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"abstract": "BACKGROUND\nThe use of intraoperative neurophysiologic monitoring (IOM) has become commonplace in many neurosurgical procedures as a tool to reduce the risk of complications through the early identification of reversible neurologic compromise. Although complications related to IOM itself are exceedingly rare, recognizing their clinical presentation in the postoperative neurosurgical patient is essential for the early identification and implementation of appropriate treatment.\n\n\nMETHODS\nThe authors present a case report of a patient who developed postoperative acute compartment syndrome in the right arm after placement of neuromonitoring needles for routine IOM during endovascular treatment of a left internal carotid artery aneurysm. Before the procedure, the patient received dual antiplatelet therapy and was noted to have a P2Y12 reaction unit value within therapeutic range. The patient had not received other anticoagulation therapy and had no family or personal history of hematologic or coagulopathic disorders. Immediately after an uncomplicated endovascular intervention, the patient began to develop symptoms of forearm swelling, tightness, and tenderness to palpation; pain with wrist flexion and extension; and paresthesias of the distal digits of the hand. She had eventual loss of a palpable radial pulse. The patient underwent emergent fasciotomies of multiple forearm compartments and had immediate return of a palpable radial pulse.\n\n\nCONCLUSIONS\nThis case represents the first report of post-procedural compartment syndrome resulting from placement of neuromonitoring needles for routine IOM. Although it is a particularly rare complication of IOM, compartment syndrome represents a surgical emergency that carries significant morbidity if not immediately recognized and treated.",
"affiliations": "Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;University of Utah School of Medicine, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA.;Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA. Electronic address: neuropub@hsc.utah.edu.",
"authors": "Eli|Ilyas M|IM|;Gamboa|Nicholas T|NT|;Guan|Jian|J|;Taussky|Philipp|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.01.192",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "112()",
"journal": "World neurosurgery",
"keywords": "Compartment syndrome; Intraoperative neuromonitoring; Motor evoked potentials; Somatosensory evoked potentials",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000368:Aged; D000783:Aneurysm; D002340:Carotid Artery Diseases; D002343:Carotid Artery, Internal; D003161:Compartment Syndromes; D004566:Electrodes; D005260:Female; D006801:Humans; D016343:Monitoring, Intraoperative",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "247-249",
"pmc": null,
"pmid": "29408593",
"pubdate": "2018-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Compartment Syndrome as a Complication of the Use of Intraoperative Neuromonitoring Needle Electrodes.",
"title_normalized": "acute compartment syndrome as a complication of the use of intraoperative neuromonitoring needle electrodes"
} | [
{
"companynumb": "US-BAYER-2018-050956",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nMethotrexate (MTX) has been utilized for the treatment of Crohn's disease (CD) for decades. Nevertheless, current data provide equivocal evidence on the efficacy of MTX in CD.The aims of this study were to describe the efficacy of MTX for maintenance of remission in CD and to identify the factors associated with the probability of steroid-free clinical remission in a multicenter European referral center cohort.\n\n\nMETHODS\nThis was a retrospective cohort analysis. Consecutive patients treated with MTX for CD were included from 11 referral centers. Patients receiving concomitant treatment with tumor necrosis factor inhibitors or thiopurines were excluded. The main outcome was steroid-free clinical remission; the secondary outcomes included the rate of complications leading to MTX discontinuation and duration of relapse-free survival in patients achieving the main outcome.\n\n\nRESULTS\nBetween July 1992 and January 2012, 118 patients were identified for inclusion. MTX administration route was oral for induction in 31.4% and for maintenance in 49.1% of the patients. Steroid-free remission was achieved in 44/118 (37.2%) patients and was maintained relapse free by 28/44 (63.6%) for a median of 12 (3.5-18.5) months. At least one adverse effect was reported by 28.9% of the patients. No clinical or demographic factors were associated with either likelihood of achieving a clinical response or duration of relapse-free survival.\n\n\nCONCLUSIONS\nMTX treatment induced steroid-free clinical remission in over a third of CD patients and maintained it for a year in almost two-thirds of the responders. MTX should be considered a viable therapeutic option in CD patients refractory to other therapies.",
"affiliations": "aDepartment of Gastroenterology, Sheba Medical Center, Ramat Gan bSackler Medical School, Tel-Aviv University, Tel-Aviv cDepartment of Gastroenterology and Hepatology, Ben-Gurion University of the Negev, Beer Sheva, Israel dDivision of Gastroenterology, University of Ioannina, Ioannina eDepartment of Gastroenterology, Venizeleio General Hospital, Heraklion fFirst Department of Gastroenterology, Evangelismos Hospital, Athens gDepartment of Gastroenterology, University Hospital Heraklion, Crete, Greece hDepartment of Gastroenterology and Hepatology, Erasmus MC, Rotterdam, The Netherlands iDepartment of Gastroenterology, Instituto de Investigacion Biomedica Ourense-Pontevedra-Vigo, Xerencia Xestion Integrada de Vigo, Spain jDepartment of Gastroenterology and Hepatology, Zvezdara University Clinical Centre, Zvezdara kMedical Faculty, University of Belgrade, Belgrade, Serbia lCentral IBD Clinic, Nicosia, Cyprus mIBD Center, Department of Gastroenterology, Humanitas Research Hospital, Milan, Italy.",
"authors": "Kopylov|Uri|U|;Katsanos|Konstantinos H|KH|;van der Woude|Christien Janneke|CJ|;Karmiris|Konstantinos|K|;Hernandez|Vicent|V|;Odes|Selwyn|S|;Papamichael|Konstantinos|K|;Koutroubakis|Ioannis E|IE|;Bojic|Daniela|D|;Kaimakliotis|Ioannis|I|;Fiorino|Gionata|G|;Papageorgiou|Neofytos|N|;Pineda|Juan R|JR|;Strongili|Konstantina|K|;Sanroman|Luciano|L|;Mantzaris|Gerassimos J|GJ|;Jojic|Njegica|N|;Paspatis|Gregorios|G|;Christodoulou|Dimitrios K|DK|;Ben-Horin|Shomron|S|;Tsianos|Epameinondas V|EV|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1097/MEG.0000000000000609",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-691X",
"issue": "28(7)",
"journal": "European journal of gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Eur J Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D003424:Crohn Disease; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D053208:Kaplan-Meier Estimate; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D012074:Remission Induction; D012189:Retrospective Studies; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9000874",
"other_id": null,
"pages": "802-6",
"pmc": null,
"pmid": "26894634",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "European experience with methotrexate treatment in Crohn's disease: a multicenter retrospective analysis.",
"title_normalized": "european experience with methotrexate treatment in crohn s disease a multicenter retrospective analysis"
} | [
{
"companynumb": "IL-FRESENIUS KABI-FK201605502",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,... |
{
"abstract": "Bordetella bronchiseptica is a rare cause of invasive human infection. The most common infection in humans is the respiratory tract infection and it is usually associated with immunosuppression, particularly acquired immunodeficiency syndrome (AIDS). We report a case of a pneumonia and peritonitis in a 42-year-old female with alcoholic liver disease. The patient died despite treatment with antibiotics. This case illustrates the potential virulence of B. bronchiseptica in susceptible patients and to our knowledge it is the first case of primary peritonitis due to this organism.",
"affiliations": "National Health Laboratory Service, Addington Hospital, Durban, South Africa. nomonde.dlamini@nhls.ac.za",
"authors": "Dlamini|Nomonde Ritta|NR|;Bhamjee|Ahmed|A|;Levick|Penelope|P|;Uniacke|Evelyn|E|;Ismail|Husna|H|;Smith|Anthony|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Italy",
"delete": false,
"doi": "10.3855/jidc.2074",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1972-2680",
"issue": "6(7)",
"journal": "Journal of infection in developing countries",
"keywords": null,
"medline_ta": "J Infect Dev Ctries",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D001885:Bordetella Infections; D016950:Bordetella bronchiseptica; D017809:Fatal Outcome; D005260:Female; D006519:Hepatitis, Alcoholic; D006801:Humans; D010538:Peritonitis; D018410:Pneumonia, Bacterial; D013902:Radiography, Thoracic",
"nlm_unique_id": "101305410",
"other_id": null,
"pages": "588-91",
"pmc": null,
"pmid": "22842947",
"pubdate": "2012-07-23",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spontaneous bacterial peritonitis and pneumonia caused by Bordetella bronchiseptica.",
"title_normalized": "spontaneous bacterial peritonitis and pneumonia caused by bordetella bronchiseptica"
} | [
{
"companynumb": "ZA-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-263383",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"d... |
{
"abstract": "BACKGROUND\nInterstitial lung disease (ILD) is a rare adverse event in patients receiving adjuvant or neoadjuvant chemotherapy (NAC) for breast cancer. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature. Given these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received epirubicin and cyclophosphamide (EC) and compared their findings with non-ILD cases.\n\n\nMETHODS\nThe present single-center retrospective study included breast cancer patients who underwent adjuvant chemotherapy or NAC at our hospital between January 2014 and January 2021.\n\n\nRESULTS\nThirty-nine patients who had received EC for operable breast cancer were enrolled in this study. ILD developed 5 out of 39 patients (12.8%). The incidence of ILD in patients with non-dose-dense (dd) or dd chemotherapy was statistically significantly different (p = 0.0149). ILD occurred in three patients during dd EC treatment and two during weekly paclitaxel (wPTX) after dd EC. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, in two patients with continuous pyrexia, and in two patients from computed tomography imaging, which was taken to estimate the efficacy of chemotherapy, in two patients. Three of the 5 ILD patients underwent bronchoalveolar lavage, and 2 of these patients were diagnosed with Pneumocystis jirovecii pneumonia (PCP). There were no cases of serious ILD that required steroid pulse therapy.\n\n\nCONCLUSIONS\nDd chemotherapy may be associated with an increased ILD frequency, which may reflect developing PCP. Careful monitoring and a timely diagnosis are useful for detecting early-stage ILD.",
"affiliations": "Department of Breast Surgery, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan. tezuken@gmail.com.;Department of Surgery, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Medical Oncology, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Respiratory Medicine, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Respiratory Medicine, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Nursing Department, Izumi City General Hospital Izumi, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Nursing Department, Izumi City General Hospital Izumi, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Pharmacy, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Pharmacy, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan.;Department of Medical Oncology, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073, Japan. takayo.ota@gmail.com.",
"authors": "Tezuka|Kenji|K|http://orcid.org/0000-0001-5763-4539;Miura|Kotaro|K|;Nakano|Yusuke|Y|;Ueda|Takahiro|T|;Yagyu|Kyoko|K|;Matsuyama|Shimako|S|;Shirai|Masami|M|;Okuda|Hiroshi|H|;Ujikawa|Miho|M|;Ota|Takayo|T|https://orcid.org/0000-0003-1630-8301",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12957-021-02289-0",
"fulltext": "\n==== Front\nWorld J Surg Oncol\nWorld J Surg Oncol\nWorld Journal of Surgical Oncology\n1477-7819\nBioMed Central London\n\n2289\n10.1186/s12957-021-02289-0\nResearch\nInterstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer\nhttp://orcid.org/0000-0001-5763-4539\nTezuka Kenji tezuken@gmail.com\n\n1\nMiura Kotaro 2\nNakano Yusuke 3\nUeda Takahiro 4\nYagyu Kyoko 4\nMatsuyama Shimako 5\nShirai Masami 5\nOkuda Hiroshi 6\nUjikawa Miho 6\nhttps://orcid.org/0000-0003-1630-8301\nOta Takayo takayo.ota@gmail.com\n\n3\n1 Department of Breast Surgery, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n2 Department of Surgery, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n3 Department of Medical Oncology, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n4 Department of Respiratory Medicine, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n5 Nursing Department, Izumi City General Hospital Izumi, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n6 Department of Pharmacy, Izumi City General Hospital, 4-5-1 Wake, Izumi, Osaka, 594-0073 Japan\n11 6 2021\n11 6 2021\n2021\n19 16921 2 2021\n4 6 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\nInterstitial lung disease (ILD) is a rare adverse event in patients receiving adjuvant or neoadjuvant chemotherapy (NAC) for breast cancer. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature.\n\nGiven these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received epirubicin and cyclophosphamide (EC) and compared their findings with non-ILD cases.\n\nMethods\n\nThe present single-center retrospective study included breast cancer patients who underwent adjuvant chemotherapy or NAC at our hospital between January 2014 and January 2021.\n\nResults\n\nThirty-nine patients who had received EC for operable breast cancer were enrolled in this study. ILD developed 5 out of 39 patients (12.8%). The incidence of ILD in patients with non-dose-dense (dd) or dd chemotherapy was statistically significantly different (p = 0.0149). ILD occurred in three patients during dd EC treatment and two during weekly paclitaxel (wPTX) after dd EC. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, in two patients with continuous pyrexia, and in two patients from computed tomography imaging, which was taken to estimate the efficacy of chemotherapy, in two patients. Three of the 5 ILD patients underwent bronchoalveolar lavage, and 2 of these patients were diagnosed with Pneumocystis jirovecii pneumonia (PCP). There were no cases of serious ILD that required steroid pulse therapy.\n\nConclusions\n\nDd chemotherapy may be associated with an increased ILD frequency, which may reflect developing PCP. Careful monitoring and a timely diagnosis are useful for detecting early-stage ILD.\n\nKeywords\n\nBreast cancer\nDose-dense chemotherapy\nInterstitial lung disease\nPneumocystis jirovecii pneumonia\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nInterstitial lung disease (ILD) is a large heterogenous group of pulmonary diseases that involve the interstitium of the lungs [1, 2]. Injury to the alveolar epithelial cells initiates an inflammatory response. Inflammatory cells activate fibroblasts in the interstitium, which damage the extracellular matrix permanently and prevent gas exchange in the lungs. The causes of ILD can be classified as idiopathic or non-idiopathic. Drug-induced interstitial lung disease (DILD) is one of the non-idiopathic ILDs.\n\nIn breast cancer patients receiving adjuvant or neoadjuvant chemotherapy (NAC), ILD is considered a rare adverse effect with a potentially fatal prognosis. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature. In pivotal phase III clinical trials, with standard adjuvant chemotherapies, such as adriamycin and cyclophosphamide (AC) [3], epirubicin and cyclophosphamide (EC) [4], docetaxel and cyclophosphamide [5], or AC followed by paclitaxel or docetaxel [6], no ILDs were reported as adverse events, with the exception of one case of pneumonia in a patient who received EC [4]. Given these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received EC and compared their findings with non-ILD cases.\n\nMethods\n\nThe present single-center retrospective study included breast cancer patients who underwent adjuvant or NAC at our hospital between January 2014 and January 2021. The ethics committee of our institution approved this study.\n\nThe study protocol was approved by the Ethics Committee of Izumi City General Hospital (20-J17, 23 October 2020).\n\nAge, estimated glomerular filtration rate (eGFR), smoking history (renal dysfunction and smoking history are known as a risk factor for ILD [7, 8]), stage, estrogen receptor (ER) status, progesterone receptor (PgR) status, human epidermal growth factor receptor 2 (HER2) overexpression, and menopausal status were studied as patient background and analyzed retrospectively. ER and PgR positive were defined as an expression by immunochemistry (IHC) in more than 10% of the cancer cells. HER2 overexpression was evaluated as positive by IHC with a score of 3+ or 2+ with a positive fluorescence in situ hybridization test.\n\nThe adjuvant or neoadjuvant chemotherapy regimens included tri-weekly or dose-dense (dd) chemotherapy, such as EC, or dd EC followed by weekly paclitaxel (wPTX) or triweekly docetaxel. NAC was administered when the clinicopathological risk was estimated high (e.g., tumors ≥ 2 cm, hormone receptor negative, HER2 overexpression were existed). Since April 2018, we implemented the dd EC regimen, and administered especially if nodal status was positive, or hormone negative with high proliferative breast cancer.\n\nPatients received four cycles of EC chemotherapy (E, 90 mg/m2; C 600 mg/m2). Dd chemotherapy every 2 weeks 4 cycles of EC. All drugs were administered via intravenous infusion on day 1 of each cycle. Prophylactic pegfilgrastim (3.6 mg) was administered via subcutaneous injection on day 3 for all dd regimens. Trastuzumab (HER) alone or in combination with pertuzumab (PER) was administered concurrently during wPTX or triweekly docetaxel in patients with the overexpression of HER2.\n\nThe diagnosis of ILD was made by computed tomography (CT). ILD was defined as an interstitial shadow on CT, and was classified into four patterns according to previous reports [9]: (i) diffuse alveolar damage (DAD)-like pattern, (ii) chronic interstitial pneumonia-like pattern, (iii) eosinophilic pneumonia-like pattern, (iv) organizing pneumonia (OP)-like pattern, and (v) hypersensitivity reaction (HR)-like pattern.\n\nPneumocystis jirovecii pneumonia (PCP) was diagnosed with (i) positive polymerase chain reaction from bronchoalveolar lavage (BAL) and (ii) high serum β-D glucan levels.\n\nAdverse events (AEs) were graded according to the common terminology criteria for adverse events 5.0 (CTCAE) [10]. The term “ILD” is considered to be in the same category as pneumonitis in the present report.\n\nComparisons between two groups were performed using Mann-Whitney test, Pearson’s chi-square test, and Fisher’s exact test. P values of < 0.05 were considered to indicate statistical significance. Data were analyzed with using GraphPad Prism version 8 (La Jolla, CA, USA).\n\nTo examine a frequency of ILDs in published literatures, we reviewed literatures and pivotal clinical trials. Using the terms, “adriamycin,” “epirubicin,” “cyclophosphamide.” “dose dense.” “breast cancer,“ “interstitial lung disease,” “pneumonitis.” we searched PubMed up to 21 April 2021 to identify published articles on neoadjuvant/adjuvant chemotherapies associated with ILD in early breast cancer. We included studies written in English. We excluded studies using other treatments, such as using liposomal doxorubicin or included radiotherapy. To review, we included papers reporting phase II or phase III clinical trials.\n\nResults\n\nPatient characteristics\n\nThirty-nine patients who had received EC for operable breast cancer were enrolled in this study. The characteristics of the patients are shown in Table 1. Five out of 39 patients developed ILD (12.8%). The median ages of patients with and without ILD were 55 and 55 (range 38–63 and 29–74) years, respectively. None of the enrolled patients with ILD had a history of smoking. There were no marked differences in the eGFR value, hormonal, HER2, or menopausal statuses of the groups, whereas the incidence of ILD in patients with non-dd or dd chemotherapy was statistically significantly different (p = 0.0149). Five of the 18 (27.8%) patients who received dd EC developed ILD. Table 1 Patient characteristics with and without ILD (n = 39)\n\n\tWith ILD (n = 5)\tWithout ILD (n = 34)\tp valueb)\t\nAge (years)\t\t\t\t\n Median (range)\t55 (38–63)\t55 (29–74)\tNS\t\neGFR (mL/min)\t\t\t\t\n Median (range)\t90 (60–95)\t79.5 (48–120)\tNS\t\nSmoking history\t\t\t\t\n Yes\t0\t4\t\t\n No\t5\t30\tNS\t\nStage\t\t\t\t\n I\t0\t7\t\t\n IIA\t2\t13\t\t\n IIB\t2\t4\t\t\n IIIA\t1\t6\t\t\n IIIB\t0\t1\t\t\n IIIC\t0\t3\tNS\t\nEstrogen receptora)\t\t\t\t\n Positive\t4\t20\t\t\n Negative\t1\t14\tNS\t\nProgesterone receptora)\t\t\t\t\n Positive\t3\t12\t\t\n Negative\t2\t22\tNS\t\nHER 2 status\t\t\t\t\n Positive\t0\t15\t\t\n Negative\t5\t19\tNS\t\nMenopausal status\t\t\t\t\n Premenopausal\t1\t13\t\t\n Postmenopausal\t4\t21\tNS\t\ndd regimen administered\t\t\t\t\n Yes\t5\t13\t\t\n No\t0\t21\t< .05\t\nILD interstitial lung disease, eGFR estimated glomerular filtration rate, HER2 human epidermal growth factor receptor 2, dd dose-dense chemotherapy, NS not significant\n\naDefined as an expression by immunochemistry in more than 10% of the cancer cells\n\nb< 0.05 were considered to indicate statistical significance\n\nIncidence and characteristics of ILD\n\nRegimens stratified by the presence of ILD are shown in Table 2. ILD occurred in three patients during dd EC and two during wPTX after dd EC. Table 2 Administered regimens with and without ILD (n = 39)\n\nAdministered regimen\tWith ILD\tWithout ILD\t\nEC only\t0\t1\t\nEC followed by wPTX\t0\t9\t\ndd EC only\t3\t0\t\ndd EC followed by wPTX\t2\t9\t\nEC followed by wPTX with HER\t0\t6\t\nEC followed by triweekly docetaxel with HER\t0\t1\t\nEC followed by wPTX with HER and PER\t0\t4\t\nddEC followed by wPTX with HER\t0\t1\t\nddEC followed by wPTX with HER and PER\t0\t3\t\nILD interstitial lung disease, E epirubicin, C cyclophosphamide, wPTX weekly paclitaxel, dd dose dense, HER trastuzumab, PER pertuzumab\n\nThe clinical characteristics and outcomes of the five patients with ILD are shown in Table 3. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, two with continuous pyrexia, and two by performing CT to estimate the anti-cancer effect after EC. Case numbers 3 and 4 in Table 3 were accompanied by a low level of percutaneous oxygen saturation. All patients were considered to have grade 1 or 2 ILD. One patient recovered with drug withdrawal alone. No patients required the administration of intravenous steroid pulse therapy. Table 3 Clinical characteristics and outcomes of 5 patients with ILD (n = 5)\n\nCase\tDiagnostic opportunity\tSpO2a) (%)\tKL-6a) (U/mL)\tGradeb)\tCT findings\tBAL and its diagnosis\tTherapy for ILD\t\n1\tContinuous pyrexia\t97\t316\t2\tHR\tDone, PCP\tPSL + TMP/SMX\t\n2\tContinuous pyrexia\t98\t468\t1\tHR\tDone, Negative\tNone\t\n3\tHigh KL-6, low SpO2\t94\t716\t2\tHR\tNone\tPSL\t\n4\tE-CTc), low SpO2\t94\t338\t2\tOP\tNone\tPSL\t\n5\tE-CT\t98\t346\t2\tHR\tDone, PCP\tTMP/SMX\t\nILD interstitial lung disease, SpO2 percutaneous oxygen saturation, KL-6 serum Krebs von den Lungen-6, CT computed tomography, BAL bronchoalveolar lavage sampling, HR hypersensitivity reaction-like pattern, PCP Pneumocystis jiroveci pneumonia, PSL orally prednisolone (a day), TMP/SMX orally trimethoprim-sulfamethoxazole (a day), OP organizing pneumonia-like pattern\n\naValues were at the onset of ILD. Standard value; SpO2 ≥ 95%, KL-6 < 500 U/mL\n\nbILD (pneumonitis) grade as in common terminology criteria for adverse events 5.0\n\ncCT to estimate the anti-cancer effect after epirubicin and cyclophosphamide\n\nFour of the five patients showed an HR-like CT pattern. Representative CT images are shown in Fig. 1. No patients showed any obvious findings on chest X-ray, whereas CT showed bilateral diffuse ground-glass opacity. Fig. 1 Computed tomography of the chest before neoadjuvant chemotherapy and at the onset of interstitial lung disease in a 63-year-old female (with a hypersensitivity reaction-like pattern similar to that seen in case number 3) and in a 57-year-old female (with an organizing pneumonia-like pattern similar to that seen in case number 4)\n\nThree of the 5 ILD patients underwent BAL, 2 of these patients were diagnosed with PCP and were orally treated with trimethoprim-sulfamethoxazole (720 mg and 3600 mg, respectively, daily). BAL culturing revealed that the remaining one was negative for P. jiroveci and Mycoplasma. Candida antigen was not measured in any cases because they were judged to have mild ILD based on CT.\n\nRegarding the subsequent clinical course, case 3 discontinued preoperative chemotherapy, and then operations were performed after they had recovered from ILD. Cases 1, 4, and 5 resumed wPTX postoperatively after preoperative EC and surgery. Case 2 developed ILD during preoperative wPTX and also recovered with drug withdrawal alone and resumed the administration of the remaining paclitaxel prior to surgery.\n\nFollowing the strategies to examine ILD cases in the literature, we retrieved 18 clinical trials and 6 case reports from PubMed (Fig. 2). The result of reviewing literatures is summarized as Table 4 [3–6, 11–30]. Fig. 2 Consort diagram for the literature search\n\nTable 4 ILD associated with neo/adjuvant AC or (F)EC chemotherapy in early breast cancer\n\nChemotherapy\tAuthor\tYear\tILD\tCause\t\nClinical trials\t\t\t\t\t\nAC\tFisher B et al. [3]\t1990\tNA\t\t\nEC\tFisher B et al. [4]\t2001\tNA\t\t\nAC→T, ddAC→T\tCitron ML et al. [11]\t2003\tNA\t\t\nddFEC\tDang CT et al. [12]\t2004\t9%\t\t\nAC→T vs →TH\tRomond EH et al. [13]\t2005\t0% vs 0.4%, 0.6%\t\t\nFEC\tVenturini M et al. [14]\t2005\t0%\t\t\nddFEC\tVenturini M et al. [14]\t2005\t< 1%\t\t\nAC\tJones SE et al. [5]\t2006\tNA\t\t\nAC→T\tSparano JA et al. [6]\t2008\t< 0.5%\t\t\nddEC→T\tDang C et al. [15]\t2008\t0%\t\t\nEC→T vs EC→TH\tShimizu et al. [16]\t2010\tNA\t\t\nT→FEC\tGonzalez-Angulo AM et al. [17]\t2014\t0%\t\t\nAC→T vs →TH\tWaks AG et al. [18]\t2015\t0% vs 0%\t\t\nddAC→T vs →TH\tWaks AG et al. [18]\t2015\t0% vs 0.6%\tPCP\t\ndd(F)EC→T, (F)EC→T\tDel Mastro L et al. [19]\t2015\tNA\t\t\nddEC→D, FEC\tFoukakis T et al. [20]\t2016\tNA\t\t\n(F)AC, (F)EC→TH, DH vs (F)AC, (F)EC→THP or DHP\tvon Minckwitz G et al. [21]\t2017\tNA\t\t\nAC, EC→DC'H vs AC, EC→DC'HP\tvon Minckwitz G et al. [21]\t2017\tNA\t\t\nddAC, ddEC→T\tTakabatake D et al. [22]\t2018\tNA\t\t\nddEC→Next treatment\tMorita S et al. [23]\t2018\t3.9%\tPCP\t\nnab-PTX→FEC\tKin T et al. [24]\t2020\tNA\t\t\nCase reports\t\t\t\t\t\nddAC\tTolaney SM et al. [25]\t2006\t1 case\tPCP\t\ndd (detailed regimen, not mentioned)\tTolaney SM et al. [25]\t2006\t1 case\tPCP\t\nFEC→T\tKawajiri H et al. [26]\t2013\t5 cases\t\t\nFEC\tShinohara A et al. [27]\t2013\t1 case\tPCP\t\nddAC→T\tBielopolsky D et al. [28]\t2017\t3 cases\t\t\nEC→H\tSugaya A et al. [29]\t2017\t1 case\t\t\nddAC\tKhoo C et al. [30]\t2019\t1 case\tPCP\t\nAbbreviations: A doxorubicin, E epirubicin, C cyclophosphamide, C' carboplatin, D docetaxel, dd dose-dense, F fluorouracil, H trastuzumab, ILD interstitial lung disease, NA not assessed, PCP pneumocystis jirovecii pneumonia, T paclitaxel, TH paclitaxel and trastuzumab, THP paclitaxel, trastuzumab, and pertuzumab\n\nIn phase II or phase III clinical trials, 55.6 % of publications (10 out of 18) did not assess ILDs. In ILD-reported clinical trials, all except two publications reported less than 1% of incidence. As case reports, 13 cases were identified in our literature search.\n\nDiscussion\n\nDd chemotherapy has been popular since it was introduced in the early 2000s and is now a standard treatment for patients with high-risk breast cancer, as several randomized controlled studies have revealed that its survival benefits are superior to those of standard chemotherapy [11, 20, 22]. In three phase III trials, in adjuvant settings, ILDs were not reported in either the dd or control groups [11, 14, 19]. In these trials, doxorubicin, cyclophosphamide followed by docetaxel [11], or fluorouracil, epirubicin, and cyclophosphamide (FEC) [14], or FEC or EC followed by paclitaxel [19] were administered for chemotherapy. In contrast, in a phase II trial of dd FEC followed by weekly alternate taxane treatment (paclitaxel or docetaxel) as adjuvant therapy, 4 of 44 patients (9%) developed ILD (pneumonitis) during dd FEC [12], and in a Brazilian population, the frequency of ILD in patients who received wPTX (80 mg/m2) was as high as 4.2% [31].\n\nIn the case of HER2-positive breast cancer, no cases of ILD were reported in a phase II trial of EC followed by PTX and HER [16]. In the B-31 trial, which investigated AC followed by PTX and HER, 4 of 864 patients developed ILD, one of whom died. In the N9381 trial, 5 of 814 patients in the trastuzumab group developed grade 3 ILD or pulmonary infiltration, one of whom died [13]. In patients who received HER and PER in addition to several adjuvant regimens, only grade 3 adverse events were reported; none of these patients developed ILD [21]. The incidence of ILDs in this study was approximately 13% and tended to be higher in patients who received a dd regimen. Although this incidence was relatively high in comparison to previously reported studies, all patients developed grade 1 or 2 ILD and recovered without intravenous steroid pulse therapy.\n\nIt is difficult to determine the culprit of ILDs in patients who receive multiple drugs simultaneously. Any drugs are capable of inducing ILDs; however, reports of FEC- or EC-related ILDs are very rare in the relevant literature. Paclitaxel-induced ILDs are also rare, with a reported incidence of 0.7–12% [28, 32]. In the present study, ILDs were identified during dd EC as well as during PTX following dd EC. Both agents might be responsible for DILDs.\n\nDd chemotherapy increases the incidence of PCP, one of representative causes of ILD. PCP has been reported in several patients receiving dd chemotherapy for early breast cancer [30, 33]. In a large cohort study, the overall incidence of PCP among 2057 patients treated with dd AC was 0.6%, whereas no PCP was diagnosed in 1001 patients treated with non-dd AC [18]. The total dose of steroids (as prophylaxis against nausea during the administration of AC) over 8 weeks of dd chemotherapy in comparison to 12 weeks of standard chemotherapy might explain the increased incidence of PCP [18]. In the present study, 5 out of 18 (27.8%) patients developed ILDs with dd chemotherapy. We also identified two cases of PCP in patients who received dd chemotherapy. We used dexamethasone (4 mg, twice daily) on days 2–3, which might have influenced the rate of PCP infection. It is important to obtain BAL samples to distinguish DILD from PCP.\n\nIn most cases of DILD, CT findings are characterized by a bilateral diffuse, extensive patchy, reticular, or ground-glass appearance, with a pattern of infiltration. Fatal lung disorders commonly have a DAD-like pattern, and the prognosis is poor, regardless of the drug that is used [7–9]. In contrast, almost all of our cases showed an HR-like pattern, which manifests as bilateral diffuse ground-glass opacity, responds well to steroid treatment, and has a good prognosis [7–9]. In the present study, we performed close monitoring of clinical findings, such as a continuous fever and KL-6 elevation, and CT imaging evaluation was proactively performed, which facilitated the early detection of ILD.\n\nThis study was limited by its retrospective nature and small population, which might have influenced on the incidence of ILD in our study. In addition, reporting methods of ILD may differ around the world [7]. Previous reports did not clarify whether or not PCP should be added as an ILD or pneumonitis and did not clearly distinguish between the two entities [12, 31]. If PCP had been excluded from ILD in our study, the ILD frequency in this study would have been a valid number.\n\nIn summary, we studied the clinical findings and imaging characteristics of ILD in early breast cancer patients receiving adjuvant or neoadjuvant chemotherapy. The incidence of ILD in the present study was relatively high; however, all cases were identified as mild ILDs. Dd chemotherapy increased the incidence of ILDs, partly because PCP cases were included. Proactively performing CT imaging evaluation might be useful for the early detection of ILD.\n\nAbbreviations\n\nAC Adriamycin and cyclophosphamide\n\nAE Adverse event\n\nBAL Bronchoalveolar lavage\n\nCT Computed tomography\n\nCTCAE Common Terminology Criteria for Adverse Events\n\nDAD Diffuse alveolar damage\n\ndd Dose-dense\n\nDILD Drug-induced interstitial lung disease\n\nEC Epirubicin and cyclophosphamide\n\neGFR Estimated glomerular filtration rate\n\nER Estrogen receptor\n\nFEC Fluorouracil, epirubicin, and cyclophosphamide\n\nHER Trastuzumab\n\nHER2 Human epidermal growth factor receptor 2\n\nHR Hypersensitivity reaction\n\nIHC Immunochemistry\n\nILD Interstitial lung disease\n\nKL-6 Krebs von den Lungen-6\n\nNAC Neoadjuvant chemotherapy\n\nOP Organizing pneumonia\n\nPCP Pneumocystis jirovecii pneumonia\n\nPER Pertuzumab\n\nPgR Progesterone receptor\n\nwPTX Weekly paclitaxel\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nKenji Tezuka conceived and designed the study. Kenji Tezuka, Kotaro Miura, and Takayo Ota drafted the manuscript. All authors involved in patient management read, critically reviewed, and approved the manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was retrospective. Patients were not required to give their informed consent for the study. We used an opt-out method to obtain consent for the study using a website (https://izumi.tokushukai.or.jp/). The research protocol and the website were approved by the Institutional Review Board.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Cosgrove GP, Schwarz MI. Approach to the evaluation and diagnosis of interstitial lung disease. In; Interstitial lung disease. 5th ed. Schwarz MI, King TE (eds): PMPH USA, Ltd. New Haven, CT, Kindle; 2019.\n2. Gulati M Diagnostic assessment of patients with interstitial lung disease Prim Care Respir J. 2011 20 2 120 127 10.4104/pcrj.2010.00079 21509417\n3. Fisher B, Brown AM, Dimitrov NV, Poisson R, Redmond C, Margolese RG, et al. 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Sparano JA, Wang M, Martino S, Jones V, Perez EA, Saphner T, et al. Weekly paclitaxel in the adjuvant treatment of breast cancer. N Engl J Med. 2008;358(16):1663–71. 10.1056/NEJMoa0707056.\n7. Skeoch S, Weatherley N, Swift AJ, Oldroyd A, Johns C, Hayton C, et al. Drug-induced interstitial lung disease: A systematic review. J Clin Med. 2018;7(10):356. 10.3390/jcm7100356.\n8. Camus P Fanton A Bonniaud P Camus C Foucher P Interstitial lung disease induced by drugs and radiation Respiration. 2004 71 4 301 326 10.1159/000079633 15316202\n9. Kubo K, Azuma A, Kanazawa M, Kameda H, Kusumoto M, Genma A, et al. Japanese Respiratory Society Committee for formulation of Consensus statement for the diagnosis and treatment of drug-induced lung injuries: Consensus statement for the diagnosis and treatment of drug-induced lung injuries. Respir Investig. 2013;51(4):260–77. 10.1016/j.resinv.2013.09.001.\n10. Common terminology criteria for adverse events 5.0 (CTCAE). 2017.\n11. Citron ML, Berry DA, Cirrincione C, Hudis C, Winer EP, Gradishar WJ, et al. Randomized trial of dose-dense versus conventionally scheduled and sequential versus concurrent combination chemotherapy as postoperative adjuvant treatment of node-positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol. 2003;21(8):1431–9. 10.1200/JCO.2003.09.081.\n12. Dang CT D'Andrea GM Moynahan ME Dickler MN Seidman AD Fornier M Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer Clin Cancer Res. 2004 10 17 5754 5761 10.1158/1078-0432.CCR-04-0634 15355903\n13. Romond EH, Perez EA, Bryant J, Suman VJ, Geyer CE Jr, Davidson NE, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med. 2005;353(16):1673–84. 10.1056/NEJMoa052122.\n14. Venturini M Del Mastro L Aitini E Baldini E Caroti C Contu A Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial J Natl Cancer Inst. 2005 97 23 1724 1733 10.1093/jnci/dji398 16333028\n15. Dang C, D'Andrea G, Lake D, Sugarman S, Fornier M, Moynahan ME, et al. Prolonged dose-dense epirubicin and cyclophosphamide followed by paclitaxel in breast cancer is feasible. Clin Breast Cancer. 2008;8(5):418–24. 10.3816/CBC.2008.n.050.\n16. Shimizu T, Hirano A, Kamimura M, Ogura K, Kim N, Watanabe O, et al. A phase II study of epirubicin and cyclophosphamide followed by weekly paclitaxel with or without trastuzumab as primary systemic therapy in locally advanced breast cancer. Anticancer Res. 2010;30(11):4665–71.\n17. Gonzalez-Angulo AM, Akcakanat A, Liu S, Green MC, Murray JL, Chen H, et al. 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Foukakis T, von Minckwitz G, Bengtsson NO, Brandberg Y, Wallberg B, Fornander T, et al. Swedish Breast Cancer Group (SweBCG), the German Breast Group (GBG), and the Austrian Breast & Colorectal Cancer Study Group (ABCSG): Effect of tailored dose-dense chemotherapy vs standard 3-weekly adjuvant chemotherapy on recurrence-free survival among women with high-risk early breast cancer: a randomized clinical trial. JAMA. 2016;316(18):1888–96. 10.1001/jama.2016.15865.\n21. von Minckwitz G, Procter M, de Azambuja E, Zardavas D, Benyunes M, Viale G, et al. APHINITY Steering Committee and Investigators: Adjuvant Pertuzumab and Trastuzumab in Early HER2-Positive Breast Cancer. N Engl J Med. 2017;377(2):122–31. 10.1056/NEJMoa1703643.\n22. Takabatake D, Kajiwara Y, Ohtani S, Itano Y, Yamamoto M, Kubo S, et al. The efficacy and feasibility of dose-dense sequential chemotherapy for Japanese patients with breast cancer. Breast Cancer. 2018;25(6):717–22. 10.1007/s12282-018-0877-1.\n23. 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Shinohara T Yasui M Yamada H Fujimori Y Yamagishi K Pneumocystis pneumonia during Postoperative Adjuvant Chemotherapy for Breast Cancer Case Rep Oncol Med. 2013 2013 954346 23762693\n28. Bielopolski D Evron E Moreh-Rahav O Landes M Stemmer SM Salamon F Paclitaxel-induced pneumonitis in patients with breast cancer: Case series and review of the literature J Chemother. 2017 29 2 113 117 10.1179/1973947815Y.0000000029 25978147\n29. Sugaya A, Ishiguro S, Mitsuhashi S, Abe M, Hashimoto I, Kaburagi T, et al. Interstitial lung disease associated with trastuzumab monotherapy: a report of 3 cases. Mol Clin Oncol. 2017;6(2):229–32. 10.3892/mco.2016.1113.\n30. Khoo C Gilchrist J Williamson JP Paul M Kefford R Pneumocystis jirovecii in a patient on dose-dense chemotherapy for early breast cancer Respirol Case Rep. 2019 7 e00459 31312456\n31. Santana IA, Oliveira JA, da Silva Lima JM, Testa L, Piato JRM, Hoff PM, et al. Feasibility of two schedules of weekly paclitaxel in HER2-negative early breast cancer in a Brazilian community setting. Breast Cancer. 2016;23(2):261–5. 10.1007/s12282-014-0564-9.\n32. Khan A McNally D Tutschka PJ Bilgrami S Paclitaxel-induced acute bilateral pneumonitis Ann Pharmacother. 1997 31 12 1471 1474 10.1177/106002809703101205 9416383\n33. Watanabe H, Kitahara Y, Murakami Y, Nihashi F, Matsushima S, Eifuku T, et al. Pneumocystis jirovecii pneumonia in a patient with breast cancer receiving neoadjuvant dose-dense chemotherapy. Intern Med. 2020;59(7):987–90. 10.2169/internalmedicine.3907-19.\n\n",
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"journal": "World journal of surgical oncology",
"keywords": "Breast cancer; Dose-dense chemotherapy; Interstitial lung disease; Pneumocystis jirovecii pneumonia",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D005260:Female; D006801:Humans; D017563:Lung Diseases, Interstitial; D020360:Neoadjuvant Therapy; D011379:Prognosis; D012189:Retrospective Studies",
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"title": "Interstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer.",
"title_normalized": "interstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer"
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"abstract": "The use of new Direct Acting Antivirals, specific of HCV, has greatly improved the HCV treatment. Most of the DAA are specific of HCV genotypes. Genotyping methods may target different regions of the HCV genome, though only the whole genome sequencing could confirm the correct genotype. The present study describes the virological investigation of a treatment failure due to the false identification of an unusual 2k/1b recombinant HCV form. It describes the sequencing methods, and the similarity analysis of the sequences to different genotype query sequences, to identify the recombination breakpoint.",
"affiliations": "Normandie Univ, UNIROUEN, EA 2656, Department of Virology, Rouen University Hospital, Rouen, France.;Normandie Univ, UNIROUEN, EA 2656, Department of Virology, Rouen University Hospital, Rouen, France.;Department of Gastroenterology, Rouen University Hospital, Rouen, France.;Department of Gastroenterology, Rouen University Hospital, Rouen, France.;Normandie Univ, UNIROUEN, EA 2656, Department of Virology, Rouen University Hospital, Rouen, France.;Institut de Biologie Structurale, UMR 5075 CEA-CNRS-UGA, Department of Virology, Grenoble-Alpes University Hospital, Grenoble, France.;Normandie Univ, UNIROUEN, EA 2656, Department of Virology, Rouen University Hospital, Rouen, France.;Department of Gastroenterology, Rouen University Hospital, Rouen, France.",
"authors": "Mourez|Thomas|T|0000-0001-6173-2908;Decroos|Amandine|A|;Goria|Odile|O|;Montialoux|Hélène|H|;De Oliveira|Fabienne|F|;Larrat|Sylvie|S|;Plantier|Jean-Christophe|JC|;Riachi|Ghassan|G|",
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"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D003951:Diagnostic Errors; D005838:Genotype; D060005:Genotyping Techniques; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D011995:Recombination, Genetic; D017422:Sequence Analysis, DNA; D017211:Treatment Failure",
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"title": "Misidentification of recombinant hepatitis C virus leading to treatment failure with direct acting antivirals.",
"title_normalized": "misidentification of recombinant hepatitis c virus leading to treatment failure with direct acting antivirals"
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"abstract": "Neurotoxicity from high-dose cytarabine, a pyrimidine metabolite used in treatment for acute myeloid leukemia, is a known but dose-limiting toxicity which has incidences in up to 14% in patients receiving high doses of the drug. Neurologic symptoms vary but range from somnolence and ataxia to more severe complications such as seizures and even death. There are no validated treatments other than discontinuation of the drug and supportive measures. We present two cases of cytarabine-related neurotoxicity treated with corticosteroids with complete resolution of symptoms.",
"affiliations": "Department of Hematology and Oncology, Marshall University, 1400 Hal Greer Blvd., Huntington, WV, 25701, USA. rose67@marshall.edu.;Department of Hematology and Oncology, Marshall University, 1400 Hal Greer Blvd., Huntington, WV, 25701, USA.",
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"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D000368:Aged; D003561:Cytarabine; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D020258:Neurotoxicity Syndromes",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "554-557",
"pmc": null,
"pmid": "29946854",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18836794;6571798;1648599;2178634;15551283;22700723;11391764;3585447;8078551;26391778;8909309;7306918",
"title": "Successful treatment of cytarabine-related neurotoxicity with corticosteroids, a case series.",
"title_normalized": "successful treatment of cytarabine related neurotoxicity with corticosteroids a case series"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201811633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
... |
{
"abstract": "Infantile spasm or West syndrome is a pediatric epileptic disorder characterized by flexor and/or extensor spasms beginning in childhood. Vigabatrin is an effective medical therapy for infantile spasm but has pronounced, potentially worrisome imaging findings in patients receiving therapy. We present the case of an 8-month-old infant with such brain magnetic resonance imaging findings after treatment initiation. In this article, we highlight the imaging changes and discuss the differential diagnosis along with the required follow-up.",
"affiliations": "Department of Radiology, Weill Cornell Medical College of Cornell University, New York, NY; Division of Transplantation-Oncology and Infectious Diseases, Weill Cornell Medical College of Cornell University, New York, NY. Electronic address: kah2025@med.cornell.edu.;Division of Transplantation-Oncology and Infectious Diseases, Weill Cornell Medical College of Cornell University, New York, NY. Electronic address: thw2003@med.cornell.edu.;Department of Radiology, Weill Cornell Medical College of Cornell University, New York, NY. Electronic address: jlc2008@med.cornell.edu.",
"authors": "Hussain|Kaiser|K|;Walsh|Thomas J|TJ|;Chazen|J Levi|JL|",
"chemical_list": "D000927:Anticonvulsants; D020888:Vigabatrin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "40(1)",
"journal": "Clinical imaging",
"keywords": "Brain MRI; Epilepsy; Infantile spasm; Vigabatrin",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000927:Anticonvulsants; D001921:Brain; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D013036:Spasms, Infantile; D020888:Vigabatrin",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "180-2",
"pmc": null,
"pmid": "26526789",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Brain MRI findings with vigabatrin therapy: case report and literature review.",
"title_normalized": "brain mri findings with vigabatrin therapy case report and literature review"
} | [
{
"companynumb": "US-LUNDBECK-DKLU2006505",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VIGABATRIN"
},
"drugadditional": null,
... |
{
"abstract": "METHODS\nA 78-year-old woman was admitted to the intensive care unit 9 hours after ingestion of 2 g of isosorbitmononitrate, 430 mg of amlodipine, 250 mg of benazepril and 600 mg of mirtazapin in suicidal intent.\n\n\nMETHODS\nClinical findings and invasive monitoring showed signs of a hyperdynamic hemodynamic cardiovascular failure caused by toxic vasodilatation.\n\n\nMETHODS\nDespite of primary detoxication, intravenous volume infusion with calcium gluconate, glucagon and naloxone and administration (norepinephrine up to 2 micro g/kg/min) no hemodynamic stabilization was achieved. Only when the vasopressin-analogue argipressin was given peripheral vasodilatation was overcome and hemodynamic stabilization resulted. 10 hours after discontinuing argipressin and norepinephrine the patient developed a mesenteric ischemia, and she finally died on the third day after admission.\n\n\nCONCLUSIONS\nIn circulatory shock due to toxic vasodilatation the use of vasopressin analogue argipressin can be helpful as an ultima therapeutic measure in catecholamine refractory shock caused by vasodilatation. Attention must be paid to overwhelming vasoconstrictor effects resulting in mesenteric ischemia.",
"affiliations": "Medizinische Klinik und Poliklinik, Innere Medizin III, Homburg/Saar.",
"authors": "Weisgerber|K|K|;Link|A|A|;Hammer|B|B|;Böhm|M|M|",
"chemical_list": "D000317:Adrenergic alpha-Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D001552:Benzazepines; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D001127:Arginine Vasopressin; D017311:Amlodipine; D008803:Mianserin; D000078785:Mirtazapine; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate; C044946:benazepril",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-2003-42979",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0012-0472",
"issue": "128(42)",
"journal": "Deutsche medizinische Wochenschrift (1946)",
"keywords": null,
"medline_ta": "Dtsch Med Wochenschr",
"mesh_terms": "D000317:Adrenergic alpha-Antagonists; D000368:Aged; D017311:Amlodipine; D000792:Angiography; D000806:Angiotensin-Converting Enzyme Inhibitors; D001127:Arginine Vasopressin; D001552:Benzazepines; D005260:Female; D006339:Heart Rate; D006439:Hemodynamics; D006801:Humans; D007262:Infusions, Intravenous; D007275:Injections, Intravenous; D007548:Isosorbide Dinitrate; D008638:Mesenteric Arteries; D008803:Mianserin; D000078785:Mirtazapine; D011041:Poisoning; D013406:Suicide, Attempted; D013997:Time Factors; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents",
"nlm_unique_id": "0006723",
"other_id": null,
"pages": "2189-92",
"pmc": null,
"pmid": "14562217",
"pubdate": "2003-10-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Vasopressin analogue injection as ultimate measure for counteracting severe catecholamine-refractory poisoning by several vasodilators taken with suicidal intent.",
"title_normalized": "vasopressin analogue injection as ultimate measure for counteracting severe catecholamine refractory poisoning by several vasodilators taken with suicidal intent"
} | [
{
"companynumb": "DE-MYLANLABS-PHBS2003DE11710",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": ... |
{
"abstract": "Several classes of recreational and prescription drugs have been associated with an increased risk of cardiovascular disease and the occurrence of arrhythmias, which may be involved in sudden deaths in chronic users even at therapeutic doses. The study presented herein focuses on pathological changes involving the heart, which may be caused by selective serotonin reuptake inhibitor use and their possible role in the occurrence of sudden cardiac death. A total of 40 cases were included in the study and were divided evenly into 2 groups: 20 cases of patients treated with selective serotonin reuptake inhibitors and 20 cases of sudden deaths involving patients void of any drug treatment. The first group included 16 patients treated with citalopram and 4 with sertraline. Autopsies, histology, biochemistry, and toxicology were performed in all cases. Pathological changes in selective serotonin reuptake inhibitor users consisted of various degrees of interstitial and perivascular fibrosis as well as a small degree of perineural fibrosis within the myocardium of the left ventricle. Within the limits of the small number of investigated cases, the results of this study seem to confirm former observations on this topic, suggesting that selective serotonin reuptake inhibitors may play a potential, causative role in the pathogenesis of sudden deaths in chronic users even at therapeutic concentrations.",
"affiliations": "From the Department of Diagnostic Medicine, Clinical and Public Health, University of Modena and Reggio Emilia, Sections of *Legal Medicine and †Clinical Pathology, Modena, Italy; and ‡University Center of Legal Medicine, Lausanne University Hospital, Lausanne, Switzerland.",
"authors": "Lusetti|Monia|M|;Licata|Manuela|M|;Silingardi|Enrico|E|;Reggiani Bonetti|Luca|L|;Palmiere|Cristian|C|",
"chemical_list": "D017367:Serotonin Uptake Inhibitors; D015283:Citalopram; D020280:Sertraline",
"country": "United States",
"delete": false,
"doi": "10.1097/PAF.0000000000000205",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "36(4)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D016022:Case-Control Studies; D015283:Citalopram; D005260:Female; D005355:Fibrosis; D006801:Humans; D008297:Male; D008875:Middle Aged; D009206:Myocardium; D032383:Myocytes, Cardiac; D012189:Retrospective Studies; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "293-7",
"pmc": null,
"pmid": "26448056",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cardiac Toxicity in Selective Serotonin Reuptake Inhibitor Users.",
"title_normalized": "cardiac toxicity in selective serotonin reuptake inhibitor users"
} | [
{
"companynumb": "US-CIPLA LTD.-2015US08126",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SERTRALINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "Syphilis is capable of compromising almost any organ; however, syphilitic hepatitis is a rare manifestation that has been described most often in HIV-infected patients. Herein, we present a 33-year-old male liver transplant recipient who presented with progressive liver dysfunction characterized by mild ALT elevation and rising cholestasis, malaise, skin rash, and alopecia. Skin biopsy was characteristic of secondary syphilis, confirmed by both skin and liver biopsy-positive immunohistochemical staining for Treponema pallidum. The patient was treated with benzathine penicillin G 2.4 million units IM q week × 3 weeks. Three months later, the patient was asymptomatic and recovered from his general malaise. He showed no skin lesions and demonstrated complete regrowth of the hair on his scalp, beard, and eyebrows. The presence of liver dysfunction with cholestasis in a transplant recipient should alert transplant providers to the possibility of syphilitic hepatitis, particularly in men who have sex with men. Though not an early manifestation, cutaneous signs of secondary syphilis may be a helpful diagnostic indicator in most cases.",
"affiliations": "Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.;Department of Dermatology, Hospital Universitari Vall d'Hebron, Barcelona, Spain.;Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.;Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Ferrándiz-Pulido|Carla|C|https://orcid.org/0000-0003-3688-9596;Ferrer|Berta|B|;Salcedo|Maria Teresa|MT|;Velasco|Marta|M|;Len|Oscar|O|;Castells|Lluis|L|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13431",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "23(1)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "lues; solid organ transplant recipients; syphilis; syphilitic hepatitis",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D018451:Homosexuality, Male; D006801:Humans; D008099:Liver; D016031:Liver Transplantation; D008297:Male; D000072339:Sexual and Gender Minorities; D013587:Syphilis",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13431",
"pmc": null,
"pmid": "32738832",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Secondary syphilis with liver involvement in a liver transplant recipient.",
"title_normalized": "secondary syphilis with liver involvement in a liver transplant recipient"
} | [
{
"companynumb": "NVSC2020ES231614",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FUROSEMIDE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Angioinvasive complications of Scedosporium infections are rare. We report two cases of mycotic aneurysm, following apparent localized infection, due to Scedosporium apiospermum and Pseudallescheria boydii. The thoracoabdominal aorta was affected in one patient, and cerebral vessels were affected in the other. Despite voriconazole therapy and surgical resection, the patients died. Previously reported cases are reviewed.",
"affiliations": "Centre for Infectious Diseases and Microbiology, Westmead Hospital, Westmead, New South Wales, Australia.",
"authors": "Ong|Adrian|A|;Blyth|Christopher C|CC|;Bency|Rosamma|R|;Vicaretti|Mauro|M|;Harun|Azian|A|;Meyer|Wieland|W|;Shingde|Meena|M|;Gilroy|Nicky|N|;Chapman|Jeremy|J|;Chen|Sharon C-A|SC|",
"chemical_list": "D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.02615-10",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "49(5)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000785:Aneurysm, Infected; D000935:Antifungal Agents; D001011:Aorta; D002536:Cerebral Arteries; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008875:Middle Aged; D008271:Mycetoma; D011541:Pseudallescheria; D011743:Pyrimidines; D021681:Scedosporium; D014230:Triazoles; D014656:Vascular Surgical Procedures; D065819:Voriconazole",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "2067-71",
"pmc": null,
"pmid": "21430108",
"pubdate": "2011-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16772225;19294403;17109292;1775852;21085536;18212110;12627286;12427626;12383359;12352630;8516902;17015631;19224064;19418347;19838745;17360002;16088460;19549223;18202441;15614697;18258122;9873163;16207945;19322683;18331448;18190310;18631862;3839532;11700493;17660058;9800807;18077629",
"title": "Fatal mycotic aneurysms due to Scedosporium and Pseudallescheria infection.",
"title_normalized": "fatal mycotic aneurysms due to scedosporium and pseudallescheria infection"
} | [
{
"companynumb": "AU-PFIZER INC-2020167272",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nGuidelines by the AAP for the use of palivizumab prophylaxis for respiratory syncytial virus (RSV) recommend administration within 72 hours prior to discharge for selected high-risk patient populations. Our institution historically administered palivizumab on a fixed-day schedule of Mondays and Thursdays, but adjusted the practice in fall 2017 to a pharmacist-driven flex-schedule based on anticipated discharge date. This review evaluated the effect of pharmacist-driven palivizumab ordering on the appropriateness of palivizumab administrations, based on AAP and institutional recommendations. Additionally, this review evaluated for effects on institutional cost.\n\n\nMETHODS\nThis was a retrospective single-center evaluation including patients for whom palivizumab was ordered between July 1, 2016, and June 30, 2018. Patients in the 2016-2017 RSV season were in the fixed-day group, while patients in the 2017-2018 RSV season were in the flex-schedule group.\n\n\nRESULTS\nA total of 142 palivizumab doses were evaluated. Overall, 97% of administrations were for an appropriate indication. All doses administered inappropriately (n = 4) occurred in the fixed-day group. In the fixed-day group, 48.6% of doses were given within 72 hours prior to discharge, which increased to 70.1% in the flex-schedule group (p = 0.01). The amount of drug saved by batching was 1 vial for every 4.9 patients in the fixed-day group, and 1 vial for every 4.8 patients in the flex-schedule group.\n\n\nCONCLUSIONS\nThere was a statistically significant improvement in compliance with AAP recommendations following the implementation of pharmacist-driven flex-schedule for palivizumab, compared to a fixed-day batching schedule. There was no significant difference in cost.",
"affiliations": null,
"authors": "Weaver|Krista L|KL|;Bondi|Deborah S|DS|;Shah|Pooja A|PA|;Bhagat|Palak H|PH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-25.7.636",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "25(7)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "antiviral prophylaxis; costs and cost analysis; palivizumab; respiratory syncytial viruses; respiratory tract infections",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "636-641",
"pmc": null,
"pmid": "33041719",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "27919877;25070304;29042834;23867491;25070315;29463335",
"title": "Evaluation of Appropriateness and Cost Savings of Pharmacist-Driven Palivizumab Ordering.",
"title_normalized": "evaluation of appropriateness and cost savings of pharmacist driven palivizumab ordering"
} | [
{
"companynumb": "US-BIOVITRUM-2020US6956",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PALIVIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "A 78-year-old woman presented with an inferior ST-segment elevation myocardial infarction in the setting of a fall resulting in facial trauma causing an unrecognized C6 cervical endplate fracture. After administration of tenecteplase, she developed a spinal epidural hematoma requiring intubation for airway protection and cessation of antiplatelet therapies. The need to delay coronary intervention in this setting led to a recurrent inferolateral ST-segment elevation myocardial infarction that eventually required coronary bypass grafting. In the first report of a spinal epidural hematoma after tenecteplase for ST-segment elevation myocardial infarction, we emphasize the need for imaging after significant trauma before initiating thrombolysis.",
"affiliations": "Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.;Section of Cardiac Surgery, Department of Surgery, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.;Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.;Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.;Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada.",
"authors": "Parr|Christopher J|CJ|;Yan|Weiang|W|;Toleva|Olga|O|;Ducas|John|J|;Garber|Philip J|PJ|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.cjco.2019.12.003",
"fulltext": "\n==== Front\nCJC Open\nCJC Open\nCJC Open\n2589-790X Elsevier \n\nS2589-790X(19)30079-4\n10.1016/j.cjco.2019.12.003\nCase Report\nSpinal Epidural Hematoma Secondary to Tenecteplase for ST-Elevation Myocardial Infarction in the Setting of Trauma and Cervical Endplate Fracture\nParr Christopher J. MDparrc@myumanitoba.caa∗ Yan Weiang MDb Toleva Olga MDa Ducas John MDa Garber Philip J. MDa a Section of Cardiology, Department of Internal Medicine, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada\nb Section of Cardiac Surgery, Department of Surgery, Max Rady College of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada\n∗ Corresponding author: Dr Christopher J. Parr, 409 Tache Ave, Winnipeg, Manitoba R3A 1R9, Canada. Tel.: +1-204-260-5425; fax: +1-204-233-9162. parrc@myumanitoba.ca\n28 12 2019 \n3 2020 \n28 12 2019 \n2 2 71 73\n17 11 2019 4 12 2019 © 2019 Canadian Cardiovascular Society. Published by Elsevier Inc.2019Canadian Cardiovascular SocietyThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 78-year-old woman presented with an inferior ST-segment elevation myocardial infarction in the setting of a fall resulting in facial trauma causing an unrecognized C6 cervical endplate fracture. After administration of tenecteplase, she developed a spinal epidural hematoma requiring intubation for airway protection and cessation of antiplatelet therapies. The need to delay coronary intervention in this setting led to a recurrent inferolateral ST-segment elevation myocardial infarction that eventually required coronary bypass grafting. In the first report of a spinal epidural hematoma after tenecteplase for ST-segment elevation myocardial infarction, we emphasize the need for imaging after significant trauma before initiating thrombolysis.\n\nRésumé\nUne femme de 78 ans a été vue en consultation pour un infarctus du myocarde inférieur avec élévation du segment ST, dans un contexte de trauma facial entraîné par une chute, causant une fracture du plateau vertébral de C6 non diagnostiquée. Après avoir reçu du ténectéplase, la patiente a présenté un hématome épidural rachidien ayant nécessité l’intubation pour protéger les voies respiratoires et l’arrêt des traitements antiplaquettaires. La nécessité de retarder l’intervention coronarienne dans ce contexte a entraîné un nouvel infarctus du myocarde inférolatéral avec élévation du segment ST, ayant par la suite nécessité un pontage aortocoronarien. Relativement au premier rapport d’hématome épidural rachidien survenu après l’administration de ténectéplase pour le traitement de l’infarctus du myocarde avec élévation du segment ST, nous insistons sur l’importance de procéder, avant d’instaurer la thrombolyse, à des examens d’imagerie chez les patients ayant subi un trauma important.\n==== Body\nNovel Teaching Points\n• Head or facial trauma often involves other unrecognized injuries, including neck fracture or basal skull fracture.\n\n• Thrombolytics should not be administered in the setting of major trauma without appropriate imaging.\n\n• Immediate imaging may significantly affect treatment decisions for acute ST-segment elevation myocardial infarction.\n\n• Spinal epidural hematoma is a rare but potentially life-threatening complication of thrombolytic treatment.\n\n• Delay in definitive therapy for myocardial infarction may lead to further ischemic coronary events.\n\n\n\n\n\nST-elevation myocardial infarction (STEMI) is a serious and time-sensitive form of acute coronary syndrome. The main tenet of therapy is to rapidly reperfuse the ischemic myocardium. Although primary percutaneous coronary intervention (PCI) is the contemporary intervention of choice, most health centres in North America are not PCI capable.1 Moreover, transfer to a PCI-capable centre within a target time frame is often not feasible. Current guidelines dictate that when a patient is more than 120 minutes away from a PCI-capable health centre, fibrinolytic therapy should be administered in the absence of any contraindications. Thus, thrombolytic therapy continues to play a critical role in early reperfusion. Thrombolysis with tenecteplase for STEMI portends a significant risk of bleeding, with an approximately 1% risk of intracranial haemorrhage and 5% risk of major bleeding.2 Intracranial bleeding in particular has an exceptionally poor prognosis, with 60% associated mortality and 25% residual disability.3,4 However, most bleeding is superficial, is procedure related, occurs at sites of vascular access, and is easily externally compressible.5\n\nWe present the case of a spinal epidural hematoma in the setting of head trauma after the administration of tenecteplase for an inferior STEMI as a unique complication of this otherwise potentially life-saving therapy.\n\nCase Report\nA 78-year-old woman presented via ambulance to a rural emergency department after syncope and an associated fall. The patient awakened with severe nausea and diaphoresis. While she was in a sitting position at the edge of her toilet, she suddenly lost consciousness and fell forward onto her face. Notably, she did not have antecedent angina. The patient’s nose appeared flattened, had a laceration on the nasal bridge, and had periorbital bruising. An electrocardiogram showed an inferior STEMI. Aspirin, clopidogrel, and enoxaparin were administered. Given that the patient presented to a hospital more than 120 minutes away from a PCI-capable centre and that the patient was thought to have nonsignificant injuries, tenecteplase 40 mg was administered intravenously 81 minutes after first medical contact time. Several hours after administration of tenecteplase, the patient developed epistaxis and bleeding from the laceration on her nasal bridge. She was then transported uneventfully to a tertiary cardiac referral centre.\n\nUpon arrival, she had dramatic electrocardiographic improvement of > 50% resolution of her inferior ST elevation. While awaiting coronary angiography, she underwent assessment of her injuries. Because of the periorbital bruising, it was thought that a basilar skull fracture and other possible associated injuries needed to be excluded. Computed tomography (CT) of the brain, facial bones, and cervical spine was performed, showing acute fractures of the bilateral nasal bones, nasal septum, and anterior inferior endplate of C6. Moreover, there was a prevertebral spinal epidural hematoma with displacement of the hypopharynx (Fig. 1). Associated with this was stridorous breathing when the patient was supine. Further antithrombotic therapies, including aspirin and clopidogrel, were held. A cervical collar was applied for stabilization. In anticipation of possible airway compromise during transfer to a specialized trauma centre, the patient was taken to the operating room, and an awake fiberoptic intubation was performed. The patient was subsequently managed under the care of a multidisciplinary trauma service that included intensive care, general surgery, orthopedic surgery, neurosurgery, and oral maxillofacial surgery. Magnetic resonance imaging (MRI) of the spine showed extensive injury of the prevertebral and posterior paravertebral cervical spine soft tissues and a small epidural hematoma at the posterior aspect of C5 and C6. Transthoracic echocardiography revealed normal left ventricular size and function. After consultation with a neurosurgeon, it was recommended to forego antiplatelet therapy. Given that the patient did not display clinical signs of neurologic injury, close observation with serial examinations was elected over operative management. She was transferred 1 week later back to the rural hospital to allow her injuries to heal further before consideration for coronary angiography.Figure 1 Sagittal computed tomography (CT) scan of the cervical spine demonstrating a prevertebral hematoma and edema extending from the mid C2 level down to the C6-7 level, anteriorly displacing and narrowing the hypopharynx, and an acute epidural hematoma along the posterior aspect of the spinal canal from C3-4 down to the C5-6 levels.\n\n\n\nOne week after discharge, the patient developed a new onset of retrosternal chest discomfort and inferolateral ST-segment elevation, and an increase in high-sensitivity serum troponin T to 8051 ng/L. She was diagnosed with a new inferolateral STEMI complicated by left ventricular dysfunction and complete heart block requiring dobutamine. This was initially managed with aspirin monotherapy and heparin. Selective coronary angiography showed severe obstructive multivessel disease, with chronic total occlusion of the left anterior descending artery, severe circumflex disease, and severe disease throughout the dominant right coronary artery. Repeat CT and MRI of the cervical spine showed interval resolution of the prevertebral soft tissue changes. Coronary artery bypass grafting was performed uneventfully on day 29 in relation to her initial presentation. The patient was discharged on day 43.\n\nDiscussion\nThis case is unusual in several respects. We describe the first reported case of spinal epidural hematoma after the specific administration of tenecteplase in the setting of STEMI. Likewise, the manifestation of spinal epidural hematoma as airway narrowing is uncommon, because spinal epidural hematoma typically manifests as central neurologic injury.\n\nSpinal epidural hematoma is a rare, potentially disabling space-occupying accumulation of blood in the epidural space that mechanically compresses the spinal cord. It is an acute and rapidly progressive myelopathy that if left untreated may result in profound sensory and motor deficits. The characteristic presentation is one of severe acute pain at the site of the lesion, followed within hours by signs of nerve root irritation, hyporeflexia, paresis, or urinary retention. Axial CT may be helpful in diagnosis spinal epidural hematoma, but MRI remains the diagnostic imaging modality of choice. Spinal epidural hematoma is a complication of thrombolysis described in both acute ischemic stroke6 and acute coronary syndrome,7 both spontaneous and in the setting of trauma. All cases reported thus far occurred after administration of streptokinase, urokinase, or tissue plasminogen activator.\n\nIn retrospect in relation to our case, the patient’s presenting history and physical findings should have been sufficient to withhold administration of thrombolytics on the basis of major facial trauma. Society-developed practice guidelines1,8 list significant recent (within the last 3 months) closed-head or facial trauma as absolute contraindications to fibrinolytic therapy for STEMI, among others. Within the literature, there are little data surveying the inappropriate use of thrombolytics for STEMI in the presence of trauma. Immediate imaging, by identifying the neck fracture, would have affected the decision to administer thrombolytics. Not only did inappropriate thrombolysis result in precautionary intubation, which has its own potential complications, but also thrombolytic-induced spinal epidural hematoma precluded the use of antiplatelet therapy. More important, this led to delayed coronary angiography and revascularization, because these interventions require the use of periprocedural heparin therapy and postprocedural antiplatelet therapy. Delay in definitive management contributed to the patient’s second presentation with recurrent STEMI.\n\nConclusion\nFor the foreseeable future, thrombolytic agents will remain a pivotal component of treatment for STEMI. As long as this is the case, patients will be at risk of major bleeding complications, including spinal epidural hematoma. As illustrated in the described case, a focused history and physical, knowledge of the contraindications of thrombolytics, and appropriate imaging are key to deliberate and judicious use of this treatment.\n\nAcknowledgements\nThe authors thank Dr Cameron Kaye, who assisted in interpreting the spinal imaging.\n\nFunding Sources\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. This study was self-funded.\n\nDisclosures\nThe authors have no conflicts of interest to disclose.\n\nEthics Statement: Written informed consent was obtained from the patient before initiation of this Case Report.\n\nSee page 73 for disclosure information.\n==== Refs\nReferences\n1 O'Gara P.T. Kushner F.G. Ascheim D.D. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Circulation 127 2013 e362 e425 23247304 \n2 Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators Van De Werf F. Adgey J. Ardissino D. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial Lancet 354 1999 716 722 10475182 \n3 White H.D. Thrombolytic therapy in the elderly Lancet 356 2000 2028 2030 11145486 \n4 Gore J.M. Granger C.B. Simoons M.L. Stroke after thrombolysis. Mortality and functional outcomes in the GUSTO-I trial. Global Use of Strategies to Open Occluded Coronary Arteries Circulation 92 1995 2811 2818 7586246 \n5 Berkowitz S.D. Granger C.B. Pieper K.S. Incidence and predictors of bleeding after contemporary thrombolytic therapy for myocardial infarction. The Global Utilization of Streptokinase and Tissue Plasminogen activator for Occluded coronary arteries (GUSTO) I Investigators Circulation 95 1997 2508 2516 9184581 \n6 Connolly E.S. Jr. Winfree C.J. McCormick P.C. Management of spinal epidural hematoma after tissue plasminogen activator. A case report Spine (Phila Pa 1976) 21 1996 1694 1698 8839474 \n7 Sawin P.D. Traynelis V.C. Follett K.A. Spinal epidural hematoma following coronary thrombolysis with tissue plasminogen activator. Report of two cases J Neurosurg 83 1995 350 353 7616284 \n8 Ibanez B. James S. Agewall S. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC) Eur Heart J 39 2018 119 177 28886621\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "2(2)",
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"pages": "71-73",
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"pmid": "32190828",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "23247304;10475182;7616284;9184581;7586246;8839474;11145486;28886621",
"title": "Spinal Epidural Hematoma Secondary to Tenecteplase for ST-Elevation Myocardial Infarction in the Setting of Trauma and Cervical Endplate Fracture.",
"title_normalized": "spinal epidural hematoma secondary to tenecteplase for st elevation myocardial infarction in the setting of trauma and cervical endplate fracture"
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"abstract": "We describe an extremely rare case of a pregnant woman who had a successful delivery despite developing bypass graft occlusion after right external iliac bypass surgery. External and common iliac artery bypass surgery is often performed when arteriosclerosis obliterans or thromboangiitis obliterans result in iliac artery occlusion or when revascularization is required because of iliac artery injury. Because arteriosclerosis obliterans and thromboangiitis obliterans rarely develop in young women or girls, most physicians have little experience with graft occlusion after iliac artery bypass surgery. Here we describe and discuss the published work pertaining to this extremely rare case.",
"affiliations": "Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Osaka, Japan.",
"authors": "Nakae|Ruriko|R|;Matsuzaki|Shinya|S|;Egawa-Takata|Tomomi|T|;Mimura|Kazuya|K|;Kanagawa|Takeshi|T|;Kimura|Tadashi|T|",
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"issue": "41(6)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "bypass surgery; graft occlusion; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D001034:Apgar Score; D001162:Arteriosclerosis Obliterans; D017604:Cesarean Section, Repeat; D003131:Combined Modality Therapy; D005260:Female; D006083:Graft Occlusion, Vascular; D006801:Humans; D007083:Iliac Artery; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D047929:Term Birth; D013919:Thromboangiitis Obliterans; D016896:Treatment Outcome; D058017:Vascular Grafting",
"nlm_unique_id": "9612761",
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"pages": "979-84",
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"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pregnancy management for a patient with graft occlusion after right iliac artery bypass surgery.",
"title_normalized": "pregnancy management for a patient with graft occlusion after right iliac artery bypass surgery"
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"companynumb": "JP-BAYER-2015-366012",
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"abstract": "we presented a case of drug-induced interstitial nephritis in a 43-year-old woman, having the history of renal calculi, as a result of sodium valproate and triamterene. Renal biopsy was used to confirm the diagnosis, however, due to poor prognosis along with discontinuation of drugs, she was treated with corticosteroids.",
"affiliations": "Department of Internal Medicine, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran.;Department of Anesthesiology and Intensive Care, AJA University of Medical Sciences, Tehran, Iran.",
"authors": "Aghsaeifard|Ziba|Z|;Alizadeh|Reza|R|",
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"doi": "10.1016/j.eucr.2020.101329",
"fulltext": "\n==== Front\nUrol Case Rep\nUrol Case Rep\nUrology Case Reports\n2214-4420 Elsevier \n\nS2214-4420(20)30218-7\n10.1016/j.eucr.2020.101329\n101329\nEndourology\nDrug-induced interstitial nephritis as a result of sodium valproate and triamterene\nAghsaeifard Ziba a Alizadeh Reza rezalizadeh@gmail.comb∗ a Department of Internal Medicine, School of Medicine, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran\nb Department of Anesthesiology and Intensive Care, AJA University of Medical Sciences, Tehran, Iran\n∗ Corresponding author. Anesthesiology, AJA University of Medical Sciences, Tehran, Iran. rezalizadeh@gmail.com\n26 6 2020 \n11 2020 \n26 6 2020 \n33 10132917 6 2020 26 6 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/).we presented a case of drug-induced interstitial nephritis in a 43-year-old woman, having the history of renal calculi, as a result of sodium valproate and triamterene. Renal biopsy was used to confirm the diagnosis, however, due to poor prognosis along with discontinuation of drugs, she was treated with corticosteroids.\n\nKeywords\nInterstitial nephritisRenalSodium valproateTriamterene\n==== Body\nIntroduction\nInterstitial nephritis can be caused by infections and hypersensitivity to drugs like methicillin, phenobarbital, diazepam, sodium valproate, diuretics, proton pump inhibitors, H2 receptor antagonists and nonsteroidal anti-inflammatory drugs.1,2 Drug-induced acute interstitial nephritis (DI-AIN) is associated with acute renal injury marked with increased creatinine levels and eosinophilia and is commonly diagnosed with renal biopsy. Infiltration of lymphocytes and macrophages, tubular atrophy and fibrosis are common findings from biopsy3 and is reported in 0.5–3% of renal biopsies.2 Discontinuation of drugs is an important step for the management of AIN. It is recommended that patients presented with acute kidney injury should be suspected for AIN.2 Herein, we presented a case of drug-induced interstitial nephritis in a 43-year-old woman, having the history of renal calculi, as a result of sodium valproate and triamterene. Renal biopsy was used to confirm the diagnosis, however, due to poor prognosis along with discontinuation of drugs, she was treated with corticosteroids.\n\nCase presentation\nA 43-year-old woman was reported to our center with muscle weakness, sharp clamping pain, muscle ache and swelling, shortness of breath and pain in the limbs. The patient had a history of bilateral renal calculi (kidney stones) for which she was hospitalized and underwent Trans Urethral Lithotripsy (TUL). For depression and obesity, she was under a number of medications including metformin, sodium valproate, fluoxetine, propranolol and triamterene-H while fenofibrate was added to her regime two weeks before her referral.\n\nAt the time of referral to the emergency department, her hemodynamic were stable: blood pressure 110/70, rate of respiration 16 and temperature 38.7 °C. Her labs showed: low density lipoprotein (LDH) > 5,000, creatine phosphokinase (CPK) > 18,000, creatinine (cr) > 6, blood urea nitrogen 128 mg/dl, white blood cell (WBC) 20,000/μl with eosinophils ≥ 500μl and increased liver enzymes and urine volume and reduced glomerular filtration rate. Her urinary sedimentation was clear and she had skin rashes on her arms and around wrist while her renal sonography was normal.\n\nDue to increased nausea and vomiting, and shortness of breath, for which she underwent temporary thoracotomy. Additionally, she underwent 15 sessions of hemodialysis, where her nausea and vomiting improved along with urine output. However, her creatinine was still 234 μmol/L (2.65 mg/dL) and the blood urea 14 mmol/L.\n\nShe underwent renal biopsy which showed interstitial inflammation and infiltration leukocytes, neutrophils, monocytes and eosinophils(Fig. 1). The epithelial cells showed necrosis and were mixed with lymphocytes. Invasion of inflammatory cells were also seen in the tubular basement membrane (tubulitis). All 16 glomeruli were normal along with vessels.Fig. 1 Drug-induced renal failure.\n\nFig. 1\n\nShe was treated with prednisone with an initial bolus of 30 mg/kg methylprednisolone for two weeks and sodium valproate and triamterene-H were discontinued. Her 4 months follow-up labs showed serum cr 130μmol/l (1.47mg/dl) and eosinophils 300/μl.\n\nDiscussion\nIn this case report, patients was presented with DI-AIN as a result of sodium valproate and triamterene H, a thiazide diuretic. Magil, Ballon4 presented three cases reports of DI-AIN patients as a result of hydrochlorothiazide and triamterene. These patients were presented with a severe increase in blood urea nitrogen and creatinine and eosinophilia, similar the patient in this report. DI-AIN was confirmed with biopsy. They were presented with fever, anorexia, malaise and hypertension. The patients presented here had fever, rashes, nausea and vomiting and dyspnea.\n\nHypersensitivity to several different types of drugs have been correlated with acute renal failure as a result of immunological reactions. Plasma cells and monocytes infiltration is usually correlated with a late-type hypersensitivity.4 Similarly, Yoshikawa, Watanabe1 reported a case of DI-AIN as a result of sodium valproate in a young, who was presented with seizures, fever, metabolic acidosis, hyperuricemia, proteinuria and aminoaciduria. Her symptoms were overlapping with that of Fanconi Syndrome. However, AIN was confirmed with renal biopsy. Sodium valproate is also commonly known to be associated with renal tubular dysfunction, which is characterized with hypocarnitinemia, contrary to AIN.\n\nConclusion\nProlonged drug-induced hypersensitivity can lead to poor prognosis. Patients on DI-AIN causing drugs presented with acute kidney injury should be suspected for AIN and are likely to require renal biopsy for confirmation. Discontinuation of drugs can improve the symptoms whereas, corticosteroid are required in moderate to severe cases.\n\nContributors’ statement\nDr. Ziba Aghsaeifard: conceptualized and designed the study, drafted the initial manuscript, and reviewed and revised the manuscript. Designed the data collection instruments, collected data, carried out the initial analyses, and reviewed and revised the manuscript.\n\nDr. Reza Alizadeh: Coordinated and supervised data collection, and critically reviewed the manuscript for important intellectual content.\n\nAll authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nDeclaration of competing interest\nThe authors deny any conflict of interest in any terms or by any means during the study.\n==== Refs\nReferences\n1 Yoshikawa H. Watanabe T. Abe T. Tubulo-interstitial nephritis caused by sodium valproate Brain Dev 24 2 2002 102 105 11891102 \n2 Nast C.C. Medication-induced interstitial nephritis in the 21st century Adv Chron Kidney Dis 24 2 2017 72 79 \n3 Krishnan N. Perazella M.A. Drug-induced acute interstitial nephritis: pathology, pathogenesis, and treatment Iranian journal of kidney diseases 9 1 2015 3 25599729 \n4 Magil A.B. Acute interstitial nephritis associated with thiazide diuretics. Clinical and pathologic observations in three cases Am J Med 69 6 1980 939 943 7446559\n\n",
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"issn_linking": "2214-4420",
"issue": "33()",
"journal": "Urology case reports",
"keywords": "Interstitial nephritis; Renal; Sodium valproate; Triamterene",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "101329",
"pmc": null,
"pmid": "33102031",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports",
"references": "11891102;25599729;28284382;7446559",
"title": "Drug-induced interstitial nephritis as a result of sodium valproate and triamterene.",
"title_normalized": "drug induced interstitial nephritis as a result of sodium valproate and triamterene"
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"companynumb": "IR-GLAXOSMITHKLINE-IR2020GSK127952",
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"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
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"abstract": "Nanoparticle albumin-bound (nab)-paclitaxel has shown promising activity in advanced gastric cancer treatment. We herein report a case of advanced gastric cancer involving long-term management with a single administration of nab-paclitaxel. A 71-year-old man diagnosed with advanced gastric cancer with malignant ascites was treated with nab-paclitaxel as a second-line chemotherapy. He refused treatment continuation because of various severe toxicities in the first treatment cycle; he was therefore followed-up without any further treatments. Despite this, no disease progression was observed over 9 months. After progression, he received dose-dense paclitaxel, but he did not respond to this treatment and eventually died.",
"affiliations": "Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.;Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, Japan.",
"authors": "Matano|Daisuke|D|;Moriwaki|Toshikazu|T|;Tange|Yoshitaka|Y|;Niisato|Yusuke|Y|;Yamaura|Masamichi|M|;Nagase|Masaomi|M|;Suganuma|Daisuke|D|;Takagi Taketa|Kaoruko|K|;Iwai|Kentaro|K|;Enami|Chiaki|C|;Yamamoto|Yoshiyuki|Y|;Hyodo|Ichinosuke|I|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D017239:Paclitaxel",
"country": "Japan",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2842084010.2169/internalmedicine.56.7783Case ReportSuccessful Long-term Management with a Single Administration of Tri-weekly Nab-paclitaxel in a Patient with Advanced Gastric Cancer with Peritoneal Dissemination Matano Daisuke 1Moriwaki Toshikazu 1Tange Yoshitaka 1Niisato Yusuke 1Yamaura Masamichi 1Nagase Masaomi 1Suganuma Daisuke 1Takagi Taketa Kaoruko 1Iwai Kentaro 1Enami Chiaki 1Yamamoto Yoshiyuki 1Hyodo Ichinosuke 11 Faculty of Medicine, Division of Gastroenterology, University of Tsukuba, JapanCorrespondence to Dr. Toshikazu Moriwaki, tmoriwak@gmail.com\n\n15 4 2017 56 8 921 923 30 5 2016 5 8 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Nanoparticle albumin-bound (nab)-paclitaxel has shown promising activity in advanced gastric cancer treatment. We herein report a case of advanced gastric cancer involving long-term management with a single administration of nab-paclitaxel. A 71-year-old man diagnosed with advanced gastric cancer with malignant ascites was treated with nab-paclitaxel as a second-line chemotherapy. He refused treatment continuation because of various severe toxicities in the first treatment cycle; he was therefore followed-up without any further treatments. Despite this, no disease progression was observed over 9 months. After progression, he received dose-dense paclitaxel, but he did not respond to this treatment and eventually died. \n\ngastric cancernab-paclitaxeldisseminationascites\n==== Body\nIntroduction\nPaclitaxel, a microtubule-stabilizing agent, is a key drug for advanced gastric cancer treatment. Dose-dense paclitaxel-containing regimens are widely used as second-line chemotherapy to treat patients with advanced gastric cancer (AGC) who experienced failure after fluoropyrimidine and platinum (1). However, steroids and anti-histamines, such as H1- and H2-receptor blockers, must be administered to patients prior to paclitaxel because CremophorⓇ, a solvent polyethoxylated castor oil contained in the paclitaxel formulation, causes allergic and hypersensitivity reactions. Nanoparticle albumin-bound (Nab)-paclitaxel is a nanoparticle preparation consisting of paclitaxel and human serum albumin that can be administered without the steroids and anti-histamines (2). Nab-paclitaxel is a current treatment option for breast cancer and non-small cell lung cancer (3, 4). Additionally, it has shown promising activity for treating patients with previously treated advanced gastric cancer in a Japanese phase II trial (5). We herein report a patient with AGC who received only one administration of nab-paclitaxel and showed long-term disease control.\n\nCase Report\nA 71-year-old man with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 was diagnosed with AGC, as he had a moderately differentiated Bormann type 1 adenocarcinoma in the posterior wall of the upper gastric corpus with synchronous liver and peritoneal metastasis. He joined a clinical trial and received S-1 plus leucovorin as first-line chemotherapy. He maintained a partial response for one year, and then malignant ascites appeared without obvious progression of other lesions (Figure A). His ECOG PS was 0 at the time of first progression. His findings on blood examinations, including carcinoembryonic antigen and carbohydrate antigen 19-9, were all within normal ranges, excluding his serum hemoglobin value. He received nab-paclitaxel (260 mg/m2 on day 1, every 21 days) as second-line chemotherapy. During the first cycle of treatment, various toxicities occurred, including grade 4 neutropenia, grade 3 peripheral sensory neuropathy (PSN), grade 3 myalgia, grade 2 constipation, grade 2 anorexia, and grade 2 oral mucositis. Most toxicities recovered to grade 0 or 1 within 7 days from their onset, including neutropenia. However, the patient experienced PSN for 67 days before recovery to grade 1. Although treatment with a reduced dose of nab-paclitaxel was recommended, he refused treatment continuation. He received follow-up without any treatments. His ascites disappeared on CT scan 2 months after administration (Figure B), and no disease progression was observed for 9.4 months. However, peritoneal dissemination with ascites reappeared (Figure C), and he was treated with dose-dense paclitaxel (80 mg/m2 on days 1, 8, and 15 every 21 days) because he refused reintroduction of nab-paclitaxel. No severe toxicities were observed (maximum grade of toxicities were grade 0 neutropenia, grade 2 myalgia, grade 2 PSN, and grade 1 anorexia), and the treatment was continued. However, peritoneal dissemination and ascites increased two months after the administration was started (Figure D). He received 5-fluorouracil plus leucovorin as third-line chemotherapy, but the ascites increased. He died 17.8 months from administration of nab-paclitaxel.\n\nFigure. (A) Pelvic computed tomography before nab-paclitaxel. Ascites were observed in the pelvic area (arrows). (B) Two months after a single administration of nab-paclitaxel, ascites no longer appeared in the pelvic area. (C) Peritoneal dissemination and ascites reappeared (arrows) 9.4 months after the single nab-paclitaxel administration. (D) Peritoneal dissemination increased (arrow) two months after administration of dose-dense paclitaxel.\n\nDiscussion\nTri-weekly nab-paclitaxel treatment resulted in a median time to response and median progression-free survival of 36 days (range, 29-57 days) and 2.9 months (95% CI, 2.4-3.6), respectively, in a phase II study for patients with previously treated AGC (5). We encountered a patient with AGC who maintained disease control over 9 months despite receiving just one administration of nab-paclitaxel. His cancer cells, especially peritoneal cancer cells, might have been highly sensitive to paclitaxel. Generally, malignant ascites in various cancers are associated with a poor prognosis (6). Indeed, the median overall survival is only 3 to 4 months when AGC patients with malignant ascites do not receive any chemotherapy (7). The single administration of nab-paclitaxel appeared to be quite effective, as he survived more than 1.5 years from its administration.\n\nInterestingly, dose-dense paclitaxel after disease progression was not effective. There may be several reasons for this result. First, it was reported in preclinical and clinical studies that conventional paclitaxel might have a smaller volume of paclitaxel distribution in the tumor than nab-paclitaxel (8, 9). This difference may be important for its therapeutic effectiveness. Second, a single dose of dose-dense paclitaxel might not have been enough. In this patient, no neutropenia was observed during dose-dense paclitaxel treatment. Because neutropenia has been shown to be correlated with survival among patients with AGC treated with a standard dose of dose-dense paclitaxel (10), a randomized phase II trial was performed to evaluate the efficacy of dose-escalated dose-dense paclitaxel guided by neutropenia, compared with standard-dose dose-dense paclitaxel for patients with previously treated AGC (11). The efficacy data favored patients who received dose-escalated dose-dense paclitaxel. Finally, the progressive cancer cells might not have been sensitive to paclitaxel. Unfortunately, it was unclear whether or not his cancer cells were paclitaxel-resistant, because they were not assessed at the time of disease progression. An ongoing randomized phase III trial (ABSOLUTE) is evaluating the overall survival after treatment with tri-weekly paclitaxel or dose-dense nab-paclitaxel compared with dose-dense paclitaxel as second-line chemotherapy for patients with AGC (12). This trial may answer some of these questions.\n\nThe patient experienced some severe adverse events in the first cycle. The most common grade 3 or 4 toxicities in a Japanese phase II trial for advanced gastric cancer were neutropenia in 49% of patients and PSN in 24% of patients, including myalgia in 5.5% of patients (5). In cases with severe toxicities, dose reduction can be used to identify a tolerated dose for the patient. However, in this patient, treatment continuation would have been difficult, as the various severe toxicities, including PSN and myalgia, were observed simultaneously. The median reported recovery time from grade 3 to grade 1 PSN is 39 days (5), but recovery from grade 3 PSN in this case took longer than in the previous report. Prevention and treatment for PSN or acute pain syndromes, such as myalgia and arthralgia, should be considered, as those toxicities reduce patients' quality of life. Although several randomized trials have been performed, optimal management has not been clarified (13).\n\nIn conclusion, we herein report the case of a patient with AGC who demonstrated long-term tumor control with a single administration of nab-paclitaxel.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nKang BW , Kwon OK , Chung HY , Yu W , Kim JG \nTaxanes in the treatment of advanced gastric cancer . Molecules \n21 : E651 , 2016 .27196887 \n2. \nNyman DW , Campbell KJ , Hersh E , et al \nPhase I and pharmacokinetics trial of ABI-007, a novel nanoparticle formulation of paclitaxel in patients with advanced nonhematologic malignancies . J Clin Oncol \n23 : 7785 -7793 , 2005 .16258082 \n3. \nGradishar WJ , Tjulandin S , Davidson N , et al \nPhase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer . J Clin Oncol \n23 : 7794 -7803 , 2005 .16172456 \n4. \nSocinski MA , Bondarenko I , Karaseva NA , et al \nWeekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial . J Clin Oncol \n30 : 2055 -2062 , 2012 .22547591 \n5. \nSasaki Y , Nishina T , Yasui H , et al \nPhase II trial of nanoparticle albumin-bound paclitaxel as second-line chemotherapy for unresectable or recurrent gastric cancer . Cancer Sci \n105 : 812 -817 , 2014 .24716542 \n6. \nAyantunde AA , Parsons SL \nPattern and prognostic factors in patients with malignant ascites: a retrospective study . Ann Oncol \n18 : 945 -949 , 2007 .17298959 \n7. \nFang N , Zhang HQ , He B , et al \nClinicopathological characteristics and prognosis of gastric cancer with malignant ascites . Tumour Biol \n35 : 3261 -3268 , 2014 .24282088 \n8. \nDesai N , Trieu V , Yao Z , et al \nIncreased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel . Clin Cancer Res \n12 : 1317 -1324 , 2006 .16489089 \n9. \nSparreboom A , Scripture CD , Trieu V , et al \nComparative preclinical and clinical pharmacokinetics of a cremophor-free, nanoparticle albumin-bound paclitaxel (ABI-007) and paclitaxel formulated in Cremophor (Taxol) . Clin Cancer Res \n11 : 4136 -4143 , 2005 .15930349 \n10. \nShitara K , Matsuo K , Takahari D , et al \nNeutropenia as a prognostic factor in advanced gastric cancer patients undergoing second-line chemotherapy with weekly paclitaxel . Ann Oncol \n21 : 2403 -2409 , 2010 .20494962 \n11. \nShitara K , Yuki S , Tahahari D , et al \nRandomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer . Br J Cancer \n110 : 271 -277 , 2014 .24281004 \n12. \nKoizumi W , Morita S , Sakata Y \nA randomized Phase III trial of weekly or 3-weekly doses of nab-paclitaxel versus weekly doses of Cremophor-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE Trial) . Jpn J Clin Oncol \n45 : 303 -306 , 2015 .25516635 \n13. \nFernandes R , Mazzarello S , Majeed H , et al \nTreatment of taxane acute pain syndrome (TAPS) in cancer patients receiving taxane-based chemotherapy: a systematic review . Support Care Cancer \n24 : 1583 -1594 , 2016 .26386706\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(8)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "ascites; dissemination; gastric cancer; nab-paclitaxel",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000972:Antineoplastic Agents, Phytogenic; D000971:Antineoplastic Combined Chemotherapy Protocols; D016503:Drug Delivery Systems; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D053758:Nanoparticles; D017239:Paclitaxel; D010534:Peritoneal Neoplasms; D013274:Stomach Neoplasms",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "921-923",
"pmc": null,
"pmid": "28420840",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16172456;24282088;17298959;16258082;15930349;26386706;20494962;27196887;24281004;25516635;22547591;24716542;16489089",
"title": "Successful Long-term Management with a Single Administration of Tri-weekly Nab-paclitaxel in a Patient with Advanced Gastric Cancer with Peritoneal Dissemination.",
"title_normalized": "successful long term management with a single administration of tri weekly nab paclitaxel in a patient with advanced gastric cancer with peritoneal dissemination"
} | [
{
"companynumb": "JP-CELGENEUS-JPN-2016043062",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "We investigated the safety and efficacy of mycophenolate mofetil (MMF) in the prevention and treatment of graft-versus-host disease (GVHD) using a nationwide retrospective survey in Japanese children undergoing hematopoietic stem cell transplantation (HSCT). Overall, 141 children undergoing allogeneic HSCT for hematological malignancy (n = 84), non-malignancy (n = 52), and solid tumors (n = 5) were administered MMF orally (median 8 years; range 0-15 years; 89 males and 52 females) during 1995-2011. Donors were primarily unrelated and mismatched related. In the GVHD prophylaxis group, 29% and 8.6% of patients developed grade II-IV and III-IV GVHD, respectively. Of the 32 evaluable patients, 16% developed chronic [limited (n = 4) and extensive (n = 1)] GVHD. In the acute GVHD treatment group, 61% had decreased grade. In the chronic GVHD treatment group, 36% had improved symptoms. Combined immunosuppressant was reduced or discontinued in 61% patients. Major adverse events (AEs) were neutropenia (4.3%), infection (3.5%), thrombocytopenia (2.1%), myelosuppression (2.1%), and diarrhea (1.4%). MMF dosage was reduced in two children due to grade ≥ 3 AEs; two children died from infection. MMF thus may be well tolerated in children, and may be an effective option for prophylaxis and treatment of acute and chronic GVHD.",
"affiliations": "Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya, 453-8511, Japan. kwnozomu@med.nagoya-u.ac.jp.;Department of Promotion for Blood and Marrow Transplantation, Aichi Medical University School of Medicine, Nagakute, Japan.;Department of Oncology and Hematology, Shimane University Hospital Innovative Cancer Center, Izumo, Japan.;Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan.;Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan.;Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan.;Department of Pediatrics, Hiroshima University Graduate School of Biomedical & Health Sciences, Hiroshima, Japan.;Department of Cell Transplantation and Regenerative Medicine, Tokai University School of Medicine, Isehara, Japan.;Department of Pediatric Hematology/Oncology, Osaka City General Hospital, Osaka, Japan.;Department of Human Health Sciences, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Hematology and Oncology, Tokyo Metropolitan Children's Medical Center, Fuchu, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Izumi, Japan.;Department of Hematology and Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, 3-35 Michishita-cho, Nakamura-ku, Nagoya, 453-8511, Japan.",
"authors": "Kawashima|Nozomu|N|http://orcid.org/0000-0001-5700-4481;Iida|Minako|M|;Suzuki|Ritsuro|R|;Fukuda|Takahiro|T|;Atsuta|Yoshiko|Y|;Hashii|Yoshiko|Y|;Inoue|Masami|M|;Kobayashi|Masao|M|;Yabe|Hiromasa|H|;Okada|Keiko|K|;Adachi|Souichi|S|;Yuza|Yuki|Y|;Kawa|Keisei|K|;Kato|Koji|K|",
"chemical_list": "D009173:Mycophenolic Acid",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-019-02601-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "109(4)",
"journal": "International journal of hematology",
"keywords": "Graft-versus-host disease; Mycophenolate mofetil; Pediatric; Prophylaxis; Treatment",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D002648:Child; D002675:Child, Preschool; D005260:Female; D006086:Graft vs Host Disease; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007564:Japan; D008297:Male; D009173:Mycophenolic Acid; D012042:Registries",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "491-498",
"pmc": null,
"pmid": "30694451",
"pubdate": "2019-04",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": "10828867;10878285;12393457;14585364;15077223;15665850;16001244;17660844;17988995;19835971;20307722;20818441;21465117;22592321;23208313;24943923;25016613;26103520;26740371;27060685;27686673;27943166;29239087;29667720;29959747;9678797;9865306",
"title": "Prophylaxis and treatment with mycophenolate mofetil in children with graft-versus-host disease undergoing allogeneic hematopoietic stem cell transplantation: a nationwide survey in Japan.",
"title_normalized": "prophylaxis and treatment with mycophenolate mofetil in children with graft versus host disease undergoing allogeneic hematopoietic stem cell transplantation a nationwide survey in japan"
} | [
{
"companynumb": "JP-MYLANLABS-2019M1044098",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to report cases of medication-related osteonecrosis of the jaws (MRONJ) associated with targeted therapy (TT) with or without concomitant antiresorptive treatment, among the Copenhagen ONJ cohort, which includes all consecutive cases of MRONJ seen in Copenhagen.\n\n\nMETHODS\nWe retrospectively studied the treatment of 204 consecutive patients with MRONJ, seen between January 2010 and May 2016, to identify those associated with TT.\n\n\nRESULTS\nWe detected 7 cases of MRONJ associated with TT (3.4%). Four patients received TT only, whereas 3 were concomitantly treated with bisphosphonates (n = 3) and/or denosumab (n = 3). The TT regimens included sunitinib (Sutent) (n = 1), everolimus (Afinitor) (n = 1), erlotinib (Tarceva) (n = 1), bevacizumab (Avastin) (n = 3), dasatinib (Sprycel) (n = 1) and imatinib (Glivec) (n = 1). The MRONJ stage included stages 1 and 2, and mean score on the visual analogue scale for pain in the jaw was 4.0.\n\n\nCONCLUSIONS\nHealth care providers should be aware of the possibility of MRONJ associated with the TT agents sunitinib, everolimus, and dasatinib and uncommon cancer types, including renal cell carcinoma, non-small-cell lung cancer, glioblastoma, and leukemia, where MRONJ may also occur.",
"affiliations": "Department of Oral & Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.;Department of Oral & Maxillofacial Surgery, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.;Tuborg Sundpark 3, Hellerup, Denmark. Electronic address: morten.schioedt@regionh.dk.",
"authors": "Abel Mahedi Mohamed|Hoda|H|;Nielsen|Charlotte Emilie Nor|CEN|;Schiodt|Morten|M|",
"chemical_list": "D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D007211:Indoles; D011758:Pyrroles; D000068338:Everolimus; D000069439:Dasatinib; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1016/j.oooo.2017.10.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "125(2)",
"journal": "Oral surgery, oral medicine, oral pathology and oral radiology",
"keywords": null,
"medline_ta": "Oral Surg Oral Med Oral Pathol Oral Radiol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D050071:Bone Density Conservation Agents; D000069439:Dasatinib; D003718:Denmark; D000068338:Everolimus; D005260:Female; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011758:Pyrroles; D012189:Retrospective Studies; D000077210:Sunitinib",
"nlm_unique_id": "101576782",
"other_id": null,
"pages": "157-163",
"pmc": null,
"pmid": "29221983",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with antiresorptives. A report of 7 cases from the Copenhagen Cohort.",
"title_normalized": "medication related osteonecrosis of the jaws associated with targeted therapy as monotherapy and in combination with antiresorptives a report of 7 cases from the copenhagen cohort"
} | [
{
"companynumb": "DK-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-12-001542",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DENOSUMAB"
},
"d... |
{
"abstract": "A 47-year-old male with acquired immune deficiency syndrome (AIDS) presented with multiple hyperpigmented papules and nodules on both ankles, dorsum of bilateral feet and soles. It was associated with mild itching and pain. The patient was diagnosed with human immunodeficiency virus (HIV) in 2007. First-line antiretroviral therapy (ART) was started in 2009 to which he responded initially. He was shifted to second-line ART 11 months ago in March 2015 due to treatment failure as suggested by CD4 count of 50 cells/mm(3). The present skin lesions started 2 months after the initiation of second-line ART. Differential diagnoses considered were Kaposi's sarcoma and immune reconstitution inflammatory syndrome (IRIS) related infections, but biopsy was suggestive of erythema elevatum diutinum (EED). Patient was started on oral dapsone 100 mg/day and increased to 200 mg/day to which he is responding gradually. In the present case, appearance of the lesions after initiation of second-line ART coupled with increase in CD4 count and decrease of viral load below undetectable level suggest that EED could be an IRIS.",
"affiliations": "Department of Skin-VD, SSG Hospital, Vadodara, Gujarat, India.;Department of Skin-VD, SSG Hospital, Vadodara, Gujarat, India.",
"authors": "Jose|Sheethal K|SK|;Marfatia|Yogesh S|YS|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0253-7184.180287",
"fulltext": "\n==== Front\nIndian J Sex Transm Dis AIDSIndian J Sex Transm Dis AIDSIJSTDIndian Journal of Sexually Transmitted Diseases and AIDS2589-05572589-0565Medknow Publications & Media Pvt Ltd India 27190420IJSTD-37-8110.4103/2589-0557.180287Case ReportErythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome? Jose Sheethal K Marfatia Yogesh S. Department of Skin-VD, SSG Hospital, Vadodara, Gujarat, IndiaAddress for correspondence: Dr. Sheethal K. Jose, Department of Skin-VD, SSG Hospital, Vadodara, Gujarat, India. E-mail: sheethaljos@gmail.comJan-Jun 2016 37 1 81 84 Copyright: © Indian Journal of Sexually Transmitted Diseases and AIDS2016This 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.A 47-year-old male with acquired immune deficiency syndrome (AIDS) presented with multiple hyperpigmented papules and nodules on both ankles, dorsum of bilateral feet and soles. It was associated with mild itching and pain. The patient was diagnosed with human immunodeficiency virus (HIV) in 2007. First-line antiretroviral therapy (ART) was started in 2009 to which he responded initially. He was shifted to second-line ART 11 months ago in March 2015 due to treatment failure as suggested by CD4 count of 50 cells/mm3. The present skin lesions started 2 months after the initiation of second-line ART. Differential diagnoses considered were Kaposi's sarcoma and immune reconstitution inflammatory syndrome (IRIS) related infections, but biopsy was suggestive of erythema elevatum diutinum (EED). Patient was started on oral dapsone 100 mg/day and increased to 200 mg/day to which he is responding gradually. In the present case, appearance of the lesions after initiation of second-line ART coupled with increase in CD4 count and decrease of viral load below undetectable level suggest that EED could be an IRIS.\n\nEEDHIV/AIDSIRIS\n==== Body\nINTRODUCTION\nErythema elevatum diutinum (EED) is a rare, chronic, and treatable skin condition that often manifests as red-brown nodules, papules, or plaques commonly distributed acrally and symmetrically on extensor surfaces. Lesions are often asymptomatic; nevertheless, pain or burning sensation may occur. It has many clinical and histological mimics and is often associated with a variety of underlying systemic diseases.[1] It has been emerging as a specific human immunodeficiency virus (HIV) associated dermatosis in recent times.[2]\n\nCASE REPORT\nA 47-year-old married male with acquired immune deficiency syndrome (AIDS) who was a shopkeeper by profession presented with skin lesions on both lower limbs for past 9 months. It was associated with mild itching and pain. There were no complaints of joint pain or redness of eyes. The patient was diagnosed with HIV in 2007 and first-line antiretroviral therapy (ART) (tenofovir, lamivudine, efavirenz) was started in 2009. He developed severe fatigue, weight loss, cough, and dyspnea, and CD4 count dropped to 50 cells/mm3 with plasma viral load of 157 copies/ml, 11 months ago in March 2015. Due to treatment failure, he was then put on second-line ART (abacavir, lamivudine, atazanavir, and ritonavir) and his CD4 count increased to 204 cells/mm3 with plasma viral load of 38 copies/ml in September 2015. The present skin lesions started 2 months after initiation of second-line ART. Patient also had history of pulmonary tuberculosis (TB) in 2007 when his CD4 count was 213 cells/mm3, and Herpes Zoster in 2012 when CD4 count was 78 for which treatment was taken.\n\nOn general examination, patient was moderately built and nourished, and his vitals were within normal limits. Cutaneous examination revealed multiple well-defined nontender hyperpigmented papules and nodules on both ankles, dorsum of bilateral feet and soles [Figure 1a–c]. Inguinal lymph nodes were not palpable. There were no lesions elsewhere in the body. Hair, nail, and oral mucosa were normal. No ocular or systemic abnormality was noted.\n\nFigure 1 Multiple well-defined hyperpigmented papules and nodules on the following: (a) Medial aspect of left foot and ankle, (b) Lateral aspect of left foot, (c) Bilateral feet\n\nDifferential diagnoses considered were Kaposi's sarcoma and immune reconstitution inflammatory syndrome (IRIS) related infection including cutaneous TB. His routine blood investigations showed hemoglobin 11.5 g%, total leukocyte count 4300/mm3; and differential count neutrophil 70%, lymphocytes 28%, eosinophils 1% and monocytes 1%, and platelets 287,000/mm3. Liver function tests and renal function tests were normal. Mantoux test, serological tests for syphilis (VDRL, TPHA), hepatitis B and C, and anti-nuclear antibodies were negative. Chest radiography and abdominal ultrasonography were normal. Biopsy taken from the nodular lesion on dorsum of left foot showed a diffused dense infiltrate in reticular dermis with mild fibroplasia. The infiltrate consisted of neutrophils and histiocytes with scattering of lymphocytes and plasma cells. The infiltrate surrounded small thickened vessels and extended extensively into the interstitium. Small amount of neutrophilic nuclear dust was also present within the infiltrate [Figure 2]. Overlying epidermis and dermoepidermal junction were largely spared. These features were suggestive of EED. Patient was started on oral dapsone 100 mg/day and then increased to 200 mg/day to which he is responding gradually.\n\nFigure 2 Photomicrograph showing diffuse dense infiltrate of neutrophils, histiocytes with scattering of lymphocytes and plasma cells, and small amount of neutrophilic nuclear dust in reticular dermis (H and E, ×400)\n\nDISCUSSION\nEED is an uncommon, chronic leukocytoclastic vasculitis (LCV) of unknown etiology that promotes tissue fibrosis. It was first described in men in 1888 by Hutchinson and women in 1889 by Bury. Radcliff-Crocker and Williams in 1894 concluded that the two types should be described as one entity, and so gave the name EED.[1]\n\nThe disease could be the expression of an immune complex-mediated vasculitis (arthus type reaction) induced by situations involving either chronic antigenic exposure or occurrence of high antibody levels.[3] Immune complex is deposited in small vessel walls which induces inflammatory cascade, activation of cytokines like interleukin 8, which causes selective recruitment of leukocytes to blood vessels, leading to repetitive damage to blood vessels resulting in fibrosis and appearance of cholesterol crystals and myelin figures.[45]\n\nJoint disease is the most common association of EED though there are isolated reports of ocular abnormalities such as nodular scleritis, panuveitis, autoimmune keratolysis, and peripheral keratitis. Immunocomplexes may induce uveitis in EED. Prabhu et al. reported a case of EED in a 45-year-old healthy man associated with severe arthritis and scleritis, with dramatic response to oral dapsone.[6] Other than HIV, EED has also been associated with infectious processes, commonly recurrent streptococcal bacterial infections, hematological diseases, hepatitis B and rheumatological disease, collagen vascular diseases, monoclonal gammopathies, and lymphomas.[6]\n\nIt is histologically characterized by early changes of LCV with an infiltrate of polymorphonuclear cells and fibrin deposition in superficial and mid-dermis. Polymorphonuclear cells, macrophages, histiocytes, and occasionally eosinophils may surround blood vessels. Blood vessel dilatation with continual damage and hypertrophic endothelial cells may protrude into vessel lumen which may then stimulate granulation. In such a condition, lesions may be mistaken for Kaposi's sarcoma or bacillary angiomatosis. Polymorphonuclear leukocytes are always present, and their absence should prompt consideration of alternative diagnoses. Nodular lesions are composed of small aggregates of Mac-387 + spindle cells. Lesions may clinically mimic cutaneous malignancies (especially Kaposi's sarcoma or xanthomatous lesions), thus a biopsy must be obtained to confirm the correct diagnosis of EED and to exclude other entities in the differential diagnoses.[1]\n\nEED is now recognized as one of the defined reactive dermatoses associated with HIV.[7] In majority of cases, it is seen in patients with low CD4+ counts (<200). However, in some cases, EED has been reported as the first clinical manifestation of HIV infection.[8] Recently, a case of erosive and bullous EED in HIV-positive patient was also reported.[9] It is believed that such an association results from HIV antigen-antibody interaction, which causes direct damage to vessel walls. It is also supposed that the immunosuppression caused by HIV predisposes towards infection by other agents trigger an antigenic stimulus for the development of EED.[2] EED has also been associated with IgA hypergammopathy, which is also a common finding in HIV. There is another hypothesis suggesting that lesions are initially caused by an IgA-associated vasculitis. Because of the induced leakage of the vessel walls, lipid droplets (which are markedly elevated in the serum after ritonavir intake) pour into the perivascular tissue and became phagocytosed by histiocytes.[1011]\n\nConsequently, even though the association of EED with HIV infection is infrequent, laboratory investigation for this virus should be requested in conventional cases, and especially in cases of atypical and exacerbated clinical manifestations. EED lesions in HIV infection have been described as nodular with palmar/plantar involvement with greater numbers of lesions occurring at an earlier age and poor responsiveness to dapsone. In addition, ART should be introduced in these cases, in association with dapsone.[12] Rao et al. reported a case of a 52-year-old HIV-infected female patient who presented with nodular EED mimicking Kaposi's Sarcoma. The patient was initially treated with oral dapsone but was switched to colchicine as she developed hypersensitivity to dapsone.[13]\n\nIn present case, the lesions of EED developed 2 months after the initiation of second-line ART for treatment failure of first-line therapy. Hence, EED could be a part of noninfectious IRIS. This is further supported by the increase in CD4 from 50 to 204 cells/mm3 and decrease in viral load to 38 copies/ml. In IRIS, there is paradoxical worsening of an existing infection or disease process or appearance of a new infection/disease process soon after initiation of therapy associated with immune recovery. Incidence of IRIS is higher at lower CD4 counts. The immunopathogenesis of the syndrome is unclear. There is a dysregulated immune response to a variety of antigenic stimuli and unbalanced reconstitution of effector and regulatory T-cells, leading to exuberant inflammatory response in patients receiving ART.[14]\n\nIRIS can result from infectious and noninfectious causes. Reported cases of noninfectious IRIS include Sweet's syndrome, Reiter's syndrome, systemic lupus erythematosus (SLE), urticaria, autoimmune thyroiditis, type B insulin resistance syndrome, myopathy, radiculopathy, porphyria, non-Hodgkin's lymphoma, Guillain–Barre syndrome, sarcoidosis, bullous disorders such as pemphigus.[15] Certain minimum criteria should be fulfilled in order to diagnose IRIS. There must be a temporal association between initiation of ART and subsequent development of symptoms (usually within 3 months), with evidence of immune restoration (viral and immunological response demonstrated by a decrease in plasma HIV RNA level by more than 1 log10 copies/mL and an increase in CD4 T-cell count from baseline), and must exhibit clinical symptoms and signs consistent with an inflammatory process. The clinical course should neither be consistent with the usual course of a previously diagnosed opportunistic infection or a new infectious process nor should the symptoms and signs be explained by drug toxicity. A falling plasma viral load is a more important indicator than rising CD4 count.[14]\n\nDapsone has been regarded as first-line therapy in EED although lesions often recur with cessation of therapy.[116] However, dapsone may be less effective in HIV-infected and those lesions that have progressed to more fibrotic stage. As our patient had fibrosis, he responded slowly to dapsone therapy. Alternative treatments are surgical excision of larger nodules and especially the removal of possible antigenic stimulus.[2] Other agents used include immunosuppressants like cyclophosphamide, especially if associated with hematological abnormalities, SLE, paraproteinemias or leukemias. Niacinamide may also help as it acts as an anti-inflammatory agent and vasodilator. Intralesional and topical steroids, colchicine, chloroquine, and tetracycline may also be tried. The course of EED is chronic and benign. Systemic complications are rare.[13]\n\nThere is no test currently available to establish a diagnosis of IRIS. Its diagnosis requires a high index of suspicion. Therefore, in unusual lesions which develop after initiating or changing ART in a patient with low CD4 count and high viral load, IRIS should be considered. Infectious causes of IRIS are easily diagnosed, but the noninfectious causes are likely to be missed. The lesions should be thoroughly evaluated. In some cases like the present one, histopathology rules the roost.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest\n==== Refs\nREFERENCES\n1 Momen SE Jorizzo J Al-Niaimi F Erythema elevatum diutinum: A review of presentation and treatment J Eur Acad Dermatol Venereol 2014 28 1594 602 25288365 \n2 Muratori S Carrera C Gorani A Alessi E Erythema elevatum diutinum and HIV infection: A report of five cases Br J Dermatol 1999 141 335 8 10468812 \n3 Walker KD Badame AJ Erythema elevatum diutinum in a patient with Crohn's disease J Am Acad Dermatol 1990 22 5 Pt 2 948 52 2335587 \n4 Gibson LE Su WP Cutaneous vasculitis Rheum Dis Clin North Am 1990 16 309 24 2189153 \n5 Farley-Loftus R Dadlani C Wang N Rosenman K Kamino H Prystowsky S Erythema elevatum diutinum Dermatol Online J 2008 14 13 \n6 Prabhu S Shenoi SD Kishanpuria PS Pai SB Erythema elevatum diutinum associated with scleritis Indian Dermatol Online J 2011 2 28 30 23130212 \n7 Cox NH Jorizzo JL Bourke JF Savage CO Burns T Breathnach S Cox N Griffiths C Vasculitis, neutrophilic dermatoses and related disorders Rook's Text Book of Dermatology 2010 8th ed Massachusetts Blackwell Science 25 7 \n8 Rover PA Bittencourt C Discacciati MP Zaniboni MC Arruda LH Cintra ML Erythema elevatum diutinum as a first clinical manifestation for diagnosing HIV infection: Case history Sao Paulo Med J 2005 123 201 3 16389420 \n9 Smitha P Sathish P Mohan K Sripathi H Sachi G A case of extensive erosive and bullous erythema elevatum diutinum in a patient diagnosed with human immunodeficiency virus (HIV) Int J Dermatol 2011 50 989 91 21781074 \n10 Chowdhury MM Inaloz HS Motley RJ Knight AG Erythema elevatum diutinum and IgA paraproteinaemia: A preclinical iceberg Int J Dermatol 2002 41 368 70 12100696 \n11 Braun-Falco M Hofmann H An HIV-positive man with slowly enlarging nodules on the extremities Clin Infect Dis 2007 44 1009 10 \n12 Kim JM Song SH Park Y Eom M Kim HS Choi EH Erythema elevatum diutinum in human immunodeficiency virus infected patient Infect Chemother 2012 44 319 22 [English] \n13 Rao GR Joshi R Phaneendra Prasad AK Amareswar A Sandhya S Sridevi M Nodular erythema elevatum diutinum mimicking kaposi's sarcoma in a human immunodeficiency virus infected patient Indian J Dermatol 2014 59 592 4 25484391 \n14 Sharma SK Soneja M HIV & immune reconstitution inflammatory syndrome (IRIS) Indian J Med Res 2011 134 866 77 22310819 \n15 Das R Sarkar S Besra M Bullous disorders as a manifestation of immune reconstitution inflammatory syndrome: A series of three cases Indian J Sex Transm Dis 2013 34 126 8 \n16 Burnett PE Burgin S Erythema elevatum diutinum Dermatol Online J 2003 9 37 14594610\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2589-0557",
"issue": "37(1)",
"journal": "Indian journal of sexually transmitted diseases and AIDS",
"keywords": "EED; HIV/AIDS; IRIS",
"medline_ta": "Indian J Sex Transm Dis AIDS",
"mesh_terms": null,
"nlm_unique_id": "101730896",
"other_id": null,
"pages": "81-4",
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"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "19061612;16389420;24339465;14594610;2189153;10468812;25484391;2335587;22310819;23130212;21781074;12100696;17342652;25288365",
"title": "Erythema elevatum diutinum in acquired immune deficiency syndrome: Can it be an immune reconstitution inflammatory syndrome?",
"title_normalized": "erythema elevatum diutinum in acquired immune deficiency syndrome can it be an immune reconstitution inflammatory syndrome"
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"abstract": "BACKGROUND\nCystic fibrosis-related diabetes (CFRD) is the most frequent extrapulmonary complication of cystic fibrosis (CF).\n\n\nMETHODS\nWe report the first combined pancreatic islet-lung-liver transplantation in a 14-year-old adolescent. CFTR was analyzed by Sanger sequencing. Further genes were analyzed by high-throughput sequencing.\n\n\nRESULTS\nThe patient was diagnosed with CF at the age of 14 months. Nine years later, after diagnosis of CFRD, the patient's BMI and lung function began to decline. Bilateral lung transplantation with simultaneous liver transplantation was performed at the age of 14.5 years. The first islet transplantation (IT) was carried out 10 days later. Six months later, C-peptide secretion after arginine stimulation showed peak values of 371 pmol/L (vs. 569 pmol/L before IT) and insulin doses had slightly increased (1.40 vs. 1.11 units/kg/day before IT). A second IT was performed at the age of 15 years, a third at 16 years. Two years after the first IT, arginine-stimulated C-peptide secretion increased to 2,956 pmol/L and insulin doses could be reduced to 0.82 units/kg/day. HbA1c decreased from 7.3% (57.4 mmol/mol) to 5.9% (41.0 mmol/mol).\n\n\nCONCLUSIONS\nIT following lung and liver transplantation, with injection of islets into a transplanted organ, is feasible. It improves C-peptide secretion, decreases insulin needs, and lowers HbA1c.",
"affiliations": "Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerlandphilippe.klee@hcuge.ch.;Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.;Cell Isolation and Transplantation Center, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.;Division of Pediatric Gastroenterology, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.;Pediatric Pneumology Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.;Cell Isolation and Transplantation Center, Department of Surgery, Faculty of Medicine, University of Geneva, Geneva, Switzerland.;Division of Pediatric Gastroenterology, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.;Service of Pulmonary Medicine, University Hospitals of Geneva, Geneva, Switzerland.;Division of Pediatric Surgery, University Centre of Pediatric Surgery of Western Switzerland, University Hospitals of Geneva, Geneva, Switzerland.;Division of Pediatric Endocrinology and Diabetology, Department of Pediatrics, University of Basel Children's Hospital, Basel, Switzerland.;Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland.;Division of Transplantation, Department of Surgery, University Hospitals of Geneva, Geneva, Switzerland.;Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, University Hospitals of Geneva, Geneva, Switzerland.",
"authors": "Klee|Philippe|P|;Dirlewanger|Mirjam|M|;Lavallard|Vanessa|V|;McLin|Valerie A|VA|;Mornand|Anne|A|;Pernin|Nadine|N|;Petit|Laetitia-Marie|LM|;Soccal|Paola M|PM|;Wildhaber|Barbara E|BE|;Zumsteg|Urs|U|;Blouin|Jean-Louis|JL|;Berney|Thierry|T|;Schwitzgebel|Valerie M|VM|",
"chemical_list": "D002096:C-Peptide; D006442:Glycated Hemoglobin A; D007328:Insulin; C517652:hemoglobin A1c protein, human",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000488107",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2818",
"issue": "90(4)",
"journal": "Hormone research in paediatrics",
"keywords": "Cystic fibrosis; Cystic fibrosis-related diabetes; Islets of Langerhans transplantation; Liver transplantation; Lung transplantation",
"medline_ta": "Horm Res Paediatr",
"mesh_terms": "D000293:Adolescent; D002096:C-Peptide; D003550:Cystic Fibrosis; D003920:Diabetes Mellitus; D006442:Glycated Hemoglobin A; D006801:Humans; D007328:Insulin; D016381:Islets of Langerhans Transplantation; D016031:Liver Transplantation; D016040:Lung Transplantation; D008297:Male",
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "270-274",
"pmc": null,
"pmid": "29669347",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Combined Pancreatic Islet-Lung-Liver Transplantation in a Pediatric Patient with Cystic Fibrosis-Related Diabetes.",
"title_normalized": "combined pancreatic islet lung liver transplantation in a pediatric patient with cystic fibrosis related diabetes"
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"abstract": "Flavonifractor plautii (formerly Eubacterium plautii) is an anaerobic gram positive rod shaped bacterium belonging to the family of Clostridiales, and a common member of the human gut microbiome. However, it is very rarely isolated from clinical human specimens, so data about its clinical significance are scarce. Here we report of a bloodstream infection due to F. plautii following gangrenous cholecystitis in a 69 year old man. After cholecystectomy and empirical antimicrobial treatment with ceftriaxone and metronidazole the patient recovered. F. plautii was the only bacterium detected in blood culture, suggesting that it might have been causative for cholecystitis. Antimicrobial resistance testing identified decreased susceptibilities against linezolid and penicillin indicating that a targeted therapy might be necessary. F. plautii can be considered a potential pathogen for cholecystitis.",
"affiliations": "Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, Homburg, Saar, Germany.;Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Saarland University Medical Center, University of Saarland, Homburg, Saar, Germany.;Department for General, Visceral, Vascular, and Pediatric Surgery, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Saar, Germany.;Institute of Pathology, Saarland University Medical Center, Saarland University, Homburg, Saar, Germany.;Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, Homburg, Saar, Germany.;Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Saarland University Medical Center, University of Saarland, Homburg, Saar, Germany.",
"authors": "Berger|Fabian K|FK|;Schwab|Nadine|N|;Glanemann|Matthias|M|;Bohle|Rainer M|RM|;Gärtner|Barbara|B|;Groesdonk|Heinrich V|HV|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2018.e00461",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30198-710.1016/j.idcr.2018.e00461e00461ArticleFlavonifractor (Eubacterium) plautii bloodstream infection following acute cholecystitis Berger Fabian K. fabian.berger@uks.eua⁎Schwab Nadine bGlanemann Matthias cBohle Rainer M. dGärtner Barbara aGroesdonk Heinrich V. ba Institute of Medical Microbiology and Hygiene, Saarland University Medical Center, Homburg, Saar, Germanyb Department of Anesthesiology, Intensive Care Medicine and Pain Medicine, Saarland University Medical Center, University of Saarland, Homburg, Saar, Germanyc Department for General, Visceral, Vascular, and Pediatric Surgery, Saarland University Medical Center and Saarland University Faculty of Medicine, Homburg, Saar, Germanyd Institute of Pathology, Saarland University Medical Center, Saarland University, Homburg, Saar, Germany⁎ Corresponding author at: Kirrberger Street, Building 43, 66424, Homburg, Saar, Germany. fabian.berger@uks.eu28 10 2018 2018 28 10 2018 14 e00461 e00461 17 10 2018 24 10 2018 24 10 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Flavonifractor plautii (formerly Eubacterium plautii) is an anaerobic gram positive rod shaped bacterium belonging to the family of Clostridiales, and a common member of the human gut microbiome. However, it is very rarely isolated from clinical human specimens, so data about its clinical significance are scarce. Here we report of a bloodstream infection due to F. plautii following gangrenous cholecystitis in a 69 year old man. After cholecystectomy and empirical antimicrobial treatment with ceftriaxone and metronidazole the patient recovered.\n\nF. plautii was the only bacterium detected in blood culture, suggesting that it might have been causative for cholecystitis. Antimicrobial resistance testing identified decreased susceptibilities against linezolid and penicillin indicating that a targeted therapy might be necessary. F. plautii can be considered a potential pathogen for cholecystitis.\n\nKeywords\nSepsisAnaerobeGall bladderAntibiotic resistanceSusceptibility\n==== Body\nIntroduction\nFlavonifractor plautii (formerly Eubacterium plautii) is a gram positive (often appearing gram variant or gram negative) rod shaped bacterium belonging to the family of Clostridiales [1].\n\nThe bacterium is part of the human gut microbiome and are strictly anaerobic [2,3]. Data about the clinical significance are scarce due to the fact that it has been rarely isolated in human clinical specimens [1]. Infections were so far only reported in two patients worldwide. Both patients were immunosuppressed either having underwent solid organ transplantation or being asplenic [4,5]. Furthermore almost no data about resistance patterns are available.\n\nWe report of a case of bloodstream infection in a 69 year old male with acute gangrenous cholecystitis and F. plautii bloodstream infection and the organism's antimicrobial resistance pattern.\n\nCase report\nA 69-year-old male patient was admitted to the hospital for chemotherapy (docetaxel) due to a local recurrence of a prostate carcinoma metastatic to bone which was first treated five years prior via endoscopic prostatectomy and adjuvant radiotherapy. The patient showed a deterioration of his general condition and tumor induced anemia (Hgb 7.2 g/dL). Detected serum prostate specific antigen (PSA) levels were > 200 ng/mL.\n\nOne week after hospital admission being under immunosuppression with docetaxel, the patient complained about upper stomach pain and diarrhea. The symptoms were suspicious for cholecystitis which was confirmed by ultrasonography. Since the infection parameters were increased (CRP: 280 mg/L; procalcitonin: 6.52 ng/mL), the patient underwent directly open cholecystectomy. A calculated anti-infective therapy with metronidazole and ceftriaxone was started before surgery and blood cultures were obtained. Intraoperatively, a purulent gangrenous gallbladder was found and removed. In addition, an ileostomy was performed due to multiple adhesions. Histologically this finding was confirmed being classified as a necrotizing/gangrenous, ulcero-phlegmonous, cholecystitis with fibrinous pericholecystitis and cholecystolithiasis. An intraoperative culture was taken for microbial examination.\n\nAfter surgery the patient was transferred to the intensive care unit. There, he was extubated and the vasopressor therapy ended. Since the following postoperative course was uneventful, the patient was transferred to the ward on postoperative day four being discharged at day 14.\n\nOne pair of blood cultures was taken on the day of surgery. F. plautii was detected in one anaerobic blood culture being positive on culture day four. Gram staining revealed a gram positive rod. It was identified using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF, Bruker Billerica, USA) directly from the blood culture on the same day when being reported to be positive (Score 1.79). The pathogen was also cultured on Columbia agar (Oxoid, Basingstoke, United Kingdom) under anaerobic conditions. The isolate initially exhibited slow growth and on culture day six Maldi-TOF could be repeated with a sufficient score > 2.0 (Score 2.29). Additionally 16S rRNA sequencing was carried out confirming the results (database: NCBI; >350 base pairs, coverage forward and reverse primer: 100%, identity >99% for F. plautii). On Columbia agar the bacterium formed grey glassy colonies (Fig. 1).Fig. 1 Culture morphology of Flavonifractor plautii on Columbia agar.\n\nFig. 1\n\nResults of resistance testing are shown in Table 1 using a gradient test (E-Test, Liofilchem, Roseto degli Abruzzi, Italy) on Columbia agar under anaerobic conditions after 48 h of incubation (McFarland 0,5). The interpretation of minimal inhibitory concentrations (MICs) was carried out in accordance to EUCAST (EUropean Committee for Antimicrobial Susceptibility Testing) criteria (version 8.0, 2018). Additional blood culture sets were not taken before initiation of antimicrobial therapy and following two pairs of blood cultures remained sterile. Intraabdominal cultures taken during surgery showed no growth.Table 1 Antimicrobial resistance patterns of Flavonifractor plautii, MIC, minimal inhibitory concentration. Breakpoints according to EUCAST for gram-positive anaerobes and non-species related breakpoints, for sensitive values the interpretation is ≤ for resistant ones > (version 8.0 2018).\n\nTable 1Substance\tMIC (mg/L)\tEUCAST (breakpoint range in mg/L)\t\nPenicillin\t0.5\tintermediate (0.25-0.5)a\t\nAmpicillin\t0.5\tsensitive (4-8)a\t\nCefuroxime\t4.0\tsensitive (4-8)b\t\nCeftriaxone\t0.75\tsensitive (1-2)b\t\nPiperacillin/tazobactam\t0.19\tsensitive (8-16)a\t\nMeropenem\t0.023\tsensitive (2-8)a\t\nImipenem\t0.064\tsensitive (2-8)a\t\nErtapenem\t0.023\tsensitive (1)a\t\nGentamicin\t4.0\t-c\t\nCotrimoxazole\n(trimethoprim-sulfamethoxazole)\t≥32\t-c\t\nCiprofloxacin\t≥32\tresistant (0.25-0.5)b\t\nLevofloxacin\t2.0\tresistant (0.5-1)b\t\nMoxifloxacin\t0.5\tsensitive (0.25)b\t\nVancomycin\t2.0\tsensitive (2)a\t\nTeicoplanin\t0.25\t-c\t\nDaptomycin\t8.0\t-c\t\nLinezolid\t3.0\tintermediate (2-4)b\t\nMetronidazole\t0.25\tsensitive (4)a\t\nClindamycin\t0.38\tsensitive (4)a\t\nTetracyclin\t0.094\t-c\t\nTigecyclin\t0.0160\tsensitive (0.25-0.5)b\t\nChloramphenicol\t0.125\tsensitive (8)a\t\nRifampicin\t3.0\t-c\t\na EUCAST breakpoints for gram positive anaerobes utilized.\n\nb EUCAST non-species related breakpoints utilized.\n\nc No breakpoints available.\n\n\n\nDiscussion\nThe clinical significance of F. plautii is not yet fully understood since there are only two published cases of infection. One of these patients was an asplenic male who developed fulminant sepsis after a dog bite [4]. The other patient received a kidney transplant and had an infected pleural effusion probably through translocation of F. plautii following ileum perforation [5]. In both case reports immunosuppression seems to favor an infection. This is in line with the patient presented here, who was immunosuppressed due to prostate cancer and docetaxel treatment.\n\nAs mode of infection it can be assumed that F. plautii ascended from the intestinal tract to the bile tract and caused cholecystitis. The patient’s immunosuppression might have facilitated disease development. F. plautii was the only infective agent isolated. This might indicate a causative role for the cholecystitis with secondary bloodstream infection despite not being isolated in the intraoperative material. Since the bacterium is anaerobic, these negative results could be contributed either to difficulties in cultivation or the antimicrobial therapy before the sample was taken.\n\nIn the gram staining of the blood culture sample the pathogen appeared gram positive. It is known that F. plautii may stain gram negative which might be caused by changes in the cell wall after oxygen exposure [6]. In the two published clinical cases F. plautii was classified as gram negative/gram variant. Since gram staining was carried out immediately after the blood culture was reported to be positive one may assume that this favored the pathogen to appear (correctly) gram positive.\n\nMoreover, data about antimicrobial resistance patterns are currently scarce. According to EUCAST (European Committee on Antimicrobial Susceptibility Testing) for non-species related and anaerobic bacteria breakpoints, metronidazole and ceftriaxone were both classified as sensitive. The patient improved under this treatment suggesting that these substances are active in vivo as well.\n\nFortunately the agent was sensitive to a large variety of substances and only resistant to cotrimoxazole, and most fluoroquinolones with intermediate resistance to penicillin and linezolid. Thus the most frequently used treatment schemes for calculated antimicrobial therapy seem to cover this pathogen. This is congruent with previous findings exhibiting sensitive MICs against most β-lactams and clindamycin which was also apparent in our isolate [4]. In one study the MICs against glycopeptides (vancomycin and teicoplanin) were tested showing elevated MICs for vancomycin (4–8 mg/L) and low MICs for teicoplanin (0.25–0.5 mg/L) [1]. Our isolate however, showed a sensitive MIC but being situated directly at the EUCAST breakpoint of 2 mg/L which might also indicate a trend towards elevated MICs for vancomycin as well. Our isolate also exhibited a low MIC for teicoplanin (025 mg/L).\n\nSince this is one of the first reports in literature including a broader susceptibility testing of F. plautii this might not necessarily reflect the real epidemiologic makeup of resistance patterns of this species and further data is required to give evidence based antimicrobial treatment proposals. Due to the acquired data it might be assumed that F. plautii can be a causative agent of cholecystitis.\n\nAuthor Statement\nPatient treatment MG, HVG, NS; microbiological diagnostics: BG, FKB; pathological diagnostics: RMB; wrote the manuscript BG, FKB, HVG.\n\nDeclaration of interest\nNone declared.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nAcknowledgments\nWe would like to thank our technical employees for assistance in microbiological laboratory testing.\n==== Refs\nReferences\n1 Carlier J.P. Bedora-Faure M. K’Ouas G. Alauzet C. Mory F. Proposal to unify Clostridium orbiscindens Winter et al. 1991 and Eubacterium plautii (Seguin 1928) Hofstad and Aasjord 1982, with description of Flavonifractor plautii gen. nov., comb. nov., and reassignment of Bacteroides capillosus to Pseudoflavonifractor capillosus gen. nov., comb. Nov Int J Syst Evol Microbiol 60 2010 585 590 19654357 \n2 Kasai C. Sugimoto K. Moritani I. Tanaka J. Oya Y. Inoue H. Comparison of the gut microbiota composition between obese and non-obese individuals in a Japanese population, as analyzed by terminal restriction fragment length polymorphism and next-generation sequencing BMC Gastroenterol 15 2015 100 26261039 \n3 Engels C. Ruscheweyh H.J. Beerenwinkel N. Lacroix C. Schwab C. The common gut microbe Eubacterium hallii also contributes to intestinal propionate formation Front Microbiol 7 2016 713 27242734 \n4 Garre M. le Henaff C. Tande Chailloux J. Bensousan T. Garo B. Fulminant Eubacterium plautii infection following dog bite in asplenic man Lancet 338 1991 384 385 \n5 Orlando G. Pisani F. Mastrantonio P. Bonanni L. Di Cocco P. D’Angelo M. Eubacterium plautii infection in a kidney transplant recipient: a noteworthy case of pleural effusion and fever Clin Transp 22 2008 520 524 \n6 Johnson M.J. Thatcher E. Cox M.E. Techniques for controlling variability in gram staining of obligate anaerobes J Clin Microbiol 33 1995 755 758 7538512\n\n",
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"issue": "14()",
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"keywords": "Anaerobe; Antibiotic resistance; Gall bladder; Sepsis; Susceptibility",
"medline_ta": "IDCases",
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"nlm_unique_id": "101634540",
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"title": "Flavonifractor (Eubacterium) plautii bloodstream infection following acute cholecystitis.",
"title_normalized": "flavonifractor eubacterium plautii bloodstream infection following acute cholecystitis"
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{
"abstract": "There has been concern that exposure to lithium early in pregnancy may be associated with a marked increase in the risk of Ebstein's anomaly (a right ventricular outflow tract obstruction defect) in infants and overall congenital cardiac defects, but data are conflicting and limited.\n\n\n\nWe conducted a cohort study involving 1,325,563 pregnancies in women who were enrolled in Medicaid and who delivered a live-born infant between 2000 and 2010. We examined the risk of cardiac malformations among infants exposed to lithium during the first trimester as compared with unexposed infants and, in secondary analyses, with infants exposed to another commonly used mood stabilizer, lamotrigine. Risk ratios and 95% confidence intervals were estimated with control for psychiatric and medical conditions, medications, and other potential confounders.\n\n\n\nCardiac malformations were present in 16 of the 663 infants exposed to lithium (2.41%), 15,251 of the 1,322,955 nonexposed infants (1.15%), and 27 of the 1945 infants exposed to lamotrigine (1.39%). The adjusted risk ratio for cardiac malformations among infants exposed to lithium as compared with unexposed infants was 1.65 (95% confidence interval [CI], 1.02 to 2.68). The risk ratio was 1.11 (95% CI, 0.46 to 2.64) for a daily dose of 600 mg or less, 1.60 (95% CI, 0.67 to 3.80) for 601 to 900 mg, and 3.22 (95% CI, 1.47 to 7.02) for more than 900 mg. The prevalence of right ventricular outflow tract obstruction defects was 0.60% among lithium-exposed infants versus 0.18% among unexposed infants (adjusted risk ratio, 2.66; 95% CI, 1.00 to 7.06). Results were similar when lamotrigine-exposed infants were used as the reference group.\n\n\n\nMaternal use of lithium during the first trimester was associated with an increased risk of cardiac malformations, including Ebstein's anomaly; the magnitude of this effect was smaller than had been previously postulated. (Funded by the National Institute of Mental Health.).",
"affiliations": "From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.;From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine (E.P., K.F.H., B.T.B., R.J.D., H.M.), and the Department of Anesthesiology, Perioperative and Pain Medicine (B.T.B.), Brigham and Women's Hospital and Harvard Medical School, the Department of Epidemiology, Harvard T.H. Chan School of Public Health (J.M.C., S.H.-D.), and the Center for Women's Mental Health, Department of Psychiatry, Massachusetts General Hospital (L.S.C.) - all in Boston.",
"authors": "Patorno|Elisabetta|E|;Huybrechts|Krista F|KF|;Bateman|Brian T|BT|;Cohen|Jacqueline M|JM|;Desai|Rishi J|RJ|;Mogun|Helen|H|;Cohen|Lee S|LS|;Hernandez-Diaz|Sonia|S|",
"chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D018020:Lithium Compounds; D014227:Triazines; D000077213:Lamotrigine",
"country": "United States",
"delete": false,
"doi": "10.1056/NEJMoa1612222",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-4793",
"issue": "376(23)",
"journal": "The New England journal of medicine",
"keywords": null,
"medline_ta": "N Engl J Med",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000928:Antidepressive Agents; D018692:Antimanic Agents; D001714:Bipolar Disorder; D015331:Cohort Studies; D005260:Female; D006330:Heart Defects, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D000077213:Lamotrigine; D018020:Lithium Compounds; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D015995:Prevalence; D014227:Triazines; D055815:Young Adult",
"nlm_unique_id": "0255562",
"other_id": null,
"pages": "2245-2254",
"pmc": null,
"pmid": "28591541",
"pubdate": "2017-06-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": "20558369;5410201;6126733;4140306;1119612;6624510;18982835;2148987;2107734;7163972;24740606;8031346;18056236;23840692;7801301;22551726;24781368;20712749;19757444;1346886;6794356;23137820;27922533;15056503;4266975;24941178;22550030;671171;24104771;18480684;6518066;2743779;6772020",
"title": "Lithium Use in Pregnancy and the Risk of Cardiac Malformations.",
"title_normalized": "lithium use in pregnancy and the risk of cardiac malformations"
} | [
{
"companynumb": "US-ALEMBIC PHARMACUETICALS LIMITED-2017SCAL000561",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"activesubstancename": "LITHIUM CARBONATE"
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... |
{
"abstract": "Background. Available treatments for Wilson disease (WD) prevent longterm complications of copper accumulation. Current anti-copper agents include zinc salts, penicillamine, and trientine. Patients with WD may switch between the agents for a number of reasons. Due to the different mechanisms of action between the copper chelators and zinc salts, transitioning could require a period of overlap and increased monitoring. There are no large studies that investigate the best transition strategies between agents. In this article, we review the treatments for WD and how to monitor for treatment efficacy. Case Summary. The patient had been diagnosed with WD for over 20 years prior to establishing care in our Hepatology Clinic. During his initial course, he was transitioned from penicillamine to zinc due to evidence suggesting penicillamine had greater adverse effects in the long term. Later, he was switched to trientine. His liver enzymes and 24-hour urine copper were monitored. During these years, he intermittently had some financial hardship, requiring him to be on penicillamine rather than trientine. He also had developed acute kidney injury. Overall, his liver disease remained under control and he never had signs of decompensated cirrhosis, but had fluctuations of liver enzymes over the years. Conclusion. Anti-copper treatment for WD has to be tailored to medication side effects profile, patient's chronic and emerging comorbidities, as well as costs. Transitioning regimens is often challenging, and it requires closer monitoring, with no predictors of response.",
"affiliations": "University of California Davis, Sacramento, CA, USA.;University of California Davis, Sacramento, CA, USA.;University of California Davis, Sacramento, CA, USA.",
"authors": "Leung|Marcia|M|0000-0002-6271-0601;Wu Lanzafame|Jaimie|J|;Medici|Valentina|V|",
"chemical_list": "D002614:Chelating Agents; D003300:Copper; D010396:Penicillamine; D015032:Zinc; D014266:Trientine",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709619896876",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961989687610.1177_2324709619896876Case ReportSwitching Pharmacological Treatment in Wilson Disease: Case Report and Recommendations https://orcid.org/0000-0002-6271-0601Leung Marcia MD1Wu Lanzafame Jaimie MD1Medici Valentina MD11 University of California Davis, Sacramento, CA, USAValentina Medici, MD, Division of Gastroenterology and Hepatology, University of California Davis, 4150 V Street #3500, Sacramento, CA 95817-1460, USA. Email: vmedici@ucdavis.edu10 1 2020 Jan-Dec 2020 8 232470961989687619 9 2019 6 11 2019 9 11 2019 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://creativecommons.org/licenses/by/4.0/) which permits any 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).Background. Available treatments for Wilson disease (WD) prevent longterm complications of copper accumulation. Current anti-copper agents include zinc salts, penicillamine, and trientine. Patients with WD may switch between the agents for a number of reasons. Due to the different mechanisms of action between the copper chelators and zinc salts, transitioning could require a period of overlap and increased monitoring. There are no large studies that investigate the best transition strategies between agents. In this article, we review the treatments for WD and how to monitor for treatment efficacy. Case Summary. The patient had been diagnosed with WD for over 20 years prior to establishing care in our Hepatology Clinic. During his initial course, he was transitioned from penicillamine to zinc due to evidence suggesting penicillamine had greater adverse effects in the long term. Later, he was switched to trientine. His liver enzymes and 24-hour urine copper were monitored. During these years, he intermittently had some financial hardship, requiring him to be on penicillamine rather than trientine. He also had developed acute kidney injury. Overall, his liver disease remained under control and he never had signs of decompensated cirrhosis, but had fluctuations of liver enzymes over the years. Conclusion. Anti-copper treatment for WD has to be tailored to medication side effects profile, patient’s chronic and emerging comorbidities, as well as costs. Transitioning regimens is often challenging, and it requires closer monitoring, with no predictors of response.\n\nWilson diseasepenicillaminezinc acetatetrientinecover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nWilson disease (WD) is an autosomal recessive disorder with a prevalence traditionally reported of 1 in 30,000 individuals,1,2 but more recent studies indicate that it could affect 1 in 7,026 individuals.3,4 The underlying genetic defect is based on disease-causing mutations in the ATP7B gene,5 which encodes a copper transporting adenosine triphosphatase crucial for biliary copper excretion as well as synthesis and maturation of functional ceruloplasmin.6,7 Absent or reduced function of this protein results in copper accumulation within multiple organs, most notably the liver, brain, and cornea. While patients may present with a variety of symptoms, the clinical manifestations of WD are predominately hepatic, neurologic, and psychiatric. There are limited medical treatment options for WD that have shown to prevent sequelae of the disease and little research has been done to determine the most effective way to transition between agents in the event of ineffective therapy or a patient’s inability to tolerate the medication.\n\nCase Presentation\nThe patient was first diagnosed with WD at age 32, when he presented with elevated liver enzymes and workup revealing low ceruloplasmin. He started to be followed at University of California Davis Hepatology Clinic when he was 56 years old. His comorbidities include well-controlled HIV on efavirenz/emtricitabine/tenofovir.\n\nAt the time of establishing care at University of California Davis in 2006, he had compensated cirrhosis with elevated liver enzymes and mild hepatomegaly. He underwent liver biopsy, which demonstrated moderate portal and lobular lymphocytic infiltrate, periportal and focal bridging fibrosis (stage 2-3), and moderate steatosis (25%). Drug-induced liver injury was considered, especially with ongoing highly active antiretroviral therapy, as approximately 20% of all patients on highly active antiretroviral therapy have liver enzymes abnormalities.8 Other causes of elevated liver enzymes including alcohol abuse, viral hepatitis, autoimmune hepatitis, α-1 antitrypsin deficiency, and hemochromatosis were excluded. He had been on penicillamine (PCA) 250 mg 3 times daily for more than 20 years, and his HIV was under control as shown by CD4 count 543 cells/mm3 and viral load <50 copies/mL. His past medical history includes nephrolithiasis, major depressive disorder, hypertension, and type 2 diabetes.\n\nOn physical examination, the patient had no scleral icterus. Abdomen nondistended, liver palpable at about 1 cm under the right costal margin with sharp edge. No collateral veins, ascites, peripheral edema, flapping tremor, signs of encephalopathy, and spider angiomata. No focal neurologic deficits on physical examination, cranial nerves intact, alert, and oriented to person, place, time, and situation.\n\nLaboratory\nNegative serology for hepatitis B (positive HBsAb) and C. chemistry panel showed normal electrolytes and kidney function (sodium 145 mEq/L, potassium 4.1 mEq/L, chloride 105 mEq/L, bicarbonate 26 mEq/L, blood urea nitrogen 11 mg/dL, creatinine 0.6 mg/dL, and calcium 9.4 mg/dL). Bilirubin levels were 0.7 mg/dL, alkaline phosphatase 96 IU/L, aspartate transaminase 54 IU/L, and alanine transaminase 84 IU/L. Blood count was within normal limits including normal platelets.\n\nImaging\nUltrasound of abdomen demonstrated hepatomegaly with moderate degree of hepatosteatosis with evidence of portal hypertension with splenomegaly, and no ascites. Magnetic resonance imaging of brain demonstrated mild cerebral cortical volume loss. There was no evidence of alterations in the striatum or in the white matter.\n\nFinal Diagnosis, Treatment, Outcome, and Follow-up\nThe patient was compliant on PCA for more than 20 years when he established care in 2007, but his transaminases were persistently elevated. Compliance was confirmed by 24-hour urinary copper levels in 300 to 400 µg range. Given growing evidence that PCA treatment is affected by several long-term side effects,9 including nephrotoxicity with proteinuria and hematuria, skin progeric changes, and autoimmune conditions,10 he was switched over to zinc acetate shortly after establishing care.6\n\nIn July 2010, given persistent elevation of liver enzymes (aspartate transaminase 55-90 IU/L, alanine transaminase 36-55 IU/L) and new published evidence that chelation treatment had lower rates of treatment failure and orthotopic liver transplantation, he was switched to trientine (Table 1).9 From 2011 to 2014, dose adjustments to trientine were made (Figures 1 and 2) mainly due to development of mild normocytic anemia, hemoglobin of 11.5 g/dL from baseline of 15 g/dL, with mean corpuscular volume of 89 fL. This was attributed to overtreatment with trientine as other causes of anemia were excluded, and there were no changes to HIV medications. In 2015, he eventually had to stop trientine due to lack of insurance coverage and was switched to PCA.\n\nTable 1. Transitioning Between Therapeutic Agents in Wilson Diseasea.\n\n\tWhen to Transition\tHow to Transition\tMonitoring\t\nPCA to trientine\t● Patient unable to tolerate PCA\n● Development of nephrotic syndrome, severe thrombocytopenia, or aplastic anemia\tNo taper or overlap indicated\tBaseline CBC, CMP, and 24-hour urinary copper prior to switch\nRepeat above laboratory tests monthly for 3 to 4 months\nGoal: Maintain 24-hour urinary copper 200 to 500 µg, stable ALT\nLong-term: Repeat blood tests, including CBC and CMP, and 24-hour urinary copper at least every 6 months; 24-hour urinary copper should be in the 200 to 500 µg/day range\t\nPCA to zinc salts\t● Patient unable to tolerate PCA\n● Development of renal failure, severe thrombocytopenia/aplastic anemia\n● Worsening neurologic symptoms\n● Pregnancy\tStart zinc at 50 mg TID, uptitrate by 50 mg increments as necessary\nContinue PCA for at least 3 months after initiating zinc therapy\nPCA and zinc dosing must be spread out so that they are not taken at the same time; PCA cannot be given at meal times\tCMP, 24-hour urinary copper prior to switch and every 3 months until urinary copper at goal/stabilizes\nGoal: Maintain urinary copper <75 µg, stable liver enzymes\nLong-term: Repeat blood tests, including CBC and CMP, and 24-hour urinary copper at least every 6 months; 24-hour urinary copper should be <75 µg/day\t\nTrientine to zinc salts\t● Financial limitations\n● Limited drug availability\n● Development of pancolitis\n● Pregnancy\tStart zinc at 50 mg TID, titrate by 50 mg increments as necessary; when starting zinc, reduce trientine dose by 250 mg and reduce by 250 mg every month until termination of trientine\nContinue trientine for at least 3 months after initiating zinc therapy\nTrientine and zinc dosing must be spread out so that they are not taken at the same time; PCA cannot be given at meal times\tCMP, 24-hour urinary copper prior to switch and every 3 months until urinary copper at goal/stabilizes\nGoal: Maintain urinary copper <75 µg, stable liver enzymes\nLong-term: repeat blood tests, including CBC and CMP, and 24-hour urinary copper at least every 6 months; 24-hour urinary copper should be <75 µg/day\t\nZinc salts to trientine\t● Ineffective therapy demonstrated by uptrending liver enzymes, development of liver synthetic dysfunction\tNo taper or overlap indicated\tBaseline CBC, CMP, and 24-hour urinary copper prior to switch\nRepeat above laboratory tests monthly for 3 to 4 months\nGoal: Maintain urinary copper 200 to 500 µg, stable liver enzymes\t\nTrientine or zinc salts to PCA\t● Financial limitations\n● Patient’s preference\tNo taper or overlap indicated\tBaseline CBC, CMP, and 24-hour urinary copper prior to switch\nRepeat above laboratory tests monthly for 1 to 2 months\nGoal: Maintain urinary copper 200 to 500 µg, stable liver enzymes\nLong-term: Repeat blood tests, including CBC and CMP, and 24-hour urinary copper at least every 6 months; 24-hour urinary copper should be in the 200 to 500 µg/day range\nRepeat UA every 6 months to check on proteinuria\t\nAbbreviations: PCA, penicillamine; CBC, complete blood count; CMP, complete metabolic panel (including liver enzymes); ALT, alanine transaminase; TID, 3 times a day; UA, urinalysis.\n\na Dose of zinc refers to elemental zinc.\n\nFigure 1. ALT and AST levels trends.\n\nAbbreviations: ALT, alanine transaminase; AST, aspartate transaminase; BID, 2 times a day; TID, 3 times a day; QID, 4 times a day.\n\nFigure 2. Twenty-four-hour urine copper trends.\n\nAbbreviations: BID, 2 times a day; TID, 3 times a day; QID, 4 times a day.\n\nIn February 2017, he developed acute kidney injury (elevation in baseline creatinine from 0.84 to 1.34 mg/dL) following a unilateral renal stone, for which he underwent cystoscopy with laser lithotripsy and stent placement. He was also noted to have proteinuria 50 mg/dL following this incident, so in an attempt to minimize contributing nephrotoxic agents, he was switched off of PCA to trientine. His antiretroviral therapy for HIV was also changed from efavirenz/emtricitabine/tenofovir to emtricitabine/rilpivirine/tenofovir alafenamide. As a result, his creatinine downtrended to baseline by June 2017. Liver enzymes were stable during this time with no acute rises.\n\nIn March 2018, new financial issues prevented him to continue with the full dose of copper chelating agent. At that point, zinc acetate was added to trientine. In October 2018, he was back on trientine alone again as he obtained full insurance coverage while transaminases remained normal.\n\nDiscussion\nTherapies for WD include chelating agents, PCA, and trientine, which increase urinary copper excretion and zinc salts that inhibit intestinal copper absorption. The goal of initial treatment of WD is to reestablish copper balance, whereas the maintenance phase serves to maintain these levels without inducing copper deficiency.6 Maintenance represents lifelong therapy, unless a patient undergoes liver transplant.11 However, despite its side effects and limitations, current medical treatment for WD is effective in avoiding disease progression and liver transplant for the majority of patients provided treatment is tailored and optimized to the patient’s needs and comorbidities. In particular, we are not aware of case reports describing WD treatment options and outcomes in patients with HIV. Therefore, connections between the available literature and the current case may appear marginal and based on the treating clinician experience and assessment.\n\nPenicillamine was among the first oral agents introduced for treating WD.12 Although multiple studies have demonstrated its efficacy in treatment of WD,13-16 PCA has an extensive side effect profile. Patients can experience early hypersensitivity reactions within 1 to 3 weeks of initiation of treatment, characterized by fever, cutaneous eruptions, cytopenias, and proteinuria. Late-onset reactions, although rare, may be fatal and include drug-induced lupus, nephrotic syndrome leading to renal failure, severe thrombocytopenia, or aplastic anemia.13,17-19 In the event of a severe reaction, PCA should be discontinued and patient should be transitioned to alternative therapy.19 PCA should be avoided in patients with a penicillin allergy, history of PCA-related aplastic anemia or agranulocytosis, or renal disease. When possible, it should also be avoided in patients with neuropsychiatric manifestations of WD, as at least 10% of those treated have had worsening of symptoms.8,20-22 In the described case, the rationale for initially switching from PCA to zinc acetate was the concern about emerging of autoimmune conditions and nephropathy in a patient with multiple comorbidities and on lifelong pharmacological treatment.\n\nTrientine was developed as a therapeutic option for patients who were unable to tolerate or had contraindications to PCA. It has been shown to be as effective for treatment of WD and associated with fewer side effects compared with PCA.23-26 Although hypersensitivity reactions and pancytopenia can occur with trientine, these side effects are rare and can often be addressed with dose reduction and use of steroids. While worsening of neuropsychiatric symptoms has also been noted with trientine use, its incidence is lower.6,18,27 Rare side effects of trientine include sideroblastic anemia, pancolitis, and hemorrhagic gastritis. Notably, a large barrier to use of trientine therapy is availability or cost of the drug, as seen in our patient described above.\n\nThe main advantage of zinc salts over chelating agents is that they are generally well tolerated by patients due to fewer side effects. Gastric irritation is the most commonly described side effect, though that may be due to the salt preparation rather than zinc itself. Unlike the chelating agents, zinc can also be safely given during pregnancy without dose reduction. Zinc has been shown to be effective in controlling copper levels during maintenance therapy,15,28-30 though in some studies, chelators have been shown to be better at slowing progression of WD if tolerated.9,31 In our patient, despite compliance with zinc therapy, he had rising liver function tests, suggesting ineffective maintenance therapy with zinc. It has also been suggested that zinc may be as effective as chelators as initial therapy,15,32-34 especially in patients who are unable to tolerate chelating agents, who have significant neuropsychiatric disease, or in patients who are presymptomatic.\n\nRegardless of therapy selection, patients must be closely monitored clinically and with routine laboratory tests while on therapy. With initiation of treatment or modification of regimen, patients should be monitored at least every 3 months for efficacy of treatment, compliance, and potential therapy adverse effects. In addition to clinical evaluation, recommended laboratory tests included liver enzymes, international normalized ratio, complete blood count, urinalysis, and surrogates of copper metabolism, including serum-free copper, ceruloplasmin, and 24-hour urinary copper excretion. Monitoring of urine copper may be the most effective way to evaluate compliance and success of therapy.6,35 When on chelating agents, elevated values of urine copper may suggest non-adherence and hepatic deterioration, whereas low values may indicate overtreatment when accompanied by low non–ceruloplasmin-bound copper.6,36 Conversely, if a patient is on zinc, marked reduction of urine copper represents reduction of total body copper, implying effective therapy with zinc. Monitoring liver enzymes also provides insight into efficacy of therapy. Rising liver enzymes despite compliance to therapy may suggest ineffective treatment and the need to transition to an alternative agent.\n\nWhile several studies have been done regarding the efficacy of chelating agents13 and zinc, as well as comparing the various agents available for treatment of WD,14,15,34,37 there is little to no commentary on dose adjustments or the most effective way to transition between different agents if necessary. As demonstrated by our patient above, patients may be transitioned between therapies for various reasons, whether it be inability to tolerate therapy due to adverse effects, ineffective treatment, comorbidities, or financial concerns. Since zinc typically requires 2 to 6 months of treatment during initial therapy to reach the maintenance phase, tapering is likely required when switching to zinc. Transitioning between agents is further complicated when on multiple agents due to timing of medications as absorption of chelators is affected by meals.6,18 In addition, clinicians can prescribe other agents including vitamin E, which may be beneficial given its antioxidant properties and some limited evidence of reduced levels of vitamin E in plasma of patients with WD.38 It is also noticeable that other treatment options may become soon available for the treatment of WD, and they include tetrathiomolybdate bis-choline39 and methanobactin.40 An additional layer of complexity is related to the possible combination treatment. Even though most clinicians are concerned about the binding of zinc by copper chelators if administered concomitantly, data from Askari at al41 showed that the combination treatment with trientine and zinc in case of decompensated cirrhosis is associated with significant improvement of liver function. As shown in Table 1, we are proposing specific recommendations for transitioning between different therapeutic agents.\n\nIn conclusion, although there have been studies exploring the efficacy of various treatments for WD and comparing these agents, there is limited research regarding effective transitions between these agents. We have proposed specific recommendations for transitioning between therapeutic agents. However, further studies are warranted to help determine the optimal transition indications, timing, and monitoring.\n\nAuthor’s Note: Marcia Leung and Jaimie Wu Lanzafame contributed equally to the paper and are both first authors.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: Funding was provided by NIH grant DK104770 to V.M.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Written informed consent was obtained from the patient for their anonymized information to be published in this article.\n\nORCID iD: Marcia Leung \nhttps://orcid.org/0000-0002-6271-0601\n==== Refs\nReferences\n1 \nFrydman M. \nGenetic aspects of Wilson’s disease . J Gastroenterol Hepatol . 1990 ;5 :483 -490 . doi:10.1111/j.1440-1746.1990.tb01427.x 2129820 \n2 \nWiggelinkhuizen M Tilanus ME Bollen CW Houwen RH. \nSystematic review: clinical efficacy of chelator agents and zinc in the initial treatment of Wilson disease . Aliment Pharmacol Ther . 2009 ;29 :947 -958 . doi:10.1111/j.1365-2036.2009.03959.x 19210288 \n3 \nCoffey AJ Durkie M Hague S , et al\nA genetic study of Wilson’s disease in the United Kingdom . Brain . 2013 ;136 (pt 5 ):1476 -1487 . doi:10.1093/brain/awt035 23518715 \n4 \nGao J Brackley S Mann JP. \nThe global prevalence of Wilson disease from next-generation sequencing data . Genet Med . 2019 ;21 :1155 -1163 . doi:10.1038/s41436-018-0309-9 30254379 \n5 \nTao TY Gitlin JD. \nHepatic copper metabolism: insights from genetic disease . Hepatology . 2003 ;37 :1241 -1247 . doi:10.1053/jhep.2003.50281 12773998 \n6 \nRoberts EA Schilsky ML ; American Association for Study of Liver Disease . Diagnosis and treatment of Wilson disease: an update . Hepatology . 2008 ;47 :2089 -2111 . doi:10.1002/hep.22261 18506894 \n7 \nTanzi RE Petrukhin K Chernov I , et al\nThe Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene . Nat Genet . 1993 ;5 :344 -350 . doi:10.1038/ng1293-344 8298641 \n8 \nMedici V Trevisan CP D’Inca R , et al\nDiagnosis and management of Wilson’s disease: results of a single center experience . J Clin Gastroenterol . 2006 ;40 :936 -941 . doi:10.1097/01.mcg.0000225670.91722.59 17063115 \n9 \nWeiss KH Gotthardt DN Klemm D , et al\nZinc monotherapy is not as effective as chelating agents in treatment of Wilson disease . Gastroenterology . 2011 ;140 :1189 -1198 . doi:10.1053/j.gastro.2010.12.034 21185835 \n10 \nCzlonkowska A Litwin T \nWilson disease—currently used anticopper therapy . In: Czlonkowska A Schilsky ML , eds. Handbook of Clinical Neurology . Vol 142 \n3rd ed. \nAmsterdam, Netherlands : Elsevier ; 2017 :181 -192 .\n11 \nCzlonkowska A Litwin T Dusek P , et al\nWilson disease . Nat Rev Dis Primers . 2018 ;4 :21 . doi:10.1038/s41572-018-0018-3 30190489 \n12 \nWalshe JM. \nPenicillamine, a new oral therapy for Wilson’s disease . Am J Med . 1956 ;21 :487 -495 . doi:10.1016/0002-9343(56)90066-3 13362281 \n13 \nWeiss KH Thurik F Gotthardt DN , et al; EUROWILSON Consortium . Efficacy and safety of oral chelators in treatment of patients with Wilson disease . Clin Gastroenterol Hepatol . 2013 ;11 :1028 -1035 . doi:10.1016/j.cgh.2013.03.012 23542331 \n14 \nWalshe JM. \nCopper chelation in patients with Wilson’s disease. A comparison of penicillamine and triethylene tetramine dihydrochloride . Q J Med . 1973 ;42 :441 -452 .4728043 \n15 \nCzlonkowska A Gajda J Rodo M. \nEffects of long-term treatment in Wilson’s disease with D-penicillamine and zinc sulphate . J Neurol . 1996 ;243 :269 -273 . doi:10.1007/bf00868525 8936358 \n16 \nFalkmer S Samuelson G Sjölin S. \nPenicillamine-induced normalization of clinical signs, and liver morphology and histochemistry in a case of Wilson’s disease . Pediatrics . 1970 ;45 :260 -268 .5413388 \n17 \nBrewer GJ Yuzbasiyan-Gurkan V. \nWilson disease . Medicine (Baltimore) . 1992 ;71 :139 -164 . doi:10.1097/00005792-199205000-00004 1635439 \n18 \nEuropean Association for Study of Liver . EASL Clinical Practice Guidelines: Wilson’s disease . J Hepatol . 2012 ;56 :671 -685 . doi:10.1016/j.jhep.2011.11.007 22340672 \n19 \nAggarwal A Bhatt M. \nAdvances in treatment of Wilson disease . Tremor Other Hyperkinet Mov (N Y) . 2018 ;8 :525 . doi:10.7916/D841881D 29520330 \n20 \nBrewer GJ Terry CA Aisen AM Hill GM. \nWorsening of neurologic syndrome in patients with Wilson’s disease with initial penicillamine therapy . Arch Neurol . 1987 ;44 :490 -493 . doi:10.1001/archneur.1987.00520170020016 3579660 \n21 \nLitwin T Dziezyc K Karlinski M Chabik G Czepiel W Członkowska A. \nEarly neurological worsening in patients with Wilson’s disease . J Neurol Sci . 2015 ;355 :162 -167 . doi:10.1016/j.jns.2015.06.010 26071888 \n22 \nRanjan A Kalita J Kumar V Misra UK. \nMRI and oxidative stress markers in neurological worsening of Wilson disease following penicillamine . Neurotoxicology . 2015 ;49 :45 -49 . doi:10.1016/j.neuro.2015.05.004 26004675 \n23 \nWalshe JM. \nTreatment of Wilson’s disease with trientine (triethylene tetramine) dihydrochloride . Lancet . 1982 ;1 :643 -647 . doi:10.1016/s0140-6736(82)92201-2 6121964 \n24 \nDubois RS Rodgerson DO Hambidge KM. \nTreatment of Wilson’s disease with triethylene tetramine hydrochloride (Trientine) . J Pediatr Gastroenterol Nutr . 1990 ;10 :77 -81 . doi:10.1097/00005176-199001000-00015 2324883 \n25 \nScheinberg IH Jaffe ME Sternlieb I. \nThe use of trientine in preventing the effects of interrupting penicillamine therapy in Wilson’s disease . N Engl J Med . 1987 ;317 :209 -213 . doi:10.1056/NEJM198707233170405 3600712 \n26 \nSarkar B Sass-Kortsak A Clarke R Laurie SH Wei P. \nA comparative study of in vitro and in vivo interaction of D-penicillamine and triethylenetetramine with copper . Proc R Soc Med . 1977 ;70 (suppl 3 ):13 -18 .\n27 \nBrewer GJ Askari F Lorincz MT , et al\nTreatment of Wilson disease with ammonium tetrathiomolybdate: IV. Comparison of tetrathiomolybdate and trientine in a double-blind study of treatment of the neurologic presentation of Wilson disease . Arch Neurol . 2006 ;63 :521 -527 . doi:10.1001/archneur.63.4.521 16606763 \n28 \nBrewer GJ. \nZinc acetate for the treatment of Wilson’s disease . Expert Opin Pharmacother . 2001 ;2 :1473 -1477 . doi:10.1517/14656566.2.9.1473 11585025 \n29 \nHoogenraad TU. \nZinc treatment of Wilson’s disease . J Lab Clin Med . 1998 ;132 :240 -241 .9794692 \n30 \nMarcellini M Di Ciommo V Callea F , et al\nTreatment of Wilson’s disease with zinc from the time of diagnosis in pediatric patients: a single-hospital, 10-year follow-up study . J Lab Clin Med . 2005 ;145 :139 -143 .15871305 \n31 \nLinn FH Houwen RH van Hattum J van der Kleij S van Erpecum KJ. \nLong-term exclusive zinc monotherapy in symptomatic Wilson disease: experience in 17 patients . Hepatology . 2009 ;50 :1442 -1452 . doi:10.1002/hep.23182 19731238 \n32 \nBrewer GJ Yuzbasiyan-Gurkan V Lee DY Appelman H \nTreatment of Wilson’s disease with zinc. VI. Initial treatment studies . J Lab Clin Med . 1989 ;114 :633 -638 .2592853 \n33 \nHoogenraad TU. \nParadigm shift in treatment of Wilson’s disease: zinc therapy now treatment of choice . Brain Dev . 2006 ;28 :141 -146 . doi:10.1016/j.braindev.2005.08.008 16466879 \n34 \nAppenzeller-Herzog C Mathes T Heeres MLS Weiss KH Houwen RHJ Ewald H. \nComparative effectiveness of common therapies for Wilson disease: a systematic review and meta-analysis of controlled studies . Liver Int . 2019 ;39 :2136 -2152 . doi:10.1111/liv.14179 31206982 \n35 \nPfeiffenberger J Lohse CM Gotthardt D , et al\nLong-term evaluation of urinary copper excretion and non-caeruloplasmin associated copper in Wilson disease patients under medical treatment . J Inherit Metab Dis . 2019 ;42 :371 -380 . doi:10.1002/jimd.12046 30746719 \n36 \nMerle U Schaefer M Ferenci P Stremmel W. \nClinical presentation, diagnosis and long-term outcome of Wilson’s disease: a cohort study . Gut . 2007 ;56 :115 -120 . doi:10.1136/gut.2005.087262 16709660 \n37 \nCzlonkowska A Litwin T Karlinski M Dziezyc K Chabik G Czerska M. \nD-penicillamine versus zinc sulfate as first-line therapy for Wilson’s disease . Eur J Neurol . 2014 ;21 :599 -606 . doi:10.1111/ene.12348 24447648 \n38 \nVon Herbay A de Groot H Hegi U Stremmel W Strohmeyer G Sies H \nLow vitamin E content in plasma of patients with alcoholic liver disease, hemochromatosis and Wilson’s disease . J Hepatol . 1994 ;20 :41 -46 .8201221 \n39 \nWeiss KH Askari FK Czlonkowska A , et al\nBis-choline tetrathiomolybdate in patients with Wilson’s disease: an open-label, multicentre, phase 2 study . Lancet Gastroenterol Hepatol . 2017 ;2 :869 -876 . doi:10.1016/S2468-1253(17)30293-5 28988934 \n40 \nLichtmannegger J Leitzinger C Wimmer R , et al\nMethanobactin reverses acute liver failure in a rat model of Wilson disease . J Clin Invest . 2016 ;126 :2721 -2735 . doi:10.1172/JCI85226 27322060 \n41 \nAskari FK Greenson J Dick RD Johnson VD Brewer GJ \nTreatment of Wilson’s disease with zinc. XVIII. Initial treatment of the hepatic decompensation presentation with trientine and zinc . J Lab Clin Med . 2003 ;142 :385 -390 . doi:10.1016/S0022-2143(03)00157-4 14713890\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Wilson disease; penicillamine; trientine; zinc acetate",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D002614:Chelating Agents; D003300:Copper; D006527:Hepatolenticular Degeneration; D006801:Humans; D008099:Liver; D008297:Male; D010396:Penicillamine; D016896:Treatment Outcome; D014266:Trientine; D015032:Zinc",
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"references": "2592853;30254379;1635439;31206982;24447648;9794692;2324883;28433101;17063115;30746719;23518715;5413388;6121964;18506894;8298641;16709660;16466879;23542331;2129820;27322060;12773998;28988934;19731238;11585025;3579660;3600712;8201221;8936358;13362281;16606763;4728043;21185835;26071888;15871305;19210288;30190489;14713890;22340672;122660;26004675;29520330",
"title": "Switching Pharmacological Treatment in Wilson Disease: Case Report and Recommendations.",
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"abstract": "The relationship between reactive arthritis and enteric infections caused by Yersinia enterocolitica, Campylobacter jejuni, and Salmonella typhimurium is well documented. Clostridium difficile colitis is a less recognized cause of reactive arthritis. We present a case of a 58-year-old woman with Clostridium difficile colitis complicated by reactive arthritis. A 58-year-old woman with no significant past medical history presented to our hospital with complaints of nonbloody watery diarrhea, abdominal pain for the past 1 week, and right knee pain starting 1 day prior. The patient had recently used antibiotics for a respiratory tract infection. On examination, the patient had a swollen and erythematous right knee. While in the hospital the patient also developed a similarly painful and swollen left knee. The patient was found to be positive for C difficile toxin in stool. Synovial fluid analysis of both the knee joints revealed a sterile and inflammatory fluid, negative for crystals and showing no growth on gram stain. We diagnosed the patient with reactive arthritis secondary to C difficile colitis once all other causes of the bilateral knee joint symptoms were ruled out with appropriate laboratory and imaging studies. Treatment with oral vancomycin and an anti-inflammatory was initiated, and the patient had complete resolution of symptoms. This case illustrates the importance of recognizing C difficile colitis as a potential differential for reactive arthritis under the appropriate circumstances. The treatment of reactive arthritis is mainly supportive and treating the underlying cause, which happens to be C difficile in this case.",
"affiliations": "Temple University, Philadelphia, PA, USA.;Temple University, Philadelphia, PA, USA.;Temple University, Philadelphia, PA, USA.;Temple University, Philadelphia, PA, USA.;Temple University, Philadelphia, PA, USA.;Temple University, Philadelphia, PA, USA.",
"authors": "Marwat|Asghar|A|;Mehmood|Hassan|H|https://orcid.org/0000-0002-6754-4913;Hussain|Ali|A|;Khan|Muzammil|M|;Ullah|Asad|A|https://orcid.org/0000-0001-7400-8724;Joshi|Medha|M|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961876768910.1177_2324709618767689Case ReportClostridium difficile Colitis Leading to Reactive Arthritis: A Rare Complication Associated With a Common Disease Marwat Asghar MD12https://orcid.org/0000-0002-6754-4913Mehmood Hassan MD12Hussain Ali MD12Khan Muzammil MD12https://orcid.org/0000-0001-7400-8724Ullah Asad MD12Joshi Medha MD121 Temple University, Philadelphia, PA, USA2 Conemaugh Memorial Medical Center, Johnstown, PA, USAAsghar Marwat, MD, Department of Internal Medicine, Conemaugh Memorial Medical Center, 1086 Franklin Street, Johnstown, PA 15905, USA. Email: asghardjk@gmail.com30 3 2018 Jan-Dec 2018 6 23247096187676892 1 2018 23 2 2018 4 3 2018 © 2018 American Federation for Medical Research2018American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 4.0 License (http://www.creativecommons.org/licenses/by/4.0/) which permits any 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).The relationship between reactive arthritis and enteric infections caused by Yersinia enterocolitica, Campylobacter jejuni, and Salmonella typhimurium is well documented. Clostridium difficile colitis is a less recognized cause of reactive arthritis. We present a case of a 58-year-old woman with Clostridium difficile colitis complicated by reactive arthritis. A 58-year-old woman with no significant past medical history presented to our hospital with complaints of nonbloody watery diarrhea, abdominal pain for the past 1 week, and right knee pain starting 1 day prior. The patient had recently used antibiotics for a respiratory tract infection. On examination, the patient had a swollen and erythematous right knee. While in the hospital the patient also developed a similarly painful and swollen left knee. The patient was found to be positive for C difficile toxin in stool. Synovial fluid analysis of both the knee joints revealed a sterile and inflammatory fluid, negative for crystals and showing no growth on gram stain. We diagnosed the patient with reactive arthritis secondary to C difficile colitis once all other causes of the bilateral knee joint symptoms were ruled out with appropriate laboratory and imaging studies. Treatment with oral vancomycin and an anti-inflammatory was initiated, and the patient had complete resolution of symptoms. This case illustrates the importance of recognizing C difficile colitis as a potential differential for reactive arthritis under the appropriate circumstances. The treatment of reactive arthritis is mainly supportive and treating the underlying cause, which happens to be C difficile in this case.\n\nClostridium difficile infectionreactive arthritiscover-dateJanuary-December 2018\n==== Body\nIntroduction\nReactive arthritis typically manifests as an acute aseptic, inflammatory, asymmetric oligoarthritis commonly affecting the large joints of the lower extremities. Associated extra-articular findings including conjunctivitis, uveitis, enthesopathy, urethritis, balanitis, and keratoderma blennorrhagicum may also be observed.1,2 Reactive arthritis usually develops after an infection in a distant part of the body, and the causative organism is never isolated from the joint.3 The relationship between reactive arthritis and enteric infections caused by Yersinia enterocolitica, Campylobacter jejuni, and Salmonella typhimurium is well documented. Clostridium difficile colitis is a less recognized because of reactive arthritis.4 Only 50 cases have been reported5 since it was first described in 1976 by Rollins and Moeller.6 We present a case of a 58-year-old woman with C difficile colitis complicated by reactive arthritis.\n\nCase Report\nA 58-year-old woman with no significant past medical history came to our hospital with complaints of abdominal pain, diarrhea, and right knee pain. The patient had an acute onset of severe, nontraumatic right knee pain, with redness and swelling of the joint for the past day. She has nonbloody, watery diarrhea going on for the past 1 week with maximum episodes up to 10 in a day. She recently suffered from an upper respiratory tract infection 3 weeks ago before this presentation and completed 10 days of oral cefuroxime subsequently. On physical examination, she was afebrile with a temperature of 99.5°F, blood pressure of 156/68 mm Hg, and pulse of 87 beats per minute. She had red, hot, and swollen right knee with restricted range of motion during extension. There was tenderness noted in the right lower abdominal quadrant with positive bowel sounds. Rest of the physical examination was unremarkable. Initial laboratory studies demonstrated white blood cell count of 11 700/µL, with 13% bands, 14% atypical lymphocytes, platelets of 237 000/µL, an erythrocyte sedimentation rate of 140 mm/h, and C-reactive protein of 27.5 mg/dL. C difficile toxin gene B was positive in stool, and oral vancomycin was started. Rest of the stool studies including testing for ova, parasites, and stool culture were negative. Rheumatoid factor, antinuclear antibody, anticyclic citrullinated peptide studies, serology for Lyme titer, and uric acid level were unremarkable. HLA B-27 came back positive. X-ray of right knee showed joint effusion. Arthrocentesis of the right knee revealed white blood cell count of 6100/µL with 86% neutrophils. Synovial fluid crystal examination, gram stain, and cultures were negative. Her pain was getting worse, and the next day she had mild to moderate discomfort in the left knee with restricted range of motion. Aspiration of the left knee was done, and it was also negative for crystals, gram stain, and cultures. Once synovial fluid was confirmed to be sterile, due to continued debility, both knees were injected with 10 mg dexamethasone resulting in significant relief. The patient was started on ibuprofen 375 mg 3 times a day for 4 weeks and vancomycin was prescribed for 14 days in total. Her diarrhea resolved in 3 days along with significant improvement in pain and ambulation. She was discharged subsequently and seen in the clinic after 4 weeks later with the knee pain resolved and return to full functional capacity.\n\nDiscussion\nClostridium difficile carries a significant disease burden in the United States. According to the Center for Diseases Control and Prevention, C difficile was responsible for almost half a million infections, resulting in roughly 29 000 deaths in 2011.7\nC difficile infection most commonly leads to pseudomembranous colitis, which presents itself as fever and diarrhea starting from 4 to 9 days after starting antibiotic treatment.8 Extracolonic manifestations of C difficile including bacteremia, osteomyelitis, visceral abscess, empyema, small bowel disease, and reactive arthritis are less frequent and rarely reported.8 Our case adds to the growing body of literature on this subject. The hypothesized pathogenesis of reactive arthritis following an enteric infection with C difficile is postulated to be an autoimmune response to bacterial antigens in joints and other tissues that gain access into the bloodstream via the intestinal mucosa.9 Our patient fulfilled the criteria for the diagnosis of C difficile reactive arthritis as established by Putterman and Rubinow in 19939: a sterile inflammatory arthritis with preceding diarrhea and prior antibiotic exposure2; stool test positive for C difficile toxin10; and no alternative diagnosis for arthritis or diarrhea.11 With the increased use of antibiotics in recent times and the associated increased incidence of C difficile colitis, many rare manifestations of this disease process that were previously unrecognized are coming to the forefront. It would be prudent for physicians to consider reactive arthritis secondary to C difficile colitis as a differential diagnosis in a patient with otherwise unexplained acute inflammatory arthritis in the right clinical setting of recent antibiotic use and diarrhea. Early diagnosis and appropriate treatment can improve patient outcomes and prevent unnecessary diagnostic procedures. Reactive arthritis secondary to C difficile colitis is managed conservatively with treatment primarily focused on eradicating the C difficile infection and has an excellent long-term prognosis.\n\nConclusion\nGiven the expected rise in the incidence of C difficile infection, both internist and rheumatologist should include this pathogen in the differential diagnosis of the enteric organism responsible for reactive arthritis. We suspect C difficile reactive arthritis may be underrecognized and recommend raising awareness in the health care profession to test C difficile toxin in undifferentiated arthritis patients.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from the Institutional Review Board Approval Committee, Conemaugh Memorial Medical Center.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nORCID iDs: Hassan Mehmood \nhttps://orcid.org/0000-0002-6754-4913\n\nAsad Ullah \nhttps://orcid.org/0000-0001-7400-8724\n==== Refs\nReferences\n1 \nFlores D Marquez J Garza M Espinoza LR. \nReactive arthritis: newer developments . Rheum Dis Clin North Am . 2003 ;29 :37 -59 .12635499 \n2 \nHill Gaston JS Lillicrap MS. \nArthritis associated with enteric infection . Best Pract Res Clin Rheumatol . 2003 ;17 :219 -239 .12787523 \n3 \nAhvonen P Sievers K Aho K. \nArthritis associated with Yersinia enterocolitica infection . Acta Rheumatol Scand . 1969 ;15 :232 .4902690 \n4 \nKeating RM Vyas AS. \nReactive arthritis following Clostridium difficile colitis . West J Med . 1995 ;162 :61 -63 .7863666 \n5 \nLegendre P Lalande V Eckert C et al \nClostridium difficile associated reactive arthritis: case report and literature review . Anaerobe . 2016 ;38 :76 -80 .26743187 \n6 \nRollins DE Moeller D. \nAcute migratory polyarthritis associated with antibiotic-induced pseudomembranous colitis . Am J Gastroenterol . 1976 ;65 :353 -356 .937333 \n7 \nLessa FC Mu Y Bamberg WM et al \nBurden of Clostridium difficile infection in the United States . N Engl J Med . 2015 ;372 :825 -834 .25714160 \n8 \nJacobs A Barnard K Fishel R Gradon JD. \nExtracolonic manifestations of Clostridium difficile infections. Presentation of 2 cases and review of the literature . Medicine (Baltimore) .2001 ;80 :88 -101 .11307591 \n9 \nPutterman C Rubinow A. \nReactive arthritis associated with Clostridium difficile pseudomembranous colitis . Semin Arthritis Rheum . 1993 ;22 :420 -426 .8342048 \n10 \nMcClusky J Riley TV Owen ET Langlands DR. \nReactive arthritis associated with Clostridium difficile . Aust N Z J Med . 1982 ;12 :535 -537 .6960877 \n11 \nAtkinson MH Mcleod BD. \nReactive arthritis with Clostridium difficile enteritis . J Rheumatol . 1988 ;15 :520 -522 .3259987\n\n",
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"keywords": "Clostridium difficile infection; reactive arthritis",
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"title": "Clostridium difficile Colitis Leading to Reactive Arthritis: A Rare Complication Associated With a Common Disease.",
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"abstract": "We present a case of acute Quetiapine (SeroQuel) overdose in an 11-y-old girl who ingested 1,300 mg (22.2 mg/kg bw). Initial lethargy developed within I h followed by an episode of agitation and combativeness 3 h after ingestion. After treatment with lorazepam the patient experienced extended somnolence followed by return to normal mental status 16 h after ingestion. No cardiotoxic or laboratory abnormalities were found. This is the first report of acute Quetiapine overdose in an adolescent and suggests a relatively benign clinical course.",
"affiliations": "Department of Emergency Medicine, University of Rochester Medical Center, NY 14642, USA.",
"authors": "Juhl|Gregory A|GA|;Benitez|John G|JG|;McFarland|Susan|S|",
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"title": "Acute quetiapine overdose in an eleven-year-old girl.",
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"abstract": "Gabapentin is almost exclusively cleared by the kidney and thus presents challenges in patients with kidney failure. Gabapentin is known to be effectively cleared by hemodialysis, but the efficiency of clearance by peritoneal dialysis (PD) has not been previously described. We report a case of gabapentin toxicity in a patient on long-term PD who was treated with continuous automated cycling PD. We find that continuous PD provides significant clearance of gabapentin. With 2-L exchanges every 2 hours, we document an apparent elimination half-life of 41.33 hours, which is substantially shorter than the reported elimination half-life of 132 hours in the absence of kidney function. Further, our patient's symptoms of gabapentin toxicity gradually improved and had fully resolved after about 36 hours of dialysis. Gabapentin clearance by PD was estimated at 94% of urea clearance. We conclude that intensive PD provides gabapentin clearance that approximates that of urea and is an effective but slow method to treat gabapentin overdose and toxicity.",
"affiliations": "Division of Nephrology, Department of Internal Medicine, Saint Louis University, St. Louis, MO.;Division of Nephrology, Department of Internal Medicine, Saint Louis University, St. Louis, MO.;Division of Nephrology, Department of Internal Medicine, Saint Louis University, St. Louis, MO.;Division of Nephrology, Department of Internal Medicine, Saint Louis University, St. Louis, MO. Electronic address: edwardjc@slu.edu.",
"authors": "Ibrahim|Hisham|H|;Oman|Zachary|Z|;Schuelke|Matthew|M|;Edwards|John C|JC|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "United States",
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"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Gabapentin; case report; drug clearance; elimination half-life; end-stage renal disease (ESRD); gabapentin clearance; hemodialysis; myoclonus; peritoneal dialysis (PD); toxicity; urea clearance",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D003928:Diabetic Nephropathies; D003929:Diabetic Neuropathies; D005260:Female; D005334:Fever; D000077206:Gabapentin; D006801:Humans; D007676:Kidney Failure, Chronic; D008875:Middle Aged; D009207:Myoclonus; D010530:Peritoneal Dialysis; D011041:Poisoning; D005680:gamma-Aminobutyric Acid",
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"title": "Treatment of Gabapentin Toxicity With Peritoneal Dialysis: Assessment of Gabapentin Clearance.",
"title_normalized": "treatment of gabapentin toxicity with peritoneal dialysis assessment of gabapentin clearance"
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"abstract": "Cryptococcal meningitis is rarely complicated by immune-mediated leukoencephalopathy, but the precise pathomechanism is uncertain. A 72-year-old Japanese man treated with prednisolone for Sweet disease developed a subacute progression of meningitis, which was considered as neuro-Sweet disease. A treatment by methylprednisolone rapidly improved CSF findings with a remarkable decrease in lymphocyte numbers in the blood, but the patient's consciousness still worsened after the cessation of the treatment. The patient developed cryptococcal meningitis and MRI showed abnormal intensities predominantly in the cerebral deep white matter along with the recovery of lymphocyte numbers in the blood, which resulted in death. A postmortem examination of the brain revealed degenerative lesions, especially at the cerebral white matter and cortex adjacent to the leptomeninges abundantly infiltrated by Cryptococcus neoformans. In the affected cerebral deep white matter, perivascular infiltration of lymphocytes was prominent in coexistence with reactive astrocytes and vascular proliferation, but these findings were not observed in the subcortical and cortical lesions. Cryptococcus neoformans was not present within the brain parenchyma. This is the first report of a case suggesting that cryptococcal meningitis can accompany lymphocytic inflammation predominantly in cerebral deep white matter as a possible manifestation of immune reconstitution inflammatory syndrome.",
"affiliations": "Department of Neurology and Neurological Science, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Department of Neurology, Yokosuka Kyosai Hospital, Kanagawa, Japan.",
"authors": "Kuwahara|Hiroya|H|;Tsuchiya|Kuniaki|K|;Kobayashi|Zen|Z|;Inaba|Akira|A|;Akiyama|Haruhiko|H|;Mizusawa|Hidehiro|H|",
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"issue": "34(1)",
"journal": "Neuropathology : official journal of the Japanese Society of Neuropathology",
"keywords": "cerebral deep white matter; corticosteroid; cryptococcal meningitis; immune reconstitution inflammatory syndrome; neuro-Sweet disease",
"medline_ta": "Neuropathology",
"mesh_terms": "D000368:Aged; D002540:Cerebral Cortex; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D007249:Inflammation; D008214:Lymphocytes; D008297:Male; D016919:Meningitis, Cryptococcal; D009413:Nerve Fibers, Myelinated",
"nlm_unique_id": "9606526",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Cryptococcal meningitis accompanying lymphocytic inflammation predominantly in cerebral deep white matter: a possible manifestation of immune reconstitution inflammatory syndrome.",
"title_normalized": "cryptococcal meningitis accompanying lymphocytic inflammation predominantly in cerebral deep white matter a possible manifestation of immune reconstitution inflammatory syndrome"
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"abstract": "Intra-alveolar bleeding is a rare and severe medical emergency due to numerous causes. We report the clinical case of a patient who could contribute to extend the literature on this subject. The study included a 62-year old man, with a history of a trial fibrillation, under anti-vitamins K antagonist admitted with dyspnoea of sudden onset associated with haemoptysis and practising self-medication using non-steroidal anti-inflammatory drugs. X-rays and chest scan showed diffuse bilateral alveolar opacities. Haemostatic screening tests on admission showed non-coagulable INR. The diagnosis of intra-alveolar bleeding was clinically and radiologically suspected and then confirmed by bronchial endoscopy with broncho-alveolar lavage (BAL) which detected uniformly hemorrhagic liquid. Previous studies of similar complications occurring after anti-vitamins K antagonists assumption are rare. In conclusion, it seems very important to emphasize the interest of strict and optimal clinico-biological monitoring of patients treated in anti-vitamins K antagonists to avoid an overdose which could contribute to a life-threatening severe haemorrhagic event.",
"affiliations": "Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc.;Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc.;Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc.;Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc.;Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc.",
"authors": "Loutfi|Anas|A|;Chibane|Sara|S|;Drighil|Abdenasser|A|;Azzouzi|Leila|L|;Habbal|Rachida|R|",
"chemical_list": "D000925:Anticoagulants; D014812:Vitamin K; D000074:Acenocoumarol",
"country": "Uganda",
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"doi": "10.11604/pamj.2019.33.160.18708",
"fulltext": "\n==== Front\nPan Afr Med JPan Afr Med JPAMJThe Pan African Medical Journal1937-8688The African Field Epidemiology Network PAMJ-33-16010.11604/pamj.2019.33.160.18708Case ReportUne complication rare et grave du traitement par l’acénocoumarol: l’hémorragie intra-alvéolaire A rare and severe complication related to acenocoumarol therapy: intra-alveolar bleeding Loutfi Anas 1&Chibane Sara 1Drighil Abdenasser 1Azzouzi Leila 1Habbal Rachida 1\n1 Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc& Auteur correspondant: Anas Loutfi, Service de Cardiologie, CHU Ibn Rochd, Casablanca, Maroc03 7 2019 2019 33 16019 3 2019 12 6 2019 © Anas Loutfi et al.2019The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.L'hémorragie intra-alvéolaire est une urgence médicale rare et grave ayant de nombreuses étiologies. Nous rapportons ainsi le cas clinique d'un patient qui pourrait contribuer à élargir la littérature sur ce sujet. Le patient est un homme âgé de 62 ans ayant un antécédent de fibrillation auriculaire sous anti-vitamines K et admis dans un tableau de dyspnée d'apparition brutale avec hémoptysie et notion d'automédication par anti-inflammatoires non stéroïdiens. La radiographie et le scanner thoracique ont montré des opacités alvéolaires bilatérales diffuses. Au bilan d'hémostase de l'admission, l'INR était incoagulable. Le diagnostic d'hémorragie intra-alvéolaire était suspecté cliniquement et radiologiquement puis confirmé par l'endoscopie bronchique avec lavage broncho-alvéolaire (LBA) retrouvant un liquide uniformément hémorragique. Les études précédentes présentant des cas similaires secondaires à la prise d'anti-vitamines K sont rares. En conclusion, Il parait très important de souligner l'intérêt d'une surveillance stricte et optimale clinico-biologique des patients traités en anti-vitamines K afin d'éviter un surdosage pouvant contribuer à un accident hémorragique grave engageant le pronostic vital.\n\nIntra-alveolar bleeding is a rare and severe medical emergency due to numerous causes. We report the clinical case of a patient who could contribute to extend the literature on this subject. The study included a 62-year old man, with a history of a trial fibrillation, under anti-vitamins K antagonist admitted with dyspnoea of sudden onset associated with haemoptysis and practising self-medication using non-steroidal anti-inflammatory drugs. X-rays and chest scan showed diffuse bilateral alveolar opacities. Haemostatic screening tests on admission showed non-coagulable INR. The diagnosis of intra-alveolar bleeding was clinically and radiologically suspected and then confirmed by bronchial endoscopy with broncho-alveolar lavage (BAL) which detected uniformly hemorrhagic liquid. Previous studies of similar complications occurring after anti-vitamins K antagonists assumption are rare. In conclusion, it seems very important to emphasize the interest of strict and optimal clinico-biological monitoring of patients treated in anti-vitamins K antagonists to avoid an overdose which could contribute to a life-threatening severe haemorrhagic event.\n\nHémorragie intra-alvéolaireanti-vitamines Kdiagnosticprise en chargepronosticIntra-alveolar bleedinganti-vitamins K antagonistsdiagnosismanagementprognosis\n==== Body\nIntroduction\nL'hémorragie intra-alvéolaire (HIA) est une urgence thérapeutique rare pouvant engager le pronostic vital. Elle se réfère à un syndrome clinique caractérisé par un saignement important provenant de la microcirculation de l'acinus pulmonaire [1]. Les lésions peuvent toucher toutes les structures de la cloison alvéolo-capillaire: épithélium, membrane basale et/ou endothélium. Classiquement, il se manifeste par la triade clinique de dyspnée, hémoptysie et anémie, avec opacités infiltrantes diffuses radiologiques. Les étiologies de l'HIA sont nombreuses et variées d'origines immunes ou non immunes incluant: infections pulmonaires, embolie pulmonaire, maladie de Wegener, syndrome de Goodpasture, maladie de Churg et Strauss, lupus érythémateux disséminé et maladie de Behçet [2, 3]. L'hémorragie intra-alvéolaire (HIA) due aux anti-vitamines K a été rarement rapportée dans la littérature [4-6]. Dans cet article, nous rapportons le cas d'un patient ayant une fibrillation auriculaire permanente traitée par anti-vitamines K admis dans notre service avec hémoptysie et dyspnée. L'hémorragie intra-alvéolaire (HIA) a été suspectée cliniquement et les résultats radiologiques ont été confirmés par bronchoscopie avec lavage broncho-alvéolaire.\n\nPatient et observation\nLe patient est un homme âgé de 62 ans, hypertendu, ayant un antécédent de fibrillation auriculaire sous anti-vitamines K depuis 13 ans bien suivi. Il s'est présenté à l'hôpital dans un tableau de dyspnée d'apparition brutale stade II NYHA, hémoptysie avec notion d'automédication par Ibuprofène depuis plusieurs jours. À son admission, le patient était apyrétique, tachypnéique à 28 cycles/min, tachycarde à 126bpm, une pression artérielle à 134/79mmHg, saturation artérielle en oxygène à 94% avec des râles crépitants diffus aux deux hémi champs pulmonaires. Au bilan biologique, nous avons noté une anémie à 7,8g/dl hypochrome microcytaire, des globules blancs à 10230/mm3, des plaquettes à 260000/mm3, un INR incoagulable, une créatininémie à 10,3g/l estimant le débit de filtration glomérulaire à 77ml/min/1,73m2 (Formule MDRD simplifiée), une albuminémie à 34g/l, protidémie à 63g/l. L'examen de la bandelette urinaire s'est révélé négatif sans hématurie ni macroalbuminurie. Les taux sériques des p-ANCA, c-ANCA, Ac anti-MBG, AC anti-DNA ainsi que le facteur rhumatoïde se sont révélés négatifs. L'échocardiographie transthoracique a montré une fonction ventriculaire normale et aucune valvulopathie. Le cliché standard du thorax a révélé à la phase d´état des opacités alvéolaires bilatérales diffuses (Figure 1), ce qui nous a incité à compléter par une TDM thoracique retrouvant des lésions alvéolaires multiples bilatérales (Figure 2). Enfin, une endoscopie bronchique avec lavage broncho-alvéolaire (LBA) fut réalisé retrouvant un liquide uniformément hémorragique avec cultures revenues stériles.\n\nFigure 1 Radio thoracique de face révélant des opacités alvéolaires bilatérales diffuses\n\nFigure 2 TDM thoracique en coupe parenchymateuse révélant une condensation alvéolaire avec des opacités en verre dépoli\n\nDiscussion\nLes accidents hémorragiques aux AVK représentent un véritable problème de santé publique. En France, ils sont la première cause d'hospitalisation pour accident iatrogène. Au Royaume Uni, ils viennent en troisième position [7]. L'hémorragie intra-alvéolaire (HIA) attribuable à l'utilisation des anti-vitamines K, est une complication rare potentiellement mortelle par insuffisance respiratoire aiguë [8, 9]. Elle est définie par la présence d'hématies dans les lumières alvéolaires constatée à l'endoscopie bronchique par un lavage broncho alvéolaire (LBA), ou par une biopsie pulmonaire après avoir éliminé les principales pathologies pouvant être incriminées dans la survenue de cette manifestation, dont les maladies auto-immunes (Maladie de Wegener, syndrome de Goodpasture, maladie de Churg et Strauss, lupus érythémateux disséminé, maladie de Behçet et syndrome des anticorps antiphospholipides), les infections pulmonaires, l'embolie pulmonaire, hypertension artérielle pulmonaire, les expositions toxiques, les réactions aux drogues (amiodarone, méthotrexate …), la sténose mitrale et l'hémosidérose pulmonaire idiopathique [10, 11]. Le traitement par acénocoumarol est guidé par le rapport international normalisé (INR). Plusieurs facteurs interviennent dans l'augmentation du risque hémorragique chez les patients sous anti-vitamines K comme l'utilisation de certains antibiotiques, antifongiques ou anti-inflammatoires, l'aspirine, l'héparine, l'amiodarone, les IPP, les anticonvulsivants, l'allopurinol,la consommation d'alcool, l'âge avancé, les insuffisances hépatiques et rénales, le diabète ainsi que l'alimentation [12, 13]. Les études précédentes présentant des cas d'hémorragies intra-alvéolaires secondaires à la prise d'anti-vitamines K sont rares. Nous rapportons ainsi le cas clinique de notre patient qui pourrait contribuer à la littérature sur ce sujet. Nous proposons ainsi une surveillance stricte et optimale clinico-biologique de ces patients afin d'éviter un surdosage pouvant contribuer à un accident hémorragique grave. L'hémorragie intra-alvéolaire est un diagnostic rare à évoquer car le risque de mortalité est important s'il n'est pas détecté rapidement et traité précocement.\n\nConclusion\nL'hémorragie intra-alvéolaire (HIA) liée à l'utilisation de l'acénocoumarol est un événement rare mais pouvant être létal du fait de sa présentation initiale et son évolution imprévisibles. Sa détection doit être rapide et le traitement agressif tout en recherchant les facteurs de risque ainsi que la probable étiologie pouvant être à l'origine de cette manifestation.\n\nConflits d’intérêts\nLes auteurs ne déclarent aucun conflit d'intérêts.\n\nContributions des auteurs\nTous les auteurs ont lu et accepté la version finale de ce manuscrit et ont contribué à sa réalisation.\n==== Refs\nRéférences\n1 Leatherman JW Davies SF Hoidal JR Alveolar hemorrhage syndromes: diffuse microvascular lung hemorrhage in immune and idiopathic disorders Medicine (Baltimore) 1984 11 63 6 343 61 6390080 \n2 Schwarz MI Brown KK Small vessel vasculitis of the lung Thorax 2000 6 55 6 502 10 10817800 \n3 Silverman ES Mark EJ Case records of the Massachusetts General Hospital, Weekly clinicopathological exercises, Case 36-2002: A 32-year-old man with hemoptysis of nearly three decades' duration N Engl J Med 2002 11 21 347 21 1693 701 12444185 \n4 Lee JH Kim WK Successful management of warfarin-exacerbated diffuse alveolar hemorrhage using an extracorporeal membrane oxygenation Multidiscip Respir Med 2013 2 27 8 1 16 23442499 \n5 Gabrilovich MI Buxton DE Lykins DM McMillen SM Onadeko OOA Diffuse alveolar hemorrhage secondary to apixaban administration Chest 2014 9 146 3 e115 e116 25180742 \n6 Emin UY Erdem CE Süleyman SO Yahya AA Mustafa YA A life threatening complication of warfarin therapy in ED: diffuse alveolar hemorrhage Am J Emerg Med 2014 6 32 6 690.e3 4 \n7 Tremey B Vigue B Prise en charge des accidents des anticoagulants Reanimation 2008 17 4 363 369 \n8 Papiris SA Manali ED Kalomenidis I Kapotsis GE Karakatsani A Roussos C Bench to bedside review: pulmonary renal syndromes an update for the intensivist Crit Care 2007 11 3 213 17493292 \n9 Green RJ Ruoss SJ Kraft SA Duncan SR Beryy GJ Raffin TA Pulmonary capllaritis and alveolar hemorrhage. Update on diagnosis and management Chest 1996 110 5 1305 16 8915239 \n10 Albelda SM Gefter WB Epstein DM Miller WT Diffuse pulmonary hemorrhage: a review and classification Radiology 1985 154 2 289 97 3155569 \n11 Newsome BR Morales JE Diffuse alveolar hemorrhage South Med J 2011 104 4 269 74 21606695 \n12 Penning-van Beest FJ van Meegen E Rosendaal FR Stricker BH Characteristics of anticoagulant therapy and comorbidity related to overcoagulation Thromb Haemost 2001 86 2 569 74 11522005 \n13 Lu Y Won KA Nelson BJ Qi D Rausch DJ Asinger RW Characteristics of the amiodarone-warfarin interaction during long-term follow-up Am J Health Syst Pharm 2008 65 10 947 52 18463344\n\n",
"fulltext_license": "CC BY",
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"issue": "33()",
"journal": "The Pan African medical journal",
"keywords": "Intra-alveolar bleeding; anti-vitamins K antagonists; diagnosis; management; prognosis",
"medline_ta": "Pan Afr Med J",
"mesh_terms": "D000074:Acenocoumarol; D000925:Anticoagulants; D004417:Dyspnea; D006469:Hemoptysis; D006470:Hemorrhage; D006801:Humans; D008297:Male; D008875:Middle Aged; D011650:Pulmonary Alveoli; D014812:Vitamin K",
"nlm_unique_id": "101517926",
"other_id": null,
"pages": "160",
"pmc": null,
"pmid": "31565122",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "6390080;8915239;25180742;10817800;3155569;21606695;17493292;12444185;24412020;18463344;23442499;11522005",
"title": "A rare and severe complication related to acenocoumarol therapy: intra-alveolar bleeding.",
"title_normalized": "a rare and severe complication related to acenocoumarol therapy intra alveolar bleeding"
} | [
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"companynumb": "MA-STRIDES ARCOLAB LIMITED-2019SP010987",
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"activesubstancename": "IBUPROFEN"
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{
"abstract": "BACKGROUND\nThe incidence of neuropathy with checkpoint inhibitors is 0.3-1%, typically occurring 2-12 weeks after treatment initiation. Common neuropathy phenotypes include inflammatory myopathies, myasthenia gravis, acute and chronic demyelinating polyradiculopathies, vasculitic neuropathies, isolated cranial neuropathies, aseptic meningitis, autoimmune encephalitis, multiple sclerosis and hypophysitis. Carpal tunnel syndrome is the most common entrapment neuropathy in the general population; however, the association of carpal tunnel syndrome with checkpoint inhibitors is exceedingly rare.\n\n\nMETHODS\nWe report two cases of patients with no prior history of carpal tunnel syndrome treated with checkpoint inhibitors that developed de novo bilateral carpal tunnel syndrome.Management & Outcome: For both patients, the neurologic symptoms improved with cessation of the checkpoint inhibitor and initiation of corticosteroids.\n\n\nCONCLUSIONS\nGiven the prevalence of carpal tunnel syndrome in the general population, a high index of suspicion for carpal tunnel in patients receiving checkpoint inhibitors and prompt treatment with corticosteroids is essential.",
"affiliations": "Department of Medicine, Division of Hematology Oncology, University of California, Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA, USA.;Department of Medicine, Division of Hematology Oncology, University of California, Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA, USA.;Department of Medicine, Division of Hematology Oncology, University of California, Irvine, Chao Family Comprehensive Cancer Center, Irvine, CA, USA.",
"authors": "Eisenbud|Lauren|L|https://orcid.org/0000-0003-0432-7580;Ejadi|Samuel|S|;Mar|Nataliya|N|https://orcid.org/0000-0003-2485-6201",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "England",
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"issue": "27(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "Checkpoint inhibitors; carpal tunnel; immunotherapy; neuropathy",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D002349:Carpal Tunnel Syndrome; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007167:Immunotherapy; D008297:Male; D008875:Middle Aged; D010523:Peripheral Nervous System Diseases",
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"references": null,
"title": "Development of carpal tunnel syndrome in association with checkpoint inhibitors.",
"title_normalized": "development of carpal tunnel syndrome in association with checkpoint inhibitors"
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"abstract": "The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has presented many diagnostic challenges and uncertainties. Little is known about common pathologies complicating pregnancy and how their behaviour is modified by the presence of SARS-CoV-2. Pregnancy itself can alter the body's response to viral infection, which can cause more severe symptoms. We report the first case of a patient affected with sudden-onset severe pre-eclampsia complicated by acute fatty liver disease of pregnancy, HELLP (haemolysis, elevated liver enzymes and low platelet) syndrome and acute kidney injury following SARS-CoV-2 infection. Although an initial diagnostic dilemma, a multidisciplinary team approach was required to ensure a favourable outcome for both the mother and the baby. Our case report highlights the need for health professionals caring for pregnant women to be aware of the complex interplay between SARS-CoV-2 infection and hypertensive disorders of pregnancy.",
"affiliations": "Obstetrics and Gynaecology, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK irshad.ahmed@heartofengland.nhs.uk.;Obstetrics and Gynaecology, Birmingham Heartlands Hospital, Birmingham, West Midlands, UK.;Obstetrics and Gynaecology, Birmingham Heartlands Hospital, Birmingham, West Midlands, UK.;Obstetrics and Gynaecology, Birmingham Heartlands Hospital, Birmingham, West Midlands, UK.",
"authors": "Ahmed|Irshad|I|;Eltaweel|Nashwa|N|;Antoun|Lina|L|;Rehal|Anoop|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237521",
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"issue": "13(8)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); hypertension; liver disease; obstetrics and gynaecology; pregnancy",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D000073640:Betacoronavirus; D000086382:COVID-19; D018352:Coronavirus Infections; D005234:Fatty Liver; D005260:Female; D017359:HELLP Syndrome; D006801:Humans; D007677:Kidney Function Tests; D058873:Pandemics; D011024:Pneumonia, Viral; D011225:Pre-Eclampsia; D011247:Pregnancy; D011248:Pregnancy Complications; D011251:Pregnancy Complications, Infectious; D000086402:SARS-CoV-2",
"nlm_unique_id": "101526291",
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"pmid": "32784239",
"pubdate": "2020-08-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12427793;18332072;29225680;32450197",
"title": "Severe pre-eclampsia complicated by acute fatty liver disease of pregnancy, HELLP syndrome and acute kidney injury following SARS-CoV-2 infection.",
"title_normalized": "severe pre eclampsia complicated by acute fatty liver disease of pregnancy hellp syndrome and acute kidney injury following sars cov 2 infection"
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"abstract": "Kratom mainly grows in Southeast Asia. It is widely used for pain management and opioid withdrawal, which is available online for cheaper prices. Alkaloids extracted from kratom such as mitragynine and 7-hydroxy mitragynine exhibit analgesic properties by acting through µ receptors. Commonly reported side effects of kratom include hypertension, tachycardia, agitation, dry mouth, hallucinations, cognitive and behavioral impairment, cardiotoxicity, renal failure, cholestasis, seizures, respiratory depression, coma, and sudden cardiac death from cardiac arrest. Rhabdomyolysis is a less commonly reported lethal effect of kratom. Limited information is available in the literature. In this article, we present a case of a 45-year-old female who is overdosed with kratom and presented with lethargy, confusion, transient hearing loss, and right lower extremity swelling and pain associated with weakness who was found to have elevated creatinine phosphokinase. She was diagnosed with rhabdomyolysis, compartment syndrome, multiorgan dysfunction including acute kidney injury, liver dysfunction, and cardiomyopathy. She underwent emergent fasciotomy and required hemodialysis. Her renal and liver function subsequently improved. We described the case and discussed pharmacology and adverse effects of kratom toxicity with a proposed mechanism and management. We conclude that it is essential for emergency physicians, internists, intensivists, cardiologists, and nephrologists to be aware of these rare manifestations of kratom and consider a multidisciplinary approach.",
"affiliations": "Quantum HC, Navicent Health, Macon, GA, USA.;Quantum HC, Navicent Health, Macon, GA, USA.;Quantum HC, Navicent Health, Macon, GA, USA.;Mercer University, Macon, GA, USA.;Quantum HC, Navicent Health, Macon, GA, USA.;Quantum HC, Navicent Health, Macon, GA, USA.",
"authors": "Sangani|Vikram|V|0000-0002-8460-9838;Sunnoqrot|Naseem|N|;Gargis|Kurdistan|K|;Ranabhotu|Akshay|A|;Mubasher|Abbas|A|;Pokal|Mytri|M|",
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"doi": "10.1177/23247096211005069",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096\nSAGE Publications Sage CA: Los Angeles, CA\n\n33764201\n10.1177/23247096211005069\n10.1177_23247096211005069\nCase Report\nUnusual Presentation of Kratom Overdose With Rhabdomyolysis, Transient Hearing Loss, and Heart Failure\nhttps://orcid.org/0000-0002-8460-9838\nSangani Vikram MD 1\nSunnoqrot Naseem MD 1\nGargis Kurdistan MD 1\nRanabhotu Akshay BS 2\nMubasher Abbas MD 1\nPokal Mytri MD 1\n1 Quantum HC, Navicent Health, Macon, GA, USA\n2 Mercer University, Macon, GA, USA\nVikram Sangani, MD, Department of Internal Medicine, Quantum HC, Navicent Health, 777 Hemlock Street, Macon, GA 31201, USA. Email: docvikramsangani@gmail.com\n25 3 2021\nJan-Dec 2021\n9 2324709621100506917 1 2021\n17 1 2021\n28 2 2021\n© 2021 American Federation for Medical Research\n2021\nAmerican Federation for Medical Research\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).\nKratom mainly grows in Southeast Asia. It is widely used for pain management and opioid withdrawal, which is available online for cheaper prices. Alkaloids extracted from kratom such as mitragynine and 7-hydroxy mitragynine exhibit analgesic properties by acting through µ receptors. Commonly reported side effects of kratom include hypertension, tachycardia, agitation, dry mouth, hallucinations, cognitive and behavioral impairment, cardiotoxicity, renal failure, cholestasis, seizures, respiratory depression, coma, and sudden cardiac death from cardiac arrest. Rhabdomyolysis is a less commonly reported lethal effect of kratom. Limited information is available in the literature. In this article, we present a case of a 45-year-old female who is overdosed with kratom and presented with lethargy, confusion, transient hearing loss, and right lower extremity swelling and pain associated with weakness who was found to have elevated creatinine phosphokinase. She was diagnosed with rhabdomyolysis, compartment syndrome, multiorgan dysfunction including acute kidney injury, liver dysfunction, and cardiomyopathy. She underwent emergent fasciotomy and required hemodialysis. Her renal and liver function subsequently improved. We described the case and discussed pharmacology and adverse effects of kratom toxicity with a proposed mechanism and management. We conclude that it is essential for emergency physicians, internists, intensivists, cardiologists, and nephrologists to be aware of these rare manifestations of kratom and consider a multidisciplinary approach.\n\nkratom\n7-hydroxy mitragynine\nmitragynine\nrhabdomyolysis and compartment syndrome\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\npmcIntroduction\n\nKratom plant (Mitragyna speciosa) is usually grown in Southeast Asia and used as a psychoactive medication. Kratom use in the United States is increasing alarmingly due to its easy availability online, and thus increasing the potential for abuse, which is leading to increased hospital admissions and deaths. The lifetime prevalence of kratom use in the adult US population is 1.3%. It was noted to be used frequently in young male students or preferably health care professionals. 1 Thus, the US Drug Enforcement Administration classified kratom as a schedule I controlled substance in 2016. 2 Kratom contains mitragynine and 7-hydroxy mitragynine, which exhibit analgesic properties by acting as µ-opioid receptor partial agonists. Mitragynine and 7-hydroxy mitragynine are much more potent than morphine, with 7-hydroxy mitragynine being 4 times more potent than mitragynine. It is widely used for opiate withdrawal and pain management. Adverse effects reported with kratom range from hypertension, tachycardia, agitation, lethargy, nausea, severe emesis, constipation, cognitive and behavioral impairment 3 to more lethal effects like cardiotoxicity, renal failure, and hepatic injury. 4 Kratom overdose is also associated with seizures, 5 respiratory depression, hallucinations, coma, and cardiac arrest. 6 There is extensive literature drawing conclusions between heroin and cocaine usage with rhabdomyolysis. But very few case reports reported that rhabdomyolysis is one of the effects of a kratom overdose. We present a case of a 45-year-old lady who used kratom for pain management and developed severe rhabdomyolysis leading to compartment syndrome, transient hearing loss, and heart failure. Thorough knowledge of kratom and its toxicities is essential to manage these appropriately especially with its increasing use.\n\nCase Report\n\nA 45-year-old Caucasian lady with a medical history of Crohn’s disease, breast cancer status post chemotherapy, radiation a year ago, and bilateral mastectomy with reconstruction 2 months ago, and chronic pain, was brought in by emergency Medical Service after she had a passing out episode.\n\nThe patient had breast reconstruction surgery 2 months ago and suffered a burn injury from a heating pad used for postoperative pain. She started taking kratom 1 month ago for pain associated with burn injury. She was initially taking up to 6 capsules per day. As she was having uncontrolled pain, she increased the dose significantly 2 weeks after starting the drug. She gradually continued to escalate the dose to more than 10 pills per day until a couple of days before admission. The patient was taking extra kratom pills for the last 2 days and was experiencing diffuse body aches particularly right-sided pain, fatigue, and generalized weakness. Eight hours before admission, she took 2 more extra pills. She passed out for 6 hours. On subsequent regaining of consciousness, she was drowsy and noted worsening right lower extremity pain and swelling with difficulty ambulating and called Emergency Medical Service. She also reported an acute decrease in hearing. She denies fever, chills, chest pain, cough, shortness of breath, nausea, vomiting, abdominal pain, seizures, and focal neurological deficit.\n\nSurgical history includes appendectomy, hysterectomy, Koch ileostomy, proctocolectomy, carpal tunnel, ureteral stents, surgery for bowel obstruction, breast reconstruction surgery, and burn wound status post debridement. She describes known medical allergies to penicillins, cephalosporins, vancomycin, and sulfa drugs. Family history was reviewed and was not contributory. She denied smoking, alcohol, or the use of other illicit drugs.\n\nIn the emergency room, vitals revealed 37.2 °C oral temperature, respiratory rate 20 breaths per minute, blood pressure 124/92 mm Hg, heart rate 99 beats per minute, saturation oxygen 95% on room air, and body mass index 22 kg/m2. On examination, she had decreased right-sided hearing, she was noted to have significant swelling of the right lower extremity with tenderness to palpation and also has weakness on the right side. Pulse on the extremity was felt to be decreased but was noted on Doppler ultrasound. The rest of the examination is unremarkable.\n\nWhile in emergency room, the patient underwent an initial workup for altered mental status with computed tomography (CT) brain, showing no acute finding. She underwent a CT neck for neck pain and swelling, which showed a nonspecific inflammatory change in the sternocleidomastoid muscle. CT thorax, abdomen, and pelvis showed pneumonia and probable colitis. Admission laboratory results and imaging are summarized in Tables 1 and 2.\n\nTable 1. Admission Laboratory Results.\n\nLaboratory findings\tResult\tNormal range\t\nWBC\t28.6 H\t4-10 × 103/µL\t\nHemoglobin\t13.3\t11.2-15.7 g/dL\t\nPlatelets\t664\t163-369 × 103/µL\t\nSodium\t140\t136-144 mEq/L\t\nPotassium\t6.5 H\t3.5-5.1 mEq/L\t\nChloride\t100\t98-110 mEq/L\t\nBicarbonate\t22\t20-30 mEq/L\t\nBUN\t12\t7-23 mg/dL\t\nCreatinine\t1.72 H\t0.57-1.11 mg/dL\t\nGlucose\t67\t70-99 mg/dL\t\nCalcium\t9.3\t8.5-10.3 mg/dL\t\nAST\t509 H\t5-42 units/L\t\nALT\t155 H\t5-49 units/L\t\nTotal bilirubin\t0.4\t0.1-1.2 mg/dL\t\nAlkaline phosphatase\t345 H\t35-141 units/L\t\nPhosphorus\t6.5 H\t2.3-4.7 mg/dL\t\nTotal protein\t7.8\t6.1-8.3 g/dL\t\nCPK\t>24 165 H\t43-237 units/L\t\nTroponin\t5.6 H\t0.0-0.028 ng/mL\t\nUrine drug screen\tNegative\t\t\nAbbreviations: WBC, white blood cell; BUN, blood urea nitrogen; AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatinine phosphokinase.\n\nTable 2. Imaging Studies.\n\nCT brain\tNo acute findings\t\nCT neck\tCT neck nonspecific inflammatory change of the right sternocleidomastoid muscle\t\nCT thorax, abdomen, and pelvis\tProbable bilateral pneumonia of the upper lobes and right middle lobe versus post-radiation changes\nMild edema of the sigmoid and descending colon suggestive of mild colitis\nNo metastasis was identified\t\nAbbreviation: CT, computed tomography.\n\nClinical Course\n\nOn admission, due to significant right lower extremity pain and swelling, an ultrasound lower extremity was done, which was negative for deep vein thrombosis. Surgery was consulted, who diagnosed the patient with compartment syndrome of the right lower extremity and planned emergent 4-compartment fasciotomy with wound vacuum-assisted closure placement. Postoperatively, the patient developed hypoxia with gross cyanosis of the upper body requiring intubation and mechanical ventilation. She noted to have worsening abnormal liver and renal function tests. Echo was done, which revealed ejection fraction (EF) <15%, a significant drop from the previous echocardiogram. She developed severe rhabdomyolysis causing acute kidney injury from acute tubular necrosis complicated with severe hyperkalemia prompting the initiation of hemodialysis emergently. She was aggressively hydrated on the presentation. Cardiology was consulted for low EF who recommended ischemic workup once more stable. After dialysis, the patient’s mental status improved, hearing loss resolved, and eventually extubated with improvement in liver function test and creatinine phosphokinase as summarized in Table 3. The patient underwent multiple debridements of the right lower extremity followed by final wound closure with a skin graft. Echocardiogram was repeated with a return to normal EF of 55%. She was eventually discharged home with home health care.\n\nTable 3. Trend of labs from day 1 to day 14.\n\nLab (normal value)\tDay 1\tDay 2\tDay 3\tDay 7\tDay 14\t\nPotassium (3.5-5.1 mEq/L)\t6.5\t7.6\t5.4\t3.8\t3.6\t\nCreatinine (0.57-1.11 mg/dL)\t1.72\t2.39\t3.80\t5.71\t4.19\t\nAST (5-42 U/L)\t509\t3113\t2049\t331\t65\t\nALT (5-49 U/L)\t155\t573\t503\t184\t52\t\nPhosphorus (2.3-4.7 mg/dL)\t6.5\t7.9\t7.0\t6.0\t5.4\t\nCPK (43-237 U/L)\t24 165\t42 670\t29 286\t6166\t736\t\nMyoglobin (0-80 ng/mL)\t>1200\t>1200\t>1200\t979\t330\t\nAbbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase; CPK, creatinine phosphokinase.\n\nDiscussion\n\nRhabdomyolysis is a breakdown of skeletal muscle leading to the release of intracellular contents into the plasma. It is predominantly caused by a crush injury, trauma, immobilization, alcohol abuse, illicit drugs including cocaine and heroin, electrolyte disturbances, heart stroke, and exertion. Rhabdomyolysis can be diagnosed early with serum and urine myoglobin and elevated creatinine phosphokinase. Prompt diagnosis and early treatment prevent life-threatening complications of rhabdomyolysis, which includes severe organ damage such as acute renal failure, hepatic injury, compartment syndrome, metabolic acidosis, disseminated intravascular coagulation, electrolyte disturbances including severe hyperkalemia, hyperphosphatemia, hypocalcemia, and hyperuricemia. Few case reports are available in the literature on kratom overdose causing rhabdomyolysis.4,7\n\nKratom serves as an analgesic by interacting with the opioid receptors, particularly through the µ-receptor, which is responsible for the analgesic effects as well as the development of physical dependence on the drug due to high affinity at the receptor. The major compounds of kratom, mitragynine and 7-hydroxy mitragynine, stimulate α-adrenergic receptors as well, which are responsible for vasoconstriction. 8 The mechanism through which kratom causes rhabdomyolysis is unknown. But it is postulated that the main compounds of kratom, mitragynine and 7-hydroxy mitragynine, can cause muscle injury by acting through the α-adrenergic receptors as this pathway can cause vasoconstriction leading to muscle ischemia and rhabdomyolysis. 9\n\nStudies show that the adverse effects of kratom are heavily dose-dependent. It has been observed that excessively high doses of kratom, 15 g or more, can lead to severe toxic effects that deviate from the expected effects of kratom use. 8 Given that high doses of kratom can cause unexpected severe effects, it is not highly unlikely that excessive kratom use could lead to rhabdomyolysis. The patient’s report of taking 10 pills of kratom per day could potentially be a significantly high dose to cause the unexpected toxic effect of rhabdomyolysis.\n\nGiven the similarities in the pharmacokinetics of scheduled stimulants and kratom, they differ in how they are available to the public. Since kratom is listed as a herbal supplement, the measures for regulation are not as extensive as seen with heroin, causing a rise in cases associated with kratom overdose. With the increasing concern with the safety of the drug and its high abuse potential, the Food and Drug Administration is advising consumers to be aware of the psychoactive compounds found in kratom, such as mitragynine and 7-hydroxy mitragynine, which is responsible for the high abuse potential. 10 Treatment of kratom toxicity is mainly supportive, and benzodiazepines should be considered for seizures and naloxone for respiratory depression. Most of the deaths with kratom toxicity occur only when it is taken with a combination of other sedative drugs. 11\n\nConclusion\n\nKratom is an emerging drug in the West and its use is increasing since the past decade especially due to its easy availability and potential use in managing pain. There is limited information available in the literature regarding its effects. Kratom overdose causing rhabdomyolysis, stress cardiomyopathy, and hearing loss have not been described. The mechanism of these effects is uncertain and more research is needed in this regard. It is essential for physicians to recognize the effects of kratom overdose and be familiar with treatment options. There is no antidote for kratom. Treatment of kratom overdose is mainly supportive care.\n\nI thank all the authors who contributed to the case report.\n\nAuthor Contributions: VS, NS, KG, and MP conducted the chart review. VK, NS, KG, AR, AM, and MP contributed to writing the introduction, discussion, and conclusion. VS drafted the manuscript, and all authors contributed substantially to its revision.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Informed verbal consent obtained.\n\nORCID iD: Vikram Sangani https://orcid.org/0000-0002-8460-9838\n==== Refs\nReferences\n\n1 Schimmel J Amioka E Rockhill K , et al . Prevalence and description of kratom (Mitragyna speciosa) use in the United States: a cross-sectional study. Addiction. 2021;116 :176-181. doi:10.1111/add.15082 32285981\n2 Drug Enforcement Administration. Schedules of controlled substances: temporary placement of mitragynine and 7-hydroxymitragynine into Schedule I. Accessed March 10, 2021. https://www.federalregister.gov/documents/2016/08/31/2016-20803/schedules-of-controlled-substances-temporary-placement-of-mitragynine-and-7-hydroxymitragynine-into\n3 Anwar M Law R Schier J . Notes from the field: kratom (Mitragyna speciosa) exposures reported to poison centers—United States, 2010-2015. MMWR Morb Mortal Wkly Rep. 2016;65 :748-749. doi:10.15585/mmwr.mm6529a4 27466822\n4 Diep J Chin DT Gupta S Syed F Xiong M Cheng J. Kratom, an emerging drug of abuse: a case report of overdose and management of withdrawal. A A Pract. 2018;10 :192-194. doi:10.1213/XAA.0000000000000658 29652682\n5 Cumpston KL Carter M Wills BK. Clinical outcomes after kratom exposures: a poison center case series. Am J Emerg Med. 2018;36 :166-168. doi:10.1016/j.ajem.2017.07.051 28751041\n6 Aggarwal G Robertson E McKinlay J Walter E. Death from kratom toxicity and the possible role of intralipid. J Intensive Care Soc. 2018;19 :61-63. doi:10.1177/1751143717712652 29456604\n7 Patel T Karle E Krvavac A. 1398: kratom: an unusual cause of rhabdomyolysis and cholestasis. Crit Care Med. 2020;48 :676. doi:10.1097/01.ccm.0000645508.54404.9a\n8 Prozialeck WC. Update on the pharmacology and legal status of kratom. J Am Osteopath Assoc. 2016;116 :802-809. doi:10.7556/jaoa.2016.156 27893147\n9 Madhusoodanan S Gupta S Calleja G Bogunovic O Brenner R. A case of rhabdomyolysis after intravenous heroin use. Prim Care Companion J Clin Psychiatry. 2004;6 :221-222. doi:10.4088/pcc.v06n0509 15514694\n10 US Food and Drug Administration. FDA and kratom. Accessed March 10, 2021. https://www.fda.gov/news-events/public-health-focus/fda-and-kratom\n11 Toce MS Chai PR Burns MM Boyer EW. Pharmacologic treatment of opioid use disorder: a review of pharmacotherapy, adjuncts, and toxicity. J Med Toxicol. 2018;14 :306-322. doi:10.1007/s13181-018-0685-1 30377951\n\n",
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"journal": "Journal of investigative medicine high impact case reports",
"keywords": "7-hydroxy mitragynine; kratom; mitragynine; rhabdomyolysis and compartment syndrome",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D062787:Drug Overdose; D034381:Hearing Loss; D006333:Heart Failure; D006801:Humans; D008875:Middle Aged; D032065:Mitragyna; D010936:Plant Extracts; D012206:Rhabdomyolysis",
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"title": "Unusual Presentation of Kratom Overdose With Rhabdomyolysis, Transient Hearing Loss, and Heart Failure.",
"title_normalized": "unusual presentation of kratom overdose with rhabdomyolysis transient hearing loss and heart failure"
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"abstract": "This article presents the case of a patient with newly developed skin erosions and ulcerations following an exanthematous drug eruption due to sultamicillin therapy. The skin lesions were treated topically with clobetasol and prednicarbate and orally with methylprednisolone. A skin smear revealed massive growth of Escherichia coli bacteria. Blood cultures were negative. The cause for developing ecthyma gangrenosum in our patient were iatrogenic immunosuppression and transient bacteremia.",
"affiliations": "Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland. aleksander.markovic@medizin.uni-leipzig.de.;Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.;Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikum Leipzig, Philipp-Rosenthal-Str. 23, 04103, Leipzig, Deutschland.",
"authors": "Markovic|A|A|;Simon|J C|JC|;Treudler|R|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; C035444:sultamicillin; D000667:Ampicillin; D013407:Sulbactam",
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"keywords": "Bacteremia; Ecthyma gangrenosum; Escherichia coli; Iatrogenic disease; Skin infection",
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"mesh_terms": "D000667:Ampicillin; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D003875:Drug Eruptions; D004473:Ecthyma; D006801:Humans; D013407:Sulbactam; D014456:Ulcer",
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"title": "Multiple well demarcated skin erosions and ulcers following exanthematous drug eruption after sultamicillin therapy.",
"title_normalized": "multiple well demarcated skin erosions and ulcers following exanthematous drug eruption after sultamicillin therapy"
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"abstract": "A developmentally normal infant presented with repeated episodes of afebrile status epilepticus following nutmeg ingestion. He had developed two episodes of afebrile status epilepticus and had received different treatments earlier, but the details of treatment were not available. On admission, he redeveloped convulsions and loading doses of phenytoin, phenobarbitone and midazolam were administered. However, seizures persisted and extrapyramidal movements, nystagmus and visual dysfunction were noted. Iatrogenic phenytoin toxicity was considered and confirmed by drug levels. His symptoms completely disappeared after discontinuation of phenytoin therapy. The initial seizures were attributed to myristicin, an active component of nutmeg, because of the temporal association. However, the subsequent seizures were due to phenytoin toxicity caused by administration of multiple loading doses. This case highlights that nutmeg, a spice, can cause serious toxic effects like status epilepticus. Furthermore, treatment of status epilepticus with phenytoin can cause iatrogenic seizures due to its narrow therapeutic range.",
"affiliations": "Department of Pediatrics, ESI-PGIMSR, Chennai, Tamilnadu, India.;Department of Pediatrics, ESI-PGIMSR, Chennai, Tamilnadu, India.;Department of Pediatrics, ESI-PGIMSR, Chennai, Tamilnadu, India.;Department of Pediatrics, ESI-PGIMSR, Chennai, Tamilnadu, India.",
"authors": "Sivathanu|Shobhana|S|;Sampath|Sowmya|S|;David|Henry Suresh|HS|;Rajavelu|Kulandai Kasthuri|KK|",
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"title": "Myristicin and phenytoin toxicity in an infant.",
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"abstract": "Tenofovir, a nucleotide analog, is one of the first-line medications recommended for the treatment of active chronic hepatitis B virus infection (CHB) and as a primary prophylaxis to prevent hepatitis B reactivation in cases of immunosuppression. We report the first case of tenofovir-induced leukocytoclastic vasculitis (LCV). A 43-year-old obese woman, who was known to have inactive CHB, was diagnosed with chronic immune thrombocytopenic purpura (ITP). She was treated with corticosteroid therapy and was put on tenofovir to prevent hepatitis B virus reactivation. A month later, she developed a skin rash, described as non-blanchable well-defined erythematous to violaceous papules and targetoid patches in her lower extremities. A skin biopsy showed features of LCV. The rash resolved completely within few days after replacing tenofovir with entecavir.",
"affiliations": "Department of Medicine, Division of Gastroenterology and Hepatology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Internal Medicine Training Program, Oman Medical Specialty Board, Muscat, Oman.;Department of Pathology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.;Department of Medicine, Division of Gastroenterology and Hepatology, College of Medicine and Health Sciences, Sultan Qaboos University, Muscat, Oman.",
"authors": "Al-Busafi|Said A|SA|;Al-Suleimani|Abdulatif|A|;Al-Hamadani|Aysha|A|;Rasool|Wasif|W|",
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"nlm_unique_id": "101526350",
"other_id": null,
"pages": "429-431",
"pmc": null,
"pmid": "29026476",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports",
"references": "24145696;2202309;9854604;23112433;17545718;16637802;7492128;8129772;7747536;9366584;2453991",
"title": "Tenofovir-induced Leukocytoclastic Vasculitis.",
"title_normalized": "tenofovir induced leukocytoclastic vasculitis"
} | [
{
"companynumb": "OM-MYLANLABS-2017M1069612",
"fulfillexpeditecriteria": "1",
"occurcountry": "OM",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TENOFOVIR"
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... |
{
"abstract": "Focal segmental glomerulosclerosis (FSGS) occurring in association with cytomegalovirus (CMV) infection in a renal transplant patient with no previous history of FSGS has rarely been reported. We present a case of a 16-year-old renal transplant recipient who developed acute hepatitis, leukopenia, nephrotic syndrome, and progressive renal dysfunction in the setting of acute infection with CMV. The cytomegalovirus infection was successfully treated with IV ganciclovir followed by oral valganciclovir but renal function deterioration and massive proteinuria continued. Features of FSGS were found on two renal allograft biopsies. Plasmapheresis and cyclophosphamide treatment was instituted with no clear effect on disease progress.",
"affiliations": "Department of Nephrology, Queensland Children's Hospital, Brisbane, Queensland, Australia.;Department of Pathology, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia.;Department of Nephrology, Queensland Children's Hospital, Brisbane, Queensland, Australia.",
"authors": "Wynd|Elsa|E|0000-0002-2509-6446;Stewart|Anne|A|;Burke|John|J|",
"chemical_list": "D003520:Cyclophosphamide",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13538",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "23(6)",
"journal": "Pediatric transplantation",
"keywords": "cytomegalovirus; focal segmental glomerulosclerosis; kidney transplantation; pediatrics",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000293:Adolescent; D064591:Allografts; D001706:Biopsy; D003520:Cyclophosphamide; D003586:Cytomegalovirus Infections; D018450:Disease Progression; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D007668:Kidney; D016030:Kidney Transplantation; D008297:Male; D009404:Nephrotic Syndrome; D010530:Peritoneal Dialysis; D010956:Plasmapheresis; D011507:Proteinuria; D066027:Transplant Recipients",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13538",
"pmc": null,
"pmid": "31271240",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Focal segmental glomerulosclerosis associated with acute cytomegalovirus infection in a renal transplant.",
"title_normalized": "focal segmental glomerulosclerosis associated with acute cytomegalovirus infection in a renal transplant"
} | [
{
"companynumb": "PHHY2019AU157671",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
... |
{
"abstract": "Single-agent pemetrexed is a treatment for recurrent non-squamous non-small cell lung cancer (NSCLC) that provides limited benefit. Preclinical studies showed promising synergistic effects when the mammalian target of rapamycin (mTOR) inhibitor sirolimus was added to pemetrexed.\nThis was a single-institution phase I/II study of pemetrexed in combination with sirolimus. The primary endpoint for the phase I was to determine the maximum tolerated dose (MTD) and safety of the combination. The primary endpoint for the phase II portion was to determine the overall response rate at the MTD. Key eligibility criteria included recurrent, metastatic NSCLC, ECOG performance status of 0-2, and adequate organ function. Sirolimus was administered orally daily after an initial loading dose, and pemetrexed was given intravenously on day 1 of every 21-day cycle.\nForty-two patients with recurrent, metastatic NSCLC were enrolled, 22 in phase I and 20 in phase II. The MTD was pemetrexed 500 mg/m2 every 3 weeks, and sirolimus 10 mg on day 1, and 3 mg daily thereafter. Treatment-related adverse events (AEs) occurred in 38 (90.5%) patients. The most common grade 3-4 treatment-related AEs were lymphopenia (31%) and hypophosphatemia (19%). Two treatment-related deaths occurred due to febrile neutropenia and infection, respectively. Among 27 total patients treated at the MTD, 6 (22.2%) had a partial response (PR), 12 (44.4%) had stable disease (SD) and 5 (18.5%) had progressive disease. Median progression-free survival (PFS) was 18.4 weeks (95% CI: 7.0-29.4).\nThe combination of pemetrexed and sirolimus is active in heavily-pretreated NSCLC (ClinicalTrials.gov Identifier: NCT00923273).",
"affiliations": "Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Biostatistics and Data Management Section, National Cancer Institute, Rockville, MD, USA.;Biostatistics and Data Management Section, National Cancer Institute, Rockville, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.;Medical Oncology Service, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.",
"authors": "Komiya|Takefumi|T|;Memmott|Regan M|RM|;Blumenthal|Gideon M|GM|;Bernstein|Wendy|W|;Ballas|Marc S|MS|;De Chowdhury|Roopa|R|;Chun|Guinevere|G|;Peer|Cody J|CJ|;Figg|William D|WD|;Liewehr|David J|DJ|;Steinberg|Seth M|SM|;Giaccone|Giuseppe|G|;Szabo|Eva|E|;Kawabata|Shigeru|S|;Tsurutani|Junji|J|;Rajan|Arun|A|;Dennis|Phillip A|PA|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/tlcr.2019.04.19",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2218-6751",
"issue": "8(3)",
"journal": "Translational lung cancer research",
"keywords": "Lung cancer; pemetrexed; phase I/II, sirolimus; thymidylate synthase (TS)",
"medline_ta": "Transl Lung Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "101646875",
"other_id": null,
"pages": "247-257",
"pmc": null,
"pmid": "31367538",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article",
"references": "10856094;11358816;12907242;15117980;16330671;16940981;16955506;17534577;19692142;20090562;21111508;21282537;21482992;21642865;21716147;21900840;23109689;24658085;26028407;26780363;8558210",
"title": "A phase I/II study of pemetrexed with sirolimus in advanced, previously treated non-small cell lung cancer.",
"title_normalized": "a phase i ii study of pemetrexed with sirolimus in advanced previously treated non small cell lung cancer"
} | [
{
"companynumb": "US-PFIZER INC-2019307408",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SIROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Intravenous administration of thrombolytic agents is considered to be contraindicated in patients with intracranial neoplasms. However, only a single case of thrombolysis-related intracranial tumour haemorrhage has been reported to our knowledge and several studies have suggested that systemic thrombolysis can be safely carried out in these patients. Here we report a patient who developed haemorrhage into a previously unknown intracranial tumour following intravenous thrombolysis for acute myocardial ST-elevation infarction. Identification of abnormal tissue during surgical haematoma evacuation initiated histopathological examination which revealed meningioma World Health Organization Grade I. Intracranial tumours may represent the causative pathology in cases of thrombolysis-related intracranial haemorrhage and this should be considered in the treatment of these patients.",
"affiliations": "Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.;Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.;Department of Neuropathology, Heidelberg University Hospital, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.;Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany.;Department of Neurosurgery, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany. Electronic address: christopher.beynon@med.uni-heidelberg.de.",
"authors": "Diehl|Christian|C|;Haux|Daniel|D|;Sahm|Felix|F|;Unterberg|Andreas W|AW|;Beynon|Christopher|C|",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Scotland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0967-5868",
"issue": "26()",
"journal": "Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia",
"keywords": "Fibrinolysis; Haemorrhage; Intracranial neoplasm; Thrombolysis",
"medline_ta": "J Clin Neurosci",
"mesh_terms": "D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D020300:Intracranial Hemorrhages; D008297:Male; D008577:Meningeal Neoplasms; D008579:Meningioma; D008875:Middle Aged; D015912:Thrombolytic Therapy",
"nlm_unique_id": "9433352",
"other_id": null,
"pages": "145-6",
"pmc": null,
"pmid": "26646504",
"pubdate": "2016-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intracranial tumour haemorrhage following intravenous thrombolysis.",
"title_normalized": "intracranial tumour haemorrhage following intravenous thrombolysis"
} | [
{
"companynumb": "DE-SHENZHEN TECHDOW PHARMACEUTICAL CO. LTD-DE-2016TEC0000029",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
... |
{
"abstract": "BACKGROUND\nMusculoskeletal involvement occurs in 25% of patients with non-Hodgkin's lymphoma (NHL). Primary lymphoma in the joint is rare. It can present as a bone lesion or as atypical soft tissue proliferation. NHL has an increased incidence in patients with autoimmune rheumatic diseases.\n\n\nMETHODS\nWe present a case in which non-Hodgkin's lymphoma was found coincidentally in the synovium during knee joint replacement surgery in a 69-year old woman with rheumatoid arthritis. Pigmented, vitreous tissue was resected, which turned out to be a diffuse large B-cell lymphoma after histological examination. The coincidental intraoperative finding of intra-articular non-Hodgkin's lymphoma was reported twice before, presenting as synovial proliferation in elbow and shoulder surgery. In a few other cases non-Hodgkin's lymphoma presented most often in the knee, as a bone lesion or, when soft tissue was involved, as arthritis.\n\n\nCONCLUSIONS\nNon-Hodgkin's lymphoma should be considered in patients with autoimmune rheumatic diseases. In case of persistent arthritis, non-respondent to anti-inflammatory drugs, a biopsy might be warranted. Moreover, when arthroscopy or arthrotomy is planned, any atypical tissue should be sent for histological analysis. Early diagnosis of NHL can contribute to improved outcome of its rapidly developing treatment options.",
"affiliations": "Sint Maartenskliniek, Department of Orthopaedics, Hengstdal 3, PO Box 9011, 6500GM, Nijmegen, The Netherlands.",
"authors": "Visser|Jetze|J|;Busch|Vincent J J F|VJ|;de Kievit-van der Heijden|Ineke M|IM|;ten Ham|Arno M|AM|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-5-449",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-5-4492290590710.1186/1756-0500-5-449Case ReportNon-Hodgkin’s Lymphoma of the synovium discovered in total knee arthroplasty: a case report Visser Jetze 1jetzevisser.jv@gmail.comBusch Vincent JJF 1v.busch@maartenskliniek.nlde Kievit-van der Heijden Ineke M 2i.d.kievit@cwz.nlten Ham Arno M 1a.tenham@maartenskliniek.nl1 Sint Maartenskliniek, Department of Orthopaedics, Hengstdal 3, PO Box 9011, 6500GM, Nijmegen, The Netherlands2 Canisius Wilhelmina Hospital, Department of Pathology, Nijmegen, The Netherlands2012 20 8 2012 5 449 449 12 7 2012 14 8 2012 Copyright ©2012 Visser et al.; licensee BioMed Central Ltd.2012Visser et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (\nhttp://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nMusculoskeletal involvement occurs in 25% of patients with non-Hodgkin’s lymphoma (NHL). Primary lymphoma in the joint is rare. It can present as a bone lesion or as atypical soft tissue proliferation. NHL has an increased incidence in patients with autoimmune rheumatic diseases.\n\nCase presentation\nWe present a case in which non-Hodgkin’s lymphoma was found coincidentally in the synovium during knee joint replacement surgery in a 69-year old woman with rheumatoid arthritis. Pigmented, vitreous tissue was resected, which turned out to be a diffuse large B-cell lymphoma after histological examination. The coincidental intraoperative finding of intra-articular non-Hodgkin’s lymphoma was reported twice before, presenting as synovial proliferation in elbow and shoulder surgery. In a few other cases non-Hodgkin’s lymphoma presented most often in the knee, as a bone lesion or, when soft tissue was involved, as arthritis.\n\nConclusion\nNon-Hodgkin’s lymphoma should be considered in patients with autoimmune rheumatic diseases. In case of persistent arthritis, non-respondent to anti-inflammatory drugs, a biopsy might be warranted. Moreover, when arthroscopy or arthrotomy is planned, any atypical tissue should be sent for histological analysis. Early diagnosis of NHL can contribute to improved outcome of its rapidly developing treatment options.\n\nNon-Hodgkin's lymphomaTotal knee arthroplastyRheumatoid arthritis\n==== Body\nBackground\nNon-Hodgkin’s Lymphoma (NHL) is a malignancy of the lymphatic system of uncontrolled proliferation of B- or T-lymphocytes. The musculoskeletal system is affected in 5-25% of the patients\n[1-4]. Musculoskeletal involvement of NHL has been reported before as a primary bone lesion or as intra-articular soft tissue proliferation with arthritis as presenting symptom. We present a case in which atypical soft tissue found during a routine knee arthroplasty led to the diagnosis systemic NHL.\n\nCase presentation\nA 69-year old woman was referred to our clinic with chronic left knee pain. Her walking distance was limited and she complained of joint stiffness.\n\nMedical History\nAfter a sports trauma 40 years ago, the patient underwent a lateral meniscectomy of the left knee. Two loose tissue parts were removed; histological analysis showed synovial tissue with chronic inflammation possibly indicating rheumatoid arthritis (RA). The following decades she had internal and rheumatological examinations for multiple joint pain and general body weakness. Multiple joint osteoarthritis and rheumatoid factor (RF)-negative RA were diagnosed. In 1997 a total knee arthroplasty was performed on the right side. In 2006 the patient consulted a rheumatologist for chronic fatigue, pain in the left knee, elbow and both wrists and feet. Further laboratory and radiographic investigation yielded no other diagnosis than RF-negative RA.\n\nExamination\nA vital woman was seen with a normal hip function. There was a correctable valgus deformity of the left leg with slight effusion of the knee and tenderness on palpation of the lateral joint space. No inflammation was seen and range of motion was normal. A conventional X-ray showed severe lateral osteoarthritis of the knee with loss of height of the lateral tibial plateau (Figure\n1A,B).\n\nFigure 1 An X-ray of the left knee showed severe osteoarthritis with evident lateral joint space narrowing, bone sclerosis, osteophytes and a calcified medial meniscus. A. anteroposterior axis. B. lateral axis.\n\nSurgery\nWith informed consent of the patient we decided to proceed to a total knee replacement. Intraoperatively, pigmented vitreous synovial tissue was seen in the subcutaneous tissue, which was resected and sent to the pathology department for further analysis. A total knee replacement could be performed without any complications. The patient recovered well and was discharged five days postoperatively.\n\nHistology\nImmunohistological analysis of the resected soft tissue showed a large cell lymphoid proliferation under the synovial tissue surface with expression of B-cell antigen CD-20 (Figure\n2A-C). This finding matches the localization of a B-cell NHL, WHO 2008 classified as diffuse large B-cell lymphoma– not otherwise specified (DLBCL-NOS). WHO guidelines suggest an Epstein Bar Virus-negative B-cell lymphoma that develops around chronically inflamed joints in a patient with RA, as in the present case, to be classified in this category.\n\nFigure 2 In the synovial biopsy (A) a atypical lymphoid cell proliferation is present under the synovial surface (hematoxylin-eosin (HE), 2.5x) that (B) consists of a diffuse proliferation of large lymphoid cells (HE, 40x), showing (C) membranous expression of B-cell antigen CD20, which can be seen as brown deposit (40x). This formed the histological diagnosis Non-Hodgkin Lymphoma.\n\nFollow-up\nAnamnesis and physical examination by an oncologist did not reveal any clues for malignancy. But a PET-CT scan showed pathologic enlarged lymph nodes along the aorta and the left iliac and inguinal vessels. Lungs and liver were clean in the scan and a bone marrow biopsy did not show signs of tumor activity. The B-cell lymphoma was staged level 2-E, therapy was started with rituximab, cyclofosfamide, vincristine, doxorubicin and prednisone (R-CHOP) combination chemotherapy in six doses.\n\nBone manifestation of NHL\nIn 5-25% of the patients with NHL, the bone is involved, sometimes resulting in joint pain\n[1-4]. When this is the primary symptom, imaging techniques can raise suspicion of a malignancy. Also, bone surfaces during surgery can be suspect. A NHL was once reported in the cutting surface of the femur in a total knee arthroplasty\n[5]. A routine analysis of 852 retrieved femoral heads in hip arthroplasty confirms the possibility of bone involvement\n[6]. In 14 femoral heads a low-grade B-cell lymphoma was detected. Systemic disease was found in only two of these patients.\n\nSynovial manifestation of NHL\nThe diagnosis in this case report was based on synovial tissue analysis. This coincidental finding was reported twice before, though this was in elbow and shoulder surgery\n[2,7]. In a literature overview till 2006, 13 cases of intra-articular synovial manifestation of NHL were presented, of which 11 cases concerned the knee\n[2]. All patients presented with inflammation of the knee joint, sometimes clinically simulating RA\n[1,2]. In later literature two more patients were strikingly described discovering NHL with arthroscopy\n[3,8]. Both patients were planned for a partial meniscectomy. One patient (51 years old) had a history of gonarthritis deformans, without signs of inflammation of the knee.\n[8] The other patient (31 years old) had a constant knee pain and swelling\n[3]. Arthroscopically obtained atypical synovial tissue appeared to be a B-cell lymphoma in both cases.\n\nImportant in this case report is that patients with active RA have an increased risk of developing lymphoma\n[7,9-11]. A recent review showed that aggressive B-cell lymphomas, particularly the diffuse large B-cell lymphoma in the present case, are stronger associated with autoimmune rheumatic diseases than more indolent lymphomas. Although the presence of NHL was less associated with RA than with Sjögren’s syndrome and systemic lupus erythematosus\n[10], a 28-fold increased risk of NHL in patients with RA was found when severe damage in the knee existed in the year prior to lymphoma diagnosis\n[11]. Most lymphomas in this population are diffuse large B-cell lymphomas, which form an aggressive subtype of NHLs. Though with new treatment methods survival has significantly increased over the last decade\n[12].\n\nThe main pathophysiological mechanisms for NHL are B-cell hyperactivity and chronic inflammation\n[10]. Nevertheless, anti-inflammatory drugs are no treatment option for NHL\n[12]. Probably through its malignant character, NHL will be persistent to anti-inflammatory drugs, also in case of musculoskeletal involvement. In relation with RA, the rheumatic disease itself appears to have a larger effect on the development of lymphoma than its therapy\n[10]. As the presented patient had used immunosuppressive drugs (salazopyrine and leflunomide) for only two years, the contribution of drugs can be expected to be minimal. Part of the patients with a lymphoma is infected with the Epstein-Barr Virus (EBV)\n[9]. The presence of EBV in the lymphoma can have therapeutic consequences. Though, in the presented case no EBV-encoded RNA was found with in-situ hybridisation.\n\nConclusions\nTo conclude we can say NHL seldom has its primary presentation in a joint. If it occurs, it presents most often in the knee as arthritis. To our knowledge we are the first to present a coincidental finding of soft tissue NHL in knee arthroplasty, without malignant bone pathology or signs of arthritis. However it is possible that the lymphoma was partly responsible for the diffuse joint pain and general body weakness this patient had for several years.\n\nIn patients with a rheumatic disease, we advice to consider NHL in the diagnostic work-up if arthritis does not respond to anti-inflammatory drugs. In these cases a biopsy may be warranted, since the risk of developing a lymphoma is significantly increased in this population. Moreover, when arthroscopy or arthrotomy is planned, any atypical tissue should be sent for histological analysis. Early diagnosis of NHL can contribute to improved outcome of its rapidly developing treatment options.\n\nConsent\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 Series Editor of this journal.\n\nAbbreviations\nNHL: Non-Hodgkin’s Lymphoma; RF: Rheumatoid Factor; RA: Rheumatoid Arthritis; DLBCL-NOS: Diffuse large B-cell lymphoma– not otherwise specified.\n\nCompeting interests\nAll four authors declare they have no competing interests. All questions underneath are answered NO by all authors.\n\nFinancial competing interests\n· In the past five years have you received reimbursements, fees, funding, or salary from an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future? Is such an organization financing this manuscript (including the article-processing charge)? NO\n\n· Do you hold any stocks or shares in an organization that may in any way gain or lose financially from the publication of this manuscript, either now or in the future? NO\n\n· Do you hold or are you currently applying for any patents relating to the content of the manuscript? Have you received reimbursements, fees, funding, or salary from an organization that holds or has applied for patents relating to the content of the manuscript? NO\n\n· Do you have any other financial competing interests? NO\n\nNon-financial competing interests\n· Are there any non-financial competing interests (political, personal, religious, ideological, academic, intellectual, commercial or any other) to declare in relation to this manuscript? NO\n\nNijmegen, 24 April 2012\n\nJetze Visser, Vincent Busch, Ineke de Kievit-van der Heijden, Arno ten Ham.\n\nAuthors’ contributions\nJV and VB designed and drafted the manuscript. VB and AH did the surgical procedure. IK did the histological analysis and contributed to the manuscript regarding the pathological sections. AH initiated this case report and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe thank dr. F.M.A. Slaats, rheumatologist, Amphia Hospital, Breda, the Netherlands for reviewing this paper with special attention to rheumatologic aspects.\n\nAuthor details\n1Sint Maartenskliniek, Department of Orthopaedics, Hengstdal 3, PO Box 9011, 6500GM Nijmegen, The Netherlands. 2Canisius Wilhelmina Hospital, Department of Pathology, Nijmegen, The Netherlands.\n==== Refs\nDorfman HD Siegel HL Perry MC Oxenhandler R Non-Hodgkin's lymphoma of the synovium simulating rheumatoid arthritis Arthritis Rheum 1987 30 155 161 10.1002/art.1780300205 3827957 \nJawa A Lieberman AE Alexieva CC Jupiter JB Primary intra-articular non-Hodgkin's lymphoma of the elbow. A case report. J Bone Joint Surg Am 2006 88 2730 2734 10.2106/JBJS.E.00094 17142425 \nMileti J Mileti L Kaeding C Non-Hodgkin's lymphoma of the knee diagnosed by arthroscopy Arthroscopy 2007 23 447 e441-444 17418346 \nVadivelu R Kar N Margetts MJ Abdul-Cader AH Non-Hodgkin's lymphoma as an unexpected diagnosis in a hip arthroplasty Arch Orthop Trauma Surg 2002 122 532 534 12483337 \nWatson AJ Cross MJ Non-Hodgkin lymphoma as an unexpected diagnosis after elective total knee arthroplasty J Arthroplasty 2008 23 612 614 10.1016/j.arth.2007.02.014 18514884 \nZwitser EW de Gast A Basie MJ van Kemenade FJ van Royen BJ B-cell lymphoma in retrieved femoral heads: a long term follow up BMC Musculoskelet Disord 2009 10 53 10.1186/1471-2474-10-53 19457261 \nArredondo J Worland RL Sinnenberg RJ JrQureshi GD Non-Hodgkin's lymphoma as an unexpected diagnosis in a shoulder arthroplasty J Arthroplasty 1999 14 108 111 10.1016/S0883-5403(99)90211-5 9926962 \nIkeda J Morii E Yamauchi A Kohara M Hashimoto N Yoshikawa H Iwasaki M Aozasa K Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type developing in gonarthritis deformans J Clin Oncol 2007 25 4310 4312 10.1200/JCO.2007.12.7092 17878483 \nStarkebaum G Rheumatoid arthritis, methotrexate, and lymphoma: risk substitution, or cat and mouse with Epstein-Barr virus? J Rheumatol 2001 28 2573 2575 11764198 \nDias C Isenberg DA Susceptibility of patients with rheumatic diseases to B-cell non-Hodgkin lymphoma Nat Rev Rheumatol 2011 7 360 368 10.1038/nrrheum.2011.62 21637317 \nBaecklund E Iliadou A Askling J Ekbom A Backlin C Granath F Catrina AI Rosenquist R Feltelius N Sundstrom C Klareskog L Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis Arthritis Rheum 2006 54 692 701 10.1002/art.21675 16508929 \nFlowers CR Armitage JO A decade of progress in lymphoma: advances and continuing challenges Clin Lymphoma Myeloma Leuk 2010 10 414 423 10.3816/CLML.2010.n.086 21156459\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1756-0500",
"issue": "5()",
"journal": "BMC research notes",
"keywords": null,
"medline_ta": "BMC Res Notes",
"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D019645:Arthroplasty, Replacement, Knee; D005260:Female; D006801:Humans; D033162:Incidental Findings; D007719:Knee Joint; D008228:Lymphoma, Non-Hodgkin; D013583:Synovial Membrane",
"nlm_unique_id": "101462768",
"other_id": null,
"pages": "449",
"pmc": null,
"pmid": "22905907",
"pubdate": "2012-08-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12483337;16508929;17142425;11764198;18514884;21156459;17878483;3827957;21637317;9926962;17418346;19457261",
"title": "Non-Hodgkin's lymphoma of the synovium discovered in total knee arthroplasty: a case report.",
"title_normalized": "non hodgkin s lymphoma of the synovium discovered in total knee arthroplasty a case report"
} | [
{
"companynumb": "NL-PFIZER INC-2020074580",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFASALAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "We present the case of a 28-year-old woman who was para 1, with end-stage renal failure secondary to reflux nephritis. She conceived after two years on peritoneal dialysis. She successfully continued this throughout pregnancy, although her antenatal course was complicated by an episode of peritonitis. Induction at 34 weeks resulted in a vaginal birth of a live boy. Her postnatal course was uncomplicated. We reviewed the literature regarding peritoneal dialysis in pregnancy. A recent systematic review identified 14 cases. When the outcomes of these women were compared with those receiving haemodialysis in pregnancy, there was a significantly higher proportion of small for gestational age fetuses, but other parameters were comparable. Two cases of peritonitis complicating peritoneal dialysis in pregnancy have been reported, both successfully treated. We conclude that peritoneal dialysis may be continued in pregnancy with successful maternal and fetal outcome, particularly in women with some residual renal function.",
"affiliations": "Department of Obstetrics and Gynaecology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Department of Obstetrics and Gynaecology, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.;Nottingham Renal and Transplant Unit, Nottingham University Hospitals NHS Trust, Nottingham, UK.",
"authors": "Malin|G L|GL|;Wallace|Svf|S|;Hall|M|M|;Ferraro|A|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X17737002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "11(2)",
"journal": "Obstetric medicine",
"keywords": "Maternal–fetal medicine; high-risk pregnancy; nephrology",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "98-100",
"pmc": null,
"pmid": "29997695",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports",
"references": "19643784;24525032;18844832;26714381;10898058;26614270",
"title": "Peritoneal dialysis throughout pregnancy with successful outcome: A case report.",
"title_normalized": "peritoneal dialysis throughout pregnancy with successful outcome a case report"
} | [
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"companynumb": "PHHY2018GB037214",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
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"activesubstancename": "DARBEPOETIN ALFA"
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... |
{
"abstract": "BACKGROUND\nSulfonylureas are used extensively for treating type-2 diabetes mellitus. Sulfonylurea poisoning can produce sustained and profound hypoglycemia refractory to IV dextrose, particularly in children and the elderly.\n\n\nOBJECTIVE\nTo review the use of octreotide, a long-acting somatostatin analog, in the treatment of sulfonylurea-induced hypoglycemia.\n\n\nMETHODS\nA computerized search of U.S. National Academy of Medicine, Embase, PubMed and Toxline databases was undertaken using the keywords \"octreotide\", \"sulfonylurea\", \"poisoning\", \"intoxication\", \"overdose\" and \"children\". Textbooks of Clinical Toxicology and Pharmacology and the articles cited in their bibliographies were also searched. Twenty-four publications (19 articles and five conference abstracts) were identified; no publication was excluded. PHARMACOLOGY OF OCTREOTIDE: Octreotide, a synthetic peptide analog of somatostatin, binds to G protein-coupled somatostatin-2 receptors in pancreatic beta-cells, resulting in decreased calcium influx and inhibition of insulin secretion. Octreotide markedly inhibited insulin secretion and decreased the number of hypoglycemic events and supplemental dextrose requirements in animal studies. In humans octreotide markedly inhibited insulin release, increased serum glucose concentration, reduced dextrose requirement, prevented recurrent hypoglycemia and was superior to IV dextrose and diazoxide after administration of sulfonylureas. EFFICACY OF OCTREOTIDE IN PEDIATRIC SULFONYLUREA POISONING: Fourteen pediatric patients were reported; 13 ingested second-generation sulfonylureas, with time to hypoglycemia of 1.5-16 hours. IV dextrose (10-25%) was administered before and after octreotide therapy. Octreotide was given after failure to correct hypoglycemia with IV dextrose in doses of 0.51-2 μg/kg IV or SC; two also required an IV octreotide infusion. Seven patients (50%) had recurrent hypoglycemia and received IV dextrose and additional octreotide. EFFICACY OF OCTREOTIDE IN ADULT SULFONYLUREA POISONING: Fifty-three patients were reported in prospective controlled (n = 22) and retrospective (n = 9) studies, case series (n = 6) and case reports. Fifty-one ingested second-generation sulfonylureas with time to hypoglycemia of 1-13 hours. All received IV dextrose (10-50%) before and after octreotide treatment. Octreotide 40-100 μg SC or IV was administered followed by additional doses in most patients; three patients also required an IV infusion. Octreotide significantly increased serum glucose concentrations, decreased dextrose requirement and recurrent hypoglycemic events compared with IV dextrose. Recurrent hypoglycemia was recorded in 22-50% of the patients treated with octreotide. THERAPEUTIC RECOMMENDATIONS: Based on the published clinical and pharmacokinetic data of sulfonylureas and octreotide, we suggest the following dose regimens: in children, octreotide 1-1.5 μg/kg IV or SC, followed by 2-3 more doses 6 hours apart. In adults, octreotide 50 μg SC or IV, followed by three 50 μg doses every 6 hours. During this treatment IV dextrose infusion should be gradually tapered off.\nHypertension and apnea were recorded in one pediatric patient 30 minutes after IV octreotide; the relationship to octreotide is unclear. One adult patient with chronic renal failure treated with atenolol developed severe hyperkalemia.\n\n\nCONCLUSIONS\nAlthough relatively limited, the available data suggest that octreotide should be considered first-line therapy in both pediatric and adult sulfonylurea poisoning with clinical and laboratory evidence of hypoglycemia. Maintenance doses of octreotide may be required to prevent recurrent hypoglycemia.",
"affiliations": "Division of Pediatric Emergency Medicine, Department of Pediatrics, Dana's Children Hospital, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.",
"authors": "Glatstein|Miguel|M|;Scolnik|Dennis|D|;Bentur|Yedidia|Y|",
"chemical_list": "D013453:Sulfonylurea Compounds; D015282:Octreotide",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2012.734626",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "50(9)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000818:Animals; D006801:Humans; D007003:Hypoglycemia; D015282:Octreotide; D013453:Sulfonylurea Compounds",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "795-804",
"pmc": null,
"pmid": "23046209",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Octreotide for the treatment of sulfonylurea poisoning.",
"title_normalized": "octreotide for the treatment of sulfonylurea poisoning"
} | [
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"companynumb": "AU-RANBAXY-2014R1-90893",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
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{
"abstract": "Methadone may offer advantages in facilitating early extubation after cardiac surgery, but very few data are available in the pediatric population.\n\n\n\nCommunity tertiary children's hospital, retrospective case series.\n\n\n\nWe performed a retrospective analysis of all pediatric cardiac surgical patients for whom early extubation was intended. A multimodal analgesic regimen was used for all patients, consisting of methadone (0.2-0.3 mg/kg), ketamine (0.5 mg/kg plus 0.25 mg/kg/h), lidocaine (1 mg/kg plus 1.5 mg/kg/h), acetaminophen (15 mg/kg), and parasternal ropivacaine (0.5 mL/kg of 0.2%). Outcome variables were collected with descriptive statistics.\n\n\n\nA total of 24 children [median = 7 (interquartile range = 3.75-13.75) years old, 23.7 (14.8-53.4) kg] were included in the study; 22 (92%) had procedures performed on bypass and 11 (46%) involved a reentry sternotomy. Methadone dosing was 0.26 (0.23-0.29) mg/kg. None of the children required intraoperative supplemental opioids; 23 (96%) were extubated in the operating room. The first paCO2 on pediatric intensive care unit admission was 51 (45-58) mmHg. Time to first supplemental opioid administration was 5.1 (3.5-9.5) h. Cumulative total supplemental opioids (in intravenous morphine equivalents) at 24 and 72 h were 0.2 (0.09-0.32) and 0.42 (0.27-0.68) mg/kg. One child required postoperative bilevel positive airway pressure support, but none required reintubation. None had pruritus; three (13%) experienced nausea.\n\n\n\nA methadone-based multimodal regimen facilitated early extubation without appreciable adverse events. Further investigations are needed to confirm efficacy of this regimen and to assess whether the excellent safety profile seen here holds in the hands of multiple providers caring for a larger, more heterogeneous population.",
"affiliations": "Creighton University School of Medicine, Omaha, NE, USA.;Randall Children's Hospital, Portland, OR, USA.;Randall Children's Hospital, Portland, OR, USA.;Randall Children's Hospital, Portland, OR, USA.;Randall Children's Hospital, Portland, OR, USA.",
"authors": "Iguidbashian|John P|JP|;Chang|Peter H|PH|;Iguidbashian|John|J|;Lines|Jason|J|;Maxwell|Bryan G|BG|",
"chemical_list": "D000701:Analgesics, Opioid; D008691:Methadone",
"country": "India",
"delete": false,
"doi": "10.4103/aca.ACA_113_18",
"fulltext": "\n==== Front\nAnn Card AnaesthAnn Card AnaesthACAAnnals of Cardiac Anaesthesia0971-97840974-5181Wolters Kluwer - Medknow India 31929251ACA-23-7010.4103/aca.ACA_113_18Original ArticleEnhanced Recovery and Early Extubation after Pediatric Cardiac Surgery Using Single-Dose Intravenous Methadone Iguidbashian John P Chang Peter H 1Iguidbashian John 1Lines Jason 1Maxwell Bryan G 1Creighton University School of Medicine, Omaha, NE, USA1 Randall Children's Hospital, Portland, OR, USAAddress for correspondence: Dr. Bryan G Maxwell, Randall Children's Hospital, 707 SW Washington St, Suite 700, Portland, OR 97205, USA. E-mail: bryanmaxwell@gmail.comJan-Mar 2020 07 1 2020 23 1 70 74 30 5 2018 09 1 2019 09 3 2019 Copyright: © 2020 Annals of Cardiac Anaesthesia2020This 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.Background/Aims:\nMethadone may offer advantages in facilitating early extubation after cardiac surgery, but very few data are available in the pediatric population.\n\nSetting/Design:\nCommunity tertiary children's hospital, retrospective case series.\n\nMaterials and Methods:\nWe performed a retrospective analysis of all pediatric cardiac surgical patients for whom early extubation was intended. A multimodal analgesic regimen was used for all patients, consisting of methadone (0.2–0.3 mg/kg), ketamine (0.5 mg/kg plus 0.25 mg/kg/h), lidocaine (1 mg/kg plus 1.5 mg/kg/h), acetaminophen (15 mg/kg), and parasternal ropivacaine (0.5 mL/kg of 0.2%). Outcome variables were collected with descriptive statistics.\n\nResults:\nA total of 24 children [median = 7 (interquartile range = 3.75–13.75) years old, 23.7 (14.8–53.4) kg] were included in the study; 22 (92%) had procedures performed on bypass and 11 (46%) involved a reentry sternotomy. Methadone dosing was 0.26 (0.23–0.29) mg/kg. None of the children required intraoperative supplemental opioids; 23 (96%) were extubated in the operating room. The first paCO2 on pediatric intensive care unit admission was 51 (45–58) mmHg. Time to first supplemental opioid administration was 5.1 (3.5–9.5) h. Cumulative total supplemental opioids (in intravenous morphine equivalents) at 24 and 72 h were 0.2 (0.09–0.32) and 0.42 (0.27–0.68) mg/kg. One child required postoperative bilevel positive airway pressure support, but none required reintubation. None had pruritus; three (13%) experienced nausea.\n\nConclusion:\nA methadone-based multimodal regimen facilitated early extubation without appreciable adverse events. Further investigations are needed to confirm efficacy of this regimen and to assess whether the excellent safety profile seen here holds in the hands of multiple providers caring for a larger, more heterogeneous population.\n\nEarly extubationenhanced recoveryenhanced recovery after surgeryERASfast-track extubationmethadoneoperating room extubationpediatric cardiac surgerypediatric open heart surgery\n==== Body\nIntroduction\nPostoperative pain in the pediatric cardiac surgical patient is hard to assess and difficult to manage. In general, postoperative pain has been shown to be most intense in the first 24 h following the procedure.[123] Many nonmodifiable factors contribute to the pain following cardiac surgery including surgical site incision, sternotomy, cardiac manipulations, and chest tube placement. Inevitably, the patient will experience acute pain that needs to be adequately controlled for optimum recovery outcomes.[4] Adverse consequences to inadequate pain control may include prolonged intubation times, longer hospital stays, substantial exposure to large opioid doses, and overall patient dissatisfaction.\n\nTraditional pain management strategies have used short-acting analgesics postoperatively based on subjective patient pain scales. The obvious shortcoming of this approach is the resulting waxing and waning pain in relation to varying blood levels of the drug and ultimately very brief episodes of high-quality pain control. Repeated boluses of short-acting opiates, whether delivered by nurse administration or patient-controlled analgesia pump, may also carry the disadvantages of risks of respiratory depression and opioid-induced hyperalgesia.\n\nThe rationale for the use of methadone as an alternative strategy for analgesia after cardiac surgery is severalfold. One, its long duration of action (24–36 h of efficacy from a single dose) may provide steadier, basal pain control during the period of greatest surgical pain.[56] Its activity on the N-methyl-D-aspartate (NMDA) receptor has also been implicated as a potential mechanism in explaining studies demonstrating higher quality and more consistent pain control in the postop period after adult cardiac and noncardiac procedures,[678] and some evidence supports the belief that acute perioperative NMDA antagonism may reduce the development of chronic pain syndromes.[9] However, very little outcome data exist in the pediatric cardiac surgical population regarding the use of methadone as the primary analgesic agent.\n\nThe aim of this small retrospective case series was to assess the efficacy and safety of a multimodal pain regimen centered around single-dose intraoperative intravenous (IV) methadone in pediatric cardiac surgical patients.\n\nMaterials and Methods\nWe performed a retrospective case series analysis of all consecutive cases in which a novel analgesic regimen was used to facilitate early extubation and enhanced recovery after pediatric cardiac surgery. Cases involved all children >6 months of age undergoing surgical interventions with a single anesthesiologist and single surgeon where the likelihood of postoperative hemodynamic instability, ongoing coagulopathy, or bleeding was anticipated to be low and early extubation was planned.\n\nWe implemented a novel multimodal analgesic regimen consisting of the components detailed in Table 1. Methadone dosing was 0.2–0.3 mg/kg, rounded to a 0.5- or 1-mg increment for the purposes of minimizing operational difficulties with procedures for controlled substance tracking. Dosing was based on actual body weight except in children whose weight was >75th percentile for height, in which case the 50th percentile weight was used as an estimate of ideal body weight for dosing calculations. No other opioid analgesics were administered in the operating room (OR). Anesthesia was induced with sevoflurane and/or propofol and maintained with sevoflurane (1.0–1.2 times age-adjusted minimum alveolar concentration (MAC); muscle relaxation was achieved with rocuronium prior to incision and reversed with sugammadex prior to emergence based on train-of-four response. Orogastric suctioning was performed and a nasopharyngeal airway was placed prior to emergence in all patients.\n\nTable 1 Analgesic regimen\n\nAgent\tDose\tRoute\tTiming\t\nMethadone\t0.2-0.3 mg/kg\tIntravenous bolus\tPrior to incision\t\nKetamine\t0.5 mg/kg\tIntravenous bolus\tPrior to incision\t\nKetamine\t0.25 mg/kg/h\tIntravenous infusion\tFrom incision to skin closure\t\nLidocaine\t1 mg/kg\tIntravenous bolus\tPrior to incision\t\nLidocaine\t1.5 mg/kg/h\tIntravenous infusion\tFrom incision to skin closure\t\nAcetaminophen\t15 mg/kg\tIntravenous bolus\tPrior to emergence\t\nRopivacaine (0.2%)\t0.5 mL/kg\tParasternal infiltration\tPrior to emergence\t\nDexamethasone (0.15 mg/kg) and ondansetron (0.1 mg/kg) were administered to all patients prior to incision and emergence, respectively, as prophylaxis for postoperative nausea and vomiting. Supplemental postoperative analgesia consisted of scheduled oral acetaminophen and IV ketorolac, plusas-needed IV fentanyl, IV morphine, and/or enteral oxycodone at the discretion of the pediatric cardiologist who assumed care for the patient after intensive care unit (ICU) admission.\n\nClinical and outcome variables were collected. Children were extubated in the OR and transported immediately to the pediatric intensive care unit (PICU) without any intervening observation period in the OR or postanesthesia care unit, as occurs in some institutions. Postoperative vital signs and arterial blood gas data were obtained within 30 min of arrival in the PICU.\n\nSupplemental postoperative opioids were converted to IV morphine equivalents (fentanyl 33:1, oxycodone 2:1, hydromorphone 4:1). Clinically significant respiratory depression after the initial postoperative handoff was defined as respiratory arrest, respiratory rate <10 (a trigger for rapid response in our institution), need for manual or assisted ventilation, or reintubation. Clinically significant pruritus was defined by the administration of diphenhydramine, hydroxyzine, or nalbuphine. Postoperative nausea was defined by the use of supplemental antiemetics after prophylactic administrations that occurred intraoperatively.\n\nThis study received Institutional Review Board approval. Data are reported as median (interquartile range) unless otherwise noted. Statistics were calculated using Microsoft Excel 2016 (Version 1802; Microsoft Co., Redmond, WA, USA).\n\nResults\nA total of 24 children [7 (3.75–13.75) years old, 23.7 (14.8–53.4) kg] were included in the study. Fifteen (63%) were male; 22 (92%) had procedures performed on bypass, and 11 (46%) involved a reentry sternotomy. The youngest and smallest patient was 8 months old and weighed 6.2 kg. Four patients (17%) had single-ventricle physiology. Table 2 reports the surgical procedures represented in this cohort. Surgery and cardiopulmonary bypass duration were 222 (192–257) and 94 (65–122) min, respectively. Methadone dosing was 0.26 (0.23–0.29) mg/kg of total body weight.\n\nTable 2 Distribution of surgical procedures\n\nSurgical procedure\tNo.\t\nAortic valve replacement, Ross procedure, or repair of subaortic stenosis\t6\t\nFontan procedure\t4\t\nRepair of atrial septal defect, partial anomalous pulmonary venous return, or Warden procedure\t3\t\nPulmonary valve replacement or right ventricle-to-pulmonary artery conduit\t2\t\nRepair of ventricular septal defect\t2\t\nAtrioventricular canal repair\t2\t\nRepair of interrupted aortic arch\t1\t\nRepair of vascular ring with diverticulum of Kommerell\t1\t\nPericardiectomy\t1\t\nReimplantation of anomalous coronary artery\t1\t\nEpicardial pacemaker revision\t1\t\nNo intraoperative supplemental opioid administration was required in any child. All but one patient (n = 23, 96%) were extubated in the OR at case end. One patient who remained intubated did so without a failed extubation attempt; a team decision was made to keep the child intubated because of a concern for ongoing coagulopathy and bleeding after fourth-time sternotomy (Fontan revision and tricuspid valve repair). This patient was extubated without difficulty at approximately 4 h after PICU admission, after the aforementioned concerns proved to be well-managed.\n\nThe first recorded respiratory rate after PICU admission was 14 (11–22). The first recorded arterial partial pressure of carbon dioxide (paCO2) was 51 (45–58) mmHg, with 17 (71%) of the patients having a paCO2 greater than 45 mmHg; the distribution of first paCO2 readings is shown in Figure 1. One child (4.2%) required rescue noninvasive ventilatory support immediately upon PICU admission because of hypoventilation resulting in moderate hypoxemia (arterial saturation of oxygen 88%–91% on 6 L oxygen delivered through a simple facemask). Support consisted of bilevel positive airway pressure (BiPAP) for approximately 60 min, after which time he transitioned to 2 L of nasal cannula oxygen and had an uneventful subsequent course. None of the children experienced late respiratory depression (after care was handed over to the cardiology team in the ICU and the anesthesiologist left the patient's side). No children required reintubation at any timepoint.\n\nFigure 1 First recorded paCO2 on PICU admission. Heavy dashed line represents median; light dashed line represents interquartile range. Arrow denotes patient who required rescue bilevel positive airway pressure\n\nThe time to first supplemental opioid administration was 5.1 (3.5–9.5) h, and the distribution of times is shown in Figure 2. Cumulative total supplemental opioid dosing (expressed in IV morphine equivalents) in the first 24 and 72 h postoperatively was 0.20 (0.09–0.32) and 0.42 (0.27–0.68) mg/kg, respectively. No children experienced clinically significant pruritus; three children (13%) experienced postoperative nausea.\n\nFigure 2 Time in hours from extubation to first supplemental opioid administration. Heavy dashed line represents median; light dashed line represents interquartile range\n\nDiscussion\nTo our knowledge, this is the first report of the routine use of IV methadone as the cornerstone of an analgesic regimen for pediatric cardiac surgery to facilitate early extubation and enhanced recovery. Methadone dosing extrapolated from the adult literature appears to be appropriate in this population, with the important note that we used ideal body weight in heavier patients. We did decrease the dose (0.15 mg/kg) for the lone child whose procedure was performed off-pump, based on the rationale that the effective volume of distribution would be lower without the bypass circuit.\n\nThis regimen involving multiple agents as a package appeared effective in facilitating early extubation and enhanced recovery, based on a high success rate of extubation in the OR (96% of children in whom we intended to do so), no occurrence of postoperative reintubation, and indications of adequate analgesia with a long interval to the first need for supplementary analgesic administration. The quantity of supplemental opioids required in this cohort is, in our view, quite modest: a median of 0.2 and 0.42 mg/kg of morphine equivalents in the first 24 and 72 h, respectively. This suggests that methadone is accomplishing the bulk of the basal pain control in the initial postoperative period.\n\nWe had one patient who did not appear appropriate for extubation because of surgical factors; this, according to us, is an appropriate failure rate. If reevaluation of the plan for early extubation at case end does not occasionally result in patients who are not quite ready, we would submit that the team is not starting with a liberal enough set of criteria for patients in whom the intent to extubate in the OR is the starting point.\n\nIt is worth highlighting that this regimen was associated, on average, with some bradypnea and hypoventilation resulting in a mild respiratory acidosis (median paCO2 = 51). Considering the suitability of a patient's physiology for this, anticipated transient perturbation is important in deciding to use this early extubation strategy. Single-ventricle (e.g., Fontan) patients may be more sensitive to hypercarbia because of passive pulmonary blood flow and the importance of low pulmonary vascular resistance. In our experience, mild hypercarbia is well-tolerated and the benefit from early negative pressure respiratory physiology is such that on balance, these patients benefit from this approach when possible. We might be reluctant to use this strategy in other populations that are sensitive to increases in pulmonary vascular resistance, for instance, in patients with pulmonary vasodilator-dependent pulmonary hypertension.\n\nSeveral observations made in passing during the evaluation of this patient cohort are worth discussion. Qualitatively, we can describe the clinical character of most of these extubations as “deep” even though they were performed when end-tidal gas analysis revealed < 0.2 MAC of residual inhaled anesthetic. It is our descriptive observation that the post-bypass period in a patient who has received this analgesic regimen appears to involve a comfortably sleeping patient who does not respond to stimuli (e.g., orogastric tube placement and removal, oropharyngeal suctioning, endotracheal tube manipulation, and removal) but has adequate respiratory mechanics. We routinely use nasopharyngeal airways, placed long before extubation, as a strategy to avoid postextubation upper airway obstruction. In the presence of this strategy, no patients required rescue placement of a nasopharyngeal, oropharyngeal, or laryngeal mask airway.\n\nWe learned two important cultural or system flaws about our system in the course of this analysis: first, our debriefing regarding the subset of patients where supplementary opioids were administered relatively early in the admission suggested that pain was already well-controlled but that certain nurses were relatively unfamiliar with early extubation and had less well-developed skills surrounding the coping strategies, family involvement, and nonpharmacologic reassurance that is routine to, for instance, postanesthesia care unit nurses. In our institution, ICU patients who are extubated in the OR go to the PACU first, so early extubation in the cardiac population presented a new challenge to PICU nurses. For instance, any spontaneous patient movement was viewed by a subset of nurses as an indication for supplementary fentanyl. Second, we set out to analyze pain scores but found the prevalence of missing or unreliable data (e.g., ”baby is sleeping” but pain recorded as 10/10) to be well over 50% of all data points so we did not analyze these data. The reliability of pain scores was higher in teenage patients and seemed most poorly documented and utilized in infants and toddlers, despite the availability of nonverbal pain scales in routine nursing assessment tools. This has led to a focus on more functional assessments of pain control (e.g., whether a child is able to move in an age-appropriate fashion without limitation).\n\nOne clear limitation of this study was the nonrandomized design without a control group. A randomized trial design was not feasible in our setting, both because of systems' and family barriers to trial enrollment and because this was already standard of care in our practice and beginning an effort to randomize patient to another analgesic regimen was not felt to be ethical if our clinical judgment deemed it to be inferior. We considered using a historical control group, but this was not viable because this regimen was introduced by a new anesthesiologist on arrival to our institution. Comparisons to others' past practice would have entailed too many confounding variables to be meaningful.\n\nThis study will guide our further efforts to improve postoperative analgesia, expediting extubation and enhancing recovery for our pediatric cardiac surgical patients. For instance, patients undergoing a Glenn procedure were not included in our target cohort, but our experience here has led us to consider using a similar strategy in Glenn patients, with a goal of extubating 4–6 h after ICU admission (instead of our current standard, 18–24 hours after ICU admission). Of course, additional studies are warranted to demonstrate whether our findings are replicable in larger populations, in the hands of other surgeons and anesthesiologists, and in other institutions and patient populations.\n\nConclusions\nThis small preliminary study provides initial evidence that a novel analgesic strategy centered around the use of a single dose of a long-acting opiate, methadone, facilitates on-table extubation and enhanced recovery after pediatric cardiac surgery. Subsequent trials are needed to better determine whether this regimen is superior to others, but we believe that our experience at least offers support for the consideration of this approach.\n\nFinancial support and sponsorship\nIntramural.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Mueller XM Tinguely F Tevaearai HT Revelly JP Chiolero R von Segesser LK Pain location, distribution, and intensity after cardiac surgery Chest 2000 118 391 6 10936130 \n2 Milgrom LB Brooks JA Qi R Bunnell K Wuestfeld S Beckman D Pain levels experienced with activities after cardiac surgery Am J Crit Care 2004 13 116 25 15043239 \n3 Gerbershagen HJ Aduckathil S van Wijck AJM Peelen LM Kalkman CJ Meissner W Pain intensity on the first day after surgery: A prospective cohort study comparing 179 surgical procedures Anesthesiology 2013 118 934 44 23392233 \n4 Lahtinen P Kokki H Hynynen M Pain after cardiac surgery: A prospective cohort study of 1-year incidence and intensity Anesthesiology 2006 105 794 800 17006079 \n5 Gourlay GK Willis RJ Wilson PR Postoperative pain control with methadone: Influence of supplementary methadone doses and blood concentration–response relationships Anesthesiology 1984 61 19 26 6742480 \n6 Kharasch ED Intraoperative methadone: Rediscovery, reappraisal, and reinvigoration Anesth Analg 2011 112 13 6 21173206 \n7 Gourlay GK Willis RJ Lamberty J A double-blind comparison of the efficacy of methadone and morphine in postoperative pain control Anesthesiology 1986 64 322 7 3954126 \n8 Gourlay GK Wilson PR Glynn CJ Pharmacodynamics and pharmacokinetics of methadone during the perioperative period Anesthesiology 1982 57 458 67 6128949 \n9 De Kock M Lavand’homme P Waterloos H “Balanced analgesia” in the perioperative period: Is there a place for ketamine? Pain 2001 92 373 80 11376910\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-9784",
"issue": "23(1)",
"journal": "Annals of cardiac anaesthesia",
"keywords": "ERAS; Early extubation; enhanced recovery; enhanced recovery after surgery; fast-track extubation; methadone; operating room extubation; pediatric cardiac surgery; pediatric open heart surgery",
"medline_ta": "Ann Card Anaesth",
"mesh_terms": "D000293:Adolescent; D060666:Airway Extubation; D000701:Analgesics, Opioid; D006348:Cardiac Surgical Procedures; D002648:Child; D002675:Child, Preschool; D006330:Heart Defects, Congenital; D006801:Humans; D007902:Length of Stay; D008297:Male; D008691:Methadone; D010149:Pain, Postoperative; D012189:Retrospective Studies; D013997:Time Factors",
"nlm_unique_id": "9815987",
"other_id": null,
"pages": "70-74",
"pmc": null,
"pmid": "31929251",
"pubdate": "2020",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "11376910;15043239;23392233;6128949;21173206;6742480;17006079;3954126;10936130",
"title": "Enhanced recovery and early extubation after pediatric cardiac surgery using single-dose intravenous methadone.",
"title_normalized": "enhanced recovery and early extubation after pediatric cardiac surgery using single dose intravenous methadone"
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ROPIVACAINE"
},
"drugadditional": "3",
... |
{
"abstract": "We report the patient of a 53-year-old woman who developed subacute-onset marked tonge protrusion and bite. She was diagnosed as dementia with Lewy bodies (DLB) from the clinical features including progressive cognitive decline, visual hallucinations, parkinsonism, and severe insomnia and depression, and the radiological finding of low dopamine transported uptake in basal ganglia by Dat SCAN and low blood circulation in occipital lobe of cerebrum. The patient received 600 mg doses of levodopa for over a year, followed by rotigotine and ropinirole with a rapid increase of dosage. It is believed that these treatments stimulated and sensitized dopamine D1 receptors, thereby inducing lingual dystonia. Furthermore, the patient demonstrated dyspnea and attacks of apnea caused by the closure of bilateral vocal cords due to laryngeal dyskinesia. After initiation of the neuroleptic, olanzapine, for a short duration, the high dose of levodopa overlapped with neuroleptic sensitivity, suggesting DOPA-induced dystonia and dyskinesia. This interaction can sometimes lead to lethal adverse events, and must be considered very important when treating patients with DLB.",
"affiliations": "Department of Neurology, Brain Attack Center Ota Memorial Hospital.",
"authors": "Shiga|Yuji|Y|;Kanaya|Yuhei|Y|;Kono|Ryuhei|R|;Takeshima|Shinichi|S|;Shimoe|Yutaka|Y|;Kuriyama|Masaru|M|",
"chemical_list": "D014150:Antipsychotic Agents; D007211:Indoles; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C046649:ropinirole; D001569:Benzodiazepines; D007980:Levodopa; C047508:rotigotine; D000077152:Olanzapine",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-000843",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "56(6)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": null,
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000208:Acute Disease; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D001733:Bites and Stings; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D004409:Dyskinesia, Drug-Induced; D004421:Dystonia; D005260:Female; D006801:Humans; D007211:Indoles; D007818:Laryngeal Diseases; D007980:Levodopa; D020961:Lewy Body Disease; D008875:Middle Aged; D000077152:Olanzapine; D017447:Receptors, Dopamine D1; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D014060:Tongue Diseases",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "418-23",
"pmc": null,
"pmid": "27212676",
"pubdate": "2016-06-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dementia with Lewy bodies presenting marked tongue protrusion and bite due to lingual dystonia: A case report.",
"title_normalized": "dementia with lewy bodies presenting marked tongue protrusion and bite due to lingual dystonia a case report"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-117899",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEROSPIRONE HYDROCHLORIDE"
},
... |
{
"abstract": "Metastatic calcinosis cutis results from abnormal calcium levels leading to the precipitation of insoluble calcium salts in the skin and subcutaneous tissue. Here, we present the case of a 67-year-old man with multiple sclerosis on chronic dexamethasone and concurrent supplementation of calcium and daily cholecalciferol presenting with painful calcified lesions. During initial presentation, corrected calcium was 13.8 mg/dL (reference range: 8.5-10.1 mg/dL), ionised calcium was 1.70 mg/dL (reference range: 1.13-1.32 mg/dL) and 25-hydroxyvitamin D was 41.6 ng/mL (reference range 30-100 ng/mL). Normocalcaemia was restored with the off-label use of denosumab, usually reserved for hypercalcaemia of malignancy and intractable osteoporosis. We discuss potential aetiologies of this patient's hypercalcaemia, calcinosis cutis diagnosis and management and the off-label use of denosumab.",
"affiliations": "Department of Medicine, UPMC Mercy, Pittsburgh, Pennsylvania, USA.;Department of Medicine, UPMC Mercy, Pittsburgh, Pennsylvania, USA.;Department of Medicine, UPMC Mercy, Pittsburgh, Pennsylvania, USA.",
"authors": "Jorge|Ahmed|A|http://orcid.org/0000-0003-3484-6197;Szulawski|Robert|R|;Abhishek|Fnu|F|",
"chemical_list": "D002762:Cholecalciferol; D000069448:Denosumab; D003907:Dexamethasone; D002118:Calcium",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-223992",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(2)",
"journal": "BMJ case reports",
"keywords": "calcium and bone; dermatology; metabolic disorders; multiple sclerosis; vitamins and supplements",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D002114:Calcinosis; D002118:Calcium; D002762:Cholecalciferol; D000069448:Denosumab; D003907:Dexamethasone; D006801:Humans; D006934:Hypercalcemia; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis; D056687:Off-Label Use; D012871:Skin Diseases; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30804155",
"pubdate": "2019-02-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17578859;22316314;2348239;25338341;15565396;22232355;20494325;17179460;22052275;25596662;27597724;20972694;28275116;25033064;16131579",
"title": "Metastatic calcinosis cutis due to refractory hypercalcaemia responsive to denosumab in a patient with multiple sclerosis.",
"title_normalized": "metastatic calcinosis cutis due to refractory hypercalcaemia responsive to denosumab in a patient with multiple sclerosis"
} | [
{
"companynumb": "US-MYLANLABS-2019M1044629",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": null,
... |
{
"abstract": "Lipodystrophy syndromes are frequently associated with marked degree of insulin resistance and lipoatrophic diabetes. Although acquired generalised lipodystrophy (AGL) has been known to be associated with various autoimmune disorders, type 1 diabetes mellitus (T1DM) is very rarely reported to occur with AGL. Combination of AGL and T1DM can lead to a totally different phenotype with very difficult-to-treat diabetes and progressive complications of both the conditions. We report a case of AGL with T1DM with poor diabetes control despite high doses of insulin, metformin and pioglitazone. Our case further progressed to develop complication of retroperitoneal fibrosis, not hitherto reported with AGL.",
"affiliations": "Department of Paediatrics, Post Graduate Institude of Medical Education and Research, Chandigarh, India.;Department of Paediatrics, Post Graduate Institude of Medical Education and Research, Chandigarh, India.;Department of Radiology, Post Graduate Institute of Medical Education and Research, Chandigarh, India.;Department of Paediatrics, Post Graduate Institude of Medical Education and Research, Chandigarh, India.",
"authors": "Kumar|Rakesh|R|http://orcid.org/0000-0002-0039-2142;Pilania|Rakesh Kumar|RK|http://orcid.org/0000-0002-9015-1704;Bhatia|Anmol|A|;Dayal|Devi|D|",
"chemical_list": "D000924:Anticholesteremic Agents; D007004:Hypoglycemic Agents; D007328:Insulin; D008687:Metformin; D000077205:Pioglitazone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2018-225553",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "diabetes; lipid disorders; metabolic disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000924:Anticholesteremic Agents; D002648:Child; D003922:Diabetes Mellitus, Type 1; D006801:Humans; D007004:Hypoglycemic Agents; D007328:Insulin; D007333:Insulin Resistance; D052497:Lipodystrophy, Congenital Generalized; D008279:Magnetic Resonance Imaging; D008297:Male; D008687:Metformin; D000077205:Pioglitazone; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30076164",
"pubdate": "2018-08-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "27967300;27710244;17940115;28324110;12640189;2322097;22084329",
"title": "Acquired generalised lipodystrophy and type 1 diabetes mellitus in a child: a rare and implacable association.",
"title_normalized": "acquired generalised lipodystrophy and type 1 diabetes mellitus in a child a rare and implacable association"
} | [
{
"companynumb": "IN-SA-2018SA234449",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
"drugadditional": "3",
... |
{
"abstract": "Second-generation antipsychotics are commonly prescribed to reproductive-age women for the treatment of a spectrum of psychiatric disorders. Quetiapine is the most commonly prescribed medication in this class, and therefore a better understanding of its reproductive safety profile is critical. The goal of this study was to determine the risk of major malformations among infants exposed to quetiapine during pregnancy compared with a group of infants whose mothers had a history of psychiatric morbidity but who did not use a second-generation antipsychotic during pregnancy.\n\n\n\nThe National Pregnancy Registry for Atypical Antipsychotics interviews pregnant women ages 18-45 during pregnancy and the postpartum period. Obstetric, labor, and delivery medical records and pediatric medical records from the first 6 months of life were screened for evidence of major malformations, followed by adjudication by a blinded dysmorphologist. Women with first-trimester exposure to quetiapine were compared with control subjects without exposure to second-generation antipsychotics.\n\n\n\nAs of March 2017, 888 women had enrolled prospectively and 357 were eligible for analysis. Of these, 152 women with first-trimester exposure to quetiapine were compared with 205 control subjects without any second-generation antipsychotic exposure. For the 155 infants born to women in the exposed group (including three sets of twins), two major malformations were confirmed (1.3%), compared with three major malformations among the 210 infants born in the unexposed group (including five sets of twins) (1.4%). The unadjusted odds ratio for major malformations between infants with and without quetiapine exposure was 0.90 (95% CI=0.15, 5.46), which is consistent with the pooled estimate of the available controlled data on fetal exposure to quetiapine.\n\n\n\nThese data regarding the safety of fetal exposure to quetiapine in a small sample of well-characterized participants are reassuring given that the confidence interval does not exceed a fivefold increased risk of major malformations relative to psychiatric control subjects. Future analyses based on ongoing data collection will produce more precise estimates.",
"affiliations": "From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.;From the Department of Psychiatry and the Ammon-Pinizzotto Center for Women's Mental Health, Massachusetts General Hospital, Boston; Harvard Medical School, Boston; the Neurological Institute, Cleveland Clinic, Cleveland; the Prenatal Diagnosis and Medical Genetics Program, Mount Sinai Hospital, Toronto; and the Harvard T.H. Chan School of Public Health, Harvard University, Boston.",
"authors": "Cohen|Lee S|LS|;Góez-Mogollón|Lina|L|;Sosinsky|Alexandra Z|AZ|;Savella|Gina M|GM|;Viguera|Adele C|AC|;Chitayat|David|D|;Hernández-Díaz|Sonia|S|;Freeman|Marlene P|MP|",
"chemical_list": "D014150:Antipsychotic Agents; D000069348:Quetiapine Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1176/appi.ajp.2018.18010098",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-953X",
"issue": "175(12)",
"journal": "The American journal of psychiatry",
"keywords": "Antipsychotics; Mood Disorders-Bipolar; Mood Disorders-Unipolar; Obstetrics-Gynecology",
"medline_ta": "Am J Psychiatry",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000293:Adolescent; D000328:Adult; D014150:Antipsychotic Agents; D016022:Case-Control Studies; D005260:Female; D006801:Humans; D008875:Middle Aged; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D000069348:Quetiapine Fumarate; D012042:Registries; D012307:Risk Factors; D055815:Young Adult",
"nlm_unique_id": "0370512",
"other_id": null,
"pages": "1225-1231",
"pmc": null,
"pmid": "30111186",
"pubdate": "2018-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Risk of Major Malformations in Infants Following First-Trimester Exposure to Quetiapine.",
"title_normalized": "risk of major malformations in infants following first trimester exposure to quetiapine"
} | [
{
"companynumb": "US-GLAXOSMITHKLINE-US2018GSK232560",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DULOXETINE"
},
"drugadditional": nul... |
{
"abstract": "Fenofibrate is a commonly used hypolipidemic associated with rare instances of hepatotoxicity, and routine liver biochemistry monitoring is recommended.\n\n\n\nThe aim of this study is to describe the presenting clinical features, liver histopathology, and outcomes of 7 cases of acute liver injury associated with fenofibrate.\n\n\n\nAll cases of definite, very likely, and probable drug-induced liver injury (DILI) attributed to fenofibrate enrolled in the DILI Network study between 2004 and 2015 were reviewed.\n\n\n\nAmong 1229 patients with confirmed DILI, 7 cases (0.6%) were attributed to fenofibrate. The median age was 43 (range 37-61) years, and latency to onset was short (5-8 weeks) in 4 patients but more prolonged (18-56 weeks) in the rest. Laboratory results at presentation showed hepatocellular, mixed, and cholestatic injury, but 6 cases presented with jaundice. No patient had undergone routine monitoring. Four patients required hospitalization and 2 in whom drug discontinuation was delayed had a severe outcome, 1 undergoing liver transplantation, and 1 developing chronic injury and death. Liver biopsy was available in 4 patients and showed diverse injury patterns. Genetic studies showed the presence of the rare HLA-A*33:01 in 3 patients (43 vs. 1% in control populations). The causality scores were highly likely in 5 and probable in 2.\n\n\n\nLiver injury after fenofibrate exposure occurs with variable latency, enzyme elevation, and histology. Although most cases are self-limited, severe injury and mortality can occur, particularly if drug withdrawal is delayed. Jaundice or abnormal laboratory tests during fenofibrate therapy should trigger prompt discontinuation.",
"affiliations": "Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA. jawad.ahmad@mountsinai.org.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.;Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA.",
"authors": "Ahmad|Jawad|J|0000-0003-1384-2349;Odin|Joseph A|JA|;Hayashi|Paul H|PH|;Chalasani|Naga|N|;Fontana|Robert J|RJ|;Barnhart|Huiman|H|;Cirulli|Elizabeth T|ET|;Kleiner|David E|DE|;Hoofnagle|Jay H|JH|",
"chemical_list": "D015234:HLA-A Antigens; D000960:Hypolipidemic Agents; D011345:Fenofibrate",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-017-4812-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "62(12)",
"journal": "Digestive diseases and sciences",
"keywords": "Fenofibrate; Hepatotoxicity; Liver injury tests",
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D011345:Fenofibrate; D015234:HLA-A Antigens; D006801:Humans; D000960:Hypolipidemic Agents; D008099:Liver; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "3596-3604",
"pmc": null,
"pmid": "29119413",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D052060:Research Support, N.I.H., Intramural; D052061:Research Support, N.I.H., Extramural",
"references": "28043905;24700436;24037963;15357112;20512999;8229111;22318764;22001865;8651092;9762291;26346867;24222016;25754159;21427374;26933753;19132805;26838599;27435324;26559762;19744016;16937543;16437706;26934567;22245887;16310551",
"title": "Identification and Characterization of Fenofibrate-Induced Liver Injury.",
"title_normalized": "identification and characterization of fenofibrate induced liver injury"
} | [
{
"companynumb": "US-IMPAX LABORATORIES, INC-2017-IPXL-03725",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FENOFIBRATE"
},
"drugadditio... |
{
"abstract": "Although livedo reticularis is a known adverse effect of amantadine, only limited studies have addressed this association. Livedo racemosa in contrast to livedo reticularis is characterized by a striking violaceous netlike pattern of the skin similar to livedo reticularis with a different histopathology and morphology (irregular, broken circular segments). In this case report, we present 2 cases of livedo racemosa and edema of lower extremities following amantadine treatment. The cutaneous biopsies in both cases showed intraluminal thrombi in subcutaneous blood vessels without evidence of vasculitis, which is consistent with livedo racemosa.",
"affiliations": "São Paulo University, São Paulo, Brazil.;University of Toronto, Toronto, Ontario, Canada afsaneh.alavi@utoronto.ca.;São Paulo University, São Paulo, Brazil.;São Paulo University, São Paulo, Brazil.",
"authors": "Criado|Paulo Ricardo|PR|;Alavi|Afsaneh|A|;Valente|Neusa Yuriko Sakai|NY|;Sotto|Mirian Nacagami|MN|",
"chemical_list": "D000978:Antiparkinson Agents; D000547:Amantadine",
"country": "United States",
"delete": false,
"doi": "10.1177/1534734615603566",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1534-7346",
"issue": "15(1)",
"journal": "The international journal of lower extremity wounds",
"keywords": "amantadine; livedo; livedo racemosa; livedo reticularis; vasculopathy",
"medline_ta": "Int J Low Extrem Wounds",
"mesh_terms": "D000547:Amantadine; D000978:Antiparkinson Agents; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D007866:Leg; D054068:Livedo Reticularis; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "101128359",
"other_id": null,
"pages": "78-81",
"pmc": null,
"pmid": "26338517",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Amantadine-Induced Livedo Racemosa.",
"title_normalized": "amantadine induced livedo racemosa"
} | [
{
"companynumb": "BR-CMP PHARMA-2016CMP00011",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMANTADINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Theophylline is a potent adenosine receptor antagonist with indirect adrenergic effects that can lead to arrhythmias and metabolic abnormalities such as hypokalemia. Therapeutic toxicity cases have declined over the years mainly due to decreased recommended therapeutic doses and overall decreased usage of this medication due to newer available COPD treatment options. We present a clinical case of symptomatic supraventricular tachycardia resistant to adenosine therapy in a patient with theophylline use. This case highlights the importance of comprehensive medication review in acute settings to aid in identifying the underlying etiologies and initiating prompt treatments. It also signifies the importance of reviewing chronic medications in each outpatient visits to ensure continued indication for their use and be able to change them to newer agents per guidelines whenever possible.",
"affiliations": "University of Arizona College of Medicine, USA.;University of Arizona College of Medicine, USA.;Carondelet Medical Group, USA.",
"authors": "Hosseini|Seyedeh Maryam|SM|https://orcid.org/0000-0003-3614-7154;Ajmal|Muhammad|M|https://orcid.org/0000-0002-2463-3035;Shetty|Ranjith|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2021/2806193",
"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404\n2090-6412\nHindawi\n\n10.1155/2021/2806193\nCase Report\nSymptomatic Supraventricular Tachycardia Resistant to Adenosine Therapy in a Patient with Chronic Theophylline Use\nhttps://orcid.org/0000-0003-3614-7154\nHosseini Seyedeh Maryam shosseini@deptofmed.arizona.edu\n1\nhttps://orcid.org/0000-0002-2463-3035\nAjmal Muhammad 1\nShetty Ranjith 2\n1University of Arizona College of Medicine, USA\n2Carondelet Medical Group, USA\nAcademic Editor: Assad Movahed\n\n2021\n27 3 2021\n2021 280619315 3 2020\n13 3 2021\n22 3 2021\nCopyright © 2021 Seyedeh Maryam Hosseini et al.\n2021\nThis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nTheophylline is a potent adenosine receptor antagonist with indirect adrenergic effects that can lead to arrhythmias and metabolic abnormalities such as hypokalemia. Therapeutic toxicity cases have declined over the years mainly due to decreased recommended therapeutic doses and overall decreased usage of this medication due to newer available COPD treatment options. We present a clinical case of symptomatic supraventricular tachycardia resistant to adenosine therapy in a patient with theophylline use. This case highlights the importance of comprehensive medication review in acute settings to aid in identifying the underlying etiologies and initiating prompt treatments. It also signifies the importance of reviewing chronic medications in each outpatient visits to ensure continued indication for their use and be able to change them to newer agents per guidelines whenever possible.\n==== Body\n1. Introduction\n\nTheophylline is well known for its bronchodilation effects. It is used for pulmonary obstructive disease, severe bradycardia, apnea, and asthma in certain premature and pediatric patients. It is also associated with adrenergic effects that can predispose patients to arrhythmias. We present a case of symptomatic supraventricular tachycardia unresponsive to adenosine.\n\n2. Clinical Case Description\n\nA 62-year-old male with a past medical history significant for hypertension, heart failure with persevered ejection fraction (HFpEF), alcohol abuse, chronic obstructive pulmonary disease (COPD) on chronic theophylline presented with epigastric abdominal pain, and vomiting after one day of heavy alcohol drinking. He denied hematemesis, melena, fall, and change in mental status. He was admitted with protocol in place for acute alcohol toxicity and alcohol withdrawal care. His initial presentation was significant for sinus tachycardia that resolved with fluid resuscitation. He had negative troponin values, positive elevated serum alcohol levels, metabolic acidosis, and normal hepatic function enzymes with no signs of acute infection or bleeding.\n\nOn the second day of admission, the patient developed shortness of breath and palpitations. EKG showed supraventricular tachycardia, atrioventricular tachycardia nodal reentrant type, with a heart rate of 181 beats per minute (Figure 1). 6 milligram (mg) of adenosine was administered as rapid IV push but did not terminate the arrhythmia, and the next dose of 12 mg of adenosine rapid IV push was administered which was also unsuccessful (Figure 2). Because of the failure of adenosine to terminate arrhythmia and decreasing blood pressure measurements most likely secondary to ongoing SVT, cardioversion for unstable SVT was considered; however, patient regained hemodynamic stability quickly with administration of intravenous bolus of fluids as well as amiodarone 150 mg which was able to terminate the arrhythmia (Figure 3). His blood pressure improved from 85/60 mmHg to 122/74 mmHg after arrhythmia termination. Patient remained responsive, alert, and oriented and only complained of palpitations while having SVT. Serum theophylline level was found to be 4.67ug/mL (Table 1).\n\nPatient's theophylline was stopped. He was started on tiotropium, an inhaled long-acting muscarinic antagonist as well as rescue inhaler albuterol, short acting beta agonist, for his COPD management. Patient was monitored in Coronary Care Unit for 24 hours and remained symptom free. He was transferred to medicine unit and discharged after two additional days of hospitalization. At discharge patient was recommended to take his new inhaler medications for COPD while stopping theophylline. Patient was discharged in stable condition with no further need or indication of amiodarone or any other antiarrhythmic drug.\n\n3. Discussion\n\nTheophylline metabolism and kinetics have a wide variation as a function of age. It is rapidly absorbed, metabolized by the liver, and excreted by the kidney. Toxic levels are seen mainly in serum concentrations of above 20 μg/mL, but symptoms of toxicity can be seen at even lower end of therapeutic levels in some older patients and in those with chronic theophylline use such as in our case [1]. Theophylline effects are well explained by its mechanism of action. It is a potent adenosine receptor antagonist. In a case series study done in Massachusetts Children's Hospital, theophylline intoxication was shown to be associated with increased catecholamine serum levels in humans [2]. This was also shown on animal studies [3]. Theophylline is an antagonism of all adenosine receptor types, A1, A2A, A2B, and A3 which leads to increased norepinephrine release causing overall indirect adrenergic effects and thus metabolic abnormalities such as hypokalemia, hyperglycemia, and metabolic acidosis. It also predisposes to arrhythmias and can cause hypotension that is likely mediated by not only arrhythmias but also by beta adrenergic vasodilatory mechanism. Theophylline is also a nonselective competitive inhibitor of phosphodiesterases (PDE) 3 and 4 which results in relaxation of smooth muscle cells in the airways, and this in fact is the main mechanism of theophylline bronchodilation effect [2]. In addition, there are studies suggesting theophylline rule in stimulation of calcium release from intracellular stores and also in IL-10 secretion and apoptosis of inflammatory cells [1].\n\nBeing an adenosine receptor antagonist, patients on theophylline, as seen in our case, when in tachycardia state, may be resistant to treatment with adenosine, due to blocked receptors by the theophylline in the serum. Therefore, failure of regular dose treatment with adenosine is not surprising. Adenosine may still be attempted however as there have been case reports of successful SVT treatment with repeated adenosine therapy [4]. It has been known that most common types of arrhythmias associated with theophylline are supraventricular tachycardia (SVT) [5]. This is seen in our patient's case as well. Adenosine, either on initial or repeated dosing, can reverse theophylline induced supraventricular tachycardia [6]. But it should be given with caution in patients with severe pulmonary obstructive disease due to its bronchoconstriction effect. In such cases, selective beta 1 antagonist such as esmolol can safely be used to terminate SVT [7]. Calcium channel blockers such as diltiazem or verapamil can also be used but in caution in patients with hypotension [8]. In our case, given failure of response to initial therapies and patient's hemodynamic instability by hypotension, amiodarone and fluid resuscitation was used with eventual success in stabilizing patient. Amiodarone is an antiarrhythmic medication with known severe potential side effects, and given no prolonged use indication or requirement in our patient, it was not continued beyond the initial bolus administration in our patient.\n\nIt is important to recognize the possibility of multifactorial etiology for our patient's presentation. Alcohol and dehydration can also contribute and exacerbate tachycardia. Termination of SVT was therefore most likely multifactorial secondary to spontaneous resolution, fluid resuscitation, and amiodarone therapy. Our patient was recommended to follow-up with cardiology and pulmonary clinics for better guideline-based therapies for his chronic conditions.\n\n4. Conclusion\n\nTheophylline and adenosine interactions are well known and used in laboratory settings for years, but clinical cases are rarely reported in literature. This case is significant in showing clinical manifestation of these interactions. Providers' careful medication review not only can aid in timely diagnosis and understanding the underlying pathophysiology of an acute situation but can also help to prevent adverse effects. It is also important to regularly review chronic medications and substitute for any possible newer options that might have less adverse effects compared to older medications.\n\nData Availability\n\nAll the data is provided in the case report; please reach out to the corresponding author if any questions.\n\nConflicts of Interest\n\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Initial EKG showing supraventricular tachycardia with heart rate of 181 beats per minute.\n\nFigure 2 Patient's rhythm strip showing no improvement in response to adenosine.\n\nFigure 3 Patient's EKG after completion of amiodarone bolus showing resolution of supraventricular tachycardia.\n\nTable 1 Complete blood count, comprehensive metabolic panel, troponin, and theophylline blood test results.\n\nBlood test\tResult\tNormal range\t\nWhite blood cell count\t4.2 K/MM3\t4-11 K/MM3\t\nRed blood cell (RBC) count\t3.86 M/MM3 L\t4.30-6.00 M/MM3 L\t\nHemoglobin\t12.0 g/dL L\t13.5-17.00 g/dL L\t\nHematocrit\t36.8% L\t40.0-53.0 L\t\nMean corpuscular volume\t95 fL\t78-100 fL\t\nMean corpuscular hemoglobin\t31.1 pg\t27.0-34.0 pg\t\nMean corpuscular hemoglobin concentration\t32.6 g/dL\t31.0-37.0 g/dL\t\nRed cell distribution width—coefficient of variation\t15.6% H\t11.0-15.0%\t\nRed cell distribution width—standard deviation\t54.4 fL H\t38.0-49.9 fL\t\nNucleated RBC, automated\t0%\t≤0%\t\nPlatelet count\t173 K/MM3\t130-450 K/MM3\t\nMean platelet volume\t10.1 fL\t9.0-12.0 fL\t\nAlbumin/globulin ration\t1.3\t1.0-2.0\t\nAlbumin\t3.9 g/dL\t3.4-5.0 g/dL\t\nAlkaline phosphatase\t89 IU/L\t40-150 IU/L\t\nAlanine aminotransferase\t19 IU/L\t10-60 IU/L\t\nAnion gap\t12\t4-16\t\nAspartate aminotransferase\t38 IU/L\t10-50 IU/L\t\nBilirubin total\t1.1 mg/dL\t0.2-1.3 mg/dL\t\nBlood urea nitrogen (BUN)\t4 mg/dL\t8-25 mg/dL\t\nBUN/creatinine ratio\t4\t10-28\t\nCalcium\t9.2 mg/dL\t8.3-10.4 mg/dL\t\nChloride\t104 mmol/L\t96-110 mmol/L\t\nCO2\t21 mmol/L\t21-31 mmol/L\t\nCreatinine\t0.90 mg/dL\t0.60-1.50 mg/dL\t\nEstimated glomerular filtration rate (African descent)\t105 mL/min/1.73 m2\t≥60 mL/min/1.73 m2\t\nGlucose\t134 mg/dL\t65-99 mg/dL\t\nInternational normalized ratio (INR)\t1.0\t0.9-1.1\t\nLipase\t24 IU/L\t8-78 IU/L\t\nPotassium\t3.5 mmol/L\t3.5-5.2 mmol/L\t\nProtein, total\t7.0 g/dL\t6.0-8.0 g/dL\t\nSodium\t137 mmol/L\t135-145 mmol/L\t\nTroponin-I, conventional\t<0.01 ng/mL\t0.00-0.02 ng/mL\t\nTheophylline\t4.67 μg/mL\t10.00-20.00 μg/mL\n==== Refs\n1 Barnes P. J. Theophylline? American Journal of Respiratory and Critical Care Medicine 2013 188 8 901 906 10.1164/rccm.201302-0388PP 2-s2.0-84886434565 23672674\n2 Shannon M. Hypokalemia, hyperglycemia and plasma catecholamine activity after severe theophylline intoxication Journal of Toxicology. Clinical Toxicology 2008 32 p. 41\n3 Biberstein M. P. Ziegler M. G. Ward D. M. Use of beta-blockade and hemoperfusion for acute theophylline poisoning The Western Journal of Medicine 1984 141 p. 485\n4 Giagounidis A. A. Schäfer S. Klein R. M. Aul C. Strauer B. E. Adenosine is worth trying in patients with paroxysmal supraventricular tachycardia on chronic theophylline medication European Journal of Medical Research 1998 3 8 380 382 9707519\n5 Shannon M. Predictors of major toxicity after theophylline overdose Annals of Internal Medicine 1993 119 12 p. 1161 10.7326/0003-4819-119-12-199312150-00002 2-s2.0-0027364964 8239246\n6 Cairns C. B. Niemann J. T. Intravenous adenosine in the emergency department management of paroxysmal supraventricular tachycardia Annals of Emergency Medicine 1991 20 7 717 721 10.1016/S0196-0644(05)80829-7 2-s2.0-0025884551 2064090\n7 Hoffman R. J. Flomenbaum N. E. Goldfrank L. R. Hoffman R. S. Methylxanthines and selective beta2-adrenergic agonists Goldfrank's Toxicologic Emergencies 2006 8th New York McGraw-Hill p. 989\n8 Minton N. A. Henry J. A. Treatment of theophylline overdose? The American Journal of Emergency Medicine 1996 14 6 606 612 10.1016/S0735-6757(96)90111-4 2-s2.0-0029795664 8857817\n\n",
"fulltext_license": "CC BY",
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"journal": "Case reports in cardiology",
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"pubdate": "2021",
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"title": "Symptomatic Supraventricular Tachycardia Resistant to Adenosine Therapy in a Patient with Chronic Theophylline Use.",
"title_normalized": "symptomatic supraventricular tachycardia resistant to adenosine therapy in a patient with chronic theophylline use"
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"abstract": "OBJECTIVE\nEpidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers.\n\n\nMETHODS\nFive candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash.\n\n\nRESULTS\nIn our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test).\n\n\nCONCLUSIONS\nThis suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.",
"affiliations": "Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.;Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.;Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.;Department of Dermatology and Allergy, Christine Kühne Center for Allergy Research and Education (CK-CARE), University Hospital-Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Christine Kühne Center for Allergy Research and Education (CK-CARE), University Hospital-Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Christine Kühne Center for Allergy Research and Education (CK-CARE), University Hospital-Bonn, Bonn, Germany.;Department of Dermatology and Allergy, Christine Kühne Center for Allergy Research and Education (CK-CARE), University Hospital-Bonn, Bonn, Germany.;Department of Pulmonology, Thorax Oncology, Sleep and Respiration Medicine, Hospital Group Allgäu, Kempten, Germany.;Medical Centre for Haematology and Oncology, Ulm, Germany.;Department of Internal Medicine I, University of Ulm, Ulm, Germany.;Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Munich, Germany.;Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany.;Institute of Clinical Pharmacology, University Hospital of the RWTH Aachen, Aachen, Germany.",
"authors": "Kemski|Sarah|S|;Molitor|Vivien|V|;Steffens|Michael|M|;Nümm|Tim J|TJ|;Herrmann|Nadine|N|;Hornung|Thorsten|T|;Bieber|Thomas|T|;Schumann|Christian|C|;Kächele|Volker|V|;Seufferlein|Thomas|T|;Heinemann|Volker|V|;Scholl|Catharina|C|;Stingl|Julia Carolin|JC|",
"chemical_list": null,
"country": "United States",
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"doi": "10.18632/oncotarget.27953",
"fulltext": "\n==== Front\nOncotarget\nOncotarget\nImpact Journals LLC\nOncotarget\n1949-2553\nImpact Journals LLC\n\n27953\n10.18632/oncotarget.27953\nResearch Paper\nAssociation between miRNA signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity\nKemski Sarah 12\nMolitor Vivien 1\nSteffens Michael 1\nNümm Tim J. 2\nHerrmann Nadine 2\nHornung Thorsten 2\nBieber Thomas 2\nSchumann Christian 3\nKächele Volker 4\nSeufferlein Thomas 5\nHeinemann Volker 6\nScholl Catharina 1\nStingl Julia Carolin 7\n1Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, Germany\n2Department of Dermatology and Allergy, Christine Kühne Center for Allergy Research and Education (CK-CARE), University Hospital-Bonn, Bonn, Germany\n3Department of Pulmonology, Thorax Oncology, Sleep and Respiration Medicine, Hospital Group Allgäu, Kempten, Germany\n4Medical Centre for Haematology and Oncology, Ulm, Germany\n5Department of Internal Medicine I, University of Ulm, Ulm, Germany\n6Department of Internal Medicine III, Ludwig-Maximilians-University of Munich, Munich, Germany\n7Institute of Clinical Pharmacology, University Hospital of the RWTH Aachen, Aachen, Germany\nCorrespondence to:Julia Carolin Stingl, email: jstingl@ukaachen.de\n11 5 2021\n11 5 2021\n12 10 982995\n09 11 2020\n19 4 2021\nCopyright: © 2021 Kemski et al.\nhttps://creativecommons.org/licenses/by/3.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.\nObjective: Epidermal growth factor receptor inhibitors (EGFRI) are used as targeted cancer therapy. On average 70% of patients treated with EGFRIs suffer from skin toxicity. Studies showed a correlation between overall survival and the appearance of a skin rash, which is used as a biomarker for therapy efficacy. Micro RNAs (miRNA) as tumor or resistance biomarkers for cancer therapy are also highly investigated. In our study, we searched for associations of miRNA expression profiles in serum, with the severity of skin rash, in order to identify tentative therapy predictive biomarkers.\n\nMaterials and Methods: Five candidate miRNAs were selected, based on an earlier in vitro next-generation-sequencing-experiment and after literature search. MiR-21, miR-31, miR-17, miR-106b and miR-520e were investigated in serum samples from patients (n = 254) treated with EGFRI. The quantitative expression of miRNA was tested for association with the occurrence/severity of the rash.\n\nResults: In our cohort of patients treated with EGFR inhibiting monoclonal antibodies, miR-21 and miR-520e serum concentrations were negatively correlated with severity of skin rash (p-value 0.000582 and 1.53e-07 linear-trend-test) whereas for miR-31, a positive correlation was observed (p-value 9.01e-06 linear-trend-test).\n\nConclusions: This suggests that miR-21, miR-31 and miR-520e expression might be a treatment dependent marker for EGFRI induced skin rash.\n\nmiRNA\nEGFR\nEGFRI\ncancer\nskin toxicity\n==== Body\nINTRODUCTION\n\nEGFR-Inhibitors\n\nEpidermal growth factor receptor inhibitors (EGFRI) belong to the so called targeted cancer therapy and are used for the treatment of different cancer types like non-small-lung-cancer (NSLC), head-and-neck-cancer (head-and-neck-ca), colon-rectal-cancer (colon-ca) and pancreas-cancer (pancreatic -ca) [1–4]. In most of these cancer types the EGF receptor (EGFR) is over expressed but a basal physiological expression of the receptor can also be found in epithelial cells such as keratinocytes [5]. EGFRI can be divided into small molecule tyrosine kinase inhibitors (e.g., erlotinib and gefitinib), which bind to the intracellular tyrosine domain of the receptor and inhibit auto phosphorylation, and monoclonal antibodies (e.g., cetuximab and panitumumab), which block the ligand binding site of the receptor [1, 2, 6, 7]. About 70–80% of patients treated with an EGFRI develop a skin reaction within the second to fourth week of the treatment. The phenotype of EGFRI-induced skin reaction is characterized by inflammatory papulo-pustular follicular rash, skin xerosis, and pruritus occurring on the scalp, face, upper chest and back [8, 9]. Earlier studies showed a strong correlation between the appearance of the skin rash and improved tumor progression and overall survival (OS) of patients treated with EGFRI [10, 11]. Therefore, skin rash is currently used as a predictive biomarker for the efficacy of EGFRI therapy [11, 12]. However, severe skin reactions, especially grade 3 or 4, can cause a break or even the end of therapy. In order to reduce this burden different treatments to reduce skin rash are used in clinical practice. For example the Germane Cancer Association published a guideline for supportive care in 2016 including preemptive and reactive treatment. For a preemptive treatment, they recommend general behavior actions like sun protection and general skin care and an oral prophylaxis with tetracyclines. The recommended reactive treatment depends on the grade of skin rash. For grad 1 skin rash same measures as preemptive treatment plus topical antibiotics, for grade 2 same measures as grade 1 plus topic steroids; for grade 3 and 4 same measures as grad 2 plus systemic steroids or oral isotretionin (but not in combination with antibiotics) is recommended [13]. The treatment recommendations of the guideline are based on different evince levels. The highest evidence can be found for a preemptive treatment of EGFRI induced skin rash with oral tetracycline. For this treatment a double-blind placebo-controlled randomized trial and different randomized trials showed a significant reduction of the severity of skin toxicity in patients treated with tetracycline’s [14–17]. The treatment of already existing skin rash with topic corticosteroids, which have an anti-inflammatory and anti-pruritic effects, shows lower evidence [18]. Also with a low evidence, due to a missing control cohort in the study, orally administrated isotretinoin and clindamycin could reduce grade 2–3 skin rash to grade 0–1 [19]. But with all these possible treatments of EGFRI induced skin rash, its treatment predictive value might get lost and new biomarkers will be needed.\n\nEGFR ligands like epiregulin (EREG), amphiregulin (AREG), and hepatocyte growth factor (HGF) were investigated as biomarkers for skin rash and found to be inversely proportional to grades of skin toxicity [20]. Also genetic variations were assessed as possible biomarkers but only a mutation in EGFR intron 1 showed significant associations toward skin toxicity [21].\n\nThe multi centric Dermatoxgen study was initiated by our research group with the aim to identify tentative biomarkers for prediction of the occurrence of EGFRI induced skin rash. Within the scope of this study, different aspects of the EGFRI-induced skin rash were investigated, all with the objective to better understand EGFRI induced skin rash and find predictive biomarkers. To avoid any bias in the appearance or grade of skin rash, patients in our study only received reactive treatment if necessary with topical corticosteroids, topical antibiotics, oral antibiotics and antihistamines. The study showed a correlation between the occurrence of the skin rash and the drug-metabolizing activity assessed by the erlotinib/O-desmethyl-erlotinib metabolic ratio [22]. An investigation of genetic variations showed that patients carrying the HLA-A*02:01 or HLA-A*03:01 alleles are less likely to develop a skin rash [23]. Also for the EGF receptor associations between skin toxicity of EGFRIs and mutations of the EGFR were found. For the SNP rs534124757 of the EGFR gene it was shown that in patients carrying at least one A allel skin toxicity was less frequently [24]. Deep sequencing of the EGFR gene locus and its downstream signaling pathway revealed also an association between a SNP rs2293348 in the EGFR gene and the rash [25]. But not only mutations in the EGFR itself seem to be associated with skin toxicity. A genotyping of cancer patients revealed an association between skin rash and a specific haplotype of phosphatidylinositol-3-kinase (PIK3CA) [24]. An investigation of biomarkers in the plasma of the Dermatogen study group showed that patients with a lower IL-8 concentration are in risk to develop a more severe skin rash but had a longer survival. The same was found for patients with a low HGF concentration in the plasma [26, 27].\n\nGene regulatory biomarkers of EGFRI-induced skin rash\n\nMicroRNAs (miRNAs) are short non-coding RNAs with a length of around 19–25 nucleotides, that are involved in the post transcriptional regulation of gene expression. One miRNA can regulate the expression of many different genes by inducing translational inhibition or transcript degradation. Therefore, miRNAs are important for cell processes like proliferation, differentiation, apoptosis, stress tolerance and immune response [28]. The role and machinery of miRNAs in skin cells have been broadly investigated [29]. MiR-21 for example is involved in migration processes of keratinocytes and fibroblasts [29]. Some miRNAs are up- or down-regulated in pathophysiological processes. In inflammatory skin diseases like psoriasis and atopic dermatitis, miRNAs are suggested to be involved in inflammatory processes and immune dysfunction [30, 31]. However, miRNAs are not only highly involved in skin physiology and in pathophysiology; they are also in the focus of research in the field of tumor diagnostic and prognostic biomarkers and the resistance to cancer therapy [32, 33]. A set of 5 miRNAs (mir-17, mir-660, mir-92a, mir-106a, and mir-19b) is most commonly dysregulated in serum and tumor tissue samples from lung cancer patients and has therefore promising diagnostic potential [34]. In a meta-analysis circulating miR-31 was determined as an effective biomarker for cancer detection and prognosis [35]. MiRNAs may also be markers for therapy resistance. Different miRNAs mediate drug resistance in colon cancer by distinct mechanisms [33]. 16 miRNAs were differentially expressed between EGFRI resistant patients and EGFRI sensitive patients and might therefor be dependent for the sensitivity to EGFRI treatment [36]. Cetuximab resistance of colon cancer patients is connected to an upregulation of miR-199a-5p and miR-375 targeting PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) a tumor suppressor [37].\n\nAll this shows the involvement of miRNAs in physiological and pathophysiological processes in skin cells, especially in inflammatory diseases like psoriasis or atopic dermatitis, and their already frequently discussed role as biomarkers in cancer. This leads to the assumption that miRNAs might also be involved in the development of EGFRI-induced skin rash and therefor can be used as possible biomarkers for therapeutic resistance. However, so far most of the studies in cancer patients focused on miRNAs expressed in cancer cells or secreted into body fluids most likely by cancer cells, while miRNAs associated with the skin rash have not been investigated. To elucidate the influence of miRNAs in the development of skin rash we previously investigated the miRNA expression in fibroblasts incubated with and without erlotinib [38]. In this analysis now, we firstly identify the miRNA expression profiles in skin cells, namely keratinocytes and fibroblasts, depending on their capability to react to erlotinib incubation. From those we depicted a set of five miRNAs which concentrations were determined in serum samples, derived from EGFRI treated patients, and evaluated with respect to the appearance and severity of the skin rash.\n\nRESULTS\n\nErlotinib induces a distinct miRNA profile in primary human keratinocytes and fibroblasts\n\nIn order to gain a first impression about the effect of EGFRI incubation on the miRNA expression in skin cells, we studied effects of in vitro EGFR inhibition with the (small molecule) EGFRI erlotinib on miRNA expression in human keratinocyte/and fibroblast cell samples from healthy donors. Cells were classified into cell samples more reactive on erlotinib incubation and less reactive ones. Detailed information on the classification is provided in the supplements (Supplementary Figures 1 and 2). Fifty-four miRNAs were exclusively up or down regulated in the cell samples that were more reactive on erlotinib incubation compared to less reactive ones (fold change ≥ 1.5 and ≤ 0.66; 32 miRNAs in keratinocytes with p-value ≤ 0.05; 22 miRNAs in fibroblasts with p-value < 0.01) (Figure 1; Supplementary Tables 1 and 2). In order to decide, which of those 54 differentially expressed miRNAs were the most promising ones to be further investigated, a literature search on miRNAs involved in regulation of EGFR pathways was conducted. The search included all publications in which the miRNAs were connected to EGFR inhibitor treatment, erlotinib treatment in particular and cancer cells or bio fluid samples from cancer patients. According to our cell culture findings and the literature reports, five miRNAs (miR-31, miR-17, miR-106b, miR-520e, miR-21) were chosen as candidates to be further investigated in serum samples from EGFRI treated patients for potential correlations with the development of a skin rash.\n\nFigure 1 Erlotinib-sensitive keratinocytes and fibroblasts express a different miRNA pattern than those insensitive to erlotinib.\n\nCells were treated with 5μM erlotinib or 0.05% DMSO and stimulated with 4 nM EGF. (A) Differentially expressed miRNAs between erlotinib sensitive and insensitive primary human keratinocyte cell samples (fold change ≥ 1.5 or fold change ≤ 0.66, p-value ≤ 0.05). (B) Differentially expressed miRNAs between erlotinib sensitive and insensitive human dermal fibroblast cell samples (fold change ≥ 1.5 or fold change ≤ 0.66, p-value < 0.01) Abbreviation: EGF: epidermal growth factor.\n\nMiRNA serum levels of EGFRI treated patients are associated to EGFRI induced skin rash\n\nDetails about the patients who provided serum samples for the analysis of genetic and epigenetic biomarkers for EGFRI related skin rash from the Dermatoxgen study, are given in Tables 1 and 2. Patients were observed on week 1, 2, 3, 4, 26 and 53 after the start of the therapy. In week 4 serum, plasma and blood samples were taken. Serum samples were available from 254 patients and total RNA including miRNA was extracted.\n\nTable 1 Patients characteristics (age, gender and smoking) and clinical characteristics (tumor type and skin rash)\n\nPatient characteristics\tPatients\tTKI treated patients\tEGFR-mAbs treated patients\t\nSample size\tN (254)\tN (156)\tN (98)\t\nAge: Mean (SD)\t66.4 (9.8)\t67.3 (9.0)\t65.0 (10.8)\t\nGender: N (%)\t\t\t\t\n Male\t161 (63.4)\t92 (59.0)\t69 (70.4)\t\n Female\t93 (36.6)\t67 (41.0)\t29 (29.6)\t\nSmoking: N (%)\t\t\t\t\n No\t94 (38.1)\t52 (34.3)\t42 (43.8)\t\n Yes (present)\t30 (12.1)\t15 (9.9)\t15 (15.6)\t\n Yes (former)\t123 (49.8)\t84 (55.6)\t39 (40.6)\t\n NA\t7\t5\t2\t\nTumor Type:\t\t\t\t\n Lung-Cancer\t136 (53.5)\t107 (68.6)\t29 (29.6)\t\n Colon-Cancer\t58 (22.8)\t2 (1.3)\t56 (57.1)\t\n Head and Neck Cancer\t11 (4.3)\t0\t11 (11.2)\t\n Pancreatic Cancer\t49 (19.3)\t47 (30.1)\t2 (2.0)\t\nSkin Rash:\t\t\t\t\n No\t51 (20.1)\t35 (22.4)\t16 (16.3)\t\n Grade 1\t98 (38.6)\t60 (38.5)\t38 (38.8)\t\n Grade 2\t92 (36.2)\t52 (33.3)\t40 (40.8)\t\n Grade 3\t13 (5.1)\t9 (5.8)\t4 (4.1)\t\n Grade 4\t0\t0\t0\t\nAbbreviations: EGFR-mAbs: epidermal growth factor receptor monoclonal antibodies; TKI: tyrosine kinase inhibitor; N: number of patients; NA: not kown.\n\nTable 2 Distribution of therapeutic agents (EGFRIs) and cancer types in the patient cohort\n\n\tCetuximab\tErlotinib\tGefitinib\tPanitumumab\tSum\t\nLung-Cancer\t29\t94\t13\t0\t136\t\nColon-Cancer\t38\t1\t1\t18\t58\t\nHead and Neck Cancer\t11\t0\t0\t0\t11\t\nPancreatic Cancer\t2\t47\t0\t0\t49\t\nSum\t80\t142\t14\t18\t254\t\n\nAll five candidate miRNAs (miR-31, miR-17, miR-106b, miR-520e, miR-21), chosen from the in vitro NGS experiments and from the literature, were quantified in serum samples of EGFRI treated patients and correlated to the clinically observed severity and course of skin rash.\n\nAll four included EGFRIs have a skin rash as possible side effect and the skin rash appears tumor type and state independently. Therefor the association between the miRNA concentration and skin rash was analyzed independently from the tumor type and treatment, in all 254 patients.\n\nOf the five miRNAs studied, miR-31, miR-21 and miR-520e showed correlations (p-value 0.00296, 0.0378 and 0.0199 [linear trend test], p-values not corrected for multiple testing) between serum concentration and the severity of the skin rash (Table 3).\n\nTable 3 Associations between the serum concentration of the six tested miRNAs and the occurrence/severity of the skin rash\n\nmiRNA\t\tAll Patients (N 254)\tEGFR-mAbs treated patients (N 98)\tTKI treaded patients (N 156)\t\nmiR-17\tAppearance of skin rash\tp = 0.376\tp = 0.264\tp = .429\t\n\tSeverity of skin rash\tp = 0.594\tp = 0.613\tp = .62\t\nmiR-21\tAppearance of skin rash\tp = 0.098\tp = 0.047\tp = .439\t\n\tSeverity of skin rash\tp = 0.002\tp < 0.001\tp = .115\t\nmiR-31\tAppearance of skin rash\tp = 0.564\tp = 0.081\tp = .472\t\n\tSeverity of skin rash\tp = 0.037\tp < 0.001\tp = .43\t\nmiR-106b\tAppearance of skin rash\tp = 0.314\tp = 0.938\tp = .256\t\n\tSeverity of skin rash\tp = 0.182\tp = 0.699\tp = 0.168\t\nmiR-520e\tAppearance of skin rash\tp = 0.126\tp = 0.044\tp = 0.651\t\n\tSeverity of skin rash\tp = 0.019\tp < 0.001\tp = 0.473\t\nCorrelation between different miRNA serum levels in EGFRI treated patients and the occurrence or severity of the skin rash. Correlation was analyzed for the whole cohort and for subgroups divided between the treatments of the patients. Correlation was analyzed using linear-trend test. P-values were not corrected for multiple testing. Abbreviations: N: number of patients; EGFR-mAbs: epidermal growth factor receptor monoclonal antibodies; TKI: tyrosine kinase inhibitor.\n\nMiR-21 and miR-520 were negatively correlated with skin rash and showed the lowest expression in patients with severe grade 3 skin rash.\n\nMiR-31 was positively correlated with skin rash with the highest expression in patients with grade 3 skin rash. For miR-17 and miR-106b, no significant association with severity of skin rash was found (Table 3).\n\nLow miR-21, miR-520e and miR-31 serum concentrations are associated with longer survival\n\nFor those three miRNAs, which were correlated to the severity of the skin rash, a survival curve analysis was performed. The Kaplan-Meier-plots showed a significant correlation between a low miRNA serum level and a longer overall survival for miR-21 and miR-520e (p-value 0.00046 and 0.0088) (Figure 2A and 2C). For miR-31 a trend could be seen between low miR-31 serum level and longer survival (p-value 0.055) (Figure 2B).\n\nFigure 2 A lower miRNA concentration is associated with a longer survival for miR-21, miR-31 and miR-520e.\n\nPatients were followed-up for 360 days after initiation of EGFRI therapy. The proportion of patients still alive is plotted over the observation period. Patients were split by delta CP values of each miRNA into four equally-sized groups. (A) Kaplan-Meier- Plot for miR-21; log rank test, p-value < 0.001; mean OS for miR-21 concentration 1: 221 days (SE: 15.3); mean OS for miR-21 concentration 2: 290 days (SE: 13.3); mean OS for miR-21 concentration 3: 271 days (SE: 14.1); mean OS for miR-21 concentration 4: 275 days (SE: 15.0). (B) Kaplan-Meier- Plot for miR-31; log rank test, p-value = 0.055; mean OS for miR-31 concentration 1: 233 days (SE: 14.8); mean OS for miR-31 concentration 2: 272 days (SE: 14.9) ; mean OS for miR-31 concentration 3: 275 days (SE: 15.0); mean OS for miR-31 concentration 4: 275 days (SE: 14.0). (C) Kaplan-Meier- Plot for miR-21; log rank test, p-value = 0.0088; mean OS for miR-520e concentration 1: 247 days (SE: 15.0); mean OS for miR-520e concentration 2: 261 days (SE: 14.8); mean OS for miR-520e concentration 3: 245 days (SE: 15.7); mean OS for miR-520e concentration 4: 302 days (SE: 12.7) Abbreviations: #: number of patients; dCP: delta crossing point; OS: overall survival.\n\nAssociation between miR-21, miR-31 and miR-520e serum concentrations and skin rash is not treatment independent\n\nSubgroup analyses of patients who had been treated with either small molecule or antibody tyrosine kinase inhibitors, revealed significant correlations between miR-21, miR-31, and miR-520e and the severity of the skin rash only in the antibody treatment group (p-values of 0.000582, 9.01e-06 and 1.53e-07 [linear trend test], not corrected for multiple testing) (Figure 3A–3C). As for the whole cohort a negative correlation of miR-21 and miR-520e serum concentration with the severity of the skin rash could be seen. For miR-31 a positive correlation with the severity of the skin rash was found. However, no significant correlation between miRNA serum concentration and skin rash in patients treated with small molecule tyrosine kinase inhibitors was observed.\n\nFigure 3 Significant correlation between miRNA serum concentration and severity of the skin rash for patients treated with monoclonal antibody EGFRIs.\n\nMiRNA concentrations were determined by qPCR (n = 98). dCP values were calculated against miR-93. A high dCP value means the miRNA is down regulated. (A) miR-21 concentration plotted against the maximum severity of the skin rash during observation period; linear trend test, p-value < 0.001. (B) miR-31 concentration plotted against the maximum severity of the skin rash during observation period; linear trend test, p-value < 0.001. (C) miR-520e concentration plotted against the maximum severity of the skin rash during observation period; linear trend test, p-value < 0.001. (0 = no skin rash, 1 = light skin rash, 2 = mild skin rash, 3 = sever skin rash). Abbreviation: dCP: delta crossing point.\n\nDISCUSSION\n\nIn our study, we analyzed the association between the typical skin rash developed under EGFRI therapy and the serum concentration of different miRNAs. Understanding this connection might lead to a better understanding of epigenetic mechanisms behind the skin rash and help to find predictive biomarkers for its development. Out of the five candidate miRNAs, chosen from a combination of literature search and prior in vitro experiments in a skin cell model, miR-21, miR-31 and miR-520e showed significant correlations between skin rash and serum concentration.\n\nSo far, there were many different studies searching for miRNAs as possible biomarkers in cancer development and disease outcome using tissue samples from the tumor, the surrounding tissue and/or blood samples [39, 40]. The objective of this study was to identify epigenetic miRNA associations with therapy-induced skin rash in patients receiving an EGFR targeting tumor treatment, since skin toxicity of EGFRI treatment has been shown to be a prognostic and therapy-predictive factor. In order to identify miRNAs that are involved in EGFR inhibition, we started by analyzing the effect of erlotinib incubation on the miRNA expression in primary human keratinocytes and fibroblasts from healthy donors. A literature search about which of the significantly regulated miRNAs from the in vitro experiments, were already connected to cancer and/or EGFRI therapy, gave us an idea, which miRNAs might be involved in the appearance of the skin rash and could potentially be found in serum samples from EGFRI treated patients.\n\nLinear trend tests revealed negative correlations between the serum concentrations of miR-21 and miR-520e and the severity of the skin rash. Survival curve analysis also showed a negative correlation between miR-21 and miR-520e serum concentrations and overall survival time. For miR-31 a positive correlation between serum concentration and severity of the skin was observed. The survival curve for miR-31 showed a negative correlation between miR-31 serum concentration and survival time.\n\nBecause of the frequent mentioning of miR-21 in publications on miRNAs and cancer treatment resistance, this miRNA was the only one we investigated in our patient cohort even though it was not significantly differentially regulated in the in vitro cell experiments. Hua Shen et al. discovered that a high miR-21 and low phosphatase and tensin homolog (PTEN) concentration might indicate a poor gefitinib clinical response [41]. Another study investigated the miR-21 expression in colon-cancer tissue compared to normal adjacent tumor tissues. The colon-cancer tissue had higher miR-21 content and tumor patients with a lower miR-21 expression had a longer overall survival (OS) and disease-free survival (DFS) [41, 42]. These results in tumor tissue fit well to our finding that lower miR-21 concentration correlated with higher grade of skin rash, since skin rash has a positive prognostic value. In our cohort, we also observed a correlation between miR-21 in serum and a longer survival of patients. However, in our study we looked at treatment related outcome of the patients, and therefor included different tumor and disease stages. The Kaplan-Meier plot demonstrates that a low miR-21 serum concentration was correlated to a longer survival and miR-21 serum concentration was inversely correlated with the grade of skin rash. Our results suggest a better response to the EGFRI treatment in patients with a low miR-21 serum concentration.\n\nMiR-520 is mostly studied in patients with non-small-lung-cancer. In NSLC metastasis miR-520 seems to be upregulated and by this down regulates transforming growth factor-β receptor 2 (TGFBR2) which regulates carcinogenesis and metastasis via the transforming growth factor-β (TGF-β) pathway [43]. In another study mmu-miR-291a-3p, a mouse homolog of miR-520e, inhibits cell senescence via the TGF-β receptor 2 signaling pathway by reducing protein expression of TGF-β receptor 2. Mmu-miR-291a-3p also seems to enhance the proliferative potential of senescent cells. [44]. In our results, patients with EGFR inhibitor induced skin rash had lower expression of miR-520e indicating a better prognosis, and this was especially significant in patients treated with monoclonal antibodies. In our study, we used serum samples instead of NSCLC tissue for miRNA isolation, but in principle, the better prognosis was correlated with lower serum concentrations, which fits well to the findings in lung tissue. In addition, the fact that the correlation between lower miR-520e serum concentrations and skin rash gets even more significant looking at patients treated with monoclonal antibodies, shows that low miR-520e in our study might be an indicator for good response to the therapy because the miR-520e we measured might not originate from tumor cells. We could also see in the Kaplan- Meier plots that patients with low miR-520e expression have a longer survival time. A possible link between the grade of skin rash and lower miR-520e expression might be TGF-β. Patients with atopic dermatitis seem to have a higher expression of TGF-β and other inflammatory cytokines like IL-6, IL-8 and IL-10 compared to healthy individuals [45].\n\nFor miR-31 a study by Ning Xu et al. showed an upregulation in keratinocytes from psoriasis patients. They demonstrated that TGF-β1, which is also upregulated in psoriasis epidermis, upregulates miR-31. Furthermore, an inhibition of miR-31 suppressed NF-kB–driven promoter luciferase activity and the basal and tumor necrosis factor-α (TNF-α) induced production of IL-1b, CXCL1/growth-related oncogene-a, CXCL5/epithelial-derived neutrophil-activating peptide 78, and CXCL8/IL-8 in human primary keratinocytes [46]. Regarding pathophysiology of the EGFRI induced skin rash, an inflammatory component is postulated by several publications. [8, 47, 48] This together with the effect of miR-31 on inflammatory cytokines is in line with our finding that a higher miR-31 concentration is associated with a higher grade of skin rash. A similar relationship can also be observed for miR-520e. On the other hand, we found a correlation between low miR-31 serum concentration and a longer survival. In a meta-analysis of 14 different studies including different tumor types, a significant correlation between low miR-31 concentration in blood and a longer overall survival was shown [35]. Studies in tumor biopsies confirm that a low miR-31 expression correlates with a longer overall survival [49]. Even for EGFR- inhibitor therapy a study comparing cetuximab treated patients with low or high miR-31 concentration in tumor tissue found that a low miR-31 expression leads to longer OS and PFS [50]. The differences in correlation between miR-31 serum concentration and skin rash or OS might lead to the assumption, that miR-31 could have a different effect on skin cells than tumor cells under EGFRI treatment. Both, the study by Anandappa et al. and the one by Laurent-Puig et al. used tumor tissue instead of serum samples. The meta-analysis by Ma et al. used blood samples but they did not take into account the treatment of the cancer patients. Those two differences might support the suggestion that the miR-31 expression we found is treatment dependent and that miR-31 has different effects on skin cells like keratinocytes or fibroblasts than on tumor cells. MiR-31 expression is elevated in keratinocytes incubated with inflammatory cytokines like TNF-α or interferon-γ [51]. Furthermore, an interferon-γ incubation of keratinocytes in which the EGFR was blocked resulted in an increased chemokine expression [52]. This might be an explanation for the correlation between high miR-31 serum concentration and high grade of skin rash reflecting the inflammatory component of the skin rash. Blocking the EGF receptor with monoclonal antibodies might lead to an inflammatory reaction in the skin cells, which in turn leads to an elevated miR-31 expression in skin cells, which then might release miR-31 to the blood.\n\nLooking at our results a correlation between miRNA serum levels and the skin rash under EGFRI treatment can be found. For three out of five candidate miRNAs, a significant association between the miRNA concentration and the severity of the skin rash was shown especially for patients treated with monoclonal antibodies. This suggests a specificity of miR-21, miR-31 and miR-520e for the therapy with monoclonal antibodies and expression of the analyzed miRNAs most likely by cells other than tumor cells, such as skin cells. As a possible mechanism, an inflammatory component could be identified by looking at the miRNAs we analyzed and their connection to other skin diseases. Inflammation is already discussed to be part of the mechanism of EGFRI induced skin toxicity [48]. Taking all this together, it makes it quite interesting to further investigate the role of miR-21, miR-31 and miR-520e for the development of EGFR inhibitor induced skin rash in patients treated with monoclonal antibodies and to understand possible mechanisms behind it. A better understanding of the mechanism might than lead to possible predictive biomarkers for EGFRI induced skin rash, which are needed as an alternative to the skin rash is self as prognostic biomarker for therapy response. Because with a better treatment of the EGFRI induced skin rash it prognostic value might get lost.\n\nLimitations\n\nThe biggest limitation might be that there are no serum samples from patients before they were treated with an EGFR inhibitor. Hence, we cannot say if the effects we found are mostly due to the therapy with an EGFRI or if those effects can be seen in patients in general. However, because of the heterogeneity of the cohort concerning the tumor type and cancer state, a treatment specific effect is possible. Still these miRNAs give us a better understanding about the skin rash, which can be used for further investigations.\n\nMATERIALS AND METHODS\n\nIn vitro miRNA profiling in human primary skin cells\n\nCell model\n\nPrimary human keratinocytes were isolated from skin samples derived from healthy controls of the Dermatox_Epigen study. This study aims to analyze epigenetic differences in skin samples of EGFR inhibitor treated cancer patients. As a control collective patients from the university women’s clinic Bonn were enrolled. These patients underwent plastic surgeries from which skin samples were derived to isolate keratinocytes. After obtaining the skin, a wash step was performed with a sterile gauze soaked in PBS to remove excess blood. Afterwards, the split thickness-skin (0.4 mm) was immediately prepared using a dermatome. The epidermal cell suspension was generated with freshly prepared trypsinization solution (PBS supplemented with 0.5% trypsin (Sigma-Aldrich) and 1% Antibiotic-Antimycotic (Gibco™, Waltham, MA, USA)). The floating split thickness-skin was incubated in the trypsin solution for 1 h at 37°C, whereby the dermal side was in contact with the trypsin solution. Afterwards, the dermis was removed and the epidermis was added to medium supplemented with 1% DNase to remove DNA and to avoid cell clumping. Next, the epidermal cell suspension was generated by several steps of pipetting up and down or by vortexing until the media became cloudy, indicating that the cells were in suspension. Written informed consent was obtained from all volunteers and the study was approved by the ethical boards of Bonn University. Donors were in average 38.8 (SD 9.6) years old and included 3 male and 9 female.\n\nPrimary human dermal fibroblasts were kindly provided be the Clinical Pharmacology Department of the University Medicine Göttingen (Dr. med. Markus Schirmer). Fibroblasts were isolated from healthy tissue removed by dermal excisions from patients at the clinic.\n\nCell culture\n\nKeratinocytes were cultured in EpiLife medium with 1% human keratinocyte growth supplements (Gibco™, Waltham, MA, USA), 1% pen/strep and 0.1% amphotericin B, medium was changed every 2–3 days and cells were passaged when reaching a confluence of 75%. Fibroblasts were cultured in basal fibroblast growth medium 2 with supplement mix fibroblast growth medium 2 (2% FCS, 5 μg/ml Insulin, 0.001 μg/ml fibroblast growth factor (FGF)) (PromoCell, Heidelberg, Germany) and 1% pen/strep. The medium was changed every 2–3 days and cells were passaged when reaching a confluence of 75% every 5–7 days. Before miRNA profiling keratinocytes were incubated with 5μM erlotinib (SantaCruz Biotechnology, Dallas, TX, USA) or 0.05% DMSO for two hours and then stimulated with 4 nM EGF (PeproTech, Rocky Hill, NJ, USA) for 5 min. Fibroblasts were incubated with 5 μM erlotinib or 0.05% DMSO for 24 hours and then stimulated with 4nM EGF for 5 min.\n\nRNA isolation and miRNA profiling with Next Generation Sequencing\n\nTotal RNA from keratinocytes and fibroblasts was extracted using Trizol/ Chloroform. RNA was precipitated from the aqueous phase with isopropanol, resuspended in RNase-free water and stored at –80°C.\n\nLibrary preparation for miRNA profiling was performed with the NEB Next Multiplex Small RNA Library Prep Set for Illumina (New England Biolabs, Ipswich, MA, USA) following the manufacturer’s protocol. Resulting cDNA library was purified with QiaQuick PCR purification kit (Qiagen, Hilden, Germany). A size selection of the generated cDNA was done with gel electrophoresis. 60 μl cDNA probes were mixed with 12 μl loading dye and 15 μl were pipetted into 5 pockets of an 10% TBE-Gel (Invitrogen by Thermo Fisher, Carlsbad, CA, USA) and separated for 1 h 20 min at 150 V in TBE buffer. Ethidium bromide was used for the visualization of the cDNA bands and the one at ~ 140 bp was cut out. Gel extraction of the cDNA was done following the manufactures protocol of the NEB Next Multiplex Small RNA Library Prep Set for Illumina. For the quantification and qualification of the size-selected cDNA the Agilent high sensitivity DNA Kit (Agilent, Santa Clara, CA, USA)) was used and analyzed with the Agilent Bioanalyzer 2100. MiRNA sequencing was performed with the MiSeq from Illumina using the MiSeq Reagent Kit v3 (Illumina, San Diego, CA, USA) following the manufactures protocol. A final concentration 15 pMol of cDNA was used.\n\nAnalysis of sequencing data\n\nSequencing data was saved as fastq files which was then used for adapter trimming with the Cutadapt 1.9 software [53]. Alignment of the trimmed sequencing data to the human genome (build37) was performed using bowtie1.0 [54]. The same software was used for the aligment to published mature and precursor (hairpin) miRNAs collected in the miRBase data base (release 21). Read counts were normalised and miRNA expression was compared between keratinocytes/fibroblasts more reactive to erlotinib against less reactive cell samples. For further research miRNAs, which were significantly differentially expressed with a fold change ≥ 1.5 or a fold change ≤ 0.66 and a p value of 0.05 for keratinocytes or a p value of 0.01 for fibroblasts, were chosen. A cut of at a p-value of 0.01 was choosen for fibroblasts, because of the high amount of segnificant miRNAs at a cut of at a p-value of 0.05. For a better comparison of the three different treatments, Venn diagrams of differentially expressed miRNAS were generated. Data was uploaded on to the GEO database under the accession number GSE159602.\n\nLiterature search to choose miRNAs for further experiments\n\nFifty-four miRNAs were significantly differentially expressed exclusively after erlotinib incubation. A literature search was used to choose the most promising miRNAs for further experiments in serum samples from EGFRI treated patients. For the search the PubMed database was used. Search terms consisted of the name of one of the 54 miRNAs together with “cancer”, “EGFR inhibitors” or “erlotinib”. We did not discriminate between miRNA found in blood samples or in tumor cells/biopsies and we included all EGFR inhibitor therapies.\n\nAnalyzing miRNAs in patients of the dermatoxgen study\n\nStudy design\n\nThe Dermatoxgen study is a prospective, multicentric study with the aim to investigate pharmacogenetics factors of EGFR inhibitor induced skin toxicity. Patients with histologically confirmed solid tumors (pancreatic, colon, head and neck or non-small-cell lung cancer) who received an EGFR inhibitor (erlotinib, gefitinib, cetuximab or panitumumab) therapy for the first time were included in the Dermatoxgen study. Patient characteristics are shown in Tables 1 and 2. The study was approved by the ethical boards of Ulm University and the Ludwig-Maximilians-University of Munich and patients gave their written informed consent to participate. EGFRI admission was carried out according to approved indications, as previously described [22]. The appearance and severity of the skin rash were documented once a week after treatment start for 4 weeks. The severity of the skin rash was graded following the Toxicity Criteria for Adverse Events of the American National Cancer Institute (NCICTCAE version 3.0, 2006). Blood, serum and plasma samples were collected after 4 weeks of treatment. The skin rash was only treated reactively if it was necessary during the treatment. As treatment topical corticosteroids, topical antibiotics, oral antibiotics and antihistamines were used depending on the grade of skin rash. A preemptive treatment was excluded to avoid any bias which may arise from the suppressing effect of the preemptive treatment. Patients were followed-up for 12 months, with visits after 6 months and 12 months. The survival status at 360 days after initiation of EGFRI treatment was used for Kaplan-Meier analyses. Serum samples from 254 patients were used for the miRNA analysis.\n\nCollection of serum samples and miRNA extraction\n\nSerum samples were collected during week 4 of the EGFRI treatment right before the admission of the next scheduled dose. About 7.5 ml blood were collected from each patient using blood-sampling tubes (Serum S-Monovette®, 7.5 ml, Sarstedt). After a rest of 20 min at room temperature blood samples were centrifuged at 2500× g for 10 min, aliquoted and stored immediately at –80°C.\n\nmiRNA was isolated with the miRNeasy serum/plasma kit (Qiagen, Hilden, Germany). Following the manufactures protocol 100 μl serum were used. 350 μl of the upper aquarious phase mixed with 525 μl 100% ethanol were pipetted onto the miRNeasy spin column. After several washing steps, RNA was eluted with 14 μl RNase-free water from the spin column.\n\nRT-qPCR\n\nIsolated miRNA was transcribed into cDNA using the miScript RT kit (Qiagen, Hilden, Germany). 5 μl miRNA sample were processed following the manufacturer’s protocol using the HiFlex Buffer. After reverse transcription the samples were diluted in 80μl RNase-free water. qPCR was performed using the miScript primer assays (miR-21, miR-31, miR-520e, miR-17, miR-106b) from Qiagen (Qiagen, Hilden, Germany). A master mix was prepared consisting of miScript Universal primer, miScript Primer assay, SyberGreen kit and RNase-free water (Qiagen, Hilden, Germany) following the manufacturer’s protocol. Samples were analyzed as triplicates in a 364 well plate with the Light Cycler 480 from Roche (Roche, Basel, Switzerland). As reference, miRNA-93 (Qiagen, Hilden, Germany) was used.\n\nSUPPLEMENTARY MATERIALS\n\nACKNOWLEDGMENTS\n\nThe authors thank the Wilhelm Sander Stiftung for founding the Dermatoxgen Study (DERMATOXGEN Nr. 2008.017). They also thank Dr. med. Markus Schirmer from the Clinical Pharmacology Department of the University Medicine Göttingen for providing the fibroblast cell lines. We thank Dr. Walgenbach of the Department of Plastic and Aesthetic Surgery, University of Bonn, Germany, for providing skin from healthy individuals for the isolation of keratinocytes.\n\nAbbreviations\n\nEGFRI Epidermal growth factor receptor inhibitor\n\nmiRNA micro RNA\n\nNSLC Non-small-lung-cancer\n\nHead-and-neck-ca head-and-neck-cancer\n\ncolon-ca colon-rectal-cancer\n\npancreatic-ca panctras-cancer\n\nEGFR epidermal growth factor receptor\n\nERFG epiregulin\n\nAREG amphiregulin\n\nSNP Single Nucleotide Polymorphism\n\nHGF hepatocyte growth factor\n\nPIK3CA phosphatidylinositol-3-kinase\n\nPHLPP1 PH domain and leucine-rich repeat protein phosphatase 1\n\nEGFR-mAbs epidermal growth factor receptor monoclonal antibodies\n\nTKI tyrosine kinase inhibitor\n\nN number of patients\n\nNA not known\n\ndCP delta crossing point\n\nOS overall survival\n\nPTEN phosphatase and tensin homolog\n\nDFS disease-free survival\n\nTGFBR2 transforming growth factor-β receptor 2\n\nTGF-β transforming growth factor-β\n\nTNF-α tumor necrosis factor-α\n\nAuthor contributions\n\nJCS, TB and TS conceptualized and supervised the study. TH, CS, SK and VM designed experiments. TH and CS supervised experimental work. ChS, VK, TS and VH recruited the patients. TJN, NH, TH and TB supplied the keratinocytes. VM performed the cell model experiments. SK performed the qPCR from patients’ serum samples. VM, SK and MS performed the statistical analysis. SK wrote the manuscript in consultation with JCS, CS, TJN, NH, VM, MS, TS and VK.\n\nCONFLICTS OF INTEREST\n\nAuthors have no conflicts of interest to declare.\n\nFUNDING\n\nThe Dermatoxgen Study was founded by the Wilhelm Sander Stiftung (DERMATOXGEN Nr. 2008.017). Dermatox_Epigen study was supported by a collaborative grant from the Federal Institute for Drugs and Medical Devices (BfArM, Bonn, Germany, V-16700/68502/2016–2019). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.\n==== Refs\nREFERENCES\n\n1. Muhsin M , Graham J , Kirkpatrick P . Gefitinib. 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Arrieta O , Vega-González MT , López-Macías D , Martínez-Hernández JN , Bacon-Fonseca L , Macedo-Pérez EO , Ramírez-Tirado LA , Flores-Estrada D , de la Garza-Salazar J . Randomized, open-label trial evaluating the preventive effect of tetracycline on afatinib induced-skin toxicities in non-small cell lung cancer patients. Lung Cancer. 2015; 88 :282–88. 10.1016/j.lungcan.2015.03.019. 25882778\n18. Annunziata MC , De Stefano A , Fabbrocini G , Leo S , Marchetti P , Romano MC , Romano I . Current Recommendations and Novel Strategies for the Management of Skin Toxicities Related to Anti-EGFR Therapies in Patients with Metastatic Colorectal Cancer. Clin Drug Investig. 2019; 39 :825–34. 10.1007/s40261-019-00811-7. 31264159\n19. Bidoli P , Cortinovis DL , Colombo I , Crippa A , Cicchiello F , Villa F , Cazzaniga ME , Altomare G . Isotretinoin plus clindamycin seem highly effective against severe erlotinib-induced skin rash in advanced non-small cell lung cancer. 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Dosing to rash?--The role of erlotinib metabolic ratio from patient serum in the search of predictive biomarkers for EGFR inhibitor-mediated skin rash. Eur J Cancer. 2016; 55 :131–39. 10.1016/j.ejca.2015.11.022. 26820683\n23. Fuerst D , Parmar S , Schumann C , Rüdiger S , Boeck S , Heinemann V , Kaechele V , Stiebel K , Paul T , Seufferlein T , Mytilineos J , Stingl JC . HLA polymorphisms influence the development of skin rash arising from treatment with EGF receptor inhibitors. Pharmacogenomics. 2012; 13 :1469–76. 10.2217/pgs.12.122. 23057547\n24. Parmar S , Schumann C , Rüdiger S , Boeck S , Heinemann V , Kächele V , Seeringer A , Paul T , Seufferlein T , Stingl JC . Pharmacogenetic predictors for EGFR-inhibitor-associated skin toxicity. Pharmacogenomics J. 2013; 13 :181–88. 10.1038/tpj.2011.51. 22158333\n25. Hasheminasab SM , Tzvetkov MV , Schumann C , Rüdiger S , Boeck S , Heinemann V , Kächele V , Steffens M , Scholl C , Hichert V , Seufferlein T , Brockmöller J , Stingl JC . High-throughput screening identified inherited genetic variations in the EGFR pathway contributing to skin toxicity of EGFR inhibitors. Pharmacogenomics. 2015; 16 :1605–19. 10.2217/pgs.15.97. 26419366\n26. Paul T , Schumann C , Rüdiger S , Boeck S , Heinemann V , Kächele V , Steffens M , Scholl C , Hichert V , Seufferlein T , Stingl JC . Cytokine regulation by epidermal growth factor receptor inhibitors and epidermal growth factor receptor inhibitor associated skin toxicity in cancer patients. Eur J Cancer. 2014; 50 :1855–63. 10.1016/j.ejca.2014.04.026. 24857781\n27. Hichert V , Scholl C , Steffens M , Paul T , Schumann C , Rüdiger S , Boeck S , Heinemann V , Kächele V , Seufferlein T , Stingl J . Predictive blood plasma biomarkers for EGFR inhibitor-induced skin rash. Oncotarget. 2017; 8 :35193–204. 10.18632/oncotarget.17060. 28456787\n28. Inui M , Martello G , Piccolo S . MicroRNA control of signal transduction. Nat Rev Mol Cell Biol. 2010; 11 :252–63. 10.1038/nrm2868. 20216554\n29. Miller KJ , Brown DA , Ibrahim MM , Ramchal TD , Levinson H . MicroRNAs in skin tissue engineering. Adv Drug Deliv Rev. 2015; 88 :16–36. 10.1016/j.addr.2015.04.018. 25953499\n30. Liu Q , Wu DH , Han L , Deng JW , Zhou L , He R , Lu CJ , Mi QS . Roles of microRNAs in psoriasis: Immunological functions and potential biomarkers. Exp Dermatol. 2017; 26 :359–67. 10.1111/exd.13249. 27783430\n31. Yu X , Wang M , Li L , Zhang L , Chan MTV , Wu WKK . MicroRNAs in atopic dermatitis: A systematic review. J Cell Mol Med. 2020; 24 :5966–72. 10.1111/jcmm.15208. 32351034\n32. Jiang C , Hu X , Alattar M , Zhao H . miRNA expression profiles associated with diagnosis and prognosis in lung cancer. Expert Rev Anticancer Ther. 2014; 14 :453–61. 10.1586/14737140.2013.870037. 24506710\n33. Zhang Y , Wang J . MicroRNAs are important regulators of drug resistance in colorectal cancer. Biol Chem. 2017; 398 :929–38. 10.1515/hsz-2016-0308. 28095367\n34. Boeri M , Verri C , Conte D , Roz L , Modena P , Facchinetti F , Calabrò E , Croce CM , Pastorino U , Sozzi G . MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer. Proc Natl Acad Sci U S A. 2011; 108 :3713–18. 10.1073/pnas.1100048108. 21300873\n35. Ma Y , Chen Y , Lin J , Liu Y , Luo K , Cao Y , Wang T , Jin H , Su Z , Wu H , Chen X , Cheng J . Circulating miR-31 as an effective biomarker for detection and prognosis of human cancer: a meta-analysis. Oncotarget. 2017; 8 :28660–71. 10.18632/oncotarget.15638. 28404921\n36. Ma Y , Pan X , Xu P , Mi Y , Wang W , Wu X , He Q , Liu X , Tang W , An HX . Plasma microRNA alterations between EGFR-activating mutational NSCLC patients with and without primary resistance to TKI. Oncotarget. 2017; 8 :88529–36. 10.18632/oncotarget.19874. 29179454\n37. Mussnich P , Rosa R , Bianco R , Fusco A , D'Angelo D . MiR-199a-5p and miR-375 affect colon cancer cell sensitivity to cetuximab by targeting PHLPP1. Expert Opin Ther Targets. 2015; 19 :1017–26. 10.1517/14728222.2015.1057569. 26107137\n38. Hichert V , Steffens M , Paul T , Scholl C , Parmar S , Rüdiger S , Schumann C , Seufferlein T , Stingl JC . Gene regulatory biomarker identification for skin toxicities induced by EGFR inhibitor treatment. Int J Clin Pharmacol Ther. 2015; 53 :1056–58. 10.5414/CPXCES14EA08. 26521924\n39. Zhao F , Wei C , Cui MY , Xia QQ , Wang SB , Zhang Y . Prognostic value of microRNAs in pancreatic cancer: a meta-analysis. Aging (Albany NY). 2020; 12 :9380–404. 10.18632/aging.103214. 32420903\n40. Ferreira P , Roela RA , Lopez RVM , Del Pilar Estevez-Diz M . The prognostic role of microRNA in epithelial ovarian cancer: a systematic review of literature with an overall survival meta-analysis. Oncotarget. 2020; 11 :1085–95. 10.18632/oncotarget.27246. 32256980\n41. Shen H , Zhu F , Liu J , Xu T , Pei D , Wang R , Qian Y , Li Q , Wang L , Shi Z , Zheng J , Chen Q , Jiang B , Shu Y . Alteration in Mir-21/PTEN expression modulates gefitinib resistance in non-small cell lung cancer. PLoS One. 2014; 9 :e103305. 10.1371/journal.pone.0103305. 25058005\n42. Sabry D , El-Deek SEM , Maher M , El-Baz MAH , El-Bader HM , Amer E , Hassan EA , Fathy W , El-Deek HEM . Role of miRNA-210, miRNA-21 and miRNA-126 as diagnostic biomarkers in colorectal carcinoma: impact of HIF-1α-VEGF signaling pathway. Mol Cell Biochem. 2019; 454 :177–89. 10.1007/s11010-018-3462-1. 30357530\n43. Kucuksayan H , Akgun S , Ozes ON , Alikanoglu AS , Yildiz M , Dal E , Akca H . TGF-β-SMAD-miR-520e axis regulates NSCLC metastasis through a TGFBR2-mediated negative-feedback loop. Carcinogenesis. 2019; 40 :695–705. 10.1093/carcin/bgy166. 30475986\n44. Bae YU , Son Y , Kim CH , Kim KS , Hyun SH , Woo HG , Jee BA , Choi JH , Sung HK , Choi HC , Park SY , Bae JH , Doh KO , Kim JR . Embryonic Stem Cell-Derived mmu-miR-291a-3p Inhibits Cellular Senescence in Human Dermal Fibroblasts Through the TGF-β Receptor 2 Pathway. J Gerontol A Biol Sci Med Sci. 2019; 74 :1359–67. 10.1093/gerona/gly208. 30239625\n45. Fedenko ES , Elisyutina OG , Filimonova TM , Boldyreva MN , Burmenskaya OV , Rebrova OY , Yarilin AA , Khaitov RM . Cytokine gene expression in the skin and peripheral blood of atopic dermatitis patients and healthy individuals. Self Nonself. 2011; 2 :120–24. 10.4161/self.2.2.16939. 22299064\n46. Xu N , Meisgen F , Butler LM , Han G , Wang XJ , Söderberg-Nauclér C , Ståhle M , Pivarcsi A , Sonkoly E . MicroRNA-31 is overexpressed in psoriasis and modulates inflammatory cytokine and chemokine production in keratinocytes via targeting serine/threonine kinase 40. J Immunol. 2013; 190 :678–88. 10.4049/jimmunol.1202695. 23233723\n47. Guttman-Yassky E , Mita A , De Jonge M , Matthews L , McCarthy S , Iwata KK , Verweij J , Rowinsky EK , Krueger JG . Characterisation of the cutaneous pathology in non-small cell lung cancer (NSCLC) patients treated with the EGFR tyrosine kinase inhibitor erlotinib. Eur J Cancer. 2010; 46 :2010–19. 10.1016/j.ejca.2010.04.028. 20621734\n48. Lacouture ME . Mechanisms of cutaneous toxicities to EGFR inhibitors. Nat Rev Cancer. 2006; 6 :803–12. 10.1038/nrc1970. 16990857\n49. Anandappa G , Lampis A , Cunningham D , Khan KH , Kouvelakis K , Vlachogiannis G , Hedayat S , Tunariu N , Rao S , Watkins D , Starling N , Braconi C , Darvish-Damavandi M , et al . miR-31-3p Expression and Benefit from Anti-EGFR Inhibitors in Metastatic Colorectal Cancer Patients Enrolled in the Prospective Phase II PROSPECT-C Trial. Clin Cancer Res. 2019; 25 :3830–38. 10.1158/1078-0432.CCR-18-3769. 30952636\n50. Laurent-Puig P , Grisoni ML , Heinemann V , Liebaert F , Neureiter D , Jung A , Montestruc F , Gaston-Mathe Y , Thiébaut R , Stintzing S . Validation of miR-31-3p Expression to Predict Cetuximab Efficacy When Used as First-Line Treatment in RAS Wild-Type Metastatic Colorectal Cancer. Clin Cancer Res. 2019; 25 :134–41. 10.1158/1078-0432.CCR-18-1324. 30108104\n51. Yan S , Xu Z , Lou F , Zhang L , Ke F , Bai J , Liu Z , Liu J , Wang H , Zhu H , Sun Y , Cai W , Gao Y , et al . NF-κB-induced microRNA-31 promotes epidermal hyperplasia by repressing protein phosphatase 6 in psoriasis. Nat Commun. 2015; 6 :7652. 10.1038/ncomms8652. 26138368\n52. Mascia F , Mariani V , Girolomoni G , Pastore S . Blockade of the EGF receptor induces a deranged chemokine expression in keratinocytes leading to enhanced skin inflammation. Am J Pathol. 2003; 163 :303–12. 10.1016/S0002-9440(10)63654-1. 12819035\n53. Martin M . Cutadapt removes adapter sequences from high-throughput sequencing reads. EMBnet J. 2011; 17 :10–12.\n54. Langmead B , Trapnell C , Pop M , Salzberg SL . Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol. 2009; 10 :R25. 10.1186/gb-2009-10-3-r25. 19261174\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "12(10)",
"journal": "Oncotarget",
"keywords": "EGFR; EGFRI; cancer; miRNA; skin toxicity",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "982-995",
"pmc": null,
"pmid": "34012511",
"pubdate": "2021-05-11",
"publication_types": "D016428:Journal Article",
"references": "26573073;31264159;16990857;12819035;32256980;20871265;30475986;28456787;25882778;19261174;25707609;24506710;26521924;17452677;32351034;23057547;23716430;12841190;27783430;28095367;18543329;23233723;15962526;30952636;30357530;29179454;22158333;21300873;18349392;29576427;29124875;26820683;25953499;20216554;18154213;20621734;29332581;17606725;25139841;26419366;26138368;26107137;28404921;22299064;30108104;30239625;17201026;15272498;32420903;24857781;20142600;25058005",
"title": "Association between miRNA signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity.",
"title_normalized": "association between mirna signatures in serum samples from epidermal growth factor inhibitor treated patients and skin toxicity"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2021114236",
"fulfillexpeditecriteria": "2",
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"activesubstancename": "CETUXIMAB"
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{
"abstract": "BACKGROUND\nAtypical teratoid/rhabdoid tumor (ATRT) is a rare malignant pediatric brain tumor with a dismal prognosis. We evaluated the efficacy of multimodal therapy in children with ATRT.\n\n\nMETHODS\nNine children diagnosed with cranial ATRT, who received multimodal therapy between 2005 and 2014, including surgical resection followed by radiotherapy (RT), systemic chemotherapy (CT), and high-dose chemotherapy/stem cell transplantation (HDCT/SCT), were analyzed retrospectively. The median age at diagnosis was 32 months. Initial treatment included surgery in eight patients (88%), CT in all (100%), RT in eight (88%), and HDCT/SCT in seven (78%).\n\n\nRESULTS\nThe median follow-up period for survivors was 21 months. The 2-year progression-free rate was 66.7%. Two patients had progression 4 and 17 months after diagnosis. One received multimodal treatment, including surgery and upfront CT with delayed RT; the other underwent surgery and upfront CT without RT. The 2-year event-free survival and overall survival rates were 46.7% and 62.2%, respectively. Hematologic toxicity of grade 3 or more was observed in six patients treated with HDCT/SCT and two who underwent craniospinal irradiation. Deaths were attributed to progressive disease (n = 2) and treatment-related toxicity (n = 2) from sepsis and acute respiratory failure after CT and HDCT/SCT.\n\n\nCONCLUSIONS\nMaximal safe resection in conjunction with upfront RT is a reasonable multimodal treatment in patients with ATRT for prolonging progression-free survival. Further research may help determine the optimal parameters for reducing treatment toxicity, such as intensity of HDCT/SCT and the RT field.",
"affiliations": "Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Neurosurgery, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Pediatrics, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Radiation Oncology, Yonsei University College of Medicine, Seoul, Republic of Korea.",
"authors": "Lee|Jeongshim|J|;Kim|Dong-Seok|DS|;Han|Jung Woo|JW|;Suh|Chang-Ok|CO|http://orcid.org/0000-0002-3375-7072",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26663",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(12)",
"journal": "Pediatric blood & cancer",
"keywords": "atypical teratoid/rhabdoid tumor; multimodal therapy; pediatric brain tumors; radiotherapy",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001932:Brain Neoplasms; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D018335:Rhabdoid Tumor; D033581:Stem Cell Transplantation",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28598565",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Atypical teratoid/rhabdoid tumors in children treated with multimodal therapies: The necessity of upfront radiotherapy after surgery.",
"title_normalized": "atypical teratoid rhabdoid tumors in children treated with multimodal therapies the necessity of upfront radiotherapy after surgery"
} | [
{
"companynumb": "KR-CORDEN PHARMA LATINA S.P.A.-KR-2017COR000233",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"d... |
{
"abstract": "Hypothermia is a rare adverse effect of risperidone and is associated with ventricular arrhythmias, which may lead to intensive care unit admission and sometimes death. We describe a patient with schizophrenia who was taking risperidone and who, after falling into a hypothermic state, suffered cardiac arrest. Observations of the case and a brief literature review are provided.",
"affiliations": "Department of Psychiatric Internal Medicine, Sunlight Brain Research Center, 4-13-18 Jiyugaoka, Hofu City, Yamaguchi, 747-0066, Japan.",
"authors": "Nagamine|Takahiko|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2158-8333",
"issue": "13(11-12)",
"journal": "Innovations in clinical neuroscience",
"keywords": "Cardiac arrest; J-wave; hypothermia; risperidone",
"medline_ta": "Innov Clin Neurosci",
"mesh_terms": null,
"nlm_unique_id": "101549695",
"other_id": null,
"pages": "28-31",
"pmc": null,
"pmid": "28210523",
"pubdate": "2016",
"publication_types": "D002363:Case Reports",
"references": "21516073;21956608;25713294;23150960;12775973;21394035;15617296;24640526;19144938;17401555;18725504;23810019;22633716",
"title": "Complete Recovery from Cardiac Arrest Caused by Risperidone-induced Hypothermia.",
"title_normalized": "complete recovery from cardiac arrest caused by risperidone induced hypothermia"
} | [
{
"companynumb": "JP-JNJFOC-20170302459",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "1",
... |
{
"abstract": "Long-term immunosuppression in the organ transplant recipient (OTR) population places these individuals at higher risk of developing skin malignancies. Oral retinoids have become a useful tool for pharmacologic prophylaxis in the OTR population. Immunosuppressants that inhibit mTOR, such as sirolimus, may be used in combination with a systemic retinoid for chemoprophylaxis of cutaneous malignancies. We present the case of a male patient status post second renal transplant who developed an abrupt and unexpected rise in sirolimus levels to supra-therapeutic levels after initiation of prophylactic acitretin for innumerable squamous cell carcinomas (SCC). The sirolimus levels returned to baseline after cessation of acitretin. Systemic drug-drug interactions are an important phenomenon, especially in the solid OTR population. It is postulated that this interaction was mediated by acitretin inhibition of CYP3A4, the primary enzyme responsible for sirolimus metabolism. The Drug Interaction Probability Scale (DIPS) indicates this was a \"probable\" drug-drug interaction. To date, this interaction has not been reported in the literature. This case accentuates the importance of close monitoring of solid OTRs for adverse medication interactions when multiple medications are taken.",
"affiliations": null,
"authors": "Rossi|Anthony M|AM|;Hibler|Brian P|BP|;Johnson-Jahangir|Hillary|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D007641:Keratolytic Agents; D017255:Acitretin; D020123:Sirolimus",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-9616",
"issue": "14(7)",
"journal": "Journal of drugs in dermatology : JDD",
"keywords": null,
"medline_ta": "J Drugs Dermatol",
"mesh_terms": "D017255:Acitretin; D002294:Carcinoma, Squamous Cell; D004347:Drug Interactions; D006801:Humans; D007166:Immunosuppressive Agents; D007641:Keratolytic Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D020123:Sirolimus; D012878:Skin Neoplasms",
"nlm_unique_id": "101160020",
"other_id": null,
"pages": "747-9",
"pmc": null,
"pmid": "26151793",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Serum Sirolimus Level Elevation Induced by Acitretin: Report of a Novel Drug-Drug Interaction.",
"title_normalized": "serum sirolimus level elevation induced by acitretin report of a novel drug drug interaction"
} | [
{
"companynumb": "PHHY2016US028505",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nDaptomycin (DAP) is a key drug for treating severe Staphylococcus infections. The emergence of DAP non-susceptible Staphylococcus aureus has been widely recognized in clinical situations, although the clinical status of DAP non-susceptible coagulase-negative Staphylococcus (CoNS) infections is unclear. We encountered 2 cases of cardiovascular device infections that were associated with DAP non-susceptible CoNS.\nThe first case involved a 60-year-old woman with a pump pocket infection in a left ventricular assist device. DAP non-susceptible Staphylococcus capitis subsp. ureolyticus was isolated from a blood culture after treatment using vancomycin (10 days) and DAP (6 days). The second case involved a 71-year-old man with an aortic graft infection. DAP non-susceptible S capitis subsp. ureolyticus was detected in pus after treatment using vancomycin (2 weeks) and DAP (1 week) without complete removal and debridement.\n\n\nMETHODS\nCardiovascular device infections caused by DAP non-susceptible CoNS.\n\n\nRESULTS\nWhole genome sequencing of these strains revealed multiple mutations in genes that are related to DAP-non-susceptibility in S aureus, which created amino acid substitutions in mprF, dltAB, dltD, rpoC, yycG, cls2, pgsA, and vraSR. To the very best of our knowledge, the substitution patterns were not identical to those previously reported in DAP non-susceptibile S aureus.\n\n\nCONCLUSIONS\nClinicians should be cautious regarding the emergence of DAP non-susceptible CoNS, especially in cases with implanted prosthetic devices, inadequate debridement, and prior usage of vancomycin and DAP. Further studies are needed to understand the relevance of these genetic changes and DAP-non-susceptibility in CoNS strains.",
"affiliations": "Division of Infection Control and Prevention, Osaka University Hospital.;Japan-Thailand Research Collaboration Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka University.;Laboratory for Clinical Investigation, Osaka University Hospital, Osaka.;Division of Infection Control and Prevention, Osaka University Hospital.;Laboratory for Clinical Investigation, Osaka University Hospital, Osaka.;Center for Conservation of Microbial Genetic Resource, Gifu University, Gifu, Japan.;Division of Infection Control and Prevention, Osaka University Hospital.;Division of Infection Control and Prevention, Osaka University Hospital.",
"authors": "Hagiya|Hideharu|H|;Sugawara|Yo|Y|;Kimura|Keigo|K|;Hamaguchi|Shigeto|S|;Nishi|Isao|I|;Hayashi|Masahiro|M|;Akeda|Yukihiro|Y|;Tomono|Kazunori|K|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000013487",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30544442MD-D-18-0563510.1097/MD.0000000000013487134874900Research ArticleClinical Case ReportEmergence of daptomycin non-susceptible coagulase-negative Staphylococci in patients with cardiovascular device infections Two cases report investigated by whole genome analysisHagiya Hideharu MD, PhDa∗Sugawara Yo PhDbKimura Keigo MTcHamaguchi Shigeto MD, PhDaNishi Isao PhDcHayashi Masahiro PhDdAkeda Yukihiro PhDabTomono Kazunori MD, PhDaNA. a Division of Infection Control and Prevention, Osaka University Hospitalb Japan-Thailand Research Collaboration Center for Infectious Diseases, Research Institute for Microbial Diseases, Osaka Universityc Laboratory for Clinical Investigation, Osaka University Hospital, Osakad Center for Conservation of Microbial Genetic Resource, Gifu University, Gifu, Japan.∗ Correspondence: Hideharu Hagiya, Division of Infection Control and Prevention, Osaka University Hospital, Osaka, Japan, 2–15 Yamadaoka, Suita, Osaka 565–0871, Japan. (e-mail: highgear@hp-infect.med.osaka-u.ac.jp).12 2018 10 12 2018 97 49 e1348713 8 2018 7 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Abstract\nRationale:\nDaptomycin (DAP) is a key drug for treating severe Staphylococcus infections. The emergence of DAP non-susceptible Staphylococcus aureus has been widely recognized in clinical situations, although the clinical status of DAP non-susceptible coagulase-negative Staphylococcus (CoNS) infections is unclear. We encountered 2 cases of cardiovascular device infections that were associated with DAP non-susceptible CoNS.\n\nPatient concerns:\nThe first case involved a 60-year-old woman with a pump pocket infection in a left ventricular assist device. DAP non-susceptible Staphylococcus capitis subsp. ureolyticus was isolated from a blood culture after treatment using vancomycin (10 days) and DAP (6 days). The second case involved a 71-year-old man with an aortic graft infection. DAP non-susceptible S capitis subsp. ureolyticus was detected in pus after treatment using vancomycin (2 weeks) and DAP (1 week) without complete removal and debridement.\n\nDiagnosis:\nCardiovascular device infections caused by DAP non-susceptible CoNS.\n\nInterventions and outcomes:\nWhole genome sequencing of these strains revealed multiple mutations in genes that are related to DAP-non-susceptibility in S aureus, which created amino acid substitutions in mprF, dltAB, dltD, rpoC, yycG, cls2, pgsA, and vraSR. To the very best of our knowledge, the substitution patterns were not identical to those previously reported in DAP non-susceptibile S aureus.\n\nLessons:\nClinicians should be cautious regarding the emergence of DAP non-susceptible CoNS, especially in cases with implanted prosthetic devices, inadequate debridement, and prior usage of vancomycin and DAP. Further studies are needed to understand the relevance of these genetic changes and DAP-non-susceptibility in CoNS strains.\n\nKeywords\namino acid substitutionantimicrobial resistancedaptomycinprosthetic devicestaphylococcus capitis subspureolyticuswhole genome analysisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nDaptomycin (DAP) is part of a new class of natural cyclic lipopeptide antibiotics that are active against Gram-positive organisms. Based on its strong bactericidal effect and good pharmacokinetics, DAP is widely recommended for treating various Staphylococcus aureus infections, including bacteremia and endocarditis.[1] However, the emergence of DAP resistance in S aureus has been described in laboratory studies,[2] clinical trials,[3] and post-marketing surveillance.[4] Exposure to DAP causes S aureus strains to develop an altered membrane potential and a more positive membrane surface charge, which leads to DAP resistance.[5]\n\nIn contrast, coagulase-negative Staphylococcus (CoNS) rarely exhibits decreased susceptibility to DAP, as a previous study[6] has indicated that DAP was active for 99.8% of CoNS isolates at a susceptibility breakpoint of ≤ 1 μg/mL. In culture results, CoNS are often considered contaminants, although their roles as real pathogens have been recognized in various clinical situations.[7] Furthermore, CoNS strains can have elevated minimum inhibitory concentration (MIC) values for glycopeptides, which may be related to poor clinical outcomes.[8] However, given the rarity of DAP non-susceptible CoNS infections, its clinical course, incidence, and genetic background remain unclear. We recently encountered 2 cases of DAP non-susceptible CoNS infections that involved patients with implanted cardiovascular devices and used whole genome sequencing to identify amino acid substitutions that could be responsible for the DAP non-susceptibility.\n\n2 Case presentation\n2.1 Case 1\nA 60-year-old woman with a history of hypertrophic cardiomyopathy had undergone implantation of a left ventricular assist device 2 years ago. Eighteen months later, the device suddenly malfunctioned and the patient underwent an emergent exchange surgery. She subsequently developed a surgical site infection that was treated using intravenous ampicillin/sulbactam.\n\nThree months later, the surgical wound infection recurred and the patient was re-hospitalized with a low-grade fever and tenderness directly around the pump. Her serum level of C-reactive protein (CRP) was slightly elevated (1.39 mg/dL) and gallium-67 scintigraphy revealed inflammation surrounding the device pump (Fig. 1A). A blood culture was positive for methicillin-resistant Staphylococcus capitis subsp. ureolyticus. Intravenous vancomycin (VCM) was empirically initiated, although the patient remained febrile. Debridement surgery was performed for the pump pocket infection on day 7 of that admission, and the organism was also detected in a culture of the purulent tissue. The VCM treatment was switched to DAP (350 mg/day [5.7 mg/kg]) on day 10 because of drug-induced neutropenia. Although the patient's condition seemed favorable, a high fever re-emerged on day 16 and 2 blood cultures were again positive for S capitis subsp. ureolyticus, with drug tests revealing non-susceptibility to DAP (Table 1). Thus, the DAP treatment was discontinued and the patient did not experience recurrence after a 1-month course of combination therapy using clindamycin and rifampicin.\n\nFigure 1 Radiological findings. Gallium-67 scintigraphy revealed uptake at the site of a cardiac pump in Case 1 (A) and in the peri-aortic space in Case 2 (B). Contrast-enhanced computed tomography revealed a massive abscess surrounding the aortic graft in Case 2 (C).\n\nTable 1 Minimum inhibitory concentrations for Staphylococcus capitis subsp. ureolyticus.\n\n2.2 Case 2\nA 71-year-old man who had undergone thoracic endovascular aortic repair 7 years previously was admitted to a hospital with a complaint of fever, back pain, and bloody sputum. Based on the results from positron emission tomography-computed tomography (CT), the patient was diagnosed with an aortic graft infection and underwent CT-guided drainage for a peri-aortic abscess. The pathogen was unclear and he received empirical antimicrobial treatments using meropenem and DAP for 1 week (dose unknown), ampicillin and sulbactam for 3 weeks, VCM for 2 weeks, and oral levofloxacin for 4 weeks. The patient was discharged with a prescription for oral levofloxacin and followed-up at an outpatient clinic. Three months later, his serum CRP level was elevated and radiographic examinations revealed an enlarged peri-aortic abscess (Fig. 1B and C). Based on a diagnosis of a recurrent aortic graft infection, he was referred to our hospital for further treatment.\n\nAt admission, the patient had stable vital signs but was febrile and had an elevated white blood cell count (12,220/μL) and CRP level (16.3 mg/dL). The patient underwent CT-guided percutaneous drainage, which removed approximately 200 mL of pus. Gram staining of the discharge revealed Gram-positive cocci and a bacterial culture revealed the presence of DAP non-susceptible S capitis subsp. ureolyticus (Table 1). Linezolid was chosen for treatment, but the patient developed thrombocytopenia after 2 weeks. The linezolid treatment was switched to a combination of VCM and clindamycin. After another 2 weeks, the antibiotic therapy was converted to a combination of oral treatment using trimethoprim/sulfamethoxazole and minocycline, and the patient was discharged.\n\n2.3 Antimicrobial susceptibility testing\nThe MIC for DAP was initially examined using a MicroScan WalkAway 96 Plus (Beckman Coulter, Brea, CA, USA) at our hospital's clinical microbiology laboratory, which revealed results of 2 μg/mL for both isolates. These results were confirmed using the E-test (bioMe′rieux, Marcy l’Etoile, France) on cation-adjusted Mueller Hinton agar according to the manufacturer's instructions. That test revealed MICs of 3 μg/mL in Case 1 and 1.5 μg/mL in Case 2 (Table 1).\n\n2.4 Whole genome analysis\nWhole genome sequencing was performed using the MiSeq system (Illumina, San Diego, CA, USA) to identify mutations that might be associated with the DAP non-susceptibility. The bacterial isolates were cultured overnight in brain heart infusion broth (BD Bacto, Franklin Lakes, NJ, USA) and genomic DNA was then prepared using a PowerSoil DNA isolation kit (Qiagen). The library preparation for the genome analysis has been described in our previous report.[9] The sequence reads were subsequently submitted to the DDBJ/Genbank/EMBL database under accession numbers DRX121940 (Case 1) and DRX121939 (Case 2).\n\nSequence data assembly revealed genome size and G+C content values of 2,508,206 bp and 32.81% for Case 1 and 2,353,499 bp and 32.78% for Case 2. The sequence reads were assembled de novo on CLC Genomics Workbench and compared to the publicly available data for S capitis subsp. ureolyticus (ATCC 49326). MIC of the reference strain for DAP was confirmed to be ≤ 0.25 μg/mL. Bacterial identification was reconfirmed using the average nucleotide identity (ANI) analysis in EzBioCloud.[10] The result demonstrated that those 2 clinical isolates were S capitis subsp. ureolyticus and not identical each other in their origins (ANI value between the 2 clinical strains; 98.72). To identify amino acid substitutions, we considered the following genes to potentially be related to DAP non-susceptibility based on previous reports:[11–14]mprF, dltABCD, rpoB, rpoC, yycF, yycG, cls2, pgsA, and vraSR. Consequently, multiple amino acids substitutions were detected in dltD, yycG, cls2, and vraSR in Case 1, and mprF, dltAB, rpoC, yycG, cls2, and pgsA in Case 2 (Table 2).\n\nTable 2 Substitutions of amino acids based on the whole genome sequencing.\n\n3 Discussion\nWe encountered 2 clinical cases of DAP non-susceptible CoNS infections. Although DAP non-susceptible strains of S aureus have been noted in various clinical settings, these cases rarely involve CoNS. Based on the guidelines from the European Committee on Antimicrobial Susceptibility Testing[15] and the Clinical and Laboratory Standards Institute,[16] DAP susceptibility in Staphylococcus spp. is defined as an MIC of ≤ 1 mg/L and strains with an MIC of > 1 mg/L are considered DAP non-susceptible. We measured the MIC values using a MicroScan WalkAway 96 Plus (Beckman Coulter, Brea, CA, USA) and confirmed the results using the E-test (bioMe′rieux). A recent study from the SENTRY Antimicrobial Surveillance Program (283 hospitals in 42 countries during 2002–2010) revealed that 99.8% of > 22,000 isolates of CoNS strains were susceptible to DAP, with only a few CoNS strains (eg, S sciuri, S auricularis, S warneri, and S capitis) having elevated MIC90 values relative to those of other Staphylococcus spp.[6]\n\nTreatment using VCM or DAP usually precedes the development of DAP resistance in S aureus.[17] and both of our patients had received these drugs before the emergence of DAP non-susceptible CoNS (Case 1: 10 days of VCM and 6 days of DAP, Case 2: 2 weeks of VCM and 1 week of DAP). A previous study has indicated that DAP non-susceptible S aureus emergence could be predicted by a low dosage of DAP, persistent infection, and high bacterial loads,[18] which indicates that an adequate dose of DAP should be administered to avoid resistance. The safety of high-dose DAP (> 6 mg/kg) has been widely recognized,[19] and the administration of a high DAP dose is recommended, especially in refractory cases. Moreover, both of our cases involved prosthetic devices (a left ventricular assist device in Case 1 and aortic graft in Case 2), and the difficulty that is associated with debridement and removal of these foreign bodies might also have contributed to the emergence of DAP non-susceptible isolates.\n\nThere are some possible mechanisms for the increased MIC of DAP in our isolates. As have reported in S aureus, a positive charge at the membrane surface[20] and a thickening of the cell wall[21] could be associated with DAP-non-susceptibility, with major mutations thought to involve mprF, dltABCD, rpoB/rpoC, and yycF/yycG.[11] To the best of our knowledge, only 1 report has described whole genome analysis of multidrug-resistant S capitis subsp. ureolyticus, although that report did not describe any genetic changes that were potentially responsible for the DAP non-susceptibility.[22] In this context, our molecular analysis detected multiple amino acids substitutions in these possibly responsible genes for both isolates (vs the publicly available isolate). Interestingly, both of the S capitis subsp. ureolyticus isolates had amino acid changes commonly in dltABCD, yycG, and cls2, which thus is speculated to be majorly related to DAP non-susceptibility in CoNS. Of note, these substitution patterns were not completely identical to the previously reported patterns for DAP non-susceptible S aureus strains.[11–14] Thus, they would be novel to be reported in the literature and also might be characteristic to CoNS strains. However, we are unable to conclude an association between the DAP non-susceptibility and these genetic changes, given the lack of available isolates before the DAP exposure. Further molecular analysis is needed to identify the genetic variant(s) that are responsible for DAP non-susceptibility in CoNS.\n\nIn conclusion, we encountered 2 cases of DAP non-susceptible CoNS infections. Both cases were associated with artificial device infections, and emergences of DAP non-susceptible strains were preceded by the administration of VCM and DAP. In general, CoNS infrequently causes refractory infections and thus has limited opportunity to become non-susceptible to DAP. The present cases demonstrated that CoNS can also develop DAP non-susceptibility in the specific situations described above. Our whole genome sequencing detected several amino acid substitutions in proteins that may be responsible for DAP non-susceptibility in S aureus. Resistance in VCM emerged after 4 decades of its clinical use, while DAP resistance occurred shortly after its debut. In this era of antibiotic shortage, emergence of DAP-resistant strain is of great concern to clinicians and should be closely monitored in various bacterial species.\n\nAuthor contributions\nConceptualization: Hideharu Hagiya.\n\nInvestigation: Yo Sugawara, Keigo Kimura, Isao Nishi, and Masahiro Hayashi.\n\nResources: Masahiro Hayashi.\n\nSupervision: Shigeto Hamaguchi, Yukihiro Akeda, and Kazunori Tomono.\n\nWriting – original draft: Hideharu Hagiya.\n\nWriting – review and editing: Shigeto Hamaguchi, Yukihiro Akeda, and Kazunori Tomono.\n\nAbbreviations: ANI = average nucleotide identity, CoNS = coagulase-negative Staphylococcus, CRP = C-reactive protein, CT = computed tomography, DAP = daptomycin, MIC = minimum inhibitory concentration, VCM = vancomycin.\n\nPatient consent: Informed consents were obtained from the patients for the publication.\n\nThe authors have no conflicts of interests to declare.\n==== Refs\nReferences\n[1] Liu C Bayer A Cosgrove SE \nClinical practice guidelines by the infectious diseases society of america for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children . Clin Infect Dis \n2011 ;52 :e18–55 .21208910 \n[2] Rose WE Rybak MJ Tsuji BT \nCorrelation of vancomycin and daptomycin susceptibility in Staphylococcus aureus in reference to accessory gene regulator (agr) polymorphism and function . J Antimicrob Chemother \n2007 ;59 :1190–3 .17434881 \n[3] Fowler VG JrBoucher HW Corey GR \nDaptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus . N Engl J Med \n2006 ;355 :653–65 .16914701 \n[4] Sader HS Moet GJ Farrell DJ \nAntimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci: trend analysis of a 6-year period in US medical centers (2005-2010) . Diagn Microbiol Infect Dis \n2011 ;70 :412–6 .21546202 \n[5] Kaatz GW Lundstrom TS Seo SM \nMechanisms of daptomycin resistance in Staphylococcus aureus . Int J Antimicrob Agents \n2006 ;28 :280–7 .16963232 \n[6] Sader HS Jones RN \nAntimicrobial activity of daptomycin in comparison to glycopeptides and other antimicrobials when tested against numerous species of coagulase-negative Staphylococcus . Diagn Microbiol Infect Dis \n2012 ;73 :212–4 .22608137 \n[7] von Eiff C Peters G Heilmann C \nPathogenesis of infections due to coagulase-negative staphylococci . Lancet Infect Dis \n2002 ;2 :677–85 .12409048 \n[8] Tacconelli E Tumbarello M Donati KG \nGlycopeptide resistance among coagulase-negative staphylococci that cause bacteremia: epidemiological and clinical findings from a case-control study . Clin Infect Dis \n2001 ;33 :1628–35 .11595984 \n[9] Sugawara Y Akeda Y Sakamoto N \nGenetic characterization of blaNDM-harboring plasmids in carbapenem-resistant Escherichia coli from Myanmar . PLoS One \n2017 ;12 :e0184720.28910381 \n[10] Yoon SH Ha SM Kwon S \nIntroducing EzBioCloud: a taxonomically united database of 16S rRNA gene sequences and whole-genome assemblies . Int J Syst Evol Microbiol \n2017 ;67 :1613–7 .28005526 \n[11] Steed ME Hall AD Salimnia H \nEvaluation of daptomycin non-susceptible Staphylococcus aureus for stability, population profiles, mprF mutations, and daptomycin activity . Infect Dis Ther \n2013 ;2 :187–200 .25134481 \n[12] Mehta S Cuirolo AX Plata KB \nVraSR two-component regulatory system contributes to mprF-mediated decreased susceptibility to daptomycin in in vivo-selected clinical strains of methicillin-resistant Staphylococcus aureus . Antimicrob Agents Chemother \n2012 ;56 :92–102 .21986832 \n[13] Friedman L Alder JD Silverman JA \nGenetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus . Antimicrob Agents Chemother \n2006 ;50 :2137–45 .16723576 \n[14] Peleg AY Miyakis S Ward DV \nWhole genome characterization of the mechanisms of daptomycin resistance in clinical and laboratory derived isolates of Staphylococcus aureus . PLoS One \n2012 ;7 :e28316.22238576 \n[15] European Committee on Antimicrobial Susceptibility Testing (EUCAST) . Breakpoint tables for interpretation of MICs and zone diameters. Version 6.0 . 2018 \nAvailable at: http://www.eucast.org/clinical_breakpoints/ \nAccessed May 5, 2018\n[16] Clinical and Laboratory Standards Institute (CLSI) . Performance standards for antimicrobial susceptibility testing. CLSI document M100-S26 . 2016 \nCLSI, Wayne, PA .\n[17] Pillai SK Gold HS Sakoulas G \nDaptomycin nonsusceptibility in Staphylococcus aureus with reduced vancomycin susceptibility is independent of alterations in MprF . Antimicrob Agents Chemother \n2007 ;51 :2223–5 .17404001 \n[18] Moise PA North D Steenbergen JN \nSusceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions . Lancet Infect Dis \n2009 ;9 :617–24 .19778764 \n[19] Falcone M Russo A Venditti M \nConsiderations for higher doses of daptomycin in critically ill patients with methicillin-resistant Staphylococcus aureus bacteremia . Clin Infect Dis \n2013 ;57 :1568–76 .24046298 \n[20] Rubio A Moore J Varoglu M \nLC-MS/MS characterization of phospholipid content in daptomycin-susceptible and-resistant isolates of Staphylococcus aureus with mutations in mprF . Mol Membr Biol \n2012 ;29 :1–8 .22276671 \n[21] Cui L Tominaga E Neoh H-m \nCorrelation between reduced daptomycin susceptibility and vancomycin resistance in vancomycin-intermediate Staphylococcus aureus . Antimicrob Agents Chemother \n2006 ;50 :1079–82 .16495273 \n[22] Li X Lei M Song Y \nWhole genome sequence and comparative genomic analysis of multidrug-resistant Staphylococcus capitis subsp. urealyticus strain LNZR-1 . Gut Pathog \n2014 ;6 :45.25649186\n\n",
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"issue": "97(49)",
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"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D017576:Daptomycin; D003937:Diagnosis, Differential; D024881:Drug Resistance, Bacterial; D005260:Female; D006321:Heart; D006801:Humans; D008297:Male; D008875:Middle Aged; D016459:Prosthesis-Related Infections; D013203:Staphylococcal Infections; D013211:Staphylococcus aureus",
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"title": "Emergence of daptomycin non-susceptible coagulase-negative Staphylococci in patients with cardiovascular device infections: Two cases report investigated by whole genome analysis.",
"title_normalized": "emergence of daptomycin non susceptible coagulase negative staphylococci in patients with cardiovascular device infections two cases report investigated by whole genome analysis"
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"abstract": "BACKGROUND\nThe cross-allergic reactions among aromatic antiepileptic drugs (AEDs) are common, but little is known about the genetic mechanisms.\n\n\nOBJECTIVE\nThe aim of this study was to investigate the genetic associations of the human leukocyte antigen (HLA) genes with the cross-reactivity of cutaneous adverse drug reactions (cADRs) induced by different aromatic AEDs.\n\n\nMETHODS\nWe reviewed 60 Chinese patients with a history of cADRs induced by an aromatic AED, and which re-challenged other aromatic AEDs as an alternative to the causative AED owing to some particular reasons. According to whether developing another episode of cADRs, these patients were automatically divided into the cross-reactivity group and tolerant control group. High-resolution HLA-A, -B, -DRB1 genotyping were performed for each patient.\n\n\nRESULTS\nOne out of 10 patients (10%, 1/10) carried the HLA-A*2402 allele in the cross-reactivity group. However, 23 patients (46%, 23/50) carried this allele in the tolerant control group. The difference of the HLA-A*2402 allele between the two groups is statistically significant (P=0.040, OR=0.130, 95% CI: 0.015-1.108). In addition, the frequency differences of other HLA alleles between the two groups, including the HLA-B*1502 allele, did not reach statistical significance (P>0.05).\n\n\nCONCLUSIONS\nThe HLA genes contribute to the genetic susceptibility of the cross-reactivity of cADRs among aromatic AEDs. Our results suggest that HLA-B*1502 is not a major responsible allele for the cross-reactivity of cADRs to aromatic AEDs, but the HLA-A*2402 allele may be a protective marker for the cross-allergic reactions among aromatic AEDs in Han Chinese. Further studies are warranted to test the potential predictive value of the HLA-A*2402 allele in future.",
"affiliations": "Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.;Department of Neurology, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China. Electronic address: zhoudong66@yahoo.de.",
"authors": "Wang|Wei|W|;Hu|Fa-Yun|FY|;Wu|Xin-Tong|XT|;An|Dong-Mei|DM|;Yan|Bo|B|;Zhou|Dong|D|",
"chemical_list": "D000927:Anticonvulsants; D054316:Biomarkers, Pharmacological; D006680:HLA Antigens; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; C483536:HLA-B*15:02 antigen; D059910:HLA-B15 Antigen",
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"journal": "Epilepsy research",
"keywords": "Aromatic antiepileptic drugs; Cross-reactivity; Cutaneous adverse drug reactions; HLA-A*2402 allele; HLA-B*1502 allele",
"medline_ta": "Epilepsy Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000483:Alleles; D000927:Anticonvulsants; D044466:Asians; D054316:Biomarkers, Pharmacological; D002648:Child; D002681:China; D003429:Cross Reactions; D003875:Drug Eruptions; D005260:Female; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006680:HLA Antigens; D059871:HLA-A24 Antigen; D059910:HLA-B15 Antigen; D006801:Humans; D008297:Male; D008875:Middle Aged; D013262:Stevens-Johnson Syndrome; D055815:Young Adult",
"nlm_unique_id": "8703089",
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"pages": "1041-5",
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"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Genetic susceptibility to the cross-reactivity of aromatic antiepileptic drugs-induced cutaneous adverse reactions.",
"title_normalized": "genetic susceptibility to the cross reactivity of aromatic antiepileptic drugs induced cutaneous adverse reactions"
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{
"abstract": "Deep vein thrombosis (DVT) is caused primarily by obstruction of blood flow in the deep veins in the lower limbs. It is a form of thrombophlebitis and can be a major cause of morbidity and mortality in hospitalized patients. This report describes an unusual case of DVT in a 21-year-old woman with Class III malocclusion who underwent bimaxillary orthognathic surgery (bilateral sagittal split osteotomy and Le Fort I osteotomy) under general anesthesia. She developed DVT unexpectedly 1 week after surgery, with episodes of sweating and chills in addition to lower limb edema, tenderness, and rigidity. D-dimer laboratory testing and venous Doppler sonography were performed and the DVT diagnosis was confirmed; therefore, the patient was admitted to the intensive care unit for anticoagulant and supportive therapy. Although the incidence rate of thromboembolism in hospitalized patients undergoing oral and maxillofacial surgery is low, it is not an operation without risk of DVT. This complication can cause fatal acute pulmonary thromboembolism and death. This case study illustrates that pharmacologic treatment of menorrhagia with mefenamic acid combined with intraoperative use of tranexamic acid for control of blood loss might put the patient at increased risk of DVT. Hence, maxillofacial surgeons should assess all their patients preoperatively for thromboembolism risk; if they suspect any risk factors in the patient, prompt diagnostic tests and management should be ordered.",
"affiliations": "Assistant Professor, Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Cardiologist, Preventive Cardiovascular Care Research Center, Department of Cardiology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.;Associate Professor, Oral and Maxillofacial Diseases Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.;Member of Kerman Dental and Oral Diseases Research Center; Associate Professor, Department of Oral Medicine, Dental School, Kerman University of Medical Science, Kerman, Iran. Electronic address: m_s_hashemipour@yahoo.com.",
"authors": "Samieirad|Sahand|S|;Tohidi|Hadi|H|;Eshghpour|Majid|M|;Hashemipour|Maryam Alsadat|MA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.joms.2018.07.024",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "76(12)",
"journal": "Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons",
"keywords": null,
"medline_ta": "J Oral Maxillofac Surg",
"mesh_terms": "D005260:Female; D006801:Humans; D008313:Malocclusion, Angle Class III; D019340:Osteotomy, Le Fort; D059229:Osteotomy, Sagittal Split Ramus; D011183:Postoperative Complications; D020246:Venous Thrombosis; D055815:Young Adult",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "2649.e1-2649.e9",
"pmc": null,
"pmid": "30145191",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "An Unusual Case of Deep Vein Thrombosis After Orthognathic Surgery: A Case Report and Review of the Literature.",
"title_normalized": "an unusual case of deep vein thrombosis after orthognathic surgery a case report and review of the literature"
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"abstract": "The demographic characteristics, performance status, frequency of comorbidities and survival rate of patients with multiple myeloma (MM) show variability geographically and different risk scoring systems have been used to assess this population. Here, we present data from a Turkish cohort, focusing on identifying similarities and differences, relative to other reports in the literature.\nA total of 310 patients diagnosed with MM were enrolled. Their demographic characteristics were investigated retrospectively. For performance assessment; the ECOG-IMWG Myeloma Frailty Score, R-MCI and HCT-SCI scoring indexes were used. PFS and OS periods, as well as the causes of deaths, were determined.\nThe mean age of all study participants was 65 ± 10 years. The mean PFS and OS periods were 24.14± 26.11 and 65.3 ± 4.4 months, respectively. The median R-MCI, CCI and HCT-CI scores were five, four and three points, respectively. Myeloma-related complications were the leading cause of death, with a frequency of 51%.\nAmong the scoring systems utilised, R-MCI was more convenient to apply due to its ease of use and practicality. Our study supports the heterogeneous course of myeloma and highlights geographic differences including comorbidities, causes of death and overall survival.",
"affiliations": "Internal Medicine Department, M.D, Adnan Menderes University, Efeler, Aydın, TURKEY.;Hematology Department, M.D.(Hematology Specialist), Adnan Menderes University, Efeler, Aydın, TURKEY.;Hematology and Bone Marrow Transplantation Department, Prof Dr, Kent Hospital, Çiğli-İZMİR, Turkey.;Hematology Department, Prof.Dr, Adnan Menderes University, Turkey.;Hematology Department, Prof.Dr, Adnan Menderes University, Turkey.",
"authors": "Şahin|Tuğba|T|;Turgutkaya|Atakan|A|;Kadıköylü|Gürhan|G|;Bolaman|Ali Zahit|AZ|;Yavaşoğlu|İrfan|İ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1080/17474086.2021.1962279",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1747-4094",
"issue": null,
"journal": "Expert review of hematology",
"keywords": "Cause of death; heterogeneous; multiple myeloma; prognosis; scoring index",
"medline_ta": "Expert Rev Hematol",
"mesh_terms": null,
"nlm_unique_id": "101485942",
"other_id": null,
"pages": "1-7",
"pmc": null,
"pmid": "34319819",
"pubdate": "2021-08-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Investigation of demographic features, performance, comorbidity status and mortality causes among multiple myeloma patients: real-life data.",
"title_normalized": "investigation of demographic features performance comorbidity status and mortality causes among multiple myeloma patients real life data"
} | [
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"companynumb": "TR-AMGEN-TURSP2022047870",
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"activesubstancename": "CARFILZOMIB"
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"abstract": "Thrombocytopaenia, one of the most common haematological disorders worldwide, is characterised by platelet counts <150,000/mm3. Patients with coronavirus disease (COVID-19) were found to commonly exhibit haematological abnormalities, often with mild forms of thrombocytopaenia. Absolute thrombocytopaenia tends to be rare among these patients and is believed to be secondary to immune-induced thrombocytopaenia.\nA 53-y-old man presented with fever and generalised body ache that persisted for a few days. His polymerase chain reaction test was positive for COVID-19, for which he was treated with acetaminophen, levofloxacin, and favipiravir. On the third day of treatment, he noticed bruising and bleeding, mainly in the oral cavity, with clot formation. A complete blood picture (CBP) revealed severe thrombocytopaenia with an almost-zero count. Prednisone 1 mg/kg/d and frequent doses of intravenous platelet transfusion were administered as rescue therapy to prevent fatal bleeding. The patient was able to recover.\nImmune thrombocytopaenia should be considered in patients presenting with bleeding tendencies after severe acute respiratory syndrome coronavirus 2 infection. Serial CBP is recommended for vulnerable patients, especially during the second and third weeks of hospitalisation, for the early detection and prevention of life-threatening COVID-19 complications.\nAbsolute thrombocytopaenia is a rare condition. Such a condition should be considered in patients presenting with bleeding tendencies with severe Covid-19 infection. With early diagnosis and appropriate treatment, patients' lives can be saved.",
"affiliations": "Department of Medicine, College of Medicine, University of Duhok, Kurdistan Region, Iraq.;Medical Student at College of Medicine, University of Duhok, Kurdistan Region, Iraq.;Department of Biomedical Science, College of Medicine, University of Zakho, Kurdistan Region, Iraq.",
"authors": "Mohammad|Ameen M|AM|;Sgery|Azri S H|ASH|;Hussein|Nawfal R|NR|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.amsu.2021.103097",
"fulltext": "\n==== Front\nAnn Med Surg (Lond)\nAnn Med Surg (Lond)\nAnnals of Medicine and Surgery\n2049-0801\nElsevier\n\nS2049-0801(21)01047-5\n10.1016/j.amsu.2021.103097\n103097\nCase Report\nA rare case of absolute thrombocytopaenia in a COVID-19 patient: Case report\nMohammad Ameen M. doctoramb@yahoo.com\na∗\nSgery Azri S.H. Azrysgery23@gmail.com\nb\nHussein Nawfal R. doctornrs@yahoo.com\nc\na Department of Medicine, College of Medicine, University of Duhok, Kurdistan Region, Iraq\nb Medical Student at College of Medicine, University of Duhok, Kurdistan Region, Iraq\nc Department of Biomedical Science, College of Medicine, University of Zakho, Kurdistan Region, Iraq\n∗ Corresponding author. Professor of Cardiovascualr Medicine, Department of Medicine, College of Medicine, University of Duhok, Duhok, Iraq. doctoramb@yahoo.com\n22 11 2021\n12 2021\n22 11 2021\n72 1030971 10 2021\n19 11 2021\n20 11 2021\n© 2021 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction\n\nThrombocytopaenia, one of the most common haematological disorders worldwide, is characterised by platelet counts <150,000/mm3. Patients with coronavirus disease (COVID-19) were found to commonly exhibit haematological abnormalities, often with mild forms of thrombocytopaenia. Absolute thrombocytopaenia tends to be rare among these patients and is believed to be secondary to immune-induced thrombocytopaenia.\n\nCase presentation\n\nA 53-y-old man presented with fever and generalised body ache that persisted for a few days. His polymerase chain reaction test was positive for COVID-19, for which he was treated with acetaminophen, levofloxacin, and favipiravir. On the third day of treatment, he noticed bruising and bleeding, mainly in the oral cavity, with clot formation. A complete blood picture (CBP) revealed severe thrombocytopaenia with an almost-zero count. Prednisone 1 mg/kg/d and frequent doses of intravenous platelet transfusion were administered as rescue therapy to prevent fatal bleeding. The patient was able to recover.\n\nClinical discussion\n\nImmune thrombocytopaenia should be considered in patients presenting with bleeding tendencies after severe acute respiratory syndrome coronavirus 2 infection. Serial CBP is recommended for vulnerable patients, especially during the second and third weeks of hospitalisation, for the early detection and prevention of life-threatening COVID-19 complications.\n\nConclusions\n\nAbsolute thrombocytopaenia is a rare condition. Such a condition should be considered in patients presenting with bleeding tendencies with severe Covid-19 infection. With early diagnosis and appropriate treatment, patients’ lives can be saved.\n\nHighlights\n\n• Absolute thrombocytopaenia is a rare condition.\n\n• Such a condition should be considered in patients presenting with bleeding tendencies with severe Covid-19 infection.\n\n• Prednisone 1 mg/kg/d and intravenous platelet transfusion should be considered as rescue therapy to prevent fatal bleeding.\n\nKeywords\n\nCOVID-19\nSARS-CoV-2\nThrombocytopaenia\nImmune thrombocytopaenia\nImmune thrombocytopaenic purpura (ITP)\nDrug-induced immune thrombocytopaenia (DITP)\n==== Body\npmc1 Introduction\n\nThrombocytopaenia, one of the most common haematological disorders, is characterized by a platelet count <150,000/mm3 with a broad variation of clinical manifestations, ranging from asymptomatic to life-threatening bleeding. Patients with thrombocytopaenia usually seek medical help when they suffer from spontaneous bruising, purpura, or other symptoms, which usually occur when the platelet count reaches <30,000/mm3 [1].\n\nThe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, which is responsible for coronavirus disease (COVID-19), is a serious public health concern worldwide with variable clinical manifestations [[2], [3], [4], [5]]. In the Kurdistan region of Iraq, we experienced three waves with devastating impacts on our health system [6,7]. With the emerging data, the virus was found to be involved in other systems, such as the vascular, gastrointestinal, and haematological systems [8].\n\nCOVID-19 patients commonly exhibit haematological abnormalities, often with mild forms of thrombocytopaenia and other haematological findings. The incidence of thrombocytopaenia in COVID-19 patients tends to be variable, with mild cases commonly observed in severe COVID-19 cases; however, absolute thrombocytopaenia with a count of almost zero tends to be very rare [9,10].\n\nIncreasingly, cases of immune-induced thrombocytopaenia have been reported in patients following their SARS-CoV-2 infection and are described as secondary immune thrombocytopenic purpura (ITP), or immune thrombocytopaenia in the absence of purpura, triggered by SARS-CoV-2 viral infection with the viral induction of autoimmunity, explained in terms of molecular mimicry, cryptic antigen expression, or epitope spreading. Hence, immune thrombocytopaenia has been reported as an important SARS-C0V-2 complication [11]. In this report, we present a case of severe thrombocytopaenia following SARS-CoV-2 infection.\n\n2 Patient information\n\nA 53-y-old male patient with no previous significant comorbidities presented to the hospital with a history of fever and generalised body ache that persisted for a few days. The polymerase chain reaction (PCR) test was positive for COVID-19, for which the patient started to receive treatment. On the third day of treatment, the patient noticed bruising and bleeding, mainly in the oral cavity, with the formation of blood clots inside the mouth. Laboratory investigation and complete blood picture (CBP) was performed, which revealed severe thrombocytopaenia with a count of almost zero. The patient was then treated for thrombocytopaenia to prevent fatal bleeding. Our case has been reported in line with THE SCARE 2020 criteria [12]. The clinical examination and all procedures were performed and supervised by two professors of internal medicine. The patient was fit and not receiving any regular medications. The family history was negative in respect to the disorder of the patient. The psychological history was negative. Written informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\n2.1 Laboratory findings\n\nOn September 26, 2020, the patient tested positive for SARS-CoV-2 via real-time PCR (RT-PCR) using nasopharyngeal and oropharyngeal swabs. His CBP results indicated severe thrombocytopaenia with a platelet count of 2/mm3, or almost zero, 2 d after testing positive. Thrombocytopaenia persisted for another 4 d. On October 3, 2020, there was a dramatic increase in the platelet count, reaching 28,000/mm3, and by October 12th, it reached 89,000/mm3.\n\nThe absolute neutrophil count in the first laboratory findings was normal. A significant rise was noticed on the fifth day after the COVID-19 test and continued until October 12, 2020. Lymphocytic counts tended to fluctuate between normal, low, and high. On the other hand, the white blood cell count was high on the fifth day post-COVID-19 test and remained the same. Haemoglobin levels tended to be in the lower normal range.\n\nOn the fourth day post-COVID-19 test, the patient's laboratory findings showed normal D-dimer (330) partial thromboplastin time (29 s), international normalised ratio (1.0), S. creatinine (1.1), and alanine aminotransferase levels (43). While lactate dehydrogenase (618), S. ferritin (1722), and c-reactive protein (29.6) levels were high. The Coombs test was negative, and he had an (A-negative) blood type (see Table 1, Table 2).Table 1 Laboratory findings of the patient after testing positive for SARS-CoV-2.\n\nTable 1\tPlatelets (*1000/mm3)\tWBC (*1000/mm3)\tHemoglobin (g/dl)\tLymphocyte (%) & Absolute count (per/UI)\tNeutrophil (%) & Absolute count (per/UI)\t\n28th/9/2020\t2*\t6.3\t13.8\t(26%) 1.64\t(70%) 4.41\t\n29th/9/2020\t2*\t4.9\t13.5\t(12%) 0.59*\t(88%) 4.31\t\n1st/10/2020\t5*\t12.5**\t11.8\t(7%) 875\t(88%) 11000**\t\n\t3*\t11.5**\t12.3\t(10%) 1.15\t(88%)10.12**\t\n3rd/10/2020\t28\t20**\t13\t(13%) 2600\t(81%) 16200**\t\n6th/10/2020\t26\t26.9**\t13.2\t(17%) 4573**\t(81%) 21789**\t\n12th/10/2020\t89\t14.7**\t13.4\t(12%) 1764\t(87%) 12789**\t\n14th/5/2021\t188\t12.4*\t13.3\t(25%) 3.1\t(69%) 8.56**\t\nAbbreviations: SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; WBC, white blood cells.\n\nTable 2 Laboratory findings on September 30, 2020.\n\nTable 2D-Dimer\tBlood Group\tPTT\tINR\tS. Creatinine\tALT\tLDH\tS. Ferritin\tCoombs Test\tCRP\t\n330\tA -ve\t29 sec.\t1.0\t1.1\t43\t618*\t1722*\tNegative\t29.6*\t\nAbbreviations: PTT, partial thromboplastin time; INR, international normalised ratio; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CRP, c-reactive protein.\n\n2.2 Therapeutic intervention\n\nThe patient received treatment for COVID-19 after confirmation. This consisted of acetaminophen, levofloxacin tablets, and favipiravir. After the diagnosis of thrombocytopaenia, he was placed on a course of prednisone 1 mg/kg/day (70 mg) and frequent doses of intravenous platelet transfusion as rescue therapy to prevent fatal bleeding.\n\n2.3 Follow-up and outcomes\n\nAfter several days of severe thrombocytopaenia and a platelet count <50r/mm3, the patient showed a good response to the treatment, with a gradual rise in the platelet count. On the 16th day after testing positive, his platelet count reached 89,000/mm3, which was considered moderate thrombocytopaenia. The patient completely recovered from the bleeding tendency and manifestations. With an outpatient follow-up for 1 month, the patient was asymptomatic when he returned and CBP was completely normal.\n\n3 Discussion\n\nDespite the strict measures taken to prevent infection in our region, the number of COVID-19 cases has increased sharply, with a concurrent increase in severity and case-fatality rate [[13], [14], [15], [16]]. In this report, we present a case of COVID-19 with severe thrombocytopaenia and presentations of a history of fever and generalised body ache for a few days, followed by features of bleeding tendency during the course of COVID-19 treatment. SARS-CoV-2 has the potential to present with a spectrum of variable presentations and can involve one or more systems of the body. Due to the variability in the presentation, cases of thrombocytopaenia, despite being common, especially in severe cases of COVID-19, can pass unnoticed until it reaches severe forms and ends in patients developing complications, such as intracranial bleeding, gastrointestinal bleeding, and haemoptysis [10,11].\n\nThe three proposed mechanisms for COVID-19-associated thrombocytopaenia include a decrease in platelet production either directly due to bone marrow invasion and cytokine storm or indirectly due to lung injury, a decrease in circulating platelets due to increased platelet consumption, such as disseminated intravascular coagulopathy (DIC), and an increase in platelet destruction due to autoantibodies [9,17].\n\nThrombocytopaenia has an important prognostic value as lower platelet counts are associated with an increased risk of in-hospital mortality among COVID-19 patients; the lower the platelet count, the higher the risk. Clinical improvement was seen with the improvement of thrombocytopaenia in COVID-19 patients ( [10,18]. Thrombocytopaenia is usually multifactorial with a complex pathogenesis; however, in the current case with a platelet count of almost zero, immune-induced thrombocytopaenia is far more likely than other aetiologies [19].\n\nIn the current case of COVID-19, severe thrombocytopaenia was observed for several days, followed by a gradual increase in the platelet count after management with steroids and platelet transfusion. In cases of thrombocytopaenia with normal D-dimer levels, prothrombin time, and activated partial thromboplastin time, and without any features of haemolysis, immune thrombocytopaenia becomes likely with SARS-CoV-2-triggered auto-antibodies against platelets as the underlying mechanism [20].\n\nIn this case, the severe degree of thrombocytopaenia, which was possibly associated with a sudden drop >50% over 24–48 h, further supports the diagnosis of immune thrombocytopaenia [17]. Additionally, immune thrombocytopaenia has previously been described following several viral infections, including hepatitis B/C viruses, cytomegalovirus, varicella zoster virus, and, recently, COVID-19 [17,20].\n\nAlthough the onset of immune thrombocytopaenia secondary to SARS-CoV-2 was commonly seen in the second and third week after COVID-19, the onset of this case within the first week could be attributed to the failure of the patient to recognise the onset of COVID-19 symptoms [17].\n\nDrug-induced immune thrombocytopaenia due to levofloxacin could be regarded as a possible differential diagnosis because it presents with severe thrombocytopaenia [21]. However, we found no cases to support favipiravir-induced thrombocytopaenia in clinical practice. Additionally, with a normal D-dimer level, DIC was unlikely. Glucocorticoids and/or immunoglobulins are regarded as first-line treatment for severe secondary thrombocytopaenia, as they interfere with platelet destruction, while second-line treatments include thrombopoietin receptor agonists, rituximab, and splenectomy [20].\n\nRecent studies have reported a significant correlation between COVID-19 and blood parameters, including platelets, and the severity of thrombocytopaenia seemed to be associated with the severity of the disease; patients with severe COVID-19 had a lower platelet count, according to a meta-analysis [8,10,19,22]. Variability in the presentation of COVID-19 leads to the under-diagnosis of thrombocytopaenia and ends in patients developing complications [11]; hence, a systemic approach will be necessary to identify thrombocytopaenia in patients with COVID-19 and to exclude other causes.\n\nWith recent reports showing cases of COVID-19-associated thrombocytopaenia [20], we recommend the following: any patient diagnosed with SARS-CoV-2 infection, especially moderate to severe cases, requires a serial laboratory check-up for platelet counts as thrombocytopaenia could be established prior to admission or during hospitalisation [11]. Conversely, patients presenting with the sole manifestation of thrombocytopaenia should be screened for SARS-CoV-2 infection.\n\n4 Conclusion\n\nIn the current pandemic, thrombocytopaenia should be considered in patients presenting with bleeding tendencies after SARS-CoV-2 infection. SARS-CoV-2-triggered autoantibodies against platelets could be regarded as a possible mechanism behind very severe thrombocytopaenia in our patient. The treatment applied for thrombocytopaenia in the index case is principally the same as that for non-COVID-induced immune thrombocytopaenia. Our case above highlights the wide spectrum of clinical presentations of Covid-19 infection. We emphasize the importance of early recognition as the early diagnosis of such a condition is crucial for timely therapeutic intervention, improved survival, and reduced morbidity.\n\nEthical approval\n\nThis study and the consent of the case report was approved by the Ethics Committee in The College of Medicine, University of Zakho, Kurdistan Region of Iraq.\n\nSources of funding\n\nNone.\n\nAuthors contribution\n\nAMM and NRH diagnosed, managed and followed up the case. ASS collected the data and followed up the patient. AMM and NRH write the draft and all authors approved the final version.\n\nTrial registry number\n\nNone.\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\nGuarantor\n\nAmeen Mosa Mohammad, Department of Medicine, College of Medicine, University of Duhok, Kurdistan region, Iraq. Email: doctoramb@yahoo.com.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nNone.\n\nAbbreviations\n\nCOVID-19 coronavirus disease\n\nSARS-CoV-2 severe acute respiratory syndrome coronavirus 2\n\nWBC white blood cells\n\nPTT partial thromboplastin time\n\nINR international normalised ratio\n\nALT alanine aminotransferase\n\nLDH lactate dehydrogenase\n\nCRP c-reactive protein\n\nDIC disseminated intravascular coagulopathy\n==== Refs\nReferences\n\n1 Izak M. Bussel J.B. Management of thrombocytopenia F1000prime Rep. 6 2014 45 24991422\n2 Mohammad A.M. The pandemic of coronavirus: misconceptions from the land of Mesopotamia IJS Glob. Health 4 3 2021 e52\n3 Musa D.H. Hussein N.R. Ibrahim N. Saleem S.M. Naqid I.A. COVID-19 associated Mesenteric ischemia in a patient from Duhok city, Kurdistan region of Iraq: a case report Int. J. Infect. 8 2 2021\n4 Hussein N.R. Musa D.H. Naqid I.A. Sidiq M. Saleem z. Ibrahim N. The first case of COVID-19 reinfection in Duhok city, Kurdistan region of Iraq: a case report J. Kermanshah Univ. Med. Sci. 24 4 2020 10.5812/jkums.111454 Online ahead of Print e111454\n5 Hussein N.R. Naqid I.A. Saleem Z.S.M. A retrospective descriptive study characterizing coronavirus disease epidemiology among people in the Kurdistan Region, Iraq, Mediterranean J. Hematol. Infect. Dis. 12 1 2020\n6 Hussein N.R. Daniel S. Mirkhan S.A. Saleem Z.S.M. Musa D.H. Ibrahim N. Naqid I.A. Impact of the Covid-19 pandemic on the elimination of hepatitis C virus in Duhok, Kurdistan, Iraq: a retrospective cross-sectional study J. Fam. Med. Prim. Care 9 12 2020 6213\n7 Hussein N.R. Saleem Z.S.M. Ibrahim N. Musa D.H. Naqid I.A. The impact of COVID-19 pandemic on the care of patients with kidney diseases in Duhok city, Kurdistan region of Iraq, diabetes & metabolic syndrome Clin. Res. Rev. 14 6 2020 1551 1553\n8 Ahmed S.S. Mohammed D.A. Mohammed A.A. Hematological parameters in adult patients with COVID-19; A case-control study Int. J. Infect. 8 4 2021 e110359\n9 Xu P. Zhou Q. Xu J. Mechanism of thrombocytopenia in COVID-19 patients vol. 99 2020 1205 1208 6\n10 Wool G.D. Miller J.L. The impact of COVID-19 disease on platelets and coagulation Pathobiology : J. Immunopathol. Mol. Cell. Biol. 88 1 2021 15 27\n11 Alonso-Beato R. Morales-Ortega A. Fernández F.J.D.l.H. Morón A.I.P. Ríos-Fernández R. Rubio J.L.C. Centeno N.O. Immune thrombocytopenia and COVID-19: case report and review of literature Lupus 30 9 2021 1515 1521 34053365\n12 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. Thoma A. Beamish A.J. Noureldin A. Rao A. Vasudevan B. Challacombe B. Perakath B. Kirshtein B. Ekser B. Pramesh C.S. Laskin D.M. Machado-Aranda D. Miguel D. Pagano D. Millham F.H. Roy G. Kadioglu H. Nixon I.J. Mukherjee I. McCaul J.A. Chi-Yong Ngu J. Albrecht J. Rivas J.G. Raveendran K. Derbyshire L. Ather M.H. Thorat M.A. Valmasoni M. Bashashati M. Chalkoo M. Teo N.Z. Raison N. Muensterer O.J. Bradley P.J. Goel P. Pai P.S. Afifi R.Y. Rosin R.D. Coppola R. Klappenbach R. Wynn R. De Wilde R.L. Surani S. Giordano S. Massarut S. Raja S.G. Basu S. Enam S.A. Manning T.G. Cross T. Karanth V.K.L. Kasivisvanathan V. Mei Z. The SCARE 2020 guideline: updating consensus surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 33181358\n13 Hussein N.R. Naqid I.A. Saleem Z.S.M. Almizori L.A. Musa D.H. Ibrahim N. A sharp increase in the number of COVID-19 cases and case fatality rates after lifting the lockdown in Kurdistan region of Iraq Ann. Med. Surg. 57 2020 140 142\n14 Hussein N.R. Naqid I.A. Saleem Z.S.M. Dildar H.M. Ibrahim N. The impact of breaching lockdown on the spread of COVID-19 in Kurdistan region, Iraq Avicenna J. Clin. Microbiol. Infect. 7 1 2020 34 35\n15 Hussein N.R. Rashad B.H. Almizori L.A. Yousif S.S. Sadeeq A.T. Abdulkareem Y.R. Mahmood A.M. Salih Z.K. The risk of SARS-CoV-2 reinfection in Duhok city, Kurdistan region of Iraq Mediterr. J. Hematol. Infect. Dis. 13 1 2021\n16 Hussein N.R. Balatay A. Naqid I.A. Jamal S.A. Rasheed N.A. Ahmed A.N. Salih R.S. Mahdi A.S. Mansour S.A. Mahdi S. COVID-19 antibody seroprevalence in Duhok, Kurdistan Region, Iraq: a population-based study medRxiv 2021 10.1101/2021.03.23.21254169\n17 Bhattacharjee S. Banerjee M. Immune thrombocytopenia secondary to COVID-19: a systematic review SN Compr. Clin. Med. 2020 1 11\n18 Yang X. Yang Q. Wang Y. Wu Y. Xu J. Yu Y. Shang Y. Thrombocytopenia and its association with mortality in patients with COVID-19 J. Thromb. Haemostasis : JTH 18 6 2020 1469 1472 32302435\n19 Pavord S. Thachil J. Hunt B.J. Practical guidance for the management of adults with immune thrombocytopenia during the COVID-19 pandemic vol. 189 2020 1038 1043 6\n20 Granat L.M. Singh A.D. Cortese M. Velez V. Lichtin A. Severe thrombocytopenia in a patient with otherwise asymptomatic COVID-19 Cleve. Clin. J. Med. 88 2 2021 86 92 33526461\n21 Polprasert C. Prayongratana K. Levofloxacin-induced severe thrombocytopenia J. Med. Assoc. Thailand = Chotmaihet thangphaet 92 Suppl 3 2009 S69 S71\n22 Bomhof G. Mutsaers P. Leebeek F.W.G. COVID-19-associated immune thrombocytopenia vol. 190 2020 e61 e64 2\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2049-0801",
"issue": "72()",
"journal": "Annals of medicine and surgery (2012)",
"keywords": "COVID-19; Drug-induced immune thrombocytopaenia (DITP); Immune thrombocytopaenia; Immune thrombocytopaenic purpura (ITP); SARS-CoV-2; Thrombocytopaenia",
"medline_ta": "Ann Med Surg (Lond)",
"mesh_terms": null,
"nlm_unique_id": "101616869",
"other_id": null,
"pages": "103097",
"pmc": null,
"pmid": "34840780",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": "34007423;32296910;32846367;32302435;34053365;33049751;32754314;33681066;32984764;24991422;33181358;19702070;33526461;32952972;32420612;32374026",
"title": "A rare case of absolute thrombocytopaenia in a COVID-19 patient: Case report.",
"title_normalized": "a rare case of absolute thrombocytopaenia in a covid 19 patient case report"
} | [
{
"companynumb": "IQ-MYLANLABS-2021M1093558",
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"activesubstancename": "LEVOFLOXACIN"
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{
"abstract": "OBJECTIVE\nTo report a case of abscess formation in bilateral ovarian endometriomas after failure of mifepristone-induced abortion.\n\n\nMETHODS\nA-36-year-old multiparous woman with bilateral ovarian endometriomas conceived spontaneously and received mifepristone to induce an abortion at 35 days' gestation. Fever and lower abdominal pain occurred 28 days after the abortion. The patient then underwent surgical curettage for an incomplete abortion complicated by endometritis. Her symptoms and signs became aggravated, and computed tomography showed a large ovarian abscess. She underwent laparoscopic drainage of the abscess plus the enucleation of the ovarian endometriomas, and received intravenous antibiotic treatment. She resumed menstruation one month later and was doing well at the 11-month follow-up.\n\n\nCONCLUSIONS\nThis case demonstrates the importance of combining antibiotic therapy with mifepristone to induce abortions in women with known ovarian endometriomas.",
"affiliations": null,
"authors": "Chao|A S|AS|;Chang|S D|SD|;Wang|C J|CJ|;Chao|A|A|;Wang|T H|TH|",
"chemical_list": "D000021:Abortifacient Agents, Steroidal; D015735:Mifepristone",
"country": "China",
"delete": false,
"doi": null,
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"issn_linking": "0390-6663",
"issue": "43(5)",
"journal": "Clinical and experimental obstetrics & gynecology",
"keywords": null,
"medline_ta": "Clin Exp Obstet Gynecol",
"mesh_terms": "D000021:Abortifacient Agents, Steroidal; D000027:Abortion, Incomplete; D000028:Abortion, Induced; D000038:Abscess; D000328:Adult; D004715:Endometriosis; D005260:Female; D006801:Humans; D015735:Mifepristone; D010049:Ovarian Diseases; D011247:Pregnancy",
"nlm_unique_id": "7802110",
"other_id": null,
"pages": "766-768",
"pmc": null,
"pmid": "30074336",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Abscess formation in ovarian endometriomas after failure of mifepristone-induced abortion.",
"title_normalized": "abscess formation in ovarian endometriomas after failure of mifepristone induced abortion"
} | [
{
"companynumb": "TW-PFIZER INC-2018383237",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MISOPROSTOL"
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"abstract": "Myasthenia gravis (MG) is a neuromuscular disorder characterized by an autoimmune defect in the neuromuscular junction. In most patients, the autoimmune attack is mediated by antibodies against the acetylcholine receptor (AChR) on the postsynaptic membrane. Deficient immunoregulation, including regulatory T cells, is consistently observed. Extracorporeal photopheresis (ECP) leads to the induction of regulatory T cells that mediate immunologic tolerance in autoimmune diseases; however, the data regarding MG are very limited.\n\n\n\nHere, we report a patient who, during ongoing ECP therapy for his severe, refractory, chronic graft-versus-host disease (cGVHD), developed MG, although he responded very well to ECP, as indicated by the lowering of his chronic cGVHD severity grade to moderate.\n\n\n\nDespite receiving ECP, our patient developed MG, which was resistant to treatment and required intensive care unit support.\n\n\n\nClose surveillance is required when ECP is planned as one of the treatment alternatives in myasthenia gravis that develop in cGVHD.",
"affiliations": "Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Bahçeşehir University.;Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Antalya, Turkey.;Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Antalya, Turkey.;Intensive Care Unit, Istanbul Kemerburgaz University Faculty of Medicine.;Pediatric Bone Marrow Transplantation Unit, Medical Park Göztepe Hospital, Bahçeşehir University.;Pediatric Hematology and Oncology and Bone Marrow Transplantation Unit, Medipol University Faculty of Medicine, Istanbul, Turkey.;Pediatric Bone Marrow Transplantation Unit, Medical Park Antalya Hospital, Bahçeşehir University.",
"authors": "Uygun|Vedat|V|;Daloğlu|Hayriye|H|;Öztürkmen|Seda Irmak|SI|;Döşemeci|Levent|L|;Karasu|Gülsün|G|;Hazar|Volkan|V|;Yeşilipek|Akif|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/trf.13821",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1132",
"issue": "56(12)",
"journal": "Transfusion",
"keywords": null,
"medline_ta": "Transfusion",
"mesh_terms": "D002908:Chronic Disease; D006086:Graft vs Host Disease; D006801:Humans; D008297:Male; D009157:Myasthenia Gravis; D017893:Photopheresis",
"nlm_unique_id": "0417360",
"other_id": null,
"pages": "3081-3085",
"pmc": null,
"pmid": "27612294",
"pubdate": "2016-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Extracorporeal photopheresis did not prevent the development of an autoimmune disease: myasthenia gravis.",
"title_normalized": "extracorporeal photopheresis did not prevent the development of an autoimmune disease myasthenia gravis"
} | [
{
"companynumb": "TR-MYLANLABS-2017M1048633",
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"activesubstancename": "CYCLOSPORINE"
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{
"abstract": "We describe a rare case of adenovirus interstitial nephritis in a 37-year-old man, 4 weeks following deceased donor renal transplantation. He presented with gross hematuria and acute graft dysfunction. A renal biopsy revealed necrotizing tubulointerstitial nephritis with intranuclear viral inclusions in the tubular epithelial cells. Immunohistochemistry and polymerase chain reaction confirmed adenovirus infection. Reduction in immunosuppression alone resulted in rapid improvement of graft function. Awareness of the clinical and characteristic biopsy findings may help establish the correct diagnosis, which is crucial as disseminated infection, if left untreated, is associated with a high mortality rate in renal allograft recipients.",
"affiliations": "Department of Nephrology, G. Kuppuswamy Naidu Memorial Hospital, Coimbatore, Tamil Nadu, India.;Center for Renal and Urological Pathology Private Limited, Chennai, Tamil Nadu, India.",
"authors": "Seralathan|G|G|;Kurien|A A|AA|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/ijn.IJN_218_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-28-38510.4103/ijn.IJN_218_16Case ReportAdenovirus Interstitial Nephritis: An Unusual Cause for Early Graft Dysfunction Seralathan G. Kurien A. A. 1Department of Nephrology, G. Kuppuswamy Naidu Memorial Hospital, Coimbatore, Tamil Nadu, India1 Center for Renal and Urological Pathology Private Limited, Chennai, Tamil Nadu, IndiaAddress for correspondence: Dr. A. A. Kurien, Center for Renal and Urological Pathology Private Limited, Chennai - 600 040, Tamil Nadu, India. E-mail: anila_abraham08@yahoo.comSep-Oct 2018 28 5 385 388 Copyright: © 2018 Indian Journal of Nephrology2018This 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.We describe a rare case of adenovirus interstitial nephritis in a 37-year-old man, 4 weeks following deceased donor renal transplantation. He presented with gross hematuria and acute graft dysfunction. A renal biopsy revealed necrotizing tubulointerstitial nephritis with intranuclear viral inclusions in the tubular epithelial cells. Immunohistochemistry and polymerase chain reaction confirmed adenovirus infection. Reduction in immunosuppression alone resulted in rapid improvement of graft function. Awareness of the clinical and characteristic biopsy findings may help establish the correct diagnosis, which is crucial as disseminated infection, if left untreated, is associated with a high mortality rate in renal allograft recipients.\n\nKeywords:\nAcute graft dysfunctionadenovirusinterstitial nephritisrenal biopsy\n==== Body\nIntroduction\nViral infections can cause significant morbidity in renal transplant recipients. BK polyomavirus (BKV) and cytomegalovirus (CMV) are the more frequently encountered viral infections. Adenovirus interstitial nephritis (ADVIN) of the renal allograft is an exceptionally rare occurrence. We describe a case of ADVIN that presented within four weeks after deceased donor renal transplantation.\n\nCase Report\nA 37-year-old male with end-stage renal disease due to chronic glomerulonephritis on maintenance hemodialysis underwent deceased donor renal transplantation in March 2015. Complement-dependent cytotoxicity crossmatch was negative and CMV serology status was donor negative/recipient positive. Basiliximab (interleukin-2 receptor antagonist 20 mg 2 doses on day 0 and day 4) was used for induction along with methylprednisolone 1 g for 3 days, followed by triple immunosuppression (tacrolimus 0.1 mg/kg/day, mycophenolate mofetil [MMF] 2 g/day, and prednisolone 20 mg/day).\n\nHe underwent reexploration on the same day for a bleeding complication. There was no vascular anastomotic leak. He was transfused with three units of leukocyte filtered packed red blood cells. During the course, he developed lower respiratory tract infection (sputum culture - Klebsiella), which was treated with intravenous (IV) meropenem and supportive treatment.\n\nHe reached a best creatinine of 1.0 mg/dl by 10th postoperative day. As his tacrolimus trough level on the 10th day was 3.76 ng/ml with a dose of 0.1 mg/kg/day in two divided doses, tablet diltiazem 30 mg once daily was added, and the tacrolimus trough level reached 7.7 ng/ml on the 15th day. He was discharged with the triple drug regimen, a beta blocker, antiviral, and antibiotic prophylaxis (Valganciclovir 450mg and Cotrimoxazole double-strength once daily).\n\nOn day 23 posttransplantation, he started passing blood clots in the urine. There was no dysuria or fever and his creatinine was 1.5 mg/dl. The double J-stent in situ was removed on day 25. The next day, his creatinine increased to 1.8 mg/dl and the hematuria persisted. Urine culture following stent removal grew Klebsiella. He was given IV antibiotics for the positive urine culture though the white blood cell count was normal. Procalcitonin level was 0.24 ng/ml. Graft ultrasound revealed normal echotexture, no hydroureteronephrosis, and a resistive index of 0.6 units. The possibility of a viral infection was considered. Urine for Decoy cells was negative. Adenovirus DNA was detected in the urine by polymerase chain reaction (PCR) using in vitro diagnostic approved Multiplex PCR Kit targeting human adenovirus using specific primers/probe, Fast Track Diagnostics, Luxembourg. PCR was carried out in Rotor-Gene Q 5Plex real-time PCR machine, Qiagen, Germany; PCR for CMV and BKV was negative.\n\nThe renal allograft biopsy showed edematous cortex and medulla diffusely infiltrated by lymphocytes, plasma cells, and neutrophils. Areas of interstitial hemorrhage were present. There was tubular epithelial cell necrosis and cell debris filled the tubular lumen [Figure 1]. Some of the tubular basement membranes were ruptured. Foci of tubular epithelial cells had enlarged nuclei with smudged nuclear material [Figure 2]. No granulomas were identified. The glomeruli and blood vessels were spared. Immunostaining for C4d was negative. Immunohistochemical staining for adenovirus (anti-adenovirus antibody clone 20/11, dilution 1:400, EMD Millipore, Germany) was positive on the abnormal tubular epithelial cells [Figure 3]. Immunohistochemical stains for CMV and BKV were negative.\n\nFigure 1 Focal necrotizing tubulointerstitial nephritis (H and E, ×200)\n\nFigure 2 Intranuclear viral inclusion body (arrow) in the tubular epithelial cell (H and E, ×400)\n\nFigure 3 Immunohistochemical stain for adenovirus antigen shows intranuclear and cytoplasmic staining in the tubular epithelial cells\n\nThe diagnosis of ADVIN was made based on viral cytopathic effects seen on light microscopy, presence of viral antigens by immunohistochemistry, and viral DNA by PCR. Electron microscopy was not performed.\n\nHis immunosuppression drugs were reduced (tacrolimus 0.08 mg/kg/day, MMF 1.5 g/day, and prednisolone 10 mg/day). Hematuria settled in a week. His creatinine returned back to 1.0 mg/dl on follow-up (day 52). His creatinine at last follow-up in June 2016 (15 months posttransplantation) was 1.1 mg/dl.\n\nDiscussion\nHuman adenoviruses are a large group of DNA viruses, which cause self-limited respiratory, gastrointestinal, and conjunctival disease in immunocompetent patients. They may be responsible for severe, protracted, and even life-threatening infections in renal and other organ transplant recipients, causing a major impact on morbidity, mortality, and graft survival.[1]\n\nAdenoviruses are classified into seven subgroups, which are further divided into 52 serotypes. The serotypes have different organ tropism. Serotypes 11, 35, and 37 cause renal allograft dysfunction.[1] Infection caused by adenovirus can be classified as (i) asymptomatic adenovirus infection when the virus is detected in urine, blood, stool, or upper airway specimens by viral culture, antigen tests, or PCR, but signs and symptoms of the infection are absent and (ii) adenovirus disease, like our patient, when there are organ-specific signs and symptoms with simultaneous detection of the virus in biopsy specimens by immunohistochemical stains, or from bronchioalveolar lavage or cerebrospinal fluid by culture or PCR, in the absence of another disease. The disease is said to be disseminated when two or more organs are involved, not including viremia.[2]\n\nThe incidence of adenovirus infection ranges from 3% to 47% in stem cell transplant recipients and from 5% to 22% in solid organ transplant recipients. In kidney transplant recipients, the reported incidence is 4.1%.[345] Majority of adenovirus infection in transplant recipients is a result of reactivation of a latent infection. It may rarely be due to a primary infection or transmitted through donor organs.[6]\n\nAdenovirus infection is commonly reported early after transplant when the immunosuppression is intense.[7] The mean time of presentation is 3 (1–8) months. Our patient presented on the 23rd posttransplant day, which is uncommon. Late-onset disease, ranging from 17 to 144 months[3] and also causing obstructive uropathy, has been reported.[8]\n\nHemorrhagic cystitis is the most common clinical manifestation of the infection in renal transplant recipients.[29] Other manifestations of urinary tract involvement include interstitial nephritis, acute tubular necrosis, and ureteral obstruction with hydronephrosis or rarely as a mass lesion in the kidney.[2810] Literature review showed that majority of patients present with gross hematuria, dysuria, fever, and acute graft dysfunction.[1011] Our patient did not have fever or dysuria at any point during this disease.\n\nThe different approaches available for the specific diagnosis of adenovirus infection include viral culture, molecular methods, and histopathology. Serologic studies are not commonly used as it has low sensitivity and its significance is uncertain in immunocompromised patients as they may not be able to elicit an immune response.[1]\n\nMany adenovirus serotypes can be isolated in cell culture lines that are commonly used in diagnostic virology laboratories but a few, such as types 40 and 41, fail to grow.[1] Viral culture has only a limited clinical significance in renal transplant recipients as adenovirus can be shed in the urine for a prolonged period in an asymptomatic individual and a positive result may not signify adenoviral disease. Furthermore, it may take up to 28 days for the result.[12]\n\nPCR methods that amplify and detect adenovirus DNA are the commonly used laboratory method to confirm infection with an adenovirus. It is a highly sensitive diagnostic test that gives rapid results. PCR also has the advantage of picking up all adenovirus serotypes and qualitative as well as quantitative assays are available. However, the PCR results should be correlated with the clinical findings to distinguish adenoviral disease from asymptomatic shedding of the virus. Although urine PCR was positive in our patient, the renal biopsy diagnosis confirmed the diagnosis. Serial quantitative PCR is useful for planning the treatment as well as to gauge the response to therapy.[313]\n\nA renal biopsy is very useful in renal transplant recipients to identify histological changes of viral infection, rejection, or other concomitant pathology. The histopathological features include (i) viral inclusion bodies in the nuclei of tubular epithelial cells, (ii) severe tubular destruction with neutrophilic infiltration, cell necrosis, and rupture of tubular basement membranes, (iii) focal necrotizing tubulointerstitial nephritis which may show small granulomas, and (iv) interstitial hemorrhage and intratubular red blood cell casts. Glomeruli and blood vessels are usually spared though very rarely the parietal epithelial cells lining the Bowman's capsule may reveal viral cytopathic changes.[141516] Our patient had the typical viral cytopathic changes along with severe tubular destruction and interstitial hemorrhage on the graft biopsy, but no granulomatous inflammatory response was identified.\n\nThe presence of adenovirus within the renal tissue can be confirmed using immunoperoxidase staining and/or in situ hybridization.[141516] The diagnosis in our patient was confirmed by the positive immunoperoxidase staining for adenovirus antigens.\n\nElectron microscopy can identify the typical 70–80 nm diameter adenoviral particles within the nuclei and cytoplasm of tubular epithelial cells. Adenoviruses are usually double the size of BKV and half of that of CMV.[16]\n\nThe common differential diagnoses for ADVIN when viral inclusions are identified include BK and CMV nephritis. The presence of interstitial hemorrhage and severe necrotizing lesions disrupting the tubular basement membranes favors adenoviral nephritis.[141516] If a granulomatous inflammation is also present, tuberculosis, sarcoidosis, fungal infections, drugs, and antineutrophil cytoplasmic autoantibody-associated vasculitis need to be ruled out.[16]\n\nRarely, ADVIN and cellular rejection may coexist and pose a diagnostic challenge. In such situations, the presence of overriding tubulitis, intimal arteritis, and a positive C4d staining on the peritubular capillaries would favor the presence of rejection.[2] There was no glomerulitis or vasculitis in our patient. His C4d immunostain was also negative and so a diagnosis of acute antibody-mediated rejection was ruled out.\n\nReduction of immunosuppression is the mainstay of treatment. IV immunoglobulin, cidofovir, and ribavirin have been reported as therapies.[39101117] However, no prospective randomized clinical trials have been performed to support the use of any antiviral agent for adenovirus infection.[2] Our patient's graft function improved dramatically just by lowering the dose of immunosuppressants. He was not given any antiviral drug except for the continuation of the CMV prophylaxis.\n\nIn summary, our case highlights that adenovirus infection should also be considered in the workup for early graft dysfunction in renal transplant recipients. Awareness of the presenting features and, characteristic biopsy findings supported by immunohistochemical stains and molecular studies help establish a correct diagnosis. This case also highlights that resolution of the infection was achieved by reduction in the immunosuppression.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Echavarria M Adenovirus in immunocompromised hosts Clin Microbiol Rev 2008 21 704 15 18854488 \n2 Florescu MC Miles CD Florescu DF What do we know about adenovirus in renal transplantation? Nephrol Dial Transplant 2013 28 2003 10 23493328 \n3 Watcharananan SP Avery R Ingsathit A Malathum K Chantratita W Mavichak V Adenovirus disease after kidney transplantation: Course of infection and outcome in relation to blood viral load and immune recovery Am J Transplant 2011 11 1308 14 21449944 \n4 McGrath D Falagas ME Freeman R Rohrer R Fairchild R Colbach C Adenovirus infection in adult orthotopic liver transplant recipients: Incidence and clinical significance J Infect Dis 1998 177 459 62 9466537 \n5 Humar A Reactivation of viruses in solid organ transplant patients receiving cytomegalovirus prophylaxis Transplantation 2006 82 2 Suppl S9 14 \n6 Kojaoghlanian T Flomenberg P Horwitz MS The impact of adenovirus infection on the immunocompromised host Rev Med Virol 2003 13 155 71 12740831 \n7 Florescua DF Hoffmanb JA AST Infectious Diseases Community of Practice. Adenovirus in solid organ transplantation Am J Transplant 2013 13 206 11 23465013 \n8 Kolankiewicz LM Pullman J Raffeld M Kopp JB Glicklich D Adenovirus nephritis and obstructive uropathy in a renal transplant recipient: Case report and literature review NDT Plus 2010 3 388 92 25949439 \n9 Hofland CA Eron LJ Washecka RM Hemorrhagic adenovirus cystitis after renal transplantation Transplant Proc 2004 36 3025 7 15686686 \n10 Emovon OE Chavin J Rogers K Self S Adenovirus in kidney transplantation: An emerging pathogen? Transplantation 2004 77 1474 5 15167614 \n11 Gaspert A Lüthi B Mueller NJ Bossart W Heim A Wüthrich RP Subacute allograft failure with dysuria and hematuria in a kidney transplant recipient Am J Kidney Dis 2009 54 154 8 19121556 \n12 Suparno C Milligan DW Moss PA Mautner V Adenovirus infections in stem cell transplant recipients: Recent developments in understanding of pathogenesis, diagnosis and management Leuk Lymphoma 2004 45 873 85 15291344 \n13 Leruez-Ville M Minard V Lacaille F Buzyn A Abachin E Blanche S Real-time blood plasma polymerase chain reaction for management of disseminated adenovirus infection Clin Infect Dis 2004 38 45 52 14679447 \n14 Ito M Hirabayashi N Uno Y Nakayama A Asai J Necrotizing tubulointerstitial nephritis associated with adenovirus infection Hum Pathol 1991 22 1225 31 1660851 \n15 Asim M Chong-Lopez A Nickeleit V Adenovirus infection of a renal allograft Am J Kidney Dis 2003 41 696 701 12612996 \n16 Singh HK Nickeleit V Kidney diseases caused by viral infections Curr Diagn Pathol 2004 10 11 21 \n17 Ison MG Green M AST Infectious Diseases Community of Practice. Adenovirus in solid organ transplant recipients Am J Transplant 2009 9 Suppl 4 S161 5 20070676\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "28(5)",
"journal": "Indian journal of nephrology",
"keywords": "Acute graft dysfunction; adenovirus; interstitial nephritis; renal biopsy",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "385-388",
"pmc": null,
"pmid": "30271002",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "9466537;25949439;18854488;12740831;15291344;16858271;21449944;1660851;23465013;14679447;15167614;15686686;23493328;12612996;20070676;19121556",
"title": "Adenovirus Interstitial Nephritis: An Unusual Cause for Early Graft Dysfunction.",
"title_normalized": "adenovirus interstitial nephritis an unusual cause for early graft dysfunction"
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"companynumb": "IN-ACCORD-073299",
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"activesubstancename": "MEROPENEM"
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{
"abstract": "Antineoplastic drugs are one of the pharmacological classes more frequently involved in occurrence of \"serious\" adverse drug reactions. However, few epidemiological data are available regarding the preventability of adverse drug reactions with ambulatory cancer chemotherapy. We assessed the rate and characteristics of \"preventable\" or \"potentially preventable\" \"serious\" adverse drug reactions induced by oral protein kinase inhibitors (PKIs). We performed a retrospective study with all \"serious\" adverse drug reactions (ADRs) recorded from 1 January 2008 to 31 December 2009 in the French Pharmacovigilance Database with the eight oral protein kinase inhibitors marketed in France: sorafenib, imatinib, erlotinib, sunitinib, dasatinib, lapatinib, nilotinib and everolimus (Afinitor®) using the French adverse drug reactions preventability scale. This study was carried out on 265 spontaneous notifications. Most of adverse drug reactions were \"unpreventable\" (63.8 %). Around one third were \"unevaluable\" due to notifications poorly documented (medical history, dosage, use of drugs as first or second intention, concomitant drugs). One (0.4 %) adverse drug reaction was \"preventable\" with dasatinib (subdural hematoma) and three (1.1 %) were \"potentially preventable\" (hepatic adverse drug reactions): two with imatinib and one with sorafenib. For these four cases, we identified some characteristics: incorrect dosages, drug interactions and off-label uses. An appropriate prescription could avoid the occurrence of 1.5 % \"serious\" adverse drug reactions with oral PKIs. This rate is low and further studies are needed to compare our results by using other preventability instruments and to improve the French ADRs Preventability Scale.",
"affiliations": "Laboratoire de Pharmacologie Médicale et Clinique, Equipe de Pharmaco Epidémiologie INSERM U 1027, Faculté de Médecine de l'Université de Toulouse and Service de Pharmacologie Clinique, Centre Midi-Pyrénées de Pharmaco Vigilance, de Pharmaco Epidémiologie et d'Informations sur le Médicament, Centre Hospitalier Universitaire, Toulouse, France.",
"authors": "Egron|Adeline|A|;Olivier-Abbal|Pascale|P|;Gouraud|Aurore|A|;Babai|Samy|S|;Combret|Sandrine|S|;Montastruc|Jean-Louis|JL|;Bondon-Guitton|Emmanuelle|E|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors",
"country": "France",
"delete": false,
"doi": "10.1007/s11523-014-0328-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1776-2596",
"issue": "10(2)",
"journal": "Targeted oncology",
"keywords": null,
"medline_ta": "Target Oncol",
"mesh_terms": "D000284:Administration, Oral; D016907:Adverse Drug Reaction Reporting Systems; D000970:Antineoplastic Agents; D016208:Databases, Factual; D054796:Drug Dosage Calculations; D004347:Drug Interactions; D064420:Drug-Related Side Effects and Adverse Reactions; D005602:France; D006801:Humans; D008508:Medication Errors; D056687:Off-Label Use; D060735:Pharmacovigilance; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "101270595",
"other_id": null,
"pages": "229-34",
"pmc": null,
"pmid": "25056801",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": "20812770;7791255;17110152;15064936;15929472;8320571;16141567;10215758;4002188;22201475;10082069;12111885;11072960;10472690;11127022;12700376;20458055",
"title": "Preventable and potentially preventable serious adverse reactions induced by oral protein kinase inhibitors through a database of adverse drug reaction reports.",
"title_normalized": "preventable and potentially preventable serious adverse reactions induced by oral protein kinase inhibitors through a database of adverse drug reaction reports"
} | [
{
"companynumb": "FR-PFIZER INC-2009247271",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANTITHROMBIN III HUMAN"
},
"drugadditional": n... |
{
"abstract": "A 72-year-old man was admitted to our hospital because of right upper limb monoplegia 8 hours after the initial intravitreal injection of aflibercept, which is an inhibitor of vascular endothelial growth factor. Magnetic resonance diffusion-weighted images showed recent ischemic lesions in the left corona radiata and the right superior frontal gyrus. Laboratory findings showed mild hyperfibrinolysis. A patent foramen ovale was diagnosed on transesophageal echocardiography; however, lower-extremity ultrasonography did not detect deep vein thrombosis. The source of embolism remained unknown. A possible mechanism of cerebral emboli in the present case was a rapidly induced hypercoagulative state due to transfer of aflibercept from the vitreous body to the systemic circulation.",
"affiliations": "Department of Neurology, Saiseikai Kumamoto Hospital.;Department of Neurology, Saiseikai Kumamoto Hospital.;Department of Neurology, Saiseikai Kumamoto Hospital.;Department of Neurology, Graduate School of Medical Sciences, Kumamoto University.;Department of Neurology, Saiseikai Kumamoto Hospital.;Department of Neurology, Graduate School of Medical Sciences, Kumamoto University.",
"authors": "Mizutani|Hironori|H|;Inatomi|Yuichiro|Y|;Singu|Takaomi|T|;Nakajima|Makoto|M|;Yonehara|Toshiro|T|;Ando|Yukio|Y|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-001162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": "58(5)",
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "age-related macular degeneration; anti-vascular endothelial growth factor therapy; brain embolism; hypercoagulative state; intravitreal injection",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": "D000368:Aged; D001921:Brain; D038524:Diffusion Magnetic Resonance Imaging; D006801:Humans; D020766:Intracranial Embolism; D058449:Intravitreal Injections; D008297:Male; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D020521:Stroke; D019851:Thrombophilia",
"nlm_unique_id": "0417466",
"other_id": null,
"pages": "314-319",
"pmc": null,
"pmid": "29710026",
"pubdate": "2018-05-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Embolic stroke immediately after initial administration of intravitreal aflibercept.",
"title_normalized": "embolic stroke immediately after initial administration of intravitreal aflibercept"
} | [
{
"companynumb": "JP-SA-2018SA154445",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AFLIBERCEPT"
},
"drugadditional": "3",
"dr... |
{
"abstract": "BACKGROUND\nFebrile infection-related epilepsy syndrome (FIRES) has been described as an epileptic encephalopathy of unknown etiology affecting previously healthy children following febrile illness. Despite large investigations on autoimmune pathogenesis no membrane antibodies has been associated since now.\n\n\nMETHODS\nWe report a 13 years-old girl with negative history for neurological or autoimmune disease that developed at the sixth day of high fever a super-refractory status epilepticus. All investigations, including the most common antibodies related to immune-mediated encephalitis were negative. Seizures continued despite several therapeutic trials with anesthetics (midazolam, propofol) and antiepileptic agents as well as i.v. immunoglobulins but responded, at day 10 from the onset, to ketamine and high dose i.v. steroids. Due the high suspicion of autoimmune encephalitis we tested patient's CSF and plasma on mouse brain with positive response. We subsequently detected a high titre of GABAAR antibodies. After the resolution of the status epilepticus the patient achieved complete recovery of neurological functions.\n\n\nCONCLUSIONS\nthis is the first reported case of a FIRES-like condition due to autoimmune encephalitis mediated by GABAAR antibodies. Our case suggests that GABAAR antibodies should be investigated FIRES.",
"affiliations": "Neurophysiology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.;Institute of Neurology, Fondazione Policlinico Universitario \"Agostino Gemelli\", Università Cattolica del Sacro Cuore, Rome, Italy.;Neurophysiology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy.;Neurophysiology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital, Rome, Italy. Electronic address: lucia.fusco@opbg.net.",
"authors": "Caputo|D|D|;Iorio|R|R|;Vigevano|F|F|;Fusco|L|L|",
"chemical_list": "D000927:Anticonvulsants; D001323:Autoantibodies; D011963:Receptors, GABA-A; D013256:Steroids; D007649:Ketamine",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejpn.2017.11.005",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3798",
"issue": "22(1)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Autoimmune encephalitis; FIRES; GABA(A) Receptors (GABA(A)-R); GABA(A) receptor Antibodies (GABA(A)-Ab); Ketamine; Super-refractory status epilepticus (SRSE)",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000293:Adolescent; D000927:Anticonvulsants; D001323:Autoantibodies; D000069279:Drug Resistant Epilepsy; D004660:Encephalitis; D000073376:Epileptic Syndromes; D005260:Female; D050031:Hashimoto Disease; D006801:Humans; D007649:Ketamine; D011963:Receptors, GABA-A; D012640:Seizures; D013226:Status Epilepticus; D013256:Steroids",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "182-185",
"pmc": null,
"pmid": "29203057",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Febrile infection-related epilepsy syndrome (FIRES) with super-refractory status epilepticus revealing autoimmune encephalitis due to GABAAR antibodies.",
"title_normalized": "febrile infection related epilepsy syndrome fires with super refractory status epilepticus revealing autoimmune encephalitis due to gabaar antibodies"
} | [
{
"companynumb": "IT-SHIRE-IT201807612",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nHepatobiliary and pancreatic manifestations have been reported in patients with Crohn's disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used.\n\n\nMETHODS\nData were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center.\n\n\nRESULTS\nOur study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated.\n\n\nCONCLUSIONS\nIn our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.",
"affiliations": "Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece.;Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece.;Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece.;Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece.;Department of Internal Medicine, Medical school and University of Ioannina, Ioannina, Greece.;Department of Surgery, Medical school and University of Ioannina, Ioannina, Greece.;Department of Internal Medicine, Medical school and University of Ioannina, Ioannina, Greece.;Department of Internal Medicine, Medical school and University of Ioannina, Ioannina, Greece.;Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece. dchristodoulou@gmail.com.",
"authors": "Fousekis|Fotios S|FS|;Katsanos|Konstantinos H|KH|;Theopistos|Vasileios I|VI|;Baltayiannis|Gerasimos|G|;Kosmidou|Maria|M|;Glantzounis|Georgios|G|;Christou|Leonidas|L|;Tsianos|Epameinondas V|EV|;Christodoulou|Dimitrios K|DK|http://orcid.org/0000-0001-9694-1160",
"chemical_list": "D000305:Adrenal Cortex Hormones; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s12876-019-0967-3",
"fulltext": "\n==== Front\nBMC GastroenterolBMC GastroenterolBMC Gastroenterology1471-230XBioMed Central London 96710.1186/s12876-019-0967-3Research ArticleHepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study Fousekis Fotios S. fotisfous@gmail.com 1Katsanos Konstantinos H. khkostas@hotmail.com 1Theopistos Vasileios I. vasileios.theopistos@gmail.com 1Baltayiannis Gerasimos gmpaltag@cc.uoi.gr 1Kosmidou Maria mkosmidou@uhi.gr 2Glantzounis Georgios gglantzounis@gmail.com 3Christou Leonidas lchristu@cc.uoi.gr 2Tsianos Epameinondas V. ep.tsianos@gmail.com 2http://orcid.org/0000-0001-9694-1160Christodoulou Dimitrios K. dchristodoulou@gmail.com 11 0000 0001 2108 7481grid.9594.1Department of Gastroenterology and Hepatology, Medical school and University of Ioannina, Ioannina, Greece 2 0000 0001 2108 7481grid.9594.1Department of Internal Medicine, Medical school and University of Ioannina, Ioannina, Greece 3 0000 0001 2108 7481grid.9594.1Department of Surgery, Medical school and University of Ioannina, Ioannina, Greece 3 4 2019 3 4 2019 2019 19 4820 3 2018 27 3 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHepatobiliary and pancreatic manifestations have been reported in patients with Crohn’s disease or ulcerative colitis. Our aim was to describe the prevalence of hepatobiliary and pancreatic manifestations in inflammatory bowel disease and their association with the disease itself and the medications used.\n\nMethods\nData were retrospectively extracted from the clinical records of patients followed up at our tertiary IBD referral Center.\n\nResults\nOur study included 602 IBD patients, with liver function tests at regular intervals. The mean follow-up was 5.8 years (Std. Dev.: 6.72). Abdominal imaging examinations were present in 220 patients and revealed findings from the liver, biliary tract and pancreas in 55% of examined patients (120/220). The most frequent findings or manifestations from the liver, biliary tract and pancreas were fatty liver (20%, 44/220), cholelithiasis (14.5%, 32/220) and acute pancreatitis (0.6%, 4/602), respectively. There were 7 patients with primary sclerosing cholangitis. Regarding hepatitis viruses, one-third of the patients had been tested for hepatitis B and C. 5% (12/225) of them had positive hepatitis B surface antigen and 13.4% had past infection with hepatitis B virus (positive anti-HBcore). In addition, most of the patients were not immune against hepatitis B (negative anti-HBs), while 3% of patients were anti-HCV positive and only one patient had active hepatitis C. Furthermore, 24 patients had drug-related side effects from the liver and pancreas. The side effects included 21 cases of hepatotoxicity and 3 cases of acute pancreatitis. Moreover, there were two cases of HBV reactivation and one case of chronic hepatitis C, which were successfully treated.\n\nConclusion\nIn our study, approximately one out of four patients had some kind by a hepatobiliary or pancreatic manifestation. Therefore, it is essential to monitor liver function at regular intervals and differential diagnosis should range from benign diseases and various drug related side effects to severe disorders, such as primary sclerosing cholangitis.\n\nKeywords\nInflammatory bowel diseaseHepatotoxicityAcute pancreatitisHepatobiliary manifestationsPancreatic manifestationsFatty liverImmunomodulatorsissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nUlcerative colitis and Crohn’s disease are inflammatory diseases which affect the gastrointestinal tract. However, both disorders can also involve other organ systems as well. It is not unusual for patients with IBD to have manifestations from the liver, pancreas, gallbladder and biliary tree. The strongest associated disease with IBD is primary sclerosing cholangitis (PSC). PSC is an idiopathic chronic progressive disease of the biliary tree and can cause stenosis and destruction of extra- and intrahepatic bile ducts. It is estimated that 5% of patients with UC develop PSC and up to 80–90% of patients with PSC have UC [1]. Other manifestations from the biliary tree in IBD patients include cholangitis and cholangiocarcinoma, mainly as complications of PSC [2]. The gallbladder is an organ that may be affected by IBD. Cholelithiasis is more common in patients with CD than in general population and patients with CD have a two-fold increased risk of gallstones. On the other hand, patients with UC do not have any additional risk [3]. The main independent risk factors for the development of gallstones are ileo-colonic CD location, the extent of ileal resection (> 30 cm), disease duration (> 15 years) and multiple or prolonged total parenteral nutrition treatments [4]. Hepatic manifestations in IBD vary and range from benign disorders, such as fatty liver to end-stage hepatic failure as a complication of PSC or primary biliary cirrhosis. Non-alcoholic fatty liver disease (NAFLD) refers to the accumulation of fat in hepatocytes without alcohol use. Hepatic steatosis can be diagnosed either by imaging or by histology (biopsy). Prevalence of NAFLD in IBD patients varies, ranging from 8.2 to 40% [5]. Furthermore, it seems that IBD patients develop NAFLD with fewer metabolic risk factors than general population [6]. Other hepatic manifestations in patients with IBD include liver abscess [7], granulomatous hepatitis, hepatic amyloidosis and primary biliary cirrhosis (PBC). The first three disorders are more frequent in CD, while PBC is more common in patients with UC [8].\n\nIn addition, drug-induced hepatotoxicity is common side effect of IBD treatment. More analytically, in the United Kingdom from 1991 to 1998, the incidence of hepatitis was 3.2 and 6 cases per million prescriptions for mesalazine and sulfasalazine, respectively. What is more, it seems that there is a stronger association between 5-ASA induced hepatotoxicity and rheumatoid arthritis than IBD [9]. Also, methotrexate has been associated with liver damage and it was proposed that the mechanism is dose dependent. A meta-analysis of clinical trials showed that the rate of abnormal aminotransferase serum levels [defined as up to a 2 fold elevate over the upper limit of the normal (ULN)] in patients treated with methotrexate for IBD was 1.4 per 100 person-months, while the incidence of hepatotoxicity (defined as greater than a 2 fold over ULN) was 0.9 per 100 person-months [10]. On the other hand, thiopurine induced liver damage is not dose dependent and the abnormalities in liver tests occur more frequently in the first months of therapy [11]. The incidence of thiopurine-induced liver injury is approximately 4% [12]. Anti–tumor necrosis factor (anti-TNF) biological agents rarely cause liver damage. Anti-TNF-induced liver damage may occur irrespectively of the number of infusions or injections, time and dose [13]. Additionally, patients with IBD have reduced immunogenicity due to the presence of IBD (malabsorption and malnutrition) and immunosuppressive treatment (immunomodulators and biological agents). Hence, IBD patients have an increased risk of hepatitis B reactivation or loss of immunity against hepatitis B and exacerbation of hepatitis C [14].\n\nAcute pancreatitis and, more infrequently, chronic pancreatitis and autoimmune pancreatitis may occur in patients with IBD due to the disease itself or side effects of medication used in the treatment. The increased incidence of acute pancreatitis in Crohn’s disease can be attributed to anatomic abnormalities of the duodenum and more frequent development of cholelithiasis in Crohn’s disease as a result of ileal disease [15]. Also, acute pancreatitis is a fairly frequent side effect of azathioprine and 6-mercaptopourine use (4%) [12] and a less common side effect of 5-aminosalicylate (5-ASA) and corticosteroid treatment [16].\n\nThe aim of this retrospective study was to document the manifestations of the liver, pancreas and biliary tree in patients with Inflammatory Bowel Disease and describe their association with the disease itself and the medications used.\n\nMethods\nIn our retrospective study, we included 602 patients with IBD, who were monitored at our tertiary University Hospital from 1977 to 2016. The diagnosis of the disease was based on histopathological findings after ileocolonoscopy with biopsies. Inclusion criteria for the study were diagnosis of IBD and regular follow-up from time of diagnosis with frequent laboratory tests. Consequently, every patient who participated in this study had baseline liver function tests measured at diagnosis of IBD and at regular intervals, at least every 6 months. All patients were followed up from the time of diagnosis of IBD in our referral center. Furthermore, 220 patients underwent imaging evaluation, such as ultrasound and computed tomography, and were tested for hepatitis viruses B and C. A complete registry of all clinical, laboratory, imaging and histologic abnormalities related to liver, biliary tree and pancreas was made.\n\nStatistical analysis\nData were analyzed using SPSS software version 22. All clinical and pathological features were categorized as either continuous or categorical variables. Continuous variables were summarized as means and standard deviation.\n\nResults\nThe average age of patients was 39 years (Std. Dev. 17.4) at diagnosis. 57.5% of IBD patients had UC, 42.5% CD 59.8% of patients were males and 40.2% were females. The predominant symptom during diagnosis was bloody stools (38.3%). Particularly, in patients with CD, diarrhea was the most common symptom (49%), while bloody stools was the most common symptom in patients with ulcerative colitis (60%). The mean follow-up time of patients was 5.8 years (Std. Dev.: 6.72). There was no difference between liver function tests at diagnosis of disease and during last measurement (Table 1).Table 1 Liver function tests of IBD patients at diagnosis and at last follow-up\n\nLiver Function Tests\tLFT at Diagnosis\tLFT at last follow-up\t\nAST (IU/L)\t23.9 (Std. Dev. 20.5)\t25.5 (Std. Dev. 16.1)\t\nALT (IU/L)\t24.8 (Std. Dev. 23.1)\t26.7 (Std. Dev. 27.3)\t\nALP (IU/L)\t90 (Std. Dev. 70.1)\t82.3 (Std. Dev. 65.8)\t\nγ-GT (IU/L)\t29.7 (Std. Dev. 49.3)\t26.9 (Std. Dev. 30.5)\t\n\n\nOver 200 out of 602 patients were tested for antibodies against hepatitis B and C. Specifically, 5.3% (12/225) had hepatitis B (Hepatitis B surface Antigen positive, HBsAg) and 13.4% (28/208) had past HBV infection (anti-HBcore positive and HBsAg negative). Also, most of the patients were not immune against hepatitis B (67/207 anti-HBs positive, 32.4%) (Fig. 1). With regard to hepatitis C, 3% of patients (6/201) were anti-HCV positive, but only one patient had active chronic hepatitis C (HCV-RNA positive).Fig. 1 Prevalence of Hepatitis B Virus in IBD patients\n\n\n\nOverall, 36.5% (220/602) of patients had at least one abdominal imaging evaluation. Most patients were males (134 versus 86 females), while the type of IBD was shared (107 UC, 113 CD). One hundred seventy-five patients (29.1%) underwent ultrasound which was the most frequent imaging test performed, as expected. MRCP, ERCP, CT and MRI were performed in 13, 6, 92 and 7 cases, respectively. The imaging tests revealed abnormal findings in 54.5% of examined patients (120 patients) (Table 2). The findings ranged from benign and innocent lesions, such as liver cyst and hemangioma to malignant and severe diseases such as cholangiocarcinoma and primary sclerosing cholangitis. Most of the findings were from the liver (74 patients) and the most frequent hepatic manifestation (20%) was fatty liver. Most of the patients with fatty liver were male (28 males versus 16 females) and had ulcerative colitis (28 UC, 16 CD). Hemangioma (11 cases), cysts (14 cases), ischemic hepatitis (1 case), multiple liver abscesses (1 case), primary biliary cirrhosis (1 case), portal vein thrombosis (1 case), fibrosis (1 case) and cirrhosis (1 case) were the other liver diseases. In the case of patient with portal vein thrombosis, the risk factors for portal vein thrombosis, such as myeloproliferative disorders, protein S and C deficiency and antiphospholipid syndrome, were investigated and were negative. So, IBD was implicated as the main risk factor. The patient had moderate ulcerative colitis. The patient with liver abscesses had Crohn’s disease, while the patient with primary biliary cirrhosis had ulcerative colitis. The most frequent manifestation of the biliary tract was cholelithiasis. The patients with cholelithiasis more frequently had Crohn’s disease (20 CD, 12 UC). Cholecystitis, PSC, polyps in the gallbladder and cholangiocarcinoma were the other findings from the biliary tract (Table 2). From the pancreatic manifestations, the most common was acute pancreatitis (4 cases). All patients with acute pancreatitis had Crohn’s disease. In 3 out of 4 cases, acute pancreatitis was caused by medication, while in one case, the cause was gallstones. Two cases of drug-induced pancreatitis were caused by azathioprine and one case was caused by mesalamine. Drug-induced pancreatitis was established as diagnosis, when there was a reasonable temporal sequence between AP development and administration of the drug and withdrawal of drug causes clinical improvement. Re-exposure (re-challenge) was not used in any patient. All patients with drug-induced pancreatitis were young (17, 21 and 36 years of age), acute pancreatitis was mild and all patients were treated with discontinuation of the suspect medication and adequate intravenous fluid resuscitation. In addition, azathioprine caused two cases of significantly elevated amylase and after azathioprine withdrawal, amylase was normalized.Table 2 Presentation of characteristics (age, sex, localization) of IBD patients at diagnosis and the frequency of suggestive imaging findings, overall and in ulcerative colitis and Crohn’s disease separately\n\n\tTotal number of IBD patients\tPatients with Ulcerative colitis\tPatients with Crohn’s disease\t\nSeverity at diagnosis of IBD\t\tAccording to MAYO score\n48% (166/346) Mild\n29% (100/346) Moderate\n23% (80/346) Severe\tAccording to CDAI score\n27% (69/256) Mild\n41% (105/256) Moderate\n32% (82/256) Severe\t\nLocalization\t\t24% (83/346) Proctitis\n41% (142/346) Left sided colitis\n35% (121/346) Pancolitis\t29% (74/256) Ileitis\n38% (97/256) Colitis\n33% (85/256) Ileitis and colitis\t\nAge at diagnosis\t39 (Std. Dev. 17.4)\t42 (Std. Dev. 18.9)\t35 (Std. Dev. 16.3)\t\nSex (Male/Female)\t360 (60%)/ 242 (40%)\t202 (58%) /144 (42%)\t162 (63%) /94 (37%)\t\nFatty liver\t44 (20%, 44/220)\t28\t(26.2%, 28/107)\t16\t(14.2%, 16/113)\t\nHemangioma\t11 (5%, 11/220)\t7\t(6.5%, 7/107)\t4\t(3.5%, 4/113)\t\nCyst\t14 (6.3%, 14/220)\t8\t(7.5%, 8/107)\t6\t(5.3%, 6/113)\t\nMultiple liver abscesses\t1 (0.4%, 1/220)\t0\t(0%)\t1\t(0.9%, 1/113)\t\nFibrosis\t1 (0.4%, 1/220)\t0\t(0%)\t1\t(0.9%, 1/113)\t\nCirrhosis\t1 (0.4%, 1/220)\t0\t(0%)\t1\t(0.9% 1/113)\t\nPortal vein thrombosis\t1 (0.4%, 1/220)\t1\t(0.9%, 1/107)\t0\t(0%)\t\nCholelithiasis\t32 (14.5%, 32/220)\t12\t(11.2%, 12/107)\t20\t(17.7%, 20/113)\t\nPrimary sclerosing cholangitis\t7 (3.2%, 7/220)\t2\t(1.9%, 2/107)\t5\t(4.4%, 5/113)\t\nCholecystitis\t7 (3.2%, 7/220)\t3\t(2.8%, 3/107)\t4\t(3.5%, 4/113)\t\nPolyps in the gallbladder\t5 (2.3%, 5/220)\t4\t(3.7%, 4/107)\t1\t(0.9%, 1/113)\t\nCholangiocarcinoma\t1 (0.4%, 1/220)\t1\t(0.9%, 1/107)\t0\t(0%)\t\nAcute pancreatitis\t4 (1.8%, 4/220)\t0\t(0%)\t4\t(3.5%, 4/113)\t\nFatty pancreas\t2 (0.9%, 2/220)\t1\t(0.9%, 1/107)\t0\t(0%)\t\nChronic pancreatitis\t1 (0.4%, 1/220)\t1\t(0.9%, 1/107)\t0\t(0%)\t\n\n\nDrug-induced hepatotoxicity\nOverall, 76% of patients in our study received 5-ASA, 68.1% corticosteroids, 31.5% azathioprine, 10.7% methotrexate, 15.8% infliximab and 4.5% adalimumab at some point during their therapy. The mean duration of methotrexate administration was 69.2 weeks (Std. Dev. 71.6) and the mean cumulative dose was 1287 mg, while the mean time of azathioprine administration was 597 days (Std. Dev. 522). In 21 cases, IBD treatment caused drug induced liver injury (DILI). DILI was defined when other causes of liver injury, such as viral hepatitis and PSC, had been excluded and withdrawal of drug caused laboratory improvement. Also, we used the Roussel Uclaf Causality Assessment Method (RUCAM) for the definition of DILI. The mean age of patients with hepatotoxicity was 37 years (17 to 72) and the majority of these patients were males (14 males versus 7 females). None of them had preexisting liver disease. The drug-induced hepatotoxicity was caused by methotrexate, azathioprine and mesalamine. Hepatotoxicity occurred in the first weeks of treatment. After drug withdrawal, the liver function tests returned to normal (Table 3).Table 3 Information about drug-induced hepatotoxicity. The table demonstrates the mean duration of drug administration, the number of cases with hepatotoxicity for each drug and the mean value (range) of liver enzymes during toxicity\n\nDrug\tDuration of medication\tOveraall number of cases\tAST (U/L)\tALT (U/L/)\tALP (U/L)\tGGT (U/L)\tCases with ALT > 3\tCases with ALT > 5\t\nMethotrexate\t10 weeks (4–20)\t9\t77 (30–128)\t170 (62–382)\t100 (43–234)\t63 (23–152)\t1\t\t\nAzathioprine\t5.5 weeks (3–9)\t9\t383 (69–1165)\t280 (113–594)\t260 (43–613)\t768 (38–2143)\t\t3\t\nMesalamine\t15 weeks (13–17)\t3\t63 (51–75)\t97 (71–123)\t83 (78–88)\t45 (42–48)\t\t\t\n\n\nParticularly, according to R factor for liver injury, in 8 of the 9 AZA-hepatotoxicity cases hepatotoxicity liver injury was observed (R > 5) and in only one case the cause of liver injury was mixed (R: 2–5). Furthermore, there were 22 cases of mild transient elevation of transaminases [definite as up to a 2-fold elevate over the upper limit of the normal range (ULN)]. Mild elevations of transaminases occurred approximately 30 weeks after inception of drug administration (Fig. 2). From patients with hepatotoxicity, there were 3 patients with ALT > 5 ULN and four patients with ALT > 3 ULN, while there was not any patient with Hy’s Law. Specifically, 10 patients suffered from UC, while 16 patients had CD.Fig. 2 Presentation of patients who were treated with azathioprine and presented mild (< 2 ULN) or severe (> 2 ULN) hepatotoxicity\n\n\n\nThere were two cases of HBV reactivation in patients with CD who were treated with azathioprine. They had inactive hepatitis B with normal liver function tests prior to the administration of azathioprine B and they did not receive any chemoprophylaxis. In both cases, at reactivation of HBV, transaminases were more than 10-fold of upper limit of the normal range (ULN), and HBV-DNA was > 20,000 IU/mL. In one case, reactivation occurred 8 months after the start of azathioprine administration and 2 months after the start of 8 mg of methylprednisolone. The patient received both drugs for 2 months. After HBV reactivation, methylprednisolone was discontinued, the patient was successfully treated with entecavir, achieving both biochemical and virological response (with negative HBV-DNA). In the other case, the reactivation of HBV occurred 50 days after azathioprine administration, with HBV-DNA: 10,000 IU/mL, ALT: 94 U/L and AST 83 U/L. The patient was treated with tenofovir and also achieved biochemical and virological response. Additionally, a female patient with UC, who was treated with azathioprine for 2 years and suffered from chronic hepatitis C, developed elevated transaminases more than 2 ULN, while HCV-RNA was positive. Eventually, she was successfully treated with ledispavir 90 mg and sofosbuvir 400 mg for 12 weeks, achieving sustained virological response after treatment. Liver biochemical tests returned to normal levels after HCV therapy.\n\nPrimary Sclerosing cholangitis\nAmong 602 patients with IBD, there were 7 patients who were diagnosed with large duct primary sclerosing cholangitis. Surprisingly, 5 of these patients suffered from Crohn’s disease and only two from ulcerative colitis. Also, five were males and two females. Apart from one case, in which IBD was diagnosed 7 years after diagnosis of PSC, in the other 6 cases, PSC and IBD were diagnosed at the same period. The average age of PSC diagnosis was 32.8 years old (17 to 56) and the mean follow-up of PSC was 10 years (1 to 19 years). One patient underwent liver transplantation because she developed liver failure 12 years after diagnosis of PSC, and another patient developed cirrhosis after 7 years from diagnosis. All patients were treated with ursodeoxycholic acid, while gallstones were found in two of the seven patients with PSC. Table 4 shows the liver function tests on the last visit to the hospital (Table 4).Table 4 Presentation of patients with primary sclerosing cholangitis, their liver function tests on the last visit to the hospital and their outcomes\n\nGender of PSC patient\tAge at diagnosis(years)\tType of IBD\tAST (U/L)\tALT (U/L)\tALP (U/L)\tGGT (U/L)\tTBL (mg/dL)\tDuration PSC (years)\tOutcome\t\n1.Male\t32\tCD\t31\t49\t53\t30\t1\t14\tSlow progression\t\n2.Male\t48\tUC\t33\t62\t103\t132\t0.8\t9\tSlow progression\t\n3.Female\t51\tCD\t133\t190\t716\t171\t3.7\t9\tBefore liver transplantation\t\n4.Male\t17\tCD\t14\t19\t50\t33\t0.7\t1\tSlow progression\t\n5.Female\t55\tCD\t41\t56\t43\t15\t0.9\t19\tSlow progression\t\n6.Male\t27\tCD\t18\t15\t61\t21\t0.9\t5\tSlow progression\t\n7.Male\t68\tUC\t97\t58\t92\t41\t0.7\t12\tCirrhosis\t\n\n\nDiscussion\nOver 50% (120/220) of patients undergoing imaging evaluation presented findings or manifestations from the liver, biliary tract and pancreas. Fatty liver was the most frequent finding (20%). Imaging evaluation was performed, when there was an indication, such abnormal biochemical liver function tests, and this is one of the limitations of our study. This prevalence of fatty liver in our patients with inflammatory bowel disease was lower than what Bargiggia et al. have found (37%) [5]. The increased prevalence of liver steatosis in IBD can be explained by improved IBD treatment, with most of the IBD patients not being malnourished and usually having normal or increased weight. Furthermore, IBD therapy includes medications such as corticosteroids and methotrexate that have been associated with liver steatosis development [17]. Unfortunately, there was no accurate information about alcohol consumption, BMI and factors-related with metabolic syndrome of our patients. Despite that, most patients did not consume alcohol at all and the remainder were barely social drinkers. In addition most of them had normal BMI. So it is unlikely that these factors had played a significant role on steatosis.\n\nConcerning the biliary tract, cholelithiasis was the most frequent finding as expected. In our study, the prevalence of cholelithiasis was 14.5% in IBD patients and 18% specifically in patients with Crohn’s disease, with a highest number of males having cholelithiasis (18 males versus 14 females). The prevalence of cholelithiasis was similar in comparison with other studies, as the prevalence of cholelithiasis in CD ranges from 11 to 34%, while in general population, it ranges from 5.5 to 15% [3]. Concerning PSC, the prevalence of PSC in IBD patients and particularly in patients with UC was lower than reported in the literature (UC 0.7% and CD 2.5% versus UC 5% and CD 3%) [18]. The decreased incidence of PSC in our retrospective study may be due to limited use of MRCP in the first two decades of retrospective study. Our tertiary center has started to use MRCP since 1993. Also, the males with PSC were more than the females with PSC and the average age of patients with PSC was 32.8 years. It has been described that PSC occurs in middle age with a 2:1 male predominance [19]. Furthermore, gallstones were found in 28% (2/7) of patients with PSC, as cholelithiasis is a common finding in patients with PSC, and approximately 25% of PSC patients have gallstones [20].\n\nRegarding the pancreas, acute pancreatitis was the most common manifestation and the cumulative incidence rate was 0.76%, with 5.8 years mean follow-up period. All cases occurred in patients with CD. The cumulative incidence rate of acute pancreatitis in patients with CD was 2%. In another study, the incidence was greater, but the follow-up time was longer (cumulative incidence 1.6% with follow-up for 14 years) [21]. In a Danish follow-up study, the risk of acute pancreatitis was four fold in patients with CD [22] and in a retrospective study of 852 patients with CD and a follow-up period of 10 years, the described frequency of acute pancreatitis was 1.4% [23]. Drug-induced acute pancreatitis is one of the most severe complications of IBD medication and many medications, such as thiopurines, corticosteroids, metronidazole and biological agents, have been implicated. In our study, in 3 out of 4 cases, acute pancreatitis was caused by medication. The drug-induced pancreatitis occurred a few days after the beginning of therapy (for azathioprine cases after 10 and 25 days and for mesalazine case after 28 days). The delay between drug introduction and acute pancreatitis was similar to that of the literature described [21]. Additionally, it is worth mentioning that the differential diagnosis of causes of acute pancreatitis in IBD patients should include DIPI, biliary pancreatitis, auto-immune pancreatitis and duodenal involvement.\n\nViral hepatitis can be a major problem in IBD patients and all IBD patients should be tested for viral hepatitis. In our study, approximately 35% of patients had evidence of their immunization for hepatitis B and C status in their medical records. Present and/or past HBV infectious was found in 24.1% of patients with UC and in 14.2% of patients with CD. Active HBV infection was found in 11 patients with UC, but only in one patient with CD. Also, past HCV infections were found in 5 patients with UC [anti-HCV positive and HCV RNA negative (undetectable), 6.2%], while one patient with UC had chronic HCV infection (anti-HCV positive and HCV RNA positive). This prevalence is very high and it seems that in the past HBV and HCV screening was probably performed selectively, when HBV and HCV infections were suspected. In a Spanish multicenter study with 2076 IBD patients, present and/or past HBV and HCV infections were found in 9.7% of IBD patients [24]. In patients, who were tested for anti-HBs (antibodies against HBsAg), only 32.4% proved positive. Furthermore, another retrospective study reported low proportion (51%) of immunity against HBV in patients with IBD [25]. The low proportion of IBD patients with immunity against HBV is partly due to the reduced immunogenicity, because of disease course and immunosuppressive treatment. Apart from that it has been also reported that IBD patients have poorer response to HBV vaccination than general population (< 50% versus 95%) [26] and a high proportion of IBD patients with protective anti-HBs titers after vaccination lose them over time [27]. The cases with HBV reactivation show that we should screen patients who will receive immunosuppressive therapy even when the liver function tests are normal (actually in all cases). All HBsAg-positive should receive entecavir or tenofovir alafenamide fumarate or tenofovir disoproxil fumarate as treatment or prophylaxis, while in patients with past HBV infection (HBsAg negative and anti-HBc positive), prophylaxis is not routinely recommended. In these patients, HBsAg and/or HBV-DNA should be monitored every 1 to 3 months during and after immunosuppressive therapy, and in case of seroconversion to positive HBsAg or detectable HBV-DNA, treatment with entecavir or tenofovir alafenamide fumarate or tenofovir disoproxil fumarate should begin immediately [28, 29]. In one of our cases with HBV reactivation, the patient was treated with simultaneous immunosuppressants (corticosteroid and azathioprine). A multicenter retrospective study reported that treatment with two or more immunosuppressants is an independent factor for HBV reactivation (OR 8.75; 95% CI 1.16 to 65.66) [30].\n\nMethotrexate and azathioprine were the drugs administered in most cases of hepatotoxicity. Approximately 15% (1.1 per person-months) of patients who received methotrexate had liver toxicity. Methotrexate is well-known to cause hepatotoxicity, and according to a meta-analysis, the pooled incidence rate of abnormal transaminase levels [definite as up to a 2-fold elevate over the upper limit of the normal range (ULN)] in IBD patients treated with methotrexate is 1.4 per 100 person-months, while the rate of hepatotoxicity (> 2 ULN) is 0.9 per 100 person-months. Also, the rate of withdrawal from treatment due to liver injury is 0.8 per 100-person months [10]. In our study, 4.6% (9/192) of patients who received azathioprine had liver injury (1 per 35 person-years) and the incidence was similar to the literature data. Specifically, the incidence of AZA-liver injury varies and ranges from 3% (in retrospective studies) to 10% (in prospective studies) [31, 32]. In addition, hepatotoxicity from AZA was dose independent and occurred only few weeks after administration of AZA, while many patients received AZA for more than 1 year without manifesting liver injury. AZA-induced DILI was dose independent. The liver toxicity from 5-ASA agents was mild. After drug withdrawal, liver function tests normalized. We suggest discontinuing azathioprine in case of persistent elevation of aminotransferases > 3 ULN. Alternative approaches include the change to 6-mercaptopurine, which may be better tolerated, or the combination of allopurinol 100 mg daily with low dose azathioprine (approximately 30% of the initial or regular dose). With such an approach, therapeutic levels of the metabolite 6-thioguanine can be achieved, with concomitant decrease of the levels of hepatotoxic metabolites of azathioprine (6-methylmercaptopurine).\n\nConclusion\nHepatobiliary and pancreatic manifestations in IBD are frequent and their range is wide. In our study, one out of four patients presented some kind of hepatobiliary or pancreatic manifestation related to the disease itself or medications. Hence, monitoring liver function in patients with IBD at regular intervals is essential and the differential diagnosis should include from side effects of therapy, and common and benign diseases, such as fatty liver, to rare and chronic diseases such as primary sclerosing cholangitis. Furthermore, we should not forget that IBD patients should be screened for viral hepatitis B and C markers and immunized against hepatitis B.\n\nAbbreviations\nCDCrohn’s disease\n\nHBVHepatitis B virus\n\nHCVHepatitis C virus\n\nIBDInflammatory Bowel Disease\n\nNAFLDNon-alcoholic Liver Disease\n\nPSCPrimary sclerosing cholangitis\n\nUCUlcerative colitis\n\nAcknowledgements\nNot Applicable.\n\nFunding\nNo funding was obtained for this study.\n\nAvailability of data and materials\nThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nET, DC, KK, Research concept and design. FF, VT, KK, GB Collection of data. MK, GG, Data Analysis, FF, ET, DC, LC, Writing. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis retrospective study was conducted according to the Ethical Guidelines for Medical and Health Research Involving Human Subjects. The present study was approved by the Ethics Review Committee of University of Ioannina. No additional permissions were required to review the patient records, including the hospitals from which the records were obtained.\n\nConsent for publication\nNot Applicable.\n\nCompeting interests\nThe authors declare that they have no competing interest.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Wang R Leong RW Primary sclerosing cholangitis as an independent risk factor for colorectal cancer in the context of inflammatory bowel disease: a review of the literature World J Gastroenterol 2014 20 27 8783 8789 25083052 \n2. Claessen MM Vieggaar FP Tytgat KM Siersema PD van Buuren HR High lifetime risk of cancer in primary sclerosing cholangitis J Hepatol 2009 50 1 158 164 10.1016/j.jhep.2008.08.013 19012991 \n3. Gizard E Ford AC Bronowicki JP Peyrin-Biroulet L Systematic review: the epidemiology of the hepatobiliary manifestations in patients with inflammatory bowel disease Aliment Pharmacol Ther 2014 40 1 3 15 10.1111/apt.12794 24815622 \n4. Parente F Pastore L Bargiggia S Cucino C Greco S Molteni M Incidence and risk factors for gallstones in patients with inflammatory bowel disease: a large case-control study Hepatology 2007 45 5 1267 1274 10.1002/hep.21537 17464998 \n5. Bargiggia S Maconi G Elli M Molteni P Ardizzone S Parente F Sonographic prevalence of liver steatosis and biliary tract stones in patients with inflammatory bowel disease: study of 511 subjects at a single center J Clin Gastroenterol 2003 36 5 417 420 10.1097/00004836-200305000-00012 12702985 \n6. Sourianarayanane A Garg G Smith TH Butt MI McCullough AJ Shen B Risk factors of non-alcoholic fatty liver disease in patients with inflammatory bowel disease J Crohns Colitis 2013 7 8 e279 e285 10.1016/j.crohns.2012.10.015 23158500 \n7. Mir-Madjlessi SH McHenry MC Farmer RG Liver abscess in Crohn's disease. Report of four cases and review of the literature Gastroenterology 1986 91 4 987 993 10.1016/0016-5085(86)90704-3 3743974 \n8. Koulentaki M Koutroubakis IE Petinaki E Tzardi M Oekonomaki H Mouzas I Ulcerative colitis associated with primary biliary cirrhosis Dig Dis Sci 1999 44 10 1953 1956 10.1023/A:1026697613173 10548342 \n9. Ransford RA Langman MJ Sulphasalazine and mesalazine: serious adverse reactions re-evaluated on the basis of suspected adverse reaction reports to the Committee on Safety of Medicines Gut 2002 51 4 536 539 10.1136/gut.51.4.536 12235076 \n10. Khan N Abbas AM Whang N Balart LA Bazzano LA Kelly TN Incidence of liver toxicity in inflammatory bowel disease patients treated with methotrexate: a meta-analysis of clinical trials Inflamm Bowel Dis 2012 18 2 359 367 10.1002/ibd.21820 21751301 \n11. Fraser AG Orchard TR Jewell DP The efficacy of azathioprine for the treatment of inflammatory bowel disease: a 30 year review Gut 2002 50 4 485 489 10.1136/gut.50.4.485 11889067 \n12. Chaparro M Ordas I Cabre E Garcia-Sanchez V Bastida G Penalva M Safety of thiopurine therapy in inflammatory bowel disease: long-term follow-up study of 3931 patients Inflamm Bowel Dis 2013 19 7 1404 1410 10.1097/MIB.0b013e318281f28f 23665964 \n13. Shelton E Chaudrey K Sauk J Khalili H Masia R Nguyen DD New onset idiosyncratic liver enzyme elevations with biological therapy in inflammatory bowel disease Aliment Pharmacol Ther 2015 41 10 972 979 10.1111/apt.13159 25756190 \n14. Rahier JF Ben-Horin S Chowers Y Conlon C De Munter P D'Haens G European evidence-based consensus on the prevention, diagnosis and management of opportunistic infections in inflammatory bowel disease J Crohns Colitis 2009 3 2 47 91 10.1016/j.crohns.2009.02.010 21172250 \n15. Pitchumoni CS Rubin A Das K Pancreatitis in inflammatory bowel diseases J Clin Gastroenterol 2010 44 4 246 253 10.1097/MCG.0b013e3181cadbe1 20087199 \n16. Douros A Bronder E Andersohn F Klimpel A Thomae M Ockenga J Drug-induced acute pancreatitis: results from the hospital-based Berlin case-control surveillance study of 102 cases Aliment Pharmacol Ther 2013 38 7 825 834 10.1111/apt.12461 23957710 \n17. Matsumoto T Yamasaki S Arakawa A Abe K Abe H Kon K Exposure to a high total dosage of glucocorticoids produces non-alcoholic steatohepatits Pathol Int 2007 57 6 388 389 10.1111/j.1440-1827.2007.02112.x 17539971 \n18. 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"fulltext_license": "CC BY",
"issn_linking": "1471-230X",
"issue": "19(1)",
"journal": "BMC gastroenterology",
"keywords": "Acute pancreatitis; Fatty liver; Hepatobiliary manifestations; Hepatotoxicity; Immunomodulators; Inflammatory bowel disease; Pancreatic manifestations",
"medline_ta": "BMC Gastroenterol",
"mesh_terms": "D000208:Acute Disease; D000305:Adrenal Cortex Hormones; D000328:Adult; D056486:Chemical and Drug Induced Liver Injury; D015209:Cholangitis, Sclerosing; D002769:Cholelithiasis; D003093:Colitis, Ulcerative; D003424:Crohn Disease; D005234:Fatty Liver; D005260:Female; D006509:Hepatitis B; D006526:Hepatitis C; D006801:Humans; D007166:Immunosuppressive Agents; D008111:Liver Function Tests; D008297:Male; D010195:Pancreatitis; D012189:Retrospective Studies",
"nlm_unique_id": "100968547",
"other_id": null,
"pages": "48",
"pmc": null,
"pmid": "30943899",
"pubdate": "2019-04-03",
"publication_types": "D016428:Journal Article",
"references": "10192201;10548342;11889067;12235076;12702985;14743886;17391318;17464998;17539971;18513380;18626441;19012991;19098850;19268981;20087199;20577000;21172250;21751301;21767410;23158500;23380936;23665964;23957710;24799986;24815622;25052345;25083052;25386085;25756190;28427875;3743974;8308212",
"title": "Hepatobiliary and pancreatic manifestations in inflammatory bowel diseases: a referral center study.",
"title_normalized": "hepatobiliary and pancreatic manifestations in inflammatory bowel diseases a referral center study"
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"abstract": "BACKGROUND\nEpithelial ovarian cancers are a rare subset of the less than 1% of ovarian cancers diagnosed in children. This case highlights considerations when caring for these patients.\n\n\nMETHODS\nEvaluation of a 12-year-old postmenarchal girl who presented with suprapubic pain revealed a solid/cystic pelvic mass involving bilateral adnexa and elevated Cancer Antigen 125 (CA-125) level. Diagnostic laparoscopy pathology confirmed low-grade papillary serous ovarian carcinoma. Treatment involved surgical tumor debulking, hysterectomy, bilateral salpingo-oophorectomy, and omentectomy; adjuvant chemotherapy with no residual disease, and normalization of Cancer Antigen 125 (CA-125) level; and an aromatase inhibitor for maintenance.\n\n\nCONCLUSIONS\nIn children with adult-type gynecologic cancers necessitating treatments including surgical sterilization and hormone-modulating therapy, psychological support and developmentally informed collaboration between adult and pediatric services is essential. Clinical decisions for long-term bone and sexual health present opportunities for future research.",
"affiliations": "Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.;Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan. Electronic address: mwoll@med.umich.edu.;Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.;Department of Surgery, University of Michigan, Ann Arbor, Michigan.;Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.;Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan.",
"authors": "Pennesi|Christine M|CM|;Rosen|Monica W|MW|;McIlwain|Carrie A|CA|;Newman|Erika A|EA|;Reynolds|R Kevin|RK|;Quint|Elisabeth H|EH|",
"chemical_list": "D018394:CA-125 Antigen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jpag.2021.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-3188",
"issue": "34(6)",
"journal": "Journal of pediatric and adolescent gynecology",
"keywords": "Aromatase inhibitor; Epithelial ovarian cancer; Fertility preservation; Hysterectomy; Multidisciplinary care; Pediatric cancer",
"medline_ta": "J Pediatr Adolesc Gynecol",
"mesh_terms": "D000290:Adnexa Uteri; D000328:Adult; D018394:CA-125 Antigen; D000077216:Carcinoma, Ovarian Epithelial; D002648:Child; D005260:Female; D006801:Humans; D007044:Hysterectomy; D010051:Ovarian Neoplasms",
"nlm_unique_id": "9610774",
"other_id": null,
"pages": "893-895",
"pmc": null,
"pmid": "34062234",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Multidisciplinary Clinical Considerations in the Treatment of Pediatric Epithelial Ovarian Cancer.",
"title_normalized": "multidisciplinary clinical considerations in the treatment of pediatric epithelial ovarian cancer"
} | [
{
"companynumb": "US-drreddys-SPO/USA/21/0145457",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LETROZOLE"
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{
"abstract": "We present the case of a 25-year-old Afro-Caribbean man with a longstanding history of ulcerative colitis and primary sclerosing cholangitis. The patient presented to clinic and reported pleuritic-type chest pain. A routine chest radiograph requested from the clinic revealed an incidental right middle zone opacity in the right lung. A subsequent high-resolution CT showed multiple lung nodules. The patient also had a positive cytoplamic anti-neutrophil cytoplasmic antibody (cANCA) and proteinase 3 antibodies. Bronchoscopy was inconclusive. A video-assisted thoracoscopic surgery biopsy was then taken. The histology revealed changes suggestive of bronchiolitis obliterans organising pneumonia. The pulmonary manifestations of inflammatory bowel disease are poorly characterised. Our literature search has revealed cases hypothesising that immune system dysregulation could display pulmonary complications of ulcerative colitis. The aetiology is thought to be related to the treatment with mesalazine. However, our patient also had a positive vasculitic screen. Previous cases have resolved with supportive management or steroid therapy.",
"affiliations": "Department of Respiratory Medicine, Birmingham Heartlands Hospital, Birmingham, UK. ambitalwar@googlemail.com",
"authors": "Talwar|Ambika|A|;Kunst|Heinke|H|;Ngatchu|Theodore|T|;Trotter|Simon|S|",
"chemical_list": null,
"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": "D000328:Adult; D003093:Colitis, Ulcerative; D018549:Cryptogenic Organizing Pneumonia; D006801:Humans; D008297:Male",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23283604",
"pubdate": "2013-01-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10028450;17296657;18591842;4872529",
"title": "A case presentation of a pulmonary complication of ulcerative colitis.",
"title_normalized": "a case presentation of a pulmonary complication of ulcerative colitis"
} | [
{
"companynumb": "GB-WARNER CHILCOTT-2013-002172",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null... |
{
"abstract": "A potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15 years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual-level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11-1.88) compared to nonusers. The IRR increased to 1.60 (95% CI = 1.20-2.13) when users in Norway and Sweden with short follow-up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1-3 years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results.",
"affiliations": "National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.;National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.;Institute of Applied Economics and Health Research, Copenhagen, Denmark.;Institute of Applied Economics and Health Research, Copenhagen, Denmark.;Copenhagen Prostate Cancer Center and Department of Urology, Rigshospitalet, Copenhagen, Denmark.;Copenhagen Prostate Cancer Center and Department of Urology, Rigshospitalet, Copenhagen, Denmark.;Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Helsinki, Finland.;Department of Economics, University of Gothenburg, Gothenburg, Sweden.;Health Services Research Unit, Akershus University Hospital, Oslo, Norway.;National Institute of Public Health, University of Southern Denmark, Copenhagen, Denmark.",
"authors": "Meijer|Mathias|M|;Thygesen|Lau Caspar|LC|;Green|Anders|A|;Emneus|Martha|M|;Brasso|Klaus|K|;Iversen|Peter|P|;Pukkala|Eero|E|;Bolin|Kristian|K|;Stavem|Knut|K|;Ersbøll|Annette K|AK|0000-0002-9407-3387",
"chemical_list": "D058891:5-alpha Reductase Inhibitors; D018120:Finasteride",
"country": "United States",
"delete": false,
"doi": "10.1002/cam4.1273",
"fulltext": "\n==== Front\nCancer MedCancer Med10.1002/(ISSN)2045-7634CAM4Cancer Medicine2045-7634John Wiley and Sons Inc. Hoboken 10.1002/cam4.1273CAM41273Original ResearchCancer PreventionOriginal ResearchFinasteride treatment and male breast cancer: a register‐based cohort study in four Nordic countries M. Meijer et al.Meijer Mathias \n1\n\n2\nThygesen Lau Caspar \n1\nGreen Anders \n3\n\n4\nEmneus Martha \n3\nBrasso Klaus \n5\nIversen Peter \n5\nPukkala Eero \n6\n\n7\nBolin Kristian \n8\n\n9\nStavem Knut \n10\n\n11\n\n12\nErsbøll Annette K. http://orcid.org/0000-0002-9407-3387ake@niph.dk \n1\n\n1 \nNational Institute of Public Health\nUniversity of Southern Denmark\nCopenhagen\nDenmark\n\n2 \nDepartment of Nursing\nMetropolitan University College\nCopenhagen\nDenmark\n\n3 \nInstitute of Applied Economics and Health Research\nCopenhagen\nDenmark\n\n4 \nOdense Patient Data Explorative Network\nOdense University Hospital and University of Southern Denmark\nOdense\nDenmark\n\n5 \nCopenhagen Prostate Cancer Center and Department of Urology\nRigshospitalet\nCopenhagen\nDenmark\n\n6 \nFinnish Cancer Registry\nInstitute for Statistical and Epidemiological Cancer Research\nHelsinki\nFinland\n\n7 \nSchool of Health Sciences\nUniversity of Tampere\nTampere\nFinland\n\n8 \nDepartment of Economics\nUniversity of Gothenburg\nGothenburg\nSweden\n\n9 \nCentre for Health Economics at the University of Gothenburg\nGothenburg\nSweden\n\n10 \nHealth Services Research Unit\nAkershus University Hospital\nOslo\nNorway\n\n11 \nDepartment of Pulmonary Medicine\nMedical Division\nAkershus University Hospital\nOslo\nNorway\n\n12 \nInstitute of Clinical Medicine\nFaculty of Medicine\nUniversity of Oslo\nOslo\nNorway\n* Correspondence\n\nAnnette Kjær Ersbøll, National Institute of Public Health, University of Southern Denmark, Øster Farimagsgade 5A, 1353 København K, Denmark. Tel: +45 6550 7775; Fax: +45 65501090; E‐mail: ake@niph.dk\n13 12 2017 1 2018 7 1 10.1002/cam4.2018.7.issue-1254 260 13 6 2017 04 11 2017 06 11 2017 © 2017 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nA potential link has been suggested between dispensed finasteride and increased risk of male breast cancer (MBC). Due to the rare occurrence of MBC, it remains to be established if such a relationship exists. The purpose of this study was to combine nationwide registers in four countries to assess the potential association between dispensed finasteride and MBC. A cohort of all males with dispensed finasteride in Denmark, Finland, Norway, and Sweden (1,365,088 person years) was followed up for up to 15 years for breast cancer, and compared to a cohort of males unexposed to finasteride. Individual‐level register data included country, dates of dispensed finasteride, MBC diagnosis, and death. Incidence rate ratios (IRRs) were estimated using a generalized linear model with a Poisson distribution. An increased risk of MBC was found among finasteride users (IRR = 1.44, 95% confidence interval [95% CI] = 1.11–1.88) compared to nonusers. The IRR increased to 1.60 (95% CI = 1.20–2.13) when users in Norway and Sweden with short follow‐up time were excluded. The highest IRR was seen among men with medium duration of dispensed finasteride, medium accumulated consumption of finasteride, and among men with first dispensed finasteride prescription 1–3 years prior to diagnosis. The analyses suggested possible ascertainment bias and did not support a clear relationship between dispensed finasteride and MBC. In conclusion, a significant association between dispensed finasteride and MBC was identified. However, due to limited data for adjustment of potential confounding and surveillance bias in the present study, further research is needed to confirm these results.\n\nBreast neoplasms malefinasterideNordic countriespharmacoepidemiologyprostatic neoplasmsregistersMerck Sharp & Dohme Corp.Institute of Applied Economics and Health Research source-schema-version-number2.0component-idcam41273cover-dateJanuary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.1 mode:remove_FC converted:19.01.2018\n\nCancer Medicine \n2018 ; 7(1):254 –260 \n\n\n\nA. G. and M. E. received finance from Merck Sharp & Dohme Corp. for the submitted work. This work was also supported by the Institute of Applied Economics and Health Research.\n==== Body\nIntroduction\nFinasteride is used primarily to relief symptoms from benign prostatic hyperplasia (5 mg pills) and to treat androgenetic alopecia (1 mg pills). Finasteride inhibits the type 2 5α‐reductase enzyme, thereby inhibiting the conversion of testosterone to dihydrotestosterone, leading to shrinkage of androgen‐dependent prostate tissue 1. Use of finasteride increases estradiol levels, which may cause gynecomastia 2. Increased estradiol levels caused by finasteride have raised concerns about a possible link between finasteride use and male breast cancer (MBC) 3, 4, 5, 6, 7, 8. In a cross‐national study in Denmark, Finland, Norway, and Sweden, dispensed finasteride was estimated at 10.8 per 1000 men in 2009 9.\n\nA review found 50 spontaneously reported MBC cases worldwide in patients treated with 5 mg finasteride and three reports in patients treated with 1 mg finasteride 6. The median time to onset of MBC after starting 5 mg finasteride treatment was 36 months (range: 5 weeks to 11 years). The review identified eight cases that were observed in three placebo‐controlled clinical trials 4, 5, 8, where individuals were exposed to 5 mg finasteride and followed up for up to 5 years, altogether for 89,496 person years (PY). The crude incidence rate of MBC in persons treated with finasteride was 7.8 per 100,000 PY (95% confidence interval [95% CI] = 3.7–16.4), which was higher although not statistically different from the MBC rate 3.8 per 100,000 PY (95% CI = 1.2–11.9) in the unexposed group (P = 0.33). On this basis, the review concluded that it could not be excluded that finasteride could be associated with an increased risk of MBC 6. Two recent studies found no significant association between finasteride use and MBC 10, 11.\n\nMBC is a rare disease with a reported age‐adjusted incidence rate of 0.4–1.0 per 100,000 PY in Europe 12, 13, 14. Investigating the possible link between finasteride use and MBC is challenging due to the combination of a limited number of MBC cases 15, 16, 17, 18, 19, 20, 21, 22, potential surveillance bias due to the association between finasteride use and breast enlargement and tenderness, and confounding from obesity, alcohol intake, liver disease, and family history 23. The objective of this study was to investigate if an association exists between dispensed finasteride and MBC incidence in Denmark, Finland, Norway, and Sweden using register data containing all dates and amounts of finasteride redeemed from pharmacies.\n\nMethods\nStudy design\nA register‐based cohort study with prospective data collection was used including all males in Denmark, Finland, Norway, and Sweden. Dispensed finasteride was the exposure variable and MBC diagnosis the study outcome. In this study, the term dispensed finasteride means that finasteride has been purchased and handed out to the patient. The incidence rate of MBC was compared between an exposed cohort of all men in the four Nordic countries having redeemed finasteride and a cohort of all men in the Nordic countries unexposed to finasteride.\n\nData sources and study period\nData were extracted from the national prescription, cancer, and cause of death registers in the four countries. All redeemed prescriptions of finasteride were extracted for 1995–2009 in Denmark, 1997–2010 in Finland, 2004–2009 in Norway, and 2005–2009 in Sweden where finasteride is a prescription‐only medicine. The Anatomic Therapeutic Classification (ATC) code is D11AX10 for 1 mg finasteride and G04CB01 for 5 mg finasteride (in Finland in 1994–1996, 5 mg finasteride was registered as ATC G04CB04 and was not included in the study). During the study period, 1 mg finasteride tablets were sold only in Denmark and Sweden. All inhabitants in the Nordic countries have a unique personal identification code (PIC), which facilitate linkage of individual‐level register data. The PIC is given at birth or immigration, and is used as the identification key in the national registers. Individual information on dates of MBC diagnoses was extracted from national cancer registers. Only the first male breast cancer tumor was included. Individual information on date of death was extracted from the national cause of death registers.\n\nInformation for the general populations on the number of MBC cases and the size of the population was obtained from the NORDCAN database for each country and calendar year (1995, 1996, …, 2010) stratified by 5‐year age groups (0–4, 5–9, 10–14, …, 80–84, ≥85 years) 21. NORDCAN is a Nordic database and program on the incidence, prevalence, mortality, and survival statistics from 50 major cancers in the Nordic countries. Data in each of the Nordic countries are available for more than five decades. NORDCAN provides access to summary data with graphic and tabulation facilities.\n\nMeasures\nThe exposed cohort consisted of all men with a dispensed finasteride prescription in the study period. Individual‐level data were obtained for the exposed cohort from the prescription registers including information on PIC, date of dispensed finasteride prescription, age of the recipient number of packages purchased, pills per package, and dose per pill. These data were linked with individual information on dates of MBC diagnoses from national cancer registers and with individual information on date of death from the national cause of death registers. For the exposed cohort, follow‐up started on the date of the first dispensed finasteride. End of follow‐up was the date of first MBC diagnose, date of death, date of emigration, or end of the study (31 December 2009 in Denmark, Norway, and Sweden, and 31 December 2010 in Finland), whichever came first. The number of PY and number of men with MBC in the exposed cohort were calculated in 5‐year age groups (i.e., 0–34, 35–39, 40–44, …, 80–84, ≥85 years), country, and calendar year.\n\nThe unexposed cohort was established as the difference between the general population and the exposed cohort. This was done by calculating PY in the unexposed cohort as the difference between the size of the general population and the PY in the exposed cohort by each 5‐year age group (i.e., 0–34, 35–39, 30–44, …, 80–84, ≥85 years), country, and calendar year. Hereby, men with a dispensed finasteride prescription contributed with nonexposed risk time before date of first dispensed finasteride prescription and with exposed risk time from first dispensed finasteride prescription. The number of men with MBC in the unexposed cohort was calculated as the difference between number of MBC in the general population and the exposed cohort.\n\nHaving ever redeemed finasteride was the primary exposure variable. Supplementary analyses of finasteride exposure were performed evaluating duration of exposure, cumulative dose, and time since first exposure. The cut‐off values for duration of finasteride exposure, dose, and time since first finasteride exposure were decided prior to analysis in consultation with specialists.\n\nStatistical analyses\nThe primary analysis investigated the association between having ever redeemed finasteride and the incidence rate of MBC among all men in the four countries and stratified by country. The interactions between age group at follow‐up and dispensed finasteride and between country and dispensed finasteride were evaluated. Further analyses on data from Denmark and Finland (with long follow‐up time) were performed evaluating the effect of duration of exposure, cumulative dose, and time since first exposure. The analyses were repeated after removing individuals with their first dispensed finasteride prescription in the first year of follow‐up (i.e., 1995 for Denmark and 1997 for Finland) to account for potential truncation bias (i.e., individuals with dispensed prescription in the first year might be prevalent users and the cumulative exposure cannot be correctly calculated).\n\nAll analyses were performed using a piecewise exponential model for survival data. The analysis was performed using a generalized linear model with a Poisson distribution of number of MBC cases and logarithmic transformation of risk time as offset value. Adjustment was made for age, calendar year, and country as fixed effects. Constant incidence rates within intervals of time were obtained by splitting the risk time for each country, 5‐year age group, and calendar year using the SAS Lexis macro 24. The incidence rate ratios (IRRs) of MBC for the exposed compared to the nonexposed and 95% CI were calculated. All analyses were performed using the PROC GENMOD procedure of SAS version 9.3 (SAS Institute Inc., Cary, NC).\n\nSample size calculation\nThe minimum detectable IRR for MBC comparing finasteride exposed to nonexposed was calculated at 2.6 and 1.9, respectively, assuming a total population of approximately 12 mill men, 10.8 per 1000 men exposed to finasteride, an incidence rate (IR) of MBC among nonexposed at 0.4 and 1 per 100,000 PY, respectively, 15 years follow‐up, a 5% significance level, and a power of 80% 25.\n\nResults\nDuring follow‐up, a total of 902 MBC cases occurred in 112 million PY in the male population in Denmark, Finland, Norway, and Sweden (Table 1). This corresponded to a crude IR of 0.80 MBC cases per 100,000 PY (Table 1). The IR per 100,000 varied between 0.92 in Denmark and 0.66 in Finland. The maximal follow‐up time in the four countries was 15, 14, 6, and 5 years in Denmark, Finland, Norway, and Sweden, respectively. Median time from initiation of finasteride use to MBC diagnosis was 40 months based on 55 MBC cases in Denmark and Finland with long follow‐up time.\n\nTable 1 Number of male breast cancer cases (N\nMBC), number of person years (N\nPY), and crude and age‐standardized (Nordic Standard Population, 2000) incidence rate of MBC (IR) per 100,000 in 1995–2010 overall and stratified by country, calendar period, and age group\n\nVariable\tLevel\t\nN\nMBC\n\t\nN\nPY\n\tIR per 100,000\t\nCrude\tAge standardized\t\nOverall\t\t902\t112,425,969\t0.80\t0.91\t\nCountry\tDenmark\t365\t39,844,762\t0.92\t1.08\t\nFinland\t236\t35,834,189\t0.66\t0.74\t\nNorway\t101\t14,011,628\t0.72\t0.82\t\nSweden\t200\t22,735,390\t0.88\t0.89\t\nYear\t1995–1998\t116\t15,424,184\t0.75\t0.98\t\n1999–2002\t165\t20,691,378\t0.80\t0.96\t\n2003–2006\t303\t36,821,669\t0.82\t0.90\t\n2007–2010\t318\t39,488,738\t0.81\t0.85\t\nAge group\t0–34\t9\t50,567,403\t0.02\t–\t\n35–39\t14\t8,288,627\t0.17\t–\t\n40–44\t22\t8,402,741\t0.26\t–\t\n45–49\t33\t8,120,563\t0.41\t–\t\n50–54\t56\t8,034,841\t0.70\t–\t\n55–59\t85\t7,512,897\t1.13\t–\t\n60–64\t117\t6,496,764\t1.80\t–\t\n65–69\t117\t4,915,216\t2.38\t–\t\n70–74\t148\t3,882,216\t3.81\t–\t\n75–79\t116\t2,964,162\t3.91\t–\t\n80–84\t99\t1,943,265\t5.09\t–\t\n≥85\t86\t1,296,790\t6.63\t–\t\nJohn Wiley & Sons, LtdIn the last year of follow‐up, the PY among finasteride users accounted for 1.1% in Denmark, 1.4% in Sweden, 3.0% in Finland, and 0.7% in Norway out of PY in the total male populations (Fig. S1). During the study period, finasteride users of 5 mg packages constituted 89% of the PY among finasteride users in Denmark and 90% in Sweden in 2009.\n\nA total of 63 men developed MBC after dispensed finasteride: 29 in Denmark, 26 in Finland, 1 in Norway, and 7 in Sweden (Table 2). There was a significantly increased incidence of MBC among finasteride users compared to nonusers with an IRR of 1.44 (95% CI = 1.11–1.88, P = 0.009). The IRR for dispensed finasteride increased to 1.60 (1.20–2.13) for the analysis of Denmark and Finland with long follow‐up time. The country‐specific IRR was highest in Denmark (IRR = 1.81, 95% CI = 1.23–2.67, P = 0.006). There was no significant interaction between country and dispensed finasteride (P = 0.18 for interaction term). The association between dispensed finasteride and MBC was modified by age at follow‐up with IRR at 5.58 (95% CI = 3.14–9.92) for age<70 years at follow‐up decreasing to 1.67 and 1.15 for age 70–79 years and ≥80 years at follow‐up, respectively (Table 2). When restricting the exposed group to finasteride users with 5 mg finasteride, a significant association was found (IRR = 1.60, 95% CI = 1.20–2.14).\n\nTable 2 Association between dispensed finasteride and male breast cancer (MBC) in Denmark, Finland, Norway, and Sweden given by MBC cases, person years, P‐value, incidence rate ratio (IRR), and 95% confidence interval (95% CI) adjusted for differences in age, calendar year, and country\n\n\tFinasteride exposure\tCancer cases\tPerson years\tOverall P‐value\tIRR\t95% CI\t\nPrimary analysis\tUser\t63\t1,365,088\t0.009\t1.44\t1.11–1.88\t\nNonuser\t839\t111,060,881\t\t1\t(ref)\t\nAge group at follow‐up\t\n0–69 years\tUser\t12\t519,340\t<0.001\t5.58\t3.14–9.92\t\nNonuser\t441\t101,820,197\t\t1\t(ref)\t\n70–79 years\tUser\t30\t511,253\t\t1.67\t1.14–2.44\t\nNonuser\t234\t6,335,125\t\t1\t(ref)\t\n≥80 years\tUser\t21\t334,494\t\t1.15\t0.73–1.81\t\nNonuser\t164\t2,905,560\t\t1\t(ref)\t\nCountry specific\t\nDenmark\tUser\t29\t379,540\t0.006\t1.81\t1.23–2.67\t\nNonuser\t336\t39,465,222\t\t1\t(ref)\t\nFinland\tUser\t26\t712,941\t0.10\t1.45\t0.95–2.23\t\nNonuser\t210\t35,121,248\t\t1\t(ref)\t\nNorway\tUser\t1\t59,605\t0.51\t0.55\t0.08–3.94\t\nNonuser\t100\t13,952,023\t\t1\t(ref)\t\nSweden\tUser\t7\t213,002\t0.92\t0.96\t0.45–2.06\t\nNonuser\t193\t22,522,388\t\t1\t(ref)\t\nJohn Wiley & Sons, LtdFurther analyses of Denmark and Finland showed that the risk of MBC was highest among men who redeemed finasteride up to 3 years (IRR = 1.89, 95% CI = 1.37–2.60) and among men whose accumulated consumption corresponded to up to three finasteride packs with 98 pills of 5 mg (IRR = 1.92, 95% CI = 1.33–2.79) (Table 3). The relative risk of MBC in finasteride users was highest during the follow‐up period of 1–3 years after first dispensed finasteride prescription (IRR = 2.28, 95% CI = 1.42–3.67), but not markedly lower during the first and fourth to fifth years of follow‐up (Table 3). The effect of duration of dispensed finasteride, accumulated dispensed finasteride prescriptions, and years after first dispensed finasteride prescription did not change when individuals with their first dispensed finasteride prescription in the first year of the prescription registers were excluded (Table 3).\n\nTable 3 Association between dispensed finasteride, duration of dispensed finasteride, dose, and time since first dispensed finasteride prescription and male breast cancer (MBC) in Denmark and Finland given by MBC cases, risk time, P‐value, incidence rate ratio (IRR), and 95% confidence interval (95% CI). Results are adjusted for differences in age, calendar year, and country\n\nExposure categories\tIncluding finasteride users with dispensed finasteride in first year of follow‐up\tExcluding finasteride users with dispensed finasteride in first year of follow‐up\t\nCancer cases\tPerson years\tOverall P‐value\tIRR\t95% CI\tCancer cases\tPerson years\tOverall P‐value\tIRR\t95% CI\t\nDispensed finasteride\t\nUser\t55\t1,092,481\t0.002\t1.60\t1.20–2.13\t33\t793,483\t0.10\t1.37\t0.95–1.96\t\nNonuser\t546\t74,586,470\t\t1\t(ref)\t535\t69,800,789\t\t1\t(ref)\t\nDuration of dispensed finasteride (years)\t\nNonuser\t546\t74,586,470\t0.001\t1\t(ref)\t535\t69,800,789\t0.09\t1\t(ref)\t\n≤3\t42\t732,084\t\t1.89\t1.37–2.60\t27\t567,664\t\t1.60\t1.08–2.37\t\n3.1–5\t8\t145,399\t\t1.71\t0.84–3.45\t4\t103,046\t\t1.25\t0.46–3.35\t\n>5\t5\t214,998\t\t0.66\t0.27–1.60\t2\t122,773\t\t0.48\t0.12–1.95\t\nDose (categorized as number of finasteride packs with 98 pills of 5 mg)\t\nNonuser\t546\t74,586,470\t0.007\t1\t(ref)\t535\t69,800,789\t0.14\t1\t(ref)\t\n≤3\t30\t528,958\t\t1.92\t1.33–2.79\t21\t415,570\t\t1.76\t1.13–2.74\t\n3.1–6\t9\t161,739\t\t1.80\t0.92–3.50\t3\t120,040\t\t0.82\t0.26–2.56\t\n>6\t16\t401,784\t\t1.15\t0.69–1.91\t9\t257,873\t\t1.04\t0.53–2.02\t\nTime since first finasteride purchase (years)\t\nNonuser\t546\t74,586,470\t0.01\t1\t(ref)\t535\t69,800,789\t0.15\t1\t(ref)\t\n<1\t8\t159,670\t\t1.85\t0.92–3.73\t5\t128,835\t\t1.41\t0.58–2.42\t\n1–2.9\t18\t271,837\t\t2.28\t1.42–3.67\t13\t215,122\t\t2.09\t1.20–3.65\t\n3–4.9\t11\t219,610\t\t1.62\t0.89–2.95\t7\t169,236\t\t1.37\t0.65–2.90\t\n5+\t18\t441,363\t\t1.16\t0.72–1.87\t8\t280,290\t\t0.85\t0.42–1.73\t\nJohn Wiley & Sons, LtdDiscussion\nIn this population‐based register study, we found a statistically significant 44% increased risk of MBC among men having finasteride prescribed compared to nonusers. The IRRs were highest for males in Denmark and Finland, that is, countries with longest follow‐up period. The IRRs were highest in the categories of medium duration or lowest dose of finasteride which is against a causality of the association. An excess risk was identified in the first year after the first known dispensed finasteride and it decreased after 5 years. Such a short time lag and a decreasing risk over time are not typical in cancer causation. If the relative risk was first nonelevated and then increased after some years, it could be a sign of causal relation.\n\nThe main strength of this study is that it includes the largest number of persons exposed to finasteride reported yet. It has relatively long maximum follow‐up time especially for the Danish and Finnish cohorts, and contains information for the total population and individual‐level register data collected independently of the research question. The quality of the prescription and cancer registers is high due to the completeness and validity of registered data 26, 27, 28, 29.\n\nThere are some study limitations to be considered. First, exposure data were based on dispensed finasteride and not finasteride consumption. Exposure may therefore be overestimated, and the found association between dispensed finasteride and MBC may as a consequence be underestimated. Second, due to the rarity of MBC, the statistical power is limited. Third, surveillance bias may have influenced the results because physicians may follow men with dispensed finasteride more closely or because of breast complaint and development of gynecomastia may lead to closer surveillance of users than nonusers. The finding of higher risk of breast cancer among short‐term finasteride users could be a reflection of surveillance bias. Fourth, information about dispensed finasteride before establishment of the prescription registers was not available. Therefore, the analyses accounting for “years after first dispensed finasteride prescription,” “cumulative dose,” and “duration of dispensed finasteride” underestimate the association. However, excluding finasteride users dispensed in the first year of data collection, as we do in Table 3, in principle corrects for this error. Fifth, the number of persons followed up for longer time periods is still quite small and hence the power of the study to reveal possible role of finasteride as a cancer initiator is limited. If the finasteride would act as a moderator in the cancer process, then the lag from exposure to outcome is essentially shorter.\n\nMost important limitation is the lack of data on potential confounding factors. Factors influencing the estrogen/testosterone balance, including testicular abnormality, benign breast disease, gynecomastia, estrogen therapy, occupational exposures, and physical inactivity, obesity, family history of breast cancer, and comorbidities such as liver disease and alcohol intake, can be associated with both dispensed finasteride and MBC thereby confounding the observed association 18, 23.\n\nThe crude incidence rate of MBC estimated in the present study at 0.8 per 100,000 PY is within the range 0.4–1.0 per 100,000 PY reported in earlier epidemiological studies 12, 13, 14. The median time from initiation of finasteride use to MBC diagnosis was 40 months in the present study. This is in accordance with previous studies, for example, MHRA reported a median time at male breast cancer developing 36 months after starting treatment with 5 mg finasteride for enlarged prostate 6, 7.\n\nConflicting results are seen for the association between finasteride use and MBC from the few published studies in this area. A number of studies have indicated a possible link between finasteride use and risk of MBC 3, 5, 6, 7, 8. Bird et al. (2013) reported no significant association, but the follow‐up time was only 1–3 years after exposure 10. This is considered a short follow‐up period. Duijnhoven et al. estimated a nonsignificant OR at 1.08 for the association between ever use of finasteride or dutasteride, but an OR at 1.29 for cumulative use for 3 or more years which is similar to the effect of cumulative use for 3–5 years in the present study with an IRR at 1.25 11.\n\nOnly few observational epidemiological studies have been performed and the estimated association between finasteride use and MBC varies between these studies. In general, the Nordic prescription databases constitute an outstanding resource for pharmacoepidemiological studies in large populations 30, and pharmacoepidemiological studies in the Nordic countries are considered to have high validity 31.\n\nWe conclude that this study showed a significant increased risk of MBC among men having finasteride prescribed compared to nonusers. The IRRs were highest for males in Denmark and Finland, that is, countries with longest follow‐up period. Due to limited data for adjustment of potential confounding, more research is warranted to confirm the results. AG and ME declare: They have received finance from Merck Sharp & Dohme Corp. for the submitted work.\n\nConflicts of Interest\nMM, LCT, KBr, PI, EP, KBo, KS, and AKE declare: no conflict of interest. AG and ME declare: They have received finance from Merck Sharp & Dohme Corp. for the submitted work. They declare no other relationships or activities that could appear to have influenced the submitted work. This article is based on data from a study conducted by Applied Economics and Health Research (ApEHR) as an independent research organization based on a regulatory request from the European Medicines Agency (EMA) and funded by Merck Sharp & Dohme Corp (MSD). MSD has had the opportunity to comment on the manuscript, but the authors retained the right to accept or reject comments and suggestions.\n\nSupporting information\n\nFigure S1. Percentage of PY among finasteride users out of PY in the total male population in each of the four Nordic countries.\n\nClick here for additional data file.\n==== Refs\nReferences\n1 \n\nWilt , T. J. \n, \nM. \nRoderick \n, \nH. \nKaren \n, \nS. \nPaul \n, \nT. \nJames \n, \nR. S. \nMark \n, et al. 2010 \n5‐alpha‐Reductase inhibitors for prostate cancer chemoprevention: an updated Cochrane systematic review . Br. J. Urol. \n106 :1444 –1451 . https://doi.org/10.111/j.64-410X.2010.09714.x.\n2 \n\nGreen , L. \n, \nD. K. \nWysowski \n, and \nJ. L. \nFourcroy \n. 1996 \nGynecomastia and breast cancer during finasteride therapy . N. Engl. J. Med. \n335 :823 .\n3 \n\nLee , S. C. \n, and \nR. J. \nEllis \n. 2004 \nMale breast cancer during finasteride therapy . J. Natl Cancer Inst. \n96 :338 –339 .14970289 \n4 \n\nMcConnell , J. D. \n, \nB. \nReginald \n, \nW. \nPatrick \n, \nA. \nGerald \n, \nL. \nMichael \n, \nH. 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G. \nFord \n, et al. 2003 \nThe influence of finasteride on the development of prostate cancer . N. Engl. J. Med. \n349 :215 –224 .12824459 \n9 \n\nKjærulff , T. M. \n, \nA. K. \nErsbøll \n, \nA. \nGreen \n, \nM. \nEmneus \n, \nE. \nPukkala \n, \nK. \nBolin \n, et al. 2015 \nPatterns of finasteride use in the male populations in four Nordic countries: a cross‐national drug utilization study . J. Urol. \n50 :220 –227 .\n10 \n\nBird , S. T. \n, \nJ. M. \nBrophy \n, \nA. G. \nHartzema \n, \nJ. A. \nDelaney \n, and \nM. \nEtminan \n. 2013 \nMale breast cancer and 5alpha‐reductase inhibitors finasteride and dutasteride . J. Urol. \n190 :1811 –1814 .23665270 \n11 \n\nDuijnhoven , R. G. \n, \nS. M. \nStraus \n, \nP. C. \nSouverein \n, \nA. \nde Boer \n, \nJ. R. \nBosch \n, \nA. W. \nHoes \n, et al. 2014 \nLong‐term use of 5alpha‐reductase inhibitors and the risk of male breast cancer . Cancer Causes Control \n25 :1577 –1582 .25135615 \n12 \n\nMiao , H. \n, \nH. M. \nVerkooijen \n, \nK. S. \nChia \n, \nC. \nBouchardy \n, \nE. \nPukkala \n, \nS. \nLarønningen \n, et al. 2011 \nIncidence and outcome of male breast cancer: an international population‐based study . J. Clin. Oncol. \n29 :4381 –4386 .21969512 \n13 \n\nMuir , C. \n, \nJ. \nWaterhouse \n, \nT. \nMack \n, \nJ. \nPowell \n, and \nS. \nWhelan \n. 1987 \nCancer incidence in five continents . International Agency for Research on Cancer , Lyon .\n14 \n\nSasco , A. J. \n, \nA. B. \nLowenfels \n, and \nJong P. \nPasker‐de \n. 1993 \nReview article: epidemiology of male breast cancer. a meta‐analysis of published case‐control studies and discussion of selected aetiological factors . Int. J. Cancer \n53 :538 –549 .8436428 \n15 \n\nEwertz , M. \n, \nL. \nHolmberg \n, \nS. \nTretli \n, \nB. V. \nPedersen \n, and \nA. \nKristensen \n. 2001 \nRisk factors for male breast cancer–a case‐control study from Scandinavia . Acta Oncologica (Stockholm, Sweden) \n40 :467 –471 .\n16 \n\nGiordano , S. H. \n, \nA. 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Proceedings of Survey Research Methods Section of the American Statistical Association .\n26 \n\nGjerstorff , M. L. \n\n2011 \nThe Danish Cancer Registry . Scand. J. Public Health \n39 :42 –45 .21775350 \n27 \n\nKildemoes , H. W. \n, \nH. T. \nSorensen \n, and \nJ. \nHallas \n. 2011 \nThe Danish National Prescription Registry . Scand. J. Public Health \n39 :38 –41 .21775349 \n28 \n\nPukkala , E \n. 2011 \nBiobanks and registers in epidemiologic research on cancer . Methods Mol. Biol. (Clifton, NJ) \n675 :127 –164 .\n29 \n\nTeppo , L. \n, \nE. \nPukkala \n, and \nM. \nLehtonen \n. 1994 \nData quality and quality control of a population‐based cancer registry. Experience in Finland . Acta Oncol. (Stockholm, Sweden) 33 :365 –369 .8018367 \n30 \n\nWettermark , B. \n, \nH. \nZoëga \n, \nK. \nFuru \n, \nM. \nKorhonen \n, \nJ. \nHallas \n, \nM. \nNørgaard \n, et al. 2013 \nThe Nordic prescription databases as a resource for pharmacoepidemiological research – a literature review . 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"fulltext_license": "CC BY",
"issn_linking": "2045-7634",
"issue": "7(1)",
"journal": "Cancer medicine",
"keywords": "Breast neoplasms male; Nordic countries; finasteride; pharmacoepidemiology; prostatic neoplasms; registers",
"medline_ta": "Cancer Med",
"mesh_terms": "D058891:5-alpha Reductase Inhibitors; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000505:Alopecia; D018567:Breast Neoplasms, Male; D002648:Child; D002675:Child, Preschool; D018120:Finasteride; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011470:Prostatic Hyperplasia; D012042:Registries; D012537:Scandinavian and Nordic Countries; D055815:Young Adult",
"nlm_unique_id": "101595310",
"other_id": null,
"pages": "254-260",
"pmc": null,
"pmid": "29239131",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": "23703712;29239131;21775350;23665270;14681504;9475762;21031070;16488803;19961477;20193984;25135615;8778596;21969512;14970289;24552677;15541050;8018367;20977593;20949386;20878100;15668471;12824459;21775349;12379069;8436428;26901820;11504305",
"title": "Finasteride treatment and male breast cancer: a register-based cohort study in four Nordic countries.",
"title_normalized": "finasteride treatment and male breast cancer a register based cohort study in four nordic countries"
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"activesubstancename": "FINASTERIDE"
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"abstract": "A 67-year-old man with relapsed anaplastic large cell lymphoma received salvage chemotherapy, and pegfilgrastim was used to prevent febrile neutropenia. On day 18 of chemotherapy, he developed a pseudogout attack. Although the first symptoms improved, another pseudogout attack occurred when he received the second course of chemotherapy and pegfilgrastim. Filgrastim was then used for the third course of chemotherapy, and a pseudogout attack did not occur. The serum granulocyte-stimulating factor (G-CSF) level was extremely elevated only when pegfilgrastim was used, suggesting a relationship between pseudogout and G-CSF. Pseudogout should be recognized as an adverse effect of pegfilgrastim.",
"affiliations": "Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.;Oncology Center, Asahikawa Medical University Hospital, Japan.;Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan.",
"authors": "Hatayama|Mayumi|M|;Ikuta|Katsuya|K|;Ishioh|Masatomo|M|;Saito|Takeshi|T|;Toki|Yasumichi|Y|;Yamamoto|Masayo|M|;Shindo|Motohiro|M|;Torimoto|Yoshihiro|Y|;Okumura|Toshikatsu|T|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.9362-17",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2943414810.2169/internalmedicine.9362-17Case ReportPseudogout Attack after Pegfilgrastim Administration in Anaplastic Large Cell Lymphoma Hatayama Mayumi 1Ikuta Katsuya 1Ishioh Masatomo 1Saito Takeshi 1Toki Yasumichi 1Yamamoto Masayo 1Shindo Motohiro 1Torimoto Yoshihiro 2Okumura Toshikatsu 1\n1 Division of Gastroenterology and Hematology/Oncology, Department of Medicine, Asahikawa Medical University, Japan\n2 Oncology Center, Asahikawa Medical University Hospital, JapanCorrespondence to Dr. Katsuya Ikuta, ikuta@asahikawa-med.ac.jp\n\n9 2 2018 15 6 2018 57 12 1779 1782 17 4 2017 24 9 2017 Copyright © 2018 by The Japanese Society of Internal Medicine2018The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 67-year-old man with relapsed anaplastic large cell lymphoma received salvage chemotherapy, and pegfilgrastim was used to prevent febrile neutropenia. On day 18 of chemotherapy, he developed a pseudogout attack. Although the first symptoms improved, another pseudogout attack occurred when he received the second course of chemotherapy and pegfilgrastim. Filgrastim was then used for the third course of chemotherapy, and a pseudogout attack did not occur. The serum granulocyte-stimulating factor (G-CSF) level was extremely elevated only when pegfilgrastim was used, suggesting a relationship between pseudogout and G-CSF. Pseudogout should be recognized as an adverse effect of pegfilgrastim. \n\npseudogoutpegfilgrastimgranulocyte-stimulating factor (G-CSF)febrile neutropenia\n==== Body\nIntroduction\nPseudogout is an arthralgia that can occur in all joints in the body, especially major joints that are more frequently used, such as the knee and wrist joints. The symptoms vary and include pain, swelling, redness of the joints and a fever. Radiographs have demonstrated chondro-calcinosis within articular joints. Aspiration of the joint fluid shows calcium pyrophosphate in the joint space and contributes to the diagnosis of pseudogout (1). The treatment for pseudogout is rest and aspiration of the joint fluid. It is important to distinguish pseudogout from other forms of septic arthritis to avoid administering too many analgesics and antibiotics. Pseudogout is not a rare disease in elderly people, but the etiology of pseudogout remains unclear. It is said that aging and metabolic disease, such as hemochromatosis, hyperparathyroidism and hypomagnesemia, are risk factors, but other risk factors for the disease are unknown (1).\n\nGranulocyte-stimulating factor (G-CSF) has been clinically used in various situations, such as for the treatment of febrile neutropenia and drug-induced neutropenia and for the mobilization of hematopoietic stem cells. Pegylated filgrastim (pegfilgrastim) is a long-acting form of filgrastim. Pegylation increases the size of filgrastim so that it becomes too large for renal clearance. The median serum half-life of pegfilgrastim is approximately 10 times that of filgrastim (pegfilgrastim's half-life: 42 hours, filgrastim's half-life: approximately 3.5 hours) (2). As a result, the clearance of pegfilgrastim is decreased, inducing sustained serum concentrations throughout the duration of neutropenia. Pegfilgrastim requires only once-per-cycle administration for the management of chemotherapy-induced neutropenia. However, its effectiveness and side effects are not sufficiently understood. \n\nWe herein report a case of pseudogout attack caused by pegfilgrastim administration.\n\nCase Report\nA 67-year-old man noticed neck lymph node swelling and was diagnosed with anaplastic large cell lymphoma (ALCL) after a biopsy of the lymph node. Positron emission tomography (PET) revealed lymphoma lesions in both sides of the neck and the left axilla. A bone marrow examination revealed no infiltration of the lymphoma cells. Therefore, a diagnosis of clinical stage IIA disease was made, according to the Ann-Arbor classification. He had chronic hypertension but no endocrine diseases or electrolyte disorders, such as calcium and magnesium disorders. A CHOP regimen [adriamycin 50 mg/m2 (day 1), vincristine 1.4 mg/m2 (day 1), cyclophosphamide 750 mg/m2 (day 1) and prednisolone 100 mg/body (days 1-5)] was started on admission, and the sizes of the lymph nodes decreased; however, 3 weeks after chemotherapy, the lymphadenopathy worsened. A dexamethasone, cyclophosphamide, cytarabine, etoposide (CHASE) regimen [dexamethasone 40 mg/body (days 1-3), cyclophosphamide 1,200 mg/m2 (day 1), cytarabine 2,000 mg/m2 (days 2-3) and etoposide 100 mg/m2 (days 1-3)] was then started as salvage chemotherapy, and pegfilgrastim (3.6 mg) was administered on day 5 of CHASE. There were no remarkable problems after the administration of pegfilgrastim, so he was discharged from the hospital. However, on day 18 of CHASE, both knee joints became swollen and were red and painful. The patient therefore had to be hospitalized again.\n\nThe patient's physical examination showed a high fever and knee joint swelling and reddening. The left knee joint showed more swelling than the right side. A patella ballottement test was positive for both knee joints. The laboratory data are shown in Table 1. The white blood cell (WBC) count, especially the neutrophil count, and the C-reactive protein level were increased. The other biochemical parameters were nearly normal.\n\nTable 1. Laboratory Findings at the Day19 of 1st Course of CHASE.\n\nWBC\t20,930\t/μL\t\tTP\t7.1\tg/dL\t\nMono\t83.5\t%\t\tAlb\t3.2\tg/dL\t\nLymp\t4.5\t%\t\tT-Bil\t0.6\tmg/dL\t\nMono\t11.5\t%\t\tD-Bil\t0.3\tmg/dL\t\nEos\t0.5\t%\t\tAST\t29\tU/L\t\nBaso\t0.0\t%\t\tALT\t43\tU/L\t\n\t\t\t\tLDH\t201\tU/L\t\nRBC\t340×104\t/μL\t\tγ-GTP\t104\tU//L\t\nHb\t9.6\tg/dL\t\tNa\t137\tmmol/dL\t\nHt\t29.4\t%\t\tK\t4.2\tmmol/dL\t\nMCV\t86.5\tfL\t\tCl\t99\tmmol/dL\t\nMCH\t28.2\tpg\t\tUA\t3.5\tmg/dL\t\nMCHC\t32.7\t%\t\tBUN\t9.2\tmg/dL\t\nPlt\t464×103\t/μL\t\tCre\t0.52\tmg/dL\t\n\t\t\t\tCRP\t17.0\tmg/dL\t\nWBC: white blood cell, RBC: red blood cell, Hb: hemoglobin, Ht: hematocrit, MCV: mean cell volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, Plt: platelet, TP: total protein, Alb: albumin, T-Bil: total bilirubin, D-Bil: direct bilirubin, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactic acid dehydrogenase, γ-GTP: gamma-glutamyl transpeptidase, Na: sodium, K: potassium, Cl: chloride, UA: uric acid, BUN: urea nitrogen, Cre: creatine, CRP: C-reactive protein, CHASE regimen: dexamethasone, cyclophosphamide, cytarabine, etoposide\n\nX-ray showed line-shape calcification in the left knee joint cartilage (Fig. 1A). Joint fluid obtained by aspiration of the left knee was yellow and muddy (Fig. 1B). Microscopic findings of the joint fluid demonstrated an increase in the WBC count and the presence of calcium pyrophosphate dihydrate (CPPD) crystals, but no uric acid crystals were observed. Phagocytosis of CPPD crystals by neutrophils and macrophages was also observed (Fig. 2).\n\nFigure 1. (A) X-ray photogram of the left knee. The white arrow indicates a crystal deposit in the left knee joint space. (B) Joint fluid obtained by aspiration from the left knee. The fluid was yellow and muddy.\n\nFigure 2. Microscopic findings of the joint fluid. The white blood cell was increased in the joint fluid, and calcium pyrophosphate dihydrate (CPPD) crystals were englobed by neutrophils and macrophages. The white arrow indicates CPPD crystals.\n\nA diagnosis of pseudogout was made, and the patient was instructed to rest the knee joints and received an analgesic. His pseudogout symptoms disappeared, and a second course of CHASE was started. Pegfilgrastim (3.6 mg) was administrated on day 5 of the second course of CHASE. A pseudogout attack occurred again on day 15 of the second course of CHASE. Because the WBC count increased when both pseudogout attacks occurred, we suspected that there might be a relationship between the pseudogout and pegfilgrastim. Therefore, for the third course of CHASE, we used filgrastim (75 μg) instead of pegfilgrastim on days 11 and 13. As a result, the WBC count did not increase as much as with pegfilgrastim, and no pseudogout attack occurred (Fig. 3).\n\nFigure 3. Clinical course. Changes of neutrophil during chemotherapy were shown. Pseudogout attack was occur when neutrophil increased after using pegfilgrastim. CHASE regimen: dexamethasone 40 mg/body (days 1-3), cyclophosphamide 1,200 mg/m2 (day 1), cytarabine 2,000 mg/m2 (days 2-3), etoposide 100 mg/m2 (days 1-3).\n\nWe suspected that pegfilgrastim might have influenced the pseudogout attack, so we tried to measure the serum G-CSF levels and the levels of other cytokines. We obtained written informed consent from the patient as well as the approval of the ethics committee and measured the G-CSF, interleukin (IL)-6, IL-8, IL-1β and tumor necrosis factor (TNF)-α levels in serum samples obtained at the following three time points: the time of the pseudogout attack (2nd CHASE day 18), the day before the 3rd course of chemotherapy (3rd CHASE day -1) and during the recovery from myelosuppression after the administration of filgrastim (3rd CHASE day 18). The G-CSF level was markedly elevated to 289.0 pg/mL (reference range: ≤ 39.0 pg/mL) when the pseudogout attack occurred but then decreased to 47.0 pg/mL when the pseudogout attack resolved. The G-CSF level was not visibly increased (40.6 pg/mL) when filgrastim was used. The IL-1β and TNF-α levels were within the reference ranges (IL-1β: ≤ 10.0 pg/mL, TNF-α: 0.6-2.8 pg/mL), regardless of whether or not a pseudogout attack had occurred. The IL-6 level seemed to increase slightly on both day 18 of the second course of CHASE (12.4 pg/mL) and the third course of CHASE (12.8 pg/mL) (reference range: ≤ 4.0 pg/mL). The IL-8 level was elevated before chemotherapy (5.4 pg/mL) and on day 18 of the third course of CHASE (13.3 pg/mL) (reference range: ≤ 2.0 pg/mL) (Table 2).\n\nTable 2. Measurement Results of Serum Cytokine Levels.\n\nCytokines (Reference range)\t2nd CHASE day 18\t3rd CHASE day -1\t3rd CHASE day 18\t\nIL-1β (≤10.0 pg/mL)\t≤10.0\t≤10.0\t≤10.0\t\nIL-6 (≤4.0 pg/mL)\t12.4\t1.9\t12.8\t\nIL-8 (≤2.0 pg/mL)\t≤2.0\t5.4\t13.3\t\nTNF-α (0.6-2.8 pg/mL)\t2.6\t1.7\t2.4\t\nG-CSF (≤39.0 pg/mL)\t289.0\t47.0\t40.6\t\nIL-1β: interleukin-1β, IL-6: interleukin-6, IL-8: interleukin-8, TNF-α: tumor necrosis factor-α\n\nCHASE regimen: dexamethasone, cyclophosphamide, cytarabine, etoposide\n\nDiscussion\nG-CSF stimulates the proliferation and differentiation of neutrophils. The present patient developed a pseudogout attack when pegfilgrastim was administered, and the neutrophil count was over 20,000 /μL, but he did not suffer a pseudogout attack when filgrastim was administrated. Some reports have suggested that filgrastim is related to pseudogout attacks (3), but there have been no reports about any attacks with pegfilgrastim. This is likely the first such report.\n\nSandor et al. reported a woman with ovarian cancer who received filgrastim after chemotherapy and developed pseudogout. In that case, the WBC count was over 20,000 /μL when the pseudogout occurred, suggesting that a relationship exists between the WBC count and pseudogout (4). However, Teramoto et al. reported a pseudogout attack after the administration of filgrastim for a patient with drug-induced neutropenia. In that case, the WBC count was in the normal range (maximum of 4,200 /μL) when the attack occurred. Those authors suggested that other factors might be involved in the development of pseudogout (5).\n\nTeramoto et al. also reported that the WBC count and G-CSF, IL-6 and IL-8 levels of the joint fluid were elevated during the pseudogout attack and considered that these changes contributed to pseudogout. In vitro, IL-6 and IL-8 production by synovial cells was elevated in the presence of calcium pyrophosphate when granulocyte macrophage colony-stimulating factor (GM-CSF) was administered. In the present case, the G-CSF level was markedly elevated to 289.0 pg/mL when the pseudogout attack occurred on day 18 of the second course of 2nd CHASE, but it subsequently decreased to 47.0 pg/mL. The G-CSF level at the pseudogout attack (13 days after the administration of pegfilgrastim) was very high. A prolonged high level of pegfilgrastim may have stimulated the proliferation and differentiation of neutrophil progenitor cells for an extended period of time, thereby resulting in excessive neutrophil production and finally contributing to the pseudogout attack. Teramoto et al. also reported that an elevated serum IL-6 level (77 pg/mL) might have contributed to the pseudogout attack in their patient, but changes in the level of IL-6 and other cytokines were not correlated with the pseudogout attack in our case; we therefore doubt that the changes in the levels of the cytokines (IL-1β, IL-6, IL-8, and TNF-α) caused the pseudogout in our case.\n\nIn the present case, we were only able to measure the serum levels of cytokines and could not measure the cytokine levels in the joint fluid. The cytokine levels in the joint fluid might have been different from those in the serum, and it is important to measure the levels of cytokines in the joint fluid in addition to the serum. This may enable the elucidation of the pathophysiology of pseudogout during the administration of G-CSF and pegylated G-CSF.\n\nThe persistence of the effectiveness of pegfilgrastim for approximately 2 weeks makes this medication very valuable, as it can prevent febrile neutropenia with only a once-per-regimen administration and reduce the need for hospitalization for patients receiving chemotherapy. However, the dosage of pegfilgrastim cannot be adjusted; there is therefore a possibility that pegfilgrastim stimulates cytokine production excessively and can cause an adverse effect with a different profile of G-CSF. Pseudogout must be recognized as an adverse effect of pegfilgrastim during its administration, and the frequency of this disease should be determined in the future.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Pang L , Hayes CP , Buac K , Yoo DG , Rada B \nPseudogout-associated inflammatory calcium pyrophosphate dihydrate microcrystals induce formation of neutrophil extracellular traps . J Immunol \n190 : 6488 -6500 , 2013 .23677474 \n2. Molineux G \nThe design and development of pegfilgrastim (PEG-rmetHuG-CSF, Neulasta) . Curr Pharm Des \n10 : 1235 -1244 , 2004 .15078138 \n3. Ames PR , Rainey MG \nConsecutive pseudogout attacks after repetitive granulocyte colony-stimulating factor administration for neutropenia . Mod Rheumatol \n17 : 445 -446 , 2007 .17929142 \n4. Sandor V , Hassan R , Kohn E \nExacerbation of pseudogout by granulocyte colony-stimulating factor . Ann Intern Med \n125 : 781 , 1996 .\n5. Teramoto S , Yamamoto H , Ouchi Y \nIncreased synovial interleukin-8 and interleukin-6 levels in pseudogout associated with granulocyte colony-stimulating factor . Ann Intern Med \n129 : 424 -425 , 1998 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "febrile neutropenia; granulocyte-stimulating factor (G-CSF); pegfilgrastim; pseudogout",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D002805:Chondrocalcinosis; D000069585:Filgrastim; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D017728:Lymphoma, Large-Cell, Anaplastic; D008297:Male; D009503:Neutropenia; D011092:Polyethylene Glycols; D011994:Recombinant Proteins",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1779-1782",
"pmc": null,
"pmid": "29434148",
"pubdate": "2018-06-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17929142;9735078;8929025;15078138;23677474",
"title": "Pseudogout Attack after Pegfilgrastim Administration in Anaplastic Large Cell Lymphoma.",
"title_normalized": "pseudogout attack after pegfilgrastim administration in anaplastic large cell lymphoma"
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"activesubstancename": "CYTARABINE"
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"abstract": "Plasmapheresis, a procedure used to remove large molecular weight, protein-bound molecules from a patient's blood, has been shown to be useful in some cases of drug overdose. Levothyroxine sodium intoxication may result from the intentional or accidental ingestion of excessive amounts of the hormone, which can trigger a thyroid storm. However, case reports about the extremely large dose of 15,000 µg of thyroxine intoxication are extremely rare, and even combined with calcium channel blockers (CCBs) poisonings. We present a case of an intentional poisoning with high doses of thyroxine, diltiazem and amlodipine successfully treated with plasma exchange. A 40-year-old woman was admitted showing unconsciousness and sustained hypotension with high levels of thyroid hormones (THs). It was discovered that she had secretly ingested at least 15,000 µg of levothyroxine sodium and CCBs with unknown amounts of diltiazem and amlodipine. Following plasmapheresis, the levels of TH declined dramatically after each of the 4 sessions, with hemodynamics gradually stabilizing and mental state improving. The early and timely use of plasmapheresis appears to be a vital therapeutic tool for the management of acute and severe forms of l-thyroxine and CCB intoxication. Its use can prevent thyroid storm and reverse the disturbances in the patient's hemodynamic status.",
"affiliations": "Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.;Department of Emergency Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.;Department of Endocrinology and Metabolism, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.;Department of Emergency Medicine, Tongji Hospital, Tongji University School of Medicine, Shanghai, China.",
"authors": "Li|Ran|R|;Xu|Yong-Wei|YW|;Xue|Ying|Y|;Wu|Xian-Zheng|XZ|",
"chemical_list": "D002121:Calcium Channel Blockers; D004364:Pharmaceutical Preparations; D013974:Thyroxine",
"country": "China",
"delete": false,
"doi": "10.21037/apm-20-190",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "10(5)",
"journal": "Annals of palliative medicine",
"keywords": "Case report; calcium channel blockers (CCBs); intoxication; levothyroxine sodium; plasmapheresis",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000328:Adult; D002121:Calcium Channel Blockers; D062787:Drug Overdose; D005260:Female; D006801:Humans; D004364:Pharmaceutical Preparations; D010956:Plasmapheresis; D013974:Thyroxine",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "5839-5845",
"pmc": null,
"pmid": "32954749",
"pubdate": "2021-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Plasmapheresis in the treatment of multi-drug intoxication involving levothyroxine sodium and calcium channel blockers: a case report.",
"title_normalized": "plasmapheresis in the treatment of multi drug intoxication involving levothyroxine sodium and calcium channel blockers a case report"
} | [
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"companynumb": "CN-STRIDES ARCOLAB LIMITED-2020SP011974",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
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"abstract": "Chronic graft-versus-host disease (cGVHD) is the main cause of late nonrelapse mortality and morbidity after allogeneic stem cell transplantation (allo-SCT). To improve such patients' outcomes, we conducted a phase 2, prospective, multicenter trial to test the efficacy of the addition of rituximab to corticosteroids (CSs) and cyclosporine A (CsA) as first-line therapy for newly diagnosed cGVHD after allo-SCT. Twenty-four patients (median age, 47 years) with mild (n = 2), moderate (n = 7), or severe (n = 15) cGVHD were included. All patients received rituximab 375 mg/m2 weekly for 4 weeks, followed by a second course 1 month later for patients with partial response. Twenty of 24 patients (83%) were in response at 1 year. Furthermore, among 19 evaluable patients, 14 (74%) were off CSs. The estimated 1-year overall survival was 83%, and the 1-year cumulative incidence of nonrelapse mortality was 14%. One patient died of progressive multifocal leukoencephalopathy. Although PD-L1hi naive B cells were significantly decreased at diagnosis of cGVHD, they increased after anti-CD20 B-cell depletion. In contrast, activated ICOShi PD-1hi circulating T follicular helper (Tfh) cells decreased after rituximab treatment. Overall, the addition of rituximab to corticosteroid and CsA appeared to be safe and effective for first-line treatment of cGVHD. Furthermore, our data suggest that this efficacy may be in part related to an effect on PD-L1hi B cells and Tfh cells. This study was registered at www.clinicaltrials.gov as identifier NCT01135641.",
"affiliations": "Centre de Recherche en Transplantation et Immunologie Unité Mixte de Recherche 1064, INSERM, Université de Nantes, Nantes, France.;Service d'Hématologie Clinique et de Thérapie Cellulaire, Assistance Publique-Hôpitaux de Paris, Hôpital, Saint Antoine, Paris, France.;Service des Maladies du Sang, Centre Hospitalo-Universitaire de Lille, Lille, France.;Service d'Hématologie Clinique, Centre Hospitalo-Universitaire de Caen, Caen, France.;Service d'Hématologie Clinique, Centre Hospitalo-Universitaire de Nantes, Nantes, France.;Institut Paoli-Calmettes, Université d'Aix-Marseille, Centre National de la Recherche Scientifique, INSERM, Centre de Recherche en Cancérologie de Marseille, Marseille, France.;Service d'Hématologie Clinique, Centre Hospitalo-Universitaire de Bordeaux, Bordeaux, France; and.;Service des Maladies du Sang, Centre Hospitalo-Universitaire de Lille, Lille, France.;Centre de Recherche en Transplantation et Immunologie Unité Mixte de Recherche 1064, INSERM, Université de Nantes, Nantes, France.;Centre de Recherche en Transplantation et Immunologie Unité Mixte de Recherche 1064, INSERM, Université de Nantes, Nantes, France.;Service d'Hématologie Clinique, Centre Hospitalo-Universitaire de Nantes, Nantes, France.;Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.;Service d'Hématologie Clinique, Centre Hospitalo-Universitaire de Nantes, Nantes, France.;Sorbonne Universités, Université Pierre et Marie Curie Université Paris 06, INSERM, Centre de Recherche Saint-Antoine, Paris, France.",
"authors": "Malard|Florent|F|0000-0002-3474-0002;Labopin|Myriam|M|;Yakoub-Agha|Ibrahim|I|;Chantepie|Sylvain|S|;Guillaume|Thierry|T|;Blaise|Didier|D|;Tabrizi|Reza|R|;Magro|Leonardo|L|;Vanhove|Bernard|B|;Blancho|Gilles|G|;Moreau|Philippe|P|;Gaugler|Béatrice|B|;Chevallier|Patrice|P|;Mohty|Mohamad|M|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D060890:B7-H1 Antigen; C423236:CD274 protein, human; D004338:Drug Combinations; D000069283:Rituximab; D016572:Cyclosporine",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-05-786137",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "130(20)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000328:Adult; D001402:B-Lymphocytes; D060890:B7-H1 Antigen; D002908:Chronic Disease; D016572:Cyclosporine; D004338:Drug Combinations; D006086:Graft vs Host Disease; D006801:Humans; D018655:Lymphocyte Count; D008875:Middle Aged; D000069283:Rituximab; D033581:Stem Cell Transplantation; D015996:Survival Rate; D006377:T-Lymphocytes, Helper-Inducer; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2186-2195",
"pmc": null,
"pmid": "28864814",
"pubdate": "2017-11-16",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Rituximab-based first-line treatment of cGVHD after allogeneic SCT: results of a phase 2 study.",
"title_normalized": "rituximab based first line treatment of cgvhd after allogeneic sct results of a phase 2 study"
} | [
{
"companynumb": "FR-MYLANLABS-2018M1000940",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
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... |
{
"abstract": "Direct oral anticoagulants (DOACs) have been shown to be safe and effective for the prevention of stroke in nonvalvular atrial fibrillation (NVAF) patients, however, experience with peri-AF ablation management of DOACs is scarce. This study aimed to investigate the safety and feasibility of periprocedural anticoagulation therapy with rivaroxaban in Japanese patients undergoing paroxysmal non-valvular AF (NVAF) ablation using radiofrequency energy.This study was a multicenter, prospective pilot study. In paroxysmal NVAF patients, rivaroxaban (15 mg or 10 mg once-daily) was started at least 4 weeks prior to AF ablation, discontinued on the day of the procedure, resumed within 24 hours after ablation, and continued at least 3 months afterwards. During the interruption of rivaroxaban, bridging anticoagulation therapy with unfractionated heparin was given. Follow-up of the patients continued for 3 months.A total of consecutive 74 patients (mean age, 62 ± 9 years, 58 [78.4%] male) were enrolled. The mean follow-up period was 108 ± 79 days. Their mean CHADS2 score and CHA2DS2-VASc score were 1.2 ± 1.0 and 0.6 ± 0.7, respectively. Their mean HAS-BLED score was 1.0 ± 0.8. Neither major bleeding nor thromboembolic events, except in a case with bleeding from gastric cancer (1.4%), were observed in the periprocedural period of the AF ablation.The present multicenter study demonstrated the safety and feasibility of periprocedural anticoagulation therapy with rivaroxaban in Japanese patients undergoing catheter ablation of paroxysmal NVAF.",
"affiliations": "Heart Rhythm Center, Tokyo Medical and Dental University.",
"authors": "Kawabata|Mihoko|M|;Sasaki|Takeshi|T|;Maeda|Shingo|S|;Shirai|Yasuhiro|Y|;Yamauchi|Yasuteru|Y|;Nitta|Junichi|J|;Goya|Masahiko|M|;Hirao|Kenzo|K|",
"chemical_list": "D065427:Factor Xa Inhibitors; D006493:Heparin; D000069552:Rivaroxaban",
"country": "Japan",
"delete": false,
"doi": "10.1536/ihj.16-147",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1349-2365",
"issue": "57(6)",
"journal": "International heart journal",
"keywords": null,
"medline_ta": "Int Heart J",
"mesh_terms": "D000368:Aged; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D004334:Drug Administration Schedule; D065427:Factor Xa Inhibitors; D005240:Feasibility Studies; D005260:Female; D005500:Follow-Up Studies; D006493:Heparin; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D010865:Pilot Projects; D011446:Prospective Studies; D000069552:Rivaroxaban; D016896:Treatment Outcome",
"nlm_unique_id": "101244240",
"other_id": null,
"pages": "712-716",
"pmc": null,
"pmid": "27818480",
"pubdate": "2016-12-02",
"publication_types": "D000068397:Clinical Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Rivaroxaban for Periprocedural Anticoagulation Therapy in Japanese Patients Undergoing Catheter Ablation of Paroxysmal Non-Valvular Atrial Fibrillation.",
"title_normalized": "rivaroxaban for periprocedural anticoagulation therapy in japanese patients undergoing catheter ablation of paroxysmal non valvular atrial fibrillation"
} | [
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"abstract": "Three patients diagnosed with HER2-negative resectable advanced gastric cancer with extensive regional lymph node metastases were treated with neoadjuvant chemotherapy(NAC), followed by gastrectomy with D2lymph node dissection. One patient received four 21-day courses of S-1 plus oxaliplatin(G-SOX), and pathological effect(PE)was Grade 3. Two patients received four 21-day courses of capecitabine plus oxaliplatin(CapeOX), and each PE was Grade 2and Grade 1a, respectively. One patient in poor PE was with recurrent liver and peritoneal metastases. This suggested that for resectable advanced gastric cancer with extensive regional lymph node metastases, NAC by SOX or CapeOX was effective for some patients.",
"affiliations": "Dept. of Digestive Surgery, Keiju Medical Center.",
"authors": "Sato|Nariatsu|N|;Nakayama|Akira|A|;Takai|Yuki|Y|;Kono|Tatsuhiko|T|;Kamata|Toru|T|;Kanno|Masahiro|M|",
"chemical_list": "D004338:Drug Combinations; D005641:Tegafur; D010094:Oxonic Acid",
"country": "Japan",
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"issue": "45(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D004338:Drug Combinations; D005743:Gastrectomy; D006801:Humans; D020360:Neoadjuvant Therapy; D010094:Oxonic Acid; D013274:Stomach Neoplasms; D005641:Tegafur",
"nlm_unique_id": "7810034",
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"pages": "2060-2062",
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"pmid": "30692284",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Three Cases of Resectable Advanced Gastric Cancer Treated with Neoadjuvant Chemotherapy.",
"title_normalized": "three cases of resectable advanced gastric cancer treated with neoadjuvant chemotherapy"
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"abstract": "Posterior reversible cerebral edema syndrome is a generally reversible neurologic condition that is diagnosed based on distinctive clinical and radiologic findings. The condition, which is mostly associated with severe arterial hypertension, has also been reported to be induced by several medications. We made the diagnosis of hypertension with posterior reversible cerebral edema syndrome in a lean 12-year-old girl treated with the second-generation antipsychotic risperidone. We applied the Naranjo Adverse Drug Reaction Probability Scale and the World Health Organization-Uppsala Monitoring Centre system for causality assessment to the present case. Both scales indicated that a relationship to risperidone was likely. Second-generation antipsychotic agents may occasionally induce an increase in blood pressure even in the absence of overweight. Given this possibility, we recommend routine monitoring of blood pressure during therapy with these agents.",
"affiliations": "Pediatric Emergency Department.",
"authors": "Milani|Gregorio Paolo|GP|;Bianchetti|Mario Giovanni|MG|;Mazzoni|Marta Benedetta Maria|MB|;Triulzi|Fabio|F|;Mauri|Massimo Carlo|MC|;Agostoni|Carlo|C|;Fossali|Emilio Filippo|EF|",
"chemical_list": "D014150:Antipsychotic Agents; D018967:Risperidone",
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"doi": "10.1542/peds.2013-1301",
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"issn_linking": "0031-4005",
"issue": "133(3)",
"journal": "Pediatrics",
"keywords": "arterial hypertension; posterior reversible cerebral edema syndrome; risperidone; second-generation antipsychotic drugs",
"medline_ta": "Pediatrics",
"mesh_terms": "D014150:Antipsychotic Agents; D001929:Brain Edema; D002648:Child; D005260:Female; D006801:Humans; D006973:Hypertension; D018967:Risperidone",
"nlm_unique_id": "0376422",
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"pmc": null,
"pmid": "24567018",
"pubdate": "2014-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Arterial hypertension and posterior reversible cerebral edema syndrome induced by risperidone.",
"title_normalized": "arterial hypertension and posterior reversible cerebral edema syndrome induced by risperidone"
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"abstract": "Nocardia infection of the central nervous system (CNS) is an uncommon but clinically important disease, often occurring in immunocompromised individuals and carrying a high mortality rate. We present 20 cases of microbiologically proven CNS nocardiosis diagnosed in Queensland from 1997 to 2015 and review the literature from 1997 to 2016.Over 50% of cases occurred in immunocompromised individuals, with corticosteroid use posing a particularly significant risk factor. Nine (45%) patients were immunocompetent and 3 had no comorbidities at time of diagnosis. Nocardia farcinica was the most frequently isolated species (8/20) and resistance to trimethoprim-sulfamethoxazole (TMP-SMX) was found in 2 isolates. Overall, 35% of our patients died within 1 year, with the majority of deaths occurring in the first month following diagnosis. Interestingly, of the 7 deaths occurring at 1 year, 6 were attributed to N farcinica with the seventh isolate being unspeciated, suggesting the virulence of the N farcinica strain.",
"affiliations": "Monash Medical Centre, Melbourne, VIC, Australia Department of Biomedical and Clinical Sciences Luigi Sacco, III Division of Infectious Diseases, Luigi Sacco Hospital, University of Milan, Milan, Italy The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Herston, QLD, Australia Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italy Department of Microbiology, Pathology Queensland, Royal Brisbane & Women's Hospital, Herston Wesley Medical Research, Auchenflower, QLD, Australia.",
"authors": "Rafiei|Nastaran|N|;Peri|Anna Maria|AM|;Righi|Elda|E|;Harris|Patrick|P|;Paterson|David L|DL|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000005255",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2786134810.1097/MD.0000000000005255052554900Research ArticleObservational StudyCentral nervous system nocardiosis in Queensland A report of 20 cases and review of the literatureRafiei Nastaran BSc, MBBSa∗Peri Anna Maria MDbcRighi Elda MD, PhDcdHarris Patrick BSc, MBBS, MRCP, FRCPA, FRACPcePaterson David L. MBBS, PhD, FRACPA, FRACPfGarg. Ravindra Kumar a Monash Medical Centre, Melbourne, VIC, Australiab Department of Biomedical and Clinical Sciences Luigi Sacco, III Division of Infectious Diseases, Luigi Sacco Hospital, University of Milan, Milan, Italyc The University of Queensland, UQ Centre for Clinical Research, Royal Brisbane & Women's Hospital, Herston, QLD, Australiad Infectious Diseases Division, Santa Maria della Misericordia University Hospital, Udine, Italye Department of Microbiology, Pathology Queensland, Royal Brisbane & Women's Hospital, Herstonf Wesley Medical Research, Auchenflower, QLD, Australia.∗ Correspondence: Nastaran Rafiei, Monash Medical Centre, Melbourne, VIC 3168, Australia (e-mail: nastaran.rafiei@uqconnect.edu.au).11 2016 18 11 2016 95 46 e525519 7 2016 30 9 2016 1 10 2016 Copyright © 2016 the Author(s). Published by Wolters Kluwer Health, Inc. All rights reserved.2016This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nNocardia infection of the central nervous system (CNS) is an uncommon but clinically important disease, often occurring in immunocompromised individuals and carrying a high mortality rate. We present 20 cases of microbiologically proven CNS nocardiosis diagnosed in Queensland from 1997 to 2015 and review the literature from 1997 to 2016.\n\nOver 50% of cases occurred in immunocompromised individuals, with corticosteroid use posing a particularly significant risk factor. Nine (45%) patients were immunocompetent and 3 had no comorbidities at time of diagnosis. Nocardia farcinica was the most frequently isolated species (8/20) and resistance to trimethoprim–sulfamethoxazole (TMP-SMX) was found in 2 isolates. Overall, 35% of our patients died within 1 year, with the majority of deaths occurring in the first month following diagnosis. Interestingly, of the 7 deaths occurring at 1 year, 6 were attributed to N farcinica with the seventh isolate being unspeciated, suggesting the virulence of the N farcinica strain.\n\nKeywords\ncentral nervous systemNocardiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nNocardia is a ubiquitous gram-positive aerobic bacteria commonly responsible for infections in the immunocompromised host, with cell-mediated immune deficiency being particularly important.[1,2] Pulmonary nocardiosis is the major clinical manifestation of systemic disease and reflects the acquisition of Nocardia through inhalation. Spread via the hematogenous route can result in disseminated infection. Nocardia has a predilection for neural tissue, and CNS infection is seen in up to 44% of all systemic infections.[1]\n\nNocardia taxonomy has undergone vast changes in recent years as a result of advancements in microbiological diagnostic techniques. It has become clear that species misidentification has been common using conventional methods of classification and many new species have been added to the genus.[3,4]\n\nAs with other uncommon disease entities, treatment of CNS nocardiosis is based on expert opinion and retrospective reviews, with sulfonamides being considered the cornerstone of treatment. This practice was called into question after publication of a study reporting high rates of resistance to sulfonamides.[5] Although this finding has not been replicated in subsequent studies, it has led to increased interest in susceptibility testing and treatment options for nocardiosis.[6–8]\n\nWe review 20 cases of microbiologically confirmed CNS nocardiosis presenting to Queensland public hospitals over an 18-year time period, with characterization of clinical and microbiological aspects.\n\n2 Methods\nPatients with a confirmed diagnosis of CNS nocardiosis treated from 1997 to 2015 in the public hospital system of Queensland, Australia were included in the study. Ethics approval was granted by the Human Research Ethics Committee. Patients were identified through use of the state-wide pathology system. Cases were defined as those with cultures positive for Nocardia species from brain, spinal cord, or cerebrospinal fluid (CSF). The clinical charts were reviewed and the following data extracted: age, sex, underlying comorbidities, immunosuppressive medications, and radiological features. We identified patients who were immunocompromised by use of prednisolone (any dose) at time of diagnosis, monoclonal antibodies, chemotherapy, underlying malignancy, or HIV. Other comorbidities and concomitant sites of Nocardia infection were determined based on clinical judgment as documented in the medical chart.\n\nWe gathered information on the species of Nocardia identified, the use of 16s ribosomal RNA for identification, the susceptibility profile of each isolate, and treatment received. Outcome at 1 year was ascertained by reviewing the medical chart and state-wide electronic records.\n\nThe literature review was performed by searching the MEDLINE database (National Library of Medicine, Bethesda, MD) using the key words “Nocardia,” “central nervous system,” “brain,” and “meningitis.” We included all case reports with 3 or more cases of microbiologically proven disease published in English from 1997 onwards.\n\n3 Results\n3.1 Case series\nTwenty-four patients were identified; the records of 3 had been destroyed and were excluded and 1 patient was identified twice having suffered a recurrence of Nocardia brain abscess. Twenty individuals were included for analysis and their main characteristics are summarized in Table 1.\n\nTable 1 Clinical characteristics of patients with central nervous system nocardiosis.\n\n3.2 Underlying conditions\nThe average age of the patients was 65 years (range 39–93 years) and 50% were female. Eleven patients were classified as being immunosuppressed with 10 patients receiving corticosteroid treatment before diagnosis. The dose of corticosteroids ranged from 5 to 25 mg of prednisolone per day. Of these, 7 individuals received other immunosuppressive agents in addition to corticosteroids and this included therapy with tacrolimus in 3, methotrexate in 2, and 1 instance each of azathioprine, cyclosporine, mycophenolate, leflunomide, and pomalidomide. Four patients had undergone organ transplantation (2 renal, 1 lung, and 1 allogeneic bone marrow transplant) and 6 patients had an autoimmune underlying condition (2 rheumatoid arthritis and single patients with ulcerative colitis, systemic lupus erythematosus/rheumatoid arthritis overlap, polymyalgia rheumatica, and scleroderma). Only 1 patient had underlying malignancy (prostate cancer). Chronic lung disease was present in 6 patients: 3 with chronic obstructive pulmonary disease (COPD) including 1 who had COPD/bronchiectasis, 1 with bronchiectasis, 1 with pulmonary arteriovenous malformation, and 1 who had undergone lung transplantation. No patients were HIV positive. Three patients were documented to have excess alcohol intake, and, for 1 patient, this was the only recorded comorbidity.\n\n3.3 Clinical characteristics\nConfusion was the most common symptom at presentation and was present in 12 of the 20 patients. Other symptoms included weakness and speech impairment present in 7 patients each, and headache in 5 individuals. Meningism was seen in 2 patients, both of whom were diagnosed with Nocardia meningitis on examination of the CSF. Two individuals were asymptomatic of CNS disease and were diagnosed after Nocardia infection of other organs prompted CT scans of the brain. Fever was recorded in 4 patients. The duration of symptoms was documented for 12 patients, and ranged from immediate onset to 6 months, with an average duration of 5.3 weeks.\n\nAll patients underwent radiological imaging with computerized tomography (CT) with or without magnetic resonance imaging (MRI) of the brain. Multiple ring-enhancing lesions were found in 11 patients and single lesions in 7 patients. Two patients had no space-occupying lesions found on brain imaging, and were diagnosed based on CSF culture.\n\nEleven patients had pulmonary nocardiosis in addition to CNS disease, and 4 had infection of skin and soft tissue. Two patients had disease affecting more than 2 organs.\n\n3.4 Species and susceptibility\nThe most common Nocardia species isolated was N farcinica (8/20, 40%), followed by N paucivorans (3/20, 15%). The remaining 9 patients were diagnosed with N abscessus (1/20), N nova complex (1/20), N cyriacigeorgica (1/20), N pseudobrasiliensis (1/20), N thailandica/novocastrensa (1/20), and N otitidiscaviarum (1/20). One patient was diagnosed with N aobensis and, in 1 case, whose admission dated back to 1997, the species was not identified.\n\nThe 16s ribosomal RNA gene sequencing method was used since 2000 in 15 patients as a complementary method to standard phenotypic cultures for species identification.\n\nResistance patterns are shown in Table 2. Only 2 isolates were resistant to trimethoprim–sulfamethoxazole (TMP-SMX) with an overall prevalence of TMP-SMX resistance in our case series of 10%. Both of these isolates were N farcinica. Neither patient had received TMP-SMX prophylaxis and both died a few days after diagnosis.\n\nTable 2 Antimicrobial susceptibility of Nocardia isolates from Queensland case series.\n\nRates of nonsusceptibility (classified as intermediate, I, or resistant, R) among isolates tested were 70% for amoxicillin–clavulanate (7/20 I, 7/20 R), 64% for cefotaxime (1/11 I, 6/11 R), 87% for erythromycin (1/15 I; 12/15 R), 50% for ciprofloxacin (2/20 I, 8/20 R), 40% for imipenem (5/20 I, 3/20 R), 55% for tobramycin (11/20 R), 55% for minocycline (9/20 I, 2/20 R), and 72% for clarithromycin (13/18 R). Few isolates were tested for ceftriaxone (3/7 S, 1/7 I, 3/7 R). All but 1 isolate was susceptible to amikacin. Only 7 isolates were tested for linezolid and all tested susceptible. As expected, N farcinica isolates were mainly resistant to third-generation cephalosporins (6/8 isolates, 75%) and tobramycin (8/8, 100%).\n\n3.5 Treatment and outcome\nThe treatment and outcomes of patients are summarized in Table 3.\n\nTable 3 Treatment and outcome.\n\nOne patient was diagnosed postmortem and did not receive any directed treatment. Of the 19 remaining individuals, 16 (84%) received in hospital treatment with TMP-SMX, and 1 with sulfadiazine. These patients all received sulfonamides as part of combination regimens with other active antibiotics; sulfonamides were combined with carbapenems in 10 cases and with ceftriaxone in 8; 2 patients received triple regimens including both carbapenems and ceftriaxone. Four patients received amikacin, 2 fluoroquinolones, and 1 linezolid.\n\nOf the 2 patients who did not receive in-hospital TMP-SMX, 1 was treated with cefepime for several days before being palliated. Subsequent susceptibility testing revealed a TMP-SMX resistant isolate. The second patient was allergic to sulfa-based compounds, and received TMP-SMX maintenance therapy after desensitization.\n\nExcluding patients who died in hospital, duration of in-hospital treatment ranged from 3 to 6 weeks.\n\nTMP-SMX was prescribed as maintenance therapy in 10 patients for a range of 6 to 24 months.\n\nTen patients received surgical treatment including 1 who had an extraventricular drain placed as the only procedure. Of these 10 patients, 1 died due to an unknown cause at 3 months (record not available). In contrast, of the remaining 10 individuals who did not undergo surgical management, 6 died within 1 year and 1 died at 18 months after recurrence of infection. The 1 year outcome for 2 patients was not able to be ascertained.\n\nFive of the 7 deaths occurring within 1 year occurred within 1 month of diagnosis. An eighth patient died 18 months after initial diagnosis, due to recurrent Nocardia brain abscess. Six of the 7 deaths at 1 year had been diagnosed with N farcinica infection. The isolate of the seventh patient was unspeciated.\n\n3.6 Literature review\nWe identified 10 case series of CNS nocardiosis which fulfilled our search criteria, comprising a total of 45 patients.[9–18] The clinical details from these studies are shown in Table 4. The mean age of patients was 57 years and 64% of the patients were male. The majority (55.6%) were immunosuppressed. The most common comorbid condition was autoimmune disease, which was reported in 26.7%, followed by malignancy in 24.4%. Chronic lung disease was present in 10 (22%). Three patients (6.7%) had undergone organ transplantation and 7 (15.5%) had a history of excess alcohol intake. A significant proportion (42.2%) received corticosteroids before the diagnosis of nocardiosis. Of these patients, 6 were receiving additional immunosuppressive agents in addition to corticosteroids.\n\nTable 4 Clinical and microbiological characteristics of literature patients (n = 45).\n\nAll patients had brain abscesses visible on imaging, and 3 had features of meningitis on examination of CSF in addition to brain abscess. There were no cases of spinal cord disease. The most commonly involved extraneural site of infection was the lung, which was seen in 11 (28.2%).\n\nThe species was reported in 34 patients only. The most frequently isolated species was N asteroides (12/34, 35.3%), followed by N farcinica (11/34, 32.3%). Speciation was performed according to molecular sequencing in 2 studies only.\n\nTMP-SMX was used for definitive treatment in the majority of patients (32/45, 71%) but a variety of other antibiotics were also used, including ceftriaxone (17/45; 37.8%) and carbapenems (15/45; 33.3%).\n\nThe outcomes were specified for 42 patients. Overall, 10 patients died, giving a mortality rate of 23.8%. Six patients suffered a relapse.\n\n4 Discussion\nCNS nocardiosis is a challenging opportunistic infection for the clinician. To date, few case series have been published on this topic due to the small numbers encountered at any single institution. We report here the largest case series of microbiologically proven CNS nocardiosis and examine the clinical and microbiological features.\n\nIt is well established that immunosuppression, particularly deficiency in cell-mediated immunity is a risk factor for invasive Nocardia infections. Excluding alcohol as a risk factor, we found that 55% of our patients were immunosuppressed, with corticosteroid use being the most frequent cause of immunosuppression (50%). Correspondingly, our review of the literature found that 55.6% of patients were immunosuppressed, with 40% receiving corticosteroid treatment. Very similar rates of corticosteroid use have been reported in other reviews of systemic nocardiosis stressing the significance of this therapy in the pathogenesis of disease and the need to consider nocardiosis in this patient population.[9,19–21]\n\nTwenty percent of our patients were transplant recipients. Previous studies have calculated the frequency of Nocardia infection in transplant patients to be between 0.7% and 3.5% with lung transplant patients having the highest risk.[22,23] High-dose corticosteroid use, preceding cytomegalovirus infection, elevated calcineurin inhibitor levels and tacrolimus use have been shown to be independent risk factors for nocardiosis posttransplantation, all of which are indicators of severe immune suppression.[22–24]\n\nA significant proportion of both our case patients and the literature patients had underlying autoimmune disease. All of these individuals were receiving immunosuppressive therapy at time of diagnosis, with a significant proportion of patients receiving combination treatment. Newer immunosuppressive therapies such as monoclonal antibodies may also be a risk factor for infection and several cases of CNS nocardiosis have been reported in the setting of monoclonal antibodies.[25–28] The concomitant use of multiple agents and corticosteroids in particular makes direct attribution of risk difficult. However, given the increasing number of individuals being placed on novel agents, this is an area which warrants further scrutiny.\n\nIn previous studies, advanced HIV has been shown to be a risk factor for systemic nocardiosis although rates of HIV vary substantially between studies.[1,20,21,29] The fact that only 1 patient in our literature review and none of our study patients were HIV positive is likely related to the availability of highly active retroviral therapy during this time period. Some postulate that HIV positive patients may be protected from Nocardia infection if taking TMP-SMX for prophylaxis against Pneumocystis jirovecii. This hypothesis is not borne out in the transplant population in which a substantial proportion who develop nocardiosis do so whilst receiving TMP-SMX prophylaxis.[9,21,23,24,30,31] The only patient in our study to be receiving TMP-SMX prophylaxis was a patient who was diagnosed with Nocardia brain abscess 2 years after allogeneic hematopoietic stem cell transplant and was receiving considerable immunosuppressive therapy with prednisolone, mycophenolate, and tacrolimus. Notably, this isolate remained susceptible to TMP-SMX. Clinicians should therefore not discount nocardiosis from the list of differential diagnoses because of the presence of prophylactic TMP-SMX.\n\nIt is of note that most individuals in our study presented with neurological complaints and few with fever or other classical infective symptoms. Furthermore, there was wide variation in symptom duration, with 1 patient having symptoms for 6 months before presentation. This may steer the clinician away from a diagnosis of intracerebral infection and cause diagnostic delay if not taken into consideration.\n\nOur study confirmed that there is geographical variation in the distribution of Nocardia species and helps to better define Nocardia species distribution in Queensland, Australia.[5,32–34] A previous study of nocardiosis in Queensland was published in 1992 and included 102 isolates from a range of clinical sites.[35] Of these, 45 isolates were classified as N asteroides. Given that this publication predates the routine use of molecular diagnostics, it is likely that a different range of species would be identified should the same isolates be tested today. In comparison, no N asteroides sensu strictu isolates were found in our study, with the most frequently represented species being N farcinica, followed by N paucivorans. These findings corroborate previous reports that N farcinica is more virulent than other members of the species and is increasingly isolated in invasive disease.[36] A recent large case series of nocardiosis in solid organ transplant patients has likewise found N farcinica to be the most prevalent organism when relying on 16s RNA sequencing for species identification.[24]N farcinica has a resistance pattern which can make treatment difficult, characteristically testing resistant to third-generation cephalosporins.[7,37]N asteroides was the most commonly isolated species in our review of published cases, accounting for 12 of the 34 speciated isolates, followed by N farcinica (11/35, 32.3%). It is important to note, however, that 16s polymerase chain reaction was used for diagnosis in only 2 studies and there were no cases of N asteroides infection in these studies. This high percentage of N asteroides in the literature is likely due to phenotypic identification which is known to be inaccurate for diagnosis. Interestingly, of the 7 deaths occurring at 1 year, 6 of these were attributed to N farcinica with the seventh isolate being unspeciated, again suggesting the virulence of this organism.\n\nTMP-SMX is the cornerstone of treatment for Nocardia infections and it is also the drug of choice for cerebral nocardiosis due to its good penetration in the CNS.[38] Due to the paucity of trials, there are no formal guidelines to direct treatment duration, however most clinicians would agree that CNS nocardiosis warrants a long course of treatment and 12 months is commonly recommended by experts.[37] Prolonged TMP-SMX treatment can be problematic due to drug toxicity issues (including blood dyscrasias and electrolyte imbalances) as well as hypersensitivity reactions, all of which can further complicate the clinical course. Two of 20 isolates showed resistance to TMP-SMX with an overall prevalence of resistance in our case series of 10%. This prevalence is lower than that reported in some recent studies from North America, Europe, and Asia, but slightly higher than reported in other studies from North America, Taiwan, and South Africa.[5–8,15,32–34,39–43] Both resistant isolates we reported were N farcinica with an intraspecies resistance prevalence of 25% (2/8).\n\nThe reported variability in TMP-SMX resistances may be due to technical differences in susceptibility testing across different laboratories rather than to a real increase in resistance. This has been documented in a recent study which demonstrated that the interpretation of Nocardia spp. MIC using the broth microdilution method can be challenging, especially for certain drugs.[44]\n\nSystemic nocardiosis carries an unsurprisingly poor prognosis given the affected patient population. The mortality rate of our patients at 1 year was 35%. This is much higher than the mortality rate of patients with other bacterial brain abscesses which is generally less than 10%.[31] Other authors have found mortality rates of 7% to 61% with immunocompromised hosts having a poorer outcome.[31] Anagnostou et al[9] found that those patient treated with a combination of neurosurgery and medical therapy had better outcomes that those treated with either alone. In our study, 80% of those who underwent surgery were alive at 1 year compared to only 33.3% of those who did not. The favorable outcome from surgery may in fact be due to bias in selecting patients who are well enough to undergo surgery; however, our study adds further weight to the suggestion that surgery is an important part of the treatment algorithm. It has to be borne in mind that our case definition of microbiologically proven nocardiosis is inherently biased toward patients who had a surgical procedure. The majority of patients will have only a presumptive diagnosis of CNS nocardiosis based on imaging results, after Nocardia infection is confirmed elsewhere and these patients may indeed have a different prognosis.\n\nOur retrospective review has several limitations. Firstly, we encountered missing data including duration of symptoms, details of immunosuppressive agent administration, and final outcomes. Secondly, not all of the case isolates underwent speciation using molecular techniques and this may have impacted on species determination. Additionally, as stated above, our case definition of microbiologically proven CNS nocardiosis may select for a different patient population than those who are diagnosed and treated without CNS sampling.\n\nIn conclusion, CNS nocardiosis is an uncommon opportunistic infection which carries a grave prognosis. We show that N farcinica is now the most commonly isolated organism in CNS disease in Queensland. Clinicians should consider Nocardia in the list of differentials when confronted with a patient with brain abscess or meningitis in the setting of immune suppression and corticosteroid use in particular. The diagnosis should not be dismissed because of the absence of fever, or in the patient with a subacute presentation of neurological complaints. Further studies are needed to determine the risk of disease with newer immunosuppressive agents.\n\nAn empiric regimen for seriously ill, immunocompromised patients with brain abscess due to Nocardia should comprise intravenous TMP-SMX (15–20 mg/kg of the trimethoprim moiety/day) plus intravenous meropenem (2 g 8-hourly also). We suggest avoiding use of imipenem due to the increased risk of seizures with this carbapenem. Given the high rates of resistance to third-generation cephalosporins (especially N farcinica) neither ceftriaxone nor cefotaxime could be reliable upon in the absence of confirmed susceptibility.\n\nCareful consideration should be given to surgical management.\n\nAbbreviations: CNS = central nervous system, COPD = chronic obstructive pulmonary disease, CSF = cerebrospinal fluid, CT = computerized tomography, HIV = human immunodeficiency virus, I = intermediate, R = resistant, S = susceptible, TMP-SMX = trimethoprim–sulfamethoxazole.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n1 Beaman BL Beaman L \nNocardia species: host-parasite relationships . Clin Microbiol Rev \n1994 ; 7 :213 –264 .8055469 \n2 Mandell GL Bennett JE Dolin R \nMandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. Vol. 7 . Philadelphia :Churchill Livingstone/Elsevier ; 2010 .\n3 Liu WL Lai CC Ko WC \nClinical and microbiological characteristics of infections caused by various Nocardia species in Taiwan: a multicenter study from 1998 to 2010 . Eur J Clin Microbiol Infect Dis \n2011 ; 30 :1341 –1347 .21461846 \n4 Roth A Andrees S Kroppenstedt RM \nPhylogeny of the genus Nocardia based on reassessed 16S rRNA gene sequences reveals underspeciation and division of strains classified as Nocardia asteroides into three established species and two unnamed taxons . J Clin Microbiol \n2003 ; 41 :851 –856 .12574299 \n5 Uhde KB Pathak S McCullum I Jr \nAntimicrobial-resistant nocardia isolates, United States, 1995–2004 . Clin Infect Dis \n2010 ; 51 :1445 –1448 .21058914 \n6 Brown-Elliott BA Biehle J Conville PS \nSulfonamide resistance in isolates of Nocardia spp. from a US multicenter survey . J Clin Microbiol \n2012 ; 50 :670 –672 .22170936 \n7 Schlaberg R Fisher MA Hanson KE \nSusceptibility profiles of Nocardia isolates based on current taxonomy . Antimicrob Agents Chemother \n2014 ; 58 :795 –800 .24247124 \n8 McTaggart LR Doucet J Witkowska M \nAntimicrobial susceptibility among clinical Nocardia species identified by multilocus sequence analysis . Antimicrob Agents Chemother \n2015 ; 59 :269 –275 .25348540 \n9 Anagnostou T Arvanitis M Kourkoumpetis TK \nNocardiosis of the central nervous system: experience from a general hospital and review of 84 cases from the literature . Medicine \n2014 ; 93 :19 –32 .24378740 \n10 Kennedy KJ Chung KH Bowden FJ \nA cluster of nocardial brain abscesses . Surg Neurol \n2007 ; 68 :43 –49 .discussion 49 .17586220 \n11 Lee GY Daniel RT Brophy BP \nSurgical treatment of nocardial brain abscesses . Neurosurgery \n2002 ; 51 :668 –671 .discussion 662–671 .12188944 \n12 Lin YJ Yang KY Ho JT \nNocardial brain abscess . J Clin Neurosci \n2010 ; 17 :250 –253 .20005722 \n13 Loeffler JM Bodmer T Zimmerli W \nNocardial brain abscess: observation of treatment strategies and outcome in Switzerland from 1992 to 1999 . Infection \n2001 ; 29 :337 –341 .11787836 \n14 Tamarit M Poveda P Baron M \nFour cases of nocardial brain abscess . Surg Neurol Int \n2012 ; 3 :88 .23050202 \n15 Wang HL Seo YH LaSala PR \nNocardiosis in 132 patients with cancer: microbiological and clinical analyses . Am J Clin Pathol \n2014 ; 142 :513 –523 .25239419 \n16 Yildiz O Alp E Tokgoz B \nNocardiosis in a teaching hospital in the Central Anatolia region of Turkey: treatment and outcome . Clin Microbiol Infect \n2005 ; 11 :495 –499 .15882201 \n17 Zheng YC Wang TL Hsu J \nClinical pathway in the treatment of nocardial brain abscesses following systemic infections . Case Rep Neurol Med \n2014 ; 2014 :584934 .25254126 \n18 Valarezo J Cohen JE Valarezo L \nNocardial cerebral abscess: report of three cases and review of the current neurosurgical management . Neurol Res \n2003 ; 25 :27 –30 .12564122 \n19 Lederman ER Crum NF \nA case series and focused review of nocardiosis: clinical and microbiologic aspects . Medicine \n2004 ; 83 :300 –313 .15342974 \n20 Ambrosioni J Lew D Garbino J \nNocardiosis: updated clinical review and experience at a tertiary center . Infection \n2010 ; 38 :89 –97 .20306281 \n21 Minero MV Marin M Cercenado E \nNocardiosis at the turn of the century . Medicine \n2009 ; 88 :250 –261 .19593231 \n22 Clark NM Reid GE \nNocardia infections in solid organ transplantation . Am J Transplant \n2013 ; 13 \n(suppl 4) :83 –92 .23465002 \n23 Peleg AY Husain S Qureshi ZA \nRisk factors, clinical characteristics, and outcome of Nocardia infection in organ transplant recipients: a matched case-control study . Clin Infect Dis \n2007 ; 44 :1307 –1314 .17443467 \n24 Coussement J Lebeaux D van Delden C \nNocardia infection in solid organ transplant recipients: a multicenter European case-control study . Clin Infect Dis \n2016 ; 63 :338 –345 .27090987 \n25 Abreu C Rocha-Pereira N Sarmento A \nNocardia infections among immunomodulated inflammatory bowel disease patients: a review . World J Gastroenterol \n2015 ; 21 :6491 –6498 .26074688 \n26 Flohr TR Sifri CD Brayman KL \nNocardiosis in a renal transplant recipient following rituximab preconditioning . Upsala J Med Sci \n2009 ; 114 :62 –64 .19242875 \n27 Wendling D Murad M Mathieu S \nSystemic nocardiosis in a case of rheumatoid arthritis treated with tumor necrosis factor blockers . J Rheumatol \n2008 ; 35 :539 –542 .\n28 Ali T Chakraburtty A Mahmood S \nRisk of nocardial infections with anti-tumor necrosis factor therapy . Am J Med Sci \n2013 ; 346 :166 –168 .23531994 \n29 McNeil MM Brown JM \nThe medically important aerobic actinomycetes: epidemiology and microbiology . Clin Microbiol Rev \n1994 ; 7 :357 –417 .7923055 \n30 Torres OH Domingo P Pericas R \nInfection caused by Nocardia farcinica: case report and review . Eur J Clin Microbiol Infect Dis \n2000 ; 19 :205 –212 .10795594 \n31 Mamelak AN Obana WG Flaherty JF \nNocardial brain abscess: treatment strategies and factors influencing outcome . Neurosurgery \n1994 ; 35 :622 –631 .7808604 \n32 Larruskain J Idigoras P Marimon JM \nSusceptibility of 186 Nocardia sp. isolates to 20 antimicrobial agents . Antimicrob Agents Chemother \n2011 ; 55 :2995 –2998 .21402847 \n33 Lai CC Liu WL Ko WC \nMulticenter 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 \n2011 ; 55 :2084 –2091 .21343461 \n34 Lai CC Liu WL Ko WC \nAntimicrobial-resistant nocardia isolates, Taiwan, 1998–2009 . Clin Infect Dis \n2011 ; 52 :833 –835 .21367741 \n35 Georghiou PR Blacklock ZM \nInfection with Nocardia species in Queensland. A review of 102 clinical isolates . Med J Aust \n1992 ; 156 :692 –697 .1620016 \n36 Desmond EP Flores M \nMouse pathogenicity studies of Nocardia asteroides complex species and clinical correlation with human isolates . FEMS Microbiol Lett \n1993 ; 110 :281 –284 .8354460 \n37 Lerner PI \nNocardiosis . Clin Infect Dis \n1996 ; 22 :891 –903 .quiz 895–904 .8783685 \n38 Welsh O Vera-Cabrera L Salinas-Carmona MC \nCurrent treatment for nocardia infections . Expert Opin Pharmacother \n2013 ; 14 :2387 –2398 .24093436 \n39 Lowman W Aithma N \nAntimicrobial susceptibility testing and profiling of Nocardia species and other aerobic actinomycetes from South Africa: comparative evaluation of broth microdilution versus the Etest . J Clin Microbiol \n2010 ; 48 :4534 –4540 .20980572 \n40 Tremblay J Thibert L Alarie I \nNocardiosis in Quebec, Canada, 1988–2008 . Clin Microbiol Infect \n2011 ; 17 :690 –696 .20636427 \n41 Rosman Y Grossman E Keller N \nNocardiosis: a 15-year experience in a tertiary medical center in Israel . Eur J Intern Med \n2013 ; 24 :552 –557 .23725690 \n42 Mootsikapun P Intarapoka B Liawnoraset W \nNocardiosis in Srinagarind Hospital, Thailand: review of 70 cases from 1996–2001 . Int J Infect Dis \n2005 ; 9 :154 –158 .15840456 \n43 Bibi S Irfan S Zafar A \nIsolation frequency and susceptibility patterns of Nocardia species at a tertiary hospital laboratory in Karachi, Pakistan . J Infect Dev Ctries \n2011 ; 5 :499 –501 .21727653 \n44 Conville PS Brown-Elliott BA Wallace RJ Jr \nMultisite reproducibility of the broth microdilution method for susceptibility testing of Nocardia species . J Clin Microbiol \n2012 ; 50 :1270 –1280 .22219309\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0025-7974",
"issue": "95(46)",
"journal": "Medicine",
"keywords": null,
"medline_ta": "Medicine (Baltimore)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020806:Central Nervous System Bacterial Infections; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009617:Nocardia Infections; D011793:Queensland; D012189:Retrospective Studies",
"nlm_unique_id": "2985248R",
"other_id": null,
"pages": "e5255",
"pmc": null,
"pmid": "27861348",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "12564122;21058914;20306281;21367741;18322977;19242875;25239419;23465002;1620016;17586220;23531994;24378740;8783685;19593231;20005722;24247124;15840456;12188944;21402847;25254126;15342974;10795594;20636427;20980572;22219309;12574299;7923055;23050202;25348540;15882201;24093436;8055469;11787836;26074688;17443467;8354460;22170936;21343461;27090987;7808604;21461846;21727653;23725690",
"title": "Central nervous system nocardiosis in Queensland: A report of 20 cases and review of the literature.",
"title_normalized": "central nervous system nocardiosis in queensland a report of 20 cases and review of the literature"
} | [
{
"companynumb": "AU-BAUSCH-BL-2019-018950",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": "3",
... |
{
"abstract": "Crizotinib is an oral tyrosine kinase inhibitor, approved by the FDA in 2011, for use in anaplastic lymphoma kinase positive, metastatic, non-small cell lung cancer. Crizotinib inhibits oncogenic protein expression and impairs cellular proliferation in tumors with an overexpressed anaplastic lymphoma kinase gene. Currently used most frequently in the adult patient population, pediatric use is becoming more prominent, specifically in disease states exhibiting anaplastic lymphoma kinase-positive, metastatic disease, such as neuroblastoma. Approximately 8% of neuroblastomas have activating anaplastic lymphoma kinase-mutations, making this a promising target for a difficult-to-treat disease. Studies in the pediatric population are limited. However, targeted anaplastic lymphoma kinase-inhibitor therapies have shown improved outcomes at both one-year and two-year marks in both overall survival and progression free survival in anaplastic lymphoma kinase-positive adult patients with non-small cell lung cancer. One Children's Oncology Group phase I trial examined toxicities associated with anaplastic lymphoma kinase inhibitor therapy in pediatric patients. Results revealed varying grades in severity of neutropenia, dizziness, and liver function test elevation. In the adult population, severe toxicities reported by the manufacturer include effects on liver, cardiac and lung function. Additionally, several cases of severe, erosive, pill-esophagitis due to crizotinib therapy have been documented in the adult population. Erosive esophagitis is common in the pediatric population due to a variety of factors. Ingestion of medications or other corrosive agents accounts for approximately 3-5% (5000-10,000 cases per year) of esophagitis presentation in the pediatric population. Common causative medications include non-steroidal anti-inflammatory drugs, antibiotics such as doxycycline and tetracycline, and ferrous sulfate. Presented here is the first reported case of crizotinib-induced pill esophagitis in a pediatric patient.",
"affiliations": "1 University of Wisconsin Hospitals and Clinics, American Family Children's Hospital, Madison, WI, USA.;2 School of Pharmacy, University of Wisconsin, Madison, WI, USA.",
"authors": "Lubcke|Nicole|N|;Van Camp|Kevin|K|",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000077547:Crizotinib; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases",
"country": "England",
"delete": false,
"doi": "10.1177/1078155217752537",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1078-1552",
"issue": "25(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": "ALK; Crizotinib; esophagitis; pediatrics",
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D002648:Child; D000077547:Crizotinib; D004941:Esophagitis; D006801:Humans; D008297:Male; D009447:Neuroblastoma; D047428:Protein Kinase Inhibitors; D020794:Receptor Protein-Tyrosine Kinases",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "724-726",
"pmc": null,
"pmid": "29357780",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Crizotinib-induced erosive esophagitis in a pediatric patient with neuroblastoma.",
"title_normalized": "crizotinib induced erosive esophagitis in a pediatric patient with neuroblastoma"
} | [
{
"companynumb": "US-ZYDUS-035877",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThe aim of this study is to evaluate the preventive effects of carvedilol on doxorubicin-induced cardiotoxicity.\n\n\nMETHODS\nIn this trial, 70 female patients with breast cancer who were candidates to receive doxorubicin were enrolled, from which 30 were selected randomly to receive carvedilol 6.25 mg daily during chemotherapy, with the rest receiving placebo as the control group. Both groups were evaluated 1 week before and 1 week after chemotherapy by measuring the left ventricular ejection fraction and strain/strain rate.\n\n\nRESULTS\nData analysis showed that the case group presented no significant reduction in strain and strain-rate parameters after intervention, while there was a significant reduction in these parameters in the control group (all p values <0.001). Also, the mean differences of strain parameters in the case group were significantly less than in the control group in all evaluated heart walls (basal septal strain, p = 0.005, basal lateral strain, p = 0.001, basal inferior strain, p < 0.001, and basal anterior strain, p < 0.001); the same was true for the strain-rate parameters (the p values for basal septal, basal lateral, basal inferior and basal anterior strain rate were 0.037, 0.037, 0.002 and <0.001, respectively).\n\n\nCONCLUSIONS\nThis study shows that carvedilol can prevent doxorubicin-induced cardiotoxicity. Whether this prophylaxis should be considered as the preferred method needs further investigation.",
"affiliations": "Cardiovascular Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.",
"authors": "Tashakori Beheshti|Ahmad|A|;Mostafavi Toroghi|Hesam|H|;Hosseini|Golkoo|G|;Zarifian|Ahmadreza|A|;Homaei Shandiz|Fatemeh|F|;Fazlinezhad|Afsoon|A|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000903:Antibiotics, Antineoplastic; D002227:Carbazoles; D011412:Propanolamines; D000077261:Carvedilol; D004317:Doxorubicin",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000442722",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0008-6312",
"issue": "134(1)",
"journal": "Cardiology",
"keywords": null,
"medline_ta": "Cardiology",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000328:Adult; D000903:Antibiotics, Antineoplastic; D001943:Breast Neoplasms; D002227:Carbazoles; D066126:Cardiotoxicity; D000077261:Carvedilol; D018890:Chemoprevention; D004311:Double-Blind Method; D004317:Doxorubicin; D016903:Drug Monitoring; D004562:Electrocardiography; D005260:Female; D006801:Humans; D008875:Middle Aged; D011412:Propanolamines; D013318:Stroke Volume; D016896:Treatment Outcome",
"nlm_unique_id": "1266406",
"other_id": null,
"pages": "47-53",
"pmc": null,
"pmid": "26866364",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Carvedilol Administration Can Prevent Doxorubicin-Induced Cardiotoxicity: A Double-Blind Randomized Trial.",
"title_normalized": "carvedilol administration can prevent doxorubicin induced cardiotoxicity a double blind randomized trial"
} | [
{
"companynumb": "IR-JNJFOC-20160224608",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "A 20-year-old college student presented with high grade, intermittent fever for 10 days associated with blood stained loose stools after taking tablet levamisole for 17 days for vitiligo vulgaris. He was febrile, had a toxic appearance and appeared pale. Investigations showed neutropaenia with thrombocytopaenia. Blood cultures were sterile and stool cultures did not grow any enteric pathogens. His bone marrow examination was suggestive of an aplastic anaemia. He was administered empirical antibiotics, granulocyte colony stimulating factor and platelet transfusions. However, his fever and blood stained stools persisted. A repeat bone marrow examination after 2 weeks still revealed a hypoplastic marrow. Hence, a diagnosis of a levamisole induced bone marrow failure was made. While being worked up for an allogeneic stem cell transplantation, he developed neutropaenic enterocolitis and refractory septic shock with carbapenem resistant Klebsiella pneumoniae and succumbed to his illness.",
"affiliations": "Department of General Medicine, Christian Medical College and Hospital Vellore, Vellore, India.;Department of General Medicine, Christian Medical College and Hospital Vellore, Vellore, India.;Department of Pathology, Christian Medical College and Hospital Vellore, Vellore, India.;Department of General Medicine, Christian Medical College and Hospital Vellore, Vellore, India.",
"authors": "George|John Titus|JT|http://orcid.org/0000-0002-5405-8289;Janeela|Asisha M|AM|;Sigamani|Elanthenral|E|;Mathuram|Alice Joan|AJ|http://orcid.org/0000-0003-2769-1211",
"chemical_list": "D000276:Adjuvants, Immunologic; D016179:Granulocyte Colony-Stimulating Factor; D007978:Levamisole",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-231167",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(9)",
"journal": "BMJ case reports",
"keywords": "general practice/family medicine; haematology (incl blood transfusion); pharmacology and therapeutics; toxicology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000276:Adjuvants, Immunologic; D000080983:Bone Marrow Failure Disorders; D003967:Diarrhea; D017809:Fatal Outcome; D005334:Fever; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007978:Levamisole; D008297:Male; D009503:Neutropenia; D017713:Platelet Transfusion; D012772:Shock, Septic; D014820:Vitiligo; D055815:Young Adult",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31570359",
"pubdate": "2019-09-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7377861;22143075;22092895;54782;10354040;24365689;72318;6967746;365327;25925993;26290761;28314885;23620110;22393119;6283678;22677078;282448;26924410;28589070;21764154;22152487;2206269;7700172;7355492;68226;28592788;25943359",
"title": "A fatal case of levamisole induced bone marrow failure.",
"title_normalized": "a fatal case of levamisole induced bone marrow failure"
} | [
{
"companynumb": "IN-PFIZER INC-2019463165",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MEROPENEM"
},
"drugadditional": "3",
... |
{
"abstract": "Neurocutaneous melanosis is caused by postzygotic NRAS mutations in neural crest cells, resulting in large or multiple nevi in the skin and proliferation of leptomeningeal melanocytes in the central nervous system. The onset of neurological symptoms is usually before the age of 2 years, but it can also occur in adults. A 35-year-old male had been asymptomatic for a long time after excision of a large congenital melanocytic nevus, but he developed headache, disturbance of consciousness, and seizure. Methotrexate was ineffective, cerebral pressure was decreased by spinal drainage, and steroid pulse therapy was temporarily effective. Seizures and disturbance of consciousness worsened and the patient died on the 92nd day. Cerebrospinal fluid human melanin black-45 immunostaining and serum 5-S-cysteinyldopa (5-S-CD) were useful in diagnosing melanocytic proliferation, and serum 5-S-CD may be useful in predicting prognosis.",
"affiliations": "Department of Neurology, Osaka Saiseikai Nakatsu Hospital.;Department of Neurology, Social Medical Corporation Kotobukikai Tominaga Hospital.;Department of Neurology, Social Medical Corporation Kotobukikai Tominaga Hospital.;Department of Neurology, Osaka Saiseikai Nakatsu Hospital.;Department of Neurology, Osaka Saiseikai Nakatsu Hospital.",
"authors": "Furukawa|Koji|K|;Kikui|Shoji|S|;Takeshima|Takao|T|;Yamamoto|Toru|T|;Ozaki|Akihiko|A|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.5692/clinicalneurol.cn-001641",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-918X",
"issue": null,
"journal": "Rinsho shinkeigaku = Clinical neurology",
"keywords": "5-S-CD; HMB-45 staining; adult; black nevus; neurocutaneous melanosis",
"medline_ta": "Rinsho Shinkeigaku",
"mesh_terms": null,
"nlm_unique_id": "0417466",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34789628",
"pubdate": "2021-11-18",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "An adult case of neurocutaneous melanosis with acute exacerbation after a long asymptomatic period following excision of a melanocytic nevus.",
"title_normalized": "an adult case of neurocutaneous melanosis with acute exacerbation after a long asymptomatic period following excision of a melanocytic nevus"
} | [
{
"companynumb": "JP-PFIZER INC-202200050378",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "4"... |
{
"abstract": "Early therapeutic decision-making is crucial in patients with higher-risk MDS. We evaluated the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with azacitidine using a combined cohort from Karolinska University Hospital (n=89) and from King's College Hospital, London (n=45). While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment. IPSS high-risk cytogenetics negatively impacted overall survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2) were associated with prolonged survival (22 vs 12 months, p=0.01). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months compared to only 10 months in patients with the opposite pattern. While TP53 was negatively associated with survival, neither RUNX1-mutations nor the number of mutations appeared to influence survival in this cohort. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS patients eligible for treatment with azacitidine.",
"affiliations": "Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.;Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.;Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.;Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom.;Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden.",
"authors": "Tobiasson|Magnus|M|;McLornan|Donal P|DP|;Karimi|Mohsen|M|;Dimitriou|Marios|M|;Jansson|Monika|M|;Ben Azenkoud|Asmaa|A|;Jädersten|Martin|M|;Lindberg|Greger|G|;Abdulkadir|Hani|H|;Kulasekararaj|Austin|A|;Ungerstedt|Johanna|J|;Lennartsson|Andreas|A|;Ekwall|Karl|K|;Mufti|Ghulam J|GJ|;Hellström-Lindberg|Eva|E|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015415:Biomarkers; D006657:Histones; D001374:Azacitidine",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.7899",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 26959885789910.18632/oncotarget.7899Research PaperMutations in histone modulators are associated with prolonged survival during azacitidine therapy Tobiasson Magnus 1McLornan Donal P. 23Karimi Mohsen 1Dimitriou Marios 1Jansson Monika 1Azenkoud Asmaa Ben 1Jädersten Martin 1Lindberg Greger 4Abdulkadir Hani 1Kulasekararaj Austin 23Ungerstedt Johanna 1Lennartsson Andreas 5Ekwall Karl 5Mufti Ghulam J. 23Hellström-Lindberg Eva 11 Center for Hematology and Regenerative Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden2 Department of Haematological Medicine, King's College Hospital NHS Foundation Trust, London, United Kingdom3 Department of Haematological Medicine, King's College, London, United Kingdom4 Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden5 Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, SwedenCorrespondence to:Magnus Tobiasson,magnus.tobiasson@ki.seEva Hellström-Lindberg,eva.hellstrom-lindberg@ki.se19 4 2016 3 3 2016 7 16 22103 22115 13 12 2015 21 2 2016 Copyright: © 2016 Tobiasson et al.2016This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Early therapeutic decision-making is crucial in patients with higher-risk MDS. We evaluated the impact of clinical parameters and mutational profiles in 134 consecutive patients treated with azacitidine using a combined cohort from Karolinska University Hospital (n=89) and from King's College Hospital, London (n=45). While neither clinical parameters nor mutations had a significant impact on response rate, both karyotype and mutational profile were strongly associated with survival from the start of treatment. IPSS high-risk cytogenetics negatively impacted overall survival (median 20 vs 10 months; p<0.001), whereas mutations in histone modulators (ASXL1, EZH2) were associated with prolonged survival (22 vs 12 months, p=0.01). This positive association was present in both cohorts and remained highly significant in the multivariate cox model. Importantly, patients with mutations in histone modulators lacking high-risk cytogenetics showed a survival of 29 months compared to only 10 months in patients with the opposite pattern. While TP53 was negatively associated with survival, neither RUNX1-mutations nor the number of mutations appeared to influence survival in this cohort. We propose a model combining histone modulator mutational screening with cytogenetics in the clinical decision-making process for higher-risk MDS patients eligible for treatment with azacitidine.\n\nmyelodysplastic syndromeazacitidinehypomethylating therapynext-generation sequencingmolecular marker\n==== Body\nINTRODUCTION\nIn Europe, azacitidine is approved for the treatment of patients with higher-risk myelodysplastic syndromes (MDS), where improvements in survival have been documented [1, 2]. The drug is an inhibitor of DNA methyl transferase resulting in reduced DNA methylation but, although believed to be its principal mode of action, other effects including immunomodulation have been identified and the exact mechanisms of action of azacitidine remain unknown [3-7]. Despite this therapeutic advance, the median survival for higher-risk MDS patients remains short, approximately 12 months, as demonstrated by the Swedish population-based registry for intermediate-2 and high-risk MDS (http://www.cancercentrum.se/inca).\n\nThe genetic landscape of the MDS-genome has been well characterized in recent years and some 40 recurrently mutated genes including epigenetic regulators, splicing factors, cohesion factors, transcription factors and others have been identified as driver mutations [8-11]. Several of these e.g. ASXL1, EZH2, RUNX1 and TP53 are associated with significantly shorter survival in several MDS cohorts [8-10, 12-14].\n\nAround fifty percent of patients with higher-risk MDS, and AML with dysplastic features and 20-29% marrow blasts, respond to azacitidine as defined by the International Working Group (IWG) criteria [2, 15-17]. Basic clinical data such as morphology and cytogenetics give sparse predictive information, although blast count >15%, extensive transfusion requirements, abnormal karyotype and previous therapy with cytarabine have been reported as negative predictors of response [15, 18, 19]. Although several studies report higher response rates for TET2–mutated patients, the presence of this mutation has not been associated with prolonged survival [19-21]. Mutated ASXL1, reported as a negative survival factor in numerous studies of heterogeneous MDS cohorts undergoing unspecified therapies [8-10, 14], was associated with shorter survival in a study by Traina et al, evaluating an azacitidine treated cohort (n=92, of which around 40 were higher-risk MDS), but had no impact on survival in a larger cohort undergoing hypomethylating agent (HMA) therapy (n=213, of which 113 were higher-risk MDS) [19, 20]. Of note, both these studies included a significant number of patients with lower-risk MDS and several patients were treated with decitabine, either sequentially or instead of azacitidine.\n\nWithin this study, we evaluated the impact of clinical and mutational parameters on response and survival in a large cohort of patients with comprehensive long-term follow-up receiving azacitidine as first-line treatment according to the European label and guidelines (Malcovati et al, Blood 2013). We report for the first time that mutations involved in genes encoding for histone modulating enzymes are associated with a significantly improved survival for patients undergoing azacitdine therapy and, together with cytogenetic analysis, provide a simple model to aid clinical decision-making.\n\nRESULTS\nBaseline characteristics and response\nWe included 134 consecutive patients from a mixed population of patients with an indication for azacitidine as first-line treatment; see Table 1 for patient characteristics. According to IPSS, the majority of patients had intermediate-2 risk (n=68) or high risk (n=38) disease. A total of 18 patients were categorized as intermediate-1 risk but were considered eligible for azacitidine either because of elevated blast count, high-risk cytogenetics or rapid deterioration of cytopenia according to European guidelines [27]. Using IPSS-R, 4, 11, 30 and 79 patients belonged to the low, intermediate, high or very high risk groups respectively. Ten patients could not be categorized according to IPSS as they were classified as CMML with white blood cell count (WBC) > 12×109/L; of these, eight were CMML-II and two CMML-I. Responses were evaluated according to IWG criteria as CR (n=30), mCR (n=17), PR (n=8), HI (n=20), SD (n=23) and PD (n=24). Patients with CR, mCR, PR and HI were considered as responders while the remaining patients were considered non-responders. Twelve patients (11%) were not evaluated for response due to early death. All patients had received ≥1 dose of azacitidine. Median number of cycles administered was 7 (range 1-45). Patient characteristics according to hospital (Karolinska or King's College London cohorts) are displayed in Table S2.\n\nTable 1 Patient characteristics\nAge at start of Azacitidine\t70.5 (35-88)\t\nDisease duration (months), median (range)\t4 (0-179)\t\nTherapy related, n\t17\t\nTransfusion dependent, n\t82\t\nWHO subgroups\t\t\n RA\t1\t\n RCMD +/− RS\t16\t\n RAEB-I\t27\t\n RAEB-II\t60\t\n MDS-AML, ≤ 30% blasts\t8\t\n AML with multilinear dysplasia, ≤ 30% blasts\t7\t\n CMML type 1\t3\t\n CMML type 2\t9\t\n MDS/MPN\t2\t\n MDS-U\t1\t\nMarrow blast %, median (range)\t11 (0-30)\t\nCellularity %, median (range)\t70 (10-100)\t\nANC, median (range)\t1.5×109/L (0-30.5)\t\nPlt, median (range)\t69×109/L (5-1237)\t\nIPSS cytogenetic risk group\t\t\n Favorable, n\t59\t\n Intermediate, n\t20\t\n Adverse, n\t55\t\nIPSS risk group\t\t\n Low, n\t0\t\n Intermediate-I, n\t18\t\n Intermediate-II, n\t68\t\n High, n\t38\t\nIPSS-R risk group\t\t\n Low\t4\t\n Intermediate\t11\t\n High\t30\t\n Very high\t79\t\nNumber of cycles given, median (range)\t7 (1-45)\t\nResponse\t\t\n Complete remission, n\t30\t\n Marrow complete remission, n\t17\t\n Partial remission, n\t8\t\n Hematological improvement, n\t20\t\n Stable disease, n\t23\t\n Progression, n\t24\t\n Not evaluated, n\t12\t\nAbbreviations: WHO, world health organization; RA, refractory anemia; RARS, Refractory anemia with ringed sideroblasts; RCMD, refractory cytopenia with multilineage dysplasia; RCMD-RS, RCMD with ringed sideroblasts; RAEB-I, Refractory anemia with excess of blasts; MPN, myeloproliferative neoplasm; CMML chronic myelomonocytic leukemia; CML chronic myeloid leukemia; AML Acute myeloid leukemia; IPSS, international prognostic score system.\n\nOf the total cohort (n=134), 110 (82%) had ≥ 1 mutation of which the most common were ASXL1 (n=29), TET2 (n=26), SRSF2 (n=24), and TP53 (n=20). Mutational frequencies of the most frequent mutations did not differ significantly between the two cohorts (see table S4A and S4B). According to IPSS cytogenetic profiling, 59, 20 and 55 patients had low-risk, intermediate-risk and high-risk cytogenetics, respectively. Eleven patients had neither mutations, nor cytogenetic abnormalities.\n\nWeak association between routine clinical parameters / mutational profile and response to azacitidine treatment\nWe observed a trend towards shorter pre-treatment disease duration among responders compared to non-responders (median 3 vs 7 months, p=0.055). No other clinical parameters, including morphological or cytogenetic characteristics were associated with azacitidine response rates. Interestingly, known unfavorable prognostic markers including adverse cytogenetics, or therapy-related disease were not significantly associated with response to azacitidine in this cohort (see Table 2).\n\nTable 2 Pre-treatment variables associated with response\nVariable\t\tResponse\tNo response\tp-value\t\nAge, median (range)\t72 (35-88)\t69 (50-85)\t0.40\t\nDisease duration, median (range)\t3 (0-117)\t7 (0-179)\t0.06\t\nMarrow blasts %, median (range)\t11 (0-30)\t12 (1-25)\t0.66\t\nCellularity %, median (range)\t70 (10-100)\t70 (10-100)\t0.41\t\nAbsolute neutrophil count, ×109/L, median (range)\t1.3×109/L (0.1-15.8)\t1.9×109/L (0-30.5)\t0.39\t\nPlatelets, ×109/L, median (range)\t70×109/L (5-1237)\t65×109/L (5-790)\t0.87\t\nTransfusion dependent, n (%)\tYes\t42 (56)\t40 (68)\t0.23\t\n\tNo\t33 (44)\t19 (32)\t\t\nTherapy-related, n (%)\tYes\t10 (13)\t7 (12)\t1.00\t\n\tNo\t65 (87)\t52 (88)\t\t\nIPSS cytogenetic risk group, n (%)\tFavorable\t37 (49)\t22 (37)\t0.38\t\n\tIntermediate\t10 (13)\t10 (17)\t\t\n\tAdverse\t28 (37)\t27 (46)\t\t\nIPSS risk score, n (%)\tLow\t0 (0)\t0 (0)\t0.55\t\n\tInt-1\t11 (16)\t7 (12)\t\t\n\tInt-2\t38 (57)\t30 (53)\t\t\n\tHigh\t18 (26)\t20 (35)\t\t\nNumber of mutations, median (range)\t2 (0-5)\t1 (0-5)\t0.98\t\nMutations, n (%)\t\nASXL1\tYes\t19 (25)\t10 (17)\t0.34\t\n\tNo\t56 (75)\t49 (83)\t\t\nTET2\tYes\t18 (24)\t8 (14)\t0.19\t\n\tNo\t57 (76)\t51 (86)\t\t\nSF3B1\tYes\t4 (5)\t5 (8)\t0.71\t\n\tNo\t71 (95)\t54 (92)\t\t\nSRSF2\tYes\t13 (17)\t11 (19)\t1.00\t\n\tNo\t62 (83)\t48 (81)\t\t\nIDH1/2\tYes\t9 (12)\t8 (14)\t0.99\t\n\tNo\t66 (88)\t51 (86)\t\t\nEpigenetic factor mutations\tYes\t47 (63)\t29 (49)\t0.16\t\n(TET2, DNMT3A, IDH1/2, MLL, EZH2, ASXL1)\tNo\t28 (37)\t30 (51)\t\t\nHistone modulator mutations\tYes\t25 (33)\t11 (19)\t0.09\t\n(ASXL1, EZH2)\tNo\t50 (67)\t48 (81)\t\t\nDNA methylation mutations\tYes\t30 (40)\t19 (32)\t0.45\t\n(TET2, DNMT3A, IDH1/2)\tNo\t45 (60)\t40 (68)\t\t\nSplicing factor mutations\tYes\t21 (28)\t22 (37)\t0.34\t\n(SF3B1, SRSF2, PRPF40B, U2AF1, U2AF35, ZRSR2)\tNo\t54 (72)\t37 (63)\t\t\nCohesion factor mutations\tYes\t2 (3)\t2 (3)\t1.00\t\n(STAG2, SMC3, PDS5B)\tNo\t73 (97)\t57 (97)\t\t\nSignaling factor mutations\tYes\t10 (13)\t15 (25)\t0.12\t\n(JAK2, MPL, CBL, FLT3, NRAS, WT1, SH2B3)\tNo\t65 (87)\t44 (75)\t\t\nTranscription factor mutations\tYes\t14 (19)\t8 (14)\t0.58\t\n(RUNX1, ETV6, CEBPA, BCOR)\tNo\t61 (81)\t51 (86)\t\t\nAbbreviations: IPSS, International prognostic score system; Int, Intermediate.\n\nFurthermore, no single mutation or group of mutations was significantly associated with response (i.e. any of CR, mCR, PR or HI). TET2-mutated patients have in previous publications been reported to have higher response rates [20, 21]. In our cohort, although the response rate was higher for these patients, the difference was not significant. (69% vs. 53%, p=0.19).\n\nWe next grouped genes into epigenetic factors, which in turn were further divided into DNA methylation factors and histone modulators, splicing factors, transcription factors, signaling factors and cohesion factors (see Table 2 for genes included in each group). Patients with epigenetic mutations had a weak trend for higher response rates (62% vs 48%, p=0.16). When the group was divided into patients with DNA methylation mutations and histone modulator mutations, respectively, a trend for higher response rates was present for those with histone modulator mutations (69% vs 51%, p=0.09), but not for DNA methylation factors (61% vs 47%, p=0.45). The number of mutations did not differ between responders and non-responders (median 2 (0-5) vs 2 (0-5); p=0.98). Due to the weak association between tested variables and response rates, multivariate analysis was not performed. Table 2 summarizes the univariate analyses with response as endpoint and Table S3 displays data as dichotomized by institution.\n\nFactors associated with survival in the univariate analysis\nEstimated median overall survival for the whole cohort was 17 months (95% confidence interval (CI): 14-20 months), which is shorter than in the AZA001 study (19-20 months) but longer than in the French GFM cohort (13.5 months) [2, 15]. Median follow up time for all patients was 14 months, and median follow-up for surviving patients was 23 months. Twenty-three patients underwent allogeneic stem cell transplantation (SCT) after a median of 8 months (range 2-45) from start of azacitidine treatment; when censoring for SCT the estimated median survival in the whole cohort was 14 months (95% CI: 11-17 months). In the subsequent analyses we used data censored for transplantation. Patients who did not achieve a response (i.e. CR, mCR, PR or HI) had, as expected, a significantly shorter survival compared to responders (median 10 months vs. 20 months, p=<0.001).\n\nAmong clinical pre-treatment variables, disease duration was associated with survival when used as a continuous variable in a univariate cox model (p=0.04; HR 1.01 (95% CI 1.00-1.02)). However, when dichotomizing this variable into above or below median, it lost statistical significance in the log-rank test (14 vs 17 months; p=0.44). Patients with thrombocytopenia (platelets <60×109/L; median value in the entire cohort), showed a non-significant trend towards shorter survival (12 vs 17 months; p=0.067). Patients belonging to IPSS-R cytogenetics risk groups ‘high’ or ‘very high’ had a significantly shorter survival compared to the very good, good or intermediate risk groups (10 vs 20 months; p<0.001).\n\nThe presence of mutations in any of the epigenetic modulators was associated with improved survival (19 vs 12 months; p=0.03). After dividing mutations into those affecting DNA methylation versus histone modulators, the former group did not show a significant impact on survival (14 vs 14 months; p=0.64). By contrast, patients with mutations in histone modulators (ASXL1 or EZH2), showed a significantly longer survival (22 vs 12 months; p=0.01). This difference remained significant for patients with ASXL1 mutations (n=29; survival 29 vs 12 months; p=0.026) while patients with mutations in EZH2 (n=12) showed a trend towards longer survival (20 vs 14 months; p=0.37). When separating the patient material into higher-risk disease (IPSS Int-2, IPSS-high, CMML-2 and AML with multilineage dysplasia; n=114) and lower-risk disease (IPSS Int-1 and CMML-1; n=20), histone modulator mutations had a strong impact on survival in the higher-risk cohort (20 vs 12 months; p=0.02). They were also associated, although not significantly, with longer survival in the lower-risk cohort (32 vs 17 months; p=0.47; n=20). It should be noted that the MLL-gene, which also possesses histone modulating activity, was only assessed in the Karolinska cohort (n=2) and was therefore not included in the histone modulator group analysis. As expected, TP53 had a significant negative impact on survival (9 vs 17 months; p<0.001) but, interestingly, neither RUNX1 mutations nor the number of mutations, previously described poor-prognostic findings, were associated with shorter survival [8-10].\n\nThe negative impact on survival of adverse cytogenetics (IPSS-R high or very high; 10 vs 23 months; p<0.001), and bone marrow cellularity (<70 or ≥70%; 14 vs 31; p=0.01) also remained significant when the patients were not censored at the time of SCT. Interestingly, the strength of the statistical association of histone modulator mutations then became less pronounced (29 vs 14 months; p=0.077), supporting the notion that mutations in histone modulators may have a specific role in the response to azacitidine. See Table 3 and Figure 2 for a list of variables analyzed using survival as an endpoint, Table S5 for the Karolinska and King's College cohort separated, and Figure 1 and Figure S1 for survival plots respectively. The survival curve for histone modulators mutations without censoring for SCT is presented in Figure S2.\n\nTable 3 Variables associated with survival\n\tEstimated median survival (months)\tUnivariate p-value\tCox regression p-value\tHazard ratio (95% CI)\t\nResponse: Yes vs No\t20 vs 10\t<0.001\t\t\t\nIPSS-R cytogenetic risk group: VG + Good+Int vs High + VH\t20 vs 10\t<0.001\t<0.001*\t3.46 (2.09-5.59)\t\nWHO group: MDS vs MDS/MPD vs AML with multilinear dysplasia\t14 vs 20 vs 28\t0.61\t\t\t\nDisease duration ≥ 4 months: Yes vs No\t14 vs 17\t0.44\t0.003**\t1.01 (1.00-1.02)**\t\nMarrow blasts ≥ 11%: Yes vs No\t14 vs 14\t0.7\t\t\t\nCellularity ≥ 70%: Yes vs No\t14 vs 20\t0.2\t0.05**\t1.01 (1.00-1.02)**\t\nANC ≥ 1.3: Yes vs No\t14 vs 17\t0.32\t\t\t\nPlatelets ≥ 60: Yes vs No\t17 vs 12\t0.07\t\t\t\nTransfusion dependent: Yes vs No\t13 vs 17\t0.43\t0.04\t1.70 (1.03-2.80)\t\nTherapy related: Yes vs No\t17 vs 14\t0.44\t\t\t\nNumber of mutations: 0 vs 1 vs ≥ 2\t17 vs 12 vs 17\t0.64\t\t\t\nEpigenetic mutation: Yes vs No\t19 vs 12\t0.03\t\t\t\nDNA methylation mutation: Yes vs No\t14 vs 14\t0.64\t\t\t\nHistone modulator mutation: Yes vs No\t22 vs 12\t0.01\t0.01\t0.50 (0.30-0.85)\t\nSplicing factor mutation: Yes vs No\t13 vs 17\t0.31\t0.05\t1.63 (1.011-2.63)\t\nTranscription factor mutation: Yes vs No\t16 vs 14\t0.93\t\t\t\nSignaling factor mutation: Yes vs No\t19 vs 14\t0.60\t\t\t\nCohesin factor mutation: Yes vs No\t19 vs 14\t0.20\t\t\t\nASXL1 mutation: Yes vs No\t29 vs 12\t0.03\t\t\t\nTET2 mutation: Yes vs No\t13 vs 16\t0.45\t\t\t\nEZH2 mutation: Yes vs No\t20 vs 14\t0.37\t\t\t\nSF3B1 mutation: Yes vs No\t13 vs 16\t0.35\t\t\t\nRUNX1 mutation: Yes vs No\t17 vs 14\t0.76\t\t\t\nSRSF2 mutation: Yes vs No\t20 vs 14\t0.5\t\t\t\nTP53 mutation: Yes vs No\t9 vs 17\t<0.001\t\t\t\nUnivariate analyses used the log-rank test.\n\n* Comparing the combined IPSS-R cytogenetic risk groups high and very high vs all other groups.\n\n** Disease duration, marrow blasts, cellularity, ANC and TPK were analyzed as a continuous variable in the cox model.\n\nAbbreviations: CI, confidence interval; CR, complete remission; mCR, marrow complete remission; PR, partial remission; HI, hematological improvement; SD, stable disease; PD, progressive disease; IPSS International prognostic score system; ANC, absolute neutrophil count; MPD myeloproliferative disease; VG very good; VH very high.\n\nFigure 1 Survival curves using Kaplan-Meier estimation\nFigure 2 Forest plot indicating hazard ratio including confidence interval for all pre-treatment variables\nThe hazard ratios were retrieved using cox univariate regression models for each variable analyzed separately.\n\nAbbreviations: IPSS International prognostic score system, ANC absolute neutrophil count, HR hazard ratio, CI confidence interval.\n\nHigh-risk cytogenetics and mutations in chromatin modifiers remain independent predictors for survival\nIn a cox model including all parameters as defined in the methods section, adverse cytogenetics (IPSS-R high or very high; p<0.001; HR 3.46 (2.09-5.59 95% CI)) and histone modulator mutations (p=0.01; HR 0.50 (0.30-0.85 95% CI)) remained strong predictors of survival. Other variables associated with survival were: cellularity (p=0.05; HR 1.01; 95% CI 1.00-1.02), disease duration (p=0.003; HR 1.01 (1.00-1.02)), transfusion dependency (p=0.04; HR 1.70 (1.03-2.80 95% CI)), splicing factor mutation (p=0.05; HR 1.63 (1.01-2.63) 95% CI). Neither transfusion dependency nor splicing factor mutation displayed an association with survival on univariate analyses (p=0.43 and p=0.31, respectively) and the impact of these parameters on survival is unclear. As expected, TP53 showed a strong association with survival in the univariate analysis but not in the multivariate analyses, probably due to co-linearity with high-risk cytogenetics.\n\nWe used the two strongest predictors, adverse cytogenetics and histone modulator mutations, to allocate patients to four prognostic groups: dependent on cytogenetic status (IPSS-R high or very high) and presence of mutations in histone modulators (HM). Survival in the four risk groups were: cyt+/HM+ 29 months; cyt-/HM- 20 months; cyt+/HM+ 13 and cyt+/HM- 10 months, respectively, see Figure 3. The differences in survival between the groups were highly significant (p<0.001). The cumulative response rates to azacitidine for patients within the prognostic groups were 73% (19 out of 26) for the best prognostic group (histone modulator mutation but no adverse cytogenetics), 53% (28 out of 53) and 58% (7 out of 12) for the two intermediate prognostic groups; and 49% (21 out of 43) for the least favorable prognostic group.\n\nFigure 3 Kaplan-Meier estimated survival stratified for the two dominant predictors in the cox regression model: Adverse cytogenetics and histone modulator mutations\nAbbreviations: HM histone modulator mutation.\n\nDISCUSSION\nPatients with higher-risk MDS have an overall poor outcome despite the survival benefits achieved by azacitidine therapy. The median survival in unselected patient cohorts is only around one year, hence the major challenge for treating physicians remains how to prolong survival [2, 15, 28]. Around 50% of patients with higher-risk MDS respond to azacitidine, but patients who are HMA-refractory have an expected survival of only 6 months, [29]. Accessible clinical tools that can therapeutically stratify patients upfront therefore remain an urgent unmet need. Since patients without response but with stable disease during azacitidine treatment demonstrate survival benefits as demonstrated by a post-hoc analysis of the AZA-001-study, we chose survival from start of treatment as the most appropriate endpoint for this study assessing the benefits of azacitidine treatment [30].\n\nThe aim was to identify clinically relevant biomarkers to determine the efficacy of azacitidine. This study uses a combined cohort of azacitidine-treated patients from the Karolinska University Hospital (n=89) and King's College Hospital (n=45). The vast majority of these patients fell within the recommended European label for the drug and had higher-risk MDS or AML with 20-30% blasts and dysplastic features. Importantly, and in contrast to other published studies, all patients received azacitidine as first-line treatment with the aim to give a minimum of 6 cycles before response evaluation. We believe that this approach, and the fact that patients were assessed according to an intention-to-treat basis, makes our cohort more homogeneous and similar to the AZA-001 cohort than other published retrospective studies. Moreover, the fact that two different sequencing platforms rendered similar results strengthens the possibility to extrapolate these data to broader clinical practice.\n\nInterestingly, no single variable was significantly associated with response, as defined by the IWG criteria, although patients with longer disease duration prior to azacitidine, and transfusion dependency displayed a trend towards worse response rates. In line with previous studies, patients with TET2 mutations displayed somewhat better response rates [19-21].\n\nFor the subsequent analyses, we used survival as the primary endpoint and, unsurprisingly, saw a poorer outcome in patients with adverse cytogenetics and TP53 mutations, both well-known adverse prognostic factors in MDS. The novel finding was, however, the strong positive impact of histone modulator mutations on survival (22 vs 12 months, p=0.01). This association was present both in the combined cohort of Karolinska and King's, as well as in each of the cohorts analyzed separately and, importantly, remained independent from the negative impact of high-risk cytogenetics. Patients with two negative biomarkers showed a median survival of only 10 months, potentially making them eligible for consideration of alternative therapeutic agents.\n\nASXL1 was the most frequent mutation within the histone modulator group and also showed a significant impact on survival (p=0.03). The pivotal finding of this study is that a molecular marker, which repeatedly has been associated with poor survival, appears as a positive biomarker in both the primary and validation cohorts of azacitidine-treated higher-risk MDS patients. The lack of a negative effect of RUNX1 mutations and total number of mutations also indicates that azacitidine may have specific biological effects on the MDS tumor clone [8]. By contrast, mutations in modulators of DNA methylation showed no association with survival following azacitidine treatment.\n\nThese results contrast findings in previous studies investigating the effects of ASXL1 mutations on survival in azacitdine-treated patients [19, 20]. An important difference is the higher proportion of lower-risk patients, around 50%, in those studies compared to only 15% in the present study with the Intermediate-1 risk patients included in our study being treated according to the European guidelines because of significant additional risk factors [27]. Moreover, in contrast to previous studies, all patients in our cohort received first-line treatment Azacitidine without previous or subsequent hypomethylating therapies. They well treated with a median of 7 cycles of azacitidine given in line with guidelines [27]. Survival was analyzed using an intention-to treat perspective in order to avoid selection bias. Since there are conflicting results of the impact of ASXL1 on survival, larger studies are certainly warranted. Interestingly, two recent publications indicate a better prognosis for ASXL1-mutated patients after SCT (however without significance calculation in the study by Fu et al and not statistically significant in the study by Bejar et al) supporting that ASXL1 mutations, despite being a negative prognostic factor in mixed MDS cases, can be a positive factor for survival during treatment [31, 32].\n\nOur data suggests that patients carrying mutations in histone modulators are more sensitive to the effects of azacitidine. Interestingly, we have previously shown that azacitidine exerts changes on chromatin structure and since histone modulator mutations are associated with increased sensitivity to azacitidine, it will be important to further delineate the chromatin structure in MDS subtypes and how this is affected by azacitidine [3]. Whether decitabine, used sequentially or instead of azacitidine in the other studies, has a differential effect cannot be excluded [19, 20]. Very recent data indicates that ASXL1 mutation results in lower expression of the tumor suppressor gene p15INK4b which has been shown to be hypermethylated in MDS [33, 34]. We have previously analyzed DNA methylation (Illumina 450k methylation array) in primary MDS cells cultured with azacitidine and observe a decrease in DNA methylation in all probes annotated to p15INK4b (mean reduction in β-value = 0.023) [35]. A hypothesis that may be tested is that reduction of DNA methylation in ASXL1mut cells induces a greater increase in expression of p15INK4b compared to ASXL1wt cells.\n\nWith the advent of next-generation sequencing, new potential biomarkers are rapidly being incorporated into routine clinical practice and are likely to influence patient management and therapeutic decisions. Adverse cytogenetics remains a well-established prognostic marker with documented negative effects on the outcome of both conventional chemotherapy and azacitidine [36, 37]. We hereby report that histone modulator mutations are associated with significantly prolonged survival following azacitidine treatment and, importantly, that this effect is independent from that of high-risk cytogenetics. The combination of these two variables, easily detected by routine karyotyping and limited targeted sequencing, respectively, provide a valuable model that, if confirmed in independent patient cohorts, can be used in routine clinical practice to guide therapeutic decision-making in patients eligible for azacitidine. In particular, patients with high-risk cytogenetics lacking mutations in histone modulators may be evaluated for alternative therapeutic pathways.\n\nMATERIALS AND METHODS\nPatient population\nThe study population included 134 patients, diagnosed with either MDS, AML secondary to MDS or primary AML with multilineage dysplasia and 20-30% blasts, treated with azacitidine. Consecutive patients were recruited retrospectively from two large centers: one cohort from Karolinska University Hospital, Stockholm, Sweden (n=89) and a second cohort from King's College Hospital, London, United Kingdom (n=45). In order to avoid selection bias and to adopt an “intention-to-treat” approach to the analysis, patients were considered evaluable if they had received ≥1 dose (day) of azacitidine. Treatment scheduling was conducted according to the European label, aiming for a minimum of 6 cycles before response evaluation. Clinical parameters evaluated included age, disease duration, peripheral blood counts, transfusion dependency, therapy related disease, bone marrow blasts, marrow cellularity, International Prognostic Scoring System (IPSS) risk group, IPSS-Revised (IPSS-R) and IPSS cytogenetic risk group determined by metaphase cytogenetics. Morphological and cytogenetic assessments were made using local, validated laboratory procedures and all patients underwent consensus diagnosis at a multidisciplinary conference. Response to azacitidine was evaluated using IWG criteria and patients were categorized as either: complete remission (CR), marrow complete remission (mCR), partial remission (PR), hematological improvement (HI), stable disease (SD) or progressive disease (PD). Responders were defined as achieving at least HI and responses were defined as the best response during the whole course of treatment. The Ethical committees at the Karolinska Institute and King's College Hospital, respectively, approved the study. All patients provided fully informed consent.\n\nMutational analysis\nThe Karolinska cohort\nPatients were analyzed for 42 genes recurrently mutated in myeloid disorders using HaloplexTM target enrichment technology (Agilent Technologies, CA, United States) followed by high throughput sequencing, see table S1 for a list of included genes. Briefly, mononuclear cells (MNCs) were isolated from bone marrow aspirates by Lymphoprep® density gradient centrifugation. Genomic DNA was extracted from 1×106 CD34- cells or MNCs using Gene Elute genomic DNA extraction kit (Sigma-Aldrich, Stockholm, Sweden). HaloplexTM target enrichment kit G9901A/B was designed using SureDesigntm wizard available by Agilent (https://earray.chem.agilent.com/suredesign/) and we achieved 99.2% coverage of the 42 selected genes. All samples were individually barcoded during enrichment and sequenced using Illumina HiSeQ 2000 system at the Sci-Life lab, Stockholm, Sweden. Sequencing reads were mapped over Human genome 19 by Bowtie and the variants were called using SAMTOOLS [22, 23]. The minimum of variant reads to consider was 20 with a minimum allelic burden of 5%. Sequence variations were annotated and functionally classified using ANNOVAR [24]. Variants previously reported as germline polymorphisms in the 1000 genome and the ESP5400 databases were excluded [25, 26]. Finally, variants located in none coding regions as well as synonymous variants were filtered out. Variant allele ratio was calculated for each mutation identified as number of variant reads divided by total reads.\n\nThe King's College London cohort\nDNA was extracted from bone marrow CD34+ cells or MNCs using the QIAamp DNA extraction kit (Qiagen, Limburg, Netherlands) according to the manufacturer's protocol. A targeted ‘24 gene’ myeloid gene panel was used for the analysis of presentation samples from MDS and AML patients (n=45). Target enrichment was achieved using an in-house True SeqCustom Amplicon (TSCA) design (Illumina, San Diego, USA). The targeted region consisted of a total of 71Kb represented by 295 amplicons. Pooled library targets were sequenced in batches of 24 samples on the MiSeq Instrument using version 3.0 MiSeq sequencing reagents (Illumina, San Diego, USA). Minimum read depth threshold was 150 reads; lower limit of sensitivity was 5-10% variant allele frequency. All variants of unknown significance were excluded. Genes in this panel included: ASXL1 exons 1-12, CBL exons 7-9, CEBPA all coding exons, DNMT3A all coding exons, ETV6/TEL all coding exons, EZH2 all coding exons, FLT3 exons 14+20, GATA2 all coding exons, IDH1 exon 4, IDH2 exon 4, JAK2 exons 12+14, KDM6A all coding exons, KIT exons 17, KRAS exons 2+3, NPM1 exon 12, NRAS exons 2+3, RUNX1 all exons except 1+2, SF3B1 exons 12 to 16, SRSF2 exon 1, STAG2 all coding exons, TET2 all coding exons, TP53 all coding exons, U2AF1 exons 2+6 and ZRSR2 all coding exons.\n\nStatistics\nContinuous variables were expressed using the mean ± Standard Deviation (SD) or the median (range) depending on whether distributions were normal or not. Frequency tables were used for summarizing categorical variables. Statistical methods used for association studies were the t-test for normally distributed data, Mann-Whitney U-test for non-normally distributed data and a Chi-squared or Fisher's exact test for categorical data. Time-to-event data were analyzed using the Kaplan–Meier method. Overall survival (OS) was defined from the time of start of treatment to the date of death or when last seen. Patients were censored at the time of allogeneic stem cell transplantation. A Cox proportional hazard model was used to assess the effect of multiple factors on survival where a backward elimination algorithm was used to identify independent predictors. Included parameters in the Cox model were: IPSS adverse cytogenetic risk group, WHO group (MDS vs MDS/MPD vs AML with multilineage dysplasia), disease duration, marrow blast percentage, marrow cellularity, ANC, platelet count, transfusion dependency, therapy related MDS, number of mutations, epigenetic mutations, DNA methylation mutations, histone modulator mutations, splice factor mutations, RUNX1 mutation and TP53 mutation. Data on marrow cellularity was missing in 8 cases. For these cases, the median value was used in the multivariate analysis.\n\nAll statistical calculations were performed using R version 3.1.1 and SPSS version 22.0 (IBM, NY, United States).\n\nSUPPLEMENTARY TABLES AND FIGURES\n CONFLICTS OF INTEREST\n\nGhulam Mufti: has received research funding from Celgene and been part of their advisory board.\n\nEva Hellström-Lindberg: has received research grant from Celgene for the national MDS registry.\n\nMartin Jädersten: has recieved honoraria for lectures for Celgene.\n\nAustin Kulasekararaj: has recieved honoraria for advisory board and lectures for Celgene.\n==== Refs\nREFERENCES\n1 Silverman LR Demakos EP Peterson BL Kornblith AB Holland JC Odchimar-Reissig R Stone RM Nelson D Powell BL DeCastro CM Ellerton J Larson RA Schiffer CA Randomized controlled trial of azacitidine in patients with the myelodysplastic syndrome: a study of the cancer and leukemia group B J Clin Oncol 2002 20 2429 40 12011120 \n2 Fenaux P Mufti GJ Hellstrom-Lindberg E Santini V Finelli C Giagounidis A Schoch R Gattermann N Sanz G List A Gore SD Seymour JF Bennett JM Efficacy of azacitidine compared with that of conventional care regimens in the treatment of higher-risk myelodysplastic syndromes: a randomised, open-label, phase III study Lancet Oncol 2009 10 223 32 19230772 \n3 Grovdal M Karimi M Tobiasson M Reinius L Jansson M Ekwall K Ungerstedt J Kere J Greco D Hellstrom-Lindberg E Azacitidine induces profound genome-wide hypomethylation in primary myelodysplastic bone marrow cultures but may also reduce histone acetylation Leukemia 2014 28 411 3 24025691 \n4 Shen L Kantarjian H Guo Y Lin E Shan J Huang X Berry D Ahmed S Zhu W Pierce S Kondo Y Oki Y Jelinek J DNA Methylation Predicts Survival and Response to Therapy in Patients With Myelodysplastic Syndromes 2010 2010-02-01 \n5 Sohlberg E Pfefferle A Andersson S Baumann BC Hellstrom-Lindberg E Malmberg KJ Imprint of 5-azacytidine on the natural killer cell repertoire during systemic treatment for high-risk myelodysplastic syndrome Oncotarget 2015 6 34178 90 10.18632/oncotarget.6213 26497557 \n6 Chiappinelli KB Strissel PL Desrichard A Li H Henke C Akman B Hein A Rote NS Cope LM Snyder A Makarov V Buhu S Slamon DJ Inhibiting DNA Methylation Causes an Interferon Response in Cancer via dsRNA Including Endogenous Retroviruses Cell 2015 162 974 86 26317466 \n7 Roulois D Loo Yau H Singhania R Wang Y Danesh A Shen SY Han H Liang G Jones PA Pugh TJ O'Brien C De Carvalho DD DNA-Demethylating Agents Target Colorectal Cancer Cells by Inducing Viral Mimicry by Endogenous Transcripts Cell 2015 162 961 73 26317465 \n8 Papaemmanuil E Gerstung M Malcovati L Tauro S Gundem G Van Loo P Yoon CJ Ellis P Wedge DC Pellagatti A Shlien A Groves MJ Forbes SA Clinical and biological implications of driver mutations in myelodysplastic syndromes Blood 2013 122 3616 27 quiz 99 24030381 \n9 Haferlach T Nagata Y Grossmann V Okuno Y Bacher U Nagae G Schnittger S Sanada M Kon A Alpermann T Yoshida K Roller A Nadarajah N Landscape of genetic lesions in 944 patients with myelodysplastic syndromes Leukemia 2014 28 241 7 24220272 \n10 Bejar R Stevenson K Abdel-Wahab O Galili N Nilsson B Garcia-Manero G Kantarjian H Raza A Levine RL Neuberg D Ebert BL Clinical effect of point mutations in myelodysplastic syndromes N Engl J Med 2011 364 2496 506 21714648 \n11 Bejar R Stevenson KE Caughey BA Abdel-Wahab O Steensma DP Galili N Raza A Kantarjian H Levine RL Neuberg D Garcia-Manero G Ebert BL Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes J Clin Oncol 2012 30 3376 82 22869879 \n12 Boultwood J Perry J Pellagatti A Fernandez-Mercado M Fernandez-Santamaria C Calasanz MJ Larrayoz MJ Garcia-Delgado M Giagounidis A Malcovati L Della Porta MG Jadersten M Killick S Frequent mutation of the polycomb-associated gene ASXL1 in the myelodysplastic syndromes and in acute myeloid leukemia Leukemia 2010 24 1062 5 20182461 \n13 Schnittger S Eder C Jeromin S Alpermann T Fasan A Grossmann V Kohlmann A Illig T Klopp N Wichmann HE Kreuzer KA Schmid C Staib P ASXL1 exon 12 mutations are frequent in AML with intermediate risk karyotype and are independently associated with an adverse outcome Leukemia 2013 27 82 91 23018865 \n14 Thol F Friesen I Damm F Yun H Weissinger EM Krauter J Wagner K Chaturvedi A Sharma A Wichmann M Gohring G Schumann C Bug G Prognostic significance of ASXL1 mutations in patients with myelodysplastic syndromes J Clin Oncol 2011 29 2499 506 21576631 \n15 Itzykson R Thepot S Quesnel B Dreyfus F Beyne-Rauzy O Turlure P Vey N Recher C Dartigeas C Legros L Delaunay J Salanoubat C Visanica S Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine Blood 2011 117 403 11 20940414 \n16 Cheson BD Greenberg PL Bennett JM Lowenberg B Wijermans PW Nimer SD Pinto A Beran M de Witte TM Stone RM Mittelman M Sanz GF Gore SD Clinical application and proposal for modification of the International Working Group (IWG) response criteria in myelodysplasia Blood 2006 108 419 25 16609072 \n17 Filì C Malagola M Follo MY Finelli C Iacobucci I Martinelli G Cattina F Clissa C Candoni A Fanin R Gobbi M Bocchia M Defina M Prospective phase II Study on 5-days azacitidine for treatment of symptomatic and/or erythropoietin unresponsive patients with low/INT-1-risk myelodysplastic syndromes Clin Cancer Res 2013 \n18 Hwang KL Song MK Shin HJ Na HJ Shin DH Kim JK Moon JH Ahn JS Song IC Hong J Lee GW Chung JS Monosomal and complex karyotypes as prognostic parameters in patients with International Prognostic Scoring System higher risk myelodysplastic syndrome treated with azacitidine Blood Res 2014 49 234 40 25548756 \n19 Bejar R Lord A Stevenson K Bar-Natan M Perez-Ladaga A Zaneveld J Wang H Caughey B Stojanov P Getz G Garcia-Manero G Kantarjian H Chen R TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients Blood 2014 124 2705 12 25224413 \n20 Traina F Visconte V Elson P Tabarroki A Jankowska AM Hasrouni E Sugimoto Y Szpurka H Makishima H O'Keefe CL Sekeres MA Advani AS Kalaycio M Impact of molecular mutations on treatment response to DNMT inhibitors in myelodysplasia and related neoplasms Leukemia 2014 28 78 87 24045501 \n21 Itzykson R Kosmider O Cluzeau T Mansat-De Mas V Dreyfus F Beyne-Rauzy O Quesnel B Vey N Gelsi-Boyer V Raynaud S Preudhomme C Ades L Fenaux P Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias Leukemia 2011 25 1147 52 21494260 \n22 Langmead B Trapnell C Pop M Salzberg SL Ultrafast and memory-efficient alignment of short DNA sequences to the human genome Genome Biol 2009 10 R25 19261174 \n23 Li H Handsaker B Wysoker A Fennell T Ruan J Homer N Marth G Abecasis G Durbin R The Sequence Alignment/Map format and SAMtools Bioinformatics 2009 25 2078 9 19505943 \n24 Wang K Li M Hakonarson H ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data Nucleic Acids Res 2010 38 e164 20601685 \n25 Abecasis GR Altshuler D Auton A Brooks LD Durbin RM Gibbs RA Hurles ME McVean GA A map of human genome variation from population-scale sequencing Nature 2010 467 1061 73 20981092 \n26 Tennessen JA Bigham AW O'Connor TD Fu W Kenny EE Gravel S McGee S Do R Liu X Jun G Kang HM Jordan D Leal SM Evolution and functional impact of rare coding variation from deep sequencing of human exomes Science 2012 337 64 9 22604720 \n27 Malcovati L Hellstrom-Lindberg E Bowen D Ades L Cermak J Del Canizo C Della Porta MG Fenaux P Gattermann N Germing U Jansen JH Mittelman M Mufti G Diagnosis and treatment of primary myelodysplastic syndromes in adults: recommendations from the European LeukemiaNet Blood 2013 122 2943 64 23980065 \n28 Dinmohamed AG van Norden Y Visser O Posthuma EF Huijgens PC Sonneveld P van de Loosdrecht AA Jongen-Lavrencic M Effectiveness of azacitidine for the treatment of higher-risk myelodysplastic syndromes in daily practice: results from the Dutch population-based PHAROS MDS registry Leukemia 2015 29 2449 51 26369829 \n29 Prébet T Gore SD Esterni B Gardin C Itzykson R Thepot S Dreyfus F Rauzy OB Recher C Adès L Quesnel B Beach CL Fenaux P Outcome of High-Risk Myelodysplastic Syndrome After Azacitidine Treatment Failure JCO 2011 2011-08-20 \n30 Gore SD Fenaux P Santini V Bennett JM Silverman LR Seymour JF Hellstrom-Lindberg E Swern AS Beach CL List AF A multivariate analysis of the relationship between response and survival among patients with higher-risk myelodysplastic syndromes treated within azacitidine or conventional care regimens in the randomized AZA-001 trial Haematologica 2013 98 1067 72 23585522 \n31 Bejar R Stevenson KE Caughey B Lindsley RC Mar BG Stojanov P Getz G Steensma DP Ritz J Soiffer R Antin JH Alyea E Armand P Somatic mutations predict poor outcome in patients with myelodysplastic syndrome after hematopoietic stem-cell transplantation J Clin Oncol 2014 32 2691 8 25092778 \n32 Fu Y Schroeder T Zabelina T Badbaran A Bacher U Kobbe G Ayuk F Wolschke C Schnittger S Kohlmann A Haferlach T Kroger N Postallogeneic monitoring with molecular markers detected by pretransplant next-generation or Sanger sequencing predicts clinical relapse in patients with myelodysplastic/myeloproliferative neoplasms Eur J Haematol 2014 92 189 94 24164563 \n33 Wu X Bekker-Jensen IH Christensen J Rasmussen KD Sidoli S Qi Y Kong Y Wang X Cui Y Xiao Z Xu G Williams K Rappsilber J Tumor suppressor ASXL1 is essential for the activation of INK4B expression in response to oncogene activity and anti-proliferative signals Cell Res 2015 25 1205 18 26470845 \n34 Lübbert M Gene silencing of the p15|[sol]|INK4B cell-cycle inhibitor by hypermethylation: an early or later epigenetic alteration in myelodysplastic syndromes? Leukemia 2003 2003-09-01 17 1762 4 12970776 \n35 Abdulkadir H Tobiasson M Lennartsson A Katayama S Marabita F Karimi M Qu Y Einarsdottir E Grövdal M Jansson M Ben Azenkoud A Lehmann S Ekwall K In vitro azacitidine culture induces DNA demethylation and increased mRNA-levels in primary MDS progenitor cells Leukemia Research 2015 39 S69 \n36 Itzykson R Thépot S Quesnel B Dreyfus F Beyne-Rauzy O Turlure P Vey N Recher C Dartigeas C Legros L Delaunay J Salanoubat C Visanica S Prognostic factors for response and overall survival in 282 patients with higher-risk myelodysplastic syndromes treated with azacitidine 2011 2011-01-13 \n37 Hast R Hellstrom-Lindberg E Ohm L Bjorkholm M Celsing F Dahl IM Dybedal I Gahrton G Lindberg G Lerner R Linder O Lofvenberg E Nilsson-Ehle H No benefit from adding GM-CSF to induction chemotherapy in transforming myelodysplastic syndromes: better outcome in patients with less proliferative disease Leukemia 2003 17 1827 33 12970783\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "7(16)",
"journal": "Oncotarget",
"keywords": "azacitidine; hypomethylating therapy; molecular marker; myelodysplastic syndrome; next-generation sequencing",
"medline_ta": "Oncotarget",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine; D015415:Biomarkers; D004252:DNA Mutational Analysis; D005260:Female; D006657:Histones; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D016016:Proportional Hazards Models; D016896:Treatment Outcome",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "22103-15",
"pmc": null,
"pmid": "26959885",
"pubdate": "2016-04-19",
"publication_types": "D016428:Journal Article",
"references": "24045501;16609072;24164563;12011120;23018865;21714648;26317466;25548756;25092778;22604720;24030381;21788559;26470845;23980065;19230772;21576631;19505943;12970776;26369829;23596104;20038729;25224413;23585522;20940414;22869879;24220272;19261174;26497557;21494260;26317465;24025691;12970783;20981092;20182461;20601685",
"title": "Mutations in histone modulators are associated with prolonged survival during azacitidine therapy.",
"title_normalized": "mutations in histone modulators are associated with prolonged survival during azacitidine therapy"
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"companynumb": "SE-CELGENE-SWE-2016034114",
"fulfillexpeditecriteria": "1",
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"abstract": "Nonsteroidal anti-inflammatory drugs (NSAIDs) are the drugs most frequently involved in allergic reactions of which two main types exist: IgE-mediated and crossintolerance. The diagnosis of crossintolerance reactions is often based on the drug provocation test. The potential value of the basophil activation test (BAT) was evaluated using different basophil markers in the diagnosis of patients with crossintolerance to NSAIDs and cutaneous symptoms. We studied 46 patients with crossintolerance to NSAIDs and 45 tolerant controls. BAT was performed with acetyl salicylic acid, paracetamol, diclofenac, dipyrone, naproxen, and ibuprofen at four different concentrations using CD193 and CD203c as basophil markers and CD63 as activation marker. We compared BAT results using CD193⁺ or CD193⁺ CD203c⁺ for basophil selection and found a significant increase in the stimulation index when using CD193⁺ CD203c⁺ in both patients and controls (P = 0.004 and P = 0.017, respectively). Selection of living cells only produced an increase in basophil stimulation in patients for both CD193⁺ and CD193⁺ CD203c⁺ (P < 0.001 for both), whereas in controls there was no change with CD193⁺ and a decrease with CD193⁺ CD203c⁺ (P = 0.001). We found that CD193⁺ CD203c⁺ increased the percentage of positive cases in patients and controls when compared with CD193⁺. When excluding dead cells, there was an increase of 21.7% in patients and 10% in controls. These results indicate that using CD193⁺ CD203⁺, excluding dead cells, is the best approach for BAT although this test is not recommended for the diagnosis of patients with crossintolerance to NSAIDs owing to its low sensitivity and specificity.",
"affiliations": "Research Laboratory, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Universitario Regional de Málaga, UMA, Málaga, Spain.",
"authors": "Ariza|Adriana|A|;Fernandez|Tahia D|TD|;Doña|Inmaculada|I|;Aranda|Ana|A|;Blanca-Lopez|Natalia|N|;Melendez|Lidia|L|;Canto|Gabriela|G|;Blanca|Miguel|M|;Torres|Maria J|MJ|;Mayorga|Cristobalina|C|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD",
"country": "United States",
"delete": false,
"doi": "10.1002/cyto.a.22443",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1552-4922",
"issue": "85(5)",
"journal": "Cytometry. Part A : the journal of the International Society for Analytical Cytology",
"keywords": "CD193; CD203c; CD63; basophils; hypersensitivity; idiosyncratic reactions; nonsteroidal anti-inflammatory drugs",
"medline_ta": "Cytometry A",
"mesh_terms": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D015703:Antigens, CD; D001491:Basophils; D005434:Flow Cytometry; D057809:HEK293 Cells; D006801:Humans; D006969:Hypersensitivity, Immediate; D007249:Inflammation",
"nlm_unique_id": "101235694",
"other_id": null,
"pages": "400-7",
"pmc": null,
"pmid": "24443418",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Basophil activation after nonsteroidal anti-inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs.",
"title_normalized": "basophil activation after nonsteroidal anti inflammatory drugs stimulation in patients with immediate hypersensitivity reactions to these drugs"
} | [
{
"companynumb": "ES-JNJFOC-20150300475",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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"activesubstancename": "IBUPROFEN"
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{
"abstract": "Cord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.\nAll patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.\nMedian age was 27 (range 1-58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).\nUsing a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.",
"affiliations": "Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Adaptive Biotechnologies, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.;Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.",
"authors": "Milano|F|F|;Emerson|R O|RO|;Salit|R|R|;Guthrie|K A|KA|;Thur|L A|LA|;Dahlberg|A|A|;Robins|H S|HS|;Delaney|C|C|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2020.583349",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X Frontiers Media S.A. \n\n10.3389/fonc.2020.583349\nOncology\nOriginal Research\nImpact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation\nMilano F. 12* Emerson R. O. 3 Salit R. 12 Guthrie K. A. 1 Thur L. A. 1 Dahlberg A. 14 Robins H. S. 13 Delaney C. 14 1Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States\n2Department of Medicine, University of Washington School of Medicine, Seattle, WA, United States\n3Adaptive Biotechnologies, Seattle, WA, United States\n4Department of Pediatrics, University of Washington School of Medicine, Seattle, WA, United States\nEdited by: Michele Malagola, University of Brescia, Italy\n\nReviewed by: Camillo Almici, Asst degli Spedali Civili di Brescia, Italy; Teresa Sadras, Beckman Research Institute, City of Hope, United States\n\n*Correspondence: F. Milano, fmilano@fredhutch.orgThis article was submitted to Hematologic Malignancies, a section of the journal Frontiers in Oncology\n\n\n09 10 2020 \n2020 \n10 58334914 7 2020 21 9 2020 Copyright © 2020 Milano, Emerson, Salit, Guthrie, Thur, Dahlberg, Robins and Delaney2020Milano, Emerson, Salit, Guthrie, Thur, Dahlberg, Robins and DelaneyThis 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.Introduction\nCord blood transplantation (CBT) recipients are at increased risk of mortality due to delayed immune recovery (IR). Prior studies in CBT patients have shown that recovery of absolute lymphocyte count is predictive of survival after transplant. However, there are no data on the association of T-cell receptor (TCR) and clinical outcomes after CBT. Here we retrospectively performed TCR beta chain sequencing on peripheral blood (PB) samples of 34 CBT patients.\n\nMethods\nAll patients received a total body irradiation based conditioning regimen and cyclosporine and MMF were used for graft versus host disease (GvHD) prophylaxis. PB was collected pretransplant on days 28, 56, 80, 180, and 1-year posttransplant for retrospective analysis of IR utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PB mononuclear cells. To test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived.\n\nResults\nMedian age was 27 (range 1–58 years) and most of the patients (n = 27) had acute leukemias. There were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths were due to relapse. Rapid turnover of T cell clones was observed at each time point, with TCR repertoires stabilizing by 1-year posttransplant. TCR diversity values at day 100 for patients who died between 100 and 365 days posttransplant were significantly lower than those of the surviving patients (p = 0.01).\n\nConclusions\nUsing a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following CBT. Importantly, this assay is easily performed on posttransplant PB samples, even as early as day 28 posttransplant, making it an excellent candidate for early identification of patients at high risk of death.\n\nimmune reconstitutioncord blood transplantationT-cell repertoire diversitydelayed immune recoveryT-cell receptor sequencing\n==== Body\nIntroduction\nPatients undergoing hematopoietic cell transplantation (HCT) are at increased risk of transplant-related morbidity and mortality, in part due to the prolonged period of pancytopenia and immune dysregulation that results from the conditioning regimen and infusion of donor stem cells. The use of umbilical cord blood as a graft source has expanded treatment options for many patients, particularly ethnic and racial minorities (1). However, umbilical cord blood transplantation (CBT) recipients appear to be at even greater risk of non-relapse mortality (NRM) in the early posttransplant period when compared to recipients of bone marrow or peripheral blood stem cell grafts from related or unrelated HLA (human leukocyte antigen) matched adult donors (2, 3). CBT recipients have a significantly higher incidence of opportunistic infections in the first year posttransplant (4–6). Despite these challenges, when considering both NRM and relapse, CBT patients’ overall mortality risk is comparable to that observed with other graft sources (7–10), and cord blood continues to be one of the graft source for patients without conventional donors (7, 9, 11).\n\nThere is a dearth of assays to accurately measure functional rather than numerical reconstitution of the adaptive immune system after transplantation. This has made it difficult to directly address the role of delayed functional immune recovery on CBT outcomes, especially in the setting of many other contributing clinical variables. Immunophenotyping by flow cytometry and quantification of thymopoiesis by detection of TCR recombination excision circles (TRECs) have demonstrated markedly reduced and prolonged T-cell recovery and thymic activity after dCBT as compared to infusion of adult stem cell grafts (12, 13). However, the period of susceptibility to infections continues after numerical recovery by these surrogate measurements, and these assays have not demonstrated substantial value in predicting infectious mortality. The ability to more accurately measure cellular immune reconstitution in patients undergoing HCT (in this case CBT), with the goal of better assessing the consequent risk of morbidity and mortality, could lead to intervention strategies aimed at reducing this risk.\n\nWe had previously investigated clonal diversity of the T cell compartment of peripheral blood is a meaningful method of assessing cellular adaptive immune reconstitution. In the blood of a healthy adult, an individual T cell primarily expresses one of millions of different T Cell Receptors (TCRs); a clone is defined as the set of T cells expressing the same TCR (14, 15). The cellular adaptive immune system plays an important role in conveying protection against pathogenic infection, in part, through the development of a highly diverse repertoire of TCR genes, which is thought to be necessary for adequate protection against pathogens. This is evident in humans with primary or acquired immunodeficiency diseases [e.g., severe combined immunodeficiency (SCIDS), common variable immune deficiency (CVID), and HIV], in aging, and following HCT where loss of TCR diversity has been implicated in the increase in morbidity and mortality from infection that is observed in these clinical settings (16–19).\n\nDue to the extremely large number of T-cell clones present in the healthy human, estimates of total T-cell repertoire diversity must be made from subsamples of the T-cell repertoire. Herein, we apply a high-throughput DNA sequencing method to immunosequence the CDR3 regions of rearranged TCRβ genes from peripheral blood mononuclear cells (PBMC) collected from 34 recipients of myeloablative conditioning CBT at Fred Hutchinson Cancer Research Center at multiple time points after transplant.\n\nMaterials and Methods\nStudy Design\nPatients undergoing myeloablative single or double CBT at the Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance (SCCA) between August 2007 and 2010 on research protocols approved by the Center’s Institutional Review Board were eligible for this retrospective analysis of data collected prospectively. All patients consented to collection of blood samples for studies of immune reconstitution posttransplant. In addition, healthy adults were enrolled as controls in a study, “Immunology studies of Normal Healthy Individuals,” at Adaptive Biotechnologies. All subjects provided written informed consent to participate in the study, which was approved by Western Institutional Review Board.\n\nPatients, Treatment Regimens, and Posttransplant Supportive Care\nPatients were eligible for a myeloablative high-dose TBI-based CBT if they were aged ≤45 years old or treosulfan-based if they were ≤65 years old and lacked a suitably matched related or unrelated donor. The underlying disease was categorized as standard or high-risk based upon previously described criteria (20). CB donor selection was based on institutional guidelines and units were selected to optimize both HLA match and cell dose, avoiding, when possible, CB units which the patient had donor specific anti-HLA antibodies. All patients received unrelated donor CB grafts, which were 4 of 6 to 6 of 6 matched to the recipient at HLA-A, B, and DRB1 antigens. HLA typing was performed at the antigen level for HLA-A and B, and high-resolution HLA typing was performed for HLA-DRB1 alleles. The selection of two CB units was mandatory when a single CB unit did not meet the following criteria: HLA match 6 of 6 with a total nucleated cell count (TNC) dose of ≥2.5 × 107/kg or HLA match 5 of 6, 4 of 6 with a TNC dose of ≥4.0 (± 0.5) × 107/kg. In patients receiving a double CBT, the individual CB units were at least three of six HLA-A, B, and DRB1 matched to each other, and each contained a minimum of 1.5 × 107 TNC per kilogram. Of 38 patients potentially eligible, three patients without any blood samples stored for TCR analysis and one patient who died before day 28 were excluded. All patients received prophylactic antimicrobial and antifungal agents per institutional guidelines (21) and remained at our institution for a minimum of 100 days posttransplant. After discharge from our center, patients were seen as clinically indicated, with follow-up assessments per protocol at 6 months and 1 year to include a formal graft-versus-host-disease (GvHD) assessment and PB obtained for immune reconstitution studies and basic lab work.\n\nSequencing Assay and Evaluation of Immune Reconstitution Posttransplant\nPB was collected pretransplant and on days 28, 56, 80–100, 180, and 1-year posttransplant for retrospective analysis of immune recovery utilizing high-throughput sequencing of TCRβ rearrangements from genomic DNA extracted from PBMCs. We sequenced the CDR3 region of TCRβ from approximately 250,000 PBMCs from each time point in surviving patients, and we sequenced four PBMC samples from each of four healthy controls over a 1-year time-course. The TCRβ CDR3 region was defined according to the IMGT collaboration (22), beginning with the second conserved cysteine encoded by the 3′ portion of the Vβ gene segment and ending with the conserved phenylalanine encoded by the 5′ portion of the Jβ gene segment. TCRβ CDR3 regions were amplified and sequenced using protocols described by Robins et al. (15). Briefly, a multiplexed PCR method was employed to amplify all possible rearranged genomic TCRβ sequences using 52 forward primers, each specific to a TCR Vβ segment, and 13 reverse primers, each specific to a TCR Jβ segment. Reads of length 60 bp were obtained using the Illumina HiSeq System. Raw HiSeq sequence data were preprocessed to remove errors in the primary sequence of each read, and to compress the data. A nearest neighbor algorithm was used to collapse the data into unique sequences by merging closely related sequences, to remove both PCR and sequencing errors.\n\nStatistical Considerations\nTo test the association between TCR repertoire diversity and patient outcomes, we conducted a permutation test on median TCR repertoire diversity for patients who died within the first year posttransplant versus those who survived by generating 10,000 permutations of mortality labels. In this case, our test is ideal because the median is robust to outliers and a permutation test makes no assumptions about the distribution of TCR repertoire diversity among patients. To maintain consistency, the same approach was used to test the association of CD3+ cell counts and TREC values with patient mortality. Differences in patient characteristics according to outcome were assessed via a two-tailed Fisher’s exact test for binary data and a two-tailed Mann-Whitney U test for continuous data. While we could not assess all possible confounding factors in a multivariate model, we did calculate and report the marginal p value associated with each possible confounding factor separately.\n\nResults\nStudy Cohort\nThirty-four patients were included in the final analysis. This cohort was composed of 11 pediatric and 23 adult recipients (median age, 26.5 years), who primarily had acute leukemia (n = 26). Conditioning consisted of either high dose TBI (1,320 cGy), cytoxan and fludarabine or treosulfan, fludarabine, and low dose TBI (200 cGy) with cyclosporine and mycophenolate mofetil as GvHD prophylaxis. Recipients who experienced graft failure were excluded. We analyzed PB prior to transplant, and then at 1, 2, 3, 6, and 12 months after CBT, based on sample availability. Median follow up among all patients was 370 days, range 34–1,657. Table 1 summarizes the recipient, disease, and transplant characteristics of the patients.\n\nTable 1 Patient and unit characteristics of 34 cord blood transplantation (CBT) recipients.\n\nCharacteristic\tTotal (n = 34)\t\nAge, y, median (range)\t27 (1–58)\t\nMale, n (%)\t15 (44.1)\t\nDiagnosis, n (%)\t\t\n AML/MDS\t18 (53)\t\n ALL\t10 (29)\t\n Myeloproliferative disorders\t4 (12)\t\n Biphenotypic leukemia\t1 (3)\t\n Chronic lymphocytic leukemia\t1 (3)\t\nNumber of units received, n (%)\t\t\n 1\n 2\t2 (5.9)\n32 (94.1)\t\nOverall CD34, median × 106/kg (range)\n†\t0.21 (0.08–1.67)\t\nOverall TNC, median × 107/kg (range)\n†\nTotal volume, ml, median (range)\n†\nAge of CB unit, mo., median (range)\t5.14 (3.5–15.9)\n65 (43–387)\n44 (8–140)\t\nPresence of donor specific anti-HLA antibodies, n\t0\t\nHLA matching to recipients, n (%)#\t\t\n 4/6\t21 (62)\t\n 5/6\t10 (29)\t\n 6/6\t3 (9)\t\nConditioning intensity, n (%)\t\t\n Cytoxan, fludarabine, TBI (1320)\t24 (71)\t\n Treosulfan, fludarabine, TBI (200)\t10 (29)\t\nGvHD prophylaxis, n (%)\t\t\n CsA/MMF\t34 (100)\t\nStatus at time of HCT, n (%)\n MRD+\n CR1\n CR>2\n Relapsed/refractory disease\n Chronic phase (CLL/CML)\n Other (refractory anemia)\t17 (50)\n13 (38.2)\n13 (38.2)\n2 (5.9)\n4 (11.7)\n2 (5.9)\t\nCBT, cord blood transplantation; AML/MDS, acute myeloid leukemia/myelodysplastic syndrome; ALL, acute lymphoblastic leukemia; TBI, total body irradiation; GvHD, graft-versus-host-disease; CsA/MM, cyclosporine A/mycophenolate mofetil; HCT, hematopoietic cell transplantation; MRD, measurable residual disease; CR1, first complete remission; CR > 2, more than two complete remissions.\n\n†Pre-thaw median CD34+, TNC, and TVOL of all units.\n\n#HLA matching reflects the lowest HLA-match of the unit.\n\nPatient Mortality in the Study Cohort\nAmong the 34 recipients, there were 15 deaths occurring between 34 to 335 days after transplant. Seven deaths involved relapse, although one recipient died of influenza while in early relapse. Eight additional recipients experienced NRM; three died before day 56 (one of hepatic failure, one of diffuse alveolar hemorrhage and one of disseminated cytomegalovirus (CMV) infection). Five patients experienced NRM between 100 days and 1 year after transplant. Primary cause of death was multi-system organ failure in three recipients (one with fungal encephalitis); respiratory failure in two recipients (one with invasive pulmonary fungal infection). Finally, a single patient died from a secondary tumor at 1,589 days post-transplant. Table 2 summarizes features of the subjects when separated by outcome (1-year overall survival), including age, sex, CMV status at transplant, CR status (complete remission 2/3 or relapsed/refractory/progressive disease vs. all others), and presence of acute and chronic GVHD after transplant. None of these factors differed significantly between patients with and without NRM except for age.\n\nTable 2 Outcomes summary.\n\n\tAlive (n = 19)\tDeath (n = 15)\tp-value\t\nMedian age, years (range)\t18 (1–58)\t33 (18-56)\t0.007\t\nCMV serostatus, n (%)\nPositive\nNegative\t12 (63)\n7 (37)\t10 (67)\n5 (33)\t1.00\t\nTBI, n (%)\n1,320 cGy\n200 cGy\t14 (74)\n5 (26)\t10 (67)\n5 (33)\t0.72\t\nAcute GvHD, n (%)\nGrade 0–II\nGrade III-IV\t15 (83)\n3 (17)\t12 (80)\n3 (20)\t1.00\t\nMRD, n (%)\n+\n−\t7 (37)\n12 (63)\t10 (67)\n5 (33)\t0.17\t\nCR at transplant, n (%)*\n≤CR1\n≥CR2\t13 (68)\n6 (32)\t7 (47)\n8 (53)\t0.30\t\nDays to engraftment\n(WBC > 500), median (range)\t19 (13–44)\t25 (7–45)\t0.20\t\nSummary of patient characteristics separated by 1-year overall survival. P-values are calculated using a Mann-Whitney U test for continuous variables and a Fisher’s exact test for categorical variables.\n\nTBI, total body irradiation; GvHD, graft-versus-host-disease; CMV, cytomegalovirus; CR, complete remission; MRD, measurable residual disease; WBC, white blood cell count.\n\n*Patients transplanted with refractory anemia or in chronic phase are considered ≤CR1 (i.e., low-risk) for this comparison. Patients not in remission are considered ≥CR2 (i.e., high-risk) for this comparison.\n\nChanges in T Cell Clonal Diversity Posttransplant\nWe utilized the distribution of T-cell clones in up to ~250,000 PBMC from each sample (subject to availability of adequate material) to estimate the species richness of unique T cell receptor beta sequences in each recipient’s peripheral blood using an unseen species analysis. (15, 23) Estimated species richness was computed for each time point sampled (Figure 1). Myeloablative conditioning resulted in a large drop in T-cell diversity from pre-transplant values. T-cell diversity nadired at 2 months after transplant, with a slow but substantial increase in T-cell repertoire diversity by 1 year. However, T-cell diversity at 1 year in CBT recipients was still lower than that in a sample of four healthy adult subjects.\n\nFigure 1 T cell receptor (TCR) repertoire reconstitution after stem cell transplant. We obtained peripheral blood samples from each of 32 patients before transplant and five times after transplant. TCR repertoire size for each patient was estimated using high-throughput sequencing of TCR rearrangements, and the geometric mean of estimated TCR repertoire size is shown. After transplant, patients had a vastly reduced TCR repertoire which reached its minimum 56 days posttransplant before beginning a slow recovery. The value for healthy subjects is the geometric mean of sixteen samples (four samples per subject from four healthy controls). One-year posttransplant, myeloablative CBT patients still had much lower TCR repertoire sizes than healthy control subjects.\n\nTracking T Cell Clones Posttransplant\nIn order to assess the stability of the reconstituting adaptive immune system over time, we investigated the persistence of TCR clones found at early time-points in later samples. Using only patients with samples collected and sequenced at 28, 56, 100, 180, and 365 days post-transplant, we determined the top 10 TCR clones by frequency in each patient at the 28, 56, 100, and 180 day time-points and tracked their frequency over time in one representative CBT patient and one healthy subject (Figure 2). This comparison revealed substantial clonal turnover within the CBT patient, with large clonal expansions appearing over a short period of time and dropping to low frequency or disappearing entirely soon afterward.\n\nFigure 2 TCRB clonal frequency over time, cord blood transplantation (CBT) patient vs. healthy subject. (A) We have charted the frequency of the 10 most frequent TCRB clones observed 28 days after transplant in one representative CBT patient. These 10 clones were tracked forward in time, and their frequencies at day 56 are plotted. Likewise, we have plotted the change in frequency of the top 10 clones for each pair of adjacent time-points in this patient. Many of the most frequent TCRB clones observed in early time-points either dropped in frequency or disappeared within weeks. By day 180, a drop-in clone frequency between time-points was still evident but most of the top 10 TCRB clones were observed again at some frequency at day 365. (B) We performed a similar analysis for one representative healthy subject. Very little clonal turnover was observed; many of the most frequent TCRB clones persisted across time-points, remaining at similar frequencies throughout the 6-month time-course.\n\nWe next considered all 14 patients with complete sequencing data and classified each of the top 10 T-cell receptor beta (TCRB) clones at each time-point as either persistent or transient. A top-10 TCR clone that was observed (at any frequency) at a later time-point was considered persistent, and clones that were never again observed in samples from the same patient were considered transient. Figure 3 shows the mean number of persistent TCR clones in the top 10, at each time-point posttransplant. At 28 and 56 days posttransplant, we observed dynamic and highly unstable TCR repertoires in which many TCR clones that were present at high frequency in an early sample were never observed again. Starting at 100 days posttransplant, this pattern began to subside and patients’ TCR repertoires became more stable. To confirm that this pattern is highly unusual, we sequenced PBMC samples from four healthy subjects over the same length of time. The median number of transient TCR clones in the top 10 was 0 for these healthy controls at each time-point we studied, confirming that the high prevalence of transient TCR clones following transplant is indicative of an unusually unstable TCR repertoire.\n\nFigure 3 Persistence of T cell receptor (TCR) clones during immune reconstitution. Starting with each patient who survived through day 365 and for whom samples were available for sequencing at each time-point (N = 14), each of the top 10 TCR clones by frequency was classified as either persistent (observed again in the same patient at any later time point) or transient (not observed again at any level in subsequent samples from the same patient). We report the mean and standard deviation of the number of persistent TCRB clones among patients. The number of persistent clones was highly variable, ranging from 1 to 10, but the mean number of persistent clones increased with time indicating a stabilizing TCRB repertoire by 1-year posttransplant. Four healthy subjects were analyzed in the same fashion over a similar time-course; and the number of persistent TCR clones ranged from 9 to 10 with a median of 10.\n\nCorrelation of T-Cell Receptor Diversity With Patient Mortality\nWe found that the evolution of TCR diversity following transplant differed between patients who did and did not survive the first year posttransplant (Figure 4). Survivors’ average TCR repertoire size reached its nadir at 28 days posttransplant followed by a period of more rapid recovery. In contrast, those who died demonstrated an average TCR repertoire size that continued to decrease until day 100 such that the median TCR repertoire size of patients who subsequently died was significantly lower than that of survivors’ (p = 0.019 by permutation). Of the 10 patients who were alive at day 100 but died before 1-year posttransplant, median survival was 216 days, indicating that a robust statistical signal present at day 100 could allow for adequate time for the implementation of potential clinical interventions.\n\nFigure 4 T cell receptor (TCR) repertoire comparison by outcome. Peripheral blood samples were taken from each cord blood transplantation (CBT) patient before transplant and five times after transplant. TCR repertoire size for each sample was estimated using high-throughput sequencing of TCR rearrangements. Patients are divided into those who survived through 1-year posttransplant (black) and patients who died within 1 year (red). At each of six time-points (pre-tx, 28, 56, 100, 180, 365 days posttransplant), we report the geometric mean and standard deviation of TCR repertoire size for each group of patients. At day 100, the median TCR repertoire size of patients who died was significantly lower than that of patients who survived (p = 0.019 by permutation). For the six time-points in order, N = 17, 16, 18, 18, 19, 17 for patients who survived through day 365; N = 15, 14, 11, 10, 8 for patients who died before day 365. At each time-point, all surviving patients with TCR sequencing data are included.\n\nOther Factors Affecting Patient Mortality\nPosttransplant immune recovery is influenced by many factors, most significantly by the immunologic effects of GvHD and of the IST used for its prevention and treatment. To better determine the association of TCR diversity with risk of mortality, we evaluated treatment with IST, total absolute CD3+ counts and TREC levels as potential confounders of the association between TCR diversity and patient mortality. Twenty-six patients developed acute GvHD at a median of 23 days posttransplant, including 20 patients with grade II and 6 with grade III–IV acute GvHD. These patients were initially treated with prednisone at a dose ranging from 0.5 to 2 mg/kg. Twenty-seven patients (80%) received prednisone in the first 100 days at a median time of 28 days (range, 15–91; death soon after transplant was responsible for most of the patients which did not receive prednisone). Of these 27, 23 (85%) and 10 (37%) patients remained on prednisone therapy at 1 year after transplantation, respectively. We saw no relationship between prednisone treatment and clinical outcome in this cohort.\n\nCorrelation of Absolute CD3 Counts With Patient Mortality\nAnother potential confounding factor in the correlation of TCR diversity measurements with clinical outcome is the recovery of total CD3+ cell numbers. However, when the kinetics of T cell recovery were measured by the absolute CD3+ cells/µl in peripheral blood at the same time as the measurement of TCR diversity, little of the observed difference in TCR diversity could be explained by variations in absolute T cell counts; the correlation between diversity and absolute CD3 counts was very weak in this cohort (r = 0.05). This finding suggests that the estimation of clonal diversity using high-throughput sequencing provides information independent from the total density of circulating T cells. Furthermore, we found that the lymphocyte count following transplant did not differ between patients who did and did not survive the first year posttransplant (Figure 5).\n\nFigure 5 Impact of lymphocyte counts on survival. Peripheral blood samples were taken from each cord blood transplantation (CBT) patient before transplant and five times after transplant. Patients are divided into those who survived through 1-year posttransplant (black) and patients who died within 1 year (red). At each of six time-points (0, 28, 56, 100, 180, 365 days posttransplant), we report the mean and the mean standard error of lymphocyte counts for each group of patients. No significant differences were seen at any time point between the two groups. For the six time-points in order, N = 14, 16, 17, 17, 14, 17 for patients who survived through day 365; N = 15, 11, 10, 10, 6 for patients who died before day 365. At each time-point, all surviving patients with TCR sequencing data are included.\n\nIn order to assess the effect of absolute CD3+ counts on patient mortality, we conducted a permutation test at 56 and 100 days posttransplant comparing median CD3+ cell counts in survivors vs. non-survivors in the same fashion as we tested TCR repertoire diversity. In this cohort, CD3+ counts do not appear to be significantly lower in non-survivors than in survivors at 56 days (p = 0.23) or 100 days (p = 0.14) posttransplant.\n\nCorrelation of T Cell Receptor Excision Circles With Patient Mortality\nT cell receptor excision circles (TRECs), created during TCR rearrangement in the thymus, provide a means to quantify thymopoiesis following stem cell transplant. To investigate the relationship of TRECs to patient outcome in our cohort, we measured TREC levels using PBMC samples taken at the same five times posttransplant used for TCR diversity analysis. Overall, TREC levels differed widely between patients. Mean TREC levels were initially very low both for patients who survived and for those who died (data not shown). TREC levels decreased over time among patients who died, but recovered in surviving patients, consistent with the important role thymopoietic reconstitution is known to play in immune recovery (24). Due to the large variation between patients and the relatively late recovery of TREC values even in survivors, TREC values did not predict clinical outcome in this cohort in the first year posttransplant. We were unable to ascertain the relationship between patient outcomes and TRECs beyond the first year posttransplant, since only a single mortality (at approximately 4.5 years posttransplant, due to secondary malignancy) was observed after the first 365 days.\n\nIn addition to GvHD treatment, total CD3+ counts, and TREC levels, the correlation of our TCR diversity measurement with clinical outcome may also be driven by other variables. Table 2 presents a comparison of characteristics of the 15 patients who died within 1 year of transplant versus the 19 patients who survived. Most factors appeared to be unrelated to mortality. However, the 15 non-survivors were significantly older than the survivors (p = 0.007), which indicates a correlation to patient mortality with or without TCR diversity acting as an intermediary. In this cohort, patient age and TCR repertoire size are not significantly correlated (r −0.28, two-tailed p = 0.15 by normal approximation), suggesting that TCR repertoire and patient age may be independently correlated with mortality risk. Taken together, our results indicate that in this cohort TCR repertoire diversity is a statistically significant correlate with patient survival and among several other clinical variables measured, patient age (which is uncorrelated to TCR repertoire diversity in this cohort) is the only other statistically significant correlate.\n\nComparison of T Cell Receptor Diversity by High-Throughput Sequencing and Spectratype\nSpectratyping is a well-established technology for the assessment of the diversity of the TCR repertoire, which uses PCR with V gene segment-specific primers coupled with an analysis of amplicon length to assess the diversity of TCRs by V gene usage and CDR3 region length. The results of our high-throughput method are expected to recapitulate those obtained with spectratype analysis, with the additional benefits of providing sequence information for each clone, the ability to distinguish a moderately diverse repertoire (with enough TCR diversity for all V gene/CDR3 length classes to be represented) from a fully diverse repertoire, and assessment of quantitative output. Spectratype analysis was performed on all patients at the same time-points used for high-throughput sequencing thereby allowing us to compare these two methods. The results of this comparison are presented for 3 patients in Figure 6; our sequencing data do agree with spectratype analysis in most patients, and in some patients, sequencing provides additional clinically relevant data.\n\nFigure 6 Comparison of spectratype data with high-throughput sequencing. Here we present a subset of the data generated, including the results for Vb1–Vb5 (i.e., one spectratype reaction) for three representative patients at 56 days posttransplant, including two patients who died during the first year posttransplant and one patient who survived. For patients B and C, spectratyping and high-throughput sequencing (HTS) agree, indicating an oligoclonal repertoire in patient B and a diverse repertoire in patient C. Patient A appears much more oligoclonal in our high-throughput sequencing (HTS) data than in the spectratype data; HTS estimated a very low TCRB repertoire size for patient A, who went on to die 195 days posttransplant. Taken together, these data indicate that HTS and spectratyping data are in agreement when analyzed in a similar fashion, and HTS offers an additional depth of data and the advantage of quantitative rather than qualitative output.\n\nDiscussion\nIn this study, we have demonstrated a significant correlation between our measurement of immune reconstitution using high-throughput TCR sequencing at day 100 posttransplant and subsequent risk of mortality in a cohort of 34 CBT patients. This result is in accordance with our initial hypothesis that delayed immune reconstitution, as measured by low diversity of TCR rearrangements in circulating T cells, puts patients at high risk. Indeed, the primary objective of this study was to evaluate whether a more direct measure of T cell clonal diversity (as measured by high-throughput sequencing) was correlated with clinical outcome, in particular an increased risk of mortality during the first year posttransplant in patients undergoing myeloablative CBT. Differently than our study, Buhler et al. recently showed that TCR diversity was not predictive of GVHD, relapse, death, or infections post-HCT in a cohort of 116 donor/recipient pairs undergoing an allogeneic HCT (unrelated = 42; related = 70; haploidentical = 4) (25). However, the latter study analyzed TCR diversity shortly before transplantation (time point 1) and at 1-year post-HCT (time point 2). Using our same approach at multiple time points after HCT, Leick et al. showed instead a significant correlation between increased clonal expansion and acute GVHD in a cohort of 99 related or unrelated donor (57 unrelated, 42 related) allogeneic HCT recipients (26).\n\nMonitoring for risk of leukemic relapse posttransplant can be determined by DNA-based analysis of patient/donor chimerism and sensitive assays for minimal residual disease. In contrast to other risks that contribute to morbidity and mortality, the risk of infectious complications is not easy to analyze in a quantitative fashion. The development of assays which provide a direct measure of immune reconstitution could help identify those patients at higher risk of life-threatening complications and could lead to medical intervention strategies. Direct measure of hematopoietic recovery is easily accomplished by obtaining complete blood counts and measurement of TRECs is adequate to assess thymopoietic reconstitution in the first years posttransplant. However, a direct measure of early immune system recovery, especially with respect to T cell function as opposed to T cell numbers, is lacking. Existing measures of TCR diversity that might fill this role, e.g., spectratype analysis, do not provide the quantitative information necessary for robust and consistent analysis.\n\nNew methods to directly measure immune recovery in post-hematopoietic cell transplant recipients, as proposed here, are vital in tailoring the medical management of individual patients. This is particularly important if we are able to identify those patients at greatest risk of future mortality through these direct measurements in time to intervene and effectively prevent mortality. The clinical utility of such foreknowledge will rely on further study: namely, the creation of a clinically meaningful scheme for stratifying patients into risk groups and the development of effective alternative therapies for high-risk patients.\n\nThe limited size of the patient cohort did not allow for a rigorous multivariate model that is necessary to prove that TCR diversity is a significant and independent predictor of mortality. Our data are also insufficient to determine whether the association of high TCR diversity with better patient outcomes is mediated by TCR diversity per se, nor can our data directly address whether higher TCR diversity necessarily indicates improved clinical immunocompetence. Yet we have demonstrated that the outcomes in this study match our a priori hypothesis, and have further demonstrated that this result cannot be immediately explained simply by alternative measures of immune reconstitution such as peripheral blood absolute CD3+ cell counts or TRECs, or by any of several other variables measured in our small cohort. It is acknowledged, however, that a thorough study of whether TCR diversity is an independent predictive measure of patient outcomes and whether low TCR diversity is directly causal of inferior outcomes must await an analysis with a larger cohort of patients.\n\nIn conclusion, using a fast high-throughput TCR sequencing assay we have demonstrated that high TCR diversity is associated with better patient outcomes following myeloablative CBT. Importantly, this assay is easily performed on posttransplant peripheral blood samples, even as early as day 28 posttransplant. Currently, there are no other clinical assays available that provide information on immune reconstitution this early posttransplant. While these data confirm that T cell clonal dynamics could serve as a predictive tool to identify patients at high risk of death this will require further investigation prospectively in larger and more homogeneous patient cohorts.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nThe studies involving human participants were reviewed and approved by Western Institutional Review Board. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.\n\nAuthor Contributions\nFM, HR, RE, and CD participated in the study design, data analysis, and interpretation of data for the manuscript. ER and FM wrote the first draft and LT, RS, AD, HR, and CD provided revisions and critical review of the final manuscript. KG performed the statistical analyses. All authors contributed to the article and approved the submitted version.\n\nFunding\nThis work was supported by the following grants: 1R43HL106868-01A1 to HR; K23 HL077446 to CD; R24HL74445 to CD; Medac GmbH to CD. CD is a Damon Runyon Clinical Investigator supported in part by the Damon Runyon Cancer Research Foundation (CI# 35-07). FM and LT were supported by the George and Fay Young Foundation.\n\nConflict of Interest\nHR and RE have employment and equity ownership with Adaptive Biotechnologies. The authors declare that this study received funding from Medac GmbH. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.\n\nThe remaining 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\nWe are grateful to the patients and families who consented to the use of clinical research results and biologic specimens in this trial. We thank, Denise Ziegler, MaryJoy Lopez and Nancy Anderson for their assistance in the preparation of this manuscript.\n==== Refs\nReferences\n1 \nBarker JN Byam CE Kernan NA Lee SS Hawke RM Doshi KA \nAvailability of cord blood extends allogeneic hematopoietic stem cell transplant access to racial and ethnic minorities\n. Biol Blood Marrow Transplant (2010 ) 16 (11 ):1541–8. 10.1016/j.bbmt.2010.08.011 \n\n2 \nBrunstein CG Gutman JA Weisdorf DJ Woolfrey AE Defor TE Gooley TA \nAllogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood\n. Blood (2010 ) 116 (22 ):4693–9. 10.1182/blood-2010-05-285304 \n\n3 \nEapen M Rocha V Sanz G Scaradavou A Zhang MJ Arcese W \nEffect of graft source on unrelated donor haemopoietic stem-cell transplantation in adults with acute leukaemia: a retrospective analysis\n. Lancet Oncol (2010 ) 11 (7 ):653–60. 10.1016/S1470-2045(10)70127-3 \n\n4 \nBarker JN Hough RE van Burik J-AH DeFor TE MacMillan ML O’Brien MR \nSerious infections after unrelated donor transplantation in 136 children: impact of stem cell source\n. Biol Blood Marrow Transplant (2005 ) 11 (15846290 ):362–70. 10.1016/j.bbmt.2005.02.004 \n\n5 \nMerindol N Charrier E Duval M Soudeyns H \nComplementary and contrasting roles of NK cells and T cells in pediatric umbilical cord blood transplantation\n. J Leukoc Biol (2011 ) 90 (21367975 ):49 –60\n. 10.1189/jlb.0111007 \n21367975 \n6 \nThomson BG Robertson KA Gowan D Heilman D Broxmeyer HE Emanuel D \nAnalysis of engraftment, graft-versus-host disease, and immune recovery following unrelated donor cord blood transplantation\n. Blood (2000 ) 96 (11023501 ):2703–11. 10.1182/blood.V96.8.2703 \n\n7 \nEapen M Rubinstein P Zhang MJ Stevens C Kurtzberg J Scaradavou A \nOutcomes of transplantation of unrelated donor umbilical cord blood and bone marrow in children with acute leukaemia: a comparison study\n. Lancet (2007 ) 369 (9577 ):1947–54. 10.1016/S0140-6736(07)60915-5 \n\n8 \nBrunstein CG Fuchs EJ Carter SL Karanes C Costa LJ Wu J \nAlternative donor transplantation after reduced intensity conditioning: results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts\n. Blood (2011 ) 118 (2 ):282–8. 10.1182/blood-2011-03-344853 \n\n9 \nKurtzberg J Prasad VK Carter SL Wagner JE Baxter-Lowe LA Wall D \nResults of the Cord Blood Transplantation Study (COBLT): clinical outcomes of unrelated donor umbilical cord blood transplantation in pediatric patients with hematologic malignancies\n. Blood (2008 ) 112 (10 ):4318–27. 10.1182/blood-2007-06-098020 \n\n10 \nMilano F Gooley T Wood B Woolfrey A Flowers ME Doney K \nCord-Blood Transplantation in Patients with Minimal Residual Disease\n. New Engl J Med (2016 ) 375 (10 ):944–53. 10.1056/NEJMoa1602074 \n\n11 \nOran B Shpall E \nUmbilical cord blood transplantation: a maturing technology\n. Hematol / Educ Program Am Soc Hematol Am Soc Hematol Educ Program (2012 ) 2012 :215–22. 10.1182/asheducation.V2012.1.215.3798291 \n\n12 \nJacobson CA Turki AT McDonough SM Stevenson KE Kim HT Kao G \nImmune reconstitution after double umbilical cord blood stem cell transplantation: comparison with unrelated peripheral blood stem cell transplantation\n. Biol Blood Marrow Transplant (2012 ) 18 (4 ):565–74. 10.1016/j.bbmt.2011.08.018 \n\n13 \nKanda J Chiou LW Szabolcs P Sempowski GD Rizzieri DA Long GD \nImmune Recovery in Adult Patients Following Myeloablative Dual Umbilical Cord Blood, Matched Sibling, and Matched Unrelated Donor Hematopoietic Cell Transplantation\n. Biol Blood Marrow Transplant (2012 ) 18 (11 ):1664–76.e1. 10.1016/j.bbmt.2012.06.005 \n\n14 \nArstila TP Casrouge A Baron V Even J Kanellopoulos J Kourilsky P \nA direct estimate of the human alphabeta T cell receptor diversity\n. Sci (New York NY) (1999 ) 286 (5441 ):958–61. 10.1126/science.286.5441.958 \n\n15 \nRobins HS Campregher PV Srivastava SK Wacher A Turtle CJ Kahsai O \nComprehensive assessment of T-cell receptor beta-chain diversity in alphabeta T cells\n. Blood (2009 ) 114 (19 ):4099–107. 10.1182/blood-2009-04-217604 \n\n16 \nBrown JA Boussiotis VA \nUmbilical cord blood transplantation: basic biology and clinical challenges to immune reconstitution\n. Clin Immunol (Orlando Fla) (2008 ) 127 (3 ):286–97. 10.1016/j.clim.2008.02.008 \n\n17 \nCohen YC Scaradavou A Stevens CE Rubinstein P Gluckman E Rocha V \nFactors affecting mortality following myeloablative cord blood transplantation in adults: a pooled analysis of three international registries\n. Bone Marrow Transplant (2011 ) 46 (1 ):70–6. 10.1038/bmt.2010.83 \n\n18 \nSauter C Abboud M Jia X Heller G Gonzales AM Lubin M \nSerious infection risk and immune recovery after double-unit cord blood transplantation without antithymocyte globulin\n. Biol Blood Marrow Transplant (2011 ) 17 (10 ):1460–71. 10.1016/j.bbmt.2011.02.001 \n\n19 \nSeggewiss R Einsele H \nImmune reconstitution after allogeneic transplantation and expanding options for immunomodulation: an update\n. Blood (2010 ) 115 (19 ):3861–8. 10.1182/blood-2009-12-234096 \n\n20 \nMielcarek M Storer BE Boeckh M Carpenter PA McDonald GB Deeg HJ \nInitial therapy of acute graft-versus-host disease with low-dose prednisone does not compromise patient outcomes\n. Blood (2009 ) 113 (19001082 ):2888–94. 10.1182/blood-2008-07-168401 \n\n21 \nNakamae H Kirby KA Sandmaier BM Norasetthada L Maloney DG Maris MB \nEffect of conditioning regimen intensity on CMV infection in allogeneic hematopoietic cell transplantation\n. Biol Blood Marrow Transplant (2009 ) 15 (19450754 ):694 –703\n. 10.1016/j.bbmt.2009.02.009 \n19450754 \n22 \nYousfi Monod M Giudicelli V Chaume D Lefranc MP \nIMGT/JunctionAnalysis: the first tool for the analysis of the immunoglobulin and T cell receptor complex V-J and V-D-J JUNCTIONs\n. Bioinf (Oxford England) (2004 ) 20 (Suppl 1 ):i379–85. 10.1093/bioinformatics/bth945 \n\n23 \nEfron B Thisted R \nEstimating the number of unseen species: How many words did Shakespeare know\n? Biometrika (1976 ) 63 :1976 . 10.2307/2335721 \n\n24 \nBrown JA Stevenson K Kim HT Cutler C Ballen K McDonough S \nClearance of CMV viremia and survival after double umbilical cord blood transplantation in adults depends on reconstitution of thymopoiesis\n. Blood (2010 ) 115 (20 ):4111–9. 10.1182/blood-2009-09-244145 \n\n25 \nBuhler S Bettens F Dantin C Ferrari-Lacraz S Ansari M Mamez AC \nGenetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation\n. Leukemia (2020 ) 34 (5 ):1422–32. 10.1038/s41375-019-0654-y \n\n26 \nLeick M Gittelman RM Yusko E Sanders C Robins H DeFilipp Z \nT Cell Clonal Dynamics Determined by High-Resolution TCR-beta Sequencing in Recipients after Allogeneic Hematopoietic Cell Transplantation\n. Biol Blood Marrow Transplant (2020 ) 26 (9 ):1567–74. 10.1158/1538-7445.AM2020-LB-272\n\n",
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"journal": "Frontiers in oncology",
"keywords": "T-cell receptor sequencing; T-cell repertoire diversity; cord blood transplantation; delayed immune recovery; immune reconstitution",
"medline_ta": "Front Oncol",
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"references": "19706884;18723429;20800103;21527516;21310254;20558104;10542151;15262823;19450754;20436518;27602666;18395491;11023501;23233584;19001082;20107229;31772297;32417490;22698485;15846290;20686119;21875503;20215642;17560447;21367975",
"title": "Impact of T Cell Repertoire Diversity on Mortality Following Cord Blood Transplantation.",
"title_normalized": "impact of t cell repertoire diversity on mortality following cord blood transplantation"
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"abstract": "Gastric mucormycosis is a rare condition that usually manifests in immunocompromised patients. It's a lethal disease with a poor prognosis requiring prompt diagnosis and aggressive management. Although found more commonly in immunocompromised patients, it can also affect the immunocompetent patient, highlighting the importance of clinical suspicion when dealing with a critically ill patient.\n\n\nMETHODS\nThis is a case report on a patient who presented with penetrating trauma to the abdomen requiring surgical intervention. Damage control surgery was performed in the form of a right hemicolectomy ('clip and drop') for extensive colonic injuries (AAST Grade V) with contamination of the abdominal cavity [1]. In the days subsequent to the injury, he developed sepsis and progressive bowel ischaemia and necrosis, requiring surgical debridement. Histological findings revealed mucormycosis of the gastrointestinal tract.\nThe diagnosis of mucormycosis depends on high clinical suspicion as well as histopathological evidence. The management comprises of surgical debridement and appropriate antifungal therapy. Timeous diagnosis and adequate treatment may improve the prognosis.\n\n\nCONCLUSIONS\nThis was a challenging case for the clinicians involved, highlighting that the clinician should consider this infection as a rare cause of bowel ischaemia in the back of their minds when dealing with such patients.",
"affiliations": "Division of Trauma, Department of General Surgery, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa. Electronic address: chido.nyatsambo@wits.ac.za.;Division of Trauma, Department of General Surgery, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa. Electronic address: krevosha.pillay@wits.ac.za.;Division of Trauma, Department of General Surgery, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa. Electronic address: Maeyane.Moeng@wits.ac.za.;Division of Anatomical Pathology, National Health Laboratory Service, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa.;Division of Trauma, Department of General Surgery, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa.",
"authors": "Nyatsambo|Chido|C|;Pillay|Krevosha|K|;Moeng|Maeyane Steve|MS|;Savage-Reid|Michael John|MJ|;Lubout|Megan|M|",
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"doi": "10.1016/j.ijscr.2021.106010",
"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)00512-5\n10.1016/j.ijscr.2021.106010\n106010\nCase Report\nA case report on a rare cause of bowel ischaemia in penetrating trauma\nNyatsambo Chido chido.nyatsambo@wits.ac.za\na⁎\nPillay Krevosha krevosha.pillay@wits.ac.za\na\nMoeng Maeyane Steve Maeyane.Moeng@wits.ac.za\na\nSavage-Reid Michael John b\nLubout Megan a\na Division of Trauma, Department of General Surgery, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa\nb Division of Anatomical Pathology, National Health Laboratory Service, Charlotte Maxeke Johannesburg Academic Hospital, 5 Jubilee Street, Parktown, Johannesburg, South Africa\n⁎ Corresponding author. chido.nyatsambo@wits.ac.za\n25 5 2021\n6 2021\n25 5 2021\n83 10601024 4 2021\n16 5 2021\n17 5 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nIntroduction and importance\n\nGastric mucormycosis is a rare condition that usually manifests in immunocompromised patients. It's a lethal disease with a poor prognosis requiring prompt diagnosis and aggressive management. Although found more commonly in immunocompromised patients, it can also affect the immunocompetent patient, highlighting the importance of clinical suspicion when dealing with a critically ill patient.\n\nCase presentation\n\nThis is a case report on a patient who presented with penetrating trauma to the abdomen requiring surgical intervention. Damage control surgery was performed in the form of a right hemicolectomy (‘clip and drop’) for extensive colonic injuries (AAST Grade V) with contamination of the abdominal cavity [1]. In the days subsequent to the injury, he developed sepsis and progressive bowel ischaemia and necrosis, requiring surgical debridement. Histological findings revealed mucormycosis of the gastrointestinal tract.\n\nClinical discussion\n\nThe diagnosis of mucormycosis depends on high clinical suspicion as well as histopathological evidence. The management comprises of surgical debridement and appropriate antifungal therapy. Timeous diagnosis and adequate treatment may improve the prognosis.\n\nConclusion\n\nThis was a challenging case for the clinicians involved, highlighting that the clinician should consider this infection as a rare cause of bowel ischaemia in the back of their minds when dealing with such patients.\n\nGraphical abstract\n\nUnlabelled Image\n\nHighlights\n\n• Emphasizing the need for a high clinical suspicion & diagnosis of rare intra-abdominal infections (gastric mucormycosis)\n\n• Identification of an unusual cause of progressive bowel ischaemia in a critically ill patient admitted to the ICU\n\n• Management principles of gastric mucormycosis centred around prompt diagnosis, antifungal therapy and surgical debridement.\n\n• A reminder of unusual abdominal complication seen in penetrating trauma\n\nKeywords\n\nPenetrating trauma\nGastric mucormycosis\nBowel ischaemia\n==== Body\n1 Introduction\n\nMucormycosis is a rare fungal infection arising from the zygomycetes species [2]. It affects patients with the following risk factors: acidosis, uncontrolled diabetes mellitus, diabetic ketoacidosis, septicaemia, leukaemia, lymphoma, HIV/AIDS, severe malnourishment, severe burns, cytotoxic therapy, immunosuppression from corticosteroids [2,3]. Other risk factors include chronic renal failure, liver pathology and dialysis patients receiving deferoxamine [2,4]. Treatment of mucormycosis is centred around surgical debridement of the necrotic tissue and administration of a lipid-based formulation of amphotericin B [3]. This case report identifies a rare case of bowel ischemia after penetrating intra-abdominal trauma. Only a few cases of this condition in trauma are reported, most of whom presented with GIT bleeding [[4], [5], [6], [7], [8], [9], [10]]. This case report has been written in line with the SCARE guidelines [11].\n\n2 Case presentation\n\nA 30-year-old man presented to our Trauma unit with penetrating abdominal trauma. He had no known background medical or surgical history. Of note were two gunshot wounds - one thoracoabdominal in the 8th intercostal space on the right and a second wound over the right buttock. He came in haemodynamically unstable with a blood pressure of 60/40 mmHg pulse of 100 beats per minute. He was resuscitated according to the ATLS® principles of Primary and Secondary survey. The arterial blood gas showed severe metabolic acidosis. Fluid resuscitation and massive transfusion protocol were initiated per standard of care. The patient was taken to theatre for an emergency damage control laparotomy by the Trauma surgeon and a senior trauma registrar (resident).\n\nHaemoperitoneum, gross faecal contamination and multiple hollow viscus injuries were confirmed at laparotomy. Bleeding from the bowel mesentery and the bowel ends was controlled first, without any overt bowel blood supply changes. Minor contusion of the second part of the duodenum (AAST Grade I) was noted at laparotomy, requiring no intervention [1]. Extensive caecal and transverse colon injuries (AAST Grade V), not amenable to repair, were noted. A right hemicolectomy was performed with a GIA stapler resulting in the typical ‘clip-and drop’ of the bowel ends [1]. The patient was transfused four units of packed red blood cells, four fresh frozen plasma units, and one mega unit of platelets intra-operatively. The abdomen was left open with a temporary vacuum-assisted abdominal closure, with a plan to return to theatre for definitive surgery.\n\nHe was transferred postoperatively to the trauma intensive care unit (ICU) for continued resuscitation and close monitoring. Given gross contamination, broad-spectrum antibiotics were continued in ICU. He still required vasoactive support to maintain acceptable mean arterial pressures. His acidosis corrected within 24 h of his ICU admission, although he still had features of Systematic Inflammatory Response Syndrome (SIRS) as evidenced by ongoing pyrexia and persistent tachycardia. A planned relook laparotomy was performed on day 2. The abdomen was noted to be clean at relook. The transverse colon stump was intact, all the remaining bowel was viable, and an end ileostomy was fashioned.\n\nDay 3 post-operation, he developed an acute kidney injury and mild hypoglycaemia attributed to possible systemic sepsis. His antibiotics were escalated to a carbapenem as per the trauma unit protocol. A septic workup (blood cultures, Chest X-rays etc.) was done, including a 1,3 Beta D glucan assay (Fungitell®). The BDG result was significantly raised (500 pg/ml), highly suggestive of invasive fungal sepsis. As per our local micro-biogram, he was started on an antifungal cover using Fluconazole at 800 mg daily. He showed good clinical improvement and was successfully weaned off a ventilator and extubated on day 5 post-operation.\n\nPreviously well-perfused ileostomy became necrotic on Day 7 post-operation. At this stage, the patient had been off vasoactive medication for more than 5 days. A relook on demand was performed in theatre. Multiple segments of patchy necrosis and ischaemia starting 160 cm from the duodenal jejunal flexure (Fig. 1a, b) were discovered. No surgical, mechanical explanation or complications could be elicited for the cause of bowel ischaemia. This finding was unusual and surprised the surgical team. Small bowel resection of necrotic bowel was done, and specimens sent off for histology. Unfortunately, in our setting, the frozen section is not available after hours. The necrosis was associated with features of early perforation in some regions.Fig. 1 a and b: intra-operative findings of small bowel showing areas of patchy necrosis.\n\nFig. 1\n\nThe pathology report confirmed a diagnosis of mucormycosis on the segment of resected small bowel that was submitted for histopathological examination. Serosal fibrinopurulent exudate and a site of perforation were identified macroscopically and features of haemorrhagic infarction. Haemotoxylin and eosin (H&E) sections were representative of small bowel wherein transmural necrosis, perforation and acute serositis were confirmed. Large areas of mucosal necrosis containing fungal hyphae were present (Fig. 2). The hyphae were large, non-septate, lacked parallel walls and demonstrated acute angle branching, including 90-degree angle branching, morphologically consistent with mucormycosis. Transmural invasion by the hyphae with extensive angioinvasion was also demonstrated (Fig. 3).Fig. 2 H&E, 400×; broad, non-septate hyphae with 90 angle branching (arrow) and background necrotic debris.\n\nFig. 2\n\nFig. 3 H&E, 200×; fungal hyphae within both a muscular vessel wall and lumen (arrow), demonstrating angioinvasion.\n\nFig. 3\n\nAt this stage, we had histological evidence of mucormycosis. This was despite negative screening for common associated medical conditions in this patient. Workup for Diabetes mellitus, Tuberculosis, Human immune deficiency virus and hypertension were all negative. There were no immunosuppressive medications identified in the history provided or administered during his stay with us before this development. The patient continued to have a turbulent course and required a further two relooks. He demised despite additional antimicrobial support and escalating antifungal therapy to include Amphotericin B therapy. Low dose physiological intravenous steroids were introduced for refractory hypotension towards the end.\n\n3 Discussion\n\nMucormycosis is an angioinvasive fungal infection arising from the zygomycetes species [2]. The organism is found in the environment on decaying vegetation and soil. Fungi are common organisms, and humans have day to day contact with them [12]. The intact innate immune system of an individual prevents the formation of various infections in the human body; however, in immunocompromised patients, especially diabetic patients, this organism can present in various syndromes. Zygomycetes has two orders: Entomophthorales and Mucorales. The latter being implicated in causing the infection, specifically, Rhizopus, Mucor, and Rhizomucor [13].\n\nThere seems to be an increase in the number of mucormycosis cases reported. A review of case reports in South America shows that the number of reported cases has increased since 1970 [14]. The overall mortality has been quoted to be up to 48% in some case series reviews and up to 70% in others [2,14]. Risk factors are well described, as already mentioned in the introduction [[2], [3], [4]]. In 19% of cases, no underlying condition can be found [6]. Our patient had no other risk factors apart from severe trauma resulting in acidosis. The use of steroids for refractory hypotension was only used later and at physiological doses.\n\nThough the usual site involves paranasal sinuses in 39% of the cases, GIT involvement has been reported in 7% [16]. The fungi have a preference for arterial invasion, where they cause extensive emboli and necrosis of surrounding tissues resulting in ischemia and necrosis of the affected tissue [2,4]. This manifests as ulceration, necrosis and infarction of the affected tissue [13]. If the GIT is affected, patients can present with upper gastrointestinal bleed, bowel perforation and even bowel ischaemia.\n\nTo make the diagnosis, the presence of predisposing conditions, signs and symptoms, and tissue specimens are required. Surgical specimens taken intraoperatively or via endoscopy should be analysed with direct microscopy and histopathology. Culture, while considered essential for identification and antimicrobial susceptibility, has a low sensitivity [16]. There are no serological or PCR tests that are diagnostic for mucormycosis at present [4,17]. Autopsy series have demonstrated that mucormycosis is often diagnosed postmortem – especially in the gastrointestinal tract infection [2,17].\n\nWe feel that the development of bowel necrosis when the patient was already off vasoactive drugs is suggestive of the contribution of mucormycosis to ischaemia in this case. No ischaemia had been noted on the prior laparotomy procedures. Though our patient did not present with gastrointestinal bleeding, the case highlights the difficulties of diagnosing this condition in trauma.\n\nThere are four management principles: prompt diagnosis, optimisation of risk factors, early initiation of appropriate antifungal therapy, and surgical debridement [17]. Immuno-suppressive medications (steroids in particular) should be stopped wherever possible, and hyperglycaemia and acidosis should be corrected. There are no prospective randomised trials to define the optimal antifungal treatment for mucormycosis [17]. Improved survival is noted with the initiation of antifungals within five days [4].\n\nWe, unfortunately, used the azoles to manage him initially before the histology report was made available to us. In our setting, most fungal sepsis does respond to azoles as resistance has not yet reached levels seen in other centres unless otherwise stated by the centres biogram [18]. The azoles are ineffective when treating Mucormycosis, except Posaconazole or Isavuconazole, which may be used in refractory mucormycosis [6,17]. Global guidelines recommend liposomal amphotericin B 5-10 mg/kg per day as first-line treatment for any site involved; duration of therapy being individualized until clearance of infection [19]. Resistance to amphotericin B has been noted, especially with prolonged therapy [2,17]. Angioinvasion, thrombosis and tissue necrosis also result in poor penetration of antifungal agents, necessitating extensive surgical debridement of necrotic tissue [4,6,17]. However, in patients who have the non-invasive form of the infection with no features of necrosis or thrombosis, medical therapy alone has found to be effective in some cases.\n\n4 Conclusion\n\nThis is an unusual case of fungal sepsis in penetrating trauma. It is a rare condition found in immunocompromised patients. However, even with the lack of significant risk factors other than acidosis, the clinician should be alerted to a possibility of this diagnosis when dealing with unexplained bowel ischaemia. We will certainly think about this diagnosis for any unexplained bowel ischaemic cases in the future, as appropriate antifungal therapy and debridement remain the cornerstone of care of this condition which is associated with high mortality.\n\nFunding\n\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n\nEthical approval\n\nThe University of Witwatersrand Johannesburg Human Research Ethics Committee (medical) approved this case report (M2011138).\n\nConsent\n\nWritten informed consent was not obtained from the patient, as the patient demised. The head of the Department of Surgery and our medical team has taken responsibility for exhaustive attempts to contact the family. The paper has been sufficiently anonymized to avoid harm to the patient and the family. A signed document stating the above is available for review by the Editor-in-chief of this journal upon request.\n\nCRediT authorship contribution statement\n\nAll authors wrote the case report. Dr. C Nyatsambo and Professor Moeng organized the manuscript and revised the paper.\n\nResearch registration\n\nNot applicable.\n\nGuarantor\n\nProfessor MS Moeng.\n\nProvenance and peer review\n\nNot commissioned, externally peer-reviewed.\n\nDeclaration of competing interest\n\nNone.\n==== Refs\nReferences\n\n1 Moore E.E. Cogbill T.H. Malangoni M.A. Jurkovich G.J. Champion H.R. Gennarelli T.A. McAninch J.W. Pachter H.L. Shackford S.R. Trafton P.G. Organ injury scaling, 11: pancreas, duodenum, small bowel, colon, and rectum J. Trauma Acute Care Surg. 30 1990 https://journals.lww.com/jtrauma/Fulltext/1990/11000/Organ_Injury_Scaling,_11__Pancreas,_Duodenum,.35.aspx\n2 Branscomb R. An overview of mucormycosis Lab. Med 2002 10.1309/ml2q-9jwn-krr7-366t\n3 Spellberg B. Gastrointestinal mucormycosis: an evolving disease Gastroenterol. Hepatol. 8 2012 140 142\n4 Chow K.L. McElmeel D.P. Brown H.G. Tabriz M.S. Omi E.C. Invasive gastric mucormycosis: a case report of a deadly complication in an immunocompromised patient after penetrating trauma Int. J. Surg. Case Rep. 40 2017 90 93 10.1016/j.ijscr.2017.09.013 28946029\n5 Sehmbey G. Malik R. Kosa D. Srinivasan I. Chuang K.-Y. Bellapravalu S. Gastric ulcer and perforation due to mucormycosis in an immunocompetent patient ACG Case Rep. J. 6 2019 e00154 10.14309/crj.0000000000000154\n6 Sickels N. Van Hoffman J. Stuke L. Kempe K. Survival of a patient with trauma-induced mucormycosis using an aggressive surgical and medical approach J. Trauma 70 2011 507 509 10.1097/ta.0b013e31820784ff 21307754\n7 Machicado J. Younes M. Wolf D. Gastric mucormycosis presenting as gastrotrointestinal bleeding in a trauma patient: 764 Am. J. Gastroenterol. 108 2013 https://journals.lww.com/ajg/Fulltext/2013/10001/Gastric_Mucormycosis_Presenting_as.764.aspx\n8 Deja M. Wolf S. Weber-Carstens S. Lehmann T.-N. Adler A. Ruhnke M. Tintelnot K. Gastrointestinal zygomycosis caused by Mucor indicus in a patient with acute traumatic brain injury Med. Mycol. 44 2006 683 687 10.1080/13693780600803888 17071566\n9 Johnson C.B. Ahmeti M. Tyroch A.H. Zuckerman M.J. Hakim M.N. Gastric mucormycosis as a cause of life-threatening upper gastrointestinal bleeding in a trauma patient Am. Surg. 76 2010 76 77 10.1177/000313481007600704\n10 Smith N.L. Phillips S. Norwood S. Mucormycosis infection following trauma Am. Surg. 83 2017 69 70 10.1177/000313481708300302\n11 Agha R.A. Franchi T. Sohrabi C. Mathew G. Kerwan A. The SCARE 2020 guideline: updating consensus Surgical CAse REport (SCARE) guidelines Int. J. Surg. 84 2020 226 230 10.1016/j.ijsu.2020.10.034 33181358\n12 Köhler J.R. Casadevall A. Perfect J. The spectrum of fungi that infects humans Cold Spring Harb. Perspect. Med. 5 2014 a019273 10.1101/cshperspect.a019273\n13 G.M. Cox, Mucormycosis (zygomycosis), UpToDate. (n.d.). https://www.uptodate.com/contents/mucormycosis-zygomycosis (accessed November 1, 2020).\n14 Nucci M. Engelhardt M. Hamed K. Mucormycosis in South America: a review of 143 reported cases Mycoses 62 2019 730 738 10.1111/myc.12958 31192488\n16 Abreu B.F.B.B. de Duarte M.L. Santos L.R. dos Sementilli A. Figueiras F.N. A rare case of gastric mucormycosis in an immunocompetent patient Rev. Soc. Bras. Med. Trop. 51 2018 401 402 29972579\n17 Spellberg B. Edwards J.J. Ibrahim A. Novel perspectives on mucormycosis: pathophysiology, presentation, and management Clin. Microbiol. Rev. 18 2005 556 569 10.1128/CMR.18.3.556-569.2005 16020690\n18 D. Webb, M. Mer, Invasive fungal and bacterial infections in the critically ill and the importance of antimicrobial stewardship, Currentcare.Za. (n.d.).\n19 O.A. Cornely, A. Alastruey-Izquierdo, D. Arenz, S.C.A. Chen, E. Dannaoui, B. Hochhegger, M. Hoenigl, H.E. Jensen, K. Lagrou, R.E. Lewis, S.C. Mellinghoff, M. Mer, Z.D. Pana, D. Seidel, D.C. Sheppard, R. Wahba, M. Akova, A. Alanio, A.M.S. Al-Hatmi, S. Arikan-Akdagli, H. Badali, R. Ben-Ami, A. Bonifaz, S. Bretagne, E. Castagnola, M. Chayakulkeeree, A.L. Colombo, D.E. Corzo-León, L. Drgona, A.H. Groll, J. Guinea, C.P. Heussel, A.S. Ibrahim, S.S. Kanj, N. Klimko, M. Lackner, F. Lamoth, F. Lanternier, C. Lass-Floerl, D.G. Lee, T. Lehrnbecher, B.E. Lmimouni, M. Mares, G. Maschmeyer, J.F. Meis, J. Meletiadis, C.O. Morrissey, M. Nucci, R. Oladele, L. Pagano, A. Pasqualotto, A. Patel, Z. Racil, M. Richardson, E. Roilides, M. Ruhnke, S. Seyedmousavi, N. Sidharthan, N. Singh, J. Sinko, A. Skiada, M. Slavin, R. Soman, B. Spellberg, W. Steinbach, B.H. Tan, A.J. Ullmann, J.J. Vehreschild, M.J.G.T. Vehreschild, T.J. Walsh, P.L. White, N.P. Wiederhold, T. Zaoutis, A. Chakrabarti, Global guideline for the diagnosis and management of mucormycosis: an initiative of the European Confederation of Medical Mycology in cooperation with the Mycoses Study Group Education and Research Consortium, Lancet Infect. Dis. (2019). doi:10.1016/S1473-3099(19)30312-3.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2210-2612",
"issue": "83()",
"journal": "International journal of surgery case reports",
"keywords": "Bowel ischaemia; Gastric mucormycosis; Penetrating trauma",
"medline_ta": "Int J Surg Case Rep",
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"publication_types": "D016428:Journal Article",
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"title": "A case report on a rare cause of bowel ischaemia in penetrating trauma.",
"title_normalized": "a case report on a rare cause of bowel ischaemia in penetrating trauma"
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"abstract": "Increased utilization of hepatitis C virus (HCV)-positive donors has increased transplantation rates. However, high levels of viremia have been documented in recipients of viremic donors. There is a knowledge gap in how transient viremia may impact acute cellular rejections (ACRs).\n\n\n\nIn this study, 50 subjects received hearts from either viremic or non-viremic donors. The recipients of viremic donors were classified as nucleic acid amplification testing (NAT)+ group, and the remaining were classified as NAT-. All patients were monitored for viremia levels. Endomyocardial biopsies were performed through 180 days, evaluating the incidence of ACRs.\n\n\n\nA total of 50 HCV-naive recipients received hearts between 2018 and 2019. A total of 22 patients (44%) who received transplants from viremic donors developed viremia at a mean period of 7.2 ± 0.2 days. At that time, glecaprevir/pibrentasvir was initiated. In the viremia period (<56 days), 14 of 22 NAT+ recipients (64%) had ACR vs 5 of 28 NAT- group (18%) (p = 0.001). Through 180 days, 17 of 22 NAT+ recipients (77%) had a repeat rejection biopsy vs 12 of 28 NAT- recipients (43%) (p = 0.02). NAT+ biopsies demonstrated disparity of ACR distribution: negative, low-grade, and high-grade ACR in 84%, 12%, and 4%, respectively, vs 96%, 3%, and 1%, respectively, in the NAT- group (p = 0.03). The median time to first event was 26 (interquartile range [IQR]: 8-45) in the NAT+ group vs 65 (IQR: 44-84) days in the NAT-. Time to first event risk model revealed that NAT+ recipients had a significantly higher rate of ACR occurrences, adjusting for demographics (p = 0.004).\n\n\n\nTransient levels of viremia contributed to higher rates and severity of ACRs. Further investigation into the mechanisms of early immune activation in NAT+ recipients is required.",
"affiliations": "Division of Cardiology, Department of Medicine. Electronic address: Claudia.Gidea@nyulangone.org.;Departments of Pathology and Laboratory Medicine.;Division of Cardiology, Department of Medicine.;Cardiothoracic Surgery.;Cardiothoracic Surgery.;Division of Cardiology, Department of Medicine.;Pharmacy, NYU Langone Medical Center, New York, New York.;Medical School, New York University School of Medicine, New York, New York.;Division of Cardiology, Department of Medicine.;Division of Cardiology, Department of Medicine.;Departments of Pathology and Laboratory Medicine.;Division of Cardiology, Department of Medicine.;Katz School at Yeshiva University, New York, New York.;Cardiothoracic Surgery.;Cardiothoracic Surgery.",
"authors": "Gidea|Claudia G|CG|;Narula|Navneet|N|;Reyentovich|Alex|A|;Fargnoli|Anthony|A|;Smith|Deane|D|;Pavone|Jennifer|J|;Lewis|Tyler|T|;Karpe|Hannah|H|;Stachel|Maxine|M|;Rao|Shaline|S|;Moreira|Andre|A|;Saraon|Tajinderpal|T|;Raimann|Jochen|J|;Kon|Zachary|Z|;Moazami|Nader|N|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.healun.2020.06.022",
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"issue": "39(11)",
"journal": "The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation",
"keywords": "direct-acting antivirals; heart transplantation; hepatitis C; rejection; viremia",
"medline_ta": "J Heart Lung Transplant",
"mesh_terms": null,
"nlm_unique_id": "9102703",
"other_id": null,
"pages": "1199-1207",
"pmc": null,
"pmid": "32739334",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Increased early acute cellular rejection events in hepatitis C-positive heart transplantation.",
"title_normalized": "increased early acute cellular rejection events in hepatitis c positive heart transplantation"
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"abstract": "Headaches are a common symptom during pregnancy. The thunderclap headache is a sudden onset headache reaching maximal intensity within seconds to minutes. It is typically a subarachnoid hemorrhage caused by rupture of an intracranial aneurysm or arteriovenous malformation. Physiologic changes of pregnancy, such as increased cardiac output and plasma volume, may increase the risk of aneurysmal rupture. The relationship between the mode of delivery and incidence of rupture is not well defined. In this case report, we discuss the anesthetic management for cesarean delivery of a parturient with an unruptured aneurysm, located on the left ophthalmic-internal carotid artery. The delivery options and anesthetic technique used are presented, together with a review of published literature.",
"affiliations": "Texas Tech University Health Sciences Center School of Medicine, 3601 4th Street, Lubbock, TX 79430, USA. Electronic address: niki.parikh@ttuhsc.edu.;Texas Tech University Health Sciences Center School of Medicine, 3601 4th Street, Lubbock, TX 79430, USA.",
"authors": "Parikh|N|N|;Parikh|N|N|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine; D002045:Bupivacaine",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijoa.2018.06.007",
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"issue": "36()",
"journal": "International journal of obstetric anesthesia",
"keywords": "Cerebral aneurysm; Cesarean section; Epidural anesthesia; Pregnancy; Subarachnoid hemorrhage",
"medline_ta": "Int J Obstet Anesth",
"mesh_terms": "D000328:Adult; D000767:Anesthesia, Epidural; D000773:Anesthesia, Obstetrical; D000779:Anesthetics, Local; D002045:Bupivacaine; D002343:Carotid Artery, Internal; D002585:Cesarean Section; D000072226:Computed Tomography Angiography; D005260:Female; D006261:Headache; D006801:Humans; D002532:Intracranial Aneurysm; D008012:Lidocaine; D009880:Ophthalmic Artery; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D055815:Young Adult",
"nlm_unique_id": "9200430",
"other_id": null,
"pages": "118-121",
"pmc": null,
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"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of anesthesia for cesarean delivery in a patient with an unruptured intracranial aneurysm.",
"title_normalized": "management of anesthesia for cesarean delivery in a patient with an unruptured intracranial aneurysm"
} | [
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"abstract": "Unilateral twin tubal pregnancy is an extremely rare condition, occurring in 1/20.000-250.000 pregnancies and represents a major health risk for reproductive-aged women, leading to even life-threatening complications.\n\n\n\nWe present a case of a 31-year-old woman with unilateral twin tubal pregnancy, treated with methotrexate and then surgically because of failure, followed by review of the literature.\n\n\n\nResearches for relevant data were conducted utilizing multiple databases, including PubMed and Ovid.\n\n\n\nThe most common type of twin ectopic pregnancy is the heterotopic (1/7000 pregnancies) in which in which both ectopic and intrauterine pregnancy occur simultaneously. Expectant, medical and surgical therapy have similar success rates in correctly selected patients. Two prospective randomized trials did not identify any statistically significant differences between groups receiving MTX as a single dose or in multiple doses. Among the 106 cases reported in literature, methotrexate was tried just in 4 patients (3 unilateral and 1 bilateral) before ours. Details are reported in the table 1.\n\n\n\nThe recent shift in the treatment of singleton ectopic pregnancies to the less invasive medical therapy might apply even in the case of twin implants.",
"affiliations": "Department of Obstetrics and Gynaecology, ASTT Lecco, Ospedale Alessandro Manzoni, Lecco, Italy. makhy14@libero.it.",
"authors": "Betti|Marta|M|;Vergani|Patrizia|P|;Damiani|Gianluca Raffaello|GR|;Pellegrino|Antonio|A|;Di Naro|Edoardo|E|;Trojano|Giuseppe|G|;Pirovano|Cecilia|C|;Stomati|Massimo|M|;Loverro|Matteo|M|",
"chemical_list": "D000020:Abortifacient Agents, Nonsteroidal; D018997:Chorionic Gonadotropin, beta Subunit, Human; D008727:Methotrexate",
"country": "Italy",
"delete": false,
"doi": "10.23750/abm.v89i3.6915",
"fulltext": "\n==== Front\nActa BiomedActa BiomedActa Bio Medica : Atenei Parmensis0392-42032531-6745Mattioli 1885 Italy 30333471ACTA-89-42310.23750/abm.v89i3.6915Case ReportUnilateral twin tubal pregnancy: a case report and review of the literature Marta Betti 1Patrizia Vergani 2Gianluca Raffaello Damiani 3Antonio Pellegrino 1Edoardo Di Naro 4Giuseppe Trojano 4Cecilia Pirovano 1Massimo Stomati 5Matteo Loverro 31 Department of Obstetrics and Gynaecology, ASTT Lecco, Ospedale Alessandro Manzoni, Lecco, Italy2 Department of Maternal Fetal Medicine, Fondazione MBBM, San Gerardo Hospital, University of Milano Bicocca, Monza, Italy3 Department of Obstetrics and Gynaecology, ASTT Lecco, Ospedale Leopoldo Mandic, Merate, Italy4 Department of Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology, University of Bari, Aldo Moro, Bari, Italy5 Department of Obstetrics and Gynaecology, Department of Obstetrics and Gynaecology, ASL Brindisi, Francavilla Fontana Hospital, Brindisi, ItalyCorrespondence: Gianluca Raffaello Damiani Department of Obstetrics and Gynecology, ASTT Lecco, Lecco, Italy Tel. +390805612443 Fax +390805478928 E-mail: damiani14@alice.it2018 89 3 423 427 30 11 2017 15 1 2018 Copyright: © 2018 ACTA BIO MEDICA SOCIETY OF MEDICINE AND NATURAL SCIENCES OF PARMA2018This work is licensed under a Creative Commons Attribution 4.0 International LicenseBackground:Unilateral twin tubal pregnancy is an extremely rare condition, occurring in 1/20.000-250.000 pregnancies and represents a major health risk for reproductive-aged women, leading to even life-threatening complications. Aim:We present a case of a 31-year-old woman with unilateral twin tubal pregnancy, treated with methotrexate and then surgically because of failure, followed by review of the literature. Methods: Researches for relevant data were conducted utilizing multiple databases, including PubMed and Ovid. Results: The most common type of twin ectopic pregnancy is the heterotopic (1/7000 pregnancies) in which in which both ectopic and intrauterine pregnancy occur simultaneously. Expectant, medical and surgical therapy have similar success rates in correctly selected patients. Two prospective randomized trials did not identify any statistically significant differences between groups receiving MTX as a single dose or in multiple doses. Among the 106 cases reported in literature, methotrexate was tried just in 4 patients (3 unilateral and 1 bilateral) before ours. Details are reported in the table 1. Conclusion: The recent shift in the treatment of singleton ectopic pregnancies to the less invasive medical therapy might apply even in the case of twin implants. (www.actabiomedica.it)\n\nunilateraltwin tubal pregnancyrare condition\n==== Body\nCase presentation\nOur 31-year-old patient (gravida 2, para 0) had a history of endometriosis and right tubal pregnancy treated with laparoscopic salpingectomy 7 months earlier at our institution.\n\nOn a routine ultrasound, at an estimated gestational age of 6 weeks and 2 days given her last menstrual period, a left ectopic pregnancy was suspected so she was sent to our emergency room. Vitals were all stable and the patient was well, conscious and well-oriented.\n\nOn physical examination her abdomen wasn’t tender and just slight left adnexal tenderness was elicited. Vaginal bleeding was light.\n\nUltrasound revealed an empty uterine cavity and in the left adnexa, adjacent to the ovary, a complex mass measuring 29 × 16 mm encompassing to a further evaluation 2 thick-walled fluid-filled cystic masses measuring 5 and 16 mm (Fig. 1). No fluid in the pouch of Douglas was identified. Serum βhCG level was 13217 mIU/ml. The patient was then diagnosed with unilateral twin tubal pregnancy. As she was stable without any sign of tubal rupture and considering as well the previous right salpingectomy, we administered a single dose of methotrexate (50 mg/m2, corresponding to 75 mg) + folinic acid rescue (5 mg once a day by mouth). 4 days later βhCG level was 23276 mIU/ml (+76%) and 7 days later 19783 mIU/ml (-15%). Ultrasound monitoring revealed no change. Patient was asymptomatic. A second dose of MTX (still 50 mg/mq) + folinic acid rescue was then administered.\n\nFigure 1. 7 days after the second MTX dose βhCG level was 16000 mIU/ml (-19%), ultrasound was unchanged and the patient asymptomatic. A third dose of MTX (still 50 mg/mq) + folinic acid rescue was administered.\n\n4 days after the last dose, the patient came to our emergency room complaining pelvic and abdominal mass. βhCG level was 3659 mIU/ml (-77%), ultrasound revealed increasing mass dimensions as 41 × 27 mm and estimated 100 ml of blood in the pouch of Douglas.\n\nLaparoscopic left salpingectomy was performed, total blood loss was 2500 ml and the patient underwent intraoperatively a blood transfusion. The pathology specimen confirmed the twin tubal pregnancy. The post-operative course was regular. The patient was well on 6-months follow up.\n\nReview and comparison\nMethodology\nResearches for relevant data were conducted utilizing multiple databases, including PubMed and Ovid. Searches included combinations of the key terms: ‘twin and ectopic pregnancy’, ‘twin and tubal pregnancy’, ‘twin heterotopic pregnancy’, ‘laparoscopy and twin pregnancy’, ‘laparoscopy and twin ectopic’, ‘laparoscopy and twin tubal pregnancy’, ‘surgery and twin pregnancy’, ‘surgery and twin ectopic’, ‘surgery and twin tubal pregnancy’, ‘methotrexate and twin pregnancy’, ‘methotrexate and twin ectopic’, ‘methotrexate and twin tubal pregnancy’.\n\nEctopic pregnancy occurs when blastocyst implants outside the uterine cavity, being this true for both singleton and multiple pregnancies.\n\nThe first un-ruptured twin tubal pregnancy was described in 1986 by Santos (1). Ectopic pregnancy develops in almost 2% while twin pregnancy counts for 1 every 80 spontaneous pregnancies (2). Unilateral twin ectopic pregnancy is though a rare condition occurring with a frequency of 1/20.000-125.000 pregnancy and 1/200 ectopic pregnancy, rarer than expected (3-5). Moreover, ectopic pregnancy has a recurrence rate of 10% for one and 25% for two or more previous (6).\n\nAlthough the trend for ectopic pregnancy has been constantly increasing over the past 30 years (mainly because of Assisted Reproductive Technology and epidemiological reasons), unilateral twin ectopic pregnancies have remained anneddoctical, just approximately 106 cases described in literature, out of whose only 8 cases had live twin 1 a year.\n\nIn addition the incidence is likely to be underreported because the diagnosis is primarily surgical (<10 out of 106 were diagnosed preoperatively) and/or pathological (consider the well-known phenomenon of the vanishing twin and the deterioration of the material after medical therapy) (7).\n\n30 years ago the mortality due to ectopic pregnancy ranged between 72 to 90% while recently, mainly thanks to early diagnosis, it dramatically dropped to 0.14% (2).\n\nRisk factors are basically all conditions that might impaire the migration of the blastocyst/embryo to the endometrial cavity by distorting tubal anatomy i.e. prior pelvic inflammatory disease, previous ectopic pregnancy, tubal surgery or ligation, assisted reproductive technology and also congenital anomalies.\n\nOther factors are, although less counting, increasing age, smoking, intrauterine contraceptive device and defects of the zygote itself or in the hormonal milieu (8). The most common type of twin ectopic pregnancy is the heterotopic (1/7000 pregnancies) in which in which both ectopic and intrauterine pregnancy occur simultaneously (1).\n\nBased on case reports from the literature, monozygotic and monoamniotic are the most frequent (95%) among unilateral twin tubal pregnancies, nonetheless a DNA analysis theorized that many of these might be dizygotic (3). The delay in tubal transport may play a role in the extensiveness of unilateral twin ectopic implantation; conversely it has been also supposed that the larger size of the twin cell mass itself causes the transport retard (9). Some authors explain the twin ectopic pregnancy as a mere result of a bilateral ovulation. Just like in singleton ectopic pregnancy, fallopian tube is the most common site.\n\nCompared to a same sized singleton pregnancy, the chance of rupture for a twin ectopic one are lower as trophoblastic invasion may be less due to lower gestational age at presentation in the latter case. Being somehow similar and somehow different, the management of twin ectopic pregnancy can’t just mirror the singleton one. The symptoms of the classic triad of amenorrhea, vaginal bleeding and pelvic pain are all presents in less than half patients.\n\nRisk factors can prop up the diagnosis, especially a previous ectopic implant.\n\nSerum βhCG can be much higher than the well-know discriminatory zone of 1500-2000 mIU/ml valid for singleton ectopic pregnancy (with a mean of 9846), due to the larger trophoblastic tissue (10). Interestingly, the value can thus resemble to the ones of normal intrauterine pregnancies: in the absence of an intrauterine gestational sac and normally rising βhCG the chance of a twin ectopic implant has to be considered, even if rare. The majority of tubal ectopic pregnancies are detected by transvaginal ultrasound with a sensitivity of 87.0-99.0% and a specificy of 94.0-99.9%.\n\nIn some cases the evaluation, even combining all the informations, is not discerning: the pregnancy is then classified of unknown location (PUL). The echographic signs might be, as well as in singleton ectopic implants, divided into direct and indirect. The only direct sign is the identification of a non homogeneous or solid-cystic adnexal mass encompassing two thick-walled fluid-filled cystic masses, formed by the gestational sacs (yolk sac and/or embryo are less often visualized than in singleton).\n\nIndirect signs are the same as singleton: no evidence of intrauterine sac, fluid in the pouch of Douglas; sometimes fluid collects in the uterine cavity appearing as so-called ‘pseudosac’.\n\nManagement\nThe primary goals are fertility preservation (being the main predictive factor the status of the controlateral tube at surgery) and avoidance of unfavorable outcome as tubal rupture (9).\n\nAs reported by Mol, “laparoscopic surgical approach in the most cost-effective method for treating ectopic pregnancy, but in carefully selected cases, the use of systemic MTX is proved to be a great alternative with similar success rates, and it is completely non-invasive (11). Moreover, some studies agreed that medical treatment doesn’t impair tubal patency nor the ovarian reserve (it might spoil oocyte production but temporarily) (12-13).\n\nLastly, as reported by Menon, “rates of treatment failure are substantially and statistically greater if the initial values of βhCG exceed 5000 mIU/ml”, simultaneously the higher the level, the higher the risk for tubal obstruction (11).\n\nSummarizing, expectant, medical and surgical therapy have similar success rates in correctly selected patients (14).\n\nTwo prospective randomized trials did not identify any statistically significant differences between groups receiving MTX as a single dose or in multiple doses (15,16).\n\nAmong the 106 cases reported in literature, methotrexate was tried just in 4 patients (3 unilateral and 1 bilateral) before ours. Details are reported in the table 1 (6, 17, 18).\n\nTable 1. Previous reported cases in literature\n\nPatient, Year\tGestation Days\tDay 0 Bhcg\tU/B\tCrl Diameter-mm\tMTX -TR\tDOF\tSimptoms\tBlood-loss\tBhcg (before surgery)\tResult\t\n1, 1993\t77\t3640\tU\t25 × 30; Crl 11 and 13\t31.5 mg of MTX Into Each Gestational Sac; 2 Days Later a Systemic Dose Of 63 Mg (IM)\t31\t-\t\t\tS\t\n2, 1997\tUnsure\t539\tB\tDiameter 25\tSingle Dose 50 Mg/M2)\t4\tAcute Abdomen\t100\t\tU\t\n3, 2008\tNon Reported\t763\tU\tNot Reported\tMultiple Dose Regimen (1 Mg/Kg on Days 1,3,4 and 7 + 0.1 Mg/Kh of Folinic Acid on Days 2,4,6 and 8) + a Single Dose on Day 14 Th (1 Mg/Kg)\t32\t-\t\t\tS\t\n4, 2009\t49\t18780\tU\tCRL 11 Ans 8 Mm\tSingle Dose (1 Mg/Kg)\t42\t-\t\t\tS\t\nOurs, 2016\t44\t13217\tU\t5 and 16\tMultiple Dose (50 Mg/Mg) on Day 1, 7 and 14 + Folic Rescue (5 Mg/Die Per Os)\t18\tAcute Abdomen\t2500\t3659\tU\t\nCRL: Crown-rump length; DOF: Duration of follow-up; U/B: Unilateral/Bilateral; U/S: Success/unsuccess; MTX-TR: Methotrexate Treatment Regimen\n\nConclusions\nWhen making a diagnosis of ectopic pregnancy, even though rare, the chance of twin implant has to be considered. The recent shift in the treatment of singleton ectopic pregnancies to the less invasive medical therapy might apply even in the case of twin implants.\n==== Refs\nReferences\n1 Santos CA Sicuranza BS Chatterjee MS Twin tubal gestation diagnosed before rupture Perinatol Neonatol 1986 10 52 3 \n2 Dede M Gezginç K Yenen M Ulubay M Kozan S Güran S Başer I Unilateral tubal ectopic twin pregnancy Taiwan J Obstet Gynecol 2008 47 2 226 8 18603515 \n3 Goswami D Agrawal N Arora V Twin tubal pregnancy: A large unruptured ectopic pregnancy J Obstet Gynaecol Res 2015 41 11 1820 2 26178425 \n4 Tam T Khazaei A Spontaneous unilateral dizygotic twin tubal pregnancy J Clin Ultrasound 2009 Feb Feb 37 2 104 \n5 Vohra S Mahsood S Shelton H Zaedi K Economides DL Spontaneous live unilateral twin ectopic pregnancy - A case presentation Ultrasound 2014 22 4 243 6 27433227 \n6 Ghanbarzadeh N Nadjafi-Semnani M Nadjafi-Semnani A Nadjfai-Semnani F Shahabinejad S Unilateral twin tubal ectopic pregnancy in a patient following tubal surgery J Res Med Sci 2015 20 2 196 8 25983775 \n7 Yamane D Stella M Goralnick E Twin ectopic pregnancy J Emerg Med 2015 Jun 48 6 e139 40 25843929 \n8 Parker J Hewson AD Calder-Mason T Lai J Transvaginal ultrasound diagnosis of a live twin tubal ectopic pregnancy Australas Radiol 1999 43 1 95 7 10901879 \n9 Hois EL Hibbeln JF Sclamberg JS Spontaneous twin tubal ectopic gestation J Clin Ultrasound 2006 34 7 352 5 16869014 \n10 Eddib A Olawaiye A Withiam-Leitch M Rodgers B Yeh J Live twin tubal ectopic pregnancy Int J Gynaecol Obstet 2006 93 2 154 5 Epub 2006 Mar 6 16564050 \n11 Cecchino GN Araujo Júnior E Elito Júnior J Methotrexate for ectopic pregnancy: when and how Arch Gynecol Obstet 2014 290 3 417 23 24791968 \n12 Elito J Han KK Camano L Tubal patency after clinical treatment of unruptured ectopic pregnancy Int J Gynaecol Obstet 205 88 309 313 15733887 \n13 Oriol B Barrio A Pacheco A Serna J Zuzuarregui JL Garcia-Velasco JA Systemic methotrexate to treat ectopic pregnancy does not affect ovarian reserve Fertil Steril 2008 90 1579 1582 18054933 \n14 Juneau C Bates GW Reproductive outcomes after medical and surgical management of ectopic pregnancy Clin Obstet Gynecol 2012 55 2 455 60 22510628 \n15 Alleyassin A Khademi A Aghahosseini M Safdarian L Badenoosh B Hamed EA Comparison of success rates in the medical management of ectopic pregnancy with single-dose and multiple-dose administration of methotrexate: a prospective, randomized clinical trial Fertil Steril 2006 85 1661 1666 16650421 \n16 Guvendag Guven ES Dilbaz S Dilbaz B Aykan Yildirim B Akdag D Haberal A Comparison of single and multiple dose methotrexate therapy for unruptured tubal ectopic pregnancy: a prospective randomized study Acta Obstet Gynecol Scand 2010 89 889 895 20583934 \n17 Hajenius PJ Engelsbel S Mol BW Van der Veen F Ankum WM Bossuyt PM Hemrika DJ Lammes FB Randomised trial of systemic methotrexate versus laparoscopic salpingostomy in tubalpregnancy Lancet 1997 350 9080 774 9 9297998 \n18 Arikan DC Kiran G Coskun A Kostu B Unilateral tubal twin ectopic pregnancy treated with single-dose methotrexate Arch Gynecol Obstet 2011 283 2 397 9 20376673\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0392-4203",
"issue": "89(3)",
"journal": "Acta bio-medica : Atenei Parmensis",
"keywords": null,
"medline_ta": "Acta Biomed",
"mesh_terms": "D000020:Abortifacient Agents, Nonsteroidal; D000328:Adult; D001803:Blood Transfusion; D018997:Chorionic Gonadotropin, beta Subunit, Human; D003131:Combined Modality Therapy; D004715:Endometriosis; D005260:Female; D059247:Fertility Preservation; D006801:Humans; D008727:Methotrexate; D011247:Pregnancy; D011248:Pregnancy Complications; D011274:Pregnancy, Tubal; D059285:Pregnancy, Twin; D012422:Rupture, Spontaneous; D058994:Salpingectomy",
"nlm_unique_id": "101295064",
"other_id": null,
"pages": "423-427",
"pmc": null,
"pmid": "30333471",
"pubdate": "2018-10-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "15733887;27433227;16869014;16564050;18054933;18465811;24791968;10901879;25843929;22510628;20376673;25983775;26178425;9297998;16650421;18603515;20583934",
"title": "Unilateral twin tubal pregnancy: a case report and review of the literature.",
"title_normalized": "unilateral twin tubal pregnancy a case report and review of the literature"
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"companynumb": "IT-MYLANLABS-2018M1088051",
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"abstract": "Nicolau syndrome is a rare complication of intramuscular injection consisting of ischemic necrosis of skin, soft tissue, and muscular tissue that arises locoregionally. The characteristic pattern is pain around the injection site, developing into erythema, a livedoid dermatitis patch, and necrosis of the skin, subcutaneous fat, and muscle tissue. Three patients were injected with drugs (diclofenac sodium, ketoprofen, meperidine) for pain relief. Three patients complained of pain, and a skin lesion was observed, after which necrosis developed on their buttocks. Each patient underwent debridement and coverage. The wound healed uneventfully. We report three cases of Nicolau syndrome in the buttocks following diclofenac intramuscular injection.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Dong-A University College of Medicine, Busan, Korea.",
"authors": "Kim|Seok-Kwun|SK|;Kim|Tae-Heon|TH|;Lee|Keun-Cheol|KC|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5999/aps.2012.39.3.249",
"fulltext": "\n==== Front\nArch Plast SurgArch Plast SurgAPSArchives of Plastic Surgery2234-61632234-6171The Korean Society of Plastic and Reconstructive Surgeons 10.5999/aps.2012.39.3.249Case ReportNicolau Syndrome after Intramuscular Injection: 3 Cases Kim Seok-Kwun Kim Tae-Heon Lee Keun-Cheol Department of Plastic and Reconstructive Surgery, Dong-A University College of Medicine, Busan, Korea.\nCorrespondence: Seok-Kwun Kim. Department of Plastic and Reconstructive Surgery, Dong-A University College of Medicine, 1 Daesingongwon-ro, Seo-gu, Busan 602-715, Korea. Tel: +82-51-240-2807, Fax: +82-51-243-5416, sgkim1@dau.ac.kr5 2012 10 5 2012 39 3 249 252 10 2 2012 08 4 2012 17 4 2012 Copyright © 2012 The Korean Society of Plastic and Reconstructive Surgeons2012This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Nicolau syndrome is a rare complication of intramuscular injection consisting of ischemic necrosis of skin, soft tissue, and muscular tissue that arises locoregionally. The characteristic pattern is pain around the injection site, developing into erythema, a livedoid dermatitis patch, and necrosis of the skin, subcutaneous fat, and muscle tissue. Three patients were injected with drugs (diclofenac sodium, ketoprofen, meperidine) for pain relief. Three patients complained of pain, and a skin lesion was observed, after which necrosis developed on their buttocks. Each patient underwent debridement and coverage. The wound healed uneventfully. We report three cases of Nicolau syndrome in the buttocks following diclofenac intramuscular injection.\n\nNecrosisNicolau syndromeInjectionsIntramuscular\n==== Body\nINTRODUCTION\nNicolau syndrome is a rare complication of intramuscular injection leading to ischemic necrosis of the skin, soft tissue, and muscular tissue that arises locoregionally. Since Nicolau reported the first case of the symptoms as having occurred after intramuscular injection of Bismuth salt for the treatment of syphilis in the early 1920s, cases of Nicolau syndrome have been reported after intramuscular injection of non-steroidal anti-inflammatory drugs, steroids, and other drugs.\n\nThe pathogenesis of necrosis is not known completely; it is presumed that ischemic necrosis is induced by direct vascular injury, perivascular inflammation, and vascular constriction. Typical findings are pain at the injection site developing into erythema or hemorrhagic lesion immediately after the injection, with eventual progression to necrosis of the skin or soft tissue, and of the muscle. Among the drugs associated with this syndrome, nonsteroidal anti-inflammatory drugs in particular have rare, severe complications of intramuscular injection leading to necrosis of the skin, subcutaneous tissue, and muscle tissue. The authors report three cases of Nicolau syndrome after diclofenac intramuscular injection.\n\nCASES\nCase 1\nA 73-year-old man received an intramuscular injection of diclofenac sodium at the orthopedic clinic for lumbar pain control three times a week for 1 month. The patient complained of pain in the upper right buttock after the injection. Three days later, the patient developed pain and redness at the injection site. After one week, a skin lesion was observed and necrosis developed.\n\nAt admission, a necrotic ulceration measuring 6×9 cm was found involving the gluteus maximus fascia of the right upper buttock. A pocket 6 cm deep was formed and a severe Pseudomonas aeruginosa infection was identified (Fig. 1). Ticarcillin sodium treatment was started. With four applications of negative pressure dressing therapy, the infection and inflammation were controlled well and granulation began to fill the pocket from the inside (Fig. 2). Two months later, the ulcerative lesion was filled with healthy granulation (Fig. 3) and a split-thickness skin graft was performed. The stitches were completely removed after twelve days. The wound healed well and uneventfully (Fig. 4).\n\nCase 2\nA 79-year-old female patient was injected with ketoprofen for knee pain relief. After the injection, she experienced severe pain and hardness at the injection site. The wound developed necrotic changes and grew to be 7×5 cm in the subcutaneous layer of her right buttock (Fig. 5). With the concurrent use of antibiotics, the authors performed debridement and direct closure. The wound healed well and the patient was discharged.\n\nCase 3\nA 36-year-old man was injected with Demerol (meperidine) every 3 hours during 4 days for operation site pain. After the injections, the patient complained of pain and an erythematous lesion was seen. Two days later, necrotic changes and a purpuric lesion developed. The necrotic wound size was 6×4 cm and the lesion was approximately 13 cm in length (Fig. 6). Histologic findings were superficial and deep perivascular dermatitis with vaculolar change in the epidermis and vasculitis were identified. The authors performed an excision and covered it with a bilateral advancement flap. The wound healed uneventfully.\n\nDISCUSSION\nNicolau syndrome is a rare complication of intramuscular injection leading to ischemic necrosis of the skin, soft tissue, and muscular tissue that arises locoregionally. Several drugs have been reported to cause necrosis, such as local anesthesia [1], antihistamine (promethazine) [1], vitamin B complexes [1], diclofenac sodium [2-4], ketoprofen [2], piroxicam [4], corticosteroids [5], diphtheria, tetanus, pertussis vaccine [6], and meperidine [1].\n\nThe pathogenesis of the disease is not known, but there have been several hypotheses. First, it is presumed that the sympathetic nerve is stimulated by pain from the intra-arterial or periarterial injection of drugs, causing vasospasms and leading to ischemia. Second, this is related to the pharmacologic properties of NSAIDS. NSIADS inhibit prostaglandin synthesis by inhibition of cyclooxygenase. Ischemic necrosis occurs after vasospasm are induced by the suppression of prostaglandin by the drug. Third, the intra-arterially injected drug causes embolic occlusion. Nicolau histologically discovered bismuth in peripheral arteries. Fourth, ischemic necrosis progresses from vascular rupture due to perivascular inflammation from a cytotoxic reaction to the drugs. Fifth, lipophilic drugs penetrate the blood vessels in a manner similar to that of fat embolism and induce physical occlusion [1].\n\nTypical findings are pain at the injection site, erythema, or a hemorrhagic lesion immediately after the injection, with eventual progression to necrosis of the skin or soft tissue and of the muscle.\n\nIn most cases, the prognosis of Nicolau syndrome is healing with remaining atrophic scars or pigmentation. In rare cases, however, it can cause complications such as hypoesthesia, paraplegia, sphincter deficiency or sepsis.\n\nWhile various treatments have been attempted for Nicolau syndrome up to the present, none has become standard. In most cases, conservative treatment such as pain control, antibiotics, and dressing may help, depending on the symptoms, and surgical methods, including debridement and skin graft, are required for necrotic areas not showing significant improvement [3]. Besides these methods, improvement has been observed with anticoagulants and vasodilators.\n\nAlthough the onset of Nicolau syndrome cannot be predicted, to reduce the risk of tissue damage as much as possible, injection is administered to the superolateral region of the gluteal muscle, for which an injection needle is used that is long enough to reach the muscle. It is recommended that the injection be administered using the Z-track method (Fig. 7) [7], and that intramuscular injections not be repeated in the same region. Moreover, if there is an attempt to inhale the syringe and if pain occurs during the injection, immediate discontinuation of the injection is recommended [1].\n\nThis study was presented at the 67th Congress of the Korean Society of Plastic and Reconstructive Surgeons on Nov 19-21, 2009 in Seoul, Korea.\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 Preoperative view\n\nNecrotic ulceration measuring 6×9 cm was found and a pocket formation 6 cm deep was observed.\n\nFig. 2 After the fourth negative pressure dressing therapy\n\nGranulation begin to fill the pocket from the inside.\n\nFig. 3 After the fourteenth negative pressure dressing therapy\n\nWith antibiotics and negative pressure dressing therapy, infection and inflammation was controlled well and the ulcerative lesion was filled with healthy granulation.\n\nFig. 4 Postoperative view (4 months later)\n\nThe wound healed well and uneventfully.\n\nFig. 5 A 79-year-old female patient\n\nNecrosis was seen on the right buttock. The wound size was approximately 7×5 cm.\n\nFig. 6 A 36-year-old male patient\n\nPurpuric necrotic change was observed on left buttock.\n\nFig. 7 Z-track method\n\n(A) Normal skin, subcutaneous tissue, and muscle. (B) The skin and subcutaneous layer was pulled to de-align it with the underlying muscle. (C) The needle was inserted at 90°, injected and withdrawn. (D) The needle was removed, and the skin release.\n==== Refs\n1 Faucher L Marcoux D What syndrome is this? Nicolau syndrome Pediatr Dermatol 1995 12 187 190 7659650 \n2 McGee AM Davison PM Skin necrosis following injection of non-steroidal anti-inflammatory drug Br J Anaesth 2002 88 139 140 11881870 \n3 Corazza M Capozzi O Virgilit A Five cases of livedo-like dermatitis (Nicolau's syndrome) due to bismuth salts and various other non-steroidal anti-inflammatory drugs J Eur Acad Dermatol Venereol 2001 15 585 588 11843224 \n4 Lee DP Bae GY Lee MW Nicolau syndrome caused by piroxicam Int J Dermatol 2005 44 1069 1070 16409285 \n5 Cherasse A Kahn MF Mistrih R Nicolau's syndrome after local glucocorticoid injection Joint Bone Spine 2003 70 390 392 14563471 \n6 Nagore E Torrelo A Gonzalez-Mediero I Livedoid skin necrosis (Nicolau syndrome) due to triple vaccine (DTP) injection Br J Dermatol 1997 137 1030 1031 9470941 \n7 Taylor C Lillis C LeMone P Fundamentals of nursing: The art and science fo nursing care 2006 6th ed Philadelphia Lippincott Williams & Wilkins\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2234-6163",
"issue": "39(3)",
"journal": "Archives of plastic surgery",
"keywords": "Injections; Intramuscular; Necrosis; Nicolau syndrome",
"medline_ta": "Arch Plast Surg",
"mesh_terms": null,
"nlm_unique_id": "101577999",
"other_id": null,
"pages": "249-52",
"pmc": null,
"pmid": "22783535",
"pubdate": "2012-05",
"publication_types": "D016428:Journal Article",
"references": "7659650;14563471;11843224;16409285;9470941;11881870",
"title": "Nicolau syndrome after intramuscular injection: 3 cases.",
"title_normalized": "nicolau syndrome after intramuscular injection 3 cases"
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"activesubstancename": "DICLOFENAC"
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"abstract": "We present the case of a 3-month-old boy with pulmonary arterial hypertension after corrective repair of total anomalous pulmonary venous connection. The patient developed severe pulmonary arterial hypertension with a high mean pulmonary arterial pressure of 45 mmHg. We performed continuous monitoring of pulmonary arterial pressure using a tip deflecting microcatheter in the intensive care unit. We successfully managed this patient based on real-time pulmonary arterial pressure measurements. Continuous real-time monitoring of pulmonary arterial pressure using this microcatheter enables individualized targeted therapy for infants with pulmonary arterial hypertension.",
"affiliations": "Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Japan.;Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Japan.;Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization, Japan.",
"authors": "Tanaka|Atsushi|A|;Sugitani|Yuichiro|Y|;Muneuchi|Jun|J|https://orcid.org/0000-0003-0500-2585",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1017/S1047951120001286",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1047-9511",
"issue": "30(7)",
"journal": "Cardiology in the young",
"keywords": "Intensive care; congenital heart disease; pulmonary venous obstruction; steerable microcatheter; total anomalous pulmonary venous return",
"medline_ta": "Cardiol Young",
"mesh_terms": "D062186:Arterial Pressure; D006801:Humans; D006976:Hypertension, Pulmonary; D007223:Infant; D008297:Male; D000081029:Pulmonary Arterial Hypertension; D011667:Pulmonary Veins; D012587:Scimitar Syndrome",
"nlm_unique_id": "9200019",
"other_id": null,
"pages": "1032-1034",
"pmc": null,
"pmid": "32484128",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Continuous real-time monitoring of pulmonary arterial pressure using a tip deflecting microcatheter in an infant with pulmonary arterial hypertension.",
"title_normalized": "continuous real time monitoring of pulmonary arterial pressure using a tip deflecting microcatheter in an infant with pulmonary arterial hypertension"
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"companynumb": "JP-JNJFOC-A-CH2020-202423",
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"activesubstancename": "NITRIC OXIDE"
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{
"abstract": "BACKGROUND\nHyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma.\nA 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise.\n\n\nMETHODS\nHe was later diagnosed with hyperammonemia encephalopathy.\n\n\nMETHODS\nHis treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week.\n\n\nRESULTS\nWith this change in dialysis regimen, patient was able to continue treatment with sunitinib.\n\n\nCONCLUSIONS\nClinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.",
"affiliations": "Division of Nephrology.;Division of Advanced Internal Medicine.;Department of Medical Oncology.;Division of Gastroenterology and Hepatology, National University Hospital Singapore, Republic of Singapore.;Division of Nephrology.;Division of Nephrology.",
"authors": "Haroon|Sabrina|S|0000-0002-7843-0065;Ko|Stephanie|S|;Wong|Alvin|A|;Tan|Poh-Seng|PS|;Lee|Evan|E|;Lau|Titus|T|",
"chemical_list": "D000970:Antineoplastic Agents; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000024313",
"fulltext": "\n==== Front\nMedicine (Baltimore)\nMedicine (Baltimore)\nMEDI\nMedicine\n0025-7974 1536-5964 Lippincott Williams & Wilkins Hagerstown, MD \n\nMD-D-20-10127\n10.1097/MD.0000000000024313\n24313\n5200\nResearch Article\nClinical Case Report\nSunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis\nA case reportHaroon Sabrina MD, MRCP (UK), FAMSa∗ Ko Stephanie MBBS, MRCP, MPHb Wong Alvin MBBS MRCPc Tan Poh-Seng MBBS, M Med, FRCP, FAMSd Lee Evan MBBS, FRCP, FAMSa Lau Titus MD, FRCP, FAMSa Saranathan. Maya a Division of Nephrology\nb Division of Advanced Internal Medicine\nc Department of Medical Oncology\nd Division of Gastroenterology and Hepatology, National University Hospital Singapore, Republic of Singapore.\n∗ Correspondence: Sabrina Haroon, Division of Nephrology, National University Hospital Singapore, Level 10, NUHS Tower Block, 1E Kent Ridge Road, Singapore 119228, Republic of Singapore (e-mail: sabrina_haroon@nuhs.edu.sg).\n05 2 2021 \n05 2 2021 \n100 5 e2431315 10 2020 15 12 2020 24 12 2020 Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.2021This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nHyperammonemia encephalopathy is a rare but severe complication that has been reported in association with the use of sunitinib, a tyrosine kinase inhibitor. We report here a unique case of a patient with end stage renal disease that was initiated on sunitinib for metastatic renal cell carcinoma.\n\nPatient concerns:\nA 65-year-old man with end stage renal disease on maintenance conventional hemodialysis and had concomitant stable Child-Pugh class B liver cirrhosis consequent of hepatitis C infection was started on sunitinib for metastatic renal cell carcinoma. He developed confusion few weeks after starting therapy with no other indication of worsening liver dysfunction otherwise.\n\nDiagnosis:\nHe was later diagnosed with hyperammonemia encephalopathy.\n\nInterventions:\nHis treatment was discontinued and reinitiated at a lower dose after recovery and titrated according to tolerance. As ammonia is a very low molecular weight molecule and is cleared well with diffusive clearance, we intensified his dialysis regimen by increasing intensity for each session and frequency per week.\n\nOutcomes:\nWith this change in dialysis regimen, patient was able to continue treatment with sunitinib.\n\nLessons:\nClinicians prescribing sunitinib should be vigilant to monitor for this complication in patients receiving sunitinib, apart from the more usual presentation of hepatotoxicity. We found that a more intensive hemodialysis regimen consisting of 4× a week conventional high-flux hemodialysis (HD) can permit the continuation of treatment with sunitinib in an end stage renal disease (ESRD) patient with Child-Pugh class B liver cirrhosis.\n\nKeywords\nhemodialysishyperammoniemia encephalopathyrenal cell carcinomaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nThe incidence of renal cell carcinoma (RCC) in end stage renal disease (ESRD) population is many-fold higher than that of the general population, especially those with acquired cystic kidney disease associated with ESRD.[1] A proportion of these are diagnosed with advanced stage metastatic RCC at the onset. Approximately 80% of RCC is of the clear cell type and with better molecular understanding of the disease biology; various targeted therapies are available today for different disease stages that require systemic therapy beyond surgical excision. Metastatic RCC is difficult to treat and treatment options are usually toxic with poor response rate. The advent of tyrosine kinase inhibitor (TKI) as effective therapy for metastatic RCC resulted from discovery that disruption of the vascular endothelial growth factor (VEGF) signaling pathway can retard tumor growth and progress.[2] Sunitinib has inhibitory effect on many receptor kinases such as VEGF receptors and platelet derived growth factor (PDGF) receptors. It is one of the current recommended evidence-based systemic therapies for metastatic RCC.[3]\n\nSunitinib is approved for use in ESRD patients on hemodialysis (HD) with no initial dose adjustment needed.[4] Sunitinib and its metabolite is also highly protein bound (>90%) and hence, very little is removed during treatment with conventional (high-flux) HD. According to the prescribing information (provided by Food and Drug Administration), the pharmacokinetic of sunitinib is not different in stable patients with Child-Pugh class A and B liver cirrhosis.[4]\n\nThis purpose of this report to highlight the occurrence of a rare complication arising from the use of sunitinib and how it was managed given the unique situation that the patient was already established on maintenance HD.\n\nThe National Healthcare Group Institutional Review Board determined that case report does not meet definition of human-subject research and approval was not required. Written informed consent for patient information to be published was provided by patient.\n\n2 Case report\nA 65-year-old man who was on maintenance HD for 27 years presented with gross hematuria for which subsequent imaging was highly suggestive of renal malignancy. He underwent left radical nephrectomy as it was a local disease and pathology confirmed RCC. Two years after the nephrectomy, he was unfortunately diagnosed with metastatic RCC. His past history was significant for Child-Pugh class B hepatitis C (HCV) related liver cirrhosis (albumin 28–35 g/L, Bilirubin <34 μmol/L, INR <1.7, presence of small amount of ascites, one past episode of grade 2 encephalopathy). The only episode of hepatic encephalopathy occurred 15 months before the diagnosis of metastatic RCC and was managed successfully with lactulose; he was subsequently started on rifaximin and had remained well since with no recurrence of encephalopathy. After deliberation of the various approaches for treatment, his oncologist considered TKI to be the best treatment option and started him on sunitinib 25 mg daily.\n\nOur patient was brought to the emergency department (ED) with confusion and bilateral asterixis 44 days after initiation of sunitinib (patient was maintained on 25 mg daily throughout this period). After appropriate investigations including computed tomography (CT) of the brain had ruled out other causes, he was managed as for metabolic encephalopathy (grade 2). His serum ammonia level was 170.5 μg/dL at presentation. His symptoms resolved 4 days later (with discontinuation of sunitinib). His serum ammonia was reduced to 48.7 μg/dL. He received the same dialysis schedule during his hospitalization and was discharged to continue with his usual HD regimen (3×/wk and 3.5 h/session).\n\nHe was later seen by his oncologist and was started at a lower dose of 12.5 mg sunitinib daily 2 weeks after his discharge, increasing to 25 mg daily 4 weeks after being stable on the lower dose with no complaints. He presented to ED again with similar presentation of confusion and asterixis 28 days later after the increase in dose. His serum ammonia level was significantly elevated again at 176.1 μg/dL pre-dialysis, declining to 68.2 μg/dL post-dialysis. He was dialyzed with a larger surface area high-flux filter (polysulfone 1.6 m2) using blood flow rate of 280 mL/min and dialysate flow rate of 500 mL/min for 4 hours. His body weight was 54.5 kg. His confusion improved significantly post dialysis and he recovered the following day. He was maintained on sunitinib 25 mg daily and discharged well with a schedule for more intensive dialysis (higher frequency 4×/wk and with better clearance achieved by increased blood flow, longer duration, and larger filter). He was successfully kept out of hospital with no recurrence of encephalopathy with that dialysis schedule. There were no adverse events and episodes of confusion.\n\nExcept for the elevation in serum ammonia level, there were no changes in coagulation profile, bilirubin, or liver enzymes during each of these 2 admissions for encephalopathy. There were also no other precipitating factors for hepatic encephalopathy that was evident in these admissions. He did not experience constipation and was compliant with lactulose and rifaximin. CT brain done during his admission did not reveal structural brain pathology. He does not consume alcohol and did not take traditional Chinese medicine. He was not given any medication that can inhibit CYP3A4. He was also not taking any therapeutic agent that has reported association with hyperammonemia. Patient was jointly managed by a multi-disciplinary team (Liver, Medical Oncology and Nephrology). All management decisions were discussed and made jointly by consensus.\n\n3 Discussion\nIt has been reported that elevations in serum aminotransferase level were common as observed from clinical trials with sunitinib (39% vs 23% in the control arm). Grade 3–4 elevation (>5× the upper limit of normal) occurred in about 2% to 3% of the trial subjects; most reversed with temporary discontinuation and were able to reinitiate at lower doses.[5] Hyperammonemia encephalopathy (HE) is a somewhat distinct entity. Ammonia is a by-product of nitrogen metabolism in human biology. Ammonia is highly toxic to the nervous system and hence, must be prevented via various physiological mechanisms from reaching a level that causes toxicity. The liver is one critical organ for ammonia catabolism by converting it to urea via the urea cycle although other organs such as the muscle and kidneys also have an important role in ammonia homeostasis. Serum ammonia level is profoundly altered in liver failure resulting in hyperammonemia due to the deficient ammonia clearance by the diseased liver and to the development of portal collateral circulation that diverts portal blood with high ammonia content to the systemic blood stream.[6] Ammonia has the ability to cross the blood brain barrier. Hyperammonemia state causes central nervous system (CNS) toxicity by inducing astrocyte swelling resulting from accumulation of intracellular glutamine as a consequent of ammonia detoxification within the astrocytes.[7]\n\nHE with the use of sunitinib is a unique condition where there is no other demonstrable cause of hyperammonemia; specifically there is no clinical evidence of new onset or worsening liver disease which is one of the major known etiologies of hyperammonemia. There have been 6 other reported cases of HE with the use of sunitinib in the literature to date.[8–12] This is the first reported in a patient with ESRD on maintenance HD. While the patient was known to have chronic liver cirrhosis associated with hepatitis C infection, his disease was in stable course and he has not had any episode of encephalopathy in the 16 months preceding the use of sunitinib. His metastatic disease did not involve the liver. None of the previously published cases had background of liver cirrhosis although some did have primary or metastatic disease involving the liver. Comparison of the cases (Table 1) revealed different doses of sunitinib exposure as well as number of days before patients manifest symptoms of HE. Most of the cases of HE reported with the use of sunitinib has onset of between 10 and 14 days. Our patient presented with HE 44 and 28 days after initiation of treatment with sunitinib. Although this may have been partly influenced by the dose of sunitinib used, we believe that this delayed manifestation was because the HD had protected the patient from high level of serum ammonia. He did present with HE eventually when his regular HD regimen was no longer able to cope with the generation of serum ammonia. The pathobiology behind this is uncertain. It is probably not related to urea cycle disorder as the patient recovered without the use of nitrogen scavenger or replacement of urea cycle intermediates.\n\nTable 1 Summary of characteristics of previously reported cases of hyperammonemia encephalopathy associated with the use of sunitinib.\n\nCase\tTumor\tLiver condition and renal function\tSunitinib dose/mg\tDays between drug initiation and encephalopathy\tAmmonia level, μmol/L\tTreatment\tDays to recovery\t\nOur patient-1st admission\tRCC\tCirrhosisALT 20 U/LAST 27 U/LNormal bilirubinESRD on hemodialysis\t25\t44\t122\tDialysis (usual)+ lactulose 3×/d+ Discontinuation of sunitinib\t4\t\nOur patient-2nd admission\t\t\t25\t28\t126\tDialysis (increased intensity)+ lactulose 3×/d+Continuation of sunitinib\t2\t\nLee et al[8]\tGIST (small bowel)\tLiver metastasesALT 50 U/LAST 79 U/LBilirubin not availableRenal function not available\t50\t14\t150\tLactulose hourly+ Discontinuation of sunitinib\t1\t\nLee et al[8]\tGIST (caecum)\tALT 53 U/LAST 44 U/LBilirubin not availableRenal function not available\t50\t10\t277\tLactulose hourly+ Discontinuation of sunitinib\t1\t\nShea et al[9]\tPNET\tLiver metastasesALT 43 U/L, AST 53 U/LNormal bilirubinNormal renal function\t12.5\t14\t147\tLactulose (ensure bowel opening 3×/d)+ Discontinuation of sunitinib\t1\t\nPilanci et al[11]\tRCC\tALT 25 U/LAST 34 U/LNormal bilirubinNo renal insufficiency\t50\t14\t104\tLactulose hourly+ Discontinuation of sunitinib\t7\t\nLipe et al[12]\tInfiltrating ductal carcinoma of breast with metastatis to liver\tLiver metastasisALT 54 U/LAST 100 U/LBilirubin not availableRenal function not available. Urinalysis normal\tNo details\t12\t202\tLactulose (frequency not mentioned)+ Discontinuation of sunitinib\t12\t\nHyperammonemia severe enough to cause encephalopathy has to be managed urgently. Lactulose is intensified and supplemented with an oral non-absorbable antibiotic rifaximin. Both these treatments work synergistically to reduce inhibit the growth of ammonia producing bacteria in the gastrointestinal tract.[13] Although reduction in ammonia load is certainly one important strategy, the removal of ammonia via HD is also very effective. Ammonia is not protein bound and much like urea, is a low-molecular-weight molecule (17 g/mol), hence clearance with HD is extremely effective and can reduce serum ammonia level by >50% after a single session (as evident in our case). Given the property of ammonia, the mode of clearance is not critical. Hemodiafiltration (HDF) has little advantage over high-efficiency HD in ammonia removal. Similar to urea clearance, increasing dialyzer (filter) size, blood flow, and dialysate flow will all enhanced the clearance of ammonia.[14] When the decision was made that TKI (sunitinib) was the better option for managing his disease condition, we increased his intensity of HD (both single session efficiency as well as frequency to avoid the 72 hours weekend interval) to permit continuation of sunitinib. Patient was able to maintain treatment with sunitinib for 3 additional months with the intensified dialysis regimen that kept his serum ammonia below 80 μg/dL. Unfortunately, he later developed various infective episodes and decision was made to manage him conservatively with best supportive care only.\n\nThis report highlight the fact that a rare but serious drug related complication associated with the use of sunitinib can be managed successfully with intensive outpatient hemodialysis without discontinuation of the medication in a patient who is already on maintenance HD. The limitation is this a single case report in 1 patient. Nevertheless, it provides insight on possible management option for continuation of sunitinib in the case of hyperammonaemia encephalopathy in a hemodialysis patient.\n\nAuthor contributions\nConceptualization: Sabrina Haroon, Stephanie Ko, Titus Lau.\n\nVisualization: Sabrina Haroon, Titus Lau.\n\nWriting – original draft: Sabrina Haroon, Stephanie Ko.\n\nWriting – review & editing: Sabrina Haroon, Stephanie Ko, Alvin Wong, Tan Poh Seng, Evan Lee, Titus Lau.\n\nAbbreviations: CT = computed tomography, ED = emergency department, ESRD = end stage renal disease, HCV = hepatitis C, HD = hemodialysis, HE = hyperammonemia encephalopathy, PDGF = platelet derived growth factor, RCC = renal cell carcinoma, TKI = tyrosine kinase inhibitor, VEGF = vascular endothelial growth factor.\n\nHow to cite this article: Haroon S, Ko S, Wong A, Tan PS, Lee E, Lau T. Sunitinib-associated hyperammonemic encephalopathy successfully managed with higher intensity conventional hemodialysis: a case report. Medicine. 2021;100:5(e24313).\n\nThe authors have no conflicts of interest to disclose.\n\nAll data generated or analyzed during this study are included in this published article [and its supplementary information files].\n\nData sharing not applicable to this article as no datasets were generated or analyzed during the current study.\n==== Refs\nReferences\n[1] Tsuzuki T Iwata H Murase Y \nRenal tumors in end-stage renal disease: a comprehensive review\n. Int J Urol \n2018 ;25 :780 –6\n.30066367 \n[2] Levitzki A Klein S \nMy journey from tyrosine phosphorylation inhibitors to targeted immune therapy as strategies to combat cancer\n. Proc Natl Acad Sci USA \n2019 ;116 :11579 –86\n.31076554 \n[3] Escudier B Porta C Schmidinger M \nRenal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up\n. Ann Oncol \n2019 ;30 :706 –20\n.30788497 \n[4] Sunitinib Product Information [Internet]; 2015. Available at: http://www.pfizer.com/products/product-detail/sutent. Accessed on December 13, 2019 .\n[5] Adams VR Leggas M \nSunitinib malate for the treatment of metastatic renal cell carcinoma and gastrointestinal stromal tumors\n. Clin Ther \n2007 ;29 :1338 –53\n.17825686 \n[6] Wright G Noiret L Olde Damink SW \nInterorgan ammonia metabolism in liver failure: the basis of current and future therapies\n. Liver Int \n2011 ;31 :163 –75\n.20673233 \n[7] Parekh PJ Balart LA \nAmmonia and its role in the pathogenesis of hepatic encephalopathy\n. Clin Liver Dis \n2015 ;19 :529 –37\n.26195206 \n[8] Lee NR Yhim HY Yim CY \nSunitinib-induced hyperammonemic encephalopathy in gastrointestinal stromal tumors\n. Ann Pharmacother \n2011 ;S0735-6747(20)30674-4 .\n[9] Shea YF Chiu WY Mok MY \nSunitinib-induced hyperammonaemia in a patient with pancreatic neuroendocrine tumour\n. J Clin Pharm Ther \n2013 ;38 :327 –9\n.23586819 \n[10] Shinde SS Sharma P Davis MP \nAcute hyperammonemic encephalopathy in a non-cirrhotic patient with hepatocellular carcinoma reversed by arginine therapy\n. J Pain Symptom Manage \n2014 ;47 :e5 –7\n.\n[11] Pilanc KN Elbüken F Ordu Ç \nA rare case of sunitinib-induced hyperammonemic encephalopathy and hypothyroidism in metastatic renal cell carcinoma\n. Am J Ther \n2016 ;23 :e583 –7\n.24901901 \n[12] Lipe DN Hoxha B Sahai SK \nSunitinib-associated hyperammonemic encephalopathy\n. Am J Emerg Med \n2020 ;10 :S0735 –6757\n.\n[13] Bass NM Mullen KD Sanyal A \nRifaximin treatment in hepatic encephalopathy\n. N Engl J Med \n2010 ;362 :1071 –81\n.20335583 \n[14] Gupta S Fenves AZ Hootkins R \nThe role of RRT in hyperammonemic patients\n. Clin J Am Soc Nephrol \n2016 ;11 :1872 –8\n.27197910\n\n",
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"abstract": "In a patient admitted for further investigation of haemoptysis and dyspnoea and known emphysema of the lung, a remarkable distribution of emphysematous bullae could be detected on CT-imaging. Further history, besides smoking, revealed apnoea diving-activity during younger adult age. The distinct appearance of partially septated pleura-based bullae lead to the suspicion of a positive-pressure barotrauma of the lungs in the past, now complicated by infection and bleeding. This case highlights the importance of thorough questioning of the patient and underlines the consideration of differential diagnoses of emphysema.",
"affiliations": "Department of Respiratory Medicine, Sleep Medicine and Ventilation (Zentrum für Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin), Deutsche Klinik für Diagnostik, Aukammalle 33, 65191 Wiesbaden, Germany.;Department of Respiratory Medicine, Sleep Medicine and Ventilation (Zentrum für Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin), Deutsche Klinik für Diagnostik, Aukammalle 33, 65191 Wiesbaden, Germany.",
"authors": "Lüttecke-Hecht|Camilla|C|;Hirche|Tim O|TO|",
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"fulltext": "\n==== Front\nRespir Med Case RepRespir Med Case RepRespiratory Medicine Case Reports2213-0071Elsevier S2213-0071(14)00025-210.1016/j.rmcr.2014.04.002Case ReportBullous emphysema – Not always nicotine-related! Unusual distribution of emphysema in a patient with a rare hobbyLüttecke-Hecht Camilla camilla.luettecke-hecht@dkd-wiesbaden.deluetteckec@googlemail.com∗Hirche Tim O. tim.hirche@dkd-wiesbaden.deDepartment of Respiratory Medicine, Sleep Medicine and Ventilation (Zentrum für Pneumologie, Allergologie, Schlaf- und Beatmungsmedizin), Deutsche Klinik für Diagnostik, Aukammalle 33, 65191 Wiesbaden, Germany∗ Corresponding author. Tel.: +49 611 57714209; fax: +49 611 5777639. camilla.luettecke-hecht@dkd-wiesbaden.deluetteckec@googlemail.com23 4 2014 2014 23 4 2014 12 44 46 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).In a patient admitted for further investigation of haemoptysis and dyspnoea and known emphysema of the lung, a remarkable distribution of emphysematous bullae could be detected on CT-imaging. Further history, besides smoking, revealed apnoea diving-activity during younger adult age. The distinct appearance of partially septated pleura-based bullae lead to the suspicion of a positive-pressure barotrauma of the lungs in the past, now complicated by infection and bleeding. This case highlights the importance of thorough questioning of the patient and underlines the consideration of differential diagnoses of emphysema.\n\nKeywords\nEmphysemaBullaeCigarette smokingApnoea-divingBarotrauma\n==== Body\n1 Introduction\nThe 67 year-old male patient was referred to our department by a respiratory physician due to persistent haemoptysis, he therefore was treated with oral Moxifloxacine over 10 days during a stay in Andalusia/Spain prior to admission. Present complaint was coughing, increased amount of phlegm and halithosis, no fevers, loss of weight or night sweats. Similar symptoms intermittendly occurred over the past three years and were successfully treated with antibiotics. A bullous emphysema was first diagnosed three years ago, the patient then suffered of pneumonia and lung abcess. An actual x-ray of the lung showed a predescribed bulla in the right apical lower lobe with an air-fluid-level. The patient quit smoking 15 years ago (regular smoking was started at the age of 36, sporadic smoking before), about 30 packyears.\n\nPast history: Coronary artery disease (2 vessel-diesease), implantation of 2 drug-eluting stents prox. RIA and dist. RCA 06/2013 (CABG was refused by the patient), hypertension, and diabetes type II (Insulin-therapy). Medication: Aspirine and Clopidogrel. The patient's father died of tuberculosis in 1989, tuberculosis skin-testing in the patient back then was reactive.\n\n1.1 Physical examination\n171 cm, 84 kg, decreased breath sounds bilaterally.\n\n1.2 Blood testing results\nC-reactive protein 1.13 mg/dl (normal max. 0.5 mg/dl), haemoglobin 12.1 g/dl (normal 13.1–16.8 g/dl), GGT 127 U/l (normal max. 61 U/l), results within the range: white blood cell count, platelet count, MCV, MCH, glucose, calcium, phosphate, creatinine, GFR, urea, ALT, AP, magnesium, sodium, potassium, total protein, INR.\n\n1.3 ECG\nSinus rhythm, 93 bpm, no axis deviation, isolated negative T in III.\n\n1.4 Echocardiography\nDiscrete hypertrophy of the basal septum and impaired diastolic function, slight mitral valve regurgitation and tricuspid valve regurgitation, PAPsys 34mmHg + central venous pressure, estimated PA-pressure of 39 mmHg within the upper normal range.\n\n1.5 Chest X-ray (external report)\nPredescribed subpleural emphysematous bulla (6.6 × 5.0 × 3.3 cm) right apical lower lobe with increasing cystwall thickness and air-fluid-level, sclerosis of the aorta and degenerative changes of the thoracic spine.\n\n1.6 CT scan of the lungs\nMarked subpleural bullous emphysema bilaterally (right 7.9 × 3.5 cm; left 4.9 × 1.8 cm) (Images 1–3), partially septated on the right side with a discrete fluid-air-level, slightly enlarged mediastinal lymphnodes (max. 7 mm), no inflammatory consolidation, no pleural effusion.\n\n1.7 Lung function testing\nRtot 0.3 kPa s/l (102%), FEV1 2.5 l (84%), VCin 3.0 l (76%), FEV1%VCmax 82%, TLC 5.7 l (87%), RV 2.7 l (108%), RV%TLC 117%, lung function testing within the normal range.\n\n1.8 Diffusion capacity\nTLCOcSB 5.4 mmol/min/kPa (63%), TLCO/VA 1.0 mmol/min/kPa/l (79%), slightly impaired.\n\n1.9 Arterial blood gas-analysis at rest on room air\npO2 76 mmHg, pCO2 35 mmHg, pH 7.40, BE -2.0 mmol/l, HCO3- 22.0 mmol/l, within the normal range.\n\n1.10 Arterial blood gas-analysis on exertion on room air (6 minutes walk-test)\nIncrease of pO2 from 76 mmHg to 86 mmHg, pCO2 37 mmHg, pH 7.42, walking distance 440 m, no hypoxaemia or hypercapnia on exertion.\n\n1.11 Bronchoscopy\nRegular endobronchial anatomy, endobronchial tissue atrophic, signs of chronic bronchitis, substantial pussy mucus in the lower lobes bilaterally, no bleeding.\n\n1.12 Bronchoalveolar lavage\nIncreased content of cells with normal differential percentage, CD4/CD8 ratio normal, cytologically signs of alveolar haemorrhage, flow cytometry normal.\n\n1.13 Microbiological results of the lavage fluid\nNo isolation of pathogenic bacteria, no proof of mycobacteria microscopically or in cultural growth.\n\n2 Diagnosis\nHaemoptysis due to therapy with dual platelet-aggregation-inhibitor and superinfected emphysematous bulla.\n\nThe patient was treated with Piperacillin/Tazobactam 4.5 g intravenously tds over 7 days. Bronchoscopy with thorough clearance of mucus and secretion was performed, also therapy with nebulised saline and Salbutamol qid, marked improvement hereunder.\n\nDue to the remarkable subpleural distribution of emphysema, the patient again was interrogated. He indicated that he practiced apnoea diving over 15 years in the past up to the age of 35, he spent about five weeks per year on this activity doing harpoon fishing. He declared the maximum diving depth 15 m. Without structured exercise, he was able to hold his breath after initial hyperventilation longer than 2 min for his dives. He never had a professional physical assessment for diving-fitness, a diving accident could not be recalled. During childhood and adolescence he practiced endurance running (half-marathon and marathon distance), during regular visits to the public pool he was able to dive distances greater than 60 m.\n\n3 Discussion\nApnoea-diving or free breath-hold diving is long practiced, historical proof exists, reaching back longer than 2000 years (wreck,-sponge,-seashell,- or pearldivers) [1]. In the past years, the popularity of this leisuretime-activity increased, nowadays it is also carried out in professional competitions, including several disciplines regarding speed, depth or distance, and underwater harpoon-fishing is still very common [2]. With regular exercise, the diver is able to increase his tolerance level for high CO2 values, and thereby can extend the time under water. By augmenting the TLC at the expense of reducing the RV, the diver can increase the diving depth, as the negative effects of increasing surrounding water pressure can be partially antagonised by this technique. Depending on the diving discipline, record depths of greater than 200 m and diving-time without breathing support exceeding several minutes can be realised [7]. Three phases in diving can physiologically be distinguished: compression-phase during descent, the surrounding water pressure increases (about 1 mbar every 10 m); isopression-phase with a constant water pressure acting on the body by having reached the desired depth (although the depth during that phase often varies due to investigation of the underwater-environment), followed by the decompression-phase on ascent with decreasing surrounding water pressure. Each phase involves specific health risks resulting from the pathophysiologic effects on the human body [8]. Our patient indicated a maximum diving depth of 15 m, which makes a decompression-illness or negative-pressure barotrauma unlikely. However, a positive-pressure barotrauma of the lungs is also possible in lower diving depths. According to the Boyle-Marriott law, the product of pressure and volume is constant (p × V = const.), so with constant temperature, given a defined gas-volume, the relation of pressure and volume is reverse [3]. Therefore, the breathing gas in the lungs, that had been compressed by the surrounding water pressure during the dive, expands again on ascent. A positive-pressure barotrauma can occur, if the air in the lungs can not disperse sufficiently and quick enough due to breathholding on ascent, resulting in an increased positive pressure in the lungs, that can lead to central (mediastinum), or peripheral (pleura) tears causing a pneumomediastinum or pneumothorax with regards to the lung. As a matter of course, all airfilled organs of the human body could potentially be affected by a barotrauma [4]. To prevent this complication, adequate time on ascent must be allowed for the air to flow off the lungs, therefore a barotrauma often occurs in very fast panic-ascents. An overextension of the lungs with the above named resulting complications is suspected to be the second most cause of death in divers after drowning [5]. With regards to our patient, pressure-related partial pleural tears with consecutive forming of emphysematous bullae must be assumed (in absence of a recalled diving trauma or incidence), located on that part of the lungs, that is highly exposed to shear stress and pressure variation in the thorax: the outer sheathing of the lungs. Fast ascent, even out of lower water depth, or fast changes in diving depth due to hunting after a fish, could have caused the marked lung changes in our patient. The intermittent cigarette smoking at this time must be taken into account as a contributing factor to the described mechanism, as it causes air trapping (as do bronchial infections with partial or complete mucus plugging in the distal bronchioles), that prevents airflow out of the airways [4]. The distinct distribution of the bullae and the septated appearance support the assumption, that the underlying cause in origin is trauma, rather than emphysematous changes resulting from cigarette-smoking. Apposedly, lung function testing showed normal values except slight impaired diffusion capacity, no further emphysematous changes throughout the lungs could be detected in the CT-scan (as should be expected in long-term cigarette smoking). No medical investigation or x-ray of the lungs took place in the past, so that the existence of the emphysematous bullae at an earlier stage (longer than three years) can only be hypothesised. In the actual context, the origin of the emphysema has no therapeutic consequence, but shows – once again – how important thorough questioning of the patient with regards to the past history could be. Due to recurrent infection of the bullae and preserved lung-function, surgical resection has to be considered intermediate-term, at this stage impossible though, as the patient is under dual platelet aggregation-inhibition and the conservative treatment results were fully satisfactory. Future aim should be close surveillance of the patient and detecting eventual corresponding changes to prevent further complications.\n\n4 Conclusion\n- Unusual distribution of emphysema in lung imaging should lead to consideration of differential diagnoses\n\n- Critical consideration and matching of investigational and imaging results, as well as symptoms, should be of paramount importance\n\n- Every respiratory physician should be familiar with diving physiology and come to terms with the particularities of this increasing popular sparetime-activity\n\n- Surgical resection of localised emphysema as a therapeutical option should be critically discussed\n\n\n\nAcknowledgements\nMany thanks to Dr. med. David Semmler, Mainz, Germany and Dr. med. Stefan Seemayer, Wiesbaden, Germany, for the support regarding the professional contents of this case report.\n\nImage 1 CT-scan of the lungs, subpleural emphysematous bullae.\n\nImage 2 CT-scan of the lungs, dorsal subpleural emphysematous bullae.\n\nImage 3 CT-scan of the lungs, dorsal subpleural, partially septated emphysematous bullae.\n==== Refs\nReferences\n1 Gierschner N. Meine illustrierte Chronologie und Bibliografie der Tauchgeschichte. Band II 2007 Alphabetically and Systematic Bibliography Tauch-Info-Büro Berlin \n2 http://www.aida-international.org.\n3 Muth C.M. Ehrmann U. Radermacher P. Physiology and clinical aspects of apnea diving Clin Chest Med 26 2005 381 394 16140133 \n4 Rüegger M. Schwarb D. Berufliches Tauchen und Arbeiten im Überdruck 2012 Abteilung Arbeitsmedizin Suva \n5 Edmonds C. Burst lung, CAGE and scuba diving deaths Med J Aust 153 1990 65 2366699 \n7 Walterspacher S. Scholz T. Tetzlaff K. Sorichter S. Breath-hold diving: respiratory function on the longer term Med Sci Sports Exerc 43 7 2011 1214 1219 21200343 \n8 König P. Lipp A. Lehrbuch für Forschungstaucher: Manuskript einer Vorlesung am Institut für Meereskunde der Universtät Hamburg, 5. Auflage 2007\n\n",
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"abstract": "A 64-year-old man was admitted because of dyspnea. He was diagnosed with rectal cancer with lymphangiosis carcinomatosa and metastases in the liver and lymph nodes. The patient was treated with cetuximab and modified FOLFOX6 (mFOLFOX6). After treatment, the primary rectal cancer and metastases were considered to have achieved a partial response (PR) and the lymphangiosis carcinomatosa remarkably improved. However, anaphylactic shock occurred in the 6 courses of treatment, 5 minutes after the infusion of oxaliplatin, and the patient was treated.",
"affiliations": "Dept. of Surgery, Oita Prefecture Saiseikai Hita Hospital.",
"authors": "Ozaki|Kunihiro|K|;Hayashida|Ryouzou|R|;Nishi|Tatsuya|T|;Ishibashi|Yoshiaki|Y|;Sakurai|Kanako|K|;Nishimura|Yutaka|Y|;Akagi|Yoshito|Y|",
"chemical_list": "D009944:Organoplatinum Compounds; D000077150:Oxaliplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "42(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000707:Anaphylaxis; D000971:Antineoplastic Combined Chemotherapy Protocols; D006801:Humans; D008113:Liver Neoplasms; D008205:Lymphangitis; D008297:Male; D008875:Middle Aged; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D012004:Rectal Neoplasms",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "2481-3",
"pmc": null,
"pmid": "26809309",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Rectal Cancer with Lymphangiosis Carcinomatosa Successfully Treated with Chemotherapy Despite Anaphylactic Reaction to Oxaliplatin.",
"title_normalized": "a case of rectal cancer with lymphangiosis carcinomatosa successfully treated with chemotherapy despite anaphylactic reaction to oxaliplatin"
} | [
{
"companynumb": "JP-ACTAVIS-2016-04486",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FLUOROURACIL"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nTissue plasminogen activator (tPA) has been successfully used to relieve obstruction of dysfunctional devices, including vascular catheters. Intrapleural tPA is used by some centers to restore flow of nondraining indwelling pleural catheters (IPCs) in symptomatic patients with malignant pleural effusions (MPEs). Because few studies have evaluated its safety and effectiveness, we conducted a retrospective cohort study of outcomes after tPA treatment during a 10-year period at our institution.\n\n\nMETHODS\nWe studied 97 patients with MPE and a nondraining IPC in the setting of persistent pleural fluid who were treated with intrapleural tPA. The primary outcome was restoration of flow after treatment. Secondary outcomes included complication rates and the need for further pleural interventions. Symptomatic relief was assessed using the Borg perceived scale.\n\n\nRESULTS\nWe identified 97 patients with MPE and a nondraining IPC who were treated with tPA. Flow was restored after 1 tPA dose in 83 of 97 patients (86%; 95% confidence interval, 77%-92%). Reocclusion after 1 dose was seen in 27 of 83 patients (32%), and 22 (81%) of these patients were treated with a second tPA dose. Among these 22, flow was restored in 16 (72%; 95% confidence interval, 44%-84%). Borg score improvement was only seen in patients who had restored flow (P=0.024). This finding was independent of the size of the effusion upon chest x-ray. There were 5 complications: 2 hemothoraxes and 3 infectious complications.\n\n\nCONCLUSIONS\nOn the basis of our finding of successful flow restoration with few complications, we recommend intrapleural tPA treatment for symptomatic patients with nondraining IPCs in the setting of persistent pleural fluid.",
"affiliations": "Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.",
"authors": "Vial|Macarena R|MR|;Ost|David E|DE|;Eapen|Georgie A|GA|;Jimenez|Carlos A|CA|;Morice|Rodolfo C|RC|;O'Connell|Oisin|O|;Grosu|Horiana B|HB|",
"chemical_list": "D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1097/LBR.0000000000000265",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1948-8270",
"issue": "23(2)",
"journal": "Journal of bronchology & interventional pulmonology",
"keywords": null,
"medline_ta": "J Bronchology Interv Pulmonol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002408:Catheters, Indwelling; D005260:Female; D005343:Fibrinolytic Agents; D006801:Humans; D008297:Male; D008875:Middle Aged; D016066:Pleural Effusion, Malignant; D012189:Retrospective Studies; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "101496866",
"other_id": null,
"pages": "98-105",
"pmc": null,
"pmid": "27058711",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Intrapleural Fibrinolytic Therapy in Patients With Nondraining Indwelling Pleural Catheters.",
"title_normalized": "intrapleural fibrinolytic therapy in patients with nondraining indwelling pleural catheters"
} | [
{
"companynumb": "US-ROCHE-1901896",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": "3",
"drugad... |
{
"abstract": "The aim of this study is to investigate long-term outcome of symptomatic type 1 cryoglobulinemia (CG) and its determinants. Retrospective cohort study was conducted in two French University Hospitals. Patients with type 1 CG were identified using laboratory databases. Inclusion criterion was the presence of persistent symptoms of CG. Among 227 screened patients, 36 were included. Skin or vasomotor symptoms were the most frequent features (75%). Nephropathy and neuropathy occurred in 30% and 47% of cases, respectively. The underlying B cell disease (BCD) was a nonmalignant monoclonal gammopathy (NMMG) in 13 (36%) and a hematologic malignancy (HM) in 23 (64%; Waldenstrom macroglobulinemia (WM) in 12, low-grade non-Hodgkin lymphoma (NHL) in 6, multiple myeloma (MM) in 4, and chronic lymphocytic leukemia in 1 patient. Severe manifestations affected half the patients and were more frequent with IgG (82 vs. 30% (P = 0.006)). At last follow-up, 64% of patients had suffered no hematologic manifestation. Potent chemotherapeutic regimens were mainly used in HM. For patients with NMMG, WM, or NHL, fludarabine or rituximab-based regimens appeared to yield better responses. Five-year survival rate was 82%. In multivariate analysis, mortality was significantly higher in older patients (HR: 1.17 per year [95% CI: 1.06-1.28], P = 0.001) and those with nephropathy (HR: 8.9 [95% CI: 1.9-43], P = 0.006). Kidney disease, infections, Richter's transformation, and second malignancies were important sources of morbi-mortality. Despite its limitations, this series provide novel information regarding type 1 CG. Further studies are needed to improve its management. To date, therapeutic strategy should be tailored according to patient's characteristics (age, comorbidities, underlying BCD), and therapeutic target.",
"affiliations": "CHU Nantes, Service de Médecine Interne, F 44093, Nantes, France.",
"authors": "Néel|Antoine|A|;Perrin|François|F|;Decaux|Olivier|O|;Dejoie|Thomas|T|;Tessoulin|Benoit|B|;Halliez|Maxime|M|;Mahé|Béatrice|B|;Lamy|Thierry|T|;Fakhouri|Fadi|F|;Jego|Patrick|P|;Agard|Christian|C|;Vigneau|Cécile|C|;Guenet|Lucienne|L|;Grosbois|Bernard|B|;Moreau|Philippe|P|;Hamidou|Mohamed|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ajh.23608",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0361-8609",
"issue": "89(2)",
"journal": "American journal of hematology",
"keywords": null,
"medline_ta": "Am J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D003449:Cryoglobulinemia; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D063868:Patient Outcome Assessment; D010951:Plasma Exchange; D016896:Treatment Outcome",
"nlm_unique_id": "7610369",
"other_id": null,
"pages": "156-61",
"pmc": null,
"pmid": "24532335",
"pubdate": "2014-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term outcome of monoclonal (type 1) cryoglobulinemia.",
"title_normalized": "long term outcome of monoclonal type 1 cryoglobulinemia"
} | [
{
"companynumb": "FR-MYLANLABS-2021M1053594",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAcute haemorrhagic leukoencephalitis (AHLE), a rare variant of acute disseminated encephalomyelitis (ADEM), often presents differently from classical ADEM, thereby posing a diagnostic challenge to the clinician.\n\n\nOBJECTIVE\nTo report AHLE, its clinic-radiological manifestations, process of diagnosis and prognosis.\n\n\nRESULTS\nEight patients presented with altered sensorium, acute focal deficits with or without seizures. Initial workup showed evidence of haemorrhagic lobar or thalamic lesions in seven patients. All patients underwent extensive evaluation for collagen vascular disease and vasculitis profile, autoimmune encephalitis panel and aquaporin-4 antibody, which were found to be normal. Cerebrospinal fluid (CSF) biochemistry and microscopy was non-contributory and CSF viral PCRs, toxoplasma antibodies, cryptococcal antigen were also negative. All patients had progressively worsening sensorium and neurological deficits. Repeat MRIs showed increase in oedema in the lesions and appearance/expansion of haemorrhage in the thalamic/hemispherical lesions. All patients received intravenous methylprednisolone (IVMP) without any benefit. Four patients underwent plasmapheresis (PLEX), one received intravenous immunoglobulin (IVIG) and one received both second line immunotherapies, without significant improvement. Brain biopsy (performed in three patients) showed inflammatory demyelination and areas of haemorrhage, thus confirming the diagnosis. Six patients succumbed in 7-30 days of the illness, despite aggressive treatment and only two survived, albeit with a significant disability.\n\n\nCONCLUSIONS\nAHLE is a rare, yet very severe variant of ADEM. MRI shows lesions with haemorrhages, oedema and mass effect and histology findings reveal inflammatory infiltrates, haemorrhagic foci and fibrinoid necrosis of vessel walls. Prognosis is worse as compared to the classic ADEM, with a high mortality rate. To the best of our knowledge, this is one of the largest series of AHLE to have been reported anywhere in the world.\nAcute encephalopathy, multifocal deficits accompanied by haemorrhagic CNS demyelinating lesions with oedema and mass effect are the key features of AHLE. It is a rare, yet very severe form of ADEM with very high morbidity and mortality.",
"affiliations": "Consultant Neurologist, Neurology Department, Deenanath Mangeshkar Hospital and Research Center, Pune, India; Consultant Neurologist, Neurology Department, Noble Hospital, Pune, India. Electronic address: drshripadpujari@gmail.com.;Consultant Neurologist, Neurology Department, Deenanath Mangeshkar Hospital and Research Center, Pune, India.;Associate Professor in Neurology, Grant Medical College, Sir J J Group of Hospitals, Mumbai, India.;Consultant Neurologist, Neurology Department, P. D. Hinduja National Hospital, Mumbai, India.;Brain and Nerve Clinic, Neurology and Neuro-Ophthalmology, Hubli, India.;Consultant Neurologist and Movement Disorder Specialist, HCG Hospital, Rajkot, India.;Associate Professor in Neurology, Grant Medical College, Sir J J Group of Hospitals, Mumbai, India.;Consultant Neurophysician, Dr. V. M. Government Medical College, Solapur, India.;Consultant Pathologist, Pathology Department, Noble Hospital, Pune, India.;Consultant Pathologist, Pathology Department, Deenanath Mangeshkar Hospital and Research Centre, Pune, India.;Consultant Radiologist, Radiology Department, Deenanath Mangeshkar Hospital and Research Centre, Pune, India.;Consultant Radiologist, Radiology Department, Noble Hospital, Pune, India.;Department of Neuropathology, National Institute of Mental Health and Neuroscience (NIMHANS), Bangalore, India.",
"authors": "Pujari|Shripad S|SS|;Kulkarni|Rahul V|RV|;Ojha|Pawan|P|;Gursahani|Roop|R|;Nadgir|Dattatraya|D|;Patil|Sarika|S|;Soni|Girish|G|;Bangar|Sachin|S|;Harshe|Amol|A|;Mandolkar|Mahesh|M|;Joshi|Aniruddha|A|;Kadam|Sagar|S|;Goyal|Aditi|A|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jneuroim.2021.577751",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-5728",
"issue": "361()",
"journal": "Journal of neuroimmunology",
"keywords": "Acute disseminated encephalomyelitis; Acute haemorrhagic leukoencephalitis; Brain biopsy; Haemorrhagic lesions; Post-infectious; Post-vaccination",
"medline_ta": "J Neuroimmunol",
"mesh_terms": null,
"nlm_unique_id": "8109498",
"other_id": null,
"pages": "577751",
"pmc": null,
"pmid": "34739912",
"pubdate": "2021-12-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Acute haemorrhagic leukoencephalitis (AHLE) - our experience and a short review.",
"title_normalized": "acute haemorrhagic leukoencephalitis ahle our experience and a short review"
} | [
{
"companynumb": "IN-PFIZER INC-PV202200006048",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE SODIUM SUCCINATE"
},
"d... |
{
"abstract": "OBJECTIVE\nTo examine associations between polypharmacy and delirium diagnosed in elderly patients hospitalized in geriatric acute care unit after emergency hospital admission.\n\n\nMETHODS\nStudy design was an observational cohort study in the acute geriatric care unit of a university hospital. We included 410 consecutive patients admitted to the acute geriatric ward during 9 months. Within 72 hours of each patient's hospitalization, a clinically trained geriatrician collected the following data: sociodemographic details (age, sex, type of residence), predisposing factors for delirium, main cause of hospitalization, and current medications. Polypharmacy was defined as 6 or more drugs a day. Delirium was assessed by a geriatrician using the Confusion Assessment Method and was diagnosed on the basis of clinical history with an acute change in usual functional status, behavioral observation, and clinical and cognitive assessment.\n\n\nRESULTS\nNearly 25% of hospitalized patients had delirium. The Confusion Assessment Method was positive in 69% of patients receiving polypharmacy and in 30% of those not receiving polypharmacy, a relative risk of 2.33. The proportion of elderly patients receiving polypharmacy was 58.53%.\n\n\nCONCLUSIONS\nIn our study, polypharmacy is an independent risk factor for delirium in a population of elderly patients after emergency admission. In the geriatric population, delirium is an underestimated scourge and because of its medicosocial and economic consequences and its impact on morbidity and mortality, we need to give increased attention to the prevention and control of polypharmacy, which is a predisposing factor for delirium.",
"affiliations": "Gérontopôle, Service de Médecine Interne Gériatrique, CHU Toulouse Hôpital Casselardit, Toulouse, France. Electronic address: hein.c@chu-toulouse.fr.;Gérontopôle, Service de Médecine Interne Gériatrique, CHU Toulouse Hôpital Casselardit, Toulouse, France.;Gérontopôle, Service de Médecine Interne Gériatrique, CHU Toulouse Hôpital Casselardit, Toulouse, France.;Pharmacologie Clinique, Faculté de Médecine, Toulouse, France; Inserm U1027, Faculté de médecine 37, Toulouse, France.;Gérontopôle, Service de Médecine Interne Gériatrique, CHU Toulouse Hôpital Casselardit, Toulouse, France; Inserm U1027, Faculté de médecine 37, Toulouse, France.",
"authors": "Hein|Christophe|C|;Forgues|Adrien|A|;Piau|Antoine|A|;Sommet|Agnès|A|;Vellas|Bruno|B|;Nourhashémi|Fati|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-8610",
"issue": "15(11)",
"journal": "Journal of the American Medical Directors Association",
"keywords": "Polypharmacy; delirium; drug-induced delirium; elderly; geriatrics",
"medline_ta": "J Am Med Dir Assoc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003693:Delirium; D004636:Emergency Service, Hospital; D005260:Female; D005602:France; D006760:Hospitalization; D006801:Humans; D007407:Interviews as Topic; D008297:Male; D008485:Medical Audit; D019338:Polypharmacy",
"nlm_unique_id": "100893243",
"other_id": null,
"pages": "850.e11-5",
"pmc": null,
"pmid": "25405712",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Impact of polypharmacy on occurrence of delirium in elderly emergency patients.",
"title_normalized": "impact of polypharmacy on occurrence of delirium in elderly emergency patients"
} | [
{
"companynumb": "FR-JNJFOC-20141111006",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nPost-transplant lymphoproliferative disorder (PTLD) is the second most common neoplasia after adult kidney transplantation (KT).\n\n\nMETHODS\nWe retrospectively analyzed 8 adult patients who underwent KT in our center, diagnosed with PTLD between 2001 and 2014.\n\n\nRESULTS\nSix patients were men. The median age at presentation was 43 years and the median time since transplantation was 7.3 years. Three patients had previously received anti-thymocyte globulin/OKT3, and all were taking calcineurin inhibitors (CNI) at diagnosis. The monomorphic type was the most common, with diffuse large B-cell lymphoma as the origin. The most frequent presentation was fever. Four in five patients had Epstein-Barr-related PTLD. All patients received various regimens of immunosuppression reduction (IR), with 4 converting CNI to mTOR inhibitor (imTOR). Subsequent treatment (when needed) was chemotherapy, radiotherapy, and surgery. The maximum follow-up time was 6.7 years, with a 50% mortality rate that occurred at a median time of 3.5 months (2 died with functioning kidney). All 4 patients who were in remission at the end of follow-up had CNI conversion to imTOR, and none lost the allograft.\n\n\nCONCLUSIONS\nDespite the small number of cases, our results confirm the high PTLD impact in overall and allograft survival. Our PTLD type distribution is in accord with the literature. First-line PTLD treatment is IR, but the best method is still unknown; our results may suggest a beneficial effect of CNI conversion to imTOR.",
"affiliations": "Nephrology Department, Centro Hospitalar de São João, Porto, Portugal. Electronic address: ferreihugo@gmail.com.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal; Department of Renal, Urological and Infectious Diseases, Faculty of Medicine, University of Porto, Portugal.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal; Department of Renal, Urological and Infectious Diseases, Faculty of Medicine, University of Porto, Portugal.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal.;Clinical Hematology Department, Centro Hospitalar de São João, Porto, Portugal.;Clinical Hematology Department, Centro Hospitalar de São João, Porto, Portugal; Faculty of Medicine, University of Porto, Portugal.;Clinical Hematology Department, Centro Hospitalar de São João, Porto, Portugal; Faculty of Medicine, University of Porto, Portugal.;Nephrology Department, Centro Hospitalar de São João, Porto, Portugal; Department of Renal, Urological and Infectious Diseases, Faculty of Medicine, University of Porto, Portugal; Instituto Nacional de Engenharia Biomédica (INEB), Porto, Portugal.",
"authors": "Ferreira|H|H|;Bustorff|M|M|;Santos|J|J|;Ferreira|I|I|;Sampaio|S|S|;Salomé|I|I|;Bastos|J|J|;Bergantim|R|R|;Príncipe|F|F|;Pestana|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "47(4)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D008875:Middle Aged; D011174:Portugal; D012189:Retrospective Studies; D015996:Survival Rate; D013997:Time Factors; D014184:Transplantation, Homologous",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "981-4",
"pmc": null,
"pmid": "26036499",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Post-transplant Lymphoproliferative Disorder: A Single-Center Experience.",
"title_normalized": "post transplant lymphoproliferative disorder a single center experience"
} | [
{
"companynumb": "PHHY2015PT068903",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Anaesthetists often stand in the front line to manage postpartum neurological deficits, although epidural analgesia is rarely responsible for these complications. An epidural analgesia was performed to relieve pain during spontaneous labor in a 34-year-old parturient. An emergency C-section was subsequently required due to fetal heart rate abnormalities. Twelve hours after catheter removal, the parturient developed a severe right leg motor and sensory neurological deficit, predominant on L5 and S1 roots and diagnosed by a neurologist as a central nerve root injury. Lumbar MRI identified a non-compressive epidural bleeding in front of the L5 vertebral body. Epidural bleeding after labor epidural analgesia is a rare complication that may jeopardize the functional prognosis. It may be difficult in some cases to differentiate an upper plexus injury due to labor and delivery from a central epidural analgesia-related nerve root lesion. Fetal head compression at the pelvic brim may induce neurological deficits in several well-differentiated nervous territories, thus mimicking an anaesthetic-induced perimedullar radiculopathy.",
"affiliations": "Département d'anesthésiologie, hôpital Antoine-Béclère, groupe hospitalier Paris Sud, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France.;Département d'anesthésiologie, hôpital Antoine-Béclère, groupe hospitalier Paris Sud, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France.;Département d'anesthésiologie, hôpital Antoine-Béclère, groupe hospitalier Paris Sud, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France.;Département d'anesthésiologie, hôpital Antoine-Béclère, groupe hospitalier Paris Sud, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France.;Département d'anesthésiologie, hôpital Antoine-Béclère, groupe hospitalier Paris Sud, 157, rue de la Porte-de-Trivaux, 92140 Clamart, France. Electronic address: frederic.mercier@abc.aphp.fr.",
"authors": "Bouattour|K|K|;Moyano-Tidou|G|G|;Le Gouez|A|A|;Martel-Jacob|S|S|;Mercier|F-J|FJ|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0750-7658",
"issue": "33(12)",
"journal": "Annales francaises d'anesthesie et de reanimation",
"keywords": "Analgésie péridurale; Anti-inflammatoires non stéroïdiens; Déficit neurologique; Epidural analgesia; Epidural bleeding; Héparine de bas poids moléculaire; Low-molecular weight heparin; Lumbosacral plexus; Neurological deficit; Nonsteroidal anti-inflammatory drugs; Obstetrical labor; Plexus lombosacré; Post-partum; Postpartum; Saignement péridural; Travail obstétrical",
"medline_ta": "Ann Fr Anesth Reanim",
"mesh_terms": "D000328:Adult; D015360:Analgesia, Epidural; D016362:Analgesia, Obstetrical; D016058:Analgesia, Patient-Controlled; D002585:Cesarean Section; D005260:Female; D006340:Heart Rate, Fetal; D006470:Hemorrhage; D006801:Humans; D009422:Nervous System Diseases; D011247:Pregnancy",
"nlm_unique_id": "8213275",
"other_id": null,
"pages": "690-2",
"pmc": null,
"pmid": "25464909",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Epidural bleeding after labor epidural analgesia.",
"title_normalized": "epidural bleeding after labor epidural analgesia"
} | [
{
"companynumb": "FR-FRESENIUS KABI-FK201710463",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "KETOPROFEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nSaline (0.9% sodium chloride) is the most commonly administered intravenous fluid; however, its use may be associated with acute kidney injury (AKI) and increased mortality.\n\n\nOBJECTIVE\nTo determine the effect of a buffered crystalloid compared with saline on renal complications in patients admitted to the intensive care unit (ICU).\n\n\nMETHODS\nDouble-blind, cluster randomized, double-crossover trial conducted in 4 ICUs in New Zealand from April 2014 through October 2014. Three ICUs were general medical and surgical ICUs; 1 ICU had a predominance of cardiothoracic and vascular surgical patients.\n\n\nMETHODS\nAll patients admitted to the ICU requiring crystalloid fluid therapy were eligible for inclusion. Patients with established AKI requiring renal replacement therapy (RRT) were excluded. All 2278 eligible patients were enrolled; 1152 of 1162 patients (99.1%) receiving buffered crystalloid and 1110 of 1116 patients (99.5%) receiving saline were analyzed.\n\n\nMETHODS\nParticipating ICUs were assigned a masked study fluid, either saline or a buffered crystalloid, for alternating 7-week treatment blocks. Two ICUs commenced using 1 fluid and the other 2 commenced using the alternative fluid. Two crossovers occurred so that each ICU used each fluid twice over the 28 weeks of the study. The treating clinician determined the rate and frequency of fluid administration.\n\n\nMETHODS\nThe primary outcome was proportion of patients with AKI (defined as a rise in serum creatinine level of at least 2-fold or a serum creatinine level of ≥3.96 mg/dL with an increase of ≥0.5 mg/dL); main secondary outcomes were incidence of RRT use and in-hospital mortality.\n\n\nRESULTS\nIn the buffered crystalloid group, 102 of 1067 patients (9.6%) developed AKI within 90 days after enrollment compared with 94 of 1025 patients (9.2%) in the saline group (absolute difference, 0.4% [95% CI, -2.1% to 2.9%]; relative risk [RR], 1.04 [95% CI, 0.80 to 1.36]; P = .77). In the buffered crystalloid group, RRT was used in 38 of 1152 patients (3.3%) compared with 38 of 1110 patients (3.4%) in the saline group (absolute difference, -0.1% [95% CI, -1.6% to 1.4%]; RR, 0.96 [95% CI, 0.62 to 1.50]; P = .91). Overall, 87 of 1152 patients (7.6%) in the buffered crystalloid group and 95 of 1110 patients (8.6%) in the saline group died in the hospital (absolute difference, -1.0% [95% CI, -3.3% to 1.2%]; RR, 0.88 [95% CI, 0.67 to 1.17]; P = .40).\n\n\nCONCLUSIONS\nAmong patients receiving crystalloid fluid therapy in the ICU, use of a buffered crystalloid compared with saline did not reduce the risk of AKI. Further large randomized clinical trials are needed to assess efficacy in higher-risk populations and to measure clinical outcomes such as mortality.\n\n\nBACKGROUND\nclinicaltrials.gov Identifier: ACTRN12613001370796.",
"affiliations": "Medical Research Institute of New Zealand, Wellington, New Zealand2Intensive Care Unit, Wellington Regional Hospital, Wellington, New Zealand.;Australian and New Zealand Intensive Care Research Center, Monash University, Melbourne, Victoria, Australia.;Medical Research Institute of New Zealand, Wellington, New Zealand.;Medical Research Institute of New Zealand, Wellington, New Zealand4Department of Intensive Care Medicine, Christchurch Hospital, Christchurch, New Zealand.;Medical Research Institute of New Zealand, Wellington, New Zealand.;Medical Research Institute of New Zealand, Wellington, New Zealand3Australian and New Zealand Intensive Care Research Center, Monash University, Melbourne, Victoria, Australia5Department of Critical Care Medicine, Auckland City Hospital, Auckland, New Zea.;Medical Research Institute of New Zealand, Wellington, New Zealand3Australian and New Zealand Intensive Care Research Center, Monash University, Melbourne, Victoria, Australia6Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckla.;Department of Intensive Care Medicine, Christchurch Hospital, Christchurch, New Zealand.;Intensive Care Unit, St George Hospital, Sydney, New South Wales, Australia8Critical Care Division, George Institute for Global Health, Sydney, New South Wales, Australia.;Intensive Care Unit, Wellington Regional Hospital, Wellington, New Zealand.;Medical Research Institute of New Zealand, Wellington, New Zealand.;Australian and New Zealand Intensive Care Research Center, Monash University, Melbourne, Victoria, Australia9Intensive Care Unit, Austin Hospital, Melbourne, Victoria, Australia.",
"authors": "Young|Paul|P|;Bailey|Michael|M|;Beasley|Richard|R|;Henderson|Seton|S|;Mackle|Diane|D|;McArthur|Colin|C|;McGuinness|Shay|S|;Mehrtens|Jan|J|;Myburgh|John|J|;Psirides|Alex|A|;Reddy|Sumeet|S|;Bellomo|Rinaldo|R|;|||;|||",
"chemical_list": "D015415:Biomarkers; D002021:Buffers; D000077324:Crystalloid Solutions; D007552:Isotonic Solutions; D012965:Sodium Chloride; D003404:Creatinine",
"country": "United States",
"delete": false,
"doi": "10.1001/jama.2015.12334",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0098-7484",
"issue": "314(16)",
"journal": "JAMA",
"keywords": null,
"medline_ta": "JAMA",
"mesh_terms": "D058186:Acute Kidney Injury; D015415:Biomarkers; D002021:Buffers; D003404:Creatinine; D018592:Cross-Over Studies; D000077324:Crystalloid Solutions; D004311:Double-Blind Method; D005240:Feasibility Studies; D005260:Female; D005440:Fluid Therapy; D017052:Hospital Mortality; D006801:Humans; D007362:Intensive Care Units; D007552:Isotonic Solutions; D008297:Male; D008875:Middle Aged; D017582:Renal Replacement Therapy; D012965:Sodium Chloride; D013997:Time Factors",
"nlm_unique_id": "7501160",
"other_id": null,
"pages": "1701-10",
"pmc": null,
"pmid": "26444692",
"pubdate": "2015-10-27",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effect of a Buffered Crystalloid Solution vs Saline on Acute Kidney Injury Among Patients in the Intensive Care Unit: The SPLIT Randomized Clinical Trial.",
"title_normalized": "effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit the split randomized clinical trial"
} | [
{
"companynumb": "NZ-BAXTER-2014BAX038243",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "MAGNESIUM CHLORIDE\\POTASSIUM CHLORIDE\\SODIUM ACETATE\\SODIUM CHL... |
{
"abstract": "Lorcaserin is a modestly selective agonist for 2C serotonin receptors (5-HT2CR) approved for weight-loss therapy. This class can attenuate cue-induced responding and drug taking in preclinical studies, but effects in humans have not been reported.\n\n\n\nWe evaluated effects of single 10 mg doses of lorcaserin on the subjective and reinforcing effects of cocaine, using a randomized, double-blind, within-subject, cross-over design. Male, non-treatment-seeking, regular cocaine users received either single doses of oral placebo (n = 9) or lorcaserin (n = 9), followed by low- or high- doses of intravenous cocaine (0.23 or 0.46 mg/kg-injection). They were then allowed to self-administer the lower dose of cocaine.\n\n\n\nCocaine was well tolerated after lorcaserin pretreatment. Oral lorcaserin did not modify the number of cocaine injections self-administered. However, it prolonged the time over which participants made intravenous choices relative to the duration of monetary (cash) decisions. Lorcaserin increased ratings of 'high' and 'stimulated' after low-dose cocaine or vehicle, but decreased craving for cocaine after intravenous vehicle. It also caused small but significant increases in heart rate following noncontingent injections of intravenous placebo or cocaine. When active cocaine was self-administered, lorcaserin decreased heart rate after selection of a monetary choice, but increased it following an intravenous choice.\n\n\n\nCombined treatment with cocaine and lorcaserin was safe in a limited number of subjects, but did not diminish cocaine-motivated behavior or drug-induced 'high'. Some positive subjective effects of cocaine were enhanced by lorcaserin, and it delayed intravenous choices and decreased craving under some conditions. Effects on heart rate depended on the type of reinforcer being self-administered.\n\n\n\nclinicaltrials.gov Identifier, NCT02680288.",
"affiliations": "Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America.;Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America.;Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America.;Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America; Department of Psychiatry, University of Kansas School of Medicine, Wichita, KS 67226, United States of America.;Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America.;Substance Abuse Research Laboratory, Kansas City Veterans Affairs Medical Center, 4801 Linwood Boulevard, Kansas City, MO 64128, United States of America; Division of Clinical Pharmacology, Department of Medicine, University of Kansas School of Medicine, Kansas City, KS 66160, United States of America. Electronic address: kgrasing@kumc.edu.",
"authors": "Pirtle|Jimmie L|JL|;Hickman|Melissa D|MD|;Boinpelly|Varun C|VC|;Surineni|Kamalakar|K|;Thakur|Hemant K|HK|;Grasing|Kenneth W|KW|",
"chemical_list": "D001552:Benzazepines; D058826:Serotonin 5-HT2 Receptor Agonists; D014662:Vasoconstrictor Agents; C506658:lorcaserin; D003042:Cocaine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.pbb.2019.02.010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-3057",
"issue": "180()",
"journal": "Pharmacology, biochemistry, and behavior",
"keywords": "Cocaine-related disorders; Dose-response relationship; Drug interactions; Infusions; Intravenous; Self-administration; Serotonin receptor agonists",
"medline_ta": "Pharmacol Biochem Behav",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D001552:Benzazepines; D001794:Blood Pressure; D003042:Cocaine; D019970:Cocaine-Related Disorders; D066249:Craving; D018592:Cross-Over Studies; D003864:Depression, Chemical; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D012646:Self Administration; D058826:Serotonin 5-HT2 Receptor Agonists; D013268:Stimulation, Chemical; D016896:Treatment Outcome; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "0367050",
"other_id": null,
"pages": "52-59",
"pmc": null,
"pmid": "30811963",
"pubdate": "2019-05",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "26534942;28868576;29246856;28720903;18977370;26427596;11561074;11594440;27857126;17568397;14584987;9403954;17429406;29217539;23331711;11224166;15056702;27650954;19057523;21412231;19836169",
"title": "The serotonin-2C agonist Lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study.",
"title_normalized": "the serotonin 2c agonist lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine a randomized controlled human laboratory study"
} | [
{
"companynumb": "US-EISAI MEDICAL RESEARCH-EC-2019-054717",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "COCAINE HYDROCHLORIDE"
},
"dru... |
{
"abstract": "We report the case of a 67-year-old female with a wide QRS complex tachycardia at 180 bpm. A diagnosis of class IC atrial flutter with aberrant ventricular conduction caused by flecainide therapy was formulated. Intravenous adenosine administration resulted in adequate slowing of the ventricular rate and normalization of QRS complexes. Restoration of sinus rhythm was achieved with intravenous amiodarone. The response to adenosine confirmed the diagnosis of supraventricular tachycardia with aberrant conduction, but the transition from arrhythmia onset to restoration of sinus rhythm showed interesting peculiarities.",
"affiliations": "Department of Cardiology and Cardiovascular Surgery, \"San Giuseppe Moscati\" Hospital, Avellino, Italy. francesco.rotondi@tin.it",
"authors": "Rotondi|Francesco|F|;Lanzillo|Tonino|T|;Manganelli|Fiore|F|;Lanni|Francesca|F|;Alfano|Ferdinando|F|;Stanco|Giovanni|G|;Rosato|Giuseppe|G|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D000241:Adenosine; D000638:Amiodarone",
"country": "Italy",
"delete": false,
"doi": "10.4081/monaldi.2011.188",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1122-0643",
"issue": "76(3)",
"journal": "Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace",
"keywords": null,
"medline_ta": "Monaldi Arch Chest Dis",
"mesh_terms": "D000241:Adenosine; D000368:Aged; D000638:Amiodarone; D000889:Anti-Arrhythmia Agents; D001282:Atrial Flutter; D004562:Electrocardiography; D005260:Female; D006801:Humans; D013617:Tachycardia, Supraventricular",
"nlm_unique_id": "9307314",
"other_id": null,
"pages": "151-4",
"pmc": null,
"pmid": "22363975",
"pubdate": "2011-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical response of class IC atrial flutter to adenosine.",
"title_normalized": "atypical response of class ic atrial flutter to adenosine"
} | [
{
"companynumb": "IT-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-123420",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drug... |
{
"abstract": "BACKGROUND\nIn patients with advanced-stage cancer, systemic thrombolysis with tissue plasminogen activator (tPA) for hyperacute ischemic stroke is not strictly off-label, but it is at higher risk of complications (including bleeding).\n\n\nMETHODS\nA 71-year-old male with unrecognizable malignancy developed a hemispheric ischemic stroke and received intra-venous tPA within 4.5 h of onset, followed by anticoagulation treatment after 24 h of throm-bolysis. Two days later, the patient had tarry stool and progressive anemia, receiving a blood transfusion. The systemic workup documented the presence of double primary cancers with advanced stage gastric and rectal cancers, and the patient subsequently received palliative care. The outcome at 3 months was a modified Rankin Scale of 5, and the patient died 6 months after the stroke.\n\n\nCONCLUSIONS\nAlthough systemic thrombolysis with tPA for ischemic stroke in patients with advanced-stage cancer may be performed relatively safely, optimal post-thrombolysis management is important to prevent the complications.",
"affiliations": "Division of Neurology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.;Division of Neurology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.;Division of Gastroenterology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.;Neurosurgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.;Division of Neurology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.;Division of Gastroenterology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan.",
"authors": "Yoneda|Yukihiro|Y|;Fukuda|Akira|A|;Yamazaki|Tomohiro|T|;Sasaki|Natsuhi|N|;Ohta|Masahiko|M|;Kageyama|Yasufumi|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000368713",
"fulltext": "\n==== Front\nCase Rep NeurolCase Rep NeurolCRNCase Reports in Neurology1662-680XS. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000368713crn-0006-0238Published online: October, 2014Intravenous Tissue Plasminogen Activator for an Ischemic Stroke with Occult Double Primary Cancer Yoneda Yukihiro a*Fukuda Akira aYamazaki Tomohiro bSasaki Natsuhi cOhta Masahiko aKageyama Yasufumi baDivision of Neurology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, JapanbDivision of Gastroenterology, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, JapancNeurosurgery, Hyogo Prefectural Amagasaki Hospital, Amagasaki City, Japan*Yukihiro Yoneda, MD, Division of Neurology, Hyogo Prefectural Amagasaki Hospital, 1-1-1 East-Daimotsu, Amagasaki City, Hyogo 660-0828 (Japan), E-Mail y-yoneda@hp.pref.hyogo.jpSep-Dec 2014 29 10 2014 29 10 2014 6 3 238 242 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Background\nIn patients with advanced-stage cancer, systemic thrombolysis with tissue plasminogen activator (tPA) for hyperacute ischemic stroke is not strictly off-label, but it is at higher risk of complications (including bleeding).\n\nCase Report\nA 71-year-old male with unrecognizable malignancy developed a hemispheric ischemic stroke and received intra-venous tPA within 4.5 h of onset, followed by anticoagulation treatment after 24 h of throm-bolysis. Two days later, the patient had tarry stool and progressive anemia, receiving a blood transfusion. The systemic workup documented the presence of double primary cancers with advanced stage gastric and rectal cancers, and the patient subsequently received palliative care. The outcome at 3 months was a modified Rankin Scale of 5, and the patient died 6 months after the stroke.\n\nDiscussion\nAlthough systemic thrombolysis with tPA for ischemic stroke in patients with advanced-stage cancer may be performed relatively safely, optimal post-thrombolysis management is important to prevent the complications.\n\nKey words\nCancerIschemic strokeStrokeThrombolysis\n==== Body\nIntroduction\nIn patients with hyperacute ischemic stroke and current active cancer, systemic thrombolysis with tissue plasminogen activator (tPA) is not strictly a contraindication [1, 2, 3], but it may carry a higher risk of complications (including bleeding). Recent studies have shown that aggressive thrombolytic reperfusion therapy is relatively safe and effective in stroke patients with cancer [4, 5, 6, 7, 8].\n\nCase Report\nA 71-year-old right-handed male with a long-term history of heavy smoking, currently taking anti-hypertensive medication at a general practitioners’ clinic, suddenly developed stupor and left hemiparesis and arrived at our hospital 130 min after symptom onset. Upon presentation, the National Institute of Health Stroke Scale (NIHSS) score was 10 points. A baseline brain CT was perfectly normal. On the 1.5-T MR scanner (Signa, General Electric, USA), diffusion-weighted image, scanned 154 min after onset, demonstrated a subtle focal high-signal intensity area around the right caudate nucleus, and MR angiography (MRA) documented an occlusion of the right internal carotid artery (ICA) (fig. 1). The electrocardiogram showed no arrhythmia. The blood test showed moderate anemia with hemoglobin values of 8.5 g/dl, a red blood cell count of 342 × 104/μl, and his hematocrit was 27.8%. Other hematological profiles, including platelet cell count, international normalized ratio and D-dimer, were all normal. Although a suspicion of a hematological disorder or gastrointestinal bleeding arose, general physical examinations, including checking the appearance of his skin and his underwear, did not show any signs of skin purpura or bloody stool, and his family members did not report any history of bleeding. Neither a digital rectal examination nor the placement of a nasogastric tube to search for active gastrointestinal bleeding was performed. Finally, after obtaining written informed consent from his family members, the patient received intravenous thrombolysis with a tPA of 0.6 mg/kg alteplase according to the Japanese guidelines [2, 3, 9] 203 min after symptom onset.\n\nThe neurological status remained unchanged with an NIHSS score of 13 points at 24 h and an anemic state with hemoglobin values of 8.4 g/dl, a red blood cell count of 334 × 104/μl, and a hematocrit of 27.0%. The status did not deteriorate after thrombolysis. Intravenous anticoagulation with the direct thrombin inhibitor argatroban, which has been licensed for ischemic stroke in Japan [2, 3], was started 24 h after thrombolysis. Two days after thrombolysis, the patient suddenly had tarry stool and progressive anemia with hemoglobin values of 6.8 g/dl, a red blood cell count of 289 × 104/μl, and a hematocrit of 22.4%. The patient received a blood transfusion of 4 units after the discontinuation of the intravenous argatroban infusion. The systemic workup, including systemic CT scans and endoscopic gastroscopy and colonoscopy, documented the presence of double primary malignancy with advanced-stage gastric and rectal cancers, associated with multiple remote lymph node metastases (fig. 1). The histopathology showed a tubular adenocarcinoma in the rectal specimen and a poorly differentiated adenocarcinoma in the stomach specimen, indicating synchronous double primary advanced-stage malignancy. The transthoracic echocardiography documented no embolic source. Eight days later, the fluid-attenuated inversion recovery image on the 3T MR scanner (Achieva, Phillips, The Netherlands) showed a moderate-sized infarction in the right middle cerebral artery (MCA) territory with no hemorrhagic transformation. MRA demonstrated mildly anterograde blood flow of the MCA via the contralateral anterior cerebral artery (fig. 1). The neck MRA showed an occlusion of the right ICA at the cervical portion, suggesting an atherothrombotic large artery stroke as an etiological mechanism for this stroke. The NIHSS score was 16 points with left dense hemiplegia and spatial neglect.\n\nThe patient was then transferred to receive palliative treatment. The outcome at 3 months was a modified Rankin Scale of 5, and the patient died from systemic dissemination of the cancers 6 months after the stroke.\n\nDiscussion\nIn this patient with occult types of synchronous double primary advanced-stage cancers in the stomach and rectum, systemic thrombolysis with tPA was performed relatively safely, but delayed gastrointestinal bleeding occurred during post-thrombolysis anticoagulation treatment.\n\nBecause net benefits decrease over time in stroke thrombolysis, the latest guidelines [1, 2, 3] have strongly encouraged urgent thrombolysis without extra investigations, delaying an initiation of thrombolysis and without procedures that are associated with an excessive risk of bleeding. In this patient with asymptomatically pretreated moderate anemia, although any hematological disorder or gastrointestinal bleeding was suspected before thrombolysis, we could not sufficiently rule out the risk of active bleeding at sites of the occult gastric and rectal cancers. Therefore, earlier post-thrombolysis non-invasive investigations such as systemic CT scans to search for bleeding risks might have at least prevented the delayed gastrointestinal bleeding. Apart from urgent stroke thrombolysis, a patient with an unrecognized tumor who received local thrombectomy and thrombolysis with tPA for acute limb artery ischemia developed rectal bleeding, leading to the diagnosis of colorectal can-cer [10].\n\nAccording to the largest cancer registry in Japan [11], the incidence of synchronous multiple primary cancers was 4.5% (2,219 patients) of all 49,751 cancer patients. The combination of synchronous gastric and rectal cancers occurred only in 42 patients, representing 0.08% of all 49,751 cancer patients and 1.9% among 2,219 patients harboring synchronous multiple primary malignancy [11].\n\nIn patients with hyperacute ischemic stroke receiving thrombolytic reperfusion therapy, the proportion of patients with cancer represented 1.6–5% [4, 5, 6, 7, 8], showing a relatively safe and effective profile. In 1 study [7], 2 out of 11 thrombolyzed cancer patients had an occult malignancy, 1 of whom had a sigmoid colon cancer that bled locally and the patient also showed a moderately decreased hemoglobin level. Since patients with known advanced-stage cancer usually do not receive aggressive stroke treatments [5, 7], to the best knowledge, this is the first thrombolyzed patient with synchronous double primary advanced-stage cancers. In ischemic stroke patients hospitalized within 7 days of onset, the incidence of occult malignancy was relatively high at 3%, and a correct diagnosis of cancer was made after several investigations during hospitalization [12].\n\nBefore urgent stroke thrombolysis, in routine clinical practice, it may be difficult to promptly make a correct diagnosis for occult type of multiple or metastatic malignancy. However, optimal post-thrombolysis management is important to at least minimize the complications.\n\nDisclosure Statement\nThe authors declare no conflicts of interest.\n\nFig. 1 Brain MR images and endoscopic examinations of the stomach and rectum. Prior to thrombolysis, diffusion-weighted image demonstrates a subtle high-signal intensity area around the right caudate nucleus, and MRA displays an occlusion of the right ICA (left column). The fluid-attenuated inversion recovery image 8 days later shows a moderate-sized high-signal intensity area in the right MCA territory. The MRA displays partially anterograde blood flow in the right MCA via contralateral anterior cerebral artery, but the right ICA remains in occlusion (middle column). Endoscopic examinations of the stomach and rectum performed 5 and 9 days after thrombolysis show both advanced-stage malignant tumors with blood oozing (right column).\n==== Refs\nReferences\n1 Jauch EC Saver JL Adams HP Jr Bruno A Connors JJ Demaerschalk BM Khatri P McMullan PW Jr Qureshi AI Rosenfield K Scott PA Summers DR Wang DZ Wintermark M Yonas H Guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association Stroke 2013 44 870 947 23370205 \n2 Shinohara Y Yanagihara T Abe K Yoshimine T Fujinaka T Chuma T Ochi F Nagayama M Ogawa A Suzuki N Katayama Y Kimura A Minematsu K Cerebral infarction/transient ischemic attack (TIA) (Japanese guidelines for the management of stroke) J Stroke Cerebrovasc Dis 2011 20 suppl S31 S73 21835356 \n3 Minematsu K Toyoda K Hirano T Kimura K Kondo R Mori E Nakagawara J Sakai N Shiokawa Y Tanahashi N Yasaka M Katayama Y Miyamoto S Ogawa A Sasaki M Suga S Yamaguchi T Guidelines for the intravenous application of recombinant tissue-type plasminogen activator (alteplase), the second edition, October 2012: a guideline from the Japan Stroke Society J Stroke Cerebrovasc Dis 2013 22 571 600 23727456 \n4 Stefan O Vera N Otto B Heinz L Wolfgang G Stroke in cancer patients: a risk factor analysis J Neurooncol 2009 94 221 226 19280119 \n5 Masrur S Abdullah AR Smith EE Hidalgo R El-Ghandour A Rordorf G Schwamm LH Risk of thrombolytic therapy for acute ischemic stroke in patients with current malignancy J Stroke Cerebrovasc Dis 2011 20 124 130 20598579 \n6 Graber JJ Nayak L Deangelis LM Use of recombinant tissue plasminogen activator in cancer patients with acute stroke J Neurooncol 2012 107 571 573 22179814 \n7 Cappellari M Carletti M Micheletti N Tomelleri G Ajena D Moretto G Bovi P Intravenous alteplase for acute ischemic stroke in patients with current malignant neoplasm J Neurol Sci 2013 325 100 102 23317922 \n8 Murthy SB Karanth S Shah S Shastri A Rao CP Bershad EM Suarez JI Thrombolysis for acute ischemic stroke in patients with cancer: a population study Stroke 2013 44 3573 3576 24065712 \n9 Yamaguchi T Mori E Minematsu K Nakagawara J Hashi K Saito I Shinohara Y for the Japan Alteplase Clinical Trial (J-ACT) Group Alteplase at 06 mg/kg for acute ischemic stroke within 3 h of onset Stroke 2006 37 1810 1815 16763187 \n10 Schellhammer F Pourhassan S Topp S Fürst G Diagnosis of colo-rectal cancer revealed by haemorrhagic complication of intraarterial thrombolysis Vasa 2007 36 143 144 17708109 \n11 Kaneko S Yamaguchi N Epidemiological analysis of site relationships of synchronous and metachronous multiple primary cancers in the National Cancer Center, Japan, 1962–1996 Jpn J Clin Oncol 1999 29 96 105 10089951 \n12 Uemura J Kimura K Sibazaki K Inoue T Iguchi Y Yamashita S Acute stroke patients have occult malignancy more often than expected Eur Neurol 2010 64 140 144 20668384\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-680X",
"issue": "6(3)",
"journal": "Case reports in neurology",
"keywords": "Cancer; Ischemic stroke; Stroke; Thrombolysis",
"medline_ta": "Case Rep Neurol",
"mesh_terms": null,
"nlm_unique_id": "101517693",
"other_id": null,
"pages": "238-42",
"pmc": null,
"pmid": "25473396",
"pubdate": "2014-09",
"publication_types": "D002363:Case Reports",
"references": "21835356;23727456;24065712;20668384;17708109;22179814;16763187;20598579;23317922;19280119;23370205;10089951",
"title": "Intravenous tissue plasminogen activator for an ischemic stroke with occult double primary cancer.",
"title_normalized": "intravenous tissue plasminogen activator for an ischemic stroke with occult double primary cancer"
} | [
{
"companynumb": "JP-ROCHE-1513740",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARGATROBAN"
},
"drugadditional": null,
"drug... |
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