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"abstract": "Cyclosporin A (CYS A) is an immunosuppressant agent administered in autoimmune diseases, and its use during pregnancy and lactation is a debated topic.\n\n\n\nThe demographic characteristics, the activity of the underlying disease, and the onset of fetal-maternal complications have been investigated in 21 consecutive patients (2 RA, 14 SLE, 2 PA, 1 SjS, 1 DM, 1 Churg-Strauss vasculitis), treated with CYS A throughout 29 gestations. A subanalysis of the SLE group was performed.\n\n\n\nWe recorded a live birth rate of 86.2%. The median gestational age at birth was 38.2 weeks. The prevalence of maternal-fetal complications showed no differences with general population. Disease flares appeared in 4% of patients during gestation and in 12% during puerperium.\n\n\n\nWe found no evidence justifying the suspension of CYS A when a pregnancy occurs. The drug does not appear to promote maternal-fetal complications and should be continued in patients who benefit from therapy. Data regarding breast-feeding during therapy are still scarce, but no evidence of toxicity has emerged.",
"affiliations": "Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy.;Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy.;Neonatology and Neonatal Intensive Care Unit, Spedali Civili and University of Brescia, Brescia, Italy.;Obstetrics and Gynecology, Spedali Civili and University of Brescia, Brescia, Italy.;Obstetrics and Gynecology, Spedali Civili and University of Brescia, Brescia, Italy.;Obstetrics and Gynecology, Spedali Civili and University of Brescia, Brescia, Italy.;Functional Rieducation, San Rocco Clinic, Brescia, Italy.;Rheumatology and Clinical Immunology, Spedali Civili and University of Brescia, Brescia, Italy.",
"authors": "Reggia|Rossella|R|;Bazzani|Chiara|C|;Andreoli|Laura|L|;Motta|Mario|M|;Lojacono|Andrea|A|;Zatti|Sonia|S|;Ramazzotto|Francesca|F|;Nuzzo|Monica|M|;Tincani|Angela|A|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine",
"country": "Denmark",
"delete": false,
"doi": "10.1111/aji.12514",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-7408",
"issue": "75(6)",
"journal": "American journal of reproductive immunology (New York, N.Y. : 1989)",
"keywords": "Autoimmune diseases; cyclosporin A; efficacy; pregnancy; safety",
"medline_ta": "Am J Reprod Immunol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001327:Autoimmune Diseases; D001942:Breast Feeding; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007558:Italy; D049590:Postpartum Period; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D015995:Prevalence; D055815:Young Adult",
"nlm_unique_id": "8912860",
"other_id": null,
"pages": "654-60",
"pmc": null,
"pmid": "27145741",
"pubdate": "2016-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Efficacy and Safety of Cyclosporin A in Pregnant Patients with Systemic Autoimmune Diseases.",
"title_normalized": "the efficacy and safety of cyclosporin a in pregnant patients with systemic autoimmune diseases"
} | [
{
"companynumb": "PHHY2018IT008258",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadm... |
{
"abstract": "OBJECTIVE\nAlthough combination pharmacotherapy is common in child and adolescent psychiatry, there has been little research evaluating it. The value of adding risperidone to concurrent psychostimulant and parent training (PT) in behavior management for children with severe aggression was tested.\n\n\nMETHODS\nOne hundred sixty-eight children 6 to 12 years old (mean age 8.89 ± 2.01 years) with severe physical aggression were randomized to a 9-week trial of PT, stimulant (STIM), and placebo (Basic treatment; n = 84) or PT, STIM, and risperidone (Augmented treatment; n = 84). All had diagnoses of attention-deficit/hyperactivity disorder and oppositional-defiant disorder (n = 124) or conduct disorder (n = 44). Children received psychostimulant (usually Osmotic Release Oral System methylphenidate) for 3 weeks, titrated for optimal effect, while parents received PT. If there was room for improvement at the end of week 3, placebo or risperidone was added. Assessments included parent ratings on the Nisonger Child Behavior Rating Form (Disruptive-Total subscale was the primary outcome) and Antisocial Behavior Scale; blinded clinicians rated change on the Clinical Global Impressions scale.\n\n\nRESULTS\nCompared with Basic treatment (PT + STIM [44.8 ± 14.6 mg/day] + placebo [1.88 mg/day ± 0.72]), Augmented treatment (PT + STIM [46.1 ± 16.8 mg/day] + risperidone [1.65 mg/day ± 0.75]) showed statistically significant improvement on the Nisonger Child Behavior Rating Form Disruptive-Total subscale (treatment-by-time interaction, p = .0016), the Nisonger Child Behavior Rating Form Social Competence subscale (p = .0049), and Antisocial Behavior Scale Reactive Aggression subscale (p = .01). Clinical Global Impressions scores were substantially improved for the 2 groups but did not discriminate between treatments (Clinical Global Impressions-Improvement score ≤2, 70% for Basic treatment versus 79% for Augmented treatment). Prolactin elevations and gastrointestinal upset occurred more with Augmented treatment; other adverse events differed modestly from Basic treatment; weight gain in the Augmented treatment group was minor.\n\n\nCONCLUSIONS\nRisperidone provided moderate but variable improvement in aggressive and other seriously disruptive child behaviors when added to PT and optimized stimulant treatment. Clinical trial registration information-Treatment of Severe Childhood Aggression (The TOSCA Study), URL: http://clinicaltrials.gov, unique identifier: NCT00796302.",
"affiliations": "The Ohio State University. Electronic address: aman.1@osu.edu.;University of Texas-Houston Medical School.;Stony Brook University.;The Ohio State University.;University of Pittsburg School of Medicine.;Case Western Reserve University.;Stony Brook University Medical Center.;The Ohio State University.;University of Pittsburg School of Medicine.;Stony Brook University Medical Center.;Nationwide Children's Hospital of Columbus.;Children's Hospital of Pittsburgh of University of Pittsburgh Medical Center.;Stony Brook University.;The Ohio State University.;University of Pittsburg School of Medicine.;The Ohio State University.;The Ohio State University.;The Ohio State University.;The Ohio State University.;The Ohio State University.;The Ohio State University.;Johns Hopkins University.",
"authors": "Aman|Michael G|MG|;Bukstein|Oscar G|OG|;Gadow|Kenneth D|KD|;Arnold|L Eugene|LE|;Molina|Brooke S G|BS|;McNamara|Nora K|NK|;Rundberg-Rivera|E Victoria|EV|;Li|Xiaobai|X|;Kipp|Heidi|H|;Schneider|Jayne|J|;Butter|Eric M|EM|;Baker|Jennifer|J|;Sprafkin|Joyce|J|;Rice|Robert R|RR|;Bangalore|Srihari S|SS|;Farmer|Cristan A|CA|;Austin|Adrienne B|AB|;Buchan-Page|Kristin A|KA|;Brown|Nicole V|NV|;Hurt|Elizabeth A|EA|;Grondhuis|Sabrina N|SN|;Findling|Robert L|RL|",
"chemical_list": "D000697:Central Nervous System Stimulants; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-8567",
"issue": "53(1)",
"journal": "Journal of the American Academy of Child and Adolescent Psychiatry",
"keywords": "disruptive behavior disorders; parent training; physical aggression; psychostimulants; risperidone",
"medline_ta": "J Am Acad Child Adolesc Psychiatry",
"mesh_terms": "D000374:Aggression; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D003131:Combined Modality Therapy; D004357:Drug Synergism; D006801:Humans; D008297:Male; D010290:Parents; D018967:Risperidone; D016896:Treatment Outcome",
"nlm_unique_id": "8704565",
"other_id": null,
"pages": "47-60.e1",
"pmc": null,
"pmid": "24342385",
"pubdate": "2014-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "19764951;15608545;8886943;1821222;21751227;11211365;9315984;4917967;18243886;12153826;2600241;22074813;9204677;12218423;12661883;11886019;20855045;2574607;22684300;10761354;15056514;17450046;17630867;18392193;12544174;15231972;17979959;15756511;12047493;15741782;9400342;18545062",
"title": "What does risperidone add to parent training and stimulant for severe aggression in child attention-deficit/hyperactivity disorder?",
"title_normalized": "what does risperidone add to parent training and stimulant for severe aggression in child attention deficit hyperactivity disorder"
} | [
{
"companynumb": "US-JNJFOC-20131215112",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": null,
... |
{
"abstract": "Hematopoietic stem cell transplantation (HSCT) using an optimized conditioning regimen is essential for the long-term survival of patients with inherited bone marrow failure syndromes (IBMFS). We report HSCT in 24 children with Fanconi anemia (FA, n = 12), Diamond-Blackfan anemia (DBA, n = 7), and dyskeratosis congenita (DC, n = 5) from a single HSCT center. The graft source was peripheral blood stem cells (n = 19) or cord blood stem cells (n = 5). FA and DC patients received reduced-intensity conditioning, while DBA patients had myeloablative conditioning. The median numbers of infused mononuclear cells and CD34+ cells were 14.20 × 108/kg and 4.3 × 106/kg, respectively. The median time for neutrophil and platelet recovery was 12 and 18 days, respectively. Complete donor engraftment was achieved in 23 of 24 patients. There was one primary graft failure. During a median follow-up of 27.5 months (range, 2-130 months), the overall survival in all patients was 95.8%. The incidence of grade II-III acute graft versus host disease (GvHD) and chronic GvHD was 29.2% and 16.7%, respectively. We conclude that HSCT can be a curative option for patients with IBMFS. Modification of the conditioning regimen based on the type of disease may lead to encouraging long-term outcomes.",
"affiliations": "Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China.;Shanghai Children's Medical Center, Affiliated Hospital of Shanghai Jiao Tong University School of Medicine, Shanghai, 200127, China. chenjing@scmc.com.cn.",
"authors": "Li|Qian|Q|;Luo|Changying|C|;Luo|Chengjuan|C|;Wang|Jianmin|J|;Li|Benshang|B|;Ding|Lixia|L|;Chen|Jing|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00277-017-3041-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "96(8)",
"journal": "Annals of hematology",
"keywords": "Children; Conditioning regimen; Hematopoietic stem cell transplantation; Inherited bone marrow failure syndromes",
"medline_ta": "Ann Hematol",
"mesh_terms": "D000293:Adolescent; D000741:Anemia, Aplastic; D029503:Anemia, Diamond-Blackfan; D001855:Bone Marrow Diseases; D000080983:Bone Marrow Failure Disorders; D002648:Child; D002675:Child, Preschool; D036101:Cord Blood Stem Cell Transplantation; D046148:Donor Selection; D019871:Dyskeratosis Congenita; D005199:Fanconi Anemia; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006417:Hematuria; D006457:Hemoglobinuria, Paroxysmal; D006801:Humans; D007223:Infant; D053208:Kaplan-Meier Estimate; D008297:Male; D017063:Outcome Assessment, Health Care; D036102:Peripheral Blood Stem Cell Transplantation; D019172:Transplantation Conditioning",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "1389-1397",
"pmc": null,
"pmid": "28623394",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Disease-specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes.",
"title_normalized": "disease specific hematopoietic stem cell transplantation in children with inherited bone marrow failure syndromes"
} | [
{
"companynumb": "PHHY2017CN091975",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
"drugadditiona... |
{
"abstract": "Adjuvant chemotherapy after surgery for gastric cancer improves survival but is difficult to administer due to poor tolerance. Combination chemotherapy with Docetaxel (Taxotere), Oxaliplatin (Eloxatin) and Capecitabine (Xeloda) (TEX) is used in the treatment of advanced gastric cancer. The efficacy and tolerability of this regimen (TEX) post resection of gastric cancer have not been studied.\nPatients diagnosed with gastric adenocarcinoma, post resection without any prior chemotherapy between July 2007 and May 2011 and treated with TEX regimen administered as T 35 mg/m2 and E 50 mg/m2 on days (d) 1, 8 and X 625 mg/m2 bid (twice daily) on d 1-14 every 21 days were included in this retrospective analysis. Patient's electronic medical records were studied and data on tolerance, progression‑free survival (PFS) and overall survival (OS) was collected.\nFifty-eight patients were treated with adjuvant TEX chemotherapy, majority 40 (68%) had distal gastric cancer. All patients underwent a D1 gastrectomy, and resection was performed for 44 (75%). Only 14 (24%) patients had more than 15 nodes studied in the resected specimen. Distribution for stages I, II and III is 14 (24%), 30 (52%) and 14 (24%), respectively. After a median follow-up of 40 months, the 3-year relapse free survival was 58% (95% CI: 42-68), and estimated median OS was 71 months (95% CI: 19-123 months). Twenty-three (40%) required dose reduction due to toxicity. Grade 3 or 4 toxicity was recorded for 22 (37%). Half (52%) of patients completed all planned chemotherapy of six cycles.\nPost resection of gastric adenocarcinoma adjuvant triplet TEX chemotherapy is a feasible and effective outpatient regimen. Diarrhoea, neutropenia and neuropathy were the common dose limiting toxicity. Post-surgery only half the numbers of patients are able to complete all planned cycles.",
"affiliations": "Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.;Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.;Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.;Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.;Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.;Department of Upper GI surgery, Division of Surgery, Christian Medical College, Vellore, India.;Department of Upper GI surgery, Division of Surgery, Christian Medical College, Vellore, India.;Department of General Pathology, Christian Medical College, Vellore, India.;Department of Radiotherapy, Christian Medical College, Vellore, India.;Department of Biostatistics, Christian Medical College, Vellore, India.;Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India.",
"authors": "Thumaty|Divya Bala|DB|;Chacko|Raju Titus|RT|;John|Ajoy Oommen|AO|;Joel|Anjana|A|;Georgy|Josh Thomas|JT|;Jacob|Myla|M|;Samarasam|Inian|I|;Masih|Dipti|D|;Isaiah|Rajesh|R|;Jeyaseelan|Visalakshi|V|;Singh|Ashish|A|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3332/ecancer.2021.1292",
"fulltext": "\n==== Front\nEcancermedicalscience\nEcancermedicalscience\necancermedicalscience\necancermedicalscience\n1754-6605\nCancer Intelligence\n\n10.3332/ecancer.2021.1292\ncan-15-1292\nClinical Study\nDocetaxel, Oxaliplatin and Capecitabine (TEX) triplet regimen as adjuvant chemotherapy in resected gastric adenocarcinoma\nThumaty Divya Bala 1\nChacko Raju Titus 1\nJohn Ajoy Oommen 1\nJoel Anjana 1\nGeorgy Josh Thomas 1\nJacob Myla 2\nSamarasam Inian 2\nMasih Dipti 3\nIsaiah Rajesh 4\nJeyaseelan Visalakshi 5\nSingh Ashish 1\n1 Department of Medical Oncology, Christian Medical College, Ida Scudder Road, Vellore, TN, India\n2 Department of Upper GI surgery, Division of Surgery, Christian Medical College, Vellore, India\n3 Department of General Pathology, Christian Medical College, Vellore, India\n4 Department of Radiotherapy, Christian Medical College, Vellore, India\n5 Department of Biostatistics, Christian Medical College, Vellore, India\nCorrespondence to: Ashish Singh todrashish@gmail.com\n2021\n21 9 2021\n15 129213 4 2021\n© the authors; licensee ecancermedicalscience.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground\n\nAdjuvant chemotherapy after surgery for gastric cancer improves survival but is difficult to administer due to poor tolerance. Combination chemotherapy with Docetaxel (Taxotere), Oxaliplatin (Eloxatin) and Capecitabine (Xeloda) (TEX) is used in the treatment of advanced gastric cancer. The efficacy and tolerability of this regimen (TEX) post resection of gastric cancer have not been studied.\n\nMaterials and methods\n\nPatients diagnosed with gastric adenocarcinoma, post resection without any prior chemotherapy between July 2007 and May 2011 and treated with TEX regimen administered as T 35 mg/m2 and E 50 mg/m2 on days (d) 1, 8 and X 625 mg/m2 bid (twice daily) on d 1–14 every 21 days were included in this retrospective analysis. Patient’s electronic medical records were studied and data on tolerance, progression‑free survival (PFS) and overall survival (OS) was collected.\n\nResults\n\nFifty-eight patients were treated with adjuvant TEX chemotherapy, majority 40 (68%) had distal gastric cancer. All patients underwent a D1 gastrectomy, and resection was performed for 44 (75%). Only 14 (24%) patients had more than 15 nodes studied in the resected specimen. Distribution for stages I, II and III is 14 (24%), 30 (52%) and 14 (24%), respectively. After a median follow-up of 40 months, the 3-year relapse free survival was 58% (95% CI: 42–68), and estimated median OS was 71 months (95% CI: 19–123 months). Twenty-three (40%) required dose reduction due to toxicity. Grade 3 or 4 toxicity was recorded for 22 (37%). Half (52%) of patients completed all planned chemotherapy of six cycles.\n\nConclusion\n\nPost resection of gastric adenocarcinoma adjuvant triplet TEX chemotherapy is a feasible and effective outpatient regimen. Diarrhoea, neutropenia and neuropathy were the common dose limiting toxicity. Post-surgery only half the numbers of patients are able to complete all planned cycles.\n\ngastric cancer\nstomach cancer\nFLOT\nTEX\nadjuvant chemotherapy\n==== Body\npmcIntroduction\n\nGastric cancer tops the list of cancers associated with deaths and disability-adjusted life-years amongst all the cancers in the recent Global Burden of Disease Study of the burden and incidence of cancers in India [1].\n\nSurgery followed by adjuvant chemotherapy with fluoropyrimidine with or without platinum is considered as a standard treatment for operable gastric cancers [2]. Docetaxel in combination with Oxaliplatin and 5 Fluorouracil has improved survival and has become the standard perioperative chemotherapy regimen in fit patients [3]. Perioperative approach can make systemic chemotherapy available to all patients. Preoperative chemotherapy however may not be possible in the presence of a bleeding ulcer or gastric outlet obstruction. Tolerance reported to adjuvant chemotherapy following gastrectomy is low with only 45%–60% of patient being able to start and complete all planned cycles following surgery [4, 5].\n\nFor advanced gastric cancers, one of the ways to make triplet chemotherapy more tolerable without compromising on efficacy is to replace 5Flurouracil (5FU) with Capecitabine and administer a lower dose of Oxaliplatin and Docetaxel on D1 and day 8 [6–9]. The efficacy of this combination when administered post operatively is not known. In the present study, we report the outcomes with use of Docetaxel, Oxaliplatin, Capecitabine (TEX) regimen in adjuvant setting at a single centre, in south India.\n\nMethods\n\nThis is a single centre, Institutional Review Board (IRB)-approved retrospective analysis of patients with gastric cancer who received TEX chemotherapy after surgery at our centre. All patients treated between May 2007 and April 2011 are included in this analysis. Patients satisfying all the following criteria were included in analysis: histologically proven gastric cancer who have undergone a complete resection (R0 or R1) and received at least one cycle of chemotherapy in our department, with no evidence of metastatic disease on CT scan of abdomen and chest imaging.\n\nThe regimen consisted of Docetaxel administered at 35 mg/m2 on day 1 and day 8, Oxaliplatin at 50 mg/m2 on days 1 and 8 and Capecitabine at 1,250 mg/m2/day, days 1–14, cycle repeated every 21 days. Toxicity assessment was done at every patient visit and recorded as per NCI–CTCAE version 4.0. End points assessed were relapse free survival defined as time from diagnosis to relapse or death and overall survival (OS) defined as time from diagnosis to death.\n\nClinical data collection and statistics\n\nFor this study, demographic data and baseline clinical data were collected retrospectively from the electronic medical records and patients were contacted by telephone regarding the disease status and survival. Follow-up data was updated till September 2019. All data were entered in SPSS Statistics version 21 (IBM) and used for analysis. Descriptive statistics including median, frequency and percentage for categorical variables was used to describe age, gender distribution, treatment and response to treatment. Median event-free survival (EFS) and OS were calculated using Kaplan–Meier estimates.\n\nResults\n\nOf all the inpatient records reviewed between May 2007 and April 2011, 384 patients were admitted for administration of chemotherapy for gastric adenocarcinoma (including adjuvant, neoadjuvant and metastatic disease). Adjuvant chemotherapy was administered to 93 patients, of which 18 patients received only a doublet chemotherapy with Oxaliplatin and 5-Flurouracil while 75 patients received TEX. Fifty-eight patients who fulfilled the inclusion criterion with available date were included in this retrospective study. Patient and disease characteristics are presented in Table 1. Median age at presentation was 53 years (range: 30–70 years). Gastric cancer as expected was commoner in men (69%), and majority (77%) had distal tumours. Patients with proximal tumour were more likely to receive neoadjuvant chemotherapy and therefore represent only 22% in this study.\n\nSurgical findings and final pathological stage are presented in Table 2. Staging was I, II and III in 14 (24%), 30 (52%) and 14 (24%), respectively; There were four patients with stage 1a tumour who received chemotherapy – indications being – distal margin positivity and lymphovascular invasion. Forty-four (76%) patients had <15 nodes harvested from the surgical specimen.\n\nThe median time to start of adjuvant chemotherapy was 3 weeks. After a median follow-up of 40 months, the 3-year relapse free survival was 58% (95% CI: 42–68), and estimated median OS was 71 months (95% CI: 19–123 months) as presented in Figure 1.\n\nToxicity recorded is presented in Table 3.\n\nTwenty-three (40%) required dose reduction due to toxicity. Grade 3 or 4 toxicity was recorded for 22 (37%). 52% of patients completed all planned chemotherapy. Ten (17%) patients discontinued chemotherapy due to grade 3 toxicity.\n\nDiscussion\n\nAbout two decades ago, the intergroup 0116 trial reported improved survival with adjuvant chemoirradiation post resection for gastric adenocarcinoma [10]. Locoregional relapse reduction accounted for majority of overall relapse reduction [11]. Since then, trials have confirmed that after a radical resection for gastric cancer and adjuvant chemotherapy, addition of chemo irradiation does not improve survival [5, 12, 13]. Oral chemotherapy with S1 or Capecitabine as a single agent or combination with Oxaliplatin is effective and is the standard treatment post resection [14, 15]. In another study for early stage gastric cancers, Epirubicin when combined with Cisplatin and Capecitabine did not improve outcomes over the doublet alone [16]. We designed the TEX adjuvant regimen based on the findings from published reports that showed addition of Docetaxel to platinum and 5FU resulted in better response rates and PFS in multiple reports [7, 8].\n\nThe assumption was Docetaxel may be better than Epirubicin in early gastric cancer. Later on it was shown that Docetaxel in combination with Oxaliplatin and infusional 5 Fluorouracil (FLOT) was superior to Epirubicin, Cisplatin, Flurouracil (ECF) in patients receiving perioperative chemotherapy for non-metastatic gastric cancer [3]. A triplet regimen like FLOT or TEX is expected to improve outcomes, provided it can be administered safely to patients post major surgery like gastrectomy. Administration of chemotherapy post-surgery is poorly tolerated with only 45%–60% of patients able to start chemotherapy after surgery and less number are able to complete the entire planned therapy [4, 5] Replacing 5-FU with Capecitabine obviates the need for an infusion pump and central line, associated with increase in cost and catheter related complications, both drugs have a similar incidence of toxicities, though a different profile. TEX is easy to administer as an outpatient treatment as compared to FLOT. Postoperatively more than six cycles are expected to be poorly tolerated due to neuropathy, hand foot syndrome and diarrhoea.\n\nSeventy-eight percent of patients had a distal cancer; upfront surgery is more common for distal cancers for reasons such as obstruction or bleeding. Perioperative chemotherapy is preferred for proximal lesions in the absence of contraindications for chemotherapy. Surgery performed was not D2 resection for any of our patients. However, D1 or an extended D1 gastrectomy is associated with lesser morbidity without any significant compromise on survival [17]. 12 (21%) patients had R1 resection. Adjuvant chemo irradiation is poorly tolerated and is not standard of care at our centre. Our results indicate that TEX is feasible and is an effective regimen with 58% of patients being free of disease recurrence at 3 years after diagnosis. These results are despite the fact that 48% of patients were unable to complete all assigned therapy. The median OS was 71 months, higher as compared to the published literature. This is probably due to the inclusion of only fit patients and early stage disease (stage 1, 2 amounting to 77% of patients) who are able to start chemotherapy and a smaller sample size.\n\nMost relapses were distant, and data on local only relapse rate is not available.\n\nFatigue, diarrhoea, hand foot syndrome, neutropenia and neuropathy were the major toxicity with this regimen. There was one treatment related death due to febrile neutropenia and septic shock that occurred soon after the first dose. Dihydropyrimidine dehydrogenase (DPD) enzyme deficiency testing may predict such severe toxicity with fluoropyrimidines but isn’t yet done for every patient at our centre. Cumulative toxicities like hand foot syndrome, fatigue and neuropathy developed over time and were the main reason for dose reduction and early discontinuation of treatment. From this experience, we suggest that a modification in the schedule which allows infusion of Oxaliplatin and Docetaxel every biweekly in order to reduce toxicity and make the regimen tolerable to more patients who are at risk of relapse.\n\nThe limitations of our study include the retrospective nature, absence of a control arm and inclusion of only patients who were able to start chemotherapy after surgery.\n\nConclusion\n\nPost resection of gastric adenocarcinoma adjuvant TEX is a feasible outpatient triplet chemotherapy regimen with acceptable results. Diarrhoea, neutropenia and neuropathy are the common toxicity requiring dose adjustments. Shortening the duration of adjuvant treatment by use as perioperative treatment may reduce toxicity, improve compliance and should be studied.\n\nConflicts of interest\n\nNil.\n\nFunding\n\nSource(s) of support: CMC Fluid Research Grant.\n\nAcknowledgments\n\nNil.\n\nFigure 1. Overall survival.\n\nTable 1. Baseline characteristics.\n\nPatient and tumour characteristic\tTotal n = 58 (%)\t\nAge (Median, range)\t53 years, Range: 30–70 years\t\nGender\nMales\nFemales\t\n40 (68%)\n18 (31%)\t\nSite\nDistal\nProximal\t\n45 (78%)\n13 (22%)\t\nHistology\nPoorly differentiated\nModerately differentiated\nWell differentiated\t\n29 (50%)\n26 (45%)\n3 (5%)\t\nSignet ring histology\t12/58 (20%)\t\nLVI present\t31/58 (53%)\t\nPNI present\t19/58 (32%)\t\nLVI: lymphovascular invasion; PNI: perineural invasion\n\nTable 2. Surgical details\n\nSurgical details\tNumber (%)\t\nType of gastrectomy\nTotal\nSubtotal\nDistal\tN = 58\n13 (22%)\n38 (65%)\n7 (12%)\t\nLymph node dissection\nD1\nD1 +\nD2\nD0\tn = 5411 (20%)\n42 (77%)\n0\n1\t\nNo of lymph node dissected\n<15\n≥15\tn = 57\n43\n14\t\nCompleteness of resection\nR0\nR1\nR2\nNot known\tN = 58\n44\n12\n0\n2\t\nFinal path TNM stage\n1\n2\n3\n4\tN = 58\n14\n30\n14\n0\t\n\nTable 3. Adverse events\n\nToxicity\tGrade 1–2, n (%)\tGrade 3–4, n = 22 (37%)\t\nAnaemia\t20 (34%)\t6 (10%)\t\nThrombocytopenia\t14 (24%)\t4 (6%)\t\nFebrile neutropenia\t2 (3%)\t4 (6%)\t\nDiarrhoea\t16 (28%)\t8 (13%)\t\nNeuropathy\t12 (20%)\t5 (9%)\t\nHand foot syndrome\t24 (41%)\t6 (10%)\t\nHypersensitivity\t3 (5%)\t1 (2%)\n==== Refs\nReferences\n\n1. Dhillon PK Mathur P Nandakumar A The burden of cancers and their variations across the states of India: the Global Burden of Disease Study 1990–2016 Lancet Oncol 2018 19 10 1289 1306 10.1016/S1470-2045(18)30447-9 30219626\n2. Paoletti X Oba K Burzykowski T Benefit of adjuvant chemotherapy for resectable gastric cancer: a meta-analysis J Am Med Assoc 2010 303 17 1729 1737 10.1001/jama.2010.534\n3. Al-Batran SE Homann N Pauligk C Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial Lancet 2019 393 10184 1948 1957 10.1016/S0140-6736(18)32557-1 30982686\n4. Mirza A Pritchard S Welch I The postoperative component of MAGIC chemotherapy is associated with improved prognosis following surgical resection in gastric and gastrooesophageal junction adenocarcinomas Int J Surg Oncol 2013 2013 24163764\n5. Cats A Jansen EP van Grieken NC Chemotherapy versus chemoradiotherapy after surgery and preoperative chemotherapy for resectable gastric cancer (CRITICS): an international, open-label, randomised phase 3 trial Lancet Oncol 2018 19 5 616 628 10.1016/S1470-2045(18)30132-3 29650363\n6. Stein A Arnold D Thuss-Patience PC Docetaxel, oxaliplatin and capecitabine (TEX regimen) in patients with metastatic gastric or gastro-esophageal cancer: results of a multicenter phase I/II study Acta Oncol 2014 53 3 392 398 10.3109/0284186X.2013.833346 24024696\n7. Evans D Miner T Akerman P A phase I study of docetaxel, oxaliplatin, and capecitabine in patients with metastatic gastroesophageal cancer Am J Clin Oncol 2007 30 4 346 349 10.1097/COC.0b013e318042d582 17762433\n8. Grothe W Hofheinz RD Mantovani Loeffler L Phase I trial of docetaxel, oxaliplatin and capecitabine (TEX) in patients with metastatic gastric cancer J Clin Oncol 2006 24 18_suppl 14051 14051 10.1200/jco.2006.24.18_suppl.14051\n9. Ajani JA Moiseyenko VM Tjulandin S Clinical benefit with docetaxel plus fluorouracil and cisplatin compared with cisplatin and fluorouracil in a phase III trial of advanced gastric or gastroesophageal cancer adenocarcinoma: the V-325 study group J Clin Oncol 2007 25 22 3205 3209 10.1200/JCO.2006.10.4968 17664467\n10. Macdonald JS Smalley SR Benedetti J Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction N Engl J Med 2001 345 10 725 730 10.1056/NEJMoa010187 11547741\n11. Smalley SR Benedetti JK Haller DG Updated analysis of SWOG-directed intergroup study 0116: a phase III trial of adjuvant radiochemotherapy versus observation after curative gastric cancer resection J Clin Oncol 2012 30 19 2327 2333 10.1200/JCO.2011.36.7136 22585691\n12. Park SH Zang DY Han B ARTIST 2: interim results of a phase III trial involving adjuvant chemotherapy and/or chemoradiotherapy after D2-gastrectomy in stage II/III gastric cancer (GC) J Clin Oncol 2019 37 15_suppl 4001 4001 10.1200/JCO.2019.37.15_suppl.4001\n13. Lee J Lim DH Kim S Phase III trial comparing capecitabine plus cisplatin versus capecitabine plus cisplatin with concurrent capecitabine radiotherapy in completely resected gastric cancer with D2 lymph node dissection: the ARTIST trial J Clin Oncol 2011 30 268 273 10.1200/JCO.2011.39.1953 22184384\n14. Bang YJ Kim YW Yang HK Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): a phase 3 open-label, randomised controlled trial Lancet 2012 379 9813 315 321 10.1016/S0140-6736(11)61873-4 22226517\n15. Sakuramoto S Sasako M Yamaguchi T Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine N Engl J Med 2007 357 18 1810 1820 10.1056/NEJMoa072252 17978289\n16. Alderson D Cunningham D Nankivell M Neoadjuvant cisplatin and fluorouracil versus epirubicin, cisplatin, and capecitabine followed by resection in patients with oesophageal adenocarcinoma (UK MRC OE05): an open-label, randomised phase 3 trial Lancet Oncol 2017 18 9 1249 1260 10.1016/S1470-2045(17)30447-3 28784312\n17. Memon MA Subramanya MS Khan S Meta-analysis of D1 versus D2 gastrectomy for gastric adenocarcinoma Ann Surg 2011 253 5 900 911 10.1097/SLA.0b013e318212bff6 21394009\n\n",
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"journal": "Ecancermedicalscience",
"keywords": "FLOT; TEX; adjuvant chemotherapy; gastric cancer; stomach cancer",
"medline_ta": "Ecancermedicalscience",
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"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "21394009;22585691;17664467;11547741;28784312;22226517;30982686;30219626;24024696;17978289;17762433;29650363;22184384;24163764;20442389",
"title": "Docetaxel, Oxaliplatin and Capecitabine (TEX) triplet regimen as adjuvant chemotherapy in resected gastric adenocarcinoma.",
"title_normalized": "docetaxel oxaliplatin and capecitabine tex triplet regimen as adjuvant chemotherapy in resected gastric adenocarcinoma"
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"abstract": "Rhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4-2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported.\n\n\n\nWe describe two cases with congenital RMS treated at Bambino Gesù Children's Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up.\n\n\n\nRMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613-20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets.",
"affiliations": "Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy. ida.russo@opbg.net.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Radiology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Laboratories - Pathology Unit, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Piazza di Sant'Onofrio 4, 00165, Rome, Italy.;Department of Pediatric Hematology/Oncology, Bambino Gesù Children's Hospital, IRCCS, Piazza di Sant'Onofrio 4, 00165, Rome, Italy.",
"authors": "Russo|Ida|I|0000-0002-7030-8639;Di Paolo|Virginia|V|;Gurnari|Carmelo|C|;Mastronuzzi|Angela|A|;Del Bufalo|Francesca|F|;Di Paolo|Pier Luigi|PL|;Di Giannatale|Angela|A|;Boldrini|Renata|R|;Milano|Giuseppe Maria|GM|",
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"fulltext": "\n==== Front\nBMC PediatrBMC PediatrBMC Pediatrics1471-2431BioMed Central London 112810.1186/s12887-018-1128-5Case ReportCongenital Rhabdomyosarcoma: a different clinical presentation in two cases http://orcid.org/0000-0002-7030-8639Russo Ida (+39) 06 68593697ida.russo@opbg.net 1Di Paolo Virginia (+39)06 68593516virginia.dipaolo@opbg.net 1Gurnari Carmelo (+39)06 68592574carmelo.gurnari01@universitadipavia.it 1Mastronuzzi Angela (+39)06 68592574angela.mastronuzzi@opbg.net 1Del Bufalo Francesca (+39)06 68592574francesca.delbufalo@opbg.net 1Di Paolo Pier Luigi (+39)0668592574pierluigi.dipaolo@opbg.net 2Di Giannatale Angela (+39)06 68593707angela.digiannatale@opbg.net 1Boldrini Renata (+39)06 68592154renata.boldrini@opbg.net 3Milano Giuseppe Maria (+39) 06 68592444giuseppemaria.milano@opbg.net 11 0000 0001 0727 6809grid.414125.7Department of Pediatric Hematology/Oncology, Bambino Gesù Children’s Hospital, IRCCS, Piazza di Sant’Onofrio 4, 00165 Rome, Italy 2 0000 0001 0727 6809grid.414125.7Department of Radiology, Bambino Gesù Children’s Hospital, IRCCS, Piazza di Sant’Onofrio 4, 00165 Rome, Italy 3 0000 0001 0727 6809grid.414125.7Department of Laboratories - Pathology Unit, Bambino Gesù Children’s Hospital, IRCCS, Rome, Italy. Piazza di Sant’Onofrio 4, 00165 Rome, Italy 15 5 2018 15 5 2018 2018 18 1661 8 2017 30 4 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nRhabdomyosarcoma (RMS), one of the most common soft tissue sarcomas of childhood, is very rare in the neonatal period (0.4–2% of cases). In order to gain a deeper understanding of this disease at such age, patient and tumor features, as well as treatment modality and outcome need to be reported.\n\nCase presentation\nWe describe two cases with congenital RMS treated at Bambino Gesù Children’s Hospital between 2000 and 2016. They represent only 2.24% of all RMS patients diagnosed during that period in our Institution; this data is in agreement with the incidence reported in the literature. They reflect the two different clinical forms in which the disease may manifest itself. One patient, with the alveolar subtype (positive for specific PAX3-FOXO1 fusion transcript) and disseminated disease, had a fatal outcome with central nervous system (CNS) progression despite conventional and high dose chemotherapy. The other child, with the localized embryonal subtype, was treated successfully with conservative surgery and conventional chemotherapy, including prolonged maintenance therapy. He is disease free at 7 years of follow-up.\n\nConclusions\nRMS can also be diagnosed during the neonatal period. Given the young age, disease management is often challenging, and especially for the alveolar subtype, the outcome is dismal despite intensified multimodality therapy. In fact, it characteristically manifests with multiple subcutaneous nodules and progression most commonly occurs in the CNS (Rodriguez-Galindo et al., Cancer 92(6):1613–20, 2001). In this context, CNS prophylaxis could play a role in preventing leptomeningeal dissemination, and molecular studies can allow a deeper tumor characterization, treatment stratification and identification of new potential therapeutic targets.\n\nKeywords\nRhabdomyosarcomaNewbornRare diseaseissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nRhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas of childhood. In 5–10% of cases, it is diagnosed in children aged less than one year old, and may be congential in 0.4–2% [1–3]. Various reports indicate that, when the diagnosis occurs in the neonatal period, the prognosis is worse than in older children [2–7]. We retrospectively reviewed the medical records of 89 children affected by RMS treated between 2000 and 2016 at our Department and, among these, we found two congenital cases. We report the clinical, radiological and histological characteristics of these patients, as well as therapeutic approach and outcome, together with a literature review of congenital RMS.\n\nCase presentation\nCase #1\nA full term newborn girl presented with widespread multiple nodular cutaneous and subcutaneous lesions on the head, limbs and trunk. Her mother’s pregnancy as well as family history were unremarkable. The color of the lesions ranged from bluish to purple, a characteristic of the so-called “blueberry muffin lesions”. She had no dysmorphic features or congenital anomalies. Excisional biopsy of one skin lesion showed a small-round-cell tumor, with an alveolar pattern of growth consistent with alveolar RMS (ARMS). Array-CGH analysis of tumor cells detected the specific PAX3-FOXO1 fusion transcript. Computed tomography (CT) revealed multiple lesions in the liver, pancreas, lungs, thoracic and abdominal walls (Fig. 1). A magnetic resonance image of the brain and spine showed a left retro-orbital mass and a paravertebral lumbosacral lesion. Bone-marrow and bones were positive for disease localization. After disease staging no primary site could be detected and the tumor was regarded as multifocal. The child was classified as group IV according to the Intergroup Rhabdomyosarcoma Study Group (IRSG) classification, and as stage IV according to TNM pretreatment staging classification [8]. She started chemotherapy with vincristine, actinomycin-D and cyclophosphamide (age and weight adapted doses). She presented a mixed response after 4 courses: complete remission in bone-marrow, skin and subcutaneous nodules; partial response of visceral, retro-orbital and lumbosacral lesions; leptomeningeal and pericardial progression. Following a discussion with the family and their request for further treatment, the child underwent chemotherapy with ifosfamide, vincristine, actinomycin-D, doxorubicin and intrathecal liposomial cytarabine arabinoside. The patient achieved complete remission of leptomeningeal and pericardial disease after 4 courses. Subsequently, she received high-dose consolidation therapy with busulfan and melphalan followed by autologous stem cell transplantation. Unfortunately, after one month, she presented central nervous system (CNS) recurrence and died of disease progression at 9 months of age.Fig. 1 a Axial contrast-enhanced CT image shows a multiple soft tissue masses in the subcutaneous fat with peripheral enhancement; some of these masses expand in the muscles. In the left posterior part of the chest the mass can be seen to lie slightly lateral to the paravertebral region (white arrow). b Axial, contrast-enhanced CT shows multiple low-density masses in the right and left lobes of the liver and in the pancreas. c Sagittal T2-weighted MR imaging shows a lobulated, hyperintense presacral mass (white arrow). d Axial T2-weighted MR imaging shows heterogeneous hyperintense intraorbital mass (white arrow)\n\n\n\nCase #2\nA 5-day-old boy presented an abdominal mass in the hypogastric region. His mother’s full-term pregnancy was uncomplicated. Physical examination and routine neonatal laboratory values were normal. Ultrasound of the abdomen and pelvis showed a solid mass (greatest diameter was > 5 cm) located between the posterior bladder wall and sacrum. No family history of cancer was reported. On the assumption that the lesion was of benign nature, the child underwent macroscopically complete surgical excision of the mass. Intraoperatively, the tumor was found to originate from the prostate gland. The pathological examination revealed an embryonal RMS (ERMS). Molecular studies regarding the tumour with real time polymerase chain reaction (RT-PCR) did not reveal any PAX3-FOXO1 and PAX7-FOXO1 fusion transcripts. The child was classified as group II according to the IRSG classification and stage III according to the TNM pretreatment staging classification [8]. According to the European ongoing protocol (NCT#00339118) for older children, he started chemotherapy with 9 courses of vincristine, actinomycin-D and ifosfamide (age and weight adapted doses). Due to paralytic ileus, vincristine was reduced by 50% from the third course onwards. Considering the young age, radiotherapy was not delivered. Thus, it was decided to use a prolonged maintenance therapy with 6 cycles of cyclophosphamide and vinorelbine. He is disease free at 7 years of follow-up and is doing well except for mild neurogenic bladder dysfunction.\n\nDiscussion and conclusion\nCongenital RMS is a very rare neoplasia, as confirmed by data collected in our Institution over a 16-year period: only 2.24% of all RMS patients were diagnosed with the congenital form. We also performed a comprehensive PubMed search and 33 reports of congenital RMS (16 ERMS and 17 ARMS) published in the last 30 years were found and reviewed (Table 1). ERMS [9–22] ARMS [23–32]Table 1 Congenital Rhabdomyosarcoma: review of the literature\n\nPatient and disease characteristics\tERMS ptse\n(n = 16)\tARMS ptse\n(n = 17)\t\nGender: female/male (sex ratio)\t5/11 (0.45)\t10/7 (1.4)\t\nPrimary site\t\n PM head & neck\t–\t1\t\n Non PM head & neck\t6\t4\t\n Orbit\t–\t–\t\n GU non bladder-prostate\t2\t–\t\n GU bladder-prostate\t2\t–\t\n Extremities\t1\t7\t\n Other site\t5a\t4b\t\n NA\t–\t1\t\nIRSG\t\n I\t1\t–\t\n II\t4\t1\t\n III\t11\t3\t\n IV\t1\t13c\t\nMolecular biology\t\n Negative\t2\t5\t\n NA\t12\t8\t\n PAX3-FOXO1 positive\t–\t3\t\n PAX7-FOXO1 positive\t–\t–\t\n Others\t2 [t(2;8)]\t1 [N-myc amplification]\t\nTherapy\t\n NA\t–\t1\t\n Surgery only\t2\t–\t\n Chemotherapy only\t2\t9\t\n Chemotherapy + surgery\t9\t4\t\n Chemotherapy + surgery + radiotherapy\t3\t2\t\n Chemotherapy + radiotherapy\t–\t1\t\nOutcome\t\n Alive [median months from dg (range)]\t8 [31.5 (6–240)]\t4 [9 (6–240)]\t\n Dead\t2\t13d\t\n NA\t6\t–\t\nERMS embryonal rhabdomyosarcoma, ARMS alveolar rhabdomyosarcoma, pts. patients, PM parameningeal, n number, GU genito-urinary, NA not available, IRSG Intergroup Rhabdomyosarcoma Study Group, dg diagnosis\n\na2-perineal, 2-chest wall, 1-trunk\n\nb2-trunk, 2-chest wall\n\ncFor all patients, cutaneous and subcutaneous tissue was a metastatic site\n\nd7/13 patients had central nervous system disease progression\n\neData about family history of cancer were not available\n\n\n\nThe most frequent primary site for ARMS was the extremities, whereas for ERMS it was non-parameningeal head and neck. The two cases we reported represent the two different clinical forms in which the disease may manifest itself. While congenital ERMS is often localized and has the same behavior as that observed in older children, congenital ARMS is a highly malignant tumor, often occurring as a disseminated disease (see Case #1). Moreover, ARMS often evolves with the development of brain metastases despite an initial good response to chemotherapy [23, 24]. For case #1, in order to obtain CNS disease remission, we used intrathecal liposomial cytarabine arabinoside, and given the well-known dismal prognosis of the disease and the absence of other suitable alternatives, we decided to use consolidation high-dose chemotherapy. However, the results with high-dose chemotherapy reported in previous published trials, did not show significant benefits in metastatic RMS [33, 34]. Currently, there are no specific guidelines regarding treatment for neonates and infants with sarcoma, with few exceptions, such as that of infantile fibrosarcoma [35]. Infants with RMS are usually treated according to the same protocols used for older children: mainly alkylating agents, vincristine, actinomycin-D, with or without anthracyclines. However, they require tailored treatments given the physiologic immaturity of various organs. Ragab et al. [2] reported an unacceptable toxicity compared with results in older children (5% versus 1% of treatment-related deaths), when full chemotherapy doses were used in infants treated in the IRSG I and II trials. Chemotherapy dose reduction in infants resulted in less fatal toxicities without affecting the overall outcome [1, 3, 4]. Moreover, to avoid cardiac and renal damage, anthracyclines and ifosfamide are omitted in patients less than 3 and 1 months old respectively. With regards to the management of congenital ARMS, we hypothesized that children affected by this disease, could benefit from early use of chemotherapeutic agents with good blood-brain barrier passage as well as early intrathecal chemotherapy, as one of the main causes of treatment failure is CNS progression. Local control, determined by extended surgery and radiotherapy, also poses special challenges in very young children due to possible sequelae. In the literature (Table 1), only 3 out of 16 patients with congenital ERMS received radiotherapy associated with conservative surgery (one of them was a female with a vaginal primary who underwent brachytherapy) [23]. Given the small number of patients and the lack of follow-up data in about one third of cases (6\\16), no conclusion can be drawn concerning the outcome. The Italian Cooperative Group reported a higher local recurrence rate in infants with RMS who did not receive appropriate local treatment [1]. In our ERMS patient, since radiotherapy was not recommended, we decided to prolong treatment with maintenance chemotherapy. In this context, our decision was taken in order to consolidate disease remission. The potential role of maintenance therapy in this setting is intriguing but impossible to define given the anecdotal nature of our case. Few data are available regarding tumor biology and fusion status, being reported in only 13 out of 33 cases (Table 1). Gene profiling, currently mandatory in RMS, is even more important in congenital forms, which present a challenging disease. In fact, it could allow more accurate prognostic predictions, as well as detection of new molecular targets. In this regard, molecular prognostic factors have already been identified for a subgroup of congenital RMS, namely the spindle-cell type [36]; the tumors carrying NCOA2 gene rearrangements indeed showed a more favorable clinical course.\n\nIn conclusion, although rarely, RMS can also arise in the neonatal period. In these patients, it is often difficult to establish a balance between the necessity to cure and the risk of long-term effects. A large effort to elaborate guidelines/protocols is desirable to homogenize treatment for this rare tumor occurring within this age group. From experience gathered in the 2 reported cases, early CNS prophylaxis should be considered for the alveolar subtype and prolonged maintenance chemotherapy rather than radiotherapy might be envisaged for the localized embryonal type. Moreover, deeper molecular biology studies are crucial for tumor characterization, treatment stratification and for the discovery of new therapeutic targets.\n\nAbbreviations\nAIEOPItalian Association of Pediatric Hematology/Oncology\n\nARMSAlveolar Rhabdomyosarcoma\n\nArray-CGHArray - Comparative Genomic Hybridization\n\nCTComputed tomography\n\nERMSEmbryonal Rhabdomyosarcoma\n\nIRSGIntergroup Rhabdomyosarcoma Study Group\n\nRMSRhabdomyosarcoma\n\nWe thank Doctor Daniel Orbach for the critical reading of this paper and suggestions, the child’s parents who gave informed consent for publication, “Il cuore grande di Flavio Onlus” for the research support, and Valentina Silenzi for editing.\n\nAvailability of data and materials\nAll data generated and analyzed during this study are included in this published article.\n\nAuthors’ contributions\nIR: collected the patient data, conducted the literature review, drafted the initial manuscript, and edited the manuscript according to feedback of the other authors. VDP: conducted the literature review, drafted the initial manuscript, and edited the manuscript according to feedback from the other authors. CG: reported clinical patient data, drafted the initial manuscript. AM and FBD: critically reviewed the manuscript. PLDP: performed the radiological image and legend, and critically reviewed the manuscript. ADG: collaborated with the design of the project, followed and supported indication for the manuscript realization, critically reviewed the manuscript. RB: performed histological diagnosis and critically reviewed the manuscript. GMM: conceptualised and designed the paper, provided feedback, reviewed and revised the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nWritten informed consent to participate in the study was obtained from the parents of the patients.\n\nConsent for publication\nWritten informed consent for publication of their clinical details and clinical images was obtained from the parents of the patients.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Ferrari A Casanova M Bisogno G Zanetti I Cecchetto G De Bernardi B Riccardi R Tamaro P Meazza C Alaggio R Ninfo V Carli M Italian Cooperative Group Rhabdomyosarcoma in infants younger than one year old: a report from the Italian Cooperative Group Cancer 2003 97 10 2597 2604 10.1002/cncr.11357 12733159 \n2. Ragab AH Heyn R Tefft M Hays DN Newton WA Jr Beltangady M Infants younger than 1 year of age with rhabdomyosarcoma Cancer 1986 58 12 2606 2610 10.1002/1097-0142(19861215)58:12<2606::AID-CNCR2820581209>3.0.CO;2-T 3779610 \n3. Koscielniak E Harms D Schmidt D Ritter J Keim M Riehm H Treuner J Soft tissue sarcomas in infants younger than 1 year of age: a report of the German soft tissue sarcoma study group (CWS-81) Med Pediatr Oncol 1989 17 2 105 110 10.1002/mpo.2950170207 2704331 \n4. Salloum E Flamant F Rey A Caillaud JM Friedman S Valteau D Lemerle J Rhabdomyosarcoma in infants under one year of age: experience of the Institut Gustave-Roussy Med Pediatr Oncol 1989 17 5 424 428 10.1002/mpo.2950170513 2796858 \n5. Orbach D Rey A Oberlin O Sanchez de Toledo J Terrier-Lacombe MJ van Unnik A Quintana E Stevens MC Soft tissue sarcoma or malignant mesenchymal tumors in the first year of life: experience of the International Society of Pediatric Oncology (SIOP) malignant mesenchymal tumor committee J Clin Oncol 2005 23 19 4363 4371 10.1200/JCO.2005.12.009 15994146 \n6. Lobe TE Wiener ES Hays DM Lawrence WH Andrassy RJ Johnston J Wharam M Webber B Ragab A Neonatal rhabdomyosarcoma: the IRS experience J Pediatr Surg 1994 29 8 1167 1170 10.1016/0022-3468(94)90302-6 7965528 \n7. Dillon PW Whalen TV Azizkhan RG Haase GM Coran AG King DR Smith M Neonatal soft tissue sarcomas: the influence of pathology on treatment and survival. Children’s Cancer Group Surgical Committee J Pediatr Surg 1995 30 7 1038 1041 10.1016/0022-3468(95)90337-2 7472928 \n8. Lawrence W Jr Anderson JR Gehan EA Maurer H Pretreatment TNM staging of childhood rhabdomyosarcoma: a report of the intergroup rhabdomyosarcoma study group. Children’s cancer study group. Pediatric oncology group Cancer 1997 80 1165 1170 10.1002/(SICI)1097-0142(19970915)80:6<1165::AID-CNCR21>3.0.CO;2-5 9305719 \n9. Hayashi Y Inaba T Hanada R Yamamoto K Translocation 2;8 in a Congenital Rhabdomyosarcoma Cancer Genet Cytogenet 1988 30 2 343 345 10.1016/0165-4608(88)90208-7 3342389 \n10. Onal B Ozdemir H Arac M Oznur I Isik S Rhabdomyosarcoma of the prostate in a newborn: sonographic and CT findings Eur J Radiol 1995 21 2 106 108 10.1016/0720-048X(95)00685-J 8850502 \n11. Skelton VA Goodwin A Perinatal management of a neonate with airway obstruction caused by rhabdomyosarcoma of the tongue Br J Anaesth 1999 83 6 951 955 10.1093/bja/83.6.951 10700800 \n12. Jogai S Radotra BD Joshi K Congenital Paratesticular Rhabdomyosarcoma Ped Path Mol Med 2009 21 5 513 516 10.1080/pdp.21.5.513.516 \n13. Matsunaga GS Shanberg AM Rajpoot D Prenatal Ultrasonographic Detection of Bladder Rhabdomyosarcoma J Urol 2003 169 4 1495 1496 10.1097/01.ju.0000053462.98574.f7 12629400 \n14. Lee M-W Chung W-K Choi J-H Moon K-C Koh J-K A case of botryoid-type Embryonal Rhabdomyosarcoma Clin Exp Dermatol 2009 34 8 e737 e739 10.1111/j.1365-2230.2009.03456.x 19663848 \n15. Singh O Gupta SS Upadhyaya V Sharma SS Lahoti BK Raj Mathur K Rhabdomyosarcoma of the posterior chest wall in a newborn: a case report Cases J 2009 2 1 6818 10.4076/1757-1626-2-6818 19829867 \n16. Meloni-Ehrig A Smith B Zgoda JA Greenberg J Perdahl-Wallace E Zaman S Mowrey P Translocation (2;8)(q35;q13): a recurrent abnormality in congenital embryonal rhabdomyosarcoma Cancer Genet Cytogenet 2009 191 1 43 45 10.1016/j.cancergencyto.2009.01.010 19389508 \n17. Kraft SM Singh V Sykes KJ Gamis A Manalang MA Wei JL Differentiating between congenital rhabdomyosarcoma versus fibromatosis of the pediatric tongue Int J Pediatr Otorhinolaryngol 2010 74 7 781 785 10.1016/j.ijporl.2010.03.057 20435354 \n18. Shahgholi E Mollaian M Haghshenas Z Honarmand M Congenital rhabdomyosarcoma, central precocious puberty, hemihypertrophy and hypophosphatemic rickets associated with epidermal nevus syndrome J Pediatr Endocrinol Metab 2011 24 11-12 1063 1066 10.1515/JPEM.2011.378 22308867 \n19. Hala Megarbane, Francois Doz, Yves Manach, Christopher Fletcher, Francis Jaubert, Yves de Prost, Dominique Hamel-Teillac, (2011) Neonatal Rhabdomyosarcoma Misdiagnosed as a Congenital Hemangioma. Pediatr Dermatol 28 (3):299-301\n20. Singh GB, Rai AK, Arora R, Garg S, Abbey P, Shukla S. A Rare Case of Congenital Simple Cystic Ranula in a Neonate. Case Rep Otolaryn. 2013;2013:1–3.\n21. Christman MP Kerner JK Cheng C Piris A Nepo AG Sepehr A Kroshinsky D Rhabdomyosarcoma Arising in a Giant Congenital Melanocytic Nevus Pediatr Dermatol 2014 31 5 584 587 10.1111/pde.12359 24913904 \n22. Lee YC Hsu YH Yang SH Huang TL Congenital Eyelid Rhabdomyosarcoma Ophthal Plast Reconstr Surg 2016 32 5 e104 e106 10.1097/IOP.0000000000000290 25216197 \n23. Rodriguez-Galindo C Hill DA Onyekwere O Pin N Rao BN Hoffer FA Kun LE Pappo AS Santana VM Neonatal alveolar rhabdomyosarcoma with skin and brain metastases Cancer 2001 92 6 1613 1620 10.1002/1097-0142(20010915)92:6<1613::AID-CNCR1487>3.0.CO;2-N 11745240 \n24. Grundy R Anderson J Gaze M Gerrard M Glaser A Gordon A Malone M Pritchard-Jones K Michalski A Congenital alveolar rhabdomyosarcoma: clinical and molecular distinction from alveolar rhabdomyosarcoma in older children Cancer 2001 91 3 606 612 10.1002/1097-0142(20010201)91:3<606::AID-CNCR1041>3.0.CO;2-M 11169945 \n25. Hayashi K Ohtsuki Y Takahashi K Sonobe H Nakamura S-i Kitagawa N Arata J Shimanouchi Y Kurashige T Congenital Alveolar Rhabdomyosarcoma with multiple skin metastases: Report of a Case Pathol Int 1988 38 2 241 248 10.1111/j.1440-1827.1988.tb01102.x \n26. Kitagawa N Arata J Ohtsuki Y Hayashi K Oomori Y Tomoda T Congenital Alveolar Rhabdomyosarcoma Presenting as a Blueberry Muffin Baby J Dermatol 1989 16 5 409 411 10.1111/j.1346-8138.1989.tb01291.x 2600281 \n27. Schmidt D Fletcher CDM Harms D Rhabdomyosarcomas with Primary Presentation in the Skin Pathol Res Pract 1993 189 4 422 427 10.1016/S0344-0338(11)80330-4 8351244 \n28. Ito F Watanabe Y Harada T Horibe K Cerebral metastases of alveolar rhabdomyosarcoma in an infant with multiple skin nodules J Pediatr Hematol Oncol 1997 19 5 466 469 10.1097/00043426-199709000-00012 9329472 \n29. Godambe SV Rawal J Blueberry muffin rash as a presentation of alveolar cell rhabdomyosarcoma in a neonate Acta Paediatr 2000 89 1 115 117 10.1111/j.1651-2227.2000.tb01199.x 10677070 \n30. Brecher AR Reyes-Mugica M Kamino H Chang MW Congenital Primary Cutaneous Rhabdomyosarcoma in a Neonate Pediatr Dermatol 2003 20 4 335 338 10.1046/j.1525-1470.2003.20413.x 12869157 \n31. Vankalakunti M Das A Rao NK Postauricular congenital alveolar rhabdomyosarcoma- a case report of an unusual entity Diagn Pathol 2006 1 37 10.1186/1746-1596-1-37 17044930 \n32. Rekhi B Qureshi SS Narula G Gujral S Kurkure P Rapidly Progressive Congenital Rhabdomyosarcoma Presenting with Multiple Cutaneous Lesions: An Uncommon Diagnosis and a Therapeutic Challenge Pathol Res Pract 2014 210 5 328 333 10.1016/j.prp.2014.02.001 24635971 \n33. Carli M Colombatti R Oberlin O European intergroup studies (MMT4–89 and MMT4–91) on childhood metastatic rhabdomyosarcoma: final results and analysis of prognostic factors J Clin Oncol 2004 22 23 4787 4794 10.1200/JCO.2004.04.083 15570080 \n34. Bisogno G Ferrari A Prete A Messina C Basso E Cecchetto G Indolfi P Scarzello G D’Angelo P De Sio L Di Cataldo A Carli M Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma Eur J Cancer 2009 45 17 3035 3041 10.1016/j.ejca.2009.08.019 19783136 \n35. Orbach D Brennan B De Paoli A Gallego S Mudry P Francotte N van Noesel M Kelsey A Alaggio R Ranchère D De Salvo GL Casanova M Bergeron C Merks JH Jenney M Stevens MC Bisogno G Ferrari A Conservative strategy in infantile fibrosarcoma is possible: the European paediatric soft tissue sarcoma study group experience Eur J Cancer 2016 57 1 9 10.1016/j.ejca.2015.12.028 26849118 \n36. Mosquera JM Sboner A Zhang L Kitabayashi N Chen CL Sung YS Wexler LH LaQuaglia MP Edelman M Sreekantaiah C Rubin MA Antonescu CR Recurrent NCOA2 gene rearrangements in congenital/infantile spindle cell rhabdomyosarcoma Genes Chromosom Cancer 2013 52 6 538 550 10.1002/gcc.22050 23463663\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "18(1)",
"journal": "BMC pediatrics",
"keywords": "Newborn; Rare disease; Rhabdomyosarcoma",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000008:Abdominal Neoplasms; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009378:Neoplasms, Multiple Primary; D012208:Rhabdomyosarcoma; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"other_id": null,
"pages": "166",
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"pmid": "29764408",
"pubdate": "2018-05-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19663848;24913904;25216197;15994146;17044930;12396906;10700800;9329472;9305719;19783136;24083044;10677070;3779610;3342389;19389508;7472928;12733159;24635971;23463663;12629400;11745240;22308867;11169945;2704331;15570080;7965528;12869157;3389151;20435354;2600281;20738798;8351244;26849118;8850502;19829867;2796858",
"title": "Congenital Rhabdomyosarcoma: a different clinical presentation in two cases.",
"title_normalized": "congenital rhabdomyosarcoma a different clinical presentation in two cases"
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"abstract": "Alveolar hemorrhage (AH) is a heterogeneous clinical syndrome with a high mortality rate, characterized by extensive bleeding into the alveolar spaces. AH secondary to systemic thrombolysis treatment in the setting of acute myocardial infarction is an uncommon complication, but potentially fatal and can lead to acute respiratory failure. This entity is rarely reported in the literature. We report two cases of acute AH after intravenous thrombolysis for acute myocardial infarction, which could contribute to the literature on the subject, and discuss the risk factors as well as the clinical and radiological findings supporting the diagnosis. We overview also the rare previous published case reports in this context, and we contrast our findings with those reported in the literature.",
"affiliations": "Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiovascular Surgery Department, Rabta Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiovascular Surgery Department, Rabta Hospital, Tunis, Tunisia.;Cardiovascular Surgery Department, Rabta Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.;Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia.",
"authors": "Ben Mrad|Imtinene|I|0000-0002-7387-4601;Ben Mrad|Melek|M|0000-0002-4281-0111;Oumaya|Zeineb|Z|;Zairi|Ihsen|I|0000-0001-5165-8257;Besbes|Boutheina|B|;Ouaghlani|Khalil|K|;Kamoun|Sofien|S|;Mleyhi|Sobhi|S|;Miri|Rim|R|;Mzoughi|Khadija|K|;Kraiem|Sondos|S|",
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"doi": "10.2147/OAEM.S324366",
"fulltext": "\n==== Front\nOpen Access Emerg Med\nOpen Access Emerg Med\noaem\noaem\nOpen Access Emergency Medicine : OAEM\n1179-1500\nDove\n\n324366\n10.2147/OAEM.S324366\nCase Series\nAlveolar Hemorrhage Following Thrombolytic Therapy for Acute Myocardial Infarction: Two Case Reports and Literature Review\nBen Mrad et al\nBen Mrad et al\nhttp://orcid.org/0000-0002-7387-4601\nBen Mrad Imtinene 1\nhttp://orcid.org/0000-0002-4281-0111\nBen Mrad Melek 2\nOumaya Zeineb 1\nhttp://orcid.org/0000-0001-5165-8257\nZairi Ihsen 1\nBesbes Boutheina 1\nOuaghlani Khalil 1\nkamoun Sofien 1\nMleyhi Sobhi 2\nMiri Rim 2\nMzoughi khadija 1\nKraiem Sondos 1\n1 Cardiology Department, Habib Thameur Hospital, Tunis, Tunisia\n2 Cardiovascular Surgery Department, Rabta Hospital, Tunis, Tunisia\nCorrespondence: Imtinene Ben Mrad Cardiology Department, Habib Thameur Hospital, App 2b, Bloc 12, cite Olympique, Tunis, 1003, TunisiaTel +011 216 20156852 Email imtinenebenmrad12@gmail.com\n27 8 2021\n2021\n13 399405\n22 6 2021\n04 8 2021\n© 2021 Ben Mrad et al.\n2021\nBen Mrad et al.\nhttps://creativecommons.org/licenses/by-nc/3.0/ This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).\nAbstract\n\nAlveolar hemorrhage (AH) is a heterogeneous clinical syndrome with a high mortality rate, characterized by extensive bleeding into the alveolar spaces. AH secondary to systemic thrombolysis treatment in the setting of acute myocardial infarction is an uncommon complication, but potentially fatal and can lead to acute respiratory failure. This entity is rarely reported in the literature. We report two cases of acute AH after intravenous thrombolysis for acute myocardial infarction, which could contribute to the literature on the subject, and discuss the risk factors as well as the clinical and radiological findings supporting the diagnosis. We overview also the rare previous published case reports in this context, and we contrast our findings with those reported in the literature.\n\nKeywords\n\nhemoptysis\nalveolar hemorrhage\nmyocardial infarction\nfibrinolytic therapy\nstreptokinase\n==== Body\npmcIntroduction\n\nAlveolar hemorrhage is a clinical syndrome resulting from bleeding into the alveolar spaces secondary to disruption of the alveolar-capillary membrane. It is a rare and serious medical emergency potentially leading to fatal acute respiratory failure (ARF).1\n\nSystemic thrombolysis in the setting of acute myocardial infarction (AMI) remains, in the absence of contraindications, an effective treatment.2 However, it exposes to a non-negligible bleeding risk that remains its major adverse event. Most of the latter occur at sites of vascular access and are mild, though patients may also present with other locations such as gastrointestinal, retroperitoneal, genitourinary, and cerebral bleeding.3,4\n\nPulmonary alveolar hemorrhage is an extremely uncommon and potentially fatal complication of intravenous thrombolytic therapy. So far, only few cases have been reported in the literature.5–21\n\nWe hereby report two cases of acute alveolar hemorrhage complicating thrombolytic therapy in myocardial infarction, hoping to contribute to expand the literature data on this subject.\n\nWe discuss in this article, through our cases and a literature review, the risk factors, the clinical and the radiographic findings that suggest and support the diagnosis, as well as the management issues related to this unusual and life-threatening situation.\n\nCases Presentation\n\nPatient 1\n\nA 61-year-old male patient, heavy smoker, with coronary heart disease history, presented to the emergency department of our hospital with ST segment elevation myocardial infarction (STEMI). He received, immediately, loading doses of aspirin and clopidogrel, and then had successful thrombolysis with Tenecteplase (Metalyse).\n\nTwo days later, he developed a moderate hemoptysis. On physical examination, he was apyretic at 37°C, he was hemodynamically stable with a blood pressure at 100/60 mmHg, a heart rate at 60 beats/minutes and no peripheral signs of shock.\n\nHowever, he was polypneic with a respiratory rate at 25 cycles/minute and his oxygen saturation (SaO2) on room air had dropped from an initial value of 96% to 89%.\n\nPulmonary auscultation revealed crackles limited to the lung bases. There was no other sign of heart failure.\n\nArterial blood gas analysis revealed normal pH of 7.45, normocapnia of 32 mmHg, but hypoxia 54 mmHg and low oxygen saturation (SaO2) of 89%.\n\nThe chest X-ray revealed bilateral alveolar infiltrates (Figure 1).Figure 1 Bedside chest X ray showing diffuse and bilateral lung infiltrates, cephalization of the pulmonary vessels, bronchial wall thickening giving the aspect or railway track in the upper right lung field and blunting of the right costophrenic angle. The cardiac silhouette is not interpretable (not standing chest x ray).\n\nThe transthoracic echocardiography showed an ejection fraction of about 50% and a posterior wall hypokinesia.\n\nGiven the context, the first diagnosis evoked was acute pulmonary oedema, and on this presumption, we started intravenous (IV) furosemide that was ineffective.\n\nMeanwhile, the urgent biologic workup carried out showed a significant drop of hemoglobin level from 15.6 g/dL to 12.8 g/dl, with normal platelet and leukocyte count. A second oriented physical examination did not reveal any other bleeding manifestations.\n\nIn front of hemoptysis, acute drop in hemoglobin level and bilateral alveolar infiltrates on chest X-ray, the diagnosis of AH was considered.\n\nHigh-resolution computed tomography (HRCT) of the chest (Figure 2) was performed and revealed bilateral alveolar patchy condensations predominating posteriorly especially at the basal area associated with diffuse micro nodules, strongly suggestive of AH.Figure 2 (A–D) High Resolution Computed Tomography showing scattered ground glass opacities, with predominant bilateral postero-basal and central distribution. It is associated occasionally with a septal thickening giving the aspect of crazy paving.\n\nWe decided to withdraw anticoagulation (Intravenous continuous heparin sodium infusion) and maintain the double antiplatelet therapy.\n\nThe patient experienced progressive improvement of his respiratory parameters over the next 48 hours under oxygen administered via facial mask, without any recurrence of hemoptysis.\n\nA coronary angiogram performed six days after myocardial infarction revealed a significant thrombotic stenosis of the distal right coronary artery, successfully treated with the implantation of a drug-eluting stent.\n\nHe was discharged, after adequate monitoring, on dual antiplatelet therapy (100 mg of aspirin and 75 mg of clopidogrel) and had an uneventful 12-month follow-up.\n\nPatient 2\n\nA 63-year-old male without any comorbidities presented to the emergency department one hour after the onset of acute constricting chest pain. Shortly thereafter, he developed an episode of sustained ventricular tachycardia, which was converted to sinus rhythm by electrical cardioversion. He soon recovered his full consciousness, with good vitals. An electrocardiogram revealed ST segment elevation in the inferior leads. After receiving loading doses of aspirin and clopidogrel, thrombolysis with Streptokinase (1.5 million units) was initiated according to standard protocol. The chest pain disappeared, and the electrocardiogram performed 90 minutes after thrombolysis showed ST segment elevation resolution.\n\nWithin the first 24 hours of monitoring in the cardiology intensive care unit, the patient experienced acute dyspnea with hemoptysis. Oxygen saturation level dropped from 97% to 89% and pulmonary auscultation revealed bilateral diffuse crackles. There were no other signs of heart failure otherwise.\n\nA bedside chest X-ray revealed alveolar opacities (Figure 3), and the thoracic CT scan (Figure 4) showed bilateral multiple alveolar lesions strongly suggesting a diffuse DAH. The blood workup results, revealed a severe drop of hemoglobin level from 13 to 9 g/dl.Figure 3 Bedside chest X ray showing diffuse interstitial lung disease, affecting predominantly the right upper lobe. The right scissure is well visible. We remark also the blunting of the right costophrenic angle. The mediastinum is not interpretable.\n\nFigure 4 (A–D) Computed Tomography Scan showing Crazy paving with ground glass opacities and bilateral thickening of the interlobular septa, located predominantly in the right upper lobe, the middle lobe and the basal segments of the right lower lobe, the apical segment of the left upper lobe and the upper segment of the left lower lobe.\n\nThe transthoracic echocardiography showed an ejection fraction of about 40% as well as posterior wall hypokinesia and pulmonary arterial hypertension.\n\nWe proceeded to coronary angiography (CAG) performed through the right radial artery, revealing a critical sub-occlusion of the left circumflex artery with TIMI grade 3 flow.\n\nThe indication of a transluminal angioplasty was evident; however, we decided to delay the angioplasty because of the severity of the hemorrhage.\n\nOxygen therapy and blood transfusion were implemented. We maintained the double antiplatelet therapy but decided on anticoagulation withdrawal (Intravenous continuous heparin sodium infusion).\n\nAfter two weeks of hospitalization and close monitoring, the hemoptysis started to improve gradually, his oxygen saturation on room air increased to 95% and his lung fields were clear. He had a steady hemoglobin level. A chest X-ray taken after 3 weeks showed resolution of lesions. Before being discharged, the patient underwent a successful angioplasty of the circumflex coronary lesion. One year later, the patient is asymptomatic at follow-up.\n\nFor our two patients, we conducted an etiological investigation, looking for arguments in favour of vasculitis: the screening for anti-glomerular basal membrane antibodies, antinuclear antibodies, anti-double stranded deoxyribonucleic acid antibodies, peripheral anti-neutrophil cytoplasmic antibodies (p-ANCAs) and cytoplasmic ANCAs was negative. The retroviral screening was negative, as well.\n\nDiscussion\n\nThrombolytic therapy is a well proven strategy for reperfusion in acute myocardial infarction and has been proven to decrease the morbidity and mortality related to this condition. However, it can lead to hemorrhagic complications. The most common types of thrombolytic-related major bleeding complications are gastrointestinal tract and intracranial hemorrhages.3,4\n\nDiffuse alveolar hemorrhage (DAH) syndrome is a very unusual complication of intravenous thrombolytic treatment for acute myocardial infarction with a high mortality rate and can go unnoticed. This pathology is defined by bleeding within the alveoli, which is due to dislocation of the alveolar-capillary membrane caused by injury or acute inflammation of the arterioles, venules, or alveolar capillaries.1 The available literature does not cover the exact incidence of this complication, but it rather consists of few case reports.\n\nThese two cases highlight a serious hemorrhagic complication of fibrinolytic treatment for AMI that can go unnoticed because it can be confused with other diagnoses. According to our knowledge, no case of AH associated with Tenecteplase (Metalyse) has been previously reported.\n\nTable 1 summarizes data from all cases reported in the literature to date. All reported cases were of males aged between 24 and 75 years old, suggesting that male sex might be a risk factor for DAH secondary to intravenous thrombolytic therapy in the setting of AMI.Table 1 Published Reports of Diffuse Alveolar Hemorrhage Following Thrombolytic Therapy for Myocardial Infarction (1990–2020)\n\nAuthor, Year\tAge (Y)/ Sex\tThrombolytic Agent\tTime Interval\tUnderlying Condition\tAnemia\tHemoptysis\tInfiltrate\tConfirmation\tOutcome\t\nDisler et al 19905\t50/M\tStreptokinase\t5 days\tRecent pneumonia\tYes\tYes\tBilateral\t\tRecovered\t\nNathan et al 19926\t52/M\tSystemic r-TPA and\nintracoronary urokinase\t24 h\tPulmonary\ncatheterization,\nheart failure and PHT\tYes\tYes\tBilateral\t\tRecovered\t\nObispo et al 19927\t60/M\tStreptokinase\t36 h\tCPR, defibrillation\tYes\tYes\tBilateral\tCOu\tRecovered\t\nTio et al 19928\t54/M\tStreptokinase\t3 days\tImmune reaction\tYes\tYes\tBilateral\t\tRecovered\t\nAwadh et al 19949\t63/M\tStreptokinase\t24 h\tHeart failure\tYes\tYes\tRUL, right upper lobe\tAutopsy\tDead*\t\nHammoud et al 199610\t70/M\tr-TPA\t12 h\tPrior ipsilateral lung trauma 2 years earlier\nDefibrillation\tYes\tYes\tRUL, right upper lobe\t\tRecovered\t\nBasher et al 199611\t66/M\tr-TPA\t15 min\tRight upper lung cavity of unknown etiology\tNo\tYes\t\tAutopsy\tDead\t\nLee et al199712\t69/M\tUrokinase\t50h\tPulmonary\ncatheterization,\npneumonia\tYes\tYes\tLeft lung\t\tRecovered\t\nSwanson et al 199713\t58/M\tStreptokinase\t48 h\tImmune reaction,\nCOPD\tYes\tYes\tBilateral\t\tRecovered\t\nGopalakrishnan et al 199714\t24/M\tr-TPA\t24 h\tCardiac catheterization\tYes\tYes\tBilateral\t\tRecovered\t\n64/M\tr-TPA\t12h\tCOPD\tYes\tYes\t\t\tRecovered\t\nMasip et al 199815\t65/M\tStreptokinase\t48 h\tImmune reaction\tYes\tYes\tBilateral\tLBA\tRecovered\t\nYigla et al 200016\t66/M\tStreptokinase\t48 h\tHeart failure and PHT\tYes\tYes\tBilateral\t\tRecovered\t\nAyyub et al 200317\t35/M\tStreptokinase\t\t\tYes\tYes\tBilateral\tLBA\tRecovered\t\nGonzalez et al 0.201118\t42/M\tStreptokinase\t20 h\t\t\tYes\tBilateral\t\tRecovered\t\nAbuosa et al 201419\t75/M\tStreptokinase\t72 h\t\tYes\tYes\tBilateral\tLBA\tDead\t\nMahjoob et al 201420)\t45/M\tStreptokinase\t\tCocaïne and Tobacco abuse\tYes\tYes\tBilateral\tLBA\tDead\t\nNarayanan et al 201721\t58/M\tStreptokinase\t6 h\t\tYes\tYes\tBilateral\t\tRecovered\t\nPrasad et al 202022\t65/M\tStreptokinase\t48 h\t\tNo\tYes\tBilateral\t\tRecovered\t\n60/M\tStreptokinase\t6 h\t\tyes\tyes\tBilateral\t\tDead\t\nNote: *Death not related to pulmonary bleeding.\n\nAbbreviations: M, male; H, hour; PHT, Pulmonary hypertension; COPD, chronic obstructive pulmonary disease; CPR, cardiopulmonary resuscitation; r-TPA, recombinant tissue-type plasminogen activator; RUL, right upper lobe; COu, lung CO uptake; LBA, bronchoalveolar lavage.\n\nThree fibrinolytic agents have been used in these cases: streptokinase, urokinase and Actilyse® (Alteplase-rtPA). Most of these patients received streptokinase, similarly to our second case.\n\nWe can see that DAH usually occurs within a few hours to 5 days after thrombolysis.\n\nThe pathogenesis of DAH attributable to thrombolytic therapy remains uncertain and may be explained by the pre-existing fibrinolytic states, the presence of parenchymal abnormalities or an immune reaction to streptokinase causing pulmonary capillaritis as it has been proposed.20 It has been mentioned that certain potential cofactors may predispose to this complication such as underlying lung diseases (chronic obstructive pulmonary disease, prior emphysema), recent pneumonia, cardiac catheterization, arrhythmias requiring defibrillation shock or cardiopulmonary resuscitation, heart failure, and substances abuse as cocaine and tobacco.21 Green et al22 described that some patients with alveolar hemorrhage had capillaritis, suggesting an immune reaction since streptokinase is associated with a wide spectrum of allergic reactions, such as anaphylaxis, bronchospasm, and type III immune reactions. Tio et al7 described the finding of antibodies against streptokinase in patients with HA treated with thrombolytics, which would support this theory. However, in some cases, no predisposing factor has been identified.\n\nFor our second patient, defibrillation prior to thrombolytic administration may have contributed to the occurrence of DAH. The potential role of defibrillation in DAH should be further clarified.\n\nThe clinical presentation is often characterized by the acute onset of a classical diagnostic triad: hemoptysis, anemia, and radiographic infiltrates. In addition, this triad is associated with acute respiratory failure. In our first case, heart failure was suspected, which led to a delay in diagnosis.\n\nOn chest X-ray, the radiological findings, consist, classically, in diffuse patchy infiltrates, and alveolar opacities involving, primarily, the central portion of the lung, particularly the middle and lower lobes. Rarely, areas of consolidation were observed. On Chest CT scan as well, the bilateral ground-glass opacities predominate in central area of the lungs with relative sparing of the lung periphery. It is also worth noting that the infiltrates were unilateral in two of the reported cases.9,10,12\n\nIn myocardial infarction, acute pulmonary edema is the first diagnosis to be suspected in the case of acute respiratory distress with alveolar opacities on chest X-ray which can lead to inappropriate treatment with diuretic. Therefore, we should also consider the diagnosis of DAH especially in the presence of hemoptysis and/or a sudden drop in hemoglobin levels with no apparent bleeding site.\n\nWhen the diagnosis is suggested, bronchial endoscopy with bronchoalveolar lavage (BAL) is the gold standard exam to confirm the diagnosis.18 However, it is not usually possible, mainly depending on the patient’s condition. In our cases, these exams were not performed.\n\nThe management of DAH is based on two pillars: the treatment of respiratory failure and the correction of the anemia with packed red cell transfusions. Nasal oxygen therapy should suffice in correcting hypoxemia in moderate forms. Otherwise, artificial ventilation with the use of positive pressure would be in order.21\n\nDiscontinuing antiplatelet and anticoagulation medication is necessary.22 Antifibrinolytic agents, such as tranexamic acid was used in one case.22\n\nThe clinical course was good in about 80% of cases with full recovery within one to two weeks. The prognosis depends on the extent of the myocardial infarction, the volume of the hemorrhage and the degree of the cardiorespiratory compromise. Before our publication, only 20 cases were reported in the English medical literature, with five deaths; therefore, the mortality rate was 25%.\n\nIt should be considered that when diagnosing DAH, systemic vasculitis or connective tissue disease should be ruled out. The analytical results of our cases were negative, so that fibrinolytic drug was the cause.\n\nConclusion\n\nDiffuse alveolar hemorrhage is an unusual complication of fibrinolytic therapy for MI, especially with streptokinase. The diagnosis of diffuse alveolar hemorrhage requires a high degree of suspicion, as signs and symptoms are nonspecific and may delay diagnosis. Diagnosis should be considered in patients with acute pulmonary distress associated to hemoptysis, acute anemia, and pulmonary infiltrates after thrombolysis. Early diagnosis and therapeutic management are critical to avoid acute respiratory failure and death. Risk factors and a probable etiology of this complication should be investigated.\n\nInstitutional Approval\n\nWe have the approval of our institution (Habib Thameur hospital of Tunis) to publish the case details.\n\nConsent\n\nWritten informed consent was obtained from the two patients for the publication of this report and accompanying images.\n\nDisclosure\n\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n\n1. ParrotA, VoiriotG, CanellasA, et al. Pulmonary alveolar hemorrhage. Med Intensive Reanim. 2018;27 (4 ):331–343. doi:10.3166/rea-2018-0060\n2. IbanezB, JamesS, AgewallS, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J. 2018;39 (2 ):119–177. doi:10.1093/eurheartj/ehx393 28886621\n3. CaliffRM, FortinDF, TenagliaAN. Clinical risks of thrombolytic therapy. Am J Cardiol. 1992;68 (2 ):12–20. doi:10.1016/0002-9149(92)91168-4\n4. DislerLJRA. Pulmonary hemorrhage following intravenous streptokinase for acute myocardial infarction. Int J Cardiol. 1990;29 (3 ):387–390. doi:10.1378/chest.101.4.1150 2283199\n5. NathanPE, TorresAV, SmithAJ, GagliardiAJRK, RapeportKB. Spontaneous pulmonary hemorrhage following coronary thrombolysis. Chest. 1992;101 (4 ):1150–1152. doi:10.1378/chest.101.4.1150 1555437\n6. Cuéllar ObispoE, Torrado GonzálezE, Alvarez BuenoM, et al. A diffuse pulmonary hemorrhage following thrombolytic therapy in an acute myocardial infarct. Rev Esp Cardiol. 1992;45 (6 ):421–424.1631392\n7. TioRA, VoorbijRH, EnthovenR. Adult respiratory distress syndrome after streptokinase. Am J Cardiol. 1992;70 (20 ):1632–1633. doi:10.1016/0002-9149(92)90477-g 1466343\n8. AwadhN, RoncoJJ, BernsteinV, GilksBWP, WilcoxP. Spontaneous pulmonary hemorrhage after thrombolytic therapy for acute myocardial infarction. Chest. 1994;106 (5 ):1622–1624. doi:10.1378/chest.106.5.1622 7956438\n9. HammoudehAJ, HaftJI, EichmanGT. Hemoptysis and unilateral intra- alveolar hemorrhage complicating intravenous thrombolysis for myocardial infarction. Clin Cardiol. 1996;19 (7 ):595–596. doi:10.1002/clc.4960190714 8818443\n10. BasherA, OduwoleA, BhalodkarN, et al. Fatal hemoptysis during coronary thrombolysis. J Thromb Thrombolysis. 1996;3 (1 ):87–89. doi:10.1007/bf00226416 10608042\n11. ChangYC, PatzEFJr, GoodmanPC, GrangerCB. Significance of hemoptysis following thrombolytic therapy for acute myocardial infarction. Chest. 1996;109 (3 ):727–729. doi:10.1378/chest.109.3.727 8617083\n12. SwansonGA, KaeleyGGS. Diffuse pulmonary hemorrhage after streptokinase administration for acute myocardial infarction. Pharmacotherapy. 1997;17 (2 ):390–394.9085336\n13. GopalakrishnanD, TioranT, EmanuelC, ClarkVL. Diffuse pulmonary hemorrhage complicating thrombolytic therapy for acute myocardial infarction. Clin Cardiol. 1997;20 (3 ):298–300. doi:10.1002/clc.4960200321 9068920\n14. MasipJ, VecillaFPJ. Diffuse pulmonary hemorrhage after fibrinolytic therapy for acute myocardial infarction. Int J Cardiol. 1998;63 (1 ):95–97. doi:10.1016/s0167-5273(97)00285-4 9482153\n15. YiglaM, SprecherE, AzzamZ, GuralnikL, KapeliovichMKN, KrivoyN. Diffuse alveolar hemorrhage following thrombolytic therapy for acute myocardial infarction. Respiration. 2000;67 (4 ):445–448. doi:10.1159/000029546 10940802\n16. AyyubM, BarlasS, IqbalM, KhurshidSM. Diffuse alveolar hemorrhages and hemorrhagic pleural effusion after thrombolytic therapy with streptokinase for acute myocardial infarction. Saudi Med J. 2003;24 (2 ):217–220.12682693\n17. GonzálezA, SagardíaJ, RedondoA, VillaverdeM, MonteverdeA. Hemorragia alveolar como complicación del uso de trombolíticos. Medicina (B Aires). 2011;71 (6 ):547–549.22167729\n18. KinsaraA, AbuosaA, EL-SheikhA. Abnormal chest x-ray postmyocardial infarction. Hear Views. 2014;15 (4 ):121. doi:10.4103/1995-705x.151086\n19. KhaheshiI, PaydaryK, MahjoobM. Diffuse pulmonary hemorrhage after fibrinolytic therapy for acute myocardial infarction in a cocaine abuser patient. Hear Views. 2014;15 (3 ):83. doi:10.4103/1995-705x.144797\n20. NarayananS, ThulaseedharanNK, SubramaniamG, PanarkandyG, ArathiN. Pulmonary alveolar hemorrhage following thrombolytic therapy. Int Med Case Rep J. 2017;10 :123–125. doi:10.2147/imcrj.s129087 28435331\n21. PrasadK, SinghP, KanabarKVR. Pulmonary haemorrhage following thrombolysis with streptokinase in myocardial infarction. BMJ Case Rep. 2020;13 (1 ):232–308. doi:10.1136/bcr-2019-232308\n22. GreenRJ, RuossSJ, KraftSA, BerryGJ, RaffanTA. Pulmonary capillaritis and alveolar hemorrhage. Chest. 1996;110 :1305–1316. doi:10.1378/chest.110.5.1305 8915239\n\n",
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"title": "Alveolar Hemorrhage Following Thrombolytic Therapy for Acute Myocardial Infarction: Two Case Reports and Literature Review.",
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"abstract": "Incidence of thrombocytopenia with drugs other than heparin, coumarin anticoagulants, anticancer drugs is less than 1%. A rare case of diclofenac induced thrombocytopenia in a 60-year-old lady is presented here. With stopping diclofenac and infusing fresh blood along with platelet concentrate made the patient revived and follow-up after one month showed her in good health.",
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"abstract": "Systemic lupus erythematosus (SLE) is a chronic autoimmune disease which can be complicated with cytomegalovirus (CMV) infection during its course. CMV reactivation can mimic an SLE flare and lead to delay in diagnosis. Here, we reported a previously diagnosed SLE patient who presented with fever, leukopenia, and cutaneous ulcers. Initially, this was diagnosed as an SLE flare and the patient was treated with higher doses of corticosteroids but no improvement was observed. Both nuclear and cytoplasmic inclusions inside the endothelial cells in the skin biopsy as well as positive immunohistochemistry (IHC) staining for CMV antigen were clues to the correct diagnosis of CMV reactivation. Treatment with ganciclovir resulted in clinical resolution. In this report, a very rare clinical form of CMV infection manifesting as cutaneous necrotizing vasculitis on the lower extremity is described and the literature regarding this case is reviewed.",
"affiliations": "Department of Rheumatology, Imam Hossein Teaching Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Pathology, Loghman Teaching Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Infectious Disease, Imam Hossein Teaching Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Skin Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.",
"authors": "Hajihashemi|Zahra|Z|;Bidari-Zerehpoosh|Farahnaz|F|;Zahedi|Khatere|K|;Eslami|Behnaz|B|;Mozafari|Nikoo|N|https://orcid.org/0000-0003-4691-2606",
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"title": "Cytomegalovirus-induced cutaneous ulcer mimicking vasculitis in a patient with systemic lupus erythematous: A case report and review of the literature.",
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"abstract": "The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [(18)F]-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Hallym University College of Medicine, Anyang, Korea.;Department of Physical Medicine and Rehabilitation, Hallym University College of Medicine, Anyang, Korea. ; Hallym Institute of Translational Genomics and Bioinformatics, Hallym University College of Medicine, Anyang, Korea.;Department of Neurology, Hallym University College of Medicine, Anyang, Korea.;Department of Neurology, Hallym University College of Medicine, Anyang, Korea.;Department of Neurology, Hallym University College of Medicine, Anyang, Korea. ; ILSONG Institute of Life Science, Hallym University College of Medicine, Anyang, Korea. ; Hallym Institute of Translational Genomics and Bioinformatics, Hallym University College of Medicine, Anyang, Korea.",
"authors": "Ahn|Hyun Jung|HJ|;Yoo|Woo-Kyoung|WK|;Park|Jaeseol|J|;Ma|Hyeo-Il|HI|;Kim|Yun Joong|YJ|",
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"fulltext": "\n==== Front\nJ Korean Med SciJ. Korean Med. SciJKMSJournal of Korean Medical Science1011-89341598-6357The Korean Academy of Medical Sciences 10.3346/jkms.2015.30.9.1328Original ArticleNeuroscienceCognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics Ahn Hyun Jung 1Yoo Woo-Kyoung 14Park Jaeseol 2Ma Hyeo-Il 2Kim Yun Joong 2341 Department of Physical Medicine and Rehabilitation, Hallym University College of Medicine, Anyang, Korea.2 Department of Neurology, Hallym University College of Medicine, Anyang, Korea.3 ILSONG Institute of Life Science, Hallym University College of Medicine, Anyang, Korea.4 Hallym Institute of Translational Genomics and Bioinformatics, Hallym University College of Medicine, Anyang, Korea.\nAddress for Correspondence: Hyeo-Il Ma, MD. Department of Neurology, Hallym University College of Medicine, 22 Gwanpyeong-ro 170-beon-gil, Anyang 431-796, Korea. Tel: +82.31-380-3742, Fax: +82.31-381-4659, hima@hallym.ac.kr9 2015 13 8 2015 30 9 1328 1333 17 11 2014 23 6 2015 © 2015 The Korean Academy of Medical Sciences.2015This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.The use of prokinetics/antiemetics is one of the leading causes of drug-induced parkinsonism (DIP) observed in neurology clinics. Cognitive dysfunction in DIP has recently been recognized, but pathologies related with cognitive dysfunction is unknown. Among our retrospective cohort of 385 consecutive parkinsonian patients enrolled in our parkinsonism registry, 14 patients were identified who satisfied our inclusion criteria: parkinsonism caused by prokinetics/antiemetics, existing T1-weighted 3D volumetric MR images, and normal [18F]-N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) nortropane PET scan images. For the comparison of volumetric MR data, 30 age- and sex-matched healthy individuals were included in this study. Among 14 patients with DIP, 4 patients were diagnosed with dementia, and all other patients had mild cognitive impairment (MCI). Comparisons of MR volumetric data between DIP patients with MCI and controls show that cortical gray matter volumes are reduced bilaterally in DIP (P=0.041) without changes in either total white matter volume or total intracranial volume. Among subcortical structures, the volume of the right hippocampus is reduced in DIP patients compared with controls (P=0.011, uncorrected). In DIP, cortical thickness is reduced in the bilateral lingual (P=0.002), right fusiform (P=0.032) and part of the left lateral occipital gyri (P=0.007). Our results suggests that cognitive dysfunction in DIP caused by prokinetics/antiemetics is common. Structural changes in the brain by 3D MRI may be associated with cognitive decline in DIP.\n\nGraphical Abstract\n\n\nDrug-induced ParkinsonismMagnetic Resonance ImagingProkineticsVolumetryCortical ThicknessSWEDD (Scans without Evidence of Dopaminergic Deficit)Hallym UniversityHURF-2015-34\n==== Body\nINTRODUCTION\nDrug-induced parkinsonism (DIP) is the second most common form of parkinsonism (1) after Parkinson's disease (PD) and constitutes 15%-60% of all parkinsonism cases (2) in the elderly. In the past, most cases of DIP were caused by classical antipsychotics, whereas more recently, a wider range of classes of drugs have been reported as responsible for DIP cases. Classes of drugs known to cause DIP include atypical antipsychotics, benzamide derivatives used to control nausea and vomiting, phenothiazine derivatives used to treat vertigo, drugs that interfere with vesicular storage of monoamines, calcium channel blockers, antidepressants and others. Among the drugs known to cause DIP, prokinetics/antiemetics such as levosulpiride, metoclopramide, and clebopride are leading causes of DIP, especially among the elderly in Korea (34).\n\nMost previous studies of cognitive dysfunction in DIP have investigated patients with schizophrenia taking typical or atypical antipsychotics. Studies on cognitive changes in DIP in the setting of a neurology clinic are rare (567). In a previous report on cognitive dysfunction in DIP, the study subjects were a heterogeneous population in terms of their underlying diseases and the drugs responsible for their DIP; because these drugs possessed varying degrees of dopamine-blocking potency, the interpretation of the results of this study is difficult (8). Because the age of onset of DIP is late in life (348), it is difficult to determine whether cognitive change in DIP is due to normal aging or to pathological processes underlying or accompanying DIP. Moreover, some DIP patients are in a prodromal stage of a neurodegenerative disease, which is associated with cognitive dysfunction (9101112).\n\nTo investigate whether DIP is associated with cognitive dysfunction and to explore the mechanisms underlying cognitive dysfunction in DIP, we analyzed clinical and neuropsychological test results together with T1-weighted 3D volumetric MR images of patients with prokinetic/antiemetic-induced parkinsonism. The subjects of our study were consecutively enrolled from our retrospective cohorts and showed no evidence of presynaptic dopaminergic deficits in [18F]-fluorinated N-3-fluoropropyl-2-β-carboxymethoxy-3-β-(4-iodophenyl) nortropane positron emission tomography ([18F]-FP-CIT PET) scans.\n\nMATERIALS AND METHODS\nSubjects\nWe analyzed magnetic resonance images and neuropsychological test results from a retrospective cohort of 14 DIP patients recruited from the movement disorders clinic at Hallym University Sacred Heart Hospital. A flow diagram illustrating the patient recruitment process is shown in Fig. 1. Briefly, among 385 consecutive parkinsonian patients who were enrolled in our standardized parkinsonism registry and had undergone a standardized protocol of history taking, neurological examination, neuropsychological evaluation and magnetic resonance imaging (MRI) from May 2011 to August 2013, we identified 61 DIP patients who had been diagnosed with parkinsonism according to the criteria used in our previous publication (3). T1-weighted 3D volumetric MR images included in our MR protocol were available for only 38 patients because MRI had been performed at a referred hospital in the other patients (n=23). Among the remaining 38 DIP patients, the drugs responsible for DIP in 21 patients were prokinetics/antiemetics such as levosulpiride, metoclopramide, or clebopride. [18F]-FP-CIT PET scans were normal in 14, abnormal in 3 and not available in 4 patients. Our routine MRI protocol included T1-weighted 3D volumetric MRI. Neuropsychological evaluations were conducted using the Seoul Neuropsychological Screening Battery (SNSB) (13) at least 24 hr after discontinuing the drugs responsible for the patient's DIP. Thirty healthy age- and gender-matched controls with no past or present neurological or psychiatric illnesses were also included in the study. All patients and controls underwent neurologic examinations and were evaluated using the Unified Parkinson disease rating scale (UPDRS) and the Mini Mental State Examination (MMSE). No study subject in the control group had parkinsonian symptoms or signs, and the mean MMSE score was 27.4 (range 25-30).\n\nMagnetic resonance image acquisition and processing\nWe used a multisequence 3T MRI scanner (Achieva, Philips, Best, The Netherlands) to acquire MR images. T1-weighted 3D MPRAGE image (1×1×1 µL resolution) files in DICOM format were analyzed using FreeSurfer software (v5.0, Athinoula A. Martinos Center for Biomedical Imaging, Charlestown, MA, USA). FreeSurfer is a semi-automated brain morphometry tool. The details of the postprocessing sequence implemented by FreeFurfer used in this study have been described elsewhere (14151617). Briefly, the processing included skull stripping, Talairach transformation, optimization of the grey matter-white matter and grey matter-CSF boundaries, and segmentation (1617). The cortical thickness was individually assessed at each vertex (16). All images were aligned to a common surface template using a high-resolution surface-based averaging technique that aligned cortical folding patterns (14). Finally, before further analysis, the cortical thickness maps were smoothed with a 10 mm full width at half maximum 2-dimensional Gaussian kernel to reduce local variations in the measurements.\n\n[18F]-FP-CIT PET scan\n[18F]-FP-CIT PET was performed using a PET/CT scanner (Gemini TF; Phillips-ADAC Medical Systems, Cleveland, OH, USA) that provides an in-plane spatial resolution of 2.0 mm full width at half maximum at the center of the field of view. The drugs that were responsible for patients' DIP were discontinued by all patients at least 24 hr before the scans were obtained. Image acquisition was started 90 min after intravenous injection of [18F]-FP-CIT (185 MBq). Emission PET data were acquired for 10 min in the 3-dimensional mode after brain CT, which was performed in the spiral mode at 120 kVp and 150 mAs. [18F]-FP-CIT PET images were reconstructed from CT data after attenuation correction using the ordered-subset expectation maximization (OSEM) algorithm and an all-pass filter with a 128×128 matrix.\n\nStatistical analysis\nStatistical analyses were performed using SPSS Statistics V21. Independent t-tests were used to assess differences between groups for all demographic variables, brain volumetric measurements and subcortical volume measurements. Variations in regional cortical thickness and volume between DIP patients and the control group were estimated using a general linear model (GLM) at each vertex across the cortical surface, with group (DIP, control) as the dependent variable and age as a nuisance variable, using Qdec implemented in FreeSurfer software. The cortical surfaces of the left and right hemispheres were analyzed separately. The maps generated by this analysis show the distribution of P values for pairwise comparisons between DIP patients and healthy controls. Clusters of vertices for which the P values for thickness-group and volume-group regression coefficients exceeded a predetermined threshold were identified, and cluster-wise statistical significances were calculated via 10,000 Monte Carlo simulations implemented in Qdec (P<0.05) (18). Subsequently, region-of-interest (ROI) analyses were performed by creating labels for gyral regions of interest and calculating the mean cortical thicknesses for each labeled ROI. Results of the neuropsychological tests for all individuals were transformed into Z-scores adjusted for age, sex, and education. Correlations between the average subcortical volume and the motor UPDRS score or between cortical thickness and neuropsychological test scores were analyzed using Kendal correlation analysis. In all analyses, the threshold for statistical significance was set at P<0.05.\n\nEthics statement\nThis study was approved by the institutional review board of Sacred Heart Hospital, Hallym University College of Medicine (IRB number 2014-1014). Informed consents were waived by the board. In case of control group, informed consent was obtained form all participant.\n\nRESULTS\nDemographic data for 14 patients with DIP are summarized in Table 1. Motor disability in DIP patients was of mild to moderate severity according to Hoehn and Yahr staging criteria (1.5 to 3) with the exception of one patient who also suffered from dementia and tuberculous spondylitis. Based on extensive neuropsychological evaluations, 4 out of 14 patients (28.6%) were diagnosed with dementia, and the remaining 10 patients had mild cognitive impairment (MCI). Two DIP patients had non-amnestic MCI, and the other patients with MCI had amnestic MCI. A history of rapid eye movement behavior disorder was present in 2 patients.\n\nTo explore whether cognitive dysfunction in DIP patients was related with underlying structural changes in the brain, we compared 3D volumetric MRI data between patients with DIP and control subjects. In a group comparison, DIP patients exhibited decreased cortical gray matter volumes in both hemispheres (P=0.041). However, cortical white matter and total intracranial volumes were not significantly different between the two groups (Table 2). When subcortical structures were examined, it was found that the volume of the right hippocampus was smaller in DIP patients (P=0.011, uncorrected), whereas the volume of the cerebellum (P=0.022, uncorrected) and the volume of the right amygdala (P=0.038, uncorrected) were larger in DIP patients compared with the control group (Table 3). The volume of the right hippocampus was inversely correlated with the Seoul Verbal learning test (SVLT) recognition score (r=-0.614, P=0.015), and the volume of the right amygdala was correlated with the SVLT immediate recall score (r=0.600, P=0.016) (Table 4). We did not observe a correlation between volumes of subcortical structures and motor UPDRS scores (data not shown). Cortical thickness was significantly decreased in the bilateral lingual gyrus (P=0.002, corrected), the right fusiform gyrus (P=0.032, corrected) and part of the left lateral occipital gyrus (P=0.07, corrected) (Table 5 and Fig. 2) in DIP patients compared with control subjects. Cortical thickness in the left lingual gyrus was correlated with recognition scores on the Rey complex figure test (r=0.674, P<0.007) (Table 4). SVLT immediate recall scores were inversely correlated with cortical thickness in the right fusiform gyrus (r=-0.511, P=0.040).\n\nDISCUSSION\nThe analysis of our retrospective cohort of patients with DIP caused by prokinetics/antiemetics showed that cognitive dysfunction was present in all patients that were studied. Analysis of 3D MR brain volumetry in DIP with MCI demonstrated that DIP patients have cortical gray matter atrophy and that the cortical thickness is significantly reduced in specific brain regions, including the bilateral lingual, right fusiform and part of the left lateral occipital gyri. To our knowledge, this is the first study to show structural changes in the brain that are associated with cognitive dysfunction in DIP. Although the number of cases in our retrospective cohort of DIP caused by prokinetic/antiemetics is relatively small, we believe that our data is not biased for several reasons. First, we enrolled consecutive parkinsonian patients based strictly on clinical criteria for the diagnosis of DIP, and neuropsychological test results and MRI data were not considered in the diagnosis. Second, we studied only patients with DIP caused by prokinetics/antiemetics, excluding those on classical or atypical antipsychotics to exclude heterogeneous underlying neurological or psychiatric disorders such as dementia, depression or schizophrenia, which may be associated with structural changes in the brain. Third, by studying only parkinsonian patients with normal [18]F-FP-CIT PET scans, we excluded the possibility of enrolling patients with Parkinson's disease or other Parkinson plus syndromes in preclinical stages to avoid including subjects in whom parkinsonian symptoms could be aggravated by dopamine antagonists. In our study, all patients had cognitive dysfunction to varying degrees ranging from MCI in a single domain to dementia. Recently, cognitive dysfunction was reported in DIP patients recruited from a neurology outpatient clinic (8). Because the DIP patients investigated in that study were drawn from a mixed population that had developed DIP as a result of taking drugs with diverse dopamine receptor-blocking capabilities and that also suffered from underlying central nervous system disorders, direct comparison of our results with the results of that study is difficult. Nevertheless, a higher prevalence of cognitive dysfunction in both studies suggests that cognitive dysfunction may be a risk factor for DIP. Kim et al. (8) observed that cognitive dysfunction was reversible in some of their patients and suggested toxic or metabolic effects as a mechanism of DIP. However, given the structural changes observed in the brains of our DIP patients, our results strongly suggest that underlying pathological processes were resulting in anatomical changes in patients with DIP caused by prokinetic drugs, although we do not know the extent to which these processes may be reversible. The possibility that underlying pathological processes may exist in DIP has been raised in a number of previous studies, although we do not know whether such pathological processes represent a distinctive pathology or a prodromal stage of known neurodegenerative disorders (101112). The cause of increased right cerebellar volume is not clear. Increased right cerebellar cortical volume could be related to the compensatory changes of the cortical thickness in the occipital cortex for adapting the lack of sensorial inputs. Our finding of volumetric changes and areas of cortical thinning in subcortical structures in our DIP patients may offer clues to increase our understanding of the pathological processes underlying DIP induced by prokinetics. Although hippocampal volumes were smaller in DIP, the brain regions in which changes in cortical thickness were observed in DIP differ from those observed in Alzheimer's disease (AD) or frontotemporal dementia (19). In AD, cortical thinning predominantly involves the temporal and parietal areas extending into the frontal lobes. In amnestic MCI, which may represent a transitional stage between a healthy, normal state and Alzheimer's disease, cortical thinning involves the left medial temporal lobe, the precuneus, and anterior and inferior basal temporal, insular, and temporal association cortices (20). In dementia with Lewy bodies (DLB), a reduction in cortical thickness was reported in the pericalcarine and lingual gyri, cuneus, precuneus, and superior parietal gyrus bilaterally (21). Interestingly, areas of cortical thinning in PD patients with cognitive dysfunction are similar to those observed in our DIP patients (22). Taken together, these results suggest that the pathology underlying DIP may be heterogeneous.\n\nOur investigation of correlations between volumetric changes or changes in cortical thickness and neuropsychological test results for the corresponding cognitive domains also suggest that anatomical changes underlie cognitive dysfunction in our DIP patients. However, verbal and visual function showed false lateralization in our results of correlation analysis. To rule out a possible coding error, we reviewed our analysis repeatedly and confirmed our results. Currently, we do not have a clear explanation for this observation; it is possible that compensatory changes or brain plasticity may have led to these changes. However, we cannot exclude the possibility that neuropsychological test results may have been confounded by the residual effects of a DIP-causing drug. Beyond these considerations, two additional potential limitations to our study should be recognized. First, we considered only patients with DIP due to prokinetics/antiemetics. Thus, the DIP patients in this study may not truly represent the whole DIP patient population. Finally, the results of this study concerned only the early stages of DIP, without long-term follow up. The examination of SNSB was done within 1 week after the discontinuation of an offending drug. Validation of our observations in a larger cohort and longitudinal studies by other groups would be useful to increase our understanding of DIP.\n\nIn conclusion, 3D volumetric MRI finds structural changes in the brains of patients with DIP caused by prokinetics/antiemetics, which may be associated with cognitive dysfunction. Whether cognitive dysfunction is a risk factor for DIP should be be validated in larger studies.\n\nThis research was supported by Hallym University Research Fund (HURF-2015-34).\n\nDISCLOSURE: All authors have no potential conflicts of interest.\n\nAUTHOR CONTRIBUTION: Research concept: Ma HI, Kim YJ. Data collection: Ahn HJ, Yoo WK, Park J. Writing: Ahn HJ, Ma HI. Statistical analysis: Kim YJ. Revision: Yoo WK, Park J, Kim YJ, Ma HI. Manuscript approval: all authors.\n\nFig. 1 Flow diagram of the patient recruitment process.\nFig. 2 Maps of differences in cortical thickness between the controls (n = 30) and DIP patients (n = 10; P < 0.05 corrected for multiple comparisons). Monte Carlo simulations consisted of 10,000 iterations. The color-coding for P values is on a logarithmic scale of 1-5. Blue color represents cortical thinning.\nTable 1 Demographic data for all drug-induced parkinsonism patients\nPatient\tOnset age (yr)\tDIP-causing drugs\tDose mg/day\tDuration of motor symptoms (yr)\tH&Y stage\tMotor UPDRS\tMMSE z-score\tCognitive diagnosis\tRBD\t\nNo.\tSex\t\n1\tF\t67.0\tLVSP\t75\t4.99\t3\t36\t-1.63\tAmnestic multiple-domain MCI\t-\t\n2\tF\t78.0\tCLBP\t2.04\t1.00\t3\t30\t-0.12\tAmnestic single-domain MCI\t-\t\n3\tM\t81.7\tLVSP\t75\t0.33\t3\t45\t-3.87\tDementia\t-\t\n4\tF\t72.4\tLVSP\t75\t0.56\t3\t43\t-1.57\tAmnestic single-domain MCI\t-\t\n5\tF\t75.0\tMCP+LVSP\t11.52+50\t0.01\t3\t29\t-0.96\tAmnestic multiple-domain MCI\t-\t\n6\tF\t74.5\tLVSP\t75\t0.48\t3\t21\t-1.22\tNon-amnestic multiple-domain MCI\t-\t\n7\tF\t71.8\tLVSP\t75\t0.18\t2.5\t20\t0.56\tAmnestic multiple-domain MCI\t-\t\n8\tF\t81.0\tLVSP\t75\t0.04\t3\t30\t-1.57\tAmnestic single-domain MCI\t-\t\n9\tF\t64.3\tLVSP\t75\t0.70\t3\t29\t-4.36\tDementia\t+\t\n10\tF\t75.0\tLVSP\t50\t2.97\t1.5\t13\t-0.97\tAmnestic multiple-domain MCI\t-\t\n11\tM\t73.9\tLVSP\t75\t6.09\t2.5\t32\t-2.84\tDementia\t+\t\n12\tF\t77.7\tLVSP\t75\t0.28\t5\t68\t-2.65\tDementia\t-\t\n13\tM\t76.0\tLVSP\t75\t2.01\t2.5\t20\t1.13\tNon-amnestic single-domain MCI\t-\t\n14\tF\t74.3\tLVSP\t75\t0.71\t3\t22\t-1.37\tAmnestic multiple-domain MCI\t-\t\nLVSP, levosulpiride; MCP, metoclopramide; CLBP, clebopride; MCI, mild cognitive impairment; H & Y stage, Hoehn & Yahr stage; UPDRS, Unified Parkinson's Disease Rating Scale score; MMSE, mini mental state examination; RBD, rapid eye movement behavior disorder.\n\nTable 2 Mean volumetric measurements of the brain\nVolume (mL)\tDIP (n=10)\tControl (n=30)\tP value\t\nMean (SD)\tMean (SD)\t\nTotal cortical gray matter\t301.46 (16.52)\t319.99 (25.75)\t0.041*\t\nLeft cortical gray matter\t150.03 (8.03)\t159.89 (13.69)\t0.046*\t\nRight cortical gray matter\t151.37 (8.75)\t160.10 (12.24)\t0.039*\t\nLeft cortical white matter\t201.12 (23.54)\t208.64 (24.12)\t0.331\t\nRight cortical white matter\t203.05 (25.59)\t208.74 (22.53)\t0.428\t\nIntracranial volume\t1383.34 (163.78)\t1301.29 (159.39)\t0.316\t\n*Significant difference (P<0.05, independent t-test) between the DIP and control groups. DIP, drug-induced parkinsonism; SD, standard deviation.\n\nTable 3 Comparison of subcortical volume measurements between DIP patients and control subjects\nVolume (mL)\tDIP (n = 10)\tControl (n = 30)\tP value\t\nMean (SD)\tMean (SD)\t\nL Cerebellar cortex\t52.12 (1.15)\t51.12 (2.09)\t0.162\t\n L Thalamus\t83.10 (4.18)\t83.07 (4.13)\t0.984\t\n L Caudate\t68.08 (4.61)\t69.22 (4.29)\t0.480\t\n L Putamen\t78.47 (5.12)\t78.42 (5.60)\t0.979\t\n L Pallidum\t96.96 (3.91)\t99.89 (4.91)\t0.095\t\nL Hippocampus\t55.96 (2.34)\t54.95 (2.74)\t0.304\t\n L Amygdala\t58.47 (2.78)\t57.72 (2.65)\t0.452\t\n L Accumbens\t66.34 (3.94)\t66.39 (3.41)\t0.968\t\nR Cerebellar cortex\t53.40 (1.15)\t51.65 (2.20)\t0.022*\t\n R Thalamus\t84.20 (2.50)\t82.63 (4.21)\t0.271\t\n R Caudate\t66.34 (3.94)\t66.39 (3.41)\t0.782\t\n R Putamen\t77.02 (4.38)\t75.85 (4.47)\t0.472\t\n R Pallidum\t98.44 (3.71)\t98.86 (5.21)\t0.816\t\nR Hippocampus\t56.41 (2.76)\t53.82 (2.63)\t0.011*\t\n R Amygdala\t57.57 (3.58)\t55.49 (2.30)\t0.038*\t\n R Accumbens\t68.92 (3.78)\t67.56 (3.86)\t0.336\t\n*Significant difference (P<0.05, uncorrected) between the DIP and Control groups. DIP, drug-induced parkinsonism; R, right hemisphere; L, left hemisphere; SD, standard deviation.\n\nTable 4 Correlations between cortical thickness and neuropsychological test scores in DIP\nBrain location\tDigit span forward\tDigit span backward\tNaming K-BNT\tRCFT copy score\tRCFT copy time\tSVLT immediate recall\tSVLT delayed recall\tSVLT recognition\tRCFT immediate recall\tRCFT delayed recall\tRCFT recognition\tCOWAT animal\tCOWAT supermarket\tK-MMSE\t\nL hippocampus\tr squared\t0.230\t-0.092\t0.289\t0.111\t-0.244\t0.067\t0.180\t-0.296\t-0.022\t-0.333\t-0.225\t0.477\t0.090\t-0.360\t\nP values\t0.365\t0.717\t0.245\t0.655\t0.325\t0.788\t0.472\t0.241\t0.929\t0.180\t0.369\t0.058\t0.719\t0.151\t\nR hippocampus\tr squared\t0.322\t-0.138\t0.289\t0.289\t-0.422\t0.156\t0.360\t-0.614\t0.067\t-0.156\t-0.180\t0.205\t0.045\t0.270\t\nP values\t0.205\t0.586\t0.245\t0.245\t0.089\t0.531\t0.151\t0.015\t0.788\t0.531\t0.472\t0.417\t0.857\t0.281\t\nR amygdala\tr squared\t0.276\t-0.046\t-0.244\t0.467\t0.111\t0.600\t0.360\t-0.386\t0.067\t-0.156\t-0.315\t0.159\t0.225\t0.045\t\nP values\t0.277\t0.856\t0.325\t0.060\t0.655\t0.016\t0.151\t0.125\t0.788\t0.531\t0.209\t0.528\t0.369\t0.857\t\nL lingual gyrus\tr squared\t0.414\t0.046\t0.333\t-0.022\t-0.200\t-0.333\t-0.225\t-0.159\t-0.156\t-0.111\t0.674\t-0.068\t0.000\t0.315\t\nP values\t0.103\t0.856\t0.180\t0.929\t0.421\t0.180\t0.369\t0.528\t0.531\t0.655\t0.007\t0.787\t1.000\t0.209\t\nR lingual gyrus\tr squared\t-0.276\t0.276\t0.022\t0.111\t-0.333\t0.067\t0.045\t0.114\t0.333\t0.378\t0.090\t-0.159\t-0.270\t0.180\t\nP values\t0.277\t0.276\t0.929\t0.655\t0.180\t0.788\t0.857\t0.652\t0.180\t0.128\t0.719\t0.528\t0.281\t0.472\t\nR fusiform gyrus\tr squared\t0.046\t0.322\t0.067\t0.244\t0.156\t-0.511\t-0.405\t0.477\t0.022\t-0.111\t0.180\t-0.068\t-0.449\t-0.315\t\nP values\t0.856\t0.204\t0.788\t0.325\t0.531\t0.040\t0.106\t0.058\t0.929\t0.655\t0.472\t0.787\t0.072\t0.209\t\nValues are Kendall's tau-b correlation coefficients and P values. L, left hemisphere; R, right hemisphere; K-BNT, Boston naming test; RCFT, Rey complex figure test; SVLT, Seoul verbal learning test; COWAT, Controlled oral word association test; K-MMSE, Korean version of mini mental state examination.\n\nTable 5 Comparison of cortical thickness measurements between DIP patients and control subjects\nCortical thickness (mm)\tDIP (n = 10)\tCON (n = 30)\tTalX\tTalY\tTalZ\tCWP\t\nMean (SD)\tMean (SD)\t\nR lingual gyrus\t1.52 (0.07)\t1.64 (0.09)\t-32.28\t29.02\t13.58\t0.0001\t\nR fusiform gyrus\t2.03 (0.11)\t2.14 (0.12)\t-21.31\t2.95\t-15.15\t0.0001\t\nL lingual gyrus\t1.47 (0.07)\t1.61 (0.01)\t-21.31\t2.95\t-15.15\t0.0001\t\nL Lateral occipital gyrus\t1.45 (0.11)\t1.75 (0.11)\t-1.50\t-99.09\t-5.29\t0.0001\t\nVertex cluster-wise statistic determined by Monte Carlo simulation. Values for DIP and CON are means and standard deviations in parentheses. CWP, The cluster-wise P value; DIP, drug-induced parkinsonism; CON, control; TalX, TalY, TalZ, Talairach x, y, and z coordinates; R, right hemisphere; L, left hemisphere; SD, standard deviation.\n==== Refs\n1 Bower JH Maraganore DM McDonnell SK Rocca WA Incidence and distribution of parkinsonism in Olmsted County, Minnesota, 1976-1990 Neurology 1999 52 1214 1220 10214746 \n2 Sethi KD Movement disorders induced by dopamine blocking agents Semin Neurol 2001 21 59 68 11346026 \n3 Ma HI Kim JH Chu MK Oh MS Yu KH Kim J Hahm W Kim YJ Lee BC Diabetes mellitus and drug-induced Parkinsonism: a case-control study J Neurol Sci 2009 284 140 143 19467671 \n4 Shin HW Kim MJ Kim JS Lee MC Chung SJ Levosulpiride-induced movement disorders Mov Disord 2009 24 2249 2253 19795476 \n5 Kim JH Byun HJ Non-motor cognitive-perceptual dysfunction associated with drug-induced parkinsonism Hum Psychopharmacol 2009 24 129 133 19204914 \n6 Kim JH Kim SY Byun HJ Subjective cognitive dysfunction associated with drug-induced parkinsonism in schizophrenia Parkinsonism Relat Disord 2008 14 239 242 17851106 \n7 López-Sendón J Mena MA de Yébenes JG Drug-induced parkinsonism Expert Opin Drug Saf 2013 12 487 496 23540800 \n8 Kim YD Kim JS Chung SW Song IU Yang DW Hong YJ Kim YI Ahn KJ Kim HT Lee KS Cognitive dysfunction in drug induced parkinsonism (DIP) Arch Gerontol Geriatr 2011 53 e222 e226 21163539 \n9 Shin HW Kim JS Oh M You S Kim YJ Kim J Kim MJ Chung SJ Clinical features of drug-induced parkinsonism based on [18F] FP-CIT positron emission tomography Neurol Sci 2015 36 269 274 25231645 \n10 Kim JS Oh YS Kim YI Yang DW Chung YA You Ie R Lee KS Combined use of (1)(2)(3)I-metaiodobenzylguanidine (MIBG) scintigraphy and dopamine transporter (DAT) positron emission tomography (PET) predicts prognosis in drug-induced Parkinsonism (DIP): a 2-year follow-up study Arch Gerontol Geriatr 2013 56 124 128 22633343 \n11 Kim JH Park J Yu KH Ma HI Lee BC Kim I Kim YJ Prodromal dementia with lewy bodies manifesting as sertraline-induced parkinsonism: a case report Alzheimer Dis Assoc Disord 2012 26 191 193 21946016 \n12 Lee PH Yeo SH Yong SW Kim YJ Odour identification test and its relation to cardiac 123I-metaiodobenzylguanidine in patients with drug induced parkinsonism J Neurol Neurosurg Psychiatry 2007 78 1250 1252 17557797 \n13 Kang Y Na DL Seoul Neuropsychological Screening Battery 2nd ed Incheon Human Brain Research & Consulting Co. 2003 \n14 Fischl B Sereno MI Dale AM Cortical surface-based analysis. II: Inflation, flattening, and a surface-based coordinate system Neuroimage 1999 9 195 207 9931269 \n15 Fischl B Salat DH Busa E Albert M Dieterich M Haselgrove C van der Kouwe A Killiany R Kennedy D Klaveness S Whole brain segmentation: automated labeling of neuroanatomical structures in the human brain Neuron 2002 33 341 355 11832223 \n16 Fischl B Dale AM Measuring the thickness of the human cerebral cortex from magnetic resonance images Proc Natl Acad Sci U S A 2000 97 11050 11055 10984517 \n17 Dale AM Fischl B Sereno MI Cortical surface-based analysis. I. Segmentation and surface reconstruction Neuroimage 1999 9 179 194 9931268 \n18 Hayasaka S Nichols TE Validating cluster size inference: random field and permutation methods Neuroimage 2003 20 2343 2356 14683734 \n19 Teipel SJ Grothe M Lista S Toschi N Garaci FG Hampel H Relevance of magnetic resonance imaging for early detection and diagnosis of Alzheimer disease Med Clin North Am 2013 97 399 424 23642578 \n20 Seo SW Im K Lee JM Kim YH Kim ST Kim SY Yang DW Kim SI Cho YS Na DL Cortical thickness in single- versus multiple-domain amnestic mild cognitive impairment Neuroimage 2007 36 289 297 17459730 \n21 Delli Pizzi S Franciotti R Tartaro A Caulo M Thomas A Onofrj M Bonanni L Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study PLoS One 2014 9 e86624 24466177 \n22 Pagonabarraga J Corcuera-Solano I Vives-Gilabert Y Llebaria G García-Sánchez C Pascual-Sedano B Delfino M Kulisevsky J Gómez-Ansón B Pattern of regional cortical thinning associated with cognitive deterioration in Parkinson’s disease PLoS One 2013 8 e54980 23359616\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "30(9)",
"journal": "Journal of Korean medical science",
"keywords": "Cortical Thickness; Drug-induced Parkinsonism; Magnetic Resonance Imaging; Prokinetics; SWEDD (Scans without Evidence of Dopaminergic Deficit); Volumetry",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000932:Antiemetics; D001921:Brain; D003072:Cognition Disorders; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D008297:Male; D010302:Parkinson Disease, Secondary; D056910:Republic of Korea; D012189:Retrospective Studies; D018570:Risk Assessment; D016896:Treatment Outcome",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "1328-33",
"pmc": null,
"pmid": "26339175",
"pubdate": "2015-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "19467671;19204914;21163539;19795476;22633343;23359616;23642578;23540800;24466177;25231645;10984517;11346026;11832223;14683734;9931268;9931269;10214746;17459730;17557797;17851106;21946016",
"title": "Cognitive Dysfunction in Drug-induced Parkinsonism Caused by Prokinetics and Antiemetics.",
"title_normalized": "cognitive dysfunction in drug induced parkinsonism caused by prokinetics and antiemetics"
} | [
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"companynumb": "KR-NOVEL LABORATORIES, INC-2016-03565",
"fulfillexpeditecriteria": "2",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "METOCLOPRAMIDE"
},
"drugaddition... |
{
"abstract": "Primary endometrial squamous cell carcinomas (PESCC) occur sporadically. It is defined as a primary carcinoma of the endometrium composed of squamous cells of varying degrees of differentiation. A 57-year-old female patient was referred to the gynaecological clinic of Faculty of Medicine, Universitas Indonesia, Dr Cipto Mangunkusumo National Referral Hospital because of abdominal enlargement with pain. Total hysterectomy and bilateral salpingectomy were performed. Histopathological examination confirmed a moderately differentiated squamous cell carcinoma, with lymph-vascular invasion. Two weeks after the operation, the patient complained of a mass on her left supraclavicular area. Fine needle aspiration biopsy revealed squamous cell carcinoma metastatic in nature. The recommended treatment was paclitaxel (175mg/m2) and carboplatin (AUC- 6), combined with pelvic radiotherapy.",
"affiliations": "Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Faculty of Medicine, Department of Obstetrics and Gynecology, Gynecology Oncology Division, Indonesia. spurbadi@gmail.com.;Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Faculty of Medicine, Department of Obstetrics and Gynecology, Indonesia.;Universitas Indonesia, Dr. Cipto Mangunkusumo National Referral Hospital, Faculty of Medicine, Department of Pathology Anatomy, Indonesia.",
"authors": "Purbadi|S|S|;Saspriyana|K Y|KY|;Hellyanti|T|T|",
"chemical_list": null,
"country": "Malaysia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-5283",
"issue": "75(5)",
"journal": "The Medical journal of Malaysia",
"keywords": null,
"medline_ta": "Med J Malaysia",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D004717:Endometrium; D005260:Female; D006801:Humans; D008875:Middle Aged",
"nlm_unique_id": "0361547",
"other_id": null,
"pages": "603-605",
"pmc": null,
"pmid": "32918438",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Primary squamous cell carcinoma of the endometrium: A rare case report.",
"title_normalized": "primary squamous cell carcinoma of the endometrium a rare case report"
} | [
{
"companynumb": "ID-TEVA-2020-ID-1846187",
"fulfillexpeditecriteria": "1",
"occurcountry": "ID",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": "3",
... |
{
"abstract": "Antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV) is a pauci-immune necrotizing vasculitis that involves small vessels. Herein, we report an extremely rare case of rifampicin (RFP)-induced AAV. A 42-yearold female was transferred to the West China Hospital due to cough with phlegm for 3 months, fever for 1 month, and fatigue for 2 weeks. The patient was diagnosed with pulmonary tuberculosis (TB) and received anti-TB treatment with isoniazid, RFP, ethambutol, and pyrazinamide (PZA) at her local hospital. After 5 days of anti-TB treatment, her creatinine level rose to 420.2 μmol/L from a normal level prior to anti-TB treatment. Serum proteinase 3 (PR3)-ANCA was positive. After discontinuing the anti-TB drugs and administering protective renal treatment, her renal function improved, whereas PR3-ANCA remained positive. With RFP rechallenge after transfer to our hospital, the patient developed oliguria. Her urine volume increased gradually after RFP was discontinued 3 days later. Therefore, RFPinduced AAV was suspected. Eventually, the patient received prednisone and anti-TB therapy, including isoniazid, ethambutol, PZA, and moxifloxacin. After 2 months, PZA was discontinued. During 6 months of normal, and PR3-ANCA became negative at 4 months. This outcome is characteristic of RFP-induced AAV.",
"affiliations": null,
"authors": "Ji|Guiyi|G|;Zeng|Xuemei|X|;Sandford|Andrew J|AJ|;He|Jian-Qing|JQ|",
"chemical_list": "D000995:Antitubercular Agents; D011241:Prednisone; D012293:Rifampin",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP202576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0946-1965",
"issue": "54(10)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000328:Adult; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D000995:Antitubercular Agents; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007677:Kidney Function Tests; D011241:Prednisone; D012293:Rifampin; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "804-7",
"pmc": null,
"pmid": "27569735",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Rifampicin-induced antineutrophil cytoplasmic antibody-positive vasculitis: a case report and review of the literature.",
"title_normalized": "rifampicin induced antineutrophil cytoplasmic antibody positive vasculitis a case report and review of the literature"
} | [
{
"companynumb": "CN-SA-2016SA191955",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional": null... |
{
"abstract": "Bupropion is an atypical antidepressant that is structurally similar to amphetamines. Its primary toxic effects include seizure, sinus tachycardia, hypertension, and agitation; however, at higher amounts of ingestion, paradoxical cardiac effects are seen. We report the case of a 21-year-old woman who ingested 13.5 g of bupropion, a dose higher than any other previously reported. The patient presented with seizure, sinus tachycardia with prolonged QTc and QRS intervals, dilated pupils, and agitation. Four days after overdose, the patient's sinus tachycardia and prolonged QTc and QRS intervals resolved with symptomatic management, but she soon developed sinus bradycardia, hypotension, and mild transaminitis. With continued conservative management and close monitoring, her sinus bradycardia resolved 8 days after the overdose. The transaminitis resolved 12 days after the overdose. Our findings are consistent with previously reported toxic effects associated with common overdose amounts of bupropion. In addition, we have observed transient cardiotoxicity manifesting as sinus bradycardia associated with massive bupropion overdose. These findings are less frequently reported and must be considered when managing patients with massive bupropion overdose. We review the psychopharmacologic implications of this and comment on previous literature.",
"affiliations": "ZHU: Cleveland Clinic Lerner College of Medicine, Cleveland, OH KOLAWOLE and JIMENEZ: Center for Behavioral Health, Cleveland Clinic, Cleveland, OH.",
"authors": "Zhu|Yuanjia|Y|;Kolawole|Tiwalola|T|;Jimenez|Xavier F|XF|",
"chemical_list": "D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion",
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000179",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "22(5)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000328:Adult; D018687:Antidepressive Agents, Second-Generation; D016642:Bupropion; D062787:Drug Overdose; D004562:Electrocardiography; D005260:Female; D006801:Humans; D012640:Seizures; D012770:Shock, Cardiogenic; D013406:Suicide, Attempted; D055815:Young Adult",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "405-9",
"pmc": null,
"pmid": "27648505",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Atypical Findings in Massive Bupropion Overdose: A Case Report and Discussion of Psychopharmacologic Issues.",
"title_normalized": "atypical findings in massive bupropion overdose a case report and discussion of psychopharmacologic issues"
} | [
{
"companynumb": "US-PRINSTON PHARMACEUTICAL INC.-2016PRN00292",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BUPROPION HYDROCHLORIDE"
},
... |
{
"abstract": "Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune demyelinating disease of the central nervous system, characterized by a specific antibody that selectively binds aquaporin-4 channel.This is a report of an NMOSD case, with severe attacks of optic neuritis and myelitis after initiate of dimethyl fumarate (DMF).We suggested that DMF could deteriorate the neuromyelitis optica (NMO) disease course, which results in serious morbidity and mortality in patients. Thus, initiation of DMF should be avoided before ruling out NMOSD in patients experiencing demyelinating attacks, especially in the case of recurrent optic neuritis or myelopathy and concurrency of other rheumatologic diseases.",
"affiliations": "From the Department of Neurology, Imam Khomeini Hospital, Iranian Center of Neurological Research, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran.",
"authors": "Javadian|Nina|N|;Magrouni|Hana|H|;Ghaffarpour|Majid|M|;Ranji-Burachaloo|Sakineh|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D000069462:Dimethyl Fumarate",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000430",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "44(1)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000069462:Dimethyl Fumarate; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D009103:Multiple Sclerosis; D009471:Neuromyelitis Optica; D009902:Optic Neuritis; D012008:Recurrence; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "21-22",
"pmc": null,
"pmid": "33449476",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe Relapses of Neuromyelitis Optica Spectrum Disorder During Treatment With Dimethyl Fumarate.",
"title_normalized": "severe relapses of neuromyelitis optica spectrum disorder during treatment with dimethyl fumarate"
} | [
{
"companynumb": "IR-TWI PHARMACEUTICAL, INC-2021SCTW000008",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIMETHYL FUMARATE"
},
"drugad... |
{
"abstract": "Two men aged 71 and 62 years were admitted for ST elevation myocardial infarction and percutaneous coronary intervention was performed to the occlusion of left anterior descending artery. Echocardiogram showed an akinetic or a dyskinetic movement of left ventricular anterior wall with mural thrombus on admission in Case 1 and 10 days from admission in Case 2. A direct oral anticoagulant (DOAC) in addition to dual antiplatelet therapy (DAPT) in both patients was started successfully for the resolution of left ventricular thrombus 3 weeks after the initiation of DOAC in Case 1, and 2 weeks after the initiation of DOAC in Case 2. However, the dose of DOAC was decreased and aspirin was stopped in Case 1 with HAS-BLED score five due to colon polyp bleeding, and there was no bleeding complication in Case 2 with HAS-BLED score two during this triple therapy. The duration of triple therapy was 2 months in Case 1 and 6 months in Case 2, and of DOAC therapy was total 6 months in both cases. <Learning objective: Anticoagulant in addition to dual antiplatelet therapy (DAPT) is necessary for left ventricular thrombus following acute myocardial infarction. However, this triple therapy is generally associated with significant bleeding hazard. We here show the efficacy of direct oral anticoagulant on left ventricular thrombus and the necessity of regimes for duration of triple therapy which should be carefully considered according to the patient characteristics. Recent stent design may allow briefer duration of DAPT for the reduction of bleeding complication.>.",
"affiliations": "Department of Cardiology, Japan Community Health Care Organization, Yokohama Chuo Hospital, Yokohama, Japan.;Department of Cardiology, Japan Community Health Care Organization, Yokohama Chuo Hospital, Yokohama, Japan.;Department of Cardiology, Japan Community Health Care Organization, Yokohama Chuo Hospital, Yokohama, Japan.;Department of Cardiology, Japan Community Health Care Organization, Yokohama Chuo Hospital, Yokohama, Japan.;Department of Cardiology, Japan Community Health Care Organization, Yokohama Chuo Hospital, Yokohama, Japan.",
"authors": "Matsumoto|Michiaki|M|;Takei|Norio|N|;Mineki|Takashi|T|;Yahata|Takayuki|T|;Oiwa|Koji|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2020.05.012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "22(3)",
"journal": "Journal of cardiology cases",
"keywords": "Direct oral anticoagulant; Left ventricular thrombus; Myocardial infarction; Triple antithrombotic therapy",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "114-116",
"pmc": null,
"pmid": "32884591",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports",
"references": "28886621;20006130;26299222;23151669;2307788;27797850;31237644;10582996;25081096;29800958",
"title": "Anticoagulant therapy with dual antiplatelet for left ventricular thrombus following acute myocardial infarction.",
"title_normalized": "anticoagulant therapy with dual antiplatelet for left ventricular thrombus following acute myocardial infarction"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-254168",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"dru... |
{
"abstract": "Little is known about interactions of other drugs with the recently marketed antipsychotic clozapine. Two cases in which the addition of phenytoin caused a decrease in plasma clozapine concentrations and worsening of psychoses are described, and possible explanations are discussed.",
"affiliations": "Department of Psychiatry, College of Medicine, University of Iowa, Iowa City 52242.",
"authors": "Miller|D D|DD|",
"chemical_list": "D010672:Phenytoin; D003024:Clozapine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "52(1)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000328:Adult; D003024:Clozapine; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D008297:Male; D010672:Phenytoin; D011618:Psychotic Disorders",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "23-5",
"pmc": null,
"pmid": "1988414",
"pubdate": "1991-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Effect of phenytoin on plasma clozapine concentrations in two patients.",
"title_normalized": "effect of phenytoin on plasma clozapine concentrations in two patients"
} | [
{
"companynumb": "US-PFIZER INC-2015227309",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHepatic complications are a major cause of illness and death after bone marrow transplantation.\n\n\nOBJECTIVE\nTo confirm the results of a pilot study that indicated that ursodiol prophylaxis could reduce the incidence of veno-occlusive disease of the liver.\n\n\nMETHODS\nRandomized, double-blind, placebo-controlled study.\n\n\nMETHODS\nTertiary care teaching hospital.\n\n\nMETHODS\n67 consecutive patients undergoing transplantation with allogeneic bone marrow (donated by a relative) in whom busulfan plus cyclophosphamide was used as the preparative regimen and cyclosporine plus methotrexate was used to prevent graft-versus-host disease.\n\n\nMETHODS\nBefore the preparative regimen was started, patients were randomly assigned to receive ursodiol, 300 mg twice daily (or 300 mg in the morning and 600 mg in the evening if body weight was > 90 kg), or placebo.\n\n\nMETHODS\nPatients were prospectively evaluated for the clinical diagnosis of veno-occlusive disease, the occurrence of acute graft-versus-host disease, and survival.\n\n\nRESULTS\nThe incidence of veno-occlusive disease was 40% (13 of 32 patients) in placebo recipients and 15% (5 of 34 patients) in ursodiol recipients (P = 0.03). Assignment to placebo was the only pretransplantation characteristic that predicted the development of veno-occlusive disease. The most significant predictor of 100-day mortality was the diagnosis of veno-occlusive disease. The difference in actuarial risk for hematologic relapse in patients with chronic myelogenous leukemia and nonhepatic toxicities between the two groups was not statistically significant (13% in the ursodiol group and 20% in the placebo group; P > 0.2).\n\n\nCONCLUSIONS\nUrsodiol prophylaxis seemed to decrease the incidence of hepatic complications after allogeneic bone marrow transplantation in patients who received a preparative regimen with busulfan plus cyclophosphamide.",
"affiliations": "Wilford Hall Medical Center, Lackland Air Force Base, Texas, USA.",
"authors": "Essell|J H|JH|;Schroeder|M T|MT|;Harman|G S|GS|;Halvorson|R|R|;Lew|V|V|;Callander|N|N|;Snyder|M|M|;Lewis|S K|SK|;Allerton|J P|JP|;Thompson|J M|JM|",
"chemical_list": "D002756:Cholagogues and Choleretics; D007166:Immunosuppressive Agents; D010919:Placebos; D014580:Ursodeoxycholic Acid; D003520:Cyclophosphamide; D002066:Busulfan",
"country": "United States",
"delete": false,
"doi": "10.7326/0003-4819-128-12_part_1-199806150-00002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4819",
"issue": "128(12 Pt 1)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D000328:Adult; D016026:Bone Marrow Transplantation; D002066:Busulfan; D002756:Cholagogues and Choleretics; D003520:Cyclophosphamide; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D006086:Graft vs Host Disease; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D010919:Placebos; D015996:Survival Rate; D014184:Transplantation, Homologous; D014580:Ursodeoxycholic Acid",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "975-81",
"pmc": null,
"pmid": "9625683",
"pubdate": "1998-06-15",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation. A randomized, double-blind, placebo-controlled trial.",
"title_normalized": "ursodiol prophylaxis against hepatic complications of allogeneic bone marrow transplantation a randomized double blind placebo controlled trial"
} | [
{
"companynumb": "US-PFIZER INC-2020509797",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "METHOTREXATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "A 30 year old lady patient of SLE on steroid and hydroxychloroquine therapy presented with lupus nephritis and later developed cardiac symptoms. Her renal biopsy revealed features of Class III lupus nephritis. Also seen was typical lamellated myelinoid material in the glomerulus. The alpha-galactosidase A activity was normal. The clinical morphological and biochemical findings were consistent with Lupus nephritis showing changes of hydroxychloroquine induced phopholipidosis. Electron microscopy along with careful clinical examination and follow up status was instrumental in the diagnosis of the latter.",
"affiliations": "Jaslok Hospital and Research Center, Histopathology, Mumbai, India. shailakhubchandani@yahoo.co.in",
"authors": "Khubchandani|Shaila Raju|SR|;Bichle|Lata Sunil|LS|",
"chemical_list": "D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D010743:Phospholipids; D006886:Hydroxychloroquine; D003520:Cyclophosphamide",
"country": "England",
"delete": false,
"doi": "10.3109/01913123.2012.751950",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0191-3123",
"issue": "37(2)",
"journal": "Ultrastructural pathology",
"keywords": null,
"medline_ta": "Ultrastruct Pathol",
"mesh_terms": "D000328:Adult; D018501:Antirheumatic Agents; D003520:Cyclophosphamide; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D006886:Hydroxychloroquine; D007166:Immunosuppressive Agents; D007678:Kidney Glomerulus; D008064:Lipidoses; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D009186:Myelin Sheath; D009404:Nephrotic Syndrome; D010743:Phospholipids; D016896:Treatment Outcome",
"nlm_unique_id": "8002867",
"other_id": null,
"pages": "146-50",
"pmc": null,
"pmid": "23573895",
"pubdate": "2013-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hydroxychloroquine-induced phospholipidosis in a case of SLE: the wolf in zebra clothing.",
"title_normalized": "hydroxychloroquine induced phospholipidosis in a case of sle the wolf in zebra clothing"
} | [
{
"companynumb": "PHHY2013IN131324",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CALCIUM"
},
"drugadditional": "3",
"drugadmi... |
{
"abstract": "Catatonia is characterized by motor and behavioral symptoms and can arise in a wide variety of medical and psychiatric conditions. We describe the case of a 16-year-old female with a history of anxiety and depression who presented with prominent symptoms of negativism, initially diagnosed as conversion disorder. She failed to respond to increasing doses of benzodiazepines; after over six weeks of hospitalization, she received electroconvulsive therapy (ECT), resulting in significant remission of symptoms. This case demonstrates the importance of prompt diagnosis and treatment of catatonia in adolescent patients, as well as the safety and efficacy of ECT in this population.Abbreviations: AACAP: American Academy of Child and Adolescent Psychiatry; BPAD: Bipolar affective disorder; DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition; DSM-5: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; ECT: Electroconvulsive therapy; NMDA: N-methyl-D-aspartate.",
"affiliations": "Weill Cornell Medical College, New York, NY, USA.;Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.;Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.;Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.;Department of Psychiatry, Weill Cornell Medicine, New York, NY, USA.",
"authors": "Clermont|Adrienne|A|0000-0002-5608-7593;Loubriel|Daphne|D|;Li|Erin|E|;Mitera|Darlene|D|;Samuels|Susan|S|",
"chemical_list": "D001569:Benzodiazepines",
"country": "England",
"delete": false,
"doi": "10.1080/13554794.2020.1859545",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1355-4794",
"issue": "27(1)",
"journal": "Neurocase",
"keywords": "Catatonia; adolescent psychiatry; benzodiazepines; bipolar disorder; conversion disorder; electroconvulsive therapy",
"medline_ta": "Neurocase",
"mesh_terms": "D000293:Adolescent; D001569:Benzodiazepines; D001714:Bipolar Disorder; D002389:Catatonia; D002648:Child; D004565:Electroconvulsive Therapy; D005260:Female; D006801:Humans",
"nlm_unique_id": "9511374",
"other_id": null,
"pages": "18-21",
"pmc": null,
"pmid": "33297838",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Electroconvulsive therapy in an adolescent patient with catatonia: a case report.",
"title_normalized": "electroconvulsive therapy in an adolescent patient with catatonia a case report"
} | [
{
"companynumb": "US-Appco Pharma LLC-2127624",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHLORPROMAZINE"
},
"drugadditional": "3",
... |
{
"abstract": "To investigate the long-term results of photodynamic therapy (PDT) in chronic central serous chorioretinopathy (CSCR).\n\n\n\nThe authors reviewed patients with chronic CSCR treated with verteporfin PDT in their hospital and followed up for 36 months or longer.\n\n\n\nAmong 94 eyes, 76 eyes underwent half-fluence PDT (80.9%), 12 eyes (12.8%) underwent half-dose PDT, and six eyes (6.4%) underwent standard PDT. Mean follow-up duration was 58.1 months± 20.3 months. Mean best-corrected visual acuity improved by 0.15 ± 0.31 logMAR. Seventy-two eyes (77%) had resolution of subretinal fluid 1 month after treatment. Nine eyes (9.6%) showed nonresponse, and 23 (24.5%) showed recurrence. Older age (P = .009) and smaller macular thickness reduction post-PDT (P = .017) were associated with nonresponse. Male sex (P = .021), bilateral CSCR (P = .008), and smaller choroidal thickness reduction (P = .024) were associated with recurrence. Retreatment using PDT resulted in a 90% success rate.\n\n\n\nVerteporfin PDT for chronic CSCR conferred good visual outcomes, as well as good safety results up to mean 5 years. Although the disease recurred in about one-fifth of the eyes, additional PDT conferred a good response rate. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:760-770.].",
"affiliations": null,
"authors": "Park|Young Joo|YJ|;Kim|Yong-Kyu|YK|;Park|Kyu Hyung|KH|;Woo|Se Joon|SJ|",
"chemical_list": "D017319:Photosensitizing Agents; D000077362:Verteporfin",
"country": "United States",
"delete": false,
"doi": "10.3928/23258160-20191119-03",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2325-8160",
"issue": "50(12)",
"journal": "Ophthalmic surgery, lasers & imaging retina",
"keywords": null,
"medline_ta": "Ophthalmic Surg Lasers Imaging Retina",
"mesh_terms": "D000328:Adult; D000368:Aged; D056833:Central Serous Chorioretinopathy; D002908:Chronic Disease; D005260:Female; D005451:Fluorescein Angiography; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010778:Photochemotherapy; D017319:Photosensitizing Agents; D012189:Retrospective Studies; D058471:Subretinal Fluid; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D000077362:Verteporfin; D014792:Visual Acuity",
"nlm_unique_id": "101599215",
"other_id": null,
"pages": "760-770",
"pmc": null,
"pmid": "31877221",
"pubdate": "2019-12-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-Term Efficacy and Safety of Photodynamic Therapy in Patients With Chronic Central Serous Chorioretinopathy.",
"title_normalized": "long term efficacy and safety of photodynamic therapy in patients with chronic central serous chorioretinopathy"
} | [
{
"companynumb": "KR-BAUSCH-BL-2021-031443",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VERTEPORFIN"
},
"drugadditional": "3",
... |
{
"abstract": "Immunosuppressed transplant recipients have increased risk for the development of basal cell carcinoma skin cancers. While oral vismodegib therapy has been successful in treating locally advanced basal cell tumors, few studies document its use and efficacy in organ transplant patients. In this immunocompromised population, topical imiquimod 5% cream has been shown to be an effective and well-tolerated option for superficial and nodular basal cell carcinomas. To the authors' knowledge, no data documents the use of optical coherence tomography, a noninvasive imaging technique, to monitor progress of such combined therapies on in vivo skin. The authors report the successful treatment of an extensive basal cell carcinoma on the nose of an immunosuppressed 54-year-old Caucasian man with a history of kidney and pancreas transplantations. By combining continuous noninvasive lesion monitoring with vismodegib 150mg/d therapy and adjuvant imiquimod 5% topical cream, the patient showed complete disease clearance on clinical, optical coherence tomography, and histological evaluation. This report supports the feasibility and efficacy of nonsurgical treatment of basal cell lesions in complicated transplant patients and the need for individualized treatment plans. A noninvasive follow-up tool, especially during nonsurgical therapy, is of critical value to ensure the best possible treatment outcome for the patient.",
"affiliations": "SUNY Downstate Medical Center, Brooklyn, New York;; New York Harbor Healthcare System, Brooklyn, New York;; Mount Sinai Medical Center, New York, New York.;SUNY Downstate Medical Center, Brooklyn, New York;; New York Harbor Healthcare System, Brooklyn, New York;; Mount Sinai Medical Center, New York, New York.",
"authors": "Markowitz|Orit|O|;Schwartz|Michelle|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-2789",
"issue": "9(8)",
"journal": "The Journal of clinical and aesthetic dermatology",
"keywords": null,
"medline_ta": "J Clin Aesthet Dermatol",
"mesh_terms": null,
"nlm_unique_id": "101518173",
"other_id": null,
"pages": "37-41",
"pmc": null,
"pmid": "27672417",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports",
"references": "15115500;19397661;24725477;23319845;26557214;24528922;22540280;25337679;24929884;25640145;10321596;22862425;22670904;2316011;24103017;25904111;15197337;22293184;25913533",
"title": "The Use of Noninvasive Optical Coherence Tomography to Monitor the Treatment Progress of Vismodegib and Imiquimod 5% Cream in a Transplant Patient with Advanced Basal Cell Carcinoma of the Nose.",
"title_normalized": "the use of noninvasive optical coherence tomography to monitor the treatment progress of vismodegib and imiquimod 5 cream in a transplant patient with advanced basal cell carcinoma of the nose"
} | [
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2017SP006192",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMIQUIMOD"
},
"drugadditional":... |
{
"abstract": "Uremic platelet dysfunction rarely causes significant bleeding in adequately dialyzed patients. When encountered, the management is complicated by a lack of well-supported treatment modalities. Estrogen use in uremic platelet dysfunction has been described, but enthusiasm for the treatment has been dampened by the risk of thrombotic events in vasculopathic dialysis patients. We present a patient on long-term peritoneal dialysis with coronary disease who developed recurrent life-threatening bleeding episodes secondary to uremia, where treatment with transdermal estrogen was used safely and effectively for a 24-month period.",
"affiliations": "Department of Internal Medicine, Rochester General Hospital, University of Rochester School of Medicine and Dentistry, N.Y., USA.;Department of Internal Medicine, Rochester General Hospital, University of Rochester School of Medicine and Dentistry, N.Y., USA ; Nephrology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, N.Y., USA.;Division of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, N.Y., USA.",
"authors": "Bali|Atul|A|;Hix|John Kevin|JK|;Kouides|Peter|P|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000365480",
"fulltext": "\n==== Front\nNephron ExtraNephron ExtraNNENephron Extra1664-55291664-5529S. 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 10.1159/000365480nne-0004-0134Case ReportSafe and Effective Use of Chronic Transdermal Estradiol for Life-Threatening Uremic Bleeding in a Patient with Coronary Artery Disease Bali Atul aHix John Kevin ab*Kouides Peter caDepartment of Internal Medicine, Rochester General Hospital, University of Rochester School of Medicine and Dentistry, N.Y., USAbNephrology Division, Department of Medicine, University of Rochester School of Medicine and Dentistry, N.Y., USAcDivision of Hematology/Oncology, Department of Medicine, University of Rochester Medical Center, Rochester, N.Y., USA*John Kevin Hix, MD, Nephrology and Hypertension Unit, 370 Ridge Road East Suite L20, Rochester, NY 14621 (USA), E-Mail john.hix@rochestergeneral.orgMay-Aug 2014 19 8 2014 19 8 2014 4 2 134 137 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.Uremic platelet dysfunction rarely causes significant bleeding in adequately dialyzed patients. When encountered, the management is complicated by a lack of well-supported treatment modalities. Estrogen use in uremic platelet dysfunction has been described, but enthusiasm for the treatment has been dampened by the risk of thrombotic events in vasculopathic dialysis patients. We present a patient on long-term peritoneal dialysis with coronary disease who developed recurrent life-threatening bleeding episodes secondary to uremia, where treatment with transdermal estrogen was used safely and effectively for a 24-month period.\n\nKey Words\nUremic plateletsTransdermal estradiolChronic kidney diseaseBleeding\n==== Body\nIntroduction\nBleeding from uremic platelet dysfunction causes significant morbidity in patients with chronic kidney disease, and treatment is complicated by our limited understanding of its exact pathophysiology and comorbid conditions [1,2,3]. Typical presentations include mucocutaneous or postprocedural bleeding [1,2]. While dialysis and improved anemia management with erythropoiesis-stimulating agents have greatly reduced the incidence of this condition, it has not yet been eliminated [1,2,3].\n\nWe report a patient with end-stage renal disease who suffered multiple spontaneous life-threatening bleeding episodes due to uremic platelet dysfunction responsive only to transdermal estrogen.\n\nCase Report\nA 79-year-old male with end-stage renal disease secondary to hypertension presented to the emergency room with lightheadedness. He had been on regular peritoneal dialysis for the preceding 18 months. Five days prior to presentation he had had a tooth extraction complicated by profuse daily bleeding at the wound site. His history was notable for coronary artery disease with coronary artery bypass graft surgery in 1996 and atrial fibrillation. He reported no prior personal or family history of bleeding. His medications included aspirin (81 mg) and warfarin. Laboratory data revealed a subtherapeutic INR (1.0) and severe anemia (hemoglobin 7.1 g/dl). He received 3 units of packed red blood cells (PRBC) and was discharged having been taken off warfarin.\n\nThree weeks later, the patient presented with acute-onset right hip pain from a spontaneous right iliacus hematoma (7.9 × 6.3 cm) and severe anemia requiring multiple PRBC transfusions (table 1). Aspirin was discontinued but was restarted shortly after discharge. Six weeks after resumption, he developed a spontaneous left psoas hematoma (7.2 × 14.6 cm) and aspirin was permanently discontinued. Over the next 6 months, he required 8 hospital admissions and 25 units of PRBC due to repeated spontaneous gluteal hematomas while being off all anticoagulant and antiplatelet therapies. Dialysis was usually adequate based on urea kinetics calculated during the periods between admissions (table 1). During admissions, peritoneal dialysis was extended up to 14 h daily to facilitate toxin removal. His hematocrit level was maintained close to 30% by means of PRBC transfusions to ensure cell availability for ‘scaffolding’ of the vascular endothelium by platelets for optimal functionality. Darbepoetin use was continued in both the inpatient and outpatient setting. Desmopressin was employed once but was subsequently abandoned due to its lack of efficacy and the possibility of tachyphylaxis. None of these measures prevented the formation of new hematomas.\n\nHematologic workup during this period showed that PT/INR, activated partial thromboplastin time, platelet count, factors VIII, IX, XI and XIII, fibrinogen, euglobulin clot lysis time and vitamin C levels were within normal limits. High levels of von Willebrand factor antigen (447%, normal range 60-150%) and ristocetin cofactor (542%, normal range 50-175%) were noted. Platelet function testing on whole blood revealed low release to thrombin and low-dose collagen, borderline low release to high-dose collagen and adenosine diphosphate, and normal release to arachidonic acid. Normal aggregation was observed to all agonists. Based on these findings, platelet dysfunction was diagnosed, which, with no other identifiable cause present, was deemed secondary to uremia.\n\nThe patient experienced such deterioration in quality of life that he even considered stopping dialysis and electing only palliative treatment. After multidisciplinary discussions and with informed consent, the patient was offered transdermal estradiol patches starting at 50 μg/day once every 3.5 days [4]. The transdermal route was offered based on data suggesting an association with lower thrombotic risk [5,6]. Treatment was started in September 2010. After a 16-month period of complete clinical stability, the dose was reduced to 25 μg/day every 3.5 days. Over a total treatment time of 25 months using estradiol patches, the patient suffered no further bleeding or new cardiac events. Repeat CT scans of the abdomen in February 2012 and July 2012 confirmed the resolution of the previous retroperitoneal hematomas without new findings. Recently, the patient has elected to come off treatment on the recommendation of his cardiology team.\n\nDiscussion\nThe mainstay of preventing uremic platelet dysfunction is regular adequate dialysis to reduce the toxic milieu that impairs platelet function and to improve their functionality. Evidence suggests that peritoneal dialysis may have a greater influence on platelet aggregation than hemodialysis [3].\n\nFor patients with persisting platelet dysfunction despite dialysis, conjugated estrogens have been utilized [4,7]. The knowledge of their efficacy and mechanism of action is based on several small studies conducted in the 1980s. The proposed mechanism is attributed to the effect of conjugated estrogens on reducing L-arginine levels, thereby reducing the production of nitric oxide, which is an inhibitor of platelet aggregation [1,3]. Consequently, estrogens promote platelet reactivity by increasing the serum levels of β-thromboglobulin and thromboxane [2,3,7]. Evidence suggests that their effects on bleeding time and clinical bleeding are dose dependent [8].\n\nThe risk of thrombotic events associated with the use of estrogen in elderly dialysis patients with cardiovascular disease is a major concern, and the long-term effects of transdermal estrogens have not yet been studied in this population. The typical dose of estrogen used for uremic bleeding is comparable to the dosages used for the purpose of hormone replacement in menopausal women. A systematic review by Hemelaar et al. [5] supported the safety of nonoral routes of estrogen administration for postmenopausal hormone replacement therapy compared to oral estrogens, with respect to the risk of developing atherosclerotic and venous thromboembolic disease. A meta-analysis conducted by Olié et al. [6] further supported these findings. Potentially, this route avoids the first-pass metabolism that oral estrogens undergo, which may subsequently increase the hepatic synthesis of inflammatory markers and alter the production of proteins participating in hemostasis [4,6]. In addition, an increased incidence of acquired activated protein C resistance has been described in oral but not in transdermal estrogen users [6]. In light of this information, the European Menopause and Andropause Society favors the transdermal route in patients who require estrogen therapy because they are suffering from coronary disease or are at high risk for venous thromboembolic disease [9,10].\n\nIt is premature to extrapolate these results to patients with uremic platelet dysfunction. However, the long-term success and safety of using transdermal estrogen outlined in this report are encouraging and warrant consideration of this option in treating uremic platelet dysfunction.\n\nDisclosure Statement\nThe authors received no financial support for this work and declare no competing interests.\n\nTable 1 Laboratory data on the days of admission along with preceding Kt/V\n\nDate\tHematocrit, %\tPlatelets,\t×103/μl\tINR\tAPTT, s\tKt/V\t\n2/15/2010\t\t\t\t\t2.23\t\n3/18/2010\t21\t195\t1.0\t24.5\t\t\n4/9/2010\t22\t355\t1.2\t\t\t\n\t\n4/23/2010\t27\t358\t\t\t\t\n6/4/2010\t34\t241\t1.0\t23.0\t\t\n7/8/2010\t\t\t\t\t\t\t1.5\t\n\t\n7/26/2010\t33\t291\t1.0\t26.7\t\t\n8/4/2010\t25\t260\t1.0\t27.5\t\t\n8/11/2010\t27\t327\t1.0\t27.8\t\t\n\t\n9/1/2010\t32\t339\t1.0\t26.9\t\t\n9/24/2010\t\t\t\t\t\t\t2.3\t\nAPTT = Activated partial thromboplastin time.\n==== Refs\nReferences\n1 Noris M Remuzzi G Uremic bleeding: closing the circle after 30 years of controversies? Blood 1999 94 2569 2574 10515859 \n2 Pavord S Myers B Bleeding and thrombotic complications of kidney disease Blood Rev 2011 25 271 278 21872374 \n3 Hedges SJ Dehoney SB Hooper JS Evidence-based treatment recommendations for uremic bleeding Nat Clin Pract Nephrol 2007 3 138 152 17322926 \n4 Sloand JA Schiff MJ Beneficial effect of low-dose transdermal estrogen on bleeding time and clinical bleeding in uremia Am J Kidney Dis 1995 26 22 7611255 \n5 Hemelaar M van der Mooren M Rad M Effects of non-oral postmenopausal hormone therapy on markers of cardiovascular risk: a systematic review Fertil Steril 2008 90 642 672 17923128 \n6 Olié V Canonico M Scarabin PY Risk of venous thrombosis with oral versus transdermal estrogen therapy among postmenopausal women Curr Opin Hematol 2010 17 457 463 20601871 \n7 Livio M Mannuccio PM Viganò G Conjugated estrogens for the management of bleeding associated with renal failure N Engl J Med 1986 315 731 3018561 \n8 Viganò G Gaspari F Locatelli M Dose-effect and pharmacokinetics of estrogens given to correct bleeding time in uremia Kidney Int 1988 34 853 2850395 \n9 Tremollieres F Brincat M Erel CT EMAS position statement: managing menopausal women with a personal or family history of VTE Maturitas 2011 69 195 198 21489728 \n10 Schenck-Gustafsson K Brincat M Erel CT EMAS position statement: managing the menopause in the context of coronary heart disease Maturitas 2011 68 94 97 21156341\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1664-5529",
"issue": "4(2)",
"journal": "Nephron extra",
"keywords": "Bleeding; Chronic kidney disease; Transdermal estradiol; Uremic platelets",
"medline_ta": "Nephron Extra",
"mesh_terms": null,
"nlm_unique_id": "101571879",
"other_id": null,
"pages": "134-7",
"pmc": null,
"pmid": "25337082",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports",
"references": "21489728;20601871;21872374;21156341;17322926;17923128;2850395;10515859;7611255;3018561",
"title": "Safe and effective use of chronic transdermal estradiol for life-threatening uremic bleeding in a patient with coronary artery disease.",
"title_normalized": "safe and effective use of chronic transdermal estradiol for life threatening uremic bleeding in a patient with coronary artery disease"
} | [
{
"companynumb": "US-BAYER-2014-161364",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ESTRADIOL"
},
"drugadditional": null,
"... |
{
"abstract": "Adverse drug reactions (ADRs) have been commonly cited as a major cause of hospital admissions in older individuals. However, despite the apparent magnitude of this problem, there are limited prospective data on ADRs as a cause of hospitalization in elderly medical patients.\n\n\n\nThe objective of this study was to evaluate the proportion, clinical characteristics, causality, severity, preventability, and outcome of ADR-related admissions in older patients admitted to two Tasmanian hospitals.\n\n\n\nWe conducted a prospective cross-sectional study at the Royal Hobart and Launceston General Hospitals in Tasmania, Australia. A convenience sample of patients, aged 65 years and older, undergoing unplanned overnight medical admissions was screened. ADR-related admissions were determined through expert consensus from detailed review of medical records and patient interviews. The causality, preventability and severity of each ADR-related admission were assessed.\n\n\n\nOf 1008 admissions, the proportion of potential ADR-related medical admissions was 18.9%. Most (88.5%) ADR-related admissions were considered preventable. Cardiovascular complaints (29.3%) represented the most common ADRs, followed by neuropsychiatric (20.0%) and renal and genitourinary disorders (15.2%). The most frequently implicated drug classes were diuretics (23.9%), agents acting on the renin angiotensin system (16.4%), β-blocking agents (7.1%), antidepressants (6.9%), and antithrombotic agents (6.9%). Application of the Naranjo algorithm found 5.8% definite, 70.1% probable, and 24.1% possible ADRs. ADR severity was rated moderate and severe in 97.9% and 2.1% of admissions, respectively. For most (93.2%) ADR-related admissions the ADR resolved and the patient recovered.\n\n\n\nHospitalization due to an ADR is a common occurrence in this older population. There is need for future studies to implement and evaluate interventions to reduce the risk of ADR-related admissions in elderly populations.",
"affiliations": "Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia. Nibu.ParameswaranNair@utas.edu.au.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.;Unit for Medication Outcomes Research and Education, Division of Pharmacy, Faculty of Health, School of Medicine, University of Tasmania, Hobart, TAS, 7001, Australia.",
"authors": "Parameswaran Nair|Nibu|N|;Chalmers|Leanne|L|;Bereznicki|Bonnie J|BJ|;Curtain|Colin|C|;Peterson|Gregory M|GM|;Connolly|Michael|M|;Bereznicki|Luke R|LR|",
"chemical_list": null,
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40264-017-0528-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0114-5916",
"issue": "40(7)",
"journal": "Drug safety",
"keywords": null,
"medline_ta": "Drug Saf",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000375:Aging; D003430:Cross-Sectional Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D006760:Hospitalization; D006801:Humans; D008297:Male; D010343:Patient Admission; D011159:Population Surveillance; D011446:Prospective Studies; D012307:Risk Factors; D013648:Tasmania",
"nlm_unique_id": "9002928",
"other_id": null,
"pages": "597-606",
"pmc": null,
"pmid": "28382494",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article",
"references": "27798708;23537588;23761351;18484788;17420201;20937924;17630042;3064953;19013378;10118597;10690693;23627189;22863443;22150441;19591522;22888275;22823502;27194906;22438900;22253191;15777140;10084421;27840102;19000586;20625022;7843344;1524068;17166186;18809816;15811171;7249508;21495975;27377393;15231615;18313773;16534045;19409112;20636675;25489239;9555760;12061133;15712622;27077231;26546335;22111719;12610749;11456032;25889849",
"title": "Adverse Drug Reaction-Related Hospitalizations in Elderly Australians: A Prospective Cross-Sectional Study in Two Tasmanian Hospitals.",
"title_normalized": "adverse drug reaction related hospitalizations in elderly australians a prospective cross sectional study in two tasmanian hospitals"
} | [
{
"companynumb": "AU-ORION CORPORATION ORION PHARMA-18_00003502",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
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{
"abstract": "Glaucoma management in pregnant patients is a real challenge, especially when the glaucoma is not controlled with medications. We report the results of 6 incisional glaucoma surgeries for the management of medically uncontrolled glaucoma patients during pregnancy. This retrospective, case series was conducted on the 6 eyes of 3pregnant patients with uncontrolled glaucoma using maximum tolerable medications. Details of the glaucoma surgical management of these patients as well as their postoperative care and pregnancy and clinical outcomes on longitudinal follow-up are discussed. All 3 patients had juvenile open-angle glaucoma and were on various anti-glaucoma medications, including oral acetazolamide. The first case described underwent trabeculectomy without antimetabolites in both eyes because of uncontrolled intraocular pressure with topical medications. The surgery was done with topical lidocaine jelly and subconjunctival lidocaine during the second and third trimesters. The second patient had an Ahmed valve implantation in both eyes during the second and third trimesters because of uncontrolled IOP with topical medications and no response to selective laser trabeculoplasty. Surgery was done with topical tetracaine and subconjunctival and sub-Tenon's lidocaine. The third case had a Baerveldt valve implantation under general anesthesia in the second trimester. In selected pregnant glaucoma patients with medically uncontrolled intraocular pressure threatening vision, incisional surgery may lead to good outcomes for the patient with no risk for the fetus.",
"affiliations": "Poostchi Eye Research Center, Poostchi Clinic, Shiraz University of Medical Sciences, Shiraz, Iran.;Poostchi Eye Research Center, Poostchi Clinic, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of Anesthesiology, Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran.;Glaucoma Service, Wills Eye Institute, Jefferson Medical College, Philadelphia, USA.;Glaucoma Service, Wills Eye Institute, Jefferson Medical College, Philadelphia, USA.",
"authors": "Razeghinejad|Mohammad Reza|MR|;Masoumpour|Masoumeh|M|;Eghbal|Mohammad Hossein|MH|;Myers|Jonathan S|JS|;Moster|Marlene R|MR|",
"chemical_list": null,
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nIran J Med SciIran J Med SciIranian Journal of Medical Sciences0253-07161735-3688Iranian Journal of Medical Sciences Iran IJMS-41-437Case SeriesGlaucoma Surgery in Pregnancy: A Case Series and Literature Review Razeghinejad Mohammad Reza MD1Masoumpour Masoumeh MD1Eghbal Mohammad Hossein MD2Myers Jonathan S. MD3Moster Marlene R. MD31 Poostchi Eye Research Center, Poostchi Clinic, Shiraz University of Medical Sciences, Shiraz, Iran2 Department of Anesthesiology, Faghihi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran3 Glaucoma Service, Wills Eye Institute, Jefferson Medical College, Philadelphia, USACorrespondence: Mohammad Reza Razeghinejad, MD; Department of Ophthalmology, Khlaili Hospital, Poostchi Clinic, Zand Street, Zip Code: 71936-16642, Shiraz, Iran Tel/Fax: +98 71 36291779 razeghinejad@yahoo.com9 2016 41 5 437 445 15 2 2015 14 4 2015 17 5 2015 Copyright: © Iranian Journal of Medical Sciences2016This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Glaucoma management in pregnant patients is a real challenge, especially when the glaucoma is not controlled with medications. We report the results of 6 incisional glaucoma surgeries for the management of medically uncontrolled glaucoma patients during pregnancy. This retrospective, case series was conducted on the 6 eyes of 3pregnant patients with uncontrolled glaucoma using maximum tolerable medications. Details of the glaucoma surgical management of these patients as well as their postoperative care and pregnancy and clinical outcomes on longitudinal follow-up are discussed. All 3 patients had juvenile open-angle glaucoma and were on various anti-glaucoma medications, including oral acetazolamide. The first case described underwent trabeculectomy without antimetabolites in both eyes because of uncontrolled intraocular pressure with topical medications. The surgery was done with topical lidocaine jelly and subconjunctival lidocaine during the second and third trimesters. The second patient had an Ahmed valve implantation in both eyes during the second and third trimesters because of uncontrolled IOP with topical medications and no response to selective laser trabeculoplasty. Surgery was done with topical tetracaine and subconjunctival and sub-Tenon’s lidocaine. The third case had a Baerveldt valve implantation under general anesthesia in the second trimester. In selected pregnant glaucoma patients with medically uncontrolled intraocular pressure threatening vision, incisional surgery may lead to good outcomes for the patient with no risk for the fetus.\n\nGlaucoma drainage implantsPregnancyTrabeculectomy\n==== Body\nWhat’s Known\n\n\nThere is a dearth of data on the safety and effectiveness of incisional glaucoma procedures in pregnant glaucoma patients.\n\n\n\n\nWhat’s New\n\n\nPregnant patients with glaucoma and uncontrolled intraocular pressure my undergo glaucoma surgery (trabeculectomy or shunt surgery) to prevent irreversible optic nerve damage.\n\nIncisional glaucoma surgery in pregnancy may confer good outcomes for the patient with no risk to the fetus.\n\n\n\n\nIntroduction\nThe coincidence of glaucoma and pregnancy is thought to be rare, but about one-quarter of respondents to a survey of ophthalmologists in the United Kingdom were faced with this clinical situation.1 The frequency of glaucoma during pregnancy seems to be increasing among women because some women wait longer to become pregnant. Therefore, we need to improve our understanding about glaucoma management in this very challenging population. There is a tendency for the intraocular pressure (IOP) to decrease during pregnancy, especially during the second and third trimesters.2,3 Additionally, a reduced diurnal variation of the IOP and an increased retrobulbar blood flow have been reported in pregnancy.2 Despite all the information indicating that the IOP typically decreases during pregnancy, many glaucoma patients continue to require medical and surgical treatment and glaucoma may progress.3\n\nGiven the paucity of reports on glaucoma management in pregnant patients and the impossibility of conducting clinical trials in this group of patients, there are no guidelines for managing this clinical situation. There is a general level of uncertainty regarding management among ophthalmologists faced with a pregnant woman who has progression of her glaucoma.1 Herein, we describe 6 glaucoma surgical procedures in 3 pregnant glaucoma patients with an uncontrolled IOP on maximum tolerable medication.\n\nCases Presentation\nA retrospective case series was performed on 3 cases of uncontrolled glaucoma during pregnancies that were managed surgically at Wills Eye Institute, Philadelphia, USA, and Poostchi Eye Research Center, Shiraz, Iran. Relevant clinical and management details were extracted from the medical records.\n\nCase 1\n\nA 26-year-old asthmatic pregnant patient whose juvenile open-angle glaucoma had been controlled for 12 years with timolol, brimonidine, and latanoprost presented to the glaucoma service in her second trimester of pregnancy because of an uncontrolled IOP (44 mm Hg in both eyes) detected by her ophthalmologist. She used albuterol and ipratropium inhalers PRN for controlling her asthma. The best-corrected visual acuity (-6.00- 0.25×95 in the right eye and – 6.25 in the left eye) was 20/20, and the vertical cup/disc ratio was 0.7 in both eyes. The visual field in the right eye was normal, and the left eye showed a shallow inferior arcuate scotoma. The central corneal thickness was 550 µm and 557 µm in the right and left eyes, respectively. The patient underwent trabeculectomy in her left eye with 2% lidocaine jelly and subconjunctival 1% lidocaine with monitored anesthetic care at 24 weeks of gestation. Postoperatively, topical neomycin-polymyxin B- dexamethasone was started and tapered over 2 months.\n\nTrabeculectomy was performed in the right eye while the IOP was 41 mm Hg at the 27th week of gestation. The IOP was 13 mm Hg 2 weeks after the second operation in both eyes and then was stable at low teens throughout pregnancy. She gave birth to a normal baby at the 38th week of gestation. The baby weighed 3050 grams and her Apgar score was 10. The course of glaucoma and the IOP (low teens) were stable during a second pregnancy 2 years later and a third pregnancy, 7 years after the first.\n\nCase 2\n\nA 24-year-old pregnant patient (16 weeks) was referred to the glaucoma service due to an uncontrolled IOP in her left eye on maximum tolerable topical anti-glaucoma medications (timolol, dorzolamide, latanoprost, and brimonidine) by her local ophthalmologist. Up to this point, the juvenile open-angle glaucoma had been controlled with timolol, dorzolamide, and latanoprost for the last 3 years. She had received all 3 medications during the first trimester due to an escalating IOP rise. Brimonidine had been added to her medications at the beginning of the second trimester. She had no history of prior glaucoma surgery.\n\nOn initial examination, the best-corrected visual acuity was 20/20 and 20/25 in right and left eyes respectively, wearing -5.25-1.75×170 OD and -6.5-2.75×170 OS. The IOP was 24 mm Hg in the right eye and 34 mm Hg in the left eye with timolol, dorzolamide, latanoprost, and brimonidine. The central corneal thickness in the right and left eyes was 550 µm and 560 µm, respectively. Heidelberg retinal tomography revealed a large optic disc (about 2.90 mm2) with a 0.6 cup/disc ratio bilaterally. Stratus optical coherent tomography also revealed a normal nerve fiber layer thickness in both eyes. Visual field testing was normal in both eyes. She underwent selective laser trabeculoplasty in the left eye (16th week of pregnancy), although no beneficial effect was observed over 4 weeks (IOP=36 mm Hg). Visual field examination showed no significant change compared to her prior visual fields. Due to the possibility of an unfavorable outcome with trabeculectomy without mitomycin in young patients, an Ahmed valve (FP7, New World Medical, Rancho Cucamonga, California, USA) implantation was done on the left eye at 20 weeks of gestation. The surgery was accomplished by employing topical tetracaine and subconjunctival 2% lidocaine. The lidocaine (2%) was injected subconjunctivally in the superotemporal quadrant; and after opening the conjunctiva, additional lidocaine was administered in the sub-Tenon’s space. No intravenous sedative was used. She tolerated the operation well and received topical chloramphenicol for 2 weeks and betamethasone for 8 weeks postoperatively. Topical chloramphenicol use in pregnancy is considered to be safe.4 Nasolacrimal occlusion and eyelid closure were recommended after topical medication application. Four weeks after surgery, the IOP in the left eye rose to 24 mm Hg and timolol/dorzolamide combination drop was started. The IOP in her right eye also rose to 44 mm Hg with topical medications. The same procedure was performed in right eye at 29 weeks of gestation. The operation was accomplished by placing the patient in the left down decubitus position to prevent systemic hypotension due to aortic and vena caval compression by the conceived uterus. The patient’s hips, abdomen, and thighs were rotated to left while maintaining a normal head position for ophthalmic surgery. She and her fetus tolerated the procedure well, and similar postoperative medication and care were tailored. At the fifth postoperative week, the IOP was 25 and 14 in the right and left eyes. The patient was advised to start timolol/dorzolamide combination drop for the right eye as well. At the beginning of the ninth month of pregnancy, the IOP in both eyes was14 mm Hg with timolol/dorzolamide combination drop. Any possible side effect of timolol on the newborn’s respiration and cardiovascular system was prevented by replacing the timolol/dorzolamide combination drop with dorzolamide in the ninth month. The IOP was 18 mm Hg in both eyes with dorzolamide over the last 2 weeks of pregnancy and 2 months after delivery. The mother gave birth to a healthy baby with a birth weight of 2750 grams and an Apgar score of 9.\n\nCase 3\n\nA 23-year-old healthy myope presented to her local ophthalmologist because of a decline in vision in both eyes. She was unaware that she might have juvenile glaucoma. She had a positive family history, as her father had juvenile glaucoma. Four days before referral to the glaucoma service, she presented with an IOP of 54 mm Hg and 60 mm Hg in the right and left eyes, respectively, and was started on medications. She smoked one pack of cigarettes per day and wore soft contact lens. The patient did not report to the treating physician or the staff that she was pregnant. She denied pregnancy when queried, and 2 pregnancy tests checked before eye operations at 20 and 24 weeks of her pregnancy with urine samples were negative. Later on, she admitted to switching urine samples with her mother in the ladies’ room, as she was fearful that surgery would be denied to her due to her pregnant state.\n\nOn examination, the best-corrected visual acuity was 20/40 in the right eye and 20/100 in the left eye. The refraction in the right and left eyes was -10.00-1.5×005 and -9.75-1.5×015, respectively. The IOP was 14 mm Hg in both eyes with latanoprost, timolol/brimonidine combination drop, and acetazolamide (125 mg twice daily). The central corneal thickness was 565 µm in both eyes. Optic nerve examination showed a vertical cup/disc ratio of 0.85 in the right eye and 0.9 in the left eye with pallor and peripapillary atrophy. The visual filed defects in both eyes showed dense superior and inferior arcuate scotomas with dense nasal steps. The patient was advised to stop acetazolamide due to symptoms of nausea and fatigue. Two weeks later, the IOP in both eyes was17 mm Hg but the patient admitted to poor compliance with this medical regimen. One month later (24th week of pregnancy), the IOP in the left eye increased to 43 mm Hg and was not reduced after resuming acetazolamide. Given her age and contact lens wear, it was decided to proceed with a Baerveldt shunt under general anesthesia. At the time, it was not known that the patient was in her second trimester of pregnancy. Therefore, under general anesthesia, a Baerveldt 350-mm2 (Advanced Medical Optics, Santa Ana, California, USA) was implanted augmented with mitomycin 0.4 mg/mL for 3 minutes in a pledget in the area of the plate. Postoperatively, topical moxifloxacin was given for 2 weeks and difluprednate for 6 weeks on a slow taper. One month after the left eye surgery, the IOP in the right eye increased to 40 mm Hg with all the aforementioned anti-glaucoma medications. Hence, the same procedure was done on the right eye at the 24th week of pregnancy. Again, the pregnancy urine test was negative. General anesthesia was used. One month later, the IOP was 14 mm Hg in the right eye and 16 mm Hg in the left eye. The IOP remained 14 mm Hg in both eyes with 0.5% timolol throughout the pregnancy and has continued to remain so over the following 2.5 years. The patient delivered a healthy baby girl with a birth weight of 2523 grams at term with an Apgar score of 10, three months after the second operation. The baby girl is completely healthy and at this point, has no known ocular disease or any other defects or pathology.\n\nDiscussion\nIn the present study, 6 eyes of 3 patients underwent surgical intervention to control their IOP. All the patients used various anti-glaucoma medications during their pregnancies, tolerated the operations very well, and gave birth to normal babies. There are limited reports on the surgical management of glaucoma in pregnancy. A successful case of trabeculectomy without adjunctive antimetabolites performed with retrobulbar anesthesia has been reported in a pregnant patient. She had uncontrolled glaucoma with 3 medications without any response to argon laser trabeculoplasty.5 Another study demonstrated IOP reduction after cyclophotocoagulation in a pregnant woman with uveitic aphakic glaucoma.6 A search on the PubMed database reveled no report on shunt implantation in pregnant patients.\n\nAlthough some studies indicate that the IOP decreases in pregnancy,7-10 some patients may develop an elevated IOP during pregnancy. There are case reports describing pregnant women with glaucoma whose IOP has been difficult to control despite medical and surgical interventions.6,11 In a retrospective study conducted on 28 eyes of 15 pregnant glaucoma patients with varying severity and types of glaucoma, Brauner et al.12 reported that in 5 (17.9%) eyes, the IOP increased, but there was no progression of visual field loss. In 5 (17.9%) eyes, visual field loss progressed, while the IOP remained stable or increased. Two of our patients had a controlled glaucoma with medication before pregnancy and developed an uncontrolled IOP during gestation. Changes in the IOP should be monitored closely in pregnant patients with glaucoma due to the highly variable course of glaucoma during pregnancy.\n\nIn glaucomatous women of childbearing age, if possible, the treatment plan should be discussed before the woman plans to become pregnant, allowing for discussion of treatment options and possible risks. As we experienced in case 3, women do not always volunteer the possibility of pregnancy during ophthalmic consultation. In the third case, 2 urine pregnancy tests were negative because the woman switched her mother’s urine for hers because of fears concerning the impact of pregnancy on her care. As the tests were negative, the patient was treated as a non-pregnant patient. She received a general anesthesia, and mitomycin was applied during shunt implantation. Another alternative would be to check serum beta-human chorionic gonadotropin (beta-HCG) in women of childbearing age.\n\nUnfortunately, there is little definitive information concerning the medical management of glaucoma during pregnancy.13 No topical anti-glaucoma agents have strong evidence of safety based on human studies.3 The Food and Drug Administration (FDA) classification of drugs safety in pregnancy can be summarized as follows: Category A: safety established using human studies; Category B: presumed safety based on animal studies, but no human studies; Category C: uncertain safety, with no human studies and animal studies showing adverse effect; Category D: unsafe; evidence of risk that in certain clinical circumstances may be justifiable; and Category X: definitely unsafe, with the risk of use outweighing any possible benefit.\n\nTable 1 lists the FDA’s classification of selected anti-glaucoma medications as well as the reported teratogenic effects in animal and human studies. While no glaucoma medications are known to be human teratogens, none has been proven to be completely risk-free either. The majority of anti-glaucoma medications are in group C and the only medications in group B (animal studies show no harm to the fetus) are sympathomimetics.\n\nTable 1 Food and Drug Administration’s classification of selected anti-glaucoma medications and potential side effects in pregnancy\n\n\tFDA’s classification\tReported effect in animal studies\tReports of side effects in human studies\t\nPreservative of medications, BAK\tC*\tDoserelated increase in fetal resorption and death and minor sternal defects14\t\t\nBetablockers\tC\t\tA case with cardiac conduction disorder. Arrhythmia and bradycardia (resolved after stopping the drug)15 Systemic use: Intrauterine growth restriction and persistent betablockade in the newborn Impairment of respiratory control in the neonate, lethargy and confusion16,17\t\nCarbonic anhydrase Inhibitors\t\t\t\t\nOral\tC\tForelimb anomalies18\tSingle case of sacrococcygealteratoma (has not been substantiated by others)19\t\nTopical\tC\tFetal vertebral body malformations and decrease fetal weights (dose 31 times)20,21\t\t\nProstaglandin analogs\t\t\t\t\nLatanoprost\tC\tDead fetus (dose 80 times)22\tA case of miscarriage in a 46 yearold woman that seems to be due to her reproductive risk related to her advance age, not the drug23\t\nTravoprost\tC\tTeratogen (dose 250 times)24\t\t\nBimatoprost\tC\tReduced duration of gestation and increased incidence of dead fetus (dose 41 times)25\t\t\nParasympathomimetics\t\t\t\t\nPilocarpine\tC\tTeratogen26\tSigns mimicking meningitis in the newborn27\t\nEchothiophate iodide\t\t\tSuppression of the infant’s pseudocholinesterase\t\nSympathomimetic\t\t\t\t\nNonselective\tB**\tCongenital cataract2\tSystemic: Delays the second stage of labor or cause a prolonged period of uterine atony with hemorrhage Topical: Local side effects and a high rate of systemic side effects28\t\nBrimonidine\tB\tNo fetal damage29\tIn infants has central nervous system effects30\t\nFixedcombination Antiglaucoma Medications\tC\t\t\t\nFixedCombination Timolol/dorzolamide\tC31\tAs each component of the drug\t\t\nFixedCombination Timolol/brimonidine\tC32\tAs each component of the drug\t\t\n* Uncertain safety, with no human studies and animal studies showing adverse effect;\n\n** Presumed safety based on animal studies\n\nAs many pregnancies are unplanned, exposure to medication often occurs before women know that they are pregnant. During the first 12 weeks of gestation, organogenesis occurs and teratogenic drug effects are more severe when medicines are administered during thisperiod.33 The last month of pregnancy is also important because the drugs pass through the placenta and reach the fetal circulation and may affect the newborn’s cardiac, respiratory, and neurologic systems functions. Nasolacrimal occlusion, eyelid closure, or blotting the excess drops away during administration and punctual plugging should be discussed with pregnant women on topical anti-glaucoma medications.13\n\nIf maximum safe topical medications fail to control the IOP or a progressive visual field loss is noted, or a woman with severe glaucoma wishes to decrease the potential risk of medications to the fetus, surgical intervention should be considered.3 A potential option before incisional surgeries is laser trabeculoplasty. The procedure would impose the least possible risk to the fetus and would not require the addition of preoperative and postoperative medications that invasive procedures would necessitate. Other advantages include it being an outpatient procedure, the use of topical anesthesia, sitting in an upright posture, faster rehabilitation, and very low risk to the patient. However, laser trabeculoplasty is less effective in patients younger than 50 years.34 In this series, one of the patients who received laser trabeculoplasty had no IOP decrease, which was in line with Pickering’s report.5\n\nThere are specific risks and considerations of glaucoma surgery in pregnant patients, including timing of surgery, position of the patient during surgery, risks of local and general anesthesia, and intra- and postoperative medications.35 Agents like narcotics, paralyzing agents, inhaled anesthetic agents, and any of the central nervous system depressants which are used to anesthetize the patient can influence the fetus. Nevertheless, there are no well-controlled human studies about the teratogenic effects of these agents. However, neither our patient who had 2 general anesthesia for both eyes surgeries nor a 22-year-old pregnant woman that had a sclerotomy operation at 32 weeks of gestation under general anesthesia experienced complications and both gave birth to normal babies.36 Nonetheless, there are reports of increased incidence of low birth weight and an increased rate of neural tube defects with exposure to general anesthesia in the first trimester.37\n\nMost local anesthetics have not been shown to be teratogen in humans and are considered relatively safe for use during pregnancy. In the FDA’s classification, etidocaine, lidocaine, and prilocaine are categorized in group B and bupivacaine and mepivacaine are placed in group C because of inducing fetal bradycardia.38 Limiting the dose to the minimum required for effective pain control is obviously advisable.39 Subconjunctival and anterior sub-Tenon’s anesthesia combined with a topical anesthesia for glaucoma surgery may be well tolerated and may allow a less systemic absorption of the medication than a retrobulbar anesthesia.39 The supine position in the second and third trimesters of gestation can induce profound systemic hypotension due to aortic and vena caval compression by the conceived uterus. Consideration should be given to rotating the patients’ hips, abdomen, and thighs on their left side while maintaining a normal head position for ophthalmic surgery.40\n\nGlaucoma filtration surgery in pregnant patients may be at relatively higher risk of failure because of young age, physiological changes during pregnancy, and contraindicated antimetabolite usage. Both mitomycin and 5-fluorouracil, which are used commonly as antimetabolite agents in glaucoma filtering surgeries, are in category X and contraindicated in pregnancy.41,42 It is well known that in pregnancy, the serum levels of vascular endothelial growth factor (VEGF)43 and placental growth factor (PGF),44 which is a ligand for VEGF Receptor-1, are elevated. Because VEGF has a major role in angiogenesis and fibroblast and inflammatory cell migration and proliferation and synergistic effect of PGF with VEGF, it seems that wound healing at the trabeculectomy site during pregnancy is augmented.\n\nThe 5-year results of the Tube Versus Trabeculectomy (TVT)45 study will probably encourage more surgeons to expand the indications for aqueous shunt surgery to include more primary surgical cases or at least encourage aqueous shunt surgery when both options are reasonable alternatives. Shunt surgery seems to be a reasonable alternative for some patients who need surgery in pregnancy.\n\nFor postoperative pain, acetaminophen may be the safest and it usually provides adequate pain relief. Because the pain may increase the possibility of premature labor, in the postoperative period the patient should receive adequate analgesia.46\n\nTable 2 summarizes the risks of some post-glaucoma surgery medications in pregnancy.\n\nTable 2 Food and Drug Administration’s category and potential complications of medications used topically after glaucoma surgery\n\nDrug\tFDA’s Classification\tReported Side Effects in Animal Studies\tReported Side Effects of Systemic Use during Pregnancy\t\nCorticosteroid\t\t\t\t\n Dexamethasone\tC*\t\tLeukocytosis in infants with in utero exposure to systemic use47\t\n Prednisolone\tC\tDevelopmental and teratogenic effect, cleft lip and palate, and sex organ abnormalities47\tIncrease in the risk of stillbirth, intrauterine growth retardation, and adrenal insufficiency47\t\nAntibiotics\t\t\t\t\n Erythromycin\tB**\t\t\t\n Polymyxin\tC\t\t\t\n Aminoglycoside\tD***\tHearing loss and nephrotoxicity48\t\t\n Sulfonamide\tC\tCleft palate and other bony abnormalities48\tHyperbilirubinemia48\t\n Fluoroquinolone\tC\tNo teratogenic effects, decreased body weight, and delayed skeletal development48\tArthropathy48\t\n Tetracycline\tD\t\tDiscoloration of the primary teeth (after the third month of pregnancy)48\t\n Chloramphenicol\tC\t\tGray baby syndrome (Topical usage is safe.)48\t\nAtropine\tC\t\tProbability of an effect on the fetal heart rate49\t\n* Uncertain safety, with no human studies and animal studies showing adverse effect;\n\n** Presumed safety based on animal studies;\n\n*** Unsafe; Evidence of risk that in certain clinical circumstances may be justifiable\n\nConclusion\nIt is now commonplace for women to choose to start families later in life; thus, the frequency of glaucoma during pregnancy may increase. It is logical not to defer the glaucoma surgery (trabeculectomy or shunt surgery) to the postpartum period in pregnant patients that have an uncontrolled IOP at a level that puts vision at risk in the short term as optic nerve damage is irreversible. Pregnant glaucoma patients present challenges, but with careful consideration regarding medication and surgery as discussed above, these patients may undergo incisional surgery with good outcomes for the patient with no risk to the fetus.\n\nConflict of Interest: None declared.\n==== Refs\nReferences\n1 Vaideanu D Fraser S Glaucoma management in pregnancy: a questionnaire survey Eye (Lond) 2007 21 341 3 10.1038/sj.eye.6702193 16311521 \n2 Sunness JS The pregnant woman’s eye Surv Ophthalmol 1988 32 219 38 10.1016/0039-6257(88)90172-5 3279558 \n3 Razeghinejad MR Tania Tai TY Fudemberg SJ Katz LJ Pregnancy and glaucoma Surv Ophthalmol 2011 56 324 35 10.1016/j.survophthal.2010.11.008 21620430 \n4 Chung CY Kwok AK Chung KL Use of ophthalmic medications during pregnancy Hong Kong Med J 2004 10 191 5 15181224 \n5 Pickering T Treating Glaucoma During Pregnancy Glaucoma Today 2009 1 18 20 \n6 Wertheim M Broadway DC Cyclodiode laser therapy to control intraocular pressure during pregnancy Br J Ophthalmol 2002 86 1318 9 [PMC Free Article ] 10.1136/bjo.86.11.1318 12386103 \n7 Kass MA Sears ML Hormonal regulation of intraocular pressure Surv Ophthalmol 1977 22 153 76 10.1016/0039-6257(77)90053-4 413203 \n8 Qureshi IA Intraocular pressure: association with menstrual cycle, pregnancy and menopause in apparently healthy women Chin J Physiol 1995 38 229 34 8925675 \n9 Qureshi IA Measurements of intraocular pressure throughout the pregnancy in Pakistani women Chin Med Sci J 1997 12 53 6 11243101 \n10 Qureshi IA Xi XR Wu XD Intraocular pressure trends in pregnancy and in the third trimester hypertensive patients Acta Obstet Gynecol Scand 1996 75 816 9 10.3109/00016349609054709 8931505 \n11 Johnson SM Martinez M Freedman S Management of glaucoma in pregnancy and lactation Surv Ophthalmol 2001 45 449 54 10.1016/S0039-6257(00)00209-5 11274697 \n12 Brauner SC Chen TC Hutchinson BT Chang MA Pasquale LR Grosskreutz CL The course of glaucoma during pregnancy: a retrospective case series Arch Ophthalmol 2006 124 1089 94 10.1001/archopht.124.8.1089 16908810 \n13 Razeghinejad MR Nowroozzadeh MH Anti-glaucoma medication exposure in pregnancy: an observational study and literature review Clin Exp Optom 2010 93 458 65 10.1111/j.1444-0938.2010.00526.x 21182661 \n14 Buttar HS Embryotoxicity of benzalkonium chloride in vaginally treated rats J Appl Toxicol 1985 5 398 401 10.1002/jat.2550050612 4078221 \n15 Wagenvoort AM van Vugt JM Sobotka M van Geijn HP Topical timolol therapy in pregnancy: is it safe for the fetus? Teratology 1998 58 258 62 10.1002/(SICI)1096-9926(199812)58:6<258:AID-TERA7>3.0.CO;2-B 9894675 \n16 Olson RJ Bromberg BB Zimmerman TJ Apneic spells associated with timolol therapy in a neonate Am J Ophthalmol 1979 88 120 2 10.1016/0002-9394(79)90766-9 464000 \n17 Magee LA Abalos E von Dadelszen P Sibai B Easterling T Walkinshaw S How to manage hypertension in pregnancy effectively Br J Clin Pharmacol 2011 72 394 401 [PMC Free Article ] 10.1111/j.1365-2125.2011.04002.x 21545480 \n18 Layton WM Jr Hallesy DW Deformity of Forelimb in Rats: Association with High Doses of Acetazolamide Science 1965 149 306 8 10.1126/science.149.3681.306-a 14300527 \n19 Worsham F Jr Beckman EN Mitchell EH Sacrococcygeal teratoma in a neonate. Association with maternal use of acetazolamide JAMA 1978 240 251 2 10.1001/jama.240.3.251 660854 \n20 Manufacturer’s Information: Azopt product monograph 1998 Texas Alcon Ophthalmics \n21 Manufacturer’s Information: Trusopt product monograph 1999 Pennsylvania Merck & Co \n22 Latanoprost prescribing information [Internet] Food and Drug Administration cited 2012 June 15 Available from: http://www.fda.gov/cder/approval/x.htm \n23 De Santis M Lucchese A Carducci B Cavaliere AF De Santis L Merola A Latanoprost exposure in pregnancy Am J Ophthalmol 2004 138 305 6 10.1016/j.ajo.2004.03.002 15289149 \n24 Manufacturer’s Information: Travatan product monograph 2004 Fort Worth Alcon Laboratories \n25 Manufacturer’s Information: Lumigan ® P product monograph 2006 Irvine Allergan \n26 Landauer W The teratogenic activity of pilocarpine, pilocarpidine and their isomers, with special reference to the importance of steric configuration J Exp Zoology 1956 132 39 50 10.1002/jez.1401320104. \n27 Rick E Bendel MSJ Zimmerman TJ Kooner KS Principles and complications of medical therapy of glaucoma Clinical pathways in glaucoma 2001 First ed New York Thieme 427 55 \n28 Kooner KS Zimmerman TJ Antiglaucoma therapy during pregnancy--Part I Ann Ophthalmol 1988 20 166 9 3408079 \n29 Manufacturer’s Information: Alphagan ®P product monograph 2008 Irvine Allergan \n30 Fudemberg SJ Batiste C Katz LJ Efficacy, safety, and current applications of brimonidine Expert Opin Drug Saf 2008 7 795 9 10.1517/17425250802457609 18983225 \n31 Netland P Glaucoma Medical Therapy: Principles and Management 2008 2 ed New York Oxford University Press 33 155 \n32 Manufacture’s information: Combigan product 2008 Irvine Allergan, Inc \n33 Coleman AL Mosaed S Kamal D Medical therapy in pregnancy J Glaucoma 2005 14 414 6 10.1097/01.ijg.0000177214.39244.da 16148592 \n34 Safran MJ Robin AL Pollack IP Argon laser trabeculoplasty in younger patients with primary open-angle glaucoma Am J Ophthalmol 1984 97 292 5 10.1016/0002-9394(84)90625-1 6702966 \n35 Cheek TG Baird E Anesthesia for nonobstetric surgery: maternal and fetal considerations Clin Obstet Gynecol 2009 52 535 45 10.1097/GRF.0b013e3181c11f60 20393407 \n36 Birks DA Prior VJ Silk E Whittaker M Echothiophate iodide treatment of glaucoma in pregnancy Arch Ophthalmol 1968 79 283 5 10.1001/archopht.1968.03850040285010 5640850 \n37 Mazze RI Kallen B Reproductive outcome after anesthesia and operation during pregnancy: a registry study of 5405 cases Am J Obstet Gynecol 1989 161 1178 85 10.1016/0002-9378(89)90659-5 2589435 \n38 Moore PA Selecting drugs for the pregnant dental patient J Am Dent Assoc 1998 129 1281 6 10.14219/jada.archive.1998.0425 9766109 \n39 Shammas HJ Milkie M Yeo R Topical and subconjunctival anesthesia for phacoemulsification: prospective study J Cataract Refract Surg 1997 23 1577 80 10.1016/S0886-3350(97)80032-6 9456419 \n40 Kuczkowski KM Nonobstetric surgery in the parturient: anesthetic considerations J Clin Anesth 2006 18 5 7 10.1016/j.jclinane.2005.11.003 16517324 \n41 Princeton NJ Mitomycin for Injection [package insert] 2000 New York Bristol-Myers Squibb \n42 Kuwagata M Takashima H Nagao T A comparison of the in vivo and in vitro response of rat embryos to 5-fluorouracil J Vet Med Sci 1998 60 93 9 10.1292/jvms.60.93 9492366 \n43 Anthony FW Evans PW Wheeler T Wood PJ Variation in detection of VEGF in maternal serum by immunoassay and the possible influence of binding proteins Ann Clin Biochem 1997 34 276 80 10.1177/000456329703400309 9158825 \n44 Autiero M Luttun A Tjwa M Carmeliet P Placental growth factor and its receptor, vascular endothelial growth factor receptor-1: novel targets for stimulation of ischemic tissue revascularization and inhibition of angiogenic and inflammatory disorders J Thromb Haemost 2003 1 1356 70 10.1046/j.1538-7836.2003.00263.x 12871269 \n45 Gedde SJ Schiffman JC Feuer WJ Herndon LW Brandt JD Budenz DL Treatment outcomes in the Tube Versus Trabeculectomy (TVT) study after five years of follow-up Am J Ophthalmol 2012 153 789 803 e2 [PMC Free Article ] 10.1016/j.ajo.2011.10.026 22245458 \n46 Anand KJ Clinical importance of pain and stress in preterm neonates Biol Neonate 1998 73 1 9 10.1159/000013953 9458936 \n47 Bongiovanni AM Mc PA Steroids during pregnancy and possible fetal consequences Fertil Steril 1960 11 181 6 10.1016/S0015-0282(16)33723-2 13802516 \n48 Korzeniowski OM Antibacterial agents in pregnancy Infect Dis Clin North Am 1995 9 639 51 7490437 \n49 Kretowicz J Studies on the influence of atropine sulfate on the rate and rhythm of the fetal heart. 1. Normal pregnancy at term Pol Med J 1966 5 1447 57 5981307\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-0716",
"issue": "41(5)",
"journal": "Iranian journal of medical sciences",
"keywords": "Glaucoma drainage implants; Pregnancy; Trabeculectomy",
"medline_ta": "Iran J Med Sci",
"mesh_terms": null,
"nlm_unique_id": "8104374",
"other_id": null,
"pages": "437-45",
"pmc": null,
"pmid": "27582594",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports",
"references": "9894675;15289149;2589435;12386103;3279558;4078221;11274697;7490437;9158825;11243101;9458936;5640850;21545480;14300527;3408079;8925675;12871269;413203;16908810;18983225;464000;21182661;16148592;9492366;20393407;5981307;8931505;15181224;13802516;16517324;9766109;6702966;16311521;9456419;660854;21620430;22245458",
"title": "Glaucoma Surgery in Pregnancy: A Case Series and Literature Review.",
"title_normalized": "glaucoma surgery in pregnancy a case series and literature review"
} | [
{
"companynumb": "ALCN2016IR006659",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DORZOLAMIDE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Chemotherapy is the standard of care for incurable advanced gastric cancer. Whether the addition of gastrectomy to chemotherapy improves survival for patients with advanced gastric cancer with a single non-curable factor remains controversial. We aimed to investigate the superiority of gastrectomy followed by chemotherapy versus chemotherapy alone with respect to overall survival in these patients.\n\n\n\nWe did an open-label, randomised, phase 3 trial at 44 centres or hospitals in Japan, South Korea, and Singapore. Patients aged 20-75 years with advanced gastric cancer with a single non-curable factor confined to either the liver (H1), peritoneum (P1), or para-aortic lymph nodes (16a1/b2) were randomly assigned (1:1) in each country to chemotherapy alone or gastrectomy followed by chemotherapy by a minimisation method with biased-coin assignment to balance the groups according to institution, clinical nodal status, and non-curable factor. Patients, treating physicians, and individuals who assessed outcomes and analysed data were not masked to treatment assignment. Chemotherapy consisted of oral S-1 80 mg/m(2) per day on days 1-21 and cisplatin 60 mg/m(2) on day 8 of every 5-week cycle. Gastrectomy was restricted to D1 lymphadenectomy without any resection of metastatic lesions. The primary endpoint was overall survival, analysed by intention to treat. This study is registered with UMIN-CTR, number UMIN000001012.\n\n\n\nBetween Feb 4, 2008, and Sept 17, 2013, 175 patients were randomly assigned to chemotherapy alone (86 patients) or gastrectomy followed by chemotherapy (89 patients). After the first interim analysis on Sept 14, 2013, the predictive probability of overall survival being significantly higher in the gastrectomy plus chemotherapy group than in the chemotherapy alone group at the final analysis was only 13·2%, so the study was closed on the basis of futility. Overall survival at 2 years for all randomly assigned patients was 31·7% (95% CI 21·7-42·2) for patients assigned to chemotherapy alone compared with 25·1% (16·2-34·9) for those assigned to gastrectomy plus chemotherapy. Median overall survival was 16·6 months (95% CI 13·7-19·8) for patients assigned to chemotherapy alone and 14·3 months (11·8-16·3) for those assigned to gastrectomy plus chemotherapy (hazard ratio 1·09, 95% CI 0·78-1·52; one-sided p=0·70). The incidence of the following grade 3 or 4 chemotherapy-associated adverse events was higher in patients assigned to gastrectomy plus chemotherapy than in those assigned to chemotherapy alone: leucopenia (14 patients [18%] vs two [3%]), anorexia (22 [29%] vs nine [12%]), nausea (11 [15%] vs four [5%]), and hyponatraemia (seven [9%] vs four [5%]). One treatment-related death occurred in a patient assigned to chemotherapy alone (sudden cardiopulmonary arrest of unknown cause during the second cycle of chemotherapy) and one occurred in a patient assigned to chemotherapy plus gastrectomy (rapid growth of peritoneal metastasis after discharge 12 days after surgery).\n\n\n\nSince gastrectomy followed by chemotherapy did not show any survival benefit compared with chemotherapy alone in advanced gastric cancer with a single non-curable factor, gastrectomy cannot be justified for treatment of patients with these tumours.\n\n\n\nThe Ministry of Health, Labour and Welfare of Japan and the Korean Gastric Cancer Association.",
"affiliations": "Department of Surgery, Osaka Prefectural General Medical Centre, Osaka, Japan.;Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.;Japan Clinical Oncology Group Data Centre/Operations Office, National Cancer Centre, Tokyo, Japan.;Department of Surgery, National Cancer Centre, Seoul, South Korea.;Department of Gastric Surgery, Shizuoka Cancer Centre, Shizuoka, Japan.;Department of Surgery, Ajou University School of Medicine, Suwon, South Korea.;Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.;Department of Surgery, Yonsei University College of Medicine, Seoul, South Korea.;Department of Surgery, Hakodate Goryokaku Hospital, Hakodate, Japan.;Department of Surgery, Seoul National University College of Medicine, Seoul, South Korea.;Department of Surgery, Kanagawa Cancer Centre, Yokohama, Japan.;Medical Research Collaborating Centre, Seoul National University College of Medicine, Seoul, South Korea.;Japan Clinical Oncology Group Data Centre/Operations Office, National Cancer Centre, Tokyo, Japan.;Department of Surgery, The Catholic University of Korea, Seoul St Mary's Hospital, Seoul, South Korea.;Department of Gastrointestinal Surgery, Osaka University Graduate School of Medicine, Osaka, Japan.;Department of Internal Medicine, Seoul National University College of Medicine, Seoul, South Korea.;Medical Research Collaborating Centre, Seoul National University College of Medicine, Seoul, South Korea.;Department of Surgery, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Surgery, Kaizuka City Hospital, Osaka, Japan. Electronic address: tsujinaka@hosp.kaizuka.osaka.jp.",
"authors": "Fujitani|Kazumasa|K|;Yang|Han-Kwang|HK|;Mizusawa|Junki|J|;Kim|Young-Woo|YW|;Terashima|Masanori|M|;Han|Sang-Uk|SU|;Iwasaki|Yoshiaki|Y|;Hyung|Woo Jin|WJ|;Takagane|Akinori|A|;Park|Do Joong|DJ|;Yoshikawa|Takaki|T|;Hahn|Seokyung|S|;Nakamura|Kenichi|K|;Park|Cho Hyun|CH|;Kurokawa|Yukinori|Y|;Bang|Yung-Jue|YJ|;Park|Byung Joo|BJ|;Sasako|Mitsuru|M|;Tsujinaka|Toshimasa|T|;|||",
"chemical_list": "D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(15)00553-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "17(3)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D005743:Gastrectomy; D006801:Humans; D007564:Japan; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016016:Proportional Hazards Models; D056910:Republic of Korea; D018570:Risk Assessment; D013274:Stomach Neoplasms; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "309-318",
"pmc": null,
"pmid": "26822397",
"pubdate": "2016-03",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non-curable factor (REGATTA): a phase 3, randomised controlled trial.",
"title_normalized": "gastrectomy plus chemotherapy versus chemotherapy alone for advanced gastric cancer with a single non curable factor regatta a phase 3 randomised controlled trial"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1016522",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GIMERACIL\\OTERACIL\\TEGAFUR"
},
"drugadditi... |
{
"abstract": "Voriconazole trough concentrations more than 1 mg/L are associated with a higher likelihood of success. It is unknown whether these trough concentrations are reached with the current recommended pediatric dosing schedule. We retrospectively analyzed the results of our therapeutic drug monitoring service for voriconazole in 18 children treated at our children's hospital. Thirty-nine voriconazole plasma concentrations were measured. In 44% of patients, the first voriconazole concentration was below the target. Dose adjustment eventually resulted in plasma concentrations within the predefined target range in all patients. Given the high proportion of patients with subtherapeutic concentrations, monitoring plasma concentrations should be performed routinely in pediatric patients receiving voriconazole.",
"affiliations": "Department of Clinical Pharmacy, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands. R.Bruggemann@akf.umcn.nl",
"authors": "Brüggemann|Roger J M|RJ|;van der Linden|Jan W M|JW|;Verweij|Paul E|PE|;Burger|David M|DM|;Warris|Adilia|A|",
"chemical_list": "D000935:Antifungal Agents; D011743:Pyrimidines; D014230:Triazoles; D065819:Voriconazole",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0b013e318204d227",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "30(6)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000935:Antifungal Agents; D002648:Child; D002675:Child, Preschool; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D009181:Mycoses; D010949:Plasma; D011743:Pyrimidines; D012189:Retrospective Studies; D016896:Treatment Outcome; D014230:Triazoles; D065819:Voriconazole",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "533-4",
"pmc": null,
"pmid": "21127454",
"pubdate": "2011-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of therapeutic drug monitoring of voriconazole in a pediatric population.",
"title_normalized": "impact of therapeutic drug monitoring of voriconazole in a pediatric population"
} | [
{
"companynumb": "NL-PFIZER INC-202101075439",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VORICONAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Mantle cell lymphoma (MCL) has the worst prognosis of B-cell subtypes owing to its aggressive clinical disease course and incurability with standard chemo-immunotherapy. Options for relapsed MCL are limited, although several single agents have been studied. Lenalidomide is available in Italy for patients with MCL based on a local disposition of the Italian Drug Agency.\n\n\n\nAn observational retrospective study was conducted in 24 Italian hematology centers with the aim to improve information on effectiveness and safety of lenalidomide use in real practice.\n\n\n\nSeventy patients received lenalidomide for 21/28 days with a median of eight cycles. At the end of therapy, there were 22 complete responses (31.4%), 11 partial responses, 6 stable diseases, and 31 progressions, with an overall response rate of 47.1%. Eighteen patients (22.9%) received lenalidomide in combination with either dexamethasone (n = 13) or rituximab (n = 5). Median overall survival (OS) was reached at 33 months and median disease-free survival (DFS) at 20 months: 14/22 patients are in continuous complete response with a median of 26 months. Patients who received lenalidomide alone were compared with patients who received lenalidomide in combination: OS and DFS did not differ. Progression-free survivals are significantly different: at 56 months, 36% in the combination group versus 13% in patients who received lenalidomide alone. Toxicities were manageable, even if 17 of them led to an early drug discontinuation.\n\n\n\nLenalidomide therapy for relapsed MCL patients is effective and tolerable even in a real-life context.\n\n\n\nSeveral factors influence treatment choice in relapsed/refractory mantle cell lymphoma (rrMCL), and the therapeutic scenario is continuously evolving. In fact, rrMCL became the first lymphoma for which four novel agents have been approved: temsirolimus, lenalidomide, ibrutinib, and bortezomib. The rrMCL therapeutic algorithm is not so well established because data in the everyday clinical practice are still poor. Lenalidomide for rrMCL patients is effective and tolerable even in a real-life context.",
"affiliations": "Institute of Hematology, University of Bologna, Bologna, Italy.;Institute of Hematology, University of Bologna, Bologna, Italy.;Institute of Hematology, University of Bologna, Bologna, Italy.;Division of Hematology, Fondazione IRCCS Ospedale Maggiore Policlinico, Università degli Studi di Milano, Milan, Italy.;Unit of Hematology, Santa Maria delle Croci Hospital, Ravenna, Italy.;Hematology Unit, University of Siena, Siena, Italy.;Division of Hematology, AOU Policlinico-Vittorio Emanuele, Catania, Italy.;Hematology, Department of Cellular Biotechnologies and Hematology, 'Sapienza' University, Rome, Italy.;Division of Hematology - SS. Antonio e Biagio e Cesare Arrigo Hospital, Alessandria, Italy.;UOC Onco-Hematology Policlinico Tor Vergata, Rome, Italy.;Hematology, Sant'Andrea Hospital, La Sapienza University, Rome, Italy.;IRCCS A.O.U. San Martino-IST, Genoa, Italy.;Division of Hematology, Niguarda Cancer Center, Milan, Italy.;Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.;Department of Hematology-Oncology, Fondazione IRCCS Policlinico San Matteo & Department of Molecular Medicine, University of Pavia, Pavia, Italy.;Hematology-Arcispedale S.Maria Nuova IRCCS, Reggio Emilia, Italy.;Department of Medical Sciences, Section of Hematology, University of Modena and Reggio Emilia, Modena, Italy.;Chair of Hematology, DRMM, University of Udine, Udine, Italy.;A.O. Città della Salute e della Scienza di Torino, Torino, Italy.;Onco-Ematologia Ospedale Pagandi, Salerno, Italy.;Medicine I and Hematology, San Paolo Hospital, Savona, Italy.;Affiliate Clinic of Hematology Ospedali Riuniti, Ancona, Italy.;S.C. Onco-Ematologia, A.O.S. Maria di Terni, Terni, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRST, IRCCS, Meldola, Italy.;Hematology Unit, ASL Napoli 1 Centro, Naples, Italy.;Department of Hematology, Lymphoma Unit, Spirito Santo Hospital, Pescara, Italy.;Institute of Hematology, University of Bologna, Bologna, Italy.;Institute of Hematology, University of Bologna, Bologna, Italy pierluigi.zinzani@unibo.it.",
"authors": "Stefoni|Vittorio|V|;Pellegrini|Cinzia|C|;Broccoli|Alessandro|A|;Baldini|Luca|L|;Tani|Monica|M|;Cencini|Emanuele|E|;Figuera|Amalia|A|;Ansuinelli|Michela|M|;Bernocco|Elisa|E|;Cantonetti|Maria|M|;Cox|Maria Christina|MC|;Ballerini|Filippo|F|;Rusconi|Chiara|C|;Visco|Carlo|C|;Arcaini|Luca|L|;Fama|Angelo|A|;Marasca|Roberto|R|;Volpetti|Stefano|S|;Castellino|Alessia|A|;Califano|Catello|C|;Cavaliere|Marina|M|;Gini|Guido|G|;Liberati|Anna Marina|AM|;Musuraca|Gerardo|G|;Lucania|Anna|A|;Ricciuti|Giuseppina|G|;Argnani|Lisa|L|;Zinzani|Pier Luigi|PL|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2017-0597",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "23(9)",
"journal": "The oncologist",
"keywords": "Lenalidomide; Mantle cell lymphoma; Real life; Refractory; Relapsed",
"medline_ta": "Oncologist",
"mesh_terms": "D000368:Aged; D020533:Angiogenesis Inhibitors; D006801:Humans; D007558:Italy; D000077269:Lenalidomide; D020522:Lymphoma, Mantle-Cell; D012189:Retrospective Studies; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "1033-1038",
"pmc": null,
"pmid": "29674440",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": "25738670;23782157;26899778;19581539;29096668;17242396;19245430;22058200;24859361;28881919;24030098;27252040;24002500;24606326;23545991;24122387;25241999;28066928;17001068;25632047;28444739",
"title": "Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice (the Lenamant Study).",
"title_normalized": "lenalidomide in pretreated mantle cell lymphoma patients an italian observational multicenter retrospective study in daily clinical practice the lenamant study"
} | [
{
"companynumb": "IT-CELGENE-ITA-2016023866",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe aim of this study was to compare the safety and efficacy profiles of R-CHOP and R-fCHOP regimes in the treatment of primary gastric diffuse large B cell lymphoma (PG-DLBCL).\n\n\nMETHODS\nData of PG-DLBCL patients admitted in our hospital from March 2010 to March 2014 were collected retrospectively. Differences in gastrointestinal bleeding and perforation between the R-CHOP group and R-fCHOP group were compared. The influence of the gastrointestinal complication on subsequent treatment was also analyzed. Treatment outcome of the two groups was also compared.\n\n\nRESULTS\nA total of 50 patients were included in this retrospective study. Forty of them were in the R-CHOP group, another ten were in the R-fCHOP group. Patients in the R-fCHOP group had a higher rate of Lugano late stage disease, and a relatively high rate of a deeper/larger ulcer. Fence occult blood test (FOBT) was positive in one (10.0%) patient in the R-fCHOP group, and 11 (31.4%) patients in the R-CHOP group, among them one had hematemesis and had to give up the subsequent chemotherapy. No perforation was observed in both groups. The response rate (RR) was 92.5% in the R-CHOP group and 90.0% in the R-fCHOP group (P > 0.05). The PFS was also comparable between the two groups (P > 0.05).\n\n\nCONCLUSIONS\nR-fCHOP regimen has a good safety profile in patients with Lugano late stage and deep/large ulcers, who are of high risk of gastrointestinal bleeding or perforation, and also has a comparable efficacy profile when compared with the R-CHOP regimen in short-term follow-up.",
"affiliations": "Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.;Department of Medical Oncology, Cancer Hospital; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Email: cao_junning@hotmail.com.",
"authors": "Ji|Dongmei|D|;Hong|Xiaonan|X|;Guo|Ye|Y|;Xue|Kai|K|;Zhang|Qunling|Q|;Shen|Weina|W|;Cao|Junning|J|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "China",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-3766",
"issue": "36(12)",
"journal": "Zhonghua zhong liu za zhi [Chinese journal of oncology]",
"keywords": null,
"medline_ta": "Zhonghua Zhong Liu Za Zhi",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008875:Middle Aged; D011241:Prednisone; D012189:Retrospective Studies; D000069283:Rituximab; D013274:Stomach Neoplasms; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "7910681",
"other_id": null,
"pages": "939-43",
"pmc": null,
"pmid": "25623771",
"pubdate": "2014-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of rituximab combined with CHOP or combined with dose fractionated CHOP in the treatment of primary gastric diffuse large B cell lymphoma.",
"title_normalized": "efficacy and safety of rituximab combined with chop or combined with dose fractionated chop in the treatment of primary gastric diffuse large b cell lymphoma"
} | [
{
"companynumb": "CN-ROCHE-1541283",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Methoxyacetylfentanyl belongs to the group of fentanyl analogues and has been associated with several deaths in recent years. We present three case reports of deceased individuals that tested positive for methoxyacetylfentanyl consumption, as well as in vitro and in vivo metabolite profiles. Methoxyacetylfentanyl was quantified by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) in femoral blood, as well as in urine and brain tissue when these were available. Metabolite profiling was performed by incubating methoxyacetylfentanyl with pooled human hepatocytes (pHH) in Leibovitz's L-15 medium supplemented with fetal bovine serum. Metabolites were identified in vivo and in vitro using UHPLC-high resolution (HR)-MS/MS. The measured methoxyacetylfentanyl concentration was 0.022-0.056mg/kg (N=3) in femoral blood, 0.12mg/kg (N=1) in urine, and 0.074mg/kg (N=1) in brain tissue homogenate. A total of 10 metabolites were identified. The observed metabolic pathways were: hydroxylation(s), N-dealkylation, O-demethylation, deamination, glucuronidation, and combinations thereof. Major analytical targets in vitro and across measured biological samples in vivo were methoxyacetylfentanyl, the O-demethyl- metabolite, and the deamide-metabolite. Intoxication with methoxyacetylfentanyl was judged as the cause of death or a major contributing factor in all three presented cases.",
"affiliations": "Section of Forensic Chemistry, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark. Electronic address: marie.mardal@sund.ku.dk.;Section of Forensic Chemistry, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.;Section of Forensic Toxicological Analysis, Department of Forensic Sciences, Oslo University Hospital, Oslo, Norway.;Section of Forensic Chemistry, Department of Forensic Medicine, University of Copenhagen, Copenhagen, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Aarhus University, Aarhus, Denmark.",
"authors": "Mardal|M|M|;Johansen|S S|SS|;Davidsen|A B|AB|;Telving|R|R|;Jornil|J R|JR|;Dalsgaard|P W|PW|;Hasselstrøm|J B|JB|;Øiestad|Å M|ÅM|;Linnet|K|K|;Andreasen|M F|MF|",
"chemical_list": "D015198:Designer Drugs; D005283:Fentanyl",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.07.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "290()",
"journal": "Forensic science international",
"keywords": "Fentanyl analogue; Hepatocytes; LC-HR-MS/MS; Metabolism; Methoxyacetylfentanyl; Postmortem",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D001921:Brain; D002853:Chromatography, Liquid; D015198:Designer Drugs; D005283:Fentanyl; D022781:Hepatocytes; D006801:Humans; D008297:Male; D008875:Middle Aged; D019966:Substance-Related Disorders; D053719:Tandem Mass Spectrometry",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "310-317",
"pmc": null,
"pmid": "30107329",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Postmortem analysis of three methoxyacetylfentanyl-related deaths in Denmark and in vitro metabolite profiling in pooled human hepatocytes.",
"title_normalized": "postmortem analysis of three methoxyacetylfentanyl related deaths in denmark and in vitro metabolite profiling in pooled human hepatocytes"
} | [
{
"companynumb": "DK-INSYS THERAPEUTICS, INC-INS201905-000362",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BENZODIAZEPINE"
},
"drugadd... |
{
"abstract": "Treatment-resistant major depression (TRMD, major depressive disorder that fails to respond to numerous therapies) is a relatively common and clinically challenging disorder. In many cases, the most severely affected TRMD patients have received surgical intervention (subcaudate tractotomy, limbic leucotomy, anterior capsulotomy, and anterior cingulotomy). New treatments, including vagus nerve stimulation (VNS) and deep brain stimulation, have emerged to treat individuals with TRMD. We describe the case of a woman, 53 years of age, with a long and sustained history of TRMD (33 years), which was unresponsive to numerous treatments (multiple pharmacotherapies, psychotherapy, electroconvulsive therapy [ECT]). Additionally, her TRMD failed to respond to a bilateral anterior cingulotomy. She underwent placement of a cervical vagus nerve stimulator and a brief course of ECT (3 unilateral treatments). Her depression improved markedly, and it has remained in sustained remission for 3.5 years. This case suggests a potential synergistic effect of VNS and ECT, as well as provides possible clues to the neural circuitry of VNS in TRMD.",
"affiliations": null,
"authors": "Conway|Charles R|CR|;Gebretsadik|Mehret D|MD|;Bucholz|Richard D|RD|",
"chemical_list": null,
"country": "United States",
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"title": "Marked Response to VNS in a Post-Cingulotomy Patient: Implications for the Mechanism of Action of VNS in TRD.",
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"abstract": "Hemolytic uremic syndrome (HUS) is the triad of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment. HUS has been associated with a variety of gastrointestinal malignancies and chemotherapeutic agents. We present a patient with pancreatic cancer treated with gemcitabine for palliation who developed gemcitabine-induced HUS (GiHUS) which responded to some extent to blood and platelet transfusions. With the increase in the use of gemcitabine therapy for pancreatic and other malignancies, it is essential to accurately and timely diagnose GiHUS to avoid the life-threatening complications.",
"affiliations": "Florida Hospital, Orlando, USA.;Internal Medicine Residency, Florida Hospital, Orlando, USA.;Internal Medicine, Dow University of Health Sciences (DUHS), Karachi, PAK.;Florida Hospital, Orlando, USA.;Internal Medicine, Florida Hospital, Orlando, USA.",
"authors": "Hasan|Askari|A|;Jain|Akriti G|AG|;Naim|Huda|H|;Munaf|Alvina|A|;Everett|George|G|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.3088Internal MedicineNephrologyOncologyDrug-induced Thrombotic Microangiopathy Caused by Gemcitabine Muacevic Alexander Adler John R Hasan Askari 1Jain Akriti G 2Naim Huda 3Munaf Alvina 1Everett George 4\n1 \nFlorida Hospital, Orlando, USA \n2 \nInternal Medicine Residency, Florida Hospital, Orlando, USA \n3 \nInternal Medicine, Dow University of Health Sciences (DUHS), Karachi, PAK \n4 \nInternal Medicine, Florida Hospital, Orlando, USA \nAkriti G. Jain akriti.jain@flhosp.org2 8 2018 8 2018 10 8 e308825 7 2018 2 8 2018 Copyright © 2018, Hasan et al.2018Hasan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/13943-drug-induced-thrombotic-microangiopathy-caused-by-gemcitabineHemolytic uremic syndrome (HUS) is the triad of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment. HUS has been associated with a variety of gastrointestinal malignancies and chemotherapeutic agents. We present a patient with pancreatic cancer treated with gemcitabine for palliation who developed gemcitabine‐induced HUS (GiHUS) which responded to some extent to blood and platelet transfusions. With the increase in the use of gemcitabine therapy for pancreatic and other malignancies, it is essential to accurately and timely diagnose GiHUS to avoid the life-threatening complications.\n\npancreas canceratypical hemolytic uremic syndromeThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nHemolytic uremic syndrome (HUS) is the triad of nonimmune (Coombs negative) hemolytic anemia, low platelet count, and renal impairment [1]. The anemia is severe and microangiopathic in nature, with a platelet count less than 60,000/mm3 in most cases [1].\n\nIn children, the disease is most commonly triggered by Shiga-like toxin (Stx)-producing Escherichia coli. Non-Shiga toxin-associated HUS can be sporadic or familial and has a poor outcome. Up to 50% of cases progress to end-stage renal disease (ESRD) or have irreversible brain damage, and has an overall 25% mortality [2-4].\n\nHUS has been associated with a variety of gastrointestinal malignancies, most commonly metastatic adenocarcinoma from the stomach, colon, rectum, or pancreas. Certain chemotherapeutic agents have been reported to be associated with HUS, including mitomycin, cisplatin, bleomycin, and more recently gemcitabine [5-6].\n\nCase presentation\nA 66-year-old male with a past medical history of hypertension and pancreatic adenocarcinoma presented to our hospital with complaints of nausea, vomiting, and generalized weakness in the arms and legs. The patient was diagnosed with locally advanced, pancreatic cancer, T1 N0 M0 a year prior to presentation. Magnetic resonance cholangiopancreatography (MRCP) revealed a 1.7 cm mass at the head of his pancreas, locally invasive but without the involvement of lymph nodes, superior mesenteric artery, superior mesenteric vein or portal vein. Endoscopic biopsy revealed adenocarcinoma. The patient was a poor surgical candidate due to social issues, alcoholism, residence at a nursing home and was at a high-risk for post-surgical complications. The patient was treated palliatively with nine cycles of gemcitabine and paclitaxel. The initial dose of gemcitabine was 2000 mg. The tumor decreased in size and CA 19-9 level declined from an initial level of 2000 to 26 units/mL. Later the dose of gemcitabine was reduced to 1400 mg (20% reduction) after the sixth cycle due to pancytopenia.\n\nOn admission to our hospital, the patient reported abdominal pain that was sharp and located in the right lower quadrant (RLQ). He denied fevers or chills. The patients' vital signs were: temperature 99.3 °F, heart rate of 73 beats per minute, blood pressure 129/60 mmHg, respiratory rate of 17 breaths per minute and oxygen saturation 100% on room air. The physical examination was remarkable for RLQ tenderness. The laboratory data revealed hemoglobin (Hb) 6.5 g/dL, hematocrit (Hct) 19.8, mean corpuscular volume (MCV) 83.2fL /red cell, red cell distribution width (RDW) 19.1 %, white cell count of 9.44 x 109/L, platelets of 54 x 109/L, alanine transaminase (ALT) 133 IU/L, aspartate transaminase (AST) 222 IU/L, alkaline phosphatase (ALP) of 147 IU/L and a total bilirubin of 5 umol/L. BUN was 42 mg/dl, creatinine 2.12 mg/dl (baseline creatinine of 0.8), LDH was 1700 u/l, reticulocyte count was 7.8%. Peripheral smear showed microcytic anemia with frequent schistocytes consistent with a microangiopathic hemolytic process (Figures 1-2). Urinalysis was positive for 1+ blood and 1+ albumin. Computed tomography (CT) scan of the abdomen without contrast showed a stable pancreatic mass and no signs of hydronephrosis (Figure 3). ERCP revealed choledocholithiasis. Choledocholithotomy was performed and subsequently the bilirubin improved. Blood cultures grew Klebsiella. He was treated with piperacillin-tazobactam. The patient received intravenous (IV) fluids, blood and platelets when the Hb and platelets declined to Hb of 6.4 g/dl and platelet counts of 8 x 109. He was treated with methylprednisone 30 mg IV q24 and the platelet count increased to 20 x 109. His creatinine increased to 12 mg/dl and BUN to 112 mg/dl. ADAMTS13 activity was 34%. A diagnosis of GiHUS was made. The patient was offered plasmapheresis, but he opted for hospice.\n\nFigure 1 Peripheral blood film showing numerous schistocytes\nFigure 2 Schistocytes under magnification\nFigure 3 Pancreatic head mass with biliary stent in place\nDiscussion\nGemcitabine is a nucleoside analog structurally related to cytarabine [7] and is indicated for use in multiple malignancies including pancreatic and non-small cell lung cancer, urothelial and ovarian cancers [8]. The incidence of gemcitabine-induced HUS (GiHUS) has been variously reported to be between 0.015% to 4% [9]. The median time between the initiation of chemotherapy and onset of GiHUS was 7.4 months [10].\n\nClinically it is very difficult to distinguish HUS associated with underlying malignancy from that caused by chemotherapy. There is considerable etiological overlap in biochemical parameters and tumor factors such as tumor necrosis factor-alpha, interleukin-1, and interleukin-6 as well as von Willebrand factor (vWF) antigen and low molecular weight vWF multimers [11-12]. Cancer-associated HUS usually occurs during widespread metastatic disease or poorly controlled carcinomas, whereas chemotherapy-associated HUS is more common when the patient is in disease remission or has minimal tumor burden [13]. Carreras [14] and Hammar [15] suggest initial testing for serum C3 concentrations; however, normal C3 levels do not necessarily exclude a complement dysfunction. More sensitive assays could be a higher-than-normal C3d/C3 ratio in plasma or the presence of C3 deposits in renal biopsy.\n\nGiHUS should be suspected in a patient with malignancy whenever renal dysfunction occurs without an obvious cause. Laboratory investigations suggestive of microangiopathic hemolysis should be obtained including red cell morphology, LDH, fibrin split products and reticulocyte count. A renal biopsy can confirm the diagnosis by revealing the classic microvascular damages with arterioles and small arteries occluded by eosinophilic hyaline thrombi containing fibrin and platelet aggregates [16].\n\nIn patients suspected of GiHUS, immediate cessation of gemcitabine is the initial step [17]. GiHUS has since its recognition has been associated with a poor prognosis. After the introduction of plasma manipulation, the mortality rate has decreased from 50% to 25% [18]. Removal of plasma and its subsequent substitution with albumin and saline has not been shown to lead to an increase in the platelet count which was seen in our patient. In patients with renal insufficiency or heart failure, plasma exchange within 24 hours of presentation should be considered as first-choice therapy [1]. In a few patients with extensive microvascular thrombosis at renal biopsy, refractory hypertension, and signs of hypertensive encephalopathy, conventional therapies including plasma manipulation are not enough to control the disease. Bilateral nephrectomy has been performed with favorable results in some patients [19]. Other treatments, including antiplatelet agents, prostacyclin, heparin or fibrinolytic agents, steroids, and intravenous immunoglobulins, have been attempted, with no consistent benefit [1].\n\nEculizumab, a terminal complement inhibitor, is a humanized monoclonal antibody that binds with high affinity to the human C5 complement protein and blocks the generation of proinflammatory C5a and C5b-9 [20]. Clinical trials report that eculizumab resulted in increases in the platelet count, with a mean increase from baseline to 73 × 109 per liter (P<0.001) by the 26th week. Eculizumab has been associated with continuous, time-dependent increases in the estimated glomerular filtration rate (GFR) and improvement in health-related quality of life.\n\nConclusions\nWith the increase in the use of gemcitabine therapy for pancreatic and other malignancies, it is essential to accurately and timely diagnose GiHUS to avoid the life-threatening complications. Our patient underwent palliative treatment with gemcitabine for pancreatic adenocarcinoma. For any patient receiving gemcitabine like our patient, either therapeutic or palliative, clinicians should have a low threshold for suspecting HUS in the presence of appropriate clinical conditions and laboratory findings especially renal dysfunction.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura Kidney Int Ruggenenti P Noris M Remuzzi G 831 846 60 2001 11532079 \n2 Haemolytic-uraemic syndrome in childhood: surveillance and case-control studies in Italy Pediatr Nephrol Gianviti A Rosmini F Caprioli A 705 709 8 1994 https://www.ncbi.nlm.nih.gov/pubmed/7696109 7696109 \n3 Renal function at hospital admission as a prognostic factor in adult hemolytic uremic syndrome J Am Soc Nephrol Schieppati A Ruggenenti P Cornejo RP 1640 1644 2 1992 https://www.ncbi.nlm.nih.gov/pubmed/1610985 1610985 \n4 Clinico-pathological findings in diarrhoea-negative haemolytic uraemic syndrome Pediatr Nephrol Taylor CM Chua C Howie AJ Risdon RA 419 425 19 2004 14986082 \n5 Carcinoma-associated hemolytic-uremic syndrome: a complication of mitomycin C chemotherapy J Clin Oncol Cantrell JE Phillips TM Schein PS 723 734 5 1985 \n6 A toxic interaction between mitomycin C and tamoxifen causing the haemolytic uraemic syndrome Eur J Cancer Montes A Powles TJ O'Brien ME Ashley SE Luckit J Treleaven J 1854 1857 29 1993 https://www.ncbi.nlm.nih.gov/pubmed/8260241 \n7 Gemcitabine a cytidine analogue active against solid tumors Am J Health Syst Pharm Hui YF Reitz J 2162 2170 54 1997 https://www.ncbi.nlm.nih.gov/pubmed/9117804 \n8 Gemcitabine-induced hemolytic uremic syndrome: a case report J Natl Cancer Inst Brodowicz T Breiteneder S Wiltschke C Zielinski CC 1895 1896 89 1997 https://www.ncbi.nlm.nih.gov/pubmed/9414181 9414181 \n9 Gemcitabine-induced thrombotic microangiopathy: a systematic review Nephrol Dial Transplant Izzedine H Isnard-Bagnis C Launay-Vacher V 3038 3045 21 2006 16968717 \n10 Gemcitabine-associated hemolytic-uremic syndrome Am J Kidney Dis Walter RB Joerger M Pestalozzi BC 0 40 2002 \n11 Chemotherapy-induced hemolytic uremic syndrome: description of a potential animal model J Med Primatol Hillyer CD Duncan A Ledford M 68 73 24 1995 https://www.ncbi.nlm.nih.gov/pubmed/8613975 8613975 \n12 Investigation of plasma von Willebrand factor and circulating platelet aggregating activity in mitomycin C-related hemolytic-uremic syndrome Am J Hematol Monteagudo J Pereira A Roig S Reverter JC Ordinas A Castillo R 46 49 33 1990 https://www.ncbi.nlm.nih.gov/pubmed/2104558 2104558 \n13 Cancer and drug-associated thrombotic thrombocytopenic purpura and hemolytic uremic syndrome Semin Hematol Gordon LI Kwaan HC 140 147 34 1997 https://www.ncbi.nlm.nih.gov/pubmed/9109216 9109216 \n14 Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype JAMA Carreras L Romero R Requesens C 602 604 245 1981 https://www.ncbi.nlm.nih.gov/pubmed/7452889 7452889 \n15 Adult hemolytic uremic syndrome with renal arteriolar deposition of IgM andC3 Am J Clin Pathol Hammar SP Bloomer HA McCloskey D 434 439 70 1978 https://www.ncbi.nlm.nih.gov/pubmed/152058 152058 \n16 Hemolytic-uremic syndrome associated with gemcitabine: a case report and review of literature JOP Saif MW McGee PJ 369 374 6 2005 https://www.ncbi.nlm.nih.gov/pubmed/16006690 16006690 \n17 Gemcitabine nephrotoxicity and hemolytic uremic syndrome: report of 29 cases from a single institution Clin Nephrol Glezerman I Kris MG Miller V Seshan S Flombaum CD 130 139 71 2009 https://www.ncbi.nlm.nih.gov/pubmed/19203505 19203505 \n18 Management of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome Semin Hematol Kwaan HC Soff GA 159 166 34 1997 https://www.ncbi.nlm.nih.gov/pubmed/9109218 9109218 \n19 Bilateral nephrectomy stopped disease progression in plasma-resistant hemolytic uremic syndrome with neurological signs and coma Kidney Int Remuzzi G Galbusera M Salvadori M Rizzoni G Paris S Ruggenenti P 282 286 49 1996 https://www.ncbi.nlm.nih.gov/pubmed/8770981 8770981 \n20 Discovery and development of the complement inhibitor eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria Nat Biotechnol Rother RP Rollins SA Mojcik CF Brodsky RA Bell L 1256 1264 25 2007 https://www.ncbi.nlm.nih.gov/pubmed/17989688 17989688\n\n",
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"issue": "10(8)",
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"keywords": "atypical hemolytic uremic syndrome; pancreas cancer",
"medline_ta": "Cureus",
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"nlm_unique_id": "101596737",
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"pages": "e3088",
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"pmid": "30324044",
"pubdate": "2018-08-02",
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"title": "Drug-induced Thrombotic Microangiopathy Caused by Gemcitabine.",
"title_normalized": "drug induced thrombotic microangiopathy caused by gemcitabine"
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"abstract": "A variety of systemic drugs including corticosteroids, amiodarone and antipsychotics have been known to cause cataract formation. Typical antipsychotics such as chlorpromazine have been reported to cause cataract formation in varying rates ranging from 22% to 80%. Cataract as an adverse effect resulting from the long term use of atypical antipsychotic has rarely been mentioned in literature, and there is only a single case report of cataract formation from prolonged use of clozapine. We report a rare case of clozpine induced cataract in a young female. The patient was advised to consult her psychiatrist for a change of drug and to undergo cataract surgery.",
"affiliations": "Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya Medical Research Foundation, Chennai, Tamil Nadu, India.;Department of Ophthalmology, Narayana Medical College, Nellore, Andhra Pradesh, India.",
"authors": "Alam|Md Shahid|MS|;Praveen Kumar|K V|KV|",
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"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-7-18410.4103/0976-500X.195904Case ReportClozapine-induced cataract in a young female Alam Md. Shahid Praveen Kumar K. V. 1Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya Medical Research Foundation, Chennai, Tamil Nadu, India1 Department of Ophthalmology, Narayana Medical College, Nellore, Andhra Pradesh, IndiaAddress for correspondence: Md. Shahid Alam, Department of Orbit Oculoplasty Reconstructive and Aesthetic Services, Sankara Nethralaya Medical Research Foundation, Chennai, Tamil Nadu, India. E-mail: mshahidalam@gmail.comOct-Dec 2016 7 4 184 186 08 9 2016 09 10 2016 13 10 2016 Copyright: © 2016 Journal of Pharmacology and Pharmacotherapeutics2016This 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 variety of systemic drugs including corticosteroids, amiodarone and antipsychotics have been known to cause cataract formation. Typical antipsychotics such as chlorpromazine have been reported to cause cataract formation in varying rates ranging from 22% to 80%. Cataract as an adverse effect resulting from the long term use of atypical antipsychotic has rarely been mentioned in literature, and there is only a single case report of cataract formation from prolonged use of clozapine. We report a rare case of clozpine induced cataract in a young female. The patient was advised to consult her psychiatrist for a change of drug and to undergo cataract surgery.\n\nKey words\nAtypical antipsychoticcataractclozapine\n==== Body\nINTRODUCTION\nCataract is defined as an opacity of the lens or its capsule and is the most common cause of preventable blindness worldwide.[1]\n\nA variety of systemic drugs such as corticosteroids, amiodarone, and antipsychotics have been implicated in the causation of cataract. Ocular adverse effects in schizophrenic patients are mostly attributed to the use of phenothiazine group of antipsychotic medications. Greiner and Berry et al. in the mid-1960s first reported dense, dark brown lenticular opacities induced by phenothiazine use.[2]\n\nChlorpromazine, a typical antipsychotic drug has been reported to cause cataract in varying rates ranging from 22% to 80%.[2] However, cataract formation as an adverse effect of atypical antipsychotics is less common and is rarely reported in literature. Cataract formation associated with the use of atypical antipsychotics has been reported with olanzapine, ziprasidone, and risperidone.[3] A thorough review of literature showed only a single case report of cataract caused by long-term use of clozapine, with no case been reported from India.[4] We herewith report a rare case of clozapine-induced cataract in a young Indian female.\n\nCASE REPORT\nA 28-year-old female presented with complaints of gradually progressive diminution of vision in the right eye for the last 6 months. The patient was taking clozapine orally, 25 mg daily at bedtime for the past 1 year. The cumulative dose of the drug was 9.1 g.\n\nOn examination, the best-corrected visual acuity in the right eye was counting fingers at 2 m distance, and 6/9 in the left eye. The cornea was clear in both eyes and there were no pigment deposits on the endothelium. Lens examination revealed a plaque-like posterior subcapsular cataract in the right eye and a faint early posterior subcapsular cataract in the left eye [Figure 1a–c]. Fundus examination of both eyes was unremarkable. On potential acuity meter testing, the visual acuity in the right eye improved to 6/9. There was no evidence of skin pigmentation. A presumptive diagnosis of clozapine-induced cataract was entertained and the patient was advised to consult the psychiatrist for alternative medication and to undergo cataract surgery in the right eye.\n\nFigure 1 (a) Slit lamp photograph (oblique illumination) of the right eye showing dense plaque-like posterior subcapsular cataract. (b) Slit lamp photograph (oblique illumination) of the left eye showing early posterior subcapsular cataract. (c) Slit lamp photograph (retroillumination) of the right eye showing dense posterior subcapsular cataract\n\nDISCUSSION\nCataract is a degenerative process affecting elderly individuals. Causes of cataract developing in young individuals include congenital and developmental cataract, trauma, and systemic disorders such as diabetes mellitus, complicated cataract secondary to ocular diseases such as chronic uveitis, retinitis pigmentosa, high myopia, and long-term usage of drugs such as steroids, amiodarone, and phenothiazines.[5] As this patient had no signs of other ocular and systemic disorders, long-term use of clozapine could have been the only causative factor inducing cataract in her.\n\nLong-term phenothiazine use is known to cause pigment deposits in the cornea, lens, and skin.[2] The etiology of phenothiazine-related ocular side effects is not clearly understood. Photosensitization of tissue proteins occurs in areas with increased sun exposure after accumulation of the drug in ocular tissues.[6]\n\nPhenothiazines can also interact with melanin in the choriocapillaris and in the retinal pigment epithelium, inducing damage to the photoreceptors. Altered dopaminergic regulation of melatonin is supposed to make photoreceptors more susceptible to phototoxic damage. However, similar ocular side effects resulting from the use of atypical antipsychotics have rarely been reported in literature.\n\nClozapine is a tricyclic dibenzodiazepine with dopamine-receptor blocking property. It is an atypical antipsychotic that can be used as an alternative for phenothiazines, in refractory schizophrenia. Since it has got similar dopamine-receptor blocking property as that of phenothiazines, it is possible that clozapine might also lead to altered dopaminergic regulation of melatonin, causing similar adverse effects.\n\nSouza et al. in their study on the development of cataract in patients on antipsychotic medications found that 18% of patients on atypical antipsychotics went on to develop cataract. However, none of the patients who developed cataract in their study was on clozapine.[3]\n\nWe herewith report the second case of clozapine-induced cataract and the first to report from India. Borovik et al. were the first to report a case of clozapine-induced lenticular opacities. Their patient also had associated pigment deposits on the corneal endothelium and anterior lens capsule along with pigmentary retinopathy. Although our patient did not have any evidence of ocular pigmentation, the nature of cataract, i.e., posterior subcapsular, was similar as reported by them. The difference in the findings can be explained by the fact that the cumulative dose and duration of usage of the drug were different in both the patients. Our patient was on clozapine for 1 year and the cumulative dose was 9.1 g as compared to the patient reported by Borovik et al. where the patient was on the drug for 16 years and cumulative dose was 4.67 kg. Since the cumulative dose of clozapine in our case was quite low, and we did not notice any associated pigment deposition either; the mechanism of developing cataract is difficult to explain. However, an association of long-term usage of clozapine, without the presence of other causative factors, strongly suggests the case to be drug induced.\n\nCataract should be considered as a possible side effect of clozapine use, particularly when used in young individuals and patient should be informed regarding the same before starting the drug. We recommend regular comprehensive ophthalmic examination in all patients who are on long-term clozapine therapy.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Brian G Taylor H Cataract blindness – Challenges for the 21 st century Bull World Health Organ 2001 79 249 56 11285671 \n2 Greiner AC Berry K Skin pigmentation and corneal and lens opacities with prolonged chlorpromazine therapy Can Med Assoc J 1964 90 663 5 14127375 \n3 Souza VB Moura Filho FJ Souza FG Rocha CF Furtado FA Gonçalves TB Cataract occurrence in patients treated with antipsychotic drugs Rev Bras Psiquiatr 2008 30 222 6 18833422 \n4 Borovik AM Bosch MM Watson SL Ocular pigmentation associated with clozapine Med J Aust 2009 190 210 1 19220190 \n5 Yanoff M Duker JS The lens Ophthalmology 2004 3rd ed St. Louisosby International Ltd 381 \n6 Deluise VP Flynn JT Asymmetric anterior segment changes induced by chlorpromazine Ann Ophthalmol 1981 13 953 5 7294636\n\n",
"fulltext_license": "CC BY-NC-SA",
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"issue": "7(4)",
"journal": "Journal of pharmacology & pharmacotherapeutics",
"keywords": "Atypical antipsychotic; cataract; clozapine",
"medline_ta": "J Pharmacol Pharmacother",
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"pages": "184-186",
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"title": "Clozapine-induced cataract in a young female.",
"title_normalized": "clozapine induced cataract in a young female"
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"abstract": "OBJECTIVE\nCardiac involvement in drug rash with eosinophilia and systemic symptoms (DRESS) syndrome varies considerably between 4% and 21%. Here we present our case and review literatures for its diagnosis and management. An algorithm for diagnosis of cardiac involvement in DRESS syndrome is proposed in this article.\n\n\nMETHODS\nData regarding DRESS-associated myocarditis and eosinophilic myocarditis were gather primarily from MEDLINE database.\n\n\nRESULTS\nDRESS syndrome is a hypersensitivity reaction which is due to massive T cell stimulation resulting in cytotoxicity and eosinophil activation and recruitment. It is characterized by fever, morbilliform rash, and various systemic symptoms, in particular hepatitis. Hypersensitivity myocarditis (acute eosinophilic myocarditis) which is typically related to a drug reaction can lead to acute necrotizing eosinophilic myocarditis, cardiac thrombosis and fibrotic stage. Cardiac symptoms range from no symptoms to cardiogenic shock. Diagnosis is based on history, clinical findings, cardiac biomarkers and cardiac imaging techniques. Endomyocardial biopsy is done in a minority of patients for definite diagnosis. If suspected, drug discontinuation and suppression of immune reactions are the first therapies. Corticosteroids are the cornerstone of systemic treatments and should be initiated at the time of diagnosis of DRESS syndrome. Additional therapy and ventricular assist devices could be considered in refractory cases.\n\n\nCONCLUSIONS\nAccording to its high morbidity and mortality, patients with DRESS syndrome should be carefully monitored or screened for cardiac involvement. Multidisciplinary care is important for a successful treatment outcome.",
"affiliations": "Department of Medicine, Buddhachinaraj Hospital, Phitsanulok, Thailand.;Department of Dermatology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.;ADR-AC GmbH, Holligenstr 91, 3008 Bern Switzerland.",
"authors": "Thongsri|Tomon|T|;Chularojanamontri|Leena|L|;Pichler|Werner J|WJ|",
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"issue": "35(1)",
"journal": "Asian Pacific journal of allergy and immunology",
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"mesh_terms": "D063926:Drug Hypersensitivity Syndrome; D006331:Heart Diseases; D006801:Humans; D008297:Male; D008875:Middle Aged",
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"pages": "3-10",
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"pubdate": "2017-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Cardiac involvement in DRESS syndrome.",
"title_normalized": "cardiac involvement in dress syndrome"
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"abstract": "Tumor necrosis factor-alpha (TNF-α) inhibitors are increasingly used for various autoimmune diseases. Demyelinating events in the CNS, including myelitis, are reportedly associated with TNF-α inhibitor exposure. Behcet's disease rarely involves the spinal cord. A 51-year-old Japanese woman presented with back pain, leg weakness, and numbness during golimumab administration, a TNF-α inhibitor, for Behcet's disease. Magnetic resonance imaging revealed multifocal myelitis in the cervical and thoracic spinal cords. Discontinuation of golimumab and steroid therapy were effective and the symptoms have not relapsed. Although it is possible that the patient's myelitis was part of the symptoms of neuro-Behcet's disease, we believe that golimumab likely played a role in the myelitis development.",
"affiliations": "Department of Neurology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan. Electronic address: kont0413@hirosaki-u.ac.jp.;Department of Gastroenterology and Hematology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan.;Department of Neurology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan.;Department of Neurology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan.;Department of Neurology, Hirosaki University, Graduate School of Medicine, Hirosaki, Japan.",
"authors": "Kon|Tomoya|T|;Hasui|Keisuke|K|;Suzuki|Chieko|C|;Nishijima|Haruo|H|;Tomiyama|Masahiko|M|",
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"journal": "Journal of neuroimmunology",
"keywords": "Adverse effect; Behcet's disease; Demyelination; Golimumab; Myelitis",
"medline_ta": "J Neuroimmunol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D001528:Behcet Syndrome; D003711:Demyelinating Diseases; D005260:Female; D006801:Humans; D008875:Middle Aged; D009187:Myelitis; D000079424:Tumor Necrosis Factor Inhibitors",
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"title": "Isolated myelitis in a patient with Behcet's disease during golimumab therapy.",
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"abstract": "BACKGROUND\nOvarian metastases from rectal cancer are infrequent; thus it might be hard to diagnose and treat them. Our study introduces a challenging case which highlights our method in addressing such an issue.\nA 74-year-old woman was admitted to our Unit showing abdominal pain, vomit, and a gross abdominal mass located in the right iliac fossa and mesogastrium. Oncological markers recorded following abnormalities: carbohydrate antigen 19.9 (Ca19.9) = 453.40 U/mL, carbohydrate antigen 125 (Ca125) = 88.3 U/mL.\n\n\nMETHODS\nSuch a metastatic tumor being difficult to diagnose, we could not achieve a precise preoperative diagnosis. We entered the operating room with a histologic diagnosis that was highly suspicious of colon adenocarcinoma. During surgery, frozen section analysis was positive for primary ovarian cancer. Thanks to the immunohistochemistry test on the histologic specimen, which might be very helpful in diagnosing such metastatic tumor, final pathology report documented ovarian metastasis from rectal cancer.\n\n\nMETHODS\nWe performed total hysterectomy with bilateral salpingo-oophorectomy and low anterior resection of the rectum with a terminal colostomy. Adjuvant chemotherapy was administered for 6 months using FOLFOX plus panitumumab in first-line therapy.\n\n\nRESULTS\nAt 8 months from surgery, during follow-up, a local pelvic progression of disease was detected, leading to second-line chemotherapy treatment.\n\n\nCONCLUSIONS\nCorrect differential diagnosis between primary and metastatic ovarian tumors is paramount in choosing the best treatment which leads to the best possible outcome. In ovarian metastatic tumors, immunohistochemistry could represent an optimal diagnostic tool.",
"affiliations": "Department of General Surgery, Chirurgia Area Nord.;Department of General Surgery, Chirurgia Area Nord.;Department of General Surgery, Chirurgia Area Nord.;Pathology Unit.;Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.;Department of General Surgery, Chirurgia Area Nord.;Department of General Surgery, Chirurgia Area Nord.",
"authors": "Biolchini|Federico|F|;Castro Ruiz|Carolina|C|;Pavesi|Erica|E|;Musci|Giovanni|G|;Zizzo|Maurizio|M|;Ugoletti|Lara|L|;Annessi|Valerio|V|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31689847MD-D-19-0061210.1097/MD.0000000000017782177827100Research ArticleClinical Case ReportDiagnostic challenges in synchronous ovarian metastasis from rectal cancer A case reportBiolchini Federico MDaCastro Ruiz Carolina MDa∗Pavesi Erica MDaMusci Giovanni MDbZizzo Maurizio MDcUgoletti Lara MDaAnnessi Valerio MDaNA. a Department of General Surgery, Chirurgia Area Nordb Pathology Unitc Surgical Oncology Unit, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy.∗ Correspondence: Carolina Castro Ruiz, Department of General Surgery, Chirurgia Area Nord, Azienda Unità Sanitaria Locale-IRCCS di Reggio Emilia, Reggio Emilia, Italy (e-mail: carolina.castroruiz85@gmail.com).11 2019 01 11 2019 98 44 e1778205 2 2019 05 9 2019 03 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This 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\nIntroduction:\nOvarian metastases from rectal cancer are infrequent; thus it might be hard to diagnose and treat them. Our study introduces a challenging case which highlights our method in addressing such an issue.\n\nPatients concerns:\nA 74-year-old woman was admitted to our Unit showing abdominal pain, vomit, and a gross abdominal mass located in the right iliac fossa and mesogastrium. Oncological markers recorded following abnormalities: carbohydrate antigen 19.9 (Ca19.9) = 453.40 U/mL, carbohydrate antigen 125 (Ca125) = 88.3 U/mL.\n\nDiagnosis:\nSuch a metastatic tumor being difficult to diagnose, we could not achieve a precise preoperative diagnosis. We entered the operating room with a histologic diagnosis that was highly suspicious of colon adenocarcinoma. During surgery, frozen section analysis was positive for primary ovarian cancer. Thanks to the immunohistochemistry test on the histologic specimen, which might be very helpful in diagnosing such metastatic tumor, final pathology report documented ovarian metastasis from rectal cancer.\n\nInterventions:\nWe performed total hysterectomy with bilateral salpingo-oophorectomy and low anterior resection of the rectum with a terminal colostomy. Adjuvant chemotherapy was administered for 6 months using FOLFOX plus panitumumab in first-line therapy.\n\nOutcome:\nAt 8 months from surgery, during follow-up, a local pelvic progression of disease was detected, leading to second-line chemotherapy treatment.\n\nConclusion:\nCorrect differential diagnosis between primary and metastatic ovarian tumors is paramount in choosing the best treatment which leads to the best possible outcome. In ovarian metastatic tumors, immunohistochemistry could represent an optimal diagnostic tool.\n\nKeywords\ndiagnosisimmunohistochemistryovarian metastasisrectal cancertreatmentOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nRectal cancer has a tendency to metastasize into thoracic organs and nervous system, whereas metastases in peritoneum (ovaries included) are less frequent. Nonetheless, when compared with generic adenocarcinomas, mucinous and signet ring adenocarcinomas show a more frequent trend to metastasize within the peritoneum,[1] with a 3% to 14% estimated incidence of ovarian metastasis from colorectal cancer.[2,3]\n\nSecondary neoplasms to the ovary, in particular, metastatic colorectal carcinomas of mucinous origin, can represent a diagnostic challenge, as they can mimic primary mucinous carcinoma of the ovaries.[4,5] Correct diagnosis before surgery is crucial to the treatment approach. At present, limited data help define an appropriate treatment of ovarian metastatic disease from colon cancer. Moreover, the consequences on the prognostic impact of metastasectomy are still unknown.[6] Our study introduces a challenging diagnostic case of rectal cancer with metastasis to the ovary.\n\nOur case report was written according to CARE guidelines.[7] Patient informed consent was obtained for the publication of the study.\n\n2 Case report\nA 74-year-old woman with no comorbidities and without any prior surgery came to our Unit with abdominal pain, vomit, and without any fever. Physical examination revealed a gross abdominal mass in the right iliac fossa and mesogastrium. Blood tests recorded 13.5 nL white blood cell count with a neutrophilic prevalence (453.40 U/mL high carbohydrate antigen 19.9 [Ca19.9] levels, and 88.3 U/mL carbohydrate antigen 125 [Ca125]), whereas AFP and carcinoembryonic antigen (CEA) were negative. Inflammatory markers, such as C-reactive protein and erythrocyte sedimentation rate, were altered.\n\nAbdomen and pelvis CT detected an inhomogeneous 18 cm × 12.4 cm solid mass with peripheral enhancement, located in the right iliac fossa. After contrast washout, the mass showed the same uterus density. The mass was tightly attached to the right and sigmoid colon with an apparent loss of the fat planes between these organs. We could not rule out an ovarian origin (Figs. 1–3).\n\nFigure 1 Computed tomography (CT) scan. Inhomogeneous mass tightly attached to the right (white arrow) and sigmoid colon (black arrow).\n\nFigure 2 Computed tomography (CT) scan. Loss of the fatty plane between the mass and the uterus (black arrow).\n\nFigure 3 Computed tomography (CT) scan. Presence of peripheral enhancement (black arrows).\n\nColonoscopy detected an unknown lesion, which occupied two-thirds of rectum's lumen. It was located about 10 cm from the anal verge and had an 8 cm cranial extension. The cecum's mucosa appeared regular with the presence of ab-extrinsic compression, which compromised the correct functioning of the ileocecal valve (Fig. 4)\n\nFigure 4 Colonoscopy. (A) Endoscopic view of the rectum's tumor. (B) Extrinsic compression of the cecum by the mass.\n\nAt our Institute, the case was discussed by the multidisciplinary group, which indicated an eco-guided biopsy. The histologic report described mucoid material with necrosis and positive for pan-keratin and CDX2 stains, which was highly suspicious for colon adenocarcinoma.\n\nThe patient underwent surgery, where a midline incision was performed and a polycystic 26-cm lesion was found (Fig. 5). The lesion arose from the ovary and frozen section analysis revealed mucinous ovarian carcinoma. The omentum appeared to be involved by the disease, so it was removed. Against this background, we decided to perform a total hysterectomy with bilateral salpingo-oophorectomy and low anterior rectal resection with terminal colostomy. After surgery, the patient experienced good recovery and was discharged on the 8th postoperative day.\n\nFigure 5 A 26-cm polycystic ovarian mass with areas containing mucin (white arrows).\n\nAt the histopathological examination, the ovarian tumor was composed of a large amount of extracellular mucin containing malignant epithelial cells, which were arranged in well-differentiated glandular structures infiltrating the stroma. Although nondiagnostic, histopathology may be compatible with primitive mucinous ovarian carcinoma or adenocarcinoma from the gastrointestinal (GI) tract.\n\nIn rectal neoplasm, we found malignant glandular structures in a large amount of extracellular mucin. We performed immunohistochemical staining and found positive CDX2 stain. It represents a nuclear transcription factor that is critical for intestinal embryonic development and is relatively specific for intestinal epithelium. We also found positive CK20—an epithelial marker expressed in lower GI epithelium track; we did not find any stain for Pax8—a member of the paired box PAX family of transcription factors genes expressed in the Müllerian tract, and thyroid, parathyroid, renal, and thymic tumors (Fig. 6).\n\nFigure 6 (A) Ovary section with the presence of a large amount of extracellular mucin containing malignant epithelial cells (frozen section H&E stain 4×). (B) Ovary section with well-differentiated glandular structures infiltrating the stroma (frozen section H&E stain 4×). (C) Rectum section with malignant glandular structures immerses in extracellular mucin (H&E stain 4×). (D) CDX2-positive immunohistochemical stain 20×. (E) CK20-positive immunohistochemical stain 20×. (F) Pax8-negative immunohistochemical stain 20×.\n\nInterpretation of immunohistochemical panel in addition to routine hematoxylin and eosin (H&E) slide and clinicopathologic correlation allowed us to identify rectum as the primary site of the tumor, having a T4bN1b pathologic stage with vascular and lymphatic invasion.\n\nThe patient has a c.2194GA genotype, which results in a reduction of the DPD enzymatic activity for fluoropyrimidine; she has mutated BRAF and KRAS wild-type. Therefore, we started a 6-month first-line FOLFOX plus panitumumab adjuvant chemotherapy with a 50% reduced dosage, due to DPD mutation.\n\nDuring this 10-month follow-up period and 8 months after surgery, radiologic tests confirmed the pelvic progression of the disease. The multidisciplinary group indicated a second-line chemotherapy protocol, which is still in progress.\n\n3 Discussion\nThis case demonstrated particularly complex, as imaging and histology did not support us in reaching a clear preoperative diagnosis. Different studies, which tried to assess the clinical features of ovarian metastases from colorectal cancer, considered abdominal pain as the most frequent symptom, followed by bowel habit change and abdominal distension while bleeding per rectum turned out less frequent.[3,8]\n\nOvarian unilateral involvement was reported in 40% cases, even though the metastatic ovarian disease was more frequently bilateral and multinodular, in contrast to primary ovarian tumors that are usually unilateral. As regarding ovarian metastases, colon-located tumors metastasize more frequently than rectal ones do, as they tend to metastasize to the liver and lungs. Synchronous ovarian metastases are more frequent than metachronous ones. A higher (III or IV) T-stage disease leads ovarian metastasis to develop more frequently in young patients in comparison to older ones.[3,4,8] According to such findings, our patient was very likely affected by a primary ovarian tumor.\n\nHistologic features of pseudo-endometroid metastases from large intestine include: garland and cribriform histologic growth patterns; abundant intraluminal “dirty” necrosis; segmental destruction of glands; and absence of squamous metaplasia. Papillary architecture or mucinous carcinoma features can be found in nearly one-third of cases.[3,4]\n\nImmunohistochemistry, on the contrary, can be very helpful in the diagnosis of ovarian involvement by metastatic colorectal cancer. Villin and CK20 are expressed in colorectal cancer metastatic to the ovary. CDX2 protein was expressed uniformly in almost all primary colonic adenocarcinomas, including 82% mucinous variants which showed strong nuclear staining. Ninety per cent of metastatic colonic adenocarcinomas expressed MUC2, but none expressed MUC5AC. On the contrary, 100% primary mucinous cystadenomas, borderline tumors, and carcinomas were positive for MUC5AC. Ca125 cancer antigen is present in only 4% to 15% of colorectal carcinomas. In another study, CEA was found to be elevated in 54.7% of patients.[3,4,8] Our patient turned out positive for both CDX2 and pan-keratin. These findings gave us the first indication of possible colorectal origin. For this reason, we are deeply convinced that further studies on immunohistochemistry of ovarian metastases from colorectal cancer could be very helpful in diagnosing difficult cases. Erroi et al[9] proposed a semiquantitative immunohistochemical staining score, where CK7−/CK20+ tumors were classified as ovarian metastases from colorectal cancer and CK7+/CK20− were considered as primary ovarian carcinoma.\n\nRegarding computed tomography (CT) scan, bilateral complex ovarian masses showing smooth tumor margins and predominantly cystic features are more suggestive for ovarian metastases than primary ovarian tumors.[10]\n\nA simple algorithm based on tumor size and laterality was suggested to tell primary ovarian tumors from metastatic ones. According to it, bilateral tumors of any size or <10 cm unilateral tumors are metastatic, whereas ≥10 cm unilateral tumors are primary ones. According to Yemelyanova et al, metastatic colorectal carcinomas behave as algorithm violators; as such tumors show up as large unilateral metastases which simulate primary ovarian tumors.[3,5] Our patient falls into this category, with a unilateral gross mass that resulted positive for ovarian carcinoma at the frozen section. We know that in such cases frozen sections might be hardly interpreted, not always being able to lead us to a correct diagnosis.[3]\n\nAs far as treatment is concerned, we had no certain indication. We decided to perform cytoreductive surgery with excision of the primary tumor by low anterior rectal resection, terminal colostomy, and complete hysterectomy with bilateral salpingo-oophorectomy, as literature advised. Indication for bilateral oophorectomy even in unilateral involvement was dictated by the late onset of metachronous metastasis to the contralateral ovary.[11] In the presence of evident metastatic disease which affects just the ovaries and has no peritoneal involvement, median survival is 61 months compared with 17-month median survival in women affected by concomitant peritoneal disease.[6,12] The Japanese guidelines for colorectal cancer treatment recommend surgery whenever primary and metastatic lesions are fully resectable.[13,14] Prophylactic oophorectomy during rectal surgery has a much more controversial role, considering that such procedure bears oncological advantages in premenopausal women, as they might not be prone to face the consequences of such procedure. On the contrary, menopausal women could often ask for the procedure, even though the benefits in this group are minor.[15,16] A combination of cytoreductive surgery and chemotherapy might increase the overall survival, especially in extra-ovarian metastases. It is widely acknowledged that ovarian metastases are less responsive to chemotherapy, as ovaries may act as a “sanctuary site” that presents a favorable microenvironment for tumor growth.[17]\n\nThe presence of ovarian metastatic disease is a marker of systemic involvement and represents a negative prognostic factor, in addition to lymphovascular invasion, combined metastases, and bilateral ovarian metastases. In difficult cases, even the evaluation of permanent sections can give a misdiagnosis, leading to incorrect oncological treatment.[8,15]\n\n4 Conclusions\nDifferential diagnosis between primary ovary tumors and colorectal ovarian metastases can be challenging, in particular, as preoperative biopsies are not often diagnostic. This situation leads the patient to the operating room without a precise diagnosis making it difficult to decide in advance which type of surgery to perform.\n\nIn ovarian masses that lack precise diagnosis, we are firmly convinced that colonoscopy is necessary to rule out the plausible colorectal origin.\n\nNonetheless, in many cases, surgery is not only therapeutic, but the only way to reach a precise assessment of the nature of ovarian mass. Only following final histopathologic diagnosis, appropriate systemic therapy can be carried out.\n\nImmunohistochemical staining is paramount in diagnosing ovarian metastatic tumors. We deeply encourage further studies on this issue, to set up a well-defined immunohistochemical diagnostic panel.\n\nAcknowledgment\nThe authors thank Daniela Masi, MD, for English editing.\n\nAuthor contributions\nConceptualization: Carolina Castro Ruiz, Erica Pavesi, Maurizio Zizzo, Lara Ugoletti, Valerio Annessi.\n\nData curation: Federico Biolchini, Carolina Castro Ruiz, Giovanni Musci, Erica Pavesi, Maurizio Zizzo.\n\nFormal analysis: Carolina Castro Ruiz, Giovanni Musci, Maurizio Zizzo.\n\nFunding acquisition: Carolina Castro Ruiz, Erica Pavesi.\n\nInvestigation: Lara Ugoletti.\n\nMethodology: Federico Biolchini, Carolina Castro Ruiz, Valerio Annessi.\n\nSoftware: Federico Biolchini, Giovanni Musci, Maurizio Zizzo.\n\nSupervision: Federico Biolchini, Giovanni Musci, Erica Pavesi, Valerio Annessi.\n\nValidation: Federico Biolchini, Carolina Castro Ruiz, Giovanni Musci, Maurizio Zizzo, Lara Ugoletti, Valerio Annessi.\n\nVisualization: Federico Biolchini, Carolina Castro Ruiz, Maurizio Zizzo, Lara Ugoletti, Valerio Annessi.\n\nWriting – original draft: Federico Biolchini, Carolina Castro Ruiz, Giovanni Musci, Erica Pavesi, Maurizio Zizzo, Lara Ugoletti.\n\nWriting – review & editing: Federico Biolchini, Carolina Castro Ruiz, Giovanni Musci, Erica Pavesi, Maurizio Zizzo, Lara Ugoletti, Valerio Annessi.\n\nCarolina Castro Ruiz orcid: 0000-0002-1594-1853.\n\nAbbreviations: Ca125 = carbohydrate antigen 125, Ca19.9 = carbohydrate antigen 19.9, CEA = carcinoembryonic antigen, CT scan = computed tomography scan, GI = gastrointestinal, H&E stain = hematoxylin and eosin stain.\n\nHow to cite this article: Biolchini F, Ruiz CC, Pavesi E, Musci G, Zizzo M, Ugoletti L, Annessi V. Diagnostic challenges in synchronous ovarian metastasis from rectal cancer. Medicine. 2019;98:44(e17782).\n\nFunding: Azienda Unità Sanitaria Locale–IRCCS di Reggio Emilia Research Founds.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Riihimäki M Hemminiki A Sudquist J \nPatterns of metastasis in colon and rectal cancer . Sci Rep \n2016 ;15 :1 –9 .\n[2] Kim DD Park IJ Kim HC Yu CS Kim JC \nOvarian metastases from colorectal cancer: a clinicopathological analysis of 103 patients . Colorectal Dis Jan ;11 :32 –38 .\n[3] Lewis MR Deavers MT Silva EG \nOvarian involvement by metastatic colorectal adenocarcinoma. Still a diagnostic challenge . Am J Surg Pathol \n2006 ;30 :177 –84 .16434891 \n[4] Hart WR \nDiagnostic challenge of secondary (metastatic) ovarian tumors simulating primary endometroid and mucinous neoplasm . Pathol Int \n2005 ;55 :231 –43 .15871720 \n[5] Yemelyanova AV Vang R Judson K \nDistinction of primary and metastatic mucinous tumors involving the ovary: Analysis of size and laterality data by primary site with reevaluation of an algorithm for tumor classification . Am J Surg Pathol \n2008 ;32 :128 –38 .18162780 \n[6] McCormick CC Giuntoli RL IIGardner GJ \nThe role of cytoreductive surgery for colon cancer metastatic to the ovary . Gynecol Oncol \n2007 ;105 :791 –5 .17408727 \n[7] Gagnier J Kienle G Altman DG \nthe CARE group . The CARE guidelines: consensus-based clinical case report guideline development . J Clin Epidemiol \n2014 ;67 :46 –51 .24035173 \n[8] Kim DD Park IJ Kim HC \nOvarian metastases from colorectal cancer: a clinicopathological analysis of 103 patients . Colorectal Dis \n2009 ;11 :32 –8 .18462217 \n[9] Erroi F Scarpa M Angriman I \nOvarian metastasis from colorectal cancer: prognostic value of radical oophorectomy . J Surg Oncol \n2007 ;96 :113 –7 .17443728 \n[10] Karaosmanoglu AD Onur MR Salman MC \nImaging in secondary tumors of the ovary . Abdom Radiol (NY) \n2018 ;[Epub ahead of print] .\n[11] Yamaguchi T Takahashi H Kagawa R \nThe role of prophylactic bilateral oophorectomy at the time of initial diagnosis of a unilateral ovarian metastasis in cases with colorectal adenocarcinoma . Hepatogastroenterology \n2008 ;55 :434 –7 .18613382 \n[12] Lee SJ Lee J Lim HY \nSurvival benefit from ovarian metastasectomy in colorectal cancer patients with ovarian metastasis: a retrospective analysis . Cancer Chemother Pharmacol \n2010 ;66 :229 –35 .19820936 \n[13] Watanabe T Muro K Ajioka Y \nJapanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer . Int J Clin Oncol \n2018 ;23 :1 –34 .28349281 \n[14] Mahmoud N Bullard Dunn K \nMetastasectomy for stage IV colorectal cancer . Dis Colon Rectum \n2010 ;53 :1080 –92 .20551764 \n[15] Banerjee S Kapur S Moran BJ \nThe role of prophylactic oophorectomy in women undergoing surgery for colorectal cancer . Colorectal Dis \n2005 ;7 :214 –7 .15859956 \n[16] Irons R McIntosh E Hageboutros A \nBilateral ovarian micrometastatic adenocarcinoma upon prophylactic oophorectomy concurrent with low anterior resection for rectal cancer . World J Surg Oncol \n2017 ;15 :40 –5 .28173877 \n[17] Sekine K Hamaguchi T Shoji H \nRetrospective analyses of systemic chemotherapy and cytoreductive surgery for patients with ovarian metastases from colorectal cancer: a single-center experience . Oncology \n2018 ;95 :220 –8 .30032147\n\n",
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"abstract": "A paradoxical reaction (PR) is an excessive immune response occurring during antitubercular therapy (ATT), but is rare in patients with miliary tuberculosis. A 78-year-old woman complained of general malaise, loss of appetite, and fever for 10 days. Chest computed tomography (CT) showed diffuse, bilateral, discrete miliary nodules. The patient was treated with ATT for miliary tuberculosis. Nine days after starting the treatment, she developed a spiking fever and worsening malaise. Repeat CT showed new localized ground-glass opacity (GGO) in the right upper lobe. After excluding possible etiologies, she was diagnosed with PR due to ATT. She was successfully managed with oral prednisolone while continuing ATT. The GGO diminished and did not recur after discontinuation of the steroids. We reviewed 28 reported cases of miliary tuberculosis with a PR in patients not infected with human immunodeficiency virus. Those not on immunosuppressive therapy were likely to develop a PR early. This case illustrates that a PR may present as localized GGO in miliary tuberculosis in the lung of patients treated with ATT. In cases of a PR with marked symptoms, steroid therapy may be valuable.",
"affiliations": "Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan.",
"authors": "Tokuyama|Yuki|Y|;Matsumoto|Takeshi|T|;Kusakabe|Yusuke|Y|;Yamamoto|Naoki|N|;Aihara|Kensaku|K|;Yamaoka|Shinpachi|S|;Mishima|Michiaki|M|",
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"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(19)30324-510.1016/j.idcr.2019.e00685e00685ArticleGround-glass opacity as a paradoxical reaction in miliary tuberculosis: A case report and review of the literature Tokuyama Yuki Matsumoto Takeshi mtakeshi@noe.saiseikai.or.jp⁎Kusakabe Yusuke Yamamoto Naoki Aihara Kensaku Yamaoka Shinpachi Mishima Michiaki Department of Respiratory Medicine, Saiseikai-Noe Hospital, Osaka, Japan⁎ Corresponding author at: Department of Respiratory Medicine, Saiseikai-Noe Hospital, 1-3-25 Furuichi, Jyoto-ku, Osaka, 536-0001, Japan. mtakeshi@noe.saiseikai.or.jp19 12 2019 2020 19 12 2019 19 e0068514 10 2019 28 11 2019 28 11 2019 © 2019 The Authors2019This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A paradoxical reaction (PR) is an excessive immune response occurring during antitubercular therapy (ATT), but is rare in patients with miliary tuberculosis. A 78-year-old woman complained of general malaise, loss of appetite, and fever for 10 days. Chest computed tomography (CT) showed diffuse, bilateral, discrete miliary nodules. The patient was treated with ATT for miliary tuberculosis. Nine days after starting the treatment, she developed a spiking fever and worsening malaise. Repeat CT showed new localized ground-glass opacity (GGO) in the right upper lobe. After excluding possible etiologies, she was diagnosed with PR due to ATT. She was successfully managed with oral prednisolone while continuing ATT. The GGO diminished and did not recur after discontinuation of the steroids. We reviewed 28 reported cases of miliary tuberculosis with a PR in patients not infected with human immunodeficiency virus. Those not on immunosuppressive therapy were likely to develop a PR early. This case illustrates that a PR may present as localized GGO in miliary tuberculosis in the lung of patients treated with ATT. In cases of a PR with marked symptoms, steroid therapy may be valuable.\n\nAbbreviations\nPR, paradoxical reactionATT, antitubercular therapyHIV, human immunodeficiency virusCT, computed tomographyGGO, ground-glass opacityKeywords\nParadoxical reactionMiliary tuberculosisMycobacterium tuberculosis\n==== Body\nIntroduction\nTuberculosis remains a common disease in both developing and developed countries. Although the global incidence of tuberculosis has been on the decline, the worldwide disease burden remains a major health problem. One-third of the world’s population is estimated to be infected with Mycobacterium tuberculosis, and 10% of these individuals develop active tuberculosis during their lifetime [1]. While treatment with appropriate antitubercular drugs is important, they have some characteristic complications. A paradoxical reaction (PR) is defined as transient worsening of pre-existing symptoms or appearance of new signs, symptoms, or radiographic manifestations of tuberculosis that occur after treatment initiation [2]. A PR can be diagnosed only after ruling out treatment failure, poor compliance, drug resistance, side effects of antitubercular therapy (ATT), or another infection. This phenomenon often occurs in individuals infected with human immunodeficiency virus (HIV), but it is not common in individuals who are HIV-negative [3]. A PR has been reported to occur in 2.4% of cases with pulmonary tuberculosis [4]. However, it is rare in miliary tuberculosis and has only been reported sporadically in case reports. Here we report a case of miliary tuberculosis in a HIV- negative patient who developed a PR during appropriate ATT and also discuss similar cases reported in the literature.\n\nCase report\nA 78-year-old woman presented to our hospital complaining of general malaise, loss of appetite for 2 weeks, and fever for 10 days. She had been diagnosed with pulmonary tuberculosis when she was in elementary school and had been treated with ATT, although the specific details of the therapy were unknown. She was admitted to our hospital for further investigation.\n\nPhysical examination revealed a heart rate of 78 beats/min; blood pressure of 153/80 mmHg; body temperature of 38.4 °C; and SpO2 of 97% (on room air). Chest auscultation revealed no rhonchi, crackles, or wheezes. A chest radiograph showed diffuse reticular nodule (Fig. 1), and computed tomography (CT) showed diffuse, bilateral, discrete miliary nodules (Fig. 2a). Laboratory findings revealed a hemoglobin level of 10.0 g/dl, white blood cell count of 4300 cells/mm3 with 67.6% neutrophils, and C-reactive protein level of 6.6 mg/dl.Fig. 1 Chest X-ray on admission showing diffuse reticular nodule.\n\nFig. 1Fig. 2 (a) Chest CT on admission showing diffuse, bilateral, discrete miliary nodules. (b) On day 9 of ATT, chest CT showing a new localized GGO in the right upper lobe. (c) On day 18, chest CT showing improvement of the GGO. (d) On day 28, chest CT showing no recurrence of the GGO after discontinuation of steroid therapy. Abbreviations: CT, computed tomography; ATT, antitubercular therapy; GGO, ground-glass opacity.\n\nFig. 2\n\nBronchoscopy was performed on the 2nd day after admission and revealed no specific abnormalities of the bronchial walls. Bronchial washings of the right upper lobe and transbronchial lung biopsies in subsegments B2b, B3a and B9 were performed. Sputum, blood, urine, bronchial lavage fluid, and lung tissue smears were negative for acid-fast bacilli. Polymerase chain reaction for M. tuberculosis DNA isolated from the bronchial lavage fluid was also negative.\n\nDespite negative test results for acid-fast bacilli, the patient was diagnosed with miliary tuberculosis on the basis of clinical history and radiological findings. She was subsequently started on a four-drug ATT comprising isoniazid (200 mg/day), rifampicin (300 mg/day), ethambutol (500 mg/day), and pyrazinamide (1000 mg/day), which temporarily improved her fever (Fig. 3). However, 9 days after starting ATT, she developed a spiking fever and worsening malaise. Repeat CT showed new localized ground-glass opacity (GGO) in the right upper lobe (Fig. 2b).Fig. 3 Hospital course depicting the patient’s fever and antitubercular therapy regimen. On day 33, because of a drug fever with eosinophilia and elevated liver enzyme levels (AST 176 U/l, ALT 120 U/l), antitubercular therapy was withdrawn for 1 week. Arrows and letters indicate when chest CT described in Fig. 2 was performed. Abbreviations: AST, aspartate aminotransferase; ALT, alanine aminotransferase.\n\nFig. 3\n\nSputum Gram staining and sputum and blood cultures were negative for secondary bacterial infection. Additional laboratory investigations revealed the following results: Krebs von den Lungen-6 level, 306 U/ml (normal level; <500 U/ml); surfactant protein-D level, 69.5 ng/ml (normal level; <110 ng/ml); procalcitonin level, 0.1 ng/ml; HIV-1 and -2 antibody, negative; and cytomegalovirus antigen, negative. Krebs von den Lungen-6 and surfactant protein-D are serum markers indicating the disease activity of interstitial pneumonia. Considering the clinical course and radiological worsening after initiation of ATT, she was considered to have a PR as a result of the therapy.\n\nBecause of her increased general fatigue, repeat bronchoscopy was waived, and she was managed with oral prednisolone at a dose of 25 mg/day while continuing ATT. Her fever and malaise gradually resolved. Eight days after the initiation of steroid therapy (18 days after the initiation of ATT), CT showed improvement in the GGO (Fig. 2c). Oral prednisolone was then tapered over a period of 2 weeks. Even after discontinuation of the steroid therapy, there was no recurrence of the GGO on follow-up CT (Fig. 2d).\n\nShe again experienced fever accompanied by eosinophilia and elevated liver enzyme levels; these findings were attributed to the drug fever. The ATT was ceased for 1 week, after which a modified regimen was administered (Fig. 3). She was discharged on day 63, and hyposensitization therapy for rifampicin was initiated. ATT with isoniazid (300 mg/day) and rifampicin (450 mg/day) was continued. On follow-up CT, the GGO had disappeared and the miliary nodule was improving.\n\nDiscussion\nA PR to ATT is a well-recognized phenomenon. In this case, an individual who was HIV-negative developed a localized GGO as a PR to ATT. Although her sputum smear was negative for acid-fast bacilli, the diagnosis of miliary tuberculosis was based on the clinical and radiological features as the sputum smear is reported to be positive in only one-third of patients with miliary tuberculosis [5]. The PR was successfully treated with a short course of steroids while ATT was continued, and the complication did not recur thereafter.\n\nOur patient developed worsening clinical and radiological features on day 9 of ATT. Bacteriological and serologic testing did not indicate any secondary infection. Drug-induced pneumonia secondary to the ATT seemed unlikely because the new GGO was unilateral and limited to the right upper lobe. It also supports the idea that serum markers, Krebs von den Lungen-6 and surfactant protein-D were normal. It did not recur with continuation of ATT even though the steroid therapy was discontinued. Exacerbation of miliary tuberculosis was also unlikely because the miliary nodule was seen to be improving with ATT. Therefore, we clinically diagnosed this phenomenon as a PR even though the patient’s condition did not allow bronchoscopy to be performed.\n\nIt has been postulated that the mechanism underlying a PR is local rebound immunological response. The destruction of mycobacteria and release of tubercular proteins invoke mixed type 1 and type 2 helper T-lymphocyte inflammatory responses [6]. The inflamed tissue becomes extremely sensitive to tumor necrosis factor-α, releasing cytokines that cause necrosis, first of the microvasculature and subsequently the whole tissue [6].\n\nTo our knowledge, besides our case, 28 cases of a PR in miliary tuberculosis in non-HIV-infected patients have been reported in the past 40 years (Table 1) [[7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32]]. The manifestations described depended on the site of involvement. It occurred most commonly in the central nervous system (39%), followed by skin (25%), lymph nodes (18%), bone and muscles (7%), lung (7%), and gastrointestinal tract (4%). However, there may be selection bias in the spectrum of findings in the PRs identified in these reports because unusual or severe cases are more likely to be reported. The occurrence of PR varied from a few days to a few months after initiation of ATT, although it was likely to occur earlier in patients not on immunosuppressive therapy. The outcome was generally good, although sequelae could occur with a central nervous system PR. Treatments included surgery and steroid administration. A PR in the lung is comparatively atypical and localized GGO is especially rare, although some cases of acute respiratory distress syndrome in miliary tuberculosis have been reported [[33], [34], [35]]. Our case illustrates that a PR in the lung may present with localized GGO. As in the other reports, our patient’s PR improved following administration of steroids with continued ATT.Table 1 Summary of paradoxical reactions in miliary tuberculosis among non-HIV infected patients.\n\nTable 1Author\tAge/sex\tImmunodeficiency\tPresentation of PR\tOnset after initiation of ATT\tAdditional treatment\tOutcome\t\nChambers et al. [7]\t34/M\tNone\tConvulsions and increase in previously noted brain lesions\t7 months\tAnticonvulsants\tImproved\t\nRietbroek et al. [8]\t64/F\tPrednisone and azathioprine for scleroderma and polymyositis\tSubcutaneous abscesses\t17 days\tDrainage\tImproved\t\nChen et al. [9]\t32/F\tSystemic lupus erythematosus\tSubcutaneous abscesses\t1 month\tNone\tImproved\t\nValdez et al. [10]\t28/M\tNone\tSubcutaneous abscesses\t2 months\tAspiration\tImproved\t\nBerg et al. [11]\t23/F\tAzathioprine and prednisone for dermatomyositis\tFever and abscesses of both thighs\t13 weeks\tFluid aspiration\tImproved\t\nMert et al. [12]\t37/F\tPrednisolone and methotrexate for rheumatoid arthritis and dermatomyositis\tSubcutaneous abscesses\t5 months\tDrainage\tImproved\t\nGarcia Vidal et al. [13]\t49/F\tInfliximab for rheumatoid arthritis\tFever and lymphadenopathy\t5 weeks\tSurgery\tImproved\t\nGarcia Vidal et al. [13]\t48/F\tInfliximab for rheumatoid arthritis\tLymphadenopathy\t8 weeks\tSurgery\tImproved\t\nToutous-Trellu et al. [14]\t81/F\tPrednisone and methotrexate for rheumatoid polyarthritis\tFever and skin ulcer\t6 weeks\tPrednisone\tImproved\t\nYoon et al. [15]\t38/M\tInfliximab and methylprednisolone for Crohn disease\tRight supraclavicular lymphadenopathy\t3 months\tSurgery\tImproved\t\nMelboucy-Belkhir et al. [16]\t56/F\tInfliximab for ankylosing spondylitis\tRight supraclavicular lymphadenopathy\t3 months\tPrednisolone and surgical excision\tImproved\t\nMatsuyama et al. [17]\t72/F\tDiabetes mellitus Prednisolone for systemic sclerosis\tLeft femur pain and swelling of lateral great adductor muscle abscess\t3 months\tPrednisolone increased\tImproved\t\nHassan et al. [18]\t29/F\tVitamin D deficiency\tAbscess of left knee\t4 months\tOral steroid\tImproved\t\nChaudhry et al. [19]\t31/F\tNone\tSpastic ataxia\t3 weeks\tPrednisolone\tImproved\t\nJorge et al. [20]\t20/M\tMethotrexate and infliximab for Juvenile idiopathic arthritis\tSevere cerebrospinal fluid and brain inflammatory reaction in pre-existing tuberculous meningitis\tNA\tCorticosteroids and infliximab\tImproved\t\nMorioka et al. [21]\t78/F\tPrednisolone for tuberculous meningitis\tDizziness and right temporal lobe infarct\t40 days\tExisting prednisolone\tImproved\t\nGupta et al. [22]\t18/M\tNone\tFever, cough, dyspnea, and pulmonary infiltration\t10 days\tPrednisone\tImproved\t\nDas et al. [23]\t22/F\tNone\tHeadache, vomiting, photophobia, and pain and erythema of the left eye; multiple small nodular and ring-enhancing lesions with edema in both cerebral hemispheres\t1 month\tDexamethasone and lamotrigine\tImproved\t\nDas et al. [23]\t10/F\tNone\tGeneralized tonic clonic seizures with right temporal conglomerated nodules and perilesional edema\t2 months\tOral phenytoin and prednisolone\tImproved\t\nYilmaz et al. [24]\t20/M\tNone\tDiminished visual acuity in the left eye due to a pre-existing choroidal tuberculoma\t7 days\tNone\tPersistent decrease in visual acuity\t\nKim et al. [25]\t76/F\tNone\tRight hemiparesis and increased size of pre-existing brain lesions\t1 month\tStopped pyrazinamide and craniotomy and mass resection\tImproved\t\nFalkenstern-Ge et al. [26]\t37/M\tAdalimumab for psoriatic arthritis\tFever and progressive bilateral pulmonary infiltrates\t6 weeks\tPrednisolone\tImproved\t\nXie et al. [27]\t55/F\tHigh-titer anti IFN-γ autoantibodies\tLytic lesions in the left humeral head\t14 weeks\tPrednisolone\tImproved\t\nSaitou et al. [28]\t61/M\tMethotrexate, tacrolimus, and prednisolone for dermatomyositis\tBowel perforation\t97 days\tSurgery\tImproved\t\nBacha et al. [29]\t21/M\tNone\tLeft cervical lymphadenopathy, pulmonary, pleural, costal and spinal location tuberculosis\t8 months\tNone\tImproved\t\nMin et al. [30]\t47/M\tNone\tSudden hearing loss, tinnitus in right ear, and multiple nodule in the brain parenchyma\t7 days\tAdded pyrazinamide and prednisolone\tPersistent hearing loss\t\nWakamiya et al. [31]\t63/M\tCyclosporine and mycophenolate mofetil for heart transplantation\tFever and confusion Cerebral tuberculomas in the subarachnoid space\t1 month\tDexamethasone\tImproved\t\nKim et al. [32]\t65/F\tTacrolimus, mycophenolate mofetil, and prednisolone for kidney transplantation\tIntramedullary enhancing spinal mass with sensory loss below T10 and marked motor weakness in both legs\t14 days\tSurgical resection of the spinal mass and prednisolone\tPartial motor paralysis\t\nOur case\t78/F\tNone\tPulmonary GGO\t9 days\tPrednisolone\tImproved\t\nAbbreviations: ATT, antitubercular therapy; GGO, ground-glass opacity; NA, not available.\n\n\n\nIn summary, we must recognize that in miliary tuberculosis being treated with ATT, a PR may present with a localized GGO in the lung. Patients without immunosuppression may be prone to developing a PR earlier than those who are immunosuppressed. In cases of PR with marked symptoms, steroid therapy may be valuable. More studies are necessary to decide the treatment course for a PR to ATT in miliary tuberculosis.\n\nAuthor contributions\nContribution to the study design: Y.T., T.M., Y.K., N.Y., K.A., S.Y., M.M.; Drafting the manuscript: Y.T., T.M.; Revising the manuscript critically: Y.T., T.M., Y.K., N.Y., K.A., S.Y., M.M.; Approval of the final version of manuscript: Y.T., T.M., Y.K., N.Y., K.A., S.Y., M.M. All authors meet the ICMJE authorship criteria.\n\nDeclaration of Competing Interest\nThe authors have no conflict of interest.\n\nAcknowledgement\nThe authors thank Enago (www.enago.jp) for the English language review.\n\nFunding\nThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\n==== Refs\nReferences\n1 Dheda K. Barry C.E. 3rd Maartens G. Tuberculosis Lancet 387 2016 1211 1226 26377143 \n2 Burman W.J. Jones B.E. Treatment of hiv-related tuberculosis in the era of effective antiretroviral therapy Am J Respir Crit Care Med 164 2001 7 12 11435232 \n3 Brown C.S. Smith C.J. Breen R.A. Ormerod L.P. Mittal R. Fisk M. Determinants of treatment-related paradoxical reactions during anti-tuberculosis therapy: a case control study BMC Infect Dis 16 2016 479 27600661 \n4 Cheng S.L. Wang H.C. Yang P.C. Paradoxical response during anti-tuberculosis treatment in hiv-negative patients with pulmonary tuberculosis Int J Tuberc Lung Dis 11 2007 1290 1295 18034948 \n5 Kim J.H. Langston A.A. Gallis H.A. Miliary tuberculosis: Epidemiology, clinical manifestations, diagnosis, and outcome Rev Infect Dis 12 1990 583 590 2385765 \n6 Grange J.M. Stanford J.L. Rook G.A. Tuberculosis and cancer: parallels in host responses and therapeutic approaches? Lancet 345 1995 1350 1352 7538622 \n7 Chambers S.T. Hendrickse W.A. Record C. Rudge P. Smith H. Paradoxical expansion of intracranial tuberculomas during chemotherapy Lancet 2 1984 181 184 6146749 \n8 Rietbroek R.C. Dahlmans R.P. Smedts F. Frantzen P.J. Koopman R.J. van der Meer J.W. Tuberculosis cutis miliaris disseminata as a manifestation of miliary tuberculosis: Literature review and report of a case of recurrent skin lesions Rev Infect Dis 13 1991 265 269 2041959 \n9 Chen C.H. Tsai J.J. Shih J.F. Perng R.P. Tuberculous subcutaneous abscesses developing during chemotherapy for pulmonary tuberculosis Scand J Infect Dis 25 1993 149 152 8460341 \n10 Valdez L.M. Schwab P. Okhuysen P.C. Rakita R.M. Paradoxical subcutaneous tuberculous abscess Clin Infect Dis 24 1997 734 9145751 \n11 Berg J. Leonard A. Clancy C.J. Nguyen M.H. Subcutaneous abscesses due to mycobacterium tuberculosis: Paradoxical expansion of disease during therapy for miliary tuberculosis Clin Infect Dis 26 1998 231 232 9455567 \n12 Mert A. Bilir M. Ozturk R. Tabak F. Ozaras R. Tahan V. Tuberculous subcutaneous abscesses developing during miliary tuberculosis therapy Scand J Infect Dis 32 2000 37 40 10716075 \n13 Garcia Vidal C. Rodriguez Fernandez S. Martinez Lacasa J. Salavert M. Vidal R. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis Clin Infect Dis 40 2005 756 759 15714425 \n14 Toutous-Trellu L. Charlet I. Hirschel B. Prins C. Masouye I. Vischer U.M. Tuberculous cutaneous ulcers associated with miliary tuberculosis in an elderly woman Case Rep Dermatol 1 2009 23 28 20652109 \n15 Yoon Y.K. Kim J.Y. Sohn J.W. Kim M.J. Koo J.S. Choi J.H. Paradoxical response during antituberculous therapy in a patient discontinuing infliximab: A case report J Med Case Rep 3 2009 6673 19830122 \n16 Melboucy-Belkhir S. Flexor G. Stirnemann J. Morin A.S. Boukari L. Polliand C. Prolonged paradoxical response to anti-tuberculous treatment after infliximab Int J Infect Dis 14 Suppl 3 2010 e333 4 20579914 \n17 Matsuyama T. 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A life-threatening central nervous system-tuberculosis inflammatory reaction nonresponsive to corticosteroids and successfully controlled by infliximab in a young patient with a variant of juvenile idiopathic arthritis J Clin Rheumatol 18 2012 189 191 22647865 \n21 Morioka H. Matsumoto S. Kojima E. Takada K. Iwata S. Okachi S. Paradoxical infarct in tuberculous meningitis: a case report Intern Med 51 2012 949 951 22504257 \n22 Gupta A. Srivastava V.K. Khanna V.N. Rizvi I. Paradoxical reaction to antitubercular therapy in miliary tuberculosis BMJ Case Rep 2012 2012 \n23 Das A. Das S.K. Mandal A. Halder A.K. Cerebral tuberculoma as a manifestation of paradoxical reaction in patients with pulmonary and extrapulmonary tuberculosis J Neurosci Rural Pract 3 2012 350 354 23188994 \n24 Yilmaz T. Selcuk E. Polat N. Mutlu K. Choroidal tuberculoma showing paradoxical worsening in a patient with miliary tb Ocul Immunol Inflamm 23 2015 97 99 25140405 \n25 Kim J.K. Jung T.Y. Lee K.H. Kim S.K. 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Cheikhrouhou S. paradoxical reaction following antituberculosis therapy in immunocompetent patient Rev Pneumol Clin 72 2016 367 372 27776947 \n30 Min S.K. Shin J.H. Mun S.K. Can a sudden sensorineural hearing loss occur due to miliary tuberculosis? J Audiol Otol 22 2018 45 47 29036759 \n31 Wakamiya A. Seguchi O. Shionoiri A. Kumai Y. Kuroda K. Nakajima S. Paradoxical reaction of tuberculosis in a heart transplant recipient during antituberculosis therapy: A case report Transplant Proc 50 2018 947 949 29661467 \n32 Kim Y. Kim S.P. Han S. Multiple tuberculomas invading the central nervous system as a paradoxical reaction in a kidney transplantation recipient Saudi J Kidney Dis Transpl 29 2018 719 722 29970752 \n33 Kim J.Y. Park Y.B. Kim Y.S. Kang S.B. Shin J.W. Park I.W. Miliary tuberculosis and acute respiratory distress syndrome Int J Tuberc Lung Dis 7 2003 359 364 12733492 \n34 Mohan A. Sharma S.K. Pande J.N. Acute respiratory distress syndrome (ards) in miliary tuberculosis: A twelve year experience Indian J Chest Dis Allied Sci 38 1996 157 162 8987289 \n35 Piqueras A.R. Marruecos L. Artigas A. Rodriguez C. Miliary tuberculosis and adult respiratory distress syndrome Intensive Care Med 13 1987 175 182 3584648\n\n",
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"keywords": "ATT, antitubercular therapy; CT, computed tomography; GGO, ground-glass opacity; HIV, human immunodeficiency virus; Miliary tuberculosis; Mycobacterium tuberculosis; PR, paradoxical reaction; Paradoxical reaction",
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"title": "Ground-glass opacity as a paradoxical reaction in miliary tuberculosis: A case report and review of the literature.",
"title_normalized": "ground glass opacity as a paradoxical reaction in miliary tuberculosis a case report and review of the literature"
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"abstract": "The prognosis for relapsed Hodgkin lymphoma after allogeneic hematopoietic cell transplantation (HSCT) is poor, partly because of limited treatment options. Here we present a case of a Hodgkin lymphoma patient who relapsed after allogeneic HSCT but remains in complete remission (CR) at 38 months from the start of extended brentuximab vedotin (BV) dosing. A 33-year-old man with refractory and relapsed nodular sclerosis classical Hodgkin lymphoma who underwent previous treatments, including adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) ; seven combination regimens; and autologous HSCT, prior to allogeneic HSCT achieved CR after three cycles of BV. BV was continued for 26 cycles and then discontinued because of a neurogenic bladder. The other adverse effects were mild paresthesia in the fingers, mild dysgeusia, and fatigue. The patient still remains in CR at 38 months from the start of BV. Thus, extended BV dosing may be a treatment option for relapsed and refractory Hodgkin lymphoma after allogeneic HSCT.",
"affiliations": "Department of Hematology, Kobe City Medical Center General Hospital.;Department of Hematology, Kobe City Medical Center General Hospital.;Department of Hematology, Kobe City Medical Center General Hospital.;Department of Hematology, Kobe City Medical Center General Hospital.;Department of Hematology, Hyogo Prefectural Amagasaki Hospital.;Department of Hematology, Kitano Hospital, The Tazuke Kofukai Medical Research Institute.;Department of Clinical Pathology, Kobe City Medical Center General Hospital.;Department of Hematology, Kobe City Medical Center General Hospital.",
"authors": "Ono|Yuichiro|Y|;Hiramoto|Nobuhiro|N|;Yoshioka|Satoshi|S|;Yabushita|Tomohiro|T|;Koba|Yusuke|Y|;Tabata|Sumie|S|;Imai|Yukihiro|Y|;Ishikawa|Takayuki|T|",
"chemical_list": "D018796:Immunoconjugates; D000079963:Brentuximab Vedotin",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.58.2397",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "58(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Allogeneic hematopoietic cell transplantation; Brentuximab vedotin; Extended dosing; Hodgkin lymphoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000328:Adult; D016026:Bone Marrow Transplantation; D000079963:Brentuximab Vedotin; D006689:Hodgkin Disease; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D012008:Recurrence; D012074:Remission Induction; D013997:Time Factors; D014184:Transplantation, Homologous",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "2397-2401",
"pmc": null,
"pmid": "29332873",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Durable remission attained by long-term brentuximab vedotin administration in a relapsed post-allogeneic bone marrow transplant Hodgkin lymphoma patient.",
"title_normalized": "durable remission attained by long term brentuximab vedotin administration in a relapsed post allogeneic bone marrow transplant hodgkin lymphoma patient"
} | [
{
"companynumb": "JP-MYLANLABS-2018M1058159",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
"drugadditional": null,
... |
{
"abstract": "Graves' disease (GD) is frequently associated with mild hypercalcemia. The hypercalcemia may be due to the activation of osteoclastic bone resorption caused by the excess thyroid hormone. In some cases of GD, the hypercalcemia can be attributable to concomitant parathyroid diseases. In this study, 21 patients with a history of GD developed parathyroid adenoma based on histology, intraoperative parathyroid hormone (IOPTH) monitoring, and other clinical features. There were 11 patients with a history of radioactive iodine therapy (RAI) for GD. The latency time of RAI was from 12 to 41 years. The case cohort was divided into two groups: patients with (group GR: 11 patients) and patients without a history of RAI (group G: 10 patients). Mean age of patients in group GR was 54.8 years compared to 62.2 years of group G (P = 0.08). There were no statistically significant differences regarding the parathyroid weight, serum calcium, and pre- and post-parathyroidectomy PTH levels. There was no histopathologic difference between the two groups. In conclusion, we report 21 cases of parathyroid adenoma in patients with Graves' disease. There may be a possible link between GD patients with a RAI history and an increased risk of parathyroid adenoma. The parathyroid adenomas showed no clinicopathological differences between GD patient with and without a history of RAI.",
"affiliations": "Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA, weishuanzeng@hotmail.com.",
"authors": "Wei|Shuanzeng|S|;Baloch|Zubair W|ZW|;LiVolsi|Virginia A|VA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s12022-014-9349-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1046-3976",
"issue": "26(1)",
"journal": "Endocrine pathology",
"keywords": null,
"medline_ta": "Endocr Pathol",
"mesh_terms": "D000236:Adenoma; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006111:Graves Disease; D006801:Humans; D049950:Hyperparathyroidism, Primary; D008297:Male; D008875:Middle Aged; D010282:Parathyroid Neoplasms; D016105:Parathyroidectomy; D012189:Retrospective Studies",
"nlm_unique_id": "9009288",
"other_id": null,
"pages": "71-4",
"pmc": null,
"pmid": "25501495",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article",
"references": "3754385;21043817;24144286;8506532;6689566;65676;6897129;1182664;12136811;9606286;18063066;17118839;16388525;67356;4161741;14715479;17693276;18322294;21848480",
"title": "Parathyroid adenoma in patients with Graves' disease: a report of 21 cases.",
"title_normalized": "parathyroid adenoma in patients with graves disease a report of 21 cases"
} | [
{
"companynumb": "US-CURIUM-2015000495",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditional": null,
... |
{
"abstract": "A 32-year-old man was admitted to our hospital with fever, chills, malaise, leukopenia, and a rash. About 3 weeks earlier, he'd had oral maxillofacial surgery and started a 10-day course of prophylactic amoxicillin/clavulanic acid. Fifteen days after the surgery, he developed a fever (temperature, 103° F), chills, arthralgia, myalgia, cough, diarrhea, and malaise. He was seen by his physician, who obtained a chest x-ray showing a lingular infiltrate. The physician diagnosed influenza and pneumonia in this patient, and prescribed oseltamivir, azithromycin, and an additional course of amoxicillin/clavulanic acid. Upon admission to the hospital, laboratory tests revealed a white blood cell count (WBC) of 3.1 k/mcL (normal: 3.2-10.8 k/mcL). The patient's physical examination was notable for lip edema, white mucous membrane plaques, submandibular and inguinal lymphadenopathy, and a morbilliform rash across his chest. Broad-spectrum antibiotics were initiated for presumed sepsis. On hospital day (HD) 1, tests revealed a WBC count of 1.8 k/mcL, an erythrocyte sedimentation rate of 53 mm/hr (normal: 20-30 mm/hr for women, 15-20 mm/hr for men), and a C-reactive protein level of 6.7 mg/dL (normal: <0.5 mg/dL). A repeat chest x-ray and orofacial computerized tomography scan were normal. By HD 3, all bacterial cultures were negative, but the patient was positive for human herpesvirus-6 on viral cultures. His leukopenia persisted and he had elevated levels of alanine transaminase ranging from 40 to 73 U/L (normal: 6-43 U/L) and aspartate aminotransferase ranging from 66 to 108 U/L (normal range: 10-40 U/L), both downtrending during his hospitalization. He also had elevated levels of antinuclear antibodies and anti-Smith antibody titers. A posterior-auricular biopsy was consistent with lymphocytic perivasculitis. The rash continued to progress, involving his chest, abdomen, and face. Bacterial and viral cultures remained negative and on HD 4, broad-spectrum antibiotics were discontinued.",
"affiliations": "Womack Army Medical Center, Fort Bragg, NC, USA. Email: robertgauer@yahoo.com.;160th Special Operations Aviation Regiment, Fort Campbell, KY, USA.;Department of Research, Fort Bragg, NC, USA.",
"authors": "Gauer|Robert|R|;Hu|Collin|C|;Beaman|Lindsey|L|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0094-3509",
"issue": "66(10)",
"journal": "The Journal of family practice",
"keywords": null,
"medline_ta": "J Fam Pract",
"mesh_terms": "D000328:Adult; D063926:Drug Hypersensitivity Syndrome; D005076:Exanthema; D005334:Fever; D006801:Humans; D007970:Leukopenia; D008297:Male",
"nlm_unique_id": "7502590",
"other_id": null,
"pages": "E7-E10",
"pmc": null,
"pmid": "28991941",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Fever, rash, and leukopenia in a 32-year-old man · Dx?",
"title_normalized": "fever rash and leukopenia in a 32 year old man dx"
} | [
{
"companynumb": "US-MICRO LABS LIMITED-BB2017-01521",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"dr... |
{
"abstract": "BACKGROUND\n• Metabolic disturbances represent a well-known side effect of second generation antipsychotics. However, studies comparing second generation antipsychotic drugs (SGAPs) and first generation antipsychotic drugs (FGAPs) through administrative databases have shown contrasting findings, which may be attributable to methodological differences.\n\n\nCONCLUSIONS\n• The definition of antipsychotic exposure impacts on the association between antipsychotics and metabolic risk in studies carried out through administrative databases. • Considering cumulative exposure to antipsychotics or including patients exposed to an antipsychotic drug for months or years is likely to over-represent patients who tolerate the drug well with a depletion of susceptible effects. • Antipsychotic drug exposure is a time-varying determinant and episodes of no use, past use and current use should be distinguished over the study period to avoid any misclassification bias that might lead to misleading findings.\n\n\nOBJECTIVE\nTo assess the influence of three definitions of antipsychotic exposure on the comparison between first generation (FGAP) and second generation (SGAP) antipsychotic drugs and 'conventional' mood stabilizers towards the risk of metabolic events using (i) a dichotomous measure (exposed/non-exposed over the follow-up), (ii) a categorical measure taking into account the chronology of exposure at the time of the metabolic event (current, recent and no use) and (iii) a continuous measure (cumulative duration).\n\n\nMETHODS\nA historical fixed cohort was identified from the 2004-2006 claims database of the French health insurance programme for self-employed workers, including 3172 patients aged 18 years and over who used conventional mood stabilizers over a 3 month period. A metabolic event was defined as an incident dispensing of an anti-diabetic or lipid-lowering drug.\n\n\nRESULTS\nA metabolic event occurred in 367 patients (11.6%). At least one FGAP had been prescribed in 29% of patients who did not develop a metabolic event and in 22% of patients who developed a metabolic event. In addition, at least one SGAP had been prescribed in 12% of patients who did not develop a metabolic event and in 7% of patients who developed a metabolic event. Compared with conventional mood stabilizers, the risk of a metabolic event was negatively associated with exposure to SGAPs over the follow-up period (HR 0.53, 95% CI 0.34, 0.82, P= 0.004), positively associated with recent, but not current, exposure to SGAPs (HR 2.1, 95% CI 1.2, 3.7, P= 0.006) and not associated with cumulative duration of SGAPs (HR 1.001, 95% CI 0.999, 1.003, P= 0.20).\n\n\nCONCLUSIONS\nThe definition of exposure to antipsychotics in epidemiological studies exploring their metabolic impact is of paramount importance in understanding this association. Different definitions can lead to opposite and seemingly nonsensical results. Not taking into account past exposure, in order to minimize the depletion of susceptible effects, may lead to absurd results.",
"affiliations": "Université de Bordeaux, U657, France. mtournier@ch-perrens.fr",
"authors": "Tournier|Marie|M|;Bégaud|Bernard|B|;Cougnard|Audrey|A|;Auleley|Guy-Robert|GR|;Deligne|Jean|J|;Blum-Boisgard|Claudine|C|;Thiébaut|Anne C M|AC|;Verdoux|Hélène|H|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "England",
"delete": false,
"doi": "10.1111/j.1365-2125.2012.04184.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "74(1)",
"journal": "British journal of clinical pharmacology",
"keywords": null,
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D015331:Cohort Studies; D016208:Databases, Factual; D005260:Female; D005602:France; D044882:Glucose Metabolism Disorders; D006801:Humans; D052439:Lipid Metabolism Disorders; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders; D012307:Risk Factors; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "189-96",
"pmc": null,
"pmid": "22257309",
"pubdate": "2012-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "18752718;16970993;18258416;20358262;18311417;10553730;18052561;16936169;20059452;8884164;18056625;20178092;19133915;18286870;12654411;15372671;22275442;12153919;16808554;9333345;15995903;19178394;16356695;12418935;16889448;17192159;7722586;11099280;15066683;11779284;18512735",
"title": "Influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood-stabilizers.",
"title_normalized": "influence of the drug exposure definition on the assessment of the antipsychotic metabolic impact in patients initially treated with mood stabilizers"
} | [
{
"companynumb": "FR-JNJFOC-20161021207",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RISPERIDONE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nSmall cell carcinoma of the ovary hypercalcemic type (SCCOHT) is a rare tumor with a peak incidence in young adulthood that historically has carried a poor prognosis.\n\n\nMETHODS\nWe present 2 advanced stage cases of SCCOHT in preadolescents successfully treated with a combination of cisplatin-based chemotherapy and surgical resection. The more recent patient also underwent consolidative high-dose chemotherapy with stem cell rescue and external beam radiotherapy. Her therapy was concluded with a maintenance course of bevacizumab. The patients are now disease-free 7 years and 30 months, respectively, after diagnosis.\n\n\nCONCLUSIONS\nWith aggressive multimodal therapy SCCOHT is curable in children.",
"affiliations": "Departments of *Pediatrics, Division of Hematology-Oncology †Pathology and Laboratory Medicine, Children's Hospital of Alabama, University of Alabama at Birmingham, Birmingham, AL.",
"authors": "Pressey|Joseph G|JG|;Kelly|David R|DR|;Hawthorne|Heather T|HT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0b013e318282cca8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "35(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D018288:Carcinoma, Small Cell; D002648:Child; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D008279:Magnetic Resonance Imaging; D009367:Neoplasm Staging; D010051:Ovarian Neoplasms; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "566-9",
"pmc": null,
"pmid": "23459374",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type.",
"title_normalized": "successful treatment of preadolescents with small cell carcinoma of the ovary hypercalcemic type"
} | [
{
"companynumb": "US-ROCHE-1304172",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Isolated mitochondrial myopathy refers to the condition of mitochondrial disorders that primarily affect the skeletal muscle system. Here we report on a case of a patient who presented with acute respiratory failure as the initial and predominant clinical manifestation after using anesthetic drugs. The diagnosis of mitochondrial myopathy was made by histochemical findings of ragged red fibers with a modified Gomori trichrome Stain in the skeletal muscle biopsy and the genetic detection of an A3243G point mutation in the tRNALeu (UUR) gene of mitochondrial DNA (mtDNA) in a peripheral blood specimen. The patient revealed a benign clinical outcome with ventilator assistance and a cocktail treatment. Further, we performed a literature review on patients with respiratory failure as the early and predominant manifestation in adult-onset isolated mitochondrial myopathy. Eleven cases in nine studies (including our case) have been reported, and five of whom underwent DNA analysis all harbored the A3243G mutation in the tRNALeu gene of the mtDNA. Use of sedative drugs tends to induce acute respiratory failure in such cases.",
"affiliations": "Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.;Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.;Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.;Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.;Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.;Department of Neurology, Huashan Hospital, Fudan University, Shanghai, China.;Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China.",
"authors": "Pan|Xiaoli|X|;Wang|Lijun|L|;Fei|Guoqiang|G|;Dong|Jihong|J|;Zhong|Chunjiu|C|;Lu|Jiahong|J|;Jin|Lirong|L|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2019.00780",
"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2019.00780NeurologyCase ReportAcute Respiratory Failure Is the Initial Manifestation in the Adult-Onset A3243G tRNALeu mtDNA Mutation: A Case Report and the Literature Review Pan Xiaoli 1†Wang Lijun 12†Fei Guoqiang 1†Dong Jihong 1Zhong Chunjiu 1Lu Jiahong 3*Jin Lirong 1*1Department of Neurology, Zhongshan Hospital & Shanghai Medical College, Fudan University, Shanghai, China2Department of Neurology & Co-innovation Center of Neurodegeneration, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China3Department of Neurology, Huashan Hospital, Fudan University, Shanghai, ChinaEdited by: Rosanna Cardani, Policlinico San Donato (IRCCS), Italy\n\nReviewed by: Antonio Di Muzio, Università degli Studi G. d'Annunzio Chieti e Pescara, Italy; Lorenzo Maggi, Neurological Institute Foundation Carlo Besta, Italy\n\n*Correspondence: Jiahong Lu lujiahong@yahoo.comLirong Jin jinlr99@163.comThis article was submitted to Neuromuscular Diseases, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n18 7 2019 2019 10 78021 3 2019 03 7 2019 Copyright © 2019 Pan, Wang, Fei, Dong, Zhong, Lu and Jin.2019Pan, Wang, Fei, Dong, Zhong, Lu and JinThis 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.Isolated mitochondrial myopathy refers to the condition of mitochondrial disorders that primarily affect the skeletal muscle system. Here we report on a case of a patient who presented with acute respiratory failure as the initial and predominant clinical manifestation after using anesthetic drugs. The diagnosis of mitochondrial myopathy was made by histochemical findings of ragged red fibers with a modified Gomori trichrome Stain in the skeletal muscle biopsy and the genetic detection of an A3243G point mutation in the tRNALeu (UUR) gene of mitochondrial DNA (mtDNA) in a peripheral blood specimen. The patient revealed a benign clinical outcome with ventilator assistance and a cocktail treatment. Further, we performed a literature review on patients with respiratory failure as the early and predominant manifestation in adult-onset isolated mitochondrial myopathy. Eleven cases in nine studies (including our case) have been reported, and five of whom underwent DNA analysis all harbored the A3243G mutation in the tRNALeu gene of the mtDNA. Use of sedative drugs tends to induce acute respiratory failure in such cases.\n\nmitochondrial myopathyA3243G mutationrespiratory failuremtDNAsedative drugNational Natural Science Foundation of China10.13039/501100001809grant no. 91332201\n==== Body\nIntroduction\nMitochondria are the cellular organelles responsible for energy production, especially by completing oxidative phosphorylation. Organ systems that rely most on aerobic metabolism, such as the brain, heart and the skeletal muscle, are more inclined to be influenced by mitochondrial dysfunction. Mitochondrial disease affects multiple organs with various severity, ranging from skeletal muscles alone, or the central nervous system to multiorgan system impairment with myopathy, and presents with heterogeneous clinical manifestations (1). The term of isolated mitochondrial myopathy refers to the condition where mitochondrial disorders primarily affect the skeletal muscle system. The clinical features of isolated mitochondrial myopathy can be highly variable, including mild exercise intolerance, fatigue, muscle weakness, myalgia, mild elevated serum creatine kinase and more rare, rhabdomyolysis (2).\n\nRespiratory failure in mitochondrial myopathy usually occurs at the late stage of the disease, and is associated with deterioration of respiratory muscle weakness (3, 4). However, an acute episode of respiratory failure as the initial and predominant clinical feature in adult-onset mitochondrial myopathy is rarely reported and is easily misdiagnosed as other neuromuscular disorders, such as Guillain-Barre syndrome (GBS) and myasthenia gravis (MG). Here we report on a 52-years-old man who presented with acute respiratory failure as the initial and predominant manifestation after receiving a painless gastroscopy and colonoscopy examination with use of anesthetic drugs. He was diagnosed with mitochondrial myopathy by histochemical findings of ragged red fibers (RRF) in the skeletal muscle biopsy and an A3243G point mutation of the mitochondrial tRNALeu gene in a peripheral blood specimen. Further, we performed a literature review on clinical features of adult-onset isolated mitochondrial myopathy with abrupt episodes of respiratory dysfunction as the early and predominant manifestation. Eleven cases have been reported in nine studies (including our study), and five of whom received DNA analysis all carried the A3243G mutation in the tRNALeu gene of the mtDNA (3, 5–11).\n\nCase Report\nA 52-years-old man was transferred to our intensive care unit in July 2016 because of an acute episode of respiratory failure after using anesthetic drugs 8 days earlier. He felt easily fatigued and developed insidiously limb weakness in the previous 6 months. He attributed this to toothache resulting in a poor appetite. However, he was still able to maintain his daily life and keep on working. His family noticed that he lost 7.5 kg of body weight in 6 months and took him to the gastroenterology department of a local hospital. He received a painless gastroscopy and colonoscopy examination using propofol on 19 July 2016. He regained consciousness very slowly for over forty min and was found to have hypoxemia with a blood oxygen saturation degree (SO2) of 86%. After expectant treatment of oxygen inhalation, he recovered to a relative stable condition and drove home. He developed increasing shortness of breath in the following days, which eventually deteriorated into acute respiratory failure. Arterial blood gas (ABG) analysis showed a pH of 7.25, and a PaCO2 of 86.25 mmHg. Although the PaO2 level was in a normal range by treatment of oxygen inhalation, the diagnosis of type II respiratory failure was considered because of hypercapnia. A pulmonary function test suggested a moderate restrictive ventilator impairment. No evidence of pneumonia or bronchitis was found through Computed Tomography (CT) scanning. Since he developed recurrent episodes of hypoxemia, hypercapnia and delirium, he received artificial ventilatory assistance on July 26th. Next day, he was transferred to our hospital.\n\nHe denied a family history of neuromuscular disease, central nervous system dysfunction, genetic disorders, diabetes mellitus, or vision and hearing dysfunction. His mother was emaciated and suddenly passed away of unknown reason at the age of 60. His siblings were reportedly healthy.\n\nOn admission the patient was in a mild agitated state. He looked very thin and his height was 1.65 meters and weighed 47 Kg. His body temperature was 36.8°C, pulse rate 90/min, respiratory rate 25/min, and blood pressure 116/69 mmHg. The SO2 level was 100% with oxygen inhalation by nasal mask at 3.0 L/min. No abnormality was found in the respiratory and cardiovascular systems. A neurological examination showed that cranial nerves function was normal. There was no ptosis, external ophthalmoplegia, diplopia or facial weakness. The proximal upper and lower limb muscle power was mildly decreased (Medical Research Council grading criterion, grade IV) and his distal muscle strength was approximately normal. His tendon reflexes were diminished. No abnormalities in the long tract, sensitive system, meningeal irritation or cerebellar signs were noted.\n\nLaboratory investigations revealed normal levels of liver function, kidney function, blood glucose, blood ammonia, serum electrolytes, blood clotting function, serum creatine phosphokinase, thyroid function, rheumatologic antibodies, tumor biomarkers, folate, and vitamin B12. The peripheral white blood cell count was normal, but the percent of segmented neutrophils increased to 84.6%. ABG analysis showed a pH of 7.24, a PaCO2 of 120 mmHg and a PaO2 of 198 mmHg with O2 inhalation. Blood lactate level at rest in the first test of our hospital was normal but fluctuated from normal to >12 mmol/L (0.7–2.1 mmol/L) in the successive tests. Because of a presumptive diagnosis of myasthenic crisis, he received pyridostigmine for a week without any improvement. No abnormalities were found in the levels of the serum anti-acetylcholine receptor (AChR) antibodies.\n\nElectrocardiogram, a computed tomography scan of the chest and Magnetic Resonance Imaging of the head and cervical spinal cord were normal (Figure S1). There was no abnormality in the repetitive nerve stimulation examination and the motor and sensory nerve conduction velocity. Needle electromyography (EMG) revealed small, short-duration and polyphasic motor unit action potentials in the musculus biceps brachii, deltoid, quadriceps femoris, sternocleidomastoid and rectus abdominis bilaterally, which is consistent with myopathic disorders. Tandem mass spectrometry analysis for organic acid in blood and urine was performed to detect lipid storage myopathy and the results remained in a normal range.\n\nA muscle biopsy of the left musculus biceps brachii was performed. Myopathic alterations were observed but no evidence of obvious inflammation, necrosis and degeneration was found. The fiber size was variable and fiber shapes were mildly irregular by Hematoxylin-eosin staining (Figure 1). Some RRF were evident as shown in Figure 1. Increased enzyme activities in some muscle fibers were observed using cytochrome c oxidase (COX). Expressions of MHC-I, R, C, N-dystrophin, α, β, γ-sarcoglycan, and dysferlin were normal. No abnormalities were seen in the staining of NADH, Periodic Acid Schiff (PAS), oil red O (ORO), and Adenosine Triphosphate (ATP) synthase. Screening for putative point mutation by polymerase chain reaction (PCR) revealed an A3243G mutation (88%) in the mitochondrial tRNALeu gene from total DNA extracted from the peripheral blood specimen (Figure 2).\n\nFigure 1 The fiber size was variable and fiber shapes were mildly irregular in Hematoxylin-eosin staining. There was one clear RRF (×20), bar = 100μ.\n\nFigure 2 Mitochondrial DNA sequencing revealed the A3243G point mutation in the mitochondrial tRNALeucine gene.\n\nAccording to the findings of EMG and muscle biopsy, the patient was diagnosed as mitochondrial myopathy with mtDNA A3243G point mutation. He was given a cocktail treatment of vitamin-C, B1, riboflavin, coenzyme Q10, cobamamide, and L-carnitine. Non-invasive ventilatory support with bilevel positive airway pressure (BiPAP) therapy via a basal mask was continued for 22 days, and then the artificial ventilator assistance was only used at night. The follow-up ABG analysis results were normal. His mental state, body weight and exercise tolerance improved gradually. He was discharged with the ventilator. The patient was reviewed for more than 2 years. Nocturnal BiPAP had been well-tolerated and ABG analysis was performed every 2 weeks. His limb power regained to the normal extent and his weight increased to 60 kg.\n\nDiscussion\nHere we report on a case of a 52-years-old man who presented with acute respiratory failure as the predominant clinical manifestation after using anesthetic drugs. He was able to maintain daily activity in spite of developing mild exercise intolerance and being easily fatigued before his admission. The patient was diagnosed with mitochondrial myopathy on the basis of the pathological findings of RRF in a muscle biopsy and genetic analysis of an A3243G point mutation in the tRNALeu (UUR) gene of mitochondrial DNA (mtDNA). He recovered gradually using ventilator assistance and a cocktail treatment and revealed a benign clinical outcome.\n\nSo far, adult-onset mitochondrial myopathy with acute episodes of respiratory failure as the early and predominant manifestation has rarely been reported. Only 11 cases including four males and seven females, in nine studies have been described (including our case, listed in Table 1) (3, 5–11). The onset age of the cases range widely from 16 to 70 years of age and all denied a history of mitochondrial myopathy. Although several cases reveled increased levels of serum creatine phosphokinase and lactate, the increased extent remains 2- or 3-fold of the normal level, which is different to other types of myopathy, such as inflammatory myopathies.\n\nTable 1 Literature review on Respiratory failure as the predominant manifestation in adult-onset mitochondrial myopathy.\n\nAuthor\tNo.\tSex\tAge\tFamily history\tOnset of age\tLactate (mmol/L)\tCreatine kinase (U/L)\tPulmonary function/arterial blood gas analysis\tElectromyography\tMuscle biopsy\tGenetic or biochemical analysis\t\nKim et al. (5)\t2\tFemale\t16\tNo\t16\t3.6 (0.5–2.2)\t–\tBoth Type II respiratory failure\tMyopathic alteration\tMitochondrial myopathy\t–\t\n\t\tMale\t22\tNo\t19\t–\tNormal\t\t\t\t–\t\nCros et al. (3)\t2\tMale\t56\tNo\t56\tNormal\tCase I: mild elevated (three times normal)\tCase I: V/Q mismatching and alveolar hypoventilation;\tCase I: Normal\tMitochondrial myopathy\tCase I: Cytochrome oxidase deficiency;\t\n\t\tFemale\t70\tNo\t70\tNormal\tCase II: Normal\tCase II: restrictive ventilator impairment\tCase II: Myopathic alteration\t\tCase II: succinate-cytochrome c reductase defect\t\n\t\t\t\t\t\t\t\tBoth Type II respiratory failure\t\t\t\t\nO'Brien et al. (6)\t1\tFemale\t27\tNo\t27\tNormal\tNormal\tRestrictive ventilatory defect/Type II respiratory failure\tNormal\tMitochondrial myopathy\tCytochrome oxidase deficiency\t\nYang et al. (7)\t1\tFemale\t55\tNo\t55\t3.0\tNormal\tMild restrictive ventilatory defect/Type II respiratory failure\tMyopathic alteration\tMitochondrial myopathy\tm.3243A>G\t\nChang et al. (8)\t1\tMale\t32\tNo\t30\t2-fold of normal\t2-fold of normal\tType II respiratory failure\tNormal\tMitochondrial myopathy\tm.3243A>G\t\nGuo et al. (10)\t1\tFemale\t47\tNo\t45\t3.3 (0.4–1.7)\t208 (18–198)\tRestrictive ventilatory defect/Type II respiratory failure\tMyopathic alteration\tMitochondrial myopathy\t–\t\nAmornvit et al. (9)\t1\tFemale\t20\tNo\t20\t9.1 (0.5–2.2)\tNormal\tMild restrictive ventilatory defect\tMyopathic alteration\tMitochondrial myopathy\tm.3243A>G\t\nNaddaf and Milone (11)\t1\tFemale\t42\tNot mentioned\tNot mentioned\tNot mentioned\t1.2 times upper limit of normal\tRestrictive ventilatory defect\tMyopathic alteration\tMitochondrial myopathy\tm.3243A>G\t\nThe case reported here\t1\tMale\t52\tNo\t52\tNormal\tNormal\tModerate restrictive ventilatory defect\tMyopathic alteration\tMitochondrial myopathy\tm.3243A>G\t\nAll the cases presented with type II respiratory failure, the condition of hypercapnia and hypoxemia coexisting simultaneously, as the initial and predominant clinical manifestation on their admission. The patients may present with mild muscle weakness and exercise intolerance before, but these conditions were not the main complaints of their admission to the hospital. The pulmonary function test usually showed restrictive ventilatory defects. Most of the patients needed artificial ventilator assistance on admission. They were finally diagnosed with mitochondrial myopathy by muscular biopsy, biochemical and genetic analysis. RRF and abnormal mitochondria were mostly observed in the muscle biopsy and altered enzyme activities associated with the respiratory chain in mitochondria were found in the biochemical analysis in some cases.\n\nWe note that the same mutation, the m.3243A>G point mutation of mtDNA, was detected in five cases who received genetic determination. Population-based studies suggest the m.3243A>G mutation is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people (12, 13). Studies have shown that mitochondrial disease remains the considerable variation in clinical features in patients with the m.3243A>G mutation. The m.3243A>G mutation is responsible for several classical syndromes, such as mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD), progressive external ophthalmoplegia (PEO) and Leigh syndrome. Other clinical phenotypes of mitochondrial disorders that cannot be classified as the above syndromes also detect this mutation, including isolated myopathy, cardiomyopathy, seizures, migraine, ataxia, cognitive impairment, bowel dysmotility and short stature (14). The A to G substitution leads to the pre termination of transcription and expression impeding of normal rRNA, thus compromising mitochondrial protein synthesis, ATP production and organic metabolism (15). Besides the A3243G mutation, the genetic defects of isolated myopathies can be caused by other abnormalities of mtDNA or nuclear DNA (nDNA) that affects the mitochondrial respiratory chain, such as m5698G>A, m618T>C, m5543T>C, 7526A>G in tRNA, thymidine kinase 2 (TK2) gene, or CoQ deficiency (16–21).\n\nExercise intolerance is the most common clinical feature in isolated mitochondrial myopathy. More often, respiratory failure occurs when the disease deteriorates to advanced periods (22). The sudden episodes of respiratory failure caused by isolated mitochondrial myopathies in the early stage is rarely described and easily misdiagnosed. Nine studies have reported 11 cases (including the case reported here) that were diagnosed with isolated mitochondrial myopathy with respiratory insufficiency as the primary and earliest clinical feature. Notably, the reduced hypoxic and hypercapnic ventilatory responses were out of proportion to their mild limb weakness. The specific mechanism of respiratory hypoventilation in mitochondrial myopathy is still unclear. Two possible pathophysiologic mechanisms may be involved in these patients: abnormality of the respiratory drive due to dysfunction of the respiratory centers in the brain stem (23, 24); weakness of the primary inspiratory muscles because of the mitochondrial insufficiency (5). Carroll et al. presumed that the depressed ventilatory drive of patients with mitochondrial myopathies was due to a CNS abnormality, possibly at the brainstem level (23). This was based on the lack of sufficient weakness to account for decreased ventilation, which was verified by Barohn et al.'s study (24). In addition, Kamakura et al. speculated that the increased abnormal mitochondria in the diaphragm may be involved in the recurrent episodes of respiratory failure (25).\n\nOn the basis of the unique clinical manifestation and the findings of the pulmonary tests of such patients, Amornvit has postulated that isolated mitochondrial myopathy predominantly affecting the respiratory muscles may be considered an uncommon clinical spectrum of the A3243G mitochondrial disease (9). Our study added new evidence to this rare clinical condition. Since acute episodes of respiratory failure caused by respiratory muscle weakness are life-threatening, isolated mitochondrial myopathy should be considered when no evidence of other neuromuscular disease exists, such as GBS, MG, Glycogen storage disease type II, and collagen VI disorders. Hence, isolated mitochondrial myopathy should be added to the differential diagnoses of neuromuscular respiratory failure.\n\nNotably, the case in our study and another case reported in Yang's study (7) both presented with respiratory failure and a history of specific drug use, such as hypnotic and narcotic. The exact mechanism of how the sedative drugs induced the development of respiratory failure in insidious mitochondrial myopathy patients is unknown. Caroll and Barohn both observed that the depressed ventilatory drive of patients with mitochondrial myopathy was attributed to abnormalities in the respiratory control system located in the brain stem (23, 24). Since sedative drugs suppress the central nervous system, this may aggravate the reduced response to hypoxemia and hypercapnia. More attention should be paid on the prescription of sedative drugs in patients with isolated myopathy, who are inclined to respiratory failure.\n\nConclusion\nIn conclusion, the case reported here presented with acute respiratory failure as the initial and predominant manifestation and the A3243G point mutation of mtDNA in isolated myopathy was detected. We expanded the evidence on a very uncommon condition, as a rare spectrum of isolated mitochondrial myopathy with the A3243G point mutation. Use of sedative drugs tends to induce respiratory failure in such cases.\n\nData Availability\nThe datasets generated for this study are available on request to the corresponding author.\n\nEthics Statement\nThe study was approved by the Committee on Medical Ethics of Zhongshan Hospital, Fudan University. Written informed consent was obtained from the patient for the publication of this case report. As this is a case report, without experimental intervention into routine care, no formal research ethics approval was required.\n\nAuthor Contributions\nLJ and JL designed the case report. XP, LW, and GF performed the histochemical studies and wrote the article. JD performed the muscle biopsy. CZ revised the manuscript. All authors contributed to the manuscript revision and approved the final manuscript.\n\nConflict of Interest Statement\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nWe gratefully acknowledge the patient and his family for the contribution to this study.\n\nFunding. This study was supported by the National Natural Science Foundation of China (grant no. 91332201) and the National Natural Science Foundation for Young Scientists of China (grant no. 81600930).\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2019.00780/full#supplementary-material\n\nFigure S1 No abnormality was found in the head MRI scan.\n\nClick here for additional data file.\n==== Refs\nReferences\n1. Scheffler IE . A century of mitochondrial research: achievements and perspectives . Mitochondrion. (2001 ) 1 :3 –31 . 10.1016/S1567-7249(00)00002-7 16120266 \n2. DiMauro S Gurgel-Giannetti J . The expanding phenotype of mitochondrial myopathy . Curr Opin Neurol. (2005 ) 18 :538 –42 . 10.1097/01.wco.0000179761.63486.1a 16155436 \n3. Cros D Palliyath S DiMauro S Ramirez C Shamsnia M Wizer B . Respiratory failure revealing mitochondrial myopathy in adults . Chest. (1992 ) 101 :824 –8 . 10.1378/chest.101.3.824 1541151 \n4. Bennett DA Bleck TP . Diagnosis and treatment of neuromuscular causes of acute respiratory failure . Clin Neuropharmacol. (1988 ) 11 :303 –47 . 10.1097/00002826-198808000-00002 3061636 \n5. Kim GW Kim SM Sunwoo IN Chi JG . Two cases of mitochondrial myopathy with predominant respiratory dysfunction . Yonsei Med J. (1991 ) 32 :184 –9 . 10.3349/ymj.1991.32.2.184 1949922 \n6. O'Brien A Blaivas M Albers J Wald J Watts C . A case of respiratory muscle weakness due to cytochrome c oxidase enzyme deficiency . Eur Respir J. (1998 ) 12 :742 –4 . 10.1183/09031936.98.12030742 9762807 \n7. Yang CC Hwang CC Pang CY Wei YH \nMitochondrial myopathy with predominant respiratory dysfunction in a patient with A3243G mutation in the mitochondrial tRNA[Leu(UUR)]gene . J Formos Med Assoc. (1998 ) 97 :715 –9 .9830283 \n8. Chang KC Mak YF Yu WC Lau KK Yan WW Chow TC . Respiratory insufficiency in a Chinese adult with mitochondrial myopathy . Hong Kong Med J. (2002 ) 8 :137 –40 .11937669 \n9. Amornvit J Pasutharnchat N Pachinburavan M Jongpiputvanich S Joyjinda Y . Fulminant respiratory muscle paralysis, an expanding clinical spectrum of mitochondrial A3243G tRNALeu mutation . J Med Assoc Thai. (2014 ) 97 :467 –72 .24964690 \n10. Guo J Palliyath S DiMauro S Ramirez C Shamsnia M Wizer B \nRespiratory failure as the presenting manifestation of adult onset mitochondrial myopathy: 1 case report with literature review . Beijing Med. (2010 ) 32 :86 –9 .\n11. Naddaf E Milone M . Hereditary myopathies with early respiratory insufficiency in adults . Muscle Nerve. (2017 ) 56 :881 –6 . 10.1002/mus.25602 28181274 \n12. Manwaring N Jones MM Wang JJ Rochtchina E Howard C Mitchell P . Population prevalence of the MELAS A3243G mutation . Mitochondrion. (2007 ) 7 :230 –3 . 10.1016/j.mito.2006.12.004 17300999 \n13. Elliott HR Samuels DC Eden JA Relton CL Chinnery PF . Pathogenic mitochondrial DNA mutations are common in the general population . Am J Hum Genet. (2008 ) 83 :254 –60 . 10.1016/j.ajhg.2008.07.004 18674747 \n14. Nesbitt V Pitceathly RD Turnbull DM Taylor RW Sweeney MG Mudanohwo EE . The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation–implications for diagnosis and management . J Neurol Neurosurg Psychiatry. (2013 ) 84 :936 –8 . 10.1136/jnnp-2012-303528 23355809 \n15. Suomalainen A . Biomarkers for mitochondrial respiratory chain disorders . J Inherit Metab Dis. (2011 ) 34 :277 –82 . 10.1007/s10545-010-9222-3 20941643 \n16. Spinazzola A Carrara F Mora M Zeviani M . Mitochondrial myopathy and ophthalmoplegia in a sporadic patient with the 5698G–>A mitochondrial DNA mutation . Neuromuscul Disord. (2004 ) 14 :815 –7 . 10.1016/j.nmd.2004.09.002 15564038 \n17. Kleinle S Schneider V Moosmann P Brandner S Krähenbühl S Liechti-Gallati S . A novel mitochondrial tRNA(Phe) mutation inhibiting anticodon stem formation associated with a muscle disease . Biochem Biophys Res Commun. (1998 ) 247 :112 –5 . 10.1006/bbrc.1998.8729 9636664 \n18. Anitori R Manning K Quan F Weleber RG Buist NR Shoubridge EA . Contrasting phenotypes in three patients with novel mutations in mitochondrial tRNA genes . Mol Genet Metab. (2005 ) 84 :176 –88 . 10.1016/j.ymgme.2004.10.003 15670724 \n19. Seneca S Goemans N Van Coster R Givron P Reybrouck T Sciot R . A mitochondrial tRNA aspartate mutation causing isolated mitochondrial myopathy . Am J Med Genet. (2005 ) 137 :170 –5 . 10.1002/ajmg.a.30854 16059939 \n20. Leshinsky-Silver E Michelson M Cohen S Ginsberg M Sadeh M Barash V . A defect in the thymidine kinase 2 gene causing isolated mitochondrial myopathy without mtDNA depletion . Eur J Paediatr Neurol. (2008 ) 12 :309 –13 . 10.1016/j.ejpn.2007.09.005 17951082 \n21. Lalani SR Vladutiu GD Plunkett K Lotze TE Adesina AM Scaglia F . Isolated mitochondrial myopathy associated with muscle coenzyme Q10 deficiency . Arch Neurol. (2005 ) 62 :317 –20 . 10.1001/archneur.62.2.317 15710863 \n22. Pfeffer G Chinnery PF . Diagnosis and treatment of mitochondrial myopathies . Ann Med. (2013 ) 45 :4 –16 . 10.3109/07853890.2011.605389 21867371 \n23. Carroll JE Zwillich C Weil JV Brooke MH . Depressed ventilatory response in oculocraniosomatic neuromuscular disease . Neurology. (1976 ) 26 :140 –6 . 10.1212/WNL.26.2.140 943069 \n24. Barohn RJ Clanton T Sahenk Z Mendell JR . Recurrent respiratory insufficiency and depressed ventilatory drive complicating mitochondrial myopathies . Neurology. (1990 ) 40 :103 –6 . 10.1212/WNL.40.1.103 2296355 \n25. Kamakura K Abe H Tadano Y Nakamura R Kobayashi H Kawaguchi S . Recurrent respiratory failure in a patient with 3243 mutation in mitochondrial DNA . J Neurol. (1995 ) 242 :253 –5 . 10.1007/BF00919602 7798128\n\n",
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"keywords": "A3243G mutation; mitochondrial myopathy; mtDNA; respiratory failure; sedative drug",
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"title": "Acute Respiratory Failure Is the Initial Manifestation in the Adult-Onset A3243G tRNALeu mtDNA Mutation: A Case Report and the Literature Review.",
"title_normalized": "acute respiratory failure is the initial manifestation in the adult onset a3243g trnaleu mtdna mutation a case report and the literature review"
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"abstract": "Cohen-Gibson syndrome is a rare genetic disorder, characterized by fetal or early childhood overgrowth and mild to severe intellectual disability. It is caused by heterozygous aberrations in EED, which encodes an evolutionary conserved polycomb group (PcG) protein that forms the polycomb repressive complex-2 (PRC2) together with EZH2, SUZ12, and RBBP7/4. In total, 11 affected individuals with heterozygous pathogenic variants in EED were reported, so far. All variants affect a few key residues within the EED WD40 repeat domain. By trio exome sequencing, we identified the heterozygous missense variant c.581A > G, p.(Asn194Ser) in exon 6 of the EED-gene in an individual with moderate intellectual disability, overgrowth, and epilepsy. The same pathogenic variant was detected in 2 of the 11 previously reported cases. Epilepsy, however, was only diagnosed in one other individual with Cohen-Gibson syndrome before. Our findings further confirm that the WD40 repeat domain represents a mutational hotspot; they also expand the clinical spectrum of Cohen-Gibson syndrome and highlight the clinical variability even in individuals with the same pathogenic variant. Furthermore, they indicate a possible association between Cohen-Gibson syndrome and epilepsy.",
"affiliations": "Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Department of Neurology, Epilepsy and Movement Disorders Center, Sana-Krankenhaus Rummelsberg, Schwarzenbruck/Nuremberg, Germany.;Department of Neurology, Epilepsy and Movement Disorders Center, Sana-Krankenhaus Rummelsberg, Schwarzenbruck/Nuremberg, Germany.;Department of Neurology, Epilepsy and Movement Disorders Center, Sana-Krankenhaus Rummelsberg, Schwarzenbruck/Nuremberg, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.;Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg FAU, Erlangen, Germany.",
"authors": "Hetzelt|Katalin L M L|KLML|https://orcid.org/0000-0002-1888-1366;Winterholler|Martin|M|;Kerling|Frank|F|;Rauch|Christophe|C|;Ekici|Arif B|AB|https://orcid.org/0000-0001-6099-7066;Winterpacht|Andreas|A|;Vasileiou|Georgia|G|https://orcid.org/0000-0002-1993-1134;Uebe|Steffen|S|;Thiel|Christian T|CT|https://orcid.org/0000-0003-3817-7277;Kraus|Cornelia|C|;Reis|André|A|https://orcid.org/0000-0002-6301-6363;Zweier|Christiane|C|https://orcid.org/0000-0001-8002-2020",
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"journal": "American journal of medical genetics. Part A",
"keywords": "EED; PRC2; epilepsy; overgrowth",
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"title": "Manifestation of epilepsy in a patient with EED-related overgrowth (Cohen-Gibson syndrome).",
"title_normalized": "manifestation of epilepsy in a patient with eed related overgrowth cohen gibson syndrome"
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"abstract": "Laboratory investigations of hypercalcemia involve testing of various biochemical parameters such as parathyroid hormone (PTH), 25-(OH) Vitamin D (25-(OH) VitD), 1,25-(OH)2 Vitamin D3 (calcitriol) and PTH related peptide (PTHrp). We herein present an atypical case of severe hypercalcemia in a patient with rheumatoid arthritis who has been treated for years by various biological disease-modifying antirheumatic drugs (DMARDs) and suddenly presented with general state alteration, oedema and ulceration of her right ankle. We illustrate how tuberculosis (TB) can cause high calcitriol concentration and subsequently lead to potentially severe hypercalcemia. Moreover, we highlight the importance of TB testing and follow-up in patients treated with biological DMARDs.",
"affiliations": "Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Rheumatology, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Rheumatology, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.;Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium.",
"authors": "Wauthier|Loris|L|;Theunssens|Xavier|X|;Durez|Patrick|P|;Fillée|Catherine|C|;Maisin|Diane|D|;Gruson|Damien|D|",
"chemical_list": "D018501:Antirheumatic Agents; D010281:Parathyroid Hormone; D002117:Calcitriol; D002118:Calcium",
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"doi": "10.11613/BM.2020.030801",
"fulltext": "\n==== Front\nBiochem Med (Zagreb)\nBiochem Med (Zagreb)\nBM\nBiochemia Medica\n1330-0962 1846-7482 Croatian Society of Medical Biochemistry and Laboratory Medicine \n\nbm-30-3-030801\n10.11613/BM.2020.030801\nCase Report\nA rare case of tuberculosis-induced hypercalcemia\nWauthier Loris 1 Theunssens Xavier 2 Durez Patrick 23 Fillée Catherine 1 Maisin Diane 1 Gruson Damien *14 1 Department of Clinical Biochemistry, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium\n2 Department of Rheumatology, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium\n3 Pôle de Pathologies rhumatismales, Institut de Recherche Expérimentale et Clinique, Université Catholique de Louvain, Brussels, Belgium\n4 Pôle de recherche en Endocrinologie, Diabète et Nutrition, Institut de Recherche Expérimentale et Clinique, Cliniques Universitaires St-Luc and Université Catholique de Louvain, Brussels, Belgium\n* Corresponding author: damien.gruson@uclouvain.be\n05 8 2020 \n15 10 2020 \n30 3 03080121 4 2020 23 6 2020 Croatian Society of Medical Biochemistry and Laboratory Medicine.2020Croatian Society of Medical BiochemistryThis is an Open Access article distributed under the terms of the Creative Commons Attribution (http://creativecommons.org/licenses/by/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Laboratory investigations of hypercalcemia involve testing of various biochemical parameters such as parathyroid hormone (PTH), 25-(OH) Vitamin D (25-(OH) VitD), 1,25-(OH)2 Vitamin D3 (calcitriol) and PTH related peptide (PTHrp). We herein present an atypical case of severe hypercalcemia in a patient with rheumatoid arthritis who has been treated for years by various biological disease-modifying antirheumatic drugs (DMARDs) and suddenly presented with general state alteration, oedema and ulceration of her right ankle. We illustrate how tuberculosis (TB) can cause high calcitriol concentration and subsequently lead to potentially severe hypercalcemia. Moreover, we highlight the importance of TB testing and follow-up in patients treated with biological DMARDs.\n\nKeywords: \nhypercalcemiatuberculosisrheumatoid polyarthritiscalcitriol\n==== Body\nIntroduction\nFrom the laboratory perspective, investigations in the course of de novo or chronic hypercalcemia require the use of various assays for the differential diagnosis between primary hyperparathyroidism, multiple myeloma, familial hypercalcemia, malignancy, Vitamin D (VitD) intoxication or granulomatosis. The most frequently used tests for this workup besides calcemia are: parathyroid hormone (PTH), PTH related peptide (PTHrp), 25-(OH) Vitamin D (25-(OH) VitD), and 1,25-(OH)2 Vitamin D3 (calcitriol) (1, 2).\n\nTuberculosis (TB) in its pulmonary and disseminated forms is known to be a rare but well-described cause of hypercalcemia and is described to be associated with high concentrations of calcitriol (3–5). Here, we report the case of hypercalcemia in a patient with disseminated TB and articular presentation, in the context of long-term treatment of rheumatoid arthritis (RA) by biological disease-modifying antirheumatic drugs (DMARDs).\n\nCase presentation\nThe patient was a 67-year-old Caucasian female who has been consulting in the rheumatology department at our facility in the course of an erosive seropositive RA, which was poorly evolving. Among other medications, the patient was treated for several years with different DMARDs, such as etanercept and more recently with infliximab and then tocilizumab, together with methotrexate. At her last outpatient visit, hospitalization was planned as her inflammatory disease was worsening and associated with general state alteration, fever, mild dyspnoea as well as seemingly chronic oedema and ulceration of her right ankle articulation. Her routine blood examination, from which relevant biochemistry results are summarized in Table 1, showed increased C-reactive protein concentrations (CRP) to 114.2 mg/L (upper reference limit (URL): 5 mg/L), concordant with her active inflammatory pathology, acute renal failure (creatinine (CREA): 234 µmol/L (reference range (RR): 53 - 115 µmol/L), urea: 43.9 mmol/L (RR: 5.4–17.9 mmol/L), estimated glomerular filtration rate (eGFR) based on the chronic kidney disease epidemiology collaboration (CKD-EPI) equation: 18 mL/min/1.73m2 (lower reference limit: 60 mL/min/1.73m2) and open hypercalcemia (total calcium (Ca) concentration: 4.38 mmol/L (RR: 2.20–2.55 mmol/L), confirmed with a clearly increased albumin-corrected Ca of 4.43 mmol/L (RR: 2.20–2.55 mmol/L)). This led to anticipated hospitalization. The patient signed an informed consent form for anonymous publication of medical data.\n\nTable 1 Relevant biochemistry results at time of hospitalization\nParameter\tObserved concentration\tReference range\t\nCRP (mg/L)\t114.2\t< 5\t\nUrea (mmol/L)\t43.9\t5.4-17.9\t\nCREA (µmol/L)\t234.3\t53-115\t\neGFR (CKD-EPI) (mL/min/1.73m2)\t18\t> 60\t\nSodium (mmol/L)\t137\t135-145\t\nPotassium (mmol/L)\t3.96\t3.5-5\t\nPhosphate (mmol/L)\t1.76\t0.81-1.45\t\nTotal calcium (mmol/L)\t4.38\t2.20-2.55\t\nAlbumin-corrected calcium (mmol/L)\t4.43\t2.20-2.55\t\nAlbumin (g/L)\t38\t35-52\t\nIntact PTH (ng/L)\t14\t15-80\t\nPTHrp (ng/L)\t< 20\t< 20\t\n25-(OH) VitD (nmol/L)\t87.5\t75-250\t\n1,25-(OH)2 Vitamin D3 (pg/mL)\t171\t20-79\t\nCRP – C-reactive protein. CREA – creatinine. eGFR – estimated glomerular filtration rate. CKD-EPI – chronic kidney disease epidemiology collaboration equation. PTH – parathyroid hormone. PTHrp – PTH related peptide. 25-(OH) VitD – 25-(OH) vitamin D.\t\nClinical and laboratory investigations\nThe clinician’s investigations included first suspicion of multiple myeloma as age, renal function and calcemia were suggestive of such pathology. However, neither serum protein electrophoresis nor immunoglobulins and free light chains assay nor urine immunofixation showed the presence of monoclonal immunoglobulin. Urinalysis exhibited no significant features.\n\nBesides, as intact PTH concentration was 14 ng/L (RR: 15–80 ng/L), hyperparathyroidism and familial hypercalcemia were excluded. PTHrp concentration was < 20 ng/L (URL: 20 ng/L), excluding a neoplastic origin for the high Ca concentration observed.\n\nNotably, 25-(OH) VitD concentration was 88 nmol/L (RR: 75–250 nmol/L) but calcitriol concentration was interestingly high (171 pg/mL (RR: 20–79 pg/mL), suggesting pathologies such as lymphoma or granulomatous diseases such as sarcoidosis and tuberculosis. Various assays were used to perform differential diagnosis. Urine Ca normalized for urine CREA was 2.26 mM/mM (URL: 0.40 mM/mM) and showed hypercalciuria. Angiotensin converting enzyme activity was 68 U/L (RR: 12–68 U/L) and blood lysozyme was 131.4 mg/L (RR: 9.6 –17.1 mg/L) (increased around 8 times the upper limit of the reference range).\n\nThe final diagnosis was achieved by performing a further examination of the patient’s right ankle. Radiography and magnetic resonance imaging showed active multifocal osteoarthritis while positron emission tomography-computed tomography showed multiple hypermetabolic lesions at the pericardial, periarticular, muscular, meningeal, and lymph nodes hypermetabolic lesions and also revealed wide pulmonary cavities. Microbiological samples were collected as surgery was performed and were sent to our bacteriology laboratory for culture and Koch’s bacillus research. Microscopic examination of auramine-stained slides showed the presence of acid-fast bacilli, which was also detected by a semi-quantitative nested polymerase chain reaction. Culture on liquid medium furthermore confirmed positivity for Mycobacterium tuberculosis complex and further identification of Mycobacterium bovis was performed by Sciensano (National Reference Center for the diagnosis of tuberculosis and human mycobacterioses, Brussels, Belgium)\n\nTreatment and outcome\nHypercalcemia and acute renal failure were treated in the emergency room by the administration of large amounts of sodium chloride, 40 mg furosemide, and 90 mg pamidronate. This temporarily decreased albumin-corrected Ca concentration to 2.80 mmol/L, which nonetheless stayed above our institution’s reference range (2.20–2.55 mmol/L) for days after the patient was taken care of. Tuberculosis was treated by classical 4-drugs therapy (rifampin, isoniazid, pyrazinamide, ethambutol + pyridoxine) until antibiogram and formal identification suggested stopping pyrazinamide because of resistance.\n\nNormalization of eGFR to 63 mL/min/1.73m2 was not achieved before one week after antibiotic treatment onset and total Ca concentration to 2.35 mmol/L (RR: 2.20–2.55 mmol/L) (no albumin-corrected value available at that time point) was documented one week later. Ulceration and oedema of the ankle also started healing at the same time, initiating a slow recovery of the wound.\n\nUsual RA treatment was suspended and limited to daily 7.5 mg prednisolone. Tocilizumab treatment was planned to be resumed when infectious symptoms would be under control.\n\nDiscussion\nHereby, we described an unusual case of hypercalcemia in the context of disseminated TB in a patient with RA treated by biological DMARDs. The patient displayed increased calcitriol concentration and normal 25-(OH) VitD whereas PTH concentration was decreased and PTHrp was within the reference range. The diagnosis of TB was later confirmed by clinical and microbiological investigations and concluded to mycobacterial infection.\n\nBiochemical results were consistent with previous reports of such cases of TB-induced hypercalcemia (6, 7). In this particular context of TB-induced hypercalcemia, a first hypothesis for the Ca raise could be the high calcitriol concentrations, leading to an increased intestinal Ca absorption and osteoclastic bone resorption (3–5). Such an increase in calcitriol concentrations can be linked to a triggered 1-α-hydroxylase activity of the macrophages within the granulomatous reaction sites of patients presenting TB or sarcoidosis (8).\n\nAdditionally, another interesting hypothesis could be the activation/reactivation of TB, and its related impact on Ca concentrations, in the context of RA, handled by long-term anti-TNFα and then IL-6 antagonist treatment. The mechanism of action of both treatments target inflammatory cytokines and therefore are well-described causes of latent TB reactivation or primary TB infection (9-11). These cytokines are indeed involved in the immuno-inflammatory response to mycobacterial infections (12, 13). This major adverse effect of these biological DMARDs is known to be higher with etanercept than with other treatments and is furthermore not only described in TB but also in nontuberculous mycobacteria infections (14, 15).\n\nOur study has several limitations. A first one is the lack of measurement of an ionized-Ca assay, a reference method to confirm hypercalcemia that displays higher sensitivity and specificity than total Ca (2). However, the hypercalcemia of our case was confirmed by albumin-corrected Ca. A second limitation could be the start of the biological DMARDs treatment in another care setting, unknown to the authors, misleading the information of an initial screening for TB in our patient in this facility.\n\nThis case is yet another proof of the importance of TB screening and follow-up in patients treated with anti-TNFα and non-anti-TNFα treatments.\n\nIn conclusion, this case illustrates how granulomatosis and by extension, TB, can cause potentially severe hypercalcemia. This was described to be associated with a granulomatosis-triggered increase in calcitriol concentration. Moreover, we highlight the importance of TB monitoring in patients treated by anti-TNFα or non-anti-TNF biological DMARDs in order to prevent infection or reactivation.\n\nPotential conflict of interest: None declared.\n==== Refs\nReferences\n1 Lafferty FW \nDifferential diagnosis of hypercalcemia.\n\nJ Bone Miner Res . 1991 ;6 :S51 –9\n. 10.1002/jbmr.5650061413 1763670 \n2 Endres DB \nInvestigation of hypercalcemia.\n\nClin Biochem . 2012 ;45 :954 –63\n. 10.1016/j.clinbiochem.2012.04.025 22569596 \n3 Sharma OP \nHypercalcemia in granulomatous disorders: A clinical review.\n\nCurr Opin Pulm Med . 2000 ;6 :442 –7\n. 10.1097/00063198-200009000-00010 10958237 \n4 Abbasi AA Chemplavil JK Farah S Muller BF Arnstein AR \nHypercalcemia in active pulmonary tuberculosis.\n\nAnn Intern Med . 1979 ;90 :324 –8\n. 10.7326/0003-4819-90-3-324 426400 \n5 Gkonos PJ London R Hendler ED \nHypercalcemia and Elevated 1,25-Dihydroxyvitamin D Levels in a Patient with End-Stage Renal Disease and Active Tuberculosis.\n\nN Engl J Med . 1984 ;311 :1683 –5\n. 10.1056/NEJM198412273112607 6548798 \n6 Rajendra A Mishra A Francis N Carey RB \nSevere hypercalcemia in a patient with pulmonary tuberculosis.\n\nJ Family Med Prim Care . 2016 ;5 :509 –11\n. 10.4103/2249-4863.192327 27843882 \n7 Chan JY Kanthaya M \nHypercalcaemic crisis in an elderly patient with pulmonary tuberculosis.\n\nOxf Med Case Reports . 2015 ;2015 :354 –7\n. 10.1093/omcr/omv061 26566450 \n8 Cadranel J Garabedian M Milleron B Guillozo H Akoun G Hance AJ \n1,25(OH)2D3 production by T lymphocytes and alveolar macrophages recovered by lavage from normocalcemic patients with tuberculosis.\n\nJ Clin Invest . 1990 ;85 :1588 –93\n. 10.1172/JCI114609 2159024 \n9 Gómez-Reino JJ Carmona L Rodríguez Valverde V Mola EM Montero MD \nTreatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter active-surveillance report.\n\nArthritis Rheum . 2003 ;48 :2122 –7\n. 10.1002/art.11137 12905464 \n10 Wallis RS Broder MS Wong JY Hanson ME Beenhouwer DO \nGranulomatous Infectious Diseases Associated with Tumor Necrosis Factor Antagonists.\n\nClin Infect Dis . 2004 ;38 :1261 –5\n. 10.1086/383317 15127338 \n11 Cantini F Nannini C Niccoli L Petrone L Ippolito G Goletti D \nRisk of Tuberculosis Reactivation in Patients with Rheumatoid Arthritis, Ankylosing Spondylitis, and Psoriatic Arthritis Receiving Non-Anti-TNF-Targeted Biologics.\n\nMediators Inflamm . 2017 ;2017 :18909834. 10.1155/2017/8909834 28659665 \n12 Bekker L-G Freeman S Murray PJ Ryffel B Kaplan G \nTNF-α Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways.\n\nJ Immunol . 2001 ;166 :6728 –34\n. 10.4049/jimmunol.166.11.6728 11359829 \n13 Clay H Volkman HE Ramakrishnan L \nTumor Necrosis Factor Signaling Mediates Resistance to Mycobacteria by Inhibiting Bacterial Growth and Macrophage Death.\n\nImmunity . 2008 ;29 :283 –94\n. 10.1016/j.immuni.2008.06.011 18691913 \n14 Tubach F Salmon D Ravaud P Allanore Y Goupille P Bréban M \nRisk of tuberculosis is higher with anti-tumor necrosis factor monoclonal antibody therapy than with soluble tumor necrosis factor receptor therapy: The three-year prospective French research axed on tolerance of biotherapies registry.\n\nArthritis Rheum . 2009 ;60 :1884 –94\n. 10.1002/art.24632 19565495 \n15 Winthrop KL Chang E Yamashita S Iademarco MF LoBue PA \nNontuberculous mycobacteria infections and anti-tumor necrosis factor-α therapy.\n\nEmerg Infect Dis . 2009 ;15 :1556 –61\n. 10.3201/eid1510.090310 19861045\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1330-0962",
"issue": "30(3)",
"journal": "Biochemia medica",
"keywords": "calcitriol; hypercalcemia; rheumatoid polyarthritis; tuberculosis",
"medline_ta": "Biochem Med (Zagreb)",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D002117:Calcitriol; D002118:Calcium; D005260:Female; D006801:Humans; D006934:Hypercalcemia; D009169:Mycobacterium tuberculosis; D010281:Parathyroid Hormone; D012720:Severity of Illness Index; D014376:Tuberculosis",
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"title": "A rare case of tuberculosis-induced hypercalcemia.",
"title_normalized": "a rare case of tuberculosis induced hypercalcemia"
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"abstract": "We encountered a rare case of severe diffuse duodenitis associated with ulcerative colitis (UC). A 23-year-old man underwent total proctocolectomy with ileal J-pouch anal anastomosis for UC. He suffered from severe abdominal pain, fever and bloody diarrhea for six months after the surgery. Upper double-balloon enteroscopy disclosed severe diffuse duodenitis, of which the findings were endoscopically and histologically similar to those of colonic lesions of UC. Although the administration of prednisolone was ineffective, treatment with intravenous tacrolimus markedly improved the clinical findings. This is the first report of the successful treatment of severe UC-associated diffuse duodenitis with intravenous tacrolimus.",
"affiliations": "Department of Gastroenterology and Nephrology (K1), Graduate School of Medicine, Chiba University, Japan.",
"authors": "Saito|Keiko|K|;Katsuno|Tatsuro|T|;Nakagawa|Tomoo|T|;Minemura|Shoko|S|;Oyamada|Arata|A|;Kanogawa|Naoya|N|;Saito|Masaya|M|;Yoshihama|Sayuri|S|;Maruoka|Daisuke|D|;Matsumura|Tomoaki|T|;Arai|Makoto|M|;Tohma|Takayuki|T|;Miyauchi|Hideaki|H|;Matsubara|Hisahiro|H|;Yokosuka|Osamu|O|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
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"doi": "10.2169/internalmedicine.53.1910",
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"issue": "53(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D003093:Colitis, Ulcerative; D039021:Colonic Pouches; D058582:Double-Balloon Enteroscopy; D004382:Duodenitis; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D016737:Proctocolectomy, Restorative; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "9204241",
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"pages": "2477-81",
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"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe diffuse duodenitis successfully treated with intravenous tacrolimus after colectomy for ulcerative colitis.",
"title_normalized": "severe diffuse duodenitis successfully treated with intravenous tacrolimus after colectomy for ulcerative colitis"
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"companynumb": "JP-MYLANLABS-2015M1025970",
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"abstract": "To reduce risk of antiretroviral resistance when stopping efavirenz (EFV)-based antiretroviral treatment (ART), staggered discontinuation of antiretrovirals (an NRTI tail) is recommended. However, no data directly support this recommendation.\nWe evaluated the prevalence of HIV drug resistance mutations in pregnant women living with HIV who stopped efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) postpartum.\nIn accordance with the prevailing Botswana HIV guidelines at the time, women with pre-treatment CD4 > 350 cells/mm3, initiated EFV/FTC/TDF in pregnancy and stopped ART at 6 weeks postpartum if formula feeding, or 6 weeks after weaning. A 7-day tail of FTC/TDF was recommended per Botswana guidelines. HIV-1 RNA and genotypic resistance testing (bulk sequencing) were performed on samples obtained 4-6 weeks after stopping EFV. Stanford HIV Drug Resistance Database was used to identify major mutations.\nFrom April 2014 to May 2015, 74 women who had stopped EFV/FTC/TDF enrolled, with median nadir CD4 of 571 cells/mm3. The median time from cessation of EFV to sample draw for genotyping was 5 weeks (range: 3-13 weeks). Thirty-two (43%) women received a 1-week tail of FTC/TDF after stopping EFV. HIV-1 RNA was available from delivery in 70 (95%) women, 58 (83%) of whom had undetectable delivery HIV-1 RNA (< 40 copies/mL). HIV-1 RNA was available for 71 women at the time of genotyping, 45 (63%) of whom had HIV-1 RNA < 40 copies/mL. Thirty-five (47%) of 74 samples yielded a genotype result, and four (11%) had a major drug resistance mutation: two with K103N and two with V106M. All four resistance mutations occurred among women who did not receive an FTC/TDF tail (4/42, 10%), whereas no mutations occurred among 18 genotyped women who had received a 1-week FTC/TDF tail (p = 0.053).\nViral rebound was slow following cessation of EFV/FTC/TDF in the postpartum period. Use of an FTC/TDF tail after stopping EFV was associated with the lower prevalence of subsequent NNRTI drug resistance mutation.",
"affiliations": "Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.;Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.;Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.;Goodtables Data Consulting, LLC., Norman, United States.;Bennett Statistical Consulting, Inc., Ballston Lake, United States.;Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.;Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.;Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana.",
"authors": "Ajibola|Globahan|G|https://orcid.org/0000-0002-5408-4823;Rowley|Christopher|C|https://orcid.org/0000-0001-9211-8476;Maruapula|Dorcas|D|https://orcid.org/0000-0003-2587-8904;Leidner|Jean|J|https://orcid.org/0000-0002-4707-3747;Bennett|Kara|K|https://orcid.org/0000-0002-9465-8983;Powis|Kathleen|K|https://orcid.org/0000-0002-4478-4471;Shapiro|Roger L|RL|https://orcid.org/0000-0002-4832-6275;Lockman|Shahin|S|https://orcid.org/0000-0002-5384-9716",
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"doi": "10.4102/sajhivmed.v21i1.1023",
"fulltext": "\n==== Front\nSouth Afr J HIV Med\nSouth Afr J HIV Med\nHIVMED\nSouthern African Journal of HIV Medicine\n1608-9693 2078-6751 AOSIS \n\nHIVMED-21-1023\n10.4102/sajhivmed.v21i1.1023\nScientific Letter\nDrug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy\nhttps://orcid.org/0000-0002-5408-4823Ajibola Globahan 1 https://orcid.org/0000-0001-9211-8476Rowley Christopher 123 https://orcid.org/0000-0003-2587-8904Maruapula Dorcas 1 https://orcid.org/0000-0002-4707-3747Leidner Jean 4 https://orcid.org/0000-0002-9465-8983Bennett Kara 5 https://orcid.org/0000-0002-4478-4471Powis Kathleen 1267 https://orcid.org/0000-0002-4832-6275Shapiro Roger L. 123 https://orcid.org/0000-0002-5384-9716Lockman Shahin 128 1 Botswana Harvard T.H. Chan School of Public Health AIDS Initiative Partnership, Gaborone, Botswana\n2 Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, United States\n3 Beth Israel Deaconess Medical Center, Boston, United States\n4 Goodtables Data Consulting, LLC., Norman, United States\n5 Bennett Statistical Consulting, Inc., Ballston Lake, United States\n6 Department of Medicine, Division of General Internal Medicine, Massachusetts General Hospital, Boston, United States\n7 Department of Pediatrics and Pediatric Surgery, Massachusetts General Hospital, Boston, United States\n8 Division of Infectious Disease, Brigham and Women’s Hospital, Boston, United States\nCorresponding author: Globahan Ajibola, gajibola@bhp.org.bw\n27 1 2020 \n2020 \n21 1 102319 8 2019 16 9 2019 © 2020. The Authors2020Licensee: AOSIS. This work is licensed under the Creative Commons Attribution License.Background\nTo reduce risk of antiretroviral resistance when stopping efavirenz (EFV)-based antiretroviral treatment (ART), staggered discontinuation of antiretrovirals (an NRTI tail) is recommended. However, no data directly support this recommendation.\n\nObjectives\nWe evaluated the prevalence of HIV drug resistance mutations in pregnant women living with HIV who stopped efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) postpartum.\n\nMethod\nIn accordance with the prevailing Botswana HIV guidelines at the time, women with pre-treatment CD4 > 350 cells/mm3, initiated EFV/FTC/TDF in pregnancy and stopped ART at 6 weeks postpartum if formula feeding, or 6 weeks after weaning. A 7-day tail of FTC/TDF was recommended per Botswana guidelines. HIV-1 RNA and genotypic resistance testing (bulk sequencing) were performed on samples obtained 4–6 weeks after stopping EFV. Stanford HIV Drug Resistance Database was used to identify major mutations.\n\nResults\nFrom April 2014 to May 2015, 74 women who had stopped EFV/FTC/TDF enrolled, with median nadir CD4 of 571 cells/mm3. The median time from cessation of EFV to sample draw for genotyping was 5 weeks (range: 3–13 weeks). Thirty-two (43%) women received a 1-week tail of FTC/TDF after stopping EFV. HIV-1 RNA was available from delivery in 70 (95%) women, 58 (83%) of whom had undetectable delivery HIV-1 RNA (< 40 copies/mL). HIV-1 RNA was available for 71 women at the time of genotyping, 45 (63%) of whom had HIV-1 RNA < 40 copies/mL. Thirty-five (47%) of 74 samples yielded a genotype result, and four (11%) had a major drug resistance mutation: two with K103N and two with V106M. All four resistance mutations occurred among women who did not receive an FTC/TDF tail (4/42, 10%), whereas no mutations occurred among 18 genotyped women who had received a 1-week FTC/TDF tail (p = 0.053).\n\nConclusions\nViral rebound was slow following cessation of EFV/FTC/TDF in the postpartum period. Use of an FTC/TDF tail after stopping EFV was associated with the lower prevalence of subsequent NNRTI drug resistance mutation.\n\ndrug resistanceresistance mutationsHIVantiretroviral treatmentBotswana\n==== Body\nIntroduction\nCessation of antiretrovirals raises concerns about the potential for the development of drug-resistant viral strains, particularly for non-nucleoside reverse transcriptase inhibitors (NNRTIs). Non-nucleoside reverse transcriptase inhibitors, such as efavirenz (EFV), have long half-lives and a low barrier to the development of drug resistance. When used in combination with other classes of drugs such as nucleoside reverse transcriptase inhibitors (NRTIs), staggered discontinuation using a 4–7-day ‘tail’ of the NRTI backbone when stopping NNRTI-based antiretroviral treatment (ART) is advised.1 This is believed to mitigate the unintended period of monotherapy with NNRTIs that ensues because of the long half-life of most drugs in this class, thus reducing the risk of developing drug resistance.2,3 There are, however, very limited data to directly support this recommendation for a tenofovir disoproxil fumarate (TDF)/emtricitabine (FTC) ‘tail’: following cessation of EFV. Of note, pharmacokinetic variability (linked genetic factor – CYP2B6) in EFV metabolism between individuals has been observed, and EFV levels may be higher in persons of African descent.4 These higher drug levels may also impact risk of drug resistance when stopping EFV-based ART.\n\nPrior to 2015, both the World Health Organization (WHO) and the Botswana programme for the prevention of mother-to-child transmission (PMTCT) recommended that pregnant women living with HIV with a CD4 cell count > 350 cells/mm3 without a WHO stage 3 or 4 illness take three-drug ART in pregnancy, but discontinue the ART postpartum or upon breastfeeding cessation (option B). Although both WHO and Botswana subsequently modified guidelines to recommend lifelong ART regardless of CD4 cell count or disease stage (option B+), the prior guidance for pregnant women, as well as the inconsistent application of an NRTI tail at the time of EFV cessation, offers an opportunity to evaluate the development of resistance and the performance of a TDF/FTC tail among women stopping an EFV/TDF/FTC regimen. Because this ART regimen remains widely used throughout the world, the natural experiment afforded by prior PMTCT guidelines is applicable to our understanding of the risk of cessation of NNRTI-based regimens generally.\n\nMethods\nStudy population\nBetween April 2014 and May 2015, we enrolled a subset of pregnant women living with HIV participating in a trial of infant cotrimoxazole prophylaxis in Botswana (the ‘Mpepu’ study) into this resistance sub-study. Mpepu was a double-blinded randomised controlled trial designed to assess the efficacy and safety of infant cotrimoxazole prophylaxis versus placebo used daily from as early as 14 days of life through 15 months among HIV-exposed uninfected infants in Botswana.5\n\nWomen were eligible for this sub-study of drug resistance following cessation of EFV/FTC/TDF if they were living with HIV, had pre-treatment CD4 > 350 cells/mm3 without evidence of WHO stage 3 or 4 disease, initiated EFV/FTC/TDF in pregnancy and stopped ART postpartum according to Botswana guidelines at the time (at 4–6 weeks postpartum if formula feeding, or 6 weeks after weaning if breastfeeding). Per Botswana national HIV treatment guidelines, a 7-day tail of TDF/FTC after cessation of EFV was recommended. However, decisions regarding receipt and cessation of maternal ART occurred at government clinics (rather than study clinics), and the 7-day tail was inconsistently applied at the time of ART cessation.\n\nData collection and laboratory testing\nWomen eligible to participate in this sub-study were identified in the Mpepu study and scheduled for a clinic visit 4–6 weeks after ART cessation. Interested and eligible women consented to participate in the study and provided data (from self-report and medical records) on PMTCT regimen received; dates on which ART and individual antiretrovirals were started and stopped as well as provided blood specimens for drug resistance and HIV-1 RNA testing. HIV RNA results at the point of enrolment into the Mpepu study, and documented nadir CD4 counts, were retrieved and served as baseline values.\n\nPrior to drug resistance testing, we first determined HIV-1 RNA viral load levels with the Abbott m2000sp/rt machine (limit of detection 40 copies/mL). Where HIV-1 RNA was detected, it was extracted using an automated validated technique.6 We then performed reverse transcription using in-house one-step RT-PCR technique.7 Polymerase chain reaction (PCR) products were then purified8 and sequenced.9 Consensus sequences were generated, and the Stanford HIV Drug Resistance Database was used to identify all drug resistance mutations in the protease and reverse transcriptase coding regions.\n\nStatistical methods\nStatistical Package for Social Sciences (SPSS) version 25 was used to perform statistical analyses, which were generally descriptive in nature; a two-sided Fisher’s exact test was used to evaluate for differences in the proportion of drug resistance by the approach to ART cessation, either with a 7-day TDF/FTC tail or with abrupt cessation of all three drugs. The small number of women with drug resistance mutations precluded more detailed analysis of predictors of drug resistance.\n\nEthical onsiderations\nThe Botswana Health Research Development Committee and the Office of Human Research Administration at Harvard T. H. Chan School of Public Health approved this drug resistance sub-study (HRDC 00732 and IRB13-2772), and women provided written informed consent for participation.\n\nResults\nBaseline characteristics\nNinety women enrolled, 74 of whom discontinued EFV/FTC/TDF postpartum and had samples collected for genetic resistance testing and are included in this analysis. Sixteen of 90 women not included in this analysis had CD4 < 350 cell/mm3 post-delivery and had to continue ART for their own health per Botswana national protocol at the time. The median time from cessation of EFV (whether or not a tail period occurred) to time sample was collected for resistance testing was 5 weeks (range: 3–13 weeks). Median age at enrolment was 29 years (range: 20–45) with median nadir CD4 count of 571 cells/mm3 (range: 361–1236). Forty-seven (64%) women had no previous exposure to antiretrovirals, 25 (34%) reported previous exposure to antiretrovirals for PMTCT purposes in a prior pregnancy and 2 (2%) were previously exposed to EFV/FTC/TDF but stopped prior to conception and then re-started EFV/FTC/TDF as three-drug prophylaxis for the index pregnancy. Thirty-two (43%) stopped ART with the recommended 1-week tail of TDF/FTC after cessation of EFV and 42 (57%) stopped all treatment at once. Of 70 women with viral load results at enrolment into the Mpepu study, 58 (83%) had HIV-1 RNA < 40 copies/mL. At 4–6 weeks post-EFV/FTC/TDF cessation, 44 (62%) of 71 women with viral load result had HIV-1 RNA < 40 copies/mL. Thirty-three (47%) women had HIV-1 RNA < 40 copies/mL at delivery and at the time of sample draw for genotyping (post-ARV cessation).\n\nMutations\nThirty-five (47%) of 74 samples were successfully sequenced, with 4 (11%) of 35 having a major drug resistance mutation: 2 with K103N and 2 with V106M (Table 1). All four resistance mutations occurred among women who did not receive a TDF/FTC tail (4/42, 10%), whereas no mutations occurred among 18 genotyped women who had received a TDF/FTC tail (p = 0.053). Eighteen (58%) of the 31 women who had a genotype result and no drug resistance mutation took a TDF/FTC tail. Of 39 samples that could not be sequenced, 37 (95%) had HIV-1 RNA < 40 copies/mL in the sample being tested.\n\nTABLE 1 Characteristics of women with successful sequencing post-antiretroviral treatment cessation.\n\nAge (years)\tPrior use of ART for own health\tPrior use of ART for PMTCT\tReceived TDF/FTC tail\tDuration of ART use (weeks)\tNadir CD4 (cell/UI)\tBaseline VL (copies/mL)\tPost ART cessation VL (copies/mL)\tMutation\t\n27\tNo\tYes\tYes\t31.6\t518\t< 40\t42 166\tE138A\t\n27\tNo\tNo\tYes\t38.4\t570\t< 40\t< 40\tE138A\t\n23\tNo\tNo\tYes\t40.7\t710\t< 40\t13 120\tK103N\t\n25\tNo\tNo\tYes\t10.1\t572\t< 40\t1719\tK103N\t\n35\tNo\tNo\tNo\t54.5\t772\t< 40\t18 259\tNone\t\n40\tNo\tYes\tYes\t31.2\t442\t< 40\t2658\tNone\t\n36\tNo\tYes\tNo\t20.4\t963\t< 40\t< 40\tNone\t\n25\tNo\tNo\tNo\t20.2\t611\t< 40\t857\tNone\t\n35\tNo\tNo\tNo\t11.4\t430\t< 40\t-\tNone\t\n25\tNo\tNo\tYes\t15.8\t575\t< 40\t33 906\tNone\t\n24\tNo\tNo\tYes\t25.2\t496\t< 40\t5688\tNone\t\n26\tNo\tYes\tNo\t25.6\t460\t< 40\t2342\tNone\t\n27\tNo\tYes\tYes\t14.0\t908\t< 40\t1805\tNone\t\n29\tNo\tNo\tYes\t23.1\t436\t58\t379\tNone\t\n42\tNo\tNo\tYes\t27.8\t533\t< 40\t< 40\tNone\t\n40\tNo\tNo\tNo\t13.5\t361\t52\t250\tNone\t\n33\tYes\tNo\tYes\t10.8\t796\t< 40\t< 40\tNone\t\n30\tNo\tNo\tNo\t21.1\t616\t-\t9764\tNone\t\n26\tNo\tNo\tNo\t24.9\t1037\t< 40\t554\tNone\t\n27\tNo\tNo\tYes\t16.1\t601\t< 40\t3648\tNone\t\n40\tNo\tNo\tYes\t24.6\t363\t< 40\t33 432\tNone\t\n27\tNo\tNo\tNo\t81.6\t673\t< 40\t196 735\tNone\t\n24\tNo\tNo\tYes\t39.2\t800\t< 40\t< 40\tNone\t\n31\tYes\tNo\tNo\t36.7\t1236\t< 40\t-\tNone\t\n31\tNo\tYes\tYes\t11.0\t589\t125\t< 40\tNone\t\n29\tNo\tNo\tNo\t18.5\t715\t< 40\t2261\tNone\t\n26\tNo\tYes\tNo\t96.2\t612\t<40\t< 40\tNone\t\n41\tNo\tNo\tNo\t82.1\t840\t-\t2229\tNone\t\n35\tNo\tYes\tNo\t45.8\t960\t< 40\t4536\tNone\t\n40\tNo\tYes\tNo\t26.8\t679\t< 40\t972\tNone\t\n28\tNo\tNo\tNo\t21.9\t436\t< 40\t40 709\tNone\t\n26\tNo\tNo\tNo\t23.2\t397\t< 40\t309\tNone\t\n24\tNo\tNo\tNo\t26.5\t468\t52\t< 40\tNone\t\n20\tNo\tNo\tYes\t22.4\t384\t45\t68†\tV106M\t\n33\tNo\tYes‡\tYes\t23.8\t468\t< 40\t145 392\tV106M\t\nART, antiretroviral treatment; FTC, emtricitabine; TDF, tenofovir disoproxil fumarate; VL, viral load.\n\n† , Genotypes were performed independent of the knowledge of the participants’ viral load; therefore, verification of the viral load on individual plasma sample was not performed.\n\n‡ , Previous exposure to zidovudine for prevention of mother-to-child transmission (PMTCT).\n\nDiscussion\nA small proportion of women stopping EFV/FTC/TDF had a major NNRTI resistance mutation detected in plasma taken a little more than a month after stopping treatment. Among women receiving a 7-day tail of TDF/FTC after stopping EFV where genetic resistance testing was able to be performed, none had detectable mutations. Our findings thus support the recommended staggered discontinuation of antiretrovirals when an EFV/FTC/TDF regimen is being stopped. Our data support prior studies that evaluated the use of an NRTI tail when discontinuing EFV-based ART.\n\nOur observation of prolonged viral suppression < 40 copies/mL for a median of 5 weeks in 62% of women post-ART cessation was similar to findings from other studies which have demonstrated that it is not unusual for viral suppression to persist for weeks after stopping ART.10 We believe this could be because of low pre-ART viral loads in our population (because of women with less advanced disease starting ART in pregnancy).\n\nOur study had several limitations. Firstly, our results are based on a small number of observations making generalisability challenging. Secondly, we did not report on minor drug resistance variants and, finally, more than half (63%) of women tested at a median time of 5 weeks from EFV cessation were still virally suppressed, which may suggest that we might have tested for resistance strain development early. Thirdly, we could not determine why the 7-day tail was inconsistently applied at the time of ART cessation and could therefore have missed evaluating possible confounders related to this factor.\n\nConclusion\nAlthough guidelines no longer recommend discontinuation of ART after pregnancy, our study has general applicability for those requiring permanent or temporary treatment discontinuation when receiving an EFV-based regimen, informing the risk of mutation emergence in the setting of abrupt three-drug discontinuation versus discontinuing with a TDF/FTC tail. Furthermore, despite the shift to the use of newer drugs such as dolutegravir for which there is less concern about the emergence of resistance than with NNRTIs, our data are relevant to millions of individuals still on EFV-based ART (and are of particular clinical importance in regions that have access to only a limited number of antiretroviral drugs and that are also generally unable to routinely assess for drug resistance mutations before initiating a new ART regimen).\n\nBased upon our results, we conclude that an TDF/FTC tail may help prevent selection of major NNRTI drug resistance mutations that can occur with the abrupt discontinuation of an EFV/FTC/TDF ART regimen.\n\nAcknowledgements\nMany thanks to the management and staff of the Botswana Harvard AIDS institute partnership for their support and to all the participants enrolled in the study.\n\nCompeting interests\nThe authors declare that no competing interests exist.\n\nAuthors’ contributions\nS.L. was the project leader, and G.A. and S.L. were responsible for experimental and project design. G.A. and C.R. performed most of the experiments. R.L.S. and K.P. made conceptual contributions, while D.M. prepared the samples. Calculations were performed by G.A., J.L. and K.B. G.A, C.R. and S.L. co-wrote the article.\n\nFunding information\nThis project was funded by the National Institute of Child Health and Human Development, and the National Institute of Allergy and Infectious Diseases, NIH grant: R01HD061265.\n\nData availability statement\nData and associated documentation from this study will be made available for external use only under a data-sharing agreement that provides for (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.\n\nDisclaimer\nThe views and opinions expressed in this article are those of the authors and do not necessarily reflect the official policy or position of any affiliated agency of the authors.\n\nProject research number: R01HD061265\n\nHow to cite this article: Ajibola G, Maruapula D, Rowley C, et al. Drug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy. S Afr J HIV Med. 2020;21(1), a1023. https://doi.org/10.4102/sajhivmed.v21i1.1023\n\nNote: For editorial commentary from Prof. Gary Maartens (University of Cape Town) on this article, please see: https://doi.org/10.4102/sajhivmed.v21i1.1036.\n==== Refs\nReferences\n1. Lamorde M , Schapiro JM , Burger D , Back DJ \nAntiretroviral drugs for prevention of mother-to-child transmission: Pharmacologic considerations for a public health approach\n. AIDS . 2014 ;28 (17 ):2551 –2563\n\n10.1097/QAD.0000000000000439 25574958 \n2. McIntyre JA , Hopley M , Moodley D , et al \nEfficacy of short-course AZT plus 3TC to reduce nevirapine resistance in the prevention of mother-to-child HIV transmission: A randomized clinical trial\n. PLoS Med . 2009 ;6 (10 ):e1000172 \n10.1371/journal.pmed.1000172 19859531 \n3. Chi BH , Sinkala M , Mbewe F , et al \nSingle-dose tenofovir and emtricitabine for reduction of viral resistance to non-nucleoside reverse transcriptase inhibitor drugs in women given intrapartum nevirapine for perinatal HIV prevention: An open-label randomised trial\n. Lancet . 2007 ;370 (9600 ):1698 –1705\n. 10.1016/S0140-6736(07)61605-5 17997151 \n4. Sinxadi PZ , Leger PD , McIlleron HM , et al \nPharmacogenetics of plasma efavirenz exposure in HIV infected adults and children in South Africa\n. Br J Clin Pharmacol . 2015 ;80 (1 ):146 –156\n. 10.1111/bcp.12590 25611810 \n5. Lockman S , Hughes M , Powis K , Ajibola G , Bennett K , Moyo S \nEffect of co-trimoxazole on mortality in HIV-exposed but uninfected children in Botswana (the Mpepu Study): A double-blind, randomized, placebo-controlled trial\n. Lancet Glob Health . 2017 ;5 (5 ):e491 –e500\n. 10.1016/S2214-109X(17)30143-2 28395844 \n6. EZ1 Virus Mini kit v2.0, Virus Handbook \nQIAGEN sample and assay technologies, USA [homepage on the Internet] . 2010 [cited 2019 Jul 04]. Available from: https://www.qiagen.com/cn/resources/download.aspx?id=ca13c92a-4b1b-4ced-9796-b0414a166803&lang=en \n7. Rowley CF , MacLeod IJ , Maruapula D , et al \nSharp increase in rates of HIV transmitted drug resistance at antenatal clinics in Botswana demonstrates the need for routine surveillance\n. J Antimicrob Chemother . 2016 ;71 (5 ):1361 –1366\n. 10.1093/jac/dkv500 26929269 \n8. BigDye Terminator v3.1 Cycle Sequencing Kit User Guide \nThermo-Fisher scientific [homepage on the Internet] . 2016 [cited 2019 Jul 04]. Available from: http://tools.thermofisher.com/content/sfs/manuals/cms_081527.pdf \n9. Applied Biosystems 3130/3130xl Genetic Analyzers User Guide \nLife technologies [homepage on the Internet] . 2012 [cited 2019 Jul 04]. Available from: http://tools.thermofisher.com/content/sfs/manuals/4477796.pdf \n10. Graham TC , Aga E , Bosch RJ , et al \nBrief report: Relationship among viral load outcomes in HIV treatment interruption trials\n. J Acquir Immune Defic Syndr . 1999 ;72 (3 ):310 –313\n. 10.1097/QAI.0000000000000964\n\n",
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"title": "Drug resistance after cessation of efavirenz-based antiretroviral treatment started in pregnancy.",
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"abstract": "Infective complications following percutaneous renal biopsy are rare, even among immunocompromised. However it is important to be vigilant about such complications, to detect them early and prevent morbidity and mortality. We report a case of retroperitoneal abscess with extension to subcutaneous plane after a renal biopsy.\n\n\n\nA 42-year-old female with long standing cutaneous lupus underwent renal biopsy for evaluation of nephrotic range proteinuria. She was on high dose prednisolone complicated with steroid induced hyperglycaemia. Eight weeks after the biopsy she presented with left flank pain, malaise and fever. There was a tender subcutaneous induration over the biopsy site. Contrast CT abdomen showed a retroperitoneal abscess with subcutaneous extension along the path of the biopsy needle. This was successfully treated with surgical drainage and broad-spectrum antibiotics.\n\n\n\nInfections and abscess formation are rare but serious complications of renal biopsy. Immunocompromised state is a potential risk factor. Possible mechanisms and measures for prevention and early detection of this rare complication are discussed.",
"affiliations": "University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka.;University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka. dissanayakeha@gmail.com.;Department of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka.",
"authors": "Illeperuma|Prashan Buddhika|PB|;Dissanayake|Harsha Anuruddhika|HA|0000-0003-3903-9917;Wijewickrama|Eranga Sanjeewa|ES|",
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"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 111210.1186/s12882-018-1112-1Case ReportRetroperitoneal abscess with subcutaneous extension: case report of a rare complication of percutaneous renal biopsy Illeperuma Prashan Buddhika buddhikamed@gmail.com 1http://orcid.org/0000-0003-3903-9917Dissanayake Harsha Anuruddhika +94 714 219893dissanayakeha@gmail.com 1Wijewickrama Eranga Sanjeewa erangasw@gmail.com 21 0000 0004 0556 2133grid.415398.2University Medical Unit, National Hospital of Sri Lanka, Colombo, Sri Lanka 2 0000000121828067grid.8065.bDepartment of Clinical Medicine, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka 9 11 2018 9 11 2018 2018 19 31914 4 2018 22 10 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nInfective complications following percutaneous renal biopsy are rare, even among immunocompromised. However it is important to be vigilant about such complications, to detect them early and prevent morbidity and mortality. We report a case of retroperitoneal abscess with extension to subcutaneous plane after a renal biopsy.\n\nCase presentation\nA 42-year-old female with long standing cutaneous lupus underwent renal biopsy for evaluation of nephrotic range proteinuria. She was on high dose prednisolone complicated with steroid induced hyperglycaemia. Eight weeks after the biopsy she presented with left flank pain, malaise and fever. There was a tender subcutaneous induration over the biopsy site. Contrast CT abdomen showed a retroperitoneal abscess with subcutaneous extension along the path of the biopsy needle. This was successfully treated with surgical drainage and broad-spectrum antibiotics.\n\nConclusions\nInfections and abscess formation are rare but serious complications of renal biopsy. Immunocompromised state is a potential risk factor. Possible mechanisms and measures for prevention and early detection of this rare complication are discussed.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s12882-018-1112-1) contains supplementary material, which is available to authorized users.\n\nKeywords\nRenal biopsyPerinephric abscessPost-renal biopsy abscessissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nInfective complications following percutaneous renal biopsy are rare. Those are limited to case reports of perinephric abscesses, pyelonephritis and bacteraemia [1]. Many patients who undergo renal biopsy are often immunocompromised either due to underlying disease or immunomodulatory therapy. Despite this, infections in relation to renal biopsy have been exceedingly rare, even among kidney transplant recipients. We report a case of retroperitoneal abscess, which extended to subcutaneous tissues through muscles of the posterior abdominal wall, developed following a renal biopsy, a phenomenon not described before.\n\nCase presentation\nA 42 year old female with cutaneous lupus for 16 years was evaluated for new onset hypertension and ankle oedema of 2 months duration. She was found to have a nephrotic range proteinuria (3.7 g per day) with microscopic haematuria and underwent renal biopsy for suspected lupus nephritis. She did not have coagulopathy, local skin sepsis or uncontrolled hypertension at the time of the biopsy. The procedure was performed under ultrasound guidance, adhering to aseptic precautions by an experienced specialty trainee in nephrology. Two cores were obtained with two passes using a Histo Automated Spring-loaded renal biopsy gun with a 16G needle. No complications were observed during the immediate post-procedure period. Patient did not develop undue pain, haematuria or overt bleeding from the biopsy site. She was discharged from hospital the next day.\n\nShe was on prednisolone 60 mg daily and had steroid induced diabetes mellitus. Her glycemic control was poor (HbA1c 9.0%, fasting plasma glucose 188 mg/dL) while being on treatment with metformin 750 mg thrice daily and gliclazide 40 mg twice daily.\n\nEight weeks later she was re-admitted with pain in the left flank, intermittent fever and malaise for 1 week. She did not have urinary symptoms, haematuria, nausea or vomiting.\n\nHer past medical, surgical, gynaecological and family history was otherwise unremarkable. She was a housewife, leading an active lifestyle, well supported by family members and was well compliant with treatment.\n\nOn admission, she was ill, febrile (37.5 °C), had tachycardia (112 beats per minute) with normal blood pressure (120/70 mmHg), respiratory rate (18 per minute) and oxygen saturation (99% on ambient air). She was pale and had bilateral symmetrical pitting ankle oedema, malar rash, and erythematous desquamating rash over sun exposed areas. Abdominal examination revealed an exquisitely tender subcutaneous induration in the left flank without overlying erythema, warmth or rash. Cardiovascular, respiratory and neurological examinations were unremarkable.\n\nInvestigations revealed a neutrophil leukocytosis (total white cell count 22 300 / mm3, neutrophils 88% with left shift and toxic granules), elevated C-reactive protein (120 mg/L, reference < 6 mg/L) and erythrocyte sedimentation rate (88 mm 1st hour). She also had normochromic normocytic anaemia (haemoglobin 8.9 g/dL), normal renal functions (Creatinine 57 micmol/L) and normal liver biochemistry except for hypoalbuminaemia (26 g/L). Renal biopsy was reported as having insufficient tissue as it contained only tubules, without any glomeruli.\n\nUrinalysis showed proteinuria and microscopic haematuria without pyuria. Urine and blood cultures grew no organisms. Ultrasound scan of the abdomen showed a subcutaneous hypoechoeic area over the left flank suggestive of a fluid collection. A contrast enhanced CT scan of the abdomen was done which showed a retroperitoneal collection of pus that extended in to the subcutaneous tissues through the muscles of the posterior abdominal wall (Fig. 1). No communication was reported between the abscess and the renal tissue.Fig. 1 Contrast enhance CT abdomen showing a retroperitoneal abscess behind the left kidney which had extended to subcutaneous tissue plane through a defect in the posterior abdominal wall\n\n\n\nShe underwent incision and drainage of the abscess, which drained 400 mL of blood stained pus. Collection was found to be extending from the retroperitoneal region to the subcutaneous tissue plane, two regions communicating through a channel that penetrated the posterior abdominal wall musculature. The abscess had no communication with renal tissues or the collecting system. Pus culture isolated an extended spectrum beta lactamase producing Escherichia coli. She was treated with intravenous meropenem 1 g 8 hourly along with regular debridement of the surgical site.\n\nHer symptoms gradually resolved with treatment and inflammatory markers returned to normal. Follow up imaging with ultrasonography did not reveal any residual collection. Two weeks later, she was discharged from in patient care with a plan for repeat biopsy from the right kidney.\n\nDiscussion & conclusions\nInfective complications are rare after renal biopsy. These include pyelonephritis, perinephric abscesses and bacteraemia. In a follow up of 1000 patients who underwent renal biopsy, González-Michaca et al. [1] reported infective complications in only 3 patients with one having a perinephric abscess, one having pyelonephritis and the other one having bacteraemia. Thus the incidence of infective complications was only 0.3% in this series. Similarly a retrospective analysis of 1832 renal biopsies over 37 years reported infections to affect only 0.2% of the biopsied patients [2]. Other prospective and retrospective data from databases have shown similar low incidence of perinephric abscesses (0.3%) [3]. In contrast, bacteraemia was shown to be commoner when renal biopsy was performed on those with pyelonephritis, affecting 6.2% of such patients [4]. However, most such cases were reported at least 20 years ago. More recent data from large cohorts of patients report no infective complications in relation to renal biopsy [5, 6].\n\nThere are several mechanisms by which an infection could develop following a renal biopsy. During the procedure, the biopsy needle may introduce skin commensals in to the renal parenchyma or surrounding connective tissues or muscles, which have relatively weak immune system. Similarly the needle may introduce skin commensals directly in to the blood stream through which the organisms may disseminate causing bacteraemia. Alternatively, path of the biopsy needle through soft tissues may leave a pathway along which the skin commensals may migrate in to the immune deprived connective tissues. Occult haemorrhage in to perinephric tissues following the biopsy may serve as a culture medium for the microorganisms to proliferate and disseminate. Occult perinephric haematoma is a common complication following renal biopsy detected on post procedure CT scans in 57–85% of those who undergo renal biopsies [7]. However infection of these haematomas are exceedingly rare [6]. Inadvertent injury to adjacent intestinal loops allowing entry of gut commensals to peritoneal cavity leading to peritonitis is a theoretical possibility, but has never been reported. Patients who undergo renal biopsy are also likely to have systemic disease with immune dysfunction due to the disease itself or as a result of immunosuppressive therapy making them more prone to infective complications.\n\nDespite the multitude of predisposing mechanisms, infective complications following renal biopsies have been exceedingly rare in clinical practice. Strict adherence to aseptic precautions may at least partly contribute to the low incidence. Although the needle would introduce organisms to the connective tissues, relatively low perfusion and therefore anaerobic environment and low supply of nutrients would not facilitate survival and replication of organisms. Rapid epithelialization of skin puncture site following biopsy will prevent continued entry of organisms in to deeper tissue planes. Epithelialization following a clean surgical wound requires no immune response and depends on integrity of the epidermis and is therefore remains unaffected by immune dysfunction. Even in kidney transplant recipients who undergo graft biopsies, infections are exceedingly rare, despite being on immunosuppressants. Use of ultrasound guidance has minimized hemorrhage and inadvertent visceral injury thus minimizing infective complications.\n\nIt is very likely that our patient developed the retroperitoneal abscess as a complication of the renal biopsy. The abscess was anatomically localized to the retroperitoneal region adjacent to the biopsied kidney. It has tracked to the subcutaneous plane across the muscles and surrounding fascia. Infections tend to track along tissue planes and it is exceedingly rare for the infections to penetrate dense fascia and muscular tissues. It is likely that the infection tracked along the path of the needle in to the subcutaneous tissue plane. However, pus collection did not spread in to renal tissues. Kidney appeared unaffected radiologically and pus collection was separated from the kidney by intact Gerota’s fascia. Furthermore, urinalysis revealed no pyuria to suggest extension of infection in to collecting system. Inadvertent visceral injury contributing to the abscess was unlikely considering that the pus collection was entirely retroperitoneal. Furthermore, a visceral perforation would have caused peritonitis and sepsis within a few days of the procedure, which did not occur in the patient.\n\nHowever, the organism isolated from the purulent drainage was an ESBL producing coliform, an organism unlikely to colonize the skin of a community dwelling otherwise healthy person [8]. We postulate that the cutaneous lupus altered the integrity of the skin as a barrier against infection resulting in it being colonized by this unusual organism during her recent hospitalization for the renal biopsy. In fact, a recent study has demonstrated that hospitalized patients have skin colonization with enterobacteriaceae [9]. Alternatively, the organism could have reached the site of infection through an occult renal infection or colonization that was present at the time of biopsy. Biopsy needle would have introduced the organisms to the soft tissue layer during the procedure.\n\nImmune dysfunction secondary to lupus flare, high dose of prednisolone and the resultant deterioration in glycaemic control would have facilitated the development of the retroperitoneal abscess.\n\nWe suggest that strict adherence to aseptic precautions, use of correct technique to minimize multiple punctures and to avoid visceral injury as potential strategies to minimize infective complications following renal biopsy. Given the rarity of such complications it is unlikely that peri-procedure antibiotic prophylaxis would be cost effective. It is also important to be aware of this rare complication and to maintain a high index of suspicion in evaluating patients with suggestive clinical features with supportive radiological imaging and treat with appropriate antibiotics and surgical drainage.\n\nIn conclusion, this case illustrates the presentation, diagnostic approach and management of a rare infective complication following percutaneous renal biopsy. Dysfunction of the skin as a barrier to infections due to cutaneous lupus, colonization of the skin with drug resistant virulent organism during hospital stay, introduction of organisms to immune deprived connective tissues along the biopsy needle path, and tracking of the infection from retroperitoneal space to subcutaneous tissue plane along the path created by the biopsy needle and systemic immune deficient state secondary to lupus flare, immunosuppressive therapy and poorly controlled diabetes are the potential mechanisms by which our patient developed this complication. We emphasize the need for strict adherence to aseptic precautions and prompt management of immune deficient states such as diabetes as measures to prevent such complications. Patients as well as health care providers should be aware of this complication and its presentation and maintain a high index of suspicion to appropriately investigate and treat in order to prevent serious sequalae of sepsis (Additional file 1).\n\nAdditional file\n\nAdditional file 1: Time line of disease evolution. (DOCX 36 kb)\n\n \n\n\nAcknowledgements\nNot applicable\n\nFunding\nNone\n\nAvailability of data and materials\nRelevant clinical details are presented in this report.\n\nAuthors’ contributions\nPBI and HAD collected data and wrote the manuscript. ESW critically reviewed the paper and developed the discussion. All authors reviewed the final manuscript and approved for submission.\n\nEthics approval and consent to participate\nEthical approval was not sought for the publication of the case report.\n\nConsent for publication\nPatient gave informed written consent for publication of her clinical details and radiological images maintaining anonymity.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Gonzalez-Michaca L Chew-Wong A Soltero L Gamba G Correa-Rotter R Percutaneous kidney biopsy, analysis of 26 years: complication rate and risk factors; comment Rev Investig Clin 2000 52 2 125 131 10846435 \n2. Parrish AE Complications of percutaneous renal biopsy: a review of 37 years’ experience Clin Nephrol 1992 38 3 135 141 1395165 \n3. Prakash J Singh M Tripathi K Rai US Complications of percutaneous renal biopsy J Indian Med Assoc 1994 92 12 395 396 7876577 \n4. Jackson GG Poirier KP Grieble HG Concepts of pyelonephritis; experience with renal biopsies and long-term clinical observations Ann Intern Med 1957 47 6 1165 1183 10.7326/0003-4819-47-6-1165 13488198 \n5. Tondel C Vikse BE Bostad L Svarstad E Safety and complications of percutaneous kidney biopsies in 715 children and 8573 adults in Norway 1988-2010 Clin J Am Soc Nephrol 2012 7 10 1591 1597 10.2215/CJN.02150212 22837269 \n6. Chen YP Yu YP Huang HE Complications of percutaneous renal biopsy: an analysis of 1000 consecutive biopsies Zhonghua Nei Ke Za Zhi 1993 32 6 392 395 8269772 \n7. Madaio MP Renal biopsy Kidney Int 1990 38 3 529 543 10.1038/ki.1990.236 2232496 \n8. Chiller K Selkin BA Murakawa GJ Skin microflora and bacterial infections of the skin J Investig Dermatol Symp Proc 2001 6 3 170 174 10.1046/j.0022-202x.2001.00043.x \n9. Kirby A Berry C West R Antibiotic consumption and Enterobacteriaceae skin colonization in hospitalized adults J Hosp Infect 2016 95 1 65 68 10.1016/j.jhin.2016.09.012 27756490\n\n",
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"title": "Retroperitoneal abscess with subcutaneous extension: case report of a rare complication of percutaneous renal biopsy.",
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"abstract": "<p>Eruptive melanocytic nevi (EMN) are a rare clinical finding characterized by sudden-onset nevi that often present in a grouped distribution. They have been associated with chemotherapy, immunosuppression, bullous diseases, and medications including multikinase and BRAF inhibitors. It is important for dermatologists to be able to identify patients with sudden development of new melanocytic nevi secondary to particular medications. Herein, we describe a case of eruptive melanocytic acral nevi secondary to 6-mercaptopurine therapy.</p> <p><em>J Drugs Dermatol. 2017;16(5):516-518.</em></p>.",
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"title": "Eruptive Melanocytic Acral Nevi in the Setting of 6-mercaptopurine Therapy.",
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"abstract": "Hyperlipidemia is not unusual in liver transplant recipients, but refractory severe hyperlipidemia is unusual. We treated a 39-year-old man who had severe dyslipidemia after liver transplant. The levels of blood lipids, liver enzymes, and essential indicators of liver pathology were monitored. The first serum sample was collected from the liver recipient 56 days after transplant surgery because samples could not be obtained sooner after the transplant. The levels of liver enzymes and blood lipids were improved with symptomatic treatment but had recurrent fluctuations. Tacrolimus and cyclosporine, even at low doses, may have been the dominant factor affecting the blood lipid levels in the recipient.",
"affiliations": "From the Department of Transplantation, 302 Hospital, Beijing, China.",
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"abstract": "Drug-induced liver injury (DILI) is among the challenging liver conditions encountered by clinicians today. It has a low incidence in the general population with an approximated annual incidence of 10 - 15 cases per 10,000 - 100,000 persons who have taken prescription medications. Nevertheless, DILI remains the most frequent cause of acute liver injury in the United States. Rosuvastatin is a commonly prescribed medication that, similar to other statins, is associated with serum aminotransferase elevations that are mild, asymptomatic and usually self-limited. Here, we report a case of a man who developed acute liver injury after taking rosuvastatin for hypercholesterolemia treatment. Moreover, DILI with autoimmune features represents a key subgroup of hepatotoxicity attributable to medication exposure. Similar to idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are often present in the serum of such individuals. However, such findings are not invariable. In the case reported here, these laboratory features were absent, but a liver biopsy demonstrated interface hepatitis with a prominent plasma cell infiltrate, histologic components consistent with an immune-mediated drug reaction. After withdrawal of the offending medication did not result in complete resolution, corticosteroid therapy was administered with a subsequent clinical response, confirming the diagnosis.",
"affiliations": "Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USA.;Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USA.;Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USA.;Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USA.",
"authors": "Shah|Jamil|J|;Lingiah|Vivek|V|;Pyrsopoulos|Nikolaos|N|;Galan|Mark|M|",
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"fulltext": "\n==== Front\nGastroenterology ResGastroenterology ResElmer PressGastroenterology Research1918-28051918-2813Elmer Press 10.14740/gr1212Case ReportAcute Liver Injury in a Patient Treated With Rosuvastatin: A Rare Adverse Effect Acute Liver Injury After Rosuvastatin TherapyShah Jamil acLingiah Vivek aPyrsopoulos Nikolaos aGalan Mark ba Division of Gastroenterology and Hepatology, Department of Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USAb Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School, Medical Science Building, 185 South Orange Avenue, Newark, NJ 07103, USAc Corresponding Author: Jamil Shah, 899 Woodmere Drive, Valley Stream, NY 11581, USA. Email: jshahid00@gmail.com10 2019 4 10 2019 12 5 263 266 8 8 2019 20 8 2019 Copyright 2019, Shah et al.2019This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Drug-induced liver injury (DILI) is among the challenging liver conditions encountered by clinicians today. It has a low incidence in the general population with an approximated annual incidence of 10 - 15 cases per 10,000 - 100,000 persons who have taken prescription medications. Nevertheless, DILI remains the most frequent cause of acute liver injury in the United States. Rosuvastatin is a commonly prescribed medication that, similar to other statins, is associated with serum aminotransferase elevations that are mild, asymptomatic and usually self-limited. Here, we report a case of a man who developed acute liver injury after taking rosuvastatin for hypercholesterolemia treatment. Moreover, DILI with autoimmune features represents a key subgroup of hepatotoxicity attributable to medication exposure. Similar to idiopathic autoimmune hepatitis, circulating autoantibodies and a hypergammaglobulinemia are often present in the serum of such individuals. However, such findings are not invariable. In the case reported here, these laboratory features were absent, but a liver biopsy demonstrated interface hepatitis with a prominent plasma cell infiltrate, histologic components consistent with an immune-mediated drug reaction. After withdrawal of the offending medication did not result in complete resolution, corticosteroid therapy was administered with a subsequent clinical response, confirming the diagnosis.\n\nRosuvastatinAcute liver injuryDrug-induced liver injuryDrug-induced hepatotoxicity\n==== Body\nIntroduction\nRosuvastatin, like other statins, is commonly used to lower cholesterol levels. Furthermore, when prescribed in higher doses, it may be used as moderate- or high-intensity statin therapy for patients with atherosclerotic cardiovascular disease to reduce the risk of coronary events and stroke. As recently as 2014, rosuvastatin was the most prescribed brand name drug in the United States with 22.3 million prescriptions filled [1].\n\nApproximately 1-3% of individuals taking rosuvastatin will develop serum aminotransferase elevations that are mild, asymptomatic and usually self-limited [2]. Furthermore, aminotransferase levels greater than three times the upper limit of normal occur no more frequently among those treated with rosuvastatin (0.2%) as those receiving placebo (0.3%). Rarely, patients taking rosuvastatin can present with frank, clinically apparent acute liver injury, occurring in less than 1 in 10,000. The threshold to investigate for drug-induced liver injury (DILI) should be low, and early identification and discontinuation of the offending agent without delay is essential. Also, in cases of autoimmune hepatitis-like injury, corticosteroids have been administered successfully.\n\nCase Report\nA 47-year-old healthy Peruvian man was transferred from a community hospital to a tertiary care liver transplant center for advanced liver care. Six weeks earlier, his primary care physician had started him on rosuvastatin 5 mg daily for hypercholesterolemia. At the time, his liver function tests (LFTs) showed an aspartate aminotransferase (AST) of 17 (10 - 40 U/L) and an alanine aminotransferase (ALT) of 19 (10 - 40 U/L). Now, his LFTs showed aminotransferase levels in the 1,000’s, and he was advised to visit his local emergency department.\n\nThe patient was admitted and the rosuvastatin was discontinued. However, his LFTs continued to rise and showed AST of 1,142 U/L (10 - 40 U/L), ALT of 2,260 U/L (10 - 40 U/L), total bilirubin (TB) of 3.53 mg/dL (0.2 - 1.2 mg/dL), alkaline phosphatase (ALP) of 277 U/L (40 - 115 U/L) and international normalized ratio (INR) of 1.1 (0.8 - 1.2). He underwent an interventional radiology-guided liver biopsy. He was then transferred to the tertiary care center for acute liver injury suspected to be secondary to rosuvastatin-induced liver injury.\n\nUpon further questioning, the patient reported a yellow tinge to the skin, mild pruritus and fatigue. He denied experiencing additional symptoms recently. He denied regular alcohol use and reported that he drank an occasional can of beer on weekends. He denied taking any medications (other than rosuvastatin), complementary and alternative medicines, or herbal/dietary/bodybuilding/weight-loss supplements. He denied any drug allergies. He denied a history of intravenous (IV) drug use, smoking, acquiring tattoos or piercings, receiving transfusions of blood or blood products, sexual promiscuity, sexually transmitted infections or rashes, occupational exposure to toxins (he worked as a truck driver), or prior liver diseases or viral hepatitis. He denied any family history of liver disease.\n\nThe patient was afebrile and hemodynamically stable. The physical exam was remarkable for icteric sclera, generalized jaundice, mild right upper quadrant tenderness and a palpable liver edge. His LFTs upon arrival to the tertiary care center showed AST of 1,400, ALT of 2,253 and TB of 9.9. The serum electrolytes and the CBC were within normal limits. The Roussel Uclaf Causality Assessment Method (RUCAM) scale, also referred to as the Council for International Organizations of Medical Sciences (CIOMS) scale, a well-established and validated tool commonly utilized to quantitatively assess causality in cases of suspected DILI, was used. The RUCAM score was calculated to be 9, which was suggestive of a highly probable adverse drug reaction. An abdominal ultrasound revealed non-specific findings often seen in acute hepatitis (Fig. 1).\n\nFigure 1 Abdominal ultrasound. The liver is mildly heterogeneous with coarsened echotexture, non-specific findings that can be seen in hepatitis.\n\nThe patient was started on IV N-acetylcysteine (NAC). Workup for chronic liver diseases was sent to evaluate for other etiologies of acute liver failure. An autoimmune panel, including anti-smooth muscle antibodies (ASMA), antinuclear antibodies (ANA) and anti-liver-kidney microsomal antibodies (anti-LKM); an immunoglobulin G (IgG) level; and workup for hepatotropic viruses were negative, and all test results were ultimately unrevealing. The liver biopsy slides were acquired from the transferring hospital and, interestingly, showed multiple histologic components of autoimmune hepatitis (Fig. 2). In particular, the liver biopsy showed acute severe hepatitis with a portal and lobular mixed inflammatory infiltrate comprised of neutrophils, lymphocytes, plasma cells and scattered eosinophils. There was interface activity and bile duct damage. The histopathology was consistent with a likely immune-mediated drug reaction. Furthermore, immunostains for herpes simplex virus (HSV), cytomegalovirus (CMV) and in situ hybridization of Epstein-Barr virus (EBV), as well as the copper, iron and trichrome stains were performed by the liver pathologist and were unrevealing.\n\nFigure 2 Histopathologic images of the patient’s DILI from liver biopsy showing acute severe hepatitis. There is a portal and lobular mixed inflammatory infiltrate comprised of neutrophils, lymphocytes, plasma cells and scattered eosinophils. There is interface activity present and bile duct damage. The histopathology is consistent with an immune-mediated drug reaction vs. less likely an infectious etiology. (a) H&E stain (× 200). (b) H&E stain (× 400). DILI: drug-induced liver injury.\n\nDespite IV NAC therapy for 5 days as well as the initiation of Ursodiol, the patient’s liver enzymes did not improve. A triple-phase abdominal computed tomography (CT) scan was performed in anticipation of possible evaluation for liver transplantation, and it revealed good hepatic vascular anatomy (Fig. 3).\n\nFigure 3 Abdominal CT scan. There is hypoattenuation around the portal area consistent with mild periportal edema. CT: computed tomography.\n\nDuring the hospital course, the patient remained hemodynamically and neurologically stable with no evidence of hepatic encephalopathy. His LFTs began to show some improvement with AST of 942, ALT of 1,312 and ALP of 167, but the TB increased to 17.2. He was discharged with a plan to closely monitor the LFTs on an outpatient basis.\n\nAfterward, repeat blood work showed an increasing TB. The patient was re-admitted and given a trial course of IV methylprednisolone after which the TB proceeded to decrease. Ultimately, his liver enzymes continued to improve, and he was discharged home in improved and stable condition.\n\nDiscussion\nDILI is among the most commonly cited reasons for medication removal from the market as well as for termination of drug development during and after preclinical studies [3-5]. Both prescription and over-the-counter drugs can cause this liver condition. DILI is frequently overlooked, particularly when patients are taking many medications. Also, the clinical presentation can imitate any type of liver disease, including acute and chronic hepatitis. Moreover, several risk factors, such as intake of acetaminophen and/or alcohol, can potentiate the harmful effects of a medication. Thus, in every patient who presents with acute liver injury, the possibility of DILI should be considered, independent of any known pre-existing liver disease.\n\nDILI can be categorized as intrinsic, or dose-dependent (e.g. acetaminophen toxicity), or idiosyncratic, or dose-independent, with the latter being frequently associated with rosuvastatin therapy [6, 7]. The etiology of hepatic injury from rosuvastatin is unclear. It is minimally (about 10%) metabolized in the liver via CYP 2C9 [8, 9]. The mild, transient serum aminotransferase elevations may be secondary to formation of an inconsequential toxic intermediate of drug metabolism. The rarer clinically apparent acute liver injury attributed to rosuvastatin is frequently accompanied by autoimmune features and, so, may be due to immune mechanisms [8, 9].\n\nIn conclusion, the threshold to investigate for DILI should be low, and early identification and discontinuation of the offending agent without delay is essential. In cases of autoimmune hepatitis-like injury, corticosteroids have been administered successfully, particularly when recovery did not occur immediately [8]. In this case, because there was a pathologic diagnosis of probable drug-induced autoimmune hepatitis, steroids could have been used earlier after the infectious etiologies had been clinically excluded. If given, the dose and duration of therapy should be held to a minimum, and close follow-up after cessation is crucial. Recovery is typically complete within 1 - 2 months. Switching treatment to another statin appears to be safe, but it should be performed with close monitoring for recurrence [7].\n\nNone to declare.\n\nFinancial Disclosure\nNone to declare.\n\nConflict of Interest\nNone to declare.\n\nInformed Consent\nInformed patient consent was obtained for publication of the details of this case.\n\nAuthor Contributions\nJS conceived of the idea for the manuscript. JS designed and drafted the manuscript. VL, NP and MG evaluated and critically revised the manuscript for important intellectual content. MG provided the images.\n==== Refs\nReferences\n1 IMS Health. 1 October 2013 to 30 September 2014. IMS Health, 2014 \n2 Shepherd J Hunninghake DB Stein EA Kastelein JJ Harris S Pears J Hutchinson HG Safety of rosuvastatin Am J Cardiol 2004 94 7 882 888 10.1016/j.amjcard.2004.06.049 15464670 \n3 Ostapowicz G Fontana RJ Schiodt FV Larson A Davern TJ Han SH McCashland TM et al Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Ann Intern Med 2002 137 12 947 954 10.7326/0003-4819-137-12-200212170-00007 12484709 \n4 Xu JJ Diaz D O'Brien PJ Applications of cytotoxicity assays and pre-lethal mechanistic assays for assessment of human hepatotoxicity potential Chem Biol Interact 2004 150 1 115 128 10.1016/j.cbi.2004.09.011 15522265 \n5 Navarro VJ Senior JR Drug-related hepatotoxicity N Engl J Med 2006 354 7 731 739 10.1056/NEJMra052270 16481640 \n6 Gunawan BK Kaplowitz N Mechanisms of drug-induced liver disease Clin Liver Dis 2007 11 3 459 475 v 10.1016/j.cld.2007.06.001 17723915 \n7 Bjornsson E Jacobsen EI Kalaitzakis E Hepatotoxicity associated with statins: reports of idiosyncratic liver injury post-marketing J Hepatol 2012 56 2 374 380 10.1016/j.jhep.2011.07.023 21889469 \n8 Wolters LM Van Buuren HR Rosuvastatin-associated hepatitis with autoimmune features Eur J Gastroenterol Hepatol 2005 17 5 589 590 10.1097/00042737-200505000-00019 15827453 \n9 Sanchez M Castiella A Zapata E Zubiaurre L Perez-Yeboles J Mendibil L Iribarren A Autoimmune hepatitis (Immune-Mediated Liver Injury) induced by rosuvastatin Gastroenterol Hepatol 2018 41 5 311 313 10.1016/j.gastrohep.2017.05.010 28655408\n\n",
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"keywords": "Acute liver injury; Drug-induced hepatotoxicity; Drug-induced liver injury; Rosuvastatin",
"medline_ta": "Gastroenterology Res",
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"title": "Acute Liver Injury in a Patient Treated With Rosuvastatin: A Rare Adverse Effect.",
"title_normalized": "acute liver injury in a patient treated with rosuvastatin a rare adverse effect"
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"abstract": "Multiple sclerosis affects mobility in over 80% of patients. Dalfampridine is the only approved treatment for walking impairment in multiple sclerosis. We assessed dalfampridine utilization in our practice and investigated response using timed 25 foot walk (T25FW) improvement and a patient-reported ambulation inventory.\nChart review identified patients with multiple sclerosis for whom dalfampridine was prescribed. T25FW data were extracted from medical records. Participants completed a dalfampridine-specific version of the multiple sclerosis walking scale (dMSWS-12) to assess the qualitative impact of dalfampridine on ambulation. We evaluated two responder categories: liberally defined as any improvement in T25FW; and over 20% T25FW improvement.\nThe dMSWS-12 questionnaire was completed by 39 patients. Eighteen patients (46%) did not show any T25FW improvement. Of the 21 patients (54%) with T25FW improvement, four patients (11%) showed improvement greater than 20%. Analysis of dMSWS-12 scores showed a median score of 40 (range 12-60). Eleven patients (28%) showed no improvement (dMSWS-12 score ≤36). In contrast to objective T25FW improvement (54%), 28 patients (72%) reported improvement in walking ability (dMSWS-12 score ≥37).\nOur results suggest that T25FW alone might not be sufficient for response characterization and that adding patient-reported measures may further elucidate the therapeutic response.",
"affiliations": "Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.;Department of Neurology, Icahn School of Medicine at Mount Sinai, USA.",
"authors": "Klineova|Sylvia|S|0000-0002-0406-0460;Farber|Rebecca|R|;Friedman|Joshua|J|;Farrell|Colleen|C|;Lublin|Fred D|FD|;Krieger|Stephen|S|",
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"fulltext": "\n==== Front\nMult Scler J Exp Transl ClinMult Scler J Exp Transl ClinMSOspmsoMultiple Sclerosis Journal - Experimental, Translational and Clinical2055-2173SAGE Publications Sage UK: London, England 10.1177/205521731878674210.1177_2055217318786742Original Research PaperObjective and subjective measures of dalfampridine efficacy in clinical practice http://orcid.org/0000-0002-0406-0460Klineova Sylvia Farber Rebecca Friedman Joshua Farrell Colleen Lublin Fred D Krieger Stephen Department of Neurology, Icahn School of Medicine at Mount Sinai, USAThe Corinne Goldsmith Dickinson Center for MS, Department of Neurology, Icahn School of Medicine at Mount Sinai, 5 East 98th Street, Box 1138, New York, NY 10029, USA. sylvia.klineova@mssm.edu09 7 2018 Jul-Sep 2018 4 3 205521731878674223 1 2018 31 5 2018 © The Author(s) 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesCreative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background\nMultiple sclerosis affects mobility in over 80% of patients. Dalfampridine is the only approved treatment for walking impairment in multiple sclerosis. We assessed dalfampridine utilization in our practice and investigated response using timed 25 foot walk (T25FW) improvement and a patient-reported ambulation inventory.\n\nMethods\nChart review identified patients with multiple sclerosis for whom dalfampridine was prescribed. T25FW data were extracted from medical records. Participants completed a dalfampridine-specific version of the multiple sclerosis walking scale (dMSWS-12) to assess the qualitative impact of dalfampridine on ambulation. We evaluated two responder categories: liberally defined as any improvement in T25FW; and over 20% T25FW improvement.\n\nResults\nThe dMSWS-12 questionnaire was completed by 39 patients. Eighteen patients (46%) did not show any T25FW improvement. Of the 21 patients (54%) with T25FW improvement, four patients (11%) showed improvement greater than 20%. Analysis of dMSWS-12 scores showed a median score of 40 (range 12–60). Eleven patients (28%) showed no improvement (dMSWS-12 score ≤36). In contrast to objective T25FW improvement (54%), 28 patients (72%) reported improvement in walking ability (dMSWS-12 score ≥37).\n\nConclusion\nOur results suggest that T25FW alone might not be sufficient for response characterization and that adding patient-reported measures may further elucidate the therapeutic response.\n\nMultiple sclerosisgaitdalfampridinetreatment responsetimed 25 foot walkoutcome measurementcover-dateJuly-September 2018\n==== Body\nBackground\nMultiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults1 and affects mobility in more than 80% of patients. Intact ambulation is one of the most highly ranked quality of life indicators2 and decreased mobility negatively affects both patients and their caregivers.3 Befitting the importance of walking for the livelihood and independence of people with MS, many therapeutic strategies have focused on this target. To date, dalfampridine is the only US Food and Drug Administration approved agent for walking impairment in multiple sclerosis. Dalfampridine is a broad spectrum potassium channel blocker, which selectively blocks voltage-sensitive potassium channels. The proposed mechanism of action in MS is the prolongation of action potentials in demyelinated axons and improved conduction.4\n\nThe efficacy of dalfampridine was demonstrated in two randomized, placebo-controlled phase III trials involving 540 patients with MS. Analyzing the difference in the proportion of responders in treatment and placebo groups, both trials demonstrated a significant improvement in walking speed, derived from the timed 25 foot walk (T25FW), in 35% and 43% of patients in active arms, respectively. Responders, defined as patients with consistent improvement of T25FW speed during treatment period, manifested an average speed improvement of 25%.5,6 The sustainability of dalfampridine response beyond 14 weeks was later demonstrated in long-term, open-label extensions of both studies. Despite the fact that walking speed declined from its peak during the duration of the extension trials, walking speed in the responders remained better than the pre-dalfampridine baseline speed.7\n\nIn the post-approval setting, dalfampridine efficacy was evaluated in smaller clinical studies, both open label and placebo controlled, showing concordant results.8,9 However, only very few were performed in a clinical care practice setting utilizing real-world data.10,11 We hypothesized that real-world dalfampridine efficacy could be better assessed through patient-reported outcomes utilized in clinical practice as compared with objective measures of T25FW speed employed in clinical trials. We assessed dalfampridine utilization in our practice setting and investigated the magnitude of response using both an objective measure (T25FW time improvement) and a patient-reported inventory of ambulatory function.\n\nMethods\nThis study was approved by the institutional review board of the Icahn School of Medicine at Mount Sinai and all participants provided informed consent.\n\nParticipants\nResearch participants were enrolled at the Corinne Goldsmith Dickinson Center for Multiple Sclerosis at Mount Sinai. Retrospective chart review identified all patients with a confirmed diagnosis of MS12 for whom dalfampridine was prescribed from March 2010 to August 2013. Only patients with dalfampridine treatment for 3 months or longer were included to ensure adequate drug exposure and to match the length of the clinical trials of this agent. Participants with at least two T25FW time measurements within 2 years pre and post-dalfampridine treatment initiation were included in the analyses.\n\nTimed 25 foot walk\nT25FW data were extracted from the electronic medical records. This measure is obtained during each clinical visit and performed as described in the Administration and Scoring Manual published by the National Multiple Sclerosis Society.13 The average time between T25FW assessments was 3 months. To address possible within-subject fluctuations in T25FW, and establish a more stable pre and post-dalfampridine T25FW values for each patient, the mean T25FW time was calculated using data from at least two separate clinical visits. T25FW measures captured after the initiation of dalfampridine were acquired while patients remained on this treatment.\n\nModified multiple sclerosis walking scale\nAll participants in the dalfampridine database were asked to complete a dalfampridine-specific version of the multiple sclerosis walking scale (dMSWS-12) to assess the qualitative impact of dalfampridine on ambulation. The MSWS-12 is a validated and reliable self-report qualitative measure of the impact MS has on ambulation.14 Building on this platform, our dalfampridine-specific version of the MSWS-12 assessed the patient-reported impression of the effect of dalfampridine on overall ambulation including gait-related features such as walking distance, effort to walk and walking speed. In particular, we asked the patients to rate the change (positive, negative or none) in walking since starting dalfampridine. Congruent with the MSWS-12, the dMSWS-12 also consists of 12 questions with Likert scale-type responses ranging from significantly worsened (1) to significantly improved (5). The minimum score of 12 represents significantly worsened ambulation, a score of 36 represents no improvement and a score of 60 indicates maximally improved ambulation during dalfampridine treatment. Mean impact scores for individual gait-related features were also calculated using previously published methodology.15\n\nStatistical analysis\nAll statistical analyses were performed using IBM SPSS Statistics 22 (Chicago, IL, USA). Basic demographic characteristics, T25FW time analysis and dMSWS-12 data analysis were performed using descriptive statistics. The distribution of data was tested using the Shapiro–Wilk normality test. We evaluated two T25FW responder categories: liberally defined as any improvement in T25FW; and as defined by Schwid et al. as greater than 20% T25FW improvement.16\n\nResults\nChart review identified 221 patients for whom dalfampridine treatment was prescribed. Dalfampridine was shipped to 174 patients, 12 of whom never began therapy. Thirty patients discontinued dalfampridine in under 3 months due to lack of subjective benefit. Sixty-seven patients had insufficient visits or documentation during the time window, and six patients treated with dalfampridine were non-ambulatory at baseline.\n\nThe dMSWS-12 questionnaire was distributed to 59 eligible patients. The response rate was 66% and yielded a sample of 39 patients with 26 women (67%). Twenty five patients had a progressive form of MS (64%) and mean disease duration was 12.2 years (range 1.3–28.9 years). The median dalfampridine pre-treatment T25FW was 9.7 seconds (range 3.6–66.3 seconds) (Table 1).\n\nTable 1. Baseline demographics.\n\nStudy participants\tN=39\t\nSex\tFemale 67% (26)\t\n\tMale 33% (13)\t\nAge\tMean 55.5 years\t\n\t(range 35–69 years)\t\nDisease course\tRRMS 36% (14)\t\n\tSPMS 36% (14)\t\n\tPPMS 15% (6)\t\n\tProgressive MS not specified: 13% (5)\t\nDisease duration\tMean 12.1 years\t\n\t(range 1.3–28.9 years)\t\nPre-treatment T25FW\tMedian 9.70 seconds\t\n\t(range 3.6–66.30 seconds)\t\nPost-treatmentT25FW\tMedian 6.65 seconds(range 4.15–48.09 seconds)\t\nCurrent dalfampridine treatment\t87% (34 patients)\t\nConcurrent physical therapy/home exercise\t59% (23 patients)\t\ndMSWS-12 score\tMedian 41 (range 12–60)\t\nRRMS: relapsing–remitting multiple sclerosis; SPMS: secondary progressive multiple sclerosis; PPMS: primary progressive multiple sclerosis; MS: multiple sclerosis; T25FW: timed 25 foot walk; dMSWS-12: dalfampridine-specific version of the multiple sclerosis walking scale.\n\nVariable degrees of T25FW improvement were seen (Figure 1). The median dalfampridine post-treatment T25FW time was 6.65 seconds (range 4.15–48.09 seconds). Eighteen patients (46%) did not show any improvement. Of the 21 patients (54%) who showed T25FW improvement, only four patients (11%) showed improvement greater than 20%. The distribution of T25FW values is shown in Figure 2(a).\n\nFigure 1. Plot of individual patients’ T25FW times pre and post-dalfampridine initiation. Graph depicts inter and intra-personal variability and walking speed trends over time. Patients are shown in ascending order of pre-treatment walking speed. Note the Y axis is the log scale of T25FW times, best to depict a broad range of 3.6–66.3 second pre-dalfampridine walking speeds.\n\nFigure 2. Objective and subjective response to dalfampridine. Graphs (a) and (b) depict the objective and subjective response to dalfampridine. A long tail of gait improvement is seen in the patient-reported measure despite a long tail of gait worsening as assessed by the T25FW, further underscoring the discordance between these two measures. (a) Objective response to dalfampridine (T25FW). (b) Subjective response to dalfampridine (dMSWS-12).\n\nRegarding the continuation of dalfampridine, our records showed that 34 patients (87%) continued dalfampridine treatment at the time of the last follow-up visit and dMSWS-12 assessment.\n\nAnalysis of dMSWS-12 (Table 2) scores demonstrated a median score of 40 (range 12–60). Eleven patients (28%) reported no improvement (dMSWS-12 score ≤36). Twenty-eight patients (72%) reported improvement in walking ability (dMSWS-12 score ≥37). The distribution of dMSWS-12 scores are shown in Figure 2(b).\n\nTable 2. Dalfampridine-specific multiple sclerosis walking scale (dMSWS-12).\n\nSince starting Ampyra, has there been:\tWorsened significantly\tWorsened somewhat\tUnchanged\tImproved somewhat\tImproved significantly\t\n1) A change in your ability to walk?\t1\t2\t3\t4\t5\t\n2) A change in your ability to run?\t1\t2\t3\t4\t5\t\n3) A change in your ability to climb up and down stairs?\t1\t2\t3\t4\t5\t\n4) A change in your ability to stand while doing things?\t1\t2\t3\t4\t5\t\n5) A change in your balance when standing or walking?\t1\t2\t3\t4\t5\t\n6) A change in how far you are able to walk?\t1\t2\t3\t4\t5\t\n7) A change in the effort needed for you to walk?\t1\t2\t3\t4\t5\t\n8) A change in how necessary it is for you to use support when walking indoors (e.g. holding on to furniture, using a stick, etc.)?\t1\t2\t3\t4\t5\t\n9) A change in how necessary it is for you to use support when walking outdoors (e.g. using a stick, a frame, etc.)?\t1\t2\t3\t4\t5\t\n10) A change in your walking speed?\t1\t2\t3\t4\t5\t\n11) A change in how smoothly you walk?\t1\t2\t3\t4\t5\t\n12) A change in how necessary it is for you to concentrate on your walking?\t1\t2\t3\t4\t5\t\nAmpyra: dalfampridine.\n\nTo examine further the impact of dalfampridine on individual gait-related components of the dMSWS-12, we calculated mean impact scores for each gait-related characteristic.15 Dalfampridine showed the highest impact on patient-reported walking ability (impact score 3.85), walking distance (3.54), effort to walk (3.54) and walking speed (3.49).\n\nWith regard to additional therapeutic interventions with a potential influence on mobility, 23 patients (59%) had documented continuous physical therapy or independent exercise routine during the pre and post-T25FW assessment period. To evaluate for confounders, we assessed if physical therapy/exercise was associated with dMSWS-12 score or either definition of T25FW responder status, and we found no independent association.\n\nDiscussion\nThis study explored the profile of objective and subjective dalfampridine impact on ambulation in clinical practice, and added to the small number of studies evaluating dalfampridine performance in this setting.\n\nRandomized clinical trials are the gold standard for the determination of treatment efficacy but the ideal conditions of a trial differ from routine clinical practice. In contrast, studies performed in a real-world setting offer a more pragmatic approach and the results are often pertinent in clinical decision-making. Unlike the dalfampridine clinical trials, which evaluated treatment response in an immediate time period after treatment start,5,6 we chose to evaluate the T25FW response in the timeframe reflective of therapeutic expectations in everyday clinical practice (at >3 months of dalfampridine treatment and up to 2 years post-treatment initiation). In addition, the use of the qualitative tool dMSWS-12 supplemented the T25FW data by evaluating not just short distance walking speed observed in the office, but patient-reported walking ability more comprehensively.\n\nOur clinical practice cohort demonstrated a lower rate and magnitude of T25FW improvement than was seen in clinical trials in which 35% and 43% of dalfampridine-treated patients demonstrated an average T25FW speed improvement of 25%. Unlike the pivotal trials, we used T25FW time as an objective measure of treatment response. We chose this approach because T25FW time, rather than speed, is the measure typically used in real-world clinical practice and provides pragmatic and relatable information for clinicians. Our results are concordant with work by German authors who examined dalfampridine responders while assessing the predictive value of motor-evoked potentials for dalfampridine response. Similar to our results, the authors found only 15% of patients with greater than 20% T25FW time improvement. The response rate increased to 45% after liberalization of response criterion to over 10% of T25FW improvement.11\n\nOur results also suggest that T25FW when used alone might be an insensitive measurement tool for patient-perceived therapeutic response to dalfampridine. The reliability of T25FW in the MS population has been validated previously but it can be offset by differences in administration and day-to-day performance variability, especially in patients with greater disability.17,18 Despite the low rate and magnitude of dalfampridine response on the T25FW in our cohort, the majority (87%) of patients continued the treatment and 72% of patients reported benefits not only for walking speed but also for walking distance and effort. It is possible that the use of different assessment tools with higher sensitivity for walking distance and endurance can provide better characterization of dalfampridine treatment response and sustainability. Cameron et al.10 evaluated dalfampridine response in veterans while using the T25FW, 2-minute timed walk test (2MTW) and MSWS-12 as assessment measures. Their results showed that while the effect of dalfampridine on T25FW was lost at 1 year follow-up, the 2MTW and MSWS-12 showed sustained significant improvement.10 This again is similar to our findings, which showed subjective improvement in ambulation despite the lack of objective T25FW improvement, with a high patient-reported impact of dalfampridine on walking distance and walking endurance. When comparing the distributions of objective and subjective dalfampridine response depicted in Figure 2(a and b), respectively, there is a clear difference in the skew of these graphs. A long tail of gait improvement is seen in the patient-reported measure despite a long tail of gait worsening as assessed by the T25FW, further underscoring the discordance between these two measures. These results suggest that T25FW alone might not be sufficient for response characterization and that adding qualitative and other objective measures sensitive to other aspects of ambulation may further elucidate the therapeutic response to dalfampridine.\n\nOur project has several limitations. This was a single center retrospective project with a modest sample size. The T25FW data were extracted from the medical records and a proportion of insufficient visits or documentation limited our sample. Dalfampridine response in patients who discontinued the drug in less than 3 months was not captured as these patients did not have adequate exposure to the treatment. Excluding those patients does not clearly bias our results in one direction, however, as this group may have comprised both T25FW responders and non-responders. Unlike in clinical trials, we used a longer timeframe and variable time points for T25FW acquisition. However, as we intended to evaluate dalfampridine efficacy in clinical practice, our parameters mirror standard of care more closely. Finally, the dMSWS-12, our modification of the MSWS-12 to identify the effect of dalfampridine as a retrospective patient-reported outcome, is an assessment tool that has not been independently validated which poses a limitation on our project. The MSWS-12 was, however, modified only insofar as we are querying patient-reported gait experience while on this agent. The content of the questions and their answers and scoring have not been altered from the validated MSWS-12. This allowed us to focus on dalfampridine impact on ambulation, whereas the unmodified MSWS-12 itself would not sufficiently instruct patients on describing the relationship between dalfampridine and gait function that we aimed to evaluate. In addition, the single time point administration of dMSWS-12 could lead to recall bias. This is an inherent disadvantage for any retrospective patient-reported measure, and the results should be interpreted with caution and will require further replication in a prospective manner.\n\nIn conclusion, this project characterized the dalfampridine response profile in clinical practice, and our results suggest that the T25FW when used alone is an insensitive measure of dalfampridine response and supports the use of supplementary assessment tools such as dMSWS-12, further to uncover additional therapeutic benefits of this agent on ambulatory function.\n\nAcknowledgements\nThe authors would like to thank Shelly Ebel and Christine Hannigan for their coordination work in support of this project.\n\nConflict of Interests\nThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: S Klineova has received compensation for advisory board work with Teva, Genentech and Biogen Idec and has given non-promotional lectures with Biogen Idec. R Farber has received compensation for advisory board work with Teva. FD Lublin has received compensation for consulting and advisory board work with Bayer HealthCare Pharmaceuticals, Biogen Idec, EMD Serono, Inc., Novartis, Teva Neuroscience, Actelion, Sanofi/Genzyme, Acorda, Questcor/Malinckrodt, Roche/Genentech, Celgene, MedImmune, Osmotica, Xenoport, Receptos, Forward Pharma, BBB Technologies, Akros, TG Therapeutics and Abbvie, and sources of funding for research from Biogen Idec, Novartis Pharmaceuticals Corp, Teva Neuroscience, Inc., Genzyme, Sanofi, Celgene, Transparency Life Sciences, NIH and NMSS. S Krieger has received compensation for consulting and advisory board work with Acorda Therapeutics, Bayer HealthCare, Biogen Idec, EMD Serono, Genentech, Genzyme, Mallinckrodt, Novartis, Teva and TG Therapeutics, and has given non-promotional lectures with Biogen Idec. C Farrell completed this work while working at Mount Sinai and now works for Novartis. J Friedman has nothing to disclose.\n\nFunding\nThe author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 Tullman MJ. \nOverview of the epidemiology, diagnosis, and disease progression associated with multiple sclerosis . Am J Managed Care \n2013 ; \n19 (2 Suppl ): S15 –S20 .\n2 Remelius JG Jones SL House JD et al \nGait impairments in persons with multiple sclerosis across preferred and fixed walking speeds. \nArch Phys Med Rehabil \n2012 ; \n93 : 1637 –1642 .22559932 \n3 Larocca NG. \nImpact of walking impairment in multiple sclerosis: perspectives of patients and care partners. \nThe Patient \n2011 ; \n4 : 189 –201 .21766914 \n4 Dunn J Blight A. \nDalfampridine: a brief review of its mechanism of action and efficacy as a treatment to improve walking in patients with multiple sclerosis. \nCurr Med Res Opin \n2011 ; \n27 : 1415 –1423 .21595605 \n5 Goodman AD Brown TR Krupp LB et al \nSustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. \nLancet \n2009 ; \n373 : 732 –738 .19249634 \n6 Goodman AD Brown TR Edwards KR et al \nA phase 3 trial of extended release oral dalfampridine in multiple sclerosis. \nAnn Neurol \n2010 ; \n68 : 494 –502 .20976768 \n7 Goodman AD Bethoux F Brown TR et al \nLong-term safety and efficacy of dalfampridine for walking impairment in patients with multiple sclerosis: results of open-label extensions of two phase 3 clinical trials. \nMult Scler (Houndmills, Basingstoke, England) \n2015 ; \n21 : 1322 –1331 .\n8 Brambilla L Rossi Sebastiano D Aquino D et al \nEarly effect of dalfampridine in patients with MS: a multi-instrumental approach to better investigate responsiveness. \nJ Neurol Sci \n2016 ; \n368 : 402 –407 .27538672 \n9 Zorner B Filli L Reuter K et al. \nProlonged-release fampridine in multiple sclerosis: Improved ambulation effected by changes in walking pattern. \nMult Scler (Houndmills, Basingstoke, England) \n2016 ; 22(11): 1463–1475.\n10 Cameron MH Fitzpatrick M Overs S et al \nDalfampridine improves walking speed, walking endurance, and community participation in veterans with multiple sclerosis: a longitudinal cohort study. \nMult Scler (Houndmills, Basingstoke, England) \n2014 ; \n20 : 733 –738 .\n11 Zeller D Reiners K Brauninger S et al \nCentral motor conduction time may predict response to fampridine in patients with multiple sclerosis. \nJ Neurol, Neurosurg Psychiatry \n2014 ; \n85 : 707 –709 .24357684 \n12 Polman CH Reingold SC Banwell B et al \nDiagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. \nAnn Neurol \n2011 ; \n69 : 292 –302 .21387374 \n13 Fisher JS Jak AJ Kniker JE et al \nMultiple Sclerosis Functional Composite Administration and Scoring Manual . \nLondon, Ontario Canada : \nNational Multiple Sclerosis Society , 2001 .\n14 Hobart JC Riazi A Lamping DL et al \nMeasuring the impact of MS on walking ability: the 12-Item MS Walking Scale (MSWS-12). \nNeurology \n2003 ; \n60 : 31 –36 .12525714 \n15 Sullivan GM Artino AR Jr. \nAnalyzing and interpreting data from Likert-type scales. \nJ Grad Med Educ \n2013 ; \n5 : 541 –542 .24454995 \n16 Schwid SR Goodman AD McDermott MP et al \nQuantitative functional measures in MS: what is a reliable change? \nNeurology \n2002 ; \n58 : 1294 –1296 .11971105 \n17 Larson RD Larson DJ Baumgartner TB et al \nRepeatability of the timed 25-foot walk test for individuals with multiple sclerosis. \nClin Rehabil \n2013 ; \n27 : 719 –723 .23426567 \n18 Kieseier BC Pozzilli C. \nAssessing walking disability in multiple sclerosis. \nMult Scler (Houndmills, Basingstoke, England) \n2012 ; \n18 : 914 –924 .\n\n",
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"keywords": "Multiple sclerosis; dalfampridine; gait; outcome measurement; timed 25 foot walk; treatment response",
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"title": "Objective and subjective measures of dalfampridine efficacy in clinical practice.",
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"abstract": "OBJECTIVE\nTo investigate differences in outcomes of acute retinal necrosis with confirmed viral polymerase chain reaction between viral types and highlight different treatment options.\n\n\nMETHODS\nThe study evaluated 22 eyes in 18 patients of polymerase chain reaction-positive acute retinal necrosis at the University of Pittsburgh Medical Center from 2007 to 2018. Outcome measures included final visual acuity, treatment paradigms, and retinal detachment rate.\n\n\nRESULTS\nEight eyes were polymerase chain reaction-positive for varicella zoster virus, two eyes for herpes simplex virus Type 1 (HSV-1), and 12 eyes for herpes simplex virus Type 2 (HSV-2). Final Snellen best-corrected visual acuity averaged 20/51 for varicella zoster virus, 20/25 for HSV-1, and 20/814 for HSV-2. Retinal detachment occurred in 2 (25%) of varicella zoster virus eyes and 8 (75%) of HSV-2 eyes. One eye with HSV-1 and three eyes with HSV-2 received cidofovir for treatment of refractory retinitis.\n\n\nCONCLUSIONS\nAcute retinal necrosis secondary to HSV-2 tended to have persistent active retinitis with a higher rate of retinal detachment despite similar treatment protocols, suggesting that in some cases combination intravenous acyclovir and adjuvant intravitreal foscarnet injections are not sufficient. Despite the risk of renal toxicity, intravenous cidofovir may be a consideration in select patients.",
"affiliations": "Retina Service, Department of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.",
"authors": "Botsford|Benjamin W|BW|;Nguyen|Vincent Q|VQ|;Eller|Andrew W|AW|",
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"title": "ACUTE RETINAL NECROSIS: Difference in Outcome by Viral Type and Options for Antiviral Therapy.",
"title_normalized": "acute retinal necrosis difference in outcome by viral type and options for antiviral therapy"
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"abstract": "Reports exist of severe upper back pain of unknown etiology after administration of large volumes into the epidural space. We present a case of an otherwise healthy parturient who developed severe upper back and neck pain after receiving only a small volume of epidural medication. Magnetic resonance imaging revealed a congenitally narrowed spinal canal because of short pedicle syndrome. Epidural injectate occupies and compresses a percentage of the spinal canal and its neuronal contents. This may result in pain and epidural intolerance when continued injectate reaches a critical point, a threshold that is lower with shortened pedicles or congenital spinal stenosis. We believe a similar mechanism may explain the pain that patients sometimes experience after administration of large epidural volumes.",
"affiliations": "From the *Department of Anesthesia and Critical Care, University of Chicago, Chicago, IL; and †Ochsner Health System, New Orleans, LA.",
"authors": "Dickerson|David M|DM|;Dai|Ran|R|;Scavone|Barbara M|BM|;McDade|William|W|",
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"title": "Labor Epidural Intolerance Due to a Congenitally Narrowed Spinal Canal.",
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"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nNatalizumab long-term effectiveness data in real-world relapsing-remitting multiple sclerosis (RRMS) is needed. Our objective is to report the long-term effectiveness and safety of natalizumab in a cohort of RRMS patients.\n\n\nMETHODS\nThis is a retrospective study of natalizumab treatment for two years or longer in RRMS. Annualized relapse rate, Expanded Disability Status Scale (EDSS), brain magnetic resonance imaging T2 lesion volume, JC virus antibody status, previous treatments and adverse events were analysed.\n\n\nRESULTS\nSeventy-one patients were included with a mean treatment duration of 44.86±17.39months. Over the treatment duration there was a significant decrease in annualized relapse rate (88.37%) and EDSS (28.57%); no evidence of clinical disease activity in 73.24% and 61.97% after one and two-years respectively; and brain magnetic resonance imaging T2 lesion volume remained stable. Forty patients suspended natalizumab, in 85% due to high risk of developing progressive multifocal leukoencephalopathy (PML). The major complication was PML (n=3).\n\n\nCONCLUSIONS\nNatalizumab showed effectiveness in the long-term follow up period of our cohort, with reduction of ARR, EDSS, and MRI lesion load stabilization. PML was the major complication.",
"affiliations": "Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal. Electronic address: mcorreia.ines@gmail.com.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neuroradiology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.;Department of Neurology, Centro Hospitalar e Universitário de Coimbra, Portugal.",
"authors": "Correia|I|I|;Batista|S|S|;Galego|O|O|;Marques|I B|IB|;Jesus-Ribeiro|J|J|;Martins|A I|AI|;Nunes|C|C|;Macário|M C|MC|;Cunha|L|L|;Sousa|L|L|",
"chemical_list": "D000069442:Natalizumab",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.intimp.2017.03.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1567-5769",
"issue": "46()",
"journal": "International immunopharmacology",
"keywords": "Monoclonal antibodies; Multiple sclerosis; Natalizumab; Relapsing-remitting; Treatment outcome",
"medline_ta": "Int Immunopharmacol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001921:Brain; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007968:Leukoencephalopathy, Progressive Multifocal; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020529:Multiple Sclerosis, Relapsing-Remitting; D000069442:Natalizumab; D011174:Portugal; D012189:Retrospective Studies; D012306:Risk; D028761:Withholding Treatment; D055815:Young Adult",
"nlm_unique_id": "100965259",
"other_id": null,
"pages": "105-111",
"pmc": null,
"pmid": "28282574",
"pubdate": "2017-05",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "Long-term effectiveness and safety of natalizumab in a Portuguese population.",
"title_normalized": "long term effectiveness and safety of natalizumab in a portuguese population"
} | [
{
"companynumb": "PT-BIOGEN-2011BI012850",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "We describe a case of reproducible asystole during endovascular treatment of a posterior fossa dural arteriovenous fistula. Catheterisation of the posterior meningeal artery, a branch of the vertebral artery in this patient, followed by dimethyl sulfoxide injection prior to Onyx administration resulted in two episodes of asystole.To the best of our knowledge, this is the first reported case of asystole occurring during endovascular intervention in the posterior meningeal artery. This may represent a previously undescribed variant of the trigemino-cardiac reflex (TGCR) caused by chemical stimulation of small areas of trigeminally innervated posterior fossa dura. Alternatively, this may represent a newly identified phenomenon with chemical stimulation of regions of posterior fossa dura innervated by branches of the vagus nerve leading to increased parasympathetic activity and resultant asystole.In either case, it is important to recognise the potential for such episodes in this vascular territory to allow case planning and management.",
"affiliations": "Neurological Intervention and Imaging Service of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.;Neurological Intervention and Imaging Service of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.;Department of Anaesthesia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.;Neurological Intervention and Imaging Service of Western Australia, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.",
"authors": "Crockett|Matthew Thomas|MT|http://orcid.org/0000-0002-3758-9395;Robinson|Anthony Ernest|AE|http://orcid.org/0000-0002-8632-0130;Aneja|Harmeet|H|;Phillips|Timothy John|TJ|http://orcid.org/0000-0001-9023-5986",
"chemical_list": "D016166:Free Radical Scavengers; D011145:Polyvinyls; D004121:Dimethyl Sulfoxide",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-221033",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "interventional radiology; neuroimaging; neurosurgery; radiology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D020785:Central Nervous System Vascular Malformations; D004121:Dimethyl Sulfoxide; D004388:Dura Mater; D005260:Female; D016166:Free Radical Scavengers; D006323:Heart Arrest; D006801:Humans; D007267:Injections; D008576:Meningeal Arteries; D008875:Middle Aged; D010275:Parasympathetic Nervous System; D011145:Polyvinyls; D059230:Reflex, Trigeminocardiac; D014630:Vagus Nerve",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28739568",
"pubdate": "2017-07-24",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15311339;15680656;17885228;20377980;21654337;22120554;25501269;25654391;27341858;27382015;28072687;4298412;9950491",
"title": "Posterior meningeal artery DMSO injection resulting in reproducible asystole prior to Onyx therapy of a dural arteriovenous fistula: a previously undescribed variant of the trigeminocardiac reflex or a new phenomenon?",
"title_normalized": "posterior meningeal artery dmso injection resulting in reproducible asystole prior to onyx therapy of a dural arteriovenous fistula a previously undescribed variant of the trigeminocardiac reflex or a new phenomenon"
} | [
{
"companynumb": "AU-MYLANLABS-2017M1059453",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIMETHYL SULFOXIDE"
},
"drugadditional": "3",... |
{
"abstract": "Understanding the long-term effect of alemtuzumab on the immune system of multiple sclerosis (MS) patients is crucial.\n\n\n\nTo report a case of acute sarcoidosis (Löfgren's syndrome) in a relapsing-remitting MS patient, 1.5 years after the second course of alemtuzumab treatment.\n\n\n\nSarcoidosis was confirmed dermatohistologically, radiologically, and serologically. Analysis of the lymphocyte subpopulations showed a persistent effect of alemtuzumab treatment (CD4/CD8 ratio increased, absolute lymphocyte count of CD19-positive cells increased while CD3/4/8-positive cells were decreased).\n\n\n\nOur case highlights the profound effect of alemtuzumab on the immune system and its possible risk for autoimmune complications.",
"affiliations": "Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Dermatopathologie Duisburg, Germany.;Gemeinschaftspraxis für Radiologie und Nuklearmedizin am Bethesda Krankenhaus, Mönchengladbach, Germany.;Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.;Department of Neurology, University Hospital Düsseldorf, Medical Faculty, Heinrich Heine University Düsseldorf, Düsseldorf, Germany.",
"authors": "Graf|Jonas|J|;Ringelstein|Marius|M|;Lepka|Klaudia|K|;Schaller|Jörg|J|;Quack|Helmut|H|;Hartung|Hans-Peter|HP|;Aktas|Orhan|O|0000-0002-2020-9210;Albrecht|Philipp|P|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D000074323:Alemtuzumab",
"country": "England",
"delete": false,
"doi": "10.1177/1352458518771276",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "24(13)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "Multiple sclerosis; alemtuzumab; immune system; immunotherapy; lymphocytes; sarcoidosis",
"medline_ta": "Mult Scler",
"mesh_terms": "D000328:Adult; D000074323:Alemtuzumab; D061067:Antibodies, Monoclonal, Humanized; D018941:Antigens, CD19; D015496:CD4-Positive T-Lymphocytes; D006801:Humans; D018655:Lymphocyte Count; D009103:Multiple Sclerosis; D012507:Sarcoidosis",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1776-1778",
"pmc": null,
"pmid": "30307371",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment.",
"title_normalized": "acute sarcoidosis in a multiple sclerosis patient after alemtuzumab treatment"
} | [
{
"companynumb": "DE-SA-2018SA014984",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": null,
"d... |
{
"abstract": "Our study aimed to analyze the risk of hematologic malignancies (HM) associated with the use of G-CSF with chemotherapy for BC. Using the French National Health Data System, we examined the HM risks in patients diagnosed with an incident breast cancer between 2007 and 2015, who received chemotherapy for BC. Main outcomes were acute myeloid leukemia (AML), Myelodysplastic syndrome (MDS), myeloproliferative neoplasms (MPNs), multiple myeloma (MM), Hodgkin lymphoma or non-Hodgkin lymphoma (HL/NHL) and acute lymphoblastic leukemia or lymphocytic lymphoma (ALL/LL). Among a total of 122 373 BC survivors, 38.9% received chemotherapy only and 61.1% received chemotherapy + G-CSF. Overall, 781 cases of hematologic malignancies occurred. We observed a nonsignificant increase in the risk of AML (aHR, 1.3; 95% CI, 1.0-1.7), of MDS (aHR, 1.3; 95% CI, 0.9-1.8) and of ALL/LL (aHR, 2.0; 95% CI, 1.0-4.4) among patients treated by chemotherapy + G-CSF compared to chemotherapy only. In analyses by dose, we observed a slight increase in the risk of AML (1-3 doses: aHR, 1.2; 95% CI, 0.8-1.7/4+ doses: aHR, 1.3; 95% CI, 1.0-1.8) and of MDS (1-3 doses: aHR, 1.1; 95% CI, 0.7-1.7/4+ doses: aHR, 1.4; 95% CI, 1.0-1.9), a significant increase in risk of ALL (1-3 doses: aHR, 1.5; 95% CI, 0.5-3.9 / 4+ doses: aHR, 2.3; 95% CI, 1.0-5.1) with increasing cycles of G-CSF. Our population-based study showed that the ALL/LL was the only HM at increased risk with the use of growth factors with a possible dose-effect relationship. Our data regarding the risk of all the other HM are reassuring.",
"affiliations": "EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France.;Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France.;Inserm, CNRS, Institut Paoli-Calmettes, CRCM, Aix-Marseille University, Marseille, France.;EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France.;EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France.;EPI-PHARE (French National Agency for Medicines and Health Products Safety (ANSM) and French National Health Insurance (CNAM)), Saint-Denis, France.",
"authors": "Jabagi|Marie Joelle|MJ|0000-0002-7946-7759;Vey|Norbert|N|;Goncalves|Anthony|A|;Le Tri|Thien|T|;Zureik|Mahmoud|M|;Dray-Spira|Rosemary|R|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.33216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "148(2)",
"journal": "International journal of cancer",
"keywords": "breast cancer; cancer complications; hematologic malignancies; real world data; therapy-related complications",
"medline_ta": "Int J Cancer",
"mesh_terms": "D001943:Breast Neoplasms; D015331:Cohort Studies; D005260:Female; D005602:France; D016179:Granulocyte Colony-Stimulating Factor; D019337:Hematologic Neoplasms; D006801:Humans; D008875:Middle Aged; D016609:Neoplasms, Second Primary",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "375-384",
"pmc": null,
"pmid": "32683691",
"pubdate": "2021-01-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Risk of secondary hematologic malignancies associated with breast cancer chemotherapy and G-CSF support: A nationwide population-based cohort.",
"title_normalized": "risk of secondary hematologic malignancies associated with breast cancer chemotherapy and g csf support a nationwide population based cohort"
} | [
{
"companynumb": "FR-AMGEN-FRASP2021030327",
"fulfillexpeditecriteria": "2",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FILGRASTIM"
},
"drugadditional": "3",
... |
{
"abstract": "Aspergillus species have angioinvasive properties and can involve extrapulmonary organs by hematogenous spread from the lungs. However, renal involvement by Aspergillus is uncommon and is usually associated with the formation of abscesses. We report an unusual case of invasive renal aspergillosis presenting with extensive renal infarction in a 5-year-old girl with acute lymphoblastic leukemia. This case emphasizes the fact that renal aspergillosis initially presents with only renal infarction, and metastatic-embolism by invasive aspergillosis should be considered in differential diagnosis for any focal lesion of kidney in a patient with leukemia.",
"affiliations": "Departments of *Radiology †Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.",
"authors": "Lee|Ju Hyun|JH|;Im|Soo Ah|SA|;Cho|Bin|B|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000010",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "36(5)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007238:Infarction; D007668:Kidney; D007674:Kidney Diseases; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e296-8",
"pmc": null,
"pmid": "24136022",
"pubdate": "2014-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Renal infarction secondary to invasive aspergillosis in a 5-year-old girl with acute lymphoblastic leukemia.",
"title_normalized": "renal infarction secondary to invasive aspergillosis in a 5 year old girl with acute lymphoblastic leukemia"
} | [
{
"companynumb": "PHHY2014KR093169",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ASPARAGINASE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Two patients with end-stage-renal-disease on continuous ambulatory peritoneal dialysis (CAPD) presented with pleural effusions. The aspirated fluid was categorised as transudate, based on alkaline pH, low protein and lactic dehydrogenase level. A striking feature of the pleural fluid was, its very high glucose content that resulted from translocation of dextrose containing peritoneal dialysate into the pleural space via a pleuroperitoneal connection. One patient was transferred to hemodialysis, which led to complete resolution of pleural effusion. The other patient was switched to automated peritoneal dialysis, using small dwell volumes with consequent reduction in size of the pleural effusion. Pleuroperitoneal leak should always be considered in the differential diagnosis of pleural effusion in CAPD patients. Although isotopic peritoneography can demonstrate reflux of the tracer in the pleural space, measurement of pleural fluid glucose is a simpler and reliable way of diagnosing pleuroperitoneal communication.",
"affiliations": "Department of Medicine, Hamad General Hospital, Doha, Qatar.",
"authors": "Asim|Muhammad|M|",
"chemical_list": "D019275:Radiopharmaceuticals; C481867:technetium Tc 99m diethylene triamine pentaacetic acid, dimethyl ester; D016284:Technetium Tc 99m Pentetate",
"country": "Pakistan",
"delete": false,
"doi": "2480",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "26(11)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D005260:Female; D006801:Humans; D006876:Hydrothorax; D007676:Kidney Failure, Chronic; D008297:Male; D010529:Peritoneal Cavity; D010531:Peritoneal Dialysis, Continuous Ambulatory; D010996:Pleural Effusion; D011859:Radiography; D011877:Radionuclide Imaging; D019275:Radiopharmaceuticals; D016284:Technetium Tc 99m Pentetate",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "926-928",
"pmc": null,
"pmid": "27981931",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pleural Effusion Developing in Two Patients on Continuous Ambulatory Peritoneal Dialysis.",
"title_normalized": "pleural effusion developing in two patients on continuous ambulatory peritoneal dialysis"
} | [
{
"companynumb": "QA-INTERNATIONAL MEDICATION SYSTEMS, LIMITED-1063240",
"fulfillexpeditecriteria": "1",
"occurcountry": "QA",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DEXTROSE MONOHYDRATE"
},
... |
{
"abstract": "The objectives of this study were to evaluate the safety profile of aflibercept and health-related quality of life (HRQL) in patients with metastatic colorectal cancer (mCRC) provided with aflibercept access before marketing authorization.\n\n\n\nPatients received aflibercept followed by FOLFIRI (fluorouracil, leucovorin, irinotecan) on day 1 of a 2-week cycle until disease progression, unacceptable toxicity, death, or patient/investigator decision to discontinue. Treatment-emergent adverse events (TEAEs) were evaluated, and HRQL was assessed at baseline, cycle 3, and every other cycle using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30, EORTC QLQ-CR29, and EuroQol 5-Dimensions 3-Levels questionnaires (NCT01571284).\n\n\n\nOverall, 779 adult patients with mCRC, who received ≥ 1 prior oxaliplatin-based regimen and had disease progression during or following their last administration of oxaliplatin-based chemotherapy, were enrolled. At data cutoff, all patients had discontinued treatment, mainly owing to disease progression (51.7%). The most common TEAEs of any grade were diarrhea (61.6%), hypertension (48.4%), and nausea (43.3%). The most common grade 3/4 TEAEs were hypertension (24.1%), neutropenia (23.1%), and diarrhea (15.3%). Clinically meaningful changes in HRQL were reported for all measures. Most patients either had an improvement in their HRQL scores or remained stable during the treatment period based on patient-reported outcomes.\n\n\n\nThe data from this study support the tolerability of the combination of aflibercept and FOLFIRI in a setting that more closely approximates real life in patients with mCRC who failed to respond to oxaliplatin-based chemotherapy, and also suggest an improvement in HRQL.",
"affiliations": "Instituto do Cancer do Estado de São Paulo, São Paulo, Brazil; Department of Clinical Oncology, AC Camargo Cancer Center, São Paulo, Brazil. Electronic address: Rachel.riechelmann@accamargo.org.br.;Ramathibodi Hospital, Siriraj Hospital, Bangkok, Thailand.;Department of Oncology, Garibaldi Nesima Hospital, Catania, Italy.;Gerald Bronfman Department of Oncology, McGill University, Segal Cancer Centre, Jewish General Hospital, Montreal, Quebec, Canada.;Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.;IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Division of Medical Oncology, Department of Internal Medicine, Balkan Oncology Hospital, Trakya University, Edirne, Turkey.;Department of Medical Oncology, Hospital Universitario Gregorio Marañón de Madrid, Madrid, Spain.;Gastrointestinal and Lymphoma Unit, The Royal Marsden NHS Foundation Trust, Sutton, United Kingdom.;Department of Clinical Pharmacology and Chemotherapy, N.N. Blokhin National Medical Research Center of Oncology, Moscow, Russia.;Department of Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain.;Thoraco-abdominal Oncosurgical Department, Clinical Central Hospital of the Presidential Administration of the Russian Federation, Moscow, Russia.;Department of Oncology, Antwerp University Hospital, Edegem, Belgium.;Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, Ontario, Canada.;Department of Medical Oncology, Cancer Institute, Hacettepe University, Ankara, Turkey.;Klinikum Neuperlach, Städtisches Klinikum München, Munich, Germany.;Hospital Universitario y Politécnico de La Fe, Valencia, Spain.;Department of Medical Oncology and Comprehensive Cancer Center, University Hospital Grosshadern, Ludwig Maximilian University of Munich, Munich, Germany.;Sanofi (contracted by Ividata-Stats), Paris, France.;Sanofi (contracted by Artech Information Systems LLC), Cambridge, MA.;Sanofi (contracted by Artech Information Systems LLC), Cambridge, MA.;IRCCS Azienda Ospedaliera Universitaria San Martino, Genova, Italy.",
"authors": "Riechelmann|Rachel P|RP|;Srimuninnimit|Vichien|V|;Bordonaro|Roberto|R|;Kavan|Petr|P|;Di Bartolomeo|Maria|M|;Maiello|Evaristo|E|;Cicin|Irfan|I|;García-Alfonso|Pilar|P|;Chau|Ian|I|;Fedyanin|Mikhail Y|MY|;Martos|Carlos Fernández|CF|;Ter-Ovanesov|Mikhail|M|;Peeters|Marc|M|;Ko|Yoo-Joung|YJ|;Yalcin|Suayib|S|;Karthaus|Meinolf|M|;Aparicio|Jorge|J|;Heinemann|Volker|V|;Picard|Pascaline|P|;Bury|Denise|D|;Drea|Edward|E|;Sobrero|Alberto|A|",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clcc.2019.05.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "18(3)",
"journal": "Clinical colorectal cancer",
"keywords": "Antiangiogenic; Colorectal neoplasms; Patient-reported outcome measures; Receptors; Vascular endothelial growth factor",
"medline_ta": "Clin Colorectal Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D003967:Diarrhea; D018450:Disease Progression; D005260:Female; D005472:Fluorouracil; D005500:Follow-Up Studies; D006801:Humans; D006973:Hypertension; D002955:Leucovorin; D008297:Male; D008875:Middle Aged; D009325:Nausea; D009503:Neutropenia; D000071066:Patient Reported Outcome Measures; D011788:Quality of Life; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012720:Severity of Illness Index; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101120693",
"other_id": null,
"pages": "183-191.e3",
"pmc": null,
"pmid": "31221542",
"pubdate": "2019-09",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Aflibercept Plus FOLFIRI for Second-line Treatment of Metastatic Colorectal Cancer: Observations from the Global Aflibercept Safety and Health-Related Quality-of-Life Program (ASQoP).",
"title_normalized": "aflibercept plus folfiri for second line treatment of metastatic colorectal cancer observations from the global aflibercept safety and health related quality of life program asqop"
} | [
{
"companynumb": "BR-PFIZER INC-2020283287",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "We present the case of a 65-year-old immunocompromised male with a history of kidney transplantation, diabetes, coronary artery bypass, and cardiac resynchronization therapy device implantation who was finally diagnosed with an unusual form of infective endocarditis due to co-infection of fungal and bacterial pathogens. He was afebrile at the time of admission and presented with decompensated heart failure and pneumonia. A spleen abscess was discovered incidentally and prompted us to search for a cardiac source of emboli. Culture of the suppurative fluid drained percutaneously from the abscess was positive for Enterococcus and Aspergillus species. Transthoracic and transesophageal echocardiography revealed a mobile vegetation attached to the scarred myocardium of anterior septum - an unusual location for intracardiac vegetations. With regard to the prohibitive risk for redo surgery, the patient was managed medically with broad spectrum antimicrobial therapy. Finally, the patient died with severe sepsis. <Learning objective: Immunocompromised patients are at risk of opportunistic infections such as fungal endocarditis. Co-infection of fungal and bacterial pathogens is very rare. Early diagnosis of such infections needs a high level of clinical suspicion due to its non-specific presentations and culture negative essence. Many patients are afebrile during the disease course. Fungal endocarditis is characterized by large vegetations highly prone to systemic embolization even in the early stages of infection. Mortality is high despite optimal antimicrobial and timely surgery.>.",
"affiliations": "Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology & Metabolism, Iran University of Medical Sciences, Tehran, Iran.;Department of Cardiovascular Disease, Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Department of Radiology, Hazrat-e Rasool General Hospital, Iran University of Medical Sciences, Tehran, Iran.;Antimicrobial Resistance Research Center, Iran University of Medical Sciences, Tehran, Iran.",
"authors": "Hajsadeghi|Shokoufeh|S|;Pakbaz|Marziyeh|M|;Aziz Ahari|Alireza|A|;Kalantari|Saeed|S|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1016/j.jccase.2018.11.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-5409",
"issue": "19(4)",
"journal": "Journal of cardiology cases",
"keywords": "Aspergillus fumigatus; Echocardiography; Endocarditis; Immunosuppression; Kidney transplantation",
"medline_ta": "J Cardiol Cases",
"mesh_terms": null,
"nlm_unique_id": "101549579",
"other_id": null,
"pages": "117-120",
"pmc": null,
"pmid": "30996756",
"pubdate": "2019-04",
"publication_types": "D002363:Case Reports",
"references": "17420802;19273776;20435834;23973985;24197888;24814126;25603977;26341945;27245170;30092074",
"title": "Co-infection with bacterial and fungal endocarditis at scar tissue in an immunocompromised patient.",
"title_normalized": "co infection with bacterial and fungal endocarditis at scar tissue in an immunocompromised patient"
} | [
{
"companynumb": "IR-PFIZER INC-2019133885",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AMPICILLIN SODIUM\\SULBACTAM SODIUM"
},
"druga... |
{
"abstract": "Idiopathic hyperammonemia (IHA) has been described as a complication of intensive chemotherapy for the treatment of hematologic malignancy but has subsequently been found in patients undergoing bone marrow transplantation and in those with solid tumors treated with 5-fluorouracil. Although IHA is a rare complication, it is sometimes associated with high mortality in hematologic malignancies. Here we report the case of a 15-year-old boy in whom hyperammonemia developed during the initial treatment with prednisolone for newly diagnosed acute lymphoblastic leukemia and who survived after early detection and oral lactulose therapy. To the best of our knowledge, this is the first report of IHA that was not induced by intensive chemotherapy, stem cell transplantation, or asparaginase therapy in a patient with newly diagnosed leukemia, but developed during an initial treatment with a steroid. Early detection of IHA by measuring the plasma ammonia level in patients with neurological symptoms may improve the outcome.",
"affiliations": "Departments of *Pediatrics †Pediatric Oncology, Fukushima Medical University School of Medicine, Fukushima, Japan.",
"authors": "Kobayashi|Shogo|S|;Ito|Masaki|M|;Sano|Hideki|H|;Mochizuki|Kazuhiro|K|;Akaihata|Mitsuko|M|;Waragai|Tomoko|T|;Ohara|Yoshihiro|Y|;Hosoya|Mitsuaki|M|;Kikuta|Atsushi|A|",
"chemical_list": "D003561:Cytarabine; D007792:Lactulose; D011239:Prednisolone; D006854:Hydrocortisone; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000255",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(6)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D006801:Humans; D006854:Hydrocortisone; D022124:Hyperammonemia; D007792:Lactulose; D008297:Male; D008727:Methotrexate; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011239:Prednisolone; D011379:Prognosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e361-3",
"pmc": null,
"pmid": "25222063",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Idiopathic Hyperammonemia That Developed During Initial Treatment With Steroid in a Patient With Newly Diagnosed Leukemia.",
"title_normalized": "idiopathic hyperammonemia that developed during initial treatment with steroid in a patient with newly diagnosed leukemia"
} | [
{
"companynumb": "JP-RANBAXY-2014R1-90119",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
... |
{
"abstract": "Primary prostatic melioidosis is a rare presentation of melioidosis even in melioidosis endemic areas. We report a case of a 58-year-old man with underlying diabetes mellitus who presented with a 5-day history of high-grade fever associated with lower urinary tract symptoms. Suprapubic tenderness and tender prostatomegaly were noted on examination. An abdominal computed tomography (CT) scan confirmed the presence of a prostatic abscess. Both blood and prostatic pus cultures grew Burkholderia pseudomallei. He was initially started on intravenous ceftazidime, followed by an escalation to intravenous meropenem. He was discharged home with oral amoxicillin-clavulanate and doxycycline after completing 12 days of meropenem. Unfortunately, his compliance to oral antibiotic therapy was poor, and he succumbed to the disease.",
"affiliations": "Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia.;Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia.;Department of Medical Microbiology and Immunology, Faculty of Medicine, Universiti Kebangsaan Malaysia, 56000 Cheras, Kuala Lumpur, Malaysia.;Department of Pathology, Kuala Lumpur General Hospital, 50586 Kuala Lumpur, Malaysia.;Department of Pathology, Kuala Lumpur General Hospital, 50586 Kuala Lumpur, Malaysia.;Department of Urology, Selayang Hospital, 68100 Batu Caves, Selangor, Malaysia.",
"authors": "Wahab|A A|AA|;Norliyana|N|N|;Ding|C H|CH|;Nurzam|S C H|SCH|;Salbiah|N|N|;Rao|K R|KR|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "Malaysia",
"delete": false,
"doi": "10.47665/tb.37.3.560",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0127-5720",
"issue": "37(3)",
"journal": "Tropical biomedicine",
"keywords": null,
"medline_ta": "Trop Biomed",
"mesh_terms": "D000038:Abscess; D000900:Anti-Bacterial Agents; D016957:Burkholderia pseudomallei; D017809:Fatal Outcome; D006801:Humans; D008296:Malaysia; D008297:Male; D055118:Medication Adherence; D008554:Melioidosis; D008875:Middle Aged; D011469:Prostatic Diseases",
"nlm_unique_id": "8507086",
"other_id": null,
"pages": "560-565",
"pmc": null,
"pmid": "33612771",
"pubdate": "2020-09-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A fatal case of primary melioidotic prostatic abscess: the peril of poor drug compliance.",
"title_normalized": "a fatal case of primary melioidotic prostatic abscess the peril of poor drug compliance"
} | [
{
"companynumb": "MY-PFIZER INC-2021269395",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
"drugaddition... |
{
"abstract": "Henoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitis characterized by deposits of immunoglobulin A in blood vessels. Renal impairment of these patients is the main determinant of prognosis. The optimal treatment of HSP nephritis (HSPN) in children remains controversial, but many clinicians administer an immunosuppressive agent with a corticosteroid. A previous study reported that leflunomide (LEF) with a corticosteroid was effective for adult patients with HSPN and nephrotic proteinuria. However, data on this treatment in pediatric patients is limited.\n\n\n\nWe described our experience at a single center on the use of LEF in 5 pediatric patients who had IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid, and biopsy-proven nephritis. All patients had class II to IIIb lesions based on the International Study of Kidney Disease in Children (ISKDC).\n\n\n\nWe successfully treated all 5 children who had IgA vasculitis with nephritis using LEF with a corticosteroid. Four patients achieved a complete remission of proteinuria, and 1 patient had significantly reduced proteinuria. The children received LEF for 6 months to 12 months, and none of them had severe adverse events.\n\n\n\nTo our knowledge, this is the first case series to report successful treatment of pediatric HSPN with LEF in combination with a corticosteroid.",
"affiliations": "Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street Heping District, 110004, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street Heping District, 110004, Shenyang, China.;Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street Heping District, 110004, Shenyang, China. 1838907885@qq.com.",
"authors": "Hou|Ling|L|0000-0003-2596-9953;Zhang|Zhou|Z|0000-0002-5603-4475;Du|Yue|Y|0000-0002-1095-1120",
"chemical_list": "D007070:Immunoglobulin A; D000077339:Leflunomide",
"country": "England",
"delete": false,
"doi": "10.1186/s12887-021-02866-y",
"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431\nBioMed Central London\n\n2866\n10.1186/s12887-021-02866-y\nResearch\nLeflunomide therapy for IgA vasculitis with nephritis in children\nhttp://orcid.org/0000-0003-2596-9953\nHou Ling\nhttp://orcid.org/0000-0002-5603-4475\nZhang Zhou\nhttp://orcid.org/0000-0002-1095-1120\nDu Yue 1838907885@qq.com\n\ngrid.412467.2 0000 0004 1806 3501 Department of Pediatrics, Shengjing Hospital of China Medical University, No. 36 Sanhao Street Heping District, 110004 Shenyang, China\n8 9 2021\n8 9 2021\n2021\n21 3911 6 2021\n30 8 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\nHenoch-Schönlein purpura (HSP), also called IgA vasculitis, is a systemic vasculitis characterized by deposits of immunoglobulin A in blood vessels. Renal impairment of these patients is the main determinant of prognosis. The optimal treatment of HSP nephritis (HSPN) in children remains controversial, but many clinicians administer an immunosuppressive agent with a corticosteroid. A previous study reported that leflunomide (LEF) with a corticosteroid was effective for adult patients with HSPN and nephrotic proteinuria. However, data on this treatment in pediatric patients is limited.\n\nMethods\n\nWe described our experience at a single center on the use of LEF in 5 pediatric patients who had IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid, and biopsy-proven nephritis. All patients had class II to IIIb lesions based on the International Study of Kidney Disease in Children (ISKDC).\n\nResults\n\nWe successfully treated all 5 children who had IgA vasculitis with nephritis using LEF with a corticosteroid. Four patients achieved a complete remission of proteinuria, and 1 patient had significantly reduced proteinuria. The children received LEF for 6 months to 12 months, and none of them had severe adverse events.\n\nConclusions\n\nTo our knowledge, this is the first case series to report successful treatment of pediatric HSPN with LEF in combination with a corticosteroid.\n\nKeywords\n\nIgA vasculitis\nHenoch-Schönlein purpura nephritis\nLeflunomide\nChildren\nImmunosuppressive agent\nCorticosteroid\nNatural Science Foundation of Liaoning Province, China2020-BS-116 issue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nHenoch-Schönlein purpura (HSP), also called IgA vasculitis, is a type of vasculitis in which small blood vessels accumulate deposits of immunoglobulin A1. HSP is more common in children [1] and is characterized by non-thrombocytopenic purpura, abdominal pain, joint swelling and pain, and hematuria or proteinuria [2]. Renal involvement is an important determinant of long-term prognosis [3–5]. About 30 to 90 % of HSP patients have mild and self-limiting proteinuria and hematuria, and these patients generally have a good prognoses [4–6]. However, an increase in the urine protein level or the development of nephrotic syndrome or rapidly progressive glomerulonephritis is indicative of poor prognosis [7, 8]. Aggressive measures are usually required to improve the long-term outcomes of these patients.\n\nCurrently, clinicians often treat these patients with a combination of corticosteroids and immunosuppressants [9], including cyclophosphamide (CTX) [10], mycophenolate mofetil (MMF) [11], cyclosporine A (CysA) [12], and azathioprine [13]. In our clinical experience, we found that many patients and families do not accept CTX therapy, mainly due to its gonadal toxicity. Although MMF is effective and safe, its high cost may impact treatment decisions. Leflunomide (LEF) is a relatively new oral immunosuppressant that is approved for treatment of rheumatoid arthritis and psoriatic arthritis, but has also been used for treatment of juvenile rheumatoid arthritis, lupus nephritis [14], IgA nephropathy [15], and other conditions. A previous study reported that LEF in combination with a corticosteroid led to good outcomes in adult patients with HSP who had nephrotic-range proteinuria [16]. In addition, LEF is less expensive than many other drugs used to treat HSPN and has a favorable safety profile. However, little is known about the effect of LEF in pediatric patients with HSPN. The present case series describes our experience in the use of LEF for 5 pediatric patients who had IgA vasculitis with nephritis.\n\nMethods\n\nFive children (3 girls and 2 boys) who had diagnoses of IgA vasculitis with nephritis were first admitted to our department between February 2014 and April 2016 and received LEF treatment (Table 1; Fig. 1). The study was approved by the research ethics board of Shengjing Hospital of China Medical University (2016PS41J), and all methods were performed in accordance with the relevant guidelines and regulations. Informed consent was obtained from the parents or legal guardians. Diagnosis was based on EULAR/PRINTO/PRES criteria [17]. Urinary protein was defined as normal (≤ 5 mg/kg/day), pathological (5–50 mg/kg/day), or nephrotic (≥ 50 mg/kg/day). Children weighing 20 to 40 kg received 20 mg of LEF for 3 days followed by a maintenance dose of 10 mg per day; children weighing more than 40 kg received 40 mg of LEF for 3 days followed by a maintenance dose of 20 mg per day. These dosing schedules are based on the drug instruction for treatment of adult rheumatoid arthritis (50 mg for 3 days followed by a maintenance dose of 10–20 mg per day) and our experience of using leflunomide for juvenile idiopathic arthritis.\n\nTable 1 Characteristics of patients at baseline and after LEF treatment\n\nPatient #\tGender\tAge\tBody weight\tPrior Mp therapy\tOrgan involvement\tISKDC grade\tLEF treatment duration\tFollow-up duration\tOutcome\t\n1\tFemale\t12 years\t55 kg\t1.45 mg/kg/day, 12 days\n\n2.18 mg/kg/day, 7 days\n\n\tS, A, K\tII\t8 months\t12 months\tNo skin rash\n\nUP: 8 mg/kg/day\n\n\t\n2\tMale\t12 years\t45 kg\t1.78 mg/kg/day, 3 days\n\n3.56 mg/kg/day, 8 days\n\n11.11 mg/kg/day, 3 days\n\n\tS, K\tIIIb\t7 months\t8 months\tNo skin rash\n\nUP: undetectable\n\n\t\n3\tFemale\t11 years\t35 kg\t2.29 mg/kg/day, 5 days\n\n4.57 mg/kg/day, 6 days\n\n\tS, K, J\tIIIb\t12 months\t18 months\tNo skin rash\n\nUP: undetectable\n\n\t\n4\tFemale\t11 years\t30 kg\t2.67 mg/kg/day, 6 days\n\n5.33 mg/kg/day, 5 days\n\n16.67 mg/kg/day, 3 days\n\n\tS, K, J\tIIIa\t6 months\t32 months\tNo skin rash\n\nUP: undetectable\n\n\t\n5\tMale\t12 years\t45 kg\t1.78 mg/kg/day, 4 days\n\n3.56 mg/kg/day, 8 days\n\n\tS, K\tII\t6 months\t7 months\tNo skin rash\n\nUP: undetectable\n\n\t\nA abdomen, ISKDC International Study of Kidney Disease in Children, K kidney, LEF leflunomide, Mp methylprednisolone, S skin, UP urine protein, J joint\n\nFig. 1 Leg purpura, and PAS staining and immunofluorescence analysis of IgA in renal tissues of 5 pediatric patients before LEF treatment\n\nResults\n\nPatient 1\n\nIn February 2014, a 12-year-old girl was admitted to our hospital for leg purpura, abdominal pain, microscopic hematuria, and proteinuria (25 mg/kg/day). The blood urea nitrogen (BUN) was 4.07 µmol/L, serum creatinine (SCr) was 51 mmol/L, serum albumin was 40.5 g/L, and estimated glomerular filtration rate (eGFR) was 116 mL/min/1.73 m2. A renal biopsy showed 21 glomeruli with diffuse moderate and focal mesangial cell proliferation and an increased mesangial matrix. Immunofluorescence (IF) analysis of the mesangial lesions indicated they were positive for IgA (predominant), IgM, and C3, leading to a diagnosis of HSPN ISKDC class II and M1 E0 S0 T0 C0 (revised Oxford classification ) (Fig. 1). We administered intravenous methylprednisolone (1.45 mg/kg/day for 12 days, followed by 2.18 mg/kg/day for 7 days), and this led to reduced abdominal pain and cutaneous vasculitis, but the proteinuria increased to 41 mg/kg/day. Because of the elevated proteinuria despite 19 days of intravenous steroid therapy, we administered LEF (40 mg/day for 3 days and followed by 20 mg/day for 8 months) and tapered the steroid to oral prednisone. We also administered an angiotension-converting enzyme inhibitor (captopril, 0.5 mg/kg, 2–3 times daily) for 3 months to reduce the proteinuria. The patient received follow-ups every 2 to 3 months. At the 12-month-follow-up, the patient had no recurrence of the skin rash or abdominal pain, normal clinical status and renal function, no hypertension, a urinary protein level of 8 mg/kg/day, 45 red blood cells (RBCs) per high power field (HPF), and no relevant adverse events (Table 1). This girl received oral prednisone for 12 months. Because her clinical status was stable, we scheduled follow-ups every 6 months.\n\nPatient 2\n\nIn July 2014, a 12-year-old boy was admitted to our hospital for microscopic hematuria and proteinuria (43 mg/kg/day). He had a history of leg purpura for 1 month. The BUN was 4.08 µmol/L, serum creatinine was 53.6 mmol/L, serum albumin was 40.7 g/L, and eGFR was 124 mL/min/1.73 m2. A renal biopsy isolated 51 glomeruli. Light microscopy indicated moderate-to-severe mesangial hypercellularity, expanded matrix, and three glomeruli with epithelial crescents. IF analysis indicated the mesangial lesions were positive for IgA (predominant), IgM, and C3, leading to a diagnosis of HSPN ISKDC class IIIb and M1 E0 S0 T0 C1 (revised Oxford classification ) (Fig. 1). We administered intravenous methylprednisolone (1.78 mg/kg/day for 3 days followed by 3.56 mg/kg/day for 8 days), but the proteinuria remained (52 mg/kg/day). We subsequently administered a pulse of intravenous methylprednisolone (11.11 mg/kg/day for 3 days) with subsequent oral prednisone, and this partially resolved the proteinuria (20 mg/kg/day), but also led to increased intraocular pressure (45 mmHg, measured with a noncontact tonometer for a weekly in hospitalized patients) with no symptoms. An intravenous steroid was used for 14 days, and we rapidly tapered the oral prednisone and administered LEF (40 mg/day for 3 days followed by 20 mg/day for 7 months). We also administered captopril (0.5 mg/kg, 2–3 times daily) for 3 months to reduce the proteinuria. The patient received follow-ups every 2 to 3 months. At the 8-month-follow-up, the patient had no recurrence of the skin rash, no detectable urinary protein, no relevant adverse events, normal clinical status and renal function, no hypertension (Table 1). He used oral prednisone for 6 months. Because his clinical status was stable, we scheduled follow-ups every 6 months.\n\nPatient 3\n\nIn April 2016, an 11-year-old girl was admitted to our hospital for leg purpura, bilateral swelling of the wrists, microscopic hematuria, and proteinuria (40 mg/kg/day). The BUN was 1.37 µmol/L, serum creatinine was 29.8 mmol/L, serum albumin was 39.2 g/L, and eGFR was 119 mL/min/1.73 m2. A renal biopsy provided 25 glomeruli. Light microscopy indicated diffuse moderate and focal severe mesangial cell proliferation and increased mesangial matrix, segmental endothelial cell proliferation, visceral and parietal epithelial swelling, two glomeruli with cellular crescents and two other glomeruli with small cellular crescents. There was also focal interstitial edema. IF analysis indicated the mesangial region was positive for IgA, and weakly positive for IgM and C3, leading to a diagnosis of HSPN ISKDC class IIIb and M1 E1 S0 T0 C1 (revised Oxford classification ) (Fig. 1). We administered intravenous methylprednisolone (2.29 mg/kg/day for 5 days followed by 4.57 mg/kg/day for 6 days), and this reduced the proteinuria to 20 mg/kg/day. We then progressively tapered the oral prednisone and administered LEF (20 mg/day for 3 days followed by 10 mg/day for 12 months) and captopril (0.5 mg/kg 2–3 times daily for 3 months) to reduce the proteinuria. The patient received follow-ups every 2 to 3 months. At the 18-month-follow-up, she had no recurrence of skin rash, no detectable urinary protein, no relevant adverse events, normal clinical status and renal function, no hypertension (Table 1). She used oral prednisone for 12 months. Because her clinical status was is stable, we scheduled follow-ups every 6 months.\n\nPatient 4\n\nIn November 2015, an 11-year-old girl was admitted to our hospital for leg purpura, bilateral swelling of the wrists and knees, microscopic hematuria, and proteinuria (25 mg/kg/day). The BUN was 4.26 µmol/L, and serum creatinine was 30.2 mmol/L, serum albumin was 37.9 g/L, and eGFR was 121 mL/min/1.73 m2. A renal biopsy was performed and 18 glomeruli were isolated. Light microscopy indicated focal moderate-to-severe mesangial hypercellularity with expanded matrix and segmental endothelial cell proliferation, visceral and parietal epithelial swelling, and two glomeruli with epithelial crescents and focal segmental necrosis. IF analysis indicated the presence of IgA (predominant), IgM, and C3 in the mesangial lesions, thus leading to a diagnosis of HSPN ISKDC class IIIa and M1 E1 S1 T0 C1 (revised Oxford classification ) (Fig. 1). We administered intravenous methylprednisolone (2.67 mg/kg/day for 6 days followed by 5.33 mg/kg/day for 5 days), and then a methylprednisolone pulse (16.67 mg/kg/day for 3 days) because of continuing proteinuria. However, the proteinuria increased to 42 mg/kg/day. We then administered LEF (20 mg/day for 3 days followed by 10 mg/day for 6 months) and tapered the steroid to oral prednisone. We also administered captopril (0.5 mg/kg, 2–3 times daily for 3 months) to reduce the proteinuria. The patient received follow-ups every 2 to 3 months. At the 32-month-follow-up, she patient had no recurrence of skin rash, no detectable urinary protein, no relevant adverse events, normal clinical status and renal function, and no hypertension (Table 1). She used oral prednisone for 9 months. Because of her stable clinical status, we scheduled follow-ups every 6 to 12 months.\n\nPatient 5\n\nIn September 2015, a 12-year-old boy was admitted to our hospital for leg purpura, microscopic hematuria, and proteinuria (34 mg/kg/day). The BUN was 3.82 µmol/L, serum creatinine was 39.4 mmol/L, serum albumin was 33.9 g/L, and eGFR was 120 mL/min/1.73 m2. A renal biopsy isolated 28 glomeruli and light microscopy indicated diffuse moderate to focal severe mesangial hypercellularity with expanded matrix and segmental endothelial cell proliferation, and visceral and parietal epithelial swelling. IF analysis indicated the presence of IgA (predominant) and C3 in the mesangial lesions, leading to a diagnosis of HSP ISKDC class II and M1 E1 S0 T0 C0 (revised Oxford classification ) (Fig. 1). We administered intravenous methylprednisolone (1.78 mg/kg/day for 4 days followed by 3.56 mg/kg/day for 8 days), and this reduced the proteinuria to 10 mg/kg/day. We then progressively tapered the patient to oral prednisone, and administered LEF (20 mg/day for 3 days followed by 10 mg/day for 6 months) and captopril (0.5 mg/kg, 2–3 times daily for 3 months) to reduce the proteinuria. Although this patient weighed 45 kg, his parents requested use of a lower dose of LEF, and this lower dose subsequently appeared to be effective. The patient received follow-ups every 2 to 3 months. At the 7-month-follow-up, he had no recurrence of the skin rash, undetectable urinary protein, no relevant adverse events, normal clinical status and renal function, and no hypertension (Table 1). He used oral prednisone for 6 months. Because of his stable clinical status, we scheduled follow-ups every 6 months.\n\nDiscussion\n\nWe described 5 children who presented with IgA vasculitis with proteinuria that was nearly 50 mg/kg (nephrotic range) and remained high despite administration of intravenous steroid. All children had biopsy-proven nephritis, and we described their successful treatment with LEF combined with a corticosteroid. None of these patients received diuretics because of their relatively disease-free status (no nephrotic syndrome or oliguria). Two patients previously received intravenous steroid without resolution of proteinuria. Steroid therapy was quickly discontinued in 1 patient who experienced increased intraocular pressure. Four patients achieved complete renal remission, and the other patient had significantly reduced proteinuria. In all cases, remission persisted for the entire follow-up period of 8 to 32 months and there were no severe adverse events.\n\nThe optimal therapeutic strategy for IgA vasculitis in children remains controversial. Some patients only receive supportive therapy in an effort to control the acute symptoms. However, more intensive and specific treatment for IgA vasculitis with nephritis should be considered in pediatric patients with severe proteinuria and/or impaired renal function [18]. Although nephritis is the most serious long-term complication of IgA vasculitis, limited data are available regarding the best therapy. Corticosteroids are currently a first-line treatment for HSPN, and this approach leads to remission in most patients. However, some patients exhibit steroid dependence or steroid resistance, and require immunosuppressant therapy in combination with a corticosteroid.\n\nThe SHARE recommended treatments for children with moderate IgA vasculitis with nephritis include oral prednisolone and/or pulsed methylprednisolone as a first-line treatment, and AZA, MMF or intravenous CTX as a first- or second-line treatment [9]. Due to the lack of evidence-based data for treatment of IgA vasculitis with nephritis and the similarities of this condition with primary IgA nephropathy, the KDIGO guidelines proposed the same treatment for both diseases. Thus, they recommend oral or intravenous corticosteroids plus oral or intravenous CTX for initial therapy, but provided no recommendations for maintain therapy [10], and did not recommend MMF or AZA. Clinicians who strictly follow the KDIGO guidelines for the treatment of HSPN may face the risk of delayed initiation of effective treatment and an increased risk of chronic kidney disease over the long term.\n\nThe adverse effects of CTX, especially on the gonads, often reduce patient compliance. MMF (which selectively suppresses the proliferation of T and B cells) is another commonly used immunosuppressant. The adverse events from MMF therapy are less severe than those from CTX, but the high-cost of MMF restricts its use in low-medium income countries. CysA (which decreases lymphocyte function) is another commonly used immunosuppressant. CysA can be very effective in pediatric patients with severe HSPN; however, administration can be difficult because it has poor water solubility and close monitoring of the blood concentration is necessary. Cys A may also cause severe adverse events [19]. Azathioprine, a prodrug of 6-mercaptopurine, has antileukemic, anti-inflammatory, and immunosuppressive properties, and is also often used in the treatment of IgA vasculitis with nephritis [9, 13]. Previous studies reported administration of tacrolimus and rituximab for treatment of HSPN [20, 21], but there is limited evidence of their efficacy and further research is required for confirmation. LEF is an affordable medication that is associated with few adverse events. Research in adults with HSPN reported that LEF in combination with a corticosteroid may lead to a slower deterioration of GFR than corticosteroid monotherapy [16].\n\nWe administered LEF treatment to these patients because their parents refused CTX due to possible side effects and they could not afford MMF treatment. AZA was not availble in our hospital, and we had limited experience with AZA and CysA. LEF is commonly used for juvenile idiopathic arthritis and lupus nephritis in our center, and we found no obvious adverse effects, suggesting suitability for our patients. LEF is an immunosuppressive agent that disrupts T and B cell function via inhibition of dihydroorotate dehydrogenase (the rate-limiting enzyme of de novo pyrimidine nucleotide biosynthesis) and also inhibits several tyrosine kinase signaling molecules involved in immune function [22]. LEF is currently a common treatment for autoimmune diseases. There is evidence that LEF is effective in treating IgA nephropathy, and nephropathy caused by systemic vasculitis and systemic lupus erythematosus [14, 15]. In this study, we prescribed LEF in combination with a corticosteroid to successfully treat 5 children who had IgA vasculitis with nephritis. The duration of LEF therapy ranged from 6 to 12 months, and there were no severe adverse events.\n\nThis study is an observational case series. Data from randomized controlled trials (RCTs) supporting the use of LEF as a treatment for IgA vasculitis with nephritis are currently lacking. Thus, we need to study more patients using a well-designed RCT to compare LEF with conventional agents (i.e., a corticosteroid and a standard immunosuppressive agent) to confirm the effectiveness and safety of LEF therapy. Nonetheless, our examination of 5 children who had IgA vasculitis with nephritis indicated that LEF in combination with a corticosteroid achieved complete or nearly complete renal remission, and that none of the patients experienced severe adverse events.\n\nAbbreviations\n\nHSP Henoch-Schönlein purpura\n\nLEF Leflunomide\n\nCTX Cyclophosphamide\n\nMMF Mycophenolate mofetil\n\nCys A Cyclosporine A\n\nSCr Serum creatinine\n\nAcknowledgements\n\nNone.\n\nAuthors' contributions\n\nLH reviewed the literature and contributed to manuscript writing; ZZ contributed to the acquisition and analysis of the clinical data. YD was responsible for revision of the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nThis work was supported by the Natural Science Foundation of Liaoning Province, China (2020-BS-116).\n\nAvailability of data and materials\n\nThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by the research ethics board of Shengjing Hospital of China Medical University (2016PS41J), all methods were carried out in accordance with relevant guidelines and regulations. Informed consents were obtained from the patients parents/legal guardian.\n\nConsent for publication\n\nWritten informed consent was obtained from the patients parents/legal guardian for publication of this study and any accompanying images.\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. Jelusic M Sestan M Cimaz R Ozen S Different histological classifications for Henoch-Schonlein purpura nephritis: which one should be used? Pediatr Rheumatol Online J 2019 17 1 10 10.1186/s12969-019-0311-z 30819179\n2. Ozen S Ruperto N Dillon MJ Bagga A Barron K Davin JC EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides Ann Rheum Dis 2006 65 7 936 41 10.1136/ard.2005.046300 16322081\n3. Trnka P Henoch-Schonlein purpura in children J Paediatr Child Health 2013 49 12 995 1003 10.1111/jpc.12403 24134307\n4. Bergey GK Morrell MJ Mizrahi EM Goldman A King-Stephens D Nair D Long-term treatment with responsive brain stimulation in adults with refractory partial seizures Neurology 2015 84 8 810 7 10.1212/wnl.0000000000001280 25616485\n5. Davin JC Coppo R Henoch-Schönlein purpura nephritis in children . Nat Rev Nephrol 2014 10 10 563 73 10.1038/nrneph.2014.126 25072122\n6. Kaku Y Nohara K Honda S Renal involvement in Henoch-Schonlein purpura: a multivariate analysis of prognostic factors . Kidney Int 1998 53 6 1755 9 10.1046/j.1523-1755.1998.00915.x 9607209\n7. Wakaki H Ishikura K Hataya H Hamasaki Y Sakai T Yata N Henoch-Schonlein purpura nephritis with nephrotic state in children: predictors of poor outcomes Pediatr Nephrol 2011 26 6 921 5 10.1007/s00467-011-1827-8 21373776\n8. Hahn D, Hodson EM, Willis NS, Craig JC. Interventions for preventing and treating kidney disease in Henoch-Schönlein Purpura (HSP). Cochrane Database Syst Rev. 2015(8):CD005128. 10.1002/14651858.CD005128.pub3.\n9. Ozen S Marks SD Brogan P Groot N de Graeff N Avcin T European consensus-based recommendations for diagnosis and treatment of immunoglobulin A vasculitis-the SHARE initiative Rheumatology (Oxford) 2019 58 9 1607 16 10.1093/rheumatology/kez041 30879080\n10. Chapter 11: Henoch-Schonlein purpura nephritis. Kidney Int Suppl (2011). 2012;2(2):218–20. 10.1038/kisup.2012.24.\n11. Du Y Hou L Zhao C Han M Wu Y Treatment of children with Henoch-Schonlein purpura nephritis with mycophenolate mofetil . Pediatr Nephrol 2012 27 5 765 71 10.1007/s00467-011-2057-9 22081165\n12. Park JM Won SC Shin JI Yim H Pai KS Cyclosporin A therapy for Henoch-Schonlein nephritis with nephrotic-range proteinuria . Pediatr Nephrol 2011 26 3 411 7 10.1007/s00467-010-1723-7 21184240\n13. Schinzel V Fernandez JD Clemente G Fraga MM Andrade MC Len CA The profile and clinical outcomes of patients with renal involvement due to IgA vasculitis: is azathioprine a good option for treatment? Adv Rheumatol 2019 59 1 21 10.1186/s42358-019-0064-x 31113470\n14. Wang HY Cui TG Hou FF Ni ZH Chen XM Lu FM Induction treatment of proliferative lupus nephritis with leflunomide combined with prednisone: a prospective multi-centre observational study Lupus 2008 17 7 638 44 10.1177/0961203308089408 18625636\n15. Lou T Wang C Chen Z Shi C Tang H Liu X Randomised controlled trial of leflunomide in the treatment of immunoglobulin A nephropathy Nephrology (Carlton) 2006 11 2 113 6 10.1111/j.1440-1797.2006.00547.x 16669971\n16. Zhang Y Gao Y Zhang Z Liu G He H Liu L Leflunomide in addition to steroids improves proteinuria and renal function in adult Henoch-Schoenlein nephritis with nephrotic proteinuria . Nephrology (Carlton) 2014 19 2 94 100 10.1111/nep.12175 24171710\n17. Ozen S Pistorio A Iusan SM Bakkaloglu A Herlin T Brik R EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria Ann Rheum Dis 2010 69 5 798 806 10.1136/ard.2009.116657 20413568\n18. Zaffanello M Fanos V Treatment-based literature of Henoch-Schönlein purpura nephritis in childhood . Pediatr Nephrol 2009 24 10 1901 11 10.1007/s00467-008-1066-9 19066976\n19. Wu Q Wang X Nepovimova E Wang Y Yang H Kuca K Mechanism of cyclosporine A nephrotoxicity: Oxidative stress, autophagy, and signalings Food Chem Toxicol 2018 118 889 907 10.1016/j.fct.2018.06.054 29960018\n20. Crayne CB Eloseily E Mannion ML Azerf SP Weiser P Beukelman T Rituximab treatment for chronic steroid-dependent Henoch-Schonlein purpura: 8 cases and a review of the literature Pediatr Rheumatol Online J 2018 16 1 71 10.1186/s12969-018-0285-2 30428889\n21. Zhang DF Hao GX Li CZ Yang YJ Liu FJ Liu L Off-label use of tacrolimus in children with Henoch-Schonlein purpura nephritis: a pilot study Arch Dis Child 2018 103 8 772 5 10.1136/archdischild-2017-313788 29535109\n22. Siemasko KF Chong AS Williams JW Bremer EG Finnegan A Regulation of B cell function by the immunosuppressive agent leflunomide . Transplantation 1996 61 4 635 42 10.1097/00007890-199602270-00020 8610393\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "21(1)",
"journal": "BMC pediatrics",
"keywords": "Children; Corticosteroid; Henoch-Schönlein purpura nephritis; IgA vasculitis; Immunosuppressive agent; Leflunomide",
"medline_ta": "BMC Pediatr",
"mesh_terms": "D000328:Adult; D002648:Child; D006801:Humans; D011695:IgA Vasculitis; D007070:Immunoglobulin A; D000077339:Leflunomide; D009393:Nephritis; D011507:Proteinuria",
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "391",
"pmc": null,
"pmid": "34496826",
"pubdate": "2021-09-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25616485;31113470;8610393;18625636;22081165;30879080;16322081;30428889;19066976;26258874;24171710;25072122;9607209;29960018;24134307;30819179;21373776;29535109;21184240;16669971;20413568",
"title": "Leflunomide therapy for IgA vasculitis with nephritis in children.",
"title_normalized": "leflunomide therapy for iga vasculitis with nephritis in children"
} | [
{
"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-324980",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
... |
{
"abstract": "Introduction: Azathioprine is an immune-modulating agent used in the management of autoimmune diseases and in preventing graft rejection. Its role in the management of refractory asthma is not very well-established.Case study: A 47-year-old female with an underlying severe refractory asthma, managed with high dose steroids, was seen as an outpatient. Her course was complicated by frequent asthma exacerbation and severe adverse effects of chronic steroid use. Her symptoms did not respond to standard asthma management per Guidelines for the Diagnosis and Management of Asthma 1. She was tried on other management which included methotrexate and omalizumab injections without success. Azathioprine was started as a steroid-sparing agent following which her symptoms showed dramatic improvement with fewer exacerbations, higher peak flow measurements, and she was able to wean down her daily prednisone dose from 60 mg/day to 5 mg/day.Conclusion: Azathioprine is still an investigational agent for the management of asthma and more research needs to be done to evaluate its role. To our knowledge, this is the second case report which details the therapeutic role of Azathioprine in the management of asthma.",
"affiliations": "Department of Pulmonary and Critical Care Medicine, University of Florida, Gainesville, FL, USA.;Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, OH, USA.",
"authors": "Kalra|Saminder Singh|SS|;Lamia|Ibrahim|I|",
"chemical_list": "D018927:Anti-Asthmatic Agents; D015507:Drugs, Investigational; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D001379:Azathioprine; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1080/02770903.2019.1628252",
"fulltext": null,
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"issn_linking": "0277-0903",
"issue": "57(9)",
"journal": "The Journal of asthma : official journal of the Association for the Care of Asthma",
"keywords": "Azathioprine; Refractory asthma; Severe Asthma; steroids resistant asthma",
"medline_ta": "J Asthma",
"mesh_terms": "D018927:Anti-Asthmatic Agents; D001249:Asthma; D001379:Azathioprine; D004351:Drug Resistance; D015507:Drugs, Investigational; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008875:Middle Aged; D011241:Prednisone; D016896:Treatment Outcome",
"nlm_unique_id": "8106454",
"other_id": null,
"pages": "1039-1041",
"pmc": null,
"pmid": "31164022",
"pubdate": "2020-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare case of refractory asthma managed with azathioprine.",
"title_normalized": "a rare case of refractory asthma managed with azathioprine"
} | [
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"companynumb": "US-TEVA-2021-US-1907162",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
... |
{
"abstract": "Pharmacological regimens with multiple medications are being used in fertility treatments. Herein, we report a case of a 40-year-old Japanese woman who developed Stevens-Johnson syndrome (SJS) with a severe ocular complication during fertility treatment. Despite early multimodal interventions, including methylprednisolone pulse therapy and plasma exchange, her ocular complications persisted for more than a year. The four drugs administered in this case (cabergoline, medroxyprogesterone acetate, clomiphene, and intravenous human chorionic gonadotropin) have never been reported to induce SJS. Based on this case, we suggest that obstetricians, gynecologists, and dermatologists should be aware of fertility treatment-induced severe drug eruptions.",
"affiliations": "Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Division of Dermatology, Chiba Aoba Municipal Hospital, Chiba, Japan.;Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.;Department of Dermatology, Graduate School of Medicine, Chiba University, Chiba, Japan.",
"authors": "Hashimoto|Hiroyo|H|;Miyachi|Hideaki|H|https://orcid.org/0000-0003-2549-6690;Kataoka|Koki|K|;Maru|Yugo|Y|;Togawa|Yaei|Y|;Matsue|Hiroyuki|H|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006063:Chorionic Gonadotropin; D005300:Fertility Agents, Female; D005938:Glucocorticoids; D002996:Clomiphene; D017258:Medroxyprogesterone Acetate; D000077525:Cefdinir; D000077465:Cabergoline",
"country": "England",
"delete": false,
"doi": "10.1111/1346-8138.15072",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-2407",
"issue": "46(11)",
"journal": "The Journal of dermatology",
"keywords": "Stevens-Johnson syndrome; adverse drug reaction; infertility; keratoconjunctivitis; plasma exchange",
"medline_ta": "J Dermatol",
"mesh_terms": "D000328:Adult; D000893:Anti-Inflammatory Agents; D000077465:Cabergoline; D000077525:Cefdinir; D006063:Chorionic Gonadotropin; D002996:Clomiphene; D004359:Drug Therapy, Combination; D005128:Eye Diseases; D005260:Female; D005300:Fertility Agents, Female; D005938:Glucocorticoids; D006801:Humans; D007247:Infertility, Female; D017258:Medroxyprogesterone Acetate; D010951:Plasma Exchange; D013262:Stevens-Johnson Syndrome",
"nlm_unique_id": "7600545",
"other_id": null,
"pages": "1042-1045",
"pmc": null,
"pmid": "31489686",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Case of fertility treatment-induced Stevens-Johnson syndrome with a severe ocular complication.",
"title_normalized": "case of fertility treatment induced stevens johnson syndrome with a severe ocular complication"
} | [
{
"companynumb": "JP-PFIZER INC-2016137347",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MEDROXYPROGESTERONE ACETATE"
},
"drugadditiona... |
{
"abstract": "Intravesical Bacillus Calmette-Guérin (BCG) has been a proven and effective immunotherapy treatment for superficial transitional cell carcinoma (TCC) of the bladder, especially for high-grade tumors and carcinoma in situ. Nevertheless, significant side effects are associated with BCG instillations, including fever, myalgia, malaise, dysuria, hematuria, and irritable lower urinary tract symptoms. We herein report the case of a patient who developed Reiter's syndrome following intravesical BCG instillations. A 39-year-old Chinese man presented with a 3-week history of dysuria, suprapubic pain, and pain at the tip of the penis postmicturition. Initial investigations revealed that he had microhematuria, and an ultrasound with computed tomography scan of the abdomen showed a bladder mass. Transurethral resection of the bladder tumor was performed and the patient received a single dose of intravesical mitomycin postoperatively. Results of histopathological examination revealed high-grade bladder TCC (G3pT1), and the patient was managed with intravesical BCG for 2 weeks following the surgery. Four weekly cycles of BCG were administered uneventfully; however, before the fifth instillation, the patient complained of urethral discharge, bilateral conjunctivitis, and low back pain. Reiter's syndrome was diagnosed as a rare but known complication of BCG instillation and the BCG immunotherapy was withheld. The patient was treated with nonsteroidal antiinflammatory drugs (for back pain) and eye ointment (for conjunctivitis) and his condition improved. This case report of Reiter's syndrome should be highlighted as a rare but significant complication of BCG immunotherapy and urologists should have a high index of suspicion to diagnose this rare complication.",
"affiliations": "Department of Surgery, University of Malaya, Kuala Lumpur, Malaysia; Department of Urology, Princess Alexandra Hospital, Brisbane, Australia. Electronic address: kenglimng@yahoo.com.;Sunway Medical Centre, Kuala Lumpur, Malaysia.",
"authors": "Ng|Keng Lim|KL|;Chua|Chong Beng|CB|",
"chemical_list": "D001500:BCG Vaccine",
"country": "China",
"delete": false,
"doi": "10.1016/j.asjsur.2014.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1015-9584",
"issue": "40(2)",
"journal": "Asian journal of surgery",
"keywords": "Bacillus Calmette–Guérin; Reiter's syndrome; intravesical",
"medline_ta": "Asian J Surg",
"mesh_terms": "D000283:Administration, Intravesical; D000328:Adult; D016918:Arthritis, Reactive; D001500:BCG Vaccine; D002295:Carcinoma, Transitional Cell; D000072700:Conservative Treatment; D003558:Cystoscopy; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D035583:Rare Diseases; D018570:Risk Assessment; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "8900600",
"other_id": null,
"pages": "163-165",
"pmc": null,
"pmid": "25183290",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reiter's syndrome postintravesical Bacillus Calmette-Guérin instillations.",
"title_normalized": "reiter s syndrome postintravesical bacillus calmette gu rin instillations"
} | [
{
"companynumb": "MY-SA-2017SA264285",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
... |
{
"abstract": "To describe the effectiveness and safety of an abacavir/lamivudine + rilpivirine regimen in naive HIV-1-infected patients, as there is a lack of data with this combination.\n\n\n\nThis was an observational, retrospective, multicentre study in eight Spanish hospitals. All antiretroviral-naive patients ≥18 years old and starting abacavir/lamivudine + rilpivirine were included. Effectiveness (ITT and on-treatment) and safety (adverse events and laboratory parameters) were assessed during follow-up. Values are expressed as n (%) or median (IQR). The Wilcoxon signed-rank test was used to compare baseline and 6 and 12 month values.\n\n\n\nEighty-four patients were included [93% males, age = 36 (30-45) years]. Time since HIV diagnosis was 12 (4-35) months. Fifty-one per cent of patients had comorbidities. Baseline CD4+ was 425 (340-519) cells/mm3 and baseline HIV-RNA was 19 000 (9500-42 000) copies/mL. Median follow-up was 18 (9-22) months; 100% and 68% patients with at least 6 and 12 months, respectively. At 6 and 12 months effectiveness was 94% and 86% by ITT analysis and 96% and 97% by on-treatment analysis. At 12 months, there were significant increases in CD4+ (+262 cell/mm3) and HDL cholesterol (+4 mg/dL) and a significant decrease in the total cholesterol/HDL cholesterol ratio (-0.2). There were two (2.4%) virological failures (HIV-RNA 50-100 copies/mL); one patient later achieving virological suppression without changing the treatment. Six patients (7.1%) changed treatment due to reasons other than virological failure or side effects. One patient discontinued treatment due to gastrointestinal complaints attributed to abacavir/lamivudine.\n\n\n\nAbacavir/lamivudine + rilpivirine was an effective and safe option in a selected group of HIV-1-infected treatment-naive patients.",
"affiliations": "Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain acurran@vhebron.net.;Hospital Clinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain.;Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.;Hospital Universitario Infanta Leonor, Madrid, Spain.;Hospital Universitari de Bellvitge-IDIBELL, L'Hospitalet, Spain.;Hospital Arnau de Vilanova, Lleida, Spain.;Hospital Clinic-IDIBAPS, Universitat de Barcelona, Barcelona, Spain.;Hospital Universitario Infanta Leonor, Madrid, Spain.;Fundación Jiménez Díaz, Universidad Autónoma de Madrid, Madrid, Spain.;Hospital Universitari de Bellvitge-IDIBELL, L'Hospitalet, Spain.;Hospital del Mar, Universitat Autònoma de Barcelona, Barcelona, Spain.;Hospital General de Elche, Universidad Miguel Hernández, Alicante, Spain.;Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.",
"authors": "Curran|Adrian|A|;Rojas|Jhon|J|;Cabello|Alfonso|A|;Troya|Jesús|J|;Imaz|Arkaitz|A|;Domingo|Pere|P|;Martinez|Esteban|E|;Ryan|Pablo|P|;Górgolas|Miguel|M|;Podzamczer|Daniel|D|;Knobel|Hernando|H|;Gutiérrez|Félix|F|;Ribera|Esteban|E|",
"chemical_list": "D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; C492871:abacavir, lamivudine drug combination; D019259:Lamivudine; D000068696:Rilpivirine",
"country": "England",
"delete": false,
"doi": "10.1093/jac/dkw347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0305-7453",
"issue": "71(12)",
"journal": "The Journal of antimicrobial chemotherapy",
"keywords": null,
"medline_ta": "J Antimicrob Chemother",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D015224:Dideoxynucleosides; D004338:Drug Combinations; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006761:Hospitals; D006801:Humans; D019259:Lamivudine; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D000068696:Rilpivirine; D013030:Spain; D016896:Treatment Outcome",
"nlm_unique_id": "7513617",
"other_id": null,
"pages": "3510-3514",
"pmc": null,
"pmid": "27591292",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Effectiveness and safety of an abacavir/lamivudine + rilpivirine regimen for the treatment of HIV-1 infection in naive patients.",
"title_normalized": "effectiveness and safety of an abacavir lamivudine rilpivirine regimen for the treatment of hiv 1 infection in naive patients"
} | [
{
"companynumb": "ES-JNJFOC-20170212725",
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"abstract": "Objective: This study was conducted to elucidate prevalence, clinical features, outcomes, and best treatment in patients with late-onset seizures due to autoimmune encephalitis (AE). Methods: This is a single-institution prospective cohort study (2012-2019) conducted at the Epilepsy Center at the University of Greifswald, Germany. A total of 225 patients aged ≥50 years with epileptic seizures were enrolled and underwent an MRI/CT scan, profiling of neural antibodies (AB) in serum and cerebrospinal fluid (CSF), and neuropsychological testing. On the basis of their work-up, patients were categorized into the following three cohorts: definite, suspected, or no AE. Patients with definite and suspected AE were subsequently treated with immunosuppressive therapy (IT) and/or anti-seizure drug (ASD) therapy and were followed up (FU) regarding clinical and seizure outcome. Results: Of the 225 patients, 17 (8%) fulfilled the criteria for definite or suspected AE according to their AB profile and MRI results. Compared with patients with no evidence of AE, those with AE were younger (p = 0.028), had mesial temporal neuropsychological deficits (p = 0.001), frequently had an active or known malignancy (p = 0.006) and/or a pleocytosis (p = 0.0002), and/or had oligoclonal bands in CSF (p = 0.001). All patients with follow-up became seizure-free with at least one ASD. The Modified Rankin scale (mRS) at hospital admission was low for patients with AE (71% with mRS ≤2) and further decreased to 60% with mRS ≤2 at last FU. Significance: AE is an important etiology in late-onset seizures, and seizures may be the first symptom of AE. Outcome in non-paraneoplastic AE was favorable with ASD and IT. AB testing in CSF and sera, cerebral MRI, CSF analysis, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late-onset seizures.",
"affiliations": "Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.;Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.;Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.;Department of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany.",
"authors": "Süße|Marie|M|;Zank|Maria|M|;von Podewils|Viola|V|;von Podewils|Felix|F|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fneur.2021.633999",
"fulltext": "\n==== Front\nFront Neurol\nFront Neurol\nFront. Neurol.\nFrontiers in Neurology\n1664-2295\nFrontiers Media S.A.\n\n10.3389/fneur.2021.633999\nNeurology\nOriginal Research\nAutoimmune Encephalitis in Late-Onset Seizures: When to Suspect and How to Treat\nSüße Marie *†\n\nZank Maria †\nvon Podewils Viola †\n\nvon Podewils Felix †\n\nDepartment of Neurology, Epilepsy Center, University Medicine Greifswald, Greifswald, Germany\nEdited by: Stephan Schuele, Northwestern University, United States\n\nReviewed by: George Culler, Dartmouth University, United States; Stephen VanHaerents, Northwestern Medicine, United States\n\n*Correspondence: Marie Süße marie.suesse@uni-greifswald.de\nThis article was submitted to Epilepsy, a section of the journal Frontiers in Neurology\n\n†These authors have contributed equally to this work\n\n07 4 2021\n2021\n12 63399926 11 2020\n24 2 2021\nCopyright © 2021 Süße, Zank, von Podewils and von Podewils.\n2021\nSüße, Zank, von Podewils and von Podewils\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nObjective: This study was conducted to elucidate prevalence, clinical features, outcomes, and best treatment in patients with late-onset seizures due to autoimmune encephalitis (AE).\n\nMethods: This is a single-institution prospective cohort study (2012–2019) conducted at the Epilepsy Center at the University of Greifswald, Germany. A total of 225 patients aged ≥50 years with epileptic seizures were enrolled and underwent an MRI/CT scan, profiling of neural antibodies (AB) in serum and cerebrospinal fluid (CSF), and neuropsychological testing. On the basis of their work-up, patients were categorized into the following three cohorts: definite, suspected, or no AE. Patients with definite and suspected AE were subsequently treated with immunosuppressive therapy (IT) and/or anti-seizure drug (ASD) therapy and were followed up (FU) regarding clinical and seizure outcome.\n\nResults: Of the 225 patients, 17 (8%) fulfilled the criteria for definite or suspected AE according to their AB profile and MRI results. Compared with patients with no evidence of AE, those with AE were younger (p = 0.028), had mesial temporal neuropsychological deficits (p = 0.001), frequently had an active or known malignancy (p = 0.006) and/or a pleocytosis (p = 0.0002), and/or had oligoclonal bands in CSF (p = 0.001). All patients with follow-up became seizure-free with at least one ASD. The Modified Rankin scale (mRS) at hospital admission was low for patients with AE (71% with mRS ≤2) and further decreased to 60% with mRS ≤2 at last FU.\n\nSignificance: AE is an important etiology in late-onset seizures, and seizures may be the first symptom of AE. Outcome in non-paraneoplastic AE was favorable with ASD and IT. AB testing in CSF and sera, cerebral MRI, CSF analysis, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late-onset seizures.\n\nautoimmune encephalitis\nlate onset seizures\nneural antibodies\nepilepsy of unknown origin\noutcome\n==== Body\nIntroduction\n\nEpilepsy and new onset seizures in elderly patients are an important health issue of the aging population (1, 2). Epileptic seizures are a core symptom of autoimmune encephalitis (AE) (3, 4), and autoimmune epilepsy has been reported to account for up to 20% of epilepsy of unknown etiology (5). The prevalence ranges from 6% up to 37% (3, 6), with non-paraneoplastic AE being more common than paraneoplastic AE. The diagnostic criteria for definite autoimmune limbic encephalitis proposed by Graus et al. (4) enable the diagnosis of AE even in the absence of neural antibodies and include neuropsychiatric symptoms of new-onset seizures, bilateral changes in magnetic resonance imaging (MRI), such as T2/fluid-attenuated inversion recovery (FLAIR) hyperintense signal alterations prominently in the medial temporal lobes, and either cerebrospinal fluid (CSF) pleocytosis or EEG abnormalities (4). Diagnostic criteria for possible AE include subacute neuropsychiatric deficits and either new focal CNS findings, seizures, CSF pleocytosis, or pathognomonic MRI features (4). The diagnostic criteria for neural antibody (AB) negative but probable AE include the detection of oligoclonal bands (OCB) in CSF (4). Small case series suggest using FDG-PET in cases of suspected AE and normal MRI, as FDG-PET has been reported to be more sensitive than MRI (7–9).\n\nThe presence of neural antibodies (AB) in serum and/or CSF can be suggestive of an autoimmune origin, but their absence does not exclude autoimmunity (10). Furthermore, their positivity is not always pathognomonic for AE (11), as described for low-titer anti-CASPR2 AB, VGKC AB not reactive with LGI1/CASPR2, AB against mouse neuropil, and low-titer GAD AB in serum (12–14). Since AE is a potentially treatable etiology of epileptic seizures (11), its identification in the diagnostic work-up of epileptic seizures is crucial (15). The application of the above-mentioned criteria proposed by Graus et al. (4) can be misleading in routine clinical practice (11, 16). For example, in the elderly, AB-associated central nervous system (CNS) syndromes often present without characteristic features of inflammation, such as pleocytosis in CSF or corresponding MRI changes, especially in patients aged 60 years or older (17). Furthermore, isolated seizures can precede other features of AE (17), thus complicating a timely recognition of possible AE (18).\n\nTherefore, the aim of this study was to investigate the prevalence of AE in a large cohort of patients with late-onset seizures and to find predictors of when to suspect AE in late-onset seizures. We furthermore aimed to characterize the long-term outcomes and provide clinicians with recommendations for an adequate treatment in this challenging group of patients.\n\nMethods and Materials\n\nIn this prospective single-institution cohort study, patients from the general neurology department, the neurological intensive care unit, and the epilepsy monitoring unit who underwent diagnostic workup after epileptic seizures including CSF analysis between 2012 and 2019 were studied at the University Hospital of Greifswald, Germany (serving a population of about 500,000 people).\n\nPatient Cohort\n\nPatients ≥50 years of age with status epilepticus, repetitive seizures for ≤6 months, or one single seizure (further referred to as seizure disorder) and CSF analysis were included. Cerebrospinal fluid analysis was performed in all patients with a first manifestation of a seizure disorder. Cerebrospinal fluid analysis after a first seizure disorder is a clinical standard in our institution, especially in patients aged 50 years or older, with certain exceptions, such as clear evidence of a generalized genetic epilepsy syndrome. All patients without CSF analysis regardless of the reason (for example, those who have refused consent or have oral anticoagulation) were excluded from the study. Patients with suspected infectious etiology of the seizure disorder based on CSF analysis (cell count, lactate, and protein elevation in CSF analysis and/or evidence of viral or bacterial infection in microbiological analysis) without further evidence of a comorbid autoimmune encephalitis were also excluded from the study. Seizures were classified according to the International League Against Epilepsy (ILAE) classification of seizure types (19). All patients underwent MRI or CT imaging (if MRI was not possible), neuropsychological testing if feasible, and CSF analysis as part of the study protocol.\n\nImmunosuppressive therapy (IT) and/or anti-seizure drug (ASD) treatment was started at the discretion of the treating physician. First-line IT included prednisolone (per os/intravenous), plasma exchange (PEX), immunoabsorption (IA), or intravenous immunoglobulins, second-line IT included further immunosuppressive therapy (rituximab, methotrexate, cyclophosphamide, azathioprine). Tumor screening, including CT scan of the thorax/abdomen and gynecological/urological investigations, was performed in cases of suspected paraneoplastic AE in 6-month intervals for at least 2 years.\n\nPatients were categorized in three cohorts and defined as follows: (1) definite autoimmune encephalitis (dAE): neural AB positivity and/or bilateral hyperintense signals in T2-FLAIR MRI sequences either restricted to the medial temporal lobes or in multifocal areas compatible with demyelination or inflammation (4); (2) suspected AE (sAE): positive neural AB at either borderline titers in serum or non-specific neuropil AB and/or unilateral mesial temporal MRI T2-FLAIR hyperintense signal alterations; additional findings consistent with AE may support the diagnosis, such as neuropsychological findings compatible with AE and/or detection of an elevated cell count in CSF or OCB in CSF and/or EEG epileptic activity or regional slowing involving the temporal lobes; and (3) no proof of AB and no signs for AE on brain imaging (AE negative, nAE).\n\nFollow-up (FU) investigation was not part of the initial study protocol and was carried out in 2019 after the end of the intended observation period. Follow-up included clinical and seizure outcomes in cohorts 1 and 2 (dAE/sAE) if available and was assessed with a structured telephone interview or data evaluation from the available medical charts. Minimum follow-up time was 6 months.\n\nNeuropsychological Assessment\n\nStandardized neuropsychological assessment was feasible in 11 out of 17 (65%) dAE/sAE patients (n = 6 for dAE and n = 5 for sAE). Test protocols focused mainly on attention and cognitive speed as well as executive, language, and memory functions. These were either assessed in seven patients using CERAD-plus (Consortium to Establish a Registry for Alzheimer's Disease) or using a comprehensive test battery (n = 4 patients) including the following tests: MWT-B (Mehrfachwahlwortschatztest, verbal intelligence) for an estimated premorbid performance level, BVMT-R (Brief Visual Memory Test-Revised) or ROCFT (Rey-Osterrieth Complex Figure Test) for figural memory, CVLT (California Verbal Learning Test) or VLMT (Verbal Learning and Memory Test, the German equivalent of the Rey Auditory Verbal Learning Test) for verbal memory, TAP (Testbatterie zur Aufmerksamkeitsprüfung), digit span (WAIS IV, Wechsler Adult Intelligence Test), TMT (Trail Making Test) or Stroop Test for attention and executive functions, and phonemic and/or semantic verbal fluency (Regensburger Wortschatz-Test) and naming for language functions (see Supplementary Tables 1, 2). Test performance of >1 SD below the mean was defined as a cognitive deficit. Neuropsychological test performance was interpreted by certified neuropsychologists. A focus of impairments on verbal and/or figural memory (especially delayed recall and recognition) was defined as a mesial temporal deficit, consistent with AE.\n\nLaboratory Analysis\n\nLaboratory analyses were performed in the Interdisciplinary CSF laboratory of the University Medicine Greifswald. Laboratory analyses were performed as described previously (20). In brief, cell counts were determined microscopically using a Fuchs-Rosenthal counting chamber. The calculation of intrathecal IgG was performed according to Reiber's formula (21). OCB were determined by isoelectric focusing with a semiautomated agarose electrophoresis system (Hydragel 9 CSF, Sebia Hydrasys 2Scan, Sebia GmbG, Fulda Germany). OCB positivity was defined with ≥2 isolated bands in CSF.\n\nThe determination of neural AB in CSF and serum was performed by the MVZ Labor Krone GbR, Siemensstraße 40, 32105 Bad Salzuflen, Germany (for details see Supplementary Material). All patients were tested for serum and CSF AB against GAD65, NMDAR, GABA(B)R, IGLON5, AMPA1/2, DPPX, LGI1, CASPR2, GlyRs, mGluR5, mGluR1, and atypical AB against neuropil as well as AB against Amphiphysin, CV2/CRMP5, Ma2/Ta, Ri, Yo, Hu, Recoverin, Sox1, Titin, Zic4, and DNER/Tr.\n\nStatistical Analysis\n\nStatistical analysis was performed using SPSS 23.0 (IBM Co., Armonk, New York, USA). Kolmogorov-Smirnov analysis was used to test for Gaussian distribution of the data. Statistical significance of nominal data was assessed using chi-square tests and Fisher's exact test with a significance defined as a probability, (p < 0.05). Intergroup comparison was performed using the Mann-Whitney U test (no Gaussian distribution of the data) and the Kruskal-Wallis test by ranks (alpha = 0.05) to compare several subgroups. The Dunn-Bonferroni method was used for post hoc analysis.\n\nStandard Protocol Approvals, Registrations, and Patient Consents\n\nThe study has been approved by the institutional review board (IRB). Patient consent was not obtained prospectively, as the diagnostic pathway for this study was integrated into the clinical routine diagnostic procedure and was required only for patients who were contacted for follow-up investigations.\n\nResults\n\nIn all, 225 patients (53.8% female) with a mean age of 73 years (range: 51–94) were prospectively enrolled in the study. Seventeen (8%) of them were classified as definite or suspected AE, the remaining 208 (92%) as AE negative (cohort III).\n\nCohort I: Definite AE\n\nA total of nine patients (n = 9/225; 4%) met the criteria for dAE: All patients presented with well-defined neural AB in CSF and serum [anti-GAD AB (n = 1), anti-LGI1 AB (n = 1), anti-CASPR2 AB (n = 3), anti-NMDAR AB (n = 1), anti-Amphiphysin/neuropil AB (n = 1), anti-Hu/Sox/Zic/GABA B AB (n = 1), and anti-Hu/Zic-4 AB (n = 1)]. Of these, three patients (n = 3/9) were newly diagnosed with small cell lung cancer after information about the typical onconeural AB profile (patients 7–9 in Tables 1, 2). These patients had OCB in CSF but only unilateral or no MRI signal alterations. In addition to IT and ASD treatment, they received tumor therapy according to local standards. Two patients (n = 2/9) had neuropsychological deficits consistent with AE (Supplementary Table 1). Neither of these patients fulfilled the clinical diagnostic criteria for definite autoimmune limbic encephalitis defined by Graus et al. (4), as they did not present with bilateral MRI brain abnormalities. Two patients (n = 2/9) fulfilled the Graus criteria for possible AE. Details are given in Tables 1, 2, and the Supplementary Table 1.\n\nTable 1 Patients with definite AE.\n\nPatients with definite AE\tAge\tMRI\tEEG\tTherapy\tFollow-up\t\n\t\t\t\tImmunotherapy\tAnti-seizure medication\t\t\nNo. 1\t87\tnormal\tgeneralized continuous slow activity\tmethylprednisolone 1,000 mg per day i.v. for 5 days\tno\tlost to follow-up\t\nNo. 2\t71\tnormal\tnormal\tmethylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o.*\tLevetiracetam 1,000 mg per day\t21 months, seizure free,\t\nNo. 3\t67\tT2/FLAIR hyperintensity right insula, mesial temporal, temporopolar\tintermittent regional slow right temporal\tprednisolone 1 mg/kg per day p.o.*, azathioprine 175 mg per day\tLamotrigine 200 mg per day\t37 months, seizure free,\t\nNo. 4\t59\tnormal\tnormal\tprednisolone 1 mg/kg per day p.o. *\tLevetiracetam 2,000 mg per day\t62 months, seizure free\t\nNo. 5\t66\tT2/FLAIR hyperintensity right temporal\tnormal\tmethylprednisolone 500 mg per day i.v. for 5 days, plasma exchange, followed by prednisolone 1 mg/kg per day p.o.*\tLevetiracetam 2,000 mg per day\t102 months, seizure free\t\nNo. 6\t80\tcontrast enhancement left parietal\tintermittent generalized slow with isolated ß-bursts\tmethylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o.* and once cyclophosphamide 2,000 mg i.v.\tvalproate (dosage unknown)\tlost to follow-up\t\nNo. 7\t67\tnormal\tnormal\tmethylprednisolone 1,000 mg per day i.v. for 5 days, plasma exchange (5 cycles), prednisolone 1 mg/kg per day p.o.*\tno\t3 months\t\nNo. 8\t61\tT2/FLAIR hyperintensity right mesial temporal\tnormal\tmethylprednisolone 1,000 mg per day i.v. for 5 days, followed by prednisolone 1 mg/kg per day p.o.*\tno\tlost to follow-up\t\nNo. 9\t67\tnormal\tintermittent regional slow left hemisphere with isolated epileptic discharges\tmethylprednisolone 1,000 mg per day i.v. for 5 days, followed by prednisolone 1 mg/kg per day p.o.*\tLevetiracetam 4,000 mg per day\t23 months, seizure free\t\n* Gradual reduction in dosage over several weeks.\n\nMRI, magnetic resonance imaging; EEG, electroencephalography; AE, autoimmune encephalitis; FLAIR, fluid attenuated inversion recovery; i.v., intravenous; p.o., per os.\n\nTable 2 Neural antibody and CSF results of patients with definite and suspected AE.\n\nAntibody (titer)\tCSF results\t\t\t\t\t\n\tCell count/μl\tLactate (mmol/l)\tAlbumin quotient\tOCB\tCell differentiation\t\nNo. 1 anti-GAD65 AB (serum: 1:1280, CSF 1:8)\t1\t2.7\t14.9\tNegative\t92% monocytes\t\n\t\t\t\t\t7% lymphocytes\t\n\t\t\t\t\t1% other cells\t\nNo. 2 anti-LGI1 AB [serum: 1:640, CSF 1:4 (+ anti-titin ab + unspecific neuropil ab in serum + CSF)]\t2\t1.7\t9.6\tNegative\t44% monocytes 56% lymphocytes\t\nNo. 3 anti-CASPR2 AB (serum 1:2,560, CSF 1:32)\t9\t1.7\t14.2\tNegative\t90% lymphocytes\t\n\t\t\t\t\t9% monocytes\t\n\t\t\t\t\t1% other cells\t\nNo. 4 anti-CASPR2 AB (serum 1:1,500,000, CSF 1:100,000)\t12\t2.2\t7\tNegative\t74% monocytes\t\n\t\t\t\t\t26% lymphocytes\t\nNo. 5 anti-CASPR2 AB (serum 1:1,000, CSF 1:100)\t1\t1.7\t5.5\tNegative\t65% monocytes\t\n\t\t\t\t\t32% lymphocytes\t\n\t\t\t\t\t3% other cells\t\nNo. 6 anti-NMDAR AB (serum 1:80, CSF 1:256)\t11\t1.5\t4.4\tPositive\t83% lymphocytes, 16% monocytes\t\n\t\t\t\t\t1% other cells\t\nNo. 7 Amphiphysin + Neuropil AB CSF and serum\t2\t2\t8.5\tPositive\t86% lymphocytes\t\n\t\t\t\t\t12% monocytes\t\n\t\t\t\t\t2% other cells\t\nNo. 8 anti-GABAbR AB serum 1:640, CSF 1:8/Hu CSF and serum; Sox/Zic CSF and serum\t2\t2.4\t3.3\tPositive\t92% lymphocytes, 7% monocytes, 1% other cells\t\nNo. 9 Hu AB CSF and serum/Zic4 AB serum\t14\t1.7\t9.2\tPositive\t92% lymphocytes\t\n\t\t\t\t\t3% other cells\t\n\t\t\t\t\t5% monocytes\t\nNo. 10 anti-GABABR AB serum 1:200; CSF negative\t1\t1.6\t3.3\tNegative\t55% lymphocytes\t\n\t\t\t\t\t45% monocytes\t\nNo. 11 Unspecific neuropil AB in CSF and serum\t9\t2.9\t15.6\tNegative\t46% lymphocytes\t\n\t\t\t\t\t1% other cells\t\n\t\t\t\t\t53% monocytes\t\nNo. 12 anti-CASPR2 AB serum 1 < 2,500, CSF negative,\t70\t3.6\t20.8\tNegative\t24% lymphocytes\t\n\t\t\t\t\t75% monocytes\t\nNo. 13 AB neg\t2\t6.5\t7.6\tNegative\t52% lymphocytes\t\n\t\t\t\t\t48% monocytes\t\nNo. 14 AB neg\t2\t3.7\t5.9\tNegative\t74% lymphocytes\t\n\t\t\t\t\t24% monocytes\t\nNo. 15 AB neg\t1\t4.2\t22.2\tNegative\t34% lymphocytes, 44% monocytes\t\n\t\t\t\t\t22% other cells\t\nNo. 16 AB neg\t1\t2\t5.5\tNegative\tNot done\t\nNo. 17 unspecific neuropil AB serum, AE following HSV encephalitis\t42\t3.1\t8.5\tPositive\tNot done\t\nCSF, cerebrospinal fluid; OCB, oligoclonal band; S, Serum; GAD, glutamic acid decarboxylase 65; LGI1, leucine-rich glioma inactivated 1 protein; CASPR-2, contactin-associated protein-like 2; NMDAR, N-methyl-D-aspartate receptor; GABA, amino-butyric acid B receptor; AB, antibody; AE, autoimmune encephalitis.\n\nCohort II: Suspected AE\n\nEight patients (n = 8/225; 3.5%) had unilateral MRI alterations suggestive for AE. Two patients (n = 2/8, 38%) had neuropsychological findings compatible with AE (Supplementary Table 2). CSF analysis revealed elevated cell count or OCB in CSF in four patients (n = 4/8; 50%). Two patients (n = 2/8; 25%) were suspected to have a paraneoplastic AE, one with anti-GABAB receptor AB in serum and a known B-cell non-Hodgkin's lymphoma and one with anti-CASPR2 AB in serum and a large cell bronchial carcinoma (Table 2). Applying the Graus criteria in this cohort revealed no patient with definite autoimmune limbic encephalitis, three patients (n = 3/8; 38%) with possible AE (2,6,7) and one patient (n = 1/8; 13%) fulfilled the criteria for AB-negative but probable AE (2). Details are given in Tables 2, 3 as well as in the Supplementary Table 2.\n\nTable 3 Patients with suspicion of AE, not fulfilling the criteria for definite AE.\n\nPatients with suspected AE\tAge\tMRI\tEEG\tTherapy\tFollow-up\t\n\t\t\t\tImmunotherapy\tAnti-seizure medication\t\t\nNo. 1\t75\tT2/FLAIR hyperintensity right temporal and left parietal\tnormal\tplasma exchange (5 cycles) followed by prednisolone 1 mg/kg per day p.o.*, azathioprine 100 mg per day\tgabapentin 1,200 mg per day p.o.\t12 months, seizure free, progressive psychiatric and memory decline\t\nNo. 2\t61\tT2/FLAIR hyperintensity right mesial temporal\tnormal\tprednisolone 1 mg/kg per day p.o.*\tlevetiracetam 2,000 mg per day\tlost to follow-up\t\nNo. 3\t67\tcontrast enhancement right cingulate gyrus and mesial temporal\tintermittent generalized slow and intermittent regional slow right hemisphere\tmethylprednisolone 1,000 mg per day i.v. for 5 days followed by prednisolone 1 mg/kg per day per os*\tphenytoin 200 mg per day, valproate 1,800 mg per day\t6 months, no information about seizure outcome available\t\nNo. 4\t79\tT2/FLAIR hyperintensity left temporal and insula\tintermittent isolated epileptic discharges left frontal and temporal\tprednisolone1 mg/kg per day p.o.*\tbrivaracetam 200 mg per day, phenobarbital 500 mg per day\tlost to follow-up\t\nNo. 5\t41\tT2/FLAIR hyperintensity right insula\tcontinuous generalized slow, continuous rhythmic pattern (sharp waves) over the right hemisphere\tmethylprednisolone 1,000 mg per day i.v. for 5 days followed by immunoadsorption, plasma exchange (5 cycles)\ttopiramate 150 mg per day, lacosamide 200 mg per day\t14 months, seizure free\t\nNo. 6\t61\tT2/FLAIR hyperintensity left mesiotemporal and medial thalamus\tintermittent regional slow with left temporal continuous rhythmic pattern\tmethylprednisolone 1,000 mg per day i.v., followed by prednisolone 1 mg/kg per day p.o.*\tphenytoin 350 mg per day, brivaracetam 200 mg per day, lacosamide 400 mg per day\t2 months, status epilepticus\t\nNo. 7\t80\tT2/FLAIR hyperintensity dorsal thalamus, mesial temporal and insula as well as bilateral occipital\tcontinuous regional slow over the left hemisphere\tPrednisolone 1mg/kg per day p.o.*\tlevetiracetam 3,000 mg per day, lacosamide 200 mg per day, valproate 1,800 mg per day\t48 months, seizure frequency >1/year\t\nNo. 8\t71\tatrophy left temporopolar and temporomesial\tintermittent regional slow over the left hemisphere with continuous rhythmic pattern (sharp waves), generalized slow\tprednisolone 1 mg/kg per day p.o.*\tlevetiracetam 1,000 mg per day, valproate 1,200 mg per day\t70 months, no information about seizure outcome available\t\n* Gradual reduction in dosage over several weeks.\n\nMRI, magnetic resonance imaging; EEG, electroencephalography; AE, autoimmune encephalitis; FLAIR, fluid attenuated inversion recovery; i.v., intravenous; p.o., per os.\n\nCohort III: No Evidence of AE\n\nThis cohort comprises 208 patients (n = 208/225; 92%) that did not fulfill the above-mentioned diagnostic criteria for definite or suspected AE. None of the patients had specific neural AB in CSF or serum. Elevated cell count in CSF (>4/μl) was detected in 6% (n = 13/205) of the patients, and elevated lactate concentrations (>2.5 mmol/l) were seen in 23% (n = 47/207) of the patients and elevated concentrations of total protein (>500 mg/dl) in 52% (n = 108/207) of the patients. OCB in CSF were present in 4.5% (n = 8/179) of the patients. Most of these patients had a cryptogenic origin of seizures (n = 121/208, 58%), 84 patients had a symptomatic origin (n = 84/208, 40%), two patients an idiopathic (n = 2/208, 1%) origin, and one patient had an acute symptomatic seizure. MRI analysis revealed no changes indicative of AE in 86% (n = 134/155) of patients. Twelve patients (n = 12/155; 8%) presented with mesial temporal unilateral volume changes and nine patients (= 9/155; 6%) demonstrated unspecific extratemporal T2/FLAIR hyperintensities. Over half of this cohort (n = 106/208, 51%) received neuropsychological testing.\n\nWhen Should We Suspect AE in Late-Onset Seizures?\n\nCompared with patients with no evidence of AE, those with definite and suspected AE (dAE/sAE) (i) were significantly younger (p = 0.028), (ii) more frequently presented with a history of/or an active tumor disease (p = 0.006), (iii) showed specific mesial temporal neuropsychological deficits (p = 0.0012), (iv) more frequently elevated CSF cell counts >4/μl (p = 0.0002) and isolated OCB (p = 0.0012) in CSF, and (v) unilateral mesial temporal T2-hyperintensities in MRI (p = 0.0001).\n\nIntergroup comparison between dAE/sAE and nAE revealed no significant differences concerning mRS (p = 0.16), frequency of abnormal EEG patterns, semiology (p = 0.06), motor vs. non-motor seizure onset (p = 0.13), and occurrence of status epilepticus (p = 0.5) (for more detail see Table 4).\n\nTable 4 Comparison of clinical characteristics between AE cohorts and cohort III.\n\n\tseizures due to AE n = 17\tseizures due to another etiology n = 208\tp-value*\t\nAge\t67 (61;75)\t75 (66;80)\t0.028*\t\nFemale (n;%)\t8;47\t113;54\t0.62\t\nmRS\t2 (0;4)\t0 (0;3)\t0.162\t\nStatus epilepticus (n;%)\t4;24\t33;15.9\t0.5\t\nSemiology\t\t\t0.06\t\nFIAS (n;%)\t8;47\t120;58\t\t\nFAS (n;%)\t4;24\t15;7.2\t\t\nGMS (n;%)\t2;12\t59;28\t\t\n≥2 (n;%)\t1;6\t9;4.3\t\t\nOnset (motor) (n;%)\t5;29\t114; 55\t0.13\t\nMalignancy (active or known) (n;%)\t8;47\t35; 16.9\t0.006*\t\nEEG\t\t\t\t\nED (n;%)\t6; 35;\t51;25.4\t0.393\t\nGeneralized slowing (n;%)\t4; 24\t63;31\t0.594\t\nRegional slowing and/or amplitude decrease (n;%)\t6;35\t44;22\t0.2311\t\nNeuropsychological impairment\t\t\t\t\nMesial temporal‡ (n;%)\t4; 36\t3; 3\t0.0012\t\nNo cognitive impairment (n;%)\t3;27\t27;25\t>0.999\t\nCSF\t\t\t\t\nCC (> 4/μl) (n;%)\t7; 41\t13;6\t0.0002*\t\nLactate (> 2.5 mmol/l) (n;%)\t8;47 (1.7;3.1)\t47;23\t0.0374\t\nTotal protein (> 500 mg/dl)\t11;65\t108;52\t0.45\t\nOCB pos (n;%)\t5;29\t8;4.5\t0.0012*\t\nMRI†\t\t\t<0.00001*\t\nNo lesion (n;%)\t5;56\t134;86\t0.0315\t\nUnilateral lesion (n;%)\t10;59\t12; 8\t0.0001\t\nBilateral lesion (n;%)\t0;0\t0;0\t\t\nExtratemporal lesion (n;%)\t1; 6\t9;6\t>0.99\t\nNominal data are given as percentages, and continuous data are expressed as the median (1st; 3rd quartile).\n\n* Significance: p-value ≤ 0.05; MRI: epileptogenic lesions of unknown origin, possible autoimmune (T2/FLAIR-hyperintensity and/or swelling and/or Gd enhancement), Neuropsychological assessment compatible with deficits in mesial temporal structures: amnestic syndrome and/or delayed verbal memory and/or impaired executive functioning.\n\nMrs, modified Rankin Scale; EEG, electroencephalography; ED, epileptic discharges; MRI, magnet resonance imaging; Gd, gadolinium; CSF, cerebrospinal fluid; CC, cell count; OCB, oligoclonal band; FIAS, focal onset impaired awareness seizure; FAS, focal onset awareness seizure; GMS, generalized motor seizure.\n\nTreatment and Outcomes\n\nA follow-up (FU) was carried out in 59% (n = 10/17) of patients with dAE or sAE, with a mean FU time of 40 months (range: 6–102) after the first seizure disorder. Of the remaining seven patients, five (29%) were lost to follow-up (three patients with dAE, two patients with sAE), and two had a follow-up of <6 months. Among those with FU, all were seizure-free at last FU, three of them with the first used ASD. First-line IT was administered to all patients. Second-line IT was needed in one patient with anti-CASPR2 AB encephalitis due to newly manifested CSF pleocytosis and increasing serum AB titers over the course of the disease (Figure 1). One patient with sAE received a second-line IT due to progressive psychiatric and neuropsychological deficits (Table 3).\n\nFigure 1 Data for an anti-CASPR2 AB positive patient. The patient had a first epileptic seizure (GMS) 3 months before the diagnosis and recurrent focal seizures until he received monotherapy with Lamotrigin, after which he became seizure-free. The first MRI showed unilateral swelling and T2-hyperintensity in the insula, the hippocampus, temporal mesial, and in the temporal lobe, compatible with possible AE, although not fulfilling the Graus criteria in the absence of neurocognitive or neuropsychiatric deficits. Immunotherapy was initialized after positive testing for anti-CASPR2 AB in serum and CSF. The patient had no clinical signs of AE until last FU; immunotherapy was reinitialized 2 years after diagnosis because of an increased titer of anti-CASPR2 AB in routine clinical FU and a recurrent pleocytosis in CSF. Anti-CASPR2 contactin-associated protein-like 2, GMS generalized motor seizure, MRI magnet resonance imaging, AE autoimmune encephalitis, CSF cerebrospinal fluid, FU follow-up, S Serum, NPS neuropsychological testing, OCB oligoclonal bands, LTG Lamotrigin, MP Methylprednisolon, AZA Azathioprin.\n\nAt hospital admission mRS was low (≤2) in the majority of dAE/sAE patients (n = 12/17, 71%), decreasing to a proportion of 60% (n = 6/10) at last FU (Figure 2). Outcome was favorable for non-paraneoplastic AE (mRS = 0 for all patients with anti-CASPR2 AB and the one patient with anti-LGI1 AB); outcomes in paraneoplastic AE and suspected AE, however, were worse (mRS = 0 in only two patients). Five of 17 patients (29%) with dAE/sAE died during FU, and after evaluation of the medical charts, three of them (60%) had paraneoplastic AE. One patient died because of infection probably associated to IT, another patient died of a comorbid disease. Of the five patients with paraneoplastic AE, three patients (60%) died.\n\nFigure 2 Modified Rankin scale score (mRS) of patients with definite AE and suspected AE at first hospital admission and FU in comparison with patients with late-onset seizures due to another etiology. Modified Rankin scale at hospital admission was low for patients with definite and suspected AE (71% with mRS ≤2), which decreased to 60% with mRS ≤2 at last FU [mean follow-up time of 40 months (range 6–102)]. Outcome was favorable for non-paraneoplastic and definite AE; outcome in paraneoplastic and suspected AE was worse. However, the generalizability of these study results is limited by the small number of patients. mRS, modified Rankin scale, AE, autoimmune encephalitis, FU, follow-up.\n\nDiscussion\n\nIn our cohort, patients with definite and suspected AE comprised 8% of the study population. Definite AE was found in 4% of all patients: all of them had AB in serum and CSF. To our knowledge, this is the largest study aimed at investigating the prevalence and clinical features of AE with late-onset seizures as the first clinical symptom.\n\nOverall information about specific age-related differences of clinical features, treatment, and outcomes of AE is scarce and prospective studies to elucidate this topic are lacking. There is only limited information about AB prevalence in elderly patients. In a patient cohort >60 years of age with no signs of inflammation, the most common antibodies detected were anti-LGI1 AB (31.4%) and anti-IGLON5 AB (28.6%), whereas, anti-NMDAR AB and anti-CASPR2 AB are less common (17). Overall, the most common antibodies >60 years are anti-LGI1 AB (34%), followed by anti-GABABR AB (17%), anti-AMPAR AB (13%), anti-NMDAR AB (11%), anti-IGLON5 AB (9%), and anti-CASPR2 AB (8%) (17). Older patients with AE have a higher risk of having a malignancy (22), but this depends on the subtype of the AE (23).\n\nWhen to Suspect AE in Patients With Late-Onset Seizures\n\nConsistent with a previous study showing that 23% of patients aged >60 years with positive AB had no signs of inflammation in their diagnostic work-up (17), 12% of our patients presented without inflammatory changes in both MRI and CSF.\n\nMagnetic resonance imaging shows that patients with AE as the cause of late-onset seizures often present with unilateral alterations in mesial temporal structures. In our cohort this was the case in 71% of patients. However, although unilateral MRI changes are common in AE, they are a limiting factor for fulfilling the diagnostic criteria proposed by Graus et al. (4, 11), at least in the absence of neural AB. As unilateral mesial temporal MRI changes are not specific for AE and may also occur in non-autoimmune disorders, such as lower grade gliomas or hippocampal sclerosis, they are not a criterion for definite AE (3, 4). Consequently, unilateral MRI alterations should always be interpreted in the context of other clinical features of AE.\n\nPatients with dAE or sAE more frequently showed a pleocytosis and/or OCB in CSF than patients without AE, which is a frequent finding in patients with AE (4, 24). The reported percentages of pathological values for the three basic CSF parameters (cell count, protein, OCB) are highly different among the AB-defined subtypes of AE (25). There are no specific age-focused studies regarding CSF changes in patients with AE. In the study by Blinder et al. (25), the median age of patients with anti-LGI1 AB, anti-CASPR2 AB, anti-GABABR AB, anti-IGLON5 AB, and anti-AMPAR AB was over 60 years old (22). Thus, it can be concluded that older patients with anti-LGI1 AB encephalitis less frequently have OCB in CSF, whereas, patients with anti-CASPR2 AB encephalitis more frequently show higher cell counts (29%−36%) as well as OCB (23%−32%) in CSF (22). All in all, inflammatory CSF changes are more often found in NMDA, GABAB, and AMPA receptors, as well as DPPX in contrast to patients with CASPR2, LGI1, GABAA, or glycine receptor AB, with mostly normal CSF findings (25). Nevertheless, we observed a significant proportion of patients with pleocytosis and/or OCB in CSF in our study, which may be indicative of AE even in older patients with different subtypes of AE. Although other studies recommend CSF analysis only to rule out infections (8, 26), our data suggest performing AB tests if the CSF cell count is increased or OCB are detected exclusively in CSF.\n\nExcept for faciobrachial dystonic seizures (FBDS) in anti-LGI1 AB encephalitis, no specific semiological features are known to be pathognomonic for AE, even in cases of status epilepticus.\n\nAlthough not confirmed by our data, an EEG often provides important ways to suspect AE (8); however, EEG interpretation strongly depends on the rater's experience to identify characteristics of AE, such as a delta brush pattern in anti-NMDAR AB encephalitis (18).\n\nOne of the most common neural AB detected in this elderly population was anti-CASPR2 AB. Only one of our patients (aged 80 years) presented with anti-NMDAR AB, which is usually found in young females with AE and only rarely (5–12%) in the elderly population (15, 27, 28). Interestingly, in contrast to the younger population with anti-NMDAR AB encephalitis, elderly patients are more often male and show a milder course of the disease. However, the long-term outcome is worse due to age-related factors and the higher risk of delayed diagnosis (15). Even though the outcome is worse in comparison with younger patients, a significant proportion of patients fully recover after the acute phase of the disease (15). Prior studies have reported a frequent occurrence of anti-CASPR2 AB in elderly patients (with a median age of 60) with AE (18), which is supported by our results. Consistent with our findings (mRS ≤2 in 71% of patients at hospital admission), the clinical appearance of anti-CASPR2 AB encephalitis is rather mild (29). Additionally, MRI changes in anti-CASPR2 AB encephalitis may evolve over a long period (29) and are, therefore, found in only about 40% at the clinical disease onset (18). It is quite conceivable that early initiation of IT prevented worse clinical outcomes in our patients and contributed to the mild appearance of clinical features and the rather minor MRI alterations.\n\nEscudero et al. (17) reported that rapidly progressive dementia was not a frequent clinical presentation of late-onset autoimmune encephalitis. Our results show that specific mesial temporal neuropsychological deficits were more frequent in patients with dAE/sAE compared with those without AE. Among patients with late-onset seizures in whom AE is at least suspected, neuropsychological testing should therefore focus on mesial temporal deficits and should be repeated during the course of the disease. Consistent with the circumscribed structural alterations of mesolimbic structures, characteristic neuropsychological deficits in AE mainly comprise impairments of episodic memory (material-specific, i.e., verbal and/or non-verbal, according to the lateralization of the lesion) and correlate with disease severity, the extent of structural (especially mesial temporal) alterations, and antibody titer and the time at which an immunotherapy is started (15, 28). Other tests comprise specific tests for figural (e.g., ROCFT, BVMT) and verbal memory (e.g., RAVLT/VLMT) that are proven to be sensitive for mesial temporal functions in patients with epilepsy (30) and especially those with in AE (31) and should be included in the test protocol (32). Especially in the higher-aged population, short dementia screenings as MMST (Mini Mental Status Test) or MoCA (Montreal Cognitive Assessment) are not adequate tools because of their low resolution to differentiate memory processes (learning, recall, recognition) and to contrast different cognitive domains. Instead, a comprehensive neuropsychological test battery focusing on verbal and figural memory but including other domains, such as attention/cognitive speed, executive functions, and language functions should be performed in order to weight the memory deficits against other cognitive functions (interpretation of the neuropsychological profile).\n\nWhen we applied the clinical diagnostic criteria from Graus et al. (4) to our patient cohort, no patient with either definite AE or suspected AE fulfilled the criteria for definite autoimmune limbic encephalitis. This is highly relevant, as these patients would have been missed for AB testing in the acute phase. This is likely due to the specific AB prevalence in this patient cohort. As many patients have either anti-CASPR2 AB or onconeural AB without typical MRI features for definite limbic encephalitis as described above, they are missed when researchers apply the Graus criteria. Newer prognostic pathways, such as the APE or RITE Score (24) may be more precise in these patients but were not yet established at the time of conception of our study.\n\nTreatment and Outcome\n\nLate-onset seizures in non-paraneoplastic AE are known to have a favorable prognosis (3, 18), corresponding to our findings with a high seizure-free rate with at least one ASD and/or IT. Overall impairment at hospital admission was low (47% mRS 0, 71% mRS ≤2), probably due to the high rate of anti-CASPR2 AB AE (24%) in our patient cohort (25). Among patients with paraneoplastic AE, 60% died, mostly due to the underlying malignancy. Other factors may influence outcome parameters in our patient cohort, such as limited capacity of recovery after brain damage in the aging brain (33). Furthermore, age itself is considered an independent risk factor for adverse outcomes in late-onset anti-NMDAR encephalitis (15).\n\nAlthough randomized controlled trials on IT in AE are lacking, about 70% of AE patients respond to gradual IT escalation (18) including those with paraneoplastic AE (34). First-line therapy comprises corticosteroids, intravenous immunoglobulins, and/or PEX/ (IA) (18, 35). Early administration of high-dose intravenous corticosteroids is associated with improved clinical outcome (18). All patients in our cohort received high-dose corticosteroids as initial therapy (administered orally or intravenously), followed by a gradual reduction in dosage in 88% of patients. Only three patients received a second-line immunotherapy. One of them developed a severe infection and died during the course of the disease. In view of the high rate of multimorbidity and polypharmacy in this patient population as well as the often favorable outcome among patients with non-paraneoplastic AE patients under first-line therapy (36), administration of second-line IT should be considered with caution. This recommendation is supported by a study among patients with multiple sclerosis that found a risk of adverse effects of immunotherapy (such as opportunistic infections and malignancies) that increases with the patient's age (37). Published immunotherapy protocols include patients aged up to 85 years; younger patients are, however, clearly overrepresented in these studies (15, 38)). Randomized controlled trials based on standard immunotherapy protocols including elderly patients with autoimmune encephalitis are lacking (38).\n\nAs most non-paraneoplastic AE patients have a favorable outcome, we suggest using second-line IT only in cases of recurrent disease attacks verified by MRI and/or CSF inflammation.\n\nLimitations\n\nOne major limitation of the study is the single-institutional design, which leads to a limited number of AE cases, further limiting statistical assertions and the possibility of comparing different subgroups (dAE and sAE). In addition, not all patients with AE received an FU investigation as this was not part of the initial study protocol.\n\nConclusion\n\nTo date, there are only limited data available concerning diagnostic strategies, clinical symptoms, treatment, and outcomes of autoimmune encephalitis in the elderly. The results of our study provide clinicians with additional information verified in a great cohort of 225 patients on the prevalence and outcomes of AE as well as predictors of when to suspect AE in patients with late-onset seizures. Although characteristic signs of inflammation in AE may be lacking especially in elderly patients, the presence of CSF and MRI signs of inflammation, mesial temporal neuropsychological alterations, younger age, a known malignancy and specific semiological features (such as FBDS) should suggest AE. An epileptic seizure may be the first symptom of AE. In short, AB testing in CSF and sera, cerebral MRI, lumbar puncture, and neuropsychological testing for mesial temporal deficits should be part of the diagnostic protocol for AE following late onset seizures. First-line therapy comprises ASD as well as corticosteroids and/or PEX/IA; in view of the potential comorbidity and polypharmacy in the elderly, administration of second-line IT should be considered with caution.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Institutional review board of the university medicine Greifswald, Germany. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.\n\nAuthor Contributions\n\nMS analyzed the data, interpreted the data, drafted the manuscript, and revised the manuscript for intellectual content. MZ had a major role in the acquisition and analysis of the data. VP revised the manuscript for intellectual content and interpreted the data. FP revised the manuscript for intellectual content and design and conceptualized the study. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nMS reports personal fees and grants from Merck Healthcare Deutschland and Bayer Vital GmbH. FP obtained honoraria for speaking engagements from Desitin Pharma (Hamburg, Germany), EISAI Pharma (Frankfurt am Main, Germany), UCB Pharma (Monheim, Germany), BIAL (Mörfelden-Walldorf, Germany), and GW Pharma (München, Germany) and was part of the speakers bureau of Desitin Pharma (Hamburg, Germany), EISAI Pharma (Frankfurt am Main, Germany), UCB Pharma (Monheim, Germany), BIAL (Mörfelden-Walldorf, Germany), and GW Pharma (München, Germany). The 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\nWe gratefully acknowledge the assistance of Dr. Michael Opolka for providing detailed neuropsychological test results as well as Roman Schimmer for proofreading and language revision. We acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 393148499) and the Open Access Publication Fund of the University of Greifswald.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fneur.2021.633999/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Cloyd J Hauser W Towne A Ramsay R Mattson R Gilliam F . Epidemiological and medical aspects of epilepsy in the elderly. Epilepsy Res. 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Autoimmune encephalitis update. Neuro Oncol. (2014) 16 :771–8. 10.1093/neuonc/nou030 24637228\n24. Dubey D Singh J Britton JW Pittock SJ Flanagan EP Lennon VA . Predictive models in the diagnosis and treatment of autoimmune epilepsy. Epilepsia. (2017) 58 :1181–9. 10.1111/epi.13797 28555833\n25. Blinder T Lewerenz J . Cerebrospinal fluid findings in patients with autoimmune encephalitis-a systematic analysis. Front Neurol. (2019) 10 :804. 10.3389/fneur.2019.00804 31404257\n26. Wang R Guan HZ Ren HAT Wang W Hong Z Zhou D . CSF findings in patients with anti-N-methyl-d-aspartate receptor-encephalitis. Seizure. (2015) 29 :137–42. 10.1016/j.seizure.2015.04.005 26076857\n27. Zhang L Liu X Jiang XY Wang YH Li JM Zhou D . Late-onset anti-N-methyl-d-aspartate receptor encephalitis in China. Epilepsy Behav. (2018) 84 :22–8. 10.1016/j.yebeh.2018.02.025 29734104\n28. Rainey K Gholkar B Cheesman M . Anti-NMDA receptor encephalitis: an easily missed diagnosis in older patients. Age Ageing. (2014) 43 :725–6. 10.1093/ageing/afu098 25156545\n29. van Sonderen A Ariño H Petit-Pedrol M Leypoldt F Körtvélyessy P Wandinger KP . The clinical spectrum of Caspr2 antibody-associated disease. Neurology. (2016) 87 :521–8. 10.1212/WNL.0000000000002917 27371488\n30. Wilson SJ Baxendale S Barr W Hamed S Langfitt J Samson S . Indications and expectations for neuropsychological assessment in routine epilepsy care: report of the ILAE Neuropsychology Task Force, Diagnostic Methods Commission, 2013-2017. Epilepsia. (2015) 56 :674–81. 10.1111/epi.12962 25779625\n31. Loring DW Lowenstein DH Barbaro NM Fureman BE Odenkirchen J Jacobs MP . Common data elements in epilepsy research: development and implementation of the NINDS epilepsy CDE project. Epilepsia. (2011) 52 :1186–91. 10.1111/j.1528-1167.2011.03018.x 21426327\n32. Frisch C Malter MP Elger CE Helmstaedter C . Neuropsychological course of voltage-gated potassium channel and glutamic acid decarboxylase antibody related limbic encephalitis. Eur J Neurol. (2013) 20 :1297–304. 10.1111/ene.12186 23678940\n33. Bishop NA Lu T Yankner BA . Neural mechanisms of ageing and cognitive decline. Nature. (2010) 464 :529–35. 10.1038/nature08983 20336135\n34. Stich O Rauer S . [Paraneoplastic neurological syndromes and autoimmune encephalitis]. Nervenarzt. (2014) 85 :485–98. 10.1007/s00115-014-4030-x 24668402\n35. Lancaster E . The diagnosis and treatment of autoimmune encephalitis. J Clin Neurol. (2016) 12 :1–13. 10.3988/jcn.2016.12.1.1 26754777\n36. Varley J Taylor J Irani SR . Autoantibody-mediated diseases of the CNS: structure, dysfunction and therapy. Neuropharmacology. (2018) 132 :71–82. 10.1016/j.neuropharm.2017.04.046 28476644\n37. Schweitzer F Laurent S Fink G Barnett M Reddel S Hartung HP . Age and the risks of high-efficacy disease modifying drugs in multiple sclerosis. Curr Opin Neurol. (2019) 32 :305–12. 10.1097/WCO.0000000000000701 30985373\n38. Behrman S Lennox B . Autoimmune encephalitis in the elderly: who to test and what to test for. Evid Based Ment Health. (2019) 22 :172–6. 10.1136/ebmental-2019-300110 31537612\n\n",
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"keywords": "autoimmune encephalitis; epilepsy of unknown origin; late onset seizures; neural antibodies; outcome",
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"title": "Autoimmune Encephalitis in Late-Onset Seizures: When to Suspect and How to Treat.",
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"abstract": "We report a case of death due to heroin leakage in a body packer, attempting to smuggle the drug by concealing it in his gastro-intestinal tract. The body was recovered 3-5 days of incidence that was confirmed by autopsy. Fifty pellets (packages) were recovered from the body, 42 identical oval shaped \"egg\" packages were found in the stomach out of which two were damaged, 6 in small intestine, 2 in large intestine. The total weight of the powder was 267 g. Toxicological analysis of the powder samples from the damaged package and other 48 packages was performed and was found positive for heroin, caffeine and codeine. The main pathological findings at autopsy were pulmonary and cerebral edema. This case illustrates the challenges in postmortem evaluation of narcotic fatalities and the need to consider factors such as ante-mortem history, thorough post mortem examination, toxicology results and photography in forensic diagnosis. This case is unique in the sense that cause of death was intoxication caused by leakage of heroin from damaged packages detected at autopsy and demonstrates that body packing is an existing problem in India.",
"affiliations": "Department of Forensic Medicine, Pt. B. D. Sharma PGIMS, Rohtak, India. jjakhar2012@yahoo.com",
"authors": "Jakhar|Jitender Kumar|JK|;Dhattarwal|S K|SK|;Aggarwal|A D|AD|;Chikara|Pankaj|P|;Khanagwal|Vijay Pal|VP|",
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"mesh_terms": "D000328:Adult; D001929:Brain Edema; D003415:Crime; D004349:Drug Packaging; D005547:Foreign Bodies; D049429:Forensic Pathology; D003932:Heroin; D006801:Humans; D007194:India; D007420:Intestine, Large; D007421:Intestine, Small; D008297:Male; D009294:Narcotics; D013270:Stomach",
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"title": "Heroin body packer's death in Haryana; India: a case report.",
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"abstract": "We conducted a multicenter randomized prospective phase 2 trial of chemoradiotherapy (CRT) versus chemotherapy (CT) as initial induction therapy for conversion surgery (CS) in clinical T4b esophageal cancer. We compared treatment effects and adverse events (AEs).\n\n\n\nAlthough induction followed by CS is potentially curative for T4b esophageal cancer, the optimal initial induction treatment is unclear.\n\n\n\nNinety-nine patients with T4b esophageal cancer were randomly allocated to chemoradiotherapy (Group A, n = 49) or CT (Group B, n = 50) as initial induction treatment. CRT consisted of radiation (50.4 Gy) with cisplatin and 5-fluorouracil. CT consisted of 2 cycles of docetaxel plus cisplatin and 5-fluorouracil (DCF). CRT or CT was followed by CS if resectable. If unresectable, the patient received the other treatment as secondary treatment. CS was performed if resectable after secondary treatment. The primary end point was 2-year overall survival.\n\n\n\nIn Group A, CS was performed in 34 (69%) and 7 patients (14%) after initial and secondary treatment. In Group B, CS was performed in 25 (50%) and 17 patients (34%) after initial and secondary treatment. The R0 resection rate after initial and secondary treatment was similar (78% vs 76%, P = 1.000). AEs including leukopenia, neutropenia, febrile neutropenia, and diarrhea were significantly more frequent in Group B. Group A had better histological complete response of the primary tumor (40% vs 17%, P = 0.028) and histological nodal status (P = 0.038).\n\n\n\nUpfront CRT was superior to upfront CT in terms of pathological effects and AEs. The Japan Registry of Clinical Trials (s051180164).",
"affiliations": "Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.;Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.;Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan.;Department of Surgery, Kindai University Faculty of Medicine, Osaka Sayama, Osaka, Japan.;Department of Surgery, Osaka General Medical Center, Osaka, Japan.;Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Department of Surgery, Kindai University Faculty of Medicine, Osaka Sayama, Osaka, Japan.;Department of Surgery, National Hospital Organization, Osaka National Hospital, Osaka, Japan.;Department of Surgery, Osaka General Medical Center, Osaka, Japan.;Department of Surgery, Kindai University Faculty of Medicine, Osaka Sayama, Osaka, Japan.;Department of Surgery and Science, Graduate School of Medical Sciences, Kyusyu University, Japan.;Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.;Department of Surgery, Osaka International Cancer Institute, Osaka, Japan.;Departments of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.",
"authors": "Sugimura|Keijiro|K|;Miyata|Hiroshi|H|;Tanaka|Koji|K|;Makino|Tomoki|T|;Takeno|Atsushi|A|;Shiraishi|Osamu|O|;Motoori|Masaaki|M|;Yamasaki|Makoto|M|;Kimura|Yutaka|Y|;Hirao|Motohiro|M|;Fujitani|Kazumasa|K|;Yasuda|Takushi|T|;Mori|Masaki|M|;Eguchi|Hidetoshi|H|;Yano|Masahiko|M|;Doki|Yuichiro|Y|",
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"title": "Multicenter Randomized Phase 2 Trial Comparing Chemoradiotherapy and Docetaxel Plus 5-Fluorouracil and Cisplatin Chemotherapy as Initial Induction Therapy for Subsequent Conversion Surgery in Patients With Clinical T4b Esophageal Cancer: Short-term Results.",
"title_normalized": "multicenter randomized phase 2 trial comparing chemoradiotherapy and docetaxel plus 5 fluorouracil and cisplatin chemotherapy as initial induction therapy for subsequent conversion surgery in patients with clinical t4b esophageal cancer short term results"
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"abstract": "This is the first report of successful deferasirox administration, using graded challenge and treating through, in a patient with mild immediate hypersensitivity reaction. Beginning with drug graded challenges could indicate the eliciting dose and reaction severity which are important for the management plan in the next step. This approach could be a safe shortcut in a stable patient with a mild reaction and a long avoidance period.",
"affiliations": "Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand.;Adverse Drug Reaction (ADR) Unit, Pharmacy Department, Siriraj Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Sompornrattanaphan|Mongkhon|M|0000-0001-8419-0873;Krikeerati|Thanachit|T|;Wongsa|Chamard|C|0000-0002-5721-4881;Thongngarm|Torpong|T|0000-0002-3182-4614;Yampayon|Kittika|K|0000-0001-7653-7101",
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"fulltext": "\n==== Front\nJ Asthma Allergy\nJ Asthma Allergy\njaa\njaa\nJournal of Asthma and Allergy\n1178-6965 Dove \n\n271742\n10.2147/JAA.S271742\nCase Report\nSuccessful Deferasirox Rechallenge and Treating Through Reaction in a Patient with Challenge-Proven Mild Immediate Reaction: A Case Report\nSompornrattanaphan et alSompornrattanaphan et alhttp://orcid.org/0000-0001-8419-0873Sompornrattanaphan Mongkhon 1 Krikeerati Thanachit 12 http://orcid.org/0000-0002-5721-4881Wongsa Chamard 1 http://orcid.org/0000-0002-3182-4614Thongngarm Torpong 1 http://orcid.org/0000-0001-7653-7101Yampayon Kittika 3 1 Division of Allergy and Clinical Immunology, Department of Medicine, Faculty of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand\n2 Department of Medicine, Faculty of Medicine, Khon Kaen University, Khon Kaen, Thailand\n3 Adverse Drug Reaction (ADR) Unit, Pharmacy Department, Siriraj Hospital, Mahidol University, Bangkok, Thailand\nCorrespondence: Kittika Yampayon Adverse Drug Reaction (ADR) Unit, Pharmacy Department, Siriraj Hospital, Mahidol University, 2 Wanglang Road, Bangkok Noi, Bangkok10700, ThailandTel +66 81 488 6887Fax +66 2 419 7376 Email kittika.yampayon@gmail.com\n30 10 2020 \n2020 \n13 557 561\n11 7 2020 02 10 2020 © 2020 Sompornrattanaphan et al.2020Sompornrattanaphan et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Abstract\nThis is the first report of successful deferasirox administration, using graded challenge and treating through, in a patient with mild immediate hypersensitivity reaction. Beginning with drug graded challenges could indicate the eliciting dose and reaction severity which are important for the management plan in the next step. This approach could be a safe shortcut in a stable patient with a mild reaction and a long avoidance period.\n\nKeywords\ndeferasiroxdrug allergyrechallengedesensitizationhypersensitivityiron overloadiron chelating agentsthalassemiapremedicationno fundingThere is no funding to report.\n==== Body\nIntroduction\nThere are three iron-chelating agents for patients with transfusion-dependent thalassemia, including deferoxamine (DFO), deferiprone (DFP), and deferasirox (DFX). There is a significant variation in the recommendations for iron chelation therapy.1–3 DFX dose of 30–40 mg/kg/day could reduce serum ferritin level, liver iron concentration (LIC), and achieved negative iron balance in transfusion-dependent thalassemia. DFX is well tolerated in most patients. Longer-term extension studies have confirmed the efficacy and safety of DFX.4\n\nThe most common adverse events consist of gastrointestinal disturbances, skin rash, nonprogressive increases in serum creatinine, and elevations in liver enzyme levels. DFX is known to cause a maculopapular eruption in up to 10% of the patients. There were reports regarding successful DFX desensitization for delayed-type drug hypersensitivity reactions (DHR), including maculopapular eruption and erythema multiforme.5,6 Those protocols took several days to achieve the target dose. There have been no reports on a challenge-proven immediate hypersensitivity reaction. Therefore, we report a case of challenge-proven immediate hypersensitivity reaction and successful DFX graded challenge with treating through the reaction.\n\nCase Presentation\nA 50-year-old woman with β-thalassemia/Hb E and secondary hemochromatosis due to blood transfusion since the age of eight. She was initially prescribed oral DFP for the treatment of iron overload, but she developed DFP-induced agranulocytosis, leading to drug discontinuation. After 2 months, her white blood cell count returned to normal range. DFX was prescribed as an alternative for iron chelation in May 2006. Three hours after taking 1000 mg of DFX, she had a generalized pruritic rash and swollen eyelids. The hematologist discontinued the drug and prescribed H1-antihistamine with prednisolone, 20 mg/day, for 3 days. The rash was completely resolved without hyperpigmentation within 1 day. Subcutaneous injection of DFO was then used as the single iron-chelating agent from the years 2006 to 2019. However, the serum ferritin level was still excessive, ranging from 1300 to 2000 ng/mL. Magnetic resonance imaging revealed T2* heart = 48.6 ms which is within the normal range (normal Cardiac T2* >25 ms; In case of iron overload, mild = 20–25 ms, moderate = 10–20 ms, and severe ≤10 ms). She had liver iron concentration (LIC) of 35.1 mg of elemental iron/g dw, which indicated severe liver iron overload (LIC ≤ 3 = normal, 3–7 = mild, 7–15 = moderate, and >15 = severe iron overload). She had persistent transaminitis (ALT, ranging 80–90 μg/L and AST, ranging 100–150 μg/L), and a mean liver stiffness value of 7.7 kilopascals indicated by fibroscan. Left and right ventricular ejection fractions were 69.4% and 59.4%, respectively. No valvular heart diseases were demonstrated.\n\nThe patient was referred to allergy consultation due to the need for DFX use in April 2020. As DFX in solution form was not available, we initially performed DFX skin prick test (SPT) by dissolving 500-mg tablet of DFX in 25 mL of 0.9% saline at room temperature for 20 minutes, giving a 20 mg/mL concentration. The SPT result was negative.\n\nThe overall timeline is summarized in Figure 1. We performed DFX graded challenge to confirm the diagnosis and indicated the eliciting dose under close monitoring (Table 1). DFX challenge started with 1 mg, followed by 10 mg, 100 mg, 250 mg, 250 mg with escalation at every 1-hour interval. Generalized pruritic papular rash (Ring and Messmer grade 1) occurred at the cumulative dose of 611 mg (Figure 2). We treated the reaction with intravenous chlorpheniramine and started bilastine 20 mg twice daily for premedication purposes. After the rash was resolved, we restarted the graded challenge on the next day, starting with 250 mg, followed by 500 mg, and 250 mg. A cumulative dose of 1000 mg/day of DFX was achieved without a breakthrough reaction. Because the elimination half-life of DFX was 8–16 hours,7 the patient then was advised to take the drug 500 mg twice daily to ensure DFX remained in the body at all times to cover the medication interval as well as to reduced plasma drug level fluctuations and gastrointestinal side effects.8,9 Bilastine was discontinued 1 week later.Table 1 DFX Graded Challenge and Treating Through Protocol in Our Case\n\nDFX Graded Challenge\t1st Graded Challenge and Treating Through Reaction (April 2020)\t2nd DFX Graded Challenge and Treating Through Reaction (June 2020)\t\nTime (Hour)\tDFX Dose (mg)\tPremedication: Bilastine 40 mg/Day\tPremedication: Bilastine 40 mg/Day\t\n0\t1\tTime (hour)\tDFX dose (mg)\tTime (Hour)\tDFX Dose (mg)\t\n1\t10\t0\t250\t0\t250\t\n2\t100\t2\t500\t2\t500\t\n3\t250\t4\t250\t4\t500\t\n4\t250\t\nPositive reaction (Generalized pruritic papules at the extremities and trunk)\tNo breakthrough reactions after the last dose (3-hour observation)\tBreakthrough reaction: Mild lip angioedema at 2 hours\t\nAbbreviations: DFX, deferasirox; mg, milligram.\n\n\nFigure 1 The timeline of the case report.\n\nAbbreviations: CPM IV, intravenous chlorpheniramine; DFX, deferasirox; mg, milligram.Figure 2 Positive DFX challenge: a few discrete ill-defined erythematous macules on the right arm.\n\n\n\nTwo months later, she was admitted to a local hospital due to acute gastroenteritis with acute hemolysis. The physician discontinued DFX during the investigation. Red cell transfusion was administered. She was discharged without taking DFX for 1 week. An allergist was consulted for repeating DFX desensitization. A hematologist requested increasing the dose of DFX to 1250 mg. We premedicated with bilastine 20 mg 1 day before desensitization and continued twice daily. DFX desensitization was performed, starting with 250 mg, followed by 500 mg, and 500 mg. She developed mild lip angioedema 45 minutes after the last dose (Figure 3), which spontaneously resolved the next day without increasing the dose of antihistamine. She then continued a combination of iron-chelating agents which included 1250 mg/day of DFX, and subcutaneous DFO 3000 mg/day, 4 times/week. She has finally achieved a desensitized state as she could discontinue antihistamine and continued DFX without any significant breakthrough reactions for the next 2 months. However, she developed a single episode of mild eyelid angioedema without visual disturbance after missing the DFX for 1 day. The reaction was resolved after taking oral bilastine 20 mg/day for 3 days. At a 3-month follow-up visit in September 2020, her ferritin level was decreased to 601 ng/mL. The liver enzymes were improved from baseline (ALT 44 μg/L and AST 56 μg/L). The serum creatinine was 0.64 mg/dL. No significant impairment of the patient’s hearing and vision during the 3-month follow-up. The patient has been continuing on DFX until now (September 2020).Figure 3 Lip angioedema during the second DFX graded challenge and treating through with H1-antihistamine.\n\n\n\nDiscussion\nThis is the first report of challenge-proven DFX-induced immediate hypersensitivity reaction. There is a tendency for the drug-specific IgE level to decline over time and the observation of tolerance developing in patients with IgE-mediated reactions.10,11 Therefore, we initially performed a graded challenge to confirm the diagnosis as some patients might develop natural tolerance after a long avoidance period. This approach could indicate the eliciting dose and the appropriate interval for designing a graded challenge/desensitization protocol. A general published desensitization protocol begins with a 1/10,000 dose, which would sometimes take a longer time to reach the target dose.\n\nWe observed that the majority of patients who underwent chemotherapy desensitization usually elicited breakthrough reactions in the terminal step at high doses.12 This implied that the eliciting dose threshold of each patient was varied. We believed that graded challenge/desensitization could be individually tailor-made and might not necessarily start at a very low dose in all cases, especially those with mild reaction and long avoidance period since the last reaction. Our patient had a high eliciting dose, >50% of therapeutic dose, demonstrated by the first graded challenge and the reaction was non-anaphylaxis. She had no risk of severe reactions, such as decompensated cardiopulmonary diseases or taking antihypertensive medications. Treating through the reaction with H1-antihistamine during graded challenges could be an alternative option in such a case. As she had recurrent reactions from DFX reexposure after short discontinuation, this was compatible with the traditional definition of desensitization, the temporary induction of tolerance.\n\nConclusion\nIn conclusion, we report the first case of challenge-proven immediate hypersensitivity reaction to DFX and performed graded challenge with treating through the reactions using H1-antihistamine. The patient finally developed tolerance to the drug as the patient could discontinue H1-antihistamine. We provide a new perspective that “not all individuals with immediate reaction require desensitization starting at a very low dose with multiple steps”. However, the decision should be based on the patient’s status, history of index reaction, the eliciting dose, and the patient’s informed consent.\n\nAcknowledgment\nWe acknowledge the contributions of Ms Orathai Theankeaw and Ms Aree Jameekornrak Taweechue for the research assistance. We also thank Dr Anthony Tan for editing the English language in the manuscript.\n\nEthical Approval\nThe institutional approval was not applicable (case report).\n\nConsent for Publication\nWritten informed consent for publication was obtained from the patient. The patient was informed that de-identified data would be used in scientific research and publications.\n\nAuthorship\nAll authors made a significant contribution to the work reported, whether that is in the conception, execution, acquisition of data, analysis, and interpretation, or in all these areas; took part in drafting, revising, or critically reviewing the manuscript; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.\n\nDisclosure\nAll authors declare no personal, professional, or other conflicts of interest.\n==== Refs\nReferences\n1. Musallam \nKM , Angastiniotis \nM , Eleftheriou \nA , Porter \nJB . Cross-talk between available guidelines for the management of patients with beta-thalassemia major\n. Acta Haematol . 2013 ;130 (2 ):64 –73\n. doi:10.1159/000345734 23485589 \n2. Huang \nV , Luini \nC , El-Ali \nA , Kessabi \nS . Iron chelation therapy: a review of the literature on the issues and importance of adherence to treatment in iron overload\n. Blood. \n2015 ;126 (23 ):4748 . doi:10.1182/blood.V126.23.4748.4748 \n3. Kontoghiorghe \nCN , Kontoghiorghes \nGJ . Efficacy and safety of iron-chelation therapy with deferoxamine, deferiprone, and deferasirox for the treatment of iron-loaded patients with non-transfusion-dependent thalassemia syndromes\n. Drug Des Devel Ther . 2016 ;10 :465 –481\n. doi:10.2147/DDDT.S79458 \n4. Chaudhary \nP , Pullarkat \nV . Deferasirox: appraisal of safety and efficacy in long-term therapy\n. J Blood Med . 2013 ;4 :101 –110\n.23966805 \n5. Bruner \nKE , White \nKM . Deferasirox desensitization\n. J Allergy Clin Immunol Pract . 2016 ;4 (1 ):171 –172\n. doi:10.1016/j.jaip.2015.09.007 26489716 \n6. Davies \nGI , Davies \nD , Charles \nS , Barnes \nSL , Bowden \nD . Successful desensitization to deferasirox in a paediatric patient with beta-thalassaemia major\n. Pediatr Allergy Immunol . 2017 ;28 (2 ):199 –201\n. doi:10.1111/pai.12677 27797415 \n7. Tanaka \nC . Clinical pharmacology of deferasirox\n. Clin Pharmacokinet . 2014 ;53 (8 ):679 –694\n. doi:10.1007/s40262-014-0151-4 24996374 \n8. Lu \nMY , Wang \nN , Wu \nWH , et al. Simultaneous determination of plasma deferasirox and deferasirox-iron complex using an HPLC-UV system and pharmacokinetics of deferasirox in patients with beta-thalassemia major: once-daily versus twice-daily administration\n. Clin Ther . 2015 ;37 (8 ):1751 –1760\n. doi:10.1016/j.clinthera.2015.05.506 26093827 \n9. Chang \nHH , Lu \nMY , Liao \nYM , et al. Improved efficacy and tolerability of oral deferasirox by twice-daily dosing for patients with transfusion-dependent beta-thalassemia\n. Pediatr Blood Cancer . 2011 ;56 (3 ):420 –424\n. doi:10.1002/pbc.22826 21072825 \n10. Isik P, Yarali N, Bay A, Ozmen S, Tunc B. Type-I hypersensitivity reaction secondary to deferasirox intake. Int J Hematol Oncol. 2010;20:42–44.\n11. Blanca \nM , Torres \nMJ , Garcia \nJJ , et al. Natural evolution of skin test sensitivity in patients allergic to beta-lactam antibiotics\n. J Allergy Clin Immunol . 1999 ;103 (5 ):918 –924\n. doi:10.1016/S0091-6749(99)70439-2 10329829 \n12. Kang \nY , Kwon \nOY , Jung \nH , et al. Breakthrough reactions during rapid drug desensitization: clinical outcome and risk factors\n. Ann Allergy Asthma Immunol . 2019 ;123 (1 ):48 –56 e41\n. doi:10.1016/j.anai.2019.05.007 31108181\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1178-6965",
"issue": "13()",
"journal": "Journal of asthma and allergy",
"keywords": "deferasirox; desensitization; drug allergy; hypersensitivity; iron chelating agents; iron overload; premedication; rechallenge; thalassemia",
"medline_ta": "J Asthma Allergy",
"mesh_terms": null,
"nlm_unique_id": "101543450",
"other_id": null,
"pages": "557-561",
"pmc": null,
"pmid": "33154654",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "26489716;10329829;27797415;26093827;24996374;23966805;26893541;31108181;23485589;21072825",
"title": "Successful Deferasirox Rechallenge and Treating Through Reaction in a Patient with Challenge-Proven Mild Immediate Reaction: A Case Report.",
"title_normalized": "successful deferasirox rechallenge and treating through reaction in a patient with challenge proven mild immediate reaction a case report"
} | [
{
"companynumb": "TH-BION-009226",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "DEFERASIROX"
},
"drugadditional": null,
"druga... |
{
"abstract": "An 8-year-old boy with hypoplastic left heart syndrome with a previous history of thrombosis within the inferior vena cava receiving stable warfarin dosing for anticoagulation was diagnosed with influenza B. He was subsequently placed on oseltamivir therapy according to the Centers for Disease Control and Prevention clinical practice guidelines. During the hospitalization, his international normalized ratio steadily increased to supratherapeutic levels and returned to baseline after discontinuation of oseltamivir therapy. This case represents a drug-drug interaction that has not been previously reported in children or adolescents. An extensive review of the pharmacokinetic and pharmacodynamic literature did not uncover a definitive etiology for this interaction. However, several undefined aspects in each drug's disposition pathway need further elucidation. Until this interaction is understood, caution is warranted, and close monitoring of the international normalized ratio should be performed in all patients prescribed oseltamivir concomitantly with warfarin.",
"affiliations": "Section of Cardiology, and Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri; and Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri jbwagner@cmh.edu.;Division of Clinical Pharmacology, Medical Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri; and Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri.",
"authors": "Wagner|Jonathan|J|;Abdel-Rahman|Susan M|SM|",
"chemical_list": "D000925:Anticoagulants; D000998:Antiviral Agents; D053139:Oseltamivir; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2014-2578",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "135(5)",
"journal": "Pediatrics",
"keywords": "congenital heart disease; hypoplastic left heart syndrome; international normalized ratio; oseltamivir; warfarin",
"medline_ta": "Pediatrics",
"mesh_terms": "D000925:Anticoagulants; D000998:Antiviral Agents; D002648:Child; D004347:Drug Interactions; D006801:Humans; D018636:Hypoplastic Left Heart Syndrome; D007251:Influenza, Human; D019934:International Normalized Ratio; D008297:Male; D053139:Oseltamivir; D013927:Thrombosis; D014859:Warfarin",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": "e1333-6",
"pmc": null,
"pmid": "25917992",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Oseltamivir-warfarin interaction in hypoplastic left heart syndrome: case report and review.",
"title_normalized": "oseltamivir warfarin interaction in hypoplastic left heart syndrome case report and review"
} | [
{
"companynumb": "US-TEVA-567792USA",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"druga... |
{
"abstract": "Mucormycosis is a rare but emerging fungal infection complicating solid organ transplantation. It is associated with a high mortality rate. We describe an unusual case of hepatic mucormycosis in a living donor liver transplant recipient presenting as delayed graft dysfunction, which was successfully treated with combination of liposomal amphotericin B and oral posaconazole therapy, without surgical resection. The patient had clinical improvement with normalization of liver function tests.",
"affiliations": "Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Department of Pathology, Medanta the Medicity, Gurugram, Haryana, India.;Department of Radiology, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.;Medanta Institute of Liver Transplantation and Regenerative Medicine, Medanta the Medicity, Gurugram, Haryana, India.",
"authors": "Chaudhary|Rohan J|RJ|;Choudhary|Narendra S|NS|;Saraf|Neeraj|N|;Gautam|Dheeraj|D|;Piplani|Tarun|T|;Thiagrajan|Srinivasan|S|;Bhangui|Prashant|P|;Saigal|Sanjiv|S|;Rastogi|Amit|A|;Soin|Arvinder S|AS|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jceh.2020.04.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-6883",
"issue": "10(6)",
"journal": "Journal of clinical and experimental hepatology",
"keywords": "CT, computed tomography; LDLT, living donor liver transplantation; LFT, liver function test; SOT, solid organ transplantation; immunosuppression; liver dysfunction; living donor liver transplantation; mucormycosis",
"medline_ta": "J Clin Exp Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101574137",
"other_id": null,
"pages": "629-632",
"pmc": null,
"pmid": "33311897",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "15859921;8852973;7618552;15356828;19485785;12884167;19127570;20218876;19659439;19435437;26864621;16568297;16080086;16925570",
"title": "Delayed Graft Dysfunction due to Invasive Hepatic Mucormycosis After Living Donor Liver Transplantation.",
"title_normalized": "delayed graft dysfunction due to invasive hepatic mucormycosis after living donor liver transplantation"
} | [
{
"companynumb": "IN-MYLANLABS-2021M1033610",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CEFTRIAXONE"
},
"drugadditional": null,
... |
{
"abstract": "The SCN5A gene, located on chromosome 3p21, has 28 exons and is a member of the human voltage-gated sodium channel gene family. Genetic variation in SCN5A is associated with a diverse range of phenotypes. Due to incomplete penetrance, delayed expression, inherent low signal-to-noise ratio, and marked phenotypic heterogeneity, rare novel variants in SCN5A could be misinterpreted. Hence, defining the phenotypic characteristics of these rare SCN5A variants in humans is of importance. We describe the phenotypic heterogeneity noted in 4 familial carriers of a rare, previously unreported, large deletion in exon 20 of SCN5A (c.3667-?_c.3840C +?del) and discuss the mechanisms that underlie this heterogeneity.",
"affiliations": "Division of Pediatric Cardiology, Department of Pediatrics, Comer Children's Hospital and the Pritzker School of Medicine of the University of Chicago, Chicago, IL, USA; Division of Pediatric Cardiology/Electrophysiology, Department of Pediatrics, West Virginia School of Medicine, Morgantown, WV, USA. Electronic address: uk10004@hsc.wvu.edu.;Division of Pediatric Cardiology, Department of Pediatrics, Children's Hospital of Michigan, Central Michigan University, Detroit, MI, USA.;Center for Arrhythmia Care, Heart & Vascular Center, Pritzker School of Medicine of the University of Chicago, Chicago, IL, USA.",
"authors": "Kohli|Utkarsh|U|;Sriram|Chenni S|CS|;Nayak|Hemal M|HM|",
"chemical_list": "D062554:NAV1.5 Voltage-Gated Sodium Channel; C568320:SCN5A protein, human",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jelectrocard.2021.04.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-0736",
"issue": "66()",
"journal": "Journal of electrocardiology",
"keywords": "Atrial fibrillation; Brugada ECG pattern; SCN5A exon 20 deletion (c.3667-?_c.3840C +?del); Sinus node dysfunction",
"medline_ta": "J Electrocardiol",
"mesh_terms": "D053840:Brugada Syndrome; D004562:Electrocardiography; D005091:Exons; D006801:Humans; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel; D010641:Phenotype",
"nlm_unique_id": "0153605",
"other_id": null,
"pages": "131-135",
"pmc": null,
"pmid": "33951591",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A novel familial SCN5A exon 20 deletion is associated with a heterogeneous phenotype.",
"title_normalized": "a novel familial scn5a exon 20 deletion is associated with a heterogeneous phenotype"
} | [
{
"companynumb": "US-MLMSERVICE-20211020-3173055-1",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nEnzalutamide and abiraterone are new androgen-axis disrupting treatments for metastatic castration-resistant prostate cancer (mCRPC). We examined the response and outcomes of enzalutamide-treated mCRPC patients in the real-world context of prior treatments of abiraterone and/or docetaxel.\n\n\nMETHODS\nWe conducted a seven-institution retrospective study of mCRPC patients treated with enzalutamide between January 2009 and February 2014. We compared the baseline characteristics, PSA declines, PSA progression-free survival (PSA-PFS), duration on enzalutamide and overall survival (OS) across subgroups defined by prior abiraterone and/or docetaxel.\n\n\nRESULTS\nOf 310 patients who received enzalutamide, 36 (12%) received neither prior abiraterone nor prior docetaxel, 79 (25%) received prior abiraterone, 30 (10%) received prior docetaxel and 165 (53%) received both prior abiraterone and prior docetaxel. Within these groups, respectively, ⩾30% PSA decline was achieved among 67, 28, 43 and 24% of patients; PSA-PFS was 5.5 (95% CI 4.2-9.1), 4.0 (3.2-4.8), 4.1 (2.9-5.4) and 2.8 (2.5-3.2) months; median duration of enzalutamide was 9.1 (7.3-not reached), 4.7 (3.7-7.7), 5.4 (3.8-8.4) and 3.9 (3.0-4.6) months. Median OS was reached only for the patients who received both prior abiraterone and docetaxel and was 12.2 months (95% CI 10.7-16.5). 12-month OS was 78% (59-100%), 64% (45-90%), 77% (61-97%) and 51% (41-62%). Of 70 patients who failed to achieve any PSA decline on prior abiraterone, 19 (27%) achieved ⩾30% PSA decline with subsequent enzalutamide.\n\n\nCONCLUSIONS\nThe activity of enzalutamide is blunted after abiraterone, after docetaxel, and still more after both, suggesting subsets of overlapping and distinct mechanisms of resistance.",
"affiliations": "1] University of Washington, Seattle, WA, USA [2] Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;British Columbia Cancer Agency, Vancouver, BC, Canada.;Sidney Kimmel Cancer Center/Johns Hopkins University, Baltimore, MA, USA.;City of Hope Cancer Center, Duarte, CA, USA.;Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.;Huntsman Cancer Institute/University of Utah, Salt Lake City, UT, USA.;Karmanos Cancer Institute/Wayne State University, Detroit, MI, USA.;City of Hope Cancer Center, Duarte, CA, USA.;Sidney Kimmel Cancer Center/Johns Hopkins University, Baltimore, MA, USA.;Tisch Cancer Institute/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Huntsman Cancer Institute/University of Utah, Salt Lake City, UT, USA.;1] University of Washington, Seattle, WA, USA [2] Fred Hutchinson Cancer Research Center, Seattle, WA, USA.;Tisch Cancer Institute/Icahn School of Medicine at Mount Sinai, New York, NY, USA.;Sidney Kimmel Cancer Center/Johns Hopkins University, Baltimore, MA, USA.;British Columbia Cancer Agency, Vancouver, BC, Canada.;1] University of Washington, Seattle, WA, USA [2] Fred Hutchinson Cancer Research Center, Seattle, WA, USA.",
"authors": "Cheng|H H|HH|;Gulati|R|R|;Azad|A|A|;Nadal|R|R|;Twardowski|P|P|;Vaishampayan|U N|UN|;Agarwal|N|N|;Heath|E I|EI|;Pal|S K|SK|;Rehman|H-T|HT|;Leiter|A|A|;Batten|J A|JA|;Montgomery|R B|RB|;Galsky|M D|MD|;Antonarakis|E S|ES|;Chi|K N|KN|;Yu|E Y|EY|",
"chemical_list": "D000736:Androstenes; D000970:Antineoplastic Agents; D001549:Benzamides; D009570:Nitriles; D043823:Taxoids; D000077143:Docetaxel; D010669:Phenylthiohydantoin; C540278:enzalutamide; C089740:abiraterone",
"country": "England",
"delete": false,
"doi": "10.1038/pcan.2014.53",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1365-7852",
"issue": "18(2)",
"journal": "Prostate cancer and prostatic diseases",
"keywords": null,
"medline_ta": "Prostate Cancer Prostatic Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001549:Benzamides; D018572:Disease-Free Survival; D000077143:Docetaxel; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009570:Nitriles; D010669:Phenylthiohydantoin; D064129:Prostatic Neoplasms, Castration-Resistant; D012189:Retrospective Studies; D043823:Taxoids; D016896:Treatment Outcome",
"nlm_unique_id": "9815755",
"other_id": null,
"pages": "122-7",
"pmc": null,
"pmid": "25600186",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17975152;18309951;18519708;20005697;21575859;21612468;21807635;22710436;22894553;23117885;23228172;23576708;23585511;23842682;23849416;24074764;24200698;24315100;24382803;24442834;24449231;24462374;24491307;24881730;25018038;26685010;26964769",
"title": "Activity of enzalutamide in men with metastatic castration-resistant prostate cancer is affected by prior treatment with abiraterone and/or docetaxel.",
"title_normalized": "activity of enzalutamide in men with metastatic castration resistant prostate cancer is affected by prior treatment with abiraterone and or docetaxel"
} | [
{
"companynumb": "US-JNJFOC-20150603244",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nImmunosuppression has a pivotal role in kidney transplantation. The new prolonged-release formulation of tacrolimus was developed to provide a more convenient once-daily dosing to improve patient adherence.\n\n\nMETHODS\nWe selected 60 stable kidney transplant recipients who underwent tacrolimus conversion in our unit. Conversion was made on a 1 mg:1 mg basis in 66.7% of patients (n = 40) and on a 1 mg:1.1 mg basis in the remaining 33.3% (n = 20). Clinical and analytical data at conversion and postconversion was analyzed retrospectively to evaluate the efficacy and safety of conversion from tacrolimus twice-daily to once-daily formulation.\n\n\nRESULTS\nA significant reduction in tacrolimus blood levels requiring an increase in tacrolimus daily dose was observed postconversion. Postconversion tacrolimus blood level reduction >25% was significantly higher in the conversion group 1 mg:1 mg basis (P = .004). In patients converted 1 mg:1 mg, female sex and higher tacrolimus level at conversion were significant risk factors for a reduction >25% in tacrolimus blood levels after conversion. No significant change was detected between mean glomerular filtration rate at conversion (57 mL/min) and at 3, 6, and 9 months postconversion.\n\n\nCONCLUSIONS\nOnce-daily tacrolimus at similar doses to the twice-daily formulation is an efficient and safe treatment option. Conversion made on 1 mg:1.1 mg basis seems advantageous at least in some patients.",
"affiliations": "Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal; Nephrology Department, Centro Hospitalar de Vila Nova de Gaia/Espinho, Vila Nova de Gaia, Portugal. Electronic address: patricia820709barreto@gmail.com.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal; Nephrology Department, Centro Hospitalar do Funchal, Funchal, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.;Nephrology Department, Centro Hospitalar do Porto, Porto, Portugal.",
"authors": "Barreto|P|P|;Malheiro|J|J|;Vieira|P|P|;Pedroso|S|S|;Almeida|M|M|;Martins|L S|LS|;Dias|L|L|;Henriques|A C|AC|;Cabrita|A|A|",
"chemical_list": "D003692:Delayed-Action Preparations; D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2016.06.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "48(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D003692:Delayed-Action Preparations; D004334:Drug Administration Schedule; D005260:Female; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010349:Patient Compliance; D012189:Retrospective Studies; D016559:Tacrolimus; D066027:Transplant Recipients; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "2276-2279",
"pmc": null,
"pmid": "27742278",
"pubdate": "2016-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Conversion From Twice-Daily to Once-Daily Tacrolimus in Stable Kidney Graft Recipients.",
"title_normalized": "conversion from twice daily to once daily tacrolimus in stable kidney graft recipients"
} | [
{
"companynumb": "PT-ASTELLAS-2015US046033",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nDabigatran etexilate is a newly approved oral anticoagulant indicated for stroke prevention in nonvalvular atrial fibrillation. There are no reliable, rapidly available laboratory markers to assess its anticoagulant activity. There is no data on the safety of r-tPA on patients who are on dabigatran and it is not known whether r-tPA is safe in patients who are on dabigatran with a normal activated partial thromboplastin time (aPTT).\n\n\nMETHODS\nWe report the case of a 59-year-old male who is reported with right hemiparesis and global aphasia. Two days prior to admission he underwent elective cardioversion for atrial fibrillation. He had begun dabigatran at 150 mg BID 3 days before cardioversion. Five days after commencing dabigatran, and 10 h after the last oral dose he presented with these symptoms. Patient fulfilled the criteria for r-tPA including a normal aPTT (30 s), normal prothrombin time (INR = 1.0) and a normal creatinine clearance (glomerular filtration rate >60 mL/min/1.73 m(2)). A brain CT without contrast was normal. After extensive discussion with the family, with clear understanding of the risks and benefits of such an approach in a patient who has been on dabigatran, consent was obtained, and r-tPA (0.9 mg/kg alteplase) was given. Patient's hospital course remained uncomplicated and he was discharged 4 days after the initial symptoms to an acute rehabilitation facility and is currently on coumadin with INR therapeutic goal between 2 and 3.\n\n\nCONCLUSIONS\nMore studies are needed to asses whether r-tPA might be safe in patients who are on dabigatran with a normal activated partial thromboplastin time and more than 10 h after the last dose.",
"affiliations": "Cleveland Clinic Florida.;Cleveland Clinic Florida.",
"authors": "Govindarajan|Raghav|R|;Galvez|Nestor|N|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1941-5893",
"issue": "7(1)",
"journal": "Journal of vascular and interventional neurology",
"keywords": null,
"medline_ta": "J Vasc Interv Neurol",
"mesh_terms": null,
"nlm_unique_id": "101511381",
"other_id": null,
"pages": "21-2",
"pmc": null,
"pmid": "24920984",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article",
"references": "22133608;20881383;21748501;20671233;21757516;22447744;17950801;20352166;21505718",
"title": "Is intravenous recombinant tissue plasminogen activator (r-tPA) safe in patients on Dabigatran?",
"title_normalized": "is intravenous recombinant tissue plasminogen activator r tpa safe in patients on dabigatran"
} | [
{
"companynumb": "US-ROCHE-1426988",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DABIGATRAN ETEXILATE MESYLATE"
},
"drugadditional": "3... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to evaluate the coverage of the pedicled buccal fat pad flap (PBFP) and the long-term results of this treatment in patients with medication-related osteonecrosis of the jaw (MRONJ).\n\n\nMETHODS\nTen patients (2 men and 8 women; average age, 72.9 yr old) diagnosed with MRONJ were selected. Patients were treated with a PBFP. Data from patients regarding MRONJ stage, defect size, bone exposure after surgery, operation time, admission period, duration of antibiotic therapy, recurrence of disease, and postoperative complications were analyzed retrospectively.\n\n\nRESULTS\nSix patients were diagnosed with MRONJ stage 2, and 4 patients were diagnosed with MRONJ stage 3. The maximum defect in the study was 62 × 18 mm. Among the 10 patients, there was only 1 bony exposure, which occurred on postoperative day 2 after receiving the PBFP. This exposure might have been due to an incomplete resection of the affected bone. There were no severe donor site morbidities, and all patients showed satisfactory healing without incident.\n\n\nCONCLUSIONS\nAccording to this evaluation, the PBFP effectively covered a relatively large surgical defect. Complications were minimal, and there was no recurrence of bony exposure during follow-up. In conclusion, using the PBFP was a reliable treatment option for the management of denuded bone in patients with MRONJ.",
"affiliations": "Associate Professor, Department of Craniomaxillofacial Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Assistant Professor, Department of Oral and Maxillofacial Surgery, Gangneung-Wonju National University, Gangneung, Korea. Electronic address: omfsmk@gwnu.ac.kr.;Associate Professor, Department of Oral and Maxillofacial Surgery, Gangneung-Wonju National University, Gangneung, Korea.;Professor, Department of Oral and Maxillofacial Surgery, Gangneung-Wonju National University, Gangneung, Korea.",
"authors": "Rotaru|Horatiu|H|;Kim|Min-Keun|MK|;Kim|Seong-Gon|SG|;Park|Young-Wook|YW|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0278-2391",
"issue": "73(3)",
"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": "D000273:Adipose Tissue; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D059266:Bisphosphonate-Associated Osteonecrosis of the Jaw; D002610:Cheek; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007902:Length of Stay; D008137:Longitudinal Studies; D008297:Male; D008336:Mandibular Diseases; D008439:Maxillary Diseases; D008875:Middle Aged; D061646:Operative Time; D011183:Postoperative Complications; D012008:Recurrence; D012189:Retrospective Studies; D013524:Surgical Flaps; D013529:Surgical Wound Dehiscence; D060053:Transplant Donor Site",
"nlm_unique_id": "8206428",
"other_id": null,
"pages": "437-42",
"pmc": null,
"pmid": "25544302",
"pubdate": "2015-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Pedicled buccal fat pad flap as a reliable surgical strategy for the treatment of medication-related osteonecrosis of the jaw.",
"title_normalized": "pedicled buccal fat pad flap as a reliable surgical strategy for the treatment of medication related osteonecrosis of the jaw"
} | [
{
"companynumb": "PHHY2014KR169151",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Henoch-Schonlein purpura (HSP) is a systemic vasculitis that occurs most often in children and rarely follows exposure to drugs or other environmental factors. Aloe is one of the most widely used traditional remedies and has been associated with gastrointestinal and renal complications. We report a case of HSP in an adult patient who had previously received the herb Aloe vera.",
"affiliations": "Academic Department of Medicine, Hippokration General Hospital, 114 Vas. Sophias Ave., GR-115 27 Athens, Greece.",
"authors": "Cholongitas|Evangelos|E|;Katsoudas|Spyros|S|;Spyros|Katsoudas|K|;Dourakis|Spyros|S|;Spyros|Dourakis|D|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ejim.2004.07.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0953-6205",
"issue": "16(1)",
"journal": "European journal of internal medicine",
"keywords": null,
"medline_ta": "Eur J Intern Med",
"mesh_terms": null,
"nlm_unique_id": "9003220",
"other_id": null,
"pages": "59-60",
"pmc": null,
"pmid": "15733825",
"pubdate": "2005-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Henoch-Schonlein purpura associated with Aloe vera administration.",
"title_normalized": "henoch schonlein purpura associated with aloe vera administration"
} | [
{
"companynumb": "GR-SHIRE-GR201926055",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "A 34-year-old woman presented at 29 weeks gestation of a twin pregnancy, with a platelet count of 1 × 109/l. She was extensively investigated and was subsequently diagnosed with severe immune thrombocytopenia. She did not respond to initial treatment with corticosteroids and intravenous immunoglobulin. She also failed to respond to second-line therapies of Anti-D immunoglobulin, Azathioprine and the thrombopoietin agonist Romiplostim. Her case was further complicated by an episode of obstetric cholestasis possibly related to Azathioprine treatment. She went on to require plasma exchange around the time of an elective Caesarean section which provided temporary improvement in the platelet count and enabled safe delivery. This case highlights some of the challenges faced in the management of patients with severe and refractory immune thrombocytopenia during pregnancy.",
"affiliations": "Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK.;Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK.;King's College London, London, UK.;Imperial College NHS Trust, London, UK.;Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK.;Guys and St Thomas' NHS Foundation Trust, Guys Hospital, London, UK.",
"authors": "Harrington|Patrick|P|;Nelson-Piercy|Catherine|C|;Williamson|Catherine|C|;Cooper|Nichola|N|;Kesse-Adu|Rachel|R|;Robinson|Susan|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X17709188",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "11(1)",
"journal": "Obstetric medicine",
"keywords": "Haematology; high-risk pregnancy; immunology; multiple pregnancy",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "35-38",
"pmc": null,
"pmid": "29636813",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports",
"references": "11967923;23856529;20620441;17309547;781930;14510957;11298610;23161577;23857305;25004319;26823041;9704772;21098742;19846889;22892336",
"title": "Refractory severe immune thrombocytopenia in a twin pregnancy.",
"title_normalized": "refractory severe immune thrombocytopenia in a twin pregnancy"
} | [
{
"companynumb": "GB-MYLANLABS-2018M1026658",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ROMIPLOSTIM"
},
"drugadditional": null,
... |
{
"abstract": "Pulmonary exacerbations of infectious cause are one of the major complications in patients with cystic fibrosis (CF). These are associated with a progressive increase in morbidity and mortality. The treatment depending on the isolated microorganism. The β-lactam antibiotics are generally used which are not exempt from adverse reactions. Next, two report of neutropenia cases are described after prolonged use of cefepime in CF patients.",
"affiliations": "Hospital Clínico San Borja Arriarán, Santiago, Chile.;Hospital Clínico San Borja Arriarán, Santiago, Chile.;Hospital Clínico San Borja Arriarán, Santiago, Chile.;Clínica Las Condes, Santiago, Chile.;Hospital Clínico San Borja Arriarán, Santiago, Chile.",
"authors": "Hernández|Rubén|R|;Delpiano|Luis|L|;Amador|Jorge|J|;Arias|Mariana|M|;Carrasco Delgado|Juan|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000077723:Cefepime",
"country": "Chile",
"delete": false,
"doi": "10.4067/S0716-10182019000100112",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0716-1018",
"issue": "36(1)",
"journal": "Revista chilena de infectologia : organo oficial de la Sociedad Chilena de Infectologia",
"keywords": null,
"medline_ta": "Rev Chilena Infectol",
"mesh_terms": "D000900:Anti-Bacterial Agents; D000077723:Cefepime; D002675:Child, Preschool; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D009503:Neutropenia; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "9305754",
"other_id": null,
"pages": "112-114",
"pmc": null,
"pmid": "31095211",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Neutropenia associated with the use of cefepime in pediatric patients with cystic fibrosis.",
"title_normalized": "neutropenia associated with the use of cefepime in pediatric patients with cystic fibrosis"
} | [
{
"companynumb": "CL-SUN PHARMACEUTICAL INDUSTRIES LTD-2019R1-231252",
"fulfillexpeditecriteria": "1",
"occurcountry": "CL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CEFEPIME HYDROCHLORIDE"
},
... |
{
"abstract": "We report the case of a renal transplant recipient with pulmonary and splenic mucormycosis whose demise was accelerated by a myocardial abscess. Once pulmonary and splenic mucormycosis was diagnosed, liposomal amphotericin B was started and immunosuppressant treatments were discontinued. The pulmonary cavities regressed during treatment, but new myocardial and peri-allograft abscesses developed. The myocardial abscess diffusely infiltrated the left ventricular wall and was associated with akinesia, which led to sudden cardiac arrest. This case demonstrates a rare manifestation of mucormycosis and highlights the fatality and invasiveness of this infection.",
"affiliations": "Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.;Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Incheon, Korea.",
"authors": "Nam|Y|Y|;Jung|J|J|;Park|S S|SS|;Kim|S J|SJ|;Shin|S J|SJ|;Choi|J H|JH|;Kim|M|M|;Yoon|H E|HE|",
"chemical_list": "D000935:Antifungal Agents; C068538:liposomal amphotericin B; D000666:Amphotericin B",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12452",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "17(6)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "mucormycosis; myocardial abscess; renal transplantation",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000328:Adult; D000666:Amphotericin B; D000935:Antifungal Agents; D017809:Fatal Outcome; D005260:Female; D006331:Heart Diseases; D006801:Humans; D016867:Immunocompromised Host; D016030:Kidney Transplantation; D009091:Mucormycosis; D009206:Myocardium",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "890-6",
"pmc": null,
"pmid": "26538076",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Disseminated mucormycosis with myocardial involvement in a renal transplant recipient.",
"title_normalized": "disseminated mucormycosis with myocardial involvement in a renal transplant recipient"
} | [
{
"companynumb": "PHHY2015KR146048",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "Clozapine is an effective antipsychotic that can lead to symptom resolution and functional recovery in patients with schizophrenia. Its available pregnancy safety data remain limited, which presents a challenge for clinicians managing women of reproductive age on clozapine. We retrospectively studied a consecutive case series of nine pregnancies where there was clozapine exposure. Our case series demonstrates that pregnant women on clozapine treatment can remain stable psychiatrically, but are vulnerable obstetrically, with high rates of obesity and gestational diabetes. Their babies also have poor neonatal adjustment, often requiring neonatal resuscitation. Furthermore, we report on clozapine-related side effects, changes in clozapine levels during pregnancy as well as variation in foetal wellbeing monitoring. These findings have implications for pregnancy care for women taking clozapine and require further exploration.",
"affiliations": "School of Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia. Thinh.Nguyen@uwa.edu.au.;Department of Health, Perth, Western Australia, Australia.;Sidra Medicine, Al Gharrafa Street, Ar-Rayyan, Doha, Qatar.;School of Medicine, The University of Western Australia, 35 Stirling Highway, Crawley, WA, 6009, Australia.",
"authors": "Nguyen|Thinh|T|;Mordecai|Jasmine|J|;Watt|Felice|F|;Frayne|Jacqueline|J|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "Austria",
"delete": false,
"doi": "10.1007/s00737-019-00985-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1434-1816",
"issue": "23(3)",
"journal": "Archives of women's mental health",
"keywords": "Clozapine; Neonatal complication; Obstetric complication; Pregnancy",
"medline_ta": "Arch Womens Ment Health",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011248:Pregnancy Complications; D011297:Prenatal Exposure Delayed Effects; D012151:Resuscitation; D012189:Retrospective Studies; D012559:Schizophrenia",
"nlm_unique_id": "9815663",
"other_id": null,
"pages": "441-445",
"pmc": null,
"pmid": "31203441",
"pubdate": "2020-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Obstetric and neonatal outcomes of clozapine exposure in pregnancy: a consecutive case series.",
"title_normalized": "obstetric and neonatal outcomes of clozapine exposure in pregnancy a consecutive case series"
} | [
{
"companynumb": "AU-MYLANLABS-2020M1059834",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "The case of a patient with a first presentation psychotic episode secondary to variant Creutzfeldt-Jakob Disease (vCJD) is presented. While psychiatric symptoms are considered a prominent feature of vCJD, they may precede characteristic neurological symptoms, which can delay diagnosis. The psychotic symptoms in this case differed in quality from typical psychotic presentations, which could have helped with earlier diagnosis. The patient's symptomatology suggested that errors in cognition and perception were largely contributing to his psychiatric symptoms. These errors appeared to be the result of prion destruction of relevant brain structures that may either be directly or secondarily involved in psychiatric disorders. The findings in this case can help elucidate how vCJD symptoms deviate from established guidelines for diagnosing primary psychiatric disorders.",
"affiliations": null,
"authors": "Patniyot|Nicholas S|NS|;Patniyot|Irene R|IR|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/PRA.0000000000000352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-4160",
"issue": "25(1)",
"journal": "Journal of psychiatric practice",
"keywords": null,
"medline_ta": "J Psychiatr Pract",
"mesh_terms": "D000328:Adult; D007562:Creutzfeldt-Jakob Syndrome; D006801:Humans; D008297:Male; D011618:Psychotic Disorders",
"nlm_unique_id": "100901141",
"other_id": null,
"pages": "58-62",
"pmc": null,
"pmid": "30633734",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Variant Creutzfeldt-Jakob Disease Presenting as New-onset Psychosis.",
"title_normalized": "variant creutzfeldt jakob disease presenting as new onset psychosis"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-02105",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"d... |
{
"abstract": "Analyses of outcomes after acute liver failure (ALF) have typically included all ALF patients regardless of whether they were listed for liver transplantation (LT). We hypothesized that limiting analysis to listed patients might provide novel insights into factors associated with outcome, focusing attention on disease evolution after listing. Listed adult ALF patients enrolled in the US Acute Liver Failure Study Group registry between 2000 and 2013 were analyzed to determine baseline factors associated with 21-day outcomes after listing. We classified 617 patients (36% of overall ALF group) by 3-week outcome after study admission: 117 were spontaneous survivors (SSs; survival without LT), 108 died without LT, and 392 underwent LT. Only 22% of N-acetyl-p-aminophenol (APAP) ALF patients were listed; however, this group of 173 patients demonstrated greater illness severity: higher coma grades and more patients requiring ventilator, vasopressor, or renal replacement therapy support. Only 62/173 (36%) of APAP patients received a graft versus 66% for drug-induced liver injury patients, 86% for autoimmune-related ALF, and 71% for hepatitis B-related ALF. APAP patients were more likely to die than non-APAP patients (24% versus 17%), and the median time to death was sooner (2 versus 4.5 days). Despite greater severity of illness, the listed APAP group still had a SS rate of 40% versus 11% for non-APAP causes (P < 0.001). APAP outcomes evolve rapidly, mainly to SS or death. Patients with APAP ALF listed for LT had the highest death rate of any etiology, whereas more slowly evolving etiologies yielded higher LT rates and, consequently, fewer deaths. Decisions to list and transplant must be made early in all ALF patients, particularly in those with APAP ALF.",
"affiliations": "Division of Gastroenterology and Hepatology, University of Pennsylvania, Philadelphia, PA.;Division of Biostatistics, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.;Section of Transplantation and Immunology, Yale University, New Haven, CT.;Department of Medicine, Virginia Commonwealth University, Richmond, VA.;Division of Gastroenterology, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI.;Division of Biostatistics, Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC.;Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX.",
"authors": "Reddy|K Rajender|KR|;Ellerbe|Caitlyn|C|;Schilsky|Michael|M|;Stravitz|R Todd|RT|;Fontana|Robert J|RJ|;Durkalski|Valerie|V|;Lee|William M|WM|;|||",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1002/lt.24347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1527-6465",
"issue": "22(4)",
"journal": "Liver transplantation : official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society",
"keywords": null,
"medline_ta": "Liver Transpl",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012042:Registries; D012307:Risk Factors; D017741:Survivors; D013997:Time Factors; D014481:United States; D055815:Young Adult",
"nlm_unique_id": "100909185",
"other_id": null,
"pages": "505-15",
"pmc": null,
"pmid": "26421889",
"pubdate": "2016-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "25039930;24369077;24126646;23837931;23439263;22213443;22447259;21948394;21200366;21274877;21274872;20949552;19479803;19479797;19070386;16436962;17697161;17901832;18318440;25019700;18798336;16317692;3921780;12484709",
"title": "Determinants of outcome among patients with acute liver failure listed for liver transplantation in the United States.",
"title_normalized": "determinants of outcome among patients with acute liver failure listed for liver transplantation in the united states"
} | [
{
"companynumb": "US-JNJFOC-20160406894",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "With an increasing number of joint replacements and the evolution of orthopaedic implants and hardware, there is increased occurrence and awareness of metal-related sensitivity. This has resulted in the development of devices using a variety of different materials to coat the implant. One popular option is to cover the metallic surface with a ceramic. One commercially available ceramic-coated prosthesis is coated with oxidized zirconium, with the trade name Oxinium. Although pseudotumor and metallosis resulting from ceramic joint arthroplasty implants have been documented, there is limited information on the occurrence of metallosis resulting from ceramic-coated knee implants. The purpose of this case report is to discuss a potential differential diagnosis for lower leg mass after total knee arthroplasty and to present a novel case of catastrophic failure of an Oxinium-coated total knee prosthesis (Smith and Nephew) that resulted in metallosis with extra-articular extravasation along the extensor digitorum longus tendon.",
"affiliations": "Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery and Rehabilitation, Lubbock, TX, USA.;Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA.;Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery and Rehabilitation, Lubbock, TX, USA.;Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery and Rehabilitation, Lubbock, TX, USA.",
"authors": "Purcell|Amanda|A|;Buckner|Shelby|S|;Brindley|George|G|;Grimes|Jerry|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.artd.2020.09.008",
"fulltext": "\n==== Front\nArthroplast Today\nArthroplast Today\nArthroplasty Today\n2352-3441 Elsevier \n\nS2352-3441(20)30180-1\n10.1016/j.artd.2020.09.008\nCase Report\nA Unique Case of Extra-articular Extravasation of Metal Into the Lower Leg Resulting From Oxidized Zirconium Wear Particles From Total Knee Arthroplasty\nPurcell Amanda MDamanda.purcell@ttuhsc.edua∗ Buckner Shelby MDb Brindley George MDa Grimes Jerry MDa a Texas Tech University Health Sciences Center, Department of Orthopaedic Surgery and Rehabilitation, Lubbock, TX, USA\nb Texas Tech University Health Sciences Center, School of Medicine, Lubbock, TX, USA\n∗ Corresponding author. 3601 4th Street, Lubbock, TX 79430, USA. Tel.: +1-806-632-5020. amanda.purcell@ttuhsc.edu\n20 11 2020 \n12 2020 \n20 11 2020 \n6 4 988 992\n2 8 2020 13 9 2020 20 9 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).With an increasing number of joint replacements and the evolution of orthopaedic implants and hardware, there is increased occurrence and awareness of metal-related sensitivity. This has resulted in the development of devices using a variety of different materials to coat the implant. One popular option is to cover the metallic surface with a ceramic. One commercially available ceramic-coated prosthesis is coated with oxidized zirconium, with the trade name Oxinium. Although pseudotumor and metallosis resulting from ceramic joint arthroplasty implants have been documented, there is limited information on the occurrence of metallosis resulting from ceramic-coated knee implants. The purpose of this case report is to discuss a potential differential diagnosis for lower leg mass after total knee arthroplasty and to present a novel case of catastrophic failure of an Oxinium-coated total knee prosthesis (Smith and Nephew) that resulted in metallosis with extra-articular extravasation along the extensor digitorum longus tendon.\n\nKeywords\nOxiniumMetallosisTotal knee arthroplastyCeramicOxidized zirconium\n==== Body\nIntroduction\nTotal joint arthroplasty has become a mainstay in the orthopaedic field. These procedures provide the ability for patients to make vast improvements in their ability to move. It is estimated that more than 750,000 total knee arthroplasty (TKA) cases were performed in 2014 [1]. By the year 2030, the demand for TKA is expected to increase by 673%. The number of total knee revisions is expected to grow by 601% by 2030 [2]. In a study by Inacio et al [3] in 2017, this number is projected to increase annually 143% by 2050, which translates to a projected volume of 1.5 million TKAs in the United States alone. A common concern regarding the implants associated with joint replacements is metal allergy and the complications that are associated with such allergic reactions. Metal sensitivity typically occurs as a type IV lymphocyte-mediated hypersensitivity. It has been documented that about 10% among the general population, 25% among patients with well-functioning total joint arthroplasty, and 60% among patients with painful total joint arthroplasty may have metal sensitivity [4]. In an attempt to reduce the allergic response to the metal implants, manufacturers have made implants with ceramic coatings to reduce the likelihood of hypersensitivity reactions. Smith and Nephew’s implants (Smith and Nephew plc, Watford, England, UK) use the oxidized zirconium coating, Oxinium. In addition to being less likely to induce an allergic response, ceramic-coated implants are considered to be more resistant to wear damage during mechanical testing [5].\n\nThere has been documentation of metallosis or pseudotumor resulting from ceramic-coated total hip arthroplasty [6] and documentation of extra-articular involvement of metallosis or pseudotumor resulting from TKA [[7], [8], [9], [10], [11], [12], [13]]. There are limited data on the prevalence of metallosis resulting after TKA; however, there are extensive data on metallosis after total hip arthroplasty. Data are especially extensive involving metal-on-metal (MoM) hip replacements. Metallosis, or metal-induced synovitis, can occur as a late complication after total joint arthroplasty. In knees, metallosis typically occurs late when there is catastrophic wear of the polyethylene. Metallosis in TKA tends to result most commonly from the use of metal-backed patellar implants or because of wear of the tibial polyethylene [8,14,15]. Although there is documentation of intra-articular metal debris after knee replacement [14,16,17], there is limited documentation of extra-articular extravasation of metal down the lower extremity compartments. One such case involved a SMILES rotating knee hinge (Stanmore Modular Individual Lower Extremity System, Stanmore Implants Worldwide Ltd., Middlesex, UK) used in a tumor-resection case. This patient developed wear debris from the polyethylene liner and metallosis of the tissue surrounding the tibial megaprosthesis [10].\n\nThere are other cases with documented cystic cavities into the calf or popliteal fossa. One particular case report discussed a patient who had an Insall-Burstein II TKA complicated with periprosthetic fracture of the tibia leading to extravasation of metal debris along the lower leg [12]. Another documented case involved a patient who developed a paratibial cyst after uncemented TKA (AMK, DePuy, Warsaw, IN). Metallosis in this case was noted due to communication with the cyst via a tract along a tibial baseplate screw [7].\n\nMetallosis is particularly concerning in that it is a sign of implant failure and eventual osteolysis. Osteolysis was found to be caused by debris rubbing together with the implant components, called third-body wear. Debris is stimulated by friction and abrasion of the metal prosthetic surfaces as a result of wear of polyethylene, typically in metal-backed patellar implants or with wear of the tibial tray. It has been concluded that a higher dose or concentration and smaller particle size may cause greater host response than do the larger particles because of their maintained location in the joint space [5]. The metallic debris stimulates an influx of cytokines and inflammatory cells, causing pain and osteolysis surrounding the implanted components. Metallosis is demonstrated histologically by extensive fibrosis, with the presence of histiocytes including macrophages, dendritic cells, Langerhans cells, and multinucleated giant cells [4,5]. Once the inflammatory cascade has been initiated, macrophages continue to indirectly cause osteolysis by releasing chronic inflammatory mediators and the activation of the RANK/RANKL pathway, which in turn manifests with further failure of the implant [5].\n\nCeramic-coated implants have been described to be stronger, albeit more brittle, with a lower incidence of wear and particle generation [5]. The total knee implants described in these articles use a surface of Oxinium, or oxidized Zirconium. If Oxinium ceramic wear particles are present, they can cause a similar inflammatory response to the MoM implants and polyethylene debris. Osteolysis associated with ceramic implants typically is noted to be secondary to an implant failure such as malpositioning, instability, or infection [5].\n\nThere is literature available reviewing the development of extra-articular extravasation of wear debris, and there is documentation of wear and metallosis resulting from MoM and Oxinium-coated hip replacements. However, we believe there has never been documentation of wear of the Oxinium-coated TKA with extravasation of metal particles to compartments outside the confines of the joint capsule. In this case report, we discuss a unique case of failed Oxinium-coated TKA with resulting metallosis along the anterior compartment of the left lower leg, thus offering an additional differential diagnosis for lower leg mass in patients who underwent TKA.\n\nCase history\nThe patient is a 69-year-old woman who underwent left TKA in 2006. Owing to metal allergy, she underwent replacement with an Oxinium-coated implant. She presented to the emergency room roughly 13 years after TKA with a 6-month history of pain and swelling of the lateral aspect of her left lower leg extending to her ankle. She had no known injury to the leg but had fallen a few times without acute injury. She noted that pain had started insidiously and was only getting worse. She could identify no alleviating factors. Activities and the range of motion of the foot and toes made the pain worse. She endorsed a “squeaking” in the knee with the range of motion.\n\nOn examination, there was palpable swelling along the anterior compartment of the lower leg. There was no erythema or warmth associated with the area. The knee itself was stable to stress, and the range of motion at the knee ranged from 0 to 110 degrees. She complains of subjective numbness over the entire foot, specifically along the course of the superficial peroneal nerve. Serum white blood cell count was slightly elevated at 12 K/uL (reference range: 3.98-10.04 K/uL), but C-reactive protein was 0.1 mg/dL (reference range: 0.0-0.5 mg/dL), and erythrocyte sedimentation rate was 13 mm/hr (reference range: 0-30 mm/hr), both of which were within normal limits, giving low concern for infectious etiology. Deep venous thrombosis was ruled out by ultrasound. Radiographs showed intact left TKA with notable “cloud sign” representing metal artifact within the synovium (Fig. 1a and b).Figure 1 (a) In this anterior-posterior view of the left knee, the hardware appears intact, without significant lucency or osteolysis surrounding the implant. Along the medial femoral condyle, there is a “cloud sign” indicative of metal artifact. (b) In this lateral view of the left knee, there is no obvious sign of failure of the implant or osteolysis surrounding the implant. Subtle opacity within the limits of the synovium suggests metal artifact.\n\n\n\nMagnetic resonance imaging (MRI) was scheduled outpatient. MRI demonstrated a loculated fluid collection along the extensor digitorum longus of the left lower leg (Fig. 2a and b). Technetium 99 bone scan verified that there was no obvious evidence of loosening of hardware.Figure 2 (a) In this T2-weighted axial cut MRI of the left lower leg, there is a loculated fluid collection within the anterior compartment. (b) The loculated fluid collection is seen extending along the anterior compartment distally in this T2-weighted coronal cut MRI of the left lower leg.\n\n\n\nFine-needle aspiration of the mass labeled in the left lower leg was documented only as “30 cc of tan cloudy” fluid, negative for pathology. Gram stain of the fluid showed no organisms or white blood cells. Culture was negative for growth at 5 days. At this time, she elected to proceed with tenolysis and debridement of the extensor digitorum longus muscle and tendon. At the time of debridement, black pigment was noted to extravasate along the proximal fascia and muscle fibers of the extensor digitorum longus muscle (Fig. 3).Figure 3 Intraoperative examination of the fluid collection along the anterior compartment of the leg yielded a large quantity of black-pigmented tissue along the extensor digitorum tendon and muscle within the anterior compartment of the left lower leg.\n\n\n\nHistological findings demonstrated necrotic skeletal muscle and tendon with collection of macrophages with iron stain, consistent with hemorrhage, and black-pigmented metal particles. Also present were negatively birefringent crystals suggestive of polyethylene wear debris vs calcium urate crystals. This result was indicative of metal and polyethylene wear debris that had extravasated from her knee along the anterior compartment of her lower leg (Fig. 4a-c).Figure 4 (a) This histology specimen was taken from the tissues of the anterior compartment of the leg. Within this high-powered field, there are multinucleated macrophages with phagocytosed black metal pigment. (b) This image is demonstrative of the presence of the same metallic particles within the multinucleated macrophages and the presence of birefringent crystals, suggestive of possible polyethylene debris. (c) This field demonstrates extensive infiltration of metallic particles within macrophages and within the skeletal muscle itself.\n\n\n\nBased on the histology reports and clinical examination, it was determined that she had developed metallosis and metal sensitivity reaction as a result of the wear products of her failed Oxinium knee that subsequently extravasated down her lower leg. At a subsequent follow-up, she was evaluated by an adult reconstruction specialist. She underwent revision to an Aesculap total knee replacement (Aesculap Implant Systems, Inc., Germany). The Aesculap system uses a zirconium nitride ceramic coating reported to have resistance to scratches, low polyethylene wear, offering another option for patients with metal sensitivity. Microbiology results were negative for infection; however, the pathology images and report were positive for mononucleate and multinucleate macrophages, lymphocytic infiltrate, and the same black metallic particles previously documented from debridement of her lower leg (Fig. 5a-c).Figure 5 (a) Our initial evaluation of the knee once entering the synovium was indicative of the obvious metallosis occurring within the capsule itself, suggesting failure of the implant due to extensive wear particles. (b) Once the polyethylene liner was removed, there were signs of wear on the surface of the tibial baseplate and along the femoral condyles. (c) Metallic debris was noted within the cement mantle and within the cut surface of the tibia, indicative of the loosening that occurred, leading up to the failure of the implants.\n\n\n\nShe had a complicated postoperative course. She was initially noncompliant with knee immobilizer and walker use despite subjective episodes of instability over the 2 weeks postoperatively, although her knee was stable with intact extensor mechanism on examination. She subsequently had a fall with a small area of superficial wound dehiscence that was irrigated and closed primarily in the emergency room. The wound slowly improved and buckling resolved by the third week postoperatively. A few weeks later, drainage returned but was purulent in nature. Infectious indices were elevated at that time. She underwent irrigation and debridement with poly exchange and was placed on IV vancomycin and Rocephin. She developed a nonoliguric prerenal azotemia after being started on IV vancomycin and Rocephin. She also developed high anion gap metabolic acidosis. Cultures grew methicillin-sensitive Staphylococcus aureus, and she was transitioned to Rocephin for 6 weeks. Acidosis and acute kidney injury improved before discharge to a skilled nursing facility. She was seen in the clinic after completing her antibiotics with no sign of infection on clinical examination. She canceled her 3-month follow-up and has not rescheduled.\n\nDiscussion\nWe believe this is a unique presentation of metallosis with extra-articular extravasation of Oxinium wear particles along the extensor digitorum longus tendon. It is an unusual presentation in that prior cases with extra-articular involvement manifested with a fracture or cortical penetration of hardware. For this patient, the MRI of the lower leg with subsequent debridement and histology gave insight into the catastrophic failure of the implant. The aspirate and bone scan were less helpful. We believe that the cystic appearance on MRI was a result of metal artifact rather than a true collection of fluid.\n\nMany conditions may result in lower extremity masses, and those should be ruled out at the time of presentation. Differential diagnosis for patients developing cystic lesions or masses after TKA should include abscess or cellulitis, aneurysm, deep vein thrombosis, soft-tissue tumors, extravasation of wear debris resulting in a granuloma, or cyst.\n\nAlthough it is documented that Oxinium-coated total hip arthroplasty components may fail because of metallosis and resulting wear particles, there is limited documentation of metallosis from Oxinium-coated TKA devices. We feel that this case highlights the importance of evaluating for metal allergy, as well as reviews the concern for metal-induced wear particles from ceramic-coated implants, specifically in this case using the Smith and Nephew Oxinium-coated knee implant. In patients with ceramic-coated implants, we recommend metal sensitivity testing and close monitoring of implants with follow-up imaging, including metal artifact reduction MRI or technetium 99 bone scan, to evaluate for loosening in those patients with an abnormal postoperative course or with local pain without an obvious clinical reason.\n\nSummary\nIn summary, we feel that proceeding with ceramic-coated implants, such as those with the Oxinium coating by Smith and Nephew, has usefulness in patients with metal sensitivity. These patients should be closely monitored radiographically and clinically. In all patients who underwent TKA, it is of importance to rule out other possible causes of lower extremity masses, while keeping a high suspicion of local-tissue extravasation of wear particles associated with TKA. The extravasation of ceramic and metal particles should be considered as part of the differential diagnosis for symptoms of swelling and pain in compartments about the knee without other clinical causes.\n\nWritten consent was obtained from our patient for the use of her health information and medical records. Consent is available on request.\n\nConflict of interests\nG. Brindley is a paid speaker for presentation for DePuy-Synthes (J&J) and is a co-investigator for Outcomes Research Project for DePuy-Synthes (J&J); J. Grimes holds stock ownership in ROM3 and is a board member in the Clinical Orthopaedic Society, Chairman of the American Academy of Orthopaedic Surgeons Foot and Ankle Evaluation Committee, and a member of the American Orthopaedic Foot and Ankle Society Physician Resource Committee and American Orthopaedic Society Abstract Review Committee; and A. Purcell and S. Buckner declare no potential conflicts of interest.\n\nAppendix A Supplementary data\nConflict of Interest Statement for Purcell\n Conflict of Interest Statement for Buckner\n Conflict of Interest Statement for Brindley\n Conflict of Interest Statement for Grimes\n \n\nAcknowledgments\nThe authors appreciate the expertise of Dr. Mitchell Wachtel for the pathology images.\n\nThis case report is funded by Texas Tech University Health Sciences Center Department of Orthopaedic Surgery and Rehabilitation, Lubbock, TX, USA.\n==== Refs\nReferences\n1 Overview of operating room procedures during inpatient stays in U.S. hospitals, 2014. the HCUP report: Healthcare cost and utilization project (HCUP): Statistical briefs; 2017 ASI 4186-20.233; statistical brief no. 233 https://www.hcup-us.ahrq.gov/reports/statbriefs/sb233-Operating-Room-Procedures-United-States-2014.jsp 2017 \n2 Kurtz S. Ong K. Lau E. Mowat F. Halpern M. Projections of primary and revision hip and knee ∖ in the United States from 2005 to 2030 J Bone Joint Surg Am 89 4 2007 780 17403800 \n3 Inacio M.C.S. Paxton E.W. Graves S.E. Namba R.S. Nemes S. Projected increase in total knee arthroplasty in the United States – an alternative projection model Osteoarthritis Cartilage 25 11 2017 1797 28801208 \n4 Hallab N. Merritt K. Jacobs J. Metal sensitivity in patients with orthopaedic implants J Bone Joint Surg 83 3 2001 428 11263649 \n5 Bitar D. Parvizi J. Biological response to prosthetic debris World J Orthop 6 2 2015 172 25793158 \n6 Campbell J. MD Rajaee S. Inflammatory pseudotumor after ceramic-on-ceramic total hip arthroplasty Arthroplasty Today 3 2 2016 83 \n7 Akisue T. Kurosaka M. Matsui N. Paratibial cyst associated with wear debris after total knee arthroplasty J Arthroplasty 16 3 2001 389 11307140 \n8 Chang F. Tseng K. Chen W. Huang C. Chen T. Lo W. Metal-backed patellar component failure in total knee arthroplasty presenting as a giant calf mass J Arthroplasty 18 2 2003 227 12629618 \n9 Mavrogenis A.F. Nomikos G.N. Sakellariou V.I. Karaliotas G.I. Kontovazenitis P. Papagelopoulos P.J. Wear debris pseudotumor following total knee arthroplasty: a case report J Med Case Rep 3 1 2009 9304 20062793 \n10 Papagelopoulos P.J. Mavrogenis A.F. Karamitros A.E. Distal leg wear debris mass from a rotating hinged knee prosthesis J Arthroplasty 22 6 2007 909 17826284 \n11 Sivananthan S. Pirapat R. Goodman S.B. A rare case of pseudotumor formation following total knee arthroplasty Malays Orthop J 9 1 2015 44 \n12 Tan G.M. Lynne G. Sarbjit S. Osteolysis and wear debris after total knee arthroplasty presenting with extra-articular metallosis in the calf J Arthroplasty 23 5 2008 775 18534390 \n13 Willis-Owen C.A. Keene G.C. Oakeshott R.D. Early metallosis-related failure after total knee replacement: a report of 15 cases J Bone Joint Surg Br 93 2 2011 205 21282760 \n14 Sharareh B. Phan D.L. Goreal W. Schwarzkopf R. Metallosis presenting as knee pain 26 years after primary total knee arthroplasty J Orthop Case Rep 5 2 2015 62 \n15 Panni A.S. Vasso M. Cerciello S. Maccauro G. Metallosis following knee arthroplasty: a histological and immunohistochemical study Int J Immunopathol Pharmacol 24 3 2011 711 21978703 \n16 Vivegananthan B. Shah R. Karuppiah A.S. Karuppiah S.V. Metallosis in a total knee arthroplasty BMJ Case Rep 2014 mar18 1 2014 bcr2013202801 \n17 Arnholt C.M. White J.B. Lowell J.A. Perkins M.R. Mihalko W.M. Kurtz S.M. Postmortem retrieval analysis of metallosis and periprosthetic tissue metal concentrations in total knee arthroplasty J Arthroplasty 35 2 2020 569 31699531\n\n",
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"title": "A Unique Case of Extra-articular Extravasation of Metal Into the Lower Leg Resulting From Oxidized Zirconium Wear Particles From Total Knee Arthroplasty.",
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"affiliations": "Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France.;Service d'Imagerie Pédiatrique et Foetale, Hôpital Femme Mère Enfant, Lyon tand Claude Bernard University, Lyon 1, France.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France; Pediatric Neurological Unit, Hôpital Femme Mère Enfant, Lyon, France.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France; Pediatric Neurological Unit, Hôpital Femme Mère Enfant, Lyon, France.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France. Electronic address: pierre-aurelien.beuriat@neurochirurgie.fr.;Pediatric Neurosurgical Unit, Hôpital Femme Mère Enfant, Lyon and Claude Bernard University, Lyon 1, France.",
"authors": "Beuriat|Pierre-Aurelien|PA|;Cattiaux|Lucile|L|;Guibaud|Laurent|L|;Szathmari|Alexandru|A|;Sabatier|Isabelle|I|;Rousselle|Christophe|C|;Mottolese|Carmine|C|;Di Rocco|Federico|F|",
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"abstract": "Hepatitis C virus (HCV) infection affects roughly 170 million people worldwide. Sofosbuvir/Ledipasvir (Sof/Led) is a new once daily direct acting antiviral combination pill that was approved in October 2014 for use in patients with HCV genotype 1 infection. Coadministration of Sof/Led is studied only with rosuvastatin which shows significantly increased level of drug and is associated with increased risk of myopathy, including rhabdomyolysis. There is no mention of such HMG-CoA reductase inhibitor interaction as a class, as pravastatin did not have any clinically significant interaction with Sof/Led. Other myotoxic drugs, including colchicine are not studied. We present a case of a serious drug interaction between Sof/Led and atorvastatin, in the background of CKD and colchicine use.",
"affiliations": "Department of Medicine, Temple University Hospital, Philadelphia, PA 19140, USA.;Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA 19140, USA.;Department of Medicine, Section of Gastroenterology, Temple University Lewis Katz School of Medicine, 3440 N. Broad Street, Philadelphia, PA 19140, USA.",
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"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2016/3191089Case ReportAn Unexpected Interaction between Sofosbuvir/Ledipasvir and Atorvastatin and Colchicine Causing Rhabdomyolysis in a Patient with Impaired Renal Function http://orcid.org/0000-0002-7673-4014Patel Shyam \n1\nAndres Jennifer \n2\nhttp://orcid.org/0000-0002-3597-9576Qureshi Kamran \n3\n\n*\n1Department of Medicine, Temple University Hospital, Philadelphia, PA 19140, USA2Department of Pharmacy Practice, Temple University School of Pharmacy, Philadelphia, PA 19140, USA3Department of Medicine, Section of Gastroenterology, Temple University Lewis Katz School of Medicine, 3440 N. Broad Street, Philadelphia, PA 19140, USA*Kamran Qureshi: kamran.qureshi@temple.eduAcademic Editor: Arduino A. Mangoni\n\n2016 22 8 2016 2016 319108925 3 2016 25 7 2016 Copyright © 2016 Shyam Patel et al.2016This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hepatitis C virus (HCV) infection affects roughly 170 million people worldwide. Sofosbuvir/Ledipasvir (Sof/Led) is a new once daily direct acting antiviral combination pill that was approved in October 2014 for use in patients with HCV genotype 1 infection. Coadministration of Sof/Led is studied only with rosuvastatin which shows significantly increased level of drug and is associated with increased risk of myopathy, including rhabdomyolysis. There is no mention of such HMG-CoA reductase inhibitor interaction as a class, as pravastatin did not have any clinically significant interaction with Sof/Led. Other myotoxic drugs, including colchicine are not studied. We present a case of a serious drug interaction between Sof/Led and atorvastatin, in the background of CKD and colchicine use.\n==== Body\n1. Case Report\nWe present a case of 66-year-old African American female with medical history of compensated liver cirrhosis related to chronic hepatitis C virus (HCV) genotype 1a infection, stage III Chronic Kidney Disease (CKD) related to hypertensive nephropathy, hypertension, coronary artery disease, and gout, who was recommended to start Sofosbuvir/Ledipasvir (Sof/Led) as 400/90 mg tablet along with renal dosed ribavirin 200 mg twice daily for 12 weeks for her HCV infection. The regimen was selected based on the presence of biopsy proven early cirrhosis and HCV infection, which was treated in the past with pegylated interferon, telaprevir, and ribavirin (she relapsed after early termination of this regimen because of intolerable side effects). Two weeks prior to the initiation of current treatment attempt with Sof/Led and ribavirin, baseline labs were unremarkable, as indicated in Table 1. Her daily home medications colchicine 0.6 mg, atorvastatin 80 mg, allopurinol, clonidine, lisinopril, labetalol, and aspirin were continued. It is unclear how long the patient had been on the colchicine and atorvastatin, but the patient had mentioned that these two medications had been chronic medications that she had been on for over 5 years.\n\nThree weeks after starting therapy, she noticed nausea, vomiting, diarrhea, and nonspecific abdominal pain. Blood tests at that time (as indicated in Figure 1, day 23), showed undetectable HCV viral load, with new elevations of liver enzymes and she was advised to increase oral hydration for symptomatic relief. One week later (day 30), she presented to emergency room with complaints of profound weakness and myalgia along with ongoing nausea and abdominal pain. On physical examination, she appeared slightly dry, with slight periumbilical tenderness and without ascites. She demonstrated diffuse muscle weakness and muscle tenderness in all extremities. No focal neurologic deficit was identified. The admission labs (as noted in Table 1 and Figure 1, day 30) were noticeable for elevated liver enzymes, creatinine, and creatine phosphokinase (CPK). Urinalysis showed large amount of blood, without RBCs. Clinical diagnosis of rhabdomyolysis was made. Her atorvastatin was stopped and she was aggressively fluid resuscitated. CPK levels subsequently trended down and renal function returned to baseline. The workup for myalgia was unremarkable, with normal aldolase, C3 and C4 complement levels, TSH, and serum protein electrophoresis. Neurology evaluation was done, and EMG was done to evaluate for profound muscular weakness. EMG showed diffuse muscle irritability with no evidence of polyneuropathy, suggesting this patient had an inflammatory myopathy.\n\nRhabdomyolysis was considered likely from an interaction between Sof/Led, atorvastatin, and colchicine in the background of abnormal renal function. The rise of AST/ALT was considered to be from her rhabdomyolysis (nonhepatic). Colchicine was also stopped and she was continued on Sof/Led and low dose ribavirin with daily monitoring of her labs. By the time of discharge, her rhabdomyolysis resolved, with return of baseline GFR of 43 mL/min/1.73 m2. Although her myalgia improved, she was discharged home with persistent muscle weakness, which subsequently improved over the next 4 weeks with physical rehabilitation. She successfully completed 12-week course of HCV therapy and did not have any recurrent symptoms or findings of rhabdomyolysis as she was kept off atorvastatin and colchicine. Her muscle weakness had resolved by the time she finished her therapy. Her follow-up labs showed SVR12 (Table 1); thus, her HCV infection was considered cured and her renal function and other laboratory testing returned to baseline.\n\n2. Discussion\nOn October 10, 2014, the FDA approved the fixed-dose combination pill Sof/Led (Harvoni, Gilead Sciences) for the treatment of chronic HCV genotype 1 infection [1]. Sof is a nucleotide NS5B polymerase inhibitor and Led is an NS5A inhibitor for HCV [2]. The common side effects of Sof/Led are fatigue and headache. Interestingly, benign, asymptomatic elevation of CPK has been reported in patients taking Sof/ribavirin or interferon/ribavirin [3].\n\nThere have been no case reports of Sof/Led interactions with atorvastatin and colchicine in causing rhabdomyolysis. In addition, the Sof/Led label does not mention many drug interactions; however both components are P-gp substrates [4]. Led is an inhibitor of the drug transporters P-gp and Breast Cancer Resistance Protein (BCRP) and may increase intestinal absorption of coadministered substrates for these transporters [5]. Sof/Led is not recommended to be given with other known P-gp-inducers due to the potential for decrease in efficacy. Led can increase absorption of colchicine by P-gp inhibition and of rosuvastatin via inhibition of BCRP. Coadministration of Sof/Led with rosuvastatin can potentially increase the risk of statin related myopathy and rhabdomyolysis [6]. Sof accumulation in renal failure can also lead to toxicity and the patient should be closely monitored for liver failure if Sof is to be used in these patients. Additionally, colchicine has the independent ability to cause myotoxicity [7]. Sof/Led has not been noted to interact adversely with atorvastatin; however, a theoretical interaction exists via P-gp inhibition by atorvastatin, causing an increased level of led. Atorvastatin can itself increase levels of colchicine due to P-gp inhibition. Using colchicine in combination with a statin has been reported to cause myotoxicity, especially in the setting of CKD [8]. Atorvastatin 80 mg was used in this patient as it was used for secondary prevention for her coronary artery disease. A lower dose of atorvastatin was not attempted as the patient was symptomatic from her rhabdomyolysis and the patient was not having any active coronary artery disease.\n\nIn our patient, the addition of the Led in the presence of atorvastatin could have further increased the levels of colchicine, increasing the likelihood of muscle toxicity and causing rhabdomyolysis. Colchicine is renally eliminated and requires dose adjustments based on renal dysfunction. Thus, this patient's stage III CKD combined with a high colchicine dose and P-gp mediated drug interactions could have played a critical role in increasing the chance of this unanticipated toxicity [8]. There was little concern for mitochondrial toxicity caused by a lactic acidosis as the patient has a normal anion gap and normal lactate levels.\n\nThe Naranjo probability score [9] was developed to help assess causality for adverse drug reactions and based on score of 6 (Table 2) this patient's adverse event correlates with a probable adverse drug reaction. Although atorvastatin levels were directly measured, the muscle toxicity described was likely attributed to drug interactions in combination with preexisting renal impairment. Sof/Led was coadministered with two drugs known to cause myositis. Drug interactions, via P-gp inhibition, caused increased levels of all drugs, potentially increasing the risk of muscle problem development. It is important for physicians' prescribing Sof/Led to be aware of the potential drug interactions.\n\nAppropriate pharmacy evaluation and medication changes should be made in such cases to avoid untoward reactions from drug interactions, including myositis and rhabdomyolysis as in our case. If rhabdomyolysis is discovered in a patient taking atorvastatin, Sof/Led, and/or colchicine, it should be treated with IV fluids and the CK levels should be trended. In addition, colchicine should be stopped, as there are other treatments for an acute gout flare (such as prednisone) that do not have a drug-drug interaction with atorvastatin and Sof/Led in causing rhabdomyolysis. In the setting of symptomatic rhabdomyolysis in a patient with no active coronary disease, atorvastatin should be stopped and can be resumed once the Sof/Led therapy is completed.\n\nCompeting Interests\nThe authors declare no competing interests.\n\nFigure 1 Timeline of laboratory changes. Interrupted line denotes hospital admission day.\n\nTable 1 Pertinent laboratory results.\n\n \tBaseline\tAdmission\tSVR12\t\nWBC (×1000/μL)\t5.3\t2.2\t3.6\t\nHgb (gm/dL)\t11.5\t10\t11.2\t\nPlt (×1000/μL)\t140\t58\t142\t\nTbili (mg/dL)\t0.4\t1.6\t0.5\t\nALT (U/L)\t61\t166\t20\t\nAST (U/L)\t60\t362\t24\t\nCr\t1.87\t2.5\t1.88\t\nGFR (mL/min/1.73 m2)\t32\t23\t32\t\nUA\t \tLarge blood, \n0 RBC\tNegative blood\t\nCPK (U/L)\t \t7979\t65\t\nHCV RNA PCR (IU/mL)\t8517000\tUndetectable\tUndetectable\t\nTable 2 Naranjo probability scale. Total scores range from −4 to +13; the reaction is considered definite if the score is 9 or higher, probable if 5 to 8, possible if 1 to 4, and doubtful if 0 or less.\n\n \tYes\tNo\tDo not know\t\nAre there previous conclusive reports of this reaction?\t+1\t0\t0\t\n\n\n\t\nDid the adverse event appear after the drug was given?\t+2\t−1\t0\t\n\n\n\t\nDid the adverse reaction improve when the drug was discontinued or a specific antagonist was given?\t+1\t0\t0\t\n\n\n\t\nDid the adverse reaction reappear upon readministering the drug?\t+2\t−2\t0\t\n\n\n\t\nWere there other possible causes for the reaction?\t−1\t+2\t0\t\n\n\n\t\nDid the adverse reaction reappear upon administration of placebo?\t−1\t+1\t0\t\n\n\n\t\nWas the drug detected in the blood or were other fluids detected in toxic concentrations?\t+1\t0\t0\t\n\n\n\t\nWas the reaction worsened upon increasing the dose? Or was the reaction lessened upon decreasing the dose?\t+1\t0\t0\t\n\n\n\t\nDid the patient have a similar reaction to the drug or a related agent in the past?\t+1\t0\t0\t\n\n\n\t\nWas the adverse event confirmed by any other objective evidence?\t+1\t0\t0\n==== Refs\n1 Raedler L. A. Once-a-day harvoni (ledipasvir plus sofosbuvir), a new oral combination for the treament of patients with genotype 1 chronic hepatitis C infection American Health & Drug Benefits 2015 8 54 58 26629267 \n2 A combination of ledipasvir and sofosbuvir (Harvoni) for hepatitis C The Medical Letter on Drugs and Therapeutics 2014 56 1455 111 112 25372848 \n3 Naggie S. Cooper C. Saag M. Ledipasvir and sofosbuvir for HCV in patients coinfected with HIV-1 The New England Journal of Medicine 2015 373 8 705 713 10.1056/nejmoa1501315 2-s2.0-84939824828 26196665 \n4 Harvoni (ledipasvir-sofosbuvir) tablets: U.S. prescribing information. Foster City, Calif, USA: Gilead Sciences 2015, https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf \n5 Gentile I. Buonomo A. R. Borgia F. Castaldo G. Borgia G. Ledipasvir: a novel synthetic antiviral for the treatment of HCV infection Expert Opinion on Investigational Drugs 2014 23 4 561 571 10.1517/13543784.2014.892581 2-s2.0-84896138890 24593285 \n6 Osinusi A. Townsend K. Kohli A. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV Co-infection The Journal of the American Medical Association 2015 313 12 1232 1239 10.1001/jama.2015.1373 2-s2.0-84925436650 25706232 \n7 Wilbur K. Makowsky M. Colchicine myotoxicity: case reports and literature review Pharmacotherapy 2004 24 12 1784 1792 10.1592/phco.24.17.1784.52334 2-s2.0-9744279740 15585444 \n8 Medani S. Wall C. Colchicine toxicity in renal patients-are we paying attention? Clinical Nephrology 2015 86 2 100 105 10.5414/CN108343 26249546 \n9 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology & Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508\n\n",
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"title": "An Unexpected Interaction between Sofosbuvir/Ledipasvir and Atorvastatin and Colchicine Causing Rhabdomyolysis in a Patient with Impaired Renal Function.",
"title_normalized": "an unexpected interaction between sofosbuvir ledipasvir and atorvastatin and colchicine causing rhabdomyolysis in a patient with impaired renal function"
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"abstract": "OBJECTIVE\nTo report a case of a male adolescent with the diagnosis of ibuprofen-induced meningitis. We discuss themain causes of drug-induced aseptic meningitis (DIAM) and highlight the importance of early recognition of DIAM, sothat the offending drug can be withdrawn, and recurrences prevented. Only few DIAM cases have been reported in pediatric age.\n\n\nMETHODS\nA healthy 15-year-old boy presented to the emergency department with headache, nausea, dizziness, fever, conjunctival hyperemia and blurred vision 30 minutes after ibuprofen-intake. During his stay, he developed emesis and neck stiffness. Cerebrospinal fluid analysis excluded infectious causes, and DIAM was considered. He totally recovered after drug withdrawal.\n\n\nCONCLUSIONS\nDIAM is a rare entity, that should be considered in the differential diagnosis of an aseptic meningitis. The major causative agents are nonsteroidal anti-inflammatory drugs, particularly ibuprofen. Suspicion is made by the chronologic link between drug intake and the beginning of symptoms, but infectious causes should always be ruled out.",
"affiliations": "Centro Hospitalar e Universitário de Coimbra, Coimbra, Portugal.;Centro Hospitalar de Leiria, Leiria, Portugal.;Centro Hospitalar de Leiria, Leiria, Portugal.;Centro Hospitalar de Leiria, Leiria, Portugal.;Centro Hospitalar de Leiria, Leiria, Portugal.",
"authors": "Pires|Sofia Alexandra Pereira|SAP|http://orcid.org/0000-0002-7621-5732;Lemos|Ana Pereira|AP|http://orcid.org/0000-0002-0167-4280;Pereira|Ester Preciosa Maio Nunes|EPMN|http://orcid.org/0000-0001-5956-0940;Maia|Paulo Alexandre da Silva Vilar|PADSV|http://orcid.org/0000-0002-0141-9458;Agro|João Patrício de Sousa E Alvim Bismarck do|JPSEABD|http://orcid.org/0000-0002-8774-0655",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen",
"country": "Brazil",
"delete": false,
"doi": "10.1590/1984-0462/;2019;37;3;00016",
"fulltext": "\n==== Front\nRev Paul PediatrRev Paul PediatrrppRevista Paulista de Pediatria0103-05821984-0462Sociedade de Pediatria de São Paulo 3116646810.1590/1984-0462/;2019;37;3;00016Case ReportsIBUPROFEN-INDUCED ASEPTIC MENINGITIS: A CASE REPORT MENINGITE ASSÉPTICA INDUZIDA POR IBUPROFENO: UM CASO\nCLÍNICO http://orcid.org/0000-0002-7621-5732Pires Sofia Alexandra Pereira \na\n\n*\nhttp://orcid.org/0000-0002-0167-4280Lemos Ana Pereira \nb\nhttp://orcid.org/0000-0001-5956-0940Pereira Ester Preciosa Maio Nunes \nb\nhttp://orcid.org/0000-0002-0141-9458Maia Paulo Alexandre da Silva Vilar \nb\nhttp://orcid.org/0000-0002-8774-0655do Agro João Patrício de Sousa e Alvim Bismarck \nb\n\na Centro Hospitalar e Universitário de Coimbra, Coimbra,\nPortugal.\nb Centro Hospitalar de Leiria, Leiria, Portugal.* Corresponding author. E-mail:\nsofia.pires88@gmail.com (S.A.P. Pires).The authors declare no conflict of interests.\n\n03 6 2019 Jul-Sep 2019 37 3 382 385 14 1 2018 15 4 2018 21 5 2019 This is an open-access article distributed under the terms of the\nCreative Commons Attribution LicenseABSTRACT\nObjective:\n To report a case of a male adolescent with the diagnosis of\nibuprofen-induced meningitis. We discuss themain causes of drug-induced\naseptic meningitis (DIAM) and highlight the importance of early recognition\nof DIAM, sothat the offending drug can be withdrawn, and recurrences\nprevented. Only few DIAM cases have been reported in pediatric age.\n\nCase description:\n A healthy 15-year-old boy presented to the emergency department with\nheadache, nausea, dizziness, fever, conjunctival hyperemia and blurred\nvision 30 minutes after ibuprofen-intake. During his stay, he developed\nemesis and neck stiffness. Cerebrospinal fluid analysis excluded infectious\ncauses, and DIAM was considered. He totally recovered after drug\nwithdrawal.\n\nComments:\n DIAM is a rare entity, that should be considered in the differential\ndiagnosis of an aseptic meningitis. The major causative agents are\nnonsteroidal anti-inflammatory drugs, particularly ibuprofen. Suspicion is\nmade by the chronologic link between drug intake and the beginning of\nsymptoms, but infectious causes should always be ruled out.\n\nRESUMO\nObjetivo:\n Descreve-se o caso de um adolescente do sexo masculino com diagnóstico de\nmeningite asséptica por ibuprofeno. Discutem-se as causas de meningite\nasséptica induzida por medicamentos (MAIM) e a importância do reconhecimento\nprecoce dessa situação, para que a medicação envolvida seja suspensa e as\nrecorrências prevenidas. Poucos casos foram descritos em idade\npediátrica.\n\nDescrição do caso:\n Adolescente de 15 anos, gênero masculino, saudável, procurou o serviço de\nurgência por cefaleia, náuseas, tonturas, febre, hiperemia conjuntival e\nvisão desfocada 30 minutos após o uso de ibuprofeno. Durante a internação,\niniciou vômitos e rigidez na nuca. A análise do líquido cefalorraquidiano\nexcluiu causas infeciosas, e considerou-se como diagnóstico mais provável a\nMAIM. A recuperação foi total após a suspensão do medicamento.\n\nComentários:\n A MAIM é rara, mas deve ser considerada no diagnóstico diferencial de\nmeningite asséptica. A principal causa são os anti-inflamatórios não\nesteroides, principalmente o ibuprofeno. A suspeita clínica é evocada pela\nrelação temporal entre o uso do medicamento e o início dos sintomas, mas as\ncausas infeciosas devem ser sempre excluídas.\n\nKeywords:\nMeningitis, asepticAnti-inflammatory agents, non-steroidalIbuprofenAdolescentPalavras-chave:\nMeningite assépticaAnti-inflamatórios não esteroidesIbuprofenoAdolescente\n==== Body\nINTRODUCTION\nAseptic meningitis is a nonbacterial inflammation of the meninges.\n1\n Most commonly, it is caused by virus infection, but a variety of infectious\nand noninfectious agents, including drugs, can be implied.\n2\n\n\n\nDrug-induced aseptic meningitis (DIAM) is a rare entity and constitutes a diagnosis\nand patient management challenge. The most commonly responsible drugs are\nnonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics,\nimmunosuppressive-immunomodulatory, antiepileptic and intrathecal drugs.\n3\n\n,\n\n4\n\n\n\nIbuprofen is the main cause of DIAM, having been described in several case reports,\nespecially in adults with autoimmunedisorders.\n4\n\n,\n\n5\n\n,\n\n6\n\n\n\nCASE DESCRIPTION\nA previously healthy 15-year-old male presented to the emergency departmentwith\nheadache, nausea, dizziness, fever andblurred vision occurring 30 minutes after\ntaking a single dose of ibuprofen 400 mg. A week earlier, he also had headache,\nnausea and fever during one day after ibuprofen-intake, prescribed due to a fracture\nof the fifth right metatarsal bone.\n\nThere was a family history of autoimmune disease. His20-year-old sister had\nautoimmune thyroiditis.\n\nOn examination, hewas febrile (auricular temperature of 38.4ºC), with blood pressure\n130/71 mmHg and pulse rate 93/minute. His neurological exam was normal with no\naltered mental status nor meningeal or focal signs. He presented conjunctival\nhyperemia, without ocular discharge. Other organ systems’ examination was\nunremarkable.\n\nLaboratory tests revealed total white cell count 9,900/µL,with a differential of\n76,9% neutrophils and 19,4% lymphocytes, C-reactive protein 1.2 mg/L and\nnegativeblood culture.\n\nHe was admitted for clinical surveillance. On day 1, the patient maintained fever,\nand headache became more intense, with emesis. On examination, he had neck\nstiffness. Lumbar puncture was performed and cerebrospinal fluid (CSF) analysis\nrevealed a clear fluid, with total white cell count 268/mm3 (0%\nneutrophils and 100% lymphocytes), glucose 58 mg/dL and total protein 720 mg/dL. No\norganisms were seen on gram stain and culture was negative. Screening for bacterial\nantigens(Haemophilus influenzae type b, Streptococcus\npneumoniae, Neisseria meningitidis A, B and C, and\nEscherichia coli k1) andenterovirus polymerase chain reaction\n(PCR) were also negative. Ibuprofen was discontinued, and the patient improved\nwithout specific treatment. Symptoms resolved within 48 hours after admission, with\nno neurologic sequelae.\n\nThe patient was discharged with a presumptivediagnosis of aseptic meningitis induced\nby ibuprofen. He was advised not to takeNSAIDs. Screening for autoimmune diseases\nwas negative and included antinuclear, antiphospholipid and antithyroid\nantibodies.\n\nA report to the National Authority of Medicines and Health Products (Infarmed) was\nmade, that considered probable the link between ibuprofen intake and aseptic\nmeningitis.\n\nDISCUSSION\nNSAIDs are the most common drugs implicated in DIAM.\n7\n\n,\n\n8\n The first report was made in 1978, in a patient with systemic lupus\nerythematosus (SLE) who had an ibuprofen-induced meningitis.\n9\nSince then, several reports of aseptic meningitis attributed to NSAIDs have\nbeen made, including dexibuprofen, dexketoprofen, flurbiprofen, diclofenac,\nsulindac, ketoprofen, tolmetin, piroxicam, indometacin, naproxen and\nprostaglandin-endoperoxide synthase 2 (COX-2) inhibitors (rofecoxib and\ncelecoxib).\n5\n\n,\n\n8\n\n,\n\n10\n Ibuprofen is, nevertheless, by far the leading cause of DIAM.\n5\n\n\n\nTo our knowledge, there are only two published case reports of NSAIDs-induced aseptic\nmeningitis that presented at pediatric age, caused by ibuprofen\n3\n and rofecoxib,\n11\n respectively. We summarize clinical and laboratorial features on Table 1.\n\n\nTable 1 Clinical and laboratorial features of three pediatric patients with\nnonsteroidal anti-inflammatory drugs-induced meningitis.\n\n\tBonnel et al. 2002\n11\n\n\tFrank-Briggs et al. 2014\n3\n\n\tPires et al. 2019*\t\nAge\t16\t15\t15\t\nGender\tFemale\tMale\tMale\t\nDrug (dose)\tRofecoxib (12,5 mg/day)\tIbuprofen (not available)\tIbuprofen (400 mg/dose)\t\nAssociated diseases\tNone\tNone\tNone\t\nTime from drug intake and symptoms\t12 days\t3 days\t30 minutes\t\nSymptoms\tHeadache, numbness in the right leg and right side\nof the face, altered mental status\tFever (39ºC), altered mental status, positive\nKerning sign, hypertonia of the lower limbs\tFever (38,4ºC), conjunctival hyperemia, headache,\ndizziness, blurred vision, emesis, neckstiffness\t\nCSF \t\n- White blood cells/mm3\n\t- 82\t- 75\t- 268\t\n- Neutrophils (%)\t- 0\t- 27\t- 0\t\n- Lymphocytes (%)\t- 100\t- 73\t- 100\t\n- Glucose (mg/dL)\t- Not available\t- 42\t- 58\t\n- Proteins (mg/dL)\t- Increased (no values available)\t- 102\t- 720\t\n- Cultures\t- Negative\t- Negative\t- Negative \t\n- Other\t- Negative for viral, fungal and bacterial\nisolates\t- Negative CMV, HSV 1 e 2, EBV, arbovirus and\nMycobacterium tuberculosis PCR\t- Negative enterovirus PCR\t\nAntibiotic treatment\tCeftriaxone and acyclovir\tVancomycin and ceftriaxone\tNone\t\nSequels\tNone\tNone\tNone\t\nCSF: cerebrospinal fluid; CMV: cytomegalovirus; HSV: herpes simplex\nvirus; EBV: Epstein-Barr virus; PCR: polymerase chain reaction.\n*This study.\n\n\n\n\nUsually, patients with DIAM present with fever, altered mental status, headache, neck\nstiffness, nausea and vomiting. However, meningoencephalitis with neurological focal\ndeficits is not infrequent. Blurred vision and conjunctivitis may occur, as in our\ncase report.\n4\n\n,\n\n5\n\n,\n\n6\n\n\n\nDIAM is a diagnosis of exclusion and infectious causes must always be ruled out.\nClinical presentation may be quite similar to acute bacterial meningitis and CSF\nanalysis doesn’t allow the exclusion of this diagnose until the culture is negative.\nCSF findings are not specific, and typically there is pleocytosis with neutrophilic\npredominance (72,2% of cases), normal-to-low glucose values, and increased\nproteins.\n5\n Therefore, if there is a clinical suspicion of bacterial meningitis,\nantibiotic therapy should be given until negativity of cultures. Also, in cases that\npresent as meningoencephalitis, antiviral treatment should be considered.\n\nOccasionally, lymphocytes and even eosinophils may predominate.\n5\n\n,\n\n12\n In our patient, however, we found pleocytosis with 100% lymphocytes,\nincreased proteins and normal glycorrhachia.\n13\n Some authors suggest that different results in CSF can be related to the\ntiming of which the lumbar puncture is done, corresponding to different stages of\nthe disease.\n10\n\n,\n\n14\n\n,\n\n15\n Normalization of CSF parameters occurs quite slowly, over several days.\n5\n\n,\n\n12\n\n\n\nOn the other hand, viral meningitis may be quite difficult to differentiate from\nDIAM. In our case report, and according to clinical manifestations and CSF findings,\nwe did CSF enterovirus PCR to exclude infection by this main viral agent.\n1\n\n\n\nDIAM is suspected by the establishment of a temporal relationship between the\nadministration of the drug and the onset of symptoms. Latency period is short,\ntypically less than 48 hours.\n3\n There is a rapid resolution of symptoms after drug withdrawal, one to five\ndays.\n4\n\n,\n\n12\n On the contrary, in viral meningitis, time to recovery is longer, 10 to 14\ndays.\n6\n\n\n\nDIAM can occur in patients that previously tolerated the offending drug.\n3\n\n,\n\n6\n Prior exposures to the drug have been noted in 35% of patients with\nibuprofen-induced meningitis.\n4\n In our patient, a shorter period between ibuprofen-intake and the onset of\nsymptoms and increased symptoms’ severity during the second exposure were helpful\nclues for the diagnosis.Moreover, the adolescent also completely recovered only 48\nhours after drug withdrawal.\n\nDIAM is more frequent in women (64%) and recurrent episodes are quite frequent (61%),\nespecially when the diagnosis is not made on the first one.\n5\n\n,\n\n15\n\n,\n\n16\n Drug challenge can confirm diagnosis,\n14\n but it is not advised, as re-exposure can lead to severe symptoms.\n17\n\n\n\nPatients must be advised to avoid not only ibuprofen, butalso all NSAIDs, because\nrecurrent episodes of aseptic meningitis related to other NSAIDs can occur.\n10\n\n,\n\n18\n We should provide medical alternatives to the patient and explain that\naseptic meningitis is independent of the dose of NSAID.\n5\n\n\n\nThere is a strong association between DIAM and autoimmune diseases (specially SLE),\nso it is recommended an analytical screening even in asymptomatic patients.\n5\n\n,\n\n17\n Thehigher incidence of ibuprofen-induced aseptic meningitis in patients with\nautoimmune diseases could be related to the widespread use of NSAIDs or by patients’\ntendency to autoreact.\n5\n\n,\n\n15\n Inpediatric population, this is quite important, because DIAM can\npotentially be the first sign that leads to the suspicion of an underlying\nautoimmune disorder. In our case report, despite family history of autoimmune\ndisease, autoantibodies were negative.\n\nThe mechanism by which NSAIDs cause meningeal inflammation is uncertain, but it\nappears to be an immunologically mediated hypersensitivity reaction (type III or\nIV).\n1\n\n,\n\n5\n\n,\n\n6\n\n\n\nThe increasing number of NSAIDs-induced aseptic meningitis, even in healthy people,\ncan be related to the broader use of this medication.\n5\n This could be a greater problem in countries where they are purchased\nover-the-counter, like in Portugal. So, it is very important to arise medical\nattention for this condition and to report drug side effects.\n\nOur case report of aseptic meningitis due to ibuprofen intake illustrates the\nimportance of early diagnosis, so that the offending drug can be withdrawal and\nrecurrences prevented. A rapid onset and resolution of symptoms with compatible CSF\nfinding suggest DIAM. As DIAM is a diagnosis of exclusion, it is important to\ninvestigate and exclude other causes of meningitis, especially infectious agents,\nand always obtain a detailed drug history.\n12\n The prognosis is usually good, with no long-term sequels.\n5\n\n\n\nFunding\nThis study did not receive funding.\n==== Refs\nREFERENCES\n1 Tunkel AR Aseptic meningitis in adults homepage on the Internet UptoDate 2017\nApril 12 Available from: https://www.uptodate.com/contents/aseptic-meningitis-in-adults \n2 Cascella C Nausheen S Cunha BA A differential diagnosis of drug-induced aseptic\nmeningitis Infect Med 2008 25 331 334 \n3 Frank-Briggs AI Oluwatade OJ Drug-induced aseptic meningitis: a diagnosis\nchallenge Niger J Paed 2014 41 138 140 \n4 Morís G Garcia-Monco JC The challenge of drug-induced aseptic meningitis\nrevisited JAMA Intern Med 2014 174 1511 1512 25003798 \n5 Rodríguez SC Olguín AM Miralles CP Viladrich PF Characteristics of meningitis caused by ibuprofen: report of 2\ncases with recurrent episodes and review of the literature Medicine (Baltimore) 2006 85 214 220 16862046 \n6 Morís G Garcia-Monco JC The challenge of drug-induced aseptic meningitis Arch Intern Med 1999 159 1185 1194 10371226 \n7 Hopkins S Jolles S Drug-induced aseptic meningitis Expert Opin Drug Saf 2005 4 285 297 15794720 \n8 Jolles S Sewell WA Leighton C Drug-induced aseptic meningitis: diagnosis and\nmanagement Drug Saf 2000 22 215 226 10738845 \n9 Widener LB Littman BH Ibuprofen-induced meningitis in systemic lupus\nerythematosus JAMA 1978 239 1062 1064 304902 \n10 Ashwath ML Katner HP Recurrent aseptic meningitis due to different non-steroidal\nanti-inflammatory drugs including rofecoxib Postgrad Med J 2003 79 295 296 12782779 \n11 Bonnel RA Villalba ML Karwoski CB Beitz J Aseptic meningitis associated with rofecoxib Arch Intern Med 2002 162 713 715 11911727 \n12 Kepa L Oczko-Grzesik B Stolarz W Sobala-Szczygiel B Drug-induced aseptic meningitis in suspected central nervous\nsystem infection J Clin Neurosci 2005 12 562 564 16051094 \n13 Mann K Jackson MA Meningitis Pediatr Rev 2008 29 417 430 19047432 \n14 Moreno-Ancillo A Gil-Adrados AC Jurado-Palomo J Ibuprofen-induced aseptic meningoencephalitis confirmed by drug\nchallenge J Investig Allergol Clin Immunol 2011 21 484 487 \n15 Pisani E Fattorello C Leotta MR Marcello O Zuliani C Recurrence of ibuprofen-induced aseptic meningitis in an\notherwise healthy patient Ital J Neurol Sci 1999 20 59 62 10933487 \n16 Kumar R Aseptic meningitis: diagnosis and management Indian J Pediatr 2005 72 57 63 15684450 \n17 Karmacharya P Mainali NM Aryal MR Lloyd B Recurrent case of ibuprofen-induced aseptic meningitis in mixed\nconnective tissue disease BMJ Case Reports 2013 2013 bcr2013009571 bcr2013009571 \n18 Seaton RA France AJ Recurrent aseptic meningitis following non-steroidal\nanti-inflammatory drugs - a reminder Postgrad Med J 1999 75 771 772 10567617\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0103-0582",
"issue": "37(3)",
"journal": "Revista paulista de pediatria : orgao oficial da Sociedade de Pediatria de Sao Paulo",
"keywords": null,
"medline_ta": "Rev Paul Pediatr",
"mesh_terms": "D000293:Adolescent; D000894:Anti-Inflammatory Agents, Non-Steroidal; D003937:Diagnosis, Differential; D004342:Drug Hypersensitivity; D005334:Fever; D006261:Headache; D006801:Humans; D007052:Ibuprofen; D008297:Male; D008582:Meningitis, Aseptic; D016896:Treatment Outcome; D014839:Vomiting",
"nlm_unique_id": "9109353",
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"pages": "382-385",
"pmc": null,
"pmid": "31166468",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19047432;304902;16862046;12782779;10933487;10567617;16051094;25003798;15794720;23632618;10371226;10738845;11911727;21995183;15684450",
"title": "IBUPROFEN-INDUCED ASEPTIC MENINGITIS: A CASE REPORT.",
"title_normalized": "ibuprofen induced aseptic meningitis a case report"
} | [
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{
"abstract": "Diffuse large B-cell lymphoma (DLBCL) is a rather aggressive disease and the natural course of this lymphoma is very dismal. However, first the introduction of anthracycline-containing chemotherapy regimens and then the addition of rituximab were important steps forward. Since no complete real-life analyses have yet been published, we analyzed all patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) in the whole region of Tyrol and compared the results to a historical CHOP(-like)-treated cohort. Two hundred and nineteen consecutive patients underwent R-CHOP and 72% achieved a complete remission (CR); 20% suffered a relapse and 31% died. 5-Year progression-free survival (PFS) and overall survival (OS) were 56% and 69%, respectively. We identified several parameters influencing PFS and OS significantly in univariate analysis, but only stage III/IV and hemoglobin <13 g/dl were independent prognosticators for PFS and age >60 years for OS. In comparison to the CHOP(-like)-treated group, the CR rate was similar, while the percentage of relapse was nearly twice in the historical cohort, namely 44%. This translated into a dramatically improved PFS and OS for the R-CHOP group. In conclusion, in a real-life setting R-CHOP results in high percentages of response and long-term remission. Moreover we showed that in the rituximab era, factors other than the single parameters of the international prognostic index significantly influence PFS and OS. Finally, we confirm the independent impact of rituximab on the outcome of an unselected population with DLBCL.",
"affiliations": "Department of Hematology & Oncology, Medical University of Innsbruck, Austria. m.mian@webmaxxi.eu.",
"authors": "Mian|Michael|M|;Augustin|Florian|F|;Kocher|Florian|F|;Gunsilius|Eberhard|E|;Willenbacher|Wolfgang|W|;Zabernigg|August|A|;Zangerl|Günther|G|;Oexle|Horst|H|;Schreieck|Stefan|S|;Schnallinger|Michael|M|;Fiegl|Michael|M|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; C571759:R-CHOP protocol; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Greece",
"delete": false,
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"issn_linking": "0250-7005",
"issue": "34(5)",
"journal": "Anticancer research",
"keywords": "Lymphoma; diffuse large B-cell lymphoma; outcome; rituximab",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D018572:Disease-Free Survival; D004317:Doxorubicin; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D011241:Prednisone; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "2559-64",
"pmc": null,
"pmid": "24778077",
"pubdate": "2014-05",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A success story: how a single targeted-therapy molecule impacted on treatment and outcome of diffuse large B-cell lymphoma.",
"title_normalized": "a success story how a single targeted therapy molecule impacted on treatment and outcome of diffuse large b cell lymphoma"
} | [
{
"companynumb": "AT-BAXTER-2014BAX036026",
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"activesubstancename": "DOXORUBICIN"
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{
"abstract": "Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment; they have a high frequency of delayed healing. The authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy. Atypical femoral fractures can be subsequent to a long-term biphosphonates treatment even if, in the literature, there is no clarity on the exact pathogenetic mechanism. The Task Force of the American Society for Bone and Mineral Research described the major and minor features to define atypical fractures and recommends that all the five major features must be present while minor features are not necessary. Another controversial aspect regarding the atypical femoral fractures is the higher frequency of the delayed healing that can be probably related to a suppressed bone turnover caused by a prolonged period of bisphosphonates treatment. This concept could be corroborated by the Spet Tc exam. In the case of a pseudoarthrosis, there is not a standardization of the treatment. In this report, the authors describe a femoral pseudoarthrosis of an atypical fracture treated with intramedullary nailing in a female after prolonged alendronate therapy; the patient was studied with clinical, bioumoral end SPECT-Tc exam of both femurs. Many studies show the relationship between bisphosphonates and the presence of atypical fractures. These fractures should be monitored more closely due to the risk of nonunion and they require considering an initial treatment with pharmacological augmentation to reduce the complications for the patient and the health care costs.",
"affiliations": "Clinica Ortopedica e Traumatologica II, Universita' Di Pisa, Via Paradisa 2, Pisa, Italy, s.giannotti@med.unipi.it.",
"authors": "Giannotti|S|S|;Bottai|V|V|;Dell'Osso|G|G|;De Paola|G|G|;Ghilardi|M|M|;Guido|G|G|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-013-2397-3",
"fulltext": null,
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"issn_linking": "0937-941X",
"issue": "24(11)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": null,
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D050071:Bone Density Conservation Agents; D005260:Female; D005264:Femoral Fractures; D005594:Fracture Fixation, Intramedullary; D017102:Fracture Healing; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D011542:Pseudarthrosis; D011859:Radiography; D012086:Reoperation",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "2893-5",
"pmc": null,
"pmid": "23681089",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23412268;23377812;23196269;21752890;20842676;22691683;23324969;23289032;23858312;23311861;23351873;22461159;22814830",
"title": "Pseudoarthrosis in atypical femoral fracture: case report.",
"title_normalized": "pseudoarthrosis in atypical femoral fracture case report"
} | [
{
"companynumb": "IT-WATSON-2014-20467",
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"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
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... |
{
"abstract": "Musculoskeletal emergencies include tendon rupture, carpal tunnel syndrome, rupture of synovial cyst (\" pseudothrombophlebitis \" syndrome), subluxations in the cervical spine, cricoarytenoid arthritis and septic arthritis. Ocular complications can be serious emergencies, as can vasculitis and rheumatoid nodules. Drug reactions represent an additional group of urgent problems. While rheumatoid arthritis is characteristically an indolent disease, failure to recognize its urgent complications can cause significant morbidity and mortality.",
"affiliations": null,
"authors": "Weiner|S R|SR|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006046:Gold; D010396:Penicillamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0002-838X",
"issue": "29(6)",
"journal": "American family physician",
"keywords": null,
"medline_ta": "Am Fam Physician",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D001170:Arthritis, Infectious; D001172:Arthritis, Rheumatoid; D002349:Carpal Tunnel Syndrome; D002574:Cervical Vertebrae; D004630:Emergencies; D005128:Eye Diseases; D006046:Gold; D006801:Humans; D004204:Joint Dislocations; D007818:Laryngeal Diseases; D010396:Penicillamine; D012218:Rheumatoid Nodule; D012422:Rupture, Spontaneous; D013581:Synovial Cyst; D013708:Tendon Injuries; D014657:Vasculitis",
"nlm_unique_id": "1272646",
"other_id": null,
"pages": "127-31",
"pmc": null,
"pmid": "6731247",
"pubdate": "1984-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Emergencies in rheumatoid arthritis.",
"title_normalized": "emergencies in rheumatoid arthritis"
} | [
{
"companynumb": "PHHY2019CH074396",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "Abscesses related to drug use are the most common cutaneous manifestations among injection drug users, often occurring when the veins become less accessible. In these cases, other techniques may be used to administer drugs, such as skin popping (subcutaneous injection) or muscle popping (intramuscular injection). The main risk factors for abscess formation include skin popping, use of unsterilized needles, and injection of speedball (a mixture of cocaine and heroin). We present a case of recurrent abscesses accompanied by fever, hypersomnia alternating with insomnia, diaphoresis, fatigue, recent weight loss, and agitation following subcutaneous injection of a tramadol, opipramol, and clonazepam mixture. Differential diagnoses included pyoderma gangrenosum on the basis of hepatitis C virus, skin lesions connected with human immunodeficiency virus infection, vasculitis, endocarditis, and serotonin syndrome. The patient was treated with oral antibiotics, surgical incision, and drainage of the abscesses, with consequent improvement.",
"affiliations": "Department of Dermatology, Venereology, and Allergology, Medical University of Gdańsk, Debinki St 7, 80-211 Gdańsk, Poland. izabelaa5@wp.pl.",
"authors": "Barańska-Rybak|Wioletta|W|;Błażewicz|Izabela|I|;Kąkol|Monika|M|;Roter|Mirosław|M|;Nowicki|Roman|R|",
"chemical_list": "D014147:Tramadol; D002998:Clonazepam; D009888:Opipramol",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "93(4)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000038:Abscess; D002998:Clonazepam; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D009888:Opipramol; D012008:Recurrence; D012307:Risk Factors; D017192:Skin Diseases, Bacterial; D018461:Soft Tissue Infections; D015819:Substance Abuse, Intravenous; D014147:Tramadol; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "185-7",
"pmc": null,
"pmid": "24818177",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cutaneous manifestations of injectable drug use: hidden secrets.",
"title_normalized": "cutaneous manifestations of injectable drug use hidden secrets"
} | [
{
"companynumb": "PL-ACTAVIS-2015-04139",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OPIPRAMOL"
},
"drugadditional": null,
... |
{
"abstract": "Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by elevated levels of immunoglobulin E (IgE), eczematous dermatitis, cold abscesses, and recurrent infections of the lung and skin caused by Staphylococcus aureus. The dominant form is characterized by nonimmunologic features including skeletal, connective tissue, and pulmonary abnormalities in addition to recurrent infections and eczema. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Several studies reported clinical improvement with omalizumab in patients with severe atopic eczema with high serum IgE level. We present the case of a 37-year-old male with HIES and cutaneous manifestations, treated with humanized recombinant monoclonal antibodies efalizumab and omalizumab. After therapy for 4 years, we observed diminished eczema and serum IgE levels.",
"affiliations": "Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.;Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico.;Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.;Dermatology Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.;Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Zaragoza, Facultad de Medicina, Mexico.;Immunodeficiencies Research Unit, Instituto Nacional de Pediatria, Secretaría de Salud, Mexico.;Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Zaragoza, Facultad de Medicina, Mexico.;Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico.;Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.;Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.;Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico.",
"authors": "Alonso-Bello|Cesar Daniel|CD|https://orcid.org/0000-0002-5249-2727;Jiménez-Martínez|María Del Carmen|MDC|https://orcid.org/0000-0003-3982-9097;Vargas-Camaño|María Eugenia|ME|;Hierro-Orozco|Sagrario|S|;Ynga-Durand|Mario Alberto|MA|https://orcid.org/0000-0002-8586-3993;Berrón-Ruiz|Laura|L|;Alcántara-Montiel|Julio César|JC|;Santos-Argumedo|Leopoldo|L|;Herrera-Sánchez|Diana Andrea|DA|;Lozano-Patiño|Fernando|F|;Castrejón-Vázquez|María Isabel|MI|https://orcid.org/0000-0002-7556-5810",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2019/6357256",
"fulltext": "\n==== Front\nCase Reports ImmunolCase Reports ImmunolCRIICase Reports in Immunology2090-66092090-6617Hindawi 10.1155/2019/6357256Case ReportPartial and Transient Clinical Response to Omalizumab in IL-21-Induced Low STAT3-Phosphorylation on Hyper-IgE Syndrome https://orcid.org/0000-0002-5249-2727Alonso-Bello Cesar Daniel cesar_alonso86@hotmail.com\n1\nhttps://orcid.org/0000-0003-3982-9097Jiménez-Martínez María del Carmen \n2\nVargas-Camaño María Eugenia \n1\nHierro-Orozco Sagrario \n3\nhttps://orcid.org/0000-0002-8586-3993Ynga-Durand Mario Alberto \n4\n\n5\nBerrón-Ruiz Laura \n6\nAlcántara-Montiel Julio César \n4\nSantos-Argumedo Leopoldo \n7\nHerrera-Sánchez Diana Andrea \n1\nLozano-Patiño Fernando \n1\nhttps://orcid.org/0000-0002-7556-5810Castrejón-Vázquez María Isabel \n1\n\n1Immunology and Allergy Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico\n2Faculty of Medicine, Universidad Nacional Autónoma de México, Mexico\n3Dermatology Department, Centro Médico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico\n4Universidad Nacional Autónoma de México, Facultad de Estudios Superiores Zaragoza, Facultad de Medicina, Mexico\n5Laboratorio de Inmunidad de Mucosas, Sección de Investigación y Posgrado, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico City, Mexico\n6Immunodeficiencies Research Unit, Instituto Nacional de Pediatria, Secretaría de Salud, Mexico\n7Department of Molecular Biomedicine, CINVESTAV-IPN, MexicoAcademic Editor: Necil Kütükçüler\n\n2019 4 7 2019 2019 635725621 4 2019 13 6 2019 Copyright © 2019 Cesar Daniel Alonso-Bello et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by elevated levels of immunoglobulin E (IgE), eczematous dermatitis, cold abscesses, and recurrent infections of the lung and skin caused by Staphylococcus aureus. The dominant form is characterized by nonimmunologic features including skeletal, connective tissue, and pulmonary abnormalities in addition to recurrent infections and eczema. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Several studies reported clinical improvement with omalizumab in patients with severe atopic eczema with high serum IgE level. We present the case of a 37-year-old male with HIES and cutaneous manifestations, treated with humanized recombinant monoclonal antibodies efalizumab and omalizumab. After therapy for 4 years, we observed diminished eczema and serum IgE levels.\n==== Body\n1. Introduction\nHyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by elevated levels of immunoglobulin E (IgE), eczematous dermatitis, cold abscesses, and recurrent infections of the lung and skin caused by Staphylococcus aureus. The diagnosis of hyper-IgE syndrome is syndromic and the most frequent laboratory meetings are eosinophilia (greater than 1500/ml) and elevated levels of IgE, which typically are above 2000 IU/ml. Leukocytes in blood and serum immunoglobulin levels IgM, IgG, and IgA are frequently normal, but they have been found in some cases of deficiencies immunoglobulins. There are two main forms of HIES: a form characterized by mutations in signal transducer and activator of transcription 3 gene (STAT3) with autosomal dominant inheritance (AD) (the Online Mendelian Inheritance in Man® (OMIM®) number registered in database is #147060) and a mutation in Dedicator of cytokinesis 8 (DOCK8) with autosomal recessive inheritance (AR), OMIM #243700, both in humans and mice. The dominant form is characterized by nonimmunologic features including skeletal abnormalities (scoliosis, retained primary teeth, and fractures with minor trauma), connective tissue, and pulmonary abnormalities in addition to recurrent infections and eczema. In contrast, the recessive form lacks skeletal abnormalities and has marked viral infections caused by molluscum contagiosum and herpes simplex virus (HSV) and neurologic complications [1]. The DOCK8 immunodeficiency syndrome (DIDS) is the predominant form of HIES autosomal recessive (AR-HIES). DOCK8 which is highly expressed in the immune system is a member of a poorly characterized family of atypical guanine dinucleotide exchange factors for Rho family GTPases. The 50-80% of these patients develop severe allergies such as asthma, anaphylaxis, and food allergy. In particular, CD8+ T cells from DIDS patients not only are decreased in number but also fail to expand normally in vitro after stimulation and produce less antiviral cytokines, which increases susceptibility to viral infections like herpes simplex virus (HSV), human papillomavirus (HPV), molluscum contagious (MCV), and varicella-zoster virus (VZV). Some patients have impaired humoral immunity, decreasing the number of immunoglobulins. DIDS patients are also highly prone to malignancy, with 10% to 36% of patients developing cancers in late childhood to early adulthood like squamous cell carcinomas, and lymphomas, including Burkitt lymphoma or Epstein Barr Virus (EBV) diffuse large B cell lymphoma, predominate [2, 3]. Since the discovery in 2009 that loss-of-function mutations in DOCK8 underlie AR-HIES, an estimated >100 patients worldwide have been identified. FOXP3 regulatory T cells that produce IL-10 play an essential role in regulating allergic inflammation. There are two types of FOXP3 regulatory T cells: the natural and induced. FOXP3 gene mutations produce immune deregulation with enteropathy, autoimmune diabetes, thyroiditis, food allergies, atopic dermatitis, and elevated levels of IgE. Cytokines produced by dendritic cells (DC) play a role in the induction and maintenance of T cell tolerance. IL-10 signaling-DC is needed for the generation of tolerogenic DC and induced regulatory T cells (iTreg) which maintain an appropriate balance Th1/Th2. In patients with HIES, signal transduction mediated by IL10-DCs is impaired, which predisposes to allergic manifestations. This generation of induced FOXP3 regulatory T cells is impaired in patients with HIES [4]. We describe a case of partial clinical response to omalizumab in IL-21-induced low STAT3-phosphorylation on a patient with HIES and very high levels of total serum IgE.\n\n2. Case Presentation\nOn April 2008, a 37-year-old male from Mexico City, with diagnosis of atopic dermatitis since he was 5 years old, presented to dermatology service and was treated with efalizumab 1 mg/kg/SC/weekly for two months. The patient received twelve doses of efalizumab, but the drug was suspended due to herpes zoster dermatitis (Figure 1), and treatment with acyclovir was indicated with adequate clinical response. Two months later, the patient developed generalized erythroderma, finding high levels of total serum IgE (48,700 UI/ml) and interleukins levels: TNF 39.7 pg/ml, IL-1β 5 pg/ml, IL-2R 1086 IU/ml, IL-6 11.9 pg/ml, and IL-8 8.66 pg/ml, showing increased levels of proinflammatory cytokines. He was sent to the service of clinical immunology and allergy, where he was diagnosed with HIES. To evaluate the pathway of IL-21, PBMCs of the patient were stimulated with rhIL-21 (militenyi) for 15 minutes and phosphorylation of STAT3 was evaluated by flow cytometry. The mAbs used were anti CD19-APC, anti-pSTAT3 (Y705)-PE, and isotype controls (mouse IgG1) from BD Pharmingen and Santa Cruz Biotechnology. Flow cytometry was performed on CYAN-ADP cytometer (Beckman Coulter). Cells were analyzed using Flow Jo 8.8 software (Tree Star). On September 2008, the clinical manifestations were dry skin and lichenified upper limbs and chest, generalized itching, peeling, and scratching scars, treated with hydroxyzine 10 mg every 8 hours, efalizumab, emollients, and general measures. On January 2009, the treatment was modified with monoclonal antibody omalizumab 300 mg every two weeks, with initial levels of total IgE 127,000 IU/ml. We made a new clinical assessment at 6 weeks; the patient presented clinical improvement with eczematous lesions on the chest and upper limbs and secondary hypochromic lesions and traces of scratching. Reassessing their total serum IgE levels in 439 UI/ml, we decided to increase omalizumab dose to 350 mg every two weeks. On May 2013, the patient presented skin lesions exacerbation with erythema, itching, eczema, and erythroderma. To 2013 the patient received 74 doses of omalizumab with stability of clinical manifestations. Eczema and total IgE levels were decreased even though with variations. The variations of CRP (C-reactive protein) do not correlate with the clinical manifestations of the patient and IgE levels (Figures 2 and 3). The patient decided to stop the treatment by personal decision.\n\n3. Discussion\nWe present the case of a patient with HIES and skin manifestations treated with humanized recombinant monoclonal antibody, omalizumab. HIES is a rare primary immunodeficiency, characterized by high levels of serum IgE, recurrent skin abscesses, eczema, and pneumonia. Inherited patterns with AD, AR have been reported, but most HIES cases are sporadic. Mutations in the signal transducer and activator of transcription 3 gene (STAT3) are a major cause of AD.\n\nInterleukin 21 (IL-21) is needed for the differentiation of subsets of T cells CD4 the Th17 cells [5]. The patient showed low phosphorylation of STAT3 after 15 minutes of stimulation with rhIL-21. Experimental controls are appended (Figures 4 and 5). The low phosphorylation of STAT3 observed in HIES patients suggested that the activation and regulation of STAT3 might have an important role in T cell activation [6]. STAT3 regulates the subset Th17 cells which are important in inflammatory response to bacterial and fungal pathogens [7]. Defective Th17 responses are a common attribute of HIES cases with different genetic forms and sporadic cases [8]. Our patient had severe eczema and elevated levels of IgE that have never been reported in the world literature.\n\nIn the present case, dermatological findings led us to suspect HIES because of IgE levels and childhood onset-atopic dermatitis. Therefore, further investigations for HIES were done and the diagnosis was made by Grimbacher Criteria [9]. Omalizumab, the humanized recombinant monoclonal antibody against IgE, is known to result in marked reduction in serum free IgE and downregulation of IgE receptors on circulating basophiles. Omalizumab is used for the treatment of moderate to severe persistent asthma in adults and adolescents older than 12 years of age who have elevated levels of IgE and positive skin test to a perennial allergen. Several studies reported clinical improvement in patients with severe atopic eczema with high serum IgE level [10–13]. However, prospective studies and long-term follow-up are required to confirm the efficacy of omalizumab in HIES. In the present case, the clinical response was partial because the patient did not fulfill his treatment schedule. The reactivation of skin manifestations was related to the serum IgE increase.\n\nAbreviations\nHIES:Hyper-IgE syndrome\n\nIgE:Immunoglobulin E\n\nAD:Autosomal dominant inheritance\n\nAR:Autosomal recessive inheritance\n\nHSV:Herpes simplex virus\n\nDIDS:DOCK8 immunodeficiency syndrome\n\nHPV:Human papillomavirus\n\nMCV:Molluscum contagious virus\n\nVZV:Varicella-zoster virus.\n\nConflicts of Interest\nThe authors have no conflicts of interest to disclose.\n\nFigure 1 Cutaneous lesions located in left costal dermatome, characterized by multiple necrotic lesions.\n\nFigure 2 Comparison between CRP levels during application of omalizumab. The variation of protein levels does not correlate with the clinical manifestations of the patient and IgE levels.\n\nFigure 3 Comparison between IgE levels during application of omalizumab. The y-axis: serum IgE expressed in IU/ml; the x-axis: the dates on which these levels were taken. The decrease in IgE levels was clearly observed during the application of omalizumab; these increased after treatment was discontinued.\n\nFigure 4 Evaluation of STAT3 phosphorylation by flow cytometry.\n\nFigure 5 The patient showed low phosphorylation of STAT3 after 15 minutes of stimulation with rhIL-21; this image shows the comparison with experimental controls.\n==== Refs\n1 Freeman A. F. Holland S. M. The hyper-IgE syndromes Immunology and Allergy Clinics of North America 2008 28 2 277 291 10.1016/j.iac.2008.01.005 18424333 \n2 Vega O. C. Hernández V. L. Segura M. N. H. Torres S. B. A. Hyper IgE syndrome. diagnosis and timely management Revista Alergia México 2008 55 1 38 45 18697452 \n3 Alcantara-Montiel J. C. Vega-Torres B. I. Hyper-IgE syndrome. lessons from function and defects of STAT-3 or DOCK-8 Revista Alergia México 2016 63 4 385 396 27795219 \n4 Shevach E. M. Mechanisms of foxp3+ T regulatory cell-mediated suppression Immunity 2009 30 5 636 645 10.1016/j.immuni.2009.04.010 2-s2.0-65549136983 19464986 \n5 Tian Y. Zajac A. J. L-21 and T cell differentiation: consider the context Trends in Immunology 2016 37 8 557 568 10.1016/j.it.2016.06.001 2-s2.0-84977104759 27389961 \n6 Bocchini C. E. Nahmod K. Katsonis P. Protein stabilization improves STAT3 function in autosomal dominant hyper-IgE syndrome Blood 2016 128 26 3061 3072 10.1182/blood-2016-02-702373 27799162 \n7 Raphael I. McGeachy M. J. STAT3 regulation of effector Th17 cells and its implications for treatment of autoimmunity The Journal of Immunology 2018 200 121.5 1 Supplement \n8 Boos A. C. Hagl B. Schlesinger A. Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern Allergy 2014 69 7 943 953 10.1111/all.12416 24898675 \n9 Grimbacher B. Holland S. M. Puck J. M. Hyper-IgE syndromes Immunological Reviews 2005 203 1 244 250 10.1111/j.0105-2896.2005.00228.x 2-s2.0-13144283631 15661034 \n10 Thaiwat S. Sangasapailiya A. Omalizumab treatment in severe adult atopic dermatitis Asian Pacific Journal of Allergy and Immunology 2011 29 4 357 360 22299316 \n11 Chularojanamontri L. Wimoolchart S. Tuchinda P. Kulthanan K. Kiewjoy N. Role of omalizumab in a patient with hyper-IgE syndrome and review dermatologic manifestations Asian Pacific Journal of Allergy and Immunology 2009 27 4 233 236 2-s2.0-77953626683 20232578 \n12 Chia J. C. Mydlarski P. R. Dermatologic uses of omalizumab Journal of Dermatological Treatment 2016 28 4 332 337 10.1080/09546634.2016.1249819 27759482 \n13 Bard S. Paravisini A. Avilés-Izquierdo J. A. Fernandez-Cruz E. Sánchez-Ramón S. Eczematous dermatitis in the setting of hyper-IgE syndrome successfully treated with omalizumab JAMA Dermatology 2008 144 12 1662 1663 2-s2.0-58049211757 10.1001/archdermatol.2008.510\n\n",
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"abstract": "Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients' outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP). An observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. In conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.",
"affiliations": "Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy.;Operative Unit of Medical Oncology, IRCCS Fondazione Maugeri, Pavia, Italy.;Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.;Division of Medical Oncology A, National Cancer Institute, Aviano, Italy.;Department of Hematology, DISM, Azienda Sanitaria Universitaria Integrata, Udine, Italy.;Division of Hematology, Department of Molecular Biotechnologies and Scienze for Health, University Torino, Torino, Italy.;Unit of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.;Hematology and Transplantation Unit, Regina Elena National Cancer Institute, Roma, Italy.;Unit of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy.;Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy.;Hematology Service, Medicine Department, Rovigo Hospital, Rovigo, Italy.;Division of Hematology, Niguarda Ca' Granda Hospital, Milano, Italy.;OncoHematology Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy.;Unit of Hematology, Vito Fazzi Hospital, Lecce, Italy.;Hematology Unit, Infermi Hospital Rimini, Rimini, Italy.;IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy.;Unit of Oncology/Hematology, Azienda Ospedaliera \"Pugliese-Ciaccio\", Catanzaro, Italy.;Unit of Hematology, Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia, Italy.;Unit of Hematology, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy.;Institute of Hematology, Università Cattolica del Sacro Cuore, Roma, Italy.;Hemato-Oncology Division, European Institute of Oncology, Milano, Italy.;Unit of Hematology, University-Hospital Città della Salute e della Scienza di Torino, Torino, Italy.;Department of Medical Sciences, Hematology Unit, University of Modena and Reggio Emilia, Modena, Italy.;Unit of Hematology, Ospedale San Gennaro di Napoli, Napoli, Italy.;Unit of Hematology, Ospedale Santa Croce E Carle, Cuneo, Italy.;Ematologia Clinica, Ospedale Maggiore, Trieste, Italy.;Clinica di Ematologia Ospedali Riuniti, Ancona, Italy.;Unit of Hematology, University of Padova, Padova, Italy.;Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy.;Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy.",
"authors": "Broccoli|Alessandro|A|;Casadei|Beatrice|B|;Morigi|Alice|A|;Sottotetti|Federico|F|;Gotti|Manuel|M|;Spina|Michele|M|;Volpetti|Stefano|S|;Ferrero|Simone|S|;Spina|Francesco|F|;Pisani|Francesco|F|;Merli|Michele|M|;Visco|Carlo|C|;Paolini|Rossella|R|;Zilioli|Vittorio Ruggero|VR|;Baldini|Luca|L|;Di Renzo|Nicola|N|;Tosi|Patrizia|P|;Cascavilla|Nicola|N|;Molica|Stefano|S|;Ilariucci|Fiorella|F|;Rigolin|Gian Matteo|GM|;D'Alò|Francesco|F|;Vanazzi|Anna|A|;Santambrogio|Elisa|E|;Marasca|Roberto|R|;Mastrullo|Lucia|L|;Castellino|Claudia|C|;Desabbata|Giovanni|G|;Scortechini|Ilaria|I|;Trentin|Livio|L|;Morello|Lucia|L|;Argnani|Lisa|L|;Zinzani|Pier Luigi|PL|",
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"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 298057462521510.18632/oncotarget.25215Research PaperItalian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma Broccoli Alessandro 1Casadei Beatrice 1Morigi Alice 1Sottotetti Federico 2Gotti Manuel 3Spina Michele 4Volpetti Stefano 5Ferrero Simone 6Spina Francesco 7Pisani Francesco 8Merli Michele 9Visco Carlo 10Paolini Rossella 11Zilioli Vittorio Ruggero 12Baldini Luca 13Di Renzo Nicola 14Tosi Patrizia 15Cascavilla Nicola 16Molica Stefano 17Ilariucci Fiorella 18Rigolin Gian Matteo 19D'Alò Francesco 20Vanazzi Anna 21Santambrogio Elisa 22Marasca Roberto 23Mastrullo Lucia 24Castellino Claudia 25Desabbata Giovanni 26Scortechini Ilaria 27Trentin Livio 28Morello Lucia 29Argnani Lisa 1Zinzani Pier Luigi 11 Institute of Hematology \"L. e A. Seràgnoli\", University of Bologna, Bologna, Italy2 Operative Unit of Medical Oncology, IRCCS Fondazione Maugeri, Pavia, Italy3 Department of Hematology Oncology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy4 Division of Medical Oncology A, National Cancer Institute, Aviano, Italy5 Department of Hematology, DISM, Azienda Sanitaria Universitaria Integrata, Udine, Italy6 Division of Hematology, Department of Molecular Biotechnologies and Scienze for Health, University Torino, Torino, Italy7 Unit of Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy8 Hematology and Transplantation Unit, Regina Elena National Cancer Institute, Roma, Italy9 Unit of Hematology, Ospedale di Circolo, Fondazione Macchi, Varese, Italy10 Department of Cell Therapy and Hematology, San Bortolo Hospital, Vicenza, Italy11 Hematology Service, Medicine Department, Rovigo Hospital, Rovigo, Italy12 Division of Hematology, Niguarda Ca’ Granda Hospital, Milano, Italy13 OncoHematology Unit, Fondazione Ca' Granda IRCCS Ospedale Maggiore Policlinico, Milano, Italy14 Unit of Hematology, Vito Fazzi Hospital, Lecce, Italy15 Hematology Unit, Infermi Hospital Rimini, Rimini, Italy16 IRCCS, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy17 Unit of Oncology/Hematology, Azienda Ospedaliera \"Pugliese-Ciaccio\", Catanzaro, Italy18 Unit of Hematology, Arcispedale Santa Maria Nuova di Reggio Emilia, Reggio Emilia, Italy19 Unit of Hematology, Azienda Ospedaliero-Universitaria di Ferrara, Ferrara, Italy20 Institute of Hematology, Università Cattolica del Sacro Cuore, Roma, Italy21 Hemato-Oncology Division, European Institute of Oncology, Milano, Italy22 Unit of Hematology, University-Hospital Città della Salute e della Scienza di Torino, Torino, Italy23 Department of Medical Sciences, Hematology Unit, University of Modena and Reggio Emilia, Modena, Italy24 Unit of Hematology, Ospedale San Gennaro di Napoli, Napoli, Italy25 Unit of Hematology, Ospedale Santa Croce E Carle, Cuneo, Italy26 Ematologia Clinica, Ospedale Maggiore, Trieste, Italy27 Clinica di Ematologia Ospedali Riuniti, Ancona, Italy28 Unit of Hematology, University of Padova, Padova, Italy29 Humanitas Cancer Center, Istituto Clinico Humanitas, Rozzano, ItalyCorrespondence to:Pier Luigi Zinzani,pierluigi.zinzani@unibo.it4 5 2018 4 5 2018 9 34 23443 23450 30 1 2018 7 4 2018 Copyright: © 2018 Broccoli et al.2018This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Although sometimes presenting as an indolent lymphoma, mantle cell lymphoma (MCL) is an aggressive disease, hardly curable with standard chemo-immunotherapy. Current approaches have greatly improved patients’ outcomes, nevertheless the disease is still characterized by high relapse rates. Before approval by EMA, Italian patients with relapsed/refractory MCL were granted ibrutinib early access through a Named Patient Program (NPP).\n\nAn observational, retrospective, multicenter study was conducted. Seventy-seven heavily pretreated patients were enrolled. At the end of therapy there were 14 complete responses and 14 partial responses, leading to an overall response rate of 36.4%. At 40 months overall survival was 37.8% and progression free survival was 30%; disease free survival was 78.6% at 4 years: 11/14 patients are in continuous complete response with a median of 36 months of follow up. Hematological toxicities were manageable, and main extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%). Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred.\n\nIn conclusions, thrombocytopenia, diarrhea and lung infections are the relevant adverse events to be clinically focused on; regarding effectiveness, ibrutinib is confirmed to be a valid option for refractory/relapsed MCL also in a clinical setting mimicking the real world.\n\nibrutinibmantle cell lymphomarelapsedrefractoryreal life\n==== Body\nINTRODUCTION\nMantle cell lymphoma (MCL) is a rare, clinically aggressive B-cell lymphoma that accounts for 6–8% of all non-Hodgkin lymphoma cases [1]. It is a disease that predominantly affects older men (median age, 65 years), usually presents as late-stage disease and is associated with a poor prognosis [2]. While high response rates are seen with induction chemo-immunotherapy, relapse is almost universal, occurring linearly even beyond 6 years from the end of therapy [3]. Management of relapsed disease is challenging, and treatment decisions are based on patient's and disease characteristics. Following progression, subsequent treatment is often ineffective and survival is short [4].\n\nIbrutinib is an oral inhibitor of B-cell receptor signaling through targeting the Bruton's tyrosine kinase (BTK) which has become the preferred therapy at relapse for a majority of patients. In the landmark phase II international trial reported by Wang et al., 111 patients with relapsed/refractory MCL (rrMCL) were treated with ibrutinib 560 mg daily until disease progression or unacceptable toxicity [5]. An ORR of 68% was achieved including 21% complete responses (CR). With extended follow-up, median progression-free survival (PFS) was 13 months with median overall survival (OS) of 22.5 months [6]. The median duration of response (DoR) was 17.5 months with 31% PFS at 24 months. Patients with refractory rather than relapsed disease at study entry had inferior outcomes with a median OS of 13 months. Ibrutinib was compared with temsirolimus in a phase III trial of 280 patients with rrMCL. Ibrutinib was associated with a greater ORR (72%, P < 0.0001) and CR rate (19%) as well as a significantly longer PFS (14.6 vs. 6.2 months, P < 0.0001) [2]. After ibrutinib approval by FDA and before official approval by EMA, patients with rrMCL with unsatisfied critical medical urgency were granted ibrutinib early access through a Named Patient Program (NPP) by compassionate use in Italy. Herein, we report the Italian multicenter experience with ibrutinib in rrMCL as we believe that data collected outside a controlled trial give useful additional information about the clinical use, effectiveness, and safety profile of the drug when applied in a real life context.\n\nRESULTS\nThirty-three Centers were initially involved, 29 Centers were actually activated. Of the 80 patients expected, 77 were actually enrolled (3.7% difference).\n\nCharacteristics of the 77 patients are summarized in Table 1. Participants had an Eastern Cooperative Oncology Group performance status score ≤2, and normal organ function including peripheral blood counts within the normal range. All patients underwent baseline assessments including physical examination, routine hematology and biochemistry as well as imaging prior to therapy. Patients received ibrutinib at the initial dose of 560 mg daily. First diagnosis of MCL was established between 1995 and 2014. The median age at ibrutinib was 65.2 years (range, 34.6–81.3 years); fifty-nine patients were males and 18 were females. Fourteen (18.2%) had systemic symptoms at baseline; an advanced stage (i.e. stage III or IV) was present in 69 (89.6%) patients.\n\nTable 1 Patient demographics and characteristics at baseline\n\tTotal population\t\nPatients, N\t77\t\nMedian age at diagnosis, years (range)\t65.2 (34.6–81.3)\t\nMedian time from diagnosis-ibrutinib, years (range)\t68.6 (38.5–83.7)\t\nMedian time from last relapse-ibrutinib, days (range)\t37 (10–360)\t\nMales, N (%)\t59 (76.6)\t\nFemales, N (%)\t18 (23.4)\t\nPrevious cardiac problems, N (%)\t2 (2.6)\t\nStage at diagnosis, N (%)\t\t\n- I/II (E*)\t4 (5.2)\t\n- III\t12 (15.6)\t\n- IV\t61 (79.2)\t\nStage at ibrutinib, N (%)\t\t\n- I/II\t8 (10.4)\t\n- III\t14 (18.2)\t\n- IV\t55 (71.4)\t\nBlastoid variant, N (%)\t3 (3.9)\t\nECOG† performance status, N (%)\t\t\n- 0\t37 (48.1)\t\n- 1\t24 (31.2)\t\n- 2\t15 (19.5)\t\n- 3\t1 (1.2)\t\nB symptoms, N (%)\t14 (18.2)\t\nLast therapy before ibrutinib, N (%)\t\t\nRCHOPa\t17 (22.1)\t\nBendamustine\t19 (24.7)\t\nLenalidomide\t20 (26.0)\t\nTemsirolimus\t4 (5.2)\t\nBortezomib\t6 (7.8)\t\nRBACb\t9 (11.7)\t\ntransplant\t2 (2.6)\t\n- Refractory to most recent therapy, N (%)\t17 (22.1)\t\n- Refractory to first line therapy, N (%)\t37 (48.1)\t\nAbbreviations: *E: extranodal; †ECOG: Eastern Cooperative Oncology Group; aRCHOP: rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; bRBAC: rituximab, bendamustine and cytarabine.\n\nThe median number of prior lymphoma-related systemic regimens was 3 (range, 1–10) including high dose chemotherapy and autologous stem cell transplantation (ASCT) in 27 (35%) patients. Twenty-one (27.3%) had already received bortezomib, 8 (10.4%) temsirolimus, and 25 (32.5%) lenalidomide. Thirty-seven (48.1%) patients had a disease that was refractory to frontline therapy (primary refractory patients) and 17 patients (22.1%) had a disease that was refractory to last therapy before ibrutinib.\n\nResponse\nAll the patients received ibrutinib for a median of 6 cycles (range, 1–20). Among the 77 patients, 14 (18.2%) achieved CR and 14 (18.2%) obtained a PR with an ORR of 36.4%; among the remaining patients, 8 (10.4%) had stable disease (SD) and 41 (53.3%) showed progression of disease (PD), respectively.\n\nAmong the 37 primary refractory patients, 3 (8.1%) achieved CR and 2 (5.4%) had a PR yielding an ORR of 13.5%; in the subset of the 17 patients who were refractory to the last line we observed 4 (23.5%) CR and 3 (17.6%) PR, with an ORR of 50.1%. The difference in ORR between these two subsets of patients is statistically significant (p < 0.05). No differences in outcome were observed between patients refractory to and patients relapsed after last therapy before ibrutinib. The number of previous therapies does not affect patients’ responses and outcomes.\n\nGlobally, at a median follow up of 38 months, OS was 37.8% at 40 months (Figure 1) with a median of 16 months. PFS at 40 months was 30% and the median was reached at 12.9 months (Figure 2). Disease free survival (DFS) was 78.6% at 48 months (Figure 3) since 3 (21.4%) out of 14 CR patients relapsed while 11 patients were in continuous CR (CCR) at the latest follow up, with a median DoR of 36 months; among these patients, three received a transplant consolidation (1 with ASCT and 2 with allogeneic transplant [alloSCT]). The DoR was 79.2% at 40 months (Figure 4).\n\nFigure 1 Overall survival\nFigure 2 Progression free survival\nFigure 3 Disease free survival\nFigure 4 Duration of response\nGlobally, 37 patients underwent further treatments after ibrutinib; among them, 32 patients received subsequent chemotherapy or chemoimmunotherapy, including 5 patients who received lenalidomide, one temsirolimus, one bortezomib; 7 were rechangelled with ibrutinib. The remaining 5 patients received ibrutinib as bridge to transplant. In particular: 1 PR patient remained in PR after alloSCT; 1 PR converted to a CR with alloSCT; 2 patients in CR consolidated their response with alloSCT and ASCT respectively; 1 patient in CR rapidly developed an acute myeloid leukemia (AML) after alloSCT. Seven patients were rechallenged with ibrutinib: 2 achieved a CR, while the other 5 acquired resistance to drug.\n\nSafety\nBesides PD, reasons for early discontinuations (N = 19) were: transplant procedure (N = 3), 1 lung cancer, 1 AML, 1 death due to unknown cause, and adverse event (AE) (N = 13). AEs in detail were: 2 diarrhea, 1 atrial fibrillation, 2 infections, 1 herpes zoster, 2 hemorrhages, 5 leukocytosis/lymphocytosis. The patient with atrial fibrillation did not interrupt ibrutinib at the onset of arrhythmia: he started enoxaparin but the treatment was complicated with an hemorrhagic syndrome (grade 2) leading to permanent interruption of ibrutinib. Six patients interrupted ibrutinib due to hematological toxicities and only one restarted at a lower dose.\n\nFifteen patients developed hematological toxicities other than lymphocytosis: thrombocytopenia in 11 cases (2 grade 4 and 1 grade 3, related to bone marrow infiltration, while the other 8 were judged related to ibrutinib); 2 cases of neutropenia, 1 AML, 1 cytopenia (all grade 4 and judged unrelated to ibrutinib). Lymphocytosis was present in 14 patients at baseline. Ten out of 14 cases of lymphocytosis persisted until the end of the treatment. On the other hand, 13 (16.9%) subjects developed lymphocytosis during therapy, and it then persisted until the end of treatment. The 80% of hematological toxicities occurred in the first 3 months of therapy.\n\nMain extra-hematological toxicities were diarrhea (9.4%) and lung infections (9.0%) which all lead to early drug discontinuation. Overall, 4 (5.2%) atrial fibrillations and 3 (3.9%) hemorrhagic syndromes occurred. The 88% of extra-hematological toxicities occurred in the first 3 months of therapy.\n\nDISCUSSION\nOutcomes are poor for patients with MCL who relapse after initial therapy. There are currently five agents licensed for the treatment of rrMCL: bortezomib (only in USA), temsirolimus (only in Europe), lenalidomide, acalabrutinib (since October 2017, only in USA) and ibrutinib. Nevertheless, there is no standard of care at present in this setting and a definitive MCL treatment algorithm is yet be established [7]. Ibrutinib seems to be one of the more active single agent in refractory/relapsed disease also in the real life setting, but direct comparisons between the four drugs have been never performed in either clinical trials or retrspectice experiences [5, 8].\n\nIn our multicenter retrospective study, we evaluated rrMCL patients who were treated with single agent ibrutinib in everyday clinical practice; the most part of the 77 patients were heavily pretreated and at least 50% were primary refractory. Our analysis reported a CR rate of 18.2% that was similar to those observed in clinical trials investigating similar MCL populations treated with ibrutinib as single agent; on the contrary, the ORR rate observed was only 36.4%, rather inferior if compared with data already published [5, 8]. One cause may be the wrong interpretation of lymphocytosis. Approximately a third of patients with MCL develops lymphocytosis during ibrutinib therapy which typically peaks 4 weeks after initiation before slowly declining over subsequent cycles. This transient lymphocytosis does not reflect resistance or disease progression and can be regarded as part of a response to treatment in the context of diminishing tissue bulk elsewhere [9]. In the present work, 14 patients at baseline presented with lymphocytosis and 10 had persistent lymphocytosis until the end of treatment. Seventeen percent developed lymphocytosis during treatment with ibrutinib and it was present at end of treatment too. Physicians wrongly considered lymphocytosis as progression of disease and stopped the treatment. Isolated lymphocytosis should not lead to a diagnosis of disease progression in ibrutinib-treated subjects as lymphocytosis is not to be considered an AE per se but reflects the pharmacodynamics of the drug [9].\n\nRegarding survivals functions, our real life data compared with the pooled data from clinical studies, show similar median PFS (12.9 vs 12.8 months, respectively) while the median OS appears inferior in our series (16.0 vs 25.0 months) [2, 5, 10, 11]. On the contrary, our median DoR was not reached in comparison with 18.6 months of the pooled data report. Of note, 11 (14.2%) patients are in still CR with a median DoR of 36 months at the latest available follow up.\n\nFailure after ibrutinib is an urgent medical need: multiple studies have shown that MCL patients demonstrate a poor outcome in this case [12, 13]. In our report, patients who failed ibrutinib therapy underwent further treatment: 5 out of the 7 patients who underwent ibrutinib rechallenge acquired resistance. This is a common issue which may presumably be solved at least partially with combination or right sequencing therapy [13, 14]. Lenalidomide could be an effective opportunity even if in our study the patients (only five) who underwent lenalidomide after ibrutinib failed to achieve response [15, 16]. On the other hand, patients who consolidated response with SCT had better outcomes.\n\nIt is confirmed that ibrutinib has a favorable safety profile, with mild and generally transient side effects. In clinical trial and real life experience, atrial fibrillation (5–8%) and bleeding (3–5%) have emerged as the most challenging safety issues and physicians are inclined to suspend the drug in some instances so as not to make mistakes in the management of these AEs. As a result, patients stop benefiting from a life-saving drug. Recently, practical guidelines for the management of ibrutinib in the real life have been published, focusing on atrial fibrillation and bleeding: this helps physicians to better manage these particular situations allowing responder patients to continue therapy with ibrutinib [17].\n\nTo note that the modest side effect profile of ibrutinib candidates this drug to potential combination therapies.\n\nDespite the known potential bias of all observational studies, the present report on the real life experience provides an important contribution to medical knowledge: we have learnt in fact that ibrutinib treatment is effective and well tolerated also in everyday clinical practice. Long-term outcomes and new structured clinical trials are awaited.\n\nPATIENTS AND METHODS\nAn observational, non-interventional, multicenter, retrospective observational study was conducted to assess effectiveness of ibrutinib and to analyze outcomes and toxicity data of patients managed in a non-trial setting. The study was approved by our institutional board (Azienda Ospedaliera-Universitaria di Bologna, Policlinico S.Orsola-Malpighi, coordinating Center) and by all involved Ethical Committees and registered in the Italian Registry of Observational Studies. All participants gave written informed consent in accordance with the Declaration of Helsinki.\n\nA shared database was used after the approval of all the authors and variables were strictly defined to avoid bias in reporting data. From July 2014 to January 2015, a total of 29 Italian centers utilized ibrutinib according to the NPP in 77 patients with rrMCL. Centers were consecutively involved to avoid selection bias. Data were collected by local investigators but were monitored and centrally reviewed.\n\nThe primary endpoints of the study were the ORR and the CR rate; secondary endpoints were the OS, PFS, disease-free survival (DFS), DoR, and the incidence, severity, and type of any AE occurring during and near after treatment.\n\nResponse was assessed by imaging using the International Working Group revised response criteria for malignant lymphoma [18].\n\nSafety and tolerability were evaluated by classifying AEs according to NCI CTCAE version 4.0. OS was defined as the time from initiation of therapy to death from any cause and was censored at the date of last available follow up. PFS was measured from initiation of therapy to progression, relapse, or death from any cause and was censored at the date of last available follow up. DFS was calculated for CR patients from the first documentation of response to the date of relapse or death due to lymphoma or acute toxicity of treatment. DoR was calculated from the first objective tumor response (CR or PR) to first documentation of progression or death [18].\n\nDemographics and patients’ characteristics were summarized by descriptive statistics.\n\nSurvival functions were estimated by using the Kaplan–Meier method and were compared using log-rank test.\n\nStatistical analyses were performed with Stata 11 (StataCorp LP, TX) and p values were set at 0.05.\n\nAuthor contributions\n\nConception and design: A. Broccoli, L. Argnani, P.L. Zinzani Acquisition of data: All authors Statistical analysis: L. Argnani Data interpretation: All authors Writing of the manuscript: A. Broccoli, L. Argnani, P.L. Zinzani Administrative, technical, or material support: L. Argnani, P.L. Zinzani Study supervision: L. Argnani, P.L. Zinzani. Review and/or revision of the manuscript: All authors.\n\nThe authors thank JANSSEN-CILAG spa for unconditional support.\n\nCONFLICTS OF INTEREST\n\nNo potential conflicts of interest were disclosed.\n\nFUNDING\n\nJANSSEN-CILAG spa provided unconditional support (IIS 54179060LYM3002).\n\nAbbreviations\nAEadverse event\n\nalloSCTallogeneic stem cell transplant\n\nAMLacute myeloid leukemia\n\nASCTautologous stem cell transplant\n\nBTKBruton's tyrosine kinase\n\nCCRcontinuous complete response\n\nCRcomplete response\n\nDFSdisease free survival\n\nDoRduration of response\n\nECOGEastern Cooperative Oncology Group\n\nMCLmantle cell lymphoma\n\nNPPnamed patient program\n\nORRobjective response rate\n\nOSoverall survival\n\nPDprogression of disease\n\nPRpartial response\n\nPFSprogression free survival\n\nrrrelapsed/refractory\n\nSDstable disease\n==== Refs\nREFERENCES\n1 Dreyling M Geisler C Hermine O Kluin-Nelemans HC Le Gouill S Rule S Shpilberg O Walewski J Ladetto M ESMO Guidelines Working Group Newly diagnosed and relapsed mantle cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2014 25 iii83 92 https://doi.org/10.1093/annonc/mdu264 25210087 \n2 Dreyling M Jurczak W Jerkeman M Silva RS Rusconi C Trneny M Offner F Caballero D Joao C Witzens-Harig M Hess G Bence-Bruckler I Cho SG Ibrutinib versus temsirolimus in patients with relapsed or refractory mantle-cell lymphoma: an international, randomised, open-label, phase 3 study Lancet 2016 387 770 8 https://doi.org/10.1016/S0140-6736(15)00667-4 26673811 \n3 Geisler CH Kolstad A Laurell A Jerkeman M Räty R Andersen NS Pedersen LB Eriksson M Nordström M Kimby E Bentzen H Kuittinen O Lauritzsen GF Nordic MCL2 trial update: six-year follow-up after intensive immunochemotherapy for untreated mantle cell lymphoma followed by BEAM or BEAC + autologous stem-cell support: still very long survival but late relapses do occur Br J Haematol 2012 158 355 62 https://doi.org/10.1111/j.1365-2141.2012.09174.x 22640180 \n4 Herrmann A Hoster E Zwingers T Brittinger G Engelhard M Meusers P Reiser M Forstpointner R Metzner B Peter N Wörmann B Trümper L Pfreundschuh M Improvement of overall survival in advanced stage mantle cell lymphoma J Clin Oncol 2009 27 511 8 https://doi.org/10.1200/JCO.2008.16.8435 19075279 \n5 Wang ML Rule S Martin P Goy A Auer R Kahl BS Jurczak W Advani RH Romaguera JE Williams ME Barrientos JC Chmielowska E Radford J Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma N Engl J Med 2013 369 507 16 https://doi.org/10.1056/NEJMoa1306220 23782157 \n6 Wang ML Blum KA Martin P Goy A Auer R Kahl BS Jurczak W Advani RH Romaguera JE Williams ME Barrientos JC Chmielowska E Radford J Long-term follow-up of MCL patients treated with single-agent ibrutinib: updated safety and efficacy results Blood 2015 126 739 45 https://doi.org/10.1182/blood-2015-03-635326 26059948 \n7 Cheah CY Seymour JF Wang ML Mantle Cell Lymphoma J Clin Oncol 2016 34 1256 69 https://doi.org/10.1200/JCO.2015.63.5904 26755518 \n8 Epperla N Hamadani M Cashen AF Ahn KW Oak E Kanate AS Calzada O Cohen JB Farmer L Ghosh N Tallarico M Nabhan C Costa LJ Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma-a “real world” study Hematol Oncol 2017 35 528 35 https://doi.org/10.1002/hon.2380 28066928 \n9 Woyach JA Smucker K Smith LL Lozanski A Zhong Y Ruppert AS Lucas D Williams K Zhao W Rassenti L Ghia E Kipps TJ Mantel R Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy Blood 2014 123 1810 7 https://doi.org/10.1182/blood-2013-09-527853 24415539 \n10 Rule S Dreyling M Goy A Hess G Auer R Kahl B Cavazos N Liu B Yang S Clow F Goldberg JD Beaupre D Vermeulen J Outcomes in 370 patients with mantle cell lymphoma treated with ibrutinib: a pooled analysis from three open-label studies Br J Haematol 2017 179 430 8 https://doi.org/10.1111/bjh.14870 28832957 \n11 Wang M Goy A Martin P Ramchandren R Alexeeva J Popat R Avivi I Advani R Le Gouill S Horowitz N Yuan Z Kranenburg B Rizo A Efficacy and safety of single-agent ibrutinib in patients with mantle cell lymphoma who progressed after bortezomib therapy Blood 2014 124 Abstract 4471 (ASH proceedings) \n12 Cheah CY Chihara D Romaguera JE Fowler NH Seymour JF Hagemeister FB Champlin RE Wang ML Patients with mantle cell lymphoma failing ibrutinib are unlikely to respond to salvage chemotherapy and have poor outcomes Ann Oncol 2015 26 1175 9 https://doi.org/10.1093/annonc/mdv111 25712454 \n13 Martin P Maddocks K Leonard JP Ruan J Goy A Wagner-Johnston N Rule S Advani R Iberri D Phillips T Spurgeon S Kozin E Noto K Postibrutinib outcomes in patients with mantle cell lymphoma Blood 2016 127 1559 63 https://doi.org/10.1182/blood-2015-10-673145 26764355 \n14 Zhao X Lwin T Silva A Shah B Tao J Fang B Zhang L Fu K Bi C Li J Jiang H Meads MB Jacobson T Unification of de novo and acquired ibrutinib resistance in mantle cell lymphoma Nat Commun 2017 8 14920 https://doi.org/10.1038/ncomms14920 28416797 \n15 Wang M Schuster SJ Phillips T Lossos IS Goy A Rule S Hamadani M Ghosh N Reeder CB Barnett E Bravo MC Martin P Observational study of lenalidomide in patients with mantle cell lymphoma who relapsed/progressed after or were refractory/intolerant to ibrutinib (MCL-004) J Hematol Oncol 2017 10 171 https://doi.org/10.1186/s13045-017-0537-5 29096668 \n16 Stefoni V Pellegrini C Gandolfi L Baldini L Tani M Cencini E Figuera A Ansuinelli M Bernocco E Cantonetti M Cox MC Ballerini F Rusconi C Lenalidomide in Pretreated Mantle Cell Lymphoma Patients: An Italian Observational Multicenter Retrospective Study in Daily Clinical Practice, the Lenamant Study Blood 2015 126 Abstract 3946. (ASH proceedings) \n17 Boriani G Corradini P Cuneo A Falanga A Foà R Gaidano G Ghia P Martelli M Marasca R Massaia M Mauro F Minotti G Molica S Practical management of ibrutinib in the real life: focus on atrial fibrillation and bleeding Hematol Oncol 2018 3 7 https://doi.org/10.1002/hon.2503 [Epub ahead of print] \n18 Cheson BD Pfistner B Juweid ME Gascoyne RD Specht L Horning SJ Coiffier B Fisher RI Hagenbeek A Zucca E Rosen ST Stroobants S Lister TA Revised response criteria for malignant lymphoma J Clin Oncol 2007 25 579 86 https://doi.org/10.1200/JCO.2006.09.2403 17242396\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "9(34)",
"journal": "Oncotarget",
"keywords": "ibrutinib; mantle cell lymphoma; real life; refractory; relapsed",
"medline_ta": "Oncotarget",
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"nlm_unique_id": "101532965",
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"pages": "23443-23450",
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"pmid": "29805746",
"pubdate": "2018-05-04",
"publication_types": "D016428:Journal Article",
"references": "24415539;23782157;17242396;28416797;26059948;29674440;22640180;29512173;25712454;26764355;28832957;26755518;29096668;25210087;26673811;28066928;19075279",
"title": "Italian real life experience with ibrutinib: results of a large observational study on 77 relapsed/refractory mantle cell lymphoma.",
"title_normalized": "italian real life experience with ibrutinib results of a large observational study on 77 relapsed refractory mantle cell lymphoma"
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"abstract": "We present two cases demonstrating safe and effective use of intramuscular clozapine for patients who are physically unwell in acute medical care settings. Both patients described were admitted to inpatient medical care units and required treatment with clozapine to control their psychotic symptoms, but were unable or unwilling to take oral clozapine. We describe the use of intramuscular clozapine in these patients, including dosing decisions, administration routes and frequency of dosing. Outcome was measured by a reduction in psychotic symptoms, sufficient to allow treatment for physical illness. Both patients successfully received intramuscular clozapine, allowing timely treatment of their physical health conditions. There were no adverse events, and significant improvement in their mental health presentations was achieved. We have shown that intramuscular clozapine is a safe and effective treatment for patients with serious mental health illness in the acute medical hospital.",
"affiliations": "Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK.;Department of Psychological Medicine, King's College Hospital, London, UK.;Department of Psychological Medicine, King's College Hospital, London, UK.;Department of Psychological Medicine, King's College Hospital, London, UK.;Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK.",
"authors": "Gee|Siobhan|S|https://orcid.org/0000-0003-1020-6777;McMullen|Isabel|I|;Wyke|Clementine|C|;Yeoh|Su Ying|SY|;Taylor|David|D|",
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"doi": "10.1177/2050313X211004796",
"fulltext": "\n==== Front\nSAGE Open Med Case Rep\nSAGE Open Med Case Rep\nSCO\nspsco\nSAGE Open Medical Case Reports\n2050-313X\nSAGE Publications Sage UK: London, England\n\n10.1177/2050313X211004796\n10.1177_2050313X211004796\nCase Report\nIntramuscular clozapine in the acute medical hospital: Experiences from a liaison psychiatry team\nhttps://orcid.org/0000-0003-1020-6777\nGee Siobhan 12\nMcMullen Isabel 3\nWyke Clementine 3\nYeoh Su Ying 3\nTaylor David 12\n1 Pharmacy Department, South London and Maudsley NHS Foundation Trust, London, UK\n2 Institute of Pharmaceutical Sciences, King’s College London, London, UK\n3 Department of Psychological Medicine, King’s College Hospital, London, UK\nSiobhan Gee, Pharmacy Department, South London and Maudsley NHS Foundation Trust, Denmark Hill, London SE5 8AZ, UK. Email: Siobhan.gee@slam.nhs.uk\n20 5 2021\n2021\n9 2050313X2110047962 3 2021\n3 3 2021\n© The Author(s) 2021\n2021\nSAGE Publications\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).\nWe present two cases demonstrating safe and effective use of intramuscular clozapine for patients who are physically unwell in acute medical care settings. Both patients described were admitted to inpatient medical care units and required treatment with clozapine to control their psychotic symptoms, but were unable or unwilling to take oral clozapine. We describe the use of intramuscular clozapine in these patients, including dosing decisions, administration routes and frequency of dosing. Outcome was measured by a reduction in psychotic symptoms, sufficient to allow treatment for physical illness. Both patients successfully received intramuscular clozapine, allowing timely treatment of their physical health conditions. There were no adverse events, and significant improvement in their mental health presentations was achieved. We have shown that intramuscular clozapine is a safe and effective treatment for patients with serious mental health illness in the acute medical hospital.\n\nClozapine\nintramuscular\nschizophrenia\nliaison psychiatry\nantipsychotic\ncover-dateJanuary-December 2021\ntypesetterts1\n==== Body\nStrengths and limitations\n\nWe describe real-world cases of complex pharmacology and clinical comorbidities.\n\nUse of intramuscular clozapine outside mental health settings and in medically unwell patients has not been previously reported.\n\nThe limitations of extrapolating outcomes from individual case reports and applying experience to other patients should be considered.\n\nIntroduction\n\nClozapine is an antipsychotic used where all else has failed. Therefore, it cannot be replaced by another antipsychotic. “Can’t you just switch it to something else?” is the sometimes exasperated plea from general medical colleagues trying to treat acute physical illness in someone receiving clozapine. The answer is frequently “no,” but the challenges in continuing a drug with multiple pharmacodynamic actions and interactions in patients with rapidly changing physical health states are many and complex. Furthermore, until recently, the availability of clozapine solely as an oral treatment limited continued use to patients who were able or willing to comply with oral therapy. The availability of intramuscular clozapine in Western Europe has changed this. Here, we discuss with illustrative cases some of the benefits and some of the practical and ethical difficulties pertaining to the use of intramuscular clozapine in the acute hospital setting.\n\nClozapine is available in the United Kingdom in three licensed forms: tablets, orodispersible tablets and solution. For decades, the only treatment option for patients who refused or were unable to comply with oral therapy was to abandon clozapine entirely. Forced administration of clozapine suspension via nasogastric (NG) tubes has been described1,2 but is seldom used outside highly secured forensic settings and has considerable practical drawbacks (not least the need to restrain patients in order to site an NG tube, potentially daily). In the last 3 years, intramuscular clozapine has been available in the United Kingdom as an unlicensed product, imported from the Netherlands. While experience is increasing,3,4 its use is (to the best of our knowledge) entirely restricted to inpatient mental health settings.\n\nNon-adherence to treatment is common in all medical specialties, but patients with psychotic disorders pose particular challenges.5 Psychotic symptoms may prevent patients from complying with treatment and monitoring of physical health conditions. Treating the psychotic symptoms may allow the patient to regain capacity to be able to make a decision concerning their physical health treatment. In the United Kingdom, decisions regarding the treatment of physical illness can be made by the treating team in the patient’s best interests if the patient is deemed to lack the capacity to make such decisions, allowing treatment against their will if necessary. However, the practicalities of performing investigations (including blood tests or diagnostic scans) or administering treatments to patients who are able to actively resist mean that doing so may only be a theoretical option, as overall the risks mean that it would not be viewed as being in their best interests. For patients with illnesses that respond to non-clozapine antipsychotics, drug treatment can usually be administered without the patient’s consent via intramuscular routes (as short-acting intramuscular or long-acting injection where response has been demonstrated to oral or short-acting intramuscular formulations).\n\nFor patients with treatment-resistant psychosis, the possibility of a parenteral non-clozapine antipsychotic gaining sufficient control of their psychosis to allow treatment of their physical health is vanishingly small: patients with “treatment-resistant” schizophrenia, defined as non-response to two different antipsychotics, have perhaps a maximal 7% chance of their psychotic symptoms responding to a non-clozapine antipsychotic.6,7 The seminal study of clozapine in treatment-resistant schizophrenia8 suggested only 4% of patients responded to a non-clozapine antipsychotic. The superiority of clozapine over other antipsychotics in treatment-resistant schizophrenia has been repeatedly demonstrated in multiple meta-analyses since these trials.9,10 Violence and agitation that can accompany untreated psychosis are difficult to manage in acute hospital settings, putting patients and staff at risk, as well as precluding medical treatment. Sedation of patients may be the only option available to maintain safety and allow any form of treatment, but this is not sustainable or desirable. With the arrival of intramuscular clozapine, treatment options for these patients are widened.\n\nIntramuscular clozapine has no UK license. It is made by Broacef (Netherlands) and imported to the United Kingdom by Durbin PLC. The strength of the injection is 25 mg/mL, and each ampoule contains 5 mL (125 mg). It is administered by deep intramuscular injection, usually into the gluteal muscle, and may be painful. The maximum volume that can be injected into any site is 4 mL (100 mg); doses greater than this must be split over different injection sites.3 Oral bioavailability of clozapine is fairly low, with the lowest estimate being 27%11 and the highest being 47%.12 Usual practice is to halve the oral dose and give the intramuscular injection once daily.3,4 All mandated blood monitoring and precautions taken with oral clozapine also apply to the intramuscular preparation. Patients must be registered with a clozapine monitoring company for this purpose.\n\nOur first case describes a patient for whom the cessation of clozapine resulted in florid psychosis, precluding investigations or treatment of her serious physical illness. Refusal to comply with oral clozapine meant that her physical condition would have gone undiagnosed were it not for rapid control of her psychosis using the intramuscular preparation. Our second case describes a patient for whom access to intramuscular clozapine meant effective control of his treatment-resistant illness during a period of lack of oral access, where untreated psychosis risked significant harm to himself and others.\n\nCase study 1\n\nMs A was a 50-year-old Black British woman with a long history of schizoaffective disorder, managed in the community on clozapine. She had a significant forensic history, but had been relatively well controlled on clozapine (although chronic delusions that she was married to Jehovah persisted).\n\nMs A presented to the emergency department with abdominal pain and nausea. She was found to have liver abscesses and was treated for a resultant sepsis, but intermittently refused intravenous antibiotics as she had delusional beliefs that the abdominal pain and nausea were signs that she was pregnant with Jehovah’s child. Further radiological investigations raised the possibility that the lesions on her liver represented metastases from a distant site instead of abscesses. The definitive investigation was a liver biopsy, but Ms A refused, stating that it would harm her unborn child. Notably, she refused to take clozapine on admission (having also been non-compliant for 48 h prior to this), resulting in deterioration in mental state.\n\nMs A became verbally aggressive, paranoid and disinhibited on the ward. She was detained under mental health legislation, but continued to refuse oral clozapine, and her floridly psychotic mental state worsened. No further investigations could be performed without physical restraint and chemical sedation. She refused all oral medication, including those for her physical health. Her inflammatory markers and liver function tests worsened, reflecting an overall deterioration in her physical health.\n\nReview of her medication history showed a clear lack of response to any other antipsychotic, so Ms A was re-titrated on clozapine via the intramuscular route. Titration was completed over a week, to a dose of 150 mg intramuscularly (split in two doses of 75 mg into each injection site). Neutrophil and white cell counts remained within normal ranges (or high, due to infection) throughout the admission. Due to morbid obesity, the clozapine was given in her deltoid muscle under restraint. Ms A’s usual dose of oral clozapine was 300 mg; she was administered 150 mg intramuscularly once daily. Consideration was made to split the dose into twice-daily administration due to the relatively large (3 mL) injection volume required per site, but the risk to the patient and staff of multiple restraint episodes was felt to be high. She tolerated the relatively large (3 mL) injection volume with no reported problems, and no other clozapine-induced side effects (including blood dyscrasias) were noted.\n\nAfter a few days of receiving her usual dose of clozapine, there was a marked improvement in her mental state; her paranoia, hostility and aggression gradually resolved, and she became more amenable to taking clozapine orally. Crucially, she also started complying with medical investigations which regrettably revealed an untreatable liver carcinoma.\n\nThe use of intramuscular clozapine, via a novel route (deltoid), on an inpatient ward in an acute hospital allowed investigation and treatment of a serious physical illness, as well as control of severe psychotic symptoms. The urgency of proceeding with medical investigations when malignancy was raised as a differential, coupled with the significant risks Ms A posed to herself and others while psychotic, made it a priority to stabilize her mental state rapidly. The use of intramuscular clozapine in this case enabled Ms A to recover quickly from her psychotic relapse. Although her cancer was ultimately sadly untreatable, her final weeks were spent in a calm, dignified and unrestricted way with her family.\n\nCase study 2\n\nMr B was a 47-year-old White British gentleman with a long-standing history of schizophrenia. He was initially brought to the emergency department by the police, having been found unresponsive in the street. He had stopped treatment with clozapine a number of months prior, and re-titration was commenced on the acute hospital ward. At this time, Mr B was compliant with oral therapy, but before therapeutic plasma levels could be reached, and despite antipsychotic “cover” with olanzapine during clozapine dose titration, he had assaulted several members of staff and was urgently transferred to psychiatric intensive care.\n\nWhen on the mental health ward, he refused oral antipsychotic treatment and was given intramuscular short-acting and then long-acting zuclopenthixol instead. He remained psychotic and 3 months later jumped from a third floor window in an attempt to abscond, sustaining significant injuries. He was transferred back to the medical hospital and titration on oral clozapine via NG tube was initiated while he was intubated in the intensive care unit. A dose of 300 mg daily with a plasma concentration of 0.21 mg/L was achieved. Mr B was stepped down to management on a surgical ward and clozapine treatment continued via NG tube. After a few days of stability on 300 mg of oral clozapine, Mr B removed his NG tube. He refused to allow the tube to be replaced, resisting any attempts to do so and attempting to assault staff members. Owing to extensive spinal fractures, Mr B’s swallowing was dangerously impaired with a high risk of aspiration. Oral drug treatment was therefore unsafe and repeated NG tube insertion also risky.\n\nGiven the significant risks posed to himself and others by Mr B when treated with non-clozapine antipsychotics, urgent arrangements were made to switch his oral clozapine prescription to the intramuscular preparation. Swift communication between medical and psychiatric teams allowed conversion of his 300 mg oral clozapine to 150 mg intramuscular clozapine within 24 h, avoiding any need for re-titration of the dose. There followed a rapid improvement in mental state, and Mr B started to comply with medical treatments and physiotherapy. He later regained his swallowing reflex and agreed to comply with oral clozapine, and was discharged back to the care of mental health services a month later. Neutrophil and white cell counts remained within normal ranges throughout treatment and no other clozapine-related side effects were reported.\n\nThe rapid availability of intramuscular clozapine allowed effective treatment of Mr B, averting likely mental health crisis in someone known to be violent and aggressive when unwell, and inevitable medical sequelae.\n\nDiscussion\n\nThe cases presented here demonstrate the safe and effective use of intramuscular clozapine in patients who are medically unwell, being treated in non-mental health settings. Little is published describing the use of intramuscular clozapine, and where data exist, they exclusively refer to patients in psychiatric settings.3,4\n\nThere are clearly legal considerations when administering any antipsychotic intramuscularly. If the patient has capacity to agree to intramuscular administration and is agreeable to this route, then it can be given with the patient’s consent. However, if a patient either lacks capacity to agree to its administration or refuses to agree, in the United Kingdom detention under the mental health legislation is required to give this treatment.\n\nThere are also ethical considerations when giving clozapine to medically unwell patients. First, it is a drug with multiple side effects which, although rare, are potentially fatal (e.g. neutropenia, myocarditis and constipation).13 Second, it interacts with many other drugs.13 Both of these factors may worsen an acute or chronic physical health problem. For example, in the case of a patient with chest pain where acute coronary syndrome is suspected, it is often felt safer to stop clozapine. However, if this results in relapse of psychotic illness, and associated non-compliance with medical investigations and treatment, it may be the least worst option to continue, with close monitoring of cardiac function.\n\nThe importance of the multi-disciplinary team and the involvement of the patient, and their family members or carers, are critical here. Making the decision to treat with clozapine, especially intramuscularly in medically unwell patients who lack capacity to consent, is not one to undertake lightly. It should be taken as part of a structured “best interests” process, where the advantages and disadvantages of various options are discussed, and with the patient if possible, or with their family or advocate.14 Patients’ families and advocates need to be informed of the risks if this option is pursued, especially as intramuscular clozapine is an unlicensed product (see below).14 There will need to be close working between the medical and liaison psychiatry teams to ensure that the patient’s physical health is monitored closely during the titration, and that clozapine plasma concentrations are checked appropriately. If the patient deteriorates physically, it may be necessary to stop or pause the clozapine titration.\n\nIntramuscular clozapine is an unlicensed product. Administration of clozapine to patients in the United Kingdom requires registration of the patient, prescriber and pharmacy with one of three clozapine monitoring companies, ensuring regular monitoring of the full blood count (this is not mandated in many other countries).15 An agreement must be reached with the relevant company (usually the company with an existing relationship with the hospital or the one with which the patient is already registered) to accept the patient on to their treatment register, despite not receiving treatment with their licensed clozapine preparation. As with all unlicensed medicines, every effort should be made to outline the reasons for the use of the unlicensed preparation to patients and/or their next of kin. Reasoning around the choice of treatment should be clearly documented.14\n\nGiven the unlicensed status of intramuscular clozapine and the paucity of experience and published data regarding its use (especially in acute medical settings), we suggest that responsibility for prescribing, monitoring and follow-up should lie with the liaison psychiatry team. It will be a local decision whether the drug should be supplied by the acute medical hospital or the affiliated mental health hospital; in either case, close relationships with prescribers and pharmacists with expertise in clozapine use are strongly encouraged.\n\nConclusion\n\nIntramuscular clozapine remains a novel and unusual treatment in mental health settings; to our knowledge, it is unheard of in acute medical hospitals. It is, however, a uniquely valuable formulation. It offers an alternative to partial or complete sedation in intensive care settings in order to provide essential medical treatment where treatment-resistant psychosis cannot be controlled with other parenteral antipsychotics. It allows therapeutically effective “bridging” for periods when oral access is temporarily lost, where the alternative is treatment with antipsychotics known to be ineffective. The cases we present here show the potential for it to allow safe and timely treatment of medical conditions for patients where the alternative would be anesthesia, delayed access to treatment or investigations, or denial of treatment entirely. Instead, use of intramuscular clozapine allowed dignified, effective treatment for patients with serious mental illness in the acute hospital.\n\nAuthors’ contributions: S.G. conceived and designed the article and drafted the manuscript. I.McM., C.W. and S.Y. wrote the case reports and legal and ethical discussion. D.T. revised and drafted the manuscript.\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\nEthics approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n\nInformed consent: Written informed consent was obtained from the patient(s) for their anonymized information to be published in this article.\n\nPatient and public involvement: This is not a clinical trial, but a case series. There was no study design, recruitment or randomized intervention. Written consent for publication was provided.\n\nORCID iD: Siobhan Gee https://orcid.org/0000-0003-1020-6777\n==== Refs\nReferences\n\n1 Till A Silva E . A case report of the successful administration of clozapine in the face of myocardial infarction, pulmonary embolism and hyperlipidaemia resulting in the termination of long-term seclusion. BMC Psychiatry 2019; 19 (1 ): 37, http://www.embase.com/search/results?subaction=viewrecord&from=export&id=L626048889\n2 Till A Selwood J Silva E . The assertive approach to clozapine: nasogastric administration. BJPsych Bull 2019; 43 (1 ): 21–26, https://pubmed.ncbi.nlm.nih.gov/30223913 30223913\n3 Henry R Massey R Morgan K , et al . Evaluation of the effectiveness and acceptability of intramuscular clozapine injection: illustrative case series. BJPsych Bull 2020; 44 : 239–243.32081110\n4 Casetta C Oloyede E Whiskey E , et al . A retrospective study of intramuscular clozapine prescription for treatment initiation and maintenance in treatment-resistant psychosis. Br J Psychiatry 2020; 217 (3 ): 506–513.32605667\n5 Kane JM Kishimoto T Correll CU . Non-adherence to medication in patients with psychotic disorders: epidemiology, contributing factors and management strategies. World Psychiatry 2013; 12 (3 ): 216–226.24096780\n6 Kinon BJ Kane JM Perovich R , et al . Influence of neuroleptic dose and class in treatment-resistant schizophrenia relapse. In: 32nd annual meeting of the new clinical drug evaluation unit, Key Biscayne, FL, 26–29 5 1992.\n7 Kinon BJ Kane JM Johns C , et al . Treatment of neuroleptic-resistant schizophrenic relapse. Psychopharmacol Bull 1993; 29 (2 ): 309–314.7904762\n8 Kane J Honigfeld G Singer J , et al . Clozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine. Arch Gen Psychiatry 1988; 45 (9 ): 789–796.3046553\n9 Siskind D McCartney L Goldschlager R , et al . Clozapine v . First- and second-generation antipsychotics in treatment-refractory schizophrenia: systematic review and meta-analysis. Br J Psychiatry 2016; 209 (5 ): 385–392.27388573\n10 Leucht S Cipriani A Spineli L , et al . Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis. Lancet 2013; 382 (9896 ): 951–962.23810019\n11 Cheng YF Lundberg T Bondesson U , et al . Clinical pharmacokinetics of clozapine in chronic schizophrenic patients. Eur J Clin Pharmacol 1988; 34 (5 ): 445–449.3203703\n12 Choc MG Lehr RG Hsuan F , et al . Multiple-dose pharmacokinetics of clozapine in patients. Pharm Res 1987; 4 (5 ): 402–405.3508549\n13 Flanagan RJ Lally J Gee S , et al . Clozapine in the treatment of refractory schizophrenia: a practical guide for healthcare professionals. Br Med Bull 2020; 135 (1 ): 73–89.32885238\n14 Royal College of Psychiatry. Use of licensed medicines for unlicensed applications in psychiatric practice. Psychiat Bull 2007; 31 (7 ): 1–17.\n15 Nielsen J Young C Ifteni P , et al . Worldwide differences in regulations of clozapine use. CNS Drugs 2016; 30 (2 ): 149–161.26884144\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2050-313X",
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"journal": "SAGE open medical case reports",
"keywords": "Clozapine; antipsychotic; intramuscular; liaison psychiatry; schizophrenia",
"medline_ta": "SAGE Open Med Case Rep",
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"nlm_unique_id": "101638686",
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"pages": "2050313X211004796",
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"pmid": "34094561",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "3203703;3508549;23810019;7904762;32885238;26884144;27388573;32081110;30223913;32605667;3046553;24096780;30674292",
"title": "Intramuscular clozapine in the acute medical hospital: Experiences from a liaison psychiatry team.",
"title_normalized": "intramuscular clozapine in the acute medical hospital experiences from a liaison psychiatry team"
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