality reduction in COVID-19 patients (29). The researchers found that in 2104 patients receiving dexamethasone 6 mg once per day for ten days vs 4321 patients on usual care, dexamethasone reduced deaths by one-third in ventilated patients and by one-fifth in other patients receiving oxygen only (30). Moreover, the REMAP CAP trial demonstrated that high dosages of intravenous hydrocortisone (50 mg or 100 mg every 6 hours or shock-dependent dosage) vs no hydrocortisone treatment in patients with severe COVID-19 were associated with 93% and 80% probabilities of better clinical outcome (31). In line with these data in our patient, the use of endovenous methylprednisolone resulted in a sudden clinical improvement, confirming the efficacy of this drug in controlling the inflammatory phase.\n\nDifferent viral agents are associated with an increased risk of more severe disease course and respiratory complications in immunocompromised patients (18, 19). However, during different coronavirus outbreaks, such as SARS and Middle East respiratory syndrome no increased mortality was reported in immunosuppressed transplanted patients, or those affected by cancer or autoimmune diseases (1, 19). Preliminary findings on patients with chronic arthritis treated with immunosuppressive therapy do not suggest an increased risk of respiratory or life-threatening complications from SARS-CoV-2 (3).\n\nDuring the COVID-19 pandemic, experts and dermatologic society opinions were divided about the obvious need to counterpart the risks and benefits of continuing or suspending immunosuppressive treatment (32). In particular, several controversies have emerged about the use of RTX with pemphigus patients. According to some authors, anti-CD20 therapies do not seem to necessarily imply higher rates of infection and risk for more severe COVID-19 disease (7). However, the cited systematic review from Kasperkiewicz and coworkers did not include pemphigus patients treated with RTX shortly before infection as in our patient (33). In contrast, in line with our findings Mahmoudi et al. found that in 13 patients with AIBDs who contracted COVID-19 after receiving RTX during the preceding 6 months, the risk of hospitalization decreased each month after RTX (13).\n\nIn conclusion, in our patient with a RTX-induced B cell depletion and inflammatory-induced lung injury, methylprednisolone treatment controlled the inflammatory phase, resulting in sudden clinical improvement. In addition, as suggested by Mahmoudi and coworkers, in our patient RTX-induced B cell depletion might be a risk factor for exacerbation of COVID-19 (13). Thus, as data are still scarce and as patients treated with anti-CD20 drugs are in general at higher risk for infections, the use of RTX during the pandemic has to be carefully pondered on a case-by-case basis (2, 7). Moreover, in the view of the recent development of COVID-19 vaccines, RTX treatment could be preferably considered at least 4 weeks after a complete vaccine cycle (34).\n\nDue to the rarity of autoimmune blistering diseases, we think that also anecdotal cases could also contribute to improving the therapeutic management of these patients during the pandemic.\n\nData Availability Statement\n\nClinical and laboratory data of patient are stored in Bolzano Hospital archives. Requests to access these datasets should be directed to Dr. Raffella Binazzi, Raffaella.binazzi@sabes.it.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nJS contributed to writing and editing of the manuscript. JS and GZ contributed to conception. JS, CV, RB, CM, FM, and AS contributed to data collecting. GZ and BD made the supervision. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis article was supported by the “Progetto Ricerca Corrente - 2020” of the Italian Ministry of Health, Rome, Italy.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nAcknowledgments\n\nIDI-IRCCS is a healthcare provider of the European Reference Network (ERN)-Skin.\n\nAbbreviations\n\nRTX, rituximab; AIBD, autoimmune blistering disease; SARS, severe acute respiratory syndrome.\n==== Refs\nReferences\n\n1 Zhou F Yu T Du R Fan G Liu Y Liu Z . Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet (2020) 395 (10229 ):1054–62. 10.1016/S0140-6736(20)30566-3\n2 Shakshouk H Daneshpazhooh M Murrell DF Lehman JS . Treatment considerations for patients with pemphigus during the COVID-19 pandemic. J Am Acad Dermatol (2020) 82 (6 ):e235–6. 10.1016/j.jaad.2020.04.005\n3 Monti S Balduzzi S Delvino P Bellis E Quadrelli VS Montecucco C . Clinical course of COVID-19 in a series of patients with chronic arthritis treated with immunosuppressive targeted therapies. Ann Rheumatic Dis (2020) 79 (5 ):667–8. 10.1136/annrheumdis-2020-217424\n4 Favalli EG Ingegnoli F Cimaz R Caporali R . What is the true incidence of COVID-19 in patients with rheumatic diseases? Ann Rheumatic Dis (2020) 80 :e18. 10.1136/annrheumdis-2020-217615\n5 Michelena X Borrell H López-Corbeto M López-Lasanta M Moreno E Pascual-Pastor M . Incidence of COVID-19 in a cohort of adult and paediatric patients with rheumatic diseases treated with targeted biologic and synthetic disease-modifying anti-rheumatic drugs. Semin Arthritis Rheumatol (2020) 52 :564–70. 10.1016/j.semarthrit.2020.05.001\n6 Didona D Maglie R Eming R Hertl M . Pemphigus: Current and future therapeutic strategies. Front Immunol (2019) 10 (June ):1–28. 10.3389/fimmu.2019.01418 30723466\n7 Kasperkiewicz M Schmidt E Amagai M Fairley JA Joly P Murrell DF . Updated international expert recommendations for the management of autoimmune bullous diseases during the COVID-19 pandemic. J Eur Acad Dermatol Venereol (2021), 10.1111/jdv.17207. 10.1111/jdv.17207 33619777\n8 Ghalamkarpour F Pourani MR . Aggressive course of pemphigus vulgaris following COVID-19 infection. Dermatol Ther (2020) 33 (6 ):e14398. 10.1111/dth.14398 33040414\n9 Joly P Maho-Vaillant M Prost-Squarcioni C Hebert V Houivet E Calbo S . First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial. Lancet (2017) 389 :2031–4. 10.1016/S0140-6736(17)30070-3\n10 Amber KT Maglie R Solimani F Eming R Hertl M . Targeted Therapies for Autoimmune Bullous Diseases: Current Status. Drugs (2018) 78 (15 ):1527–48. 10.1007/s40265-018-0976-5\n11 Murrell DF Peña S Joly P Marinovic B Hashimoto T Diaz LA . Diagnosis and Management of Pemphigus: recommendations by an International Panel of Experts. J Am Acad Dermatol (2018) 82 :3. 10.1016/j.jaad.2018.02.021\n12 Elmas ÖF Demirbaş A Türsen Ü Atasoy M Lotti T . Pemphigus and COVID-19: Critical overview of management with a focus on treatment choice. Dermatol Ther (2020) 33 (6 ):e14265. 10.1111/dth.14265 32882079\n13 Mahmoudi H Farid AS Nili A Dayani D Tavakolpour S Soori T . Characteristics and outcomes of COVID-19 in patients with autoimmune bullous diseases: A retrospective cohort study. J Am Acad Dermatol (2020) 14 (4 ):337–9. 10.1016/j.jaad.2020.12.043\n14 Shahidi-Dadras M Abdollahimajd F Ohadi L Tabary M Araghi F Mozafari N . COVID-19 in pemphigus vulgaris patients with previous rituximab therapy: a tele-medicine experience. J Dermatol Treat (2020) 1–2. 10.1080/09546634.2020.1789041\n15 Uzuncakmak TK . Can rituximab be used in the treatment of pemphigus vulgaris during the COVID-19 pandemic? (2021) 34 (1 ):e14647. 10.1111/dth.14647\n16 Chen G Wu D Guo W Cao Y Huang D Wang H . Clinical and immunological features of severe and moderate coronavirus disease 2019. J Clin Invest (2020) 130 (5 ):2620–9. 10.1101/2020.02.16.20023903\n17 Hsiao CH Wu MZ Chen CL Hsueh PR Hsieh SW Yang PC . Evolution of pulmonary pathology in severe acute respiratory syndrome. J Formos Med Assoc (2005) 104 (2 ):75–81.15765160\n18 Zhao J Li K Wohlford-Lenane C Agnihothram SS Fett C Zhao J . Rapid generation of a mouse model for Middle East respiratory syndrome. Proc Natl Acad Sci USA (2014) 111 (13 ):4970–5. 10.1073/pnas.1323279111\n19 Niu X Li S Li P Pan W Wang Q Feng Y . Corrigendum: Longitudinal Analysis of T and B Cell Receptor Repertoire Transcripts Reveal Dynamic Immune Response in COVID-19 Patients (Front. Immunol., (2020), 11, (582010), 10.3389/fimmu.2020.582010). Front Immunol (2020) 11 (September ):1–9. 10.3389/fimmu.2020.633815 32038653\n20 Yang X Yu Y Xu J Shu H Xia J Liu H . Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med (2020) 8 (5 ):475–81. 10.1016/S2213-2600(20)30079-5\n21 Yager EJ Ahmed M Lanzer K Randall TD Woodland DL Blackman MA . Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J Exp Med (2008) 205 (3 ):711–23. 10.1084/jem.20071140\n22 Bost P De Sanctis F Canè S Ugel S Donadello K Castellucci M . Deciphering the state of immune silence in fatal COVID-19 patients. Nat Commun (2021) 12 (1 ):1428. 10.1038/s41467-021-21702-6 33674591\n23 Zhang Q Meng Y Wang K Zhang X Chen W Sheng J . In fl ammation and Antiviral Immune Response Associated With Severe Progression of COVID-19. Front Immunol (2021) 12 (February ):1–12. 10.3389/fimmu.2021.631226\n24 Prompetchara E Ketloy C Palaga T . Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pacific J Allergy Immunol (2020) 38 (1 ):1–9. 10.12932/AP-200220-0772\n25 Gallo Marin B Aghagoli G Lavine K Yang L Siff EJ Chiang SS . Predictors of COVID-19 severity: A literature review. Rev Med Virol (2021) 31 (1 ):1–10. 10.1002/rmv.2146\n26 Shang W Dong J Ren Y Tian M Li W Hu J . The value of clinical parameters in predicting the severity of COVID-19. J Med Virol (2020) 92 (10 ):2188–92. 10.1002/jmv.26031\n27 Ciceri F Castagna A Rovere-Querini P De Cobelli F Ruggeri A Galli L . Early predictors of clinical outcomes of COVID-19 outbreak in Milan, Italy. Clin Immunol (2020) 217 (January ):108509. 10.1016/j.clim.2020.108509 32535188\n28 Liu Y Mao B Liang S Yang JW Lu HW Chai YH . Association between age and clinical characteristics and outcomes of COVID-19. Eur Respir J (2020) 55 (5 ):2001112. 10.1183/13993003.01112-2020 32312864\n29 Horby P Landray M Haynes R Juszczak E Baillie K Jaki T . Randomised Evaluation of Covid-19 Therapy (RECOVERY). EudraCT (2020) 2020-001113-21.\n30 Horby P Lim WS Emberson J Mafham M Bell J Linsell L . Effect of Dexamethasone in Hospitalized Patients with COVID-19: Preliminary Report. N Engl J Med (2020) 384 (8 ):693–704. 10.1101/2020.06.22.20137273 32678530\n31 Angus DC Derde L Al-Beidh F Annane D Arabi Y Beane A . Effect of Hydrocortisone on Mortality and Organ Support in Patients with Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA J Am Med Assoc (2020) 324 (13 ):1317–29. 10.1001/jama.2020.17022\n32 Di Altobrando A Patrizi A Bardazzi F . Should SARS-CoV-2 influence immunosuppressive therapy for autoimmune blistering diseases? J Eur Acad Dermatol Venereol (2020) 34 (7 ):e295–7. 10.1111/jdv.16491\n33 Kasperkiewicz M . COVID-19 outbreak and autoimmune bullous diseases: A systematic review of published cases. J Am Acad Dermatol (2021) 84 (2 ):563–8. 10.1016/j.jaad.2020.08.012\n34 Waldman RA Creed M Sharp K Adalsteinsson J Imitola J Durso T . Toward a COVID-19 vaccine strategy for patients with pemphigus on rituximab. J Am Acad Dermatol (2021) 84 (4 ):e197–8. 10.1016/j.jaad.2020.10.075\n\n",
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"medline_ta": "Front Immunol",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D001402:B-Lymphocytes; D000086382:COVID-19; D005260:Female; D005334:Fever; D006801:Humans; D007074:Immunoglobulin G; D007249:Inflammation; D008875:Middle Aged; D010102:Oxygen Inhalation Therapy; D010392:Pemphigus; D000069283:Rituximab",
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"title": "Case Report: Complete and Fast Recovery From Severe COVID-19 in a Pemphigus Patient Treated With Rituximab.",
"title_normalized": "case report complete and fast recovery from severe covid 19 in a pemphigus patient treated with rituximab"
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"abstract": "Cryptococcus neoformans and Cryptococcus gatti both cause infection in immunocompromised patients. We report a case of meningitis with C. gatti in an AIDS patient. This case to our knowledge is the first case of C. gatti being reported from Sikkim (North East India).",
"affiliations": "Department of Microbiology, Sir Thotub Namgyal Memorial Hospital, Gangtok 737101, Sikkim, India.;Department of Medicine, Sir Thotub Namgyal Memorial Hospital, Gangtok 737101, Sikkim, India.;Department of Microbiology, Sir Thotub Namgyal Memorial Hospital, Gangtok 737101, Sikkim, India.;Department of Microbiology, Sir Thotub Namgyal Memorial Hospital, Gangtok 737101, Sikkim, India.;Department of Microbiology, Kasturba Medical College and Hospital, Manipal 576104, Karnataka, India.",
"authors": "Gurung|Shrijana|S|;Sherpa|Nagyal T|NT|;Yoden Bhutia|Pema|P|;Pradhan|Jagat|J|;Peralam Yegneshwaran|Prakash|P|",
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"title": "Cryptococcus gatti serotype B isolated in Sikkim (North-East India)-A new geographical niche.",
"title_normalized": "cryptococcus gatti serotype b isolated in sikkim north east india a new geographical niche"
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"abstract": "Solid organ transplant recipients are vulnerable to severe infection during induction therapy. We report a case of a 67-year-old male who died unexpectedly 10 days after receiving a kidney transplant on February 10, 2020. There was no clear cause of death, but COVID-19 was considered retrospectively, as the death occurred shortly after the first confirmed case of COVID-19 in Canada. We confirmed the presence of SARS-CoV-2 components in the renal allograft and native lung tissue using immunohistochemistry for SARS-CoV-2 spike protein and RNA scope in situ hybridization for SARS-CoV-2 RNA. Results were reaffirmed with the Food and Drug Administration Emergency Use Authorization approved Bio-Rad SARS-CoV-2 digital droplet PCR for the kidney specimen. Our case highlights the importance of patient autopsies in an unfolding global pandemic and demonstrates the utility of molecular assays to diagnose SARS-CoV-2 post-mortem. SARS-CoV-2 infection during induction therapy may portend a fatal clinical outcome. We also suggest COVID-19 may be transmittable via renal transplant.",
"affiliations": "Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada.;Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Pathology and Laboratory Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.;Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.",
"authors": "Simms|Emily Lauren|EL|;Chung|Hyunjae|H|;Oberding|Lisa|L|;Muruve|Daniel A|DA|;McDonald|Braedon|B|;Bromley|Amy|A|;Pillai|Dylan R|DR|;Chun|Justin|J|0000-0002-3820-7192",
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"mesh_terms": "D000368:Aged; D001344:Autopsy; D000086382:COVID-19; D002170:Canada; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D012367:RNA, Viral; D012189:Retrospective Studies; D000086402:SARS-CoV-2; D064370:Spike Glycoprotein, Coronavirus; D066027:Transplant Recipients",
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"title": "Post-mortem molecular investigations of SARS-CoV-2 in an unexpected death of a recent kidney transplant recipient.",
"title_normalized": "post mortem molecular investigations of sars cov 2 in an unexpected death of a recent kidney transplant recipient"
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"abstract": "Aspergillus calidoustus, previously classified as Aspergillus ustus, is an emerging pathogen in immunocompromised persons. We describe four recent cases of A. calidoustus and review 37 additional cases of A. calidoustus (n = 8) or A. ustus (n = 29) published through June 2016. Twenty (49%) cases occurred in patients with hematologic malignancy and/or receipt of hematopoietic cell transplantation, and 13 (32%) occurred in solid organ transplant recipients. Antifungal susceptibility was reported in 49% of cases and in 42% treatment failed. Overall mortality was 66% and, where reported, attributable mortality was 30%. A. calidoustus infection is associated with a high mortality rate and frequently displays in vitro antifungal resistance.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA.;Division of Infectious Diseases, Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA.;Division of Infectious Diseases, Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA.;Division of Infectious Diseases, Department of Internal Medicine, Rush University Medical Center, Chicago, IL, USA.;Department of Pathology, Rush University Medical Center, Chicago, IL, USA.;Division of Infectious Diseases, Department of Internal Medicine, Loyola University Medical Center, Maywood, IL, USA.",
"authors": "Seroy|Justin|J|;Antiporta|Philip|P|;Grim|Shellee A|SA|;Proia|Laurie A|LA|;Singh|Kamaljit|K|;Clark|Nina M|NM|http://orcid.org/0000-0001-5670-4443",
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"keywords": "\nAspergillus calidoustus\n; \nAspergillus ustus\n; fungal epidemiology; invasive aspergillosis",
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"mesh_terms": "D000328:Adult; D000368:Aged; D000935:Antifungal Agents; D001228:Aspergillosis; D001230:Aspergillus; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D008875:Middle Aged",
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"title": "Aspergillus calidoustus case series and review of the literature.",
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"abstract": "Anabolic androgenic steroids (AAS) are the main class of doping agents and their consumption produces adverse effects involving several organs and systems. Three cases of sudden cardiac death (SCD) and one of death due to congestive heart failure of previously healthy athletes who were AAS users are herein reported. Concentric cardiac hypertrophy with focal fibrosis (one case), dilated cardiomyopathy with patchy myocyte death (two cases) and eosinophilic myocarditis (one case) were observed and most probably relate to the final event. Molecular investigation for viral genomes was positive in one case (Ebstein virus). Our data confirm previous findings, showing that the most typical cardiac abnormality in AAS abusers is left ventricular hypertrophy, associated with fibrosis and myocytolysis. An exceptional cardiovascular substrate was represented by the case with drug induced eosinophilic myocarditis. These features are at risk of ventricular arrhythmias as well as congestive heart failure. The cause-effect relationship between AAS abuse and cardiac death can be established only by a rigorous methodology with the use of standardized protocols, including precise morphological studies of all target organs to search for chronic toxic effects. Laboratory investigations should focus on AAS searching on a wide range of biological matrices to demonstrate type, magnitude and time of exposure.",
"affiliations": "Department of Environmental Medicine and Public Health, Section of Legal Medicine, University of Padua Medical School, Via G. Falloppio 50, 35121 Padova, Italy. massimo.montisci@unipd.it",
"authors": "Montisci|Massimo|M|;El Mazloum|Rafi|R|;Cecchetto|Giovanni|G|;Terranova|Claudio|C|;Ferrara|Santo Davide|SD|;Thiene|Gaetano|G|;Basso|Cristina|C|",
"chemical_list": "D045930:Anabolic Agents; D000728:Androgens",
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"mesh_terms": "D000328:Adult; D045930:Anabolic Agents; D000728:Androgens; D006332:Cardiomegaly; D016757:Death, Sudden, Cardiac; D004300:Doping in Sports; D004802:Eosinophilia; D020031:Epstein-Barr Virus Infections; D005234:Fatty Liver; D005355:Fibrosis; D049429:Forensic Pathology; D006333:Heart Failure; D006801:Humans; D008297:Male; D009205:Myocarditis; D009206:Myocardium; D032383:Myocytes, Cardiac; D009929:Organ Size; D054060:Pulmonary Infarction",
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"title": "Anabolic androgenic steroids abuse and cardiac death in athletes: morphological and toxicological findings in four fatal cases.",
"title_normalized": "anabolic androgenic steroids abuse and cardiac death in athletes morphological and toxicological findings in four fatal cases"
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"abstract": "Inducing remission in nephrotic children on anti-tubercular therapy is difficult due to the increased metabolism of prednisolone induced by rifampicin. We report a child with nephrotic syndrome treated successfully with an increased dose of steroids without discontinuing anti-tubercular therapy.",
"affiliations": "Department of Pediatric Disciplines, North Eastern Indira Gandhi Regional Institute of Health and Medical Sciences, Shillong, India.",
"authors": "Barman|H|H|;Dass|R|R|;Duwarah|S G|SG|",
"chemical_list": "D005938:Glucocorticoids; D019384:Nucleic Acid Synthesis Inhibitors; D011239:Prednisolone; D012293:Rifampin",
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"journal": "Saudi journal of kidney diseases and transplantation : an official publication of the Saudi Center for Organ Transplantation, Saudi Arabia",
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"medline_ta": "Saudi J Kidney Dis Transpl",
"mesh_terms": "D002648:Child; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D009404:Nephrotic Syndrome; D019384:Nucleic Acid Synthesis Inhibitors; D011239:Prednisolone; D012293:Rifampin",
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"title": "Use of high-dose prednisolone to overcome rifampicin-induced corticosteroid non-responsiveness in childhood nephrotic syndrome.",
"title_normalized": "use of high dose prednisolone to overcome rifampicin induced corticosteroid non responsiveness in childhood nephrotic syndrome"
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"abstract": "Lenalidomide is indicated in the front-line management of multiple myeloma. More recently, it has been introduced for use in treating other hematologic malignancies. Although the drug is known to cause myelosuppression, there have been rare reports of lenalidomide-associated immune thrombocytopenia (ITP). Here, we review the literature on lenalidomide-associated ITP and report upon a 59-year-old man who was administered lenalidomide due to concern of progressive multiple myeloma more than a year following his having undergone an autologous hematopoietic stem cell transplant. His platelet count precipitously declined and lead to his hospitalization. Despite our withholding of the drug, he did not respond to platelet transfusions or administration of corticosteroids. He was successfully managed with intermittent immune globulin for several months before definitive treatment with splenectomy, which resulted in the complete resolution of his thrombocytopenia. A literature search identified a total of six additional cases of lenalidomide-associated ITP. Similarly, many of the reported cases were associated with persistent thrombocytopenia after discontinuation of the drug. Furthermore, these patients were generally managed successfully with standard ITP therapies, such as corticosteroids or intravenous immune globulin.",
"affiliations": "Division of Hematology-Oncology, Medical College of Georgia, Augusta University, Georgia Cancer Center, Augusta, Georgia.;Division of Hematology-Oncology, Medical College of Georgia, Augusta University, Georgia Cancer Center, Augusta, Georgia.;Department of Pathology and Laboratory Medicine, Augusta University, Augusta, Georgia.;Division of Hematology-Oncology, Medical College of Georgia, Augusta University, Georgia Cancer Center, Augusta, Georgia.;Division of Hematology-Oncology, Medical College of Georgia, Augusta University, Georgia Cancer Center, Augusta, Georgia.",
"authors": "Forehand Iii|William|W|https://orcid.org/0000-0002-5344-6474;Ajebo|Germame|G|https://orcid.org/0000-0002-5590-8003;Toscano|Michael|M|https://orcid.org/0000-0002-1772-6479;Jillella|Anand|A|https://orcid.org/0000-0002-6279-7567;Dainer|Paul|P|https://orcid.org/0000-0002-5466-6321",
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"doi": "10.1155/2020/8825618",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/8825618\nCase Report\nLenalidomide-Associated Immune Thrombocytopenia: A Case Report and Review of the Literature\nhttps://orcid.org/0000-0002-5344-6474Forehand III William \n1\n https://orcid.org/0000-0002-5590-8003Ajebo Germame \n1\n https://orcid.org/0000-0002-1772-6479Toscano Michael \n2\n https://orcid.org/0000-0002-6279-7567Jillella Anand \n1\n https://orcid.org/0000-0002-5466-6321Dainer Paul pdainer@augusta.edu\n1\n \n1Division of Hematology-Oncology, Medical College of Georgia, Augusta University, Georgia Cancer Center, Augusta, Georgia\n\n2Department of Pathology and Laboratory Medicine, Augusta University, Augusta, Georgia\nAcademic Editor: Vincent Ribrag\n\n\n2020 \n12 11 2020 \n2020 882561827 7 2020 29 10 2020 30 10 2020 Copyright © 2020 William Forehand III 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.Lenalidomide is indicated in the front-line management of multiple myeloma. More recently, it has been introduced for use in treating other hematologic malignancies. Although the drug is known to cause myelosuppression, there have been rare reports of lenalidomide-associated immune thrombocytopenia (ITP). Here, we review the literature on lenalidomide-associated ITP and report upon a 59-year-old man who was administered lenalidomide due to concern of progressive multiple myeloma more than a year following his having undergone an autologous hematopoietic stem cell transplant. His platelet count precipitously declined and lead to his hospitalization. Despite our withholding of the drug, he did not respond to platelet transfusions or administration of corticosteroids. He was successfully managed with intermittent immune globulin for several months before definitive treatment with splenectomy, which resulted in the complete resolution of his thrombocytopenia. A literature search identified a total of six additional cases of lenalidomide-associated ITP. Similarly, many of the reported cases were associated with persistent thrombocytopenia after discontinuation of the drug. Furthermore, these patients were generally managed successfully with standard ITP therapies, such as corticosteroids or intravenous immune globulin.\n\nAugusta University\n==== Body\n1. Introduction\nImmune thrombocytopenia (ITP) is a disorder characterized by immune-mediated thrombocytopenia [1]. Idiopathic ITP is reportedly more common; however, ITP secondary to underlying conditions or drugs has been identified not infrequently and may be underdiagnosed [2–4]. Several subtypes of drug-induced ITP (DITP) have been described based on their proposed mechanisms: hapten-dependent, drug-dependent, fiban-induced, drug-specific, autoantibody, and immune complex.\n\nIn most circumstances, there must be ongoing exposure to the offending drug for the thrombocytopenia to persist [5]. Hence, the mainstay of managing DITP has been to discontinue the drug whenever possible. Furthermore, criteria have been proposed by George and others for assessing possible DITP cases [6]. Based on such criteria, a case of definitive DITP would require that the patient's thrombocytopenia recovers after the drug is discontinued; however, this definition would exclude cases of DITP of the autoantibody subtype from being considered definite DITP. In the autoantibody subtype of DITP, thrombocytopenia can persist following the removal of the offending drug. The mechanism of this subtype of DITP is thought to involve the production of autoantibodies to platelets that do not depend upon the presence of the drug for binding, such as in primary ITP. Autoantibody-type DITP has been reported with gold and sulfamethoxazole [5, 7].\n\nThere have been very few cases of lenalidomide-associated ITP reported in the literature [8–10]. Of these cases, several have been reported in which the thrombocytopenia persisted after stopping the lenalidomide [10]. Here, we report another distinct case of lenalidomide-associated ITP that persisted for months after stopping this agent, possibly placing it among the drugs which can cause the autoantibody subtype of DITP.\n\n2. Case Presentation\nThe patient was a 59-year-old male who had been diagnosed with plasma cell myeloma in 2004 when he presented with pain and lytic lesions on a skeletal survey and an associated monoclonal IgG on a serum protein electrophoresis (SPEP) and immunofixation. A bone marrow biopsy demonstrated 30% lambda-restricted plasma cells at that time. He was treated with dexamethasone and thalidomide and achieved a very good partial response prior to receiving high-dose melphalan and underwent an autologous peripheral hematopoietic stem cell transplant (auto-HSCT) in July 2005. He achieved a complete response as a bone marrow aspirate, and biopsy in January 2006 revealed less than five percent polyclonal plasma cells. By the following month, his platelet count had recovered to 208,000/mm3.\n\nFollowing his recovery, the patient's care was transitioned back to his local hospital. In September 2006, he experienced increasing hip pain. Radiographic imaging revealed bilateral lesions in the femoral necks and pelvis. A bone marrow aspirate and biopsy at that time demonstrated maturing trilineage hematopoiesis and no monoclonal plasma cell population. An SPEP on September 25, 2006, demonstrated a rising M-spike of 0.65 g/dL. In October 2006, he underwent a right hip nail procedure to avoid an impending fracture. The pathologic specimen retrieved from that surgery showed fragments of bone with necrosis and interspersed poorly preserved crushed cells, which could not be definitively characterized.\n\nBy November 2006, his M-spike further increased to 0.77 g/dL. Based on the bone lesions and an increasing M-spike, a decision was made to initiate an attenuated course of lenalidomide and dexamethasone, along with a low dose of warfarin. The patient's transplant physician had recommended a 21-day 10 mg daily dose, which was initiated on December 30, 2006. He also received 40 mg dexamethasone every two weeks. No other new medications were initiated at that time. His chronic medications included metformin, glipizide, atenolol, pamidronate aspirin, fosinopril, gabapentin, lansoprazole, simvastatin, and ezetimibe. On January 26, 2007, the patient was admitted to the hospital for severe thrombocytopenia with a platelet count of 9,000/mm3; his other blood counts at the time of admission included Hgb, 10.7 g/dL, which was similar to his Hgb level before initiating lenalidomide. His WBC count was normal at 5.8 k/mm3. Further lenalidomide was withheld, and he was administered a 3-day course of 1 mg/kg prednisone along with a platelet transfusion; however, there was no increment in his platelet count. His HIV, hepatitis B, hepatitis C, and ANA screens were negative. On February 5, 2007, he underwent an abdominal ultrasound which demonstrated no evidence of portal hypertension or splenomegaly. Subsequently, he was transferred to the Augusta University Medical Center. At the time of transfer on February 6, 2007, his platelet count was 17,000/mm3.\n\nFollowing his transfer, he received transfusions of several more units of platelets on February 8th and 9th, but his platelets continued to decline and fell to a nadir of 5,000/mm3 on February 9th. A bone marrow aspirate and biopsy were performed. The specimens obtained demonstrated maturing hematopoiesis with adequate megakaryopoiesis and no morphologic evidence of recurrent myeloma (Figure 1). His hepatic function tests and renal function remained normal throughout his clinical course. In the absence of abnormal bleeding, he was discharged and maintained under close observation as an outpatient.\n\nDespite having had the lenalidomide withheld, his thrombocytopenia persisted, and he was readmitted to the hospital on February 18, 2007, after the onset of epistaxis, petechiae over his ankles, and melenic stools. He received intravenous gamma globulin (IVIG) on February 18th and achieved a rapid and robust platelet response. His platelets increased to 48,000/mm3 on the following day and peaked at 110,000/mm3 on February 22nd. The response was not sustained, and his platelets again decreased to 19,000/mm3. He received an additional dose of IVIG, which again resulted in a transient response. A course of rituximab was added to the treatment regimen. He remained dependent on intermittent IVIG infusions until July 2, 2007, when he underwent a splenectomy, resulting in a sustained rise in his platelet count (Figure 2). His spleen had a normal weight of 244.5 gm, and microscopic examination demonstrated red pulp congestion and no abnormal cell populations (Figure 3). Within a few months, he developed new bone lesions with an associated hip fracture, and his serum paraprotein increased further. He was treated sequentially with thalidomide and prednisone and, later, bortezomib, liposomal doxorubicin, and dexamethasone with symptomatic improvement and no recurrence of significant thrombocytopenia. He was lost to follow-up after a year of treatment and reportedly expired of uncertain causes.\n\n3. Methods\nUsing PubMed and Ovid, we searched the MEDLINE database using a date range from 1980–2020 for the keywords (lenalidomide) and (ITP) or (lenalidomide) and (immune thrombocytopenia). There were 24 search results. Only one result reported on a case of lenalidomide-associated ITP. A separate search using Google Scholar was conducted, using the keywords (lenalidomide) and (ITP). There were 569 search results. There were two additional articles or abstracts that reported on cases of lenalidomide-associated ITP. A summary of the search results is shown in Figure 4.\n\n4. Discussion\nLenalidomide is a drug supported by national guidelines for the front-line management of plasma cell myeloma [11]. More recently, the U.S. Food and Drug Administration (FDA) approved the use of lenalidomide as maintenance therapy after auto-HSCT for patients with myeloma. The approval was based on evidence from two randomized, blinded trials of maintenance lenalidomide versus placebo [12]. One of its well-known toxicities has been reversible myelosuppression; however, there have only been rare reports of DITP from lenalidomide [8–10]. Our MEDLINE and Google Scholar search only identified three reports with a total of six cases of lenalidomide-associated ITP (summarized in Table 1).\n\nMost cases of DITP related to drugs other than lenalidomide have been associated with platelet recovery after stopping the drug. Improvement in platelet counts after removing exposure to the offending drug establishes drug dependence of the immune-mediated platelet destruction. Such cases, especially with recurrence of the thrombocytopenia upon re-exposure to the drug, can be considered definitive DITP by criteria proposed by George and others [6]; however, such criteria do not capture those few cases characterized by autoantibodies able to destroy platelets without depending upon the presence of the inciting drug. Such cases of DITP can be associated with ongoing thrombocytopenia that resembles primary ITP. Here, we reported a case of secondary ITP associated with lenalidomide exposure that persisted after stopping lenalidomide for several months, long after its biotransformation and rapid renal clearance. Our case suggests that lenalidomide may be able to induce persistent immune-mediated platelet destruction. While cases of thrombocytopenia resolution after discontinuation of lenalidomide have been reported, our case is consistent with the report of Pompa and colleagues [10]. They describe four cases of lenalidomide-associated ITP (Table 1). These cases were also associated with persistent thrombocytopenia or ITP-therapy dependence after discontinuation of lenalidomide. In one case, thrombocytopenia was successfully treated with steroids, but immune thrombocytopenia recurred after the patient resumed lenalidomide. In a case reported by Meguri and colleagues, a patient with lenalidomide-associated ITP also developed a rash and proteinuria (Table 1). The authors implicated a broader immunologic dysregulation as the underlying mechanism of lenalidomide-associated ITP [9].\n\nIn conclusion, lenalidomide may be an underrecognized cause of the autoantibody subtype of DITP resulting from the induction of nondrug-dependent autoantibody-mediated platelet destruction. As in primary ITP, our patient was successfully managed with IVIG and splenectomy. To our knowledge, this is the first case to report the successful treatment of lenalidomide-associated ITP with splenectomy. Our case, along with the other cases reported in the literature, suggests that the management of lenalidomide-associated ITP may require both drug discontinuation and therapies traditionally used in primary ITP. Splenectomy may be a successful approach to attain a durable response in patients who otherwise remain steroid-refractory or IVIG-dependent; however, it should be noted that thrombopoietin receptor agonists were not clinically available during that time and should be considered in recalcitrant cases. Our report and those of others should alert the clinician to this unusual mechanism of lenalidomide toxicity as this drug is currently being utilized in the treatment of an increasing number of malignant hematologic neoplasms.\n\nAcknowledgments\nThis work was supported by The Georgia Cancer Center of Augusta University.\n\nData Availability\nThe data used to support the findings of this study are included within the manuscript.\n\nConflicts of Interest\nThe authors declare no conflicts of interest.\n\nAuthors' Contributions\nP.D., W.F., and G.A. devised the study, collected data, and conducted the data analysis. W.F. drafted the manuscript. The manuscript was revised by P.D. and G.A. M.T. reviewed the pathology and provided pathology images. A.J. and P.D. provided the clinical care of the patient. All authors reviewed and approved the manuscript.\n\nFigure 1 Bone marrow biopsy (200x). The bone marrow is normocellular with adequate trilineage hematopoiesis and normal maturation. Several megakaryocytes are present.\n\nFigure 2 The platelet count and treatment history of the case.\n\nFigure 3 The spleen was 244.5 gm showing red pulp congestion, but no abnormal cell population. The perivascular white pulp is intact but attenuated.\n\nFigure 4 Literature search results, exclusion, and inclusion. A MEDLINE search for the keywords (lenalidomide) and (ITP) or (lenalidomide) and (immune thrombocytopenia) resulted in 24 results. 23 of these results were excluded, and 1 was assessed and included. Google Scholar was also searched using the keywords (lenalidomide) and (ITP). There were 569 results. 566 of these results were assessed and excluded as not related to lenalidomide and ITP. 3 of the 569 results were included in our report. Because one of the included Google Scholar results was a duplicate with the included MEDLINE, there were a total of 3 reports that were identified that those were case reports or case series of lenalidomide-associated ITP.\n\nTable 1 A comparison of the cases of lenalidomide-associated ITP reported in the literature along with our case.\n\n\tCase 1[10]\tCase 2 [10]\tCase 3 [10]\tCase 4 [10]\tCase 5 [8]\tCase 6 [9]\tOur case\t\nAge\t66\t76\t78\t66\t27\t74\t59\t\n\n\n\t\nSex\tF\tF\tF\tF\tM\tF\tM\t\n\n\n\t\nPlasma cell dyscrasia subtype\tIgGk MM\tIgGλ MM\tIgAλ amyloid\tMM (subtype not reported)\tMM (subtype not reported)\tLight chain λ MM\tIgGλ MM\t\n\n\n\t\nDose of len\t15 mg\t15 mg\t15 mg\t25 mg\t25 mg\t15 mg\t10 mg\t\n\n\n\t\nPrevious autologous bone marrow transplant\tNo\tNo\tNo\tNo\tYes\tNo\tYes\t\n\n\n\t\nCycle of lenalidomide before developing thrombocytopenia\t5\t3\t6\t3\tReceived consolidation × 4 VRD and maintenance lenalidomide × 3 months\t1\t1\t\n\n\n\t\nTreatment of ITP\tSteroids, IVIg, rituximab\tSteroids\tSteroids\tSteroids (prednisone)\tSteroids and IVIG\tSteroids\tSteroids, IVIg, rituximab, splenectomy\t\n\n\n\t\nPersistent thrombocytopenia after stopping lenalidomide\tYes\tYes, until steroids initiated. Responded to steroids at around 1 month after stopping lenalidomide\tYes, patient remained steroid-dependent\tYes\tNo, responded to steroid tapering\tNo, responded to steroid tapering\tYes, patient eventually obtained a long-term remission with splenectomy\t\n\n\n\t\nRetreatment with lenalidomide was associated with recurrence of thrombocytopenia\tYes\tRetreated, but no recurrent thrombocytopenia\tNot retreated\tNot retreated\tNot retreated\tNot retreated\tNot retreated\t\n\n\n\t\nOther manifestations\tNone reported\tNone reported\tNone reported\tNone reported\tAlopecia, leukopenia\tRash, proteinuria\tNone\n==== Refs\n1 Kashiwagi H. Tomiyama Y. Pathophysiology and management of primary immune thrombocytopenia International Journal of Hematology 2013 98 1 24 33 10.1007/s12185-013-1370-4 2-s2.0-84880263929 23702914 \n2 Schoonen W. M. Kucera G. Coalson J. Epidemiology of immune thrombocytopenic purpura in the general practice research database British Journal of Haematology 2009 145 2 235 244 10.1111/j.1365-2141.2009.07615.x 2-s2.0-63149096236 19245432 \n3 Moulis G. Palmaro A. Montastruc J.-L. Godeau B. Lapeyre-Mestre M. Sailler L. Epidemiology of incident immune thrombocytopenia: a nationwide population-based study in France Blood 2014 124 22 3308 3315 10.1182/blood-2014-05-578336 2-s2.0-84911926954 25305203 \n4 Cines D. B. Bussel J. B. Liebman H. A. Luning Prak E. T. The ITP syndrome: pathogenic and clinical diversity Blood 2009 113 26 6511 6521 10.1182/blood-2009-01-129155 2-s2.0-69249240344 19395674 \n5 Aster R. H. Curtis B. R. McFarland J. G. Bougie D. W. Drug-induced immune thrombocytopenia: pathogenesis, diagnosis, and management Journal of Thrombosis and Haemostasis 2009 7 6 911 918 10.1111/j.1538-7836.2009.03360.x 2-s2.0-65849492850 19344362 \n6 George J. N. Raskob G. E. Shah S. R. Drug-induced thrombocytopenia Annals of Internal Medicine 1998 129 11_Part_1 886 890 10.7326/0003-4819-129-11_part_1-199812010-00009 9867731 \n7 Aster R. H. Can drugs cause autoimmune thrombocytopenic purpura? Seminars in Hematology 2000 37 3 229 238 10.1016/s0037-1963(00)90101-x 2-s2.0-0033858040 10942217 \n8 Herold C. I. Gasparetto C. Arepally G. M. Lenalidomide-associated ITP Case Reports in Hematology 2011 2011 4 638020 10.1155/2011/638020 \n9 Meguri Y. Kamara Y. Yamamoto A. Masunari T. Sezaki N. Kiguchi T. Development of unexpected severe thrombocytopenia just after initiating lenalidomide: possible involvement of an immunologic mechanism International Journal of Myeloma 2018 8 1 1 3 \n10 Pompa A. Guidotti F. Gregorini A. I. Four cases of Lenalidomide-associated immune thrombocytopenia Blood 2016 128 22 p. 4927 10.1182/blood.v128.22.4927.4927 \n11 Kumar S. K. Management of multiple myeloma Journal of the National Comprehensive Cancer Network 2018 16 5S 624 627 10.6004/jnccn.2018.0040 2-s2.0-85048306630 29784741 \n12 Pulte E. D. Dmytrijuk A. Nie L. FDA approval summary: lenalidomide as maintenance therapy after autologous stem cell transplant in newly diagnosed multiple myeloma The Oncologist 2018 23 6 734 739 10.1634/theoncologist.2017-0440 2-s2.0-85041686853 29438096\n\n",
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"title": "Lenalidomide-Associated Immune Thrombocytopenia: A Case Report and Review of the Literature.",
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"abstract": "OBJECTIVE\nTo assess the efficacy of a financial incentive added to routine specialist pregnancy stop smoking services versus routine care to help pregnant smokers quit.\n\n\nMETHODS\nPhase II therapeutic exploratory single centre, individually randomised controlled parallel group superiority trial.\n\n\nMETHODS\nOne large health board area with a materially deprived, inner city population in the west of Scotland, United Kingdom.\n\n\nMETHODS\n612 self reported pregnant smokers in NHS Greater Glasgow and Clyde who were English speaking, at least 16 years of age, less than 24 weeks pregnant, and had an exhaled carbon monoxide breath test result of 7 ppm or more. 306 women were randomised to incentives and 306 to control.\n\n\nMETHODS\nThe control group received routine care, which was the offer of a face to face appointment to discuss smoking and cessation and, for those who attended and set a quit date, the offer of free nicotine replacement therapy for 10 weeks provided by pharmacy services, and four, weekly support phone calls. The intervention group received routine care plus the offer of up to £400 of shopping vouchers: £50 for attending a face to face appointment and setting a quit date; then another £50 if at four weeks' post-quit date exhaled carbon monoxide confirmed quitting; a further £100 was provided for continued validated abstinence of exhaled carbon monoxide after 12 weeks; a final £200 voucher was provided for validated abstinence of exhaled carbon monoxide at 34-38 weeks' gestation.\n\n\nMETHODS\nThe primary outcome was cotinine verified cessation at 34-38 weeks' gestation through saliva (<14.2 ng/mL) or urine (<44.7 ng/mL). Secondary outcomes included birth weight, engagement, and self reported quit at four weeks.\n\n\nRESULTS\nRecruitment was extended from 12 to 15 months to achieve the target sample size. Follow-up continued until September 2013. Of the 306 women randomised, three controls opted out soon after enrolment; these women did not want their data to be used, leaving 306 intervention and 303 control group participants in the intention to treat analysis. No harms of financial incentives were documented. Significantly more smokers in the incentives group than control group stopped smoking: 69 (22.5%) versus 26 (8.6%). The relative risk of not smoking at the end of pregnancy was 2.63 (95% confidence interval 1.73 to 4.01) P<0.001. The absolute risk difference was 14.0% (95% confidence interval 8.2% to 19.7%). The number needed to treat (where financial incentives need to be offered to achieve one extra quitter in late pregnancy) was 7.2 (95% confidence interval 5.1 to 12.2). The mean birth weight was 3140 g (SD 600 g) in the incentives group and 3120 (SD 590) g in the control group (P=0.67).\n\n\nCONCLUSIONS\nThis phase II randomised controlled trial provides substantial evidence for the efficacy of incentives for smoking cessation in pregnancy; as this was only a single centre trial, incentives should now be tested in different types of pregnancy cessation services and in different parts of the United Kingdom.\n\n\nBACKGROUND\nCurrent Controlled Trials ISRCTN87508788.",
"affiliations": "PEACH Unit, Child Health, Glasgow University, Yorkhill, Glasgow G3 8SJ, UK david.tappin@glasgow.ac.uk.;Institute for Social Marketing and UK Centre for Tobacco and Alcohol Studies, University of Stirling, Stirling, UK.;Strathclyde University, Glasgow, UK.;Health Economics and Health Technology Assessment Unit, Institute of Health and Wellbeing, Glasgow University, Glasgow, UK.;Institute for Social Marketing and UK Centre for Tobacco and Alcohol Studies, University of Stirling, Stirling, UK.;Institute for Social Marketing and UK Centre for Tobacco and Alcohol Studies, University of Stirling, Stirling, UK.;Institute for Social Marketing and UK Centre for Tobacco and Alcohol Studies, University of Stirling, Stirling, UK.;Public Health, NHS Greater Glasgow and Clyde, Glasgow, UK.;Robertson Centre for Biostatistics and Glasgow Clinical Trials Unit, Glasgow University, Glasgow, UK.;Public Health, NHS Greater Glasgow and Clyde, Glasgow, UK.;Glasgow Centre for Population Health, Glasgow, UK.;Directorate of Public Health, NHS Tayside, Dundee, UK.;Division of Primary Care and, UK Centre for Tobacco and Alcohol Studies, University of Nottingham, Nottingham, UK.",
"authors": "Tappin|David|D|;Bauld|Linda|L|;Purves|David|D|;Boyd|Kathleen|K|;Sinclair|Lesley|L|;MacAskill|Susan|S|;McKell|Jennifer|J|;Friel|Brenda|B|;McConnachie|Alex|A|;de Caestecker|Linda|L|;Tannahill|Carol|C|;Radley|Andrew|A|;Coleman|Tim|T|;|||",
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"mesh_terms": "D000293:Adolescent; D000328:Adult; D001724:Birth Weight; D001944:Breath Tests; D002248:Carbon Monoxide; D003367:Cotinine; D005260:Female; D006293:Health Promotion; D006801:Humans; D009042:Motivation; D011247:Pregnancy; D011295:Prenatal Care; D012201:Reward; D012463:Saliva; D012606:Scotland; D016540:Smoking Cessation; D055815:Young Adult",
"nlm_unique_id": "8900488",
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"pages": "h134",
"pmc": null,
"pmid": "25627664",
"pubdate": "2015-01-27",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Financial incentives for smoking cessation in pregnancy: randomised controlled trial.",
"title_normalized": "financial incentives for smoking cessation in pregnancy randomised controlled trial"
} | [
{
"companynumb": "GB-GLAXOSMITHKLINE-GB2015020201",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NICOTINE"
},
"drugadditional": null,
... |
{
"abstract": "The association of Cyclosporine A (CsA) and mycophenolate mofetil (MMF) has increased in the setting of reduced intensity conditioning (RIC). Nevertheless, the use of CsA or CsA+MMF has not been reported in a large and uniform cohort. We analyzed 497 patients with acute myeloid leukemia in complete remission (CR) who underwent matched unrelated donor (MUD) hematopoietic stem cell transplantation (HSCT). All patients received a fludarabine busulfan RIC regimen and anti-thymocyte globulin (ATG) with either CsA alone or in combination with MMF. The cumulative incidence (CI) of grade II-IV acute GvHD was 27% (95% CI 21-33%) for CsA and 33% (95% CI 27-38%) for CsA+MMF (p = 0.25). The 2-year CI of chronic GvHD was 38% (95% CI 31-45%) and 33% (95% CI 28-39%) for the CsA and the CsA+MMF group, respectively (p = 0.26). On multivariate analysis, no statistically significant differences with respect to relapse incidence (RI), non-relapse mortality (NRM), leukemia-free survival (LFS), overall survival (OS), acute and chronic GvHD were found between the two groups, also when conducting a subgroup analysis in peripheral blood stem cells (PBSC) recipients. Our results support the importance of randomized trial to identify patients who could benefit from the addition of MMF in MUD HSCT.",
"affiliations": "Sorbonne University, Service d'Hématologie Clinique et Thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, Paris, France. annalisa.paviglianiti@gmail.com.;Sorbonne University, Service d'Hématologie Clinique et Thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, Paris, France.;Programme de Transplantation & Thérapie Cellulaire, Centre de Recherche en Cancérologie de Marseille, Institut Paoli Calmettes, Marseille, France.;Hopital St. Louis, Department of Hematology - BMT, Paris, France.;CHU Grenoble Alpes - Université Grenoble Alpes, Service d'Hématologie, Grenoble, France.;Hopital de Hautepierre, CHU de Strasbourg, Service Hématologie adulte, F-67200, Strasbourg, France.;CHU Lapeyronie, Département d'Hématologie Clinique, Montpellier, France.;Charité Universitaetsmedizin Berlin, Campus Virchow Klinikum, Medizinische Klinik m. S. Hämatologie/Onkologie, Berlin, Germany.;C.H.R.U de Brest, Service Onco-Hematologie, Brest, France.;University Hospital Gasthuisberg, Department of Hematology, Leuven, Belgium.;CHU Nantes, Département d'Hématologie, Nantes, France.;CHU - Institut Universitaire du Cancer Toulouse, Oncopole, I.U.C.T-O, Toulouse, France.;CHRU Limoges Service d'Hématologie Clinique, Limoges, France.;Hopital Jean Minjoz, Service d'Hématologie, Besancon, France.;CHU Bordeaux, Service d'hematologie et thérapie Cellulaire, F-, 33000, Bordeaux, France.;Chaim Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Tel-Aviv, Israel.;Sorbonne University, Service d'Hématologie Clinique et Thérapie cellulaire, Hôpital Saint-Antoine, INSERM UMRs 938, Paris, France.",
"authors": "Paviglianiti|Annalisa|A|http://orcid.org/0000-0002-4243-9252;Labopin|Myriam|M|http://orcid.org/0000-0003-4514-4748;Blaise|Didier|D|http://orcid.org/0000-0002-5684-9447;Socié|Gerard|G|http://orcid.org/0000-0002-2114-7533;Bulabois|Claude Eric|CE|;Lioure|Bruno|B|;Ceballos|Patrice|P|;Blau|Igor Wolfgang|IW|;Guillerm|Gaelle|G|;Maertens|Johan|J|;Chevallier|Patrice|P|;Huynh|Anne|A|;Turlure|Pascal|P|;Deconinck|Eric|E|;Forcade|Edouard|E|http://orcid.org/0000-0002-8873-2868;Nagler|Arnon|A|http://orcid.org/0000-0002-0763-1265;Mohty|Mohamad|M|",
"chemical_list": "D065095:Calcineurin Inhibitors; D009173:Mycophenolic Acid",
"country": "England",
"delete": false,
"doi": "10.1038/s41409-020-01155-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-3369",
"issue": "56(5)",
"journal": "Bone marrow transplantation",
"keywords": null,
"medline_ta": "Bone Marrow Transplant",
"mesh_terms": "D065095:Calcineurin Inhibitors; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D009173:Mycophenolic Acid; D012189:Retrospective Studies; D019172:Transplantation Conditioning; D061349:Unrelated Donors",
"nlm_unique_id": "8702459",
"other_id": null,
"pages": "1077-1085",
"pmc": null,
"pmid": "33249424",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor-based graft-versus-host-disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia. A study from the ALWP of the EBMT.",
"title_normalized": "comparison of mycophenolate mofetil and calcineurin inhibitor versus calcineurin inhibitor based graft versus host disease prophylaxis for matched unrelated donor transplant in acute myeloid leukemia a study from the alwp of the ebmt"
} | [
{
"companynumb": "NVSC2020FR328208",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
... |
{
"abstract": "Inborn errors of metabolism (IEMs) are thought to present in infancy with acute decompensation including feeding intolerance and vomiting, lethargy, and coma. Most practitioners assume that children will be diagnosed in their first months of life. However, certain IEMs present more insidiously, and occasionally children fail to receive newborn screening resulting in delayed diagnoses, as metabolic and genetic disorders are overlooked causes of cognitive and neurologic deficits. Although signs and symptoms may be present but subtle, careful and detailed history taking, particularly of a child's diet and neurologic medical history, in addition to certain physical examination findings may suggest a diagnosis that is later supported by laboratory and radiographic testing. We present the case of an 11-year-old girl who presented with a diagnosis of cerebral palsy, seizure disorder, and concerns of fatigue and increasing seizure frequency. During hospitalization, she was found to have hyperammonemia, and a diagnosis of arginase deficiency was made. More thorough review of her previous records may have raised suspicion for IEM earlier.",
"affiliations": "From the Department of Pediatrics, Children's National Health System, Washington, DC. Electronic address: agropman@childrensnational.org.;Department of Neurology, Children's National Health System, Washington, DC.;Department of Radiology, Children's National Health System, Washington, DC.;Department of Neurology, Children's National Health System, Washington, DC.",
"authors": "Jichlinski|Amanda|A|;Clarke|Lindsay|L|;Whitehead|Matthew T|MT|;Gropman|Andrea|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.spen.2017.03.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1071-9091",
"issue": "26()",
"journal": "Seminars in pediatric neurology",
"keywords": null,
"medline_ta": "Semin Pediatr Neurol",
"mesh_terms": "D001921:Brain; D002547:Cerebral Palsy; D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D020162:Hyperargininemia",
"nlm_unique_id": "9441351",
"other_id": null,
"pages": "110-114",
"pmc": null,
"pmid": "29961498",
"pubdate": "2018-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "\"Cerebral Palsy\" in a Patient With Arginase Deficiency.",
"title_normalized": "cerebral palsy in a patient with arginase deficiency"
} | [
{
"companynumb": "US-PFIZER INC-2019021796",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": "3",
... |
{
"abstract": "Psoriasis is thought to result from an influx of Th1 and Th17 cells driven by the production of cytokines such as interferon (IFN)-gamma, IL-2, and tumor necrosis factor (TNF)-alpha elicited by skin immunocytes. We report three cases of patients with chronic plaque psoriasis and concomitant Down syndrome. Although there is no direct link between Down syndrome and the Th17 pathway, there are data supporting a dysregulation of the IFN system in this patient population. The percentage of Th1 lineage cells (IFN-gamma producing CD4+ and CD8+ T cells) is substantially higher in patients with Down syndrome and serum levels of IFN-gamma in patients with Down syndrome are significantly elevated when compared to healthy controls. We propose that people with Down syndrome have a greater prevalence of psoriasis secondary to both high serum levels of and an enhanced sensitivity to IFN-gamma.",
"affiliations": null,
"authors": "Marmon|Shana|S|;De Souza|Aieska|A|;Strober|Bruce E|BE|",
"chemical_list": "D007371:Interferon-gamma",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "18(6)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000293:Adolescent; D002648:Child; D004314:Down Syndrome; D006801:Humans; D007371:Interferon-gamma; D008297:Male; D011565:Psoriasis; D018417:Th1 Cells; D055815:Young Adult",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": "13",
"pmc": null,
"pmid": "22747937",
"pubdate": "2012-06-15",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Psoriasis and Down syndrome: a report of three cases and a potential pathophysiologic link.",
"title_normalized": "psoriasis and down syndrome a report of three cases and a potential pathophysiologic link"
} | [
{
"companynumb": "US-AMGEN-USASP2020193340",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETANERCEPT"
},
"drugadditional": "3",
... |
{
"abstract": "The aim was to analyze safety data associated with the maternal use of antiepileptic drugs in pregnancy and to assess the risk of cleft lip and/or palate (CL/P) as an outcome in the neonate. A parallel objective was to assess the completeness of the safety information concerning pregnancy exposures in the Summary of Product Characteristics (SmPCs) and the Patient Information (PI) in the USA and the UK.\n\n\n\nWe analyzed individual case safety reports of CL/P associated with antiepileptic drugs in the FDA Adverse Event Reporting System. For the antiepileptic drugs with signals (EB05 ≥ 2), we reviewed Drug Analysis Prints for CL/P cases in the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed descriptive analyses of relevant SmPCs and PIs in the UK and the USA using a checklist of recommendations collected from the literature.\n\n\n\nIn total 817 CL/P reports were identified for 12 antiepileptic drugs in the FDA Adverse Event Reporting System. Ten of the 12 antiepileptic drugs were associated with 156 CL/P cases in the MHRA Sentinel. Safety information concerning pregnancy was found to be more comprehensive in UK SmPCs than in the US equivalents.\n\n\n\nThere is statistical disproportionality in individual case safety reports indicative of an increased risk of CL/P with 12 antiepileptic drugs studied. More studies are required to explore the association between in utero exposure to antiepileptic drugs and the risk of CL/P. There are inconsistencies between the UK and US safety labels. CL/P associated with antiepileptic drugs is an important topic and requires providing inclusive, unbiased, up-to-date information to prescribers and women of childbearing age.",
"affiliations": "1 Department of Clinical Research, University of Basel, Basel, Switzerland.;2 Patient Safety, Novartis Global Drug Development, Novartis Pharma Basel, Switzerland.;4 Department of Cranio-Maxillofacial Surgery, University Hospital Basel, Basel, Switzerland.;4 Department of Cranio-Maxillofacial Surgery, University Hospital Basel, Basel, Switzerland.",
"authors": "Rezaallah|Bita|B|;Lewis|David John|DJ|;Zeilhofer|Hans-Florian|HF|;Berg|Britt-Isabelle|BI|0000-0002-4267-0761",
"chemical_list": "D000927:Anticonvulsants",
"country": "Switzerland",
"delete": false,
"doi": "10.1177/2168479018761638",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-4790",
"issue": "53(1)",
"journal": "Therapeutic innovation & regulatory science",
"keywords": "antiepileptic drugs; cleft lip and palate; labeling; patient information leaflets; pregnancy outcomes; prescribing information; safety signal detection",
"medline_ta": "Ther Innov Regul Sci",
"mesh_terms": "D016907:Adverse Drug Reaction Reporting Systems; D000927:Anticonvulsants; D002971:Cleft Lip; D002972:Cleft Palate; D005260:Female; D006282:Health Personnel; D006801:Humans; D007231:Infant, Newborn; D008431:Maternal-Fetal Exchange; D010361:Patients; D011247:Pregnancy; D011358:Product Surveillance, Postmarketing; D012306:Risk; D014481:United States; D014486:United States Food and Drug Administration",
"nlm_unique_id": "101597411",
"other_id": null,
"pages": "110-119",
"pmc": null,
"pmid": "29714593",
"pubdate": "2019-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of Cleft Lip and/or Palate Associated With Antiepileptic Drugs: Postmarketing Safety Signal Detection and Evaluation of Information Presented to Prescribers and Patients.",
"title_normalized": "risk of cleft lip and or palate associated with antiepileptic drugs postmarketing safety signal detection and evaluation of information presented to prescribers and patients"
} | [
{
"companynumb": "CH-JNJFOC-20190229611",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nTo alert clinicians of the possibility of reversible drug-induced occult hypotony and choroidal effusion following the long-term use of pergolide.\n\n\nMETHODS\nAnnotations were made while the case was observed. The clinical records of the patient were reviewed retrospectively.\n\n\nRESULTS\nA 74-year-old Caucasian male with primary open-angle glaucoma presenting with reduced vision in both eyes and an inflamed right eye. Examination revealed bilateral hypotony, right anterior chamber inflammation, and right choroidal effusion. The right intraocular inflammation resolved completely after a short course of topical and oral antibiotics in addition to topical steroids. Nevertheless, the bilateral hypotony and right choroidal effusion persisted. Only the discontinuation of pergolide allowed the complete resolution of the patient's presenting symptoms and signs.\n\n\nCONCLUSIONS\nPergolide is known to cause pericardial and pleural effusion, and generalized oedema. However, its association with choroidal effusion and hypotony has never been reported.",
"affiliations": "a Birmingham & Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust , Birmingham , UK .;a Birmingham & Midland Eye Centre, Sandwell and West Birmingham Hospitals NHS Trust , Birmingham , UK .",
"authors": "Andreatta|Walter|W|;Shah|Peter|P|",
"chemical_list": "D018491:Dopamine Agonists; D010479:Pergolide",
"country": "England",
"delete": false,
"doi": "10.3109/08820538.2013.849271",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0882-0538",
"issue": "30(5-6)",
"journal": "Seminars in ophthalmology",
"keywords": "Choroidal effusion; Parkinson’s disease; glaucoma; hypotony; pergolide",
"medline_ta": "Semin Ophthalmol",
"mesh_terms": "D000368:Aged; D015862:Choroid Diseases; D018491:Dopamine Agonists; D005902:Glaucoma, Open-Angle; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D015814:Ocular Hypotension; D010300:Parkinson Disease; D010479:Pergolide; D014463:Ultrasonography",
"nlm_unique_id": "8610759",
"other_id": null,
"pages": "423-5",
"pmc": null,
"pmid": "24251433",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reversible Hypotony and Choroidal Effusion Following the Use of Pergolide for Parkinson's Disease.",
"title_normalized": "reversible hypotony and choroidal effusion following the use of pergolide for parkinson s disease"
} | [
{
"companynumb": "GB-TEVA-633267ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BENSERAZIDE"
},
"drugadditional": null,
"dr... |
{
"abstract": "A diabetic foot ulcer (DFU) is one of the major diabetes complications that may lead to limb amputation. Amputation can have profound physical and psychological effects on an individual's life. Nowadays, the prevention of limb amputation and treatment of DFUs are known as the major health challenges.\n\n\nMETHODS\nThe present case report is of a 72-year-old woman with a 20-year history of type 2 diabetes who has had asymmetrical and superficial DFUs with sizes of 6 × 5 cm and 3 × 3 cm on the heel and the sole of the right foot, respectively. The ulcers were infected by S. aureus and E. coli. The patient had been hospitalized several times for receiving treatment, and not only the ulcers had not been healed, but also they had considerably extended so that the risk of foot amputation had been greatly increased. The patient was transferred to our wound care service. After conducting one session of surgical debridement, the patient underwent ten sessions of maggot therapy (one session every two days) using sterile Lucilia sericata. After about six months, the patient's DFUs were completely healed.\nDFU can affect a patient's quality of life and lead to infection, sepsis, amputation, and even patient death. Therefore, using effective treatment approaches is very important for the management of DFUs.\n\n\nCONCLUSIONS\nThe combined use of surgical debridement and maggot therapy is a safe and effective method for improving diabetic foot ulcers and preventing amputation.",
"affiliations": "Imam Khomeini Teaching Hospital, Urmia University of Medical Sciences, Urmia, Iran.;Patient Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran.;Department of Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran.;Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran. Electronic address: Rasoulgoli94@gmail.com.",
"authors": "Hajimohammadi|Kazem|K|;Parizad|Naser|N|;Hassanpour|Amireh|A|;Goli|Rasoul|R|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2021.106334",
"fulltext": "\n==== Front\nInt J Surg Case Rep\nInt J Surg Case Rep\nInternational Journal of Surgery Case Reports\n2210-2612\nElsevier\n\nS2210-2612(21)00836-1\n10.1016/j.ijscr.2021.106334\n106334\nCase Report\nSaving diabetic foot ulcers from amputation by surgical debridement and maggot therapy: A case report\nHajimohammadi Kazem a1\nParizad Naser b2\nHassanpour Amireh c2\nGoli Rasoul Rasoulgoli94@gmail.com\nGoli.r@umsu.ac.ir\nd⁎\na Imam Khomeini Teaching Hospital, Urmia University of Medical Sciences, Urmia, Iran\nb Patient Safety Research Center, Urmia University of Medical Sciences, Urmia, Iran\nc Department of Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran\nd Department of Medical-Surgical Nursing, School of Nursing and Midwifery, Urmia University of Medical Sciences, Urmia, Iran\n⁎ Corresponding author at: Nursing and Midwifery Faculty, Campus Nazlu, 11 KM Road Seru, Urmia, West Azerbaijan 575611-5111, Iran. Rasoulgoli94@gmail.comGoli.r@umsu.ac.ir\n1 Imam Khomeini University Hospital-Ershad Ave-Modarres Blvd, Urmia, West Azerbaijan, Iran.\n\n2 Nursing and Midwifery Faculty, Campus Nazlu, 11 KM Road Seru, Urmia, West Azerbaijan, Iran, Postal Code: 575611-5111.\n\n25 8 2021\n9 2021\n25 8 2021\n86 10633411 7 2021\n19 8 2021\n21 8 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 and importance\n\nA diabetic foot ulcer (DFU) is one of the major diabetes complications that may lead to limb amputation. Amputation can have profound physical and psychological effects on an individual's life. Nowadays, the prevention of limb amputation and treatment of DFUs are known as the major health challenges.\n\nCase presentation\n\nThe present case report is of a 72-year-old woman with a 20-year history of type 2 diabetes who has had asymmetrical and superficial DFUs with sizes of 6 × 5 cm and 3 × 3 cm on the heel and the sole of the right foot, respectively. The ulcers were infected by S. aureus and E. coli. The patient had been hospitalized several times for receiving treatment, and not only the ulcers had not been healed, but also they had considerably extended so that the risk of foot amputation had been greatly increased. The patient was transferred to our wound care service. After conducting one session of surgical debridement, the patient underwent ten sessions of maggot therapy (one session every two days) using sterile Lucilia sericata. After about six months, the patient's DFUs were completely healed.\n\nClinical discussion\n\nDFU can affect a patient's quality of life and lead to infection, sepsis, amputation, and even patient death. Therefore, using effective treatment approaches is very important for the management of DFUs.\n\nConclusion\n\nThe combined use of surgical debridement and maggot therapy is a safe and effective method for improving diabetic foot ulcers and preventing amputation.\n\nHighlights\n\n• DFUs can lead to infection, sepsis, and limb amputation.\n\n• Effective treatment approaches is important for the management of DFUs.\n\n• Surgical debridement and maggot therapy are effective method for repairing DFUs.\n\nKeywords\n\nDiabetic foot\nLarva\nDebridement\nAmputation\nCase report\n==== Body\npmc1 Introduction\n\nOne of the most serious and costly complications of diabetes is the refractory and non-healing diabetic foot ulcer (DFU) [1]. DFU can lead to infection, gangrene, necrosis, and skin defects in all layers from the distal to proximal areas of the body [2]. DFU can be caused by a defective healing process resulting from intrinsic (neuropathy, vascular disorders, and other systemic effects of diabetes) and extrinsic factors (wound infection, callus formation, and high-pressure injection) [3]. Approximately 20% of patients with diabetes refer to the medical centers with the chief complaint of DFU [2]. It is estimated that about 15–34% of patients with diabetes suffer from DFU, 20% of moderate to severe forms of which may eventually lead to foot amputation [1], [4]. Over the last decade, the yearly rate of DFU-related amputation has increased from 1.5 to 3.5 cases per 1000 patients with diabetes [3]. Lower limb amputation can lead to disability, increased length of hospital stay, and premature death [5].\n\nThere are many conventional and modern methods for managing DFUs and preventing amputation, including antibiotic therapy, necrotic tissue debridement, wound dressing, Negative Pressure Wound Therapy (NPWT), Hyperbaric Oxygen Therapy (HBOT), stem cell-based therapy, growth factor therapy, and Maggot Debridement Therapy (MDT) [6], [7]. The single use of different methods may not be considerably efficient and cause pain and mechanical damage to healthy underlying tissues [3]. In this regard, MDT is an effective method for treating DFUs and preventing foot amputation in patients with diabetes [8].\n\nMDT, also known as larval therapy, refers to the medical use of fly larvae (under sterile conditions) to treat refractory DFUs [9]. The main mechanism of MDT is to reduce the bacterial burden of the infection site through the digestion of bacteria, production of antibacterial secretions, and destruction of biofilms [10]. The effectiveness of Lucilia sericata larvae has been proven as an influential factor in MDT, disinfection, and improvement of DFU healing processes [3]. Following the successful use of MDT in various countries, especially the United States and Europe, the United States Food and Drug Administration (FDA) has approved the medical use of Lucilia sericata larvae [11].\n\nRefractory DFUs do not readily respond to standard pharmacological therapies, and the prevention of DFU-related amputation is of paramount importance since limb amputation can have a significant impact on an individual's life [5], [10]. This case report is of a female patient with DFUs who was a candidate for amputation, although she recovered using surgical debridement and MDT.\n\n2 Case presentation\n\nThe patient was a 72-year-old woman from the Armenian minority living in Urmia city who had a 20-year history of type 2 diabetes, which led to the formation of DFUs on the heel and sole of her right foot four years ago. The patient was from a family with low socioeconomic status and only had primary education. She has also been sewing in a workshop for 25 years. She had uncontrolled diabetes and also reported a history of hypertension on physical examinations. To control her blood sugar level, she had undergone a pharmacological treatment with metformin 500 mg tablet three times a day (TDS). In addition, Losartan 40 mg tablet had been prescribed for her hypertension twice a day (BID). The patient had a family history of diabetes and hypertension. She denied any history of drug or alcohol abuse, although she smoked a pack of cigarettes a day. No pathological findings were indicated on neurological examinations. Despite that the patient had been hospitalized several times for receiving DFU treatment, she had not recovered. This case report was reported according to the SCARE 2020 Guidelines to ensure the quality of reporting. [12].\n\nThe patient had referred to Imam Reza Hospital in Urmia, Iran on 24 July 2020 with a chief complaint of persistent fever and vomiting. The patient was admitted with a diagnosis of sepsis caused by a DFU infection. Upon arrival to the emergency department, the patient's vital signs were as following: 39.2 °C, Respiration Rate: 18 bpm, Pulse Rate: 112 bpm, Blood Pressure: 150/95 mmHg. The patient had asymmetrical and superficial DFUs with sizes of 6 × 5 cm and 3 × 3 cm on the heel and the sole of the right foot, respectively (Fig. 1). Moreover, some of the patient's laboratory data on admission are presented in Table 1.Fig. 1 Patient's DFUs before the beginning of MDT.\n\nFig. 1\n\nTable 1 Patient's laboratory data on admission.\n\nTable 1Urine analysis (UA)\tCell blood count (CBC)\tBiochemistry\t\nColor: yellow\tWBC: 22500 uL\tBUN: 14.8 mg/dl\t\nAppearance: semi-clear\tRBC: 4240000 uL\tCreatinine: 0.9 mg/dl\t\nPH: 5\tHGB: 10.2 g/dl\tUrea: 40.9 mg/dl\t\nSpecific gravity: 1013\tHCT: 32.9%\tCalcium: 8.70 mg/dl\t\nProtein: negative\tMCV: 77.6 fL\tPhosphorous: 4.9 mg/dl\t\nSugar: negative\tMCH: 24.1 pg\tSodium: 130 mEq/dl\t\nBlood: negative\tMCHC: 31 g/dl\tPotassium: 3.9 mEq/dl\t\nUrobilinogen: negative\tPLT: 548000 uL\tBlood sugar: 644 mg/dl\t\nKetone: negative\tNeutrophils 92.2%\tLDL: 288 mg/dl\t\nCast: not seen\tLymphocytes 6.5%\tHDL: 37 mg/dl\t\nBacteria: few\tESR 1 h 120 mm/h\tCholesterol: 195 mg/dl\t\nWBC: 3–5\tSerology\tTriglycerides: 130 mg/dl\t\nRBC: 0–1\tCRP: positive(+3)\tHemoglobinA1C: 7.5%\t\n\nThe culture antibiogram obtained from DFUs showed drug resistance to S. aureus and E. coli (Table 2). The patient received intravenous (IV) antibiotics, including Meropenem 1 g TDS, Clindamycin 600 mg BID, and Vancomycin 1 g BID. Furthermore, the patient's blood sugar level was checked using a glucometer every 6 h, and the insulin administration protocol was performed using regular insulin. In addition, the levels of blood glucose were also controlled using Neutral Protamine Hagedorn (NPH) insulin (subcutaneous injection of 16 units in the morning and 8 units in the evening).Table 2 The results of the patient's wound culture.\n\nTable 2Wound culture\tResults\t\nCulture\tStaphylococcus aureus\t\nSensitive\tImipenem - Meropenem - Ceftriaxone\t\nResistant\tTrimethoprim-Sulfamethoxazole\t\nIntermediate\tClindamycin - Ciprofloxacin\t\nWBC\t3–5\t\nRBC\t2–3\t\nBacteria\tModerate\t\n\nThe osteomyelitis was examined in the patient's right leg by Color Doppler Imaging (CDI) and Magnetic Resonance Imaging (MRI). The findings of CDI showed no signs of Deep Vein Thrombosis (DVT) in the right lower limb. However, imaging examination of the right lower limb showed numerous small and calcified atheroma that had led to multiple arterial stenoses. The findings of the MRI were as follows:“Soft tissue swelling was se en at the dorsal and plantar aspect of the foot. There is an abnormal sign (bone marrow edema) associated with adjacent soft tissue swelling in the cuboid, talus, navicular, calcaneus, and phalanges of 2ndfinger.”\n\nUnfortunately, the patient did not recover from DFU using conventional methods, although she received treatments including antibiotic therapy and normal saline dressing (TDS). The patient was asked for orthopedic consultation, based upon which she became a candidate for right foot amputation. The patient withheld consent to the amputation and was then referred to our wound care service. Moreover, the patient was bedridden at this stage.\n\nConcerning the presence of necrotic and infectious tissue, surgical debridement of DFUs was initially performed by a surgeon on 18 August 2020. Infected living and non-living tissues were isolated from the wound bed. This action causes the release of Platelet-Derived Growth Factors (PDGFs), which can improve wound healing and provide a suitable environment for it. PDGF begins inflammatory reaction by stimulating chemotaxis and mitogenicity abilities of macrophages, neutrophils, fibroblasts, and smooth muscle cells to the site of the wound [13]. Then the larvae of L. sericata were prepared under sterile condition, and the patient underwent MDT. These larvae consume dead tissue and bacteria at the wound site and secrete antimicrobial enzymes that improve wound healing. MDT was performed in four stages of wound preparation, applying larvae to the wound, hydrocolloid dressing, and removing larvae after 48 h (Fig. 2). Wound preparation was done by placing the surgical drape on the patient's wound and irrigating it with physiological saline. At each phase of the intervention, the patient was inquired a query about tolerating the maggot therapy and continuing the intervention every twenty minutes. If the response was “yes,” the intervention was continued, but if the response was “no,” the intervention was stopped. Overall, ten sessions of MDT were conducted (one session every 48 h). The procedures were performed by a nurse (first author) who was trained and certified in this field. Furthermore, after the completion of MDT sessions, the patient's DFUs were re-stimulated using mechanical debridement and normal saline, so that all the dead tissues were removed again and the granulation tissues appeared (Fig. 3). The patient's DFUs had partially healed on 16 October 2020 (Fig. 4) and closed three months after the intervention. After treatments were done with MDT in 3 weeks, the silver-containing dressing was applied to the wound by a trained nurse for five months to make granulation tissue grow faster and promote the healing process. The patient was discharged from our wound care service with a good general health condition (Fig. 5). Before discharging the patient, she was instructed to avoid placing excessive pressure on the tissue and be on a crutch or wheelchair until the completion of recovery. Offloading is important for DFU healing. Moreover, the patient was educated about the complications of the procedures after the intervention and their warning signs, and how to manage them. No adverse effects were presented during or after therapeutic intervention. The patient's DFUs healed completely after about six months (Fig. 6) and the patient declared that “I am scared of losing my leg, but I have completely recovered with the proper therapeutic procedure.”Fig. 2 The application of MDT for repairing the patient's DFUs.\n\nFig. 2\n\nFig. 3 The patient's DFUs after the completion of MDT sessions.\n\nFig. 3\n\nFig. 4 The patient's DFUs one month after the intervention.\n\nFig. 4\n\nFig. 5 The patient's DFUs three months after the intervention.\n\nFig. 5\n\nFig. 6 The patient's DFUs six months after the intervention.\n\nFig. 6\n\n3 Discussion\n\nSevere DFU can affect a patient's quality of life and lead to infection, sepsis, amputation, and even patient death. Therefore, using effective treatment approaches is very important for the management of DFUs [2]. Nowadays, regarding the emergence of antibiotic-resistant bacteria, many physicians have turned their attention to the use of maggot therapy [14]. The FDA approved the use of this method for medical purposes in 2004 [11]. MDT is also applied to treat health conditions, including other types of diabetic ulcers, bedsores, burns, carbuncles, abscesses, and boils where other treatment methods are not advantageous [9]. MDT is a very simple and relatively cost-effective treatment approach so that, unlike antibiotic therapy, it causes no dangerous side effects. However, some patients may encounter itchy skin, such that something crawls on the skin. Regarding the stimulation of the nervous system resulting from larvae distension, some patients may experience different levels of pain, which can be relieved by removing the larvae at the right time or using medication. Anxiety is another complication caused by MDT. Therefore, it is very important to psychologically prepare the patient before the procedure begins [15]. MDT can be easily performed by trained healthcare professionals, even without the need for hospitalization.\n\nThe present case report was of a female patient who had a 20-year history of uncontrolled type 2 diabetes, which had led to the formation of DFUs. The patient had a poor general health condition, and her DFUs were not treated using routine hospital treatment methods (IV antibiotic therapy and normal saline dressing) so that she was at a considerable risk of foot amputation.\n\nGiven that the patient was from strata with low socioeconomic status and had no underlying disease other than hypertension and that there was no evidence of osteomyelitis, she was found to be very susceptible to the implementation of MDT. In this study, necrotic tissues were first removed surgically using a new approach, and a suitable environment was then provided for wound healing. After conducting surgical debridement, ten sessions of MDT were performed (one session every 48 h) using sterile L. sericata. The patient's DFUs miraculously healed after about six months, and the patient was also discharged from our wound care service with a good general health condition.\n\nIn line with our study results, Parizad et al. showed that the combined use of MDT, surgical debridement, silver dressing, and NPWT is very effective in treating refractory DFUs [16]. In a clinical trial, Malekian et al. concluded that MDT using sterile maggots of L. sericata is a safe and effective method for treating the DFUs infected with Staphylococcus aureus and Pseudomonas aeruginosa [10], which is consistent with our results. Siavash et al. and Dehghan et al. also revealed that MDT, as a new treatment approach, is effective in treating atypical DFUs that are refractory to conventional therapies [17], [3]. In line with the results of our study, Mirabzadeh et al. showed the MDT as an acceptable and easy-to-use method for the treatment of complicated and extensive DFUs [18]. Most studies in this area have demonstrated the effectiveness of MDT in improving DFUs. However, the findings of this case report boldly indicated that MDT could be also utilized in patients who have complicated and non-healing DFU and are candidates for foot amputation.\n\n4 Conclusion\n\nFoot amputation causes irreparable damage to the patient's performance and quality of life. Therefore, new and effective treatment methods are required to prevent foot amputation. This case report study was shown that the combined use of surgical debridement and MDT is a safe and effective approach to improve the healing of DFUs and prevent foot amputation. Consequently, wound care teams are recommended to use this method to accelerate the healing process and prevent foot amputation.\n\nSources of funding\n\nNone.\n\nEthical approval\n\nIt was waived because it's a case report according to the policies of the affiliated University institutional review committee.\n\nConsent\n\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthors' contributions\n\nRasoul Goli: Study concept, data collection, writing the paper and making the revision of the manuscript following the reviewer's instructions. Naser Parizad: Study concept, reviewing and validating the manuscript's credibility. Kazem Hajimohammadi and Amireh Hassanpour: reviewing and validating the manuscript's credibility.\n\nResearch registration\n\nNot applicable.\n\nGuarantor\n\nRasoul Goli.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nNone.\n==== Refs\nReferences\n\n1 Armstrong D.G. Boulton A.J. Bus S.A. Diabetic foot ulcers and their recurrence N. Engl. J. Med. 376 24 Jun 15 2017 2367 2375 10.1056/NEJMra1615439 28614678\n2 Alsanawi Y. Alismail H. Alabd Rabalnabi M. Alturki H. Alsuhaibani A. Mahbub M. Pathogenesis and management of diabetic foot ulcers Int. J. Commun. Med. Public Health 5 11 2018 Nov 4953\n3 Dehghan O. Mehdi T.S. Rafinejad J. Toutonnchy M. Tiyuri A. Akbarzadeh K. A new approach to maggot therapy for healing of diabetic foot ulcers Acta Fac. Med. Naissensis 37 4 2020 387 395 10.5937/afmnai2004387D\n4 Hurlow J.J. Humphreys G.J. Bowling F.L. McBain A.J. Diabetic foot infection: a critical complication Int. Wound J. 15 5 2018 Oct 814 821 10.1111/iwj.12932 29808598\n5 Hoffstad O. Mitra N. Walsh J. Margolis D.J. Diabetes, lower-extremity amputation, and death Diabetes Care 38 10 2015 Oct 1 1852 1857 10.2337/dc15-0536 26203063\n6 Hajmohammadi K. Zabihi R.E. Akbarzadeh K. Parizad N. Using a combination therapy to combat scalp necrosis: a case report J. Med. Case Rep. 14 1 2020 1 5 10.1186/s13256-020-02450-5 31900197\n7 Baltzis D. Eleftheriadou I. Veves A. Pathogenesis and treatment of impaired wound healing in diabetes mellitus: new insights Adv. Ther. 31 8 2014 817 836 10.1007/s12325-014-0140-x 25069580\n8 Nishijima A. Yamamoto N. Yoshida R. Yanagibayashi S. Takikawa M. Hayasaka R. Maggot debridement therapy with a direct dressing can cause compression injuries in patients with chronic limb ischemia Case Rep. Plast. Surg. Hand Surg. 4 1 2017 Jan 1 84 88 10.1080/23320885.2017.1373596\n9 Stadler F. The maggot therapy supply chain: a review of the literature and practice Med. Vet. Entomol. 34 1 2020 1 9 10.1111/mve.12397 31350920\n10 Malekian A. Djavid G.E. Akbarzadeh K. Soltandallal M. Rassi Y. Rafinejad J. Efficacy of maggot therapy on staphylococcus aureus and pseudomonas aeruginosa in diabetic foot ulcers: a randomized controlled trial J. Wound Ostomy Cont. Nurs. 46 1 2019 25 29 10.1097/WON.0000000000000496\n11 Food and Drug Administration (2007) 510(k) Summary. Monarch Labs LLC. FDA. https://www.accessdata.fda.gov/cdrh_docs/pdf7/ K072438.pdf [accessed on d Month 2019].\n12 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Thoma A. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 1 84 2020 Dec 226 230 10.1016/j.ijsu.2020.10.034\n13 Zarei F. Soleimaninejad M. Role of growth factors and biomaterials in wound healing Artif. Cells Nanomed. Biotechnol. 46 sup1 2018 Oct 31 906 911 10.1080/21691401.2018.1439836 29448839\n14 King C. Changing attitudes toward maggot debridement therapy in wound treatment: a review and discussion J. Wound Care 29 Sup2c 2020 Feb 1 S28 S34 10.12968/jowc.2020.29.Sup2c.S28\n15 Naik G. Harding K.G. Maggot debridement therapy: the current perspectives Chronic Wound Care Manag. Res. 3 4 2017 Oct 121 128 10.2147/CWCMR.S117271\n16 Parizad N. Hajimohammadi K. Goli R. Surgical debridement, maggot therapy, negative pressure wound therapy, and silver foam dressing revive hope for patients with diabetic foot ulcer: a case report Int. J. Surg. Case Rep. 29 2021 Apr 105931 10.1016/j.ijscr.2021.105931\n17 Siavash M. Najjarnezhad A. Mohseni N. Abtahi S.M. Karimy A. Sabzevari M.H. Efficacy of maggot debridement therapy on refractory atypical diabetic foot ulcers: an open-label study Int. J. Low Extrem Wounds 5 2020 May 1534734620920403 10.1177/1534734620920403\n18 Mirabzadeh A. Ladani M.J. Imani B. Rosen S.A. Sherman R.A. Maggot therapy for wound care in Iran: a case series of the first 28 patients J. Wound Care 26 3 2017 Mar 2 137 143 10.12968/jowc.2017.26.3.137 28277993\n\n",
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"abstract": "Pleural effusion, as a side effect of tyrosine kinases, may be seen as most commonly associated with dasatinib and very rarely seen with nilotinib. In this report we present a chronic phase of CML case that was treated with nilotinib due to imatinib (Gleevec) allergy and had pleural effusion with nilotinib at 5th year of treatment. If pleural effusion develops in patients taking nilotinib and if this effusion is exudative and lymphocyte predominant, after ruling out pulmonary and cardiac etiologies, it must be associated with nilotinib; according to stage of effusion drug should be discontinued and/or steroid should be started and/or surgery should be performed.",
"affiliations": "Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.;Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.;Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.;Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.;Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.;Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey.",
"authors": "Usküdar Teke|Hava|H|;Akay|Olga Meltem|OM|;Gören Şahin|Deniz|D|;Karagülle|Mustafa|M|;Gündüz|Eren|E|;Andıç|Neslihan|N|",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2014/203939Case ReportPleural Effusion: A Rare Side Effect of Nilotinib—A Case Report Üsküdar Teke Hava *Akay Olga Meltem Gören Şahin Deniz Karagülle Mustafa Gündüz Eren Andıç Neslihan Hematology, Medical Faculty, Eskişehir Osmangazi University, 26090 Eskişehir, Turkey*Hava Üsküdar Teke: havaus@yahoo.comAcademic Editor: Werner Rabitsch\n\n2014 9 9 2014 2014 2039398 6 2014 24 8 2014 25 8 2014 Copyright © 2014 Hava Üsküdar Teke et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Pleural effusion, as a side effect of tyrosine kinases, may be seen as most commonly associated with dasatinib and very rarely seen with nilotinib. In this report we present a chronic phase of CML case that was treated with nilotinib due to imatinib (Gleevec) allergy and had pleural effusion with nilotinib at 5th year of treatment. If pleural effusion develops in patients taking nilotinib and if this effusion is exudative and lymphocyte predominant, after ruling out pulmonary and cardiac etiologies, it must be associated with nilotinib; according to stage of effusion drug should be discontinued and/or steroid should be started and/or surgery should be performed.\n==== Body\n1. Introduction\nChronic myeloid leukemia (CML) is a chronic myeloproliferative disease characterized by tyrosine kinase activity caused by translocation between chromosomes 9 and 22 [1]. Oral medications for CML include tyrosine kinase inhibitors as imatinib, dasatinib, and nilotinib. The incidence of dasatinib related pleural effusion is about 7–35% [2]. While pleural effusions are seen less often with imatinib, those seen with nilotinib are very rare (<1%) [3].\n\nIn this report, we present a chronic phase of CML case that was treated with nilotinib due to imatinib (Gleevec) allergy and had pleural effusion with nilotinib at 5th year of treatment.\n\n2. Case\nA 68-year-old male patient presented to emergency department with complaints of high fever, in April 2008. The only pathological finding in physical examination was presence of palpable spleen 2 cm below costal margin. Blood analysis showed Hb 11 g/dL, hematocrit 30.2%, white blood cell count 126800/mm3, absolute neutrophil count (ANC) 93800/mm3, platelets 672000/mm3, and C-reactive protein 1.15 mg/dL (0 to 0.8). In biochemical analysis, lactate dehydrogenase (LDH) was found as 1164 U/L apart from other biochemical parameters, which were within normal limits. In peripheral blood smear immature granulocytes, basophilia and eosinophilia were observed. In bone marrow aspiration, increased myeloid cells and myeloid/erythroid ratio of 50–60/1 were found. Cytogenetic and PCR analyses showed the presence of Philadelphia chromosome. Calculated Sokal risk score was 0.98 (intermediate). Imatinib mesylate 400 mg/day was started. After 1 month of Gleevec treatment, patient presented with swelling and burning sensation in his eyes and itchy red lesions on arms and legs. Imatinib mesylate treatment was discontinued due to skin rashes and dexamethasone treatment was started. Lesions disappeared and treatment was continued with nilotinib. Patient was free of Ph chromosome in cytogenetic analysis of bone marrow and had major molecular response in PCR during nilotinib treatment. Then he admitted with dyspnea limiting daily activities. Physical examination revealed normal vital findings, O2 saturation of 95%, and absence of respiratory sounds at basal and middle zones of right lung. The complete blood count showed Hb of 11.4 g/dL, WBC of 6.7 × 103/μL, and platelet count of 327 × 103/μL. Presence of pleural effusion was found in chest X-ray (Figure 1(a)). The patient was hospitalized and nilotinib treatment was discontinued. Viral markers for hepatitis, cytomegalovirus, and HIV were negative. Catheter thoracostomy was performed (Figure 1(b)). Analysis of pleural fluid was exudative and lymphocyte predominant (400/μL [98%]). Cytology of pleural fluid was also negative for malignancy. Thorax tomography was performed (Figure 1(c)) and pulmonary thromboembolism was ruled out. Because of the exudative effusion, findings of a suspicious mass appearance in chest X-ray, and pleural thickening in thorax tomography, he was operated on by thoracic surgery with preliminary diagnosis of pulmonary malignancy. Total decortication and intercostal blockage were performed. Cytology and pathology results were negative for malignancy. After exclusion of pulmonary and cardiac etiologies, clinic picture of the patient was attributed to nilotinib and treatment with diuretic and methylprednisolone 32 mg/day was started. Approximately 1.5–2 months after steroid treatment pleural effusion almost completely regressed, nilotinib 2 × 200 mg/day was started again and steroid treatment was gradually discontinued. After complete disappearance of pleural effusion (Figure 1(d)) nilotinib dose was increased to 2 × 400 mg/day.\n\n3. Discussion\n2nd generation tyrosine kinase inhibitors, dasatinib and nilotinib, were used in the treatment of imatinib intolerant or resistant CML patients [4]. In our patient due to imatinib related skin reactions, he was regarded as imatinib intolerant and treatment was switched to nilotinib. The frequency of dasatinib related pleural effusion is more than that of nilotinib. Dasatinib related pleural effusion risk was found increased in CML patients with previous cardiac problems and hypertension and receiving dasatinib twice daily instead of one [5]. Although the mechanism of dasatinib related pleural effusion is not fully understood, it is thought to be associated with PDGFRβ inhibition [6]. Nilotinib is a second generation tyrosine kinase inhibitor, inhibiting KIT and PDGFR besides ABL. It is 30 times more potent than imatinib to Bcr-Abl. When nilotinib is compared with imatinib and dasatinib, its selectivity to ABL is more than that to KIT and PDGFR. Its significantly low selectivity to PDGFR explains why nilotinib related pleural effusion is seen less than 1% [4, 7]. Analysis of clinical studies suggests that cross-intolerance to nilotinib is rare in imatinib intolerant patients [4]. Our patient is one of the rare cases that developed nilotinib related pleural effusion. Because of imatinib intolerance presenting with skin reactions, his treatment had been switched to nilotinib. He developed nilotinib related pleural effusion after 5 years of treatment.\n\nIn case of pleural effusion caused by tyrosine kinase inhibitors, treatment should be performed according to degree of effusion. When an asymptomatic patient with effusion is detected, they must be closely monitored without interrupting treatment [8]. If grade 2 or 3 symptomatic pleural effusion is present, discontinuing tyrosine kinase inhibitors may provide a response to treatment. If symptoms are severe, resolution can be achieved in 72 hours with prednisone 40 mg/day [5]. Over grade 3, if severe shortness of breath is present, usually therapeutic thoracentesis, catheter thoracostomy, and pleuroperitoneal shunt may be required [6]. Since our patient was grade 3 and had pleural effusion extending to middle zone of right lung and preventing daily activities, catheter thoracostomy was performed. In our patient, pulmonary thromboembolism, malignancy, and cardiac etiology were ruled out and right-sided lymphocyte predominant exudative effusion was considered as a side effect of nilotinib. Bergeron et al. reported [9] a case series of dasatinib related lung abnormalities and showed that four out of nine patients had right-sided pleural effusion the same as in our case. In analogy to the management of dasatinib, related pleural effusion prednisolone 32 mg/day was started to the patient whose treatment was discontinued for nilotinib related pleural effusion. However, in our patient significant reduction and/or disappearance of pleural effusion occurred weeks later rather than days as in dasatinib related pleural effusion treatment. After significant decrease of effusion, nilotinib was started again with low dose of 400 mg/day; then dose was increased to 800 mg/day and during this period recurrence of pleural effusion was not observed.\n\n4. Conclusion\nPleural effusion, as a side effect of tyrosine kinases, may be seen as most commonly associated with dasatinib and very rarely seen with nilotinib. If pleural effusion develops in patients taking nilotinib and if this effusion is exudative and lymphocyte predominant, after ruling out pulmonary and cardiac etiologies, it must be associated with nilotinib; according to stage of effusion, drug should be discontinued and/or steroid should be started and/or surgery should be performed.\n\nConflict of Interests\nThe authors stated that they had no conflict of interests.\n\nFigure 1 Posteroanterior chest X-ray in admission (a), after catheter thoracostomy (b) and thorax tomography (c), and posteroanterior chest X-ray after steroid treatment (d).\n==== Refs\n1 Jemal A Siegel R Xu J Ward E Cancer statistics, 2010 CA Cancer Journal for Clinicians 2010 60 5 277 300 2-s2.0-77955635233 \n2 Masiello D Gorospe G Yang AS The occurrence and management of fluid retention associated with TKI therapy in CML, with a focus on dasatinib Journal of Hematology and Oncology 2009 2, article 46 2-s2.0-72449169564 \n3 Chakraborty K Bossaer JB Patel R Krishnan K Successful treatment of nilotinib-induced pleural effusion with prednisone Journal of Oncology Pharmacy Practice 2013 19 2 175 177 2-s2.0-84879291669 23154573 \n4 Kantarjian HM Giles F Gattermann N Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome-positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance Blood 2007 110 10 3540 3546 2-s2.0-36348968931 17715389 \n5 Quintás-Cardama A Kantarjian H O’Brien S Pleural effusion in patients with chronic myelogenous leukemia treated with dasatinib after imatinib failure Journal of Clinical Oncology 2007 25 25 3908 3914 2-s2.0-34548523623 17761974 \n6 Kelly K Swords R Mahalingam D Padmanabhan S Giles FJ Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors Targeted Oncology 2009 4 2 99 105 2-s2.0-67349222815 19381453 \n7 Buchdunger E Cioffi CL Law N Abl protein-tyrosine kinase inhibitor STI571 inhibits in vitro signal transduction mediated by c-Kit and platelet-derived growth factor receptors Journal of Pharmacology and Experimental Therapeutics 2000 295 1 139 145 2-s2.0-0033816156 10991971 \n8 Porkka K Khoury HJ Paquette RL Matloub Y Sinha R Cortes JE Dasatinib 100 mg once daily minimizes the occurrence of pleural effusion in patients with chronic myeloid leukemia in chronic phase and efficacy is unaffected in patients who develop pleural effusion Cancer 2010 116 2 377 386 2-s2.0-75649105405 19924787 \n9 Bergeron A Réa D Levy V Lung abnormalities after dasatinib treatment for chronic myeloid leukemia: a case series The American Journal of Respiratory and Critical Care Medicine 2007 176 8 814 818 2-s2.0-35349001079 17600277\n\n",
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"abstract": "Mediastinal haematoma is a rare complication of laparoscopic paraoesophageal hernia repair with few documented cases in the current literature. Presentation of this unique clinical problem can range from extrinsic oesophageal obstruction to life-hreatening cardiac tamponade and therefore, warrants further discussion of at-risk population aetiology, diagnosis and successful management strategies. We present the case of a 71-year-old woman who underwent laparoscopic paraoesophageal hernia repair with nissen fundoplication complicated by severe dysphagia on postoperative day 12. Further evaluation with oesophagram and CT imaging revealed a large mediastinal haematoma with near obstruction of the distal oesophagus. This was managed successfully with laparoscopic transhiatal washout and drainage.",
"affiliations": "Surgery, Memorial University Medical Center, Savannah, Georgia, USA tmfinnegan1@gmail.com.;Mercer University School of Medicine, Macon, Georgia, USA.;Surgery, Memorial University Medical Center, Savannah, Georgia, USA.;Surgery, Memorial University Medical Center, Savannah, Georgia, USA.",
"authors": "Finnegan|Tim|T|;MacDonald|Nicholas|N|;Gianis|Thomas|T|;Senkowski|Christopher|C|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-232560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(12)",
"journal": "BMJ case reports",
"keywords": "gastro-oesophageal reflux; general surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D004322:Drainage; D004947:Esophagus; D005260:Female; D006406:Hematoma; D006551:Hernia, Hiatal; D059685:Herniorrhaphy; D006801:Humans; D010535:Laparoscopy; D008477:Mediastinal Diseases; D011183:Postoperative Complications",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31811097",
"pubdate": "2019-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20004917;21944871;3606244",
"title": "Large mediastinal haematoma after paraoesophageal hernia repair.",
"title_normalized": "large mediastinal haematoma after paraoesophageal hernia repair"
} | [
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"companynumb": "US-BAYER-2020-001028",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "ASPIRIN"
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{
"abstract": "Metastatic breast cancer (BC) is considered incurable, and it is generally treated with sequential single-agent therapies to control it with palliative intent. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are used in the front-line setting of hormone receptor (HR)-positive, HER2-negative BC, and guidelines discourage the use of a second-line CDK4/6i after failure of first-line use of this class of drugs due to lack of data supporting this practice. We report a case of a postmenopausal woman with HR-positive and HER2-negative advanced BC who was treated with four lines of hormonal therapy and more than five chemotherapy regimens, with progression. Palbociclib was used in the sixth-line therapy and discontinued after 5 months. We then tried abemaciclib in the 11th-line setting, where it induced a response that lasted 16 months.",
"affiliations": "Escola de Medicina da Pontifícia, Universidade Católica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS, 90619-900, Brazil.;Florida Precision Oncology, a Division of 21st Century Oncology, Boca Raton, FL, USA.;Florida Precision Oncology, a Division of 21st Century Oncology, Boca Raton, FL, USA. mohammad.jahanzeb@21co.com.",
"authors": "Wender|Isabella O|IO|;Haines|Kayla|K|;Jahanzeb|Mohammad|M|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40487-020-00126-0",
"fulltext": "\n==== Front\nOncol Ther\nOncol Ther\nOncology and Therapy\n2366-1070 2366-1089 Springer Healthcare Cheshire \n\n32876928\n126\n10.1007/s40487-020-00126-0\nCase Report\nResponse to Abemaciclib After 10 Lines of Therapy Including Palbociclib in Metastatic Breast Cancer: A Case Report With Literature Review\nWender Isabella O. 1 Haines Kayla 2 Jahanzeb Mohammad mohammad.jahanzeb@21co.com 2 1 grid.412519.a0000 0001 2166 9094Escola de Medicina da Pontifícia, Universidade Católica do Rio Grande do Sul (PUC-RS), Porto Alegre, RS 90619-900 Brazil \n2 Florida Precision Oncology, a Division of 21st Century Oncology, Boca Raton, FL USA \n2 9 2020 \n2 9 2020 \n12 2020 \n8 2 351 358\n24 7 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.Metastatic breast cancer (BC) is considered incurable, and it is generally treated with sequential single-agent therapies to control it with palliative intent. Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) are used in the front-line setting of hormone receptor (HR)-positive, HER2-negative BC, and guidelines discourage the use of a second-line CDK4/6i after failure of first-line use of this class of drugs due to lack of data supporting this practice. We report a case of a postmenopausal woman with HR-positive and HER2-negative advanced BC who was treated with four lines of hormonal therapy and more than five chemotherapy regimens, with progression. Palbociclib was used in the sixth-line therapy and discontinued after 5 months. We then tried abemaciclib in the 11th-line setting, where it induced a response that lasted 16 months.\n\nKeywords\nBreast carcinomaCyclin-dependent kinaseMetastatic breast cancerissue-copyright-statement© The Author(s) 2020\n==== Body\nKey Summary Points\n\nWhile metastatic breast carcinoma is incurable, palliative therapy, chosen according to surface markers, is still warranted in patients with adequate performance status and organ function.\t\nNational Comprehensive Cancer Network Breast Cancer Guidelines recommend multiple lines of systemic therapy to palliate advanced breast cancer after failure of three lines of hormonal therapy, where clinicians should assess the value of ongoing treatment, risks and benefits, and patient preferences before moving to supportive care. Some patients are offered additional therapy if they maintain an excellent performance status and desire more treatment, especially if there are viable options.\t\nWe report a case of a postmenopausal woman with breast carcinoma with 9-year survival, where we tried multiple lines of systemic therapy, most with response or stabilization followed by progression. Palbociclib plus letrozole was her sixth line of therapy, then we tried abemaciclib, another cyclin-dependent kinase 4/6 inhibitor, in the 11th line therapy and achieved a sustained benefit for 16 months.\t\nWith this brief report we can raise awareness about this option and allude to this lack of complete cross-resistance between these two CDK4/6 inhibitors.\t\n\n\nIntroduction\nExcluding nonmelanoma skin cancer, breast cancer (BC) is the most common cancer diagnosed in women and is the second leading cause of cancer death among women after lung cancer [1, 2]. Metastatic disease is generally considered incurable, but it is known that we can control the disease with sequential single-agent therapies (unless there is a rapid tempo of disease, life-threatening visceral involvement and large tumor burden). We report a case of a postmenopausal woman with estrogen-receptor (ER)-positive, progesterone-receptor (PR)-negative and HER2-negative BC. She was treated with four lines of hormonal therapy (HT) and more than five chemotherapy regimens, with initial response or stabilization, followed by progression. Palbociclib, a cyclin-dependent kinase 4/6 inhibitor (CDK4/6i), was used in the sixth line and discontinued after 5 months. After the 10th-line therapy we tried abemaciclib, another CDK4/6i, and it induced a response including in the liver.\n\nCase Report\nA 70-year-old white woman was diagnosed in October 2010 with metastatic right-sided BC, hormone-receptor-positive (ER-positive, PR-negative) and HER2-negative, with widespread bone metastasis. The patient underwent palliative radiation to her lumbar spine with 10 meV photon beam via an anterior–posterior/posterior–anterior (AP-PA) technique, 2 Gy per day to 30 Gy, elapsed count of 12 days in March and April of 2011. She received denosumab for prevention of skeletal-related events and also chemotherapy with vinorelbine from December 2010 to May 2011, which was poorly tolerated and caused a rare occurrence of near total alopecia. She was then started on letrozole, but after 2 years the cancer progressed. She was given fulvestrant until July 2014, with progression again. Tamoxifen was started in August 2014 and discontinued in December of the same year because of progression.\n\nIn January 2015 she developed left lower extremity swelling and underwent a left lower extremity venous duplex ultrasound. The image showed a left inguinal mass measuring 4.9 × 2.5 × 6.8 cm with a complex hypoechoic center and abnormal vascularity, compatible with necrotic lymphadenopathy, and additional lymph nodes were present. A left inguinal lymph node mass biopsy was performed and revealed small lymphocytes in a marginal zone pattern and occasional colonization of reactive follicles. By immunohistochemistry, lymphocytes were positive for CD20 and BCL2, and negative for CD3, CD5 and CD10. A diagnosis of marginal-zone lymphoma was made, an indolent B-cell non-Hodgkin lymphoma. A bone marrow biopsy at that time showed involvement of the same lymphoma. She was given rituximab for 4 weeks until April 2015, and from June through October 2015 she received bendamustine with rituximab every 28 days. The patient had a complete response with no recurrence of her lymphoma.\n\nLymphoma treatment ended in October 2015, and a PET-CT from November 2015 showed progression in her bony disease. She started letrozole with palbociclib until April 2016 with progression. She was placed on capecitabine, which she received from May 2016 to September 2016, but the cancer progressed. The patient had exhausted her HT options, so we switched to chemotherapy and re-treated her with vinorelbine at a lower dose of 20 mg/m2 given every other week, which she tolerated better, but after 3 months the disease progressed. She received liposomal doxorubicin for a year from November 2016 with a good clinical response, but the drug had to be stopped because of reaching the maximum recommended cumulative dose over which the risk of cardiotoxicity would be significantly increased. She was then treated with gemcitabine from November 2017 to March 2018, but PET-CT from March showed widespread hypermetabolic liver and osseous metastases with increasing metabolism compared to the prior exam, with the majority of the lesions showing increasing metabolism, as well as new hypermetabolic osseous lesions. Due to these findings, gemcitabine was discontinued and she started eribulin.\n\nThe next PET-CT scan in May 2018 showed widespread hypoattenuating hypermetabolic liver and new osseous metastases, with progression. She was given paclitaxel but progressed with new liver lesions. A liver biopsy was done in June 2018 and pathology reported metastatic carcinoma consistent with breast primary, immunoperoxidase stains positive for cytokeratin AE1/AE3, ER (100% with strong intensity), clone SP1, PR (20% with weak intensity) and GATA-3. FoundationOne genomic testing from the liver biopsy showed stable microsatellite status and low tumor mutational burden, and other genomic findings: CCND1, C11orf30, FGF19, FGF3, FGF4 amplifications and AXIN1 R533_H534insQVHH and MAP2K4 splice site 336_393+6del64 mutations. Paclitaxel was discontinued and she started abemaciclib 200 mg BID in August 2018, but the dose had to be reduced to 150 mg BID due to diarrhea. She was treated with abemaciclib 150 mg twice daily beginning 08/09/2018, with initial response followed by stable disease, while working full-time as an accountant.\n\nThe patient progressed on abemaciclib in late January 2020 confirmed by a new PET-CT. She maintained Eastern Cooperative Oncology Group (ECOG) I performance status. After discussion with the patient and her family, she was given a reduced dose of irinotecan. When she returned for follow-up on day 8, she presented with complaints of shaking chills, fever and weakness, which she had been having for a few days but had not notified anyone. The patient was admitted to the hospital for intravenous antibiotics for febrile neutropenia but died of sepsis the day after admission (day 9 of cycle 1). Table 1 summarizes the patient’s treatment chronology.Table 1 Treatment chronology\n\nAgents\tStart date\tEnd date\tReason for discontinuation\t\nVinorelbine\tDecember 2010\tMay 2011\tProgression\t\nLetrozole\tMay 2011\tJune 2013\tProgression\t\nFulvestrant\tJune 2013\tJuly 2014\tProgression\t\nTamoxifen\tAugust 2014\tDecember 2014\tProgression\t\nLetrozole and palbociclib\tJanuary 2016\tApril 2016\tProgression\t\nCapecitabine\tMay 2016\tSeptember 2016\tProgression\t\nVinorelbine\tSeptember 2016\tNovember 2016\tProgression\t\nLiposomal doxorubicin\tNovember 2016\tNovember 2017\tMaximum allowable cumulative dose reached\t\nGemcitabine\tDecember 2017\tMarch 2018\tProgression\t\nEribulin\tApril 2018\tMay 2018\tProgression\t\nPaclitaxel\tMay 2018\tJuly 2018\tProgression\t\nAbemaciclib\tAugust 2018\tDecember 2019\tProgression\t\nIrinotecan\tJanuary 2020\tJanuary 2020\tDeath\t\n\n\nInformed consent was obtained from the patient and her family for the inclusion of her medical and treatment history within this case report.\n\nDiscussion\nThe American Cancer Society reports a 5-year relative survival rate for metastatic BC of 27% based on women diagnosed between 2009 and 2015 [3]. Although patients with HR-positive disease have longer survival, statistics show us that long-term survival for stage IV disease is quite uncommon [4]. Here we report an unusual patient with a more than 9-year survival after being diagnosed with bone metastasis from primary right-sided BC, who later developed liver metastases and a non-Hodgkin lymphoma that had to be treated with bendamustine and rituximab.\n\nThe use of multiple lines of HT before resorting to chemotherapy in patients with HR-positive and HER2-negative advanced disease is recommended by National Comprehensive Cancer Network (NCCN) and European School of Oncology (ESO)-European Society of Medical Oncology (ESMO) current treatment guidelines for breast cancer [5, 6]. After failure of three lines of HT, multiple lines of systemic therapy can be used to palliate BC considering risks and benefits [6].\n\nCDK4/6i (abemaciclib, palbociclib and ribociclib) are typically employed and have the best efficacy if given in the front-line therapy in patients with HR-positive, HER-negative BC. Literature has demonstrated that patients who received CDK4/6i plus HT versus HT alone as the first-line setting had longer progression-free survival, but they were not available when our patient presented in 2010 [7–10]. Palbociclib plus letrozole was her 6th line of therapy.\n\nAbemaciclib is the only CDK4/6i approved for single-agent use in the subsequent-line therapy of metastatic HR-positive and HER2-negative BC [11]. However, NCCN Clinical Practice Guidelines and 4th ESO-ESMO International Consensus Guidelines for BC state that a second-line CDK4/6i should not be tried after failure of the first-line use of these agents due to lack of data supporting this practice. Since our patient maintained a good performance status and desired more therapy after four HT regimens, including letrozole and palbociclib, and more than five chemotherapy regimens, it seemed reasonable to try abemaciclib due to lack of other good options and a significant interval since prior exposure to a CDK4/6 inhibitor. Since the patient started this therapy, additional data emerged from multiple institutions indicating activity of abemaciclib after failure of palbociclib in a prior line of therapy [12–15] as summarized in Table 2. The purpose of this report is to raise awareness about this option and to allude to this lack of complete cross-resistance between the two CDK4/6 inhibitors.Table 2 Systematic literature search of abemaciclib post-palbociclib therapy in BC patients\n\nStudy ID\tDesign\tFindings\t\nWander et al. 2018 [12]\tEvaluated patients (pts) of one institution with HR+/HER2− metastatic BC (MBC) who had received abemaciclib following an initial course of palbociclib-based therapy\tTwelve pts were included. Five pts (41.7%) had early progression on abemaciclib, while three (25%) had ongoing benefit (progression-free survival [PFS] greater than 120 days). Three pts had recently initiated abemaciclib therapy (less than 120 days prior to the current analysis). A subset of pts derived clinical benefit with continued exposure to CDK4/6i\t\nWander et al. 2019 [13]\tEvaluated clinical outcomes in pts with HR+/HER2− MBC who received abemaciclib following progression on prior palbociclib at four US academic centers\tTwenty-one pts (36%) had abemaciclib treatment duration exceeding 6 months (alone or combined), including 10 who remained on treatment at interim analysis (range 181–413 days). This is the first multi-center experience demonstrating a substantial proportion of pts with clinical benefit with abemaciclib after prior CDK4/6i exposure\t\nTamragouri et al. 2019 [14]\tPerformed a chart review of pts with HR+, HER2− MBC who progressed on palbociclib and were subsequently treated with abemaciclib with or without fulvestrant\tTwenty-one pts were included. The clinical benefit rate for using abemaciclib after previous exposure to palbociclib was 29% (6/21). All pts received abemaciclib alone, demonstrating some activity of this agent in pts previously treated with palbociclib\t\nMariotti et al. 2019 [15]\tAnalyzed the efficacy of abemaciclib-based therapy (ABT) after exposure to palbociclib in estrogen receptor-positive MBC patients\tTwenty-two pts who progressed on palbociclib were included. Five (22.7%) pts had durable response to abemaciclib. Of those, two (33.3%) had longer PFS compared to prior palbociclib PFS. Abemaciclib can result in durable response in selected pts who progressed on palbociclib\t\n\n\nAfter 10 lines of therapy, our patient had a good response with abemaciclib alone, remaining on this treatment for almost 16 months, while palbociclib plus HT had controlled her disease for only 5 months.\n\nMariotti et al. described metastatic BC patients who responded to abemaciclib after previous exposure to palbociclib. They reported 19 patients who received a mean of 5.6 prior therapies, including palbociclib plus HT (fulvestrant or letrozole), before trying abemaciclib in combination with HR or as a single agent. Four cases (21%) had longer progression-free survival (PFS) on abemaciclib compared to prior palbociclib PFS, and although no partial or complete response was observed, 33% had stable disease [15].\n\nEvidence for giving abemaciclib as a single agent in subsequent lines of therapy of refractory HR-positive and HER2-negative metastatic BC is found in the MONARCH 1 trial [11]. Abemaciclib demonstrated positive anti-tumor activity in 26 patients of a total of 132 who previously progressed on or after HT and chemotherapy. MONARCH 1 excluded patients previously treated with CDK4/6i; however, our patient was previously exposed to palbociclib and progressed on it, but she still had good clinical benefit from abemaciclib. Additionally, we administered more than five chemotherapy regimens in the metastatic setting in our patient, while MONARCH 1 administered no more than two lines of chemotherapy during metastatic disease.\n\nIt is important to discuss why our patient might have responded to abemaciclib despite failing palbociclib. There are some structural differences between abemaciclib and the other two CDK4/6i, palbociclib and ribociclib. Besides being considered agents from the same drug class, it is known that abemaciclib has greater selectivity for CDK4 than for CDK6 and that it can inhibit other kinases which are not inhibited by the other two CDK4/6i, such as CDK9/7/2/1, GSK3α/β and CAMK2γ/δ. It is suggested that inhibition of these kinases by abemaciclib overcomes known mechanisms of resistance to CDK4/6 inhibition. Moreover, these agents have some differences in pharmacokinetics. Abemaciclib has the ability to induce cell death and apoptosis and arrest in the G2 phase of the cell cycle, and it is the most effective inhibitor of CDK4/6. Nonetheless, the three agents seem to have similar anti-tumor activity [16].\n\nNavarro-Yepes et al. suggested a differential mechanism of resistance to abemaciclib versus palbociclib. Western blot analysis revealed dose-dependent downregulation of ERα, Rb, p-Rb and p27 in palbociclib-resistant cells, which were only partially cross-resistant to abemaciclib. Also, a key mediator of DNA repair (Rad51) was downregulated only in abemaciclib-resistant cells. The authors examined the combination of abemaciclib plus niraparib, a PARP inhibitor, in organoid cultures created from patient-derived xenograft (PDX) models with surrogate palbociclib-resistance cells, and found significantly reduced viability, number and density of these organoids. In vivo, with the same PDX models, the treatment reduced the rate of tumor growth and increased survival [17].\n\nAmong metastatic BC patients, there are clearly some exceptional cases, such as this patient who remained fully functional and a productive member of society, that deserve consideration from their providers. Besides the heavy treatment with chemotherapy regimens and the previous exposure to another CDK4/6i, abemaciclib showed a 16-month response and 11-month longer PFS than palbociclib-based therapy. This lack of complete cross-resistance between these two CDK4/6i should be better investigated.\n\nThe US Food and Drug Administration approved the first CDK4/6i, palbociclib, less than 5 years ago, and now we see ongoing trials to find more uses for these agents [18]. There are some ongoing studies that will generate prospective data regarding response to CDK4/6i after failure in a prior line of therapy. The MAINTAIN trial (NCT02632045) will investigate whether there is continued benefit for remaining on a CDK4/6i at the time of switching to anti-estrogen therapy in a randomized open-label trial [19]. Another study, a phase II trial with 100 participants in a single group assignment, will determine the role of continuing palbociclib treatment in combination with another type of HT (fulvestrant) after disease progression with palbociclib plus an aromatase inhibitor (NCT02738866) [20].\n\nInvestigations into the use of CDK4/6i with novel drugs can also be found. The TRINITI-1 study (NCT02732119), a single-arm open-label trial, is looking to determine whether ribociclib in combination with everolimus and exemestane is effective in treating men and postmenopausal women with HR+, HER2– locally advanced or metastatic BC following progression on a CDK4/6i [21]. Initial results of TRINITI-1 were already presented, and it achieved its primary efficacy end point with clinical benefit and tolerability [22]. The PACE trial (NCT03147287) is a phase II research study which is recruiting patients with metastatic HR-positive HER2-negative BC to evaluate the activity of fulvestrant alone, fulvestrant and palbociclib, or fulvestrant, palbociclib and avelumab combined, in participants who previously stopped responding to prior palbociclib and HT. Trials are ongoing and results are expected [23].\n\nConclusion\nOur case report shows an unusually durable response in such a late line of therapy in this 70-year-old woman with metastatic right-sided BC. The patient responded to abemaciclib as her 11th-line therapy after previous exposure to palbociclib. This illustrates the potential for reintroducing a dissimilar member from the same class of a drug that had been used many lines before in unusual patients who exhibit long-term survival, have responded to several agents before, and have run out of new options. As we look for the best treatment for our patients, it is important to develop individualized therapeutic strategies based on their performance status, biology of disease, individual track record and personal preferences.\n\nDigital Features\n\nTo view digital features for this article go to 10.6084/m9.figshare.12793790.\n\nAcknowledgements\nWe thank the patient for giving us the opportunity to report her medical case.\n\nFunding\nNo funding or sponsorship was received for this study or publication of this article.\n\nAuthorship\nAll named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthorship Contributions\nI Wender and K Haines were responsible for data acquisition, analysis and manuscript drafting and editing. M Jahanzeb was responsible for study conception and design, patient clinical examination, data analysis and manuscript review.\n\nDisclosures\nI Wender and K Haines have nothing to disclose. M Jahanzeb is speaker and consultant for Pfizer and Novartis.\n\nCompliance with Ethics Guidelines\nInformed consent was obtained verbally from the patient for the inclusion of her medical and treatment history within this case report. The patient’s family was also notified of this case submission and consented. This case report was performed in line with the principles outlined in the Declaration of Helsinki of 1964 for all human or animal experimental investigations.\n==== Refs\nReferences\n1. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries CA Cancer J Clin 2018 68 6 394 424 10.3322/caac.21492 30207593 \n2. Siegel RL Miller KD Jemal A Cancer statistics, 2018 CA Cancer J Clin 2018 68 1 7 30 10.3322/caac.21442 29313949 \n3. American Cancer Society Web Page. Cancer.org. Available at: https://www.cancer.org/cancer/breast-cancer/understanding-a-breast-cancer-diagnosis/breast-cancer-survival-rates.html. Accessed 3 Jun 2019.\n4. Miller KD Nogueira L Mariotto AB Cancer treatment and survivorship statistics, 2019 CA Cancer J Clin 2019 69 5 363 385 10.3322/caac.21565 31184787 \n5. Network NCC. Breast Cancer (Version 3.2019). https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf. Accessed 28 Oct 2019.\n6. Cardoso F Senkus E Costa A 4th ESO-ESMO International Consensus Guidelines for Advanced Breast Cancer (ABC 4)† Ann Oncol 2018 29 8 1634 1657 10.1093/annonc/mdy192 30032243 \n7. Finn RS Crown JP Lang I The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of estrogen receptor-positive, HER2negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study Lancet Oncol 2015 16 25 35 10.1016/S1470-2045(14)71159-3 25524798 \n8. Cristofanilli M Turner NC Bondarenko I Fulvestrant plus palbociclib versus fulvestrant plus placebo for treatment of hormone-receptor-positive, HER2-negative metastatic breast cancer that progressed on previous endocrine therapy (PALOMA-3): final analysis of the multicentre, double-blind, phase 3 randomised controlled trial Lancet Oncol 2016 17 425 439 10.1016/S1470-2045(15)00613-0 26947331 \n9. Sledge GW Jr Toi M Neven P MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2– advanced breast cancer who had progressed while receiving endocrine therapy J Clin Oncol 2017 35 25 2875 2884 10.1200/JCO.2017.73.7585 28580882 \n10. Hortobagyi GN Stemmer SM Burris HA Ribociclib as first-line therapy for HR-positive, advanced breast cancer N Engl J Med 2016 375 1738 1748 10.1056/NEJMoa1609709 27717303 \n11. Dickler MN Tolaney SM Rugo HS MONARCH 1, a phase II study of Abemaciclib, a CDK4 and CDK6 inhibitor, as a single agent, in patients with refractory HR+/HER2– metastatic breast cancer Clin Cancer Res 2017 23 17 5218 5224 10.1158/1078-0432.CCR-17-0754 28533223 \n12. Wander SA, Spring LM, Stein CR, et al. Abemaciclib after prior palbociclib exposure in patients with metastatic hormone-receptor positive (HR+)/HER2- breast cancer. In. 2018 San Antonio Breast Cancer Symposium; San Antonio, TX; December 4–8, 2018. Abstract P-06-18-39. https://www.abstracts2view.com/sabcs/view.php?nu=SABCS18L_1832.\n13. Wander SA Zangardi M Niemierko A A multicenter analysis of abemaciclib after progression on palbociclib in patients (pts) with hormone receptor-positive (HR+)/HER2– metastatic breast cancer (MBC) J Clin Oncol. 2019 37 15 suppl 1057 10.1200/JCO.2019.37.15_suppl.1057 \n14. Tamragouri K Cobleigh MA Rao RD Abemaciclib with or without fulvestrant for the treatment of hormone receptor-positive and HER2-negative metastatic breast cancer with disease progression following prior treatment with palbociclib J Clin Oncol 2019 37 15 suppl e12533 10.1200/JCO.2019.37.15_suppl.e12533 \n15. Mariotti V Khong HT Soliman HH Efficacy of abemaciclib (abema) after palbociclib (palbo) in patients (pts) with metastatic breast cancer (MBC) J Clin Oncol. 2019 37 15 suppl e12521 e12521 10.1200/JCO.2019.37.15_suppl.e12521 \n16. Lee KA Shepherd STC Johnston SRD Abemaciclib, a potent cyclin-dependent kinase 4 and 6 inhibitor, for treatment of ER-positive metastatic breast cancer Fut Oncol 2019 15 29 3309 3326 10.2217/fon-2019-0169 \n17. Navarro-Yepes J Chen X Bui T Kettner NM Hunt KK Keyomarsi K Abstract PD2–05: differential mechanisms of acquired resistance to abemaciclib versus palbociclib reveal novel therapeutic strategies for CDK4/6 therapy-resistant breast cancers Cancer Res. 2020 10.1158/1538-7445.SABCS19-PD2-05 \n18. US FDA. FDA Approved Drug Products (abemaciclib, palbociclib, ribociclib). https://www.accessdata.fda.gov/scripts/cder/daf/ Accessed 4 Jul 2020.\n19. ClinicalTrials.gov Web Page. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT02632045, Study of Efficacy of Ribociclib After Progression on CDK4/6 Inhibition in Patients With HR+ HER2– Advanced Breast Cancer (MAINTAIN); 2016 Mar. Available from: https://clinicaltrials.gov/ct2/show/NCT02632045. Cited Nov 2019.\n20. ClinicalTrials.gov Web Page. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT02738866, Palbociclib With Fulvestrant for Metastatic Breast Cancer After Treatment With Palbociclib and an Aromatase Inhibitor; 2016 Oct. Available from: https://clinicaltrials.gov/ct2/show/NCT02738866. Cited Nov 2019.\n21. ClinicalTrials.gov Web Page. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29 -. Identifier NCT02732119, Study of Ribociclib With Everolimus + Exemestane in HR+ HER2- Locally Advanced/Metastatic Breast Cancer Post Progression on CDK 4/6 Inhibitor. (TRINITI-1); 2016 Jun. Available from: https://clinicaltrials.gov/ct2/show/NCT02732119. Cited Nov 2019.\n22. Bardia A Hurvitz SA DeMichele A Triplet therapy (continuous ribociclib, everolimus, exemestane) in HR+/HER2− advanced breast cancer postprogression on a CDK4/6 inhibitor (TRINITI-1): Efficacy, safety, and biomarker results J Clin Oncol 2019 37 15 e1016 e1016 10.1200/JCO.2019.37.15_suppl.1016 \n23. ClinicalTrials.gov Web Page. Bethesda (MD): National Library of Medicine (US). 2000 Feb 29. Identifier NCT03147287, Palbociclib After CDK and Endocrine Therapy (PACE). 2017 May. Available from: https://clinicaltrials.gov/ct2/show/NCT03147287. Cited Apr 2020.\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2366-1089",
"issue": "8(2)",
"journal": "Oncology and therapy",
"keywords": "Breast carcinoma; Cyclin-dependent kinase; Metastatic breast cancer",
"medline_ta": "Oncol Ther",
"mesh_terms": null,
"nlm_unique_id": "101677510",
"other_id": null,
"pages": "351-358",
"pmc": null,
"pmid": "32876928",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": "27717303;29313949;25524798;31184787;28533223;26947331;31464525;30032243;30207593;28580882",
"title": "Response to Abemaciclib After 10 Lines of Therapy Including Palbociclib in Metastatic Breast Cancer: A Case Report With Literature Review.",
"title_normalized": "response to abemaciclib after 10 lines of therapy including palbociclib in metastatic breast cancer a case report with literature review"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-05740",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"d... |
{
"abstract": "Following an alert on neural tube defects and dolutegravir, we sought to evaluate if the exposure integrase strand transfer inhibitors (INSTIs) at conception was associated with birth defects or other adverse pregnancy outcomes.\n\n\n\nIn the prospective national French Perinatal Cohort (EPF), we studied birth defects and other perinatal outcomes by matching each pregnant woman exposed to INSTIs with a pregnant woman exposed to darunavir/ritonavir receiving the same backbone of nucleoside reverse transcriptase inhibitors and matched for other characteristics such as age, geographic origin, centre and year of delivery.\n\n\n\nAmong 808 women exposed to INSTIs during pregnancy (raltegravir = 703, dolutegravir = 57 and elvitegravir = 48), we reported a slightly higher rate of birth defects in infants exposed at conception to raltegravir (6.7%) vs. infants exposed to raltegravir later in pregnancy: 2.9% if initiated during pregnancy as first-line, and 2.5% as second-line treatment, P =0.04. When compared with matched controls, raltegravir exposure at conception was not significantly associated with birth defects: 6.4 vs. 2.3%, P = 0.08. There was no cluster of birth defect type and no neural tube defects were observed. Other perinatal outcomes, such as preterm birth and stillbirths, did not differ significantly between raltegravir-exposed women and matched counterparts. No difference in any outcome was observed for elvitegravir/cobicistat or dolutegravir.\n\n\n\nWe found a nonsignificant trend for an association between exposure to raltegravir at conception and birth defects, which needs to be evaluated by larger prospective surveillance data, as these drugs are increasingly prescribed in women living with HIV.",
"affiliations": "Service de gynécologie-obstétrique, AP-HP Hôpital Louis Mourier, Colombes.;Département d'Epidémiologie, Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Université Paris-Saclay, APHP Public Health Department, Le Kremlin-Bicêtre.;Service de gynécologie-obstétrique, AP-HP Hôpital Louis Mourier, Colombes.;Unité d'Hémato-oncologie, Hôpital Armand Trousseau, Groupe hospitalier Sorbonne Université.;Université de Paris, INSERM UMR1137, IAME, Paris.;INSERM U1153 (Obstetrical, Perinatal and Pediatric Epidemiology Research Team, Center for Biostatistics and Epidemiology), Maternité Port Royal.;Université Paris Descartes, Sorbonne Paris Cité, Faculté de Médecine.;Département d'Epidémiologie, Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Université Paris-Saclay, APHP Public Health Department, Le Kremlin-Bicêtre.;AP-HP, Laboratoire de Microbiologie Clinique, Hôpital Necker-Enfants Malades.;Service de Maladies Infectieuses et Tropicales, CHU Nantes.;Département d'Epidémiologie, Centre de Recherche en Épidémiologie et Santé des Populations, INSERM U1018, Université Paris-Saclay, APHP Public Health Department, Le Kremlin-Bicêtre.;Service de Maladies infectieuses et tropicales, APHP, Hôpitaux Universitaires Pitié Salpêtrière-Charles Foix.",
"authors": "Sibiude|Jeanne|J|;Le Chenadec|Jérôme|J|;Mandelbrot|Laurent|L|;Dollfus|Catherine|C|;Matheron|Sophie|S|;Lelong|Nathalie|N|;Avettand-Fenoel|Véronique|V|;Brossard|Maud|M|;Frange|Pierre|P|;Reliquet|Véronique|V|;Warszawski|Josiane|J|;Tubiana|Roland|R|;|||",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D000068898:Raltegravir Potassium; D019426:Integrases",
"country": "England",
"delete": false,
"doi": "10.1097/QAD.0000000000002719",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-9370",
"issue": "35(2)",
"journal": "AIDS (London, England)",
"keywords": null,
"medline_ta": "AIDS",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000013:Congenital Abnormalities; D005260:Female; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D007231:Infant, Newborn; D019426:Integrases; D010078:Oxazines; D010879:Piperazines; D011247:Pregnancy; D047928:Premature Birth; D011446:Prospective Studies; D011728:Pyridones; D000068898:Raltegravir Potassium",
"nlm_unique_id": "8710219",
"other_id": null,
"pages": "219-226",
"pmc": null,
"pmid": "33048878",
"pubdate": "2021-02-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of birth defects and perinatal outcomes in HIV-infected women exposed to integrase strand inhibitors during pregnancy.",
"title_normalized": "risk of birth defects and perinatal outcomes in hiv infected women exposed to integrase strand inhibitors during pregnancy"
} | [
{
"companynumb": "FR-JNJFOC-20201049397",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RALTEGRAVIR"
},
"drugadditional": null,
... |
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