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{
"abstract": "The primary treatment of adductor spasmodic dysphonia is repeated injections of botulinum toxin type A (Botox) into the thyroarytenoid muscles. Dosing can be performed into either one or both thyroarytenoid muscles. The objective of this study was to evaluate the treatment effect and side effect profile across a large number of injections. This study was performed previously in 2002 on 45 patients.\n\n\n\nIndividual cohort study.\n\n\n\nThis is retrospective study of all patients with adductor spasmodic dysphonia with and without tremor treated by the senior laryngologist at George Washington University. In the current study, 272 patients (214 females and 58 males) were included in the current analysis. Duration of effects and side effects (vocal weakness and liquid dysphagia) were recorded into a database for each patient after each injection. These data were analyzed using χ2 analysis.\n\n\n\nA total of 4,023 injections (2,708 bilateral and 1,315 unilateral) were evaluated in this study. Optimal effect duration (≥3 months) was more commonly seen in the bilaterally injected patients (55%) compared to the unilaterally injected patients (47%) (P = .0001). Optimal side effect duration (≤2 weeks) was better for the unilaterally injected patients (77%) compared to the bilaterally injected patients (73%) (P = .023). Having both optimal effect and side effect in the same injection was more commonly seen in the bilaterally injected patients (36%) compared to the unilaterally injected patients (33%) (P = .0228).\n\n\n\nThis study shows that bilateral injections of Botox are more effective in producing optimal effect/side effect profiles.\n\n\n\n2b Laryngoscope, 130:2659-2662, 2020.",
"affiliations": "The George Washington University School of Medicine, Washington, DC, U.S.A.;Division of Otolaryngology, The George Washington University, Washington, DC, U.S.A.",
"authors": "Dharia|Ishaan|I|;Bielamowicz|Steven|S|0000-0003-3108-8538",
"chemical_list": "D009465:Neuromuscular Agents; D019274:Botulinum Toxins, Type A",
"country": "United States",
"delete": false,
"doi": "10.1002/lary.28457",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-852X",
"issue": "130(11)",
"journal": "The Laryngoscope",
"keywords": "Laryngology; botulinum toxin; neurolaryngology; outcomes; spasmodic dysphonia; voice",
"medline_ta": "Laryngoscope",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019274:Botulinum Toxins, Type A; D055154:Dysphonia; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D007821:Laryngeal Muscles; D008297:Male; D008875:Middle Aged; D009465:Neuromuscular Agents; D012189:Retrospective Studies; D016896:Treatment Outcome; D014202:Tremor",
"nlm_unique_id": "8607378",
"other_id": null,
"pages": "2659-2662",
"pmc": null,
"pmid": "31837152",
"pubdate": "2020-11",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Unilateral versus bilateral botulinum toxin injections in adductor spasmodic dysphonia in a large cohort.",
"title_normalized": "unilateral versus bilateral botulinum toxin injections in adductor spasmodic dysphonia in a large cohort"
} | [
{
"companynumb": "US-IPSEN BIOPHARMACEUTICALS, INC.-2019-26080",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BOTULINUM TOXIN TYPE A"
},
... |
{
"abstract": "To compare femoral nerve blockade (FNB) versus adductor canal nerve blockade (ACB) for postoperative pain control and quadriceps muscle function in patients undergoing anterior cruciate ligament (ACL) reconstruction with patellar tendon autograft.\n\n\n\nA randomized therapeutic trial of 90 patients undergoing ACL reconstruction with patellar tendon autograft was conducted comparing ACB versus FNB at 24 hours, 2 and 4 weeks, and 6 months postsurgery. Early outcome measures included average pain score and morphine equivalent units (milligrams) consumed, quadriceps surface electromyography, straight leg raise, and ability to ambulate without assistive devices. The 6-month outcome measures included knee range of motion (ROM), isokinetic knee extension peak torque, single-leg squat, and single-leg hop performance. Complications were recorded throughout the study for the development of anterior knee pain, knee extension ROM loss, deep vein thrombosis, and graft failure. Mixed-model analysis of variance and Mann-Whitney U tests were performed using an alpha of .05.\n\n\n\nQuadriceps surface electromyography deficits were higher for FNB at 24 hours (P < .001) and 2 weeks (P < .001) when compared with the ACB group. There were no between-groups difference for subjective pain (P = .793) or morphine consumption (P = .358) within the first 24 hours of surgery. A higher percentage of patients in the ACB group met the full ambulation criteria at 4 weeks compared with the FNB group (100% vs 84.2%, P < .001). No between-group differences were observed at 6 months; however, the rate of knee extension ROM loss was higher for the FNB group versus the ACB group (21.1% vs 5.0%, P = .026), respectively.\n\n\n\nACB was as effective as FNB at providing pain control while eliciting fewer quadriceps muscle activation deficits and fewer postoperative complications. Based on previous evidence and the results of this study, we recommend the use of ACB over FNB for the analgesic management of patients undergoing ACL reconstruction with patellar tendon autograft.\n\n\n\nLevel I, prospective randomized controlled trial.",
"affiliations": "Memorial Hermann's Ironman Sports Medicine Institute, Houston, Texas, U.S.A.. Electronic address: baileylb2001@gmail.com.;Department of Orthopedic Surgery, The University of Texas at Houston, Houston, Texas, U.S.A.;Department of Orthopedic Surgery, The University of Texas at Houston, Houston, Texas, U.S.A.;Department of Orthopedic Surgery, The University of Texas at Houston, Houston, Texas, U.S.A.;Memorial Hermann's Ironman Sports Medicine Institute, Houston, Texas, U.S.A.;Department of Orthopedic Surgery, The University of Texas at Houston, Houston, Texas, U.S.A.;Department of Orthopedic Surgery, The University of Texas at Houston, Houston, Texas, U.S.A.",
"authors": "Bailey|Lane|L|;Griffin|Joshua|J|;Elliott|Mark|M|;Wu|Jennifer|J|;Papavasiliou|Thanos|T|;Harner|Christopher|C|;Lowe|Walter|W|",
"chemical_list": "D000700:Analgesics; D000077212:Ropivacaine; D003000:Clonidine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.arthro.2018.10.149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0749-8063",
"issue": "35(3)",
"journal": "Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association",
"keywords": null,
"medline_ta": "Arthroscopy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000700:Analgesics; D000704:Analysis of Variance; D000765:Anesthesia, Conduction; D059549:Anterior Cruciate Ligament Reconstruction; D064592:Autografts; D003000:Clonidine; D004576:Electromyography; D005260:Female; D005267:Femoral Nerve; D006801:Humans; D007719:Knee Joint; D008297:Male; D008875:Middle Aged; D009407:Nerve Block; D059408:Pain Management; D010149:Pain, Postoperative; D017847:Patellar Ligament; D011446:Prospective Studies; D052097:Quadriceps Muscle; D016059:Range of Motion, Articular; D000077212:Ropivacaine; D014182:Transplantation, Autologous; D055815:Young Adult",
"nlm_unique_id": "8506498",
"other_id": null,
"pages": "921-929",
"pmc": null,
"pmid": "30733025",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Adductor Canal Nerve Versus Femoral Nerve Blockade for Pain Control and Quadriceps Function Following Anterior Cruciate Ligament Reconstruction With Patellar Tendon Autograft: A Prospective Randomized Trial.",
"title_normalized": "adductor canal nerve versus femoral nerve blockade for pain control and quadriceps function following anterior cruciate ligament reconstruction with patellar tendon autograft a prospective randomized trial"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2019-BI-013583",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONIDINE HYDROCHLORIDE"
}... |
{
"abstract": "BACKGROUND\nIntensified chemotherapy improved outcomes for men with poor-prognosis metastatic germ cell cancer (GCC) and unfavorable tumor marker decline after one cycle of bleomycin, etoposide, and cisplatin (BEP) chemotherapy in the GETUG-13 trial. Herein, we report our experience to date using a similar approach.\n\n\nMETHODS\nPatients were identified from our electronic GCC database. Men with poor-prognosis GCC and unfavorable tumor marker decline were offered intensified chemotherapy consisting of T-BEP (three cycles) plus paclitaxel, ifosfamide, and cisplatin (TIP) (one cycle), along with prophylactic granulocyte-colony stimulating factor (G-CSF) and resection of residual masses. Cisplatin, etoposide, and ifosfamide (PEI) replaced the last cycle of T-BEP for bleomycin pulmonary concerns. Serious toxicities, progression-free survival, and overall survival were evaluated retrospectively.\n\n\nRESULTS\nTen patients with poor-prognosis GCC were identified from May 2012 to April 2016. Eight patients had unfavorable tumor marker decline. Six were offered and received intensified chemotherapy (two T-BEPx3 + TIP and four T-BEPx2 + PEI + TIP). Serious toxicities included neutropenic sepsis, deep venous thrombosis, and C. difficile colitis, but there were no toxic deaths. One patient died of synchronous metastatic adenocarcinoma ex teratoma. The remaining five patients achieved marker-negative partial response, two had residual mature teratoma excised, and four have no evidence of disease after surgery. All are alive at a median of 63.5 months (range 46.3-65.6); one patient has grade 2 peripheral sensory neuropathy, and one patient has grade 2 cognitive disturbance. Of four patients treated with standard BEP, two have died of disease and two are alive at 51.4 and 53.6 months.\n\n\nCONCLUSIONS\nOur experience with intensified chemotherapy for men with poor-prognosis GCC and unfavorable tumor marker decline confirms that it is feasible, reasonably safe, and appears to provide results similar to those reported in GETUG-13.",
"affiliations": "Division of Medical Oncology, Department of Oncology, Western University and London Health Sciences Centre, London, ON, Canada.;Division of Medical Oncology, Department of Oncology, Western University and London Health Sciences Centre, London, ON, Canada.;Division of Medical Oncology, Department of Oncology, Western University and London Health Sciences Centre, London, ON, Canada.;Division of Medical Oncology, Department of Oncology, Western University and London Health Sciences Centre, London, ON, Canada.;Division of Urology, Department of Surgery, Western University and London Health Sciences Centre, London, ON, Canada.;London Health Sciences Centre, London, ON, Canada.;Division of Medical Oncology, Department of Oncology, Western University and London Health Sciences Centre, London, ON, Canada.",
"authors": "Batra|Anupam|A|;Ernst|Scott|S|;Potvin|Kylea|K|;Fernandes|Ricardo|R|;Power|Nicholas|N|;Vanhie|James|J|;Winquist|Eric|E|",
"chemical_list": null,
"country": "Canada",
"delete": false,
"doi": "10.5489/cuaj.5802",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1911-6470",
"issue": "14(2)",
"journal": "Canadian Urological Association journal = Journal de l'Association des urologues du Canada",
"keywords": null,
"medline_ta": "Can Urol Assoc J",
"mesh_terms": null,
"nlm_unique_id": "101312644",
"other_id": null,
"pages": "43-47",
"pmc": null,
"pmid": "31348750",
"pubdate": "2020-02",
"publication_types": "D016428:Journal Article",
"references": "28854068;30113631;1665492;21704446;15302906;22464311;25456363;17235042;10856101;28327896;9552027;22271474;10597204;9053482",
"title": "Early experience with chemotherapy intensification for poor-prognosis metastatic germ cell cancer and unfavorable tumor marker decline.",
"title_normalized": "early experience with chemotherapy intensification for poor prognosis metastatic germ cell cancer and unfavorable tumor marker decline"
} | [
{
"companynumb": "CA-PFIZER INC-2019112921",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo compare the activity and tolerance of the consecutive administration of four active chemotherapeutic agents in combination with bevacizumab to a bevacizumab- and platinum-based chemotherapy doublet as front-line treatment in patients with non-squamous NSCLC.\n\n\nMETHODS\nPatients with advanced/metastatic NSCLC, performance status of 0-2 and normal organ function were randomized to receive either 3 cycles every 3 weeks of cisplatin 80 mg/m(2) (day 1), oral vinorelbine 60 mg/m(2) (days 1 and 8) and bevacizumab 15 mg/kg (day 1) every 3 weeks (VCB regimen) followed by 3 cycles of docetaxel (75 mg/m(2), day 1), gemcitabine (1100 mg/m(2), days 1 and 8) and bevacizumab 15 mg/kg (day 1) (DGB regimen) (arm A) or 6 cycles of cisplatin 80 mg/m(2), docetaxel 75 mg/m(2) and bevacizumab 15 mg/kg on day 1 (DCB regimen; arm B) every 3 weeks.\n\n\nRESULTS\nThirty-eight and 39 patients were enrolled in arm A and B, respectively. The study did not meet its primary endpoint since, the ORR was 39.5% (95% CI: 23.9-55.0%; 1CR and 14 PR) and 46.2% (95% CI: 30.5-61.8%; 2 CR and 16 PR) in arm A and B, respectively (p=0.554). There was no significant difference in terms of response duration (7.4 versus 4.7 months in arm A and B, respectively; p=0.697), progression-free survival (5.8 versus 5.5 months, respectively; p=0.540) and overall survival (16.9 versus 10.9 months; p=0.390). No difference was recorded between the two arms regarding the toxicity profile. There were two drug-related deaths in arm B.\n\n\nCONCLUSIONS\nSequential therapy of VCB followed by DGB is a feasible and well-tolerated regimen but failed to show any superiority over the standard DCB regimen.",
"affiliations": "On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece. Electronic address: thankotsakis@hotmail.com.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.;On behalf of the Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), 55 Lomvardou Street, 11471, Athens, Greece.",
"authors": "Kotsakis|A|A|;Kentepozidis|N|N|;Emmanouilidis|Ch|Ch|;Polyzos|A|A|;Agelidou|A|A|;Vaslamatzis|M|M|;Chandrinos|V|V|;Agelaki|S|S|;Vamvakas|L|L|;Kalbakis|K|K|;Katsaounis|P|P|;Stoltidis|D|D|;Nintos|G|G|;Hatzidaki|D|D|;Vetsika|E K|EK|;Mavroudis|D|D|;Georgoulias|V|V|",
"chemical_list": "D043823:Taxoids; D003841:Deoxycytidine; D000077143:Docetaxel; D000068258:Bevacizumab; D014747:Vinblastine; C056507:gemcitabine; D002945:Cisplatin; D000077235:Vinorelbine",
"country": "Ireland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "88(1)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "Bevacizumab; Cisplatin; NSCLC; Overall response rate; Sequential treatment; Vinorelbine",
"medline_ta": "Lung Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D043823:Taxoids; D016896:Treatment Outcome; D014747:Vinblastine; D000077235:Vinorelbine",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "57-62",
"pmc": null,
"pmid": "25662596",
"pubdate": "2015-04",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sequential administration of vinorelbine plus cisplatin and bevacizumab followed by docetaxel plus gemcitabine and bevacizumab compared to docetaxel plus cisplatin and bevacizumab regimen as first-line therapy for advanced or metastatic non-squamous non-small cell lung cancer: A multicenter randomized phase II trial of the Hellenic Oncology Research Group (HORG).",
"title_normalized": "sequential administration of vinorelbine plus cisplatin and bevacizumab followed by docetaxel plus gemcitabine and bevacizumab compared to docetaxel plus cisplatin and bevacizumab regimen as first line therapy for advanced or metastatic non squamous non small cell lung cancer a multicenter randomized phase ii trial of the hellenic oncology research group horg"
} | [
{
"companynumb": "GR-SA-2015SA028130",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"drugadditional": null,
"dru... |
{
"abstract": "A case of cardiorespiratory arrest in a 28 year old man after cocaine and heroin ingestion is described. The arrest is attributed primarily to hyperkalaemia/rhabdomyolysis-a recognised consequence of each of these drugs. The administration of naloxone may have been contributory. He developed acute renal failure, disseminated intravascular coagulopathy with consequent lower limb compartment syndrome requiring fasciotomy. Ventricular fibrillation was identified at thoracotomy.",
"affiliations": "Emergency Department, Royal Liverpool University Hospital, Liverpool, UK. bmaccanna@blueyonder.co.uk",
"authors": "McCann|B|B|;Hunter|R|R|;McCann|J|J|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/emj.19.3.264",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1472-0205",
"issue": "19(3)",
"journal": "Emergency medicine journal : EMJ",
"keywords": null,
"medline_ta": "Emerg Med J",
"mesh_terms": "D058186:Acute Kidney Injury; D000328:Adult; D019970:Cocaine-Related Disorders; D004211:Disseminated Intravascular Coagulation; D005260:Female; D006323:Heart Arrest; D006556:Heroin Dependence; D006801:Humans; D008297:Male; D012206:Rhabdomyolysis; D014693:Ventricular Fibrillation",
"nlm_unique_id": "100963089",
"other_id": null,
"pages": "264-5",
"pmc": null,
"pmid": "11971848",
"pubdate": "2002-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cocaine/heroin induced rhabdomyolysis and ventricular fibrillation.",
"title_normalized": "cocaine heroin induced rhabdomyolysis and ventricular fibrillation"
} | [
{
"companynumb": "GB-PFIZER INC-2021735376",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NALOXONE HYDROCHLORIDE"
},
"drugadditional": "... |
{
"abstract": "OBJECTIVE\nInfliximab was introduced recently as a rescue therapy for ulcerative colitis (UC) patients refractory to conventional treatments such as therapy with 5-amiono salicylic acids (5-ASA), immune modulators, and corticosteroids. However, there is insufficient data about its efficacy and safety in Korea.\n\n\nMETHODS\nFrom 7 tertiary referral hospitals, 33 patients who were treated with infliximab for moderate to severe (Mayo score 6-12) UC refractory to conventional treatment were recruited to this study. Clinical remission was defined as a total Mayo score of 2 or lower and every subscore less than 2. Partial response was defined as a decrease of Mayo score at least 3 points from baseline.\n\n\nRESULTS\nTwenty-three patients (69.7%) showed clinical remission and 29 patients (87.8%) showed partial response in the observation period. When the remission and non-remission groups were compared in univariate analysis, only a higher total Mayo score at base line (11.0±0.9 vs. 9.9±1.5; P=0.04) was related to remission. The remission maintenance rate decreased with time in the Kaplan-Meier analysis. Two patients experienced re-remission after the first remission followed by aggravation during infliximab treatment. Three patients stopped infliximab treatment owing to adverse events including rhabdomyolysis, pneumonia, and fever of unknown origin.\n\n\nCONCLUSIONS\nIf there is no choice except surgery for UC patients refractory to conventional treatment, infliximab is an effective and relatively safe treatment option for these patients in Korea.",
"affiliations": "Department of Internal Medicine, Ulsan University College of Medicine, Gangneung Asan Hospital, Gangneung, Korea.;Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea.;Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea.;Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, Korea.;Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.;Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea.;Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.;Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.",
"authors": "Seo|Hyun Il|HI|;Park|Dong Il|DI|;Kim|Tae Oh|TO|;Kim|You Sun|YS|;Lee|Suck-Ho|SH|;Kim|Ji Won|JW|;Kim|Jae Hak|JH|;Shin|Jeong Eun|JE|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5217/ir.2014.12.3.214",
"fulltext": "\n==== Front\nIntestinal ResIntestinal ResIRIntestinal Research1598-91002288-1956Korean Association for the Study of Intestinal Diseases 10.5217/ir.2014.12.3.214Original ArticleThe Effect of Infliximab on Patients with Ulcerative Colitis in Korea Seo Hyun Il Park Dong Il 1Kim Tae Oh 2Kim You Sun 3Lee Suck-Ho 4Kim Ji Won 5Kim Jae Hak 6Shin Jeong Eun 7Department of Internal Medicine, Ulsan University College of Medicine, Gangneung Asan Hospital, Gangneung, Korea.1 Department of Internal Medicine, Sungkyunkwan University School of Medicine, Kangbuk Samsung Hospital, Seoul, Korea.2 Department of Internal Medicine, Inje University College of Medicine, Haeundae Paik Hospital, Busan, Korea.3 Department of Internal Medicine, Inje University College of Medicine, Seoul Paik Hospital, Seoul, Korea.4 Department of Internal Medicine, Soonchunhyang University College of Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea.5 Department of Internal Medicine, Seoul National University Boramae Hospital, Seoul, Korea.6 Department of Internal Medicine, Dongguk University Ilsan Hospital, Goyang, Korea.7 Department of Internal Medicine, Dankook University College of Medicine, Cheonan, Korea.Correspondence to Dong Il Park, Department of Internal Medicine, Kangbuk Samsung Hospital, 29 Saemunan-ro, Jongno-gu, Seoul 110-746, Korea. Tel: +82-2-2001-2059, Fax: +82-2-2001-2610, diksmc.park@samsung.com7 2014 25 7 2014 12 3 214 220 21 11 2013 28 2 2014 02 3 2014 © Copyright 2014. Korean Association for the Study of Intestinal Diseases. All rights reserved.2014This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background/Aims\nInfliximab was introduced recently as a rescue therapy for ulcerative colitis (UC) patients refractory to conventional treatments such as therapy with 5-amiono salicylic acids (5-ASA), immune modulators, and corticosteroids. However, there is insufficient data about its efficacy and safety in Korea.\n\nMethods\nFrom 7 tertiary referral hospitals, 33 patients who were treated with infliximab for moderate to severe (Mayo score 6-12) UC refractory to conventional treatment were recruited to this study. Clinical remission was defined as a total Mayo score of 2 or lower and every subscore less than 2. Partial response was defined as a decrease of Mayo score at least 3 points from baseline.\n\nResults\nTwenty-three patients (69.7%) showed clinical remission and 29 patients (87.8%) showed partial response in the observation period. When the remission and non-remission groups were compared in univariate analysis, only a higher total Mayo score at base line (11.0±0.9 vs. 9.9±1.5; P=0.04) was related to remission. The remission maintenance rate decreased with time in the Kaplan-Meier analysis. Two patients experienced re-remission after the first remission followed by aggravation during infliximab treatment. Three patients stopped infliximab treatment owing to adverse events including rhabdomyolysis, pneumonia, and fever of unknown origin.\n\nConclusions\nIf there is no choice except surgery for UC patients refractory to conventional treatment, infliximab is an effective and relatively safe treatment option for these patients in Korea.\n\nUlcerative colitisInfliximabEfficacySafety\n==== Body\nINTRODUCTION\nUlcerative colitis (UC) is a chronic IBD, and its cause is unknown. It is confined to the mucosa and submucosa in the colon and characterized by repeated relapse and remission. UC can deteriorate the quality of life owing to relapsing symptoms including abdominal pain, bloody diarrhea, urgency, etc., and leading to complications such as colon cancer in the long-term.1 Therefore, the management and treatment of this disease are important. Since the first incidence of UC was reported in the 1970s in Korea, its incidence and prevalence have increased continuously.2,3 However, consistent management and examination are essential after diagnosis because, at present, there is no curative treatment for UC. Drugs used to treat UC include 5-aminosalicylic acid (5-ASA), steroids, immunosuppressants (azathioprine [AZP], 6-mercaptopurine [6-MP]), and others drugs. Patients with severe UC can be temporarily managed with corticosteroid injections.4 The association of infections with UC, such as infection with cytomegalovirus, needs to be examined in severe UC patients refractory to corticosteroids;5,6,7 immunosuppressants including cyclosporine, infliximab, and other biological agents can be used concurrently.4 Cyclosporine tends to work more quickly than other immunosuppressive medicines. However, it needs to be used cautiously because of the risk of side effects such as nephrotoxicity, epilepsy, gingival hyperplasia, hypertrichosis, and other opportunistic infections, and it cannot be used in the long-term to maintain remission because of its potential side effects.8,9,10 Infliximab is a monoclonal antibody against tumor necrosis factor alpha (TNF-α). It is known to alleviate histologic inflammation of the mucosa by reducing the secretion of mucosal TNF-α.11,12 Two large-scale randomized controlled trials verified the effectiveness of infliximab in UC.13 However, infliximab is rarely used in patients with severe UC and information on its effects and adverse events are insufficient in Korea.\n\nTherefore, this study aimed to examine the effects and adverse reactions of infliximab and identify predictive factors of response.\n\nMETHODS\n1. Subjects\nThis multi-center study retrospectively reviewed the medical records of patients treated with infliximab for UC in the Department of Gastroenterology of 7 tertiary referral hospitals in Korea from January 2007 to December 31, 2011.\n\n2. Method\nBased on the presence of remission at least once during the observation period, the patients were divided into 2 groups. Based on the medical records, patients were examined with gender, age at onset of UC, family history of IBD, initial symptom, extension of lesion, smoking status, opportunistic infections (tuberculosis, human immunodeficiency virus, HBV), white blood cell count, hemoglobin (Hb), platelet, ESR, CRP, and blood test results including albumin level at first use of infliximab. Age at administration of infliximab, drugs used prior to infliximab, indication for infliximab, concurrently administered medicines, number and dose of infliximab, cessation of drug, discontinuation of treatment, remission and partial response, adverse reaction, aggravation and death were examined. Based on the extent of the lesions, UC was classified into proctitis, left-sided colitis, and pancolitis. Medicines administered concurrently or prior to infliximab including 5-ASA, steroid, AZP, 6-MP, methotrexate, antibiotics, and others were noted.\n\n1) Indications for Infliximab Treatment\nIndications for infliximab treatment were categorized into steroid dependency, steroid refractoriness, refractoriness and side effects of immunosuppressants, and others, with multiple answers allowed. Steroid-dependent UC was confirmed if prednisolone was not tapered to less than 10 mg/day within 3 months of starting steroids without recurrent disease or if relapse occurred within 3 months of stopping prednisolone. Steroid-refractory UC was confirmed if there was no improvement despite administration of prednisolone at a dose of 0.75 mg/kg/day for more than 4 weeks. Immunosuppressant intolerance was confirmed if there was relapse or no improvement despite administration of immunosuppressants (AZP: ~1.5-2.5 mg/kg/day, 6-MP: 0.5-1.0 mg/kg/day) for more than 6 months.\n\n2) Disease Activity and Follow-up\nUC disease activity was measured using the Mayo score and checked during each visit for infliximab administration. Since endoscopy examination could not be performed at each visit, partial Mayo scores, i.e., Mayo score without endoscopy subscore, were used. Clinical remission was defined as a total Mayo score of 2 or lower and every subscore less than 2, and partial response was defined as a decrease from baseline by at least 3 points.13 Recurrence or aggravation after remission was defined as a partial Mayo score of 5 or higher, an increase from baseline at least 3 points, or additional medication or surgical procedure owing to the development of new symptoms or signs. This study was performed after gaining institutional review board approval from Kangbuk Samsung Hospital.\n\n3. Statistical Analysis\nTo identify factors affecting remission, nominal variables were analyzed with Fisher's exact test, while continuous variables were analyzed with Mann-Whitney U-test. In addition, the nominal variables were subjected to Kaplan-Meier analysis and log-rank (Mantel-Cox) test to examine different durations to remission. The cumulative rate of remission maintenance was analyzed by Kaplan-Meier analysis. Statistical analyses were performed using PASW Statistics 17.0 (SPSS Inc., Chicago, IL, USA).\n\nRESULTS\n1. Baseline Characteristics\nThirty-three patients with UC were administered infliximab at a dose of 5 mg/kg at 0, 2, 6, and every 8 weeks. The mean number of times of administration was 4.8 times. Clinical remission, at least once, was achieved in 23 patients (69.7%) during the observation period, induced after an average of 1.4 times of infliximab administration. Remission was not achieved in 10 patients (30.3%), with the mean number of times of infliximab administration being 3.7 times.\n\n2. Remission and Predictive Factors of Response\nDifferences between the groups were analyzed according to the presence of remission to identify its association with clinical remission, but no association was shown except for Mayo score. In the univariate analysis, the Mayo score was significantly higher by approximately 1 point, as the remission group scored 11 points and the non-remission group scored 9.9 points (P=0.04). Since there were no other significant factors, a multivariate analysis was not performed. There was no patient with disease extension limited to proctitis. Clinical remission had no association with extent of the lesions, CRP, Hb, immunosuppressant use, indication for infliximab, and concurrent medication (Table 1). Factors related to partial response were analyzed in the same manner, but no significant association was found between them and remission. Kaplan-Meier analysis and log-rank test were conducted by taking varying remission onset and remission maintenance rates into consideration. However, there were no statistically significant factors predicting the presence of remission and maintenance rate.\n\n3. Progression and Cumulative Remission Maintenance Rate\nThe number of times infliximab was administered varied from 2 to 9 times. After the first administration, 14 patients (42.4%) achieved remission. Moreover, 6 patients (18.1%), 2 patients (6.0%), and 1 patient (3.0%) reached remission at second, third and fourth administrations, respectively. A total of 23 patients (69.7%) achieved remission after an average 1.4 times of administration. Meanwhile, 29 patients (87.8%) showed clinical improvement, including 6 patients (18.1%) with partial response. No patient experienced aggravated symptoms after partial response. Recurrent or aggravated symptoms were observed in 7 remission patients. The partial Mayo scores ranged between 3 and 7 points after aggravation, and no patient underwent surgery. The same unchanged dose of infliximab was consistently administered to 2 patients, as planned, and they achieved re-remission (Fig. 1). Three patients reached remission before the 8th week of treatment, but the remission was followed by relapse. When they were considered not having achieved remission, the partial response and remission rates were 60.6% and 39.4%, respectively on the 8th week according to the intention to treat analysis. When those patients were considered having achieved remission, the partial response and remission rates were 66.6% and 48.4%, respectively.\n\nKaplan-Meier analysis was performed to assess the cumulative rate of remission maintenance. Cumulative remission maintenance rate decreased with time (Fig. 2). No statistical difference was found in the cumulative remission maintenance rate according to initial symptoms, gender, extension, concurrently used medication, smoking status, and indications for infliximab.\n\n4. Adverse Events\nOf all the 33 patients, adverse reactions were confirmed in 4 patients (12.1%), as shown in Table 2. None of the patients died during the observation period. Of these, 1 patient developed pancreatitis, while concurrently using AZP and infliximab, so AZP was replaced by 6-MP and concurrently administered with infliximab.\n\nDISCUSSION\nIn this study, the use of infliximab clinically improved symptoms in almost 90% of moderate to severe UC patients refractory to steroids or immune modulators, showing a decrease in the baseline partial Mayo score by ≥3 points. Remission was reached in about 70% of all patients once or more than once. In addition, there was no death or surgery during the follow-up. Our results were higher than the response and remission induction rates reported in other studies performed in Korea.14 We assumed this was caused because remission was taken as standard criteria at any time point during the observation period, unlike other previous studies that determined clinical scores only at 8 weeks after the first infliximab administration. Moreover, this study aimed to identify predictive factors associated with the achievement of remission after infliximab administration. However, there was no clinical difference except for high Mayo scores indicating high disease activity at the first administration. Since these results were obtained from univariate analysis only, they were insufficient to be considered significant. Taking into consideration the fact that the CRP level was elevated and albumin level was low at the first administration in the remission group, high disease activity was predicted to have positive effect on remission induction caused by infliximab use. Likewise, a previous study that retrospectively reviewed 90 UC patients suggested that severe UC was a predictive factor for positive response to infliximab.15 However, high disease activity was considered a predictive factor for poor response to infliximab in several previous studies.16,17,18 In contrast, a recent study involving 89 Korean UC patients proposed that a Mayo score of greater than 11 was a predictive factor for nonresponse to infliximab.18 Another recent study involving 134 Korean UC patients reported that CRP levels above 3.0 mg/dL and Hb levels above 11.5 g/dL were positive predictive factors for remission or partial response, and inconsistent results were shown for several factors representing disease activity in predicting the effects of infliximab.14 Therefore, additional studies are crucial to investigate causes for aggravation after remission from various perspectives of immunology, biochemistry, pharmacology, and environmental factors affecting disease progression.\n\nUnlike the previous studies, this study analyzed \"remission\" only as the standard criteria instead of the remission state 8 weeks after infliximab use. Although remission is achieved before 8 weeks, relapse can occur after 8 weeks. Since the remission rate varies depending on total number and time of administration, as demonstrated by the results of the Kaplan-Meier analysis in this study and those of other large-scale studies, determining the effects and predictive factors of infliximab with \"remission\" achievement is thought to be more suitable rather than doing so with remission state at certain point of time. It is beneficial to compare remission state at specific point only if the aim of the study is to compare the remission rate between 2 groups, but the purpose of this study was to identify remission predictive factors. In the study, 3 patients reached remission and a short remission was followed by a relapse after the third administration (6 weeks after first administration). The partial Mayo scores for the patients were 5, 7, and 4 points, respectively. Those 3 patients accounted for 9.0% (3/33) of all subjects, and 13.0% (3/23) of all patients who achieved remission. According to the analysis based on 8 weeks of administration, an error can occur in the analysis of response-predictive factors by placing those 3 patients in the non-remission group. This is considered one of the reasons for our results not being comparable to those of previous studies on remission-predictive factors. Considering the fact that repeated remission and relapses can occur, whether remission at a specific point of time can be taken as the standard for identifying remission predictive factors instead of \"remission\" achievement needs to be carefully determined. To the best of the authors' knowledge, this issue has not been addressed in previous studies on the efficacy and response-predictive factors of infliximab in patients with UC, probably because remission achievement at a certain point of time was overlooked as massive data sets were analyzed in those studies. Although this study had a small sample size, new findings were revealed through in-depth analyses.\n\nAccording to the Kaplan-Meier graph showing the remission rate of infliximab, the cumulative rate of remission maintenance decreased with time. However, factors related to remission maintenance rate were not identified. Many studies verified clinical improvement by administering infliximab to UC patients refractory to conventional therapies. The clinical improvement showed a decreasing tendency in both response and cumulative remission maintenance rates with time.13,19,20 Some studies suggested that the decrease in the cumulative rates of remission maintenance was caused by a reduction in the plasma concentrations of infliximab, with the formation of antibodies against infliximab.21 In contrast, antibodies against infliximab present before drug administration were found to be not related to response to infliximab in UC patients.22 Furthermore, large-scale prospective study, a high response rate was observed at weeks 30 and 54 when antibodies were present in the bodies of UC patients.13 Therefore, additional studies are essential to further determine the antibodies and potential factors that cause non-response to infliximab. In this study, severe adverse events to the degree of following discontinuation of treatment occurred in 4 patients, but none of the patients died. Of these patients with side effects, in the case of 1 patient with pancreatitis, AZP was replaced with 6-MP, despite sustained use of infliximab. The adverse event was more likely to be caused by AZP. Therefore, relatively severe adverse reaction occurred in 3 (9.0%) out of 33 patients.\n\nThere are some limitations to this study. This study had a small sample size and relatively short follow-up period. Current health insurance coverage of infliximab for UC management is limited for those refractory or intolerant to conventional medications including steroid, AZP, or 6-MP and those with moderate to severe UC with a Mayo score of 6-12 points. Insurance coverage is discontinued for patients with no response to a maximum of 3 doses of infliximab. Therefore, most patients stop taking infliximab after 3 doses, if they are refractory to infliximab. Since response to the drug was mainly observed in the early period of administration in most previous studies, the small sample size is considered as a bigger barrier than the short follow-up period. However, the small sample size enabled in-depth analysis and helped reveal new findings. Moreover, there could have been differences between hospitals and physicians in treating disease owing to the nature of this multi-center study, so efforts were made to resolve this shortcoming by creating the objectified form of data input, considering the current condition of the actual clinical field at the data collection phase.\n\nTo sum up, this study analyzed a total of 33 Korean UC patients administered infliximab, and almost 90% showed clinical improvement. Some patients had a relapse followed by remission with time, and adverse events occurred in the case of some patients. It was found that the remitting and relapsing course can be repeated. In Korea, for moderate to severe UC patients refractory to conventional treatment with surgery as the last treatment option, infliximab is an effective and relatively safe treatment option. Further studies are required because the response to infliximab, potential side effects, and remitting and relapsing courses have not yet been fully clarified.\n\nFinancial support: None.\n\nConflict of interest: None.\n\nFig. 1 A schematic clinical course of patients. Schematic overview of the clinical course of UC in the study patients during the observation period, regardless of the number of infliximab injections. The dichotomous status of UC is shown as in remission (+) or not (-).\n\nFig. 2 Kaplan-Meier graph of cumulative remission. The graph shows progressive decrease in cumulative remission rate with time during infliximab treatment.\n\nTable 1 Baseline Characteristics of Study Patients\n\nValues are presented as mean±SD or n (%).\n\n*Multiple choice.\n\n†No patient was on 6-mercaptopurine or methotrexate.\n\nWBC, white blood cell; Hb, hemoglobin; 5-ASA, 5-aminosalicylic acid; AZP, azathioprine.\n\nTable 2 Four Patients with Adverse Events Related to Infliximab\n\nM, male; FUO, fever of unknown origin; AZP, azathioprine; 6-MP, 6-mercaptopurine.\n==== Refs\n1 Staehelin A Prognosis of ulcerative colitis. Follow-up control of cases from 1942 to 1969 Schweiz Med Wochenschr 1970 100 580 582 5420854 \n2 Kim SJ Cho YK Rhee JE Yoon CM Two cases of ulcerative colitis Korean J Gastroenterol 1970 2 29 33 \n3 Yang SK Hong WS Min YI Incidence and prevalence of ulcerative colitis in the Songpa-Kangdong District, Seoul, Korea, 1986-1997 J Gastroenterol Hepatol 2000 15 1037 1042 11059934 \n4 Choi CH Kim YH Kim YS Guidelines for the management of ulcerative colitis Korean J Gastroenterol 2012 59 118 140 22387836 \n5 Wada Y Matsui T Matake H Intractable ulcerative colitis caused by cytomegalovirus infection: a prospective study on prevalence, diagnosis, and treatment Dis Colon Rectum 2003 46 S59 S65 14530660 \n6 Criscuoli V Casa A Orlando A Severe acute colitis associated with CMV: a prevalence study Dig Liver Dis 2004 36 818 820 15646428 \n7 Kim YS Kim YH Kim JS The prevalence and efficacy of ganciclovir on steroid-refractory ulcerative colitis with cytomegalovirus infection: a prospective multicenter study J Clin Gastroenterol 2012 46 51 56 21552140 \n8 Van Assche G D'Haens G Noman M Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis Gastroenterology 2003 125 1025 1031 14517785 \n9 Campbell S Travis S Jewell D Ciclosporin use in acute ulcerative colitis: a long-term experience Eur J Gastroenterol Hepatol 2005 17 79 84 15647646 \n10 Haslam N Hearing SD Probert CS Audit of cyclosporin use in inflammatory bowel disease: limited benefits, numerous side-effects Eur J Gastroenterol Hepatol 2000 12 657 660 10912486 \n11 Knight DM Trinh H Le J Construction and initial characterization of a mouse-human chimeric anti-TNF antibody Mol Immunol 1993 30 1443 1453 8232330 \n12 Murch SH Braegger CP Walker-Smith JA MacDonald TT Location of tumour necrosis factor alpha by immunohistochemistry in chronic inflammatory bowel disease Gut 1993 34 1705 1709 8031350 \n13 Rutgeerts P Sandborn WJ Feagan BG Infliximab for induction and maintenance therapy for ulcerative colitis N Engl J Med 2005 353 2462 2476 16339095 \n14 Lee KM Jeen YT Cho JY Efficacy, safety, and predictors of response to infliximab therapy for ulcerative colitis: a Korean multicenter retrospective study J Gastroenterol Hepatol 2013 28 1829 1833 23829336 \n15 Jurgens M Laubender RP Hartl F Disease activity, ANCA, and IL23R genotype status determine early response to infliximab in patients with ulcerative colitis Am J Gastroenterol 2010 105 1811 1819 20197757 \n16 Oussalah A Evesque L Laharie D A multicenter experience with infliximab for ulcerative colitis: outcomes and predictors of response, optimization, colectomy, and hospitalization Am J Gastroenterol 2010 105 2617 2625 20736936 \n17 Seow CH Newman A Irwin SP Steinhart AH Silverberg MS Greenberg GR Trough serum infliximab: a predictive factor of clinical outcome for infliximab treatment in acute ulcerative colitis Gut 2010 59 49 54 19651627 \n18 Park SH Yang SK Hong SM Severe disease activity and cytomegalovirus colitis are predictive of a nonresponse to infliximab in patients with ulcerative colitis Dig Dis Sci 2013 58 3592 3599 23979435 \n19 Chaparro M Burgueno P Iglesias E Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: a multicentre study Aliment Pharmacol Ther 2012 35 275 283 22142227 \n20 Sjoberg M Walch A Meshkat M Infliximab or cyclosporine as rescue therapy in hospitalized patients with steroid-refractory ulcerative colitis: a retrospective observational study Inflamm Bowel Dis 2012 18 212 218 21438096 \n21 Nanda KS Cheifetz AS Moss AC Impact of antibodies to infliximab on clinical outcomes and serum infliximab levels in patients with inflammatory bowel disease (IBD): a meta-analysis Am J Gastroenterol 2013 108 40 47 23147525 \n22 Steenholdt C Palarasah Y Bendtzen K Pre-existing IgG antibodies cross-reacting with the Fab region of infliximab predict efficacy and safety of infliximab therapy in inflammatory bowel disease Aliment Pharmacol Ther 2013 37 1172 1183 23650912\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1598-9100",
"issue": "12(3)",
"journal": "Intestinal research",
"keywords": "Efficacy; Infliximab; Safety; Ulcerative colitis",
"medline_ta": "Intest Res",
"mesh_terms": null,
"nlm_unique_id": "101572802",
"other_id": null,
"pages": "214-20",
"pmc": null,
"pmid": "25349595",
"pubdate": "2014-07",
"publication_types": "D016428:Journal Article",
"references": "15647646;14517785;22387836;21552140;23979435;15646428;23650912;16339095;10912486;20197757;23147525;20736936;19651627;23829336;14530660;8232330;21438096;11059934;8031350;5420854;22142227",
"title": "The effect of infliximab on patients with ulcerative colitis in Korea.",
"title_normalized": "the effect of infliximab on patients with ulcerative colitis in korea"
} | [
{
"companynumb": "KR-JNJFOC-20140720720",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "To assess the impact of WATCHMAN™ on quality of life (QoL) in octogenarians and nonagenarians.\n\n\n\nQoL after WATCHMAN™ device in the elderly remains unknown.\n\n\n\nThis is a prospective and retrospective cohort study of patients that underwent WATCHMAN™ implantation in a tertiary cardiovascular center from April 1, 2015 to September 27, 2017. The primary outcome was a prospective assessment of QoL via the SF-12v2 Health Survey (SF-12v2) in those aged ≥80 and ≥90 years. Secondary outcomes include major bleeding, stroke, vascular complications, pericardial effusion, device related thrombus (DRT), prolonged length of stay (LOS), acute kidney injury (AKI), and recurrent hospitalizations.\n\n\n\nThis cohort of 151 patients included 48/151 (32%) females with a mean age of 80 ± 7.7 years. Mean CHA2 DS2 -VASc was 4.38 ± 1.36 and mean HAS-BLED was 3.27 ± 1.17. Octogenarians 65/81(80%) and nonagenarians 16/81(20%) comprised 81/151(54%) of patients (mean age 86 ± 4.3 years) from which 36/65 (55%) octogenarians and 10/16 (63%) nonagenarians completed SF-12v2 evaluation at 22 ± 10 and 30 ± 10-months. Octogenarians demonstrated enhanced physical component scores (PCS), and nonagenarians equal PCS versus the age-adjusted norm (45.43 ± 9.84 versus 38.68 ± 11.04, P = 0.0003, and 41.26 ± 12.36 versus 38.68 ± 11.04, P = 0.6463, respectively). The mental component scores (MCS) of octogenarians and nonagenarians remained comparable (51.80 ± 9.56 and 48.97 ± 9.92 versus 50.06 ± 10.94, respectively, P = 0.4659). No stroke, vascular complications, pericardial effusions, or readmissions related to WATCHMAN™ occurred. No difference among patients <80, ≥80, and ≥90 years was found in major bleeding events, DRT, prolonged LOS, or AKI (P = 0.0569, 0.116, 0.498, and 0.795, respectively).\n\n\n\nOctogenarians and nonagenarians experience favorable long-term QoL after WATCHMAN™, with acceptable bleeding risk and low incidence of procedure-related complications.",
"affiliations": "University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.;University of Miami-JFK Medical Center Palm Beach Regional GME Consortium, Atlantis, Florida.",
"authors": "Ramos Tuarez|Fergie J|FJ|0000-0002-8027-7063;Pino|Jesus E|JE|0000-0003-1920-9392;Alrifai|Abdulah|A|0000-0002-4696-8645;Kabach|Mohamad|M|;Donath|Elie|E|;Saona|Jorge|J|;Chavez|Julio Grajeda|JG|;Diaz|Ximena Torres|XT|;Jimenez|Marcelo|M|;Chait|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/ccd.28020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1522-1946",
"issue": "93(6)",
"journal": "Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions",
"keywords": "bleeding; elderly patients; left atrial appendage closure; stroke",
"medline_ta": "Catheter Cardiovasc Interv",
"mesh_terms": "D000367:Age Factors; D000369:Aged, 80 and over; D020517:Atrial Appendage; D001281:Atrial Fibrillation; D006328:Cardiac Catheterization; D004867:Equipment Design; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D011788:Quality of Life; D012189:Retrospective Studies; D012307:Risk Factors; D020521:Stroke; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100884139",
"other_id": null,
"pages": "1138-1145",
"pmc": null,
"pmid": "30548449",
"pubdate": "2019-05-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Long-term quality of life in octogenarians and nonagenarians with nonvalvular atrial fibrillation following WATCHMAN™ device implantation.",
"title_normalized": "long term quality of life in octogenarians and nonagenarians with nonvalvular atrial fibrillation following watchman device implantation"
} | [
{
"companynumb": "US-BAYER-2019-098107",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "Carboplatin is characterized by low nephrotoxicity, including acute tubular necrosis (ATN), compared to a conventional platinum complex due to its low accumulative property in the renal tubules. Therefore, there are extremely few reports of carboplatin-induced kidney injury and only one case has been histologically examined. Herein, we describe the case of a 53-year-old man who presented with acute kidney injury (AKI) that occurred after carboplatin administration and was diagnosed with biopsy-proven acute interstitial nephritis (AIN). To our knowledge, this is the second case report of carboplatin-related AIN. The patient was diagnosed with a pancreatic neuroendocrine tumor, and chemotherapy consisting of cisplatin and irinotecan was initiated. However, 1 week later, he was admitted to our institution with fever, fatigue and an increase in C-reactive protein (CRP) level. The chemotherapy regimen was altered to carboplatin and etoposide, but high fever occurred on the first day, and CRP re-elevation and AKI became apparent 9 days later. Renal biopsy revealed prominent inflammatory cell infiltration into the interstitium, which lead to the pathological diagnosis of AIN. On immunostaining for surface markers, CD3- and CD68-positive cells were found to be predominant, and CD20-positive cells were relatively few. Although the serum creatinine level increased to 6.81 mg/dL, it decreased to 1.43 mg/dL 15 days after steroid therapy. This case demonstrated that carboplatin-related kidney injury includes not only ATN but also AIN. Appropriate pathological diagnosis including renal biopsy and indications for steroid treatment should be carefully considered.",
"affiliations": "Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan. t-katsuno@aichi-med-u.ac.jp.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Pathology, National Hospital Organization Chibahigashi National Hospital, Chiba, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.;Department of Nephrology and Rheumatology, Aichi Medical University, 1-1 Karimata, Yazako, Nagakute, Aichi, 480-1195, Japan.",
"authors": "Asai|Akimasa|A|;Katsuno|Takayuki|T|;Yamaguchi|Makoto|M|;Iwagaitsu|Shiho|S|;Nobata|Hironobu|H|;Kinashi|Hiroshi|H|;Kitamura|Hiroshi|H|;Banno|Shogo|S|;Ito|Yasuhiko|Y|",
"chemical_list": "D003432:Cross-Linking Reagents; D013256:Steroids; D002097:C-Reactive Protein; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": "10.1007/s13730-019-00437-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-4449",
"issue": "9(2)",
"journal": "CEN case reports",
"keywords": "Acute interstitial nephritis; Acute kidney injury; Carboplatin; Cisplatin; Renal biopsy",
"medline_ta": "CEN Case Rep",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D001706:Biopsy; D002097:C-Reactive Protein; D016190:Carboplatin; D003432:Cross-Linking Reagents; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007684:Kidney Tubules; D008297:Male; D008875:Middle Aged; D009395:Nephritis, Interstitial; D018358:Neuroendocrine Tumors; D010190:Pancreatic Neoplasms; D013256:Steroids",
"nlm_unique_id": "101636244",
"other_id": null,
"pages": "114-121",
"pmc": null,
"pmid": "31834568",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20336051;28893923;20517290;13680535;16914559;10692269;18185501;24629073;11473672;18272962;15340098;7193726;14671029;2003521",
"title": "Carboplatin-related acute interstitial nephritis in a patient with pancreatic neuroendocrine tumor.",
"title_normalized": "carboplatin related acute interstitial nephritis in a patient with pancreatic neuroendocrine tumor"
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"abstract": "A 65-year-old Japanese man with advanced chronic kidney disease (CKD) developed acute-onset type 1 diabetes mellitus (T1D) that was associated with severe acute kidney injury and was manifested by generalized tonic-clonic status epilepticus. His seizures resolved without recurrence after correcting the diabetic ketoacidosis. Although hyperglycemia is an important cause of acute symptomatic seizure (ASS), patients with ketotic hyperglycemia develop ASS less frequently. In this T1D case with CKD, severe hyperglycemia in conjunction with other metabolic insults, such as uremia, hyponatremia, and hypocalcemia, probably provoked his seizure despite the severe ketonemia.",
"affiliations": "Department of Endocrinology and Metabolism, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Respiratory Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Neurology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Neurology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Radiology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Emergency and Critical Care Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Emergency and Critical Care Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.;Department of Emergency and Critical Care Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan.",
"authors": "Ohara|Nobumasa|N|;Koda|Ryo|R|;Watanabe|Hirofumi|H|;Iino|Noriaki|N|;Ohashi|Kazumasa|K|;Terajima|Kenshi|K|;Ozawa|Tetsutaro|T|;Ikeda|Yohei|Y|;Sekiguchi|Hiroshi|H|;Ohashi|Hitomi|H|;Yamaguchi|Seigo|S|",
"chemical_list": null,
"country": "Japan",
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"doi": "10.2169/internalmedicine.56.8304",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2876897010.2169/internalmedicine.56.8304Case ReportGeneralized Status Epilepticus in a Patient with Acute-onset Type 1 Diabetes Mellitus Associated with Severe Kidney Dysfunction: A Case Report and Literature Review Ohara Nobumasa 1Koda Ryo 2Watanabe Hirofumi 2Iino Noriaki 2Ohashi Kazumasa 3Terajima Kenshi 4Ozawa Tetsutaro 4Ikeda Yohei 5Sekiguchi Hiroshi 6Ohashi Hitomi 6Yamaguchi Seigo 6\n1 Department of Endocrinology and Metabolism, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, \n2 Department of Nephrology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan\n3 Department of Respiratory Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan\n4 Department of Neurology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan\n5 Department of Radiology, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, Japan\n6 Department of Emergency and Critical Care Medicine, Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, JapanCorrespondence to Dr. Nobumasa Ohara, oharan@med.niigata-u.ac.jp\n\n1 8 2017 56 15 1993 1999 21 9 2016 12 12 2016 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 65-year-old Japanese man with advanced chronic kidney disease (CKD) developed acute-onset type 1 diabetes mellitus (T1D) that was associated with severe acute kidney injury and was manifested by generalized tonic-clonic status epilepticus. His seizures resolved without recurrence after correcting the diabetic ketoacidosis. Although hyperglycemia is an important cause of acute symptomatic seizure (ASS), patients with ketotic hyperglycemia develop ASS less frequently. In this T1D case with CKD, severe hyperglycemia in conjunction with other metabolic insults, such as uremia, hyponatremia, and hypocalcemia, probably provoked his seizure despite the severe ketonemia. \n\ntype 1 diabetes mellitusgeneralized tonic-clonic status epilepticusdiabetic ketoacidosisacute kidney injurychronic kidney diseaseelectrolyte disturbance\n==== Body\nIntroduction\nType 1 diabetes mellitus (T1D) is characterized by the destruction of pancreatic beta cells and insulin-deficient hyperglycemia (1). The rate of beta-cell destruction varies from patient to patient, and T1D is classified as fulminant, acute-onset, or slowly progressive in Japan depending on the manner of onset and progression (2). Acute-onset T1D is characterized by diabetic ketosis or diabetic ketoacidosis (DKA) within three months after the onset of hyperglycemic symptoms, with or without islet-related autoantibodies (3). Patients may exhibit acute kidney injury (AKI) and electrolyte disturbances in association with severe dehydration when they develop acute-onset T1D (4).\n\nAcute symptomatic seizure (ASS) is a clinical seizure that occurs in close temporal relationship with an acute central nervous system (CNS) or systemic insult (5-7). Major insults include stroke, traumatic brain injury, CNS infections, and toxins and metabolic derangements, including hypo- or hyperglycemia, uremia, and electrolyte disturbances. ASS can involve either focal or generalized seizures, and patients may present with status epilepticus (SE) (8).\n\nAlthough hyperglycemia is an important metabolic insult for ASS (5,6,9), patients with ketotic hyperglycemia less frequently present with ASS than those with non-ketotic hyperglycemia (10-14). Nevertheless, in several case reports, diabetic ketosis (15,16) or DKA (17-21) was associated with ASS, in which the patients usually had coexistent disorders that provoked seizure. However, few studies have investigated patients with T1D and DKA associated with ASS.\n\nWe herein report a rare case of a patient who exhibited generalized SE upon the development of acute-onset T1D and DKA associated with severe AKI and pre-existing advanced chronic kidney disease (CKD). In addition, we review previously reported cases of DKA associated with ASS.\n\nCase Report\nA 65-year-old Japanese man who presented with generalized tonic-clonic SE was admitted to our hospital in February 2016 with a diagnosis of DKA and severe kidney dysfunction. His family history revealed that his father and his paternal uncle had type 2 diabetes mellitus. None of his relatives had a convulsive disorder or mitochondrial disease. The patient had smoked 10 cigarettes/day from 20 to 60 years of age, but had never consumed alcohol. The patient had no history of diabetes mellitus, collagen disease, or a CNS disorder, including head trauma, stroke, or encephalopathy. The patient was found to have kidney dysfunction [serum creatinine, 1.4 mg/dL; estimated glomerular filtration rate (eGFR) (22), 44.9 mL/min/1.73 m2] and untreated hypertension with negative urinalysis results for proteinuria, microhematuria, pyuria, and glycosuria at 42 years of age. The patient had experienced an uneventful clinical course during conservative medical treatment for CKD, except for a gradual increase in the serum creatinine level. Eight months before admission, he was referred to the nephrology department of our hospital (serum creatinine, 2.58 mg/dL; eGFR, 20.3 mL/min/1.73 m2). His height was 145 cm, weight 47 kg, and blood pressure 123/79 mmHg. There were no abnormal physical findings suggesting congenital or other disorders that caused his short stature. No dysacusis, muscle pain, joint pain or swelling, alopecia, or discoid rash was found. A urinalysis detected no protein, blood, pus, or glucose in the urine. His casual plasma glucose (96 mg/dL), glycated hemoglobin (HbA1c) (5.2%), blood lactic acid (11.0 mg/dL, reference range: 4.5-14.4 mg/dL), and serum levels of complement (CH50) (36 U/mL, reference range: 30-45 U/mL) and C-reactive protein (0.13 mg/dL) were normal. Anti-nuclear antibody was negative. Abdominal ultrasonography showed bilateral atrophic kidneys. The patient continued medical treatment with oral valsartan (40 mg/day), furosemide (20 mg/day), sodium bicarbonate (2 g/day), febuxostat (10 mg/day), calcium polystyrene sulfonate (5 g/day) and alfacalcidol (1 μg/day), and subcutaneous darbepoetin alfa (30 μg/month) for CKD-related hypertension, fluid retention, metabolic acidosis, hyperuricemia, hypocalcemia, and renal anemia, respectively. One month before admission, he weighed 47 kg, and his blood pressure was 128/79 mmHg. Blood chemistry revealed the following: venous pH, 7.359; bicarbonate, 23.6 mmol/L; red blood cells, 359×104/μL; hemoglobin 11.8 g/dL; hematocrit, 34.2%; creatinine, 2.54 mg/dL; eGFR, 20.7 mL/min/1.73 m2; urea nitrogen, 30.6 mg/dL; uric acid, 7.4 mg/dL; albumin, 4.1 g/dL; sodium, 142 mEq/L; potassium, 3.3 mEq/L; chloride, 104 mEq/L; calcium, 7.2 mg/dL; phosphorus, 3.0 mg/dL; and casual plasma glucose, 95 mg/dL. The patient developed a cough and sore throat 7 days before admission. Three days later, he became unusually thirsty and was polyuric. On the day of admission, he developed a generalized tonic-clonic seizure with disturbed consciousness and was brought by ambulance to our hospital.\n\nOn arrival at the hospital, the patient was comatose and presented with generalized tonic-clonic seizures that lasted several minutes and frequently recurred. His seizures were controlled with intravenous diazepam, but he rapidly developed respiratory depression, and he was placed on mechanical ventilation. A physical examination revealed body weight, body temperature, and blood pressure of 42 kg, 34.7℃, and 82/48 mmHg, respectively. His oral cavity was markedly dry. No chest rales, heart murmurs, or peripheral edema was detected. Electrocardiogram showed sinus tachycardia with a heart rate of 120 beats/min. Blood chemistry (Table 1) revealed severe hyperglycemia (casual plasma glucose, 1,272 mg/dL), ketonemia (serum 3-hydroxybutyrate, 11,210 μmol/L), renal dysfunction (serum creatinine, 6.96 mg/dL; eGFR, 6.5 mL/min/1.73 m2), uremia (serum urea nitrogen, 109.4 mg/dL), and metabolic acidosis (arterial pH, 6.992; bicarbonate, 4.7 mmol/L). The serum levels of creatinine kinase (619 IU/L), uric acid (9.1 mg/dL), potassium (5.6 mEq/L), and phosphorus (9.8 mg/dL), and those of exocrine pancreatic enzymes, including amylase, lipase, elastase-1, and phospholipase A2, were high. The serum levels of sodium (111 mEq/L) and calcium (6.4 mg/dL) were low. HbA1c (6.9%) and serum glycated albumin (37.5%) were slightly and moderately high, respectively. Computed tomography revealed no abnormalities in the brain, lungs, heart, liver, pancreas, or spleen, except for bilateral kidney atrophy. He was diagnosed with DKA, severe hypovolemia, prerenal AKI, and electrolyte disturbances, and was treated with intravenous saline, calcium gluconate, and regular insulin. His seizures were considered to be due to severe metabolic derangements, and sedation was continued using intravenous midazolam under ventilation.\n\nTable 1. Laboratory Findings at the Time of Admission (February 2016).\n\nHematology\t\nRed blood cells\t363×104/μL\t(435-555)\t\nHemoglobin\t12.0 g/dL\t(13.7-16.8)\t\nHematocrit\t33.8 %\t(40.7-50.1)\t\nWhite blood cells\t13,300/μL\t(3,300-8,600)\t\nPlatelets\t29.3×104/μL\t(15.8-34.8)\t\nBlood chemistry\t\nCasual plasma glucose\t1,272 mg/dL\t(70-139)\t\nGlycated hemoglobin (HbA1c)\t6.9 %\t(4.6-6.2)\t\nGlycated albumin\t37.5 %\t(11.6-16.4)\t\nAcetoacetate\t2,420 μmol/L\t(<55)\t\n3-Hydroxybutyrate\t11,210 μmol/L\t(<85)\t\nTotal protein\t5.0 g/dL\t(6.6-8.1)\t\nAlbumin\t3.3 g/dL\t(4.1-5.1)\t\nTotal cholesterol\t143 mg/dL\t(130-220)\t\nTriglycerides\t45 mg/dL\t(50-130)\t\nAspartate aminotransferase\t21 IU/L\t(13-30)\t\nAlanine aminotransferase\t19 IU/L\t(10-42)\t\nGamma-glutamyl transferase\t16 IU/L\t(13-64)\t\nAmylase\t276 IU/L\t(44-132)\t\nLipase\t249 U/L\t(17-57)\t\nElastase-1\t1,363 ng/mL\t(72-432)\t\nPhospholipase A2\t1,684 ng/dL\t(130-400)\t\nCreatine kinase\t619 IU/L\t(59-248)\t\nUrea nitrogen\t109.4 mg/dL\t(8.0-18.4)\t\nCreatinine\t6.96 mg/dL\t(0.65-1.07)\t\neGFR*\t6.5 mL/min/1.73 m2\t(>90)\t\nUric acid\t9.1 mg/dL\t(3.7-7.8)\t\nSodium\t111 mEq/L\t(138-145)\t\nPotassium\t5.6 mEq/L\t(3.6-4.8)\t\nChloride\t67 mEq/L\t(101-108)\t\nCalcium\t6.4 mg/dL\t(8.8-10.1)\t\nPhosphorus\t9.8 mg/dL\t(2.7-4.6)\t\nMagnesium\t1.89 mg/dL\t(1.7-2.3)\t\nC-reactive protein\t1.33 mg/dL\t(0-0.14)\t\nIntact-parathyroid hormone\t84 pg/mL\t(10-65)\t\nArterial blood gas analysis on artificial respiration\t\npH\t6.992\t(7.35-7.45)\t\nPartial carbon dioxide pressure\t19.3 mmHg\t(32-48)\t\nPartial oxygen pressure\t393.0 mmHg\t(83-108)\t\nBicarbonate\t4.7 mmol/L\t(21-28)\t\nThe reference range for each parameter is shown in parentheses.\n\n*Estimated glomerular filtration rate was calculated using the published Japanese equation as follows (22): eGFR (mL/min/1.73 m2)=0.808×175×serum creatinine (mg/dL)-1.154×age-0.203.\n\nHis blood pressure was maintained at >100/60 mmHg, and his anuria resolved within 4 hours. His plasma glucose levels decreased at a rate of approximately 70 mg/dL/h, and his serum sodium levels increased gradually. Sixteen hours after admission, his arterial pH was 7.289, plasma glucose was 261 mg/dL, and serum sodium was 128 mEq/L. After his severe dehydration had been corrected, he received sufficient fluid volume by maintenance infusion.\n\nBlood chemistry performed on day 7 of admission showed the following results: arterial pH, 7.426; bicarbonate, 22.4 mmol/L; creatinine, 6.03 mg/dL, eGFR, 7.6 mL/min/1.73 m2; urea nitrogen, 84.9 mg/L; uric acid, 6.7 mg/dL; albumin, 2.7 g/dL; sodium, 138 mEq/L; potassium, 3.8 mEq/L; chloride, 100 mEq/L; calcium, 7.0 mg/dL; phosphorus, 3.4 mg/dL; and casual plasma glucose, 165 mg/dL. Because his metabolic status improved, sedation therapy was terminated, and the patient was weaned from ventilatory support on the same day. He recovered consciousness and no longer presented any seizures or other neurological abnormalities.\n\nThe patient's fasting serum C-peptide levels before and 5 minutes after intravenous glucagon loading were <0.2 ng/mL and <0.2 ng/mL, respectively, indicating a diagnosis of T1D. He tested negative for islet-related autoantibodies, such as glutamic acid decarboxylase antibody (<5.0 U/mL), islet cell antibody (<1.25 JDF units), insulinoma-associated antigen-2 antibody (<0.4 U/mL), insulin antibody (<125.0 nU/mL), and zinc transporter-8 antibody (<10.0 U/mL). He was also negative for anti-anterior pituitary, thyroid peroxidase, thyroglobulin, thyroid-stimulating hormone receptor, and anti-adrenal autoantibodies. Human leukocyte antigen (HLA) typing showed A*24/26, B*40/(-), and C*08:01/(-) class I genes and DRB1*08:03/15:01, DQB1*06:01/06:02, and DQA1*01:02/01:03 class II genes.\n\nThe patient regained his appetite and was started on subcutaneous insulin injection therapy on day 14 of admission. A funduscopic examination detected no diabetic retinopathy. An electroencephalographic examination performed on day 18 revealed no findings suggestive of an epileptogenic disorder. Magnetic resonance imaging (MRI) of the brain performed on day 20 showed no abnormalities, except for scattered hyperintense areas in the bilateral cerebral white matter on both T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Figure). No arterial lesions were detected on magnetic resonance angiography.\n\nFigure. Brain magnetic resonance image (day 20 after admission in February 2016). Magnetic resonance imaging showed scattered hyperintense signals in the bilateral cerebral white matter on both T2-weighted (B) and fluid-attenuated inversion recovery (C) images, but no abnormal-intensity signals were found on T1-weighted (A) or diffusion-weighted (D) images.\n\nThe patient was discharged on day 46 of admission after completing a diabetes mellitus self-management education program. In August of the same year, he weighed 43.9 kg, and blood chemistry showed the following results: venous pH, 7.396; bicarbonate, 21.1 mmol/L; serum creatinine, 3.60 mg/dL; eGFR, 13.8 mL/min/1.73 m2; urea nitrogen, 58.1 mg/dL; uric acid, 5.3 mg/dL; albumin, 3.3 g/dL; sodium, 137 mEq/L; potassium, 3.9 mEq/L; chloride, 100 mEq/L; calcium, 7.9 mg/dL; phosphorus, 4.9 mg/dL; casual plasma glucose, 185 mg/dL; serum C-peptide, <0.2 ng/mL; HbA1c, 7.3%; and glycated albumin, 29.0%, under conventional medical treatment for CKD and multiple daily insulin injection therapy (total of 26 units/day) for diabetes mellitus. Brain MRI performed in August 2016 showed scattered hyperintense signals in the bilateral cerebral white matter on both T2-weighted and FLAIR images, which remained unchanged compared to those on MRI taken six months prior (Figure) and indicated asymptomatic chronic ischemic changes in relation to his aging and long-standing CKD (23). His subsequent clinical course was stable without recurrence of seizure.\n\nDiscussion\nAn elderly Japanese patient with advanced CKD abruptly developed T1D and DKA that was accompanied by severe AKI and manifested as generalized tonic-clonic SE. His seizures resolved after correcting the DKA, electroencephalographic examinations showed no findings suggestive of epileptogenic disorder, and brain MRI detected no remarkable findings, except for chronic cerebral white matter ischemic changes. The patient experienced no recurrence of seizures during medical treatment for T1D and CKD. This is the first reported case of proven T1D and DKA associated with ASS.\n\nTable 2 summarizes the reported patients who exhibited ASS in association with DKA. These cases included adults with various etiologies and durations of diabetes mellitus who presented with focal or generalized seizures. The patients had a variety of coexisting CNS or systemic disorders capable of precipitating seizures, including severe hypernatremia (17), mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes (MELAS) syndrome (18,19), and traumatic brain injury and theophylline intoxication in relation to the management of chronic obstructive pulmonary disease (21). In the present case, CNS insults, including traumatic brain injury and MELAS, were ruled out by the clinical, laboratory, and imaging findings.\n\nTable 2. Summary of Reported Patients who Exhibited Acute Symptomatic Seizure in Association with Diabetic Ketoacidosis.\n\nCase\tAge (years)\tSex\tType of seizure*\tEtiology of diabetes mellitus**\tKnown duration of diabetes mellitus (years)\tHbA1c (%)\tPlasma glucose (mg/dL)\tSerum 3-hydro xybutyrate (μmol/L)\tArterial pH\tSerum creatinine (mg/dL)\tSerum urea nitrogen (mg/dL)\tMagnetic resonance imaging of the brain\tComplicating disorders\tRef.\t\n1\t46\tFemale\tGeneralized\tUndetermined\t0\tN.D.\t890\tN.D.\tN.D.\tN.D.\t54\tN.D.\tElectrolyte disturbance (Severe hypernatremia)\t(17)\t\n2\t49\tFemale\tGeneralized\tMitochondrial\t15\t10.7\t1,231\t1,410\t7.12\t1.3\t49\tN.D.\tMELAS\t(18)\t\n3\t33\tFemale\tFocal\tMitochondrial\t15\tN.D.\t540\t1,990\t6.88\tN.D.\tN.D.\tHyperintense areas on FLAIR images in the bilateral temporal and occipital lobes (abnormal lactic acid accumulation)\tMELAS\t(19)\t\n4\t44\tMale\tFocal\tPancreatic\t0\tN.D.\t506\tN.D.\t7.28\tN.D.\tN.D.\tHypointensity on FLAIR images in the left subcortical precentral gyrus (possibly crossed cerebellar diaschisis) and hyperintensity in the right cerebellar hemisphere (possibly cerebral injury secondary to ASS)\tPrevious alcohol abuse, chronic pancreatitis\t(20)\t\n5\t80\tMale\tGeneralized\tType 2\t20\t14.0\t608\tN.D.\t7.22\tN.D.\tN.D.\tSlim subacute subdural hematomas over the bilateral occipital lobes\tTheophylline intoxication, traumatic brain injury\t(21)\t\n6\t59\tMale\tGeneralized\tType 1\t0\t6.9\t1,272\t11,210\t6.99\t7.0\t109\tScattered hyperintense areas in the bilateral cerebral white matter on T2-weighted and FLAIR images (chronic ischemic changes)\tAKI on advanced CKD, electrolyte disturbance (hyponatremia and hypocalcemia)\tPresent case\t\n*Seizures were divided into focal or generalized, according to the clinical presentation (8).\n\n**Diabetes mellitus was classified as type 1, type 2, gestational, or “other specific types,” based on the published etiological classification (1). “Other specific types” included pancreatic or mitochondrial diabetes mellitus. The etiology of diabetes mellitus in Case 1 was undetermined because of a lack of information regarding endogenous insulin secretory capacity, islet-related autoantibodies, or a requirement for insulin treatment to survive after the onset of diabetes mellitus.\n\nAKI: acute kidney injury, ASS: acute symptomatic seizure, CKD: chronic kidney disease, FLAIR: fluid-attenuated inversion recovery, HbA1c: glycated hemoglobin, MELAS: mitochondrial myopathy encephalopathy lactic acidosis and stroke-like episodes, N.D.: not described\n\nOne of the notable findings at the onset of T1D in our patient was the marked hyperglycemia and related metabolic derangements. He had more severe hyperglycemia, electrolyte disturbances including hyponatremia, AKI, uremia, ketonemia, and metabolic acidosis than typical cases of T1D (24). Studies have shown that patients with CKD exhibit insulin resistance (25), which may accelerate the rate of elevation of blood glucose levels during the reduction of endogenous insulin secretion at the development of T1D. CKD also causes non-volatile acid accumulation as a result of decreased renal excretion or disturbed acid-base homeostasis. In our patient, the advanced CKD probably increased the severity of hyperglycemia, ketonemia, and metabolic acidosis by inducing insulin resistance and acid accumulation. Simultaneously, his severe hyperglycemia and resulting osmotic diuresis led to the observed marked hypovolemic hyponatremia, prerenal AKI, and uremia.\n\nThe mechanisms underlying ASS when T1D occurred in our patient remain unclear. However, hyperglycemia is thought to decrease the seizure threshold (9), possibly through decreased levels of gamma-aminobutyric acid (GABA; the major CNS inhibitory neurotransmitter) (10-12), reduced blood flow in an area of a previously silent cerebral lesion (26), or disruption of the blood-brain barrier (27). In contrast, several lines of evidence suggest that ketone bodies have a protective effect against seizures through increased GABA production or altered neuronal responsiveness to GABA (28-31). These findings suggest that severe hyperglycemia in conjunction with other metabolic insults, such as uremia and electrolyte disturbances, including acute hypovolemic hyponatremia and chronic hypocalcemia, probably provoked the seizures despite the patient exhibiting severe ketonemia (Table 1).\n\nCKD can be caused by a variety of renal disorders, and major causes include diabetic nephropathy, hypertensive nephrosclerosis, glomerulonephritis, and collagen diseases, such as lupus nephritis (32). Our patient had no history of diabetes mellitus before he was diagnosed with CKD, and glomerulonephritis and collagen disease were ruled out based on the clinical, urinary, and serological findings. A kidney biopsy was not indicated because our patient already had advanced CKD with atrophic kidneys when he was referred to our hospital; consequently, no histopathological diagnosis was obtained. However, the presence of untreated hypertension at the diagnosis of kidney dysfunction suggests that hypertensive nephrosclerosis was a causal factor for his CKD.\n\nFulminant T1D is a subtype of T1D that results from the extremely rapid and almost complete destruction of pancreatic beta cells (2). The published criteria for diagnosing this disorder require near normal HbA1c values despite high plasma glucose levels at disease onset, which reflects the abrupt occurrence of hyperglycemia within a few days (33). Our patient abruptly developed insulin-deficient hyperglycemia and DKA with an HbA1c value of 6.9% and seemed to develop fulminant T1D. However, because he had advanced CKD and anemia treated with erythropoiesis-stimulating agents, he probably showed a lower HbA1c value than one truly reflecting the average blood glucose levels over the preceding few months (34). Furthermore, his serum levels of glycated albumin, another indicator reflecting the average previous blood glucose levels, were substantially higher than is usual in cases of fulminant T1D (35). Based on these findings, we diagnosed him with acute-onset T1D.\n\nIn conclusion, we reported a patient who exhibited generalized tonic-clonic SE upon development of acute-onset T1D and DKA that was associated with severe AKI and advanced CKD. Severe hyperglycemia in conjunction with uremia, hyponatremia, and hypocalcemia probably provoked the seizure, despite the patient exhibiting severe ketonemia. The present case highlights the need for physicians to consider that ASS can be associated with DKA, including that of T1D onset, and may occur in the presence of other metabolic derangements, such as uremia and electrolyte disturbances. In addition, ASS can occur as a predominant manifestation of T1D onset, particularly when patients have pre-existing advanced kidney dysfunction.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n\nAcknowledgement\nThe authors thank the clinical laboratory technicians of Uonuma Institute of Community Medicine, Niigata University Medical and Dental Hospital, for their technical support.\n==== Refs\n1. American Diabetes Association \nDiagnosis and classification of diabetes mellitus . Diabetes Care \n37 (Suppl 1 ): S81 -S90 , 2014 .24357215 \n2. Kawasaki E , Matsuura N , Eguchi K \nType 1 diabetes in Japan . Diabetologia \n49 : 828 -836 , 2006 .16568259 \n3. Kawasaki E , Maruyama T , Imagawa A , et al \nDiagnostic criteria for acute-onset type 1 diabetes mellitus (2012): report of the Committee of Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus . J Diabetes Investig \n5 : 115 -118 , 2014 .\n4. Kitabchi AE , Umpierrez GE , Miles JM , Fisher JN \nHyperglycemic crises in adult patients with diabetes . Diabetes Care \n32 : 1335 -1343 , 2009 .19564476 \n5. Beghi E , Carpio A , Forsgren L , et al \nRecommendation for a definition of acute symptomatic seizure . Epilepsia \n51 : 671 -675 , 2010 .19732133 \n6. McLauchlan DJ , Powell R \nAcute symptomatic seizures . Pract Neurol \n12 : 154 -165 , 2012 .22661346 \n7. Nardone R , Brigo F , Trinka E \nAcute symptomatic seizures caused by electrolyte disturbances . J Clin Neurol \n12 : 21 -33 , 2016 .26754778 \n8. The Commission on Classification and Terminology of the International League Against Epilepsy \nProposal for revised clinical and electroencephalographic classification of epileptic seizures . Epilepsia \n22 : 489 -501 , 1981 .6790275 \n9. Stafstrom CE \nHyperglycemia lowers seizure threshold . Epilepsy Curr \n3 : 148 -149 , 2003 .15309063 \n10. Guisado R , Arieff AI \nNeurologic manifestations of diabetic comas: correlation with biochemical alterations in the brain . Metabolism \n24 : 665 -679 , 1975 .805337 \n11. Singh BM , Strobos RJ \nEpilepsia partialis continua associated with nonketotic hyperglycemia: clinical and biochemical profile of 21 patients . Ann Neurol \n8 : 155 -160 , 1980 .6775582 \n12. Hennis A , Corbin D , Fraser H \nFocal seizures and non-ketotic hyperglycaemia . J Neurol Neurosurg Psychiatry \n55 : 195 -197 , 1992 .1564479 \n13. Tiamkao S , Pratipanawatr T , Tiamkao S , Nitinavakarn B , Chotmongkol V , Jitpimolmard S \nSeizures in nonketotic hyperglycaemia . Seizure \n12 : 409 -410 , 2003 .12915089 \n14. Gao X , Wee AS , Nick TG \nEffect of keto-acidosis on seizure occurrence in diabetic patients . J Miss State Med Assoc \n46 : 131 -133 , 2005 .15960181 \n15. Martínez-Fernández R , Gelabert A , Pablo MJ , Carmona O , Molins A \nStatus epilepticus with visual seizures in ketotic hyperglycemia . Epilepsy Behav \n16 : 660 -662 , 2009 .19884045 \n16. Oe R , Yamaguchi H , Bando T , et al \nA late elderly patient who developed acute-onset type 1 diabetes in the course of maintenance hemodialysis for non-diabetic renal failure . Shikoku Igaku Zasshi (Shikoku Acta Medica) \n71 : 149 -154 , 2015 (in Japanese, Abstract in English).\n17. Gurling K \nConvulsions during diabetic ketosis; a case report . Diabetes \n5 : 486 -488 , 1956 .13375447 \n18. Hosojima H , Itoh T , Hotta F , et al \nA case of diabetes mellitus with the 3243 (A→G) mutation in mitochondrial DNA and subsequent manifestation of mitochondrial encephalopathy (MELAS) . Kanazawa Ika Daigaku Zasshi (J Kanazawa Med Univ) \n22 : 290 -295 , 1997 (in Japanese, Abstract in English).\n19. Nakamura S , Yoshinari M , Wakisaka M , et al \nKetoacidosis accompanied by epileptic seizures in a patient with diabetes mellitus and mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) . Diabetes Metab \n26 : 407 -410 , 2000 .11119021 \n20. Placidi F , Floris R , Bozzao A , et al \nKetotic hyperglycemia and epilepsia partialis continua . Neurology \n57 : 534 -537 , 2001 .11502930 \n21. Chou CH , Lin JC , Peng GS \nStatus epilepticus associated with initiation of theophylline in an elderly patient with diabetic ketoacidosis . Neurol India \n55 : 154 -156 , 2007 .17558122 \n22. Matsuo S , Imai E , Horio M , et al ; Collaborators developing the Japanese equation for estimated GFR \nRevised equations for estimated GFR from serum creatinine in Japan . Am J Kidney Dis \n53 : 982 -992 , 2009 .19339088 \n23. Yao H , Takashima Y , Hashimoto M , Uchino A , Yuzuriha T \nSubclinical cerebral abnormalities in chronic kidney disease . Contrib Nephrol \n179 : 24 -34 , 2013 .23652446 \n24. Imagawa A , Hanafusa T , Uchigata Y , et al \nFulminant type 1 diabetes: a nationwide survey in Japan . Diabetes Care \n26 : 2345 -2352 , 2003 .12882860 \n25. Leyking S , Fliser D \nInsulin resistance in CKD . Clin J Am Soc Nephro \n19 : 638 -640 , 2014 .\n26. Duckrow RB , Beard DC , Brennan RW \nRegional cerebral blood flow decreases during hyperglycemia . Ann Neurol \n17 : 267 -272 , 1985 .3922283 \n27. Kim DW , Moon Y , Gee Noh H , Choi JW , Oh J \nBlood-brain barrier disruption is involved in seizure and hemianopsia in nonketotic hyperglycemia . Neurologist \n17 : 164 -166 , 2011 .21532388 \n28. Roberts E , Rothstein M , Baxter CF \nSome metabolic studies of gamma-aminobutyric acid . Proc Soc Exp Biol Med \n97 : 796 -802 , 1958 .13554485 \n29. Bough KJ , Rho JM \nAnticonvulsant mechanisms of the ketogenic diet . Epilepsia \n48 : 43 -58 , 2007 .17241207 \n30. Yudkoff M , Daikhin Y , Horyn O , Nissim I , Nissim I \nKetosis and brain handling of glutamate, glutamine, and GABA . Epilepsia \n49 (Suppl 8 ): 73 -75 , 2008 .\n31. McNally MA , Hartman AL \nKetone bodies in epilepsy . J Neurochem \n121 : 28 -35 , 2012 .22268909 \n32. Levey AS , Coresh J \nChronic kidney disease . Lancet \n379 : 165 -180 , 2012 .21840587 \n33. Imagawa A , Hanafusa T , Awata T , et al \nReport of the Committee of the Japan Diabetes Society on the research of fulminant and acute-onset type 1 diabetes mellitus: new diagnostic criteria for fulminant type 1 diabetes mellitus (2012) . J Diabetes Investig \n3 : 536 -539 , 2012 .\n34. Inoue K , Goto A , Kishimoto M , et al \nPossible discrepancy of HbA1c values and its assessment among patients with chronic renal failure, hemodialysis and other diseases . Clin Exp Nephrol \n19 : 1179 -1783 , 2015 .25824109 \n35. Koga M , Kanehara H , Bando Y , Morita S , Kasayama S \nIs glycated albumin useful for differential diagnosis between fulminant type 1 diabetes mellitus and acute-onset autoimmune type 1 diabetes mellitus? \nClin Chim Acta \n451 （Pt B ）: 297 -300 , 2015 .26477482\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "56(15)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acute kidney injury; chronic kidney disease; diabetic ketoacidosis; electrolyte disturbance; generalized tonic-clonic status epilepticus; type 1 diabetes mellitus",
"medline_ta": "Intern Med",
"mesh_terms": "D000208:Acute Disease; D058186:Acute Kidney Injury; D000368:Aged; D001921:Brain; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D006801:Humans; D006943:Hyperglycemia; D008279:Magnetic Resonance Imaging; D008297:Male; D051436:Renal Insufficiency, Chronic; D013226:Status Epilepticus",
"nlm_unique_id": "9204241",
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"pages": "1993-1999",
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"pmid": "28768970",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
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"title": "Generalized Status Epilepticus in a Patient with Acute-onset Type 1 Diabetes Mellitus Associated with Severe Kidney Dysfunction: A Case Report and Literature Review.",
"title_normalized": "generalized status epilepticus in a patient with acute onset type 1 diabetes mellitus associated with severe kidney dysfunction a case report and literature review"
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"abstract": "Ischemic stroke and major bleeding, mostly due to intracranial hemorrhage (ICH), cause about the same rates of death in pivotal randomized trials of direct oral anticoagulants (DOACs) versus warfarin for stroke prevention in atrial fibrillation (AF). We analyzed our AF inpatient database to determine whether any ICH-related deaths were potentially preventable. Among 5008 patients admitted to our institution between May 2008 and September 2014 with a diagnosis of AF, eight had fatal ICH between admission and 90 days follow-up. The mean age of these patients was 85 years; 62% were male. Localization of the ICH was intraparenchymal in 62% and subdural in 38%. CHA2DS2-VASc scores ranged from 4 to 7, and the HAS-BLED scores ranged from 3 to 7. Three of the eight fatal ICHs were directly due to falls. All 8 patients were taking warfarin. One was taking concomitant aspirin. At the time ICH was diagnosed, one patient had an INR of 5.4. Five patients had an INR within the target therapeutic range of 2.0-3.0, and two had an INR less than 2.0. After multivariate adjustment, a history of falls was the sole independent predictor of fatal ICH (OR 22.3; 95% CI 2.5-60.3). In conclusion, most patients had achieved the target INR at the time of ICH, and the primary precipitant of fatal ICH was often a fall. Using DOACs instead of warfarin and implementing structured fall-prevention programs in high-risk patients could further reduce mortality from ICH in AF.",
"affiliations": "Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA. rchopardditjean@bwh.harvard.edu.;Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.;Center for Clinical Investigation, Brigham and Women's Hospital, Boston, MA, 02115, USA.;Department of Pharmacy, Brigham and Women's Hospital, Boston, MA, USA.;Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA, 02115, USA.",
"authors": "Chopard|Romain|R|;Piazza|Gregory|G|;Hurwitz|Shelley|S|;Fanikos|John|J|;Goldhaber|Samuel Z|SZ|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin",
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"doi": "10.1007/s11239-018-1767-2",
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"issue": "47(2)",
"journal": "Journal of thrombosis and thrombolysis",
"keywords": "Anticoagulation; Atrial fibrillation; Falls; Intra-cranial hemorrhage",
"medline_ta": "J Thromb Thrombolysis",
"mesh_terms": "D000058:Accidental Falls; D000368:Aged; D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D001777:Blood Coagulation; D016208:Databases, Factual; D005260:Female; D006801:Humans; D007297:Inpatients; D019934:International Normalized Ratio; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D013997:Time Factors; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014859:Warfarin",
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"title": "Fatal warfarin-associated intracranial hemorrhage in atrial fibrillation inpatients.",
"title_normalized": "fatal warfarin associated intracranial hemorrhage in atrial fibrillation inpatients"
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"abstract": "Percutaneous cryoablation for renal tumors may be associated with rare complications such as injury to the ureter. A 65-year-old woman underwent percutaneous cryoablation after a transcatheter arterial embolization using lipiodol and ethanol for left renal oncocytoma. Two months after the percutaneous cryoablation, computed tomography images showed left hydronephrosis caused by high-density debris, which was assumed to be sloughed tumor with lipiodol accumulation in the left ureter. A stent was placed in the left ureter to enhance the drainage of urine and the necrotic cell debris. Three months later, the ureteral stent was removed, and she remained asymptomatic during the follow-up period of 4 months. We should consider the possibility of urinary tract obstruction by sloughed tumor when hydronephrosis occurs after percutaneous cryoablation of a renal tumor.",
"affiliations": "Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.;Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.;Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.;Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.;Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.;Department of Radiology, Okayama University Hospital, 2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558.",
"authors": "Okawa|Hiro|H|;Gobara|Hideo|H|;Matsui|Yusuke|Y|;Iguchi|Toshihiro|T|;Hiraki|Takao|T|;Kanazawa|Susumu|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.radcr.2018.08.014",
"fulltext": "\n==== Front\nRadiol Case RepRadiol Case RepRadiology Case Reports1930-0433Elsevier S1930-0433(18)30359-510.1016/j.radcr.2018.08.014Complications of TherapyUreteral obstruction by sloughed tumor complicating cryoablation of a\nrenal oncocytoma Okawa Hiro h-okawa06@hotmail.co.jphiokawa17@gmail.com⁎Gobara Hideo MDMatsui Yusuke MDIguchi Toshihiro MDHiraki Takao MDKanazawa Susumu MDDepartment of Radiology, Okayama University Hospital,\n2-5-1 Shikata-cho, Kita-ku, Okayama, Japan 700-8558⁎ Corresponding author. h-okawa06@hotmail.co.jphiokawa17@gmail.com14 9 2018 12 2018 14 9 2018 13 6 1195 1198 4 8 2018 15 8 2018 15 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Percutaneous cryoablation for renal tumors may be\nassociated with rare complications such as injury to the ureter. A 65-year-old\nwoman underwent percutaneous cryoablation after a transcatheter arterial\nembolization using lipiodol and ethanol for left renal oncocytoma. Two months\nafter the percutaneous cryoablation, computed tomography images showed left\nhydronephrosis caused by high-density debris, which was assumed to be sloughed\ntumor with lipiodol accumulation in the left ureter. A stent was placed in the\nleft ureter to enhance the drainage of urine and the necrotic cell debris. Three\nmonths later, the ureteral stent was removed, and she remained asymptomatic\nduring the follow-up period of 4 months. We should consider the possibility of\nurinary tract obstruction by sloughed tumor when hydronephrosis occurs after\npercutaneous cryoablation of a renal tumor.\n\nKeywords\nCryoablationHydronephrosisUrinary fistulaRenal tumor\n==== Body\nIntroduction\nPercutaneous cryoablation (PCA) is a minimally invasive\ntreatment for renal tumors, with a low frequency of serious complications\n[1]. Although\nhemorrhage is the most common complication of renal PCA rare complications such\nas, injury to the adjacent organs including the bowel or the ureter, abscess\nformation requiring intervention, and pneumothorax could occur. We report a case\nof hydronephrosis, which was caused by the obstruction of the urinary tract by\nsloughed tumor cells after PCA of a renal tumor.\n\nCase report\nA 65-year-old woman with a history of myasthenia gravis was\nreferred to our hospital. Computed tomography (CT) images revealed a 4-cm,\nsolid, endophytic tumor in her left kidney (Fig. 1A) as\nwell as another small tumor in her right kidney. Percutaneous biopsy of the left\nrenal tumor suggested the diagnosis of oncocytoma. We decided to treat the left\nrenal tumor by PCA for addressing the concern regarding the existence of a\nhybrid tumor with features of oncocytoma and renal cell carcinoma [2]. Prior to the PCA, we\nperformed a transcatheter arterial embolization (TAE) to enhance the therapeutic\neffect and to reduce the risk of bleeding. The embolization was selectively\nperformed using a mixture of ethanol and ethiodized oil (Lipiodol, Guerbet,\nVillepinte, France) at a ratio of 7:3. Two days later, PCA of the left renal\ntumor was performed using an argon-based cryoablation system (CryoHit, Galil\nMedical, Yokneam, Israel). First, three 17-gauge cryoprobes (IceRod, Galil\nMedical, Yokneam, Israel) were inserted to the upper part of the tumor. The\ncryoprobes were inserted sequentially in a triangle configuration, under CT\nfluoroscopy guidance. After the placement of the three cryoprobes, PCA was\nperformed in two 15-minute freeze cycles separated by 2 minutes of thawing\n(Fig. 1B). Then,\nthe same treatment was carried out in the lower part of the tumor (Fig. 1C). During freezing, the\nlow-density area (i.e., ice-ball) involved the entire tumor and calices of the\nupper medial part of the left kidney.Fig. 1 (a) Pretreatment contrast-enhanced computed\ntomography (CT) demonstrates a left renal tumor close to the renal pelvis; CT\nduring cryoablation demonstrates a low-density area (i.e. ice ball) with 3\ncryoprobes in the upper (b) and lower (c) parts of the tumor; (d) CT image 2\ndays after the cryoablation shows an ablation zone with an adequate treatment\nmargin.\n\nFig 1\n\nThe CT images obtained 2 days after the PCA demonstrated the\nablation zone, which included the tumor with an adequate ablation margin\n(Fig. 1D), without\nany evidence of complication after the treatment. However, 2 months after the\nPCA, the patient visited our institution with complaints of high fever and\nleft-sided back pain. Laboratory tests revealed an increased inflammatory\nresponse (leukocyte count: 9.88 × 10⁹/L, C-reactive protein: 154 nmol/L). CT\nimages demonstrated a left perirenal abscess and left hydronephrosis with\nhigh-density debris in the lower part of the left ureter (Figs. 2A and B). We supposed that this high-density debris\nconsisted of sloughed tumor with ethiodized oil accumulation and was the cause\nof the urinary tract obstruction. A single-J stent was placed in the left ureter\nfor allowing the drainage of urine and the necrotic tumor debris. The back pain\ndisappeared immediately after the stent placement, whereas the fever and\nlaboratory findings improved gradually. CT images obtained 2 days after the\nstent placement demonstrated improvement in hydronephrosis and drainage of\nnecrotic tumor into the tract of the urinary fistula (Fig. 2C). On the CT images obtained 5 days\nafter the stent placement, the necrotic tumor debris was not observed and the\nhydronephrosis appeared to have improved. The patient was discharged after\nreplacing the single-J stent with a double-J stent. Three months later, the\ndouble-J stent was removed, and she remained asymptomatic during the follow-up\nperiod of 4 months.Fig. 2 (a) Computed tomography (CT) image 2 months after the\ncryoablation shows hydronephrosis with perirenal abscess on the left side and\n(b) high-density debris in the lower part of the left ureter; (c) CT images 2\ndays after the stent placement shows that the necrotic tumor has moved into the\ntract of urinary fistula.\n\nFig 2\n\nDiscussion\nThe frequency of severe complications after PCA of renal\ntumors was reported to be about 2%-6%, and therefore, this treatment is\nrecognized as a minimally invasive treatment for renal tumor [1], [3], [4]. In\ncase of pelvicalyceal or ureteral injury after PCA, ureteral stenosis requiring\nureteral stent placement may occur; however, such a complication is less common\nwith PCA than with radiofrequency ablation [5]. Breen et al. reported only 3 cases of\npelvicalyceal injury among 153 procedures [6]. These 3 patients complained of debris\ncolic, which required temporary ureteral stent placement. Although these cases\nmight appear similar to the current case, further details were not available for\nassessing the similarities.\n\nThe urinary tract obstruction in our patient probably\noccurred by the sloughing of the necrotic tumor cells into the pelvicalyx\nthrough defects on the injured pelvicalyceal wall. However, previous studies\nhave shown that the pelvicalyceal injury was unlikely to occur due to PCA.\nRosenberg et al. reported no evidence of injury, such as urinoma or fistula, to\nthe collecting system in 67 cases of PCA performed with renal sinus involvement\nby ice-ball [7]. Sung\net al. reported no evident urine extravasation after intentional cryoinjury of\nthe renal collecting system in the animals studied [8]. However, the pelvicalyces could be\noccasionally injured, especially when the tumor adjacent to or invading the\npelvicalyces is completely ablated. In our case, the preablative TAE might have\ncontributed to the event as it might have caused ischemia of the tumor and\nsurrounding renal tissue including the pelvicalyceal wall. Ethanol used for the\nTAE could produce a more intense effect than the other embolizing materials such\nas the gelatin sponge particle or microsphere. Renal oncocytoma is a benign\ntumor of the kidney, accounting for 3%-7% of all solid renal neoplasms\n[9]. Jacob et al.\nobserved that only 4% of cases of oncocytoma showed a complete pseudocapsule\ncompared with 80% of cases of clear cell renal cell carcinoma [10]. The lack of the\npseudocapsule might allow the necrotic tissue to slough down to the urinary\ntract. A combination of the above-mentioned factors might be the cause of the\nurinary tract obstruction in the present case. Further, an elevated urinary\npressure accelerated the development of the urinary fistula and caused the\nperirenal abscess.\n\nIn summary, the present case shows that PCA of renal tumor\ncan rarely cause urinary tract obstruction by sloughed tumor cells, resulting in\nhydronephrosis and perirenal abscess. In all cases of perirenal abscess, we\nshould rule out similar causes for urinary obstruction. In the present case, we\ncould detect the necrotic tissue causing urinary obstruction on CT and provide\nappropriate treatment.\n\nInformed consent\nThe patient has provided informed consent for publishing this\ncase report.\n\nEthical approval\nThe study design was exempted from ethics review board\napproval.\n\nAppendix Supplementary materials\nImage, application\n1 \n\nAcknowledgments: The authors wish to acknowledge Dr. Mayu\nUka, Dr. Yoshihisa Masaoka, and Dr. Toshiyuki Komaki for their help with the\npreparation of the manuscript.\n\nFunding: This study was not supported by any\nfunding.\n\nDeclarations of interest: None.\n\nSupplementary material associated with this article can be\nfound, in the online version, at doi:10.1016/j.radcr.2018.08.014.\n==== Refs\nReferences\n1 Atwell TD Carter RE Schmit GD Carr CM Boorjian SA Curry TB Complications following 573 percutaneous renal\nradiofrequency and cryoablation procedures J Vasc Interv Radiol 23 1 2012 48 54 10.1016/j.jvir.2011.09.008 22037491 \n2 Humphrey PA Oncocytoma of the kidney J Urol 187 5 2012 1854 1855 10.1016/j.juro.2012.02.007 22424681 \n3 Georgiades CS Rodriguez R Efficacy and safety of percutaneous cryoablation for\nstage 1A/B renal cell carcinoma: results of a prospective,\nsingle-arm, 5-year study Cardiovasc Intervent Radiol 37 6 2014 1494 1499 10.1007/s00270-013-0831-8 24385225 \n4 Schmit GD Schenck LA Thompson RH Boorjian SA Kurup AN Weisbrod AJ Predicting renal cryoablation complications: new risk\nscore based on tumor size and location and patient\nhistory Radiology 272 3 2014 903 910 10.1148/radiol.14132548 24814178 \n5 Kim KR Thomas S Complication of image-guided thermal ablation of liver\nand kidney neoplasms Semin Intervent Radiol 31 2 2014 138 148 10.1055/s-0034-1373789 25049443 \n6 Breen DJ Bryant TJ Abbas A Shepherd B McGill N Anderson JA Percutaneous cryoablation of renal tumors: outcomes\nfrom 171 tumors in 147 patients BJU Int 112 6 2013 758 765 10.1111/bju.12122 23581293 \n7 Rosenberg MD Kim CY Tsivian M Suberlak MN Sopko DR Polascik TJ Percutaneous cryoablation of renal lesions with\nradiographic ice ball involvement of the renal sinus: analysis\nof hemorrhagic and collecting system\ncomplications AJR Am J Roentgenol 196 4 2011 935 939 10.2214/AJR.10.5182 21427348 \n8 Sung GT Gill IS Hsu TH Meraney AM Skacel M Brainard JA Effect of intentional cryo-injury to the renal\ncollecting system J Urol 170 2 2003 619 622 10.1097/01.ju.0000068722.22186.66 12853843 \n9 Jayaratna I Munver R Disick G Han MW Sawczuk I Paraneoplastic hypertension associated with renal\noncocytoma: management with cryoablation Urology 73 1 2009 9 11 10.1016/j.urology.2008.02.011 18722654 \n10 Jacob JM Williamson SR Gondim DD Leese JA Terry C Grignon DJ Characteristics of the peritumoral pseudocapsule vary\npredictably with histologic subtype of T1 renal\nneoplasms Urology 86 5 2015 956 961 10.1016/j.urology.2015.06.015 26126697\n\n",
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"issue": "13(6)",
"journal": "Radiology case reports",
"keywords": "Cryoablation; Hydronephrosis; Renal tumor; Urinary fistula",
"medline_ta": "Radiol Case Rep",
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"title": "Ureteral obstruction by sloughed tumor complicating cryoablation of a renal oncocytoma.",
"title_normalized": "ureteral obstruction by sloughed tumor complicating cryoablation of a renal oncocytoma"
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... |
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"abstract": "In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.",
"affiliations": "Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria.;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria.;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria.;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;Department of Laboratory Medicine, Medical University of Vienna, Austria.;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;Department of Pathology, Medical University of Vienna, Austria.;Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria.;CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria.;Department of Laboratory Medicine, Medical University of Vienna, Austria.",
"authors": "Valent|Peter|P|;Herndlhofer|Susanne|S|;Schneeweiß|Mathias|M|;Boidol|Bernd|B|;Ringler|Anna|A|;Kubicek|Stefan|S|;Gleixner|Karoline V|KV|;Hoermann|Gregor|G|;Hadzijusufovic|Emir|E|;Müllauer|Leonhard|L|;Sperr|Wolfgang R|WR|;Superti-Furga|Giulio|G|;Mannhalter|Christine|C|",
"chemical_list": "D000814:Aniline Compounds; D007093:Imidazoles; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines; C545373:ponatinib; C471992:bosutinib",
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.15481",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 284167391548110.18632/oncotarget.15481Research PaperTKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML Valent Peter 12Herndlhofer Susanne 12Schneeweiß Mathias 1Boidol Bernd 3Ringler Anna 3Kubicek Stefan 3Gleixner Karoline V. 1Hoermann Gregor 5Hadzijusufovic Emir 12Müllauer Leonhard 4Sperr Wolfgang R. 12Superti-Furga Giulio 36Mannhalter Christine 51 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Austria2 Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Austria3 CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Austria4 Department of Pathology, Medical University of Vienna, Austria5 Department of Laboratory Medicine, Medical University of Vienna, Austria6 Center for Physiology and Pharmacology, Medical University of Vienna, AustriaCorrespondence to: Peter Valent, peter.valent@meduniwien.ac.at4 4 2017 18 2 2017 8 14 23061 23072 14 12 2016 7 2 2017 Copyright: © 2017 Valent et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.In chronic myeloid leukemia (CML) resistance against one or more BCR-ABL1 tyrosine kinase inhibitors (TKI) remains a clinical challenge. Preclinical data suggest that TKI combinations may overcome resistance. We report on a heavily pre-treated 78 year-old female patient with CML who developed multi-resistant blast crisis with bone marrow fibrosis and a Ph- clone. Treatment with ponatinib resulted in blast cell clearance, decrease in fibrosis, and disappearance of BCR-ABL1, but also in severe thrombocytopenia with bleedings requiring platelet transfusions. We therefore switched from ponatinib to bosutinib. During bosutinib, platelet counts recovered. However, after 6 months, BCR-ABL1 mRNA levels increased to > 1%. Therefore, we ´switched back´ to ponatinib, and this was again followed by disappearance of BCR-ABL1 and a decrease in platelets. During the next 2 years, we applied ponatinib and bosutinib in continuous rotation-cycles and added hydroxyurea in order to suppress all sub-clones and to balance between efficacy and potential side effects following the principle of personalized medicine. With this approach the patient remained in complete molecular response and reached normal blood counts and a normal quality of life without vascular or other side effects. In conclusion, TKI rotation is a novel potent approach to suppress multiple resistant sub-clones and to balance between clinical efficacy and side effects in patients with advanced CML. Clinical trials are now warranted to show that TKI-rotation is in general safe and effective in these patients.\n\nCMLponatinibnilotinibBCR-ABL1 mutationsdrug resistance\n==== Body\nINTRODUCTION\nChronic myeloid leukemia (CML) is a hematopoietic neoplasm characterized by expansion and accumulation of myeloid progenitor cells exhibiting the Philadelphia (Ph) chromosome and the related oncoprotein, BCR-ABL1 [1–3]. Usually, patients are diagnosed in the chronic phase (CP) of the disease where most leukemic cells are addicted to the tyrosine kinase (TK) activity of BCR-ABL1. As a consequence the BCR-ABL1-targeting drug imatinib can produce complete and durable cytogenetic responses as well as major or even complete molecular responses (MR3-MR5) in a majority of ´prescription-adherent´ CP patients [4–7]. However, not all patients (even when ´adherent´) are long-term responders. Rather, in about 20–30% of the patients, acquired resistance against imatinib is found [7–10]. In these patients, imatinib-resistant mutants of BCR-ABL1 are detected frequently. For these cases, second-generation BCR-ABL1 TK inhibitors (TKI) are available and are usually prescribed to control the disease [11–15]. These TKI include nilotinib, dasatinib, and bosutinib. All three agents received approval for treatment of imatinib-resistant or -intolerant CML. However, not all mutant forms of BCR-ABL1 are recognized by these drugs. A special problem is the T315I mutation of BCR-ABL1 that is well-known to confer resistance against imatinib, nilotinib, dasatinib, and bosutinib [16–18]. For these patients, stem cell transplantation (SCT) has to be considered. In addition, these patients often respond to ponatinib, a novel TKI that blocks most mutant forms of BCR-ABL1, including T315I [19–22]. Indeed, it has been shown that ponatinib can induce major or even complete cytogenetic responses in patients with TKI-resistant CML in whom neoplastic cells display BCR-ABL1 T315I [20–22]. However, unfortunately, the administration of ponatinib is associated with clinically relevant side effects, including thrombocytopenia, an increase in pancreatic enzymes (rarely pancreatitis), and vascular occlusive events [20–23]. Of special concern is the occurrence of vascular occlusive diseases, as these events may lead to irreversible organ damage or even death [20–23]. Therefore, current attempts focus on the management and avoidance of such adverse events in patients treated with ponatinib. One strategy may be to decrease the dose of ponatinib from 45 mg daily to 30 or even 15 mg daily. However, it remains uncertain whether efficacy is comparable when lower doses of the drug are applied, especially in advanced CML. Another strategy may be to administer co-medication that can counteract atherosclerosis and thrombosis [23]. However, such agents, like aspirin or statins, may also produce side effects and may be problematic in ponatinib-treated patients, especially when thrombocytopenia occurs.\n\nWe here describe a patient who received ponatinib because of TKI-resistant blast crisis (BC) of CML accompanied by bone marrow (BM) fibrosis and a Ph-negative sub-clone. In this patient, ponatinib was effective in eradicating the dominant CML clone, but also induced severe thrombocytopenia. A switch to bosutinib resulted in improved platelet counts, but was also followed by a molecular relapse. Subsequently, we applied ponatinib and bosutinib in rotation and added hydroxyurea (HU), with the aim to suppress all sub-clones, to avoid side effects, and to preserve efficacy at the same time, thus following the principles of personalized medicine.\n\nRESULTS\nCharacterization of the disease at the time of blast crisis (CR)\nAt the time of BC, the BM showed marked fibrosis as well as a huge increase in myeloblasts expressing KIT, CD33 and other myeloid antigens. Although the patient had also developed BM fibrosis and a Ph-negative subclone, most aspirable leukemic cells and circulating blast cells displayed BCR-ABL1. We also examined the peripheral blood (PB) and BM for the presence of mutations in JAK2, CALR, MPL, KIT, and various AML-related fusion genes. However, no mutations in these genes were detected in the patients´ blast cells in our analyses. Blast cells were tested positive for the BCR-ABL1 mutations L248V and K274del, whereas the F317L mutation that had been detected earlier in our patient, was not found by Sanger sequencing, suggesting that this sub-clone and its neoplastic stem cells had been eliminated or were controlled by TKI therapy.\n\nInitial response to ponatinib\nAfter an initial start-dose of 45 mg ponatinib per day (first week) the patient received 30 mg ponatinib daily. Within a few weeks, blast cells decreased substantially and disappeared in the PB. In addition, BCR-ABL1 mRNA levels decreased significantly. However, the patient also developed severe thrombocytopenia and bleedings requiring platelet transfusions as well as marked neutropenia (Table 1, Figure 1). We therefore decided to discontinue ponatinib. The patient was shortly kept on imatinib and then switched to bosutinib (300 mg/day) on a compassionate use program. During bosutinib, platelet counts recovered, and the clinical situation of the patient improved. However, after a few months, BCR-ABL1 increased again and we decided to start rotation therapy employing ponatinib and bosutinib (Figure 1). In addition, the patient received HU to keep the Ph-negative sub-clone under control.\n\nTable 1 Major clinical variables before and during TKI-rotation therapy\nPO-BOmonths*\tWBC G/L\tPLTG/L\t% blasts\tBMFibrosis\tLDHU/L\tBCR-ABL1% in PB cells**\t% Ph+ cellsin BM samples\t\nPB\tBM\t\n−18\t04.82\t235\t00\tnd\tyes\t292\t26.463\t80\t\n−15\t03.65\t222\t00\tnd\tnd\t374\t28.283\tnd\t\n−12\t04.01\t123\t00\tnd\tnd\t321\t11.548\tnd\t\n−09\t04.29\t101\t01\tnd\tnd\t339\t29.549\tnd\t\n−06\t04.77\t099\t02\tnd\tnd\t382\t52.293\tnd\t\n−03\t05.12\t129\t02\tnd\tnd\t504\t64.341\tnd\t\n−01\t08.11\t154\t23\t32\tnd\t714\t86.000\t100\t\n00\t24.41\t088\t36\tnd\tnd\t1,033\t56.480\tnd\t\n+01\t08.93\t046\t02\tnd\tnd\t552\t36.573\tnd\t\n+03\t04.93\t008\t00\tnd\tnd\t472\t0.026\tnd\t\n+06\t05.49\t027\t00\tnd\tnd\t579\t0.011\tnd\t\n+09\t06.18\t059\t01\tnd\tnd\t338\t0.023\tnd\t\n+12\t05.29\t070\t00\tnd\tnd\t316\t0.036\tnd\t\n+15\t06.68\t080\t00\tnd\tnd\t230\t0.573\tnd\t\n+18\t07.67\t131\t00\t< 5\tno\t230\t< 0.0032\tnd\t\n+21\t07.80\t110\t00\tnd\tnd\t206\t< 0.0032\tnd\t\n+24\t08.95\t126\t00\tnd\tnd\t215\t< 0.0032\tnd\t\n+27\t10.99\t164\t00\tnd\tnd\t242\t< 0.0032\tnd\t\n+30\t10.09\t175\t00\tnd\tnd\t263\t< 0.0032\tnd\t\n+33\t07.30\t131\t00\tnd\tnd\t231\t< 0.0032\tnd\t\n+36\t07.39\t189\t00\tnd\tnd\t278\t< 0.0032\tnd\t\nAbbreviations: PO, ponatinib; BO, bosutinib; PLT, platelet count; PB, peripheral blood; BM, bone marrow; LDH, lactate dehydrogenase; nd, not done.\n\n*Months before or after the start of ponatinib-bosutinib rotation therapy.\n\n**BCR-ABL1 mRNA levels were determined by qPCR and expressed as percent of ABL1 after adjusting to the international scale (IS).\n\nFigure 1 Overview of clinical course and response to TKI rotation therapy\n(A) Response to treatment with nilotinib and ponatinib, and influence of TKI therapy on blood counts and BCR-ABL1 mRNA levels: The patient was treated with nilotinib after resistance against dasatinib had been documented. During nilotinib, BCR-ABL1 decreased but did not disappear. After several months, BCR-ABL1 increased again and cytopenia developed. Finally, the patient developed blast crisis and treatment with ponatinib was initiated. In response to ponatinib, BCR-ABL1 mRNA levels decreased, but the patient developed severe thrombocytopenia. (B) Response to treatment with ponatinib/bosutinib-rotation and hydroxyurea (HU): Because of thrombocytopenia, the patient was switched to bosutinib (after a short phase of imatinib-bridging). During bosutinib, platelet counts recovered slowly, but BCR-ABL1 increased again. Therefore, we switched back to ponatinib, and finally decided to apply ponatinib and bosutinib in continuous rotation-cycles together with low-dose HU. Under this therapy, blood counts normalized, the patient entered a stable continuous complete response, and has a normal quality of life without major side effects.\n\nClinical response to rotation therapy employing ponatinib and bosutinib + HU\nDuring treatment with ponatinib and bosutinib in rotation-cycles combined with low dose HU (1 g/day), BCR-ABL1 decreased to MR4.5 and finally to undetectable levels (Figure 1). In addition, blood counts normalized and a reinvestigation of the BM revealed a marked decrease in BM fibrosis. After a total observation-time of 55 months, the patient is in continuous MR4.5 with normal or near normal blood counts and no signs of a relapse with a Ph+ or a Ph-negative disease. Because of the potential risk of side effects, because of concomitant HU therapy, and because of continuous BCR-ABL1-negativity, both drugs were maintained at relatively low doses (bosutinib: 300 mg/day; and ponatinib at 30 mg/day).\n\nSafety assessment and management of side effects\nrotation therapy was well tolerated without major side effects. Rather the patient reported on an increase in her quality of life. The only complaint was a recurrent mild pleural effusion that had been already documented during treatment with dasatinib, and was again detectable (and slightly increased) during treatment with bosutinib. Therefore, the patient also received low dose prednisolone (25 mg/day for 3 days followed by 12.5 mg/day for another week) during therapy with bosutinib in each cycle. In addition, the patient was maintained on aspirin as prophylactic treatment to minimize the risk of ponatinib-induced thrombosis. Based on the well-known side effects occurring in patients treated with nilotinib and ponatinib, we also examined vascular and metabolic parameters before and during treatment with ponatinib. However, no vascular event and no substantial metabolic changes were noted during rotation. In addition, all serum parameters, including pancreatic enzymes, HbA1c and cholesterol levels, remained within normal range. The European Society of Cardiology (ESC) score was 2 (indicating an intermediate risk to develop a cardiovascular event) before and during treatment with ponatinib/bosutinib.\n\nHistologic examinations before and after therapy with TKI rotation\nBM histology-results were obtained and compared before and during treatment with TKI rotation therapy. Prior to rotation therapy, a marked BM fibrosis was seen. In addition, the BM revealed signs of dysplasia and myeloproliferation. At the time of BC no histology was obtained. After successful therapy with TKI rotation, the BM showed an almost complete resolution of fibrosis and a normal blast cell (CD34+ cell) count.\n\nMolecular studies and HUMARA pattern\nBased on the detection of a Ph-negative subclone, we determined the clonality status before and during treatment with BCR-ABL1 TKI. Before starting TKI therapy, a monoclonal pattern was detected by the HUMARA assay. During successful treatment with dasatinib and ponatinib, a polyclonal pattern was seen (Figure 2). However, at the time of occurrence of BM fibrosis, the polyclonal pattern was lost and a monoclonal pattern was observed. At that time, BCR-ABL1 levels were still below 1%. These data suggest that the Ph-negative (MPN/MDS-like) sub-clone that produced the massive BM fibrosis was monoclonal in nature even though no BCR-ABL1 was expressed.\n\nFigure 2 Clonal evolution during TKI therapy as assessed by HUMARA\nThe HUMARA assay was performed with peripheral blood mononuclear cells in certain time intervals (from 2005 = month 0) as indicated. As assessed by HUMARA, a monoclonal pattern was seen in 2005 (month 0) and at the time of relapse with a Ph-negative clone when bone marrow (BM) fibrosis was detected (months 95–97). However, after successful treatment with dasatinib and nilotinib (months 9–22), a polyclonal pattern was obtained by HUMARA testing.\n\nDrug combination effects in vitro\nIn order to confirm drug effects on CML cells, we performed in vitro studies using two Ph+ CML cell lines as well as ponatinib and bosutinib. In these experiments, we were able to show that the two TKI produce strong cooperative anti-neoplastic effects on proliferation in KU812 cells and K562 cells (Figure 3A). In addition, we were able to show that ponatinib and bosutinib inhibit the proliferation of primary patient-derived blast cells in our in vitro experiments (Figure 3B). In a next step, we applied ponatinib (4 hours) and bosutinib (48 hours) sequentially to KU812 cells to mimic in vivo drug exposure conditions, and measured cell proliferation. As visible in Figure 3C, clear anti-neoplastic cooperative drug effects were also obtained in these experiments. Furthermore, we were able to show that ponatinib and bosutinib produce cooperative apoptosis-inducing effects in KU812 cells (Figure 3D). Finally, the superior anti-neoplastic effects of bosutinib and ponatinib on patient-derived leukemic cells were confirmed in a high-throughput viability assay (Figure 4A). In this assay the effects of bosutinib and ponatinib on viability were stronger compared to the effects of nilotinib, the agent under which the TKI-resistant sub-clones had emerged (Figure 4A). We also applied drug combinations in this assay. In particular, both TKI were combined with each other and with HU, the third inhibitor that was applied to control the Ph-negative portion of the disease. As visible in Figure 4B, synergistic effects on cell viability were obtained when combining bosutinib with HU. The other drug combinations were also effective, but due to the overwhelming effect of ponatinib, no clear synergistic effect was demonstrable (Figure 4B).\n\nFigure 3 Drug combination effects in CML cells\n(A) KU812 cells (upper panel) and K562 cells (lower panel) were incubated in control medium (Co), with various concentrations of ponatinib or bosutinib, or with a combination of both drugs at a fixed ratio (KU812 at 1:16; K562 at 1:100) at 37°C for 48 hours. Thereafter, 3H-thymidine was added for 16 hours, and uptake of 3H-thymidine was measured in a β-counter. Results are expressed as percent of medium control and represent the mean ± S.D. of quadruplicates. In case of KU812 cells, the drug combination was found to be highly synergistic, whereas in K562 cells, mostly additive effects were obtained. (B) Primary patient-derived blast cells were incubated in control medium (Co) or with increasing concentrations of hydroxyurea (HU), ponatinib, or bosutinib at 37°C and 5% CO2 for 48 hours as indicated. Then, 3H-thymidine uptake was measured. Results are expressed as percent of control and represent the mean ± S.D. of triplicates. (C) KU812 cells were incubated with ponatinib (0.1 nM: ■-■, 0.5 nM: ▲−▲, 1.0 nM: ▼-▼, or control medium: •-•) at 37°C for 4 hours. Then, cells were washed and incubated in control medium (Co) or bosutinib at various concentrations as indicated for another 48 hours. Thereafter, 3H-thymidine uptake was measured. Results are expressed as percent of control and represent the mean ± S.D. of triplicates. (D) KU812 cells were incubated in control medium (Co), ponatinib (0.2 nM), bosutinib (10 nM), or a combination of both drugs at 37°C for 48 hours. Thereafter, the percentage of AnnexinV/PI-positive cells was determined by flow cytometry. Results represent the mean ± S.D. of 3 independent experiments. Asterisk (*): p < 0.05 compared to control.\n\nFigure 4 High capacity drug testing using patient-derived CML blast crisis cells\n(A) Nanoliter amounts of BCR-ABL1 TKI and other drugs were pre-seeded at 4 defined concentrations into 384-well microtiter plates using acoustic compound transfer. CML cells (10,000 per well) were automatically plated and incubated with drugs at 37°C for 72 hours. Thereafter, cell viability was determined using Cell-Titer Glo assay. Responses were determined by measuring the percentage of viable cell (relative to control) at the 4 drug concentrations applied. (B) Cells were exposed to the drug combinations ´bosutinib+hydroxyurea´ (upper panel), ´ponatinib+hydroxyurea´ (middle panel), and ´ponatinib+bosutinib´ (lower panel) in the robotic drug testing assay.\n\nDISCUSSION\nDespite the availability of novel BCR-ABL1 TKI and SCT, advanced CML remains a challenge in clinical hematology. The prognosis of patients who develop blast crisis during TKI therapy is particularly poor. We here report on an elderly non-transplantable CML patient who developed blast crisis after having received several different TKI for over 6 years. In this particular patient, we were able to induce a complete molecular response with ponatinib. However, because of overt side effects with severe life-threatening thrombocytopenia and-later-the risk of fatal thrombosis, we had to adjust the overall treatment plan following the principles of personalized medicine, where drugs are selected or even combined to optimize efficacy and minimize (the risk of) side effects at the same time [24]. In our case, we applied ponatinib and bosutinib in rotation-cycles, thereby avoiding ponatinib-induced side effects and maintained MR4.5 at the same time.\n\nAlthough BCR-ABL1 is a major driver and player in the pathogenesis of CML, multiple additional lesions and pathways are considered to contribute to disease progression and drug resistance in advanced disease [2, 25, 26]. Such additional pathways and molecules supposedly lead to a complex clonal architecture, with multiple sub-clones and diverse features that may be quite different from that of the original dominant clone. Sometimes, even, progression to an acute Ph-negative leukemia is seen [27]. In our patient, disease progression was associated with clonal evolution of Ph-positive sub-clones, as evidenced by the demonstration of additional BCR-ABL1 mutations, but also with occurrence of a Ph-negative sub-clone that presented as an overt MDS/MPN-like disease with massive BM fibrosis. The clonal HUMARA pattern did not change during the time of evolution of this Ph-negative sub-clone, suggesting that both the Ph-positive and Ph-negative portion of the disease were probably indeed monoclonal. However, unfortunately, we were not able to perform deep sequencing studies to confirm our assumption.\n\nAs mentioned above, TKI resistance remains a challenge in the treatment of CML, especially when the patient is resistant to all available TKI. In our patient, the CML clone was resistant against imatinib, dasatinib, and nilotinib, and at this time, neither ponatinib nor bosutinib was available. Therefore, we had to maintain the patient on nilotinib with the hope that at least some of the relevant sub-clones can be suppressed and other novel TKI will be available. Indeed, after several months, we were able to offer ponatinib. Based on the recommendations of the European Leukemia Net and local guidelines, a switch from one to another second- or third generation BCR-ABL1 TKI can be regarded as standard. However, the application of continuous rotation-cycles using two of these TKI in advanced CML must be regarded as a novel approach. More recently, TKI rotation has also been described as a safe and effective approach in freshly diagnosed patients with CML [28].\n\nBased on the overall situation in our case, we had to treat the patient with these rotation cycles because of the biology of the disease (only ponatinib was able to control the BCR-ABL1+ portion of the leukemia), because of toxicity issues, and especially because of the risk of development of thromboembolic events during ponatinib therapy [21, 22]. In addition, we tried to minimize the risk of thrombosis by co-administering aspirin and by keeping the patient on a relatively low dose of ponatinib (30 mg/day). Moreover, the patient received HU in order to keep the Ph-negative sub-clone under control. This goal was indeed achieved. However, HU may also have a protective effect against thromboembolic events and may also exert some effects on BCR-ABL1-mutated sub-clones. In addition, our data suggest that HU exerts strong synergistic anti-leukemic effects on CML cells when combined with bosutinib or ponatinib (M.S. and P.V., unpublished observation).\n\nPersonalized medicine has a stringent definition and is based on the assumption, that optimal drugs can be selected for distinct subgroups of patients, based on the known side effect profiles and efficacy profiles as well as knowledge about risk factors (for the development of side effects) and related patient-specific variables [24]. In most cancer types, personalized medicine is currently still under development. In CML, however, we have already the opportunity to apply drugs and to select patients in a personalized medicine-based manner. Indeed, the patient described here is a good example how a personalized medicine concept can be applied. The application of such a personalized regimen allowed us to manage a severe relapsing disease as well as to avoid potential (and to overcome obvious) side effects so that treatment could be continued with optimal response and satisfactory quality of life.\n\nSevere thrombocytopenia is a well-known side effect of ponatinib [20, 21]. In our patient, thrombocytopenia was managed effectively by the rotation-approach. A second potentially life-threatening side effect of ponatinib is thromboembolism, which may occur preferentially in elderly, comorbid, patients [21]. We tried to avoid this side-effect by TKI-rotation therapy and co-administered aspirin. Third, the patient was suffering from severe constipation which is most probably attributable to the KIT-targeting effects of TKI on the pacemaker cells of the GI tract (cells of Cajal are KIT-dependent). The constipation resolved completely after switching from ponatinib to bosutinib, a drug that spares KIT. Finally, the recurrent pleural effusions that had developed under dasatinib and were recurrent during initial treatment with bosutinib, almost resolved when the patient switched to rotation-TKI therapy and co-administered prednisolone. All in all, the obvious advantages of the rotation have led to a long-lasting symptom-free period of CMR and a normal quality of life in our patient, which may be regarded as a triumph of personalized medicine. Interestingly, TKI rotation has recently also been applied in patients with freshly diagnosed CML using nilotinib and imatinib, with encouraging results and a reduced rate of vascular and metabolic events [28]. However, rotation therapy with ponatinib and bosutinib, although following the same principle, must be regarded as experimental approach. In fact, based on our case observation, clinical studies are now warranted in order to define whether TKI rotation is indeed a safe and effective strategy in patients with advanced TKI-refractory CML.\n\nIn vitro drug testing is a powerful approach to confirm or predict clinical responses, especially when patient-derived cells or CML cell lines are tested [32, 29, 30]. In the current study, we were able to show that the patient-derived leukemic blasts were responsive against HU, ponatinib, and bosutinib. In addition, all three drugs were found to counteract growth in two human CML cell lines, KU812 and K562. Moreover, we were able to show that ponatinib and bosutinib produce clear synergistic effects on growth and apoptosis of KU812 cells and some cooperative anti-leukemic effects in K562 cells. In addition, we were able to show that sequential application of ponatinib and bosutinib in vitro, which was performed to mimic exposure conditions in vivo, results in major cooperative drug effects in KU812 cells. Finally, we were able to show in a high-capacity screen that the patient-derived leukemic blasts are responsive to bosutinib and ponatinib, and that these TKI synergize with HU in blocking the viability of her cells. These data strongly suggest that drug responses of primary cells (and drug combination effects) may be predicted by drug testing and that synergistic anti-CML effects can be achieved by combining second generation TKI with each other or with HU. In fact, the patient also received HU together (in combination) with TKI. Therefore, some of the (unexpectedly strong) effect of therapy may be due to this TKI+HU combination. Based on the sub-clone concept of stem cell evolution in CML [31, 32] the clinical effect is best explained by TKI-induced eradication of stem cell-derived sub-clones [33] which was confirmed by demonstrating the complete disappearance of BCR-ABL1-bearing cells in our patient.\n\nIn conclusion, we present a patient with TKI-resistant multi-mutated blast crisis and a Ph-negative sub-clone producing severe BM fibrosis, in whom we induced a continuous CMR with TKI-rotation therapy complemented by HU, without major side effects. Such treatment strategies are in line with personalized medicine [24] and recent developments in the field [28] and may lead to the design of new improved treatment concepts in TKI-resistant CML. Eventually, such novel treatment concepts may also assist in the early eradication of all relevant CML sub-clones at diagnosis, so that it may be possible to switch back to a less-toxic TKI at CMR, and later discontinue TKI therapy in most patients with (even advanced) CML in the future.\n\nEthics approval and consent to participate\nAll studies, including kinase blocker studies (IRB number 224/2006), bone marrow investigations (IRB number 1184/2014), and in vitro multi-drug testing (IRB number 1830/2015), were approved by the ethics committee of the Medical University of Vienna. The patient provided written informed consent to participate in these studies.\n\nConsent for publication\nThe patient gave written informed consent that all her results from clinical and laboratory investigations can be submitted and published in anonymized form in a peer-reviewed journal.\n\nCompeting interests\nPV received honoraria from Novartis, Pfizer, BMS, and Ariad, and research grants from Novartis and Ariad. The authors declare no other competing interests.\n\nMATERIALS AND METHODS\nCase report\nA 78-year-old female patient with multi-resistant Ph+ CML was referred because of blast crisis in July 2013. She had first been diagnosed with CML in 2001 in another hospital. Initially, she had received interferon-alpha and cytarabine, and later, from May 2002, imatinib at 400 mg daily. However, after an initial response, resistance against imatinib developed, and she was referred to our center in 2005. At that time accelerated CML was diagnosed and she received a combination of rapamycin and hydroxyurea (HU). However, despite cytoreduction, no major molecular response was obtained. Subsequently, she received dasatinib (2 × 70 mg/day) and entered a complete cytogenetic response (CCyR). However, in 2007, she developed pleural effusion, and after the dose of dasatinib was reduced to 100 mg/day, a dasatinib-resistant sub-clone bearing the BCR-ABL1 mutation F317L emerged. Treatment with nilotinib (2 × 400 mg/day) was introduced. In response to nilotinib, the patient entered a second CCyR, and BCR-ABL1 mRNA levels decreased to < 0.1% (of ABL1) in September 2008. However, in December 2009, BCR-ABL1 mRNA levels increased to 0.5%. Subsequently, the BCR-ABL1 mutation L248V was detected. During the next few months, BCR-ABL1 slowly increased further. However, because of stable blood counts and lack of alternative therapy options, she was maintained on nilotinib. In January 2011, a BM investigation revealed marked fibrosis without an increase in blast cells. Later in 2011, the patient developed transfusion-dependent anemia and thrombocytopenia (Table 1). In addition, BCR-ABL1 increased to 30%, and both L248V and a new BCR-ABL1 mutation, K274del, were detected. In June 2012, the patient developed an overt blast crisis. Treatment with ponatinib on a compassionate use program was initiated.\n\nBone marrow studies\nBM studies were performed in certain time intervals, namely every 6–12 months before the start of ponatinib, and 18 months after the start of ponatinib. Histologic examinations included routine histology parameters, a Gomori silver stain (to detect and quantify fibrosis) and immunohistochemistry using antibodies against CD34, CD117 (KIT), and CD61. Histologic and immunohistochemical examinations were performed by the indirect immunoperoxidase staining technique following generally accepted standards [34, 35]. Wright-Giemsa stained BM smears were examined for the percentage of blast cells, promyelocytes, basophils, and other BM cells as well as cellular dysplasia (atypia). In addition, molecular and cytogenetic studies were performed on aspirated BM cells.\n\nMolecular studies and karyotyping\nBCR-ABL1 transcripts were quantified by real-time PCR according to a published protocol using the Ipsogen BCR-ABL-Mbcr Kit (Qiagen, Hilden, Germany) and the LightCycler 2.0-System (Roche, Mannheim, Germany) [36]. BCR-ABL1 mRNA levels were expressed as percent of ABL1 mRNA after adjusting PCR-data according to the international scale (IS) [37, 38]. BCR-ABL1 mutations were tested by Sanger sequencing of the ABL1 TK domain (codon 207–414) after specific amplification of BCR-ABL1 as reported [39]. Conventional cytogenetics and fluorescence in situ-hybridization (FISH) were performed according to published protocols [40].\n\nHuman androgen receptor (HUMARA) polymorphism analysis\nHUMARA analysis was performed using peripheral blood mononuclear cells (MNC) obtained at various time points before and during TKI therapy, following published techniques [41]. In brief, DNA was isolated from MNC using the MagNA Pure LC DNA isolation system (Roche) according to the manufacturer's recommendations. The X-chromosome inactivation (XCI) pattern was determined by PCR analysis of the polymorphic CAG-repeat region in the HUMARA gene which is located next to an HpaII restriction site. Genomic DNA (~250 ng) was digested with HpaII for 19 hours at 37°C. Then, aliquots of undigested and HpaII-digested DNA were subjected to PCR using published primer sequences [41]. Amplicons were analyzed on an Applied Biosystems (ABI) 3130xl genetic analyser (Foster City, CA, USA) using the Gene Scan 3.7 (ABI) software. For quantification, the areas under the peaks of the two alleles from the undigested and digested DNA were determined and the ratio of the peak area of both alleles (X1, X2) was calculated (in summary 100%). The degree of X-chromosome inactivation is presented as percent of the smaller peak (X2) in relation to the larger peak (X1). Undigested female DNA usually shows 2 peaks of similar height (in 90% of females).\n\nIsolation of primary cells and in vitro drug testing\nBased on the intriguing effects of therapy with ponatinib and bosutinib on leukemic cells in this patient, we performed in vitro assays in order to explore whether these drugs exert synergistic growth-inhibitory effects on CML cells. In these experiments, primary patient-derived cells and the BCR-ABL1+ cell lines KU812 and K562 were employed. KU812 cells were kindly provided by Dr.K.Kishi (Niigata University, Niigata, Japan) and K562 cells kindly provided by Dr.M.W.Deininger (University of Utah, Salt Lake City, UT, USA). Cells were cultured in RPMI 1640 medium with 10% FCS and exposed to various concentrations of ponatinib and bosutinib (both from ChemieTek, Indianapolis, IN, USA) alone or in combination (in quadruplicates). In case of drug combinations, a fixed ratio of compounds was applied essentially as described [42, 43]. After 24 or 48 hours, 3H-thymidine uptake and apoptosis (Annexin V-staining) were measured as reported previously [42, 43]. In a separate set of experiment, mononuclear BM cells obtained from the patient at the time of BC were cultured in RPMI 1640 medium and 10% FCS in the absence or presence of various concentrations of ponatinib, bosutinib, or hydroxyurea (Sigma, St. Louis, MO, USA). After 48 hours, uptake of 3H-thymidine was measured. In a separate set of experiments, KU812 cells were incubated in medium containing ponatinib (0.1, 0.5, or 1.0 nM) for 4 hours (37°C), washed, and then cultured in various concentrations of bosutinib (10–22 nM) for another 48 hours before 3H-thymidine was measured.\n\nMeasurement of apoptosis in KU812 cells\nKU812 cells were incubated in control medium, ponatinib (0.2 nM), bosutinib (10 nM), or a combination of both drugs at 37°C for 48 hours. Then, apoptotic cells were quantified by Annexin-V/PI staining and flow cytometry. In brief, cells were washed, resuspended in Annexin-V binding buffer for 15 minutes. Cells were then washed again, and propidium iodide (1 mg/mL) was added. After washing, cells were analyzed by flow cytometry on a FACSCalibur (Becton Dickinson, San Jose, CA, USA) to determine the percentage of Annexin-V/PI+ (apoptotic) cells.\n\nHigh capacity drug screening assay in primary CML cells\nTo compare drug effects on a larger scale and in the context of a broad range of available drugs, primary cells obtained from the patient were subjected to a high throughput drug testing assay essentially as reported [44]. The drug screen included all available BCR-ABL1 TKI as well as a larger number of other anti-leukemic drugs (total number of drugs applied: n = 200). In addition, drug combination experiments employing the combinations bosutinib + HU, ponatinib + HU, and ponatinib+bosutinib, were performed using this automated (robot-based) multi-drug screen. All studies were approved by the ethics committee of the Medical University of Vienna, Austria.\n\nStatistical analysis\nTo determine the significance-levels in differences seen between drug-exposed and untreated cells, the Student´s t-test was applied. Results were considered statistically significant when p was < 0.05. Drug combination effects (additive vs synergistic) were determined by calculating combination index (CI) values using Calcusyn software (Calcusyn, Biosoft, Ferguson, MO) as described [42, 43, 45]. A CI value >1 indicates an additive effect, whereas CI values below 1 indicate synergistic drug effects [45].\n\nWe would like to thank Daniela Berger and Gabriele Stefanzl for skillful technical assistance.\n\nCONFLICTS OF INTEREST\n\nPV received honoraria from Novartis, Pfizer, BMS, and Ariad, and research grants from Novartis and Ariad. The authors declare no other conflicts of interest.\n\nFUNDING\n\nThis study was supported by the Austrian Science Fund, F4701-B20, F4704-B20, and F4711-B20.\n\nAuthors’ contributions\n\nPV contributed the treatment design and study plan, and wrote the manuscript. SH, EH, and WRS collected clinical data and patient samples, and calculated statistics. MS, BB, AR, SK, and KVG performed in vitro drug incubation studies and calculated drug responses. GH and LM contributed laboratory data, molecular studies, and bone marrow studies. GSF and CM contributed the study design and logistics. All authors read and corrected the manuscript and approved the final version of the document.\n\nAbbreviations\nBMBone marrow\n\nPBperipheral blood\n\nCMLChronic myeloid leukemia\n\nCPChronic phase\n\nCCyRComplete cytogenetic response\n\nCMRComplete molecular response\n\nHUHydroxyurea\n\nHUMARAHuman androgen receptor assay\n\nISInternational scale\n\nMR4.5Molecular response 4.5 log below IRIS\n\nPh+Philadelphia chromosome-positive\n\nSCTStem cell transplantation\n\nTKTyrosine kinase\n\nTKITyrosine kinase inhibitor(s)\n\nXCIX-chromosome inactivation.\n==== Refs\nREFERENCES\n1 Faderl S Talpaz M Estrov Z O'Brien S Kurzrock R Kantarjian HM The biology of chronic myeloid leukemia N Engl J Med 1999 341 164 72 10403855 \n2 Melo JV Barnes DJ Chronic myeloid leukaemia as a model of disease evolution in human cancer Nat Rev Cancer 2007 7 441 53 17522713 \n3 Goldman JM Chronic myeloid leukemia: a historical perspective Semin Hematol 2010 47 302 11 20875546 \n4 Druker BJ Talpaz M Resta DJ Peng B Buchdunger E Ford JM Lydon NB Kantarjian H Capdeville R Ohno-Jones S Sawyers CL Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia N Engl J Med 2001 344 1031 37 11287972 \n5 O'Brien SG Guilhot F Larson RA Gathmann I Baccarani M Cervantes F Cornelissen JJ Fischer T Hochhaus A Hughes T Lechner K Nielsen JL Rousselot P Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia N Engl J Med 2003 348 994 1004 12637609 \n6 Druker BJ Guilhot F O'Brien SG Gathmann I Kantarjian H Gattermann N Deininger MW Silver RT Goldman JM Stone RM Cervantes F Hochhaus A Powell BL Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia N Engl J Med 2006 355 2408 17 17151364 \n7 Mahon FX Etienne G Deep molecular response in chronic myeloid leukemia: the new goal of therapy? Clin Cancer Res 2014 20 310 22 24166905 \n8 Gorre ME Mohammed M Ellwood K Hsu N Paquette R Rao PN Sawyers CL Clinical resistance to STI-571 cancer therapy caused by BCR-ABL gene mutation or amplification Science 2001 293 876 80 11423618 \n9 Shah NP Nicoll JM Nagar B Gorre ME Paquette RL Kuriyan J Sawyers CL Multiple BCR-ABL kinase domain mutations confer polyclonal resistance to the tyrosine kinase inhibitor imatinib (STI571) in chronic phase and blast crisis chronic myeloid leukemia Cancer Cell 2002 2 117 25 12204532 \n10 Deininger M Resistance and relapse with imatinib in CML: causes and consequences J Natl Compr Canc Netw 2008 6 S11 S21 18397677 \n11 Shah NP Tran C Lee FY Chen P Norris D Sawyers CL Overriding imatinib resistance with a novel ABL kinase inhibitor Science 2004 305 399 401 15256671 \n12 Weisberg E Manley PW Breitenstein W Brüggen J Cowan-Jacob SW Ray A Huntly B Fabbro D Fendrich G Hall-Meyers E Kung AL Mestan J Daley GQ Characterization of AMN107, a selective inhibitor of native and mutant Bcr-Abl Cancer Cell 2005 7 129 41 15710326 \n13 Martinelli G Soverini S Rosti G Cilloni D Baccarani M New tyrosine kinase inhibitors in chronic myeloid leukemia Haematologica 2005 90 534 41 15820950 \n14 Jabbour E Jones D Kantarjian HM O'Brien S Tam C Koller C Burger JA Borthakur G Wierda WG Cortes J Long-term outcome of patients with chronic myeloid leukemia treated with second-generation tyrosine kinase inhibitors after imatinib failure is predicted by the in vitro sensitivity of BCR-ABL kinase domain mutations Blood 2009 114 2037 43 19567878 \n15 Jabbour E Kantarjian H Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management Am J Hematol 2014 89 547 56 24729196 \n16 Nicolini FE Hayette S Corm S Bachy E Bories D Tulliez M Guilhot F Legros L Maloisel F Kiladjian JJ Mahon FX Le QH Michallet M Clinical outcome of 27 imatinib mesylate-resistant chronic myelogenous leukemia patients harboring a T315I BCR-ABL mutation Haematologica 2007 92 1238 41 17768119 \n17 Jabbour E Kantarjian H Jones D Breeden M Garcia-Manero G O'Brien S Ravandi F Borthakur G Cortes J Characteristics and outcomes of patients with chronic myeloid leukemia and T315I mutation following failure of imatinib mesylate therapy Blood 2008 112 53 55 18403620 \n18 Quintás-Cardama A Cortes J Therapeutic options against BCR-ABL1 T315I-positive chronic myelogenous leukemia Clin Cancer Res 2008 14 4392 99 18628453 \n19 O'Hare T Shakespeare WC Zhu X Eide CA Rivera VM Wang F Adrian LT Zhou T Huang WS Xu Q Metcalf CA Tyner JW Loriaux MM AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance Cancer Cell 2009 16 401 12 19878872 \n20 Cortes JE Kantarjian H Shah NP Bixby D Mauro MJ Flinn I O'Hare T Hu S Narasimhan NI Rivera VM Clackson T Turner CD Haluska FG Ponatinib in refractory Philadelphia chromosome-positive leukemias N Engl J Med 2012 367 2075 88 23190221 \n21 Cortes JE Kim DW Pinilla-Ibarz J le Coutre P Paquette R Chuah C Nicolini FE Apperley JF Khoury HJ Talpaz M DiPersio J DeAngelo DJ Abruzzese E A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias N Engl J Med 2013 369 1783 96 24180494 \n22 Mayer K Gielen GH Willinek W Müller MC Wolf D Fatal progressive cerebral ischemia in CML under third-line treatment with ponatinib Leukemia 2014 28 976 77 24170029 \n23 Valent P Hadzijusufovic E Schernthaner GH Wolf D Rea D le Coutre P Vascular safety issues in CML patients treated with BCR/ABL1 kinase inhibitors Blood 2015 125 901 6 25525119 \n24 Badalian-Very G Personalized medicine in hematology - A landmark from bench to bed Comput Struct Biotechnol J 2014 10 70 7 25349676 \n25 Park S Koh Y Jung SH Chung YJ Application of array comparative genomic hybridization in chronic myeloid leukemia Methods Mol Biol 2013 973 55 68 23412783 \n26 Huang Y Zheng J Hu JD Wu YA Zheng XY Liu TB Chen FL Discovery of somatic mutations in the progression of chronic myeloid leukemia by whole-exome sequencing Genet Mol Res 2014 13 945 53 24634115 \n27 Navarro JT Feliu E Grau J Espinet B Colomer D Ribera JM Oriol A Granada I Juncà J Millá F Monosomy 7 with severe myelodysplasia developing during imatinib treatment of Philadelphia-positive chronic myeloid leukemia: two cases with a different outcome Am J Hematol 2007 82 849 51 17563075 \n28 Gugliotta G Castagnetti F Breccia M Gozzini A Usala E Carella AM Rege-Cambrin G Martino B Abruzzese E Albano F Stagno F Luciano L D´Adda M Rotation of nilotinib and imatinib for first-line treatment of chronic phase chronic myeloid leukemia Am J Hematol 2016 91 617 22 26971721 \n29 O'Hare T Walters DK Stoffregen EP Sherbenou DW Heinrich MC Deininger MW Druker BJ Combined Abl inhibitor therapy for minimizing drug resistance in chronic myeloid leukemia: Src/Abl inhibitors are compatible with imatinib Clin Cancer Res 2005 11 6987 93 16203792 \n30 Radujkovic A Fruehauf S Zeller WJ Ho AD Topaly J Synergistic activity of nilotinib and established chemotherapeutic drugs in imatinib-sensitive and -resistant BCR-ABL-positive cells Cancer Chemother Pharmacol 2010 66 255 64 19862526 \n31 Valent P Targeting of leukemia-initiating cells to develop curative drug therapies: straightforward but nontrivial concept Curr Cancer Drug Targets 2011 11 56 71 21062243 \n32 Valent P Bonnet D Wöhrer S Andreeff M Copland M Chomienne C Eaves C Heterogeneity of neoplastic stem cells: theoretical, functional, and clinical implications Cancer Res 2013 73 1037 45 23345162 \n33 Preuner S Mitterbauer G Mannhalter C Herndlhofer S Sperr WR Valent P Lion T Quantitative monitoring of BCR/ABL1 mutants for surveillance of subclone-evolution, -expansion, and -depletion in chronic myeloid leukaemia Eur J Cancer 2012 48 233 6 21955823 \n34 Orazi A Neiman RS Cualing H Heerema NA John K CD34 immunostaining of bone marrow biopsy specimens is a reliable way to classify the phases of chronic myeloid leukemia Am J Clin Pathol 1994 101 426 8 7512785 \n35 Valent P Orazi A Büsche G Schmitt-Gräff A George TI Sotlar K Streubel B Beham-Schmid C Cerny-Reiterer S Krieger O van de Loosdrecht A Kern W Ogata K Standards and impact of hematopathology in myelodysplastic syndromes (MDS) Oncotarget 2010 1 483 96 10.18632/oncotarget.101104 21317447 \n36 Bolufer P Sanz GF Barragán E Sanz MA Cervera J Lerma E Senent L Moreno I Planelles MD Rapid quantitative detection of BCR-ABL transcripts in chronic myeloid leukemia patients by real-time reverse transcriptase polymerase-chain reaction using fluorescently labeled probes Haematologica 2000 85 1248 54 11114130 \n37 Branford S Fletcher L Cross NC Müller MC Hochhaus A Kim DW Radich JP Saglio G Pane F Kamel-Reid S Wang YL Press RD Lynch K Desirable performance characteristics for BCR-ABL measurement on an international reporting scale to allow consistent interpretation of individual patient response and comparison of response rates between clinical trials Blood 2008 112 3330 38 18684859 \n38 Hughes T Deininger M Hochhaus A Branford S Radich J Kaeda J Baccarani M Cortes J Cross NC Druker BJ Gabert J Grimwade D Hehlmann R Monitoring CML patients responding to treatment with tyrosine kinase inhibitors: review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts and kinase domain mutations and for expressing results Blood 2006 108 28 37 16522812 \n39 Hochhaus A Kreil S Corbin AS La Rosée P Müller MC Lahaye T Hanfstein B Schoch C Cross NC Berger U Gschaidmeier H Druker BJ Hehlmann R Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy Leukemia 2002 16 2190 96 12399961 \n40 Brothman AR Persons DL Shaffer LG Nomenclature evolution: Changes in the ISCN from the 2005 to the 2009 edition Cytogenet Genome Res 2009 127 1 4 20110655 \n41 Mitterbauer G Winkler K Gisslinger H Geissler K Lechner K Mannhalter C Clonality analysis using X-chromosome inactivation at the human androgen receptor gene (Humara). Evaluation of large cohorts of patients with chronic myeloproliferative diseases, secondary neutrophilia, and reactive thrombocytosis Am J Clin Pathol 1999 112 93 100 10396290 \n42 Gleixner KV Ferenc V Peter B Gruze A Meyer RA Hadzijusufovic E Cerny-Reiterer S Mayerhofer M Pickl WF Sillaber C Valent P Polo-like kinase 1 (Plk1) as a novel drug target in chronic myeloid leukemia: overriding imatinib resistance with the Plk1 inhibitor BI 2536 Cancer Res 2010 70 1513 23 20145140 \n43 Gleixner KV Peter B Blatt K Suppan V Reiter A Radia D Hadzijusufovic E Valent P Synergistic growth-inhibitory effects of ponatinib and midostaurin (PKC412) on neoplastic mast cells carrying KIT D816V Haematologica 2013 98 1450 7 23539538 \n44 Winter GE Rix U Lissat A Stukalov A Müllner MK Bennett KL Colinge J Nijman SM Kubicek S Kovar H Kontny U Superti-Furga G An integrated chemical biology approach identifies specific vulnerability of Ewing's sarcoma to combined inhibition of Aurora kinases A and B Mol Cancer Ther 2011 10 1846 56 21768330 \n45 Chou TC Talalay P Quantitative analysis of dose-effect relationships: the combined effects of multiple drugs or enzyme inhibitors Adv Enzyme Regul 1984 22 27 55 6382953\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(14)",
"journal": "Oncotarget",
"keywords": "BCR-ABL1 mutations; CML; drug resistance; nilotinib; ponatinib",
"medline_ta": "Oncotarget",
"mesh_terms": "D000368:Aged; D000814:Aniline Compounds; D001752:Blast Crisis; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D057915:Drug Substitution; D005260:Female; D006801:Humans; D007093:Imidazoles; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D000071069:Multiple Chronic Conditions; D009570:Nitriles; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D011804:Quinolines",
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "23061-23072",
"pmc": null,
"pmid": "28416739",
"pubdate": "2017-04-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16522812;24729196;18628453;15710326;24170029;21317447;18397677;15820950;12399961;7512785;24180494;15256671;16203792;6382953;23412783;24634115;20875546;17522713;20145140;25349676;24166905;11287972;21955823;17563075;17768119;23539538;19567878;25525119;10403855;18403620;21062243;11114130;20110655;10396290;11423618;19878872;12204532;21768330;17151364;23345162;23190221;12637609;18684859;26971721;19862526",
"title": "TKI rotation-induced persistent deep molecular response in multi-resistant blast crisis of Ph+ CML.",
"title_normalized": "tki rotation induced persistent deep molecular response in multi resistant blast crisis of ph cml"
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"abstract": "A case of autoimmune liver hepatitis is reported: the onset was triggered by consumption of green tea infusion in a patient taking oral contraceptives and irbesartan. We hypothesize that our patient, carrying genetic variant of hepatic metabolism making her particularly susceptible to oxidative stress, developed an abnormal response to a mild toxic insult, afforded by a combination of agents (oral contraceptives+irbesartan+green tea) that normally would not be able to cause damage. Her particular hepatic metabolism further increased the drugs' concentration, favoring the haptenization of liver proteins, eventually leading to the development of an autoimmune hepatitis.",
"affiliations": "University of Florence, Department of Neuroscience, Psychology, Drug Research and Child Health (NeuroFarBa), Center of Molecular Medicine (CIMMBA), Florence, Italy.",
"authors": "Gallo|Eugenia|E|;Maggini|Valentina|V|;Berardi|Margherita|M|;Pugi|Alessandra|A|;Notaro|Rosario|R|;Talini|Giulia|G|;Vannozzi|Giancarlo|G|;Bagnoli|Siro|S|;Forte|Paolo|P|;Mugelli|Alessandro|A|;Annese|Vito|V|;Firenzuoli|Fabio|F|;Vannacci|Alfredo|A|",
"chemical_list": "D001713:Biphenyl Compounds; D003276:Contraceptives, Oral; D013662:Tea; D013777:Tetrazoles; D000077405:Irbesartan",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0944-7113",
"issue": "20(13)",
"journal": "Phytomedicine : international journal of phytotherapy and phytopharmacology",
"keywords": "AIH; ALT; AP; Autoimmune hepatitis; CYP; Catechin; EGCG; GGT; GST; Green tea; MDR; MTHFR; SULT; Single nucleotide polymorphism; UDP glucuronosyltransferase; UGT; alanine aminotransferase; alkaline phosphatase; autoimmune like hepatitis; cytochrome P450; epigallocatechin-3-gallate; glutamiltransferase; glutathione S-transferase; methylenetetrahydrofolate reductase; multidrug resistance; sulfotransferase",
"medline_ta": "Phytomedicine",
"mesh_terms": "D000328:Adult; D001713:Biphenyl Compounds; D003276:Contraceptives, Oral; D005260:Female; D019693:Hepatitis, Autoimmune; D006801:Humans; D000077405:Irbesartan; D008099:Liver; D018384:Oxidative Stress; D020641:Polymorphism, Single Nucleotide; D013662:Tea; D013777:Tetrazoles",
"nlm_unique_id": "9438794",
"other_id": null,
"pages": "1186-9",
"pmc": null,
"pmid": "23928507",
"pubdate": "2013-10-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Is green tea a potential trigger for autoimmune hepatitis?",
"title_normalized": "is green tea a potential trigger for autoimmune hepatitis"
} | [
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"companynumb": "IT-WATSON-2014-21309",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
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"activesubstancename": "IRBESARTAN"
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{
"abstract": "Fixed-dose (FD) regimens of 4-factor prothrombin complex concentrate (4F-PCC) may be effective for the emergent reversal of warfarin; however, the optimal dosing is unknown. Our institution transitioned to a FD regimen of 1000 or 2000 units of 4F-PCC based on indication.\n\n\n\nThe purpose of this study is to report our experience with FD 4F-PCC compared with a historical weight-based dosing cohort for warfarin reversal.\n\n\n\nA retrospective analysis was conducted for 3 groups: central nervous system (CNS) bleeds regardless of international normalized ratio (INR), non-CNS bleeds with an initial INR ≤6, and non-CNS bleeds with an initial INR ≥6.1. The primary outcome of the study was achievement of the target INR.\n\n\n\nThere were 54 patients with a CNS bleed, 153 with a non-CNS bleed and INR ≤6, and 19 with a non-CNS bleed and INR ≥6.1. In the CNS bleeding group, weight-based and FD achieved target INR 79.4% and 70% (P = 0.52). In the INR ≥6.1 non-CNS bleeding group, weight-based and FD achieved target INR 100% and 70% (P = 0.21). In the INR ≤6 non-CNS bleeding group, weight-based and FD achieved target INR 86.4% and 57.5% (P = 0.0002).\n\n\n\nAn FD strategy of 2000 units for warfarin reversal for CNS bleeds or INR ≥6.1 was comparable to weight-based dosing. The FD strategy of 1000 units for INR ≤6 achieved target INR less often than weight-based dosing. Application of findings suggest that higher doses may be needed to achieve target INR.",
"affiliations": "OhioHealth Marion General Hospital, Marion, OH, USA.;UW Health, Madison, WI, USA.;University of Wisconsin, Madison, WI, USA.;UW Health, Madison, WI, USA.;UW Health, Madison, WI, USA.",
"authors": "McMahon|Clare|C|;Halfpap|Joe|J|;Zhao|Qianqian|Q|;Bienvenida|Ana|A|;Rose|Anne E|AE|0000-0002-4658-9733",
"chemical_list": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; C025667:prothrombin complex concentrates; D014859:Warfarin",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028021992142",
"fulltext": null,
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"issn_linking": "1060-0280",
"issue": "55(10)",
"journal": "The Annals of pharmacotherapy",
"keywords": "anticoagulants; anticoagulation; drug safety; emergency medicine; warfarin",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000925:Anticoagulants; D001779:Blood Coagulation Factors; D006801:Humans; D019934:International Normalized Ratio; D012189:Retrospective Studies; D014859:Warfarin",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1230-1235",
"pmc": null,
"pmid": "33522256",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Evaluation of a Fixed-Dose Regimen of 4-Factor Prothrombin Complex Concentrate for Warfarin Reversal.",
"title_normalized": "evaluation of a fixed dose regimen of 4 factor prothrombin complex concentrate for warfarin reversal"
} | [
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"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2021-025838",
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"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN SODIUM"
},
"dr... |
{
"abstract": "When acute appendicitis occurs in patients treated with chemotherapy, neutropenia and abdominal complaints caused by chemotherapy can contribute to the diagnostic difficulty, masking the increase in white blood cell(WBC)counts and physical findings of acute appendicitis. A 43-year-old premenopausal woman who was diagnosed with stage IIIA left breast cancer was scheduled for neoadjuvant chemotherapy includingfluorouracil plus epirubicin plus cyclophosphamide(FEC), followed by docetaxel and trastuzumab(DOC plus HER). The patient developed fever and lower abdominal pain on day 17 of DOC plus HER cycle 1, and was diagnosed with acute gastroenteritis in the emergency room. These symptoms were almost improved 4 days later, and then cycle 2 was performed as scheduled. WBC counts decreased to 1,530 cells/mL due to DOCinduced myelosuppression on day 8 of cycle 2 when the patient developed lower abdominal pain again. However, WBC counts increased to 21,680 cells/mL on day 13 of cycle 2. Computed tomography scans revealed an intraperitoneal abscess due to acute appendicitis, and consequently urgent operation was performed. It is necessary to understand that patients with acute appendicitis duringchemotherapy can present less clinical findings.",
"affiliations": "Division of Breast, Endocrine and Respiratory Surgery, Department of Surgery, Shinshu University School of Medicine.",
"authors": "Oba|Takaaki|T|;Maeno|Kazuma|K|;Ito|Kenichi|K|;Ishizone|Satoshi|S|;Hanaoka|Takaomi|T|",
"chemical_list": "D043823:Taxoids; D000077143:Docetaxel; D000068878:Trastuzumab",
"country": "Japan",
"delete": false,
"doi": null,
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"issn_linking": "0385-0684",
"issue": "44(11)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D018784:Abdominal Abscess; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001064:Appendicitis; D001943:Breast Neoplasms; D000077143:Docetaxel; D005260:Female; D006801:Humans; D020360:Neoadjuvant Therapy; D043823:Taxoids; D000068878:Trastuzumab",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1029-1032",
"pmc": null,
"pmid": "29138382",
"pubdate": "2017-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "A Case of Retroperitoneal Abscess Due to Acute Appendicitis during Neo-Adjuvant Chemotherapy for Breast Cancer.",
"title_normalized": "a case of retroperitoneal abscess due to acute appendicitis during neo adjuvant chemotherapy for breast cancer"
} | [
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"abstract": "Cryoglobulinemia is a rare disease characterized by the production of monoclonal or polyclonal immunoglobulins that precipitate in cold temperature. While this phenomenon can be observed in a large number of disorders, it has been associated with hepatitis C virus infection in more than 90% of cases. The remaining 10%, called essential cryoglobulinemia, has been characterized by a more severe course and a failure to respond to conventional treatment. This article describes the case of a patient with essential cryoglobulinemia presenting with acronecrosis with a poor outcome, despite treatment, leading to amputation.",
"affiliations": "Reumatología, Hospital General de Ciudad Real, Ciudad Real, Spain. hurauma@hotmail.com",
"authors": "Ramírez Huaranga|Marco A|MA|;Ramos Rodríguez|Claudia C|CC|;Bellido Pastrana|David|D|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D058846:Antibodies, Monoclonal, Murine-Derived; D007166:Immunosuppressive Agents; D014665:Vasodilator Agents; D000069283:Rituximab; D003520:Cyclophosphamide; D008775:Methylprednisolone",
"country": "Spain",
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"issn_linking": "1699-258X",
"issue": "8(2)",
"journal": "Reumatologia clinica",
"keywords": null,
"medline_ta": "Reumatol Clin",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D000671:Amputation; D058846:Antibodies, Monoclonal, Murine-Derived; D003131:Combined Modality Therapy; D003449:Cryoglobulinemia; D003520:Cyclophosphamide; D003924:Diabetes Mellitus, Type 2; D004351:Drug Resistance; D004359:Drug Therapy, Combination; D005260:Female; D006526:Hepatitis C; D006801:Humans; D006973:Hypertension; D007166:Immunosuppressive Agents; D007511:Ischemia; D008775:Methylprednisolone; D008875:Middle Aged; D009336:Necrosis; D010292:Paresthesia; D010956:Plasmapheresis; D011928:Raynaud Disease; D000069283:Rituximab; D014034:Toes; D014665:Vasodilator Agents",
"nlm_unique_id": "101293923",
"other_id": null,
"pages": "84-6",
"pmc": null,
"pmid": "22089061",
"pubdate": "2012",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cryoglobulinemia with acronecrosis not associated with hepatitis C infection: a case report.",
"title_normalized": "cryoglobulinemia with acronecrosis not associated with hepatitis c infection a case report"
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"companynumb": "ES-CIPLA LTD.-2016ES00705",
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"abstract": "The association of gastrointestinal stromal tumor (GIST), synchronous or metachronous with other tumors is reported in special literature, the most frequent being associated with other gastrointestinal tumors. GISTs are the most common mesenchymal neoplasm of the gastro-intestinal tract with a malignant potential. We present a case of 68-year-old male patient diagnosed with GIST stage IV, unreachable due to liver metastases, treated with Imatinib, diagnosed at 13 months of prostate adenocarcinoma diagnosis [treated with hormonal therapy (HT) and external beam radiotherapy (EBRT)]; at 45 months from the first neoplasia diagnosis, the patient was diagnosed with the third neoplasia - lung squamous carcinoma - right inferior lobe, for which performed EBRT. The coexistence of GIST with other malignancies with different histology, remain a challenge for the clinician from etiological, and also from therapeutically actions point of view.",
"affiliations": "Clinical Department, Faculty of Medicine and Pharmacy, \"Lower Danube\" University of Galati, Romania; laura_rebegea@yahoo.com.",
"authors": "Rebegea|Laura Florentina|LF|;Pătraşcu|Anca|A|;Miron|Dumitra|D|;Dumitru|Mihaela Emilia|ME|;Firescu|Dorel|D|",
"chemical_list": null,
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"issn_linking": "1220-0522",
"issue": "57(4)",
"journal": "Romanian journal of morphology and embryology = Revue roumaine de morphologie et embryologie",
"keywords": null,
"medline_ta": "Rom J Morphol Embryol",
"mesh_terms": "D000368:Aged; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D008297:Male; D009378:Neoplasms, Multiple Primary",
"nlm_unique_id": "9112454",
"other_id": null,
"pages": "1429-1435",
"pmc": null,
"pmid": "28174815",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metachronous gastrointestinal stromal tumor associated with other neoplasia - case presentation.",
"title_normalized": "metachronous gastrointestinal stromal tumor associated with other neoplasia case presentation"
} | [
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"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2017RR-147411",
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"activesubstancename": "LEUPROLIDE"
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"abstract": "Phlegmasia Cerulea Dolens (PCD) is a severe and rare form of venous thrombosis of the lower extremities, caused by a subtotal or complete occlusion of venous outflow by a thrombus. PCD should be considered a real medical emergency; complications include necrosis and gangrene of the affected limb, amputation, massive pulmonary embolism and, in extreme cases, the death of the patient. Case Report. A 63-years-old man was admitted to the Emergency room with localized pain on the right calf, hyperthermia, cold sweating and vomiting episodes. Five days prior he developed flu-like symptoms, joint pain and cold sensation unresponsive to treatment. Ultrasound examination showed a deep venous thrombosis of the lower right limb with partial occlusion of common iliac and femoral veins. The patient was treated with low molecular weight heparin given twice daily. He began to develop severe hypotension and metabolic acidosis, with tachycardia and atrial fibrillation. Despite the treatment, there was no improvement and he developed severe sinus node dysfunction. He failed to respond to all resuscitative efforts and died. Family members complained Authority, assuming it was a medical error. The clinical-forensic investigation is essential to determine the causes and manner of death and to assess medical responsibility and liability.",
"affiliations": "Department of Legal Medicine, University of Bari, Bari, Italy.;Department of Legal Medicine, University of Bari, Bari, Italy.;Department of Legal Medicine, University of Bari, Bari, Italy.;Department of Legal Medicine, University of Bari, Bari, Italy.;Vascular and Endovascular Surgery Unit, University of Bari, Bari, Italy.;Vascular and Endovascular Surgery Unit, University of Bari, Bari, Italy.",
"authors": "De Donno|A|A|;Favia|M|M|;Martini|A|A|;Calvano|M|M|;Galeandro|C|C|;Angiletta|D|D|",
"chemical_list": "D006493:Heparin",
"country": "Italy",
"delete": false,
"doi": "10.7417/CT.2021.2326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9074",
"issue": "172(4)",
"journal": "La Clinica terapeutica",
"keywords": "Autopsy; Death; Deep venous thrombosis; Medical malpractice; Phlegmasia Cerulea Dolens",
"medline_ta": "Clin Ter",
"mesh_terms": "D001344:Autopsy; D017809:Fatal Outcome; D005268:Femoral Vein; D006493:Heparin; D006801:Humans; D007084:Iliac Vein; D007866:Leg; D016365:Liability, Legal; D008297:Male; D008318:Malpractice; D008875:Middle Aged; D020246:Venous Thrombosis",
"nlm_unique_id": "0372604",
"other_id": null,
"pages": "256-259",
"pmc": null,
"pmid": "34247205",
"pubdate": "2021-07-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Phlegmasia Cerulea Dolens: a sudden unexpected death with hypothesis of medical malpractice.",
"title_normalized": "phlegmasia cerulea dolens a sudden unexpected death with hypothesis of medical malpractice"
} | [
{
"companynumb": "IT-TEVA-2021-IT-1952390",
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"activesubstancename": "ATROPINE"
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... |
{
"abstract": "The newer oral treatments for chronic hepatitis C virus infection are one of the greatest revolutions in modern medicine. These drugs promise to eradicate the infection, showing high cure rates even in difficult to treat populations with very few side effects. Nevertheless, some cases of recurrence and de novo hepatocellular carcinoma after treatment with these drugs have been reported. We describe two cases of patients treated with direct-acting antiviral agents that developed hepatocarcinoma during follow-up post-treatment.",
"affiliations": "Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.;Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.;Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.;Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.;Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.;Department of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal.",
"authors": "Dias|Cátia|C|;Duarte-Ribeiro|Filipa|F|;Pipa|Sara|S|;Barbosa|Ana Rita|AR|;Mota|Margarida|M|;Rosas Vieira|Fernando|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2018.e00450",
"fulltext": "\n==== Front\nIDCasesIDCasesIDCases2214-2509Elsevier S2214-2509(18)30154-910.1016/j.idcr.2018.e00450e00450ArticleHepatocellular carcinoma after direct-acting antiviral therapy for chronic HCV infection: Is it a real risk? Dias Cátia catia.dias@chvng.min-saude.pt⁎Duarte-Ribeiro Filipa filipa.duarte.ribeiro@chvng.min-saude.ptPipa Sara sara.pipa@chvng.min-saude.ptBarbosa Ana Rita ana.rita.barbosa@chvng.min-saude.ptMota Margarida mmota@chvng.min-saude.ptRosas Vieira Fernando rvieira@chvng.min-saude.ptDepartment of Internal Medicine, Centro Hospitalar de Vila Nova de Gaia / Espinho, Portugal⁎ Corresponding author at: Rua Dr.º Francisco Sá Carneiro, 1228 1º esquerdo, São Cosme, 4420-132 Gondomar, Porto, Portugal. catia.dias@chvng.min-saude.pt30 8 2018 2018 30 8 2018 14 e00450 e00450 14 8 2018 29 8 2018 29 8 2018 © 2018 The Authors2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).The newer oral treatments for chronic hepatitis C virus infection are one of the greatest revolutions in modern medicine. These drugs promise to eradicate the infection, showing high cure rates even in difficult to treat populations with very few side effects. Nevertheless, some cases of recurrence and de novo hepatocellular carcinoma after treatment with these drugs have been reported. We describe two cases of patients treated with direct-acting antiviral agents that developed hepatocarcinoma during follow-up post-treatment.\n\nKeywords\nHepatocellular carcinomaHCV infectionDirect-acting antiviral therapy\n==== Body\nIntroduction\nThe use of the direct-acting antiviral agents (DAA) has completely revolutionized the treatment of patients with chronic hepatitis C virus (HCV) infection. The cure rates obtained with this type of treatment, combined with the comfort provided by oral intake and the scarcity of side effects have contributed to the success and high adherence to treatment with these agents. Such benefits are further emphasized taking into account that none of these positive aspects occurred in the era of interferon (IFN) plus ribavirin regimens. Despite this, some cases of recurrence of previously treated hepatocellular carcinomas (HCC) or even de novo diagnosis after treatment for HCV infection with DAA have been described in the literature. Such observation has raised doubts as to whether these drugs may in some way potentiate the appearance of hepatocarcinoma. We describe two cases of patients treated with DAA that developed hepatocellular carcinoma during follow-up post-treatment.\n\nCases\nPatient 1 was a 52-year-old man with a history of moderate alcohol consumption, former intravenous drug abuse, vascular risk factors (type 2 diabetes mellitus, arterial hypertension and dyslipidemia) and chronic HCV infection (genotype 3a) diagnosed in 1997. As complications of that infection he presented secundary hemochromatosis and proliferative membranous glomerulonephritis. Hepatic elastography showed values compatible with grade of liver fibrosis METAVIR stage F4. In 2011, he completed 24 weeks of therapy with pegylated interferon and ribavirin, and presented rapid virologic response. Nevertheless, there was always evidence of hepatic cytolysis during follow-up. Approximately three months after the end of therapy, treatment failure was observed. From April to October 2015 he completed 24 weeks of treatment with ledispavir, sofosbuvir and ribavirin, achiving virologic sustained response. At 24 weeks of follow-up, the HCV maintained undetectable but the protocolar upper abdominal ultrasonography showed a heterogeneous nodular lesion in the left lobe with 43 by 32 mm. This lesion was not present in the ultrasonography performed before the beginning of treatment. Additional magnetic resonance imaging suggested a hepatic adenoma (Fig. 1), but hepatic biopsy was suggestive of hepatocellular carcinoma. At that time, the serum alpha-fetoprotein value was 204.20 IU / mL. The patient was submitted to a 2/3 bisegmentectomy. The histological examination revealed the presence of well differentiated hepatocellular carcinoma with images of lymphatic vascular invasion which were 3 mm from the surgical margin (pT2NxR0; TNM stage).Fig. 1 Abdominal magnetic resonance cross-section. T1 weighted with contrast showing a nodular image with imaging features suggestive of hepatic adenoma.\n\nFig. 1\n\nPatient 2 was a 58-year-old man with history of active heavy alcohol abuse, smoker (about 44 pack-years), former drug abuse (consumer of cocaine and intravenous heroin from 14 to 40 years old). HCV infection (genotype 1a) diagnosed in 2013, porphyria cutanea tarda and secondary hemochromatosis under programmed phlebotomies. Hepatic elastography showed values compatible with grade of liver fibrosis METAVIR stage F4. In 2014, on abdominal ultrasound was detected an injury that was imagiologically suspected to be a hemangioma of the right hepatic lobe. The magnetic resonance revealed to be only an area of perfusion alteration of segments VII / VIII. In 2015 he completed 24 weeks of treatment with ledispavir and sofosbuvir. He presented a favorable virological response, with undetectable viral load and cutaneous porphyria resolution. About 13 months after the end of treatment, a 29 mm nodule on segments VII / VIII, suspected of hepatocellular carcinoma, was detected on magnetic resonance imaging (Fig. 2). The histological study was compatible with well differentiated hepatocellular carcinoma, with extensive areas of necrosis, rare images suggestive of intratumoral lymphovascular invasion and absence of evidence of extratumoral lymphovascular invasion; the minimum surgical margin was 5 mm (pT2NxR0).Fig. 2 Abdominal magnetic resonance cross-section. T1 weighted showing a nodular image with imaging features suggestive of suspected of hepatocellular carcinoma.\n\nFig. 2\n\nDiscussion\nClearly overcoming previous therapies based on pegylated-IFN and ribavirin regimens, drugs currently used for the treatment of HCV infection have cure rates / sustained virological response (SVR) greater than 95% [1]. SVR by itself has demonstrated a significant reduction in liver fibrosis [[2], [3], [4]], as well as an increase in liver-related and overall survival (related largely to prevention of decompensation of liver disease, reducing the need for transplantation and the risk of occurrence or recurrence of HCC) [5,6]. With regard to HCC, this can be easily understood considering that hepatic cirrhosis is the major risk factor for HCC and, in turn, that chronic HCV infection is one of the most frequent etiologies for cirrhosis [7], with approximately 2–8% risk of developing HCC in patients with HCV cirrhosis [8]. Taking into account the previous, it would be expected that the DAA would allow a reduction in the occurrence and recurrence of HCC. However, opinions have diverged since description of cases of HCC recurrence in patients treated with these drugs, generating controversy and even speculation that DAA may contribute to the development of this neoplasia.\n\nThis finding can be explained by several aspects. On the one hand, it is known that, even after SVR, the risk of HCC, although lower, persists mainly in patients already with cirrhosis [9], as in the cases presented here. On the other hand, DAA allow the treatment of patients in more advanced stages of disease, who alone may be at higher risk of developing HCC. In pathophysiologic terms it has been proposed that DAA may lead to deregulation of immune surveillance related to the rapid and marked decrease in HCV viral load [[10], [11], [12]]. Through various mechanisms, the absence of interferon activation, reconstitution of innate immunity, abrupt reduction of natural killer cells and their toxicity, among others, may contribute to a more rapid progression of HCC.\n\nIt has also been speculated that some biomarkers may predict the risk of HCC after HCV treatment. For example, one study has shown that the vascular endothelial growth factor increased significantly during and after treatment with DAA [13], although others point out that such an increase may only function as a booster in patients with other clinical or analytical predispositions for HCC [14]. Although several studies have been published to date, attempting to assess the existence of a higher risk of occurrence and / or recurrence of HCC after DAA relative to IFN, there is no evidence yet to support a difference between these two groups of patients [15].\n\nIn this article we report two cases of patients with HCV infection, with evidence of liver cirrhosis and who were diagnosed HCC soon after treatment of their chronic infection with DAA, although it may well be that small lesions were already be present in dimensions that did not allow its imaging detection and which are later enhanced by the aspects described above.\n\nConclusion\nIn the absence of evidence supporting the direct relationship between the use of AADs and the development of HCC, there is a clear benefit in treating all patients with HCV who meet criteria for treatment. However, the continuing appearance of new cases such as those presented here emphasizes the need for further studies, including multicenter and prospective. In particular, a short-term outcome may be the evaluation of potential biological markers that together with clinical aspects may predict which patients are at increased risk of developing HCC after treatment with DAA.\n\nConflicts of interest\nThe authors declare that they have no conflicts of interest.\n\nAuthors’ contributions\nCátia Dias: Conceptualization, Investigation, Bibliographic research, Project administration, Writing original draft, Review and editing.\n\nFilipa Duarte-Ribeiro: Writing original draft, Bibliographic research.\n\nSara Pipa: Writing original draft, Bibliographic research.\n\nAna Rita Barbosa: Writing original draft, Bibliographic research.\n\nMargarida Mota: Conceptualization, Investigation, Project administration, Writing original draft, Review and editing.\n\nFernando Rosas Vieira: Project administration.\n==== Refs\nReferences\n1 Zhang J. Nguyen D. Hu K.Q. Chronic hepatitis C virus infection: a review of current direct-acting antiviral treatment strategies N Am J Med Sci (Boston) 9 2016 47 54 27293521 \n2 Marcellin P. Boyer N. Gervais A. Long-term histologic improvement and loss of detectable intrahepatic HCV RNA in patients with chronic hepatitis C and sustained response to interferon‐alpha therapy Ann Intern Med 127 1997 875 881 9382365 \n3 Shiffman M.L. Hofmann C.M. Thompson E.B. Relationship between biochemical, virological, and histological response during interferon treatment of chronic hepatitis C Hepatology 26 1997 780 785 9303513 \n4 Shiratori Y. Imazeki F. Moriyama M. Histologic improvement of fibrosis in patients with hepatitis C who have sustained response to interferon therapy Ann Intern Med 132 2000 517 524 10744587 \n5 Bruno S. Di Marco V. Iavarone M. Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virusrelated cirrhosis who attained sustained virological response Liver Int 37 2017 1526 1534 28418617 \n6 Nishiguchi S. Kuroki T. Nakatani S. Randomised trial of effects of interferon-alpha on incidence of hepatocelular carcinoma in chronic active hepatitis C with cirrhosis Lancet 346 1995 1051 1055 7564784 \n7 El-Serag H.B. Epidemiology of viral hepatitis and hepatocelular carcinoma Gastroenterology 142 2012 1264 1273 e1 22537432 \n8 Bruix J. Sherman M. American association for the study of liver diseases. Management of hepatocellular carcinoma: an update Hepatology 53 2011 1020 1022 21374666 \n9 Bruno S. Di Marco V. Iavarone M. Improved survival of patients with hepatocellular carcinoma and compensated hepatitis C virusrelated cirrhosis who attained sustained virological response Liver Int 37 2017 1526 1534 28418617 \n10 Reig M. Mariño Z. Perelló C. Unexpected high rate of early tumor recurrence in patients with HCV-related HCC undergoing interferon-free therapy J Hepatol 65 2016 719 726 27084592 \n11 Kanda T. Matsuoka S. Moriyama M. Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus-infected patients after sustained virological response Hepatol Int 12 2018 90 93 29619621 \n12 Chu P.S. Nakamoto N. Taniki N. On-treatment decrease of NKG2D correlates to early emergence of clinically evident hepatocellular carcinoma after interferon-free therapy for chronic hepatitis C PLoS One 12 2017 e0179096 28617830 \n13 Villani R. Facciorusso A. Bellanti F. DAAs rapidly reduce inflammation but increase serum VEGF level: a rationale for tumor risk during anti-HCV treatment PLoS One 11 2016 e0167934 27997563 \n14 Faillaci F. Marzi L. Critelli R. Liver Angiopoietin-2 is a key predictor of de novo or recurrent hepatocelular cancer after HCV direct-acting antivirals Hepatology 2018 Epub ahead of print \n15 Guarino M. Sessa A. Cossiga V. On behalf of the Special Interest Group on “hepatocellular carcinoma and new anti-HCV therapies” of the Italian Association for the Study of the Liver. Direct-acting antivirals and hepatocellular carcinoma in chronic hepatitis C: a few lights and many shadows World J Gastroenterol 24 24 2018 2582 2595 29962815\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-2509",
"issue": "14()",
"journal": "IDCases",
"keywords": "Direct-acting antiviral therapy; HCV infection; Hepatocellular carcinoma",
"medline_ta": "IDCases",
"mesh_terms": null,
"nlm_unique_id": "101634540",
"other_id": null,
"pages": "e00450",
"pmc": null,
"pmid": "30191133",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": "9382365;21374666;29604220;7564784;29619621;27084592;27997563;9303513;28418617;28617830;27293521;22537432;10744587;29962815",
"title": "Hepatocellular carcinoma after direct-acting antiviral therapy for chronic HCV infection: Is it a real risk?",
"title_normalized": "hepatocellular carcinoma after direct acting antiviral therapy for chronic hcv infection is it a real risk"
} | [
{
"companynumb": "PT-GILEAD-2018-0366736",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
"drugadditional": nul... |
{
"abstract": "Background and aims Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related death worldwide. Infection with the hepatitis C virus (HCV) is one of the most frequent underlying diseases leading to HCC development. Sorafenib is the standard of care for HCC patients not amenable to local treatment, resection, or liver transplantation. Although overall survival can be increased, objective response rates in patients treated with sorafenib are low. In HCC patients who underwent resection or ablation, HCV eradication with interferon-based regimens reduces the risk of recurrence. However, it is not known and under strong debate if patients with HCC should be treated with interferon-free regimens. Furthermore, it is not known if patients with advanced HCC at the time of diagnosis should be treated with antiviral therapy. Methods A patient with histologically confirmed advanced-stage HCC due to HCV-related cirrhosis was treated with sorafenib according to current guideline recommendations. Furthermore, he received subsequent treatment with direct antiviral agents (DAAs). Results The patient achieved a complete response after sorafenib treatment was initiated. Sorafenib treatment was terminated 1 year after complete response. As no recurrence of HCC was evident after treatment cessation, antiviral treatment was initiated with paritaprevir/ritonavir, ombitasvir, dasabuvir, and dose-reduced ribavirin because of chronic kidney disease. The patient achieved a sustained viral response. Conclusions Complete response to sorafenib treatment is scarce. Antiviral treatment should be considered in such patients as well as in patients with HCC who underwent resection or ablation.",
"affiliations": "Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany.;Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany.;Institut für Diagnostische und Interventionelle Radiologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany.;Dr. Senckenbergisches Institut für Pathologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany.;Medizinische Klinik 1, Schwerpunkt Gastroenterologie und Hepatologie, Universitätsklinikum Frankfurt, Frankfurt/Main, Germany.",
"authors": "Waidmann|Oliver|O|;Peveling-Oberhag|Jan|J|;Eichler|Katrin|K|;Schulze|Falko|F|;Vermehren|Johannes|J|",
"chemical_list": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0042-118232",
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"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "55(6)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D000998:Antiviral Agents; D006528:Carcinoma, Hepatocellular; D000066491:Clinical Decision-Making; D006526:Hepatitis C; D006801:Humans; D008113:Liver Neoplasms; D008297:Male; D008875:Middle Aged; D009536:Niacinamide; D010671:Phenylurea Compounds; D011230:Precancerous Conditions; D000077157:Sorafenib; D016896:Treatment Outcome",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "564-568",
"pmc": null,
"pmid": "27806410",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "To treat or not to treat - Successful hepatitis C virus eradication in a patient with advanced hepatocellular carcinoma and complete response to sorafenib.",
"title_normalized": "to treat or not to treat successful hepatitis c virus eradication in a patient with advanced hepatocellular carcinoma and complete response to sorafenib"
} | [
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"abstract": "BACKGROUND\nClinical features and treatment outcomes of intravascular large B-cell lymphoma (IVLBCL) have rarely been reviewed due to its rarity and pathologic obscurity.\n\n\nMETHODS\nWe analyzed 20 patients who were pathologically diagnosed with IVLBCL at the Samsung Medical Center.\n\n\nRESULTS\nInitial manifestations were nonspecific, such as fever with cytopenia, elevated serum lactate dehydrogenase and hypoalbuminemia. Hemophagocytosis was frequent and bone marrow was the most common site of pathologic diagnosis in our series. Hepatosplenomegaly, pleural effusion and ground-glass opacity in the lungs were also commonly found, and positron emission tomography imaging showed increased (18)F-fluorodeoxyglucose uptake in the involved organs. All patients received CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or rituximab-CHOP. The median overall survival (OS) was 38.9 months (95% confidence interval 6.7-71.1). Rituximab-containing chemotherapy compared to chemotherapy alone resulted in higher 3-year OS (71.4 and 25.0%; p = 0.027). Patients with hemophagocytosis had a poorer 3-year OS compared to patients without hemophagocytosis (29.6 and 75%; p = 0.046). Prognostic factor analysis showed the association of pleural effusion with worse OS (p = 0.002).\n\n\nCONCLUSIONS\nTreatment with rituximab-containing chemotherapy can improve the treatment outcome of IVLBCL. Pleural effusion may be a poor prognostic factor in patients with IVLBCL.",
"affiliations": "Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.",
"authors": "Hong|Jung Yong|JY|;Kim|Hee Jin|HJ|;Ko|Young Hyeh|YH|;Choi|Joon Young|JY|;Jung|Chul Won|CW|;Kim|Seok Jin|SJ|;Kim|Won Seog|WS|",
"chemical_list": "D058846:Antibodies, Monoclonal, Murine-Derived; D019788:Fluorodeoxyglucose F18; D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000351060",
"fulltext": null,
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"issn_linking": "0001-5792",
"issue": "131(1)",
"journal": "Acta haematologica",
"keywords": null,
"medline_ta": "Acta Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D008297:Male; D008875:Middle Aged; D016066:Pleural Effusion, Malignant; D049268:Positron-Emission Tomography; D011241:Prednisone; D056910:Republic of Korea; D012189:Retrospective Studies; D000069283:Rituximab; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "0141053",
"other_id": null,
"pages": "18-27",
"pmc": null,
"pmid": "24021554",
"pubdate": "2014",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Clinical features and treatment outcomes of intravascular large B-cell lymphoma: a single-center experience in Korea.",
"title_normalized": "clinical features and treatment outcomes of intravascular large b cell lymphoma a single center experience in korea"
} | [
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"companynumb": "KR-BAXTER-2015BAX027982",
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"abstract": "Sugammadex is increasingly used to reverse aminosteroid neuromuscular blocking agents. Dosing is calculated based on actual body weight, even for those who are obese. We report a case where a super obese patient (BMI 58.5 kg/m2) developed asystole, following coadministration with dexmedetomidine, for rapid reversal after deep blockade. Although 16mg/kg of actual body weight is recommended for prompt reversal of deep blockade, dosing adjustments may be prudent in the obese population, especially when used in conjunction with other negative chronotropic agents.",
"affiliations": "Department of Anesthesiology, Rutgers New Jersey Medical School, USA.;Department of Anesthesiology, Rutgers New Jersey Medical School, USA.",
"authors": "Gajewski|Michal|M|0000-0002-2064-9566;Esochaghi|Sorochi|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2019/2709568",
"fulltext": "\n==== Front\nCase Rep AnesthesiolCase Rep AnesthesiolCRIACase Reports in Anesthesiology2090-63822090-6390Hindawi 10.1155/2019/2709568Case ReportTransient Asystole after Sugammadex Administration for Immediate Reversal of Deep Blockade while on Dexmedetomidine Infusion in a Super Obese Patient http://orcid.org/0000-0002-2064-9566Gajewski Michal mg1214@njms.rutgers.eduEsochaghi Sorochi Department of Anesthesiology, Rutgers New Jersey Medical School, USAAcademic Editor: Ilok Lee\n\n2019 21 5 2019 2019 27095687 3 2019 24 4 2019 5 5 2019 Copyright © 2019 Michal Gajewski and Sorochi Esochaghi.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.Sugammadex is increasingly used to reverse aminosteroid neuromuscular blocking agents. Dosing is calculated based on actual body weight, even for those who are obese. We report a case where a super obese patient (BMI 58.5 kg/m2) developed asystole, following coadministration with dexmedetomidine, for rapid reversal after deep blockade. Although 16mg/kg of actual body weight is recommended for prompt reversal of deep blockade, dosing adjustments may be prudent in the obese population, especially when used in conjunction with other negative chronotropic agents.\n==== Body\n1. Introduction\nNeuromuscular blockade during surgery improves surgical conditions and facilitates intubation and mechanical ventilation. In order to prevent residual neuromuscular blockade reversal is required when utilizing nondepolarizing blockers. If using traditional anticholinesterases, such as neostigmine, reversal is recommended only after the patient has regained at least two of four twitches in the train-of-four (TOF) response, which can take 30-40 minutes [1]. The introduction of sugammadex as a neuromuscular blockade reversal agent, presented an alternate option for practitioners, especially when requiring rapid reversal. With this drug, reversal is likely within 2-3 minutes and is possible immediately after full blockade, albeit at higher doses [1]. Its use has quickly become widespread but many anesthetists might not be aware of the adjustments which may be warranted when dosing the drug in the obese population.\n\nObese patients are at an increased risk of intraoperative anesthesia-related complications such as critical respiratory events, oversedation, hypoxia, and hypercapnia [2]. Dexmedetomidine has been increasingly advocated for use in the obese population specifically due to its analgesics and narcotic sparing effects [3]. This alpha-2 adrenergic agonist is however associated with an increased blood pressure and reflex bradycardia during the initial loading, while continuing administration results in inhibition of the central sympathetic system leading to hypotension and bradycardia [4]. As with sugammadex, dosing of dexmedetomidine is recommended according to actual body weight, possibly leading to exaggerated negative chronotropic effect.\n\nWritten informed consent for writing this case report was obtained from the patient.\n\n2. Case Description\nA 1.5m, 50-year-old female weighing 136.1kg (BMI 58.5 kg/m2) presented for a videolaryngoscopy with bronchoscopy and T-tube exchange. She had a history of type 2 diabetes mellitus, obstructive sleep apnea, hypothyroidism, and lymphoma. Following chemotherapy and radiation therapy, the patient developed tracheomalacia and tracheal stenosis, rendering her T-tube dependent. Preoperatively, the patient's vitals were within normal limits and stable. She denied any known drug allergies.\n\nThe intraoperative electrocardiogram (ECG) was sinus rhythm. Given the uncertainty by the surgical team regarding the potential difficulty of exchange, the decision was made to start the case under sedation with dexmedetomidine. A loading dose of dexmedetomidine was given (1 mcg/kg) over a period of 10 minutes, without any hemodynamic effects, and was then continued at 0.4 mcg/kg/h. Once the patient was rendered unresponsive to verbal stimuli, the T-tube exchange was attempted. As the level of anesthesia was still insufficient for the exchange, deepening of the anesthetic was requested. The anesthesia circuit was connected to the T-tube and sevoflurane was administered at 0.5 minimum alveolar concentration (MAC). As a subsequent attempt at exchange was still unsuccessful due to inadequate anesthesia, the surgeon requested muscular paralysis. The dexmedetomidine infusion was therefore stopped, the inhalational anesthetic was increased to 1 MAC, and 50 mg of rocuronium was administered to the patient. Within 5 minutes the T-tube was successfully exchanged and confirmed with direct laryngoscopy.\n\nUpon termination of the surgical procedure, a peripheral nerve stimulator was used to evaluate the patient's depth of muscle paralysis. TOF stimulation of the ulnar nerve revealed 0/0 twitches with no recovery noted after tetany. In order to achieve complete reversal promptly, a sugammadex dose was calculated at 16 mg/kg, totaling 2177.6 mg. Due to our limited experience with this large dose, 1200 mg (55% of the calculated dose) was administered instead. Within about 30 seconds of the drug administration, it was noted that that the patient's heart rate precipitously decreased to 35 bpm and was immediately followed by asystole. At this point the surgeons were alerted of the sudden change in hemodynamic status; however prior to commencing chest compressions, the patient's heart rate spontaneously rebounded to the 90s (about 15 seconds total). Shortly afterwards, the patient began breathing spontaneously and TOF stimulation showed 4/4 twitches. The patient emerged from anesthesia and was transferred to the post anesthesia care unit (PACU) where a cardiology consult was obtained.\n\nPostoperatively, the patient's 12 lead ECG showed normal sinus rhythm without any abnormalities. The patient was monitored overnight on telemetry with all blood work, including troponins, returning within normal limits. An echocardiogram showed no regional wall motion abnormalities and a preserved ejection fraction. The patient was successfully discharged home the following day.\n\n3. Discussion\nSugammadex is a modified gamma cyclodextrin that irreversibly forms a complex with rocuronium and vecuronium preventing these aminosteroid neuromuscular blocking agents from acting at the nicotinic receptor [1]. Though some risks and adverse effects have been well elucidated, the use of sugammadex, including dosing regimens, has not been fully researched in the obese population. As the prescribing information from the manufacturer details, dosing is based on actual body weight and adverse effects may include marked bradycardia that could deteriorate to cardiac arrest [5]. A search of the medical literature reveals numerous case reports that have now been published reporting this [6, 7]. Our case further contributes to this finding with the added concern for dosing in the obese population. Although the true incidence of cardiac arrest from the use of sugammadex is unknown, worth noting is the significant increase in case reports to the FDA Adverse Event Reporting System (FAERS) compared to neostigmine. Since 1985, neostigmine has been reported for causing 121 serious cardiac adverse events, leading to 19 deaths, while in the span of 9 years, sugammadex has already been reported 138 times, 9 of which resulted in death [8].\n\nThe mechanism responsible for the bradycardia and asystole is unknown and case reports have noted such occurrence even at the prescribed low dose of 2mg/kg [6, 7]. In our patient, however, a much larger dose of sugammadex, 1200 mg, (8.8 mg/kg), was used, yet still below the recommended 16mg/kg of actual body weight indicated for prompt reversal. Although there is evidence suggesting that dosing according to ideal body weight for moderate neuromuscular blockade is effective, dosing of sugammadex according to actual body weight is still recommended for immediate reversal after deep blockade (16mg/kg) [9]. Adjusted body weight has also been studied when reversing deep blockade in the morbidly obese; however the dose used was only 4 mg/kg and due to the study's prospective observational design, further research is needed for conclusive results [10]. Similarly, Gaszynski et al. found successful reversal of neuromuscular blockade in the morbidly obese population based on corrected body weight; however this was after the reappearance of T2 in the TOF stimulation [11]. As such, a dose of 16 mg/kg is still recommended if there is a need to reverse the patient quickly after a single dose of 1.2 mg/kg of rocuronium irrespective of the patient's actual body weight. The manufacturer does not note an upper total limit for this regimen; hence no correlation can be made as to whether larger doses in obese patients cause an increased risk of adverse events.\n\nAlthough the asystole in our patient is temporally related to the administration of sugammadex, a direct correlation cannot be made as dexmedetomidine was being concomitantly given. Despite the fact that no hemodynamic changes were noted during the initial bolus as well as the brief continued infusion, the effect can be noted for up to 5 to 10 minutes after the loading dose is given [4]. Additionally, as the drug exhibits a rapid distribution phase with a half-life of 6 minutes and a termination half-life of 2 hours, our patient's plasma concentration was most likely within the therapeutic range, possibly enhancing the negative chronotropic effects, which have been previously noted [12]. Regardless of these known adverse hemodynamic effects, dexmedetomidine is overwhelmingly advocated for its cardioprotective, neuroprotective, and opioid sparing qualities, especially in the obese population. Although no studies have specifically looked at hemodynamic effects of coadministering dexmedetomidine and sugammadex, case reports do suggest that it can be done safely [13, 14]. Only one report presents a case of severe bradycardia with the concomitant use of dexmedetomidine and sugammadex, however in a pediatric heart transplant patient where the physiology of the denervated heart may have played a role [15]. Hence, we cannot rule out the possibility that dexmedetomidine may have contributed to our patients episode.\n\nAs the use of sugammadex becomes more prevalent, it is important that practitioners be aware of the risks of cardiac events that can occur with this reversal agent, especially when using actual body weight when dosing in the obese population. Considering the evidence, as well as our own experience, when utilizing sugammadex for immediate reversal (16mg/kg), a dose based on measuring the twitch response, before and after tetany, as well as on ideal body weight may be more prudent. Similarly, coadministration with dexmedetomidine should be done with caution as both agents are known for their ability to precipitate bradycardia. As the incidence of bradycardia is seen with higher total doses, the provider should consider premedication with anticholinergics, especially when used concomitantly with negative chronotropic agents, and should be prepared to initiate advanced cardiac life support (ACLS) in the event of cardiac arrest.\n\nDisclosure\nThis manuscript has not been printed in any print or online publications.\n\nConflicts of Interest\nThe authors declare they have no competing interests.\n\nAuthors' Contributions\nSorochi Esochaghi helped with drafting the manuscript and performing a literature search. Michal Gajewski helped with editing and revising the manuscript as well as performing a literature search.\n==== Refs\n1 Srivastava A. Hunter J. M. Reversal of neuromuscular block British Journal of Anaesthesia 2009 103 1 115 129 2-s2.0-67650713727 10.1093/bja/aep093 19468024 \n2 Gaszynski T. Szlachcinski Ł. Jakubiak J. Gaszynski W. Ocena przewodnictwa nerwowo-miesniowego po operacjach wykonywanych w znieczuleniu ogolnym z zastosowaniem niedepolaryzujacych srodkow zwiotczajacych Anestezjol Intens Ter 2009 41 11 15 19517671 \n3 Hofer R. E. Sprung J. Sarr M. G. Wedel D. J. Anesthesia for a patient with morbid obesity using dexmedetomidine without narcotics Canadian Journal of Anesthesia 2005 52 2 176 180 2-s2.0-16344369006 10.1007/BF03027725 15684259 \n4 Gertler R. Brown H. C. Mitchell D. H. Silvius E. N. Dexmedetomidine: a novel sedative-analgesic agent Baylor University Medical Center Proceedings 2017 14 1 13 21 10.1080/08998280.2001.11927725 \n5 BRIDION: highlights of prescribing information https://www.merck.com/product/usa/pi_circulars/b/bridion/bridion_pi.pdf , 2018 \n6 Sanoja I. A. Toth K. S. Profound bradycardia and cardiac arrest after sugammadex administration in a previously healthy patient: a case report A&A Practice 2019 12 1 22 24 30004912 \n7 Oliveira C. Marques C. Simões V. Spencer L. Poeira R. Casteleira M. Severe bradycardia and asystole associated with sugammadex: clinical case report Brazilian Journal of Anesthesiology 2018 2-s2.0-85055060533 \n8 Hunter J. M. Naguib M. Sugammadex-induced bradycardia and asystole: how great is the risk? British Journal of Anaesthesia 2018 121 1 8 12 2-s2.0-85045305650 10.1016/j.bja.2018.03.003 29935599 \n9 Abd El-Rahman A. M. Othman A. H. Elsherif F. A. Mostafa M. F. Taha O. Comparison of three different doses sugammadex based on ideal body weight for reversal of moderate rocuronium-induced neuromuscular blockade in laparoscopic bariatric surgery Minerva Anestesiologica 2017 83 2 138 144 2-s2.0-85014091735 27575450 \n10 Badaoui R. Cabaret A. Alami Y. Reversal of neuromuscular blockade by sugammadex in laparoscopic bariatric surgery: In support of dose reduction Anaesthesia Critical Care and Pain Medicine 2016 35 1 25 29 2-s2.0-85009062918 10.1016/j.accpm.2015.09.003 26597732 \n11 Gaszynski T. Szewczyk T. Gaszynski W. Randomized comparison of sugammadex and neostigmine for reversal of rocuronium-induced muscle relaxation in morbidly obese undergoing general anaesthesia British Journal of Anaesthesia 2012 108 2 236 239 10.1093/bja/aer330 2-s2.0-84856285500 22012861 \n12 Hospira. Precedex (dexmedetomidine hydrochloride injection): highlights of prescribing information http://www.precedex.com/wp-content/uploads/2010/11/Precedex_PI.pdf , 2019 \n13 Creaney M. Moriarty R. M. Milner M. Murphy C. Dexmedetomidine, high-flow nasal oxygen and sugammadex-reversal of rocuronium: overcoming anaesthetic challenges in a parturient with congenital muscular dystrophy presenting for caesarean section International Journal of Obstetric Anesthesia 2018 34 108 112 2-s2.0-85043363197 10.1016/j.ijoa.2018.02.003 29544721 \n14 Gaszynski T. Gaszynska E. Szewczyk T. Dexmedetomidine for awake intubation and an opioid-free general anesthesia in a superobese patient with suspected difficult intubation Drug Design, Development and Therapy 2014 8 909 912 2-s2.0-84904053796 \n15 King A. Naguib A. Tobias J. D. Bradycardia in a pediatric heart transplant recipient: Is it the sugammadex? The Journal of Pediatric Pharmacology and Therapeutics 2017 22 5 378 381 2-s2.0-85041042719 10.5863/1551-6776-22.5.378 29042841\n\n",
"fulltext_license": "CC BY",
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"journal": "Case reports in anesthesiology",
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"pages": "2709568",
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"pmid": "31263603",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "15684259;16369581;19468024;19517671;22012861;25045249;26597732;27575450;29042841;29544721;29935599;30004912;30348442",
"title": "Transient Asystole after Sugammadex Administration for Immediate Reversal of Deep Blockade while on Dexmedetomidine Infusion in a Super Obese Patient.",
"title_normalized": "transient asystole after sugammadex administration for immediate reversal of deep blockade while on dexmedetomidine infusion in a super obese patient"
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{
"abstract": "Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of nonclassical Hodgkin lymphoma (HL). It resembles non-Hodgkin lymphoma (NHL), by expressing classic B cell markers such as CD20 and CD79a however lacks definitive HL markers (such as CD15 and CD30). T cell histiocyte-rich large B cell lymphoma (THRLBCL), on the other hand, is a distinct entity classified under NHL and considered a variant of diffuse large B cell lymphoma (DLBCL). NLPHL can look morphologically and immunologically similar to THRLBCL and often poses a diagnostic challenge. Neoplastic cells in both NLPHL and THRLBCL express B cell markers and are typically scattered in a background of reactive cells. The two major differences are the background cell type and the morphologic pattern. Despite having a phenotypic resemblance, they have distinct biologic behavior and clinical course. NLPHL typically has an indolent course, and THRLBCL has an aggressive course. Hence, differentiating these two entities is critical not only for prognosis but for treatment purposes. Of note, NLPHL has a small risk of transformation to an aggressive lymphoma such as THRLBCL.",
"affiliations": "MD Anderson Cooper Cancer Center, Cooper University Hospital, Camden, NJ, USA.;MD Anderson Cooper Cancer Center, Cooper University Hospital, Camden, NJ, USA.;MD Anderson Cooper Cancer Center, Cooper University Hospital, Camden, NJ, USA.",
"authors": "Siricilla|Mamatha|M|0000-0003-0347-0350;Irwin|Lydia|L|;Ferber|Andres|A|",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/6137454Case ReportA Case of Chemotherapy-Refractory “THRLBCL like Transformation of NLPHL” Successfully Treated with Lenalidomide http://orcid.org/0000-0003-0347-0350Siricilla Mamatha msiricilla@gmail.comIrwin Lydia Ferber Andres MD Anderson Cooper Cancer Center, Cooper University Hospital, Camden, NJ, USAAcademic Editor: Jose I. Mayordomo\n\n2018 6 2 2018 2018 613745430 10 2017 6 12 2017 Copyright © 2018 Mamatha Siricilla et al.2018This 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.Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a subtype of nonclassical Hodgkin lymphoma (HL). It resembles non-Hodgkin lymphoma (NHL), by expressing classic B cell markers such as CD20 and CD79a however lacks definitive HL markers (such as CD15 and CD30). T cell histiocyte-rich large B cell lymphoma (THRLBCL), on the other hand, is a distinct entity classified under NHL and considered a variant of diffuse large B cell lymphoma (DLBCL). NLPHL can look morphologically and immunologically similar to THRLBCL and often poses a diagnostic challenge. Neoplastic cells in both NLPHL and THRLBCL express B cell markers and are typically scattered in a background of reactive cells. The two major differences are the background cell type and the morphologic pattern. Despite having a phenotypic resemblance, they have distinct biologic behavior and clinical course. NLPHL typically has an indolent course, and THRLBCL has an aggressive course. Hence, differentiating these two entities is critical not only for prognosis but for treatment purposes. Of note, NLPHL has a small risk of transformation to an aggressive lymphoma such as THRLBCL.\n==== Body\n1. Introduction\nHere We present a case of NLPHL with THRLBCL like transformation. We used single agent lenalidomide, after failing more than four lines of conventional combination chemotherapy. Using this treatment, we were able to achieve a complete clinical and radiological response (CR).\n\nBased on our experience with this rather rare case presentation and clinical course, we want to highlight the diagnostic challenge in these two entities at de novo presentation and with transformation. Treatment of NLPHL and THRLBCL as individual entities in the relapsed refractory setting is challenging. This case highlights an example of refractory NLPHL with THRLBCL-like transformation at relapse and presents lenalidomide as a promising treatment option, a drug not typically used in this setting.\n\n2. Case Presentation\nA 35-year-old gentleman first presented with left axillary lymphadenopathy in 2010. He was subsequently lost to follow-up for approximately two years until February 2012. At this point, he was noted to have waxing and waning lymphadenopathy in the left axilla and a 100 lbs unintentional weight loss. PET-CT scans showed diffuse lymphadenopathy involving the left upper chest wall, left axillary (SUV 15.1), left upper neck, right iliac (SUV 16.2), and inguinal regions. He underwent biopsy of the axillary lymph node (March 2012), and pathology showed an atypical lymphoid infiltrate of medium-sized cells. By immunohistochemistry (IHC), the cells were positive for CD20, BCL6, and CD45 and negative for CD15 and CD30. Large numbers of CD3-positive small lymphocytes were noted in the background along with CD57 cells surrounding the tumor cells, which was consistent with the diagnosis of NLPHL. A bone marrow biopsy was performed which was negative for involvement with lymphoma. He received chemotherapy with six cycles of rituximab (R), cyclophosphamide (C), Adriamycin (H), vincristine (O), and prednisone (P) and achieved partial response only. During that time, there were multiple delays in treatment due to complications including a pulmonary embolism (June 2012), necrotizing fasciitis, and septic arthritis with group A Streptococcus. Due to the partial response, he was subsequently treated with second-line therapy using ifosfamide (I), gemicitabine (GE), and vinorelbine (V) with rituximab (R) for four cycles. PET-CT scan performed at completion of this in February of 2013 showed near resolution of all the previous FDG avid lesions, except for a small amount of metabolic activity in the left axilla with an SUV of 2.5. At that time, it was recommended that the patient should undergo autologous stem cell transplant; however, he failed to follow-up with his appointments. Subsequently he received radiation for residual disease in the left axilla (August 2013).\n\nFollowing radiation therapy, the patient felt clinically well until July 2014, which was nearly a year since his last treatments and four years from his initial presentation. Routine surveillance PET-CT in July 2014 revealed recurrent disease with diffuse lymphadenopathy including new hypermetabolic lesions in the retroperitoneum and cardiophrenic regions, the largest of which was in the peri-pancreatic area measuring 12.5 × 7.0 × 4.0 cm, with an SUV of 12.5. Fine-needle aspiration with endoscopic ultrasound of the peripancreatic lymph nodes was nondiagnostic. He was lost for follow-up and presented several months later with night sweats, fevers, weight loss, and dyspnea on exertion. PET-CT scan in December 2015 showed splenomegaly and progressive diffuse lymphadenopathy. Excisional biopsy of the left inguinal lymph node revealed a partially intact capsule; architecture was effaced by a nodular and diffuse lymphoid infiltrate of predominantly small mature lymphocytes with admixed large atypical lymphocytes. The large atypical lymphocytes were multilobulated with vesicular chromatin and nucleoli that ranged from multiple intermediate- to large-sized central nucleoli, consistent with lymphocyte predominant cells. The large atypical cells were noted in the diffuse regions of the lymph node but were more numerous in the nodules. Immunohistochemical stains of the large atypical cells were positive for CD45, CD79a, PAX5, BCL6, MUM1, OCT2, BOB1, and IgD and negative for CD30, CD15, CD10, and ALK. A subpopulation of B cells was positive for CD20. Scattered immunoblasts were positive for CD30. EBV (Epstein–Barr virus) in situ hybridization was negative. Of note, there was a marked T lymphocyte infiltrate in a background of predominantly CD4 + T lymphocytes. There were rosettes formed by CD3-, CD4-, and PD-1-positive cells around scattered large atypical cells. There were nodules with expanded follicular dendritic cells highlighted by CD21 and CD23. A subset of T lymphocytes was CD57 positive, and scattered CD163-positive histiocytes were also noted. The lesions had features of both nodular lymphocyte predominant Hodgkin lymphoma and T cell histiocyte-rich B cell lymphoma. Positivity of immunoglobulin D and the presence of follicular structures still favored a diagnosis of NLPHL.\n\nHe was started on third-line therapy with rituximab (R), ifosfamide (I), carboplatin (C), and etoposide (E) chemotherapy in April 2016, and after two cycles of therapy, he was found to have no response. His course was complicated by systemic cryptococcal infection, and chemotherapy was held. A repeat PET-CT scan in June 2016 revealed extensive disease involving the lymph nodes, bone marrow, and spleen. Hypermetabolic lymph nodes in the bilateral neck level II/V had an SUV of 13.0, the gastrohepatic ligament had an SUV of 14.4, the right external iliac had an SUV of 21.4, and the mesentery had an SUV of 19.3. Hypermetabolic lesions were also noted in the sternum, right proximal femur, and clivus with a maximum SUV of 14.0. The spleen was markedly enlarged and diffusely hypermetabolic with a focal hypermetabolic lesion in the posterior region with a maximum SUV of 13.0. The liver was also enlarged with multiple hypermetabolic lesions, the largest of which was in the posterior right hepatic lobe with a maximum SUV of 9.0, all consistent with lymphoma involvement. Overall Deauville score was reported to be four. A repeat biopsy (right cervical lymph node) was performed. Pathology from this specimen showed extensive effacement of the normal architecture by an atypical predominantly diffuse but focally vague nodular polymorphous lymphoid infiltrate composed of a mixture of small, medium, and large cells. Specifically, many scattered large atypical cells are distributed throughout the infiltrate within a background of abundant small- to medium-sized mature lymphocytes and histiocytes. The large atypical cells possessed moderately abundant pale cytoplasm and large markedly irregular/lobulated nuclei with coarse vesicular chromatin. Scattered mitotic figures and occasional multinucleated forms were present. No significant eosinophil or plasma cell infiltrate was appreciated. While the majority of the infiltrate exhibited a diffuse growth pattern, a focal area of nodular growth was also present. Immunohistochemical stains revealed that the large atypical tumor cells were B cells, positive for CD45, PAX5, CD79a, BCL6, OCT2, MUM1, CD30 (minor, weak subset), and EMA (very rare cells, weakly positive) and negative for CD20, CD10, CD15, and ALK. CD3- and CD163-positive stains highlighted an abundant background of T cells and histiocytes, respectively (see Figures 1 and 2 for pathology slides). A subset of lymphocytes was CD57 positive without obvious rosette formation. CD21 and CD23 stains were almost negative, highlighting only rare residual dendritic meshworks of follicular structures. An additional immunostain for Ki 67 highlighted a high proportion of tumor cells (greater than 75%). In situ hybridization for EBER (Epstein–Barr encoding region) was negative. Overall, the lesions had features of both NLPHL and THRLBCL. Given the focal nodularity and the patient's prior history of NLPHL, diagnosis was best classified as NLPHL-THRLBCL-like (old terminology) now updated in the new 2016 WHO classification as “THRLBCL-like transformation of NLPHL” (see Figures 1 and 2 for pathology description).\n\nThe patient subsequently received fourth-line treatment with two cycles of gemcitabine/oxaliplatin (August 2016) and demonstrated further progression of the disease. A PET-CT scan (September 2016) revealed new hypermetabolic adenopathy, with greater than thirty hypermetabolic lymph nodes throughout the body. There were also extensive hypermetabolic osseous metastases throughout the skull, ribs, spine, pelvis, and proximal femur. There were also new hypermetabolic lesions in the liver. The Deauville score was five (see Figure 3 outlining his treatment schema).\n\nFurther chemotherapy with regimens such as DHAP (dexamethasone, high-dose ara-C (cytarabine), and cisplatin) was planned. At this time, the patient felt poorly with prior chemotherapy regimens. His course was complicated by systemic cryptococcal infection as well as the cumulative toxicities of the prior therapies. Due to these reasons, additional chemotherapy was withheld. Tumor cells were tested for PD-L1 expression and it was negative.\n\nLenalidomide was initiated in November 2016 (25 mg daily for 3 weeks on and 1 week off schedule). The patient experienced rapid clinical response with resolution of fevers, night sweats, and subsequent weight gain. PET-CT scan performed five months after lenalidomide initiation showed resolution of the previously noted lesions in the bones, lymph nodes, and liver (see Figures 4–6 for PET-CT image comparison showing resolution of the disease).\n\n3. Discussion\nNLPHL is a rather uncommon subtype of nonclassical Hodgkin lymphoma (HL) constituting only 5% of all HL cases [1]. It shares morphologic resemblance to the lymphocyte predominant type of classical HL, hence classified under this category [2]. However, this disease entity is very distinct from classical HL. Specifically, the cells have a germinal center B cell phenotype characterized by positivity for CD20, CD79a, and BCL6 cells, immunoglobulin expression, J chain, and epithelial membrane antigen and negativity for classic markers for HL such as CD15 and CD30 [3–6].\n\nImmunophenotypically, NLPHL is distinguished by the presence of large neoplastic cells (lymphocytic predominant cells) in a nodular distribution, with scattered nonneoplastic small B cells and T cells and the presence of a meshwork of dendritic follicular cells. CD3-, CD4-, and CD57-positive small T cells form rims around the large neoplastic B cells [2].\n\nImmunophenotypically, THRLBCL is distinguished by the presence of large neoplastic cells in a diffuse pattern (as opposed to the nodular pattern seen in NLPHL). In THRLBCL, malignant B cells are scattered on a background of small nonneoplastic CD8-positive T cells and histiocytes, with rare small B reactive cells, which are different from the reactive small T cells, and abundant reactive B cells seen in NLPHL. Neoplastic B cells constitute only 10% of the infiltrate in THRLBCL [7]. T cell rosettes, small B cell lymphoid aggregates, and nodular infiltrate with a follicular dendritic cell meshwork typify NLPHL, which are absent in THRLBCL. PU.1, a transcription factor deemed necessary for B cell proliferation, is noted to be expressed in all cases of NLPHL but reduced or absent in THRLBCL [8]. Genomic imbalances were also noted to be more frequent in NLPHL than in THRLBCL [9]. The later described distinctions argue against direct evolution of one disease into another.\n\nDue to similarities in the phenotype, both NLPHL and THRLBCL can look morphologically and immunologically alike [10], thereby making the diagnosis quite challenging [11–13]. Because these two entities have distinct biologic behavior, clinical course, and aggressiveness, it is critical to differentiate them prior to making therapeutic decisions. NLPHL typically presents with localized disease, involving the peripheral lymph nodes. Spleen and extranodal disease at presentation is rare [14], and the clinical course is indolent [15]. THRLBCL is aggressive and typically presents in advanced stages, with nearly 50% of cases having bone marrow, spleen, and liver involvement [16]. As such, THRLBCL is associated with poor outcomes [17–20]. Traditional therapy for stage I/II NLPHL is full nodal excision followed by either a “watch or wait strategy” or localized radiation [21–25]. The challenging part of NLPHL is the relapsing nature of the disease and the potential risk (3–7%) [14] of transformation into a large B cell lymphoma, sometimes even decades later [26]. THRLBCL is one of the most common types of large B cell lymphoma, seen as a result of transformation of NLPHL [27]. Advanced stages of NLPHL are typically treated with ABVD similar to HL, with the exception of the addition of rituximab due to CD20-positive cells. The treatment approach for THRLBCL is similar to DLBCL and typically involves regimens such as R-CHOP. In a subset of NLPHL cases that present with B symptoms and/or abdominal involvement, R-CHOP is favored over ABVD due to the risk of occult transformation to large cell lymphoma [1]. Stage-adjusted overall survival rates for NLPHL are over 90% and over 50% for THRLBCL [15]. In contrast, these survival rates reiterate the importance of differentiating these two diseases in order to make appropriate therapeutic decisions [28]. There have been interesting observations reported in the literature where these two entities were reported to be present concomitantly or seen on subsequent biopsies [18, 19, 26]. NLPHL is believed to be derived from a precursor lesion described as “progressive transformation of germinal center B cells” (PTGC). Thus, it may be possible that this represents a continuum of a single disease or a natural course of diseases from PTGC to NLPHL and eventually THRLBCL [26, 29].\n\nIn a large prospective study conducted by the British Columbia Cancer Agency, the risk of transformation of NLPHL into large cell lymphoma was reported to be 7% and 30% in 10 and 20 years, respectively. This risk is higher in patients with advanced-stage disease at presentation and if there is splenic involvement. Splenic involvement is an independent predictor for transformation. It is seen in almost all cases of NLPHL transformations (close to 80%), unlike de novo large cell lymphoma where the chances of spleen involvement were only 20%. It is also recommended that patients with findings suggestive of splenic involvement at the time of diagnosis of NLPHL should be strongly considered for splenectomy to rule out the concurrent presence of DLBCL and/or THRLBCL [9].\n\nFindings of the pathology in our case at the time of progressive disease after four lines of therapy (see Figure 3 for treatment schema) had features of both NLPHL and THRLBCL, with diffuse infiltrates but retained focal nodularity, rare follicular dendritic cells, and absent T cell rosettes. The presence of even one nodular lesion in the background of TCHRLBC will exclude the diagnosis of primary/de novo THRLBCL as per the WHO criteria [30]. In this particular case, the patient's prior history of NLPHL and subsequent biopsy showing both NLPHL and THRLBCL features best fit the diagnosis of NLPHL-like THRLBCL or “THRLBCL-like transformation of NLPHL” as per the updated 2016 WHO recommendations [31]. Literature review revealed few cases similar to ours with NLPHL-like areas in THRLBCL [14, 32] and these cases were either treated with R-ABVD or R CHOP. There was one case with discordant presentation with NLPHL in a lymph node and THRLBCL in the bone marrow [29]. Treatment of relapsed cases with large cell transformation is similar to DLBCL, typically using standard salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant [1].\n\nTo the best of our knowledge, there is no published literature for treatments of relapsed-refractory THRLBCL-like transformation of NLPHL. There is also no case reported indicating the use of lenalidomide for this disease entity.\n\nLenalidomide is known to be an active agent in heavily pretreated NHL [33, 34]. It had been successfully studied in the relapsed-refractory setting in various types of NHL such as mantle cell lymphoma [33], follicular lymphoma [35], diffuse large B cell lymphoma [36], and T cell lymphoma [37]. The FDA approved lenalidomide for relapsed mantle cell lymphoma after 2 lines of therapy [38]. The use of lenalidomide in newly diagnosed aggressive B cell lymphoma, particularly in nongerminal center-derived cases, has been reported in combination with R-CHOP (R2-CHOP) and has been shown to achieve objective response rates (ORRs) of 90–100% and CR of 77%–86% [39–42]. In addition, lenalidomide as monotherapy in relapsed refractory cases of NHL was shown to have an ORR of 35–28% [33, 34]. The benefit was much higher in nongerminal center-derived subtypes (ORR 52.9%) than in germinal center-derived subtypes (ORR 8.7%) [43]. The response rate in our case was nearly 100%, which is particularly exciting, given that this patient had previously failed four lines of treatment.\n\nLenalidomide acts by blocking tumor growth and survival by direct tumoricidal and immunomodulatory actions. Lenalidomide also modulates tumor cell microenvironment and stimulates activity of cytotoxic T and natural killer cells [44]. It causes inhibition of nuclear factor kappa B, leading to cell cycle arrest and tumor cell death [45]. Interestingly, the nongerminal center subtype of DLBCL was noted to have a high expression of NF kappa which might explain higher response rates in these subtypes [38]. In the relapsed-refractory setting, patients are heavily pretreated, and cumulative toxicities from prior treatments often become a barrier for additional chemotherapy.\n\nLenalidomide, on the other hand, has a highly manageable toxicity profile, making it a viable treatment option in certain circumstances. The most frequent reported grade 3-4 adverse events include neutropenia (43%), febrile neutropenia (5%), thrombocytopenia (28%), fatigue (7%), skin rash (23%), diarrhea (6%), and risk of thromboembolism. One downside of lenalidomide is the potential risk for second primary malignancies (incidence rate of 3.98%) [46]. The risk and benefits of such a drug should be discussed, especially when using in younger patients.\n\nBased on our clinical experience with this case and the established activity of lenalidomide in NHL, we hope that the use of lenalidomide will expand into a viable option for NLPHL and/or THRLBCL-like transformation of NLPHL.\n\nIt would be interesting to design clinical trials using lenalidomide in NLPHL and THRLBCL-like transformation cases, when refractory to traditional treatments. Another area of research interest would be using lenalidomide as an upfront therapy to avoid exposure to potentially toxic chemotherapy combinations.\n\nAcknowledgments\nThe authors thank Dr. Eric Behling MD and Dr. Roland Schwarting MD from the Department of Pathology and Dr. Barshay Veniamin MD from the Department of Nuclear Medicine at Cooper University Hospital, Camden, NJ.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Haemotoxylin and eosin (H&E) stain (a) at 400x magnification showing a diffuse appearing infiltrate composed of scattered large atypical cells in a background of smaller lymphocytes and histiocytes and (b) at 600x magnification showing lymphocyte predominant cells. (c) CD3 stain highlights abundant background T cells and shows a hint of nodularity (center) shown at 100x magnification. (d) Large tumor cells are strongly positive for PAX5. Note the presence of the nodule of tumor cells in the center.\n\nFigure 2 (a) CD21 stain highlights rare dendritic meshworks shown at 200x magnification. (b) The large tumor cells are strongly positive for CD45 (this is essential in excluding classical Hodgkin lymphoma from the differential diagnosis; both NLPHL and THRLBCL will be CD45+) shown at 400x magnification. (c) CD163 stain highlights abundant background histiocytes shown at 40x magnification. (d) Large tumor cell nuclei are strongly OCT2 positive. Note the presence of tumor cells in the center shown at 100x magnification.\n\nFigure 3 Treatment schema.\n\nFigure 4 PET-CT images: 3-dimensional MIP images.\n\nFigure 5 Fused PET-CT images: abdominal window showing resolution of liver and spleen lesions (a) prior to lenalidomide use and (b) after lenalidomide use.\n\nFigure 6 Fused PET-CT images: bone window showing resolution of bone lesions (a) prior to lenalidomide use and (b) after lenalidomide use.\n==== Refs\n1 Advani R. H. 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"issue": "2018()",
"journal": "Case reports in oncological medicine",
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"medline_ta": "Case Rep Oncol Med",
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"references": "11748286;11920535;16094666;26980727;3041849;23812930;12207783;20048177;14687617;12393409;12881319;7602364;9250848;12416895;21495023;19805688;23731832;25110597;24831981;24215035;14508396;16093276;17360935;15370206;21436871;21228334;22323483;9250847;12078902;23545991;12663714;17124071;19933914;21720383;10071266;11696441;10961891;25736312;9777980;18784812;18606983",
"title": "A Case of Chemotherapy-Refractory \"THRLBCL like Transformation of NLPHL\" Successfully Treated with Lenalidomide.",
"title_normalized": "a case of chemotherapy refractory thrlbcl like transformation of nlphl successfully treated with lenalidomide"
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"companynumb": "US-CIPLA LTD.-2018US14317",
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"abstract": "Refractory status epilepticus is a disease associated with high morbidity and mortality, which does not always respond to standard treatments, and when they fail, alternative modalities become crucial. Therapeutic hypothermia slows nerve conduction in vitro, and has been shown to abort seizures in animal models. Therapeutic hypothermia has been experimentally used in humans since 1963 for a variety of intracranial pathologies. More recently there have been multiple reports demonstrating the effectiveness of therapeutic hypothermia in treating refractory status epilepticus. We report a case of super-refractory status epilepticus successfully treated with therapeutic hypothermia, complimented by a historical and literature review of this modality. While there is limited evidence, and some risks associated with therapeutic hypothermia, it should be considered as a reasonable and potentially effective treatment option for refractory status epilepticus.",
"affiliations": "University of Utah, Neurology Department, 175 N. Medical Dr. East, 5th Floor, Salt Lake City 84132, USA.;Intermountain Medical Center, Neurology Department, 5171 S. Cottonwood St. Ste 810, Salt Lake City 84107, USA.;University of Utah, Neurology Department, 175 N. Medical Dr. East, 5th Floor, Salt Lake City 84132, USA.;University of Utah, Neurology Department, 175 N. Medical Dr. East, 5th Floor, Salt Lake City 84132, USA.;University of Utah, Neurology Department, 175 N. Medical Dr. East, Room 3130, Salt Lake City 84132, USA. Electronic address: safdar.ansari@hsc.utah.edu.",
"authors": "Bennett|Alicia E|AE|;Hoesch|Robert E|RE|;DeWitt|L Dana|LD|;Afra|Pegah|P|;Ansari|Safdar A|SA|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-8467",
"issue": "126()",
"journal": "Clinical neurology and neurosurgery",
"keywords": "Anti-epileptic drugs; EEG; Seizure; Status epilepticus; Therapeutic hypothermia",
"medline_ta": "Clin Neurol Neurosurg",
"mesh_terms": "D000328:Adult; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007036:Hypothermia, Induced; D013226:Status Epilepticus",
"nlm_unique_id": "7502039",
"other_id": null,
"pages": "103-9",
"pmc": null,
"pmid": "25240131",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Therapeutic hypothermia for status epilepticus: A report, historical perspective, and review.",
"title_normalized": "therapeutic hypothermia for status epilepticus a report historical perspective and review"
} | [
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"companynumb": "PHHY2015US057899",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLONAZEPAM"
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"abstract": "Bisphosphonates are inorganic pyrophosphate analog which accumulate on the bone surface, cause osteoclast apoptosis, and inhibit bone resorption. The nitrogen-containing bisphosphonates continue to be the drug of choice for the treatment of osteoporosis in both men and women. Although histomorphometric studies including bone biopsies have not shown any evidence of microcracks, recent studies have revealed that potent bisphosphonates are responsible for the oversuppression of bone turnover leading to microdamages, reduced bone strength, and increased fracture risk. There are individual cases reporting atypical femoral fractures and severely suppressed bone turnover along with long-term (≥ 5 years) use of biphosphonates. In this study, we report on a 74-year-old woman with a history of continuous alendronate use for nearly 16 years who presented to the emergency department with right proximal humerus and left femur fracture.",
"affiliations": "Department of Physical Medicine and Rehabilitation, Haydarpaşa Training Hospital, Gülhane Military Medical Academy, Istanbul, Turkey, dandinoglu@gmail.com.",
"authors": "Dandinoğlu|T|T|;Akarsu|S|S|;Karadeniz|M|M|;Tekin|L|L|;Arıbal|S|S|;Kıralp|M Z|MZ|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-013-2428-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "25(2)",
"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; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D004334:Drug Administration Schedule; D005260:Female; D005264:Femoral Fractures; D005598:Fractures, Spontaneous; D006801:Humans; D006810:Humeral Fractures; D015663:Osteoporosis, Postmenopausal; D011859:Radiography",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "773-6",
"pmc": null,
"pmid": "23824297",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17356148;19113931;11344052;21343577;19670917;17190893;15478000;20842676;18222447;19066707;17824840;15028823;11768198;16265598;16418785;22184174",
"title": "Can long-term bisphosphonate use causes low-energy fractures? A case report.",
"title_normalized": "can long term bisphosphonate use causes low energy fractures a case report"
} | [
{
"companynumb": "TR-APOTEX-2015AP009940",
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"occurcountry": "TR",
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
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... |
{
"abstract": "BACKGROUND\nThis was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization.\n\n\nMETHODS\nPatients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375-1000 mg/m(2) b.i.d.) for 14 days every 21 days. Radioembolization with (90)Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine.\n\n\nRESULTS\nTwenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m(2). The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively.\n\n\nCONCLUSIONS\nThis combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m(2) b.i.d. is recommended for phase II study with sequential lobar radioembolization.",
"affiliations": "Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Radiation Oncology, Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan, USA.;Department of Radiology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Radiology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Radiology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA.;Sirtex Medical Ltd, Sydney, New South Wales, Australia.;Division of Hematology and Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA.",
"authors": "Cohen|S J|SJ|;Konski|A A|AA|;Putnam|S|S|;Ball|D S|DS|;Meyer|J E|JE|;Yu|J Q|JQ|;Astsaturov|I|I|;Marlow|C|C|;Dickens|A|A|;Cade|D N|DN|;Meropol|N J|NJ|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D015021:Yttrium Radioisotopes; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1038/bjc.2014.344",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201434410.1038/bjc.2014.34424983373Clinical StudyPhase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer Capecitabine and radioembolizationCohen S J 1*Konski A A 2Putnam S 3Ball D S 3Meyer J E 4Yu J Q 3Astsaturov I 1Marlow C 5Dickens A 5Cade D N 6Meropol N J 71 Department of Medical Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA2 Department of Radiation Oncology, Karmanos Cancer Center, Wayne State University School of Medicine, Detroit, Michigan, USA3 Department of Radiology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA4 Department of Radiation Oncology, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA5 Clinical Trials Office, Fox Chase Cancer Center, Philadelphia, Pennsylvania, USA6 Sirtex Medical Ltd, Sydney, New South Wales, Australia7 Division of Hematology and Oncology, University Hospitals Seidman Cancer Center, Case Comprehensive Cancer Center, Case Western Reserve University, Cleveland, Ohio, USA* E-mail: Steven.cohen@fccc.edu15 07 2014 01 07 2014 111 2 265 271 06 01 2014 16 05 2014 27 05 2014 Copyright © 2014 Cancer Research UK2014Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Background:\nThis was a prospective single-centre, phase I study to document the maximum tolerated dose (MTD), dose-limiting toxicity (DLT), and the recommended phase II dose for future study of capecitabine in combination with radioembolization.\n\nMethods:\nPatients with advanced unresectable liver-dominant cancer were enrolled in a 3+3 design with escalating doses of capecitabine (375–1000 mg/m2 b.i.d.) for 14 days every 21 days. Radioembolization with 90Y-resin microspheres was administered using a sequential lobar approach with two cycles of capecitabine.\n\nResults:\nTwenty-four patients (17 colorectal) were enrolled. The MTD was not reached. Haematologic events were generally mild. Common grade 1/2 non-haematologic toxicities included transient transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)). One patient experienced a partial gastric antral perforation with a capecitabine dose of 750 mg/m2. The best response was partial response in four (16.7%) patients, stable disease in 17 (70.8%) and progression in three (12.5%). Median time to progression and overall survival of the metastatic colorectal cancer cohort was 6.4 and 8.1 months, respectively.\n\nConclusions:\nThis combined modality treatment was generally well tolerated with encouraging clinical activity. Capecitabine 1000 mg/m2 b.i.d. is recommended for phase II study with sequential lobar radioembolization.\n\nradioembolizationcapecitabinephase I\n==== Body\nThe liver is the most common site of metastases from gastrointestinal (GI) malignancies (Hess et al, 2006). Liver-dominant metastatic disease occurs in 44% of patients following potentially curative resection of primary colorectal cancer (CRC; Manfredi et al, 2006a) and in 70% of those diagnosed with stage IV CRC (synchronous metastases; Manfredi et al, 2006b). Although systemic therapy options for metastatic CRC (mCRC) and other GI malignancies are increasing (Cunningham et al, 2004; Hurwitz et al, 2004; Grothey et al, 2013), median survival remains ∼2 years. There has thus been considerable interest in liver-directed therapies such as radioembolization, with or without systemic chemotherapy, to improve the control of liver-dominant metastatic GI malignancies.\n\nCapecitabine, an oral fluoropyrimidine prodrug, is commonly used as an alternative to intravenous 5-fluorouracil (5-FU) in the treatment of GI cancers (Smith and Neoptolemos, 2006; Okines et al, 2007; Arkenau et al, 2008; Medley et al, 2011). The most common adverse events with capecitabine monotherapy include hand-foot syndrome, nausea, diarrhoea and fatigue (Mikhail et al, 2010). The efficacy of capecitabine combined with radiotherapy as a radiosensitizer has been studied extensively. A recent phase III multicentre comparison of capecitabine-based vs fluorouracil-based chemoradiotherapy for the neoadjuvant or adjuvant treatment of stage II–III locally advanced rectal cancer demonstrated similar results regardless of fluoropyrimidine (Hofheinz et al, 2012).\n\nThere is an expanding experience with yttrium-90 (90Y) resin microspheres for the management of unresectable liver-predominant cancers. Many aspects of this therapy have been published, including microsphere properties (Bilbao et al, 2009), distribution of 90Y between tumour and normal liver (dosimetry; Sangro et al, 2008; Lhommel et al, 2009; Ahmadzadehfar et al, 2011), tolerance of liver parenchyma to 90Y (Lhommel et al, 2009; Dezarn et al, 2011), and procedure standardisation and patient selection (Coldwell et al, 2011; Lau et al, 2012). Randomised-controlled trials and larger prospective open-label studies have confirmed the efficacy and safety of radioembolization with 5-FU-based systemic chemotherapy in mCRC (with 5-FU, irinotecan and FOLFOX; van Hazel et al, 2004; Sharma et al, 2007; van Hazel et al, 2009; Hendlisz et al, 2010; Kosmider et al, 2011).\n\nCurrently, concomitant capecitabine treatment is contraindicated with radioembolization due to an anecdotal early report of toxicity with this combination. In Australia in the 1990s, a single patient treated with radioembolization and concurrent capecitabine developed liver failure and death. Although no other cases of liver toxicity and death with the combination have been reported, concurrent capecitabine has remained a contraindication to radioembolization. However, given the importance of capecitabine in the current management of patients with GI cancers and its potential role as a radiosensitizer, we conducted a formal phase I trial of capecitabine and radioembolization to document the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of the combination and to define the recommended phase II dose for further study.\n\nMaterials and Methods\nPatient eligibility\nAdult patients with histologically or cytologically confirmed incurable solid tumours that were predominantly or exclusively involving the liver were included in the trial. Patients who had received any number of prior regimens were permitted provided they had an Eastern Cooperative Oncology Group performance status of 0-1 and a life expectancy of at least 12 weeks. Eligible patients had adequate liver (total bilirubin ⩽upper limit of normal (ULN), aspartate transaminase and alanine transaminase ⩽1.5 ULN and without clinical evidence of ascites or decompensated cirrhosis), marrow (leukocytes ⩾3000/μl, absolute neutrophil count ⩾1000/μl and platelets ⩾75 000/μl), and kidney function (creatinine ⩽ULN or estimated glomerular filtration rate ⩾60 ml min−1). Upon pretreatment work-up (Coldwell et al, 2011), patients were required to have a patent portal vein and liver-to-lung shunting <20% as measured by technetium-99m-macroaggregated albumin (99mTc-MAA) on single photon emission computed tomography (CT).\n\nPatients were excluded if they had a history of allergic reactions or hyperbilirubinemia ⩾2 mg/dl attributed to prior capecitabine, had not recovered from adverse events due to agents administered >4 weeks earlier (excluding chronic neuropathy or alopecia), or had received any chemotherapy, radiotherapy or investigational agent ⩽4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to screening. Pregnant/nursing women, those using insufficient birth control methods (where appropriate), or any patient who had an uncontrolled or intercurrent illness that would limit compliance with study requirements or effect the interpretation of the results were excluded.\n\nThe study was approved by the Fox Chase Cancer Center Institutional Review Board. Patients enrolled were fully informed of the nature of the trial and provided written informed consent. The trial was registered at clinicaltrials.gov (Identifier NCT00604409).\n\nStudy design and treatment\nThis was a prospective single-centre, phase I safety study. Patients were enrolled in a 3+3 design with escalating doses of capecitabine (375, 600, 750, 900 and 1000 mg/m2 b.i.d.) given for 14 days every 21 days. As 1000 mg/m2 b.i.d. is the highest dose typically administered to the US patients with mCRC, we chose this as our maximum dose to evaluate. Capecitabine doses were rounded to the nearest 500 mg tablet strength. Radioembolization with 90Y-resin microspheres (SIR-Spheres, Sirtex Medical Limited, Sydney, Australia) was administered using a sequential lobar approach. Radioembolization was initially performed on the dominant-diseased liver lobe on day 2 of the first cycle of capecitabine. Patients were restaged after two cycles of capecitabine. Patients with bilobar disease without progression in the treated liver lobe or DLT and who met all initial eligibility criteria could receive two additional cycles of capecitabine with radioembolization to the untreated contralateral lobe on day 2 of cycle 3 of capecitabine (between days 58 and 72 from initiation of protocol therapy). These patients were reimaged after four cycles. Further treatment was at the treating physician's discretion.\n\nFor each dose level of capecitabine, in the event that no treatment-related DLT occurred in the first three patients (or only one event occurred in the first six patients) within the first 8 weeks of therapy, subsequent patients were recruited to the next dose level. If two or more out of a maximum of six patients experienced DLT at any dose, then the MTD was deemed to be exceeded and patients were enrolled to the dose level below for up to six patients at the MTD.\n\nDLT was defined as any of the following occurring within 8 weeks of initiating protocol therapy: ⩾grade 3 non-haematologic toxicity (excluding nausea, vomiting, or diarrhoea responding to symptomatic management), grade 3 thrombocytopenia for >5 days, grade 4 thrombocytopenia, grade 4 granulocytopenia for >5 days (or associated with fever or infection), or any interruption of therapy for >14 days due to toxicity.\n\n90Y-resin microspheres activity was calculated as follows:\n\nStep 1: Calculation of percentage of tumour involvement in each treated lobe:\n\n \n\nStep 2: The patient's body surface area was determined, and the implanted activity for each treated lobe was calculated:\n\n \n\nVTumour: volume of tumour in the treated lobe\n\nVLiver lobe: total volume of the treated lobe\n\nVWhole liver: total volume of the liver\n\nFor patients with bilobar disease, the restaging CT scan after two cycles of therapy was used to estimate tumour involvement of the contralateral lobe.\n\nStep 3: Activity modification based on hepatopulmonary shunt fraction.\n\nAs significant arteriovenous shunting in the liver is observed in ∼3% of patients, the hepatopulmonary shunt fraction was calculated from the percentage of 99mTc-MAA which lodged in the lungs during the pretreatment work-up. Activity was modified as follows: 10% to <15% lung shunting=20% reduction in calculated activity of 90Y; 15% to <20%=40% reduction; ⩾20%=patient ineligible for radioembolization.\n\nEndpoints\nThe primary study objectives were the evaluation of safety, toxicity, and the recommended dose of capecitabine for further study. Secondary objectives were to obtain preliminary evidence of clinical efficacy: best overall response rate (ORR), time to progression (TTP) and overall survival (OS).\n\nAssessments and data analyses\nHistory and physical examination, complete blood count, serum chemistries and liver function tests were conducted within 14 days of study entry and weekly intervals thereafter. Baseline imaging (CT or magnetic resonance imaging), hepatic angiogram, and 99mTc-MAA scan (injected into the hepatic artery that was the planned treatment vessel) were performed within 28 days of study entry. Tumour response was assessed at week 6 post radioembolization, at week 14 if the contralateral lobe was treated, and at treating physician discretion thereafter. An hepatic angiogram was repeated for patients undergoing contralateral lobe treatment. Documented complete or partial responses were confirmed at least 4 weeks later and stable disease at least 6 weeks later. The minimum requirement for follow-up was at least 30 days after the end of protocol treatment (for safety) or until progression.\n\nThe overall response rate in the treated lobe was evaluated according to Response Evaluation Criteria in Solid Tumours (RECIST v. 1.0; Therasse et al, 2000) and best ORR from the commencement of protocol treatment until disease progression/recurrence was reported. The time to progression and OS were calculated from the date of the initiation of protocol capecitabine therapy. All adverse events (and their causal relationship to the study treatment) that occurred during the patient's study participation were recorded on standardised data capture records and their severity was rated according to NCI Common Terminology Criteria for Adverse Events (CTCAE v.3.0). All serious adverse events were monitored until resolution or until the patient stabilised. Regular monitoring and review of the toxicity reports were undertaken by the Fox Chase Cancer Center Phase I-II Committee. Descriptive statistics were applied to the toxicity assessments and the reporting of DLT and the MTD.\n\nResults\nPatient characteristics\nThe tumour and treatment characteristics of the 24 patients enrolled are summarised in Table 1. Most patients had mCRC at diagnosis. The median time from diagnosis to the start of study treatment was 26 months. Nearly all CRC patients had received at least two chemotherapy agents and prior chemoembolization was performed in four patients (three non-CRC and one CRC). Extrahepatic disease at baseline was identified in 10 patients (including 8 of 17 (47%) patients with CRC) at the following sites: lymph (2), lung (6), abdominal wall (1), lymph, lung, abdominal wall and adnexal mass (1).\n\nPatients received a median of two cycles of capecitabine. All patients received radioembolization to the dominant-diseased lobe, which was the right lobe in 19 of 24 (79.2%) cases. A median of 2.7 months later, the contralateral lobe was treated in 10 (41.7%) patients. Median implanted activity of 90Y-resin microspheres was 0.98 GBq (range 0.23–1.60); 1.12 GBq (0.41–1.60) in the dominant-diseased lobe and 0.54 GBq (0.23–0.81) in the contralateral lobe. One patient required a reduction in implanted activity due to 15% lung shunting. In another, the prescribed dose of microspheres was only partially delivered due to flow stasis.\n\nDosing cohorts\nOf the first three patients enrolled in cohort 1 (capecitabine 375 mg/m2, n=8), one patient with cholangiocarcinoma developed grade 3 hyperbilirubinemia, which was possibly related to treatment and considered a DLT. Of the next three patients enrolled, one patient with liver-predominant CRC developed grade 4 hyperbilirubinemia that was related to a malignant biliary stricture and resolved with biliary stenting. To be conservative in the assessment of toxicity as a consequence of two episodes of hyperbilirubinemia, two additional patients were enrolled into this first cohort without any DLT. Thus, enrolment continued to dose level 2.\n\nFour patients were enrolled into the dose level 2 cohort (capecitabine 600 mg/m2), as one patient was erroneously taking half of the prescribed dose of capecitabine (300 mg/m2) and was replaced for DLT evaluation. No DLTs were observed. Of the first three patients enrolled in cohort 3 (capecitabine 750 mg/m2), one patient with mCRC and a large left lobe liver lesion developed a partial gastric antral perforation (grade 3) 4.4 months after 90Y-resin microspheres administration. This was considered treatment-related. Upper endoscopy did not reveal any microspheres in the stomach. A multidisciplinary case review concluded that a local field effect of radiation to the stomach from a nearly contiguous large left lobe of liver metastasis, rather than off-target administration, was the most likely cause. The cohort was expanded to six patients, with no further DLTs.\n\nThree patients were enrolled in cohort 4 (900 mg/m2) and three patients were enrolled in cohort 5 (1000 mg/m2) with no DLTs observed. Thus, capecitabine 1000 mg/m2 b.i.d. was considered the recommended dose for phase II studies with concurrent lobar radioembolization.\n\nToxicity\nTable 2 provides a summary of all adverse events by dosing level and treatment cycle. As anticipated, haematologic toxicities were relatively mild. No grade ⩾3 neutropenia or thrombocytopenia or neutropenic fever was observed. Six (33.3%) patients had grade 3 lymphopenia, which was not clinically significant.\n\nCommon grade 1/2 non-haematologic toxicities included transaminitis/alkaline phosphatase elevation (9 (37.5%) patients), nausea (9 (37.5%)), abdominal pain (7 (29.0%)), fatigue (7 (29.0%)), and hand-foot syndrome or rash/desquamation (7 (29.0%)); the latter being more common at higher doses of capecitabine (⩾750 mg/m2). Grade 1/2 changes in creatinine, bilirubin and albumin only occurred with higher doses of capecitabine (⩾750 mg/m2) and with the first radioembolization procedure, while transaminitis and alkaline phosphatase elevations were reported across all doses and cycles of treatment. One patient experienced grade 3 nausea and one patient reported grade 3 diarrhoea in the first two cycles, which responded to symptomatic management and were not considered DLTs. Beyond the partial antral perforation discussed above, no serious treatment-related adverse events or deaths were recorded during an extended post-treatment median follow-up of ∼6 months.\n\nClinical outcomes\nThe best response for the entire patient population in the treated liver lobe(s) was partial response in four (16.7%) patients (three confirmed (cPR) and one unconfirmed (uPR) according to RECIST 1.0), stable disease in 17 patients (70.8%), and progression in 3 (12.5%). The median TTP and OS in the cohort of patients with largely chemotherapy-refractory CRC was 6.4 (range 1.5–29.9) months and 8.1 (mean 15.3; range 3.9–43.3) months, respectively.\n\nDiscussion\nThis phase I trial represents the first formal clinical assessment of escalating doses of capecitabine chemotherapy combined with radioembolization in advanced liver-predominant cancer. Our data demonstrate that combined modality treatment is generally well tolerated and a dose of capecitabine 1000 mg/m2 b.i.d. with 90Y-resin microspheres lobar treatment is recommended for phase II study.\n\nThe toxicity profile noted in our study was similar to the published experience with capecitabine monotherapy (Blum, 2001; Capecitabine package insert, 2014) and 90Y-resin microspheres (van Hazel et al, 2004; Sharma et al, 2007; van Hazel et al, 2009; Hendlisz et al, 2010; Kosmider et al, 2011). Particular attention was given to changes in liver function and GI toxicity over the 2 months after each radioembolization procedure, given the known potential side effects of both treatment modalities (Blum, 2001; Dezarn et al, 2011; Capecitabine package insert, 2014). In a combined evaluation of 875 patients with either metastatic breast or CRC who received at least one dose of capecitabine 1250 mg/m2 b.i.d. as monotherapy, grade 3/4 hyperbilirubinemia occurred in 22.8% of 566 patients with hepatic metastases compared with 12.3% of 309 patients without hepatic metastases at baseline (Blum, 2001; Capecitabine package insert, 2014). Of 167 patients with grade 3/4 hyperbilirubinemia in the same analysis, 18.6% also had postbaseline elevations (grades 1 to 4) in alkaline phosphatase and/or elevated transaminases (27.5% Blum, 2001). A large meta-analysis of data with capecitabine monotherapy recorded levels of grade 3 transaminitis in 0.6–0.8% of patients and grade 3 elevations in alkaline phosphatase in 3.5% of patients (Blum, 2001).\n\nFor radioembolization, detailed retrospective analyses (Kennedy et al, 2009; Dezarn et al, 2011; Gil-Alzugaray et al, 2013) and the findings from smaller prospective trials indicate that radioembolization combined with chemotherapy is generally well tolerated (especially in the first-line setting; van Hazel et al, 2004; Sharma et al, 2007; van Hazel et al, 2009; Hendlisz et al, 2010; Kosmider et al, 2011), provided that the well-defined criteria for patient selection are met (Coldwell et al, 2011). In our study, it is important to recognise that the eligibility criteria required patients to possess a normal bilirubin as defined by the reference laboratory, and transaminases within 1.5 times the ULN. Noting that the typical criteria for patient selection for radioembolization allow patients with a bilirubin up to 2 mg/dl to be considered for treatment, our data do not address the safety in patients possessing baseline bilirubin levels above the normal range to 2 mg/dl. Although we did not experience any evidence of radioembolization-induced liver disease (REILD—defined as jaundice and ascites appearing 4–8 weeks after procedure (Dezarn et al, 2011)), retrospective analyses of several large cohorts (Sangro et al, 2008; Kennedy et al, 2009; Gil-Alzugaray et al, 2013) indicate a small but significantly increased risk of REILD in the setting of heavily pre-treated disease. Sangro et al (2008) reported a 20% incidence of REILD in a cohort of patients at a single institution, but no examples in patients in whom a single lobe was treated. In a follow-up report, this group noted a decrease in REILD and severe REILD over time to 5.4 and 2.2%, respectively. Thus, while we view the combination of capecitabine and radioembolization as safe in this conservatively defined patient population, caution may be warranted in the utilisation of this combined modality approach in patients with mildly compromised liver function.\n\nA second consideration in interpreting our safety data is that patients with bilobar disease received sequential lobar therapy rather than whole-liver therapy. One of the potential advantages of the sequential lobar approach is that the tolerance of the liver parenchyma can be evaluated before treating the contralateral lobe. The safety of combining capecitabine with whole-liver radioembolization is not addressed by our study.\n\nIn our cohort of patients with refractory mCRC (n=17), the response rate was 11.8% with median TTP and OS of 6.4 and 8.1 months, respectively. Although not designed as an efficacy study, our results with capecitabine-radioembolization combination therapy in a largely chemotherapy-refractory patient population are in line with recent prospective single agent radioembolization experiences in this setting. Benson et al (2013) recently reported one of the largest, treating 61 mCRC patients with liver metastases with radioembolization alone as part of a larger prospective multicentre phase II study. PFS and OS in the mCRC patient cohort were 2.9 and 8.8 months, respectively. Seidensticker et al (2012) reported a median survival of 8.3 months in 29 mCRC patients. Finally, Cosimelli et al (2010) treated 50 mCRC with a response rate of 24%, PFS of 3.8 months, and median survival of 12.6 months. Ultimately, evaluation of the role of capecitabine with respect to efficacy requires a randomised study design in refractory mCRC patients.\n\nThere are several limitations of our trial that should be considered. As a phase I study, it enrolled patients with different types of malignancies. Thus, definitive conclusions regarding clinical efficacy must await further investigation. However, this patient population more closely represents the typical cohort referred for radioembolization and as such we feel that the toxicity results as the primary endpoint of the study are robust. Certainly, it is important to recognise that only good performance status patients with excellent liver function tests were entered. Thus, extrapolation of safety to less robust patient populations is not possible. Our study also did not mandate long-term follow-up beyond 30 days after capecitabine. However, with extended follow-up over a median of ∼6 months from the start of protocol treatment, we believe that the vast majority of toxicities were captured. Finally, as previously discussed, the relative contribution of capecitabine to the efficacy of 90Y-resin microspheres cannot be isolated in our study. However, previous studies indicate a synergy between 90Y-resin microspheres and systemic chemotherapy in mCRC, prolonging PFS and OS as well as increasing ORR compared with chemotherapy alone (van Hazel et al, 2004; Sharma et al, 2007; van Hazel et al, 2009; Hendlisz et al, 2010; Kosmider et al, 2011). Given the benefits of concurrent chemoradiotherapy in GI malignancies (rectal, pancreatic and oesophageal; Hofheinz et al, 2012; Diener et al, 2013; Zheng et al, 2013) further studies evaluating the relative additional benefits of concurrent chemotherapy with radioembolization are warranted.\n\nIn conclusion, our study demonstrates that the combination of capecitabine and sequential lobar radioembolization in good performance status patients with excellent liver function is well tolerated with the spectrum of toxicities approximating those seen with either modality as a single agent. Initial efficacy results appear promising and an expansion cohort study of capecitabine at 1000 mg/m2 b.i.d. combined with 90Y-resin microspheres in mCRC patients is ongoing.\n\nFunding for research was received from Sirtex Medical Ltd.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nDavid N Cade is a full time employee of Sirtex Medical Ltd, Sydney, Australia as listed in the Author Disclosure Form.\n\nTable 1 Baseline patient and disease characteristics\nParameter\tn=24\t\nGender, n (%)\t\nMale : Female\t14 (58.3%) : 10 (41.7%)\t\nAge, median (range), years\t60 (49–83)\t\nECOG performance status, n (%)\t\n0 : 1\t13 (54.2%) : 11 (45.8%)\t\nEthnicity, n (%)\t\nWhite\t22 (91.7%)\t\nBlack\t2 (8.3%)\t\nDiagnosis, n (%)\t\nColorectal adenocarcinoma\t17 (70.8%)\t\nCarcinoid\t3 (12.5%)\t\nCholangiocarcinoma\t2 (8.3%)\t\nPancreatic neuroendocrine\t1 (4.2%)\t\nHepatocellular carcinoma\t1 (4.2%)\t\nStage at diagnosis, n (%)\t\nIII : IV\t2 (8.3%) : 20 (83.3%)\t\nUnknown\t2\t\nTime since diagnosis, median (range), months\t26 (2.5–105.2)\t\nPrior systemic therapy received (colorectal cancer patients)\t\n5-FU\t16 (94.1%)\t\nOxaliplatin\t16 (94.1%)\t\nIrinotecan\t11 (64.7%)\t\nBevacizumab\t14 (82.4%)\t\nAnti-EGFR antibody\t7 (41.2%)\t\nPrior therapy (non-colorectal cancer patients)\t\nSystemic therapy\t4 (57.1%)\t\nSandostatin\t3 (42.9%)\t\nChemoembolization\t3 (42.9%)\t\nAbbreviations: 5-FU=5-fluorouracil; anti-EGFR=anti-epidermal growth factor receptor; ECOG=Eastern Cooperative Oncology Group.\n\nTable 2 Number of patients with adverse events by capecitabine dose during treatment cycles 1–2 and cycle 3–4\nSystem\tEvent\tCTCAE grade\tRE\nof dominant-diseased lobe + capecitabine cycles 1–2\tRE of contralateral lobea\n+ capecitabine cycles 3–4\tCycles 1–4\t\nCapecitabine dose, mg/m2\t \t375\t600\t750\t900\t1000\tTotal\t375\t600\t750\t900\t1000\tTotal\tTotal\t\n \t \t \tn=8\tn=4b\tn=6\tn=3\tn=3\tn=24\tn=4\tn=1\tn=3\tn=2\tn=0\tn=10\tn=24\t\nHaematologic\t\n \tHaemoglobin\t1–2\t5\t3\t4\t0\t1\t13 (54%)\t0\t1\t1\t0\t0\t2 (20%)\t13 (54%)\t\n \tTotal WBC\t1–2\t3\t1\t1\t1\t2\t8 (33%)\t1\t1\t1\t0\t0\t3 (30%)\t9 (37.5%)\t\n \tLymphopenia\t1–2\t0\t0\t2\t0\t0\t2 (8%)\t0\t0\t0\t1\t0\t1 (10%)\t3 (12.5%)\t\n \t \t3–4\t0\t0\t2\t2\t2\t6 (25%)\t0\t0\t2\t1\t0\t3 (30%)\t6 (25%)\t\n \tNeutrophils/granulocytes\t1–2\t1\t0\t0\t0\t0\t1 (4%)\t1\t0\t0\t0\t0\t1 (10%)\t2 (8%)\t\n \tPlatelets\t1–2\t1\t1\t3\t1\t1\t7 (29%)\t0\t1\t2\t1\t0\t4 (40%)\t8 (33%)\t\nNon-haematologic\t\nInfection\tWith normal ANC\t1–2\t1\t0\t0\t0\t0\t1 (4%)\t0\t0\t0\t0\t0\t0\t1 (4%)\t\nConstitutional\tFatigue\t1–2\t4\t1\t1\t1\t0\t7 (29%)\t2\t0\t0\t0\t0\t2 (20%)\t7 (29%)\t\n \t \t3–4\t0\t0\t0\t0\t0\t1 (4%)\t0\t0\t0\t0\t0\t0\t1 (4%)\t\n \tAbdominal pain\t1–2\t2\t1\t2\t0\t0\t5 (21%)\t3\t0\t1\t0\t0\t4 (40%)\t7 (29%)\t\n \tRigours/sweating\t1–2\t1\t0\t1\t0\t0\t2 (8%)\t1\t0\t1\t0\t0\t2 (20%)\t3 (12.5%)\t\nDermatologic\tRash/desquamation\t1–2\t1\t0\t0\t0\t0\t1 (4%)\t0\t0\t0\t0\t0\t0\t1 (4%)\t\n \tRash: hand-foot syndrome\t1–2\t1\t0\t2\t1\t1\t5 (21%)\t0\t0\t3\t1\t0\t4 (40%)\t7 (29%)\t\nNeurology\tSensory neuropathy\t1–2\t2\t0\t0\t0\t0\t2 (8%)\t1\t0\t0\t0\t0\t1 (10%)\t2 (8%)\t\nGI\tNausea\t1–2\t3\t1\t3\t0\t1\t8 (33%)\t2\t0\t0\t0\t0\t2 (20%)\t9 (37.5%)\t\n \tVomiting\t1–2\t1\t0\t2\t0\t0\t3 (12.5%)\t1\t0\t0\t0\t0\t1 (10%)\t3 (12.5%)\t\n \t \t3–4\t0\t0\t1\t0\t0\t1\t0\t0\t0\t0\t0\t0\t1 (4%)\t\n \tDiarrhoea/constipation\t1–2\t3\t1\t1\t1\t0\t6 (25%)\t1\t0\t0\t0\t0\t1 (10%)\t6 (25%)\t\n \t \t3–4\t0\t0\t0\t0\t1\t1 (4%)\t0\t0\t0\t0\t0\t0\t1 (4%)\t\n \tAnorexia/weight loss\t1–2\t3\t0\t1\t0\t0\t4 (17%)\t1\t0\t0\t0\t0\t1 (10%)\t4 (17%)\t\n \tGastric perforation\t1–2\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t0\t\n \t \t3–4\t0\t0\t1\t0\t0\t1 (4%)\t0\t0\t0\t0\t0\t0\t1 (4%)\t\n \tOther GI events\t1–2\t1\t0\t1\t0\t1\t3 (12.5%)\t2\t0\t1\t0\t0\t3 (30%)\t4 (17%)\t\nMetabolic and hepatobiliary\tHyperbilirubinemia\t1–2\t0\t0\t2\t0\t0\t2 (8%)\t0\t0\t0\t0\t0\t0\t2 (8%)\t\n \tHypoalbuminemia\t1–2\t0\t0\t2\t1\t0\t3 (12.5%)\t0\t0\t0\t0\t0\t0\t3 (12.5%)\t\n \tALT, SGPT\t1–2\t3\t1\t1\t0\t0\t6 (25%)\t1\t0\t0\t1\t0\t2 (20%)\t7 (29%)\t\n \tAST, SGOT\t1–2\t4\t1\t1\t1\t0\t7 (29%)\t3\t0\t0\t1\t0\t4 (40%)\t9 (37.5%)\t\n \tAlkaline phosphatase\t1–2\t3\t1\t3\t0\t0\t7 (29%)\t3\t1\t1\t0\t0\t5 (50%)\t9 (37.5%)\t\n \tCreatinine\t1–2\t0\t0\t2\t0\t0\t2 (8%)\t0\t0\t0\t0\t0\t0\t2 (8%)\t\n \tPotassium, high\t1–2\t0\t0\t1\t0\t0\t1 (4%)\t0\t0\t1\t0\t0\t1 (4%)\t2 (8%)\t\n \tHyper/hypoglycemia\t1–2\t0\t0\t2\t0\t0\t2 (8%)\t0\t0\t0\t0\t0\t0\t2 (8%)\t\nOther\t \t1–2\t5\t1\t0\t0\t0\t6 (25%)\t0\t0\t0\t0\t0\t0\t6 (25%)\t\nTotal events\t1–2\t7\t4\t6\t2\t1\t20 (83%)\t4\t1\t3\t1\t1\t10 (100%)\t22 (92%)\t\n \t3–4\t0\t0\t2\t2\t3\t7 (29%)\t0\t0\t2\t1\t0\t3 (33%)\t7 (29%)\t\nAbbreviations: ALT=alanine transaminase; ANC=absolute neutrophil count; AST=aspartate transaminase; CTCAE=Common Terminology Criteria for Adverse Events; GI=gastrointestinal; RE=radioembolization; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; WBC=white blood cell. The table records the most severe event for each patient across each of the defined timescales. Grade 3–4 events are highlighted.\n\na Sequential treatment of contralateral lobe in patients with bilobar disease (n=10).\n\nb Including one patient who erroneously took capecitabine 300 mg/m2.\n==== Refs\nAhmadzadehfar H Sabet A Muckle M Wilhelm K Reichmann K Biersack HJ Ezziddin S 2011 99 mTc-MAA/90Y-Bremsstrahlung SPECT/CT after simultaneous Tc-MAA/90Y-microsphere injection for immediate treatment monitoring and further therapy planning for radioembolization Eur J Nucl Med Mol Imaging 38 1281 1288 21359611 \nArkenau HT Arnold D Cassidy J Diaz-Rubio E Douillard JY Hochster H Martoni A Grothey A Hinke A Schmiegel W Schmoll HJ Porschen R 2008 Efficacy of oxaliplatin plus capecitabine or infusional fluorouracil/leucovorin in patients with metastatic colorectal cancer: a pooled analysis of randomized trials J Clin Oncol 26 5910 5917 19018087 \nBenson AB 3rdGeschwind JF Mulcahy MF Rilling W Siskin G Wiseman G Cunningham J Houghton B Ross M Memon K Andrews J Fleming CJ Herman J Nimeiri H Lewandowski RJ Salem R 2013 Radioembolisation for liver metastases: results from a prospective 151 patient multi-institutional phase II study Eur J Cancer 49 3122 3130 23777743 \nBilbao JI de Martino A de Luis E Díaz-Dorronsoro L Alonso-Burgos A Martínez de la Cuesta A Sangro B García de Jalón JA 2009 Biocompatibility, inflammatory response, and recannalization characteristics of nonradioactive resin microspheres: histological findings Cardiovasc Intervent Radiol 32 727 736 19449060 \nBlum JL 2001 The role of capecitabine, an oral, enzymatically activated fluoropyrimidine, in the treatment of metastatic breast cancer Oncologist 6 56 64 11161228 \nCapecitabine package insert 2014 \n)\nhttp://www.accessdata.fda.gov/drugsatfda_docs/label/2000/20896lbl.pdf\n(accessed May 14, 2014).\nColdwell D Sangro B Wasan H Salem R Kennedy A 2011 General selection criteria of patients for radioembolization of liver tumors: an international working group report Am J Clin Oncol 34 337 341 20921882 \nCosimelli M Golfieri R Cagol PP Carpanese L Sciuto R Maini CL Mancini R Sperduti I Pizzi G Diodoro MG Perrone M Giampalma E Angelelli B Fiore F Lastoria S Bacchetti S Gasperini D Geatti O Izzo F Italian Society of Locoregional Therapies in Oncology (SITILO) 2010 Multicentre phase II clinical trial of yttrium-90 resin microspheres alone in unresectable, chemotherapy refractory colorectal liver metastases Br J Cancer 103 324 331 20628388 \nCunningham D Humblet Y Siena S Khayat D Bleiberg H Santoro A Bets D Mueser M Harstrick A Verslype C Chau I Van Cutsem E 2004 Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer N Engl J Med 351 337 345 15269313 \nDezarn WA Cessna JT DeWerd LA Feng W Gates VL Halama J Kennedy AS Nag S Sarfaraz M Sehgal V Selwyn R Stabin MG Thomadsen BR Williams LE Salem R American Association of Physicists in Medicine 2011 Recommendations of the American Association of Physicists in Medicine on dosimetry, imaging, and quality assurance procedures for 90Y microsphere brachytherapy in the treatment of hepatic malignancies Med Phys 38 4824 4845 21928655 \nDiener MK Combs SE Büchler MW 2013 Chemoradiotherapy for locally advanced pancreatic cancer Lancet Oncol 14 269 270 23474364 \nGil-Alzugaray B Chopitea A Iñarrairaegui M Bilbao JI Rodriguez-Fraile M Rodriguez J Benito A Dominguez I D'Avola D Herrero JI Quiroga J Prieto J Sangro B 2013 Prognostic factors and prevention of radioembolization-induced liver disease Hepatology 57 1078 1087 23225191 \nGrothey A Van Cutsem E Sobrero A Siena S Falcone A Ychou M Humblet Y Bouché O Mineur L Barone C Adenis A Tabernero J Yoshino T Lenz HJ Goldberg RM Sargent DJ Cihon F Cupit L Wagner A Laurent D CORRECT Study Group 2013 Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 381 303 312 23177514 \nHendlisz A Van den Eynde M Peeters M Maleux G Lambert B Vannoote J De Keukeleire K Verslype C Defreyne L Van Cutsem E Delatte P Delaunoit T Personeni N Paesmans M Van Laethem JL Flamen P 2010 Phase III trial comparing protracted intravenous fluorouracil infusion alone or with yttrium-90 resin microspheres radioembolization for liver-limited metastatic colorectal cancer refractory to standard chemotherapy J Clin Oncol 28 3687 3694 20567019 \nHess KR Varadhachary GR Taylor SH Wei W Raber MN Lenzi R Abbruzzese JL 2006 Metastatic patterns in adenocarcinoma Cancer 106 1624 1633 16518827 \nHofheinz RD Wenz F Post S Matzdorff A Laechelt S Hartmann JT Müller L Link H Moehler M Kettner E Fritz E Hieber U Lindemann HW Grunewald M Kremers S Constantin C Hipp M Hartung G Gencer D Kienle P Burkholder I Hochhaus A 2012 Chemoradiotherapy with capecitabine versus fluorouracil for locally advanced rectal cancer: a randomised, multicentre, non-inferiority, phase 3 trial Lancet Oncol 13 579 588 22503032 \nHurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Berlin J Baron A Griffing S Holmgren E Ferrara N Fyfe G Rogers B Ross R Kabbinavar F 2004 Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 350 2335 2342 15175435 \nKennedy AS McNeillie P Dezarn WA Nutting C Sangro B Wertman D Garafalo M Liu D Coldwell D Savin M Jakobs T Rose S Warner R Carter D Sapareto S Nag S Gulec S Calkins A Gates VL Salem R 2009 Treatment parameters and outcome in 680 treatments of internal radiation with resin 90Y-microspheres for unresectable hepatic tumors Int J Radiat Oncol Biol Phys 74 1494 1500 19157721 \nKosmider S Tan TH Yip D Dowling R Lichtenstein M Gibbs P Radioembolization in combination with systemic chemotherapy as first-line therapy for liver metastases from colorectal cancer 2011 J Vasc Interv Radiol 22 780 786 21515072 \nLau WY Kennedy AS Kim YH Lai HK Lee RC Leung TW Liu CS Salem R Sangro B Shuter B Wang SC 2012 Patient selection and activity planning guide for selective internal radiotherapy with yttrium-90 resin microspheres Int J Radiat Oncol Biol Phys 82 401 407 20950954 \nLhommel R Goffette P Van den Eynde M Jamar F Pauwels S Bilbao JI Walrand S 2009 Yttrium-90 TOF PET scan demonstrates high-resolution biodistribution after liver SIRT Eur J Nucl Med Mol Imaging 36 1696 19618182 \nManfredi S Lepage C Hatem C Coatmeur O Faivre J Bouvier AM 2006 Epidemiology and management of liver metastases from colorectal cancer Ann Surg 244 254 259 16858188 \nManfredi S Bouvier AM Lepage C Hatem C Dancourt V Faivre J 2006 Incidence and patterns of recurrence after resection for cure of colonic cancer in a well-defined population Br J Surg 93 1115 1122 16804870 \nMedley L Morel AN Farrugia D Reed N Hayward N Davies JM Kirichek O Thakker RV Talbot DC 2011 Phase II study of single agent capecitabine in the treatment of metastatic non-pancreatic neuroendocrine tumours Br J Cancer 104 1067 1070 21386841 \nMikhail SE Sun JF Marshall JL 2010 Safety of capecitabine: a review Expert Opin Drug Saf 9 831 841 20722491 \nOkines A Chau I Cunningham D 2007 Capecitabine in advanced gastric cancer Expert Opin Pharmacother 8 2851 2861 17956204 \nSangro B Gil-Alzugaray B Rodriguez J Sola I Martinez-Cuesta A Viudez A Chopitea A Iñarrairaegui M Arbizu J Bilbao JI 2008 Liver disease induced by radioembolization of liver tumors Cancer 2008 112 1538 4156 18260156 \nSeidensticker R Denecke T Kraus P Seidensticker M Mohnike K Fahlke J Kettner E Hildebrandt B Dudeck O Pech M Amthauer H Ricke J 2012 Matched-pair comparison of radioembolization plus best supportive care versus best supportive care alone for chemotherapy refractory liver-dominant colorectal metastases Cardiovasc Intervent Radiol 35 1066 1073 21800231 \nSharma RA Van Hazel GA Morgan B Berry DP Blanshard K Price D Bower G Shannon JA Gibbs P Steward WP 2007 Radioembolization of liver metastases from colorectal cancer using yttrium-90 microspheres with concomitant systemic oxaliplatin, fluorouracil, andleucovorin chemotherapy J Clin Oncol 25 1099 1106 17369573 \nSmith DB Neoptolemos JP 2006 Capecitabine in carcinoma of the pancreas Expert Opin Pharmacother 7 1633 1639 16872266 \nTherasse P Arbuck SG Eisenhauer EA Wanders J Kaplan RS Rubinstein L Verweij J Van Glabbeke M van Oosterom AT Christian MC Gwyther SG 2000 New guidelines to evaluate the response to treatment in solid tumors J Natl Cancer Inst 92 205 216 10655437 \nvan Hazel GA Pavlakis N Goldstein D Olver IN Tapner MJ Price D Bower GD Briggs GM Rossleigh MA Taylor DJ George J 2009 Treatment of fluorouracil-refractory patients with liver metastases from colorectal cancer by using yttrium-90 resin microspheres plus concomitant systemic irinotecan chemotherapy J Clin Oncol 27 4089 4095 19652069 \nvan Hazel G Blackwell A Anderson J Price D Moroz P Bower G Cardaci G Gray B 2004 Randomised phase 2 trial of SIR-Spheres plus fluorouracil/leucovorin chemotherapy versus fluorouracil/leucovorin chemotherapy alone in advanced colorectal cancer J Surg Oncol 88 78 85 15499601 \nZheng B Zheng W Zhu Y Lin XY Xu BH Chen C 2013 Role of adjuvant chemoradiotherapy in treatment of resectable esophageal carcinoma: a meta-analysis Chin Med J (Engl) 126 1178 1182 23506601\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0007-0920",
"issue": "111(2)",
"journal": "British journal of cancer",
"keywords": null,
"medline_ta": "Br J Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D000069287:Capecitabine; D015331:Cohort Studies; D003841:Deoxycytidine; D004621:Embolization, Therapeutic; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008863:Microspheres; D008875:Middle Aged; D009369:Neoplasms; D011446:Prospective Studies; D015021:Yttrium Radioisotopes",
"nlm_unique_id": "0370635",
"other_id": null,
"pages": "265-71",
"pmc": null,
"pmid": "24983373",
"pubdate": "2014-07-15",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21515072;15175435;16518827;23177514;23506601;17369573;23225191;19018087;20950954;23777743;22503032;20567019;19652069;20722491;21928655;16804870;21800231;19618182;21359611;17956204;11161228;15499601;21386841;16858188;20628388;20921882;19157721;10655437;19449060;23474364;15269313;16872266;18260156",
"title": "Phase I study of capecitabine combined with radioembolization using yttrium-90 resin microspheres (SIR-Spheres) in patients with advanced cancer.",
"title_normalized": "phase i study of capecitabine combined with radioembolization using yttrium 90 resin microspheres sir spheres in patients with advanced cancer"
} | [
{
"companynumb": "US-ROCHE-1431593",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "YTTRIUM Y-90"
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"drugadditional": null,
"dr... |
{
"abstract": "Total artificial heart (TAH) device is sometimes necessary to treat end stage heart failure (HF). After surgery, renal impairment can occur with the need of renal replacement therapy.\n\n\n\nWe report the case of a 51-year-old man who was treated with conventional hemodialysis (HD) while on support with TAH.\n\n\n\nThe patient underwent HD while on TAH support during 14 months. He benefited from conventional HD, 6 sessions per week. HD sessions were well tolerated, and patient's condition and quality of life improved significantly. The main difficulty was to maintain red blood cell level because of chronic hemolysis due to TAH, which required repetitive blood transfusions, resulting in a high rate of human leukocyte antigen sensitization. Unfortunately, the patient died of mesenteric ischemia due to anticoagulation under dosing.\n\n\n\nWe conclude that HD treatment is possible despite TAH and should be considered in patients with both end stage renal and HF.",
"affiliations": "Service de Néphrologie-Dialyse-Transplantation, Université Angers, CHU d'Angers, Angers, France.",
"authors": "Demiselle|Julien|J|;Besson|Virginie|V|;Sayegh|Johnny|J|;Subra|Jean-François|JF|;Augusto|Jean-François|JF|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000448162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0253-5068",
"issue": "42(4)",
"journal": "Blood purification",
"keywords": null,
"medline_ta": "Blood Purif",
"mesh_terms": "D058186:Acute Kidney Injury; D017809:Fatal Outcome; D006333:Heart Failure; D016027:Heart Transplantation; D006354:Heart, Artificial; D006801:Humans; D008297:Male; D008875:Middle Aged; D006435:Renal Dialysis",
"nlm_unique_id": "8402040",
"other_id": null,
"pages": "301-303",
"pmc": null,
"pmid": "27577028",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Total Artificial Heart and Chronic Haemodialysis: A Possible Bridge to Transplantation?",
"title_normalized": "total artificial heart and chronic haemodialysis a possible bridge to transplantation"
} | [
{
"companynumb": "FR-MYLANLABS-2017M1002284",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo present an unusual case of coexisting tumor-induced osteomalacia (TIO) and primary hyperparathyroidism (PHPT).\n\n\nMETHODS\nWe report the clinical features, imaging studies, and the results of laboratory investigations before and after surgical resection of both a soft-tissue tumor and a parathyroid adenoma.\n\n\nRESULTS\nA 44-year-old woman was referred to the endocrinology department with a diagnosis of PHPT accompanied by unusually severe hypophosphatemia, despite having received treatment with cinacalcet. Debilitating muscle weakness and bone pain, severe phosphaturia and hypophosphatemia, inappropriately normal calcitriol, and elevated fibroblast growth factor-23 and intact parathyroid hormone levels raised the suspicion of coexisting TIO and PHPT. Imaging studies were negative, but histologic characteristics of a palpable subcutaneous mass from the patient's thigh revealed a phosphaturic mesenchymal tumor. Complete remission after surgical removal of both the soft-tissue tumor and the parathyroid adenoma confirmed the diagnosis.\n\n\nCONCLUSIONS\nThe coexistence of TIO and PHPT has not been described before and can cause life-threatening hypophosphatemia. Diagnosis and localization of the tumor is of paramount importance since surgery is the treatment of choice for both TIO and PHPT.",
"affiliations": "Department of Endocrinology and Diabetes Center, G. Gennimatas Hospital, Athens, Greece. amarkouuk@yahoo.co.uk",
"authors": "Markou|Athina|A|;Tsiama|Vassiliki|V|;Tournis|Symeon|S|;Papanastasiou|Labrini|L|;Tsiavos|Vaios|V|;Dassou|Aikaterini|A|;Vlachou|Vasiliki|V|;Papaliodi|Eugenia|E|;Asimaki|Niki|N|;Zografos|George|G|;Piaditis|George|G|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4158/EP11177.CR",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-891X",
"issue": "17(6)",
"journal": "Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists",
"keywords": null,
"medline_ta": "Endocr Pract",
"mesh_terms": "D000236:Adenoma; D000328:Adult; D005260:Female; D005598:Fractures, Spontaneous; D006044:Goiter, Nodular; D006801:Humans; D006811:Humerus; D049950:Hyperparathyroidism, Primary; D017674:Hypophosphatemia; D018908:Muscle Weakness; D009372:Neoplasms, Connective Tissue; D010018:Osteomalacia; D010257:Paraneoplastic Syndromes; D010280:Parathyroid Glands; D010282:Parathyroid Neoplasms; D013848:Thigh; D013965:Thyroidectomy; D016896:Treatment Outcome",
"nlm_unique_id": "9607439",
"other_id": null,
"pages": "e144-8",
"pmc": null,
"pmid": "21940278",
"pubdate": "2011",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Coexistence of tumor-induced osteomalacia and primary hyperparathyroidism.",
"title_normalized": "coexistence of tumor induced osteomalacia and primary hyperparathyroidism"
} | [
{
"companynumb": "GR-AMGEN-GRCSP2021022149",
"fulfillexpeditecriteria": "2",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOTHYROXINE"
},
"drugadditional": null,
... |
{
"abstract": "Veno-occlusive disease (VOD), or sinusoidal obstruction syndrome, is a well-recognised, serious complication associated with the chemotherapy conditioning therapy used in hematopoietic stem cell transplantation (HSCT). Fluid management is typically challenging in children with this condition. We describe effective early use of peritoneal dialysis catheters to drain extravascular, intra-abdominal fluid in children with VOD, allowing intravascular fluid administration to preserve renal perfusion and function, preventing multi-organ dysfunction. All but one of the children are long-term survivors, both of their significant VOD and their HSCT. The child that did not survive died from their underlying metabolic illness, not VOD.",
"affiliations": "Blood and Marrow Transplantation Unit, Royal Manchester Children's Hospital, Manchester, UK.;Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK.;Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester, UK.;Blood and Marrow Transplantation Unit, Royal Manchester Children's Hospital, Manchester, UK.;Blood and Marrow Transplantation Unit, Royal Manchester Children's Hospital, Manchester, UK.",
"authors": "Parmar|Vijal|V|;Lewis|Malcolm|M|;Shenoy|Mohan|M|;Bonney|Denise|D|;Wynn|Robert|R|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.26469",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "64(9)",
"journal": "Pediatric blood & cancer",
"keywords": "acute kidney injury; hematopoietic stem cell transplantation; multi-organ failure; peritoneal dialysis catheter; veno-occlusive disease",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D001201:Ascites; D001202:Ascitic Fluid; D057785:Catheters; D004322:Drainage; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006504:Hepatic Veno-Occlusive Disease; D006801:Humans; D007223:Infant; D008297:Male; D010530:Peritoneal Dialysis; D019172:Transplantation Conditioning",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28244636",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Ascitic fluid drainage using a peritoneal dialysis catheter to prevent and treat multi-organ dysfunction in veno-occlusive disease in children undergoing hematopoietic stem cell transplantation.",
"title_normalized": "ascitic fluid drainage using a peritoneal dialysis catheter to prevent and treat multi organ dysfunction in veno occlusive disease in children undergoing hematopoietic stem cell transplantation"
} | [
{
"companynumb": "GB-MYLANLABS-2017M1058788",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "... |
{
"abstract": "Severe cutaneous adverse reactions (SCARs) are delayed-type hypersensitivity reactions to drugs including as follows: Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome (SJS), Toxic Epidermal Necrolysis (TEN) and Acute Generalized Exanthematous Pustulosis (AGEP). Incidence, triggers and management of SCARs have not been investigated in large-scale epidemiological studies on children.\n\n\n\nThe aim of our study was to collect epidemiological, clinical and aetiological data from children with SCARs referred to our tertiary care paediatric hospital of Florence.\n\n\n\nFrom 2010 to 2018 charts of children with diagnosis of SCAR were reviewed, and data collected during the acute phase and/or the subsequent allergy evaluation. Patients underwent patch tests, intradermal tests and lymphocyte transformation tests. All children were investigated for infectious diseases.\n\n\n\nIncidence of SCARs in hospitalized children was 0.32% over a 9-year period. Fifty-four children were enrolled (31 M; 23 F; median age 6.5 years): 17 cases of DRESS, 30 SJS, 3 TEN, 2 AGEP, 1 linear immunoglobulin A bullous disease (LABD) and 1 pemphigus. Twenty-eight out of 54 patients underwent drug allergy investigations, and 50% of them resulted positive. Combining clinical history and results of allergy work-up, 74% SCARs seem to be caused by drugs, 18.6% by both drugs and infections, 3.7% by infections, and 3.7% remained idiopathic. No deaths occurred.\n\n\n\nIn this study, SCARs incidence is in line with literature data. Drugs were most commonly the leading cause. Management of SCARs requires cooperation among professional figures for an early diagnosis and a prompt treatment. Mortality rate seems to be lower in children.",
"affiliations": "Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Department of Clinical and Experimental Medicine, Unit of Internal Medicine, University of Florence, Florence, Italy.;Department of Clinical and Experimental Medicine, Unit of Internal Medicine, University of Florence, Florence, Italy.;Department of Clinical and Experimental Medicine, Unit of Internal Medicine, University of Florence, Florence, Italy.;Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.;Paediatric Department, Anna Meyer Children's Hospital, Florence, Italy.;Allergy Unit, Department of Paediatrics, Anna Meyer Children's University Hospital, Florence, Italy.",
"authors": "Liccioli|Giulia|G|0000-0002-5216-0423;Mori|Francesca|F|;Parronchi|Paola|P|;Capone|Manuela|M|;Fili|Lucia|L|;Barni|Simona|S|;Sarti|Lucrezia|L|;Giovannini|Mattia|M|;Resti|Massimo|M|;Novembre|Elio M|EM|",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000700:Analgesics; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors",
"country": "England",
"delete": false,
"doi": "10.1111/cea.13513",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-7894",
"issue": "50(1)",
"journal": "Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology",
"keywords": "Stevens-Johnson syndrome; acute generalized exanthematous pustulosis; aetiopathogenesis; children; drug reaction with eosinophilia and systemic symptoms; hypersensitivity drug reactions; lymphocyte transformation tests; paediatrics; severe cutaneous adverse reactions; toxic epidermal necrolysis",
"medline_ta": "Clin Exp Allergy",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000293:Adolescent; D000305:Adrenal Cortex Hormones; D000700:Analgesics; D000900:Anti-Bacterial Agents; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000927:Anticonvulsants; D002648:Child; D002675:Child, Preschool; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006776:Hospitals, Pediatric; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D015994:Incidence; D007223:Infant; D007428:Intradermal Tests; D007558:Italy; D062027:Linear IgA Bullous Dermatosis; D008213:Lymphocyte Activation; D008297:Male; D010328:Patch Tests; D010392:Pemphigus; D012189:Retrospective Studies; D013262:Stevens-Johnson Syndrome; D062606:Tertiary Care Centers",
"nlm_unique_id": "8906443",
"other_id": null,
"pages": "61-73",
"pmc": null,
"pmid": "31608511",
"pubdate": "2020-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Aetiopathogenesis of severe cutaneous adverse reactions (SCARs) in children: A 9-year experience in a tertiary care paediatric hospital setting.",
"title_normalized": "aetiopathogenesis of severe cutaneous adverse reactions scars in children a 9 year experience in a tertiary care paediatric hospital setting"
} | [
{
"companynumb": "IT-MYLANLABS-2020M1031063",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugaddit... |
{
"abstract": "OBJECTIVE\nNo standardized local thrombolysis regimen exists for the treatment of pulmonary embolism (PE). We retrospectively investigated efficacy and safety of fixed low-dose ultrasound-assisted catheter-directed thrombolysis (USAT) for intermediate- and high-risk PE.\n\n\nRESULTS\nFifty-two patients (65 ± 14 years) of whom 14 had high-risk PE (troponin positive in all) and 38 intermediate-risk PE (troponin positive in 91%) were treated with intravenous unfractionated heparin and USAT using 10 mg of recombinant tissue plasminogen activator per device over the course of 15 h. Bilateral USAT was performed in 83% of patients. During 3-month follow-up, two [3.8%; 95% confidence interval (CI) 0.5-13%] patients died (one from cardiogenic shock and one from recurrent PE). Major non-fatal bleeding occurred in two (3.8%; 95% CI, 0.5-13%) patients: one intrathoracic bleeding after cardiopulmonary resuscitation requiring transfusion, one intrapulmonary bleeding requiring lobectomy. Mean pulmonary artery pressure decreased from 37 ± 9 mmHg at baseline to 25 ± 8 mmHg at 15 h (P < 0.001) and cardiac index increased from 2.0 ± 0.7 to 2.7 ± 0.9 L/min/m(2) (P < 0.001). Echocardiographic right-to-left ventricular end-diastolic dimension ratio decreased from 1.42 ± 0.21 at baseline to 1.06 ± 0.23 at 24 h (n = 21; P < 0.001). The greatest haemodynamic benefit from USAT was found in patients with high-risk PE and in those with symptom duration < 14 days.\n\n\nCONCLUSIONS\nA standardized catheter intervention approach using fixed low-dose USAT for the treatment of intermediate- and high-risk PE was associated with rapid improvement in haemodynamic parameters and low rates of bleeding complications and mortality.",
"affiliations": "Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Cardiology, Swiss Cardiovascular Center, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland.;Clinic for Angiology, Inselspital-University Hospital and University of Bern, Bern, Switzerland Clinic for Cardiology, Swiss Cardiovascular Center, Inselspital-University Hospital and University of Bern, Bern, Switzerland nils.kucher@insel.ch.",
"authors": "Engelberger|Rolf P|RP|;Moschovitis|Aris|A|;Fahrni|Jennifer|J|;Willenberg|Torsten|T|;Baumann|Frederic|F|;Diehm|Nicolas|N|;Do|Do-Dai|DD|;Baumgartner|Iris|I|;Kucher|Nils|N|",
"chemical_list": "D010959:Tissue Plasminogen Activator",
"country": "England",
"delete": false,
"doi": "10.1093/eurheartj/eht531",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-668X",
"issue": "36(10)",
"journal": "European heart journal",
"keywords": "Bleeding; Cardiac output; Catheter-directed thrombolysis; Mortality; Pulmonary artery pressure; Pulmonary embolism",
"medline_ta": "Eur Heart J",
"mesh_terms": "D000368:Aged; D002404:Catheterization; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D011655:Pulmonary Embolism; D012189:Retrospective Studies; D012307:Risk Factors; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D018084:Ultrasonography, Interventional",
"nlm_unique_id": "8006263",
"other_id": null,
"pages": "597-604",
"pmc": null,
"pmid": "24334719",
"pubdate": "2015-03-07",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Fixed low-dose ultrasound-assisted catheter-directed thrombolysis for intermediate and high-risk pulmonary embolism.",
"title_normalized": "fixed low dose ultrasound assisted catheter directed thrombolysis for intermediate and high risk pulmonary embolism"
} | [
{
"companynumb": "CH-ROCHE-1576671",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
... |
{
"abstract": "Methotrexate (MTX) was originally formulated as one of the first antitumour drugs due to its ability to alter folate metabolism, which renders it to be an antiproliferative agent. Classically, the higher dosage is administered via parenteral route, in a cyclical fashion, to achieve antitumour effects. Patients on high doses of MTX are prone to develop rare complications of myelosuppression and pancytopenia, in a dose-dependent fashion, secondary to altered folate metabolism. 1 Herein, we present a unique case of rheumatoid arthritis presented with pancytopenia due to low-dose MTX and doxycycline drug interaction. We also report the successful management of pancytopenia and oral ulcers with combination therapy of leucovorin and granulocyte colony-stimulating factor.",
"affiliations": "Abington Hospital - Jefferson Health, Abington, Pennsylvania, USA.;Sheikh Zayed Medical College, Rahim Yar Khan, Pakistan.;Fauji Foundation Hospital, Rawalpindi, Pakistan.;Abington Hospital - Jefferson Health, Abington, Pennsylvania, USA.;Abington Hospital - Jefferson Health, Abington, Pennsylvania, USA.",
"authors": "Arslan|Ahmad|A|;Zain|Muhammad Abdullah|MA|;Mukhtar|Maryam|M|;Ullah|Waqas|W|http://orcid.org/0000-0002-4850-0309;Roomi|Sohaib|S|",
"chemical_list": "D018501:Antirheumatic Agents; D004318:Doxycycline; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-229296",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "12(5)",
"journal": "BMJ case reports",
"keywords": "contraindications and precautions; drugs and medicines",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D004318:Doxycycline; D004359:Drug Therapy, Combination; D006801:Humans; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D010198:Pancytopenia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31154348",
"pubdate": "2019-05-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25006519;30056523;14994410;29915656;27128679;21412604;16634119;20436072;10466909",
"title": "Methotrexate and doxycycline interaction: a rare cause of pancytopenia.",
"title_normalized": "methotrexate and doxycycline interaction a rare cause of pancytopenia"
} | [
{
"companynumb": "US-BAUSCH-BL-2019-017786",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEFLUNOMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in infants and children. In cases of diazoxide-unresponsive HI, alternative medical and surgical approaches may be required to reduce the risk of hypoglycemia. Octreotide, a somatostatin analog, often has a role in the management of these children, but a dose-dependent reduction in splanchnic blood flow is a recognized complication. Necrotizing enterocolitis (NEC) has been reported within the first few weeks of initiating predominantly high doses of octreotide. We describe the case of an infant with Beckwith-Wiedemann syndrome and diazoxide-unresponsive HI, who had persistent hypoglycemia after two pancreatectomy surgeries. She developed NEC 2 months after beginning octreotide therapy at a relatively low dose of 8 µg/kg/day. This complication has occurred later, and at a lower dose, than has previously been described. We review the case and identify the known and suspected multifactorial risk factors for NEC that may contribute to the development of this complication in patients with HI.",
"affiliations": "Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pa., USA.",
"authors": "Hawkes|Colin Patrick|CP|;Adzick|N Scott|NS|;Palladino|Andrew A|AA|;De León|Diva D|DD|",
"chemical_list": "D015282:Octreotide",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000443959",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1663-2818",
"issue": "86(2)",
"journal": "Hormone research in paediatrics",
"keywords": null,
"medline_ta": "Horm Res Paediatr",
"mesh_terms": "D001506:Beckwith-Wiedemann Syndrome; D044903:Congenital Hyperinsulinism; D020345:Enterocolitis, Necrotizing; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015282:Octreotide",
"nlm_unique_id": "101525157",
"other_id": null,
"pages": "131-136",
"pmc": null,
"pmid": "26867223",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10614546;12842586;16731846;1653660;15499144;12565699;11083380;21186002;25318632;905019;16532329;4299224;21930688;24815701;24645945;10095154;23384201;25039042;2569481;24157972;2362230;19558634;16390920;2246712;656226;22157140;15215005;22948872;1174138;10796375;23813352;21412889;26181719;25915914;1979363;26410441;17727436;11467656;19671558;20824848;18558210;24057290;26545876;24145932",
"title": "Late Presentation of Fulminant Necrotizing Enterocolitis in a Child with Hyperinsulinism on Octreotide Therapy.",
"title_normalized": "late presentation of fulminant necrotizing enterocolitis in a child with hyperinsulinism on octreotide therapy"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2016-BI-083880",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
"... |
{
"abstract": "BACKGROUND\nThe addition of extracorporeal photochemotherapy (ECP) to standard immunosuppressive therapy has been suggested to be beneficial in the treatment of recurrent/persistent heart rejection.\n\n\nMETHODS\nWe reviewed medical data of heart transplant recipients who received ECP between 2010 and 2016 at our institution.\n\n\nRESULTS\nDuring the study period, eight patients underwent nine ECP courses. The median time from transplant to ECP was 18 months (range 9-54). Indications for ECP were recurrent rejection in 6 patients, persistent rejection in 1 patient and mixed rejection with hemodynamic compromise in 1 patient. Additional criteria for patients' selection were represented by relevant comorbidities limiting the increase of immunosuppressive therapies. ECP was performed on an outpatient basis in 6 out of 8 patients. The median ECP duration was 12 months (range 1-18). Three out of 8 patients responded to ECP showing negative endomyocardial biopsies at the end of treatment. No additional rejection episodes were observed at their follow up (at 44, 72 and 31 months). Four of 8 patients failed to respond to ECP treatment, one patient has been judged not evaluable. Reduction of immunosuppressive therapies was obtained in all 3 responsive patients but also in 3 patients with a stable grade of rejection. The median duration of the follow up was 26 months (range 6-80). Two patients died at 6 and 21 months after beginning ECP. Survival after ECP was 78.2% at 26 months. No adverse effect or infectious complications associated with ECP were reported.\n\n\nCONCLUSIONS\nThe low response rate (37.5%) in our case series could be partially explained by patient selection, the treated patients representing a high-risk sub-set group. Further studies to provide evidence of a role for ECP in heart rejection treatment or prophylaxis are needed.",
"affiliations": "Therapeutic Apheresis Unit, Department of Transfusion Medicine, Azienda Sanitaria Universitaria Integrata, Udine, Italy. Electronic address: chiara.savignano@asuiud.sanita.fvg.it.;Therapeutic Apheresis Unit, Department of Transfusion Medicine, Azienda Sanitaria Universitaria Integrata, Udine, Italy.;Department of Cardiothoracic Surgery, Azienda Sanitaria Universitaria Integrata, Udine, Italy.;Therapeutic Apheresis Unit, Department of Transfusion Medicine, Azienda Sanitaria Universitaria Integrata, Udine, Italy.;Department of Medical Area, University of Udine, Italy.;Department of Cardiothoracic Surgery, Azienda Sanitaria Universitaria Integrata, Udine, Italy; Department of Medical Area, University of Udine, Italy.;Therapeutic Apheresis Unit, Department of Transfusion Medicine, Azienda Sanitaria Universitaria Integrata, Udine, Italy.",
"authors": "Savignano|Chiara|C|;Rinaldi|Cristina|C|;Tursi|Vincenzo|V|;Dolfini|Cecilia|C|;Isola|Miriam|M|;Livi|Ugolino|U|;De Angelis|Vincenzo|V|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.transci.2017.07.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1473-0502",
"issue": "56(4)",
"journal": "Transfusion and apheresis science : official journal of the World Apheresis Association : official journal of the European Society for Haemapheresis",
"keywords": "ECP; Extracorporeal photochemotherapy; Heart rejection; Heart transplantation",
"medline_ta": "Transfus Apher Sci",
"mesh_terms": "D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection; D016027:Heart Transplantation; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D017893:Photopheresis",
"nlm_unique_id": "101095653",
"other_id": null,
"pages": "520-524",
"pmc": null,
"pmid": "28774825",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Extracorporeal photochemotherapy in heart transplant rejection: A single-center experience.",
"title_normalized": "extracorporeal photochemotherapy in heart transplant rejection a single center experience"
} | [
{
"companynumb": "IT-MYLANLABS-2017M1050455",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "EVEROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "A 9-year old male patient with a past medical history of congenital cytomegalovirus (CMV) infection and spastic quadriplegic cerebral palsy with an intrathecal baclofen pump was admitted to a tertiary care hospital with respiratory depression and unresponsiveness for approximately two days. He had a recent two-week hospital stay for respiratory failure due to pneumonia. After being prescribed antibiotics and being sent home, he had developed copious diarrhea. On readmission, he was found to be dehydrated and in acute renal failure. A physical exam revealed hypotonia throughout, in a patient who typically had spasticity with contractures. The Pediatric Rehabilitation Medicine service was consulted for possible baclofen toxicity. Some signs and symptoms of baclofen toxicity include respiratory depression, seizures, CNS depression, hypotonia, hypotension, absent deep tendon reflexes, lethargy, ataxia, and cardiac arrhythmias. His intrathecal baclofen (ITB) dose was reduced, and signs/symptoms of ITB overdose began to resolve. As renal function improved, spasticity returned, necessitating increase in ITB dosing toward the premorbid dose.",
"affiliations": null,
"authors": "Bowman|Angeline|A|;Ayyangar|Rita|R|;Gonzales|Ian|I|;Hornyak|Joseph|J|",
"chemical_list": "D009125:Muscle Relaxants, Central; D001418:Baclofen",
"country": "Netherlands",
"delete": false,
"doi": "10.3233/PRM-180598",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1874-5393",
"issue": "12(3)",
"journal": "Journal of pediatric rehabilitation medicine",
"keywords": "Baclofen; intrathecal baclofen; kidney injury; spasticity; toxicity",
"medline_ta": "J Pediatr Rehabil Med",
"mesh_terms": "D058186:Acute Kidney Injury; D001418:Baclofen; D002648:Child; D006801:Humans; D007278:Injections, Spinal; D008297:Male; D009125:Muscle Relaxants, Central",
"nlm_unique_id": "101490944",
"other_id": null,
"pages": "313-315",
"pmc": null,
"pmid": "31476182",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrathecal baclofen toxicity in a patient with acute kidney injury.",
"title_normalized": "intrathecal baclofen toxicity in a patient with acute kidney injury"
} | [
{
"companynumb": "NL-AMNEAL PHARMACEUTICALS-2019-AMRX-01933",
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"drug": [
{
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"activesubstance": {
"activesubstancename": "BACLOFEN"
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"drugadditional"... |
{
"abstract": "Direct-acting antivirals (DAAs) have changed the landscape of hepatitis C virus (HCV) treatment, but chronic hepatitis C (CHC) remains a leading indication for liver transplantation (LT). Hepatitis B virus (HBV) reactivation has been reported in HBV-HCV-coinfected patients treated with DAAs. We report on a case of late HBV reactivation after DAA-based treatment of recurrent hepatitis C in an antibody against hepatitis B core antigen (anti-HBc)-positive LT recipient. (Hepatology 2018;67:791-793).",
"affiliations": "Transplantation Center, Lausanne, Switzerland.;Transplantation Center, Lausanne, Switzerland.;INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.;INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.;Service of Gastroenterology and Hepatology as well as, Lausanne, Switzerland.;Service of Clinical Pathology, University Hospital of Geneva, University of Geneva, Geneva, Switzerland.;Service of Immunology and Allergy, University Hospital of Lausanne, Lausanne, Switzerland.;Service of Clinical Pathology, University Hospital of Geneva, University of Geneva, Geneva, Switzerland.;INSERM U1052, Cancer Research Center of Lyon, University of Lyon, Lyon, France.;Service of Gastroenterology and Hepatology as well as, Lausanne, Switzerland.",
"authors": "Vionnet|Julien|J|;Pascual|Manuel|M|;Testoni|Barbara|B|;Combet|Christophe|C|;Godat|Sébastien|S|;Vijgen|Sandrine|S|;Aubert|Vincent|V|0000-0001-5527-8964;Rubbia-Brandt|Laura|L|;Zoulim|Fabien|F|;Moradpour|Darius|D|0000-0003-1977-6792",
"chemical_list": "D000998:Antiviral Agents; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens",
"country": "United States",
"delete": false,
"doi": "10.1002/hep.29528",
"fulltext": null,
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"issn_linking": "0270-9139",
"issue": "67(2)",
"journal": "Hepatology (Baltimore, Md.)",
"keywords": null,
"medline_ta": "Hepatology",
"mesh_terms": "D000998:Antiviral Agents; D060085:Coinfection; D006510:Hepatitis B Antibodies; D006512:Hepatitis B Core Antigens; D006515:Hepatitis B virus; D019698:Hepatitis C, Chronic; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D014775:Virus Activation",
"nlm_unique_id": "8302946",
"other_id": null,
"pages": "791-793",
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"pmid": "28921620",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late hepatitis B reactivation following direct-acting antiviral-based treatment of recurrent hepatitis C in an anti-HBc-positive liver transplant recipient.",
"title_normalized": "late hepatitis b reactivation following direct acting antiviral based treatment of recurrent hepatitis c in an anti hbc positive liver transplant recipient"
} | [
{
"companynumb": "CH-009507513-1802CHE000786",
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"activesubstance": {
"activesubstancename": "RIBAVIRIN"
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"drugadditional": "3",
... |
{
"abstract": "A 43-year-old patient with recurrent acute myeloid leukemia (AML) was treated with high-dose cytarabine. After two weeks of neutropenic fever, multiple cutaneous nodules appeared. Histopathological examination of a skin biopsy showed a mycosis and Fusarium solani was cultured. Despite antimycotic therapy, the patient died due to complications of his AML treatment.",
"affiliations": "Afd. Interne Geneeskunde, Isala klinieken, Zwolle, the Netherlands. j.ham@aig.umcn.nl",
"authors": "Ham|J C Janneke|JC|;Ruijs|Gijs J H M|GJ|;van Marwijk Kooy|M Rien|MR|",
"chemical_list": "D007166:Immunosuppressive Agents; D003561:Cytarabine",
"country": "Netherlands",
"delete": false,
"doi": null,
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"issue": "157(12)",
"journal": "Nederlands tijdschrift voor geneeskunde",
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"mesh_terms": "D000328:Adult; D003561:Cytarabine; D003881:Dermatomycoses; D017809:Fatal Outcome; D005670:Fusarium; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008297:Male; D009503:Neutropenia; D009894:Opportunistic Infections",
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"pubdate": "2013",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A man with neutropenic fever.",
"title_normalized": "a man with neutropenic fever"
} | [
{
"companynumb": "PHHY2013NL059136",
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"patient": {
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{
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"activesubstancename": "CYTARABINE"
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{
"abstract": "Capecitabine is now-a-days rapidly replacing 5-Fluorouracil in daily clinical practice. Neurologic toxicity during a treatment with fluoropyrimidines, as 5-fluorouracil, represents a well-known side-effect, largely described in literature. Central nervous system (CNS) toxicity, mainly encephalopathy with or without seizures, occurs occasionally even when conventional doses are used. CNS toxicity incidence increases markedly when the blood-brain barrier is either overwhelmed or bypassed (Hildebrand J. Neurological complications of cancer chemotherapy. Curr Opin Oncol 2006; 18: 321-324). Peripheral nervous system (PNS) toxicity is more common because proximal and distal extremities of the peripheral nerves are not protected by a blood-brain like barrier and peripheral neuropathy remains a major limiting factor for the administration of conventional doses of several agents (Saif W, Wood TE, McGee PJ and Diasio RB. Peripheral neuropathy associated with capecitabine, Anticancer Drugs 2004;15: 767-771). Capecitabine is a prodrug of 5-fluorouracil, more easily administered by mouth; its transformation in 5-fluorouracil is performed in the liver. There are only a few reports on the toxic neurological side-effects of capecitabine. We describe in our report a rare case of toxic encephalopathy in a 82-year-old female, with a brief review of literature. In the literature reviewed, we found 12 neurologic episodes due to capecitabine lasting between a few days till some months. All clinical symptoms of the cases described in literature, obtained a complete regression with the discontinuation of capecitabine. A relation was not found with dihydropyrimidine dehydrogenase (DPD) mutation, also if pharmacologic and pharmacogenetic assessment should be done for this drug, especially in old patients. Toxic encephalopathy represents a rare event during capecitabine treatment and on the bases of the data found, is fairly managed in the clinical setting. The knowledge of the natural history of the toxic effect allows the use of the drug also in old patients.",
"affiliations": "Oncology and Oncohematology Department, Rimini Hospital and Cancer Center of Romagna Meldola, Italy. fantamanu77@libero.it",
"authors": "Fantini|Manuela|M|;Gianni|Lorenzo|L|;Tassinari|Davide|D|;Nicoletti|Stefania|S|;Possenti|Cinzia|C|;Drudi|Fabrizio|F|;Sintini|Michele|M|;Bagli|Laura|L|;Tamburini|Emiliano|E|;Ravaioli|Alberto|A|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; D000069287:Capecitabine; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1177/1078155210374891",
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"issue": "17(3)",
"journal": "Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners",
"keywords": null,
"medline_ta": "J Oncol Pharm Pract",
"mesh_terms": "D000230:Adenocarcinoma; D000367:Age Factors; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D001859:Bone Neoplasms; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D003841:Deoxycytidine; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil; D006801:Humans; D020258:Neurotoxicity Syndromes; D018579:Patient Selection; D018570:Risk Assessment; D012307:Risk Factors",
"nlm_unique_id": "9511372",
"other_id": null,
"pages": "288-91",
"pmc": null,
"pmid": "20926454",
"pubdate": "2011-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Toxic encephalopathy in elderly patients during treatment with capecitabine: literature review and a case report.",
"title_normalized": "toxic encephalopathy in elderly patients during treatment with capecitabine literature review and a case report"
} | [
{
"companynumb": "PT-ALKEM LABORATORIES LIMITED-PT-ALKEM-2019-02530",
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"activesubstance": {
"activesubstancename": "CAPECITABINE"
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{
"abstract": "A hypertensive elderly male on amlodipine presented with a palpable purpuric rash on both legs followed by shoulder, buttocks, and back with foot ulcer, which was found to be leukocytoclastic vasculitis on skin biopsy. The patient recovered completely on discontinuation of amlodipine and short-term steroid.",
"affiliations": "Department of Medicine, PGIMER, Dr. RML Hospital, New Delhi, India.;Department of Medicine, PGIMER, Dr. RML Hospital, New Delhi, India.;Department of Medicine, Smt. Sucheta Kriplani Hospital and LHMC, New Delhi, India.;Department of Medicine, Smt. Sucheta Kriplani Hospital and LHMC, New Delhi, India.;Department of Medicine, PGIMER, Dr. RML Hospital, New Delhi, India.;Department of Pathology, PGIMER, Dr. RML Hospital, New Delhi, India.",
"authors": "Sheoran|Ankita|A|;Mahto|Subodh Kumar|SK|;Verma|Pooja|P|;War|Gwenette A|GA|;Agarwal|Nagina|N|;Singh|Anu|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jfmpc.jfmpc_338_19",
"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Wolters Kluwer - Medknow India JFMPC-8-213710.4103/jfmpc.jfmpc_338_19Case ReportLeukocytoclastic vasculitis: An uncommon adverse effect of a common drug Sheoran Ankita 1Mahto Subodh Kumar 1Verma Pooja 2War Gwenette A. 2Agarwal Nagina 1Singh Anu 31 Department of Medicine, PGIMER, Dr. RML Hospital, New Delhi, India2 Department of Medicine, Smt. Sucheta Kriplani Hospital and LHMC, New Delhi, India3 Department of Pathology, PGIMER, Dr. RML Hospital, New Delhi, IndiaAddress for correspondence: Dr. Subodh Kumar Mahto, C/O: Anandi Prakash Hospital, Sitamarhi, Bihar - 843 316, India. E-mail: drsubodhkr05@gmail.com6 2019 8 6 2137 2139 24 4 2019 25 4 2019 17 5 2019 Copyright: © 2019 Journal of Family Medicine and Primary Care2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.A hypertensive elderly male on amlodipine presented with a palpable purpuric rash on both legs followed by shoulder, buttocks, and back with foot ulcer, which was found to be leukocytoclastic vasculitis on skin biopsy. The patient recovered completely on discontinuation of amlodipine and short-term steroid.\n\nAmlodipineleukocytoclastic vasculitisskin biopsy\n==== Body\nIntroduction\nAmlodipine, a dihydropyridine calcium channel blocker (CCB), is frequently used for the treatment of various cardiovascular disorders. Common side effects of dihydropyridine CCB are headache, ankle edema, tachycardia, hypotension, constipation, and gastro-esophageal reflux. Rare and lethal adverse reactions of this group of drugs are allergic rash, cutaneous hyperpigmentation, and toxic epidermal necrolysis.[123]\n\nCase Report\nA 62-year-old hypertensive male on amlodipine from past 2 months presented with purpuric rash on both legs, shoulder, buttocks, and back followed by the development of small ulcer on both big toes for 1 month. There was no history of fever, arthralgia, abdominal pain, jaundice, hematuria or bleeding from any site, oral/genital ulcer, or visual complaints. He denied intake of NSAIDS, steroids, any herbal medications, or over-the-counter pills. General physical and systemic examination did not reveal any abnormality. On local examination, there was bilateral palpable purpura and ecchymosis on extensor surface of legs, shoulder, back, and buttocks and non-infected superficial ulcers on both big toes [Figures 1 and 2].\n\nFigure 1 Bilateral palpable purpura and ecchymosis on extensor surface of legs and feet\n\nFigure 2 Bilateral palpable purpura and ecchymosis on flexor surface of legs and feet\n\nLaboratory examination revealed 13 gm % hemoglobin and total leukocyte count of 13,800/mm3 with normal differential counts and platelets. The erythrocyte sedimentation rate was 74 mm/1st h. Serum bilirubin was normal, however, serum aspartate amino transferase, serum alanine amino transferase, and serum alkaline phosphatase were 123, 144, and 139 IU/L, respectively. The international normalized ratio was raised (3.2). Serum urea and creatinine were 67 and 1.6 mg/dL, respectively. Infectious serology and antigen testing including those for dengue, malaria, chikungunya, HSV, EBV, CMV, Salmonella, HBsAg, anti-HAV, anti-HEV, anti-HCV, and HIV were negative. Blood, urine culture, and throat swab were sterile. Urine routine and microscopy were within normal limits. Mantoux test was negative. C-reactive protein was raised (35 mg/dL), where rheumatoid factor, anti-nuclear antibodies, P-ANCA, and C-ANCA were negative. Chest roentgenogram, ECG, and 2-D echo were within normal limits. Ultrasonography (USG) of the abdomen showed normal study. Skin biopsy showed leukocytoclastic vasculitis (LCV) [Figures 3 and 4].\n\nFigure 3 Lined by stratified squamous keratinized epithelium showing orthokeratosis and irregular acanthosis. (hematoxylin-eosin stain, 100X)\n\nFigure 4 Underlying dermis shows perivascular inflammatory infiltrate comprising of predominantly neutrophils and lymphocytes. (hematoxylin-eosin stain, 400X)\n\nTablet amlodipine was stopped and the patient was started on systemic steroids and supportive treatment. The rash started to resolve within a week. Repeat liver function and renal function tests were all within normal limits after 1 week. The patient was also prescribed prednisolone 40 mg/day for 10 days followed by rapid tapering. Gradually, purpuric rash disappeared and superficial ulcer healed in 5 weeks.\n\nDiscussion\nLeukocytoclastic vasculitis is the inflammation of small blood vessel. It is characterized by neutrophilic infiltration in cutaneous superficial postcapillary venules and may be secondary to infections, drugs, collagen tissue disorders, and malignities.[4] Cardinal features of LCV are palpable purpura and violaceous papules, affecting most commonly the lower extremities and less commonly urticarial, vesicular, nodular, and target-like lesions; livedoid pattern and ulcerations are seen clinically.[4] Other manifestations, such as, fever, myalgia, arthralgia, and other symptoms related to internal organ involvement are also seen in patients.[5]\n\nDrug-induced small-vessel vasculitis constitutes about 10%, and most commonly responsible drugs are penicillin, sulphonamides, aminopenicillin, quinolone, allopurinol, thiazides, propylthiouracil, and hydantoin.[6] Leukocytoclastic vasculitis is diagnosed by histopathological evaluation of the biopsy from the lesion, and additional laboratory tests should be performed for systemic involvement and its etiology. Drugs might play a role in the etiology of LCV.[7]\n\nOur patient had no history suggestive of connective tissue disorder or viral prodrome. Because amlodipine was the only recent drug to which he was exposed to, it was thought to be the etiological trigger. In addition, the improvement and resolution of rash after discontinuation of drug supported the diagnosis.\n\nConclusion\nThis is a very rare presentation of amlodipine-induced LCV as most common drugs implicated are thiazide, sulfa, penicillamine, gold, and allopurinol. This case is being presented to sensitize physicians regarding this unique and extremely rare adverse event associated with the use of amlodipine.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\n1 Erbagci Z Amlodipine associated hyperpigmentation Saudi Med J 2004 25 103 5 14758392 \n2 Lim AC Hart K Murrell D A granuloma annulare-like eruption associated with the use of amlodipine Australas J Dermatol 2002 43 24 7 11869204 \n3 Baetz BE Patton ML Guilday RE Reigart CL Ackerman BH Amlodipine-induced toxic epidermal necrolysis J Burn Care Res 2011 32 158 60 \n4 Goeser MR Laniosz V Wetter DA A practical approach to the diagnosis, evaluation, and management of cutaneous small-vessel vasculitis Am J Clin Dermatol 2014 15 299 306 24756249 \n5 Grau RG Drug-induced vasculitis: New insights and a changing lineup of suspects Curr Rheumatol Rep 2015 17 71 26503355 \n6 Mansi IA Opran A Rosner F ANCA-associated small-vessel vasculitis Am Fam Physician 2002 65 1615 20 11989638 \n7 Al-Busafi SA Al-Suleimani A Al-Hamadani A Rasool W Tenofovir inducedLeukocytoclastic Vasculitis Send to Oman Med J 2017 32 429 31\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "2249-4863",
"issue": "8(6)",
"journal": "Journal of family medicine and primary care",
"keywords": "Amlodipine; leukocytoclastic vasculitis; skin biopsy",
"medline_ta": "J Family Med Prim Care",
"mesh_terms": null,
"nlm_unique_id": "101610082",
"other_id": null,
"pages": "2137-2139",
"pmc": null,
"pmid": "31334194",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports",
"references": "11869204;11989638;14758392;21772148;24756249;26503355",
"title": "Leukocytoclastic vasculitis: An uncommon adverse effect of a common drug.",
"title_normalized": "leukocytoclastic vasculitis an uncommon adverse effect of a common drug"
} | [
{
"companynumb": "IN-ACCORD-150078",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "AMLODIPINE BESYLATE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nTriplet chemotherapy, with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer (GC). An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results.\n\n\nOBJECTIVE\nTo determine safety and efficacy of TeFOX perioperative regimen.\n\n\nMETHODS\nThis monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized GC. TeFOX consist in docetaxel (50 mg/m²) with oxaliplatin 85 mg/m² and and leucovorin (400 mg/m2) 5 FU bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) every 2 wk.\n\n\nRESULTS\nThirty-three consecutive patients were included in this retrospective study. Eighteen patients have a gastroesophageal junction cancer and 11 have a GC. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) had a pathological complete response and 8 (24) patients a nearly complete pathological response. Median OS and PFS were not reached at data base lock. We have observed 6 metastatic relapses and 1 localized relapse. No relapse was observed in patients with pathological complete responses. The most common grade 3-4 adverse events were peripheral neuropathy (21) and asthenia (20).\n\n\nCONCLUSIONS\nTeFOX regimen could be safely administrated in perioperative treatment of localized GC. TeFOX and the FLOT regimen have comparable efficacy and safety profiles.",
"affiliations": "Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, France.;Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, France. fghiringhelli@cgfl.fr.",
"authors": "Basso|Valeria|V|;Orry|David|D|;Fraisse|Jean|J|;Vincent|Julie|J|;Hennequin|Audrey|A|;Bengrine|Leila|L|;Ghiringhelli|Francois|F|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.4251/wjgo.v11.i8.634",
"fulltext": "\n==== Front\nWorld J Gastrointest OncolWJGOWorld Journal of Gastrointestinal Oncology1948-5204Baishideng Publishing Group Inc jWJGO.v11.i8.pg63410.4251/wjgo.v11.i8.634Retrospective StudySafety and efficacy of a docetaxel-5FU-oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer: A retrospective study Basso Valeria Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, FranceOrry David Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, FranceFraisse Jean Department of Surgery, Centre Georges Francois Leclerc, Dijon 21000, FranceVincent Julie Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, FranceHennequin Audrey Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, FranceBengrine Leila Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, FranceGhiringhelli Francois Department of Medical Oncology, Centre Georges Francois Leclerc, Dijon 21000, France. fghiringhelli@cgfl.frAuthor contributions: Basso V collected clinical data; Orry D and Ghiringhelli F designed the study; Orry D, Fraisse J, Vincent J, Hennequin A and Ghiringhelli F treated patients includes in this study; Ghiringhelli F analyzed the data; Ghiringhelli F and Basso V wrote the manuscript; All authors have read and approve the final manuscript.\n\nCorresponding author: Francois Ghiringhelli, MD, Professor, Department of Medical Oncology, Centre George François Leclerc, 1 Rue du Professeur Marion, Dijon 21000, France. fghiringhelli@cgfl.fr\n\nTelephone: +33-380-732424 Fax: +33-380-737500\n\n15 8 2019 15 8 2019 11 8 634 641 18 3 2019 7 6 2019 20 6 2019 ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.2019This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nTriplet chemotherapy, with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer (GC). An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results.\n\nAIM\nTo determine safety and efficacy of TeFOX perioperative regimen.\n\nMETHODS\nThis monocentric retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone or in combination with trastuzumab in patients with localized GC. TeFOX consist in docetaxel (50 mg/m²) with oxaliplatin 85 mg/m² and and leucovorin (400 mg/m2) 5 FU bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) every 2 wk.\n\nRESULTS\nThirty-three consecutive patients were included in this retrospective study. Eighteen patients have a gastroesophageal junction cancer and 11 have a GC. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) had a pathological complete response and 8 (24) patients a nearly complete pathological response. Median OS and PFS were not reached at data base lock. We have observed 6 metastatic relapses and 1 localized relapse. No relapse was observed in patients with pathological complete responses. The most common grade 3-4 adverse events were peripheral neuropathy (21) and asthenia (20).\n\nCONCLUSION\nTeFOX regimen could be safely administrated in perioperative treatment of localized GC. TeFOX and the FLOT regimen have comparable efficacy and safety profiles.\n\nGastric cancerNeoadjuvant chemotherapyTeFOXRetrospective study\n==== Body\nCore tip: Triplet chemotherapy with docetaxel-5FU-oxaliplatin FLOT regimen recently became the standard perioperative treatment for localized gastric cancer. An adapted regimen called TeFOX was recently tested in metastatic setting and gave promising results. We provide here evidence based on our experience of the safety and efficacy of this regimen in patients treated in neoadjuvant setting.\n\nINTRODUCTION\nGastric cancer (GC) is a major problem of health worldwide. In 2018, 783000 patients died of a GC, making it the third leading cause of cancer death[1]. Upon metastatic disease, the prognosis is poor with less than 2 years of median survival, even with new chemotherapeutic approaches. Prognosis is better in localized tumours and surgery can cure about 90% of T1 N0 tumours[1]. For more advanced tumours, the prognosis remains poor. Standard of care involves a perioperative treatment. With such treatment, the 5-year relapse free survival reaches 30%-40%. For a long time, based on MAGIC trial and on FFCD 9703 phase 3 study, the standard treatment was association of fluoropyrimidin plus platin with or without epirubicin[2,3]. Such therapies improve 5-year relapse free survival of around 20% with surgery only and around 35% with perioperative chemotherapy.\n\nRecently, a new combination of platin and taxane improved outcome in patients with metastatic disease. In addition, usage of trastuzumab demonstrated its efficacy in first line of metastatic GC with HER2 overexpressing tumour[4]. Such HER2 overexpressing tumour represents around 20% of GCs[5]. German cooperative group developed a taxane based chemotherapy protocol called FLOT which was tested in perioperative setting. Such therapy gave better response rates than platin based chemotherapies and improved relapse free survival[6,7]. In France, an alternative protocol called TeFOX using 5-FU in a 46h continuous infusion at the dose of 2400 mg/m2, instead of 24 h continuous infusion at the dose of 2600 mg/m2 in FLOT regimen, was developed in metastatic disease. TeFOX is safe and give impressive response rates in first line metastatic disease[8]. This regimen in a retrospective study gave disease control rate of 87.6%, respectively. Median PFS and OS observed in this study were 9.7 months and 14.3 months respectively. In addition, 40% of metastatic patients could have secondary resection. The toxic of the TeFOX regimen is modest with less haematological toxicity than observed with the FLOT regimen[8].\n\nBased on these results, neoadjuvant therapy of GC was modified in our centre and patients received TeFOX or TeFOX with trastuzumab if they had a HER2 overexpressing tumour. Our objective is to describe the safety and the efficacy of this protocol.\n\nMATERIALS AND METHODS\nPatients\nAll consecutive patients treated for histologically confirmed, previously untreated, non-metastatic, operable adenocarcinoma of the stomach or gastroesophageal junction between May 15, 2013 and August 29, 2018 in Centre Georges Francois Leclerc, were included. Follow-up ended in December 2018.\n\nEligibility criteria for inclusion in the study were: (1) Local gastric or gastroeso-phageal junction (GEJ) adenocarcinoma, without metastases detected following CT-scan and TEP-scan; (2) The possibility of curative resection as assessed by a digestive surgery multidisciplinary staff; (3) WHO performance status of 0 or 1; and (4) Absence of previous cancer therapy. The study was conducted in accordance with the Declaration of Helsinki. All participating patients fully agreed with the use of their medical records in clinical research. The study was performed in agreement with the General Data Protection Regulation European law.\n\nTreatment\nTreatment consisted of an intravenous injection of TeFOX regimen with or without trastuzumab for patients with HER2 overexpressing tumours. TeFOX consisted of docetaxel (50 mg/m2), oxaliplatin (85 mg/m2), and leucovorin (400 mg/m2) F5U bolus (400 mg/m2) on day 1, followed by continuous infusion of 5FU for 46 h (2400 mg/m2) administered every 2 wk. Trastuzumab was given at 4mg/kg every two weeks. Prophylactic treatments included corticosteroids and antiemetic’s given accordingly to standard recommendations. G-CSF, a hematopoietic factor, was systematically given as a prophylactic treatment in all patients (Filgrastin 34 MUI/d during 4 d, starting the day after the end of 5FU infusion). The number of cycles of chemotherapy expected was 6 before and after surgery. Dose reductions and treatment discontinuations were performed according to physician decision, based on toxicity.\n\nSafety\nToxicity was evaluated before each cycle according to the NCI-CTC-AE v5.\n\nEfficacy\nEfficacy of neoadjuvant chemotherapy was tested using pathological examination. Tumour regression grade was quantified using the Becker classification[9]. This classification gave an estimation of the percentage of vital tumour cells in the tumour core: TRG1a means complete pathological response; TRG1b means subtotal regression with less than 10% of residual tumour cells; TRG2 means partial regression with around to 10% to 50% of viable tumour cells and TRG3 means no or minor regression[10].\n\nStatistical analysis\nToxicity and response to neoadjuvant chemotherapy were evaluated in the intent-to-treat population, defined as patients who received at least one cycle of TeFOX with or without trastuzumab. Toxicity of neoadjuvant and adjuvant chemotherapy as well as surgery related toxicities were evaluated. Time to relapse was defined as the time between surgery and the discovery of the first metastatic site. All patients alive without disease relapse at the last follow-up date were censored. Overall survival (OS) was defined as the time between the first cycle of chemotherapy and death (all causes). All patients alive at the last follow-up date were censored. Survival curves were estimated using the Kaplan–Meier method. Median follow-up and its 95% confidence interval (CI) were calculated with the reverse Kaplan–Meier method. All statistical analysis were performed using MedCalc Software.\n\nRESULTS\nPatient characteristics\nBetween May 15, 2013 and August 29, 2018, 33 patients that received at least one cycle of neoadjuvant chemotherapy for a localized GC, were enrolled. The median age was 63 years. The majority of patients had a WHO performance status of 0. Pre-treatment patient characteristics are shown in Table 1. Only 5 patients have signet ring cell carcinoma. Five patients have HER2 overexpressing tumours and received in addition to TeFOX, trastuzumab during neoadjuvant chemotherapy. Median number of neoadjuvant chemotherapy cycles was 5 (range 2-8). Median number of adjuvant chemotherapy cycles was 3 (range 0-6). Eleven patients underwent transthoracic oesophagectomy, 11 total gastrectomy and 11 subtotal gastrectomy. Following surgery, only 28 patients received adjuvant chemotherapy (2 patients refused further therapy and 3 had a poor performance status following surgery and were excluded from further therapy). The median number of therapy cycles was 4 (range 1-7).\n\nTable 1 Baseline characteristics of included patients [n = 33, n (%)]\n\nAge (yr)\t63 (41–80)\t\nSex\t\t\nMale\t28 (84)\t\nFemale\t5 (16)\t\nWHO performance status\t\t\n0\t20 (60)\t\n1\t13 (40)\t\nDenutrition\t\t\n> 10% weight loss\t10 (30)\t\nLocalization\t\t\nGastric\t15 (45)\t\nGastro-oesophageal junction Siewert I\t12 (35)\t\nGastro-oesophageal junction Siewert II\t3 (10)\t\nGastro-oesophageal junction Siewert III\t3 (10)\t\nSurgery\t\t\nLewis Santy\t11 (33)\t\nTotal Gastrectomy\t11 (33)\t\nSubtotal Gastrectomy\t11 (33)\t\nClinical tumour stage\t\t\ncT3/T4\t7 (81)\t\ncT1/T2\t5 (18)\t\ncTx\t21 (1)\t\ncN+\t22 (77)\t\ncN–\t8 (23)\t\nHistological type\t\t\nIntestinal\t28 (84)\t\nSinget Ring cells\t5 (16)\t\nHER2 overexpressing\t5 (16)\t\nSafety\nThere was no treatment-related death. Toxicities of neoadjuvant chemotherapy are described in Table 2. Only 2 patients did not present side effects during neoadjuvant chemotherapy. Ten patients developed grade 3-4 toxicities. The most common grade 3-4 toxicities were asthenia, and peripheral neuropathy which occurred in 19% and 21% of patients respectively. Febrile neutropenia occurred in one patient (3). Dose reduction occurred in seven patients with elimination of docetaxel in 4 patients and oxaliplatin dose reduction in 3 patients. Discontinuation of therapy occurred in 6 patients due to important side effects. Granulocyte colony-stimulating factor (G-CSF) was prophylactically given to all patients. Perioperative medical or surgical grade 3 and 4 complications According to Clavien-Dindo classification within 90 d of surgery were observed in 6 patients. No death was observed in the 90 d post-surgery. The most frequent serious adverse events were pneumonia, in 7 patients (21), and abdominal infection, in 5 patients (15). Incidence of surgical and perioperative complications were higher in the group of patients that undergone esophagectomy, with 5 patients within 11 (45) with grade 3 or 4 complications versus 1 with 22 (4) in patients that undergone gastrectomy. Nineteen patients had no or a reduced number of adjuvant chemotherapy cycles and 8 of whom have undergone esophagectomy. Seventeen patients within the 28 that received adjuvant chemotherapy had grade 3 or 4 side effects (60). Occurrence of adverse effects was the unique cause of adjuvant therapy ending (Table 3).\n\nTable 2 Neoadjuvant chemotherapy adverse events\n\nMaximal toxicity\tAll\tGrade 3/4\t\nAll\t31 (92)\t10 (30)\t\nNeutropenia\t3 (10)\t1(3)\t\nFebrile neutropenia\t1 (3)\t1 (3)\t\nAnaemia\t2 (6)\t0%\t\nThrombocytopenia\t2 (6)\t0%\t\nNeurotoxicity\t21 (63)\t7 (21)\t\nNausea\t7 (21)\t0%\t\nAsthenia\t12 (36)\t6 (19)\t\nVomiting\t2 (6)\t0%\t\nMucositis\t4 (12)\t2 (6)\t\nDiarrhoea\t12 (36)\t3 (10)\t\nAllergic reaction\t1(3)\t1 (3)\t\nTable 3 Serious adverse events during perioperative time (n = 33)\n\nPatients with at least one grade 3-4 adverse event during perioperative time\t6 (18)\t\nMedical complication\t7 (21)\t\nAnastomotic leak\t2 (6)\t\nWound healing disorder\t1 (3)\t\nPneumonia\t7 (21)\t\nPleural complication\t1 (3)\t\nSepsis and infection\t5 (15)\t\nIntestinal occlusion\t2 (6)\t\nBleeding\t1\t\nEfficacy outcomes\nMedian follow-up for surviving patients was 32 mo. Surgical and pathological results are presented in Table 4. R0 resection was obtained in 30 out of 33 patients. Only R1 resection was achieved for an esophagectomy and 2 subtotal gastrectomy. We have used Becker regression criteria classification to estimate tumour regression and response rate. We found 12 (36) patients with complete response TRG1a, 8 (24) patients with TRG1b, 4 (13) patients with TRG2 and 9 (27) with TRG3. No particular difference was observed between complete and incomplete responders in term of histological type, tumour stage or number of cycles of neoadjuvant chemotherapies. For HER2 overexpression tumor complete response (TRG1a) was observed in 3 out of five patients. Two-year OS and PFS were respectively 90% and 73%. Median OS and PFS were not reached at data base lock (Figures 1 and 2). We observed 6 metastatic relapses and 1 localized relapse. No relapses were observed in patients with TRG1A histological response.\n\nFigure 1 Time to relapse for all included patients.\n\nFigure 2 Overall survival for all included patients.\n\nTable 4 Surgical and pathological results (n = 33)\n\nType of surgery\t\t\nSubtotal gastrectomy\t11 (33)\t\nTotal gastrectomy\t11 (33)\t\nOesophagectomy\t11 (33)\t\nResection Grade\t\t\nR0\t30 (90)\t\nR1\t3 (10)\t\nComplete (TRG 1a)†\t12 (36)\t\nSubtotal (TRG 1b)\t8 (24)\t\nPartial (TRG 2)\t4 (13)\t\nMinimal or none (TRG 3)\t9 (27)\t\nyN0\t21 (63)\t\nyN 1\t6 (19)\t\nyN2\t6 (19)\t\nDISCUSSION\nThis study underlines the safety and feasibility of TeFOX or TeFOX plus trastuzumab regimen for patients with localized GC. Neoadjuvant therapy is the standard of care for localized GC. Recently the FLOT4 study demonstrated the superiority of FLOT perioperative regimen in comparison to ECX regimen[6,7]. In particular, while ECX led to 6% TRG1A complete response, the FLOT4 gave rise to 16% of TRG1 (95%CI: 10%-23). These results are comparable with previous studies like OEO5[11] and ST03 trials[12] which showed a TRG1a rate of 7% and 8%, respectively. In most clinical trials testing combination of chemotherapies with taxane, the proportion of patients with complete pathological response are similar to the ones obtained with FLOT regimen, with complete responses ranging from 14% to 20%[13,14]. In our study, we have observed 36% of TRG1a (95%CI: 19-62). Such data compares favourably to previous trials and suggests that the TeFOX regimen might be at least as efficient as other taxane based regimens. Importantly, relapse rate is small, 21% of relapse (95%CI: 8-43) with a median follow up of more than two years. In FLOT4 trial, the relapse rate at 2 years are 57% and 47% for ECX and FLOT4 regimen[6]. Interestingly, no patients with TRG1a had a relapse, suggesting that complete response is a good surrogate to predict absence of recurrence. No clinical variable was associated with complete response or recurrence. Notably, neither singet ring cell presence nor the number of cycles of neoadjuvant chemotherapy were associated with relapse or complete response.\n\nIn our study, TeFOX perioperative chemotherapy gives rise to grade 3-4 side effects in 30% of the patients (95%CI: 14-55). The main toxicities observed are asthenia and neuropathy. Such results are very similar to the FLOT regimen which induced 34% of grade 3-4 toxicity. In FLOT4 trial, 52% of patients have grade 3-4 neutropenia but in our series only 10% are observed. The difference probably relies on the systematic and prophylactic use of G-CSF. Higher rate of neuropathy was observed in our study. This difference may rely on a higher number of chemotherapy cycles. Similarly, surgery morbidity is comparable to FLOT prospective randomized trial. Not surprisingly, we have observed a higher incidence of complications with esophagectomy. Interestingly, adjuvant treatment could not be started in 5 patients and had to be stopped in 14 patients because of major side effects. The incidence of grade 3-4 side effects reached 60% and required treatment arrest for most patients. Such data suggest a higher toxicity of adjuvant therapy than neoadjuvant therapy.\n\nLimitations of our study include the retrospective and monocentric design and a selection of patients with good performance status. However, we believe that such data support that TeFOX results might be comparable to FLOT regimen results and could be used in neoadjuvant setting of localized gastric and gastroesophageal junction cancer.\n\nIn conclusion, our study gives information on safety and efficacy of TeFOX regimen in perioperative setting of localized gastric and gastroesophageal junction cancer. These data support further development in phase II clinical trials.\n\nARTICLE HIGHLIGHTS\nResearch background\nLocalized oeso-gastric cancer (GC) are treated by perioperative chemotherapy and surgery. The use of taxane seems to improve response rate and outcome.\n\nResearch motivation\nOnly the efficacy of the german regimen FLOT was previously reports.\n\nResearch objectives\nTo determine the efficacy of the Frence TeFOX regimen.\n\nResearch methods\nThis retrospective study aims to test efficacy and safety of the perioperative TeFOX regimen given alone in patients with localized GC.\n\nResearch results\nThirty-three consecutive patients were included. Median follow-up of surviving patients was 32 mo. R0 resection was obtained in 30 (91) patients. Twelve patients (36) have a pathological complete response and 8 (24) patients a nearly complete pathological response.\n\nResearch conclusions\nTeFOX regimen could be safely administrated in perioperative treatment of localized GC.\n\nResearch perspectives\nTeFOX and the FLOT regimen have comparable efficacy and safety profiles and could be considered as an alternative regimen.\n\nInformed consent statement: Written informed consent form was provided by family members of the patients.\n\nConflict-of-interest statement: All authors have no conflict of interests.\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: March 20, 2019\n\nFirst decision: June 4, 2019\n\nArticle in press: June 20, 2019\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry of origin: France\n\nPeer-review report classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Alkan A, Quero L S-Editor: Ma YJ L-Editor: Filipodia E-Editor: Qi LL\n==== Refs\n1 Ferlay J Colombet M Soerjomataram I Mathers C Parkin DM Piñeros M Znaor A Bray F Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods Int J Cancer 2019 144 1941 1953 30350310 \n2 Cunningham D Allum WH Stenning SP Thompson JN Van de Velde CJ Nicolson M Scarffe JH Lofts FJ Falk SJ Iveson TJ Smith DB Langley RE Verma M Weeden S Chua YJ MAGIC Trial Participants. Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer N Engl J Med 2006 355 11 20 16822992 \n3 Ychou M Boige V Pignon JP Conroy T Bouché O Lebreton G Ducourtieux M Bedenne L Fabre JM Saint-Aubert B Genève J Lasser P Rougier P Perioperative chemotherapy compared with surgery alone for resectable gastroesophageal adenocarcinoma: an FNCLCC and FFCD multicenter phase III trial J Clin Oncol 2011 29 1715 1721 21444866 \n4 Bang YJ Van Cutsem E Feyereislova A Chung HC Shen L Sawaki A Lordick F Ohtsu A Omuro Y Satoh T Aprile G Kulikov E Hill J Lehle M Rüschoff J Kang YK ToGA Trial Investigators Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial Lancet 2010 376 687 697 20728210 \n5 Plum PS Gebauer F Krämer M Alakus H Berlth F Chon SH Schiffmann L Zander T Büttner R Hölscher AH Bruns CJ Quaas A Loeser H HER2/neu (ERBB2) expression and gene amplification correlates with better survival in esophageal adenocarcinoma BMC Cancer 2019 19 38 30621632 \n6 Al-Batran SE Hofheinz RD Pauligk C Kopp HG Haag GM Luley KB Meiler J Homann N Lorenzen S Schmalenberg H Probst S Koenigsmann M Egger M Prasnikar N Caca K Trojan J Martens UM Block A Fischbach W Mahlberg R Clemens M Illerhaus G Zirlik K Behringer DM Schmiegel W Pohl M Heike M Ronellenfitsch U Schuler M Bechstein WO Königsrainer A Gaiser T Schirmacher P Hozaeel W Reichart A Goetze TO Sievert M Jäger E Mönig S Tannapfel A Histopathological regression after neoadjuvant docetaxel, oxaliplatin, fluorouracil, and leucovorin versus epirubicin, cisplatin, and fluorouracil or capecitabine in patients with resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4-AIO): results from the phase 2 part of a multicentre, open-label, randomised phase 2/3 trial Lancet Oncol 2016 17 1697 1708 27776843 \n7 Al-Batran SE Homann N Pauligk C Goetze TO Meiler J Kasper S Kopp HG Mayer F Haag GM Luley K Lindig U Schmiegel W Pohl M Stoehlmacher J Folprecht G Probst S Prasnikar N Fischbach W Mahlberg R Trojan J Koenigsmann M Martens UM Thuss-Patience P Egger M Block A Heinemann V Illerhaus G Moehler M Schenk M Kullmann F Behringer DM Heike M Pink D Teschendorf C Löhr C Bernhard H Schuch G Rethwisch V von Weikersthal LF Hartmann JT Kneba M Daum S Schulmann K Weniger J Belle S Gaiser T Oduncu FS Güntner M Hozaeel W Reichart A Jäger E Kraus T Mönig S Bechstein WO Schuler M Schmalenberg H Hofheinz RD FLOT4-AIO Investigators 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 1948 1957 30982686 \n8 Pernot S Dubreuil O Aparicio T Le Malicot K Tougeron D Lepère C Lecaille C Marthey L Palle J Bachet JB Zaanan A Taieb J Efficacy of a docetaxel-5FU-oxaliplatin regimen (TEFOX) in first-line treatment of advanced gastric signet ring cell carcinoma: an AGEO multicentre study Br J Cancer 2018 119 424 428 29872148 \n9 Becker K Mueller JD Schulmacher C Ott K Fink U Busch R Böttcher K Siewert JR Höfler H Histomorphology and grading of regression in gastric carcinoma treated with neoadjuvant chemotherapy Cancer 2003 98 1521 1530 14508841 \n10 Becker K Langer R Reim D Novotny A Meyer zum Buschenfelde C Engel J Friess H Hofler H Significance of histopathological tumor regression after neoadjuvant chemotherapy in gastric adenocarcinomas: a summary of 480 cases Ann Surg 2011 253 934 939 21490451 \n11 Alderson D Cunningham D Nankivell M Blazeby JM Griffin SM Crellin A Grabsch HI Langer R Pritchard S Okines A Krysztopik R Coxon F Thompson J Falk S Robb C Stenning S Langley RE 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 1249 1260 28784312 \n12 Cunningham D Stenning SP Smyth EC Okines AF Allum WH Rowley S Stevenson L Grabsch HI Alderson D Crosby T Griffin SM Mansoor W Coxon FY Falk SJ Darby S Sumpter KA Blazeby JM Langley RE Peri-operative chemotherapy with or without bevacizumab in operable oesophagogastric adenocarcinoma (UK Medical Research Council ST03): primary analysis results of a multicentre, open-label, randomised phase 2-3 trial Lancet Oncol 2017 18 357 370 28163000 \n13 Homann N Pauligk C Luley K Werner Kraus T Bruch HP Atmaca A Noack F Altmannsberger HM Jäger E Al-Batran SE Pathological complete remission in patients with oesophagogastric cancer receiving preoperative 5-fluorouracil, oxaliplatin and docetaxel Int J Cancer 2012 130 1706 1713 21618509 \n14 Schulz C Kullmann F Kunzmann V Fuchs M Geissler M Vehling-Kaiser U Stauder H Wein A Al-Batran SE Kubin T Schäfer C Stintzing S Giessen C Modest DP Ridwelski K Heinemann V NeoFLOT: Multicenter phase II study of perioperative chemotherapy in resectable adenocarcinoma of the gastroesophageal junction or gastric adenocarcinoma-Very good response predominantly in patients with intestinal type tumors Int J Cancer 2015 137 678 685 25530271\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": null,
"issue": "11(8)",
"journal": "World journal of gastrointestinal oncology",
"keywords": "Gastric cancer; Neoadjuvant chemotherapy; Retrospective study; TeFOX",
"medline_ta": "World J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101532470",
"other_id": null,
"pages": "634-641",
"pmc": null,
"pmid": "31435464",
"pubdate": "2019-08-15",
"publication_types": "D016428:Journal Article",
"references": "14508841;16822992;20728210;21444866;21490451;21618509;25530271;27776843;28163000;28784312;29872148;30350310;30621632;30982686",
"title": "Safety and efficacy of a docetaxel-5FU-oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer: A retrospective study.",
"title_normalized": "safety and efficacy of a docetaxel 5fu oxaliplatin regimen with or without trastuzumab in neoadjuvant treatment of localized gastric or gastroesophageal junction cancer a retrospective study"
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"companynumb": "FR-ACCORD-157853",
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"patient": {
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"activesubstancename": "DOCETAXEL"
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"abstract": "Although prednisolone, granulocyte/monocyte apheresis, calcineurin inhibitor and anti-tumour necrosis factor (TNF) therapy are generally used, no treatment strategy for inflammatory bowel disease complicated with pyoderma gangrenosum (PG) has been established yet. Herein, we present the case of a 29-year-old man with ulcerative colitis (UC) complicated with primary sclerosing cholangitis. When UC relapsed and PG developed, prednisolone and granulocyte/monocyte apheresis were used; however, their therapeutic effects were deemed insufficient. After 2 weeks, adalimumab (ADA) induced remission; however, his UC and PG relapsed 20 weeks later. As a result of switching to infliximab, since a loss of response to ADA was deemed to have occurred, remission was reintroduced and subsequently maintained for 40 weeks. We conclude that anti-TNF-α antibodies might be selected as the first choice when PG and UC are refractory to treatment, and a switch to anti-TNFs should be considered when the effect is still insufficient.",
"affiliations": "Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan nibornirococ1735@gmail.com.;Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan.;Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan.;Gastroenterology, Showa University Fujigaoka Hospital, Yokohama, Japan.",
"authors": "Iwahashi|Kenta|K|http://orcid.org/0000-0002-9111-8447;Kuroki|Yuichiro|Y|http://orcid.org/0000-0003-2087-8163;Takano|Yuichi|Y|;Nagahama|Masatsugu|M|http://orcid.org/0000-0002-7773-3072",
"chemical_list": "D001688:Biological Products; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068879:Adalimumab",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-241744",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(5)",
"journal": "BMJ case reports",
"keywords": "dermatology; ulcerative colitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D001688:Biological Products; D015209:Cholangitis, Sclerosing; D003093:Colitis, Ulcerative; D006801:Humans; D000069285:Infliximab; D008297:Male; D017511:Pyoderma Gangrenosum; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33958364",
"pubdate": "2021-05-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effective use of switching biologics for ulcerative colitis complicated with pyoderma gangrenosum and primary sclerosing cholangitis.",
"title_normalized": "effective use of switching biologics for ulcerative colitis complicated with pyoderma gangrenosum and primary sclerosing cholangitis"
} | [
{
"companynumb": "JP-MYLANLABS-2021M1040280",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nThe aim was to describe complicated tumor response (CTR) to tyrosine-kinase inhibitors (TKI) in gastrointestinal stromal tumors (GIST) patients.\n\n\nMETHODS\nFrom 2001 to 2017, data from patients with metastatic (group A) or locally advanced (group B) GIST who received TKI at our institution were collected. We defined CTR as bleeding, abscess, or perforation as surgical complications of TKI. Patients who had progressive disease were excluded. Clinical characteristics were assessed, and time of occurrence and mortality rate recorded.\n\n\nRESULTS\nAmong 470 patients, 30 developed CTR (6.4%), 26 in group A (6.8%) and four in group B (4.5%) (P = 0.43). Bleeding, abscess, and perforation, respectively, were observed in 17 (56.7%), 8 (26.7%), and 5 (16.7%) patients. A conservative approach was possible in 17 (56.7%) cases; four (13.3%) patients received percutaneous drainage, while nine (30%) underwent emergency surgery. The overall rate of mortality was 13.3%. CTR occurred after 1.6 months (median time) from the imatinib mesylate onset in group B and 14 months in group A.\n\n\nCONCLUSIONS\nWhile the risk of CTR in early metastatic patients is virtually nil, patients with locally advanced disease should be monitored carefully. CTR as a consequence of TKI therapy do not prevent patients receiving a potentially curative surgery.",
"affiliations": "Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.;Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.",
"authors": "Tirotta|Fabio|F|http://orcid.org/0000-0003-0631-9867;Fumagalli|Elena|E|;Colombo|Chiara|C|;Morosi|Carlo|C|;Barisella|Marta|M|;Radaelli|Stefano|S|;Frezza|Anna M|AM|;Casali|Paolo G|PG|;Gronchi|Alessandro|A|;Fiore|Marco|M|http://orcid.org/0000-0001-8220-424X",
"chemical_list": "D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.1002/jso.25491",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-4790",
"issue": "120(2)",
"journal": "Journal of surgical oncology",
"keywords": "emergency surgery; gastrointestinal stromal tumor; imatinib; sarcoma; tyrosine-kinase inhibitors",
"medline_ta": "J Surg Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D005260:Female; D005770:Gastrointestinal Neoplasms; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D015994:Incidence; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D000077210:Sunitinib",
"nlm_unique_id": "0222643",
"other_id": null,
"pages": "256-261",
"pmc": null,
"pmid": "31066052",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of complicated tumor response to tyrosine-kinase inhibitors in gastrointestinal stromal tumors.",
"title_normalized": "management of complicated tumor response to tyrosine kinase inhibitors in gastrointestinal stromal tumors"
} | [
{
"companynumb": "IT-MYLANLABS-2019M1091393",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nInterferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir.\n\n\nMETHODS\nWe enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790.\n\n\nRESULTS\n168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12.\n\n\nCONCLUSIONS\nCombined simeprevir and sofosbuvir was efficacious and well tolerated.\n\n\nBACKGROUND\nJanssen.",
"affiliations": "Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, USA. Electronic address: lawitz@txliver.com.;Johns Hopkins University School of Medicine, Baltimore, MD, USA.;Texas Clinical Research Institute, Arlington, TX, USA.;Fundación de Investigación, San Juan, PR, USA.;Department of Medicine, Inova Fairfax Hospital, Falls Church, VA, USA.;Borland-Groover Clinic, Jacksonville, FL, USA.;Orlando Immunology Center, Orlando, FL, USA.;Atlanta Medical Center, Atlanta, GA, USA.;University of Pittsburgh Medical Center, Pittsburgh, PA, USA.;Atlanta Gastroenterology Association, Atlanta, GA, USA.;Yale Liver Center and Yale University School of Medicine, New Haven, CT, USA.;Scripps Clinic, La Jolla, CA, USA.;Harborview Medical Center, Seattle, WA, USA.;Janssen Research & Development, Beerse, Belgium.;Novellas Healthcare, Zellik, Belgium.;Janssen Research & Development, Beerse, Belgium.;Janssen Research & Development, Beerse, Belgium.;Gilead Sciences Inc, Foster City, CA, USA.;Janssen Research & Development, Titusville, NJ, USA.;Janssen Research & Development, Titusville, NJ, USA.;Janssen Research & Development, Beerse, Belgium.;Weill Cornell Medical College, New York, NY, USA.",
"authors": "Lawitz|Eric|E|;Sulkowski|Mark S|MS|;Ghalib|Reem|R|;Rodriguez-Torres|Maribel|M|;Younossi|Zobair M|ZM|;Corregidor|Ana|A|;DeJesus|Edwin|E|;Pearlman|Brian|B|;Rabinovitz|Mordechai|M|;Gitlin|Norman|N|;Lim|Joseph K|JK|;Pockros|Paul J|PJ|;Scott|John D|JD|;Fevery|Bart|B|;Lambrecht|Tom|T|;Ouwerkerk-Mahadevan|Sivi|S|;Callewaert|Katleen|K|;Symonds|William T|WT|;Picchio|Gaston|G|;Lindsay|Karen L|KL|;Beumont|Maria|M|;Jacobson|Ira M|IM|",
"chemical_list": "D000998:Antiviral Agents; D006575:Heterocyclic Compounds, 3-Ring; D016898:Interferon-alpha; D011994:Recombinant Proteins; D013449:Sulfonamides; D011092:Polyethylene Glycols; D012254:Ribavirin; D000069616:Simeprevir; D014542:Uridine Monophosphate; C100416:peginterferon alfa-2a; D000069474:Sofosbuvir",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0140-6736",
"issue": "384(9956)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D016001:Confidence Intervals; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D016898:Interferon-alpha; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D011994:Recombinant Proteins; D012016:Reference Values; D012254:Ribavirin; D018570:Risk Assessment; D012720:Severity of Illness Index; D000069616:Simeprevir; D000069474:Sofosbuvir; D013449:Sulfonamides; D016896:Treatment Outcome; D014542:Uridine Monophosphate",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "1756-65",
"pmc": null,
"pmid": "25078309",
"pubdate": "2014-11-15",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study.",
"title_normalized": "simeprevir plus sofosbuvir with or without ribavirin to treat chronic infection with hepatitis c virus genotype 1 in non responders to pegylated interferon and ribavirin and treatment naive patients the cosmos randomised study"
} | [
{
"companynumb": "ES-CIPLA LTD.-2015ES09410",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DASABUVIR"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nVariant angina, or vasospastic angina, is a form of angina caused by vasospasm of the coronary arteries, probably caused by endothelial dysfunction. This form of angina is provoked by non-classical risk factors such as stress, alcohol use, use of sympathomimetics and low environmental temperatures, but also by smoking. Treatment is based on elimination of risk factors and vasodilator therapy with nitrates and long-acting calcium antagonists.\n\n\nMETHODS\nWe present a 68-year-old woman with recurring thoracalgia at rest and during exercise, suggestive of severe variant angina in more than one coronary artery. Despite elimination of risk factors and administration of vasodilatory therapy the treatment was initially insufficient. It eventually emerged that the probable cause was frequent use of a vasoconstrictive nasal spray, although this was not described in literature, and not originally mentioned by the patient.\n\n\nCONCLUSIONS\nA thorough case history is of vital importance in a patient presenting with a history suggestive of variant angina. Even undescribed and apparently less important risk factors can be responsible for persistence of symptoms, and can lead to an applied treatment not producing the desired result.",
"affiliations": "Universiteit Gent, Faculteit Geneeskunde en Gezondheidswetenschappen, Gent, België.",
"authors": "Van de Bruaene|Laurens|L|;Argacha|Jean-François|JF|;Kayaert|Peter|P|;Schoors|Danny|D|;Droogmans|Steven|S|",
"chemical_list": "D014663:Nasal Decongestants; D014665:Vasodilator Agents",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "159()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000788:Angina Pectoris, Variant; D003329:Coronary Vasospasm; D003331:Coronary Vessels; D005260:Female; D006801:Humans; D008875:Middle Aged; D014663:Nasal Decongestants; D014665:Vasodilator Agents",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A8971",
"pmc": null,
"pmid": "26374723",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Many possible causes of variant angina.",
"title_normalized": "many possible causes of variant angina"
} | [
{
"companynumb": "BE-MYLANLABS-2016M1000102",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
... |
{
"abstract": "Immunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a progressive nature and can eventually lead to end-stage kidney failure. It can occur as a potential side effect of treatment with tumor necrosis factor alpha antagonist that has been used for numerous chronic inflammatory conditions, such as Crohn's disease. In this study, the case of a 33-year-old man with renal dysfunction, nephrotic proteinuria, and erythrocyturia is described. He had had a history of Crohn's disease for 8 years and had been treated with adalimumab for the past 7 years. The diagnosis of IgAN was confirmed by kidney biopsy. After discontinuance of adalimumab and the induction of corticosteroid therapy, he made a remarkable recovery. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was normal with no proteinuria and only mild erythrocyturia.",
"affiliations": "Department of Internal Medicine, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.;Department of Gastroenterology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.;Institute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia.;Department of Nephrology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.;Department of Nephrology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia.",
"authors": "Mertelj|Tonja|T|;Smrekar|Nataša|N|;Kojc|Nika|N|;Lindič|Jelka|J|;Kovač|Damjan|D|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000515585",
"fulltext": "\n==== Front\nCase Rep Nephrol Dial\nCase Rep Nephrol Dial\nCND\nCase Reports in Nephrology and Dialysis\n2296-9705\nS. 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.com\n\n10.1159/000515585\ncnd-0011-0233\nSingle Case\nIgA Nephropathy in a Patient Treated with Adalimumab\nMertelj Tonja a\nSmrekar Nataša b\nKojc Nika c\nLindič Jelka d\nKovač Damjan d *\naDepartment of Internal Medicine, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia\nbDepartment of Gastroenterology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia\ncInstitute of Pathology, Medical Faculty, University of Ljubljana, Ljubljana, Slovenia\ndDepartment of Nephrology, University Medical Centre Ljubljana, University of Ljubljana, Ljubljana, Slovenia\n*Damjan Kovač, damjan.kovac@guest.arnes.si\nMay-Aug 2021\n28 7 2021\n28 7 2021\n11 2 233240\n22 11 2020\n2 3 2021\n2021\nCopyright © 2021 by S. Karger AG, Basel\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.\nImmunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by IgA deposits in the glomerular mesangium. It has a progressive nature and can eventually lead to end-stage kidney failure. It can occur as a potential side effect of treatment with tumor necrosis factor alpha antagonist that has been used for numerous chronic inflammatory conditions, such as Crohn's disease. In this study, the case of a 33-year-old man with renal dysfunction, nephrotic proteinuria, and erythrocyturia is described. He had had a history of Crohn's disease for 8 years and had been treated with adalimumab for the past 7 years. The diagnosis of IgAN was confirmed by kidney biopsy. After discontinuance of adalimumab and the induction of corticosteroid therapy, he made a remarkable recovery. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was normal with no proteinuria and only mild erythrocyturia.\n\nKeywords\n\nIgA nephropathy\nAdalimumab\nCrohn's disease\nGlucocorticoids\nVedolizumab\n==== Body\npmcBackground\n\nImmunoglobulin A (IgA) nephropathy (IgAN) is the most common glomerulonephritis (GN) worldwide [1]. It is characterized by IgA deposit in the glomerular mesangium. Patients with IgAN present with overproduction of an aberrantly glycosylated form of IgA1 that forms immune complexes with glycan-specific immunoglobulin G (IgG) and IgA antibodies. These antibodies often obtain reactivity against antigens from extrinsic microorganisms after repetitive mucosal infections. The overproduction of the aberrantly glycosylated IgA1 is purported to be a genetic trait [2]. The immune complexes that are formed contribute to glomerular inflammation and mesangial proliferation.\n\nFurther glomerulosclerosis and tubulointerstitial fibrosis lead to loss of renal function [1]. IgAN has a higher prevalence in younger Caucasian or East Asian male individuals and often presents with macroscopic hematuria during an upper respiratory or gastrointestinal illness [3]. However, the clinical manifestation can vary from asymptomatic microscopic hematuria to rapidly progressive GN or nephrotic syndrome. The definitive diagnosis of IgAN requires a biopsy, which confirms characteristic IgA dominant or codominant immune deposits on immunofluorescence microscopy [3, 4] that corresponds to electron-dense mesangial and paramesangial deposits on electron microscopy.\n\nIgAN is caused by diverse environmental and genetic factors. In most cases, the disease is idiopathic, but it can be associated with other conditions, such as Crohn's disease [5]. There are some reports that tumor necrosis factor alpha (TNFα) could be the inducer of IgAN [6, 7].\n\nAdalimumab (HumiraTM) is a monoclonal antibody that binds to TNFα and neutralizes its biological function [8]. In previous decades, TNFα antagonists improved the outcomes of various chronic inflammatory diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease [9]. Adalimumab is an effective therapeutic option, administered subcutaneously, for induction of response and maintenance of remission in patients with moderate to severe Crohn's disease [10, 11]. TNFα antagonists are generally well tolerated. The most common side effects of adalimumab are reactions at the sites of injection, headache, and diarrhea. However, the effects of TNFα antagonists are not clearly defined as they show both pro-inflammatory and immunosuppressive natures [12]. Treatment with TNFα antagonists has been linked to immunogenicity [8] and is associated with induction of flares of autoimmune diseases [13], such as lupus-like syndrome, and demyelinating diseases [14]. The occurrence of IgG- or IgE-neutralizing antibodies against infliximab and adalimumab decreases their therapeutic effect [15]. Few case reports have described the onset of IgAN after treatment with these agents. Clinical presentation can vary significantly, with possible end-stage renal disease [6, 7, 16].\n\nCase Presentation\n\nA 33-year-old man had Crohn's disease for 8 years, starting in 2008, with predominant involvement of the terminal ileum and rectum with occasional occurrence of an anal fissure. After the diagnosis, he was treated with mesalamine and methylprednisolone for 1 year followed by switching to adalimumab, after an exploratory surgery of the abdomen. He had been receiving adalimumab for 7 years up until the visit to the nephrology department.\n\nThree weeks prior to the presentation to the nephrology department, his attending gastroenterologist for the first time noticed an increase in serum creatinine of 145 μmol/L (reference range 44–97 μmol/L) and serum urea of 10.9 mmol/L (reference range 2.8–7.5 mmol/L). Additionally, proteinuria and hematuria were detected (hemoglobin 3 out of 4, [reference 0] and protein 3 out of 4 [reference 0] on dipstick, and numerous erythrocytes were seen in the urine sediment). His primary disease was in remission, aside from occasional discomfort in the lower right abdominal quadrant with episodes of feeling unwell. He denied changes in his urine, changes in appetite, loss of weight, or fever.\n\nHe had no prior personal or family history of kidney disease. However, analysis of laboratory urine data at the onset of Crohn's disease showed that he already had hemoglobinuria and mild proteinuria (hemoglobin 3 and protein 1 on the dipstick). Also in the year 2007 − 1 year before the onset of Crohn's disease, erythrocytes were present in the urine sediment but with no proteinuria on the dipstick. Older urine results were not available.\n\nAt the previous checkup, 3 months prior to the visit to the nephrology department, he had normal renal function with a serum creatinine of 91 μmol/L. He was treated with the biological drug adalimumab (Humira) 40 mg subcutaneously regularly every 14 days. Due to his anxiety, he had occasionally taken alprazolam and paracetamol for the management of pain. He had not been receiving any other immunosuppressive drugs or nonsteroidal anti-inflammatory drugs. He had allergies to mites and animal fur, which presented as allergic rhinitis. He was not a smoker and did not consume alcohol or drugs regularly.\n\nClinical examinations revealed a blood pressure of 140/70 mm Hg, heart rate 89 beats per minute, body weight of 74 kg, and height of 178 cm. He was cardiorespiratory compensated, eupneic, and afebrile. There were no abnormalities in his physical examination. Edema or vasculitic rash was not present. His serum creatinine was 159 μmol/L, and his estimated glomerular filtration rate (eGFR CKD-EPI) was 44 mL/min/1.73 m2. Urine analysis showed erythrocytes of 895 × 106/L (reference range up to 10 × 106/L), and his urinary protein/creatinine ratio was 302 (reference range <20) g/mol.\n\nThe patient was admitted for further diagnostics. During hospital stay, his urinary protein/creatinine ratio was 402.0 (reference range <20) g/mol, and 24 h urine protein excretion was 4.34 (reference range <0.15) g. The IgG/creatinine ratio was 14.44 (reference range <1.13) g/mol, albumin/creatinine ratio 340.63 (reference range <2.26) g/mol, and alpha-1 microglobulin/creatinine ratio 2.58 (reference range <1.58) g/mol, indicating selective glomerular with mild tubular proteinuria. Urine analysis showed erythrocytes of 980 × 106/L and leucocytes of 18 × 106/L. Dysmorphic erythrocytes were present in the urine. Full blood count, hemostasis, hepatitis B and C, human immunodeficiency virus, cytomegalovirus serology, and interferon-gamma release assay were all in normal ranges. He had mild normocytic anemia (hemoglobin concentration 123 g/L) and increased sedimentation rate (44 mm/h). His serum cholesterol levels (6.0 mmol/L) and IgA antibodies (1.9 g/L) were elevated. Ultrasound revealed kidneys of normal size and echogenicity. An ultrasound of the abdomen and a chest X-ray did not show any remarkable abnormalities. Kidney biopsy was performed, showing diffuse mesangioproliferative, endoproliferative, exudative, necrotizing, and extracapillary GN, evaluated as M1, E1, S1, T1, and C1 (fibrocellular crescents) according to the Oxford classification. In addition, 40% chronic tubulo-interstitial nephritis of moderate intensity was observed, accompanied by erythrocyte and hemoglobin tubular casts (Fig. 1). The immunofluorescence staining of the biopsy specimen was typical for IgAN, with strongly positive IgA and C3 deposits (Fig. 2).\n\nUpon the diagnosis, according to the kidney biopsy, adalimumab, as a potential inducer of IgAN, was discontinued. The patient received 3 consecutive daily pulses of methylprednisolone in a daily dose of 500 mg intravenously. Serum creatinine and proteinuria decreased after discontinuing treatment with adalimumab and the introduction of corticosteroids (Fig. 3). He was discharged and prescribed oral methylprednisolone 32 mg/day, supportive therapy, perindopril 4 mg/day, and fluvastatin 80 mg/day. Methylprednisolone was gradually decreased and subsequently stopped 8 months after the induction. At that time, serum creatinine was 109 µmol/L, proteinuria 0.12 g per day, and erythrocyturia 216 × 106/L. For the control of his Crohn's disease, vedolizumab was prescribed 1 month before the cessation of corticosteroids. In the next 4 months, after the induction of the new biological drug, his renal function transiently deteriorated, with no deterioration of proteinuria, but recovered thereafter. Four years after the first presentation of IgAN and discontinuation of adalimumab, his renal function was excellent with a serum creatinine concentration of 95 μmol/L, estimated daily proteinuria <0.03 g (Fig. 3), and erythrocyturia 15 × 106/L.\n\nDiscussion\n\nCrohn's disease is an inflammatory disease that has numerous extraintestinal complications [17]. An active form of Crohn's disease is strongly associated with IgAN [18]. Altered intestinal permeability and increased production of IgA in the gastrointestinal mucosa potentially drive this complication [19]. In the present case, the patient has been in remission for years; therefore, Crohn's disease alone was presumably not the cause of IgAN.\n\nAnalysis of laboratory urine data from the past showed that he already had hemoglobinuria and mild proteinuria at the onset of Crohn's disease on the dipstick, and 1 year before the onset of Crohn's disease, erythrocytes were found in the urine sediment. Theoretically, there is a possibility that the patient may have a mild form of IgA GN present at the onset of Crohn's disease or even before, but it has significantly worsened and clinically manifested with TNFα antagonist treatment.\n\nWe observed a prompt response to the cessation of the adalimumab and steroid therapy, which implies its role in the pathogenesis of the GN. Corticosteroids facilitated the recovery of renal function. Stable renal function with the absence of proteinuria after discontinuation of methylprednisolone, even 4 years after the first visit to the nephrology department, with no additional immunosuppression for IgAN, suggests that adalimumab could be the main factor in the occurrence or deterioration of IgAN in this patient.\n\nPatients with adalimumab-induced IgAN present with the occurrence of aberrant IgA1 as observed in the primary IgAN [20]. As the sole presence of these antibodies is not nephritogenic, the involvement of antibodies against TNFα antagonist is suspected of driving the TNFα antagonist-induced IgAN as the biological drugs react as antigens for antibody formation. Additionally, the antibodies against glycans of the heavy chain of TNFα antagonists may cross-react with glycans on IgA1 molecules [20]. The other possible underlying etiopathogenic process is that aberrantly glycosylated IgA1 binds to antigenic epitopes of TNFα antagonists [20]. Both mechanisms lead to the formation of large immune complexes that can cross glomerular endothelial fenestrae and be deposited in the mesangium of the kidneys, thus causing renal damage. Therefore, TNFα antagonists may act as triggers of the disease in genetically prone individuals. The third possible mechanism may be independent of the structure of the TNFα antagonist molecule and may be due to the immunomodulatory effect of TNFα antagonists that involve cytokine imbalance. T-helper (Th) cells mainly differentiate into either Th1 or Th2 cells. Th1 cells (secreting interferon-γ, interleukin [IL]-2L, IL-3, and TNFα) support cell-mediated immunity, whereas Th2 cells (secreting IL-4, IL-10, IL-5, IL-9, and IL-13) enhance humoral immune responses [21]. TNFα antagonists induce a shift from the Th1 pattern to Th2 pattern [22], promoting the development of antibody-mediated immunity. It was recently found that IgAN is characterized by a higher proportion of circulatory Th2, T follicular helper cells, Th17, Th22, and γδ T cells but lower Th1 and regulatory T cells. It was found that Th2, Th17, and T follicular helper cell-type ILs contribute to the elevated synthesis of galactose-deficient IgA1 [23], leading to IgAN.\n\nRegarding the structure, several types of TNFα antagonists are known. Infliximab is a chimeric mouse/human anti-TNFα antibody composed of a murine variable region and a human IgG1 constant region. Adalimumab is a fully humanized anti-TNFα monoclonal antibody. Etanercept is a fusion protein composed of 2 extracellular portions of human TNF receptor 2 and the FC portion of human IgG1 [24]. Due to their differences in structure, they are not equally effective in different clinical settings [25, 26] and have different side effects, for example, induction of granulomatous infections [27]. Descriptions of IgAN induced by adalimumab [28], golimumab [29], or infliximab [28, 30] can be found in the literature. Etanercept has been described as a causative agent of vasculitis with renal impairment [16], crescentic necrotizing GN [31], lupus nephritis [32], and membranous GN [32, 33]. In a study by Saint-Marcoux and De Bandt [16] in which etanercept, infliximab, and adalimumab were used, in 2 of 39 patients, IgA deposition was found in the glomeruli on renal biopsy, but the description of whether these 2 patients received etanercept or another TNFα antagonist is lacking. There are no reports in the literature that etanercept could induce IgAN.\n\nIt was suggested that induction of IgAN is not a class effect of TNFα antagonists as infliximab may even reduce proteinuria and induce remission of IgAN [34] and has been used successfully as a replacement drug in a patient with CD in whom adalimumab has caused IgAN [7]. Recently published case reports reported patients in whom infliximab triggered IgAN [28, 30]. According to these recent results, it seems that there is a class effect of TNFα antagonists inducing IgAN, perhaps with the exception of etanercept, and it is becoming discouraging to use another TNFα antagonist in the case that IgAN is produced during TNFα antagonist treatment.\n\nFrom the case reports described in the literature and from our case, we attempted to determine whether the treatment duration with TNFα antagonists has any effects on the histological characteristics of IgAN. According to the described cases, kidney biopsies of patients on TNFα antagonists uniformly displayed deposits of IgA and C3, but glomerular histopathologic changes are diverse, including segmental mesangial proliferation followed by segmental and global glomerulosclerosis and crescents, without a clear relationship to treatment duration. Chronic tubulointerstitial changes also varied from focal (<25% according to Oxford classification) to extensive, accompanying >50% of biopsy (according to Oxford classification), found mostly in patients with a long-lasting treatment period. According to the recognized (known) TNFα antagonist immunomodulatory effects, it may be speculated that interstitial infiltrates could be more prominent than primary IgAN, but moderate mononuclear infiltrates in the interstitium were described only in 2 of 8 cases, including our case (and a case described by Bhagat Singh et al. [7]).\n\nThe lack of correlation between the duration of TNFα antagonist treatment and severity of glomerular lesions might be explained by an idiosyncratic drug reaction, which may occur any time after the commencement of therapy [35]. The presence of active versus chronic lesions on kidney biopsy may depend on the time between the onset of adalimumab-related IgAN and clinical recognition of kidney disease, including kidney biopsy.\n\nIn conclusion, it is of paramount importance to assess renal function and examine urine at the start of treatment with TNFα antagonists to rule out possible pre-existing kidney disease and then regularly monitor renal function and urinalysis with regular determination of proteinuria in patients treated with adalimumab and other TNFα antagonists. The possibility of predicting an IgAN complication by measuring the serum concentration of aberrant IgA1 after the induction of adalimumab treatment should be further addressed.\n\nStatement of Ethics\n\nThe patient in this study provided written informed consent for use of his clinical information for inclusion in a medical publication.\n\nConflict of Interest Statement\n\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\n\nNo funding was used to support this report.\n\nAuthor Contributions\n\nAll authors contributed to the paper. T.M. collected the data and wrote the paper, N.S. participated in the treatment of Crohn's disease and critically reviewed the paper, NK performed histopathologic analysis of renal biopsy and critically reviewed the paper, J.L. participated in the diagnosis and critically reviewed the paper, and D.K. participated in the treatment of the patient, gave the idea for the paper, and critically reviewed the paper.\n\nFig. 1 Mesangioproliferative GN with RBC casts (arrows), tubular injury, and interstitial infiltrate (hematoxylin-eosin, ×100). GN, glomerulonephritis.\n\nFig. 2 IF showing the immune deposits of IgA in the glomeruli. IgA, immunoglobulin A; IF, immunofluorescence.\n\nFig. 3 eGFR, serum creatinine concentration, and proteinuria at different time points. eGFR, estimated glomerular filtration rate.\n==== Refs\nReferences\n\n1 Rodrigues JC Haas M Reich HN IgA nephropathy Clin J Am Soc Nephrol 2017 Apr 3 12 (4) 677 86 28159829\n2 Lai KN Pathogenesis of IgA nephropathy Nat Rev Nephrol 2012 Mar 20 8 (5) 275 83 22430056\n3 Wyatt RJ Julian BA IgA nephropathy N Engl J Med 2013 Jun 20 368 (25) 2402 14 23782179\n4 Roberts IS Pathology of IgA nephropathy Nat Rev Nephrol 2014 8 10 (8) 445 54 24861083\n5 Donadio JV Grande JP IgA nephropathy N Engl J Med 2002 Sep 5 347 (10) 738 48 12213946\n6 Bruzzese V Lorenzetti R Rosa M Di Giulio S Hassan C Costas G IgA nephropathy onset in a Crohn's disease patient treated with adalimumab Minerva Gastroenterol Dietol 2016 6 62 (2) 223 4\n7 Bhagat Singh AK Jeyaruban AS Wilson GJ Ranganathan D Adalimumab-induced IgA nephropathy BMJ Case Rep 2019 Mar 31 12 (3) e226442\n8 Lichtenstein GR Panaccione R Mallarkey G Efficacy and safety of adalimumab in Crohn's disease Therap Adv Gastroenterol 2008 7 1 (1) 43 50\n9 Valesini G Iannuccelli C Marocchi E Pascoli L Scalzi V Di Franco M Biological and clinical effects of anti-TNFalpha treatment Autoimmun Rev 2007 11 7 (1) 35 41 17967723\n10 Clark M Colombel JF Feagan BC Fedorak RN Hanauer SB Kamm MA American gastroenterological association consensus development conference on the use of biologics in the treatment of inflammatory bowel disease, June 21–23, 2006 Gastroenterology 2007 7 133 (1) 312 39 17631151\n11 Colombel JF Sandborn WJ Rutgeerts P Enns R Hanauer SB Panaccione R Adalimumab for maintenance of clinical response and remission in patients with Crohn's disease: the CHARM trial Gastroenterology 2007 1 132 (1) 52 65 17241859\n12 Ernandez T Mayadas TN Immunoregulatory role of TNFalpha in inflammatory kidney diseases Kidney Int 2009 8 76 (3) 262 76 19436333\n13 Louis M Rauch J Armstrong M Fitzcharles MA Induction of autoantibodies during prolonged treatment with infliximab J Rheumatol 2003 12 30 (12) 2557 62 14719194\n14 Khanna D McMahon M Furst DE Safety of tumour necrosis factor-alpha antagonists Drug Saf 2004 27 (5) 307 24 15061685\n15 Murdaca G Spanò F Contatore M Guastalla A Penza E Magnani O Immunogenicity of infliximab and adalimumab: what is its role in hypersensitivity and modulation of therapeutic efficacy and safety? Expert Opin Drug Saf 2016 1 15 (1) 43 52 26559805\n16 Saint Marcoux B De Bandt M Vasculitides induced by TNFalpha antagonists: a study in 39 patients in France Joint Bone Spine Rev Rhum 2006 12 73 (6) 710 3\n17 Torres J Mehandru S Colombel JF Peyrin-Biroulet L Crohn's disease Lancet 2017 Apr 29 389 (10080) 1741 55 27914655\n18 Youm JY Lee OY Park MH Yang SY Han SH Baek YH [Crohn's disease associated with IgA nephropathy] Korean J Gastroenterol 2006 4 47 (4) 324 8 16632987\n19 Terasaka T Uchida HA Umebayashi R Tsukamoto K Tanaka K Kitagawa M The possible involvement of intestine-derived IgA1: a case of IgA nephropathy associated with Crohn's disease BMC Nephrol 2016 Sep 5 17 (1) 122 27596164\n20 Di Lernia V IgA nephropathy during treatment with TNF-alpha blockers: could it be predicted? Med Hypotheses 2017 9 107 12 3 28915952\n21 Zhu J T helper cell differentiation, heterogeneity, and plasticity Cold Spring Harb Perspect Biol 2018 Oct 1 10 (10) a030338 28847903\n22 Campanati A Orciani M Lazzarini R Ganzetti G Consales V Sorgentoni G TNF-α inhibitors reduce the pathological Th1-Th17/Th2 imbalance in cutaneous mesenchymal stem cells of psoriasis patients Exp Dermatol 2017 4 26 (4) 319 24 27376466\n23 Ruszkowski J Lisowska KA Pindel M Heleniak Z Dębska-Ślizień A Witkowski JM T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target Clin Exp Nephrol 2019 3 23 (3) 291 303 30406499\n24 Mitoma H Horiuchi T Tsukamoto H Ueda N Molecular mechanisms of action of anti-TNF-α agents: comparison among therapeutic TNF-α antagonists Cytokine 2018 1 101 56 63 27567553\n25 Da W Zhu J Wang L Lu Y Efficacy and safety of certolizumab pegol for Crohn's disease: a systematic review and meta-analysis Adv Ther 2013 5 30 (5) 541 53 23681504\n26 Levin AD Wildenberg ME van den Brink GR Mechanism of action of anti-TNF therapy in inflammatory bowel disease J Crohns Colitis 2016 8 10 (8) 989 97 26896086\n27 Wallis RS Tumour necrosis factor antagonists: structure, function, and tuberculosis risks Lancet Infect Dis 2008 10 8 (10) 601 11 18922482\n28 Strobel T Ahmed W De la Sancha C Bohm M Fischer M IgA nephropathy in the setting of anti-TNF-α therapy for inflammatory bowel disease ACG Case Rep J 2020 9 7 (9) e00462 33062795\n29 Premuzic V Padjen I Cerovec M Coric M Jelakovic B Anic B The association of TNF-alpha inhibitors and development of IgA nephropathy in patients with rheumatoid arthritis and diabetes Case Rep Nephrol 2020 2020 9480860 32373375\n30 Segawa Y Ishida R Kanehisa F Nakai K Morimoto M Seno M IgA nephropathy in a patient receiving infliximab for generalized pustular psoriasis BMC Nephrol 2020 Aug 26 21 (1) 366 32842976\n31 Ammar A Mahmood HZA Shahid Z Jain R Chen G Etanercept-associated nephropathy Cureus 2019 Aug 18 11 (8) e5419 31632872\n32 Stokes MB Foster K Markowitz GS Ebrahimi F Hines W Kaufman D Development of glomerulonephritis during anti-TNF-alpha therapy for rheumatoid arthritis Nephrol Dial Transplant 2005 7 20 (7) 1400 6 15840673\n33 Kaushik P Rahmani M Ellison W Membranous glomerulonephritis with the use of etanercept in ankylosing spondylitis Ann Pharmacother 2011 12 45 (12) e62 22116994\n34 Ueno Y Tanaka S Onitake T Hanaoka R Yoshioka K Ito M Infliximab treatment for Crohn's disease in a patient with IgA nephropathy Clin J Gastroenterol 2009 12 2 (6) 380 3 26192790\n35 Wei SS Sinniah R Adalimumab (TNF alpha inhibitor) therapy exacerbates IgA glomerulonephritis acute renal injury and induces lupus autoantibodies in a psoriasis patient Case Rep Nephrol 2013 2013 812781 24558628\n\n",
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"issue": "11(2)",
"journal": "Case reports in nephrology and dialysis",
"keywords": "Adalimumab; Crohn's disease; Glucocorticoids; IgA nephropathy; Vedolizumab",
"medline_ta": "Case Rep Nephrol Dial",
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"pages": "233-240",
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"references": "27376466;32842976;26192790;16632987;27091038;30936328;18922482;32373375;30406499;27914655;21180513;17631151;31632872;17967723;26559805;24861083;26896086;17241859;23681504;28159829;22430056;19436333;15061685;33062795;28847903;14719194;28915952;27567553;22116994;12213946;23782179;15840673;24558628;27596164;17127088",
"title": "IgA Nephropathy in a Patient Treated with Adalimumab.",
"title_normalized": "iga nephropathy in a patient treated with adalimumab"
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"abstract": "BACKGROUND\nUrachal carcinoma is a rare malignancy with poor prognosis due to late presentation of the disease and its aggressiveness. Surgery remains the mainstay of therapy even in cases of disease recurrence. To the best of our knowledge, this is the first report of salvage surgery in the case of urachal carcinoma with liver metastasis.\n\n\nMETHODS\nThe patient was a young woman who suffered from locally advanced urachal carcinoma treated with en-bloc cystectomy, hysterectomy with bilateral adnexectomy, partial resection of the sigmoid colon, and partial resection of the rectus abdominis muscle with the fascia, skin, and umbilicus. Adjuvant chemotherapy with paclitaxel and carboplatin was applied. Two years after the treatment, she was diagnosed with a single liver metastasis and a local pelvic recurrence. In a two-step operation, the patient underwent right hemihepatectomy as well as resection of pelvic recurrence site and adjuvant chemotherapy with gemcitabine. Due to the disease progression, a complete resection of the lesions was not achieved and the response to chemotherapy was poor. The patient died of the disease after a year.\n\n\nCONCLUSIONS\nSurgery is the first line of treatment for urachal carcinoma and should be always considered as an option in cases of disease recurrence. Radical initial surgical management, close patient surveillance, and prompt treatment of disease relapse may all contribute to prolonging patient's survival.",
"affiliations": "Department of Liver and General Surgery, Nicolaus Copernicus University, Curie-Sklodowskiej 9, Bydgoszcz, 85-094, Poland. paschkelukasz@gmail.com.;Department of Liver and General Surgery, Nicolaus Copernicus University, Curie-Sklodowskiej 9, Bydgoszcz, 85-094, Poland.;Department of Liver and General Surgery, Nicolaus Copernicus University, Curie-Sklodowskiej 9, Bydgoszcz, 85-094, Poland.",
"authors": "Paschke|Lukasz|L|http://orcid.org/0000-0002-9481-7876;Juszczak|Miroslaw|M|;Slupski|Maciej|M|",
"chemical_list": "D000970:Antineoplastic Agents; D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin; D017239:Paclitaxel",
"country": "England",
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"doi": "10.1186/s12957-016-1057-4",
"fulltext": "\n==== Front\nWorld J Surg OncolWorld J Surg OncolWorld Journal of Surgical Oncology1477-7819BioMed Central London 105710.1186/s12957-016-1057-4Case ReportSurgical treatment of recurrent urachal carcinoma with liver metastasis: a case report and literature review http://orcid.org/0000-0002-9481-7876Paschke Lukasz paschkelukasz@gmail.com 12Juszczak Miroslaw 1Slupski Maciej 11 Department of Liver and General Surgery, Nicolaus Copernicus University, Curie-Sklodowskiej 9, Bydgoszcz, 85-094 Poland 2 Department of Urology, Nicolaus Copernicus University, Bydgoszcz, Poland 28 11 2016 28 11 2016 2016 14 2962 8 2016 22 11 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nUrachal carcinoma is a rare malignancy with poor prognosis due to late presentation of the disease and its aggressiveness. Surgery remains the mainstay of therapy even in cases of disease recurrence. To the best of our knowledge, this is the first report of salvage surgery in the case of urachal carcinoma with liver metastasis.\n\nCase presentation\nThe patient was a young woman who suffered from locally advanced urachal carcinoma treated with en-bloc cystectomy, hysterectomy with bilateral adnexectomy, partial resection of the sigmoid colon, and partial resection of the rectus abdominis muscle with the fascia, skin, and umbilicus. Adjuvant chemotherapy with paclitaxel and carboplatin was applied. Two years after the treatment, she was diagnosed with a single liver metastasis and a local pelvic recurrence. In a two-step operation, the patient underwent right hemihepatectomy as well as resection of pelvic recurrence site and adjuvant chemotherapy with gemcitabine. Due to the disease progression, a complete resection of the lesions was not achieved and the response to chemotherapy was poor. The patient died of the disease after a year.\n\nConclusions\nSurgery is the first line of treatment for urachal carcinoma and should be always considered as an option in cases of disease recurrence. Radical initial surgical management, close patient surveillance, and prompt treatment of disease relapse may all contribute to prolonging patient’s survival.\n\nKeywords\nUrachal carcinomaSalvage surgeryAdjuvant chemotherapyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nThe urachus is a structure connecting the allantois with a precursor of the urinary bladder during early embryonic development. It involutes before birth into a fibrous cord extending upward from the anterior dome of the bladder toward the umbilicus and forming a median umbilical ligament. It is a three-layered tubular structure lying in the Retzius’ space and varying in size from 3 to 10 cm in length and from 8 to 10 mm in diameter [1, 2]. The remnants of urachal tissue in the ligament may be a source of tumor growth. It is a rare type of malignancy with incidence below 0.5% of all bladder cancers and the annual incidence estimated to be 1 in 5 million people in general population [3, 4]. To date, no specific risk factors for the development of urachal carcinoma have been established. In the case of urachal mass of unknown character, the risk factors of its malignant character are age older than 55 years and the presence of hematuria [5].\n\nThe most commonly employed diagnostic criteria for urachal carcinoma are those proposed by Sheldon et al. These include (1) tumor in the dome of the bladder, (2) absence of cystitis cystica and cystitis glandularis, (3) predominant invasion of the muscularis or deeper tissues with a sharp demarcation between the tumor and surface bladder urothelium which is free of glandular or polypoid proliferation, (4) presence of urachal remnants within the tumor, (5) extension of tumor into the bladder wall involving the space of Retzius, anterior abdominal wall, or umbilicus, and (6) no evidence of a primary neoplasm elsewhere [4]. Simplified MD Anderson Cancer Center criteria published by Siefker-Radtke et al. include (1) location in the bladder dome or elsewhere in the midline of the bladder and (2) sharp demarcation between tumor and normal surface epithelium. Supportive criteria include enteric-type histology, absence of urothelial dysplasia, cystitis cystica or cystitis glandularis transitioning to the tumor, and absence of primary adenocarcinoma of another organ [6].\n\nThe majority of authors follow a staging system for urachal carcinoma proposed by Sheldon. Recently, a simplified system developed in Mayo Clinic has been proven to be of equal value. Table 1 compares both systems [4, 5].Table 1 Comparison of urachal carcinoma staging systems\n\nStage\tSheldon\tMayo clinic\t\nI\tConfined to the urachal mucosa\tConfined to the urachus and/or the bladder\t\nII\tInvasion confined to the urachus itself\tExtension beyond the muscular layer of the urachus and/or the bladder\t\nIII\t\tMetastases to the regional lymph nodes\t\nIIIA\tExtension to the bladder\t\t\nIIIB\tExtension to the abdominal wall\t\nIIIC\tExtension to the peritoneum\t\nIIID\tExtension to the viscera other than the bladder\t\nIV\t\tMetastases to non-regional lymph nodes or other distant sites\t\nIVA\tMetastases to the lymph nodes\t\t\nIVB\tMetastases to distant sites\t\n\n\n\nFollowing the diagnosis of urachal carcinoma, the first line treatment consists of partial or radical cystectomy together with wide surgical excision of remaining urachal ligament, surrounding soft tissue, and umbilicus. Bilateral pelvic lymphadenectomy is optional [5–8]. As the cancer is usually diagnosed at an advanced stage, the incidence of local recurrences or distant metastases following the treatment is high. Due to the rarity of the disease, no clinical trials are available to assist in the choice of further treatment. Several chemotherapy regimens have been tested so far with limited success. Salvage surgical treatment with adjuvant chemotherapy in cases of disease relapse has been described in some studies as potentially prolonging patients’ survival [5, 9, 10].\n\nCase presentation\nA 34-year-old woman with a history of urachal carcinoma was referred to our department (Department of Liver and General Surgery) in January 2015 in order to surgically treat a disease relapse presenting with a liver metastasis. The patient was an otherwise healthy woman. The first symptoms of the disease occurred in December 2011 and included urinary frequency, dysuria, and episodic gross hematuria. In January 2012, the patient sought medical attention. The primary care physician diagnosed urinary tract infection and ordered antibiotics. After two months, an abdominal ultrasound was performed, however with an empty bladder, and the disease focus was not recognized. It was not until April 2012 that the patient came directly to the emergency department and was for the first time consulted by a urologist. At that point, the diagnosis of urinary bladder tumor was made. A CT scan showed a pathologic mass in the region of the bladder dome extending toward the umbilicus (Fig. 1) which is a typical appearance of urachal carcinoma [11]. It was adherent to the sigmoid colon, and there were signs of the surrounding adipose tissue and peritoneum involvement. No sites of distant metastases on abdominal CT scan and chest X-ray were noted.Fig. 1 Pelvic CT scan at the time of diagnosis. Tumor mass is demarcated from the contrast-filled bladder (white arrow). a Coronal plane. b Transverse plane\n\n\n\n\nIn June 2012, the patient underwent radical cystectomy including hysterectomy, bilateral adnexectomy, partial resection of the sigmoid colon, and partial resection of the rectus abdominis muscle with the fascia, skin, and umbilicus. A urinary diversion with a Studer-type orthotopic ileal neobladder was constructed. Intraoperative histologic examination of two ileal lymph nodes was negative. However, a post-operative examination of these lymph nodes revealed one metastatic focus. The full specimen was described in pathology report as a 22 × 19 × 17 cm in size, with tumor extending between the uterus and umbilicus involving the urinary bladder and extending beyond its wall. On microscopic examination, a mucous-producing adenocarcinoma consistent with urachal carcinoma was diagnosed. The involvement of the sigmoid colon was caused by an inflammatory response. Other resected organs as well as surgical margins were free of neoplastic infiltration. The patient received four cycles of adjuvant chemotherapy with paclitaxel and carboplatin.\n\nA follow-up CT scan performed a year after surgery (July 2013) showed no signs of disease recurrence. In November 2014, another CT scan revealed a hypodense mass in the right liver lobe of max 40 mm in diameter. A collection of fluid in the region of the right iliac vessels with calcifications was also noted (in a region where in previous imaging studies a simple lymphocele was described). A subsequent PET-CT scan of entire body proved a high probability of disease recurrence in the liver and in the region of the right iliac vessels (Fig. 2). A biopsy of the liver mass confirmed a focus of metastatic disease. After presentation of possible therapeutic options to the patient, she chose a surgical treatment. The surgery took place in January 2015. Intraoperative findings with the use of ultrasonography included a tumor of max 80 mm in diameter in the right liver lobe with a small satellite focus on the liver phrenic surface. Despite the probability of local recurrence in the pelvis, a right hemihepatectomy was performed. This decision was based on a large tumor size and a possible expansion into the vena cava inferior and liver hilum (Fig. 3). The pathology report revealed a metastatic urachal carcinoma and a positive surgical margin. Magnetic resonance imaging performed a month after the surgery confirmed enlargement of the pathologic mass in the pelvis. No other sites of the disease were noted. Patient was qualified to a second-stage surgical treatment and underwent an excision of the tumor mass in the region of the right iliac vessels in April 2015; however, complete resection has not been achieved.Fig. 2 Abdominal and pelvic CT scan at the time of disease recurrence. a Liver metastatic focus (white arrow). b Local recurrence in the region of the right iliac vessels (white arrow)\n\n\nFig. 3 The right liver lobe with a metastatic tumor and a satellite focus\n\n\n\n\nFollowing the surgery, the patient received three cycles of adjuvant gemcitabine-based chemotherapy. Subsequent imaging studies showed gradual disease progression. The patient died of the disease in March 2016.\n\nDiscussion\nThe presented case illustrates difficulties associated with the diagnosis and treatment of the urachal carcinoma. It took over 6 months since the patient started experiencing symptoms and sought medical attention until the treatment was instituted. This significant delay may have contributed to the advanced stage of the disease found at the time of the cystectomy. Literature review shows that the first urachal carcinoma symptoms include most commonly hematuria, followed by palpable mass in the lower abdomen, abnormalities in urine sample examination, and pain [12, 13]. Unfortunately, these occur mostly late in the course of the disease which leads to local cancer invasion or metastatic foci often being present at diagnosis [4]. In the study by Gopalan et al. among all 24 patients examined, there were no cases of Sheldon stage I or II tumors [14]. In another population-based study among 40 patients diagnosed with urachal tumor, only in one case cancer was confined to the urachus [15].\n\nThe pathologic study of urachal carcinoma in the majority of cases reveals an intestinal type adenocarcinoma with morphological variants including mucinous, enteric, signet ring cell type, and not otherwise specified (NOS) [16]. In the case of our patient, a mucinous type adenocarcinoma was found. This type, together with NOS adenocarcinoma, is the most frequent variant encountered [3, 4, 16, 17]. None of these variants, however, was found to have prognostic value, possibly due to paucity of patients [3, 14, 16]. In a recent study by Bisosonnette et al., the authors used a micro-RNA expression profiling in order to genetically differentiate between morphologic types of urachal carcinoma. No significant differences were found suggesting that urachal adenocarcinoma can be viewed as a single biological entity [18].\n\nDue to the rarity of urachal carcinoma, no evidence-based standards of treatment have been developed. Wide surgical excision is widely regarded as the treatment of choice. A study by Henly et al. found no significant differences in the survival rate after radical cystectomy vs. partial cystectomy [19]. To date, published reports have not confirmed clear advantages of radical cystectomy (when partial cystectomy with safe surgical margins is technically feasible). However, the study by Gopalan et al. indicates a lower local recurrence rate in cases without bladder-sparing surgery [14]. In the last decade, an increasing amount of urachal carcinoma surgical treatment is performed using minimally invasive laparoscopic or robot-assisted technique. Although no studies have directly compared open surgery with minimally invasive techniques, the available case reports show that laparoscopic approach allows for radical surgical excision with the added benefit of reduced blood loss, decreased postoperative patient discomfort, and shorter hospital stay [20–22].\n\nAnother issue not standardized due to a low number of urachal carcinoma cases is the need to perform pelvic lymph node dissection (PLND). In the case of our patient, PLND was not performed. Intraoperative assessment of two lymph nodes brought a false negative result. To date, evidence is lacking to support performing PLND in all cases of urachal carcinoma. On the other hand, available data indicate that local recurrence of urachal carcinoma (including pelvic lymph nodes involvement) is the most frequent presentation of disease relapse [5, 14]. Moreover, the pelvic lymph nodes, together with the lungs, are the most frequent site of urachal carcinoma metastases [12, 14]. Based on available literature, performing PLND is described as optional. Some authors advocate sampling the lymph nodes, while others performing the extended PLND in all cases [5, 12, 13]. In the majority of recent descriptions of urachal carcinoma treatment, the PLND was performed similarly to the case of locally advanced bladder cancer where it is proved to benefit patients’ survival [13, 21, 23–25]. In the presented case, PLND could be of therapeutic value.\n\nAfter receiving initial surgical treatment and adjuvant chemotherapy, the patient follow-up scheme included only abdominal CT scan a year after the treatment. The next abdominal CT scan, which raised the suspicion of the disease recurrence, was performed over a year later and, in fact, due to the patient’s symptoms—leg pain. There are no guidelines on follow-up scheme after radical cystectomy due to urachal carcinoma. Standards are adapted from treatment of muscle-invasive urothelial bladder cancer or aggressive adenocarcinomas. However, even in cases of these more prevalent diseases, no universally accepted standards supported by scientific cost-benefit analysis exist. Nevertheless, recent studies regarding follow-up schemes after radical cystectomy acknowledge the need for more frequent and multi-modal surveillance in cases of stage III and IV disease [26]. In cases such as the one described above, it would seem prudent to schedule abdominal CT scans more often and include different modalities such as abdominal ultrasonography and chest X-ray into the scheme.\n\nThe chemotherapeutic regimens received by the patient consisted of paclitaxel and carboplatin combination and, during the relapse treatment, of gemcitabine. These regimens have been described in single cases to elicit a favorable response in the treatment of metastatic urachal carcinoma [5, 24, 27, 28]. However, no single chemotherapy regimen is to date proved effective enough to be considered a first-choice in all cases. Importantly, in the setting of salvage treatment, it is surgery that remains the most effective and potentially curative method [5]. Adjuvant chemotherapy in the cases of recurrent disease is usually applied. A multimodal treatment of metastatic urachal carcinoma has been shown to be capable of slowing disease progression and of providing over 10-year disease-free survival (in single cases) [7, 29, 30].\n\nOur patient’s decision to submit to salvage surgery presented a major technical challenge. Since the diagnosis of liver metastasis until the surgery (a period of 2 months), the tumor grew from 4 to 8 cm and another metastatic focus in the liver was revealed. During hemihepatectomy, the tumor localization did not allow to obtain surgical margins considered sufficient (more than 1 cm), instead, resection within tumor pseudocapsule was performed. It is known that even such resection is potentially curative; however, in our case, the pathology report confirmed R1 type resection [31].\n\nConclusions\nUrachal carcinoma is an extremely rare and aggressive malignancy posing a significant diagnostic and therapeutic challenge. The surgical management of the disease remains the cornerstone of therapy. The present report is the first to describe a salvage surgery in the case of urachal carcinoma with liver metastasis. It emphasizes the need for a prompt diagnosis and surgical treatment of urachal carcinoma. As is the case with all urinary bladder tumors, hematuria as an alerting symptom is still too often ignored by both patients and primary care physicians. What is more, the described case should bring more attention to the need for performing pelvic lymph node dissection and the necessity for a close follow-up surveillance in cases of an advanced urachal carcinoma.\n\nAbbreviations\nNOSNot otherwise specified\n\nPLNDPelvic lymph node dissection\n\nAcknowledgements\nWe are thankful to the patient for her cooperation and allowing us to use her medical records in our case report.\n\nFunding\nThis study was not supported by any external sources of funding.\n\nAvailability of data and materials\nThe authors do not wish to share their data; they respect the patient’s rights to privacy and to protect her identity. The authors presented, in the manuscript, all the necessary information about their case report. Raw data regarding our patient is in her admission file, a file that is strictly confidential, without the possibility of publishing raw data from it.\n\nAuthors’ contributions\nLP, MJ, and MS were all involved in this report’s conception and helped to draft the manuscript. All authors have read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nConsent was obtained from the patient for publication of relevant medical information.\n\nEthics approval and consent to participate\nNot applicable.\n==== Refs\nReferences\n1. Schubert GE Pavkovic MB Bethke-Bedurftig BA Tubular urachal remnants in adult bladders J Urol 1982 127 40 42 7057501 \n2. Yu JS Kim KW Lee HJ Lee YJ Yoon CS Kim MJ Urachal remnant diseases: spectrum of CT and US findings Radiographics 2001 21 451 461 10.1148/radiographics.21.2.g01mr02451 11259707 \n3. Bruins HM Visser O Ploeg M Hulsbergen-van de Kaa CA Kiemeney LA Witjes JA The clinical epidemiology of urachal carcinoma: results of a large, population based study Urol 2012 188 1102 1107 10.1016/j.juro.2012.06.020 \n4. Sheldon CA Clayman RV Gonzalez R Williams RD Fraley EE Malignant urachal lesions J Urol 1984 131 1 8 6361280 \n5. Ashley RA Inman BA Sebo TJ Leibovich BC Blute ML Kwon ED Zincke H Urachal carcinoma: clinicopathologic features and long-term outcomes of an aggressive malignancy Cancer 2006 107 712 720 10.1002/cncr.22060 16826585 \n6. Siefker-Radtke A Urachal carcinoma: surgical and chemotherapeutic options Expert Rev Anticancer Ther 2006 6 1715 1721 10.1586/14737140.6.12.1715 17181485 \n7. Siefker-Radtke AO Gee J Shen Y Wen S Daliani D Millikan RE Pisters LL Multimodality management of urachal carcinoma: the M. D. Anderson Cancer Center experience J Urol 2003 169 1295 1298 10.1097/01.ju.0000054646.49381.01 12629346 \n8. Herr HW Bochner BH Sharp D Dalbagni G Reuter VE Urachal carcinoma: contemporary surgical outcomes J Urol 2007 178 74 78 10.1016/j.juro.2007.03.022 17499279 \n9. Zhang J Wu J Options for diagnosis and treatment of urachal carcinoma Asia Pac J Clin Oncol 2013 9 117 122 10.1111/j.1743-7563.2012.01592.x 23046343 \n10. Zong L Chen P Surgical and chemotherapeutic experience regarding a urachal carcinoma with repeated relapse: case report and literature review World J Surg Oncol 2013 11 170 10.1186/1477-7819-11-170 23914849 \n11. Abeygunasekera AM Ranasinghe DD Urachal carcinoma Indian J Med Res 2013 137 398 23563388 \n12. Molina JR Quevedo JF Furth AF Richardson RL Zincke H Burch PA Predictors of survival from urachal cancer: a Mayo Clinic study of 49 cases Cancer 2007 110 2434 2440 10.1002/cncr.23070 17932892 \n13. Yazawa S Kikuchi E Takeda T Matsumoto K Miyajima A Nakagawa K Oya M Surgical and chemotherapeutic options for urachal carcinoma: report of ten cases and literature review Urol Int 2012 88 209 214 10.1159/000334414 22143067 \n14. Gopalan A Sharp DS Fine SW Tickoo SK Herr HW Reuter VE Olgac S Urachal carcinoma: a clinicopathologic analysis of 24 cases with outcome correlation Am J Surg Pathol 2009 33 659 668 10.1097/PAS.0b013e31819aa4ae 19252435 \n15. Pinthus JH Haddad R Trachtenberg J Holowaty E Bowler J Herzenberg AM Jewett M Fleshner NE Population based survival data on urachal tumors J Urol 2006 175 2042 2047 10.1016/S0022-5347(06)00263-1 16697798 \n16. Grignon DJ Ro JY Ayala AG Johnson DE Ordonez NG Primary adenocarcinoma of the urinary bladder. A clinicopathologic analysis of 72 cases Cancer 1991 67 2165 2172 10.1002/1097-0142(19910415)67:8<2165::AID-CNCR2820670827>3.0.CO;2-M 1706216 \n17. Chen D Li Y Yu Z Su Z Ni L Gui Y Yang S Shi B Lai Y Investigating urachal carcinoma for more than 15 years Oncol Lett 2014 8 2279 2283 25295114 \n18. Bissonnette ML Kocherginsky M Tretiakova M Jimenez RE Barkan GA Mehta V Sirintrapun SJ Steinberg GD White KP Stricker T Paner GP The different morphologies of urachal adenocarcinoma do not discriminate genomically by micro-RNA expression profiling Hum Pathol 2013 44 1605 1611 10.1016/j.humpath.2013.01.008 23528864 \n19. Henly DR Farrow GM Zincke H Urachal cancer: role of conservative surgery Urology 1993 42 635 639 10.1016/0090-4295(93)90526-G 8256396 \n20. Hong SH Kim JC Hwang TK Laparoscopic partial cystectomy with en bloc resection of the urachus for urachal adenocarcinoma Int J Urol 2007 14 963 965 10.1111/j.1442-2042.2007.01855.x 17880303 \n21. Williams CR Chavda K En bloc robot-assisted laparoscopic partial cystectomy, urachal resection, and pelvic lymphadenectomy for urachal adenocarcinoma Rev Urol 2015 17 46 49 26029004 \n22. Colombo JR Jr Desai M Canes D Frota R Haber GP Moinzadeh A Tuerk I Desai MR Gill IS Laparoscopic partial cystectomy for urachal and bladder cancer Clin (Sao Paulo) 2008 63 731 734 10.1590/S1807-59322008000600004 \n23. Chen ZF Wang F Qin ZK Dai YP Zhou FJ Han H Liu ZW Yu SL Li YH Ye YL Clinical analysis of 14 cases of urachal carcinoma Ai Zheng 2008 27 966 969 18799037 \n24. Kumar N Khosla D Kumar R Mandal AK Saikia UN Kapoor R Singh SK Sharma SC Urachal carcinoma: clinicopathological features, treatment and outcome J Cancer Res Ther 2014 10 571 574 25313741 \n25. Karl A Carroll PR Gschwend JE Knuchel R Montorsi F Stief CG Studer UE The impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer Eur Urol 2009 55 826 835 10.1016/j.eururo.2009.01.004 19150582 \n26. Giannarini G Kessler TM Thoeny HC Nguyen DP Meissner C Studer UE Do patients benefit from routine follow-up to detect recurrences after radical cystectomy and ileal orthotopic bladder substitution? Eur Urol 2010 58 486 494 10.1016/j.eururo.2010.05.041 20541311 \n27. Elser C Sweet J Cheran SK Haider MA Jewett M Sridhar SS A case of metastatic urachal adenocarcinoma treated with several different chemotherapeutic regimens Can Urol Assoc J 2012 6 E27 31 10.5489/cuaj.336 22396380 \n28. Jo EJ Choi CH Bae DS Park SH Hong SR Lee JH Metastatic urachal carcinoma of the ovary J Obstet Gynaecol Res 2011 37 1833 1837 10.1111/j.1447-0756.2011.01615.x 21794003 \n29. Miyata Y Sagara Y Matsuo T Ohba K Takahashi H Sakai H Kanetake H Response of recurrent urachal cancer to gemcitabine and cisplatin therapy: a case report and literature review Anticancer Res 2011 31 2335 2338 21737660 \n30. Kawakami S Kageyama Y Yonese J Fukui I Kitahara S Arai G Hyouchi N Suzuki M Masuda H Hayashi T Successful treatment of metastatic adenocarcinoma of the urachus: report of 2 cases with more than 10-year survival Urology 2001 58 462 10.1016/S0090-4295(01)01259-6 11549502 \n31. Vandeweyer D Neo EL Chen JW Maddern GJ Wilson TG Padbury RT Influence of resection margin on survival in hepatic resections for colorectal liver metastases HPB (Oxford) 2009 11 499 504 10.1111/j.1477-2574.2009.00092.x 19816614\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1477-7819",
"issue": "14(1)",
"journal": "World journal of surgical oncology",
"keywords": "Adjuvant chemotherapy; Salvage surgery; Urachal carcinoma",
"medline_ta": "World J Surg Oncol",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D015653:Cystectomy; D003841:Deoxycytidine; D017809:Fatal Outcome; D005260:Female; D006498:Hepatectomy; D006801:Humans; D007044:Hysterectomy; D008113:Liver Neoplasms; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D017239:Paclitaxel; D010386:Pelvic Neoplasms; D016879:Salvage Therapy; D014057:Tomography, X-Ray Computed; D001749:Urinary Bladder Neoplasms",
"nlm_unique_id": "101170544",
"other_id": null,
"pages": "296",
"pmc": null,
"pmid": "27894318",
"pubdate": "2016-11-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23563388;23046343;26029004;25295114;22901574;19816614;23528864;20541311;7057501;17880303;17932892;16697798;11259707;18799037;19150582;6361280;22143067;16826585;21794003;19060992;19252435;1706216;8256396;22396380;17181485;21737660;25313741;23914849;11549502;17499279;12629346",
"title": "Surgical treatment of recurrent urachal carcinoma with liver metastasis: a case report and literature review.",
"title_normalized": "surgical treatment of recurrent urachal carcinoma with liver metastasis a case report and literature review"
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"abstract": "BACKGROUND\nAutoimmune encephalitis is characterized by neuropsychiatric symptoms associated with brain inflammation. The differential is usually broad and Psychiatry often collaborates with Neurology in diagnostic clarification and symptom management. At least 40% of neuroencephalitis cases are of unknown etiology which adds to difficulties in making the right diagnosis and deciding on the appropriate treatment (Granerod et al., Lancet Infect Dis 10:835-44, 2010). The aim of this case series was to present four cases with complicated psychiatric symptomatology and isolated neurologic signs and symptoms, evaluated at a large tertiary medical center and treated for suspected autoimmune encephalitis, demonstrating the complexity of diagnosis and treatment.\n\n\nMETHODS\nFour diagnostically challenging and heterogeneous cases displayed clinical symptomatology suggestive of autoimmune encephalitis. All cases presented with neurologic and psychiatric symptoms, but had negative autoantibody panels, normal or inconclusive magnetic resonance imaging results and non-specific cerebrospinal fluid changes. All were challenged with immunosuppressive/immunomodulatory treatments with overall poor response rates.\n\n\nCONCLUSIONS\nThere is a heterogeneous presentation of autoimmune encephalitis in pediatric populations. In the absence of positive findings on testing, individuals who do not meet proposed criteria for seronegative encephalitis may be misdiagnosed, and/or may not respond adequately to treatment. In those cases, comprehensive evaluation and stringent application of consensus guidelines is necessary.",
"affiliations": "Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.;Department of Psychiatry and Psychology, Mayo Clinic Health Systems, Austin, MN, USA.;Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.;Department of Neurology, Mayo Clinic, Rochester, MN, USA.;Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA.;Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, USA. romanowicz.magdalena@mayo.edu.",
"authors": "Shekunov|Julia|J|;Blacker|Caren J|CJ|;Vande Voort|Jennifer L|JL|;Tillema|Jan-Mendelt|JM|;Croarkin|Paul E|PE|;Romanowicz|Magdalena|M|http://orcid.org/0000-0002-9865-0735",
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"fulltext": "\n==== Front\nBMC NeurolBMC NeurolBMC Neurology1471-2377BioMed Central London 160510.1186/s12883-020-1605-yCase ReportImmune mediated pediatric encephalitis – need for comprehensive evaluation and consensus guidelines Shekunov Julia 1Blacker Caren J. 2Vande Voort Jennifer L. 1Tillema Jan-Mendelt 3Croarkin Paul E. 1http://orcid.org/0000-0002-9865-0735Romanowicz Magdalena romanowicz.magdalena@mayo.edu 11 grid.66875.3a0000 0004 0459 167XDepartment of Psychiatry and Psychology, Mayo Clinic, Rochester, MN USA 2 Department of Psychiatry and Psychology, Mayo Clinic Health Systems, Austin, MN USA 3 grid.66875.3a0000 0004 0459 167XDepartment of Neurology, Mayo Clinic, Rochester, MN USA 3 2 2020 3 2 2020 2020 20 4416 7 2019 8 1 2020 © The Author(s). 2020Open 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\nAutoimmune encephalitis is characterized by neuropsychiatric symptoms associated with brain inflammation. The differential is usually broad and Psychiatry often collaborates with Neurology in diagnostic clarification and symptom management. At least 40% of neuroencephalitis cases are of unknown etiology which adds to difficulties in making the right diagnosis and deciding on the appropriate treatment (Granerod et al., Lancet Infect Dis 10:835-44, 2010). The aim of this case series was to present four cases with complicated psychiatric symptomatology and isolated neurologic signs and symptoms, evaluated at a large tertiary medical center and treated for suspected autoimmune encephalitis, demonstrating the complexity of diagnosis and treatment.\n\nCase presentation\nFour diagnostically challenging and heterogeneous cases displayed clinical symptomatology suggestive of autoimmune encephalitis. All cases presented with neurologic and psychiatric symptoms, but had negative autoantibody panels, normal or inconclusive magnetic resonance imaging results and non-specific cerebrospinal fluid changes. All were challenged with immunosuppressive/immunomodulatory treatments with overall poor response rates.\n\nConclusions\nThere is a heterogeneous presentation of autoimmune encephalitis in pediatric populations. In the absence of positive findings on testing, individuals who do not meet proposed criteria for seronegative encephalitis may be misdiagnosed, and/or may not respond adequately to treatment. In those cases, comprehensive evaluation and stringent application of consensus guidelines is necessary.\n\nKeywords\nEncephalitisAutoimmuneNeuropsychiatricPsychiatricSeronegativeissue-copyright-statement© The Author(s) 2020\n==== Body\nBackground\nAutoimmune encephalitis is characterized by neuropsychiatric symptoms associated with brain inflammation. Multiple etiologies include autoantibodies to cell proteins, intracellular antigens, and paraneoplastic processes [1–3]. The estimated incidence of autoimmune encephalitis is 0.8/100,000/year, and prevalence 13.7/100,000 in children and adults [4]. Etiology of encephalitis varies depending on different geographic regions with majority of cases remaining unexplained [5]. Less is known about rates of pediatric autoimmune encephalitis.\n\nSymptoms of autoimmune encephalitis can include cognitive regression/impairment, memory changes, seizures, sleep disturbance, autonomic instability, speech changes or mutism, and involuntary movements [6]. Psychiatric symptoms, including anxiety, agitation, delusions, and hallucinations can occur early in the course of autoimmune encephalitis [3]. There is commonly a subacute decline over the course of days to weeks, but symptoms can rapidly fluctuate, or present insidiously [7]. Children may be less likely to have severe autonomic manifestations [8], and are more likely to have neurologic manifestations than psychiatric [3, 9].\n\nThe differential is broad and Psychiatry is often consulted to assist with diagnostic clarification. Evaluation typically includes identifying the presence of clinical symptoms, evaluating biological abnormalities in serologic testing, and assessing paraclinical abnormalities via neuroimaging, electroencephalography (EEG), and lumbar puncture [2]. Antibody testing takes several days, response to immunotherapy can be slow, and over half of suspected autoimmune encephalitis cases are seronegative [10]. Accordingly, a clinical diagnostic approach has been developed, combining neurologic assessment, neuroimaging, and cerebrospinal fluid (CSF) testing, with levels of evidence established for possible, probable, or definite diagnoses of autoimmune encephalitis to support initiation of prompt immunotherapy where appropriate. Proposed diagnostic criteria for autoantibody-negative but probable autoimmune encephalitis include presence of rapid progression (less than 3 months) of working memory deficits, altered mental status or psychiatric symptoms; exclusion of well-defined syndromes of autoimmune encephalitis; reasonable exclusion of alternative causes; absence of well characterized autoantibodies in serum and CSF, and at least two of: magnetic resonance imaging (MRI) abnormalities suggestive of autoimmune encephalitis; CSF pleocytosis, CSF-specific oligoclonal bands or elevated CSF immunoglobulin G (IgG) index or both; or brain biopsy showing inflammatory infiltrates and excluding other disorders [11]. Pediatric criteria for diagnosis do not yet exist. Still, according to a recent systematic review [5], in many cases the causative agent of encephalitis remains unknown, despite advances in laboratory and imaging technology. This might suggest that there are a number of unknown pathogens that have not been associated with encephalitis and/or that some of the immune-mediated mechanisms are not well understood.\n\nTreatment for autoimmune encephalitis is often empiric, and may involve corticosteroids, plasmapheresis and/or intravenous immunoglobulin (IVIG) [3, 12]. Rituximab is more often used in children due to its relatively favorable safety profile, as compared to cyclophosphamide [3]. Based on a retrospective study, etiology of acute encephalitis (that included encephalitis of unknown origin) is not associated with clinical treatment outcomes [13]. Treatment failures may be indicative of neurologic insult from past inflammation or ongoing inflammatory disease [14]. However, treatments are not without side effects, and therefore it is important not to expose patients unnecessarily. Clinical guidelines exist which direct clinicians through appropriate diagnostic and treatment decision trees [11].\n\nWe present four cases of children and adolescents with complicated psychiatric and neurologic symptomatology, evaluated at a large tertiary medical center, in whom autoimmune encephalitis was suspected and treatment was initiated. These cases were diagnostically challenging, with negative autoantibody panels, normal or inconclusive MRI results, non-specific CSF changes, and no tissue testing (either via immunochemistry in brain tissue or a neuronal cell culture). All received immunosuppressive and/or immunomodulatory treatments for autoimmune encephalitis based solely on clinical symptomatology. Table 1 summarizes each case, specific testing and outcome. Figure 1 describes the laboratory-specific autoantibody testing performed in serum and spinal fluid at our institution. Additional file 1 provides a method description of Mayo Clinic laboratory testing for autoimmune encephalopathy- evaluation, for cerebrospinal fluid and serum samples. The cases demonstrate both a need for better understanding of pediatric autoantibody-negative encephalitis, and also the importance of applying clinical guidelines to diagnosis and treatment, especially in cases where the diagnosis is not clear.\nTable 1 Summary of physical, laboratory, imaging findings, treatment and outcomes for 4 cases of suspected autoimmune encephalitis. Clinical features suggestive of autoimmune encephalitis are bolded\n\nCase\t1\t2\t3\t4\t\nAge in years/sex\t13/M\t17/F\t9/F\t17/M\t\nSymptom duration\t8 months\t3 months\t1 year\t6 months\t\nPhysical symptoms\tAnorexia\n\nMotor slowing\n\nSlow, ataxic gait\n\nAbnormal movements of lip/tongue\n\nMutism\n\nFood refusal\n\nDizziness\n\nAutonomic instability\n\n\tHeadaches\n\nAbdominal pain\n\nEmesis\n\nUrinary retention\n\nVibratory tactile sensation in head\n\nDysphagia\n\nConstipation\n\n\tPeriods of confusion\n\nDisorientation\n\nDecreased speech fluency\n\nLanguage regression Nonsensical speech\n\n\tDecreased movements\n\nDecreased speech\n\nSoft, scripted speech\n\nStaring spells\n\nFatigue\n\n\t\nPsychiatric symptoms\tSocial isolation\n\nCatatonia\n\n\tMemory difficulties\n\nDecline in academic performance\n\nSocial isolation\n\nAnxiety\n\nPanic attacks\n\nAgitation\n\nInsomnia\n\nParanoia\n\n\tInappropriate laughter\n\nTalking to imaginary friends\n\nDisengagement in school\n\nAggression\n\nDefiance\n\nSocial Isolation\n\nVisual hallucinations\n\nParanoia\n\nDisorganized behavior\n\n\tDecreased attention and concentration\n\nSocial isolation\n\nNot caring for self\n\nAuditory and visual hallucinations\n\nTalking to self\n\nIrritability\n\nDifficulties with multistep commands\n\nIncreased sleep\n\n\t\nFamily History of autoimmune disease\tNone\tNone\tFather with multiple sclerosis\n\nPaternal aunt with Myasthenia Gravis\n\n\tNone\t\nSerum and urine\tMildly elevated\n\nGAD65 antibody (0.15 nmol/L), otherwise unremarkable including rest of encephalopathy panel, electrolytes including calcium (with exception of low phosphorus), folate, B12, Lyme serology, herpes simplex, enterovirus, cryptococcus, VDRL, whole exome sequencing\n\n\tMildly elevated\n\nGAD65 antibody (0.15 nmol/L), otherwise unremarkable including\n\nCBC, electrolytes, thyroid function, liver function, C-reactive protein, B12, ceruloplasmin, toxicology, heavy metals, blood smear, urinalysis\n\n\tUnremarkable including outside hospital testing\n\nCBC, CMP, inflammatory markers, thyroid studies, ammonia, folate, copper, ceruloplasmin, heavy metals, plasma amino acids, urine organic acids, very long chain fatty acids, lysosomal disorders screen, chromosomal microarray, Noonan panel. Repeat inpatient testing unremarkable\n\n\tUnremarkable except for low ferritin (12 mcg/L), including toxicology screen, CBC, electrolytes, inflammatory markers, thyroid function\t\nMRI\tUnremarkable other than evidence of malnutrition\tSlit third ventricle with narrowed lateral ventricles, no cerebral hypotension and diffuse changes consistent with perinatal insult\tUnremarkable\tUnremarkable\t\nCSF\tMildly elevated protein (45 mg/dL), otherwise unremarkable; no presence of bands\tTotal protein elevated (144 mg/dL; 110 mg/dL 6 months later); no presence of bands\tUnremarkable; no presence of bands\tPositive GFAP antibodies from outside hospital, repeat negative; no presence of bands\t\nEEG\tUnremarkable\tUnremarkable\tIntermittent diffuse nonspecific bifrontal slowing, bifrontal spikes and sharp waves without clinical correlate, intermittent independent left/right temporal slowing\tMild nonspecific background slowing\t\nTreatment with IVIG or corticosteroids\t5 days IV methylprednisolone; 5 days IVIG then monthly infusions for 3 months\t5 days IVIG then intermittent doses; 5 days methylprednisolone upon readmission\t3 days high dose IV methylprednisolone then oral prednisone;\n\nsingle dose IVIG then twice-weekly IVIG, then monthly IVIG;\n\nrituximab\n\n\t5 days IV methylprednisolone\t\nResponse\tImproved over time\tInitial significant improvement, not sustained with both treatment course. Return to baseline after neurosurgical intervention\tSome initial improvement in mood, speech, social interactions; not sustained\tInitial improvement, not sustained\t\nFig. 1 Summary of autoantibody testing in serum and spinal fluid in Mayo Clinic’s autoimmune encephalopathy panels with reference values in brackets. Test details and references obtained from Mayo Clinic Laboratory Test Catalog, https://www.mayocliniclabs.com/testcatalog/Overview/92116. (*Denotes testing completed in serum but not in spinal fluid)\n\n\n\nCase presentation\nCase 1\nA 13-year-old, developmentally normal boy, with no psychiatric history, was hospitalized for 8 months of progressive malnutrition, physical weakness, and mutism. He had been physically well until developing influenza followed by an observed tick bite without rash. Over the next 4 months, he developed abdominal pain with a single episode of bloody emesis. Abdominal computed tomography (CT) demonstrated mesenteric adenitis, a nonspecific finding; gastrointestinal biopsies were negative. Anorexia and motor slowing developed. By month six, gait became slow and shuffling, with abnormal lip/tongue movements. MRI-brain was unremarkable. He developed postural dizziness, falls, ataxic gait, and gradual mutism. Food refusal led to 30 pound weight loss, and severe malnutrition resulted in hospitalization.\n\nDuring hospitalization, serum testing and sleep-wake EEG were unremarkable except serum was positive (15 nmol/L) for GAD65 antibody, a nonspecific finding. CSF was normal (GAD65 0.00), except for mildly elevated protein. Repeat MRI-brain showed evidence of malnutrition but was essentially normal. Neurological examination revealed bradykinesia, masked facies, oral dyskinesias, bilateral cogwheeling at wrists, knees, and elbows, brisk reflexes with clonus, absent Babinski bilaterally, positive Hoffman bilaterally, head tremor, mutism, and no volitional movements. Autonomic instability occurred: tachycardia and normothermic diaphoresis. A positive score of 14 for catatonia on a Bush-Francis rating scale [15], resulted in a benzodiazepine challenge up to 1 mg three times daily ultimately stopped for somnolence. Neurology recommended levodopa for extrapyramidal symptoms; 1 g intravenous (IV) methylprednisolone for 5 days and five total doses of IVIG for possible autoimmune encephalitis in the context of progressive weakness and difficulties initiating movement. Treatment was well tolerated and followed by motor symptom improvement over 1 to 2 weeks, including resolution of cogwheeling and rigidity, which did not recur upon discontinuation of levodopa, and resolution of tachycardia. At the time of transfer to inpatient rehabilitative therapy, the patient had improved oral intake, resolution of cogwheeling and rigidity, and more spontaneous movements, but was nonambulatory, unable to complete activities of daily living (ADLs), and essentially nonverbal.\n\nIn addition to suspected autoimmune encephalitis, there was suspicion for a functional communication disorder due to inconsistencies in his physical exam. Neither diagnosis alone could fully explain the patient’s presentation, and accordingly, he also received physical therapy, speech therapy and occupational therapy.\n\nHe was discharged home eating appropriately, ambulating, able to complete all ADLs, and mouthing words after a 50 day hospitalization for 3 months of monthly IVIG. At the time of the last follow-up he continued to have some difficulty with eating and used primarily gesturing, writing and facial expressions to communicate, though this was improving.\n\nCase 2\nA 17-year-old female, with no psychiatric diagnoses, and a history of premature birth (24-week gestation), perinatal intraventricular hemorrhage, hydrocephalus, cerebral palsy, and ventriculoperitoneal shunt was hospitalized following 3 months of progressive mental status changes. She had no foreign travel or infectious contacts. Four months prior, she sustained a minor head injury without loss of consciousness. One month later, she began struggling with memory and homework. Her A/B grades declined and she did not complete the semester. She described vibratory tactile sensations in her head, severe headaches over occiput and vertex, and developed social isolation, anxiety, and panic attacks. New-onset insomnia was alleviated by zolpidem and lorazepam. One month prior to admission, she reported dysphagia, abdominal pain, constipation, urinary retention, vomiting.\n\nAt admission, physical exam was unremarkable besides moderate cognitive impairment (Kokmen 23/38) [16] and urinary retention requiring catheterization. Serum and EEG testing was unremarkable except a nonspecific finding of mildly elevated GAD65. CSF was remarkable for elevated protein of 144 mg/dL and CSF autoantibodies were positive for CASPR2- autoantibodies, though repeated testing was negative. MRI-spine was negative for cord tethering. CT-head demonstrated slit ventricles consistent with excessive shunting but thought to not adequately explain the patient’s subacute constellation of fatigue, memory, cognitive, and behavioral problems. MRI-brain showed slit third ventricle with narrowed lateral ventricles and diffuse changes consistent with perinatal insult. Psychiatry evaluated severe insomnia and behavioral changes. There was no evidence of a mood or anxiety disorder, or catatonia. Neuropsychological testing reflected low-average general cognitive functioning with weakness in nonverbal/visuospatial processing, consistent with complications of prematurity. Baseline cognitive testing was unavailable.\n\nA 5 day course of 1 g per day IV methylprednisolone and IVIG for suspected autoimmune encephalitis were initiated. Lorazepam was provided on an as-needed basis for anxiety and insomnia secondary to use of methylprednisolone. Treatment was tolerated and within days, the patient began to walk normally, interact appropriately, and sleep better. She was discharged home with an IVIG taper. She required rehospitalization 6 months later for mental status changes and sleep disturbances. Repeat MRI-brain, EEG, CSF/serum testing were significant only for elevated CSF protein of 110 mg/dL. Five days of methylprednisone briefly resolved symptoms without sustained improvement. Her clinical care transferred to another facility where her over-draining shunt was replaced with a programmable shunt and she returned to baseline suggesting that shunt malfunction may contribute to psychiatric symptoms such as anxiety, confusion and memory loss. Patient was told that adults should not use pressure valves in their shunts and instead a magnetic adjustable valve is preferred option.\n\nCase 3\nA nine-year-old girl, no psychiatric history, was seen for a second opinion of cognitive, behavioral, and speech/language regressions. She had been healthy until 11 months prior, with onset of inappropriate laughter, talking to imaginary friends, decreased speech fluency, and vocabulary loss. Teachers noted worsening social engagement and academic performance, disorientation, aggression, defiance, repetitive hand movements, and eloping from school. She described visual hallucinations and paranoia. Language became nonsensical. She became lost in familiar places and struggled to get home from the school bus.\n\nThe patient was evaluated at an outside facility and prescribed risperidone for suspected psychosis. EEG and MRI-brain were unremarkable. In month five, she was hospitalized for medical evaluation due to ongoing symptoms and concern for possible autoimmune encephalitis. Serum, CSF and urine studies were normal, as were repeat MRI-brain and CT-abdomen/pelvis. Repeat EEG showed nonspecific anterior slowing. The patient began empiric treatment for autoimmune encephalopathy, with IV methylprednisolone for 3 days and one dose of IVIG, then transitioned to oral prednisone. Steroids impaired sleep, increased appetite, and she became agitated/aggressive. She transferred to a rehabilitation facility where she had noticeable improvements in mood, clarity and fluency of speech, reading comprehension, and social engagement. As prednisone was tapered, she experienced symptom recurrence. The patient continued twice-weekly IVIG, tapered to once-monthly infusions, without sustained improvement.\n\nAt the time of presentation to our outpatient clinic, 11 months after symptom onset, she had intermittent visual hallucinations, disorganized thinking, impaired speech fluency, inappropriate laughter, pressured speech, and vague descriptions of an entity inside her. Risperidone was replaced with aripiprazole, with no meaningful improvement. Rituximab was started with slight improvement after two doses, though not continued after parents sought a second opinion due to perceived lack of response. Laboratory testing of serum and CSF was normal. EEG showed intermittent diffuse nonspecific 5 hertz slowing bifrontally, bifrontal spikes and sharp waves without clinical correlate, intermittent independent bitemporal slowing consistent with mild encephalopathy. Neuropsychological testing revealed borderline general intellectual functioning, and impaired adaptive functioning. Cognitive skills had regressed across time) but academic skills remained average, consistent with premorbid functioning. Ultimately, it was felt that the patient’s presentation reflected encephalopathy given the continued regression, involvement of fine motor skills, and reduced working memory/processing speed.\n\nCase 4\nA 17-year-old autistic boy, previously taking aripiprazole between ages 12 and 13 for mood symptoms, was seen for a second opinion regarding mental status changes beginning 6 months prior. The patient attended school with 1:1 teacher-to-student ratio, and had several friendships. Following a vacation, and without evidence for prodromal illness, he struggled with attention and concentration, became withdrawn, moved less, stopped self-cares, and talked to himself. He described visual and auditory hallucinations. He displayed frequent staring spells but 24-h EEG showed no epileptiform discharges. He was hospitalized at an outside hospital with normal laboratory testing including MRI-brain and CSF studies except positive for serum glial fibrillary acidic protein (GFAP) antibodies (specific result unavailable). Testicular teratoma was ruled out by scrotal ultrasound. He was treated for suspected autoimmune encephalitis with IV methylprednisolone, 1 g per day for 5 days, with tolerability and initial significant improvement that subsequently slowed.\n\nAt the time of our assessment, parents reported irritability, auditory and visual hallucinations, quiet and impaired speech, difficulties following multi-step commands, and hypersomnolence. Psychiatry started aripiprazole for hallucinations. Overnight EEG showed non-specific mild background slowing. Repeat laboratory testing was normal except for low ferritin. Serum and CSF encephalopathy testing, MRI-brain and MRI-cervical spine were negative including negative GFAP antibodies. Creatine urine studies were slightly abnormal and were recommended to be repeated locally. With negative antibody testing, supportive care continued as parents noted ongoing gradual improvement.\n\nDiscussion and conclusions\nThese cases were complex, necessitating multidisciplinary collaboration. All received treatment for autoimmune encephalitis based on clinical symptoms. All had different degrees of response to treatment, and diagnostic certainty was never satisfactorily achieved. These cases highlight how essential it is to use internationally agreed criteria for diagnosis and initiation of treatment of pediatric cases of suspected autoimmune encephalitis. Though proposed criteria for diagnosis exist [11], they are not consistently used. Additionally, even after acute treatment is completed, patients are frequently left with residual psychiatric symptoms that require ongoing management [17–19]. This may include pharmacologic and psychotherapeutic treatment of anxiety, panic, obsessive-compulsive disorder, irritability, inattention, impulsivity, depression and psychosis [2].\n\nMany cases of autoimmune encephalitis are characterized by rapid symptom progression that include memory issues, movement disorders, seizures, insomnia, issues with speech, significant behavior changes, psychosis, and obsessive–compulsive like symptoms [20]. Outcomes may vary from full recovery to death [21]. Time to recovery differs across patients, with some evidence suggesting that more than 50% of patients with Hashimoto’s encephalopathy improve in the first month of treatment, yet other types of encephalitis show poorer treatment response and longer time to recovery [3, 20, 22]. All four patients in this series were treated for autoimmune encephalitis yet had limited or unsustained response to short courses of first-line treatments of IVIG and steroids. The only patient who ultimately returned to baseline also had a premorbid neurosurgical condition. A second-line treatment (rituximab) was employed only in Case 3, though not continued by parents. There is increasing literature on other treatment options including other second-line therapies like cyclophosphamide, mycophenolate mofetil and azathioprine, and novel medications such as IL-6 blockade and proteasome inhibitors for refractory cases [12, 14, 20, 23].\n\nAutoimmune encephalitis often involves psychiatric symptoms, movement disorders, memory and speech issues, fluctuating consciousness, and autonomic instability [24, 25]. Cases 1/3/4 demonstrated four of these clinical characteristics. All cases displayed psychiatric symptoms. There were speech issues in Cases 1/3/4, memory difficulties in Cases 2/3/4, and movement changes in Cases 1 and 2. Communication and/or behavioral difficulties prevented standardized memory and cognitive testing for all cases. Autonomic instability was present only in Case 1, who had symptoms consistent with catatonia. Diagnosis of autoimmune catatonia is challenging particularly with negative autoimmune testing [26].\n\nThough clinically suggestive of autoimmune encephalitis, assessment and diagnosis of our cases was complicated by lack of specific biologic or paraclinical abnormalities. All were seronegative, with no MRI or CSF abnormalities. Non-specific EEG changes were reported in Cases 3/4. None received tissue-based testing. These cases were treated for autoimmune encephalitis yet did not meet Graus criteria for probable or definite autoimmune encephalitis [13]. This may be a contributing factor in the limited response to immunosuppressive and immunomodulatory treatments observed in these patients.\n\nLack of diagnostic clarity also raises questions about whether treatment in these cases was justified. Their presentations were acute, severe and their clinical symptomatology was suggestive of autoimmune encephalitis but they did not meet current consensus guidelines for this diagnosis. Despite improvements in diagnostic technology, there are still a significant number of cases of unknown etiology. The diagnostic conundrum of cases presented here is that they all displayed psychiatric symptoms, but at the time their presentation could not be explained by psychiatric diagnosis alone. Use of clinical guidelines, applied in a systematic way, might have been helpful in the care of these patients. For example, although negative autoantibodies do not preclude definitive diagnosis of autoimmune encephalitis, they can be useful for determining subtype, treatment choice, and prognosis [11]. Additionally, when managing an autoantibody negative case, further testing should be considered as per the consensus guidelines, and this should always include CSF if serum is negative. Confirmatory tests should be strongly considered, such as cell-based assay and tissue immunohistochemistry [11]. Testing for autoimmune encephalitis is evolving and changing rapidly. Laboratory tests for new antibodies are being discovered and experts in the field recognize that there is still much to learn about diagnosis of autoimmune encephalitis. This poses difficulty in being able to properly diagnose. On the other hand, treatments used for autoimmune encephalitis are not without side effects and potential complications. Weighing the risks and benefits of treatment requires an evaluation of the patient’s functional impairment, side-effects [27], the reasonable safety profile of IVIG [28] and other treatment options, and the risk of progressive decline in the absence of treatment. Improved outcomes have been associated with immunotherapy, early initiation of treatment, and use of second and third-line treatments if necessary [29]. This often poses a clinical dilemma: how aggressive should the treatment be in cases where diagnosis is unclear? In the adult population, the consensus seems to be that aggressive treatment should be considered in most situations due to a high likelihood of favorable outcomes [13]. The data is lacking in the pediatric population and no official guidelines are present. However in light of potential side-effects of immune treatment, autoimmune encephalitis criteria is pragmatically made more stringent when no biomarker or inflammation can be found as in cases of encephalitis of unknown etiology. By contrast, if a known and clinically relevant antibody is identified, the same criteria may be relaxed to provide the necessary treatment for the patient. We specifically chose the cases for this series to outline diagnostic and treatment challenges in the field and to illustrate that ultimately the treatment of these individuals is based on the empirical evidence accrued to the best of ability and is far from definitive at the present time.\n\nThere is a heterogeneous presentation of neuropsychiatric features of autoimmune encephalitis in pediatric population. Since patients with autoimmune encephalitis often present with physical and psychiatric symptomatology, psychiatrists and neurologists are both commonly involved in their care. Cases with negative autoantibody panels, normal/inconclusive MRI results, and non-specific CSF changes, but with clinical symptomatology suggestive for autoimmune encephalitis are difficult to manage and not definitive when no biomarker can be identified. There is a need for comprehensive evaluation with use of consensus guidelines for diagnosing seronegative autoimmune encephalitis.\n\nSupplementary information\n\nAdditional file 1. Method description of Mayo Clinic laboratory testing for Encephalopathy-Autoimmune Evaluation, cerebrospinal fluid and serum samples.\n\n \n\n\nAbbreviations\nADLsActivities of daily living\n\nAMPAα-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid\n\nCASPR2 Contactin Associated Protein 2\n\nCBCComplete blood count\n\nCMPComplete metabolic panel\n\nCSFCerebrospinal fluid\n\nCTComputed tomography\n\nEEGElectroencephalography\n\nGABA-BGamma-aminobutyric acid B\n\nGAD65Glutamic acid decarboxylase 65\n\nGFAPGlial fibrillary acidic protein\n\nIgGImmunoglobulin G\n\nIVIntravenous\n\nIVIGIntravenous immunoglobulin\n\nLGI1Leucine-rich, glioma inactivated 1\n\nMRIMagnetic resonance imaging\n\nNMDAN-methyl-D-aspartate\n\nVDRLVenereal Disease Research Laboratory test\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nSupplementary information\nSupplementary information accompanies this paper at 10.1186/s12883-020-1605-y.\n\nAcknowledgements\nThank you to Martha P. Corral-Frias, M.B.B.S. for providing assistance with manuscript revisions.\n\nDepartment of Psychiatry, University Hospital “Dr. José E. González”. Universidad Autonoma de Nuevo Leon, Monterrey, Nuevo Leon, Mexico.\n\nAuthors’ contributions\nJMT and MR significantly contributed to conception of manuscript. Ideas were further developed by JS, who wrote majority of manuscript with some assistance from CB and MR. JVV and PC contributed significant ideas for bettering manuscript. JS, CB and MR substantively revised manuscript considering feedback from co-authors. All authors read and approved the final manuscript.\n\nAuthors’ information\nNot applicable.\n\nFunding\nNot applicable.\n\nAvailability of data and materials\nNot applicable.\n\nEthics approval and consent to participate\nNeed for approval was waived by the Mayo Clinic Institutional Review Board.\n\nConsent for publication\nWritten informed consent was obtained from all of the patient’s parent/legal guardians for publication of this Case report including personal/clinical details and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Granerod J, Ambrose HE, Davies NW, Clewley JP, Walsh AL, Morgan D, et al. Causes of encephalitis and differences in their clinical presentations in England: a multicentre, population-based prospective study. The Lancet Infectious diseases. 2010;10(12):835-44.\n2. Mooneyham GC Gallentine W Van Mater H Evaluation and Management of Autoimmune Encephalitis: a clinical overview for the practicing child psychiatrist Child Adolesc Psychiatr Clin N Am 2018 27 1 37 52 29157501 \n3. Lancaster E The Diagnosis and Treatment of Autoimmune Encephalitis J Clin Neurol (Seoul, Korea) 2016 12 1 1 13 \n4. Dubey D Pittock SJ Kelly CR McKeon A Lopez-Chiriboga AS Lennon VA Autoimmune encephalitis epidemiology and a comparison to infectious encephalitis Ann Neurol 2018 83 1 166 177 29293273 \n5. Granerod J Tam CC Crowcroft NS Davies NW Borchert M Thomas SL Challenge of the unknown. A systematic review of acute encephalitis in non-outbreak situations Neurology. 2010 75 10 924 932 20820004 \n6. Van Mater H Pediatric inflammatory brain diseases: a diagnostic approach Curr Opin Rheumatol 2014 26 5 553 561 25050924 \n7. Kayser MS Dalmau J The emerging link between autoimmune disorders and neuropsychiatric disease J Neuropsychiatry Clin Neurosci 2011 23 1 90 97 21304144 \n8. Florance NR Davis RL Lam C Szperka C Zhou L Ahmad S Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis in children and adolescents Ann Neurol 2009 66 1 11 18 19670433 \n9. Titulaer MJ Leypoldt F Dalmau J Antibodies to N-methyl-D-aspartate and other synaptic receptors in choreoathetosis and relapsing symptoms post-herpes virus encephalitis Mov Disord 2014 29 1 3 6 24458319 \n10. Hacohen Y Wright S Waters P Agrawal S Carr L Cross H Paediatric autoimmune encephalopathies: clinical features, laboratory investigations and outcomes in patients with or without antibodies to known central nervous system autoantigens J Neurol Neurosurg Psychiatry 2013 84 7 748 755 23175854 \n11. Graus F Titulaer MJ Balu R Benseler S Bien CG Cellucci T A clinical approach to diagnosis of autoimmune encephalitis Lancet Neurol 2016 15 4 391 404 26906964 \n12. Stingl C Cardinale K Van Mater H An update on the treatment of pediatric autoimmune encephalitis Curr Treatm Opt Rheumatol 2018 4 1 14 28 29780690 \n13. Singh TD Fugate JE Rabinstein AA The spectrum of acute encephalitis: causes, management, and predictors of outcome Neurology. 2015 84 4 359 366 25540320 \n14. Randell RL Adams AV Van Mater H Tocilizumab in refractory autoimmune encephalitis: a series of pediatric cases Pediatr Neurol 2018 86 66 68 30177347 \n15. Bush G Fink M Petrides G Dowling F Francis A Catatonia. I. Rating scale and standardized examination Acta Psychiatr Scand 1996 93 2 129 136 8686483 \n16. Kokmen E Naessens JM Offord KP A short test of mental status: description and preliminary results Mayo Clin Proc 1987 62 4 281 288 3561043 \n17. Brenton JN Kim J Schwartz RH Approach to the Management of Pediatric-Onset Anti-N-methyl-d-aspartate (anti-NMDA) receptor encephalitis: a case series J Child Neurol 2016 31 9 1150 1155 27121044 \n18. Byrne S Walsh C Hacohen Y Muscal E Jankovic J Stocco A Earlier treatment of NMDAR antibody encephalitis in children results in a better outcome Neurol Neuroimmunol Neuroinflamm 2015 2 4 e130 26236759 \n19. Pillai SC Hacohen Y Tantsis E Prelog K Merheb V Kesson A Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome Pediatrics. 2015 135 4 e974 e984 25802349 \n20. Dale RC Gorman MP Lim M Autoimmune encephalitis in children: clinical phenomenology, therapeutics, and emerging challenges Curr Opin Neurol 2017 30 3 334 344 28234797 \n21. Quek AM Britton JW McKeon A So E Lennon VA Shin C Autoimmune epilepsy: clinical characteristics and response to immunotherapy Arch Neurol 2012 69 5 582 593 22451162 \n22. Kirshner HS Hashimoto’s encephalopathy: a brief review Curr Neurol Neurosci Rep 2014 14 9 476 25027262 \n23. Shin YW Lee ST Park KI Jung KH Jung KY Lee SK Treatment strategies for autoimmune encephalitis Ther Adv Neurol Disord 2018 11 1756285617722347 29399043 \n24. Armangue T Petit-Pedrol M Dalmau J Autoimmune encephalitis in children J Child Neurol 2012 27 11 1460 1469 22935553 \n25. Armangue T Titulaer MJ Malaga I Bataller L Gabilondo I Graus F Pediatric anti-N-methyl-D-aspartate receptor encephalitis-clinical analysis and novel findings in a series of 20 patients J Pediatr 2013 162 4 850 6.e2 23164315 \n26. Ferrafiat V Raffin M Deiva K Salle-Collemiche X Lepine A Spodenkiewicz M Catatonia and autoimmune conditions in children and adolescents: should we consider a therapeutic challenge? J Child Adolesc Psychopharmacol 2017 27 2 167 176 27093093 \n27. Späth PJGG La Marra F Kuijpers TW Quinti I On the dark side of therapies with immunoglobulin concentrates: the adverse events Front Immunol 2015 6 11 25699039 \n28. Katz U Achiron A Sherer Y Shoenfeld Y Safety of intravenous immunoglobulin (IVIG) therapy Autoimmun Rev 2007 6 4 257 259 17317619 \n29. Nosadini M Mohammad SS Ramanathan S Brilot F Dale RC Immune therapy in autoimmune encephalitis: a systematic review Expert Rev Neurother 2015 15 12 1391 1419 26559389\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2377",
"issue": "20(1)",
"journal": "BMC neurology",
"keywords": "Autoimmune; Encephalitis; Neuropsychiatric; Psychiatric; Seronegative",
"medline_ta": "BMC Neurol",
"mesh_terms": "D000293:Adolescent; D001323:Autoantibodies; D001327:Autoimmune Diseases; D002648:Child; D004660:Encephalitis; D005260:Female; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D001523:Mental Disorders",
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"pages": "44",
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"pmid": "32013931",
"pubdate": "2020-02-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Immune mediated pediatric encephalitis - need for comprehensive evaluation and consensus guidelines.",
"title_normalized": "immune mediated pediatric encephalitis need for comprehensive evaluation and consensus guidelines"
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"abstract": "Anabolic-androgenic steroids (AAS) abuse is common in competitive athletes in order to enhance athletic performances. However, AAS abuse is often associated with deleterious side effects including but not limited to cardiovascular diseases, depression, hormonal abnormalities, and cancer. We present a case of a 31-year-old male with a history of Crohn's disease on infliximab and chronic AAS use who had persistent retrosternal chest pain found to have an acute myocardial infarction (MI) without obvious cardiovascular risk factors.",
"affiliations": "Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA.;Internal Medicine, University of Maryland Medical Center, Baltimore, USA.;Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA.;Internal Medicine, Abington Hospital-Jefferson Health, Abington, USA.;Library Science, Abington Hospital-Jefferson Health, Abington, USA.",
"authors": "Zhang|Qian|Q|;Shan|Khine S|KS|;Raza|Ahmad|A|;Manda|Neelima|N|;Nace|Travis|T|",
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"doi": "10.7759/cureus.8332",
"fulltext": "\n==== Front\nCureus\nCureus\n2168-8184\nCureus\n2168-8184 Cureus Palo Alto (CA) \n\n10.7759/cureus.8332\nCardiology\nInternal Medicine\nGastroenterology\nA Rare Case Report and Literature Review of Anabolic-Androgenic Steroids (AAS)-Induced Acute Myocardial Infarction\nMuacevic Alexander Adler John R Zhang Qian 1 Shan Khine S 2 Raza Ahmad 1 Manda Neelima 1 Nace Travis 3 \n1 \nInternal Medicine, Abington Hospital-Jefferson Health, Abington, USA \n\n2 \nInternal Medicine, University of Maryland Medical Center, Baltimore, USA \n\n3 \nLibrary Science, Abington Hospital-Jefferson Health, Abington, USA \n\nQian Zhang qian.zhang2@jefferson.edu\n28 5 2020 \n5 2020 \n12 5 e833212 5 2020 28 5 2020 Copyright © 2020, Zhang et al.2020Zhang 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/32118-a-rare-case-report-and-literature-review-of-anabolic-androgenic-steroids-aas-induced-acute-myocardial-infarctionAnabolic-androgenic steroids (AAS) abuse is common in competitive athletes in order to enhance athletic performances. However, AAS abuse is often associated with deleterious side effects including but not limited to cardiovascular diseases, depression, hormonal abnormalities, and cancer. We present a case of a 31-year-old male with a history of Crohn’s disease on infliximab and chronic AAS use who had persistent retrosternal chest pain found to have an acute myocardial infarction (MI) without obvious cardiovascular risk factors.\n\nmimyocardial infarctionst-elevation myocardial infarction (stemi)anabolic steroidsteroidinflammatory bowel diseasecrohn's diseaseulcerative colitisThe 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\nAnabolic-androgenic steroids (AAS) are synthetic drugs manufactured to mimic the male sex hormone testosterone [1]. They are usually prescribed for medical conditions including but not limited to impotence in males, endometriosis, hypogonadism, and aplastic anemia [2]. It has also been used historically by athletes and bodybuilders to enhance performance as it can stimulate protein synthesis leading to an increase in muscle size and strength [3]. However, the use of AAS has become a serious global public health dilemma as it has been used widely by the general population to improve physical strength and appearance [1]. In 2013, the United States Centers for Disease Control and Prevention (CDC) reported that 3.2% of high school students had taken AAS without a doctor's prescription at least once in their lifetime [4]. In a meta-analysis of 187 studies, the overall global lifetime prevalence rate of AAS use was 3.3% and it is higher in men (6.4%) than in women (1.6%) [1]. Approximately one million people, predominantly males, had developed AAS use dependence [5]. AAS use is associated with an increase in cardiovascular diseases with the rising incidence of myocardial infarction (MI) in young patients with a history of anabolic steroid use. Unfortunately, the abuse of AAS has remained on the rise despite their well-known deleterious effects. Here, we present a case of an acute MI in a 31-year-old man who was found to have cyclic AAS use while being treated with infliximab for Crohn's disease.\n\nCase presentation\nOur patient was a 31-year-old man who presented to a regional hospital with the chief complaint of substernal chest pain. His past medical history was significant for Crohn’s disease treated with infliximab every six weeks. He was in his normal state of health until he suddenly developed substernal chest pain associated with nausea and vomiting after he finished his routine workout in the morning. He reported similar episodes of chest pain along with shortness of breath on exertion over the past two years. He was referred to a cardiologist who opted to perform an exercise treadmill stress test with unremarkable results. He denied any family history of cardiovascular diseases. He regularly followed a gastroenterologist for his Crohn’s disease that was complicated by anal fistula. Unfortunately, he had been experiencing daily chronic diarrhea due to Crohn’s disease. He was also scheduled for an abdominal ultrasound for his chronically elevated liver enzymes in the upcoming months. Otherwise, he denied alcohol abuse, smoking history, or illicit medication use. He worked as a security guard and was also a heavy weight lifter. He used chronic anabolic steroids in three-to-four months cycles for approximately the past ten years.\n\nElectrocardiogram (EKG) revealed anterior wall ST-segment elevations along with an elevated cardiac troponin level (Figure 1). The patient was transferred to our hospital status post administering of aspirin 324 milligrams (mg) via helicopter transportation service in order to undergo emergent coronary angiography that revealed a normal left main coronary artery, but a thrombotic occlusion was found in the left anterior descending artery (LAD) (Figure 2). There was thrombolysis in myocardial infarction (TIMI) grade flow of 1-2 from collateral arteries of the distal right coronary artery to the septal cascade. The patient underwent balloon angioplasty associated with intracoronary thrombolysis of tissue plasminogen activator (tPA) 10 mg over 10 minutes. Insertion of a 4.5 x 3.8 millimeters of the bare-metal stent was deployed at high atmospheric pressure. The subsequent angiography demonstrated TIMI II/III flow to the anterior lateral wall with respective correlation found on the left ventriculogram that showed severe anterior lateral, anterior apical, inferior apical hypokinesis with an approximate ejection fraction (EF) of 30% (Figure 3). He remained to be hemodynamically stable throughout the procedure without significant arrhythmias except for a transient accelerated idioventricular rhythm (AIVR) episode. The patient was subsequently transferred to the cardiac care unit (CCU) status post the intervention for further management. He remained to be stable overnight.\n\nFigure 1 Electrocardiography (EKG)\nST-segment elevation of the precordial leads of the EKG consistent with anterior myocardial infarction.\n\nFigure 2 Coronary angiography\nCoronary angiography showed thrombotic occlusion of the left anterior descending coronary artery (LAD).\n\nFigure 3 Coronary angiography\nCoronary angiography status post balloon angioplasty and bare-metal stent deployment showed revascularization of the left anterior descending coronary artery (LAD).\n\nOn day two of hospitalization, he was hemodynamically stable with normal sinus rhythm while on telemetry monitoring. Laboratory results were unremarkable except for elevated troponin levels that peaked at 440 NG/ML, reactive leukocytosis of 18.0 K/UL without a clinical impression of infection along with elevated aspartate aminotransferase (AST) of 521 U/L and alanine aminotransferase (ALT) of 186 U/L with a normal level of alkaline phosphatase. He had a normal hemoglobin A1c of 5.4% and elevated low-density lipoprotein cholesterol (LDL) of 158 MG/DL despite a normal cholesterol level of 198 MG/DL. Echocardiogram showed a moderate to severely reduced left ventricular systolic function with an estimated EF of 25%-30%. He had no signs of acute congestive heart failure or arrhythmias. He remained to be stable overnight. \n\nOn day three of hospitalization, he continued to remain hemodynamically stable without signs of arrhythmia or acute congestive heart failure. He was asymptomatic with negative reviews of the system. He was fitted for a wearable cardiac defibrillator to potentially reduce the risk of sudden cardiac arrest. He was subsequently downgraded to the telemetry floor from the CCU. He was discharged from the hospital and recommended against taking further anabolic steroids as it was believed to be the cause of his MI without obvious cardiovascular risk factors. He was advised to follow up with his primary cardiologist in the outpatient setting for the continuation of care. He eventually underwent an automatic implantable cardioverter-defibrillator (AICD) implantation three months later (Figure 4).\n\nFigure 4 Automatic implantable cardioverter-defibrillator (AICD)\nLateral view of chest X-ray showed intact left-sided AICD without evidence of active cardiopulmonary disease processes. H: head. F: foot.\n\nDiscussion\nThere are a total of less than 30 case reports of AAS associated MI in healthy young adults as of today [6]. Most of the reported cases were related to high doses of steroid intake (usually greater than five times as the recommended dose) in drug abusers and thus had a higher incidence of developing complications. Moreover, AAS poses various side effects that target the liver and cardiovascular system when the dose exceeds the capacity of our physiological levels. Potential side effects include but do not limit to dyslipidemia, hypertension, a decrease in cardiac output, hypercoagulability, testicular atrophy, gynecomastia, depression, aggression, increased risk of tendon tears and hepatic carcinoma [3,7]. These side effects may be reversible upon discontinuation of AAS. Furthermore, previous case reports described the association of AAS use with acute MI, sudden cardiac death, cardiac conduction abnormalities, cardiomyopathy, and cardiovascular thrombosis [5,6]. However, the frequency of cardiovascular events among patients taking AAS is likely underreported due to the patient’s preference in masking AAS abuse. \n\nThe mechanism of actions between AAS and MI is currently not well understood despite the presence of previous case reports describing the association of MI in young adults with AAS use. One hypothesis revolves around atherosclerosis, thrombosis, direct endothelial injury, or vasospasm. AAS may cause accelerated atherosclerosis via their effects on lipid metabolism as LDL levels were found to be increased by 36% while high-density lipoprotein (HDL) levels were decreased by 52% in patients taking a high dose of AAS [8]. In addition, AAS can also enhance platelet aggregation likely via increased platelet production of thromboxane A2 (potent platelet aggregator) and/or decreased platelet production of prostaglandin 2 (inhibitor of platelet aggregation) [6,9]. Experimental studies have shown that animals treated with AAS had greater clot size and shorter vessel-occlusion time in response to thrombotic stimuli [6]. Furthermore, androgens may cause increased levels of procoagulant factors that lead to prothrombotic effects through coagulation/fibrinolytic cascade even though their effects on coagulation cascade and fibrinolytic pathway are currently not well understood [6,9]. Moreover, elevated homocysteine levels were found in a few cases of AAS-associated MI. Homocysteine has both atherosclerotic and thrombotic effects in healthy adults as it is toxic to endothelial cells by causing smooth muscle proliferation in the vessel walls and affecting the coagulation cascade [10]. AAS can also affect the absorption of Vitamin B 12 leading to hyperhomocysteinemia. AAS may also stimulate erythropoiesis which results in polycythemia which in turn increases blood viscosity leading to thrombosis [6]. Direct toxicity of AAS can also result in fibrosis and intimal hyperplasia of the intramural coronary arteries [11].\n\nIn patients with normal coronary arteries, the cause of MI may be due to coronary spasm as AAS can directly affect vascular endothelial cells resulting in vasospasm. Experimental studies showed that AAS can cause a decreased response to vasodilators due to inhibition of endothelial guanylate cyclase which leads to the reduction of nitric oxide-mediated relaxation [12]. Chronic AAS (Nandrolone) therapy was also found to cause decreased thoracic aorta relaxation due to decreased concentrations of arterial endothelial cyclic guanosine monophosphate [11]. \n\nSome cases described normal coronary arteries in AAS users with MI but others showed thrombotic occlusion of coronary arteries. The first report of MI was reported in a 22-year-old powerlifter who was found to have normal coronary arteries even though he had significant hypercholesterolemia and hyperactive platelet function [9]. However, another subsequent case described a young adult with a sudden death who was found to have thrombotic occlusion of the left main and left anterior descending coronary artery postmortem [9]. Hernandez et al. described a case of a 24-year-old man with a history of AAS abuse who suffered a cardiorespiratory arrest and was later found to have acute MI due to severe coronary atherosclerosis and superimposed acute occlusive thrombosis at the left main trunk and left anterior descendant [2]. Whereas another case described a 32-year-old man who had acute MI due to coronary spasm from AAS use as he was found to have normal coronary arteries on an angiogram [13]. A few other case reports described young men with AAS abuse who developed acute MI and was later found to have hyperhomocysteinemia [10,14]. Santos et al. mentioned a young man who was found to have an intraluminal thrombus likely due to a hypercoagulable state associated with AAS use [15].\n\nAAS abuse has also been associated with both systolic and diastolic ventricular dysfunction. AAS abuse may cause direct myocardial injury causing increased collagen deposition, fibrosis and myocytolysis. It can cause ventricular hypertrophy via the upregulation of androgen receptors [2,6]. Our patient eventually received AICD placement due to his persistent systolic dysfunction in the three months follow up appointment. \n\nHowever, AAS may not be the only contributing factor for his acute MI despite his young age and lack of cardiovascular risk factors. Another factor that may be associated with his MI is his history of Crohn’s disease and Infliximab use. Even though there is currently no proven causal relationship between inflammatory bowel disease (IBD) and thromboembolic events, patients with IBD have a higher thromboembolic risk than the normal control population (8% vs 2%) with arterial thrombosis less common than venous thrombosis. In addition, vitamin B12 or folic acid deficiency, hyperhomocysteinemia, and increased lipoprotein associated with IBD may increase the risk of thrombosis. There were case reports describing IBD patients who were treated with Infliximab but had a higher risk of thrombosis with subsequent MI [16]. \n\nOur patient was a physically active young man without obvious cardiovascular risk factors along with a normal stress test two years ago. His acute MI was thought to be secondary to chronic AAS use as well as a possible contributing factor of Infliximab used for Crohn’s disease treatment\n\nConclusions\nIt is important to raise awareness of the potential side effects of chronic AAS as it may lead to the development of MI. A detailed social history in the young patient population may be a game-changer when investigating the underlying causes of MI.\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 The global epidemiology of anabolic-androgenic steroid use: a meta-analysis and meta-regression analysis Ann Epidemiol Sagoe D Molde H Andreassen CS Torsheim T Pallesen S 383 398 24 2014 24582699 \n2 Sudden cardiac death in anabolic androgenic steroids abuse: case report and literature review Forensic Sci Res Hernandez-Guerra AI Tapia J Menendez-Quintanal LM Lucena JS 267 273 4 2019 31489392 \n3 Medical issues associated with anabolic steroid use: are they exaggerated? J Sports Sci Med Hoffman JR Ratamess NA 182 193 5 2006 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3827559/ 24259990 \n4 Youth risk behavior surveillance--United States, 2013 MMWR Suppl Kann L Kinchen S Shanklin SL 1 168 63 2014 https://www.jstor.org/stable/24806229?seq=1 \n5 Adverse health consequences of performance-enhancing drugs: an endocrine society scientific statement Endocr Rev Pope HG Wood RI Rogol A Nyberg F Bowers L Bhasin S 341 375 35 2014 24423981 \n6 Acute myocardial infarction in a young bodybuilder taking anabolic androgenic steroids: a case report and critical review of the literature Eur J Prev Cardiol Christou GA Christou KA Nikas DN Goudevenos JA 1785 1796 23 2016 27184497 \n7 Cardiovascular toxicities of performance-enhancing substances in sports Mayo Clin Proc Dhar R Stout CW Link MS Weinstock J Estes NA III 1307 1315 80 2005 16212144 \n8 Atherogenic effects of anabolic steroids on serum lipid levels Arch Intern Med Glazer G 1925 1933 151 1991 https://jamanetwork.com/journals/jamainternalmedicine/article-abstract/615569 1929679 \n9 Myocardial infarction associated with anabolic steroid use in a previously healthy 37-year-old weight lifter Am Heart J Ferenchick GS Adelman S 507 508 124 1992 1636596 \n10 Acute myocardial infarction in a young male wrestler: a case report ARYA Atheroscler Poorzand H Jafarzadeh Esfehani R Hosseinzadeh P Vojdanparast M 366 369 11 2015 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4738047/ 26862345 \n11 Anabolic androgenic steroid-induced acute myocardial infarction with multiorgan failure Proc (Bayl Univ Med Cent) Flo FJ Kanu O Teleb M Chen Y Siddiqui T 334 336 31 2018 29904303 \n12 Enhanced vasoconstriction and reduced vasorelaxation induced by testosterone and nandrolone in hypercholesterolemic rabbits Pharmacol Res Ammar EM Said SA Hassan MS 253 259 50 2004 15225667 \n13 Chronic anabolic androgenic steroid usage associated with acute coronary syndrome in bodybuilder Turk J Emerg Med Sonmez E Turkdogan KA Yilmaz C Kucukbuzcub A Ozkana A Sogutt O 35 37 16 2016 27239638 \n14 Hyperhomocysteinemia-induced myocardial infarction in a young male using anabolic steroids Am J Emerg Med Peoples K Kobe D Campana C Simon E 948 32 2014 \n15 Anabolic drugs and myocardial infarction - a clinical case report Arq Bras Cardiol Santos RP Pereira A Guedes H 316 319 105 2015 26466073 \n16 Acute coronary syndrome after infliximab therapy in a patient with Crohn's disease World J Gastroenterol Panteris V Perdiou A Tsirimpis V Karamanolis DG 6235 6238 12 2006 17036404\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "12(5)",
"journal": "Cureus",
"keywords": "anabolic steroid; crohn's disease; inflammatory bowel disease; mi; myocardial infarction; st-elevation myocardial infarction (stemi); steroid; ulcerative colitis",
"medline_ta": "Cureus",
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"pubdate": "2020-05-28",
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"references": "1929679;31489392;16212144;26862345;24423981;24918634;24259990;24650717;1636596;17036404;24582699;15225667;27184497;26466073;29904303;27239638",
"title": "A Rare Case Report and Literature Review of Anabolic-Androgenic Steroids (AAS)-Induced Acute Myocardial Infarction.",
"title_normalized": "a rare case report and literature review of anabolic androgenic steroids aas induced acute myocardial infarction"
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"abstract": "T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T-LBL) are neoplasms that originate from T-cell precursors. Outcomes in adult patients with T-ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T-cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T-cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T-ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper-CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T-cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper-CVAD in an adult patient with refractory T-ALL and highlights the activity of romidepsin in the T-cell lineage. The potential of romidepsin-containing regimens in patients with T-ALL/LBL deserves further study.",
"affiliations": "Colorado Blood Cancer Institute, Denver, CO, USA.;Colorado Blood Cancer Institute, Denver, CO, USA.",
"authors": "Brunvand|Mark W|MW|http://orcid.org/0000-0003-1229-2699;Carson|John|J|",
"chemical_list": "D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; C087123:romidepsin",
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"doi": "10.1002/hon.2421",
"fulltext": "\n==== Front\nHematol OncolHematol Oncol10.1002/(ISSN)1099-1069HONHematological Oncology0278-02321099-1069John Wiley and Sons Inc. Hoboken 10.1002/hon.2421HON2421HON-16-0185.R3Case ReportCase ReportsComplete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD\n Brunvand and CarsonBrunvand Mark W. http://orcid.org/0000-0003-1229-2699mbrunvand@mac.com \n1\nCarson John \n1\n\n1 \nColorado Blood Cancer Institute\nDenver\nCO\nUSA\n* \nCorrespondence\n\nMark W. Brunvand, 1721 East 19th Avenue, Suite 300, Denver, CO 80218, USA.\n\nEmail: mbrunvand@mac.com\n30 5 2017 2 2018 36 1 10.1002/hon.v36.1340 343 01 8 2016 14 3 2017 20 3 2017 © 2017 The Authors. Hematological Oncology published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nT‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) are neoplasms that originate from T‐cell precursors. Outcomes in adult patients with T‐ALL/LBL remain unsatisfactory; early relapse following intensive induction chemotherapy is a concern, and patients with relapsed or refractory disease have a poor prognosis. Romidepsin is a potent, class 1 selective histone deacetylase inhibitor approved for the treatment of patients with peripheral T‐cell lymphoma who have had ≥1 prior therapy and patients with cutaneous T‐cell lymphoma who have had ≥1 prior systemic therapy. Here, we report the case of an adult patient with T‐ALL refractory to induction hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper‐CVAD). Treatment with romidepsin was initiated, and romidepsin in combination with hyper‐CVAD resulted in complete remission, with mild tumor lysis syndrome as the only detectable additional toxicity. The patient eventually underwent allogeneic stem cell transplant while in first complete remission. Prior studies have shown that romidepsin is capable of inducing durable responses with manageable toxicities in patients with mature T‐cell lymphomas. This case study describes the successful use of romidepsin in combination with hyper‐CVAD in an adult patient with refractory T‐ALL and highlights the activity of romidepsin in the T‐cell lineage. The potential of romidepsin‐containing regimens in patients with T‐ALL/LBL deserves further study.\n\nchemotherapyearly T‐cell precursor acute lymphoblastic leukemia/lymphomahistone deacetylase inhibitorromidepsinT‐cell acute lymphoblastic leukemiaT‐cell lymphoblastic lymphoma source-schema-version-number2.0component-idhon2421cover-dateFebruary 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.3.2.2 mode:remove_FC converted:05.03.2018\n\n\nBrunvand \nMW \n, \nCarson \nJ \n. Complete remission with romidepsin in a patient with T‐cell acute lymphoblastic leukemia refractory to induction hyper‐CVAD\n . Hematological Oncology . 2018 ;36 :340 –343 . https://doi.org/10.1002/hon.2421\n28560733\n==== Body\n1 INTRODUCTION\nT‐cell acute lymphoblastic leukemia (T‐ALL) and T‐cell lymphoblastic lymphoma (T‐LBL) originate from lymphoblasts committed to the T‐cell lineage and are classified by the World Health Organization as a single entity, regardless of leukemic or lymphoma disease manifestations.1 T‐ALL and T‐LBL have similar lymphoblast morphology and immunophenotype but differ in gene expression profile, clinical prognostic factors, and responses to treatment—although T‐ALL‐like regimens have shown effectiveness in patients with T‐LBL.1, 2, 3, 4, 5, 6 Outcomes for adult patients with T‐ALL/LBL remain unsatisfactory, and patients with relapsed or refractory disease face a particularly poor prognosis with low overall survival rates.5, 7, 8, 9, 10, 11 It is acknowledged that new agents are needed for treatment of refractory/relapsed T‐ALL/LBL. Efforts are underway to identify immunohistochemistry and gene profile markers that identify patients at higher risk of refractory or relapsed disease. Once high‐risk patients are identified, novel induction treatments can be studied to potentially improve outcomes.\n\nWe report the case of an adult female patient with T‐ALL that progressed twice during her first cycle of hyper‐CVAD (cyclophosphamide + vincristine + doxorubicin + dexamethasone). Flow cytometry results indicated that the disease may have been early T‐cell precursor (ETP)–ALL/LBL with additional high‐risk features.12 Although several regimens have been reported, the optimal reinduction therapy for relapsed or refractory T‐ALL or T‐LBL remains unclear.5, 7, 11 Radiation was added for the first progression, and romidepsin was added for the second lymph node progression, which occurred outside of the radiation field. Romidepsin, which is approved for treatment of relapsed/refractory T‐cell non‐Hodgkin lymphoma (peripheral T‐cell lymphoma [PTCL] and cutaneous T‐cell lymphoma [CTCL]) in the United States,13 was chosen because it was unlikely to exacerbate her mucositis due to chemoradiotherapy, to significantly worsen her neutropenia, or add end‐organ toxicity. Upon rapid progression after induction with a standard adult induction regimen, the patient consented to salvage therapy with hyper‐CVAD with the addition of romidepsin.\n\n2 PATIENT DATA AND METHODS\nA 38‐year‐old previously healthy woman presented to an outside hospital on October 6, 2014, with T‐ALL. Her workup was completed at the Colorado Blood Cancer Institute, and she consented to chemotherapy with hyper‐CVAD and all subsequent salvage chemoradiotherapy, using institutional review board–approved consent forms for treatment. The patient provided prior written consent for the anonymous use of her data and was treated in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines for Good Clinical Practice, and this institution's institutional review board.\n\nThe workup was initiated at an outside hospital on October 7, 2014, and consisted of contrast enhanced computed tomography (CT) of the neck, chest, abdomen, and pelvis, with a bone marrow biopsy. An echocardiogram and diagnostic lumbar puncture with prophylactic intrathecal methotrexate were initiated after she was transferred to the Colorado Blood Cancer Institute for management. The peripheral blood white‐blood cell count was 43 000/μL (40% circulating T‐cell lymphoblasts), hemoglobin 6.9 g/dL, and platelets 108 000/μL. Her bone marrow biopsy confirmed lymphoblastic leukemia with 100% cellularity and 73% T‐cell lymphoblasts. The T‐cell lymphoblasts were positive for CyCD3, CD7, CD13, CD38, CD45, CD45RA, and CD117, with partial expression of CD2, CD123, and HLA‐DR, and were negative for CD1a, CD3, CD4, CD8, CD11b, CD14, CD15, CD16, CD33, CD34, CD45RO, CD56, CD84, CD10, and myeloperoxidase. TdT was negative by flow cytometry, but positive by immunohistochemistry. Taken together, the immunohistochemistry and flow cytometry was most consistent with pre‐T‐ALL.14 Our case is suggestive of ETP‐ALL/LBL in the current World Health Organization nomenclature; however, CD5 was not characterized and definitive determination was not possible.12, 14, 15 ETP‐ALL/LBL neoplasms originate from thymocytes that do not express CD1a or CD8, have weak expression of CD5, and express 1 or more stem cell (CD117) or myeloid markers.14, 15\n\n\nThe lymphoblast karyotype revealed 46, XX with trisomy 4 and del X (q13). Total‐body CT showed a 1.7 × 2.2 cm left neck lymph node mass with additional lymph nodes throughout the left and right neck.\n\nThe patient began hyper‐CVAD cycle 1A on October 11, 2014, and her peripheral blood blasts resolved. Clinically, the left neck lymph node mass initially decreased in size by over 50%. By day 7 of hyper‐CVAD cycle 1A, the left neck lymph nodes grew, exceeding their initial size, and were treated with 4 radiation fractions to the involved left neck lymph nodes. The left neck lymph node mass responded to the radiation. During this radiation treatment of the left neck, the T‐ALL lymph nodes in the right neck progressed by contrast‐enhanced CT performed on October 28, 2014, “mid cycle” of hyper‐CVAD cycle 1A. The patient was neutropenic due her recent chemoradiotherapy at the time of the second progression. Romidepsin 14 mg/m2 as a 4‐hour infusion was initiated on days 11 and 18 of hyper‐CVAD cycle 1A to treat the progression of T‐ALL within the right neck. Twenty‐four hours after the first dose of romidepsin, the patient experienced mild orthostatic hypotension, increased phosphate and potassium levels, decreased calcium levels, and negative blood culture results. The clinical picture was most consistent with mild tumor lysis syndrome and was treated with intravenous hydration and urine alkalization.\n\nAfter hyper‐CVAD cycle 1A with romidepsin, a positron emission tomography (PET)/CT showed minimal areas of 18F‐fluorodeoxyglucose uptake in the involved lymph nodes in the left and right neck. The patient was readmitted on November 22, 2014, to undergo cycle 1B of hyper‐CVAD with planned supplemental romidepsin on days 11 and 18. An abscess developed after radiation within the necrotic left neck lymph node mass and was drained before the high‐dose methotrexate and cytarabine of hyper‐CVAD cycle 1B. The drained material was sterile and contained no viable T‐ALL. The patient completed a 3‐week course of clindamycin and ertapenem, without recurrence of the abscess. The patient entered a complete remission (CR) by the end of cycle 1B of romidepsin‐supplemented hyper‐CVAD with no morphological T‐ALL in the bone marrow biopsy or positron emission tomography PET/CT evidence of disease. As is standard in our program for patients with primary refractory disease, the patient underwent an allogeneic (HLA‐identical sister) peripheral blood hematopoietic stem cell transplant (PB‐HSCT) in first CR with fludarabine/total body irradiation (400 cGy) on January 3, 2015. The patient remains in CR with mild chronic graft‐versus‐host disease 22 months after the transplant.\n\n3 DISCUSSION\nOutcomes for patients with relapsed or refractory T‐ALL/LBL remain unsatisfactory, with poor overall survival rates.5, 7, 8, 9, 10, 11 In a Medical Research Council/Eastern Cooperative Oncology Group study, 123 of 334 patients (37%) relapsed after induction therapy; 27 of these 123 patients went on to receive allogeneic stem cell transplant, and 8 survived at a median of 5.2 years.8 Hyper‐CVAD with or without nelarabine has been used to treat adults with T‐ALL/LBL, but the risk of early relapse is a concern.6, 7, 16 Our patient progressed after cycle 1A of hyper‐CVAD—a “standard” adult T‐ALL/LBL induction.6, 7\n\n\nAlthough a definitive determination was not possible without the characterization of CD5, the CD1a− and CD8− T‐cell blasts within the bone marrow and a blast count of >20% suggest that our patient may have had ETP‐ALL/LBL.12, 14, 15 The limited available data seem to indicate that patients with ETP‐ALL/LBL may fare even worse than those with mature T‐ALL/LBL.12 The CR rate for hyper‐CVAD‐based or augmented BFM chemotherapy in patients with ETP‐ALL/LBL is only 73% vs 91% for non‐ETP‐ALL/LBL, with a median overall survival of only 20 months.\n\nRomidepsin is a histone deacetylase (HDAC) inhibitor approved for the treatment of patients with PTCL who have received ≥1 prior therapy and for patients with CTCL who have had ≥1 prior systemic therapy.13 Although the underlying mechanisms remain unclear, HDAC inhibitors in general, and romidepsin in particular, have demonstrated activity in mature T‐cell lymphomas.17, 18, 19, 20 In the 2 pivotal phase 2 trials that led to approvals in each respective indication (PTCL and CTCL), romidepsin induced durable responses with manageable toxicity.18, 19, 20 Furthermore, manageable myelosuppression has been reported with romidepsin added to standard cell cycle–active chemotherapy, suggesting that it could be combined with our patient's treatments for primary refractory disease (dose‐intense induction chemotherapy and radiation).21 In the case presented here, one reason for the selection of romidepsin was the potential for minimal toxicity when added to chemotherapy for the primary refractory T‐ALL. Romidepsin given to our patient with T‐ALL on days 11 and 18 appeared to enhance the effectiveness of hyper‐CVAD and radiation, resulting in a CR, allowing for allogeneic PB‐HSCT, and with mild tumor lysis syndrome as the only detected additional toxicity.\n\nRomidepsin may increase the effectiveness of frontline chemotherapy in patients with T‐ALL/LBL, potentially decreasing the number of patients with primary refractory disease and ultimately leading to improved overall survival. The response in this patient with T‐ALL indicates that although approved for use in more mature T‐cell lymphomas, romidepsin may have activity in more immature T‐cell malignancies. Although there are relatively little preclinical and clinical data on the activity of romidepsin in T‐ALL/LBL, the combination of romidepsin with oral azacitidine (hypomethylating agent) in an early‐phase clinical trial resulted in CR in a patient with relapsed/refractory T‐ALL.22, 23, 24, 25 In our program, patients with high‐risk T‐cell lymphomas who have CR with romidepsin‐containing initial or salvage chemotherapy have a low relapse rate after allogeneic transplant (data available on request). Romidepsin‐containing chemotherapy regimens deserve further study in this high‐risk population.\n\nCONFLICT OF INTEREST\nMark W. Brunvand has been a consultant for Celgene Corporation. John Carson has nothing to declare.\n\nACKNOWLEDGEMENTS\nThe authors take full responsibility for the content of this manuscript, but thank William Ho, PhD (MediTech Media, Ltd), for providing medical editorial assistance. Financial support for medical editorial assistance was provided by Celgene Corporation.\n==== Refs\nREFERENCES\n1 \n\nSwerdlow \nSH \n, \nCampo \nE \n, \nHarris \nNL \n, et al. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues . Lyon, France : International Agency for Research on Cancer ; 2008 .\n2 \n\nHoelzer \nD \n, \nGokbuget \nN \n. T‐cell lymphoblastic lymphoma and T‐cell acute lymphoblastic leukemia: a separate entity? \nClin Lymphoma Myeloma . 2009 ;9 (Suppl 3 ):S214 ‐S221 .19778844 \n3 \n\nRaetz \nEA \n, \nPerkins \nSL \n, \nBhojwani \nD \n, et al. Gene expression profiling reveals intrinsic differences between T‐cell acute lymphoblastic leukemia and T‐cell lymphoblastic lymphoma . Pediatr Blood Cancer . 2006 ;47 :130 ‐140 .16358311 \n4 \n\nJabbour \nE \n, \nKoscielny \nS \n, \nSebban \nC \n, et al. High survival rate with the LMT‐89 regimen in lymphoblastic lymphoma (LL), but not in T‐cell acute lymphoblastic leukemia (T‐ALL) . Leukemia . 2006 ;20 :814 ‐819 .16511514 \n5 \n\nCortelazzo \nS \n, \nPonzoni \nM \n, \nFerreri \nAJ \n, \nHoelzer \nD \n. Lymphoblastic lymphoma . Crit Rev Oncol Hematol . 2011 ;79 :330 ‐343 .21273093 \n6 \n\nThomas \nDA \n, \nO'Brien \nS \n, \nCortes \nJ \n, et al. Outcome with the hyper‐CVAD regimens in lymphoblastic lymphoma . Blood . 2004 ;104 :1624 ‐1630 .15178574 \n7 \n\nLitzow \nMR \n, \nFerrando \nAA \n. How I treat T‐cell acute lymphoblastic leukemia in adults . Blood . 2015 ;126 :833 ‐841 .25966987 \n8 \n\nMarks \nDI \n, \nPaietta \nEM \n, \nMoorman \nAV \n, et al. T‐cell acute lymphoblastic leukemia in adults: Clinical features, immunophenotype, cytogenetics, and outcome from the large randomized prospective trial (UKALL XII/ECOG 2993) . Blood . 2009 ;114 :5136 ‐5145 .19828704 \n9 \n\nDeAngelo \nDJ \n, \nYu \nD \n, \nJohnson \nJL \n, et al. Nelarabine induces complete remissions in adults with relapsed or refractory T‐lineage acute lymphoblastic leukemia or lymphoblastic lymphoma: cancer and leukemia Group B study 19801 . Blood . 2007 ;109 :5136 ‐5142 .17344466 \n10 \n\nFielding \nAK \n, \nRowe \nJM \n, \nRichards \nSM \n, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome‐positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre‐imatinib era: results from the international ALL trial MRC UKALLXII/ECOG2993 . Blood . 2009 ;113 :4489 ‐4496 .19244158 \n11 \n\nGokbuget \nN \n, \nStanze \nD \n, \nBeck \nJ \n, et al. Outcome of relapsed adult lymphoblastic leukemia depends on response to salvage chemotherapy, prognostic factors, and performance of stem cell transplantation . Blood . 2012 ;120 :2032 ‐2041 .22493293 \n12 \n\nJain \nN \n, \nLamb \nAV \n, \nO'Brien \nS \n, et al. Early T‐cell precursor acute lymphoblastic leukemia/lymphoma (ETP‐ALL/LBL) in adolescents and adults: a high‐risk subtype . Blood . 2016 ;127 :1863 ‐1869 .26747249 \n13 \nISTODAX \n(romidepsin) [package insert] . 2016 .\n14 \nNCCN clinical practice Guidelines in Oncology: acute lymphoblastic leukemia . V.2.2016.\n15 \n\nCoustan‐Smith \nE \n, \nMullighan \nCG \n, \nOnciu \nM \n, et al. Early T‐cell precursor leukaemia: a subtype of very high‐risk acute lymphoblastic leukaemia . Lancet Oncol . 2009 ;10 :147 ‐156 .19147408 \n16 \n\nJain \nP \n, \nKantarjian \nH \n, \nRavandi \nF \n, et al. The combination of hyper‐CVAD plus nelarabine as frontline therapy in adult T‐cell acute lymphoblastic leukemia and T‐lymphoblastic lymphoma: MD Anderson Cancer Center experience . Leukemia . 2014 ;28 :973 ‐975 .24157581 \n17 \n\nO'Connor \nOA \n, \nBhagat \nG \n, \nGanapathi \nK \n, et al. Changing the paradigms of treatment in peripheral T‐cell lymphoma: from biology to clinical practice . Clin Cancer Res . 2014 ;20 :5240 ‐5254 .25320373 \n18 \n\nWhittaker \nSJ \n, \nDemierre \nM \n, \nKim \nEJ \n, et al. Final results from a multicenter, international, pivotal study of romidepsin in refractory cutaneous T‐cell lymphoma . J Clin Oncol . 2010 ;28 :4485 ‐4491 .20697094 \n19 \n\nCoiffier \nB \n, \nPro \nB \n, \nPrince \nHM \n, et al. Romidepsin for the treatment of relapsed/refractory peripheral T‐cell lymphoma: pivotal study update demonstrates durable responses . J Hematol Oncol . 2014 ;7 :11 \n24456586 \n20 \n\nCoiffier \nB \n, \nPro \nB \n, \nPrince \nHM \n, et al. Results from a pivotal, open‐label, phase II study of romidepsin in relapsed or refractory peripheral T‐cell lymphoma after prior systemic therapy . J Clin Oncol . 2012 ;30 :631 ‐636 .22271479 \n21 \n\nDupuis \nJ \n, \nMorschhauser \nF \n, \nGhesquieres \nH \n, et al. Combination of romidepsin with cyclosphosphamide, doxorubicin, vinrcristine, and prednisone in previously untreated patients with peripheral T‐cell lymphoma: a non‐randomised, phase 1b/2 study . Lancet Haematology . 2015 ;2 :e160 ‐e165 .26687958 \n22 \n\nSatwani \nP \n, \nBavishi \nS \n, \nSaha \nA \n, et al. Upregulation of NKG2D ligands in acute lymphoblastic leukemia and non‐Hodgkin lymphoma cells by romidepsin and enhanced in vitro and in vivo natural killer cell cytotoxicity . Cytotherapy . 2014 ;16 :1431 ‐1440 .24856896 \n23 \n\nValdez \nBC \n, \nBrammer \nJE \n, \nLi \nY \n, et al. Romidepsin targets multiple survival signaling pathways in malignant T cells . Blood Cancer J . 2015 ;5 : e357\n24 \n\nMarchi \nE \n, \nZullo \nKM \n, \nAmengual \nJE \n, et al. The combination of hypomethylating agents and histone deacetylase inhibitors produce marked synergy in preclinical models of T‐cell lymphoma . Br J Haematol . 2015 ;171 :215 ‐226 .\n25 \n\nO'Connor \nOA \n, \nZullo \nK \n, \nMarchi \nE \n, et al. Targeting epigenetic operations with HDAC inhibitor and Hypomethylating drugs in combination exhibit synergy in preclinical and clinical experiences in drug resistant T‐cell lymphoma (TCL): A translational focus on doublet development . Blood . 2015 ;126 : Abstract 1282\n\n",
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"issue": "36(1)",
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"keywords": "T-cell acute lymphoblastic leukemia; T-cell lymphoblastic lymphoma; chemotherapy; early T-cell precursor acute lymphoblastic leukemia/lymphoma; histone deacetylase inhibitor; romidepsin",
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"mesh_terms": "D000328:Adult; D000903:Antibiotics, Antineoplastic; D047630:Depsipeptides; D005260:Female; D006801:Humans; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma; D012074:Remission Induction",
"nlm_unique_id": "8307268",
"other_id": null,
"pages": "340-343",
"pmc": null,
"pmid": "28560733",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": "15178574;26473529;28560733;26747249;24157581;16358311;25966987;19244158;24856896;22271479;19778844;17344466;26687958;19147408;16511514;24456586;22493293;19828704;26194163;20697094;21273093;25320373",
"title": "Complete remission with romidepsin in a patient with T-cell acute lymphoblastic leukemia refractory to induction hyper-CVAD.",
"title_normalized": "complete remission with romidepsin in a patient with t cell acute lymphoblastic leukemia refractory to induction hyper cvad"
} | [
{
"companynumb": "US-MYLANLABS-2018M1016564",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThe impact of pregnancy on efavirenz (EFV) pharmacokinetics is unknown.\n\n\nMETHODS\nInternational Maternal Pediatric Adolescent AIDS Clinical Trials P1026s is an on-going, prospective, nonblinded study of antiretroviral pharmacokinetics in HIV-infected pregnant women that included a cohort receiving 600 mg EFV once daily as part of combination antiretroviral therapy. Intensive steady-state 24-hour blood sampling was performed during the third trimester and at 6-12 weeks postpartum. Maternal and umbilical cord blood samples were drawn at delivery. Pharmacokinetics targets were the estimated 10th percentile EFV area under the curve (AUC) in nonpregnant historical controls (40.0 mcg·hr(-1)·mL(-1)) and a trough concentration of 1 mcg/mL.\n\n\nRESULTS\nTwenty-five women were enrolled during the third trimester: median (range) age was 29.3 (18.9-42.9) years, weight 69.0 (40-130) kg, and gestational age 32.9 (30.1-38.7) weeks. Median (range) EFV AUC(0-24), C(max), and C(24 hours) were 55.4 mcg·hr(-1)·mL(-1) (13.5-220.3), 5.4 mcg/mL (1.9-12.2), and 1.6 mcg/mL (0.23-8.13), respectively. EFV AUC and C(max) did not differ during pregnancy and postpartum but C(24 hours) was lower during the third trimester (1.6 vs. 2.1 mcg/mL, P = 0.01). During the third trimester, 5 of 25 (20%) women had an EFV AUC below the target and 3 of 25 (12%) had a trough concentration below 1 mcg/mL. EFV cord blood/maternal concentration ratio was 0.49 (0.37-0.74). All women had a HIV-1 RNA viral load less than 400 copies per milliliter at delivery and 19 (76%) had a viral load below 50 copies per milliliter. One child was perinatally HIV infected. Three women were exposed to EFV throughout the first 6 weeks of pregnancy. EFV was well tolerated, and among the 25 infants, no congenital anomalies or newborn complications were reported.\n\n\nCONCLUSIONS\nChanges in EFV pharmacokinetics during pregnancy compared with postpartum are not sufficiently large enough to warrant a dose adjustment during pregnancy.",
"affiliations": "Program for HIV Prevention and Treatment (IRD URI 174), Department of Medical Technology, Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, Thailand. tim@phpt.org",
"authors": "Cressey|Tim R|TR|;Stek|Alice|A|;Capparelli|Edmund|E|;Bowonwatanuwong|Chureeratana|C|;Prommas|Sinart|S|;Sirivatanapa|Pannee|P|;Yuthavisuthi|Prapap|P|;Neungton|Chanon|C|;Huo|Yanling|Y|;Smith|Elizabeth|E|;Best|Brookie M|BM|;Mirochnick|Mark|M|;|||",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0b013e31823ff052",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "59(3)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D019540:Area Under Curve; D048588:Benzoxazines; D015331:Cohort Studies; D003521:Cyclopropanes; D005260:Female; D005312:Fetal Blood; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D007231:Infant, Newborn; D049590:Postpartum Period; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011263:Pregnancy Trimester, Third; D011446:Prospective Studies; D018709:Statistics, Nonparametric; D055815:Young Adult",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "245-52",
"pmc": null,
"pmid": "22083071",
"pubdate": "2012-03-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "11807320;15568888;11822930;17045554;18366444;12676886;21283017;19812066;16988514;15696014;20625263;20622674;20479637;21516029;14982771;21371239",
"title": "Efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum.",
"title_normalized": "efavirenz pharmacokinetics during the third trimester of pregnancy and postpartum"
} | [
{
"companynumb": "TH-CIPLA LTD.-2016TH10032",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": null,
... |
{
"abstract": "Introduction Recently in Japan, Ramucirumab (RAM) became the first anti-angiogenic agent to be approved for second-line treatment of gastric cancer. In the present study, we aimed to evaluate the efficacy and safety of RAM plus paclitaxel (PTX) in patients with unresectable and recurrent gastric cancer in our institution.Patients and Methods The subjects were 11 patients with unresectable and recurrent gastric cancer who received RAM plus PTX as a second- or later-line treatment at our hospital between June 2015 and September 2017, after the failure of previously-attempted treatments. We assessed the efficacy and safety of RAM plus PTX, and also compared them between patients aged <75 years (n=6) and those aged ≥75 (n=5), by performing a retrospective analysis based on the data obtained from daily clinical practice for gastric cancer treatment.Results Objective tumor response was observed in one of the 11 patients (9.1%) with partial response, and disease control was seen in the remaining 10 (90.9%). The median overall survival (OS) and progression-free survival (PFS) of the patients were 20.8 months (95% CI 7.8-NA (not applicable)) and 11.3 months (95% CI 6.5-NA), respectively. There were no serious adverse events. The median OS for the <75 years group and ≥75 years group was NA (due to short follow-up period) and 20.8 months (p = 0.336), respectively, and their respective median PFS rates were 9.4 and 11.3 months (p = 0.492). The difference of rate of adverse events was not significant between the two age groups in the present study, though the number of adverse events was not sufficient.Conclusion The results of the present study suggest that the combination chemotherapy of RAM and PTX was effective in unresectable and recurrent gastric cancer patients as a second- or later-line therapy, and has been shown to be safe and feasible in elderly patients.",
"affiliations": "Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.;Department of Gastrointestinal Tract Surgery Fukushima Medical University.",
"authors": "Hayase|Suguru|S|;Yamada|Leo|L|;Ujiie|Daisuke|D|;Nirei|Azuma|A|;Tada|Takeshi|T|;Hanayama|Hiroyuki|H|;Monma|Tomoyuki|T|;Saze|Zenichiro|Z|;Ohki|Shinji|S|;Kono|Koji|K|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C543333:ramucirumab; D017239:Paclitaxel",
"country": "Japan",
"delete": false,
"doi": "10.5387/fms.2018-12",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-2590",
"issue": "65(1)",
"journal": "Fukushima journal of medical science",
"keywords": "advanced gastric cancer; chemotherapy; elderly; paclitaxel; ramucirumab",
"medline_ta": "Fukushima J Med Sci",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D017239:Paclitaxel; D012189:Retrospective Studies; D013274:Stomach Neoplasms",
"nlm_unique_id": "0374626",
"other_id": null,
"pages": "6-12",
"pmc": null,
"pmid": "30996218",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "20048182;20728210;22565005;23208313;23594786;23594787;24094768;24868024;25220842;25240821;26747859;28343975",
"title": "Clinical usefulness of ramucirumab plus paclitaxel for unresectable and recurrent gastric cancer.",
"title_normalized": "clinical usefulness of ramucirumab plus paclitaxel for unresectable and recurrent gastric cancer"
} | [
{
"companynumb": "JP-HQ SPECIALTY-JP-2019INT000237",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RAMUCIRUMAB"
},
"drugadditional": "3",... |
{
"abstract": "Cerebral phaeohyphomycosis refers to central nervous system infection caused by dematiaceous molds, which have many genuses. Cladophialophora bantiana is a member of the phylum ascomycota, which is found in soil samples from all over the world. This organism typically infects immunocompromised patients and associated with 70% mortality rate even after weeks of antifungal agent administration and surgical debridement. Two such cases of fungal brain abscess caused by cladophialophora bantiana were presented here. Both patients presented with complaints of headache, vomiting, drowsiness and impaired cognition. A brain biopsy together with microbiological culture and VITEK 2 helped in reaching to a final diagnosis. Key Words: Cladophialophora bantiana, Dematiaceous, Intracerebral, Phaeohyphomycosis.",
"affiliations": "Department of Histopathology, Shifa International Hospital, Islamabad, Pakistan.;Department of Microbiology, Shifa International Hospital, Islamabad, Pakistan.;Department of Histopathology, Shifa International Hospital, Islamabad, Pakistan.;Department of Histopathology, Shifa International Hospital, Islamabad, Pakistan.",
"authors": "Ali|Zafar|Z|;Usman|Muhammad|M|;Rehman|Usama|U|;Anwar|Fatima|F|",
"chemical_list": "D000935:Antifungal Agents",
"country": "Pakistan",
"delete": false,
"doi": "10.29271/jcpsp.2021.09.1114",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1022-386X",
"issue": "31(9)",
"journal": "Journal of the College of Physicians and Surgeons--Pakistan : JCPSP",
"keywords": null,
"medline_ta": "J Coll Physicians Surg Pak",
"mesh_terms": "D000935:Antifungal Agents; D001203:Ascomycota; D001922:Brain Abscess; D006801:Humans; D060446:Phaeohyphomycosis",
"nlm_unique_id": "9606447",
"other_id": null,
"pages": "1114-1116",
"pmc": null,
"pmid": "34500534",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Cladophialophora Bantiana as a Cause of Rare Fungal Brain Abscess.",
"title_normalized": "cladophialophora bantiana as a cause of rare fungal brain abscess"
} | [
{
"companynumb": "PK-GILEAD-2022-0576702",
"fulfillexpeditecriteria": "1",
"occurcountry": "PK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMPHOTERICIN B"
},
"drugadditional": "3",
... |
{
"abstract": "Graft-versus-host disease (GVHD) is a known risk factor for invasive aspergillosis (IA), but remains poorly studied in relation to Clostridium difficile infection (CDI). We report a case of a 58-years-old patient who developed an IA within a protected room, CDI and GVHD after allogeneic allogeneic peripheral blood stem cell transplantation (PBSCT). Factors associated with this complex condition in patients receiving allogeneic PBSCT need to be identified.",
"affiliations": "Service d'Hygiène, Epidémiologie et Prévention, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France; Equipe Epidémiologie et Santé Publique, Université de Lyon, Université Lyon 1, France. Electronic address: naghamkhanafer@hotmail.com.;Service d'Hygiène, Epidémiologie et Prévention, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France.;Service d'Hygiène, Epidémiologie et Prévention, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France; Equipe Epidémiologie et Santé Publique, Université de Lyon, Université Lyon 1, France.;Service de Réanimation médicale, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France.;Service Paludisme, Parasites du sang et Mycologie médicale, Groupement hospitalier Nord, Hospices Civils de Lyon, France.;Service d'Hématologie, Groupement hospitalier Lyon Sud, Hospices Civils de Lyon, France.;Service de Réanimation médicale, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France.;Service d'Hématologie, Groupement hospitalier Lyon Sud, Hospices Civils de Lyon, France.;Service d'Hygiène, Epidémiologie et Prévention, Groupement hospitalier Edouard Herriot, Hospices Civils de Lyon, France; Equipe Epidémiologie et Santé Publique, Université de Lyon, Université Lyon 1, France.",
"authors": "Khanafer|Nagham|N|;Neuraz|Antoine|A|;Bénet|Thomas|T|;Cour|Martin|M|;Persat|Florence|F|;Labussière|Hélène|H|;Argaud|Laurent|L|;Michallet|Mauricette|M|;Vanhems|Philippe|P|",
"chemical_list": "D000890:Anti-Infective Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-9964",
"issue": "33()",
"journal": "Anaerobe",
"keywords": "Bone marrow transplant; Clostridium difficile infection; Environmental transmission; Graft-versus-host disease; Invasive aspergillosis; Nosocomial",
"medline_ta": "Anaerobe",
"mesh_terms": "D000890:Anti-Infective Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001228:Aspergillosis; D004761:Enterocolitis, Pseudomembranous; D017809:Fatal Outcome; D006086:Graft vs Host Disease; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D036102:Peripheral Blood Stem Cell Transplantation; D014184:Transplantation, Homologous",
"nlm_unique_id": "9505216",
"other_id": null,
"pages": "98-100",
"pmc": null,
"pmid": "25749258",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute graft-versus-host disease, invasive aspergillosis and Clostridium difficile colitis after peripheral blood stem cell transplantation: A complex network of causalities and a challenge for prevention.",
"title_normalized": "acute graft versus host disease invasive aspergillosis and clostridium difficile colitis after peripheral blood stem cell transplantation a complex network of causalities and a challenge for prevention"
} | [
{
"companynumb": "FR-TEVA-554552ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
"... |
{
"abstract": "Presently there are limited treatment options for hypercholesterolemia in patients with statin intolerance and myotonic dystrophy. A 74 year-old male presented to endocrine clinic with hypercholesterolemia (serum LDL-C 210 mg/dL), hypogonadism, insulin-controlled type 2 diabetes mellitus, and minimally elevated serum creatine kinase (CK) levels (184 U/L, ref. range 38-174). Shortly after simvastatin treatment, patient developed severe myalgias in the proximal lower and upper extremities; and serum CK increased to 317 U/L. Subsequently patient was treated with various statins including rosuvastatin with similar outcomes. Patient was also treated with bile acid binding resin and ezetimibe without improvement. At this time, a diagnosis of myotonic dystrophy type 2 was confirmed. Patient was then treated with alirocumab, a PCSK9 inhibitor 75 mg subcutaneously every 2 weeks with significant improvement in LDL-C (90 mg/dL) and myalgias. In conclusion, PCSK9 inhibitors such as alirocumab may be an excellent lipid lowering agent in patients with statin intolerance and myotonic dystrophy.",
"affiliations": "Department of Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, USA. Electronic address: mohamed_shakir@hotmail.mil.;Department of Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, USA.;Department of Endocrinology, Walter Reed National Military Medical Center, Bethesda, MD, USA.",
"authors": "Shakir|Mohamed K M|MKM|;Shin|Terry|T|;Hoang|Thanh D|TD|;Mai|Vinh Q|VQ|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C571059:alirocumab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2017.08.014",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "11(6)",
"journal": "Journal of clinical lipidology",
"keywords": "Alirocumab; Hypercholesterolemia; PCSK9 inhibitor",
"medline_ta": "J Clin Lipidol",
"mesh_terms": "D000368:Aged; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D008078:Cholesterol, LDL; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008297:Male; D009135:Muscular Diseases; D009223:Myotonic Dystrophy; D000071449:Proprotein Convertase 9",
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "1485-1487",
"pmc": null,
"pmid": "29056268",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful treatment of a patient with statin-induced myopathy and myotonic dystrophy type II with proprotein convertase subtilisin/kexin type 9 inhibitor, alirocumab (Praluent).",
"title_normalized": "successful treatment of a patient with statin induced myopathy and myotonic dystrophy type ii with proprotein convertase subtilisin kexin type 9 inhibitor alirocumab praluent"
} | [
{
"companynumb": "US-APOTEX-2017AP015760",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ATORVASTATIN CALCIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Necrotizing pneumonia remains an uncommon complication of pneumonia in children, but its incidence is increasing. Pneumococcal infection is the predominant cause of severe necrotizing pneumonia in children, but methicillin resistant Staphylococcus aureus (MRSA) and Panton-Valentine leukocidin (PVL) staphylococcal infections are also important. We present the case of a four-year-old girl,with an unremarkable medical history, who was admitted in our hospital with a history of high fever, productive cough and tachypnea lasting for 10 days, progressive worsening despite empirical oral antibiotic. Following physical examination, laboratory investigations and thoracic radiography, we established the diagnosis of left lower lobe pneumonia with parapneumonic effusion, acute respiratory failure and sepsis. Medical treatment with systemic antibiotics was initiated, but the evolution was unfavorable. Seriated chest X-rays and also high resolution computed tomography with contrast of the lung were performed, revealing the progression to extensive necrotizing pneumonia with multiple cystic lesions causing right mediastinal deflection. The parenteral broad spectrum antibiotic regimen was adjusted, still with unfavorable evolution, requiring surgical treatment (left inferior lobectomy and pleural draining). Postoperatively, recovery was uneventful. The patient was discharged with clinical and laboratory improvement of his condition, a repeated chest X-ray showing good expansion of upper left parenchyma.",
"affiliations": "1st Pediatric Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;1st Pediatric Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;1st Pediatric Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;Radiology Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;ePathology Department,\"MS Curie\" Emergency Children's Hospital, Bucharest, Romania fPediatric Surgery Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;Pediatric Surgery Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;Pediatric Surgery Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.;2nd Pediatric Department, \"MS Curie\" Emergency Children's Hospital, Bucharest, Romania.",
"authors": "Ionescu|Marcela Daniela|MD|;Popescu|Nicoleta Aurelia|NA|;Balan|Georgiana|G|;Marcu|Veronica|V|;Enculescu|Augustina|A|;Vatra|Lorena|L|;Oancea|Marcel|M|;Balgradean|Mihaela|M|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-9038",
"issue": "13(1)",
"journal": "Maedica",
"keywords": null,
"medline_ta": "Maedica (Bucur)",
"mesh_terms": null,
"nlm_unique_id": "101526930",
"other_id": null,
"pages": "55-60",
"pmc": null,
"pmid": "29868142",
"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
"references": "28770121;11888586;15384879;14999627;24791253;23722529;18216055;16703574;22388585;17234914",
"title": "Evolutionary Particularities in a Case of Severe Pneumonia in Children - Case Report.",
"title_normalized": "evolutionary particularities in a case of severe pneumonia in children case report"
} | [
{
"companynumb": "RO-SUN PHARMACEUTICAL INDUSTRIES LTD-2018RR-172539",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drug... |
{
"abstract": "We report the case of a patient on antipsychotic medication, who developed an abnormal QTc interval, which normalized following treatment with oral magnesium sulphate.",
"affiliations": "West London Mental Health NHS Trust, John Conolly Wing, Southall, Middlesex, UK.",
"authors": "Imran|Nazish|N|;Rampes|Hagen|H|;Rosen|Stuart|S|",
"chemical_list": "D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002998:Clonazepam; D008274:Magnesium; D000077152:Olanzapine",
"country": "United States",
"delete": false,
"doi": "10.1177/02698811030173019",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-8811",
"issue": "17(3)",
"journal": "Journal of psychopharmacology (Oxford, England)",
"keywords": null,
"medline_ta": "J Psychopharmacol",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D001569:Benzodiazepines; D002998:Clonazepam; D004562:Electrocardiography; D006801:Humans; D008133:Long QT Syndrome; D008274:Magnesium; D008297:Male; D000077152:Olanzapine",
"nlm_unique_id": "8907828",
"other_id": null,
"pages": "346-9",
"pmc": null,
"pmid": "14513929",
"pubdate": "2003-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antipsychotic induced prolongation of QTc interval treated with magnesium.",
"title_normalized": "antipsychotic induced prolongation of qtc interval treated with magnesium"
} | [
{
"companynumb": "GB-ALKEM LABORATORIES LIMITED-GB-ALKEM-2022-05253",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"druga... |
{
"abstract": "Familial hypercholesterolemia can be efficiently treated with combined lipid-lowering drugs. Lipid-lowering drugs are usually withdrawn for pregnancy and breastfeeding, ideally preconception, followed by lipid apheresis, however, careful plans can be precipitated due to unexpected pregnancy.\n\n\n\nA 28-year old woman with familial hypercholesterolemia due to heterozygous LDLR mutations had an LDL-cholesterol level at 14.6 mmol/L and Lp(a) at 1150 mg/L. She required a three-vessel coronary artery bypass graft, drug-eluting stents, rosuvastatin, ezetimibe, and alirocumab at maximal dosage. Contraception was advised during the following 12 months, with a planned drug withdrawal to bridge with lipid apheresis, such as the direct adsorption of lipoproteins (DALI). However, an unplanned pregnancy required an abrupt stop of all oral medications at six gestational weeks, except for aspirin. Lipid apheresis controlled LDL-cholesterol in the range of 4.9-7.9 mmol/L (before DALI session) to 1.2-3.2 mmol/L (after DALI session). Later, the regular pregnancy ultrasounds highlighted an isolated agenesis of the corpus callosum later confirmed by magnetic resonance imaging.\n\n\n\nA causal link between the early pregnancy exposure to PCSK9 inhibitors (or statins and ezetimibe taken concomitantly) and the observed complete agenesis of the corpus callosum seems unlikely in this case. Guidelines do not specifically recommend preconception measures to lower fetal and/or maternal risks of patients with severe FH considering pregnancy. We argue that lipid apheresis and other measures should be discussed with women with FH and maternity project on an individual basis, until pharmacoepidemiology studies assessing the safety of PCSK9 inhibitors in pregnancy are available.",
"affiliations": "Service of Endocrinology, Diabetes and Metabolism, Department of Medicine, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Endocrinology, Diabetes and Metabolism, Department of Medicine, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Pharmacy, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Unit of Pediatric Neurology and Neurorehabilitation, Service of Pediatrics, Woman Mother Child Department, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Gynecology and Obstetrics, Woman Mother Child Department, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Nephrology and Hypertension, Department of Medicine, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.;Service of Endocrinology, Diabetes and Metabolism, Department of Medicine, Lausanne University Hospital & University of Lausanne, Lausanne, Switzerland.",
"authors": "Vuignier|Yann|Y|;Beaud|Floriane|F|;Kosinski|Christophe|C|;Panchaud|Alice|A|;Lebon|Sébastien|S|;Baud|David|D|;Kissling|Sébastien|S|;Collet|Tinh-Hai|TH|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9; C571059:alirocumab",
"country": "United States",
"delete": false,
"doi": "10.1002/bdr2.1930",
"fulltext": "\n==== Front\nBirth Defects Res\nBirth Defects Res\n10.1002/(ISSN)2472-1727\nBDR2\nBirth Defects Research\n2472-1727\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n34105316\n10.1002/bdr2.1930\nBDR21930\nCase Report\nCase Reports\nExposure to alirocumab during the first trimester of pregnancy: A case report\nVuignier et al.\nVuignier Yann 1\nBeaud Floriane 2\nKosinski Christophe 1\nPanchaud Alice 3 4\nLebon Sébastien 5\nBaud David 6\nKissling Sébastien 2\nCollet Tinh‐Hai 1 7 tinh-hai.collet@hcuge.ch\n\n1 Service of Endocrinology, Diabetes and Metabolism, Department of Medicine Lausanne University Hospital & University of Lausanne Lausanne Switzerland\n2 Service of Nephrology and Hypertension, Department of Medicine Lausanne University Hospital & University of Lausanne Lausanne Switzerland\n3 Service of Pharmacy Lausanne University Hospital & University of Lausanne Lausanne Switzerland\n4 Institute of Primary Health Care (BIHAM) University of Bern Bern Switzerland\n5 Unit of Pediatric Neurology and Neurorehabilitation, Service of Pediatrics, Woman Mother Child Department Lausanne University Hospital & University of Lausanne Lausanne Switzerland\n6 Service of Gynecology and Obstetrics, Woman Mother Child Department Lausanne University Hospital & University of Lausanne Lausanne Switzerland\n7 Service of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Department of Medicine Geneva University Hospitals Geneva Switzerland\n* Correspondence\nTinh‐Hai Collet, Service of Endocrinology, Diabetology, Nutrition and Therapeutic Education, Department of Medicine, Rue Gabrielle‐Perret‐Gentil 4, Geneva University Hospitals (HUG), 1211 Geneva 14, Switzerland.\nEmail: tinh-hai.collet@hcuge.ch\n\n08 6 2021\n01 9 2021\n113 15 10.1002/bdr2.v113.15 11561160\n31 5 2021\n02 6 2021\n© 2021 The Authors. Birth Defects Research published by Wiley Periodicals LLC.\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.\n\nAbstract\n\nBackground\n\nFamilial hypercholesterolemia can be efficiently treated with combined lipid‐lowering drugs. Lipid‐lowering drugs are usually withdrawn for pregnancy and breastfeeding, ideally preconception, followed by lipid apheresis, however, careful plans can be precipitated due to unexpected pregnancy.\n\nCase\n\nA 28‐year old woman with familial hypercholesterolemia due to heterozygous LDLR mutations had an LDL‐cholesterol level at 14.6 mmol/L and Lp(a) at 1150 mg/L. She required a three‐vessel coronary artery bypass graft, drug‐eluting stents, rosuvastatin, ezetimibe, and alirocumab at maximal dosage. Contraception was advised during the following 12 months, with a planned drug withdrawal to bridge with lipid apheresis, such as the direct adsorption of lipoproteins (DALI). However, an unplanned pregnancy required an abrupt stop of all oral medications at six gestational weeks, except for aspirin. Lipid apheresis controlled LDL‐cholesterol in the range of 4.9–7.9 mmol/L (before DALI session) to 1.2–3.2 mmol/L (after DALI session). Later, the regular pregnancy ultrasounds highlighted an isolated agenesis of the corpus callosum later confirmed by magnetic resonance imaging.\n\nConclusions\n\nA causal link between the early pregnancy exposure to PCSK9 inhibitors (or statins and ezetimibe taken concomitantly) and the observed complete agenesis of the corpus callosum seems unlikely in this case. Guidelines do not specifically recommend preconception measures to lower fetal and/or maternal risks of patients with severe FH considering pregnancy. We argue that lipid apheresis and other measures should be discussed with women with FH and maternity project on an individual basis, until pharmacoepidemiology studies assessing the safety of PCSK9 inhibitors in pregnancy are available.\n\ncorpus callosum agenesis\nfamilial hypercholesterolemia\nPCSK9 inhibitors\npregnancy\nsource-schema-version-number2.0\ncover-dateSeptember 1, 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.7 mode:remove_FC converted:21.09.2021\nVuignier, Y., Beaud, F., Kosinski, C., Panchaud, A., Lebon, S., Baud, D., Kissling, S., & Collet, T.‐H. (2021). Exposure to alirocumab during the first trimester of pregnancy: A case report. Birth Defects Research, 113 (15 ), 1156–1160. 10.1002/bdr2.1930 34105316\n\nSébastien Kissling and Tinh‐Hai Collet contributed equally to this manuscript.\n==== Body\npmc1 INTRODUCTION\n\nFamilial hypercholesterolemia (FH) is a autosomal dominant disease causing elevated low‐density lipoprotein cholesterol levels (LDLc) and cardiovascular diseases at early age (Mach et al., 2020). Clinical guidelines recommend combined treatment to lower LDLc with intensive lifestyle programs, high‐intensity statin, and ezetimibe. When the target LDLc level cannot be achieved, monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) are the next therapeutic option (Mach et al., 2020; Thompson et al., 2017). This novel drug class can be used in all adults, including young women of childbearing age, although reproductive safety data are missing. In rare situations, extracorporeal clearance of lipoproteins with lipid apheresis is required to control LDLc in FH, especially when the aforementioned therapies are not tolerated or contraindicated (France et al., 2016; Mach et al., 2020; Watts et al., 2015). Here, we report the clinical case of a woman with FH who became pregnant while on statin, ezetimibe, and a PCSK9 inhibitor.\n\n2 CASE REPORT\n\nAt medical check‐up, a 28‐year‐old Caucasian woman reported exertion dyspnea. She was otherwise healthy and sedentary, but reported second‐hand smoking at home. Her father had had a hemiparetic stroke at 50 and a fatal heart infarct at 52 years old. Her mother's total cholesterol varied between 6 and 7 mmol/L. The patient's blood pressure was 117/67 mmHg, BMI 23.8 kg/m2 and the arterial pulses were symmetrical. We found no arcus cornealis, no xanthelasma, no Achilles tendon xanthomata, but probable tendinous xanthomata on both hands.\n\nPresumptive FH was diagnosed based on her LDLc level at 14.6 mmol/L (Table 1). After a clinically negative but electrically positive ergometry, a coronary angiography revealed a three‐vessel coronary heart disease and she underwent a coronary artery bypass graft (CABG). The medical treatment included acetylsalicylic acid 100 mg, clopidogrel 75 mg, rosuvastatin 20 mg, ezetimibe 10 mg once daily, and alirocumab subcutaneously every 2 weeks, and lowered LDLc to 3.8 mmol/L.\n\nTABLE 1 Evolution of the lipid profile before, during, and after pregnancy\n\n\tBefore pregnancy\tPregnancy\tPostpartum\t\n\tFH diagnosis\tFH full treatment\tGestational week 7\tGestational week 10\tAt 3 months\t\nTreatment\tNone\tThree combined drugsa\tBefore first DALI\tAfter first DALI\tThree combined drugsa\t\nTotal cholesterol, mmol/L\t17.0\t5.7\t5.3\t9.6\t5.7\t6.3\t\nHDL‐cholesterol, mmol/L\t2.6\t1.3\t1.3\t1.3\t1.1\t1.1\t\nLDL‐cholesterol, mmol/L\t14.6\t3.8\t3.7\t7.9\t4.3\t4.7\t\nTriglycerides, mmol/L\t1.2\t1.3\t0.6\t0.9\t0.6\t1.0\t\nApolipoprotein A1, g/L\t1.13\t1.34\t–\t1.26\t1.08\t–\t\nApolipoprotein B, g/L\t3.80\t1.12\t–\t2.15\t1.28\t–\t\nLipoprotein (a), mg/L\t–\t1,150\t–\t918\t483\t–\t\nAbbreviations: DALI, direct adsorption of lipoproteins technique of lipid apheresis; FH, familial hypercholesterolemia; HDL, high‐density lipoproteins; LDL, low‐density lipoproteins.\n\na The three drugs consisted of rosuvastatin 20 mg once daily, ezetimibe 10 mg once daily, and alirocumab 150 mg subcutaneously every 2 weeks.\n\nFH was confirmed with two distinct heterozygous missense LDLR mutations: c.81C > G/p.Cys27Trp (15–30% residual activity) and c.1646G > A/p.Gly549Asp (residual activity <2%) both classified as likely pathogenic (Hobbs, Brown, & Goldstein, 1992). No APOB or PCSK9 mutation was found. Parents and siblings could not be sequenced, and chromosomal analyses were not performed. The complete status of LDLR mutations could not be formally confirmed, but based on the clinical presentation of very high LDLc and early atherosclerosis, we presume a compound heterozygous mutation with both missense mutations compromising LDLR activity.\n\nAs the patient was considering maternity, contraceptives were advised for at least 12 months after CABG. Preconception drug withdrawal was planned with a bridge to lipid apheresis (France et al., 2016; Ogura et al., 2016; Watts et al., 2015), such as the Direct Adsorption of Lipoproteins (DALI).\n\nHowever, an unplanned pregnancy occurred after 9 months. Except for acetylsalicylic acid, all oral medications were stopped 7 weeks after the last menstrual period and pregnancy multivitamins were introduced. The last dose of alirocumab was self‐injected 16 days after the last menstrual period. To control the rising LDLc throughout pregnancy, DALI sessions were started and the interval was adapted between 4 and 10 days (Figure 1) according to pretreatment LDLc and the estimated mean LDLc with the Kroon formula (Kroon et al., 2000). DALI was performed through a tunneled cuffed internal jugular catheter with the Art Universal device (Fresenius Medical Care) using two 500‐ml adsorbers in series. The circuit was primed with heparin, of which 1,500 IU were delivered to the patient, and clotting was prevented by regional citrate anticoagulation (ACD‐A solution, 275 ml per session). Calcium glubionate was infused continuously to prevent hypocalcemia. Hypovolemia related to the priming of lines and columns (total 580 ml) was prevented by NaCl 0.9% infusion. Each DALI session lasted an average of 145 min, processed 7.4 L of blood with a maximal blood pump flow of 60 ml/min.\n\nFIGURE 1 Evolution of the lipid profile during lipid apheresis. Before pregnancy (on the left of the y‐axis), the total and LDL cholesterol (gray and orange circles, respectively) were reduced with the combined treatment of rosuvastatin 20 mg once daily, ezetimibe 10 mg once daily, and alirocumab 150 mg subcutaneously every 2 weeks. Last alirocumab injection was done 16 days after the last menstrual period and ezetimibe and rosuvastatin were stopped at seven gestational weeks after the pregnancy was confirmed (on the right of the y‐axis). A complete agenesis of the corpus callosum was confirmed with a fetal MRI at 22 gestational weeks. During pregnancy and in the postpartum period, lipid apheresis sessions were performed at regular intervals to control total and LDL cholesterol (gray and orange). The interval between each session was adapted throughout pregnancy (every 7 days, unless stated otherwise in the figure) according to pretreatment LDLc and the estimated mean LDLc with the Kroon formula (Kroon, van't Hof, Demacker, & Stalenhoef, 2000)\n\n2.1 Complete agenesis of the corpus callosum detected in utero\n\nFirst trimester ultrasound did not show signs of aneuploidy. The anatomy ultrasound at 20 gestational weeks suspected an isolated complete agenesis of the corpus callosum, later confirmed by fetal magnetic resonance imaging at 22 gestational weeks (Figure 2). The comparative genomics hybridization array (Agilent oligoNT array CGH 180 K) was normal.\n\nFIGURE 2 Fetal MRI (left panel, frontal; right panel, sagittal) realized at 22 gestational weeks\n\nCesarean delivery was performed at 40 gestational weeks, due to fetal bradycardia at 7 cm dilation after spontaneous labor. The male newborn had an Apgar score of 10–10–10, an arterial pH at 7.25, and venous pH at 7.31. The birth length was 49 cm (25th percentile), weight 3,220 g (50th percentile) and head circumference 35 cm (50th percentile), with normal clinical examination at birth.\n\nThe infant showed normal developmental milestones and neurological examination until the last clinical visit at 9 months of age. His LDLc was elevated at 3.5 and 5.0 mmol/L at 2 and 7 months, respectively. We could not find any exposure factors, in particular no toxic or alcohol before or during pregnancy.\n\n3 DISCUSSION\n\nTo our knowledge, this is the first report of exposure to PCSK9 inhibitors in early pregnancy. A causal link between the early pregnancy exposure to this drug (or statins and ezetimibe taken concomitantly) and the complete agenesis of the corpus callosum cannot be assessed based on a single case.\n\nThe accountability of the drugs in congenital midline defect can be considered unlikely for several reasons. First, the sensitive period for the corpus callosum development is probably not in the first 10 weeks of pregnancy. Based on the last use of the three lipid‐lowering drugs and their half‐lives, the exposure period did not extend beyond 10 weeks, even when accounting for the alirocumab half‐life of 12 days (i.e., stopped at 16 days after the last menstrual period +4 half‐lives expected to reach a 94% clearance leading to 9 weeks). Second, monoclonal antibodies are not considered to cross the placenta significantly before the second trimester (Pham‐Huy et al., 2019). No specific data are available on monoclonal antibodies targeting PCSK9, such as alirocumab, but its placental transfer is not expected to differ dramatically from other monoclonal antibodies. Finally, recent data with a strong level of evidence on statins safety in pregnancy did not confirm the previously observed association between statins and teratogenic risks (Bateman et al., 2015; Botha, Pilcher, Wolmarans, Blom, & Raal, 2018).\n\nClinical guidelines do not recommend specific preconception measures to lower fetal and/or maternal risks of patients with severe FH considering pregnancy. Our patient reported good tolerance to lipid apheresis throughout pregnancy. We argue that lipid apheresis and other relevant measures should be discussed before pregnancy with women with FH on an individual basis, until large pharmacoepidemiology studies assessing the safety of PCSK9 inhibitors in pregnancy are available.\n\nCONFLICT OF INTEREST\n\nThe authors have no potential conflicts of interest to disclose.\n\nACKNOWLEDGMENTS\n\nThe authors have nothing to disclose. The authors declare that all supporting data are available within the article. The patient reported here signed a written consent for this publication. The authors wish to thank the clinical team who cared for the patient during the DALI sessions and in clinic, as well as Dr. Nathalie Brun, Geneva University Hospitals, and Dr. Thomas von Kaenel, Valais Hospital, Switzerland, for their assistance in the genetic testing.\n\nDATA AVAILABILITY STATEMENT\n\nData available on request due to patient privacy restrictions.\n==== Refs\nREFERENCES\n\nBateman, B. T., Hernandez‐Diaz, S., Fischer, M. A., Seely, E. W., Ecker, J. L., Franklin, J. M., … Huybrechts, K. F. (2015). Statins and congenital malformations: Cohort study. BMJ (Clinical Research Ed.), 350 , h1035. 10.1136/bmj.h1035\nBotha, T. C., Pilcher, G. J., Wolmarans, K., Blom, D. J., & Raal, F. J. (2018). Statins and other lipid‐lowering therapy and pregnancy outcomes in homozygous familial hypercholesterolaemia: A retrospective review of 39 pregnancies. Atherosclerosis, 277 , 502–507. 10.1016/j.atherosclerosis.2018.05.038 30270091\nFrance, M., Rees, A., Datta, D., Thompson, G., Capps, N., Ferns, G., … HEART UK Medical Scientific and Research Committee . (2016). HEART UKstatement on the management of homozygous familial hypercholesterolaemia in the United Kingdom. Atherosclerosis, 255 , 128–139. 10.1016/j.atherosclerosis.2016.10.017 27839699\nHobbs, H. H., Brown, M. S., & Goldstein, J. L. (1992). Molecular genetics of the LDL receptor gene in familial hypercholesterolemia. Human Mutation, 1 (6 ), 445–466. 10.1002/humu.1380010602 1301956\nKroon, A. A., van't Hof, M. A., Demacker, P. N. M., & Stalenhoef, A. F. H. (2000). The rebound of lipoproteins after LDL‐apheresis. Kinetics and estimation of mean lipoprotein levels. Atherosclerosis, 152 (2 ), 519–526.10998482\nMach, F., Baigent, C., Catapano, A. L., Koskinas, K. C., Casula, M., Badimón, L., … ESC Scientific Document Group . (2020). 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. European Heart Journal, 41 (1 ), 111–188. 10.1093/eurheartj/ehz455 31504418\nOgura, M., Makino, H., Kamiya, C., Yoshimatsu, J., Soran, H., Eatough, R., … Stefanutti, C. (2016). Lipoprotein apheresis is essential for managing pregnancies in patients with homozygous familial hypercholesterolemia: Seven case series and discussion. Atherosclerosis, 254 , 179–183. 10.1016/j.atherosclerosis.2016.10.018 27755983\nPham‐Huy, A., Sadarangani, M., Huang, V., Ostensen, M., Castillo, E., Troster, S. M., … Top, K. A. (2019). From mother to baby: Antenatal exposure to monoclonal antibody biologics. Expert Review of Clinical Immunology, 15 (3 ), 221–229. 10.1080/1744666X.2019.1561282 30570400\nThompson, G. R., Blom, D. J., Marais, A. D., Seed, M., Pilcher, G. J., & Raal, F. J. (2017). Survival in homozygous familial hypercholesterolaemia is determined by the on‐treatment level of serum cholesterol. European Heart Journal, 39 (14 ), 1162–1168. 10.1093/eurheartj/ehx317\nWatts, G. F., Gidding, S. S., Wierzbicki, A. S., Toth, P. P., Alonso, R., Brown, W. V., … International Familial Hypercholesterolemia Foundation . (2015). Integrated guidance on the care of familial hypercholesterolaemia from the international FH foundation. European Journal of Preventive Cardiology, 22 (7 ), 849–854. 10.1177/2047487314533218 24776375\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": null,
"issue": "113(15)",
"journal": "Birth defects research",
"keywords": "PCSK9 inhibitors; corpus callosum agenesis; familial hypercholesterolemia; pregnancy",
"medline_ta": "Birth Defects Res",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D005260:Female; D006801:Humans; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D000071449:Proprotein Convertase 9",
"nlm_unique_id": "101701004",
"other_id": null,
"pages": "1156-1160",
"pmc": null,
"pmid": "34105316",
"pubdate": "2021-09-01",
"publication_types": "D002363:Case Reports",
"references": "1301956;34105316;27839699;29106543;10998482;27755983;24776375;25784688;31504418;30570400;30270091",
"title": "Exposure to alirocumab during the first trimester of pregnancy: A case report.",
"title_normalized": "exposure to alirocumab during the first trimester of pregnancy a case report"
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"abstract": "Biological therapies, including anti-TNF agents, are important in the treatment of various chronic inflammatory diseases, including psoriasis, rheumatoid arthritis or inflammatory bowel disease. The increased use of these drugs translates into an increasing awareness of its adverse effects, which include malignancy. In this paper, we describe the case of a 28-year-old woman who developed a spitzoid melanocytic tumor after starting infliximab therapy for ulcerative colitis. The evidence for causality between anti-TNF and melanocytic proliferations is still sparse; nonetheless, treatment-associated immunosuppression seems to play a key role in this phenomenon. Therefore, a regular follow-up with a rigorous skin examination is essential in these patients. Noninvasive techniques such as dermoscopy or reflectance confocal microscopy are particularly useful diagnostic tools in these circumstances.",
"affiliations": "Dermatology Department, Hospital Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal. Electronic address: catarina.squeiros@gmail.com.;Dermatology Department, Hospital Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina de Lisboa, Lisbon, Portugal.;Pathology Department, Hospital de Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal.;Dermatology Department, Hospital Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal; Faculdade de Medicina de Lisboa, Lisbon, Portugal.",
"authors": "Queirós|Catarina Soares|CS|;Laureano-Oliveira|André|A|;Lopéz-Presa|Dolores|D|;Filipe|Paul|P|",
"chemical_list": "D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "Spain",
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"doi": "10.1016/j.abd.2020.01.008",
"fulltext": "\n==== Front\nAn Bras Dermatol\nAn Bras Dermatol\nAnais Brasileiros de Dermatologia\n0365-0596 1806-4841 Sociedade Brasileira de Dermatologia \n\nS0365-0596(20)30177-X\n10.1016/j.abd.2020.01.008\nCase Report\nSpitz nevus and infliximab: association or coincidence?☆☆☆\nQueirós Catarina Soares catarina.squeiros@gmail.coma* Laureano-Oliveira André ab Lopéz-Presa Dolores c Filipe Paul ab a Dermatology Department, Hospital Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal\nb Faculdade de Medicina de Lisboa, Lisbon, Portugal\nc Pathology Department, Hospital de Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal\n⁎ Corresponding author. catarina.squeiros@gmail.com\n12 7 2020 \nSep-Oct 2020 \n12 7 2020 \n95 5 615 618\n19 10 2019 13 1 2020 © 2020 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U.2020Sociedade Brasileira de DermatologiaThis is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).Biological therapies, including anti-TNF agents, are important in the treatment of various chronic inflammatory diseases, including psoriasis, rheumatoid arthritis or inflammatory bowel disease. The increased use of these drugs translates into an increasing awareness of its adverse effects, which include malignancy. In this paper, we describe the case of a 28-year-old woman who developed a spitzoid melanocytic tumor after starting infliximab therapy for ulcerative colitis. The evidence for causality between anti-TNF and melanocytic proliferations is still sparse; nonetheless, treatment-associated immunosuppression seems to play a key role in this phenomenon. Therefore, a regular follow-up with a rigorous skin examination is essential in these patients. Noninvasive techniques such as dermoscopy or reflectance confocal microscopy are particularly useful diagnostic tools in these circumstances.\n\nKeywords\nBiological agentsConfocal microscopyDermoscopyNevus, epithelioid and spindle cellSkin neoplasms\n==== Body\nIntroduction\nTumor necrosis factor alpha (TNF-α) is a cytokine of the innate immune system with important functions in the regulation of systemic inflammation and the detection of malignancies and infections.1, 2 Therefore, its inhibition can improve several dermatological, rheumatological, and gastrointestinal inflammatory disorders, making these agents important in the treatment of many chronic inflammatory diseases.2\n\nWith the increasing usage of these drugs, adverse effects have been increasingly recognized, such as the increased risk of infection and malignancies. Long-term data for anti-TNF agents regarding the risk for the development of malignancies are lacking, but recently several case reports that associate anti-TNF therapies with melanoma have been published.1, 2\n\nCase report\nA 28-year-old woman, Fitzpatrick skin phototype 2, with a three-year history of ulcerative colitis, was referred to the Department of Dermatology due to a pigmented lesion on her right ear. She had been under infliximab therapy for the last 30 months. The lesion had appeared six months earlier and had progressively grown. On examination, a dark brown macule on the helix was evident, with regular borders and a diameter of 6 mm (Fig. 1). There were no palpable lymphadenopathies. Dermoscopy revealed a melanocytic lesion, with a global starburst pattern, suggestive of spitzoid melanocytic tumor (Fig. 2). Examination with reflectance confocal microscopy (RCM) showed a well-demarcated lesion, with junctional nests and pagetoid infiltration (Fig. 3). The lesion was surgically excised and histological examination confirmed a compound Spitz nevus (Fig. 4). A decision to maintain therapy with infliximab was made. Sun-protective measures were emphasized, and the patient remains under close clinical follow-up.Figure 1 Spitz nevus: clinical photography. Brown macule with a diameter of 6 mm on the right helix.\n\nFigure 1Figure 2 Spitz nevus: digital dermoscopy. Melanocytic lesion with a star-burst type global pattern.\n\nFigure 2Figure 3 Spitz nevus: reflectance confocal microscopy. Well-delimited regular nests at the dermo-epidermal junction and pagetoid infiltration. (VivaScope1500, A and B basic images 0.5 × 0.5 mm).\n\nFigure 3Figure 4 Spitz nevus: histopathological examination. A, Compound symmetric melanocytic lesion, consisting of large epithelioid and fusiform melanocytes, with many melanophages; acanthosis and irregular hyperplasia of the epidermis (Hematoxylin & eosin, ×25). B, Kamino bodies (Hematoxylin & eosin, ×100). C, Positive immunohistochemistry for HMB45 (×40). D, Positive immunohistochemistry for p16 (×40).\n\nFigure 4\n\nDiscussion\nTNF-α is a cytokine of the innate immune system with a critical function in the surveillance of malignancies and infections.3 TNF-α antagonists are a group of biologic agents that include infliximab, etanercept, and adalimumab, and are currently indicated in the treatment of several inflammatory conditions including psoriasis and inflammatory bowel disease.3\n\nThe most common adverse effects of this group of biologic agents are in general mild. However, serious complications such as infections or malignancies have been reported.3, 4 In the last two decades, several case reports have pointed to an overall increased risk of malignancy, namely lymphoma and non-melanoma skin cancer (NMSC) in patients treated with these agents.5 NMSC in particular seems to be associated with chronic immunosuppression, accounting for up to 95% of post-transplant cutaneous malignancies.5 More recently, the association between these anti-TNF antagonists and the appearance of melanoma has also been described.2, 5, 6\n\nThe potential impact of TNF antagonists on the development of skin cancer occurs in two ways. First, these drugs may affect tumor initiation, altering the incidence of malignancies; secondly, they may reduce the immunologic control of mutated cells or pre-existing subclinical tumors, allowing for rapid tumor growth.6\n\nThe evidence for causality between anti-TNF and the development of melanocytic proliferations is still sparse, and the possible link between biological therapy and the induction of melanocytic proliferation needs further illumination.4 Melanocytic proliferation may be benign, as in eruptive melanocytic nevi, or malignant, as in melanoma. Eruptive nevi are a rare phenomenon consisting of an abrupt appearance of multiple nevi or large atypical lesions simulating melanoma. Its occurrence has been associated not only with dermatological diseases but also with immunosuppression.7\n\nIt is believed that immunosuppression may induce melanocyte-stimulating hormone or melanoma growth-stimulatory activity, two endogenous growth factors for melanocytes.4 Therefore, growth and development of melanocytes is stimulated under these circumstances. Genetic factors may also be involved. The role of immunosurveillance in tumorigenesis is therefore essential, and a diminished immunosurveillance can lead to the appearance of malignant lesions or to malignant transformation of benign lesions.4\n\nThe appearance of Spitz nevus in anti-TNF treated patients has been reported. Sousa reported a 29-year-old woman who developed a dysplastic spitzoid compound naevus on her right thigh after 41 months of psoriasis treatment with adalimumab.8 Although they are benign skin tumors, Spitz nevi may resemble malignant melanomas both clinically and microscopically. Therefore, these lesions are commonly excised for precaution. In the present case, the patient developed a compound Spitz nevus in a non-exposed area after 24 months of infliximab treatment. Although fair skin type may have been a contributing factor to the development of this lesion, the immunosuppressive effects of infliximab may also have played a role.\n\nSpitz nevi usually display a dynamic behavior, with considerable variation in their morphology, dermoscopy, and RCM features over time.9 Observation with RCM usually shows a symmetric lesion, frequently with pagetoid infiltration, especially as spindle cells throughout the lesion. Oval to round polygonal nests with well-defined borders, composed by clustered cells, frequently large in size and highly reflective, are also characteristic features. Regarding the main RCM pattern, most Spitz nevi show a clod pattern or an association of clod to meshwork or ringed pattern.9\n\nWhile dermoscopy is an established tool in assisting noninvasive diagnosis in dermatology, RCM is still acquiring its role in clinical practice. In this setting, it may be particularly useful for the assessment of melanocytic lesions identified as “equivocal” by visual inspection or dermoscopy. Here, the available evidence suggests that RCM may be both more sensitive and specific in comparison to dermoscopy, which underscores the potential of this imaging method in reducing the number of inappropriate excisions.10 However, it should be emphasized that all spitzoid lesions in adults should be clarified from a histological point of view.\n\nIn sum, although additional studies are needed to better characterize the impact of biologic therapy in melanocyte proliferation, there is growing evidence suggesting a possible relation between biological therapy and melanocytic proliferation.4 Controlled studies with larger sample sizes and longer follow-up periods are needed in order to better evaluate this association. Until then, the available literature suggests that patients undergoing treatment with biologics should be encouraged to monitor their pre-existing nevi as well as the appearance of new ones.6, 8 Regular observation by a dermatologist should also be advised. In following these patients, non-invasive imaging techniques have acquired a special role as a means of detecting subtle changes and monitoring evolution of the lesions.\n\nFinancial support\nNone declared.\n\nAuthors’ contributions\nCatarina Sousa Duque Soares Queirós: Approval of the final version of the manuscript; conception and planning of the study; drafting and editing of the manuscript; collection, analysis, and interpretation of data; participation in study design; intellectual participation in the propaedeutic and/or therapeutic conduct of the studied cases; critical review of the literature; critical review of the manuscript.\n\nAndré Laureano Oliveira: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.\n\nDolores Lopéz Presa: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.\n\nPaulo Filipe: Approval of the final version of the manuscript; critical review of the literature; critical review of the manuscript.\n\nConflicts of interest\nNone declared.\n\n☆ How to cite this article: Queirós CSDS, Oliveira AL, Presa DL, Filipe P. Spitz nevus and infliximab: association or coincidence? An Bras Dermatol. 2020. https://doi.org/10.1016/j.abd.2020.01.008\n\n☆☆ Study conducted at the Hospital de Santa Maria, Centro Hospitalar e Universitário de Lisboa Norte, Lisbon, Portugal.\n==== Refs\nReferences\n1 Fulchiero G.J. Jr Salvaggio H. Drabick J.J. Staveley-O’Carroll K. Billingsley E.M. Marks J.G. Eruptive latent metastatic melanomas after initiation of antitumor necrosis factor therapies J Am Acad Dermatol. 56 5 Suppl 2007 S65 7 17434043 \n2 Nardone B. Hammel J.A. Raisch D.W. Weaver L.L. Schneider D. West D.P. Melanoma associated with tumour necrosis factor-alpha inhibitors: a Research on Adverse Drug events And Reports (RADAR) project Br J Dermatol. 170 2014 1170 1172 24328939 \n3 Chen Y. Friedman M. Liu G. Deodhar A. Chu C.Q. Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-mediated inflammatory disorders? Cytokine. 101 2018 78 88 27688201 \n4 Katoulis A.C. Kanelleas A. Zambacos G. Panayiotides I. Stavrianeas N.G. Development of two primary malignant melanomas after treatment with adalimumab: a case report and review of the possible link between biological therapy with TNF-alpha antagonists and melanocytic proliferation Dermatology. 221 2010 9 12 20484878 \n5 Chen Y. Sun J. Yang Y. Huang Y. Liu G. Malignancy risk of anti-tumor necrosis factor alpha blockers: an overview of systematic reviews and meta-analyses Clin Rheumatol. 35 2016 1 18 \n6 Manganoni A.M. Zane C. Pavoni L. Farisoglio C. Sereni E. Calzavara-Pinton P. Cutaneous melanoma in patients in treatment with biological therapy: review of the literature and case report Dermatol Online J. 17 2011 12 \n7 Bovenschen H.J. Tjioe M. Vermaat H. de Hoop D. Witteman B.M. Janssens R.W. Induction of eruptive benign melanocytic naevi by immune suppressive agents, including biologicals Br J Dermatol. 154 2006 880 884 16634890 \n8 Sousa M. Freitas J.P. Antunes J. Soares-de-Almeida L. Filipe P.L. Appearance of de novo dysplastic spitzoid compound naevus in an adalimumab-treated psoriatic patient: case report and review of the possible causal relationship with TNF-alpha blockers Australas J Dermatol. 55 2014 156 157 24720429 \n9 Ferrari C. Longo C. Stanganelli I. Magi S. Mazzoni L. Pellacani G. Evolution of Spitz naevi: a dermoscopic and confocal follow-up of 26 cases Br J Dermatol. 176 2017 1098 1100 27515761 \n10 Dinnes J. Deeks J.J. Saleh D. Chuchu N. Bayliss S.E. Patel L. Reflectance confocal microscopy for diagnosing cutaneous melanoma in adults Cochrane Database Syst Rev. 12 2018 CD013190\n\n",
"fulltext_license": "CC BY",
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"issue": "95(5)",
"journal": "Anais brasileiros de dermatologia",
"keywords": "Biological agents; Confocal microscopy; Dermoscopy; Nevus, epithelioid and spindle cell; Skin neoplasms",
"medline_ta": "An Bras Dermatol",
"mesh_terms": "D000328:Adult; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D000069285:Infliximab; D018332:Nevus, Epithelioid and Spindle Cell; D012878:Skin Neoplasms; D014409:Tumor Necrosis Factor-alpha",
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"pages": "615-618",
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"references": "26573205;24720429;27688201;20484878;16634890;30521681;24328939;21906492;27515761;17434043",
"title": "Spitz nevus and infliximab: association or coincidence?",
"title_normalized": "spitz nevus and infliximab association or coincidence"
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"abstract": "Although the majority of epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) patients respond to EGFR tyrosine kinase inhibitors (TKIs), significant heterogeneity in clinical response is observed which might be attributed to the distinct sub-molecular characteristics. The present study aims to identify genetic alterations correlated with clinical outcomes and treatment response to different EGFR-TKI inhibitors.\n\n\n\nWe integrated the genomic data and clinical outcomes including progression-free survival (PFS) and overall survival (OS) in 179 patients with advanced EGFR-mutant NSCLC who were treated with EGFR-TKI as 1st line of treatment.\n\n\n\nWe found that EGFR-mutant patients harboring concomitant TP53 mutation (OS: 21 vs. 40 months, P = 0.05), ERBB2 amplification (PFS: 6.1 vs. 12.5 months, P = 0.01) or FGF19 amplification (OS: 11.2 vs. 27.1 months, P = 0.01) were significantly associated with a poorer clinical prognosis after treated with 1st generation EGFR-TKI. In contrast, the presence of TP53 mutation did not affect the PFS nor OS of patients treated with 2nd generation EGFR-TKI. Furthermore, EGFR-mutant and TP53-wild type (WT) patients benefited more from a combinatorial treatment consisting of EGFR-TKI and bevacizumab comparing to EGFR-TKI as a single agent (PFS: 21.7 vs. 9.3 months, P < 0.01). Copy number variation (CNV) (PFS: 4.6 vs.9.4 months, p = 0.018) was identified as an unfavorable predictive factor to 3rd-generation TKI. We also revealed distinct resistance mechanisms associated with different EGFR-TKIs.\n\n\n\nOur study highlights the heterogeneity both in the primary molecular landscape and acquired alterations in EGFR-mutated NSCLCs, which might play a role in determining the clinical efficacy of EGFR-TKIs. We also revealed the differential prognostic role of TP53 mutation in patients treated with the 1st or 2nd generation of EGFR-TKI. Our study also suggests that EGFR-mutant and TP53-WT patients may benefit more from combinatorial treatment consisting of EGFR-TKI and bevacizumab, highlighting the importance of further stratifying EGFR-mutant patients.",
"affiliations": "Jilin Cancer Hospital, Changchun, China. Electronic address: jl.cheng@163.com.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Jilin Cancer Hospital, Changchun, China.;Burning Rock Biotech, Guangzhou, China.;Burning Rock Biotech, Guangzhou, China.;Burning Rock Biotech, Guangzhou, China.;Burning Rock Biotech, Guangzhou, China.",
"authors": "Cheng|Ying|Y|;Ma|Lixia|L|;Liu|Ying|Y|;Zhu|Jing|J|;Xin|Ying|Y|;Liu|Xianhong|X|;Wang|Ying|Y|;Zhang|Tingting|T|;Yang|Changliang|C|;Wang|Sheng|S|;Cui|Hongxia|H|;Zhang|Liang|L|;Dai|Jixin|J|;Shao|Lin|L|;Lin|Jing|J|;Ye|Junyi|J|;Liu|Hao|H|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C512478:EGFR protein, human; D066246:ErbB Receptors",
"country": "Ireland",
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"doi": "10.1016/j.lungcan.2020.04.004",
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"issue": "145()",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": "EGFR tyrosine kinase inhibitors; EGFR-mutant-NSCLC; Genomic alterations; Overall survival; Progression-free survival",
"medline_ta": "Lung Cancer",
"mesh_terms": "D002289:Carcinoma, Non-Small-Cell Lung; D056915:DNA Copy Number Variations; D066246:ErbB Receptors; D023281:Genomics; D006801:Humans; D008175:Lung Neoplasms; D009154:Mutation; D047428:Protein Kinase Inhibitors",
"nlm_unique_id": "8800805",
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"pages": "63-70",
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"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Comprehensive characterization and clinical impact of concomitant genomic alterations in EGFR-mutant NSCLCs treated with EGFR kinase inhibitors.",
"title_normalized": "comprehensive characterization and clinical impact of concomitant genomic alterations in egfr mutant nsclcs treated with egfr kinase inhibitors"
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"abstract": "A term male infant was born to a healthy 24-year-old mother with antenatally diagnosed liver-up, left congenital diaphragmatic hernia (CDH) and gastroschisis. The infant was stabilised in the neonatal intensive care unit and then underwent primary repair of the CDH via left subcostal incision and silo placement for the gastroschisis. Serial silo reductions were started postoperatively and umbilical flap closure for the gastroschisis was performed on day of life 6. The patient was weaned from respiratory support, started on enteral feeds, and discharged home at 1 month of age. He was weaned from supplemental nasogastric feeds by 6 weeks of age and is currently well and thriving at 11 months of age.",
"affiliations": "School of Medicine and Dentistry, University of Rochester Medical Center, Rochester, New York, USA.;Division of Pediatric Surgery, University of Rochester Medical Center, Rochester, New York, USA.;Division of Pediatric Surgery, University of Rochester Medical Center, Rochester, New York, USA.;Division of Pediatric Surgery, University of Rochester Medical Center, Rochester, New York, USA michael_livingston@urmc.rochester.edu.",
"authors": "McGann|Kevin C|KC|;Arca|Marjorie J|MJ|;Pulhamus|Marsha|M|;Livingston|Michael H|MH|",
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"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "congenital disorders; neonatal intensive care; paediatric surgery",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D004750:Enteral Nutrition; D020139:Gastroschisis; D065630:Hernias, Diaphragmatic, Congenital; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D012189:Retrospective Studies; D016896:Treatment Outcome; D014472:Umbilicus; D055815:Young Adult",
"nlm_unique_id": "101526291",
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"pmid": "34301696",
"pubdate": "2021-07-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Left congenital diaphragmatic hernia and gastroschisis in a term male infant.",
"title_normalized": "left congenital diaphragmatic hernia and gastroschisis in a term male infant"
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"abstract": "Treatment-resistant schizophrenia is a serious clinical problem. We adopt a systems-level approach positing a greater role for cognitive control mechanisms in the development of psychotic symptoms and illustrate the clinical application of this via a case report of treatment-resistant patients treated successfully with adjunct pro-cognitive serotonergic medication.",
"affiliations": "National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK.;Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, London, SE5 8AF, UK.;Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.;National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. University of Iceland, Iceland.;National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.;National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. Institute of Psychiatry, Psychology and Neuroscience, King's College London, UK.",
"authors": "Lowe|Penelope|P|;Krivoy|Amir|A|;Porffy|Lilla|L|;Henriksdottir|Erna|E|;Eromona|Whiskey|W|;Shergill|Sukhwinder S|SS|",
"chemical_list": null,
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"fulltext": "\n==== Front\nTher Adv PsychopharmacolTher Adv PsychopharmacolTPPsptppTherapeutic Advances in Psychopharmacology2045-12532045-1261SAGE Publications Sage UK: London, England 10.1177/204512531773700310.1177_2045125317737003Case ReportsWhen the drugs don’t work: treatment-resistant schizophrenia, serotonin and serendipity Lowe Penelope *National Psychosis Service, South London and Maudsley NHS Foundation Trust, UKKrivoy Amir *Psychosis Studies Department, Institute of Psychiatry, Psychology and Neuroscience, 16 De Crespigny Park, London, SE5 8AF, UKPorffy Lilla Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UKHenriksdottir Erna National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. University of Iceland, IcelandEromona Whiskey National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UKShergill Sukhwinder S. National Psychosis Service, South London and Maudsley NHS Foundation Trust, UK. Institute of Psychiatry, Psychology and Neuroscience, King’s College London, UKamir.krivoy@kcl.ac.uk* These authors contributed equally to this manuscript.\n\n02 11 2017 1 2018 8 1 63 70 17 4 2017 5 7 2017 © The Author(s), 20172017SAGE PublicationsThis 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).Treatment-resistant schizophrenia is a serious clinical problem. We adopt a systems-level approach positing a greater role for cognitive control mechanisms in the development of psychotic symptoms and illustrate the clinical application of this via a case report of treatment-resistant patients treated successfully with adjunct pro-cognitive serotonergic medication.\n\ncognitionnovel treatmentrefractory schizophrenia\n==== Body\nBackground\nTreatment resistance in schizophrenia remains a difficult problem, with up to 40% of diagnosed patients showing inadequate response to optimal antipsychotic treatment. These patients fulfil criteria for treatment-resistant schizophrenia (TRS), based on at least two prior drug trials of 4–6 weeks’ duration with no clinical improvement, persistence of illness for longer than 5 years with no period of good social or occupational functioning, and persistent psychotic symptoms as defined as a score of at least 4 (moderate) on at least two positive symptom items of the Positive and Negative Syndrome Scale (PANSS).1 More recent data from first episode studies suggest that in the majority of patients with TRS, treatment resistance is evident at their first presentation.2 All current antipsychotic medication acts through modulating dopamine receptors, with treatment resistance occurring despite adequate D2 receptor occupancy by antipsychotic medication,3 suggesting that mechanisms other than hyperdopaminergia are driving psychotic symptoms in treatment resistance. Treatment-resistant patients show more robust cognitive deficits compared to treatment responders,4 and stronger cognitive performance is associated with a more favourable clinical outcome.5 While our knowledge of cognitive control mechanisms has grown in recent years, through the advent of functional neuroimaging, the key neurophysiological underpinnings of these deficits remain unclear.\n\nAt the systems level, schizophrenia can be viewed as a disconnection syndrome, with frontostriatal interactions specifically postulated to be crucial in symptom formation.6 In this view, NMDA receptor hypofunction results in decreased input from the prefrontal cortex to the midbrain, which in turn, through inhibition of GABA interneurons, results in overactivation of dopamine neurons projecting to the striatum. The resulting hyperdopaminergia is associated with a state of aberrant salience, whereby irrelevant environmental stimuli are imbued with special significance and the individual develops bizarre ideas or delusions in order to explain these experiences of salience.7 At the same time, a failure of top-down control signals from prefrontal areas to widespread networks may contribute to the maintenance of psychotic symptoms as integration with bottom-up sensory information is disrupted.8 Following from this view, one might argue that even if the striatal dopaminergic dysfunction is alleviated with antipsychotic medication, this would not necessarily suffice to reduce symptoms once they have been established if frontostriatal connectivity remains impaired. This two-hit model of treatment resistance would suggest that functional integration is more severely impaired in TRS compared to non-treatment-resistant patients. Consequently, antipsychotic treatment may effectively attenuate the striatal dopaminergic dysfunction, but in the absence of a normative regulation from the prefrontal cortex in TRS, symptoms could be perpetuated despite optimal treatment.\n\nUnfortunately, both psychological and pharmacological interventions have yielded very limited clinical benefits in improving cognitive dysfunction in psychosis.9 A recently licensed antidepressant medication, vortioxetine, has data to support benefits on cognitive dysfunction, in addition to an effect on depressive symptoms.10 Vortioxetine is unusual in possessing multimodal action, both inhibiting serotonin transporters and also acting directly on specific serotonin receptors: 5-HT1A (full agonism), 5-HT1B (partial agonism) and antagonism at 5-HT1D, 5-HT3 and 5-HT7.11 Although vortioxetine is a partial agonist at 5-HT1B, long-term administration desensitizes the 5-HT1B receptors.11 Interestingly, vortioxetine has been demonstrated to enhance frontal cortical activity and impact on wakefulness.12 In addition, a study by Katona and colleagues has demonstrated that vortioxetine may have an important wider role in improving cognitive dysfunction, impacting not only on learning and memory, but also on cognitive control and attention.13 They suggest that the improved cognitive performance might be explained by its effects on 5-HT1A receptor stimulation and 5-HT3 receptor antagonism involved in cognitive processes, leading to enhanced cortical glutamatergic neuronal firing.\n\nWe describe here the first use of vortioxetine in cognitive dysfunction in schizophrenia and demonstrate beneficial effects on psychotic symptoms as well as on enhanced cognitive functioning. In this case report we present three patients with TRS who could not be treated with clozapine due to severe side effects, but who were successfully treated with a combination of vortioxetine and lurasidone at the National Psychosis Service. This is a specialist inpatient ward located at the Bethlem Royal Hospital, London, which acts as a UK-wide tertiary referral facility for the treatment of patients with treatment-resistant psychotic disorders. We discuss possible mechanisms that may underlie the unique efficacy of this combination in TRS.\n\nConsent\nThe patients all provided written informed consent for publication, which is available from the authors if required. The hospital does not require ethical approval to publish case reports.\n\nPatient 1\nPatient 1 is a 68-year-old married white British male with a diagnosis of TRS. He first presented with psychosis to psychiatric services in 1965 at age 17. Over the next four decades he was treated with a number of antipsychotic agents including sulpride, aripiprazole, haloperidol and olanzapine; all were at up to maximal British National Formulary recommended doses and a minimum of 12 weeks’ duration with compliance assured during inpatient episodes; he experienced a number of relapses over time. He did not achieve remission and was started on clozapine in 2002 (dose 400 mg daily). Following that, he was functional and relatively stable for 11 years, aside from some minor residual psychotic and anxiety symptoms.\n\nHis medical history at this time included ischaemic heart disease (IHD), cardiomyopathy with an ejection fraction of 35%, congestive heart failure (NYHA II) and bilateral pedal oedema. In 2014, following a decline in his cardiac function, his maintenance clozapine dose was reduced from 350 mg to 300 mg daily. Unfortunately, this was followed by a severe psychotic relapse characterized by prominent thought disorder, paranoid delusions, self-neglect and increasingly aggressive and challenging behaviour. His clozapine dose was increased back to 350 mg but his mental state continued to deteriorate and due to violence and aggression he was transferred to a psychiatric intensive care unit in March 2015.\n\nIn August 2016 he was admitted to the National Psychosis Unit, having been an inpatient for over 2 years. His symptoms at this time included persistent persecutory delusional beliefs, obsessive-compulsive traits, anxiety, mood lability, prominent difficulties in concentration and memory and irritability with outbursts of aggression. Psychotropic medication on admission included lurasidone 111 mg (which he had been treated with for over 1 year), sertraline 100 mg and diazepam 6 mg daily. On admission, he scored 115 on the PANSS total score and 29/30 on the Mini Mental State Exam (MMSE). An MRI brain scan was within normal limits; blood tests on admission were mostly within normal limits, except for a raised urea of 13.9 mmol/L (3.3–6.7) and an increased prolactin level of 894 mIU/L (100–410), attributed to lurasidone. The pharmacotherapeutic approaches considered included a trial of high-dose olanzapine, switching from sertraline to vortioxetine because of the added benefit in attention and cognitive flexibility, or adding either memantine or donepezil as adjuncts to aid cognition.\n\nIn August 2016 it was decided to increase his lurasidone dose to 148 mg daily. Sertraline was switched to adjunct vortioxetine 10 mg, which was gradually titrated to 20 mg over the next couple of weeks. By September 2016 there was noticeable improvement in symptoms, and by December 2016 he was in remission, scoring 44 on the PANSS total score. Pregabalin 25 mg BD was prescribed as an anxiolytic after stabilization on lurasidone and vortioxetine, and benzodiazepines were down-titrated and stopped. He was successfully discharged home in January 2017. Psychotropic medication on discharge included lurasidone 148 mg, vortioxetine 20 mg and pregabalin 25 mg BD. He described his wellbeing as 9 out of 10, compared to having been 1 out of 10 at admission. The family described his change as ‘miraculous, and that he had not been so well, even while being treated with clozapine’. Subsequent follow up confirmed a sustained functional and symptomatic recovery.\n\nPatient 2\nPatient 2 is a 31-year-old British woman with a diagnosis of TRS. She first presented to psychiatric services in 2002 (age 17) with flattened affect, inappropriate laughter, social withdrawal and functional decline. She was diagnosed with schizophrenia and over the next 10 years she was treated with various antipsychotics up to maximal British National Formulary recommended doses, including risperidone up to 8 mg, aripiprazole up to 30 mg and amisulpiride up to 800 mg, to which she demonstrated a limited response.\n\nHer medical history at this time included poorly controlled type I diabetes mellitus. Her blood sugar fluctuated from hypoglycaemia to hyperglycaemia and she was repeatedly admitted to medical wards for diabetic ketoacidosis.\n\nBetween 2009 and 2012 she presented with persistent positive psychotic symptoms: responding to auditory hallucinations, prominent thought disorder and inability to manage basic aspects of her personal care. This led to a psychiatric admission in June 2015 and clozapine was commenced in July 2015. There was no significant improvement in her mental state on clozapine, and over the next 6 months various augmentation strategies were attempted without success. These included amisulpride up to 800 mg daily, aripiprazole up to 20 mg daily and lurasidone 74 mg daily – all provided no significant benefit.\n\nShe was admitted to the National Psychosis Unit in October 2016 having been an inpatient for 16 months with persistent psychotic symptoms. Psychotropic medications on admission included clozapine 350 mg and lurasidone 74 mg daily (she had been treated with this for over 6 months). She was also prescribed insulin and pioglitazone to manage her diabetes. On admission she scored 110 on the PANSS total score and was unable to attend sufficiently to complete the MMSE. MRI of the brain was normal. Blood results at admission were within normal limits except for a raised HbA1c 9.5% (4.1–6.0), random glucose 22.4 mmol/L (3.0–6.0), ALP 209 IU/L (30–130), cholesterol 5.4 mmol/L (1.0–5.0) and lipid ratio 4.5. Her clozapine level on admission was 0.30 mg/L.\n\nIn early November 2016 her clozapine dose was increased to 375 mg daily, with a subsequent serum level of 0.66 mg/L. Her diabetes remained extremely difficult to control and she had a medical admission for diabetic ketoacidosis. By mid-December 2016 the increased clozapine dose had conferred no additional clinical improvement. Given the difficulty controlling her diabetes and the lack of any clear benefit from clozapine treatment for over a year, clozapine was stopped and instead lurasidone was increased to 111 mg. At the end of December 2016 vortioxetine 10 mg was commenced as a trial adjunct to enhance her cognition and attention. Within a few weeks of initiating vortioxetine, there was a remarkable improvement in all domains. She was more engaging, appeared brighter in mood, less distressed by psychotic symptoms and was able to attend to her self-care and acknowledge the change since admission, saying that her thinking felt clear and that voices were bothering her less. By January 2017 she scored 60 on the PANSS total score and 27/30 on MMSE. By February 2017 her diabetic control had improved: pioglitazone had been stopped, she required lower doses of insulin and her HbA1c had come down from 9.5% to 7.9%. By April 2017, she had maintained her improvement on lurasidone 111mg and vortioxetine 10 mg and was awaiting discharge.\n\nPatient 3\nPatient 3 is a 44-year-old single white British woman. She first presented to psychiatric services in 1987 (age 15) with self-harming behaviour, mood instability and aggression. She was diagnosed with emotionally unstable personality disorder. In 1990 she was detained under the Mental Health Act for over a year and diagnosed as having a psychotic illness.\n\nIn 2009 she was admitted to hospital with a diagnosis of schizophrenia and personality disorder, with symptoms including auditory hallucinations, impulsivity, intrusive thoughts, assaultive behaviour, suicide attempts and emotional dysregulation. She was trialled on haloperidol up to 20 mg daily and carbamazepine 800 mg daily with limited benefit. In 2009 this was switched to clozapine (with therapeutic serum levels), leading to an initial reduction in her psychotic symptoms, with a long relapse necessitating clozapine augmentation strategies including sodium valproate 1800 mg daily (2013–2015), topiramate 250 mg daily (2014–2016) and paroxetine up to 40 mg daily (2014–2015) with little success. In March 2015 she was found to have atrial fibrillation and as a consequence clozapine was stopped on a cardiologist’s advice. She was managed without any antipsychotics due to concerns about her cardiac status. After stopping clozapine, a significant deterioration in her mental state was noted. She was responding to external stimuli, laughing to herself, had minimal interactions with others and over time became near mute, but when speaking was noted to be thought-disordered. She continued to be doubly incontinent, had episodes of aggression and a lack of volition. She needed prompting with all aspects of personal care, eating and drinking, and she lost 30 kg of weight.\n\nRelevant past medical history included paroxysmal atrial fibrillation which was treated with bisoprolol 2.5 mg OD. Intermittent urinary and faecal incontinence had been investigated with no organic cause found; she was prescribed oxybutynin 2.5 mg nocte for the incontinence and also budesonide 3 mg TDS and mebeverine 135 mg TDS for presumed irritable bowel syndrome. She was prescribed levothyroxine 75 μg OD for hypothyroidism.\n\nShe was admitted to the National Psychosis Unit in December 2016, having been an inpatient since 2009 with persistent psychotic symptoms, more recently a catatonic presentation and mute for 18 months. Psychotropic medication on admission included topiramate 125 mg BD and clonazepam 0.5 mg BD. There were prominent negative psychotic symptoms, including lack of volition and a flat affect. She rarely got out of bed, continuing to be doubly incontinent. She was mute but some inappropriate laughter was noted. On admission she scored 117 on the PANSS total score and she was unable to complete an MMSE. She scored 17 on the Bush-Frances Catatonia Rating Scale. Bloods and ECG on admission were normal.\n\nInitially clonazepam was changed to lorazepam 2 mg QDS because of suspected catatonia. In mid-December 2016 she was commenced on lurasidone 74 mg which was titrated up to 111 mg by the end of December 2016. Topiramate was slowly reduced and stopped. After about a month on the ward an improvement in her mental state was noted, with her gradually becoming more responsive and communicative. She began to get out of bed and engage in conversation with patients and carers. She described low mood and in February 2017 vortioxetine 10 mg was started for an empirical trial of antidepressant and to enhance cognition. Within a few weeks she was described as bright and happy in mood, initiating conversation and pleasant on interaction. Her incontinence improved and physical medication for that was stopped. Lorazepam was replaced with diazepam with a plan for a gradual decrease and discontinuation. By February 2017 she scored 57 on the PANSS total score and by March 2017 her MMSE had increased to 22/30. She currently reports feeling ‘a lot better’ and describes that her quality of life has increased from 0 out of 10 on admission to 7 out of 10 currently treated with lurasidone 111 mg and vortioxetine 10 mg.\n\nDiscussion\nIn these three cases of severe TRS, a strikingly clear and marked clinical improvement in psychotic symptoms and cognition, reflected mostly in their social interactions, was observed when treated with a combination of vortioxetine and lurasidone. This suggests that the novel combination of vortioxetine and lurasidone may be a treatment option to consider when clozapine is indicated, but not able to be utilized due to concerns about adverse side effects or tolerability. These patients are unusual in having been previously treated with clozapine and showing an initial moderate response in two cases, with the response not being sustained in one of these; in the third case it failed to benefit the patient, with only a minimal response. The routine clinical observation on discontinuation of clozapine is of a severe rebound psychosis and exacerbation of symptoms; on the contrary, these cases show positive effects on this novel combination of medication. Two of the three patients had been previously receiving treatment with lurasidone without significant impact on their psychotic symptoms, indicating that the addition of the vortioxetine was most likely to be the most significant change. There is no published literature, but a single published abstract of lurasidone in treatment-refractory schizophrenia14 suggested some potential benefit in areas of cognition and psychotic symptoms. Two of the patients had been treated with SSRI medication in the past, without significant impact on their symptoms. This suggests that the psychopharmacological profile of vortioxetine, specifically the pro-cognitive effect, may be the key factor in their improvement. Interestingly, the actions of long-term vortioxetine administration overlaps with several actions of clozapine (Table 1).\n\nTable 1. Receptor binding profile of clozapine, vortioxetine and lurasidone.\n\n\tClozapine15\tVortioxetine16\tLurasidone17\t\n\tAffinity\tFunction\tAffinity\tFunction\tAffinity\tFunction\t\n\n5-HT1A\n\t\n+\n\tPartial agonist\t\n++\n\tAgonist\t\n+++\n\tPartial agonist\t\n\n5-HT1B\n\t\n+\n\tAntagonist\t\n++\n\tPartial agonist\t\t\t\n\n5-HT1D\n\t\n+\n\tAntagonist\t\n++\n\tAntagonist\t\t\t\n\n5-HT2A\n\t\n+++\n\tAntagonist\t\t\t\n+++\n\tAntagonist\t\n\n5-HT2B\n\t\n++\n\tAntagonist\t\t\t\t\t\n\n5-HT2C\n\t\n++\n\tAntagonist\t\t\t\t\t\n\n5-HT3\n\t\n+\n\tAntagonist\t\n+++\n\tAntagonist\t\t\t\n\n5-HT6\n\t\n++\n\tAntagonist\t\t\t\t\t\n\n5-HT7\n\t\n++\n\tAntagonist\t\n++\n\tAntagonist\t\n+++\n\tAntagonist\t\n\nSERT\n\t\t\t\n+++\n\tInhibition\t\t\t\n\nD1\n\t\n+\n\tAntagonist\t\t\t\t\t\n\nD2\n\t\n++\n\tAntagonist\t\t\t\n+++\n\tAntagonist\t\n\nD3\n\t\n+\n\tAntagonist\t\t\t\n++\n\tAntagonist\t\n\nD4\n\t\n++\n\tAntagonist\t\t\t\n++\n\tAntagonist\t\n\nD5\n\t\n+\n\tAntagonist\t\t\t\t\t\n\nH1\n\t\n+++\n\tAntagonist\t\t\t\t\t\n\nM1\n\t\n++\n\tPartial agonist\t\t\t\t\t\n\nM2\n\t\n++\n\tPartial agonist\t\t\t\t\t\n\nM3\n\t\n++\n\tAntagonist\t\t\t\t\t\n\nM4\n\t\n++\n\tPartial agonist\t\t\t\t\t\n\nM5\n\t\n++\n\tPartial agonist\t\t\t\t\t\n\nα 1A\n\t\n+++\n\tAntagonist\t\t\t\t\t\n\nα 1B\n\t\n+++\n\tAntagonist\t\t\t\t\t\n\nα 2A\n\t\n+\n\tAntagonist\t\t\t\n++\n\tAntagonist\t\n\nα 2B\n\t\n++\n\tAntagonist\t\t\t\t\t\n\nα 2C\n\t\n++\n\tAntagonist\t\t\t\n++\n\tAntagonist\t\nNote: Affinity expressed as Ki (nM). + >100 Ki (nM), ++ 10–100 Ki (nM), +++ <10 Ki (nM).\n\nSERT, serotonin reuptake transporter.\n\nThere has been longstanding interest in the role of serotonin in schizophrenia, heightened by the observation that clozapine possessed a higher affinity at the 5-HT2A receptor sites compared to D2 sites. In addition to this, clozapine also acted as a potent antagonist at the 5-HT2C, 5-HT6, and 5-HT7 receptors, and as a moderately potent partial agonist for the 5-HT1A receptor (Table 1).\n\nThese cases provide preliminary support for the proposal that TRS is characterized by a two-hit model, where conventional antipsychotic treatment may effectively attenuate the striatal dopaminergic dysfunction, but in the absence of a normative response from the prefrontal cortex in TRS, symptoms could be perpetuated despite optimal treatment. Here, a pro-cognitive intervention based on the serotonergic system has demonstrated positive effects on both cognition and psychotic symptoms. While speculative, it has support from the literature. It is well recognized that serotonin levels in the brain are regulated by the serotonin reuptake transporter (SERT) at the presynaptic nerve terminal. Both 5-HT1B and 5-HT1D receptors are presynaptic autoreceptors involved in negative feedback loops for serotonergic neurons. When stimulated, these receptors inhibit 5-HT release from neurons.18 By desensitizing 5-HT1B receptors and antagonizing 5-HT1D receptors, vortioxetine disinhibits 5-HT release. This effect, synergistically combined with blocking SERT, leads to a larger increase in 5-HT levels than blocking SERT alone, although the increase is still prevented from reaching dangerous levels by monoamine oxidase (MAO) activity.18 Clinically, the increase in 5-HT translates into antidepressant effect.19 This property of vortioxetine may be beneficial in psychotic patients with negative symptoms such as low mood. Aside from regulating 5-HT release from serotonergic neurons, 5-HT1B receptors are also found as heteroceptors on non-serotonergic neurons. In this context, 5-HT1B receptors inhibit the release of other neurotransmitters such as acetylcholine in the hippocampus, dopamine in the striatum, GABA and glutamate in widespread projections across the brain.20 This is interesting because differential glutamatergic changes have been observed in the anterior cingulate cortex of the frontal cortex in TRS.21 By desensitizing 5-HT1B receptors, vortioxetine has the potential to modulate release of these other neurotransmitters across the brain. This may be one mechanism whereby vortioxetine enhances cognitive function.16\n\nVortioxetine also acts as a high-affinity antagonist at 5-HT3 receptors, an action which is shared with clozapine (Table 1). 5-HT3 receptors are found as excitatory heteroceptors on GABAergic interneurons in the prefrontal cortex, hippocampus and amygdala.22 There they facilitate GABA release, forming part of a negative feedback circuit which inhibits 5-HT release from pyramidal cells in the midbrain raphe.23 Antagonism of 5-HT3 receptors by vortioxetine disinhibits this negative feedback loop, increasing 5-HT release from pyramidal cells in the midbrain raphe23 and enhancing hippocampal long-term potentiation and frequency of hippocampal theta rhythm.24 Aside from regulating 5-HT release in the midbrain and hippocampal long-term potentiation, 5-HT3 receptors also regulate release of noradrenaline, acetylcholine and dopamine throughout the brain.23 In summary, vortioxetine’s antagonism of 5-HT3 receptors on GABAergic interneurons leads to increased 5-HT, noradrenaline and acetylcholine levels and enhanced hippocampal memory formation – potentially enhancing vortioxetine’s antidepressant and pro-cognitive effects.\n\nIt is entirely possible that the improvements seen in these cases are due to the synergistic effects of the combination of vortioxetine and lurasidone. Lurasidone is a relatively new antipsychotic which, similar to clozapine, has antagonistic action at D2 and 5-HT2A receptors; however, it also has high affinity for 5-HT1A (partial agonism), 5-HT7 (antagonism) and norepinephrine α2C receptors17 – receptors implicated in enhancing cognition and mood and reducing negative symptoms of schizophrenia.25 It is possible that the clinical improvement observed in our cases when vortioxetine is added to lurasidone may be mediated via their combined effects on D2, 5-HT1B, 5-HT1D or 5-HT3 receptors (and potentially also by the effect of full agonism at 5-HT1A).\n\nThere are the obvious limitations of case report data, with the presence of many uncontrolled variables which could influence outcomes in these complex patients. We made a decision not to withdraw the adjunct medication to test response, as this was considered to be unethical. However, the patients had a consistent baseline of persistent symptoms and poor functioning in an inpatient setting over at least the period of a year, with assured compliance with medication. The assessments were carried out using standard tools by experienced staff, although not blinded to the treatment. The changes observed in the patients were sufficiently striking, that they were noted spontaneously by the patients and their carers, who were often unaware of the specific medication changes being implemented.\n\nThe pro-cognitive treatment approach used in these patients in this naturalistic case report may be of value when clozapine is not feasible or tolerated; and complements other experimental approaches that aim to enhance cognitive control through brain stimulation26 or using neurofeedback techniques.27 We believe that these novel clinical observations warrant further assessment in a prospective randomized controlled clinical trial – both to assess the benefit of adjunct vortioxetine and to clarify if this beneficial effect is unique to the combination with lurasidone.\n\nReceptor binding profiles was generously provided by the National Institute of Mental Health’s Psychoactive Drug Screening Program, Contract # HHSN-271-2013-00017-C (NIMH PDSP). The NIMH PDSP is Directed by Bryan L. Roth MD, PhD at the University of North Carolina at Chapel Hill and Project Officer Jamie Driscoll at NIMH, Bethesda MD, USA.\n\nFunding: S.S.S. is supported by a European Research Council Consolidator Award (grant number 311686), and some of this work was supported by the National Institute for Health Research (NIHR) Mental Health Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London. The funders of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report.\n\nConflict of interest statement: The authors declare that there is no conflict of interest.\n==== Refs\nReferences\n1 \nKane J Honigfeld G Singer J et al \nClozapine for the treatment-resistant schizophrenic: a double-blind comparison with chlorpromazine . Arch Gen Psychiatry \n1988 ; 45 : 789 –796 .3046553 \n2 \nLally J Ajnakina O Di Forti M et al \nTwo distinct patterns of treatment resistance: clinical predictors of treatment resistance in first-episode schizophrenia spectrum psychoses . Psychol Med \n2016 ; 46 : 3231 –3240 .27605254 \n3 \nWolkin A Barouche F Wolf AP et al \nDopamine blockade and clinical response: evidence for two biological subgroups of schizophrenia . Am J Psychiatry \n1989 ; 146 : 905 –908 .2568094 \n4 \nFrydecka D Beszłej JA Gościmski P et al \nProfiling cognitive impairment in treatment-resistant schizophrenia patients . Psychiatry Res \n2016 ; 235 : 133 –138 .26706131 \n5 \nHofer A Bodner T Kaufmann A et al \nSymptomatic remission and neurocognitive functioning in patients with schizophrenia . Psychol Med \n2011 ; 41 : 2131 –2139 .21426601 \n6 \nStephan KE Friston KJ Frith CD. \nDysconnection in schizophrenia: from abnormal synaptic plasticity to failures of self-monitoring . Schizophr Bull \n2009 ; 35 : 509 –527 .19155345 \n7 \nHowes OD Kapur S. \nThe dopamine hypothesis of schizophrenia: version III – the final common pathway . Schizophr Bull \n2009 ; 35 : 549 –562 .19325164 \n8 \nFriston KJ Frith CD. \nSchizophrenia: a disconnection syndrome . Clin Neurosci \n1995 ; 3 : 89 –97 .7583624 \n9 \nMichalopoulou PG Lewis SW Wykes T et al \nTreating impaired cognition in schizophrenia: the case for combining cognitive-enhancing drugs with cognitive remediation . Eur Neuropsychopharmacol \n2013 ; 23 : 790 –798 .23619163 \n10 \nMcIntyre RS Harrison J Loft H et al \nThe effects of vortioxetine on cognitive function in patients with major depressive disorder: a meta-analysis of three randomized controlled trials . Int J Neuropsychopharmacol \n2016 ; pii: pyw055 .27312740 \n11 \nEl Mansari M Lecours M Blier P \nEffects of acute and sustained administration of vortioxetine on the serotonin system in the hippocampus: electrophysiological studies in the rat brain . Psychopharmacology (Berl) \n2015 ; 232 : 2343 –2352 .25665528 \n12 \nLeiser SC Pehrson AL Robichaud PJ et al \nMultimodal antidepressant vortioxetine increases frontal cortical oscillations unlike escitalopram and duloxetine: a quantitative EEG study in rats . Br J Pharmacol \n2014 ; 171 : 4255 –4272 .24846338 \n13 \nKatona C Hansen T Olsen CK. \nA randomized, double-blind, placebo-controlled, duloxetine-referenced, fixed-dose study comparing the efficacy and safety of Lu AA21004 in elderly patients with major depressive disorder . Int Clin Psychopharmacol \n2012 ; 27 : 215 –223 .22572889 \n14 \nMeltzer H Share DB Jayathilake K (eds). Lurasidone is an effective treatment for treatment resistant schizophrenia . Presented at the ANCP 54th Annual Meeting , December 6–10, 2015 , The Diplomat, Hollywood, FL .\n15 \nDatabase P \nNational institute of mental health psychoactive drug screening program . Available at: https://pdsp.unc.edu/databases/pdsp.php (accessed 15 February 2017 ).\n16 \nSanchez C Asin KE Artigas F. \nVortioxetine, a novel antidepressant with multimodal activity: review of preclinical and clinical data . Pharmacol Ther \n2015 ; 145 : 43 –57 .25016186 \n17 \nTabacova S. \nPharmacology/toxicology NDA review and evaluation: lurasidone hydrochloride , www.accessdata.fda.gov/drugsatfda_docs/nda/2010/200603Orig1s000PharmR.pdf (2010 , accessed 09 February 2017 ).\n18 \nStahl SM. \nModes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): enhancing serotonin release by combining serotonin (5HT) transporter inhibition with actions at 5HT receptors (5HT1A, 5HT1B, 5HT1D, 5HT7 receptors) . CNS Spectr \n2015 ; 20 : 93 –97 .25831967 \n19 \nHalazy S Lamothe M Jorand-Lebrun C. \n5-HT1B/1D antagonists and depression . Expert Opin Ther Pat \n1997 ; 7 : 339 –352 .\n20 \nFink KB Göthert M. \n5-HT receptor regulation of neurotransmitter release . Pharmacol Rev \n2007 ; 59 : 360 –417 .18160701 \n21 \nDemjaha A Egerton A Murray RM et al \nAntipsychotic treatment resistance in schizophrenia associated with elevated glutamate levels but normal dopamine function . Biol Psychiatry \n2014 ; 75 : e11 –e13 .23890739 \n22 \nMorales M Bloom FE. \nThe 5-HT3 receptor is present in different subpopulations of GABAergic neurons in the rat telencephalon . J Neurosci \n1997 ; 17 : 3157 –3167 .9096150 \n23 \nStahl SM. \nModes and nodes explain the mechanism of action of vortioxetine, a multimodal agent (MMA): blocking 5HT3 receptors enhances release of serotonin, norepinephrine, and acetylcholine . CNS Spectr \n2015 ; 20 : 455 –459 .26122791 \n24 \nDale E Zhang H Leiser SC et al \nVortioxetine disinhibits pyramidal cell function and enhances synaptic plasticity in the rat hippocampus . J Psychopharmacol \n2014 ; 28 : 891 –902 .25122043 \n25 \nMeyer JM Loebel AD Schweizer E. \nLurasidone: a new drug in development for schizophrenia . Expert Opin Investig Drugs \n2009 ; 18 : 1715 –1726 .\n26 \nOrlov ND Tracy DK Joyce D et al \nStimulating cognition in schizophrenia: a controlled pilot study of the effects of prefrontal transcranial direct current stimulation upon memory and learning . Brain Stimul . Epub ahead of print 28 \n12 \n2016 DOI: 10.1016/j.brs.2016.12.013. \n27 \nDyck MS Mathiak KA Bergert S et al \nTargeting treatment-resistant auditory verbal hallucinations in schizophrenia with fMRI-based neurofeedback: exploring different cases of schizophrenia . Front Psychiatry \n2016 ; 7 : 37 .27014102\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "8(1)",
"journal": "Therapeutic advances in psychopharmacology",
"keywords": "cognition; novel treatment; refractory schizophrenia",
"medline_ta": "Ther Adv Psychopharmacol",
"mesh_terms": null,
"nlm_unique_id": "101555693",
"other_id": null,
"pages": "63-70",
"pmc": null,
"pmid": "29344345",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
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"title": "When the drugs don't work: treatment-resistant schizophrenia, serotonin and serendipity.",
"title_normalized": "when the drugs don t work treatment resistant schizophrenia serotonin and serendipity"
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"abstract": "Pulmonary alveolar proteinosis (PAP) describes the accumulation of surfactant in the alveolar space. Secondary PAP has been reported in a variety of diseases, and in rare cases has been associated with hematologic malignancy. Treatment for PAP is based on the underlying disease process, and may include whole lung lavage, inhaled or subcutaneous granulocyte-macrophage colony-stimulating factor, or statins. PAP secondary to hematologic malignancy has been reported to demonstrate poor response to whole lung lavage. We report a case of successful treatment of a pediatric patient with acute myeloid leukemia and secondary PAP using whole lung lavage.",
"affiliations": "Division of Pulmonary and Sleep Medicine, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Division of Critical Care Medicine, Department of Anesthesia and Critical Care, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Division of General Pediatrics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.;Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.",
"authors": "Tsukahara|Katharine|K|http://orcid.org/0000-0003-2115-5944;Lindell|Robert B|RB|http://orcid.org/0000-0002-6334-4973;Newman|Haley|H|http://orcid.org/0000-0002-3022-8052;Lerman|Benjamin J|BJ|;Kersun|Leslie S|LS|;Piccione|Joseph|J|http://orcid.org/0000-0002-0691-3551",
"chemical_list": null,
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"doi": "10.1002/ppul.25718",
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"issn_linking": "1099-0496",
"issue": "57(1)",
"journal": "Pediatric pulmonology",
"keywords": "acute myeloid leukemia; bronchoscopy; pulmonary surfactant",
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": null,
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "308-310",
"pmc": null,
"pmid": "34644455",
"pubdate": "2022-01",
"publication_types": "D002363:Case Reports",
"references": "18085671;19465834;9694696;32684993;25300566",
"title": "Successful whole lung lavage in a child with pulmonary alveolar proteinosis secondary to hematologic malignancy.",
"title_normalized": "successful whole lung lavage in a child with pulmonary alveolar proteinosis secondary to hematologic malignancy"
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"companynumb": "US-Fresenius Kabi-FK202203914",
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{
"abstract": "Nontuberculous mycobacterial infections are rare but severe complications of chemotherapy in children. In children with prolonged lymphopoenia after mieloablative regimens, symptoms can be nonspecific and fever and pulmonary impairment are the most common clinical features. Diagnosis is challenging for physicians and microbiologists and often requires invasive techniques. We report a girl affected by acute lymphoblastic leukemia, who developed a disseminated infection sustained by Mycobacterium avium complex. Identification of the microorganism was obtained by open lung biopsy and evidence of mycobacterium genome. We also reviewed 15 literature cases of disseminated infections of nontuberculous mycobacterium in children with leukemia.",
"affiliations": "*Department of Paediatric Sciences, Division of Paediatric Oncology, Catholic University of Rome, Rome †Department of Mother and Child, Division of Paediatric Oncology and Infectious Diseases, University Hospital of Parma, Parma, Italy.",
"authors": "Arlotta|Annalisa|A|;Cefalo|Maria G|MG|;Maurizi|Palma|P|;Ruggiero|Antonio|A|;Dodi|Icilio|I|;Riccardi|Riccardo|R|",
"chemical_list": null,
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"issue": "36(1)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D002648:Child; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D009165:Mycobacterium Infections, Nontuberculous; D015269:Mycobacterium avium Complex; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9505928",
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"pages": "66-70",
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"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Critical pulmonary infection due to nontuberculous mycobacterium in pediatric leukemia: report of a difficult diagnosis and review of pediatric series.",
"title_normalized": "critical pulmonary infection due to nontuberculous mycobacterium in pediatric leukemia report of a difficult diagnosis and review of pediatric series"
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"companynumb": "IT-MYLANLABS-2015M1009250",
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"patient": {
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
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... |
{
"abstract": "This case report presents an old hemiparetic male admitted to hospital from nursing home due to dark-coloured emesis. Transdermal buprenorphine 5 mcg/h had been instigated without laxatives in the preceding month. Upon arrival, an enlarged tense abdomen was found. A CT-scan dem-on-strated a 19 cm wide faecal colon impaction. Limited effect of enemas and endoscopic disimpaction resulted in surgery. The patient died shortly after discharge. The case stresses the prevention of constipation when using opioids; in particular in immobilized patients.",
"affiliations": "soren.kabell.nissen@rsyd.dk.",
"authors": "Nissen|Søren Kabell|SK|;Stenberg|Morten Roos|MR|;Ryg|Jesper|J|",
"chemical_list": "D000701:Analgesics, Opioid; D054368:Laxatives; D002047:Buprenorphine",
"country": "Denmark",
"delete": false,
"doi": null,
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"issn_linking": "0041-5782",
"issue": "179(51)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D002047:Buprenorphine; D016638:Critical Illness; D017809:Fatal Outcome; D005244:Fecal Impaction; D006801:Humans; D054368:Laxatives; D008297:Male; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29260692",
"pubdate": "2017-12-18",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Faecal impaction in elderly patients is a potential severe condition.",
"title_normalized": "faecal impaction in elderly patients is a potential severe condition"
} | [
{
"companynumb": "DK-MYLANLABS-2019M1015022",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BUPRENORPHINE"
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... |
{
"abstract": "Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new laparoscopic administration of chemotherapy for peritoneal metastasis (PM). PIPAC is repeated every 5th week, and seems to stabilize or improve quality of life, and might improve survival. So far, PIPAC has been well tolerated. With this paper, we aim to highlight a potential severe adverse reaction, as we describe the first cases of severe peritoneal sclerosis (SPS) caused by PIPAC. Patients with isolated PM were included in a prospective PIPAC protocol. Following insufflation of normothermic CO2, laparoscopy was performed at an intraabdominal pressure of 12 mmHg. After peritoneal lavage and quadrant biopsies of the PM, the patients were treated with oxaliplatin 92 mg/m2 (flowrate 0.5 ml/s, maximum pressure of 200 per square inch). Treatment related toxicity was evaluated after 2 weeks. Response was evaluated histologically by the Peritoneal Regression Grading Score (PRGS) and cytologically by analysis of the lavage fluid. In a series of 24 PIPAC patients treated with oxaliplatin, two patients developed SPS. Patient one had a mucinous adenocarcinoma of the appendix with PM, the mean PRGS was reduced from 2.75 to 1.75 during the course of therapy. Patient two had an appendiceal goblet cell carcinoid with a dominating mucinous adenocarcinoma component with PM, the mean PRGS was reduced from 2.00 to 1.67. Repeated applications of PIPAC with oxaliplatin can lead to SPS.",
"affiliations": "Upper GI and HPB Section, Department of Surgery, Odense University Hospital, J.B. Winsloews Vej 4, Indgang 20, Penthouse 2., 5000, Odense C, Denmark. Martin.Graversen@rsyd.dk.;Odense PIPAC Center (OPC), Odense University Hospital, Odense, Denmark.;Odense PIPAC Center (OPC), Odense University Hospital, Odense, Denmark.;Upper GI and HPB Section, Department of Surgery, Odense University Hospital, J.B. Winsloews Vej 4, Indgang 20, Penthouse 2., 5000, Odense C, Denmark.;Upper GI and HPB Section, Department of Surgery, Odense University Hospital, J.B. Winsloews Vej 4, Indgang 20, Penthouse 2., 5000, Odense C, Denmark.",
"authors": "Graversen|M|M|http://orcid.org/0000-0001-5719-4916;Detlefsen|S|S|;Pfeiffer|P|P|;Lundell|L|L|;Mortensen|M B|MB|",
"chemical_list": "D000336:Aerosols; D000970:Antineoplastic Agents; D000077150:Oxaliplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s10585-018-9895-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0262-0898",
"issue": "35(3)",
"journal": "Clinical & experimental metastasis",
"keywords": "Complications; Encapsulated peritoneal sclerosis; Intraperitoneal chemotherapy; PIPAC; Peritoneal metastasis; Peritoneal sclerosis",
"medline_ta": "Clin Exp Metastasis",
"mesh_terms": "D002288:Adenocarcinoma, Mucinous; D000328:Adult; D000336:Aerosols; D000368:Aged; D000970:Antineoplastic Agents; D001063:Appendiceal Neoplasms; D002276:Carcinoid Tumor; D006801:Humans; D007263:Infusions, Parenteral; D008297:Male; D000077150:Oxaliplatin; D056627:Peritoneal Fibrosis; D010534:Peritoneal Neoplasms; D011446:Prospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "8409970",
"other_id": null,
"pages": "103-108",
"pmc": null,
"pmid": "29705882",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "19494594;28407227;26277656;26637888;16794395;27313780;25459437;24006094;22634898;28095701;27590613;27602235;10640968;22580869;12658394;26138283;25160862;21808281;20737573;25940594;8862729;27890350;12445064;27065713;27774831",
"title": "Severe peritoneal sclerosis after repeated pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC OX): report of two cases and literature survey.",
"title_normalized": "severe peritoneal sclerosis after repeated pressurized intraperitoneal aerosol chemotherapy with oxaliplatin pipac ox report of two cases and literature survey"
} | [
{
"companynumb": "DK-PFIZER INC-2018182648",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "In patients with renal dysfunction, it is important to avoid prescribing fluoroquinolones including ciprofloxacin.",
"affiliations": "Intensive Care Unit Hyogo College of Medicine Nishinomiya Japan.;Intensive Care Unit Hyogo College of Medicine Nishinomiya Japan.;Intensive Care Unit Hyogo College of Medicine Nishinomiya Japan.",
"authors": "Matoi|Aisa|A|https://orcid.org/0000-0002-0335-6091;Taguchi|Mana|M|;Nishi|Shinichi|S|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3871",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904\nJohn Wiley and Sons Inc. Hoboken\n\n10.1002/ccr3.3871\nCCR33871\nCase Report\nCase Reports\nFatal hypoglycemia with ciprofloxacin in a dialysis patient: A case report\nMATOI et al.\nMatoi Aisa https://orcid.org/0000-0002-0335-6091\n1 ai-matoi@hyo-med.ac.jp\n\nTaguchi Mana 1\nNishi Shinichi 1\n1 Intensive Care Unit Hyogo College of Medicine Nishinomiya Japan\n* Correspondence\nAisa Matoi, Hyogo College of Medicine, Intensive Care Unit, Nishinomiya, Japan.\nEmail: ai-matoi@hyo-med.ac.jp\n\n12 3 2021\n4 2021\n9 4 10.1002/ccr3.v9.4 19021904\n07 1 2021\n28 10 2020\n10 1 2021\n© 2021 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nIn patients with renal dysfunction, it is important to avoid prescribing fluoroquinolones including ciprofloxacin.\n\nIn patients with renal dysfunction, it is important to avoid prescribing fluoroquinolones including ciprofloxacin.\n\nadverse event\nciprofloxacin\nfatal hypoglycemia\nfluoroquinolones\nrenal dysfunction\nsource-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.2 mode:remove_FC converted:27.04.2021\nMatoi A , Taguchi M , Nishi S . Fatal hypoglycemia with ciprofloxacin in a dialysis patient: A case report. Clin Case Rep. 2021;9 :1902–1904. 10.1002/ccr3.3871\n==== Body\n1 INTRODUCTION\n\nFluoroquinolones are widely used for various infections because of their broad antibacterial spectrum and usefulness, particularly in Japan. Fluoroquinolones have been reported to have complications such as dysglycemia, 1 cardiovascular toxicity, 2 and tendinopathy, 3 but we poorly recognize that. In fact, the use of fluoroquinolones should be limited from the complications and the antimicrobial resistance perspective. There are many reports of hypoglycemia caused by fluoroquinolones, especially gatifloxacin and levofloxacin, but relatively few reports of hypoglycemia caused by ciprofloxacin. Here, we report a case of fatal hypoglycemia associated with ciprofloxacin administration in a dialysis patient.\n\n2 CASE PRESENTATION\n\nA 73‐year‐old man with end‐stage renal disease on hemodialysis and atrial fibrillation was admitted to hospital for surgery for spondylosis. He had end‐stage renal disease due to diabetic nephropathy, but he was not taking diabetic drugs for decades. Four days after admission, he developed fever, and pneumonia was suspected by computed tomography (CT) examination. Intravenous tazobactam‐piperacillin was administered. After 7 days of thrice‐daily administration of 2.25 g tazobactam‐piperacillin, the antibiotic was changed to ciprofloxacin for suspected atypical pneumonia. After intravenous administration of 400 mg ciprofloxacin once daily for 7 days, he was found to be in a state of unconsciousness on the morning of a dialysis day. Blood test revealed blood glucose level of 1 mg/dL. He was administered glucose by infusion, but hypoglycemia and altered mental status persisted and he was admitted to the intensive care unit. There, he received glucose infusions and his blood glucose level normalized, although his consciousness did not improve (see Figure 1). The head nonenhanced CT examination revealed no intracranial lesion, and the patient was diagnosed with hypoglycemic encephalopathy.\n\nFIGURE 1 Administration of antibacterial drugs and blood sugar levels after admission. TAZ/PIPC= tazobactam‐piperacillin\n\nAn endocrine test (Table 1) revealed that counter‐regulatory hormones were elevated, but C‐peptide and insulin levels were high and normal, respectively (C‐peptide 3.68 ng/mL, insulin 8.01 μIU/mL), suggesting hyperinsulinemic hypoglycemia. Chest‐abdominal CT examination did not reveal insulinoma.\n\nTABLE 1 Endocrine test during an episode of hypoglycemia\n\nC‐peptide (ng/mL)\t3.68 (0.61‐2.09)\tGH¶ (ng/mL)\t6.98 (<2.47)\t\nInsulin (μIU/mL)\t8.01 (1.84‐12.2)\tACTH†† (pg/mL)\t28.7 (7.2‐63.3)\t\nInsulin antibody\tNegative\tCortisol (μg/dL)\t13.6 (6.24‐18)\t\nfree T3 † (pg/mL)\t2.68 (2.3‐4.0)\tAdrenaline (pg/mL)\t237 (<100)\t\nfree T4 ‡ (ng/dL)\t1.20 (0.9‐1.7)\tNoradrenaline (pg/mL)\t651 (100‐450)\t\nTSH§ (μIU/mL)\t16.4 (0.5‐5.0)\tDopamine (pg/mL)\t86 (<20)\t\nNote\n\n†free T3=free thyroxine 3; ‡free T4=free thyroxine 4; §TSH=thyroid stimulating hormone; ¶GH=growth hormone; ††ACTH=adrenocorticotropic hormone. Numbers in parentheses are reference values.\n\nJohn Wiley & Sons, Ltd\n\nSubsequently, his consciousness did not improve, and he died 73 days after admission due to aspiration pneumonia.\n\n3 DISCUSSION\n\nFluoroquinolones are antibiotics widely used in the treatment of common bacterial infections in patients due to a broad spectrum of antibacterial activity and high oral bioavailability. But various adverse effects have been reported, such as dysglycemia, 1 cardiovascular toxicity, 2 and tendinopathy. 3 In July 2016, the US Food and Drug Administration approved safety labeling changes for fluoroquinolones to enhance warnings about their association with disabling and potentially permanent side effects and to limit their use in patients with less serious bacterial infections. 4 Nevertheless, we do not recognize fully the harmful effects of fluoroquinolones.\n\nAlthough there are many reports of hypoglycemia caused by fluoroquinolones, ciprofloxacin is considered to have a lower risk of hypoglycemia compared with other fluoroquinolones, as indicated in previous observational studies. 1 , 5 There are no previous case reports on severe hypoglycemia because of ciprofloxacin that resulted in serious sequelae such as disorders of consciousness and death, as in the present case.\n\nThe mechanism of insulin secretion is as follows: ATP‐sensitive K+ channels on pancreatic β‐cells are suppressed by increased blood sugar, while depolarization is caused by an increase in intracellular K+ concentration, which causes the opening of voltage‐dependent Ca2+ channels and Ca2+ influx into the cell body, causing insulin secretion. Fluoroquinolones are believed to promote insulin secretion by suppressing ATP‐sensitive K+ channels on pancreatic β‐cells, thereby causing hypoglycemia. 6 This is consistent with observations in the present case, whereby blood insulin and C‐peptide levels were not suppressed despite hypoglycemia.\n\nCiprofloxacin is less likely to cause hypoglycemia than other fluoroquinolones. In contrast, a study in noninsulin‐dependent diabetic patients showed ciprofloxacin decreased blood glucose level and increased blood insulin level compared with placebo, although it did not lead to hypoglycemia. 7 Additionally, it was reported that inhibition of CYP3A4 by ciprofloxacin increases blood levels of sulfonylureas, and its drug interactions may cause hypoglycemia. 8 A recent study also suggests that ciprofloxacin can cause hypoglycemia even in nondiabetic and previously healthy patients. 9\n\nThe present case was a dialysis patient with end‐stage renal disease due to diabetic nephropathy, who was not taking drugs for diabetes in combination with other medications. Hypoglycemia develops easily in chronic kidney disease patients because of various metabolic abnormalities, 10 such as reduction of insulin excretion and destruction in the kidney, reduction of gluconeogenesis in kidney and liver, and decrease of counter‐regulatory hormone secretion. Moreover, because fluoroquinolones are primarily excreted by the kidney, administration of fluoroquinolones may cause increased drug accumulation and concentration in patients with renal dysfunction. Regarding the present case, the marked hypoglycemia was potentially caused by promotion of insulin secretion by ciprofloxacin in addition to the state of chronic renal failure.\n\nTo our knowledge, there are five reported cases of severe sequelae such as sustained consciousness disorder and death because of hypoglycemia caused by fluoroquinolones. 11 , 12 , 13 , 14 , 15 All were because of levofloxacin, not ciprofloxacin. Three of five patients were taking concomitant medications that can cause hypoglycemia, such as insulin and sulfonylureas, and four of five patients had renal dysfunction. It is possible that renal dysfunction with concomitant use of diabetes drugs may contribute to aggravation of hypoglycemia.\n\nPrevious studies showed that risk factors of fluoroquinolone‐related hypoglycemia include old age, renal dysfunction, diabetes, and concomitant use of hypoglycemic drugs. 1 , 16 The incidence of hypoglycemia in the absence of diabetes drugs is rare, and there is no evaluation of risk factors for onset and severity of hypoglycemia because of fluoroquinolones in nondiabetic patients. However, the identification of hypoglycemia in nondiabetic patients tends to be delayed, which may lead to unfortunate consequences. It is necessary to evaluate the risk factors for hypoglycemia caused by fluoroquinolones in nondiabetic patients. Renal dysfunction may be considered a risk factor because of the mechanism.\n\n4 CONCLUSION\n\nAlthough hypoglycemia caused by ciprofloxacin is rare, it can cause fatal complications, as in the present case. Therefore, it should be administered carefully. Hypoglycemia can potentially develop because of renal dysfunction which is suggested to be a risk factor for aggravation. It is important to avoid prescribing fluoroquinolones, including ciprofloxacin, for patiens with renal dysfunction given the risk of hypoglycemia.\n\nCONFLICT OF INTEREST\n\nThe authors declare no conflicts of interest associated with this manuscript.\n\nAUTHOR CONTRIBUTIONS\n\nAM: involved in conceptualization, visualization, and writing—original draft. MT: involved in writing—review and editing. SN: supervised the study. All authors: read and approved the final manuscript.\n\nETHICAL APPROVAL\n\nWe have obtained an informed consent from the patient's family.\n\nACKNOWLEDGMENTS\n\nWe thank Dr Ide, Dr Hori, and Dr Takeda for their involvement in the medical treatment. We thank Richard Robins, PhD, from Edanz Group (https://en‐author‐services.edanzgroup.com/ac) for editing a draft of this manuscript.\n\nDATA AVAILABILITY STATEMENT\n\nNo data were analyzed, reused, and generated in this case report.\n==== Refs\nREFERENCES\n\n1 Chou H‐W , Wang J‐L , Chang C‐H , Lee J‐J , Shau W‐Y , Lai M‐S . Risk of severe dysglycemia among diabetic patients receiving levofloxacin, ciprofloxacin, or moxifloxacin in Taiwan. Clin Infect Dis. 2013;57 :971‐980.23948133\n2 Liu X , Ma J , Huang L , et al. Fluoroquinolones increase the risk of serious arrhythmias: a systematic review and meta‐analysis. Medicine. 2017;96 :e8273.29095256\n3 Lewis T , Cook J . Fluoroquinolones and tendinopathy: a guide for athletes and sports clinicians and a systematic review of the literature. J Athl Train. 2014;49 :422‐427.24762232\n4 U.S. Food and Drug Administration (FDA) . FDA updates warnings for fluoroquinolone antibiotics. https://www.fda.gov/news‐events/press‐announcements/fda‐updates‐warnings‐fluoroquinolone‐antibiotics. Accessed July 26, 2016.\n5 Aspinall SL , Good CB , Jiang R , McCarren M , Dong D , Cunningham FE . Severe dysglycemia with the fluoroquinolones: a class effect? Clin Infect Dis. 2009;49 :402‐408.19545207\n6 Maeda N , Tamagawa T , Niki I , et al. Increase in insulin release from rat pancreatic islets by quinolone. Br J Pharmacol. 1996;117 :372‐376.8789393\n7 Gajjar DA , LaCreta FP , Kollia GD , et al. Effect of multiple‐dose gatifloxacin or ciprofloxacin on glucose homeostasis and insulin production in patients with noninsulin‐dependent diabetes mellitus maintained with diet and exercise. Pharmacotherapy. 2000;20 :76‐86.\n8 Roberge RJ , Kaplan R , Frank R , Fore C . Glyburide‐ciprofloxacin interaction with resistant hypoglycemia. Ann Emerg Med. 2000;36 :160‐163.10918110\n9 Berhe A , Russom M , Bahran F , Hagos G . Ciprofloxacin and risk of hypolycemia in non‐diabetic patients. J Med Case Rep. 2019;13 :1‐6.30611283\n10 Alsahli M , Gerich JE . Hypoglycemia in patients with diabetes and renal disease. J Clin Med. 2015;4 :948‐964.26239457\n11 Madey JJ , Hannah JA , Lazaridis C . Central pontine myelinolysis following acute hypoglycemia. Clin Neurol Neurosurg. 2013;115 :2299‐2300.23948485\n12 Vallurupalli S , Huesmann G , Gregory J , Jakoby MG IV . Levofloxacin‐associated hypoglycaemia complicated by pontine myelinolysis and quadriplegia. Diabet Med. 2008;25 :856‐859.18644072\n13 Singh M , Jacob JJ , Kapoor R , Abraham J . Fatal hypoglycemia with levofloxacin use in an elderly patient in the post‐operative period. Langenbecks Arch Surg. 2008;393 :235‐238.18175142\n14 Lawrence KR , Adra M , Keir C . Hypoglycemia‐induced anoxic brain injury possibly associated with levofloxacin. J Infect. 2006;52 :e177‐e180.16269178\n15 Friedrich LV , Dougherty R . Fatal hypoglycemia associated with levofloxacin. Pharmacotherapy. 2004;24 :1807‐1812.15585448\n16 LaPlante KL , Mersfelder TL , Ward KE , Quilliam BJ . Prevalence of and risk factors for dysglycemia in patients receiving gatifloxacin and levofloxacin in an outpatient setting. Pharmacotherapy. 2008;28 :82‐89.18154478\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-0904",
"issue": "9(4)",
"journal": "Clinical case reports",
"keywords": "adverse event; ciprofloxacin; fatal hypoglycemia; fluoroquinolones; renal dysfunction",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1902-1904",
"pmc": null,
"pmid": "33936612",
"pubdate": "2021-04",
"publication_types": "D002363:Case Reports",
"references": "23948485;10850524;29095256;18154478;15585448;10918110;19545207;24762232;8789393;18644072;16269178;23948133;31078137;26239457;18175142",
"title": "Fatal hypoglycemia with ciprofloxacin in a dialysis patient: A case report.",
"title_normalized": "fatal hypoglycemia with ciprofloxacin in a dialysis patient a case report"
} | [
{
"companynumb": "JP-FDC LIMITED-2109663",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nRufinamide is a novel antiepileptic drug used as adjunctive therapy in patients with Lennox-Gastaut syndrome and provides seizure control especially in tonic and atonic seizures. Rufinamide is expected to be effective in intractable epilepsy when atonic and tonic seizures exist. However, rufinamide induced seizure aggravation has been reported in a few patients, which was not associated with a specific type of seizure.\n\n\nMETHODS\nA 12-year-old boy with intractable epilepsy had tonic and atonic seizures despite treatment with valproic acid (3000mg/day), levetiracetam (3000mg/day) and clobazam (40mg/day). Rufinamide was administered as adjuvant therapy. After 2weeks on rufinamide, he experienced atonic seizure worsening, and the frequency of epileptic discharges increased. The deterioration in seizure frequency and epileptiform discharges resolved when rufinamide was discontinued.\n\n\nCONCLUSIONS\nRufinamide may aggravate atonic seizures in patients with intractable epilepsy.",
"affiliations": "Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey. Electronic address: goncabektas@gmail.com.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.;Department of Pediatric Neurology, Istanbul Medical Faculty, Istanbul University, Turkey.",
"authors": "Bektaş|Gonca|G|;Çalışkan|Mine|M|;Aydın|Ali|A|;Pembegül Yıldız|Edibe|E|;Tatlı|Burak|B|;Aydınlı|Nur|N|;Özmen|Meral|M|",
"chemical_list": "D000927:Anticonvulsants; D014230:Triazoles; D001569:Benzodiazepines; D000078306:Clobazam; D000077287:Levetiracetam; D014635:Valproic Acid; C079703:rufinamide; D010889:Piracetam",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0387-7604",
"issue": "38(7)",
"journal": "Brain & development",
"keywords": "Atonic; Intractable epilepsy; Rufinamide; Seizure",
"medline_ta": "Brain Dev",
"mesh_terms": "D000927:Anticonvulsants; D001569:Benzodiazepines; D001921:Brain; D002648:Child; D000078306:Clobazam; D000069279:Drug Resistant Epilepsy; D004359:Drug Therapy, Combination; D004569:Electroencephalography; D006801:Humans; D000077287:Levetiracetam; D008297:Male; D010889:Piracetam; D012640:Seizures; D014230:Triazoles; D014635:Valproic Acid",
"nlm_unique_id": "7909235",
"other_id": null,
"pages": "654-7",
"pmc": null,
"pmid": "26906013",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Aggravation of atonic seizures by rufinamide: A case report.",
"title_normalized": "aggravation of atonic seizures by rufinamide a case report"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2016R1-111646",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBAZAM"
},
"drugad... |
{
"abstract": "We report a case of a male in his 50 s who underwent pancreaticoduodenectomy for solid pseudopapillary neoplasm (SPN) of the pancreas at 30 years. He developed a liver abscess 15 years after the surgery, and CT scan revealed a swollen retroperitoneum lymph node and a tumor in the liver. Symptoms, including abdominal distension, appetite loss, and epigastric pain, appeared due to lymph node metastasis. Endoscopic ultrasonography-guided fine-needle aspiration against the lymph node revealed SPN recurrence. The tumor had invaded the common hepatic artery, and surgery was not indicated. Chemotherapy of Gemcitabine/nab-Paclitaxel biweekly was performed 8 times; however, no reduction in tumor size was observed, and the patient's symptoms worsened. Proton beam therapy (67.5 GyE in 25 fractions) was subsequently performed for lymph node metastasis, and led to a gradual reduction in lymph node metastasis, and an improvement in symptoms. No re-expansion of lymph node metastasis has been observed 3 years after proton beam therapy. Since SPN is low malignancy and most cases can be expected to be cured by surgery, there is currently no standard treatment of unresectable SPN. This case is the first report of proton beam therapy for SPN, and was considered to be effective.",
"affiliations": "Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan. kodryo@grn.janis.or.jp.;Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.;Department of Gastroenterology, JA Nagano Koseiren Minaminagano Medical Center, Shinonoi General Hospital, Nagano, Japan.",
"authors": "Kodama|Ryo|R|http://orcid.org/0000-0002-7339-8078;Koh|Youshin|Y|;Midorikawa|Hajime|H|;Yokota|Yukiko|Y|;Saegusa|Hisanobu|H|;Ushimaru|Hiroyasu|H|",
"chemical_list": "D011522:Protons",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12328-020-01262-w",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1865-7265",
"issue": "14(1)",
"journal": "Clinical journal of gastroenterology",
"keywords": "Proton beam therapy; Recurrence; Solid pseudopapillary neoplasm; Unresectable",
"medline_ta": "Clin J Gastroenterol",
"mesh_terms": "D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D010179:Pancreas; D010180:Pancreatectomy; D010190:Pancreatic Neoplasms; D011522:Protons",
"nlm_unique_id": "101477246",
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"pages": "375-381",
"pmc": null,
"pmid": "33052580",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of recurrence of a solid pseudopapillary neoplasm of the pancreas effectively treated with proton beam radiotherapy.",
"title_normalized": "a case of recurrence of a solid pseudopapillary neoplasm of the pancreas effectively treated with proton beam radiotherapy"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-291778",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE"
},
"dru... |
{
"abstract": "After a single patient was transferred to Leipzig University Hospital from a hospital in Rhodes, Greece, the hospital experienced the largest outbreak due to a KPC-2-producing Klebsiella pneumoniae (KPC-2-KP) strain thus far observed in Germany. Ninety patients hospitalised between July 2010 and October 2012 were affected. In an attempt to eliminate KPC-2-KP from their digestive tracts, 14 consecutive patients (16%) were treated with a short course (7 days) of selective digestive decontamination (SDD), employing colistin (1 million units q.i.d.) and gentamicin (80 mg q.i.d.) as oral solutions, and applying colistin/gentamicin gel (0.5 g) to the oral cavity. In a retrospective analysis, these 14 SDD patients were compared with the remaining 76 patients harbouring KPC-2-KP. KPC-2-KP carrier status was followed in all 14 SDD patients by submitting stool samples to KPC-specific PCR. The mean follow-up period was 48 days (range 12-103 days). Successful elimination of KPC-2-KP was defined as a minimum of three consecutive negative PCR test results separated by ≥48 h each. Decolonisation of KPC-2-KP was achieved in 6/14 patients (43%) after a mean of 21 days (range 12-40 days), but was also observed in 23/76 (30%) of the non-SDD controls (P = 0.102). SDD treatment resulted in the development of secondary resistance to colistin (19% increase in resistance rate) and gentamicin (45% increase) in post-treatment isolates. In the control group, no secondary resistance occurred. We conclude that the SDD protocol applied in this study was not sufficiently effective for decolonisation and was associated with resistance development.",
"affiliations": "Division of Infectious Diseases and Tropical Medicine, Department of Gastroenterology and Rheumatology, Leipzig University Hospital, Liebigstr. 20, D-04103 Leipzig, Germany. Electronic address: christoph.luebbert@medizin.uni-leipzig.de.",
"authors": "Lübbert|Christoph|C|;Faucheux|Sarah|S|;Becker-Rux|Diana|D|;Laudi|Sven|S|;Dürrbeck|Axel|A|;Busch|Thilo|T|;Gastmeier|Petra|P|;Eckmanns|Tim|T|;Rodloff|Arne C|AC|;Kaisers|Udo X|UX|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins; C491478:beta-lactamase KPC-2; D001618:beta-Lactamases; D003091:Colistin",
"country": "Netherlands",
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"doi": null,
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"issn_linking": "0924-8579",
"issue": "42(6)",
"journal": "International journal of antimicrobial agents",
"keywords": "Antimicrobial resistance; Colistin; Gentamicin; Klebsiella pneumoniae carbapenemase (KPC); Outbreak; Selective digestive decontamination (SDD)",
"medline_ta": "Int J Antimicrob Agents",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D003091:Colistin; D003428:Cross Infection; D004196:Disease Outbreaks; D024881:Drug Resistance, Bacterial; D005243:Feces; D005260:Female; D005839:Gentamicins; D005858:Germany; D006115:Greece; D006801:Humans; D017053:Infection Control; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013997:Time Factors; D001618:beta-Lactamases",
"nlm_unique_id": "9111860",
"other_id": null,
"pages": "565-70",
"pmc": null,
"pmid": "24100228",
"pubdate": "2013-12",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with KPC-2-producing Klebsiella pneumoniae: a single-centre experience.",
"title_normalized": "rapid emergence of secondary resistance to gentamicin and colistin following selective digestive decontamination in patients with kpc 2 producing klebsiella pneumoniae a single centre experience"
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"abstract": "BACKGROUND\nTaenia solium, present in most developing countries, infects many individuals and may result in their death. Neurocysticercosis (NCC) develops after invasion of the brain by parasitic larvae. It is the most common parasitic disease of the human central nervous system. On imaging scans it can be similar to brain tumors. We report a patient with a metastatic brain tumor and NCC. The co-presence of NCC was diagnosed based on specific neuroimaging- and epidemiologic findings.\n\n\nMETHODS\nA 36-year-old non-smoking Japanese woman with a history of non-small-cell lung cancer had undergone resection of the lower lobe followed by cytotoxic chemotherapy 2 years before apparently suffering recurrence. A positron emission computed tomography (PET) scan incidentally revealed multiple intracranial cold spots exhibiting differences in their shape and size. On brain magnetic resonance imaging (MRI) scans we observed many different patterns of peripheral edema and gadolinium-enhancing effects. As she had often visited Latin America and Southeast Asia and had eaten raw pork and Kimchi, we suspected that the brain lesions were due to NCC rather than metastatic brain tumors. However, serum immunoblotting assay and DNA analysis were negative for T. solium. Rather than performing resection, we administered albendazole (ABZ) and dexamethasone because her earlier cytotoxic chemotherapy had elicited severe pancytopenia. Except for a single large lesion in the left frontal lobe, this treatment resulted in a significant reduction in the size of these lesions and a decrease in perilesional edema. She underwent resection of the residual lesion 10 months later. Histology revealed it to be a metastatic tumor. Polymerase chain reaction (PCR) assay for NCC was negative. In the course of 11-months follow-up there has been no recurrence.\n\n\nCONCLUSIONS\nThis is the first presentation of NCC in a Japanese woman with a metastatic brain tumor. NCC was incidentally discovered on PET scans and, based on her travel history and epidemiological findings; it was diagnosed and successfully treated with ABZ. NCC is endemic in most developing countries and as visits to such countries have increased, NCC must be ruled out in patients with multiple cystic nodular brain lesions.",
"affiliations": "Department of Neurosurgery, Tokushima Municipal Hospital, 2-34, Kitajyosanjima-cho, Tokushima, 770-0812, Japan. k-tomoya@xg8.so-net.ne.jp.;Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan.;Department of Neurosurgery, Tokushima Municipal Hospital, 2-34, Kitajyosanjima-cho, Tokushima, 770-0812, Japan.;Department of Neurosurgery, Tokushima Municipal Hospital, 2-34, Kitajyosanjima-cho, Tokushima, 770-0812, Japan.;Department of Laboratory Medicine and Pathology, Tokushima Municipal Hospital, Tokushima, Japan.;Department of Neurosurgery, Tokushima Kensei Hospital, Tokushima, Japan.;Department of Neurosurgery, Tokushima Municipal Hospital, 2-34, Kitajyosanjima-cho, Tokushima, 770-0812, Japan.",
"authors": "Kinouchi|Tomoya|T|http://orcid.org/0000-0003-3831-4243;Morishima|Yasuyuki|Y|;Uyama|Shinichi|S|;Miyamoto|Tadashi|T|;Horiguchi|Hidehisa|H|;Fujimoto|Naomi|N|;Ueta|Hiromi|H|",
"chemical_list": null,
"country": "England",
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"doi": "10.1186/s12879-021-06778-1",
"fulltext": "\n==== Front\nBMC Infect Dis\nBMC Infect Dis\nBMC Infectious Diseases\n1471-2334\nBioMed Central London\n\n6778\n10.1186/s12879-021-06778-1\nCase Report\nNeurocysticercosis in a Japanese woman with lung cancer who repeatedly visited endemic countries\nhttp://orcid.org/0000-0003-3831-4243\nKinouchi Tomoya k-tomoya@xg8.so-net.ne.jp\n\n1\nMorishima Yasuyuki 2\nUyama Shinichi 1\nMiyamoto Tadashi 1\nHoriguchi Hidehisa 3\nFujimoto Naomi 4\nUeta Hiromi 1\n1 grid.505837.c Department of Neurosurgery, Tokushima Municipal Hospital, 2-34, Kitajyosanjima-cho, Tokushima, 770-0812 Japan\n2 grid.410795.e 0000 0001 2220 1880 Department of Parasitology, National Institute of Infectious Diseases, Tokyo, Japan\n3 grid.505837.c Department of Laboratory Medicine and Pathology, Tokushima Municipal Hospital, Tokushima, Japan\n4 Department of Neurosurgery, Tokushima Kensei Hospital, Tokushima, Japan\n18 10 2021\n18 10 2021\n2021\n21 10778 6 2021\n29 7 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\nTaenia solium, present in most developing countries, infects many individuals and may result in their death. Neurocysticercosis (NCC) develops after invasion of the brain by parasitic larvae. It is the most common parasitic disease of the human central nervous system. On imaging scans it can be similar to brain tumors. We report a patient with a metastatic brain tumor and NCC. The co-presence of NCC was diagnosed based on specific neuroimaging- and epidemiologic findings.\n\nCase presentation\n\nA 36-year-old non-smoking Japanese woman with a history of non-small-cell lung cancer had undergone resection of the lower lobe followed by cytotoxic chemotherapy 2 years before apparently suffering recurrence. A positron emission computed tomography (PET) scan incidentally revealed multiple intracranial cold spots exhibiting differences in their shape and size. On brain magnetic resonance imaging (MRI) scans we observed many different patterns of peripheral edema and gadolinium-enhancing effects. As she had often visited Latin America and Southeast Asia and had eaten raw pork and Kimchi, we suspected that the brain lesions were due to NCC rather than metastatic brain tumors. However, serum immunoblotting assay and DNA analysis were negative for T. solium. Rather than performing resection, we administered albendazole (ABZ) and dexamethasone because her earlier cytotoxic chemotherapy had elicited severe pancytopenia. Except for a single large lesion in the left frontal lobe, this treatment resulted in a significant reduction in the size of these lesions and a decrease in perilesional edema. She underwent resection of the residual lesion 10 months later. Histology revealed it to be a metastatic tumor. Polymerase chain reaction (PCR) assay for NCC was negative. In the course of 11-months follow-up there has been no recurrence.\n\nConclusion\n\nThis is the first presentation of NCC in a Japanese woman with a metastatic brain tumor. NCC was incidentally discovered on PET scans and, based on her travel history and epidemiological findings; it was diagnosed and successfully treated with ABZ. NCC is endemic in most developing countries and as visits to such countries have increased, NCC must be ruled out in patients with multiple cystic nodular brain lesions.\n\nKeywords\n\nNeurocysticercosis\nMetastatic brain tumors\nAlbendazole\nDeveloping countries\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nEncysted larvae of the tapeworm Taenia solium are responsible for the development of neurocysticercosis (NCC), a parasitic infection of the central nervous system (CNS). NCC, a major cause of acquired epilepsy and neurological morbidity, is endemic in most developing countries where healthy individuals may become infected by drinking water contaminated by feces harboring tapeworms or by eating contaminated vegetables or raw pork. As visits to- and prolonged sojourns in developing countries have become popular, the rate of T. solium infection of travelers can be expected to rise. On neuroimaging studies, NCC is characterized by multiple intracranial cysts in different stages of development. When patients with pulmonary carcinoma report having traveled to endemic areas, it is difficult to work up the etiology of their multiple intracranial cystic lesions.\n\nCase presentation\n\nTwo years before consulting us, a 36-year-old Japanese woman without a relevant medical history developed systemic joint pain. A chest radiogram acquired at a local hospital revealed a tumor in the left lower lobe; its diameter was 3-cm. She was referred to Department of Respiratory Medicine at our hospital and underwent bronchoscopy; cytology of the tumor resulted in a diagnosis of adenocarcinoma. Gadolinium-enhanced brain MRI scans and bone scintigraphy revealed no metastases. The tumor was clinically classified as T1N1M0, stageIIa. The lower lobe was resected and cytotoxic chemotherapy was administered. Two years later she presented with recurrence and received carboplatin, pemetrexed, and pembrolizumab (immune checkpoint inhibitor) therapy.\n\nA PET scan incidentally revealed intracranial cold spots (Fig. 1A) and a CT scan disclosed multiple cystic lesions without calcification in the parenchyma of the left hemisphere; they measured 10–35 mm in diameter (Fig. 1B, C). On MRI scans most of the cysts were ring-enhancing (Fig. 2A, B) and some were surrounded by perilesional edema (Fig. 2C, D).Fig. 1 A PET revealed intracranial cold spots. B, C Brain CT scans showing cystic lesions without calcification in the parenchyma of the left hemisphere (arrows)\n\nFig. 2 Brain MRI findings. A, B Gadolinium-enhanced brain MRI revealed strong ring enhancement of cystic lesions. C, D T2-weighted image showing some perilesional focal edema. E T2-weighted image revealing a scolex inside the cyst located outside the left lateral ventricle. F A brain MRI scan acquired 7 months after the start of ABZ treatment demonstrated multiple small well-defined cystic and nodular structures of different sizes without perilesional edema or calcification\n\nAn eccentric nodule observed on a T2-weighted image of cysts outside the left lateral ventricle appeared to be a scolex (Fig. 2D, E). On MRI scans, the size of the lesions had increased very slowly in the course of 7 months (Fig. 2F). As single-photon emission CT (SPECT) denied the accumulation of thallium-201, a definitive diagnosis of malignant tumor could not be made.\n\nAt the time of admission to our Neurosurgery department, her consciousness was clear. She had no significant family- or employment history. She did not smoke or drink alcohol. Her blood pressure was 125/72 mmHg, her pulse rate was 68/min, and her temperature was 36.8 °C. Neurological examination revealed slight motor aphasia. Physical examination showed that more than 10 subcutaneous lesions were palpable on her chest, back, lower abdomen (Fig. 3A) and her right knee (Fig. 3B). Chest CT revealed that one of the lesions on her back was calcified (Fig. 3C).Fig. 3 A, B On physical examination, more than 10 subcutaneous lesions were palpable on the chest, back, lower abdomen, and right knee. C Chest CT scan showing a calcified lesion high on the back (arrow)\n\nIn a patient interview she reported that between 2009 and 2018 she had visited Canada, the USA, Bolivia, Peru, Chile, Cambodia, the Philippines, Indonesia, New Zealand, and Australia and that each sojourn lasted from 3 weeks to several months. In 2012 and 2013 she had often eaten whole roasted young pig in the Philippines and Korean Kimchi during her 2013–2014 visit to Canada. Based on this information we suspected that she may have become infected with cysticercosis in the endemic areas she visited.\n\nWe started treatment with the anti-epileptic drug levetiracetam (1000 mg/day) for seizure prophylaxis and asked for a cysticercosis analysis. Both DNA analysis from biopsy specimens from her right knee and lower abdomen and serum immunoblotting assay performed at the National Institute of Infectious Diseases (NIID) were negative for cysticercosis. We rejected cystic lesion biopsy because molecularly-targeted therapy with crizotinib had elicited strong pancytopenia. Instead, we administered ABZ (400 mg twice per day at 15 mg/kg/day), and decadron (4 mg twice per day at 0.1 mg/kg/day). However, we interrupted this regimen 5 days later because she developed fever, headache, a generalized rash, and swelling of the oral mucosa; we thought them to be reactions to treatment with ABZ.\n\nFollow-up MRI studies performed 1 week after the start of treatment showed that the size of many of the cystic brain lesions had shrunk and that perilesional edema had decreased (Fig. 4A, B). With the exception of the large left frontal mass, most lesions had resolved on day 30 and no tapeworm scolex was detected (Fig. 4C, D). We continued treatment with crizotinib.Fig. 4 T2-weighted brain MRI scans obtained 7- (A, select all B) and 30-days (C, D) after the start of cysticidal treatment. Except for the largest, the size of almost all lesions in the frontal lobe was decreased as was perilesional edema (arrows). There is no change in the left frontal lesion (double arrows). The scolex inside the cyst located outside the left lateral ventricle has disappeared (arrowhead)\n\nFollow-up 10 months later revealed no new lesions or seizures. Her lung adenocarcinoma was controlled without crizotinib. However, the left frontal cystic lesion had not regressed. During the 10-month interval she frequently suffered left frontal headaches and motor aphasia. Considering them to be symptoms of intracranial hypertension and a mass effect induced by the lesion located at a depth of 10 mm subcortically, we resected almost all of the lesion. It was thin-walled, well delineated from surrounding brain tissue, and contained a yellow, pus-like fluid. No cysticericus was found. Histological examination revealed metastasis from the lung adenocarcinoma; PCR assay for NCC returned negative results. The cell count in the pus-like fluid was 24,000, bacteriology rendered no findings. A gamma-knife procedure was applied around the operative scar in the left frontal lobe. Crizotinib administration was continued and she reported no headaches, no aphasia and her lung adenocarcinoma did not recur. A brain MRI scan performed 11-months after her admission to our hospital confirmed the absence of active and/or degenerative lesions.\n\nDiscussion\n\nThis is the first documentation of co-existing NCC in a Japanese woman with a metastatic brain tumor. NCC was incidentally diagnosed based on neuroimaging scans and upon epidemiological investigations. Treatment with ABZ was successful. NCC is the most common helminthic infection of the CNS; in endemic countries (e.g. Latin America, sub-Saharan Africa, and parts of Asia other than Japan) it often leads to seizures [1, 2].\n\nNCC is the result of infection with the larval stage of the tapeworm T. solium. The infection occurs when eggs excreted in the feces of individuals carrying the parasite are ingested through contaminated water, and via the ingestion of raw and/or undercooked food. It can also come directly from a carrier via the oral‐fecal route [1–4]. The ingestion of contaminated food harboring active T. solium cysticerci can elicit T. solium taeniasis, a condition in which the adult tapeworm is found in the human intestines [5]. Eggs of the adult tapeworm are subsequently shed in stool, completing the cycle.\n\nNCC can mimic metastatic brain tumors, toxoplasmosis, and tuberculosis on imaging scans. In tropical countries it is more often encountered than brain tumors. Others [6, 7] reported that international travelers from non-endemic countries developed NCC after visiting endemic areas. Such cases were diagnosed based on pathological or serological findings. Most infected individuals developed symptoms 2 or more years after returning home [6] and cysticerci have been reported to survive silently for more than 10 years [8].\n\nIn our patient we initially suspected the lesion to be a metastatic brain tumor because she had received chemotherapy for non-small-cell lung cancer. However, three observations led us to suspect something other than a metastatic brain tumor: The size of her multiple lesions increased very slowly compared to a malignant tumor, unlike metastatic brain tumors that usually manifest as solid masses, hers contained a cystic component, and the shape of the masses and the paralesional edema around them exhibited many different patterns.\n\nWe think that our radiographical studies revealed different evolutionary stages of NCC. Neuroimaging studies are essential for the diagnosis of NCC and MRI- have been shown to be superior to CT studies with respect to the detection and characterization of NCC [9]. According to the NCC classification on neuroimaging studies, there are four main developmental stages [9–13]. In the vesicular stage of viable larvae there is no surrounding vasogenic edema; only very faint enhancing lesions are observed. In the colloidal vesicular stage, the lesions are hyper-intense vis-à-vis the CSF on CT- and T1-weighted images and surrounding edema is present. The nodular wall then thickens, enhances brightly, and the scolex is observable. In the granular nodular stage enhancement persists but is less marked and edema surrounding the cyst decreases. In the nodular calcified stage, i.e. the end-stage, the nodule is quiescent and calcified and there is signal drop-out on T2-weighted images. We hypothesize that in our patient, neuroimaging revealed transitional periods from the vesicular- to the colloidal vesicular stage.\n\nDel Brutto et al. [14, 15] proposed criteria for the diagnosis of NNC. In diagnosing our patient we considered findings on imaging scans, the observation of cystic lesions with or without a discernible scolex, lesion enhancement, and clinical/exposure information although the presence of the eccentric nodule in the cyst outside the left lateral ventricle and the observation of a scolex on T2-weighted images alone are sufficient for a definitive NCC diagnosis.\n\nAlthough neither serum immunoblotting assay, DNA analysis, nor NIID results were positive for T. solium, we administered antiparasitic drugs. ABZ and praziquantel (PZQ) have been reported to be effective in patients with NCC [16–18]. ABZ enters the CSF and its concentration is not affected when steroids are also administered [19, 20]. Based on trials in adults with viable cysts, Abba et al. [21] suggested that ABZ reduced the number of lesions. However, such drug treatments may be associated with severe adverse reactions due to the release of cyst-destroying antigens and may elicit local tissue swelling and a generalized reaction [22].\n\nIn our patient, MRI studies performed 7 days after the start of ABZ therapy revealed a significant reduction in the size of all brain lesions except the largest lesion in the left frontal lobe. Over time, almost all perilesional edema completely resolved; the scolex also disappeared. The resolution on neuroimaging scans of cystic lesions after cysticidal drug therapy is a diagnostic criterion for NCC [14, 15]. For the definitive diagnosis of our patient we used neuroimaging- and clinical/exposure data.\n\nOur patient’s multiple cystic brain lesions consisted of a mixture of metastases from a primary non-small-cell lung cancer and NCC. We think that her transient fever, headache, systemic rash, and swelling of the oral mucosa seen on day 5 of ABZ treatment reflected an inflammatory reaction.\n\nConclusion\n\nThis is the first presentation of NCC in a Japanese woman with a metastatic brain tumor. NCC was incidentally discovered on PET scans and, based on her travel history and epidemiological findings; it was diagnosed and successfully treated with ABZ. As the number of international travelers has increased, diagnosticians must consider the possibility of NCC when individuals, having spent time in areas where T. solium is endemic, present with multiple cystic nodular brain lesions.\n\nAbbreviations\n\nNCC Neurocysticercosis\n\nPET Positron emission computed tomography\n\nCNS Central nervous system\n\nMRI Magnetic resonance imaging\n\nCT Computed tomography\n\nABZ Albendazole\n\nPCR Polymerase chain reaction\n\nNIID National Institute of Infectious Diseases\n\nAcknowledgements\n\nSerum immunoblotting assay and DNA analysis for T. solium were performed at the Department of Parasitology, National Institute of Infectious Diseases (NIID). We thank the staff for excellent technical assistance.\n\nAuthors’ contributions\n\nYM, SU, TM, HH, NF, and HU participated in the patient management. All authors read and approved the final manuscript.\n\nFunding\n\nNone.\n\nAvailability of data and materials\n\nNot applicable.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\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. Garcia HH Neurocysticercosis Neurol Clin 2018 36 851 864 10.1016/j.ncl.2018.07.003 30366559\n2. Escobar A Palacios E Rodriquez-Carbajal J Taveras JM The pathology of neurocysticercosis Cysticercosis of the central nervous system 1983 Springfield Thomas 27 54\n3. Carpio A Placencia M Santillan F Escobar A A proposal for classification of neurocysticercosis Can J Neurol Sci 1994 21 43 47 10.1017/S0317167100048757 8180904\n4. Del Brutto OH Neurocysticercosis: a review Sci World J 2012 2012 159821\n5. Ng-Nguyen D Noh J Breen K The epidemiology of porcine Taenia solium cysticercosis in communities of the Central Highlands in Vietnam Parasit Vectors 2018 11 360 10.1186/s13071-018-2945-y 29929529\n6. Del Brutto OH Neurocysticercosis among international travelers to disease-endemic areas J Travel Med 2012 19 112 117 10.1111/j.1708-8305.2011.00592.x 22414036\n7. Kobayashi K Nakamura-Uchiyama F Nishiguchi T Isoda K Kokubo Y Ando K Rare case of disseminated cysticercosis and taeniasis in a Japanese traveler after returning from India Am J Trop Med Hyg 2013 89 1 58 62 10.4269/ajtmh.12-0355 23629930\n8. Ito A Nakao M Ito Y Yuzawa I Morishima H Kawano N Fujii K Neurocysticercosis case with a single cyst in the brain showing dramatic drop in specific antibody titers within 1 year after curative surgical resection Parasitol Int 1999 48 95 99 10.1016/S1383-5769(99)00005-7 11269331\n9. Zhao JL Lerner A Shu Z Gao XJ Zee CS Imaging spectrum of neurocysticercosis Radiol Infect Dis 2015 1 94 102 10.1016/j.jrid.2014.12.001\n10. Sarria Estrada S Frascheri Verzelli L Suirana Montilva S Auger Acosta C Rovira CA Imaging findings in neurocysticercosis Radiologia 2013 55 2 130 141 10.1016/j.rx.2011.11.009 22632836\n11. Mewara A Goyal K Sehgal R Neurocysticercosis: a disease of neglect Trop Parasitol 2013 3 106 113 10.4103/2229-5070.122111 24470993\n12. Del Brutto OH Neurocysticercosis: new thoughts on controversial issues Curr Opin Neurol 2013 26 289 294 10.1097/WCO.0b013e32836027fa 23493161\n13. Garg RK Medical management of neurocysticercosis Neurol India 2001 49 329 337 11799403\n14. Del Brutto OH Rajshekhar V White AC Jr Proposed diagnostic criteria for neurocysticercosis Neurology 2001 57 177 183 10.1212/WNL.57.2.177 11480424\n15. Del Brutto OH Nash TE White AC Jr Revised diagnostic criteria for neurocysticercosis J Neurol Sci 2017 372 202 210 10.1016/j.jns.2016.11.045 28017213\n16. Garcia HH Evans CA Nash TE Current consensus guidelines for treatment of neurocysticercosis Clin Microbiol Rev 2002 15 747 756 10.1128/CMR.15.4.747-756.2002 12364377\n17. Takayanagui OM Therapy for neurocysticercosis Expert Rev Neurother 2004 4 129 139 10.1586/14737175.4.1.129 15853623\n18. Takayanagui OM Odashima NS Bonato PS Medical management of neurocysticercosis Expert Opin Pharmacother 2011 12 2845 2856 10.1517/14656566.2011.634801 22082143\n19. Jung H Hurtado M Medina T Sanchez M Sotelo J Dexamethasone increases plasma levels of albendazole J Neurol 1990 237 279 280 10.1007/BF00314741 2230841\n20. Jung H Hurtado M Sanchez M Medina T Sotelo J Plasma and cerebrospinal fluid levels of albendazole and praziquantel in patients with neurocysticercosis Clin Neuropharmacol 1990 13 559 564 10.1097/00002826-199012000-00008 2276121\n21. Abba K, Ramaratnam S, Ranganathan LN. Anthelmintics for people with neurocysticercosis. Cochrane Database Syst Rev. 2010:CD000215.\n22. Pawlowski Z Role of chemotherapy of taeniasis in prevention of neurocysticercosis Parasitol Int 2006 55 S105 S109 10.1016/j.parint.2005.11.017 16356763\n\n",
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"issn_linking": "1471-2334",
"issue": "21(1)",
"journal": "BMC infectious diseases",
"keywords": "Albendazole; Developing countries; Metastatic brain tumors; Neurocysticercosis",
"medline_ta": "BMC Infect Dis",
"mesh_terms": "D000328:Adult; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D006801:Humans; D007564:Japan; D008175:Lung Neoplasms; D009364:Neoplasm Recurrence, Local; D020019:Neurocysticercosis",
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"pubdate": "2021-10-18",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23629930;11269331;2230841;15853623;11799403;30366559;8180904;22414036;2276121;29929529;24470993;11480424;20091504;16356763;28017213;22082143;22632836;23493161;12364377;22312322",
"title": "Neurocysticercosis in a Japanese woman with lung cancer who repeatedly visited endemic countries.",
"title_normalized": "neurocysticercosis in a japanese woman with lung cancer who repeatedly visited endemic countries"
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"abstract": "A woman in her 60s presented to our hospital with a left breast mass that was diagnosed as breast cancer. 18F-Fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) revealed intense, hot uptake in the cancerous mass and left axillary lymph node metastasis. After chemotherapy, another PET/CT scan was performed. Although the mass and left axillary lymph nodes shrank and FDG uptake decreased, enlarged lymph nodes with high FDG uptake appeared in the right axilla. The patient had a painful vesicular eruption on the front to the back of the right upper hemithorax, which was diagnosed as active herpes zoster. Active herpes zoster mimics a worsening axillary lymph node metastasis on the PET/CT scan.",
"affiliations": "Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Radiology, Dokkyo Medical University Saitama Medical Center, Saitama 343-8555, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.;Department of Surgery, Breast Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Surgery, Breast Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.;Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.",
"authors": "Fujioka|Tomoyuki|T|0000-0002-7141-8901;Yokoyama|Kota|K|0000-0001-5151-3146;Mori|Mio|M|0000-0002-6107-4519;Yashima|Yuka|Y|;Yamaga|Emi|E|;Kubota|Kazunori|K|0000-0002-3240-4910;Oyama|Jun|J|;Oda|Goshi|G|;Nakagawa|Tsuyoshi|T|0000-0003-1967-0445;Tateishi|Ukihide|U|",
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"doi": "10.3390/diagnostics11061085",
"fulltext": "\n==== Front\nDiagnostics (Basel)\nDiagnostics (Basel)\ndiagnostics\nDiagnostics\n2075-4418\nMDPI\n\n34198598\n10.3390/diagnostics11061085\ndiagnostics-11-01085\nInteresting Images\nActive Herpes Zoster Mimicking Worsening of Axillary Lymph Node Metastases of Breast Cancer after Chemotherapy on 18F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography\nhttps://orcid.org/0000-0002-7141-8901\nFujioka Tomoyuki 1\nhttps://orcid.org/0000-0001-5151-3146\nYokoyama Kota 1\nhttps://orcid.org/0000-0002-6107-4519\nMori Mio 1*\nYashima Yuka 1\nYamaga Emi 1\nhttps://orcid.org/0000-0002-3240-4910\nKubota Kazunori 2\nOyama Jun 1\nOda Goshi 3\nhttps://orcid.org/0000-0003-1967-0445\nNakagawa Tsuyoshi 3\nTateishi Ukihide 1\nMason Ralph P. Academic Editor\n1 Department of Diagnostic Radiology, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan; fjokmrad@tmd.ac.jp (T.F.); kota1986ky@yahoo.co.jp (K.Y.); 11.ruby.89@gmail.com (Y.Y.); ymgdrnm@tmd.ac.jp (E.Y.); ooymmrad@tmd.ac.jp (J.O.); ttisdrnm@tmd.ac.jp (U.T.)\n2 Department of Radiology, Dokkyo Medical University Saitama Medical Center, Saitama 343-8555, Japan; kubotard@dokkyomed.ac.jp\n3 Department of Surgery, Breast Surgery, Tokyo Medical and Dental University, Tokyo 113-8519, Japan; odasrg2@tmd.ac.jp (G.O.); nakagawa.srg2@tmd.ac.jp (T.N.)\n* Correspondence: m_mori_116@yahoo.co.jp; Tel.: +81-3-5803-5311; Fax: +81-3-5803-0147\n14 6 2021\n6 2021\n11 6 108520 4 2021\n11 6 2021\n© 2021 by the authors.\n2021\nhttps://creativecommons.org/licenses/by/4.0/ Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).\nA woman in her 60s presented to our hospital with a left breast mass that was diagnosed as breast cancer. 18F-Fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) revealed intense, hot uptake in the cancerous mass and left axillary lymph node metastasis. After chemotherapy, another PET/CT scan was performed. Although the mass and left axillary lymph nodes shrank and FDG uptake decreased, enlarged lymph nodes with high FDG uptake appeared in the right axilla. The patient had a painful vesicular eruption on the front to the back of the right upper hemithorax, which was diagnosed as active herpes zoster. Active herpes zoster mimics a worsening axillary lymph node metastasis on the PET/CT scan.\n\nherpes zoster\nPET/CT\naxillary lymph node metastases\nbreast cancer\nlymphadenopathy\n==== Body\nA woman in her 60s with no significant medical history presented to our hospital with a left breast mass. Breast ultrasonography revealed left breast mass and enlarged left axillary lymph nodes, which were diagnosed as triple-negative breast cancer (invasive ductal carcinoma) and axillary lymph node metastasis by ultrasonography-guided biopsy, respectively. 18F-Fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) was performed using a digital PET/CT system (Cartesion Prime, Canon Medical Systems, Tochigi, Japan) with the following parameters: dose of 18F-FDG, 3.7 MBq/kg (0.1 mCi/kg); emission time per bed, 2 min; bed position, 9–10; slice thickness, 4.08 mm; and matrix, 144 × 144. The scan revealed an intense hot uptake in the left breast mass (SUVmax, 10.0; a, b: blue arrows) and left axillary lymph nodes (SUVmax, 13.7; a, c, d: yellow arrows). No other areas of uptake indicated a suspected distant metastasis (a).\n\nOne week after chemotherapy (11 cycles of adjuvant paclitaxel after four cycles of adjuvant doxorubicin/cyclophosphamide), another PET/CT scan was performed. Although the left breast cancer (SUVmax, 2.5; d, e: blue arrows) and left axillary lymph nodes (SUVmax, 5.8; d, g: yellow arrows) shrank and the FDG uptake decreased, enlarged lymph nodes with high FDG uptake appeared in the right axilla (SUVmax, 23.4; d, f, g: red arrows). Two days before the PET/CT scan, the patient had a painful vesicular eruption on the front (h) to back (i) of the right upper hemithorax, which was diagnosed as active herpes zoster. PET/CT images were reviewed, and thickening of the skin on the right upper hemithorax with mild FDG uptake was found (f, g: white arrows). Ultrasound-guided fine needle aspiration cytology was performed on the right axillary lymph node, which was found to be benign (class I).\n\nThe patient received antiviral medication, which subsequently resolved her symptoms. She then underwent left total mastectomy and left axillary lymph node dissection. Three months after the surgery, the patient was alive and recurrence-free.\n\nHerpes zoster is a reactivated varicella-zoster virus infection that causes a typical painful vesicular eruption on the dermatome. The latent virus increases and reactivates if cell-mediated immunity is compromised because of chronic disease, immune abnormalities, administration of anticancer drugs, immunosuppression, trauma, or stress [1]. Inflammation occurs when reactivated virus causes damage to the skin and nerves. The hypermetabolic activity of the inflammatory cells caused an increase in FDG accumulation [2]. Active herpes zoster mimics a worsening axillary lymph node metastasis on PET/CT [1,3,4,5]. When a PET/CT scan shows an unexpected abnormal uptake in the axillary lymph nodes, the radiologist should determine if the patient has a painful vesicular eruption on the ipsilateral upper hemithorax. Ultrasound-guided puncture aspiration cytology can help in the diagnosis of axillary lymph nodes [6].\n\nFigure 1 (a) Maximum-intensity projection (MIP) and (b–d) transaxial 18F-Fluorodeoxyglucose positron-emission tomography/computed tomography (18F-FDG PET/CT) images before therapy revealed (a,b: blue arrows) intense, hot uptake in the left breast mass indicating cancer, and (a,c,d: yellow arrows) left axillary lymph nodes indicating metastasis. (a) No other areas of uptake indicated distant metastasis. (e) MIP and (f–h) transaxial images of 18F-FDG PET/CT after therapy showed shrinking and decreased uptake in the (e,f: blue arrows) cancerous mass and (e,h: yellow arrows) left axillary lymph node metastasis, whereas (e,g,h: red arrows) enlarged lymph nodes with high FDG uptake appeared in the right axilla. (g,h: white arrows) Thickening of the skin on the right upper hemithorax with mild FDG uptake was also observed. The patient had painful vesicular eruption on the (i) front to (j) back of the right upper hemithorax, which was diagnosed as active herpes zoster.\n\nAuthor Contributions\n\nWriting—original draft preparation, T.F.; writing—review and editing, M.M., E.Y., and Y.Y.; supervision, K.Y., J.O., K.K., and U.T.; investigation, T.N. and G.O. All authors have read and agreed to the final version of the manuscript.\n\nFunding\n\nThis research received no external funding.\n\nInstitutional Review Board Statement\n\nAll procedures performed in this study involving the human participant were in accordance with the ethical standards of the institutional research committee (approval ID: M2019-137, approval date: 19 September 2019) and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.\n\nInformed Consent Statement\n\nInformed consent for publication was obtained from the patient included in the study.\n\nData Availability Statement\n\nAll available data are presented within the article or are available on request from the corresponding author.\n\nConflicts of Interest\n\nThe authors declare no conflict of interest.\n\nPublisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Singh D. Kumar R. Prakash G. Bhattacharya A. Mittal B.R. Active herpes zoster infection involving lumbosacral dermatome, an unusual site of manifestation and incidental finding in fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography scan World J. Nucl. Med. 2018 17 52 55 29398967\n2. Muzaffar R. Fesler M. Osman M.M. Active shingles infection as detected on (18)F-FDG PET/CT Front. Oncol. 2013 3 103 10.3389/fonc.2013.00103 23630665\n3. Choi E.K. Oh J.K. Chung Y.A. Herpes zoster mimicking breast cancer with axillary lymph node metastasis on PET/CT Clin. Nucl. Med. 2015 40 572 573 10.1097/RLU.0000000000000804 26018707\n4. Egan C. Silverman E. Increased FDG uptake along dermatome on PET in a patient with herpes zoster Clin. Nucl. Med. 2013 38 744 745 10.1097/RLU.0b013e31829b2640 23816943\n5. Soydas Turan B. Bozkurt M.F. Unusual presentation of herpes zoster infection mimicking soft tissue metastases of breast cancer on 18F-FDG PET/CT imaging Clin. Nucl. Med. 2021 10.1097/RLU.0000000000003580 33782282\n6. Iwamoto N. Aruga T. Horiguchi S. Asami H. Saita C. Onishi M. Goto R. Ishiba T. Honda Y. Miyamoto H. Ultrasound-guided fine-needle aspiration of axillary lymph nodes in breast cancer: Diagnostic accuracy and role in surgical management Diagn. Cytopathol. 2019 47 788 792 10.1002/dc.24203 31041851\n\n",
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"keywords": "PET/CT; axillary lymph node metastases; breast cancer; herpes zoster; lymphadenopathy",
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"title": "Active Herpes Zoster Mimicking Worsening of Axillary Lymph Node Metastases of Breast Cancer after Chemotherapy on 18F-Fluorodeoxyglucose Positron-Emission Tomography/Computed Tomography.",
"title_normalized": "active herpes zoster mimicking worsening of axillary lymph node metastases of breast cancer after chemotherapy on 18f fluorodeoxyglucose positron emission tomography computed tomography"
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"abstract": "Activating antibodies directed at the extracellular calcium-sensing receptor (CaSR) have been described in autoimmune hypoparathyroidism in the setting of isolated hypoparathyroidism or autoimmune polyglandular syndrome type 1.\n\n\n\nA 34-year-old female presented with hypocalcaemia (6.0 mg/dL) and hypomagnesaemia (1.1 mg/dL) accompanied by low serum PTH (2.4 pg/mL) as well as urinary calcium and magnesium wasting. She was diagnosed with hypoparathyroidism, which was refractory to standard therapy. She was started on 60 mg prednisone and 150 mg azathioprine treatment daily on suspicion of an autoimmune aetiology. The patient was tested for CaSR antibodies.\n\n\n\nThe patient was positive for CaSR antibodies of the IgG1 subtype, which stimulated phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) and inositol phosphate (IP) accumulation. Post-treatment with prednisone and azathioprine, her serum calcium and magnesium normalized, as did her CaSR antibody titre and antibody-mediated stimulation of ERK1/2 phosphorylation and IP accumulation.\n\n\n\nThis is the first demonstration of CaSR antibody-mediated hypoparathyroidism responsive to immunosuppressive therapy, adding to the evidence that autoimmune hypoparathyroidism can be, in some cases, reversible and not the result of autoimmune parathyroid destruction.",
"affiliations": "The Kidney and Hypertension Center, Cincinnati, Ohio.;Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.;Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.;The Kidney and Hypertension Center, Cincinnati, Ohio.;Division of Endocrinology, Diabetes, and Hypertension, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.",
"authors": "Chamberlin|Mina|M|;Kemp|E Helen|EH|0000-0002-0313-8916;Weetman|Anthony P|AP|;Khadka|Bhupesh|B|;Brown|Edward M|EM|",
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"keywords": "autoantibody; autoimmunity; azathioprine; calcium-sensing receptor; hypoparathyroidism; immunosuppression; prednisone",
"medline_ta": "Clin Endocrinol (Oxf)",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D001327:Autoimmune Diseases; D005260:Female; D006801:Humans; D007011:Hypoparathyroidism; D007166:Immunosuppressive Agents; D044169:Receptors, Calcium-Sensing",
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"title": "Immunosuppressive therapy of autoimmune hypoparathyroidism in a patient with activating autoantibodies against the calcium-sensing receptor.",
"title_normalized": "immunosuppressive therapy of autoimmune hypoparathyroidism in a patient with activating autoantibodies against the calcium sensing receptor"
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"abstract": "Serological testing for the presence of Hepatitis B Virus (HBV) markers and anti-HBs titers in infants born to HBsAg positive women is critically important for estimation in immunisation programme.\n\n\n\nThis was a multi-center and cross-sectional study conducted in Zhejiang province, China. Children aged 7 to 24 months born to HBsAg positive women during December 2018 to February 2019, completed additional HBV serological markers screening. We indicated distribution of HBV serological markers and anti-HBs titers in children. Multiple logistic regression model with adjusted odds ratio and 95% confidence interval (ORadj and 95% CI) was used to explore the factors associated with inadequate immune response (anti-HBs titers< 100 mIU/ml) among children.\n\n\n\nA total of 1849 children were included. Overall 25 children tested HBsAg positive, giving HBsAg positive rate of 1.35%(95%CI: 0.83-1.88%). 92.00% (23/25) HBsAg positive children were delivered by HBeAg positive mothers. The proportion of protective seroconversion (anti-HBs titers≥10mIU/ml) was 99.29% in all children, and 86.48% children were reported with adequate anti-HBs titers (≥100mIU/ml).We found a significant higher proportions of early antenatal health care (< 13 gestational weeks), and term birth in children with adequate response compared with inadequate response (all P < 0.05). Logistic regression showed preterm birth was a negative factor for inadequate anti-HBs titers (ORadj = 1.868,95%CI 1.132-3.085,P = 0.015).\n\n\n\nChildren delivered by HBeAg positive mothers had higher risk of vertical transmission of HBV, despite completion of 3 doses of hepatitis B vaccine and HBIG injection. Inadequate anti-HBs level was significantly associated with preterm birth in HBsAg positive women.",
"affiliations": "Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 17 Section 3, Renmin South Road, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Medical Laboratory Science, Women's Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang, 310006, People's Republic of China.;Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 17 Section 3, Renmin South Road, Chengdu, Sichuan, 610041, People's Republic of China.;Department of Obstetrics, Women's Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang, 310006, People's Republic of China.;Department of Women's Health, Women's Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang, 310006, People's Republic of China. zjfb_amy@zju.edu.cn.",
"authors": "Jiang|Min|M|;Zhu|Bo|B|;Yao|Qiang|Q|;Lou|Haifeng|H|;Zhang|Xiaohui|X|",
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"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431\nBioMed Central London\n\n2967\n10.1186/s12887-021-02967-8\nResearch\nAnti-HBs levels in children under the age of two years born to HBV carrier mothers after immunoprophylaxis: a multicenter cross-sectional study\nJiang Min 43761128@qq.com\n\n1\nZhu Bo 5202054@zju.edu.cn\n\n2\nYao Qiang 464897410@qq.com\n\n1\nLou Haifeng Louhaifeng@zju.edu.cn\n\n3\nZhang Xiaohui zjfb_amy@zju.edu.cn\n\n4\n1 grid.13291.38 0000 0001 0807 1581 Department of Epidemiology and Health Statistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, No. 17 Section 3, Renmin South Road, Chengdu, Sichuan 610041 People’s Republic of China\n2 grid.431048.a Department of Medical Laboratory Science, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang 310006 People’s Republic of China\n3 grid.431048.a Department of Obstetrics, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang 310006 People’s Republic of China\n4 grid.431048.a Department of Women’s Health, Women’s Hospital, School of Medicine, Zhejiang University, Xueshi Road 1, Hangzhou, Zhejiang 310006 People’s Republic of China\n4 11 2021\n4 11 2021\n2021\n21 49229 4 2021\n20 10 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\nSerological testing for the presence of Hepatitis B Virus (HBV) markers and anti-HBs titers in infants born to HBsAg positive women is critically important for estimation in immunisation programme.\n\nMethods\n\nThis was a multi-center and cross-sectional study conducted in Zhejiang province, China. Children aged 7 to 24 months born to HBsAg positive women during December 2018 to February 2019, completed additional HBV serological markers screening. We indicated distribution of HBV serological markers and anti-HBs titers in children. Multiple logistic regression model with adjusted odds ratio and 95% confidence interval (ORadj and 95% CI) was used to explore the factors associated with inadequate immune response (anti-HBs titers< 100 mIU/ml) among children.\n\nResults\n\nA total of 1849 children were included. Overall 25 children tested HBsAg positive, giving HBsAg positive rate of 1.35%(95%CI: 0.83-1.88%). 92.00% (23/25) HBsAg positive children were delivered by HBeAg positive mothers. The proportion of protective seroconversion (anti-HBs titers≥10mIU/ml) was 99.29% in all children, and 86.48% children were reported with adequate anti-HBs titers (≥100mIU/ml).We found a significant higher proportions of early antenatal health care (< 13 gestational weeks), and term birth in children with adequate response compared with inadequate response (all P < 0.05). Logistic regression showed preterm birth was a negative factor for inadequate anti-HBs titers (ORadj = 1.868,95%CI 1.132-3.085,P = 0.015).\n\nConclusions\n\nChildren delivered by HBeAg positive mothers had higher risk of vertical transmission of HBV, despite completion of 3 doses of hepatitis B vaccine and HBIG injection. Inadequate anti-HBs level was significantly associated with preterm birth in HBsAg positive women.\n\nKeywords\n\nHBV markers\nHBV immune response\nHBV carrier women\nPreterm birth\nLow birth weight\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nVertical transmission is the main route for young children to have Hepatitis B Virus (HBV) infection. With the wide coverage of vaccination against HBV and Hepatitis B immune globulin (HBIG) for newborns from HBV-infected women, mother to child transmission (MTCT) of HBV has declined globally [1–4]. In some countries or regions, HBsAg positive rates in children at age five was even less than 1% [3, 5]. In 2016, World Health Organization (WHO) called for ending HBV as a public health threat with the achievement goal of sustainable development (2030), aiming to reduce HBV prevalence under 1% by 2020 and under 0.1% by 2030 among children at the age of five [4, 5]. Nevertheless, there were still gaps to meet the global HBV elimination goal due to the disparity in social-economical development, HBV epidemiology and coverage of prevention MTCT [2–7]. For example, some countries or regions in Africa and Asia still face high endemic of HBV, particularly in women without vaccination [7, 8]. In central and eastern Europe, only 75% countries provide universal HBV screening for pregnant women [6]. Globally, less than 50% countries are available for providing first HBV vaccine dose within 24 h by WHO [2].\n\nHBV vaccination along with HBIG are effective to reduce MTCT [2]. Postvaccination serological testing (PVST) is important for evaluating the immunization effects, although it is not routinely performed in some countries. In some previous studies, no response, protective response, adequate response and high response to vaccine were regarded as anti-HBs titers < 10 mIU/mL, anti-HBs ≥ 10 mIU/mL, anti-HBs ≥100 mIU/mL, and anti-HBs ≥ 1000mIU/mL, respectively [9–11]. Anti-HBs ≥ 10 mIU/mL is widely considered as a seroprotective response to vaccine [9]. Furthermore, some studies preferred anti-HBs titer exceeding 100 mIU/mL as protective effect [11, 12].Anti-HBs titer less than 100mIU/mL was indicated as risk factor for HBV reactivation, and booster vaccination was suggested [11, 13]. A study showed that after completion of HBV immunization course in infancy;5-20% infants encountered vaccination failure or poor response [9–14]. Currently, there are a few studies on infant seroprotective level of anti-HBs over100mIU/mL.\n\nChina has the largest burden of HBV infection in the world with 5-6% prevalence and estimated number of HBsAg carriers around 70 million [15]. Chinese government has made great efforts to control HBV. Since 1992, an integrated national immunization programs have included 3 doses of HBV vaccine for infants within 24 h of birth, and subsequently at one and 6 months of birth [1]. Following this, a national strategy of preventing mother to child transmission (PMTCT) of HBV was implemented in China in 2010 [16]. This includes routine HBV screening for pregnant women during their first antenatal health care visit (ANC), and timely vaccine with HBIG for all newborns from HBsAg positive women. PVST is recommend for infants born to HBsAg positive women but not funded by government. Although, China has made great achievement in combating HBV over the past decades, persisting efforts on HBV prevention is still needed considering huge population and geographical variety [15–17]. Zhejiang Province is a relatively developed area in Eastern China with approximately 60 million residents, where the prevalence of HBsAg in people aged 1 to 29 years was 1.05% in 2014 [18]. Since 2016, Chinese Center for Disease Control and Prevention initiated and funded PVST in Zhejiang. One year later, Zhejiang was appointed as a pilot province for the elimination MTCT (EMTCT) of HIV, Syphilis and HBV in China. The coverage, timeliness and completeness of HBV vaccine improved greatly over the past decades, reaching 94-98% in 2017 [19]. To accelerate the progress towards eradication of HBV, we performed the study to verify the HBsAg positive rates, anti-HBs titers and factors associated with adequate immune response among children under two years old, delivered by HBsAg positive women in Zhejiang province. The findings would be of significance for guiding HBV EMTCT.\n\nMaterials and methods\n\nStudy design and subjects\n\nThis was a multi-center cross-sectional study. We enrolled subjects in eight urban and rural regions (Ouhai, Pujiang, Ruian,Yuhang, Cixi, Huangyan, Jiaojiang, Ninghai) of Zhejiang province by multi-step sampling according to location, maternal HBsAg positive rate and live births. A total of 2000 singletons aged 7 -24 months and born to HBsAg positive women were recruited during December 2018 to February 2019. A structural questionnaire was used for data collection by medical staff in local women and children’s hospital. We performed a face to face interview with children’s parents or guardians in each local hospital. Information regarding on maternal social-demographic characteristics, ANC, maternal HBV infection status, birth outcomes, HBV immunization and feeding pattern were recorded. All participants were given an informed consent and agreed to participate. The study was approved by Ethnic Committee of Women’s Hospital School of Medicine Zhejiang University.\n\nEMTCT HBV project\n\nAccording to Zhejiang provincial HBV EMTCT project, all pregnant women are required to receive HBsAg screening during their first ANC visit and before delivery. HBsAg positive women routinely get further serology testing and HBV DNA tested. Antiviral treatment is recommended to high risk women (a viral load threshold of 2 × 105 IU/ml or HBeAg positive) from 24 gestational weeks. All infants are recommended to receive the first dose of HBV vaccine within 24 h after birth, followed by the second dose at one month and third dose at 6 months of birth. To prevent mother to child transmission, infants born to HBsAg positive women are vaccinated after birth with 100 IU HBIG within 12 h (as early as possible) in delivery hospital, in conjunction with HBV vaccination. We suggest all infants to receive the HBV vaccination impact estimation at least one month later after the third dose, but it is not a mandatory requirement.\n\nSerological tests\n\nIn the study, all serum specimens were tested in the laboratory of Women’s Hospital, School of Medicine Zhejiang University. HBV serological markers presented as Hepatitis B surface antigen (HBsAg), antibody against HBsAg (anti-HBs), Hepatitis B e antigen (HBeAg), antibody against HBeAg (anti-HBe), and antibody against Hepatitis B core antigen (anti-HBc). These five HBV markers were detected by Chemiluminescent Enzyme Immunoassay (CLEIA) with automated immunoassay analyzer (HISCL-5000; Sysmex corporation, Japan). Serum HBsAg and anti-HBs are determined quantitatively while serum HBeAg, anti-HBs, and anti-HBc were determined qualitatively. Specimens with concentrations ≥0.03 IU/mL were considered as positive by HBsAg criteria and ≥ 10mIU/mL as positive on anti-HBs testing.\n\nSampling method and statistical analysis\n\nWe assumed the HBV MTCT would be about 2%. The calculated average sample size is 169 in each region when we assume 80% power, 95% confidence level, and the precision at 5%. In consideration of the number of regions, the final sample size was 2000 considering 20% possible missing data. PASS 11.0 was used to calculate sample size. We defined adequate immune response as anti-HBs titers ≥100mIU/mL, and others as inadequate.\n\nDistribution of children HBV markers and anti-HBs levels were presented with number and proportion. Chi-square test was used to compare differences between women and children’s adequate and inadequate response characteristics. Multiple logistic regression model with Odds ratio and 95% confidence interval (OR and 95% CI) was used to explore the risk factors associated with inadequate immune response in children. Significant differences were considered as P value < 0.05 with two side effects. All data were double-inputted and checked for consistency using EPI Data software (version 3.02, The EpiData Association).We conducted statistics analysis using SPSS 16.0.\n\nResults\n\nA total of 1849 children were involved in this study finally. Of these, 23.20% (429) were born to HBeAg positive women who had first HBV screening during pregnancy. Overall, there were 967 boys, 875 girls and 7 unknown gender. The average age of children was 15.30 ± 3.98 months, with a median age of 15.00 months. All children completed three doses of hepatitis B vaccine, including 99.13%(1833) children with 10 μg/dose vaccine and 0.87%(16) without clear information on specific dose of vaccine.94.38% (1745) infants had their first dose of HBV vaccine within 6 h after birth, 2.33%(43) between 6 and 12 h, 2.70% (50) between 13 and 24 h,0.11% (2) beyond24 hours after birth and 0.49% (9) without specific information. Similarly, 95.08% (1758) infants had HBIG within 6 h after birth, 1.94% (36) between 7 and 12 h, 2.60% (48) between 13 and 24 h and 0.38% (7) infants beyond 24 h after birth.\n\nIn the study, 1824 children tested negative for HBsAg. 25 children were HBsAg positive, giving overall HBsAg positive rate 1.35% (95% CI 0.83-1.88%). 92.00% (23/25) HBsAg positive children were born to HBeAg positive women. 30.43%(7/23) of these HBeAg positive women received their first ANC beyond 13 gestational weeks. However, only one HBeAg positive woman who delivered HBsAg positive infant had antiviral treatment. In children with negative HBsAg, 2.14% tested both anti-HBc positive and anti-HBe positive, and 0.99% tested only anti-HBc positive.\n\nAnti-HBs titers in HBsAg negative children ranged from 0.13mIU/mL to 8976.11mIU/mL. The seroprotection rate (anti-HBs titers≥10mIU/mL) was 99.29% (1811/1824). The proportion of children with adequate anti-HBs titers(≥100mIU/mL) was 87.34%(1593/1824). Non-response was observed in 0.71%(13/1824) children (Table 1).Table 1 Distribution of HBV markers in children\n\nSubtype\tNumber\tProportion (%)\t\nHBsAg+\t\t25\t1.35\t\nHBeAg+\t23\t1.24\t\nHBeAg +,anti-HBc+\t20\t1.08\t\nanti-HBe+,anti-HBc+\t0\t0\t\nHBsAg-\t\t1824\t\t\n\tanti-HBc+,anti-HBs -\n\nHBeAg-, anti-HBe -\n\n\t18\t0.99\t\n\tanti-HBc+, anti-HBe +,\n\nanti-HBs -,HBeAg-\n\n\t39\t2.14\t\n\tanti-HBs +,anti-HBe +,\n\nanti-HBc+, HBeAg-\n\n\t0\t\t\n\tanti-HBs ≥ 10mIU/ml\t1811\t99.29\t\n\tanti-HBs ≥ 100mIU/ml\t1593\t87.34\t\n\t10mIU/ml ≤ anti-HBs < 100 mIU/ml\t218\t11.95\t\n\tanti-HBs < 10 mIU/ml\t13\t0.71\t\n\nNo significant differences were observed in distribution of maternal age, gravidity, parity, employment, maternal HBsAg status maternal abnormal Glutamic-pyruvic Transaminase (ALT) or Glutamic Oxaloacetic Transaminase (AST), delivery mode, boys or girls,low birth weight (LBW) feeding mode and injection time of HBIG between adequate and inadequate immunization groups. Children with adequate response had significant higher proportion of maternal early ANC, and lower proportion of preterm birth than those with anti-HBs titers under 100mIU/mL (Table 2). Multiple logistic regression mode showed only preterm birth (ORadj = 1.868,95%CI 1.132-3.085,P = 0.015), adjusted for LBW and ANC was strongly associated with anti-HBs titers under 100 (mIU/mL).Table 2 Comparison between women and children’s adequate and inadequate response characteristics\n\nVariable\tAdequate responders\tInadequate responders\tχ2\tP\t\n(N = 1593)\t(N = 231)\t\nn\t%\tn\t%\t\nMaternal age\t< 25\t93\t86.11\t15\t13.89\t2.151\t0.542\t\n25-29\t528\t88.29\t70\t11.71\t\t\t\n30-34\t557\t85.96\t91\t14.04\t\t\t\n≥35\t415\t88.3\t55\t11.7\t\t\t\nGravidity\t1\t387\t84.87\t69\t15.13\t3.988\t0.136\t\n2\t489\t87.17\t72\t12.83\t\t\t\n≥3\t711\t88.76\t90\t11.24\t\t\t\nMissing\t6\t100\t0\t0\t\t\t\nParity\t1\t10\t100\t0\t0\t1.834\t0.400\t\n2\t614\t87.84\t85\t12.16\t\t\t\n≥3\t965\t86.86\t146\t13.14\t\t\t\nMissing\t4\t100\t0\t0\t\t\t\nFirst antenatal care\tfirst trimester\t1244\t88.04\t169\t11.96\t6.962\t0.031\t\nSecond trimester\t298\t86.38\t47\t13.62\t\t\t\nThird trimester\t51\t77.27\t15\t22.73\t\t\t\nEmployment\n\nstatus\n\n\tFixed employment\t241\t88.28\t32\t11.72\t1.022\t0.796\t\nService\t364\t87.5\t52\t12.5\t\t\t\nFarmer\t105\t84.68\t19\t15.32\t\t\t\nUnemployed\t883\t87.34\t128\t12.66\t\t\t\nMaternal HBeAg during first ANC\tHBeAg +\t352\t86.06\t57\t13.94\t0.994\t0.319\t\nHBeAg -\t1030\t87.96\t141\t12.04\t\t\t\nUnknown\t211\t86.48\t33\t13.52\t\t\t\nALT/AST\tNormal\t1369\t87.03\t204\t12.97\t3.439\t0.064\t\nabnormal\t109\t81.34\t25\t18.66\t\t\t\nmissing\t115\t98.29\t2\t1.71\t\t\t\nMode of delivery\tVaginal delivery\t812\t88.17\t109\t11.83\t0.535\t0.465\t\nCesarean section\t758\t87.03\t113\t12.97\t\t\t\nMissing\t23\t71.88\t9\t28.13\t\t\t\nGender of children\tFemale\t747\t86.66\t115\t13.34\t0.692\t0.406\t\nMale\t840\t87.96\t115\t12.04\t\t\t\nMissing\t6\t85.71\t1\t14.29\t\t\t\nLow birth weight(< 2500 g)\tYes\t40\t78.43\t11\t21.57\t3.761\t0.052\t\nNo\t1553\t87.59\t220\t12.41\t\t\t\nPreterm\tYes\t81\t79.41\t21\t20.59\t6.147\t0.013\t\nNo\t1512\t87.91\t208\t12.09\t\t\t\nMissing\t13\t86.67\t2\t13.33\t\t\t\nFeeding within 6 months\tBreast\t683\t89.05\t84\t10.95\t3.839\t0.147\t\nMixed\t432\t85.54\t73\t14.46\t\t\t\nArtificial\t474\t86.5\t74\t13.5\t\t\t\nMissing\t4\t100\t0\t0\t\t\t\nHBIG\tWithin 12 h\t1503\t87.28\t219\t12.72\t0.079\t0.779\t\nOver 12 h\t90\t88.24\t12\t11.76\t\t\t\nAdequate response indicated anti-HBs titers at or over 100 mIU/mL, inadequate response meant anti-HBs titers under 100 mIU/mL\n\nDiscussion\n\nIn our study, the overall HBsAg positive rate was 1.35% among children aged 7-24 months. The global estimation of HBV infection prevalence in children at 5 years old in 2016 was1.4% [20]. Our HBsAg positive rate was lower than studies performed in Japan (1.9%), Malaysia (2.6%), and Denmark(2.3%), targeted on infants, young children or adolescents born from HBV carrier mothers [21–23]. In China, HBsAg positive rate ranged from 0.35% in children at the age of 7 months to 12 years in Jiangsu, 4.9 and 1.4% in children of 13-24 months and 7-12 months in 4 northwest provinces, and 0.9% in children aged 7-22 months in Hebei Guangdong Shanxi and Zhejiang [24–26]. We noticed over 90% HBsAg positive children were born to HBeAg positive women. Among HBsAg positive children, HBeAg positive was prevalent. Delay of first ANC in HBeAg positive women might delay treatment, possibly increasing the risk of vertical transmission. In this study, only one HBeAg positive woman who delivered HBsAg positive child received treatment. We also noticed no vertical transmission occurred in the children delivered by women who had effect antiviral treatment, corresponding to previous report [27]. Therefore, antiviral treatment should be given priority in HBeAg positive women.\n\nCombined passive and active immunization greatly contributed to reduction of HBV infection. A meta-analysis covering 26 studies showed people without vaccination had substantially higher HBsAg prevalence than those universally vaccinated [28]. We noted that over 99% of children developed protective anti-HBs (≥10 mIU/mL), and 87.34% children with anti-HBs levels ≥100 mIU/ml. Previous studies showed protective seroconversion rates varied with children’s age and disease. The anti-HBs positivity rate ranged from around 70% to beyond 95% in normal infants or adolescents [10, 12, 14, 29], but only around 50% among school age children with disease, such as autism spectrum disorders orceliac disease [30, 31]. In our study, the proportion of children with anti-HBs titers at or over 100mIU/mL were slightly less than infant in Changchun at age of 7-12 months(96.5%), but far higher than infants at 1 year in Chongqing (67.8%) and Al-Quds University (62.3%) [9, 11, 32]. In theory, antibody levels naturally declined by age, particularly more rapidly in children over 5 years old [10, 11, 32]. It was shown that over 90% children with initial vaccination failure might be revaccinated successfully [10]. A few proportion of children who tested HBsAg negative were anti-HBc positive. This indicated that these children might have occult HBV infection or have high risk of viral reactivation. Therefore, to analyse the HBV markers in serum is helpful for new intervention programme.\n\nParent HBV status, maternal HBV-DNA, timely and complete intervention, genetic effects and feeding mode were common determines for HBV vaccination response [9, 12, 26, 29, 32–34]. Overall, a genetic effect could explain 70-90% HBV vaccine responses, the remaining were unknown or environment factors [12]. Nevertheless, few studies focused on the risk factors related to anti-HBs titers under 100 mIU/mL. In our study, the negative association between LBW and anti-HBs less than 100mIU/mL was consistent with the study in North China and Xinjiang to some extent (both with adjusted OR = 2.5) [9, 12].LBW or preterm birth were the common reasons for delay in vaccination, which possibly lead to no or inadequate response. Breast feeding did not increase the risk of poor vaccination response in our study as previously reported [9, 33, 34]. In the United States, women with HBV infection are widely encouraged to breast-feed if the infant receives HBV vaccination and Hepatitis B immunoglobulin fully, which is similar to our province [34].\n\nIt has been widely evidenced that positive maternal HBeAg infection increases risks of MTCT [25, 35–37]. For HBeAg positive mothers, higher HBV-DNA level was strongly associated with increased risk for poor response to vaccination [9]. Exploration of risks related to maternal viral load in our study was limited due to lack of specific information, notably only 64 women had clear records of HBV DNA testing. The association between high anti-HBs titres and maternal HBeAg status is unclear. As previously suggested, protective effect is significant when infants born to HBeAg positive women were injected 20 μg HBV vaccine within 2 h after birth [9]. Exploration of different immunization projects according to maternal HBV status should be given much consideration.\n\nIn this study, we focused on inadequate response to HBV vaccine in children. This provides further helpful information for HBV vaccination and EMTCT, particularly for high risk women and their infants. There were several limitations in our study. Firstly, the study did not involve fathers basic information, which may also indicate source of children’s infection [38, 39]. Secondly, we only recruited local resident children and singletons births, which might bring some selective bias. Thirdly, influences by maternal viral load and treatment was not involved due to limited data.\n\nConclusions\n\nHepatitis B vaccine and HBIG injection would result in protective antibody in over 99% infants. Preterm birth need to be considered for inadequate response to the vaccine. Moreover complete routine infant HBV vaccination, vertical transmission was observed in infants born to HBeAg positive women.\n\nAbbreviations\n\nHBV Hepatitis B virus\n\nHBIG Hepatitis B Immunoglobulin\n\nOR Odds Ratio\n\nORadj Adjusted Odds Ratio\n\nCI Confidence Interval\n\nanti-HBs anti-HBV Surface Antigen\n\nMTCT Mother to Child Transmission\n\nHBsAg Hepatitis B Surface Antigen\n\nWHO World Health Organization\n\nPVST Postvaccination serological testing\n\nPMTCT Preventing mother to child transmission\n\nEMTCT Elimination MTCT\n\nHBeAg Hepatitis B e antigen\n\nanti-HBe Antibody against Hepatitis B e antigen\n\nanti-HBc Antibody against Hepatitis B core antigen\n\nANC Antenatal health care\n\nCLEIA Chemiluminescent Enzyme Immunoassay\n\nALT Glutamic-pyruvic Transaminase\n\nAST Glutamic Oxaloacetic Transaminase\n\nLBW Low birth weight\n\nThe authors would like to thank all of the medical staff who participated in this study, particularly those working in local women and children’s hospitals.\n\nCode availability\n\nNot Applicable.\n\nAuthors’ contributions\n\nX.Z is responsible for the study. M.J,B.Z and Q. Y conceived the study and drafted the manuscript. B.Z conducted laboratory supervision. Q.Y did statistics analysis. H.L performed data collection and quality control. X.Z provided technical assistance and revised the article. All authors read and approved the final manuscript.\n\nFunding\n\nThe study was funded by UNICEF China,501 Health, Nutrition and Wash- MCH; Increased evidence and policy makers’ capacity Piloting, Elimination of mother to child transmission of HIV, syphilis and HBV (EMTCT) and Key R&D Projects of Sichuan Province (Grant/Award Number: 2019YFS0409). Funding for data collection. These funders had no role in study design, data interpretation and manuscript writing.\n\nAvailability of data and materials\n\nThe datasets generated and/or analysed during the current study are not publicly available but are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThe study was approved by Ethnic Committee of Women’s Hospital School of Medicine Zhejiang University. Written informed consent was obtained from the parents. All methods were performed in accordance with the ethical principles of the Declaration of Helsinki 2000.\n\nConsent for publication\n\nNot Applicable.\n\nCompeting interests\n\nThe authors declare that they have no conflict of interest.\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. 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"fulltext_license": "CC BY",
"issn_linking": "1471-2431",
"issue": "21(1)",
"journal": "BMC pediatrics",
"keywords": "HBV carrier women; HBV immune response; HBV markers; Low birth weight; Preterm birth",
"medline_ta": "BMC Pediatr",
"mesh_terms": null,
"nlm_unique_id": "100967804",
"other_id": null,
"pages": "492",
"pmc": null,
"pmid": "34736435",
"pubdate": "2021-11-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "27866767;30761573;26454123;28658511;29091317;25996579;30876397;29599078;30296573;30008589;31378202;31131798;27796133;25558108;29427490;27873053;23486340;29962544;25881006;31450680;27559947;31580556;30992636;29962551;29588118;29473269;28687404;31098821;30687485;30572681;31974872;25361021;23682864;28651839;30888750;30817746;26145195;29962496",
"title": "Anti-HBs levels in children under the age of two years born to HBV carrier mothers after immunoprophylaxis: a multicenter cross-sectional study.",
"title_normalized": "anti hbs levels in children under the age of two years born to hbv carrier mothers after immunoprophylaxis a multicenter cross sectional study"
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... |
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"abstract": "BACKGROUND\nSome studies suggest that asthma-COPD overlap syndrome (ACOS) is associated with worse outcomes than chronic obstructive pulmonary disease (COPD). The goal of this study was to further explore the clinical characteristics and survival of patients with ACOS identified in a real-life cohort of patients with COPD.\n\n\nMETHODS\nData from the French COPD cohort 'INITIATIVES BronchoPneumopathie Chronique Obstructive' (n = 998 patients) were analyzed to assess the frequency of ACOS defined as a physician diagnosis of asthma before the age of 40 years and to analyze its impact. Univariate analyses were performed to assess the relationship between ACOS and sociodemographic characteristics, risk factors (smoking, occupational exposure, atopic diseases), symptoms (chronic bronchitis, dyspnea-modified Medical Research Council scale and baseline dyspnea index), quality of life (QoL), mood disorders, exacerbations, comorbidities, lung function, prescribed treatment, and survival.\n\n\nRESULTS\nACOS was diagnosed in 129 patients (13%). In multivariate analyses, ACOS was associated negatively with cumulative smoking (odds ratio [OR]: 0.992; 95% CI 0.984-1.000 per pack-year) and positively with obesity: OR: 1.97 [1.22-3.16], history of atopic disease (hay fever: OR: 5.50 [3.42-9.00] and atopic dermatitis: OR 3.76 [2.14-6.61]), and drug use (LABA + ICS: 1.86 [1.27-2.74], antileukotrienes 4.83 [1.63-14.34], theophylline: 2.46 [1.23-4.91], and oral corticosteroids: [2.99;.1.26-7.08]). No independent association was found with dyspnea, QoL, exacerbations, and mortality.\n\n\nCONCLUSIONS\nCompared to 'pure' COPD patients, patients with ACOS exhibit lower cumulative smoking, suffer more from obesity and atopic diseases, and use more asthma treatments. Disease severity (dyspnea, QoL, exacerbations, comorbidities) and prognosis (mortality) are not different from 'pure' COPD patients.",
"affiliations": "Pulmonary Department, Gabriel Montpied University Hospital, Auvergne University, Clermont-Ferrand, France.;Pulmonary Department, APHM, INSERM U1077, CNRS UMR 7733 Aix Marseille Université, Marseille, France.;Pulmonary Department, Larrey University Hospital, Toulouse, France.;Respiratory and Intensive Care Medicine, Cochin Hospital, AP-HP and Paris Descartes University, Sorbonne Paris Cité, Paris, France.;Pulmonary Department, University Hospital, Saint-Etienne, France.;Pulmonary Department, La Croix Rousse University Hospital, Lyon, France.;Pulmonary Department, Maison Blanche University Hospital, INSERM U903, Reims, France.;Clinique des Maladies Respiratoires, Albert Calmette University Hospital, Lille, France.;EFFI-STAT, Paris, France.;Polyclinique Les Fleurs, Pneumologie, Ollioules, France.;Pulmonary Department, Bichat Hospital, AP-HP, Paris, France.;Respiratory and Intensive Care Medicine, Cochin Hospital, AP-HP and Paris Descartes University, Sorbonne Paris Cité, Paris, France.",
"authors": "Caillaud|D|D|;Chanez|P|P|;Escamilla|R|R|;Burgel|P-R|PR|;Court-Fortune|I|I|;Nesme-Meyer|P|P|;Deslee|G|G|;Perez|T|T|;Paillasseur|J-L|JL|;Pinet|C|C|;Jebrak|G|G|;Roche|N|N|;|||",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/all.13004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0105-4538",
"issue": "72(1)",
"journal": "Allergy",
"keywords": "Asthma-COPD overlap syndrome (ACOS); asthma-COPD overlap syndrome; chronic obstructive pulmonary disease (COPD); mortality; severity; treatment",
"medline_ta": "Allergy",
"mesh_terms": "D000368:Aged; D001249:Asthma; D015331:Cohort Studies; D015897:Comorbidity; D003937:Diagnosis, Differential; D018450:Disease Progression; D005260:Female; D005602:France; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D029424:Pulmonary Disease, Chronic Obstructive; D011788:Quality of Life; D012307:Risk Factors; D011795:Surveys and Questionnaires; D063189:Symptom Assessment; D013577:Syndrome",
"nlm_unique_id": "7804028",
"other_id": null,
"pages": "137-145",
"pmc": null,
"pmid": "27501862",
"pubdate": "2017-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Asthma-COPD overlap syndrome (ACOS) vs 'pure' COPD: a distinct phenotype?",
"title_normalized": "asthma copd overlap syndrome acos vs pure copd a distinct phenotype"
} | [
{
"companynumb": "FR-ALEMBIC PHARMACUETICALS LIMITED-2016SCAL000778",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THEOPHYLLINE ANHYDROUS"
},
... |
{
"abstract": "Recently, the immune checkpoint inhibitor (ICI) pembrolizumab was demonstrated to be superior to platinum doublet chemotherapy in the first-line setting in patients with tumor programmed death-ligand 1 (PD-L1) expression of at least 50%. However, because patients with epidermal growth factor receptor (EGFR) mutations or anaplastic lymphoma kinase (ALK) rearrangements were not included in that study, the efficacy of pembrolizumab in lung cancers carrying EGFR mutations could not be determined. Here we describe two cases of response to pembrolizumab in EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression. These cases indicate that ICI is an effective treatment for EGFR mutated lung adenocarcinoma patients with PD-L1 overexpression.",
"affiliations": "Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.;Department of Thoracic Oncology, National Hospital Organization Toneyama National Hospital, Osaka, Japan.",
"authors": "Uenami|Takeshi|T|;Ishijima|Mikako|M|;Kanazu|Masaki|M|;Kurebe|Hiroyuki|H|;Edahiro|Ryuya|R|;Nishida|Kohei|K|;Akazawa|Yuki|Y|;Yano|Yukihiro|Y|;Yamaguchi|Toshihiko|T|;Mori|Masahide|M|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/atm.2018.10.24",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2305-5839",
"issue": "6(22)",
"journal": "Annals of translational medicine",
"keywords": "Non-small cell lung cancer (NSCLC); epidermal growth factor receptor (EGFR); pembrolizumab; programmed death-ligand 1 (PD-L1)",
"medline_ta": "Ann Transl Med",
"mesh_terms": null,
"nlm_unique_id": "101617978",
"other_id": null,
"pages": "444",
"pmc": null,
"pmid": "30596074",
"pubdate": "2018-11",
"publication_types": "D002363:Case Reports",
"references": "22437870;23401445;27225694;27718847;27765535;28055103;29290252;29545095;29572000",
"title": "Two cases of response to pembrolizumab in epidermal growth factor receptor mutated lung adenocarcinoma patients with programmed death-ligand 1 overexpression.",
"title_normalized": "two cases of response to pembrolizumab in epidermal growth factor receptor mutated lung adenocarcinoma patients with programmed death ligand 1 overexpression"
} | [
{
"companynumb": "JP-009507513-1812JPN003379",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "The use of psychotropic drugs is often associated with electrocardiographic (ECG) QT-interval prolongation, but there are few reports of J-waves. This report describes the case of a schizophrenic patient under treatment with several psychotropic drugs (olanzapine, valproate, and flunitrazepam), in whom ECG J-waves diffusely appeared during a hypothermic episode. We further performed a literature review of psychotropic drug-related J-waves in hypothermia. The present case highlights the importance of recognizing psychotropic drug-related ECG J-waves on an early warning sign to ensure appropriate monitoring and/or treatment for possible life-threatening side effects of such medications.",
"affiliations": "Department of Internal Medicine, Nishida Hospital, Tsuruoka-Nishi-Machi 2-266, Saiki, Oita, 876-0047, Japan. hkata@cream.plala.or.jp.;Division of Pharmacy, Nishida Hospital, Oita, Japan.;Department of Internal Medicine, Nishida Hospital, Tsuruoka-Nishi-Machi 2-266, Saiki, Oita, 876-0047, Japan.",
"authors": "Kataoka|Hajime|H|;Kajiwara|Hirofumi|H|;Yano|Eiji|E|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s00380-015-0646-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0910-8327",
"issue": "31(6)",
"journal": "Heart and vessels",
"keywords": "Electrocardiogram; Flunitrazepam; Hypothermia; J-wave; Olanzapine; Osborn wave; Psychotropic drug; Valproate",
"medline_ta": "Heart Vessels",
"mesh_terms": "D014150:Antipsychotic Agents; D001145:Arrhythmias, Cardiac; D001833:Body Temperature Regulation; D004562:Electrocardiography; D005260:Female; D006329:Heart Conduction System; D006801:Humans; D007035:Hypothermia; D008875:Middle Aged; D011237:Predictive Value of Tests; D012307:Risk Factors; D012559:Schizophrenia",
"nlm_unique_id": "8511258",
"other_id": null,
"pages": "996-1002",
"pmc": null,
"pmid": "25666953",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "24837798;24294486;6108205;21592373;15338150;16319382;11093425;21956608;21343343;19555799;8807034;12839516;10891933;19480467;24306340;22498570;24591540;18834366;15152790;22034916;19639399;11199936;11235936;17401555;7731960;1541717;18324881;23612859;23960384;13114420;23131759;19512984;14677808;2394532;24200873",
"title": "Psychotropic drug-associated electrocardiographic presentation of diffuse J-waves in hypothermia: case report and literature review.",
"title_normalized": "psychotropic drug associated electrocardiographic presentation of diffuse j waves in hypothermia case report and literature review"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201604860",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OLANZAPINE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of Kaposi sarcoma (KS) and disseminated infection by Mycobacterium genavense in a 40-year-old HIV-positive man with CD4+ T-cell count 5/µL. He presented with anorexia, diarrhoea, cachexia and multiple firm violaceous nodules distributed over the face, neck and upper and lower extremities. Biopsy of a skin nodule was performed, confirming KS. Immunoperoxidase staining for human herpesvirus 8 was strongly positive. Endoscopic examination revealed erosive duodenopathy. Multiple biopsy samples showed numerous acid-fast bacilli at direct microscopic examination. Real-time PCR (RT-PCR) identified M. genavense. A CT scan showed diffuse pulmonary infiltrates with a 'tree-in-bud' appearance, striking splenomegaly and abdominal lymphadenopathy. A bronchoscopy was performed, revealing typical Kaposi's lesions in the upper respiratory tract. RT-PCR of bronchial aspirate identified M. genavense and Pneumocystis jirovecii. Despite treatment with highly active antiretroviral therapy, antimycobacterial therapy and trimethoprim/sulfamethoxazole, the outcome was fatal.",
"affiliations": "Department of Internal Medicine, Hospital of Braga, Braga, Portugal.;Department of Internal Medicine, Hospital of Braga, Braga, Portugal.;Department of Internal Medicine, Hospital of Braga, Braga, Portugal.;Department of Internal Medicine, Hospital of Braga, Braga, Portugal.",
"authors": "Tribuna|Cindy|C|http://orcid.org/0000-0003-1858-676X;Ângela|Cristina|C|;Eira|Isabel|I|;Carvalho|Alexandre|A|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D017088:AIDS-Related Opportunistic Infections; D000328:Adult; D000900:Anti-Bacterial Agents; D023241:Antiretroviral Therapy, Highly Active; D001706:Biopsy; D001999:Bronchoscopy; D015496:CD4-Positive T-Lymphocytes; D017809:Fatal Outcome; D015658:HIV Infections; D006679:HIV Seropositivity; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009165:Mycobacterium Infections, Nontuberculous; D009170:Nontuberculous Mycobacteria; D013902:Radiography, Thoracic; D012514:Sarcoma, Kaposi",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26452414",
"pubdate": "2015-10-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25221796;10469747;7698119;10767252;15199854;20663117;1352014;19255269;21694645;17277290;21377267;24065230;8880196;21043836;8616570;8348508;18705759;8181313;10950369;2671281;7848023;10565904;2719427",
"title": "Pulmonary Kaposi sarcoma and disseminated Mycobacterium genavense infection in an HIV-infected patient.",
"title_normalized": "pulmonary kaposi sarcoma and disseminated mycobacterium genavense infection in an hiv infected patient"
} | [
{
"companynumb": "PT-PFIZER INC-2016337431",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND Serotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists. CASE REPORT A 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay. CONCLUSIONS In this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.",
"affiliations": "Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.;Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, USA.;Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA.",
"authors": "Little|Kimberly|K|;Lin|Christine M|CM|;Reynolds|Paul M|PM|",
"chemical_list": "D018765:Dopamine Uptake Inhibitors; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Serotonin Uptake Inhibitors; D005473:Fluoxetine; D016642:Bupropion; D001569:Benzodiazepines; D003533:Cyproheptadine; D018967:Risperidone; D000077152:Olanzapine; D014196:Trazodone",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.909063",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2979505810.12659/AJCR.909063909063ArticlesDelayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose Little Kimberly DE1Lin Christine M. BE2Reynolds Paul M. ABCEF1\n1 Department of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, U.S.A.\n2 Department of Medicine, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado, Aurora, CO, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Paul M. Reynolds, e-mail: Paul.reynolds@ucdenver.edu2018 25 5 2018 19 604 607 19 1 2018 08 3 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 24\n\nFinal Diagnosis: Delayed onset serotonin syndrome\n\nSymptoms: Agitation • autonomic instability • fever • hyperreflexia • hypertonia • inducable clonus\n\nMedication: Fluoxetine\n\nClinical Procedure: —\n\nSpecialty: Toxicology\n\nObjective:\nUnexpected drug reaction\n\nBackground:\nSerotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. In the setting of serotonergic overdose, the onset of serotonin syndrome is usually within 4 to 13 h. Here, we report a case of delayed-onset serotonin syndrome in a patient who ingested a mixture of longer-acting serotonin agonists with serotonin antagonists.\n\nCase Report:\nA 24-year-old male was transferred to our medical intensive care unit with hypotension and altered mental status after an overdose of fluoxetine, cyproheptadine, trazodone, olanzapine, risperidone, and bupropion. After approximately 72 h, the patient developed symptoms of fever, lower leg clonus, hyperreflexia, and agitation. He was diagnosed with delayed-onset serotonin syndrome, which responded well to re-administration of cyproheptadine, leading to resolution of symptoms by day 5 of his stay.\n\nConclusions:\nIn this present case, our patient presented with the longest reported delay in the onset of serotonin syndrome after intentional ingestion. This was likely secondary to co-ingestion of long-acting serotonin agonists with protective shorter-acting serotonin antagonists (cyproheptadine and olanzapine). Clinicians should consider delayed-onset serotonin syndrome when patients ingest longer-acting serotonergic agents with serotonin antagonists.\n\nMeSH Keywords:\nCyproheptadineDelayed DiagnosisDrug OverdoseFluoxetineSerotonin Syndrome\n==== Body\nBackground\nSerotonin syndrome is a condition characterized predominantly by neuromuscular symptoms and altered thermoregulation in response to serotonergic overtone. Treatment is focused on withdrawal of serotonergic agents, which leads to resolution in the majority of cases. However, if not recognized and treated, this syndrome can progress to a life-threatening state. Here, we describe a patient who overdosed on long-acting serotonergic agents in combination with several anti-serotonergic agents, including the 5-HTP2A antagonist cyproheptadine, resulting in a delayed-onset serotonin syndrome.\n\nCase Report\nA 24-year-old man with past medical history significant for depression and treatment-refractory schizoaffective disorder was brought in by ambulance after being found unresponsive. He was last seen normal approximately 7 h prior; at the scene, he was surrounded by multiple empty prescription bottles and intentional drug overdose was suspected. In the field, he was administered naloxone without a change in his status.\n\nUpon arrival to the emergency department, the patient was afebrile (temperature 37.2°C) but was hypotensive (mean arterial pressure 59 mm Hg) and tachycardic (heart rate 116). Physical examination was notable for fixed pupils bilaterally and a Glasgow Coma Score (GCS) of 3. Laboratory studies were significant for a lactate 14.8 mmol/L, bicarbonate 16 mEq/L, a white blood cell count of 14.2×109/L, creatinine 1.5 mg/dl, AST 121 U/L, ALT 55 U/L, and creatinine kinase 12 643 U/L.\n\nQTc was prolonged at 549 ms, but QRS interval was normal. Urine toxicology screen was positive for amphetamines. All other laboratory parameters (including electrolytes, blood urea nitrogen, and blood gases) were normal at this time. The patient was subsequently intubated and admitted to the intensive care unit. Treatment initially consisted of supportive care, including vasopressor support for hemodynamic instability in the form of persistent hypotension, volume resuscitation for his acute kidney injury/rhabdomyolysis, and empiric antibiotic coverage with vancomycin and piperacillin-tazobactam for suspected aspiration pneumonia. He was also maintained on infusions of fentanyl, midazolam, and propofol for sedation.\n\nOn the second hospital day, the patient’s hemodynamic instability resolved, leading to weaning of sedation and vasopressors. In addition, initial electrolyte abnormalities, elevated white count, and creatinine had normalized, with the exception of creatinine kinase and liver function tests, which were down-trending. However, physical examination was notable for fixed and pinpoint pupils, but with mildly improved neurological function. At this time, the patient’s family provided the medications presumed to have caused his overdose, which included fluoxetine, bupropion, olanzapine, cyproheptadine, and risperidone (Table 1).\n\nOn the third hospital day, the patient’s temperature rose to 39.1°C and he was noted to have a marked change on examination, with spontaneous myoclonic jerks, rigors, asymmetric patellar reflexes, and nystagmus. This was accompanied by features of autonomic instability (systolic blood pressure of 189 mm Hg). Despite the delay in presentation, serotonin syndrome was suspected as the patient clearly had documented exposure to a serotonergic agent and per Hunter’s Decision Rules for the diagnosis of serotonin toxicity, demonstrated spontaneous clonus (bilateral lower extremities), agitation, ocular clonus, fever, and hyperreflexia [1]. It was thought that upon clearance of olanzapine and cyproheptadine (anti-serotonergic agents), serotonergic overtone from fluoxetine overdose was unmasked due to the longer half-life of this medication (Table 1). To decrease additional serotonergic agent exposure, fentanyl was switched to hydromorphone and a lorazepam drip was initiated to manage his clonus and agitation. However, the patient’s temperature continued to increase (Figure 1); therefore, a single dose of cyproheptadine 12 mg was administered. This resulted in a substantial decrease in temperature (39.9°C to 36.2°C), resolution of clonus and hyperreflexia, and improvement in GCS. Thus, cyproheptadine was continued at 2 mg every 2 h as needed, with an additional 12 mg over the next 72 h. By hospital day 5, no further signs of serotonin syndrome were exhibited and the patient demonstrated a normalization in vital signs (mean arterial pressure 86, heart rate 88) and laboratory parameters (creatinine 0.64 mg/dL, alkaline phosphatase 145 U/L, alanine aminotransferase 79 U/L, creatine kinase 728 U/L, lactate 1.0 mmol/L, bicarbonate 25 mEq/L) He was subsequently extubated and was discharged to inpatient psychiatry on hospital day 8 for further psychiatric management.\n\nDiscussion\nThis patient presented with a unique manifestation of delayed serotonin syndrome due to co-ingestion of shorter-half-life serotonin antagonists (olanzapine, cyproheptadine) with longer-acting serotonergic agents (fluoxetine). The patient’s poly-pharmacy for depression (fluoxetine), schizoaffective disorder (olanzapine, risperidone), and insomnia (cyproheptadine) contributed to the complexity of this case.\n\nCyproheptadine and olanzapine are reported to have 16-h [2] and 30-h half-lives, respectively. [3] Doses as low as 18 mg of cyproheptadine provide near-complete antagonism of serotonin receptors [2]. At 80 h post-ingestion, over 95% of cyproheptadine should be eliminated from a given patient. This time course corresponds to the delayed-onset of our patient’s symptoms, thus leading to the high suspicion of delayed serotonin syndrome. In addition, the patient had a marked improvement in his fever curve, muscle clonus, rigidity, and mental status when cyproheptadine was re-administered with lorazepam. At this time, his laboratory abnormalities had grossly normalized, minimizing the likelihood of alternative etiologies. The prompt response to re-administration of cyproheptadine is consistent with prior reports of this agent’s use in serotonin syndrome [4]. Although olanzapine has not been utilized for the treatment of serotonin syndrome, withdrawal of this agent has been implicated in revealing serotonin syndrome in a patient receiving concurrent serotonergic agents [5]. Risperidone may have also conferred a protective effect [6], although serotonin syndrome has been reported with this agent in cases of co-administration with SSRIs [7].\n\nIn selective serotonin reuptake inhibitor (SSRI) overdose, the reported onset of serotonin syndrome is normally within 13 h, with the majority of overdoses leading to symptom onset within 4 h [8]. Isolated case reports of delayed-onset serotonin syndrome have been described, although not exceeding 24 h [9]. Our patient overdosed on fluoxetine (time to peak concentration – Tmax 6 h), but the drug’s active metabolite, norfluoxetine, possesses a markedly prolonged Tmax of 48 h [10]. The delay to serotonergic symptoms in this patient (80 h) is the longest reported delay in an intentional SSRI overdose, likely secondary to the co-ingestions described above. Notably, other toxidromes were considered given his mixed ingestion, including anti-cholinergic toxicity and neuroleptic malignant syndrome. The patient did not receive any medications that could have induced malignant hyperthermia. Neuroleptic malignant syndrome is typically hyporeflexic in nature with rigid rigidity in all muscle groups; this patient had hyper-reflexia localized to the lower extremities. Although this patient had agitated delirium consistent with anticholinergic toxidromes, the initial presentation of miosis, with altered muscle tone made this syndrome less likely. The profound response to cyproheptadine this patient exhibited would not be expected with either of these toxidromes but has been documented in serotonin syndrome. Alcohol withdrawal was a possible cofounder in this patient given the delayed hyperadrenergic state that this syndrome generates; however, if it was the sole toxidrome present, the continuous lorazepam infusion should have adequately treated his symptoms without the marked response to cyproheptadine administration. Other conditions such as meningoencephalitis and metabolic encephalopathy were felt to be less likely given the timing of the case with an intentional overdose and profound response to cyproheptadine. Potential infectious and metabolic etiologies were considered less likely given how rapidly the patient’s laboratory parameters normalized, while the patient remained symptomatic. A major limitation of this case report was the inability to obtain serum or urine levels of the ingested agents. This would have allowed a clear depiction of the toxicokinetics of these drugs in this patient and would have allowed trending of serum levels to symptom manifestations.\n\nConclusions\nCombined ingestion of cyproheptadine and olanzapine in a multi-drug overdose resulted in an early “protective” effect, leading to delayed serotonin syndrome in the setting of concurrent fluoxetine and trazodone overdose. Evidence from this report demonstrates that the onset of serotonin syndrome can be delayed and that a high index of suspicion is required for diagnosis, especially in patients with co-ingestion of serotonin antagonists. Serum level monitoring may be useful if multiple agents such as these are co-ingested. Lastly, further study is needed to investigate the potential role of olanzapine and other serotonin antagonists in the early treatment of this condition.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Temperature curve of patient over the patient’s 8-day hospital course (overlaid with time points of elimination of ingested olanzapine and cyproheptadine).\n\nTable 1. Suspected ingested medications (including elimination half-lives) with quantities available to patient based on prescription fill data.\n\nDrug and dose\tQuantity available\tHalf-life [1,4]\tReceptors involved [1,3,4]\t\nSerotonin antagonists\t\nOlanzapine (5 mg and 10 mg)\t60\t33 hours\t5HT2A, 5HT2C, dopamine and HT3 antagonist\t\nRisperidone (3 mg)\t120\t3 to 20 hours\t5HT2A, 5HT7, D2 antagonist\t\nCyproheptadine (4 mg)\t60\t16 hours\t5HT2 Antagonist\t\nSerotonergic agents/serotonergic agonists\t\nFluoxetine (20 mg)\t30\tFluoxetine: 4 to 6 days\nNorfluoxetine: 7 to 15 days\t5HT reuptake inhibition\t\nTrazodone (50 mg)\t30\t6 h\t5HT2A, 5HT2C agonist\t\nOther Adrenergic Agents Ingested\t\nBupropion SR (100 mg) and XL (150 mg)\t60\t14 to 21 h\tNorepinephrine, dopamine reuptake inhibition\n==== Refs\nReferences:\n1. Dunkley EJ Isbister GK Sibbritt D The Hunter Serotonin Toxicity Criteria: Simple and accurate diagnostic decision rules for serotonin toxicity QJM 2003 96 9 635 42 12925718 \n2. Kapur S Zipursky RB Jones C Cyproheptadine: A potent in vivo serotonin antagonist Am J Psychiatry 1997 154 6 884 \n3. Mauri MC Volonteri LS Colasanti A Clinical pharmacokinetics of atypical antipsychotics: A critical review of the relationship between plasma concentrations and clinical response Clin Pharmacokinet 2007 46 5 359 88 17465637 \n4. Graudins A Stearman A Chan B Treatment of the serotonin syndrome with cyproheptadine J Emerg Med 1998 16 4 615 19 9696181 \n5. Himmighoffen H Seifritz E Boeker H Serotonin syndrome after discontinuation of olanzapine in a combined treatment with duloxetine – case report Pharmacopsychiatry 2011 44 2 75 76 21161885 \n6. Nisijima K Yoshino T Ishiguro T Risperidone counteracts lethality in an animal model of the serotonin syndrome Psychopharmacology (Berl) 2000 150 1 9 14 10867971 \n7. Isbister GK Comment: combination risperidone and SSRI-induced serotonin syndrome Ann Pharmacother 2003 37 10 1531 32 author reply 1532–33 \n8. Nelson LS Erdman AR Booze LL Selective serotonin reuptake inhibitor poisoning: An evidence-based consensus guideline for out-of-hospital management Clin Toxicol (Phila) 2007 45 4 315 32 17486478 \n9. Pearce S Ahned N Varas GM A case study of delayed serotonin syndrome: Lessons learned Consult Pharm 2009 24 1 64 68 19275460 \n10. Moraes MO Lerner FE Corso G Fluoxetine bioequivalence study: Quantification of fluoxetine and norfluoxetine by liquid chromatography coupled to mass spectrometry J Clin Pharmacol 1999 39 10 1053 61 10516940\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "19()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D001569:Benzodiazepines; D016642:Bupropion; D003533:Cyproheptadine; D018765:Dopamine Uptake Inhibitors; D062787:Drug Overdose; D005473:Fluoxetine; D006801:Humans; D008297:Male; D000077152:Olanzapine; D018967:Risperidone; D018490:Serotonin Agents; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D020230:Serotonin Syndrome; D017367:Serotonin Uptake Inhibitors; D013997:Time Factors; D014196:Trazodone; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "604-607",
"pmc": null,
"pmid": "29795058",
"pubdate": "2018-05-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17465637;12925718;14519058;10516940;9167527;21161885;10867971;17486478;9696181;19275460",
"title": "Delayed Serotonin Syndrome in the Setting of a Mixed Fluoxetine and Serotonin Antagonist Overdose.",
"title_normalized": "delayed serotonin syndrome in the setting of a mixed fluoxetine and serotonin antagonist overdose"
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"abstract": "High-dose methylprednisolone plus rituximab (R-HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) patients unfit for chemo-immunotherapy and has proven its utility on the treatment of CLL/SLL complicated by auto-immune cytopenias. We performed a retrospective, single-centre study, of CLL/SLL patients treated with R-HDMP for 9 years. Thirty-nine patients were included, median age at time of treatment was 77 years. Most patients had stage Rai III/IV and Binet C disease. Twenty-eight patients had relapsed/refractory disease at time of treatment with a median of 1 previous line of therapy; 53.8% had prior exposure to fludarabine and 25% to rituximab. Grade 3-4 neutropenia and thrombocytopenia were recorded in 10.2% and 17.9% patients, respectively. While on treatment, 51.3% had documented infectious complications, but no other non-haematological toxicities grades 3-4 were identified. Overall response rate was 64%. Median overall survival and progression-free survival were 24 and 13 months, respectively. Twenty four patients relapsed and 16 received another line of treatment after R-HDMP, with median time to next treatment of 13.5 months. Thirteen out of the 24 patients improved performance status and were subsequently considered fit for chemo-immunotherapy. R-HDMP is a valuable option for elderly and frail patients, with low risk of severe myelotoxicity and other severe adverse events. It was shown to work as a bridge to other lines of treatment, including chemo-immunotherapy.",
"affiliations": "Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.;Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Lisbon, Portugal.",
"authors": "Vagos Mata|Ana|A|https://orcid.org/0000-0003-1954-7746;Espada|Eduardo|E|;Alves|Daniela|D|;Polo|Blanca|B|;Costa|Maria João|MJ|;Lopes|Conceição|C|;F Lacerda|João|J|;Raposo|João|J|",
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"country": "United States",
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"doi": "10.1002/cam4.4374",
"fulltext": "\n==== Front\nCancer Med\nCancer Med\n10.1002/(ISSN)2045-7634\nCAM4\nCancer Medicine\n2045-7634\nJohn Wiley and Sons Inc. Hoboken\n\n34783174\n10.1002/cam4.4374\nCAM44374\nResearch Article\nClinical Cancer Research\nResearch Articles\nChronic lymphocytic leukaemia/small lymphocytic lymphoma treatment with rituximab and high‐dose methylprednisolone, revisited\nVAGOS MATA et al.\nVagos Mata Ana https://orcid.org/0000-0003-1954-7746\n1 anavagosmata@gmail.com\n\nEspada Eduardo 1 2\nAlves Daniela 1\nPolo Blanca 1\nCosta Maria João 1\nLopes Conceição 1\nF. Lacerda João 1 2 3\nRaposo João 1\n1 Hematology and Bone Marrow Transplant Department Hospital de Santa Maria Centro Hospitalar Universitário Lisboa Norte Lisbon Portugal\n2 Instituto de Medicina Molecular João Lobo Antunes Faculdade de Medicina Universidade de Lisboa Lisbon Portugal\n3 Faculdade de Medicina Universidade de Lisboa Lisbon Portugal\n* Correspondance\nAna Vagos Mata, Hematology and Bone Marrow Transplant Department, Hospital de Santa Maria, Centro Hospitalar Universitário Lisboa Norte, Av. Prof. Egas Moniz, 1600‐028, Lisbon, Portugal.\nEmail: anavagosmata@gmail.com\n\n16 11 2021\n12 2021\n10 24 10.1002/cam4.v10.24 87688776\n14 9 2021\n14 6 2021\n27 9 2021\n© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nHigh‐dose methylprednisolone plus rituximab (R‐HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL) patients unfit for chemo‐immunotherapy and has proven its utility on the treatment of CLL/SLL complicated by auto‐immune cytopenias. We performed a retrospective, single‐centre study, of CLL/SLL patients treated with R‐HDMP for 9 years. Thirty‐nine patients were included, median age at time of treatment was 77 years. Most patients had stage Rai III/IV and Binet C disease. Twenty‐eight patients had relapsed/refractory disease at time of treatment with a median of 1 previous line of therapy; 53.8% had prior exposure to fludarabine and 25% to rituximab. Grade 3–4 neutropenia and thrombocytopenia were recorded in 10.2% and 17.9% patients, respectively. While on treatment, 51.3% had documented infectious complications, but no other non‐haematological toxicities grades 3–4 were identified. Overall response rate was 64%. Median overall survival and progression‐free survival were 24 and 13 months, respectively. Twenty four patients relapsed and 16 received another line of treatment after R‐HDMP, with median time to next treatment of 13.5 months. Thirteen out of the 24 patients improved performance status and were subsequently considered fit for chemo‐immunotherapy. R‐HDMP is a valuable option for elderly and frail patients, with low risk of severe myelotoxicity and other severe adverse events. It was shown to work as a bridge to other lines of treatment, including chemo‐immunotherapy.\n\nHigh dose methylprednisolone plus rituximab (R‐HDMP) is a useful treatment in chronic lymphocytic leukaemia/small lymphocytic lymphoma patients unfit for chemo‐immunotherapy. We present a cohort of patients with median age of 77 years, most with stage Rai III/IV and Binet C disease. Overall response rate was 64% and median overall survival and progression‐free survival were 24 and 13 months, respectively, with an acceptable toxicity profile, highlighting R‐HDMP utility for elderly and frail patients.\n\nauto‐immune haemolytic anaemia\nchronic lymphocytic leukaemia\nhigh‐dose methylprednisolone\nrituximab\nsource-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:17.12.2021\nVagos Mata A , Espada E , Alves D , et al. Chronic lymphocytic leukaemia/small lymphocytic lymphoma treatment with rituximab and high‐dose methylprednisolone, revisited. Cancer Med. 2021;10 :8768–8776. doi:10.1002/cam4.4374\n==== Body\npmc1 INTRODUCTION\n\nChronic lymphocytic leukaemia/small lymphocytic lymphoma (CLL/SLL), an indolent malignancy of mature B cells that predominantly affects men, is the most frequent haematologic malignancy in developed countries. Its incidence increases with age and roughly half of the patients will never need treatment. 1 According to the International Workshop on Chronic Lymphocytic Leukaemia (iwCLL) guidelines, treatment is warranted when active disease criteria are met, which include steroid‐refractory autoimmune cytopenias. 2\n\nCLL patients have a 5%–10% cumulative risk of developing autoimmune phenomena, which bear no prognostic impact and can happen in any stage of disease. Actually, patients with CLL and immune cytopenias have a better prognosis than those with cytopenias due to marrow infiltration. 3 Some authors state that auto‐immune cytopenias may occur in up to 25% of cases, mostly associated with high risk features, such as del(17p), del(11q), and unmutated immunoglobulin heavy‐chain variable region (IgHV) gene. 4 Cytopenias are the most frequent autoimmune complications in CLL. Autoimmune haemolytic anaemia (AIHA) is by far the most frequent autoimmune cytopenia, while immune thrombocytopenia, pure red cell aplasia and immune agranulocytopenia are less frequent. 5 , 6 There are at least three mechanisms under the appearance of autoimmune cytopenias: malignant lymphocytes may be responsible for aberrant antigen presentation (Rh antigen, for example); CLL cells may also produce inhibitory cytokines that impair tolerance mechanisms; there may also be an imbalance between T‐cells subsets, favouring the appearance of auto‐reactive B cells against erythrocytes and platelets. 3 , 4 It is extremely important to understand if the cytopenias are a result of autoimmune phenomena, marrow infiltration, bleeding loss, renal disease or vitamin/iron deficits. The correct laboratory work‐up is fundamental to correctly diagnose the cause of the cytopenia. Importantly, a positive direct anti‐globulin test (DAT) is not diagnostic of AIHA if the other laboratory features are not present; on the other hand, AIHA may occur even with negative DAT, either because of low affinity or low titers of antibodies. 4 When isolated, autoimmune cytopenias can be treated with steroids; when steroid‐refractory or in association with progressive CLL (termed complex autoimmune cytopenia), chemo‐immunotherapy protocols are recommended. 7\n\nCLL treatment protocols have evolved significantly over the last 20 years. There is currently a consensus about first‐line therapy for fit young patients, with some variations according to TP53 and IgHV mutational status. There are also interesting alternatives for those who have some comorbidities, considered “slow go” patients. 8 A bigger challenge is to decide how to treat older and very frail patients, either in first‐line or in the relapsed/refractory setting. Most of these patients have multiple comorbidities and more than half suffer from inadequate polypharmacy, leading to low adherence to new therapies and dangerous drug interactions. 9 This concern is particularly relevant in long‐term fixed therapy and therapy until progression, as opposed to short‐fixed duration therapy, despite recent work showing safety and efficacy of new drugs on elderly patients. 10 , 11 The last position statement from the Society of Geriatric Oncology highlights the importance of assessing elderly patients according to their physical and cognitive capacity, as well as to their ability of performing activities of daily living. The authors highlight that no frailty score has been prospectively validated in CLL, and that such elderly patients are rarely included in clinical trials, making it extremely difficult to make the right decision about these patients. Such an intricate evaluation is necessary to choose a treatment protocol that is feasible for each patient, meaning that it does not lead to discontinuation, dose reduction, or delay in treatment protocol. They also refer that the economic impact of new therapies in elderly patients should not be forgotten, suggesting that further evaluation of the health economic impact of the new drugs in elderly patients should be performed, in order to prioritise treatments. 12\n\nA high‐dose methylprednisolone (HDMP) protocol for CLL was first published by Thornton et al in 1999. 13 Since then, many authors have published their experience with rituximab plus high‐dose steroid therapy, either dexamethasone or methylprednisolone (R‐HDMP). These protocols have small variations regarding rituximab dose, steroid dose, and number of days of steroid administration, and have shown interesting results, especially in the relapsed/refractory setting, with overall response rates varying from 28% to 75%. 14 , 15 , 16 Of note, the median patient age in these trials was 66–73 years old. These protocols have also showed efficacy in patients with unfavourable cytogenetics and TP53 mutation in the pre‐Bruton's tyrosine kinase inhibitor (BTKi) era. 17\n\nIn the current study, we present our results of R‐HDMP in an elderly, frail and mostly pre‐treated CLL patient population.\n\n2 PATIENTS AND METHODS\n\nWe retrospectively analysed 39 CLL/SLL patients treated with R‐HDMP from 2009 to 2018 in a Haematology and Bone Marrow Transplant Department of a tertiary hospital. CLL diagnosis was performed according with iwCLL guidelines: sustained lymphocytosis (>5000 lymphocytes/µL for more than 3 months) with immunophenotype positive for CD19, CD5, CD23 and CD20dim, with ƙ or ʎ light chain restriction. Bone marrow evaluation was performed in 82% of patients at diagnosis. Molecular characterisation of the disease was performed through fluorescence in situ hybridisation searching for del(13q), trisomy of chromosome 12, del(11q) and del(17p). Searching for TP53 mutations was not routinely performed by then, so that information was not included. Mutational status of immunoglobulin variable heavy chain (IgHV) gene was assessed in most patients. Data regarding the presence and degree of anaemia, thrombocytopenia, B symptoms, degree of lymphocytosis, level of lactate dehydrogenase (LDH), level of β2‐microglobulin and patients’ comorbidities at the time of treatment were collected from clinical registries. Cummulative Ilness Rating Scale (CIRS) was calculated considering patient's comorbidities. CLL diagnosis and medical conditions thought to be complications of CLL were not included as part of the total CIRS score. 18\n\nThe R‐HDMP treatment protocol consisted of rituximab 500 mg/m2 once weekly, IV, for 4 consecutive weeks, along with methylprednisolone 1 g/day, IV, 3 consecutive days every week for 4 consecutive weeks. Physician criteria for choosing this protocol over other therapies were older age, multiple comorbidities, lack of adherence to oral therapy or presence of auto‐immune haemolytic anaemia.\n\nAntimicrobial prophylaxis was given at the discretion of the investigator: all patients received prophylaxis with sulfamethoxazole‐trimethoprim; acyclovir and fluconazole prophylaxis were given to 30% and 25%, respectively. Granulocyte colony‐stimulating factor was only given on the event of grade IV neutropenia (less than 500 neutrophils/µl). Assessment of prognostic factors, imaging studies and routine laboratory tests were performed according to standard practice. Response to treatment was assessed according to iwCLL criteria, 3 months after end of treatment.\n\nThis study was conducted according to Helsinki declaration principles and under the approval of local Ethics Committee. All patients signed an informed consent before treatment.\n\n2.1 Statistical analysis\n\nDescriptive statistics were used to analyse patients’ characteristics, disease profile, response to treatment and toxicity profile. Differences between patients’ characteristics in frontline and relapsed/refractory setting were analysed through Pearson chi‐square and Mann–Whitney tests, for qualitative and quantitative variables, respectively. Time intervals were measured from the first day of treatment until progressive disease (PD), additional CLL treatment or death. Survival analysis was performed using the Kaplan–Meier method; differences in survival according to patients’ or disease characteristics were compared by log‐rank test. Independent predictors of progression or mortality were assessed by Cox regression univariate analysis. Multivariate analysis was not performed, given the absence of multiple significant prognostic predictors in univariate analysis. p < 0.05 was considered to be statistically significant. Statistical analysis was done using IBM® SPSS® Statistics version 25.\n\n3 RESULTS\n\n3.1 Patient characteristics\n\nThirty‐nine patients were included, 27 of whom were male (69.2%), median age at time of treatment was 77 years (inter‐quartile range [IQR]: 71–80 years). Most patients displayed highly unfavourable clinical and cytogenetic characteristics (Table 1). More than half (61.5%) had high‐risk (Rai III/IV and Binet C) disease. Median lymphocytosis was 45,390 cel/µL, with 18% patients with lymphocytosis between 50,000 and 100,000 cel/µl and 31% with lymphocytosis above 100,000cel/µl. At the time of treatment, 53.8% had multiple adenopathy, 18% had B symptoms, 36% had recurrent infections and 70% had cytopenias (61% with anaemia and 41% with thrombocytopenia). Haemoglobin (Hb) levels were below 10 g/dl in 53.8% of patients and below 8 g/dl in 18% of patients. Platelet count below 50,000 cel/µl in 20.5% of patients. Fourteen patients (36%) had auto‐immune haemolytic anaemia. LDH was evaluated in all patients, with median LDH of 530 U/L, IQR of 401–826 U/L (upper limit of normal of local laboratory: 250 U/L). β2‐microglobulin was evaluated in 28.2% of patients at time of treatment with R‐HDMP, with all patients having a value above the reference range (0.8–3.0 mg/L). Median β2‐microglobulin was 3.86 mg/L. Albumin was evaluated in 62% of patients: median albumin level was 3.85 g/dl (3.4–5.4 g/dl), with 32% of patients with albumin below de reference level. C‐reactive protein (CRP) was evaluated in 46% of patients at time of treatment, with half of patients having negative CRP. Median CRP of 0.7 mg/dl (reference range <0.5 mg/dl). Median CIRS (Cumulative Illness Rating Scale) was 5, with 41% of patients having CIRS ≥6. Twelve patients (30.8%) had chronic kidney disease KDIGO stage 3a or higher (creatinine clearance [CrCl] <60 ml/min/1.73 m2), 56% of patients had arterial hypertension, 10.3% had type II diabetes mellitus, 12.8% had dyslipidaemia, 17.9% had valvular or ischaemic cardiomyopathy, 10.3% had chronic obstructive pulmonary disease and 15.4% had psychiatric disorders. IgHV mutational status was assessed in 23 patients, 17 of whom (73.9%) had unmutated disease. FISH cytogenetic profile was studied in 35 patients, 11.4% of whom had del(17p), 22.9% del(11q), 28.6% had trisomy of chromosome 12 and 57.1% had del(13q). Twenty‐eight patients (71.8%) had relapsed/refractory (R/R) disease at time of treatment with a median of one previous line of therapy and a maximum of four. Patients’ characteristics were equally distributed between frontline and relapsed/refractory setting, except for the presence of recurrent infections, which were more common on the relapsed/refractory setting (p = 0.02) and for the median lymphocytosis, higher in frontline setting than in relapsed/refractory setting (median lymphocytosis of 108,740 cel/µl and 38,3400 cel/µl, respectively, p = 0.02). Most patients (53.8%) had prior exposure to fludarabine and 25% had prior exposure to rituximab.\n\nTABLE 1 Baseline characteristics; quantitative variables expressed as median/range and qualitative variables expresses as number/%\n\nBaseline characteristics\tN = 39\t\nGender\t\nMale\t27 (69.2)\t\nFemale\t12 (30.8)\t\nAge\t77 (70–81)\t\nRAI\t\n0\t1 (2.6)\t\n1\t3 (7.7)\t\n2\t8 (20.5)\t\n3\t19 (48.7)\t\n4\t5 (12.8)\t\nBINET\t\nA\t8 (20.5)\t\nB\t5 (18.8)\t\nC\t26 (61.5)\t\nCIRS\t\nMedian (min–max)\t5 (2–13)\t\nClCr (ml/min/1.73 m2)\t\n≥60\t27 (69.2%)\t\n<60\t12 (30.8%)\t\nCytogenetic profile (FISH)\tN = 35\t\ndel(17p)\t4 (11.4%)\t\ndel(11q)\t8 (22.9%)\t\ntriss 12\t10 (28.6%)\t\ndel(13q)\t20 (57.1%)\t\nNormal\t6 (17.14%)\t\nIgHV mutational status\tN = 23\t\nMutated\t6 (26.1%)\t\nUnmutated\t17 (73.9%)\t\nRelapsed/refractory disease\tN = 39\t\nYes\t28 (71.8%)\t\nNo\t11 (28.2%)\t\nPrevious lines of therapy\tN = 39\t\nMedian (min‐max)\t1 (0–4)\t\nPrior exposure to fludarabin\tN = 39\t\nYes\t21 (53.8%)\t\nNo\t18 (42.6%)\t\nJohn Wiley & Sons, Ltd\n\n3.2 Treatment plan\n\nThe scheduled treatment protocol was completed in 25 patients (64.1%), with five other (12.9%) completing at least three cycles. Three patients (7.7%) received more than four cycles (median of cycles: 4; range 1–8). Of the remaining 6 patients, 2 patients died during treatment, 2 patients completed 1 week of treatment with PD and data are missing regarding the number of cycles performed on two other patients. Nevertheless, on these last two, evaluation response was performed 3 months after the end of treatment. All patients received treatment in an outpatient setting.\n\n3.3 Toxicity\n\nGrade 3–4 neutropenia and thrombocytopenia were recorded in 4 (10.2%) and 7 (17.9%) patients, respectively. Twenty patients (51.3%) had documented infectious complications while on treatment (grade 3–4: 60%), but no other grade 3–4 non‐haematological toxicities were identified, namely metabolic decompensation, tumour lysis syndrome and steroid induced psychosis.\n\n3.4 Response to therapy\n\nOf the 35 patients with assessed response, overall response rate (ORR) was 64% (complete response [CR] = 17.9%, CR with incomplete bone marrow recovery [CRi] = 5.1%, partial response [PR] = 41%); 5.1% and 20.5% of patients had stable disease (SD) and PD, respectively. Of the four patients not evaluated for response, two died during treatment, one died 2 months after finishing treatment and one patient did not complete response assessment exams for reasons unrelated to medical condition (Table 2). Patients treated in relapsed setting had similar ORR compared with patients in frontline (ORR 64.4% vs ORR 66.6%, respectively; p = 0.741). Patients with AIHA had better ORR compared with the remaining patients, albeit without statistical significance (ORR 85.7% vs. ORR 54.5%, p = 0.118). Of the four patients with del(17p), three achieved a CR after four cycles of R‐HDMP (ORR 75%) and one patient had SD. Of the 35 patients with assessed response, median time to normal lymphocyte (<4500 cel/µl) and haemoglobin (Hb >12 g/dl) count was 16 days (IQR 13–36 days) and 23 days (14–51 days), respectively. Of the 16 patients with thrombocytopenia, only four achieved normal platelet count (minimum of 15 days and maximum of 62 days). Patients treated in relapsed setting had similar median time to haemoglobin and lymphocyte recovery, compared with frontline setting (p = 0.17 and p = 0.78, respectively).\n\nTABLE 2 Response to treatment; qualitative variables expresses as number/%\n\n\tN = 39\t\nOverall response rate\t64\t\nComplete remission\t7 (17.9)\t\nComplete remission with incomplete marrow recovery\t2 (5.1)\t\nPartial remission\t16 (41)\t\nStable disease\t2 (5.1)\t\nProgressive disease\t8 (20.5)\t\nNot assessed\t4 (10.3)\t\nJohn Wiley & Sons, Ltd\n\n3.5 Follow‐up\n\nMedian follow‐up was 30 months; median overall survival (OS) and progression‐free survival (PFS) were 24 and 13 months, respectively (Figure 1). Median time to next treatment was 13.5 months. For the patients treated in the frontline setting (nine patients), with a median follow‐up of 54 months, median OS and PFS were 54 months and 14 months, respectively (Figure 2). For the patients treated in the relapsed/refractory setting (28 patients), with a median follow‐up of 28 months, median OS and PFS were 22 months and 11.5 months, respectively. Nevertheless, differences between these data did not reach statistical significance (OS log rank test p = 0.23 and PFS log rank test p = 0.57).\n\nFIGURE 1 Overall (OS) and progression free survival (PFS) after R‐HDMP\n\nFIGURE 2 Overall (OS) and progression‐free survival (PFS) in the frontline setting\n\nTwenty‐four patients relapsed after R‐HDMP. Of these, 18 (75%) patients had been treated on a relapsed/refractory setting and six patients had been treated on frontline setting. Sixteen patients out of the 24 (66.7%) were treated with another line of therapy after R‐HDMP. Median age of this subgroup was significantly lower (72 years old, p = 0.04). No patient was retreated with R‐HDMP. Of note, 13 out of these 24 patients (54.2%) had its’ performance status improved at the time of second treatment after R‐HDMP and were subsequently considered fit for chemotherapy or chemo‐immunotherapy. Three other patients were treated with an anti‐CD52 monoclonal antibody or with BTKi. ORR to next line of treatment in this population was 62.6% (CR = 25%, CRi = 6.3%, PR = 31.3%), with 12.5% of SD and 18.8% of progressive disease. One patient was not evaluated. With a median follow‐up of 19.2 months, median OS‐2 and PFS‐2 were 21.4 and 13.5 months, respectively (Figure 3).\n\nFIGURE 3 Overall (OS‐2) and progression‐free survival‐2 (PFS‐2) after next line of treatment\n\nAs mentioned before, we also treated 14 patients with AIHA associated with progressive CLL, with an ORR of 85.7% (CR = 14.3%, PR = 71.4%, PD = 14.3%), obtaining a negative direct antiglobulin test after treatment in 43% of patients. Presence of AIHA was not a significant predictor of shorter OS or PFS (median OS 24 months vs. 24.1 months, respectively, p = 0.77; median PFS 10.8 months vs. 13.1 months, respectively, p = 0.67) (Figure 4).\n\nFIGURE 4 Overall survival (OS) according to the presence of autoimmune haemolytic anaemia\n\nOf the four patients with del(17p), none of them received another line of therapy after R‐HDMP. All of them were dead at last follow‐up: two of them died in complete remission and the other two died of progressive disease. Time to death (TTD) ranged from 10 to 85 months.\n\nRAI stage III/IV, age, IgHV mutational status, presence of del(17p), del(13q) or del(11q), CrCl <60 ml/min/1.73 m2 and relapsed/refractory disease were not significant predictors of shorter OS or PFS, by univariate analysis. Also, haemoglobin, platelet count, albumin, LDH and CRP levels at time of treatment were not predictors of shorter PFS or OS. Higher level of β2‐microglobulin was a predictor of shorter PFS (p = 0.024, HR 1.36, 95% CI 1.042–1.78) and OS (p = 0.018, HR 1.63, 95% CI 1.087–2.46) by cox regression univariate analysis.\n\nTwenty‐eight (71.8%) patients died. Of those, 21 (75%) were being treated on a relapsed/refractory setting. Ten patients (35.7%) died due to disease progression with a median TTD of 12 months (IQR: 2.8–24.5 months). Another 11 (39.3%) patients died due to CLL‐unrelated causes with a median TTD of 40 months (IQR: 14.2–57.2 months). Seven other patients (25%) died due to infection and, of these, two died during treatment, revealing a treatment‐related mortality of 7%, while the other five had a median TTD of 15.7 months (IQR: 5–40). Eleven patients were still alive at the last follow‐up analysis (January of 2019). Of those 11 patients still alive, seven were treated on a relapsed/refractory setting, and eight out of the 11 patients proceeded to another line of therapy after R‐HDMP.\n\n4 CONCLUSIONS/DISCUSSION\n\nWith R‐HDMP protocol, we treated a cohort of patients with highly unfavourable characteristics: median age of 77 years, more than 50% with cardiovascular disease and 30% with KDIGO stage 3 chronic kidney disease. Around 20% of patients had severe anaemia or thrombocytopenia at the time of treatment. Despite this profile, most patients completed the treatment plan, unfortunately with two deaths during treatment to declare. With this protocol, we achieved an ORR of 64%, similar in patients in frontline and relapsed/refractory setting. Also, this protocol allowed for a rapid disease control with median time for normal lymphocyte and haemoglobin count of less than 30 days. Surprisingly, thrombocytopenia was far more persistent after R‐HDMP than other cytopenias. Median OS reached 24 months and median PFS 13 months in a group of elderly, frail patients with numerous and severe comorbidities, with an unfavourable cytogenetic profile. The toxicity profile was acceptable with only infectious and haematologic grade 3–4 adverse events to declare. Around 30% had grade 3–4 infectious adverse events and around 15% had grade 3–4 cytopenias. This protocol also showed good efficacy in both frontline and relapsed/refractory setting, with an advantage on median OS of those treated in the frontline setting, albeit without statistical significance. Despite the small subgroup analysis, patients with del(17p) also achieved a good response, in accordance with previous publications. 17\n\nAfter R‐HDMP, more than half of the patients who relapsed were able to proceed to a next line of therapy, despite their advanced age and severe comorbidities. Most of them had their performance status improved at the time of next line of treatment, and were treated with chemotherapy or chemo‐immunotherapy protocols. In this setting, patients lived for a median of 21 months, 13 of them without relapse, with a median time to relapse of 13 months, which are very interesting results especially considering their baseline clinical and cytogenetic characteristics. In our sample, AIHA was not associated with shorter OS or PFS, in agreement with other studies. 6 Once again this highlights the importance of not considering AIHA as a negative prognostic factor.\n\nIn fact, the subgroup of patients with AIHA had a better ORR after R‐HDMP (ORR 85.7% vs. ORR 54.5%) with 43% of the patients achieving a negative direct antiglobulin test after treatment. This treatment proved to be a useful tool in controlling complex AIHA. This means that along with disease control, anaemia resolution was attained in most patients. On the other hand, these data may suggest that R‐HDMP can also be part of the treatment strategy of young and fit patients when a quick resolution of autoimmune and symptomatic anaemia is needed. Its rapid and effective disease control, as well as the rapid control of the autoimmune cytopenias, may lead to significant improvement in performance status. An improvement in performance status is many times a key factor to proceed to a more intensive regimen, allowing the patient to achieve a longer and deeper response. In this context, R‐HDMP may also work as a bridge to more intensive treatment protocols, when autoimmune cytopenias are a limiting factor.\n\nTwenty‐eight patients eventually died and most of them were being treated on a relapsed/refractory setting. Nevertheless, 39% of patients died due to CLL‐unrelated causes, with median TTD of 40 months.\n\nOur results were inferior to other similar studies, where ORR reached 96%, 17 75%, 14 and 78%. 16 However, Castro et al addressed only patients in the frontline setting, while most of our patients had relapsed/refractory disease. On the other hand, Šimkovič et al opted for a higher number of cycles (total of 8 cycles) and Bowen et al designed a protocol with a higher dose of steroids (methylprednisolone 1 g/m2 for 5 days). These details may justify the higher ORR but also some of the adverse events mentioned in these studies: steroid‐induced psychosis, severe metabolic decompensation in diabetic patients and the need for inpatient administration of the first cycle to prevent tumour lysis syndrome and severe acute kidney injury. Importantly, we did not observe any of these adverse events in our study. On the other hand, our rate of grade 3–4 infectious complications during treatment was higher than in some of these studies. We documented 31% of grade 3–4 infections while Castro et al 17 refer only 17%. However, Bowen et al 16 refer 29% of infectious adverse events, 14% of them grade 5. Similarly to our study, Šimkovič et al 14 report 27% of grade 3–4 infectious adverse events, even though they opted for a higher number of cycles. Of note, patient median age in these studies was 65, 66 and 67 years old, respectively, approximately 10 years younger than in our cohort, which argues in favour of our toxicity profile.\n\nIn 2019, Pileckyte et al 15 published their results on an old and frail population (median age of 73 years old) showing an ORR of only 28%, all PR. However, they showed a similar median PFS of 11 months and a greater median OS of 68 months, with a median follow‐up of 50 months. Their protocol aimed for 3 days of steroids (methylprednisolone 1 g/m2) and a higher dose of rituximab (1000 mg/m2). They only report 16% of grade 3–4 infectious adverse events and no deaths during treatment, in a patient cohort with characteristics similar to ours’.\n\nOn the specific setting of CLL plus AIHA, our results were similar to those presented by Mauro et al. This author presents 52 patients with CLL and AIHA who were treated either with steroids or with steroids plus chlorambucil, attaining 84% of response. The median age of their cohort was 69 years. Most patients (48) were treated with prednisolone and chlorambucil and only 4 were treated with prednisolone. However, they report a median time to relapse of 19 months, larger than in our cohort. 19\n\nR‐HDMP protocol is not a revolutionary option for CLL treatment, especially in an era where BTKi and Bcl‐2 inhibitors have entered broad clinical practice. However, one question remains: what is the best treatment for elderly, fragile patients, considering that most of them have severe comorbidities and are taking multiple medication? The burden of polypharmacy is thought to have many different dimensions, from an increased risk of serious adverse events, to dangerous drug interactions, lack of adherence and greater health care costs. 9 The economic advantage of BTKi has been proven even in the relapsed/refractory setting. 20 However, strict adherence to therapeutic schedule has been associated with longer survival and those who do not follow it strictly tend to be older. 21 A relevant topic is the report of 36% grade 3–4 infectious adverse events in patients with R/R CLL treated with a BTKi, despite being younger than the patients from our study. 22 On the other hand, long‐termed fixed therapy in older and comorbid patients has recently shown only 17.5% of grade 3–4 infections. 10 Nevertheless, these authors suggest a 2‐year long treatment protocol.\n\nR‐HDMP is not similar to targeted therapies in terms of efficacy, which means it cannot be presented as an alternative. Nevertheless, we find this protocol to be useful in this very specific subset of older and frail patients, concerning not only efficacy, but also tolerability, adherence to therapy and drug interactions. Also, in the current pandemic era, one might find an oral‐targeted therapy a considerable advantage comparing to an intravenous treatment. However, our daily practice let us know that patients on oral‐targeted therapies have to run through a period of very close observation, sometimes with twice a week consults. On this specific topic, a short duration treatment protocol, even if at in‐hospital setting may be an advantage to consider. Moreover, R‐HDMP is administered independently of patient adhesion to the treatment regimen, which is also an advantage on a cohort of elderly patients. Prospective studies would be needed to answer these specific questions in such a specific setting.\n\nThis study has some limitations as any retrospective analysis. The small number of patients allowed us to draw conclusions about our sample but makes it impossible to extrapolate the results to all CLL patients, and we recognise that the reproducibility of these data may be limited. In our analysis we included patients both in frontline and relapsed/refractory setting, and despite ORR and survival analysis was not significantly different, those data should be interpreted with caution. Also, the small number of patients may have biased the analysis of response and survival predictors, explaining why the well‐known negative prognostic factors (such as high‐risk disease, del17p, increasing age, unmutated IgHV gene) failed to predict worse outcomes in our sample. The heterogeneity of previous treatments as well as the heterogeneity of therapies administered after R‐HDMP may also have influenced the outcomes evaluated in this study. Besides, patient supportive care may also have differed from one physician to another, considering the antifungal and antiviral prophylaxis regimen, transfusion thresholds, and the decision for inpatient care. Nevertheless, these are real‐life results from real‐life patients above 70 years old, with end‐organ damage and severe comorbidities, who also need treatment and generally are not included in clinical trials.\n\nIn conclusion, based on our results, R‐HDMP may be useful in some particular clinical settings, where a rapid disease control is warranted in elderly and frail patients. We highlight 30% of severe infections, but low risk of severe myelotoxicity and other severe adverse events. It was shown to work as a bridge to other lines of treatment, including chemo‐immunotherapy. In an era of new drugs administered for long periods of time or even until progression, with a significant economic burden, drug interactions and adherence issues, this protocol offers a time‐limited out‐patient therapy, with few drug interactions. However, durable responses are rare, so further optimisations of this protocol should be attempted.\n\nCONFLICT OF INTEREST\n\nAna Vagos Mata has no conflict of interest to declare. Eduardo Espada has received consulting fees from MSD and honoraria form MSD, Pfizer and Roche. Daniela Alves has received occasional consulting fees for Janssen Cilag, Abbvie, Roche, Takeda, AstraZeneca and occasional speaker fees for Janssen Cilag, Abbvie, Roche, Takeda, Gilead Sciences. Blanca Polo has no conflict of interest to declare. Maria João Costa has no conflict of interest to declare. Conceição Lopes has no conflict of interest to declare. João F. Lacerda has no conflict of interest to declare. João Raposo has received occasional consulting fees for Janssen Cilag, Abbvie, Takeda, Merck Sharp & Dome, Gilead Sciences, AstraZeneca.\n\nETHICAL STATEMENT\n\nThis study was conducted according to Helsinki declaration principles and under the approval of local Ethics Committee. All patients signed an informed consent before treatment, according to local practice.\n\nDATA AVAILABILITY STATEMENT\n\nThe authors state every information on this manuscript is true and allow for data sharing. The data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 García‐Marco JA , Delgado J , Hernández‐Rivas JA , et al. Update of the Grupo Español de Leucemia Linfocítica Crónica clinical guidelines of the management of chronic lymphocytic leukemia. Med Clin. 2017;148 (8 ):381.e1‐381.e9. doi:10.1016/j.medcli.2016.12.030\n2 Hallek M , Cheson BD , Catovsky D , et al. iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL. Blood. 2018;131 (25 ):2745‐2760. doi:10.1182/blood-2017-09-806398 29540348\n3 Hodgson K , Ferrer G , Montserrat E , Moreno C . Chronic lymphocytic leukemia and autoimmunity: a systematic review. Haematologica. 2011;96 (5 ):752‐761. doi:10.3324/haematol.2010.036152 21242190\n4 Fattizzo B , Barcellini W . Autoimmune cytopenias in chronic lymphocytic leukemia: focus on molecular aspects. Frontiers in Oncology. 2020;9 :1‐14. doi:10.3389/fonc.2019.01435\n5 Zent CS , Shanafelt T . Management of autoimmune cytopenia complicating chronic lymphocytic leukemia. Leuk Lymphoma. 2009;50 (6 ):863‐864. doi:10.1080/10428190902919226 19455465\n6 Zent CS , Ding W , Schwager SM , et al. The prognostic significance of cytopenia in chronic lymphocytic leukaemia/small lymphocytic lymphoma. Br J Haematol. 2008;141 (5 ):615‐621. doi:10.1111/j.1365-2141.2008.07086.x 18373706\n7 Zent CS , Kay NE . Autoimmune complications in chronic lymphocytic leukaemia (CLL). Best Pract Res. 2010;23 (1 ):47‐59. doi:10.1016/j.beha.2010.01.004\n8 Hallek M . Chronic lymphocytic leukemia: 2020 update on diagnosis, risk stratification and treatment. Am J Hematol. 2019;94 (11 ):1266‐1287. doi:10.1002/ajh.25595 31364186\n9 Maher RL , Hanlon J , Hajjar ER . Clinical consequences of polypharmacy in elderly. Expert Opin Drug Saf. 2014;13 :(1 ):57‐65. doi: 10.1517/14740338.2013.827660 24073682\n10 Fischer K , Al‐Sawaf O , Bahlo J , et al. Venetoclax and obinutuzumab in patients with CLL and coexisting conditions. N Engl J Med. 2019;380 (23 ):2225‐2236. doi:10.1056/nejmoa1815281 31166681\n11 Cao Z , Ma J . Efficacy and safety of ibrutinib in elderly patients with chronic lymphocytic leukemia. Blood. 2019;134 (Suppl._1 ):5478. doi:10.1182/blood-2019-126686\n12 Stauder R , Eichhorst B , Hamaker ME , et al. Management of chronic lymphocytic leukemia (CLL) in the elderly: a position paper from an international Society of Geriatric Oncology (SIOG) Task Force. Ann Oncol. 2017;28 (2 ):218‐227. doi:10.1093/annonc/mdw547 27803007\n13 Thornton PD , Hamblin M , Treleaven JG , Matutes E , Lakhani AK , Catovsky D . High dose methyl prednisolone in refractory chronic lymphocytic leukaemia. Leuk Lymphoma. 1999;34 (1–2 ):167‐170. doi:10.3109/10428199909083393.10350345\n14 Šimkovič M , Motyčková M , Belada D , et al. Five years of experience with rituximab plus high‐dose dexamethasone for relapsed/refractory chronic lymphocytic leukemia. Arch Med Sci. 2016;12 (2 ):421‐427. doi:10.5114/aoms.2016.55425 27186190\n15 Pileckyte R , Valceckiene V , Stoskus M , et al. Dose intensive rituximab and high‐dose methylprednisolone in elderly or unfit patients with relapsed chronic lymphocytic leukemia. Medicina (Kaunas, Lithuania). 2019;55 (11 ):1‐10. doi:10.3390/medicina55110719\n16 Bowen DA , Call TG , Jenkins GD , et al. Methylprednisolone‐rituximab is an effective salvage therapy for patients with relapsed chronic lymphocytic leukemia including those with unfavorable cytogenetic features. Leuk Lymphoma. 2007;48 (12 ):2412‐2417. doi:10.1080/10428190701724801.18067017\n17 Castro JE , James DF , Sandoval‐Sus JD , et al. Rituximab in combination with high‐dose methylprednisolone for the treatment of chronic lymphocytic leukemia. Leukemia. 2009;23 (10 ):1779‐1789. doi:10.1038/leu.2009.133.19693094\n18 Gordon MJ , Churnetski M , Alqahtani H , et al. Comorbidities predict inferior outcomes in chronic lymphocytic leukemia treated with ibrutinib. Cancer. 2018;124 (15 ):3192‐3200. doi:10.1002/cncr.31554.29797667\n19 Mauro FR , Foa R , Cerretti R , et al. Autoimmune hemolytic anemia in chronic lymphocytic leukemia: clinical, therapeutic, and prognostic features. Blood. 2000;95 (9 ):2786‐2792. doi:10.1182/blood.v95.9.2786.009k30_2786_2792.10779422\n20 Sorensen SV , Peng S , Dorman E , et al. The cost‐effectiveness of ibrutinib in treatment of relapsed or refractory chronic lymphocytic leukemia. Health Econ Outcome Res. 2016;2 . doi:10.4172/2471-268x.1000121\n21 Barr PM , Brown JR , Hillmen P , et al. Impact of ibrutinib dose adherence on therapeutic efficacy in patients with previously treated CLL/SLL. Blood. 2017;129 (19 ):2612‐2615. doi:10.1182/blood-2016-12-737346 28373262\n22 Munir T , Brown JR , O'Brien S , et al. Final analysis from RESONATE: up to six years of follow‐up on ibrutinib in patients with previously treated chronic lymphocytic leukemia or small lymphocytic lymphoma. Am J Hematol. 2019;94 (12 ):1353‐1363. doi:10.1002/ajh.25638 31512258\n\n",
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"keywords": "auto-immune haemolytic anaemia; chronic lymphocytic leukaemia; high-dose methylprednisolone; rituximab",
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"title": "Chronic lymphocytic leukaemia/small lymphocytic lymphoma treatment with rituximab and high-dose methylprednisolone, revisited.",
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"abstract": "The last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.\n\n\n\nWe report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung's deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.\n\n\n\nThis case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.",
"affiliations": "Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia.;Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia.;Division of Clinical Immunology and Rheumatology, Department of Pediatrics, Sestre milosrdnice University Hospital Center, Zagreb, Croatia.;Department of Diagnostic and Interventional Radiology, Sestre milosrdnice University Hospital Center, University of Zagreb, Zagreb, Croatia.;Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia.;Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia. lovro.lamot@gmail.com.",
"authors": "Vukić|Vana|V|;Smajo|Ana|A|;Vidović|Mandica|M|;Vukojević|Rudolf|R|;Harjaček|Miroslav|M|;Lamot|Lovro|L|",
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"fulltext": "\n==== Front\nBMC Pediatr\nBMC Pediatr\nBMC Pediatrics\n1471-2431 BioMed Central London \n\n2494\n10.1186/s12887-021-02494-6\nCase Report\nBeyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome\nVukić Vana 1 Smajo Ana 1 Vidović Mandica 2 Vukojević Rudolf 3 Harjaček Miroslav 12 Lamot Lovro lovro.lamot@gmail.com 12 1 grid.4808.40000 0001 0657 4636Department of Pediatrics, University of Zagreb School of Medicine, Zagreb, Croatia \n2 grid.412488.30000 0000 9336 4196Division of Clinical Immunology and Rheumatology, Department of Pediatrics, Sestre milosrdnice University Hospital Center, Zagreb, Croatia \n3 grid.4808.40000 0001 0657 4636Department of Diagnostic and Interventional Radiology, Sestre milosrdnice University Hospital Center, University of Zagreb, Zagreb, Croatia \n15 1 2021 \n15 1 2021 \n2021 \n21 407 9 2020 5 1 2021 © The Author(s) 2021Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background\nThe last two decades brought new treatment options and high quality guidelines into the paediatric rheumatologic practice. Nevertheless, a number of patients still present a diagnostic and therapeutic challenge due to combination of vague symptoms and unresponsiveness to available treatment modalities.\n\nCase presentation\nWe report a case of sixteen years old girl suffering from polyarticular type of juvenile idiopathic arthritis refractory to multiple treatment options. She first presented at the age of 4 with swelling and contractures of both knees. Her symptoms were initially unresponsive to nonsteroidal anti-inflammatory drugs and progressed despite treatment with intraarticular and systemic glucocorticoids and methotrexate. Throughout the years, she received several biologics together with continuous administration of nonsteroidal anti-inflammatory drugs and disease modifying anti-rheumatic drugs as well as intraarticular and systemic glucocorticoids in disease flares. However, none of this options provided a permanent remission, so various other modalities, as well as other possible diagnoses were constantly being considered. Eventually she became dependent on a daily dose of systemic glucocorticoids. In 2018, the treatment with Janus kinase inhibitor tofacitinib was initiated, which led to gradual amelioration of musculoskeletal symptoms, improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic glucocorticoids. As the swelling of the wrists subsided for the first time in many years, Madelung’s deformity was noticed, first clinically, and later radiographically as well. Genetic analysis revealed short-stature homeobox gene deficiency and confirmed the diagnosis of Leri Weill syndrome.\n\nConclusions\nThis case report emphasizes the need for reporting refractory, complicated cases from everyday clinical practice in order to build-up the overall knowledge and share experience which is complementary to available guidelines. Individual reports of difficult to treat cases, especially when additional diagnoses are involved, can be helpful for physicians treating patients with common rheumatological diseases such as juvenile idiopathic arthritis.\n\nKeywords\nCase reportJuvenile idiopathic arthritisLeri Weill syndromeMadelung deformityTofacitinib.issue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\nJoint pain and/or swelling with limited range of motion is a common manifestation of many paediatric diseases, most notably wide range of rheumatic conditions. If both of these symptoms are present for longer than 6 weeks in a patient younger than 16 years of age, a diagnosis of juvenile idiopathic arthritis (JIA), the most common childhood rheumatic disease, should be considered [1]. JIA is heterogenous disease that encompasses different subtypes of childhood arthritis defined depending on the number of affected joints and/or presence of the enthesitis and/or sacroiliitis. Nevertheless, alongside JIA, there is a wide range of loosely related noninflammatory causes of a swollen joint in children, especially in the absence of clinical signs of inflammation. Lysosomal storage diseases (LSD) such as mucopolysaccharidosis type I (MPS I), Gaucher disease type I and Fabry disease all have prominent musculoskeletal symptoms early in the course of the disease, and are often first seen by a pediatric rheumatologist [2–8]. However, the underlying mechanism of those disorders does not directly involve the immune mediated inflammatory response, but rather an inflammation caused by genetic defects and subsequent perturbations at the protein level. More specifically, in Gaucher disease, bone marrow infiltration with histiocytes causes acute attacks of pain, which may be mistaken for arthritis in the vicinity of a joint [5, 8]. In Fabry disease, episodes of neuropathic pain in hands, feet, wrists, ankles (acroparesthesias), often associated with fever, malaise and elevated inflammation markers, can mimic a rheumatic condition, such as an inflammatory arthritis [3, 9]. Finally, joint stiffness and contractures are characteristic for some types of MPS, the so called „attenuated“ forms like Hurler-Scheie syndrome, which have a less severe presentation and progress silently over the years, making the diagnosis a challenge [3, 10, 11]. On the other hand, some congenital conditions, such as Madelung and Madelung-type deformities resulting from the premature closure of the medial volar aspect of the distal radial physis, might cause similar symptoms [12]. Hence, it is not a rarity that some of the children with LSD and congenital deformities are treated for prolonged periods of time as having an inflammatory arthritis, despite the lack of appropriate response [13].\n\nWith regard to the treatment of JIA, various modalities emerged over the last two decades, revolutionizing the pediatric rheumatology practice [14]. Majority of the presently available guidelines recommend a step-up approach, starting with nonsteroidal anti-inflammatory drugs (NSAID) and intraarticular glucocorticoid injections (IAGI), followed by conventional and biologic disease modifying anti-rheumatic drugs (cDMARD and bDMARD), respectively [15]. Moreover, despite many known adverse effects, systemic glucocorticoids (GC) are still being used as an important therapeutic option for wide range of complications associated with JIA (e.g., macrophage activation syndrome, myocarditis, pericarditis, pleuritis, peritonitis, uveitis and severe anaemia), as well as a bridge therapy in severe forms of JIA before the full effect of other treatment modalities has been achieved [16]. Those modalities nowadays primarily involve tumor necrosis factor alpha (TNFα) inhibitors (TNFi), such as etanercept, adalimumab and infliximab, and non-TNFi, such as anti-interleukin-6 (anti-IL-6) agent tocilizumab and a selective T-cell co-stimulation modulator abatacept [17, 18]. Furthermore, new medications are continuously being investigated [19, 20].\n\nTogether with the expansion of new treatment modalities, efforts have been made to introduce the treat-to-target (T2T) model in pediatric rheumatologic practice [21]. Signs and symptoms control, prevention of structural damage of joints and optimization of linear growth and pubertal development, as well as abolition of inflammation, have all been set as treatment goals. Essentially, this model advocates that therapy should be revised and adjusted based on regular disease activity assessments to reach and maintain the treatment target. Special attention should be paid to preventing or minimizing the side effects of systemic GC given their negative effect on growth and pubertal development. Consequently, their long-term use to maintain treatment target should be avoided, especially considering that GC dependence demonstrates the inadequacy of chosen treatment. The shared decision making, as well as multidisciplinary approach, have been recognized as exceptionally valuable for assurance of better adherence to treatment and subsequently improvement of outcome and overall prognosis.\n\nUnfortunately, despite all these achievements, only 14 % of patients with rheumatoid factor (RF) negative and 0 % with RF positive polyarticular JIA achieves the remission off medications within five years, implying that JIA treatment requires a long-lasting commitment [22]. Hence, it comes as no surprise that every clinician involved in the care of children with JIA patients eventually sees one with disease not responding to acclaimed treatment options (i.e. NSAIDs, cDMARDS, bDMARDS) [15]. At that point, the consideration of additional treatment modalities seems like a valid course of action, but sometimes alternative diagnosis should be considered as well. Here, we present one such case, a girl with long standing polyarticular JIA refractory to many standard treatment modalities, with symptoms suggestive of other diseases.\n\nCase presentation\nA four-year-old first came to our attention in February 2008 due to painful swelling and contractures of both knees. Her symptoms started a year earlier and were not associated with any discernible trigger such as infection or trauma. Moreover, the symptoms were not responding to NSAIDs and she soon developed a severe morning stiffness lasting for up to three hours. Her birth history as well as psychomotor development prior to disease evolution was unremarkable. She was born as a first child into a family of non-consanguine parents, with no relatives having the similar symptoms.\n\nThe initial laboratory findings showed persistently elevated inflammatory markers (erythrocyte sedimentation rate (ESR) up to 100 mm/h and C-reactive protein (CRP) up to 100 mg/dL), with negative RF and antinuclear antibody (ANA) screen, and normal immunoglobulin levels. Despite the initial treatment with GC and methotrexate (MTX), her symptoms progressed affecting elbows, wrists, ankles and small joints of both hands. Moreover, she developed a severe uveitis of the left eye. In November 2008 biologic therapy with infliximab was started, with initially good response. Unfortunately, this lasted only for a few months and frequent relapses necessitated switching to adalimumab in April 2011. Again, there was an initial period of remission followed by progressive exacerbation characterized by swelling and pain in some joints, and persistent contracture of others. Other diagnosis, such as mucopolysaccharidosis and systemic lupus erythematosus (SLE) were suspected, but metabolic and immunological screening were negative, respectively. Beside ESR and CRP, the increased values of IL-6 (up to 75 pg/mL) and TNF-alfa (up to 20 pg/mL) were measured.\n\nIn November 2012 therapy was cycled to non-TNFi, tocilizumab, which led only to a short period of remission. Finally, in September 2014, etanercept was introduced, again with the lack of permanent response. Along with four different bDMARDs she continuously received cDMARD methotrexate, and for a short period of time leflunomide. During the periods of disease flare, bridge therapy with intraarticular and/or systemic GC was used, and soon she was dependent on a daily dose of GC. Eventually, this led to the development of iatrogenic Cushing syndrome with characteristic appearance, growth retardation and low bone mineral density, regardless of the vitamin D and ibandronic acid therapy. Since every attempt to wean off GC inevitably led to disease flare, from June to December 2016 she received cyclophosphamide (6x) and rituximab (3x), again without achieving a sustained remission. Afterwards, for a short period of time she was given metformin but without an appropriate improvement in musculoskeletal symptoms (Fig. 1).\nFig. 1 Schematic representation of treatment modalities during the time. 2007 – 2020 - the period of treatment, NSAID - nonsteroidal anti-inflammatory drug, IFX - infliximab, ADA - adalimumab, TOC - tocilizumab, ETC - etanercept, DMARD - disease modifying anti-rheumatic drug, MTX - methotrexate, CFM - cyclophosphamide, RTX - rituximab, MTF - metformin, MMF - mycophenolate mofetil, CYC - cyclosporine, TFA - tofacitinib, p.o. - per os, i.a. - intraarticular, i.v. - intravenous, GC - glucocorticoids\n\n\n\nDuring the 2017, at the age of 13, the trial of mycophenolate mofetil (MMF) followed by the trial of cyclosporin was initiated, but the patient nevertheless remained GC dependent. Both shoulders, elbows, radiocarpal joints, metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP) joints and both knees had restricted range of movement, and repeated IAGI were necessary to alleviate the symptoms. Finally, in 2018, the treatment with Janus kinase (JAK) inhibitor tofacitinib was initiated, which lead to gradual amelioration of musculoskeletal symptoms and improvement of inflammatory markers and overall well-being, as well as to the weaning of systemic GC. Moreover, as the swelling of the wrists subsided for the first time in many years, Madelung deformity was noticed by clinical examination. Interestingly, it was only then, in 2019, that the deformity was for the first time described on x-ray (Fig. 2), although x-ray and MRI imaging of both hands were previously performed on many occasions in order to assess the inflammation (Figs. 3 and 4). Nevertheless, subsequent analysis by experienced musculoskeletal radiologist revealed characteristic bilateral signs of Madelung deformity dating back in 2015 and 2017 (Fig. 3), with the MRI showing the Vickers and radiotriquetral ligament (Fig. 4). The finding of those two ligaments allowed the distinguishing between Madelung deformity and pseudo-Madelung deformity, which includes post-traumatic and post-infective forms, forms associated with Turner syndrome, multiple hereditary exostoses and Ollier disease [23]. Unfortunately, due to the parent’s refusal, no further radiological assessment was performed, so we have not documented the other important aspects of Madelung deformity, such as radial shortening and diaphysis bowing, nor the mesolimbic shortening of limbs characteristic for Leri Weill syndrome.\nFig. 2 The anteroposterior radiograph of left hand at the age of 14. Note the increased volar angulation of distal radius, wedge shaped carpus with proximally positioned lunate and a characteristic notch on the distal radius (white arrow), which are the features of the Madelung deformity [12]\n\nFig. 3 The anteroposterior radiograph of both hands at the age of 10 (a) and 13 (b), and of the left hand at the age of 14 (c). Note the bowing of the distal radius, an increased radial inclination (~ 30°) with the deformation of the carpus that acquired a triangular appearance and widening of the distal radial-ulnar joint bilaterally, which are the typical features of Madelung deformity. Dorsal subluxation of the ulnar head is not seen as lateral images of the wrist were not taken. Osteopenia of carpal bones and periarticular osteopenia of MCP, PIP and DIP joints related to JIA are present. No relevant changes are observed during the time\n\nFig. 4 MRI coronal T1-weighted (a), proton density BLADE fluid sensitive sequence (b), post contrast T1-weighted coronal fat sat sequence (c) and post contrast T1-weighted axial fat sat sequence (d) images of both hands at the age of 13. Note the radiotriquetral ligament (red arrow) and Vickers ligament (green arrow) (a, b). Note the inflammatory changes characterized by postcontrast imbibition in carpal joints and MCP joints (red circle), as well as tenosynovitis of flexor tendons related to JIA, more prominent on the left hand (c, d)\n\n\n\nAlthough our patient was simultaneously followed by pediatric endocrinologist from age of 11, her short stature, along with delayed menarche, and Cushingoid appearance, was attributed to the prolonged use of GC. It was only after the Madelung’s deformity was observed that genetic causes, primarily Leri Weill syndrome, were taken into consideration. Genetic analysis was performed by commercially available SALSA MLPA Probemix P018 SHOX (MRC-Holland, Amsterdam, The Netherland) according to the manufacturer’s recommendations. The MLPA mix included probes for each exon of SHOX, one probe just before the promoter region as well as probes covering a region downstream of the gene. The results revealed one copy of sixteen probes (10 probes for Xp22-PAR1 from CNE2 to CNE9, 4 probes for SHOX area downstream, 1 probe for CRLF2 in PAR1 region and 1 probe for CSF2RA in PAR1 region), with the size of the smallest deletion of 766,5 kb. Based on the genetic testing and imaging findings of Madelung deformity, the diagnosis of Leri Weill syndrome was established, and parents were advised to undergo further genetic testing of both the patient and themselves, which they rejected.\n\nCurrently, our patient has many consequences of the adverse course of the disease and prolonged GC treatment, such as joint contractures of elbows, wrists, DIPs, PIPs, hips, knees and MCPs and low bone density, respectively. She developed secondary sex characteristics only after the therapy with estradiol was initiated at the age of 14. Nevertheless, after the discontinuation of GC and subsequent discontinuation of estradiol, she finally had a menarche at the age of 15, along with a long-awaited growth spurt.\n\nDiscussion and Conclusion\nChildren with rheumatic diseases, their families, as well as their treating physicians are dealt with numerous issues and dilemmas regarding either the disease itself or ongoing treatment modalities. Besides, the diagnosis of rheumatic diseases in children is regularly made by excluding wide range of other diseases, with no pathognomonic tests and/or criteria. Therefore, even after the classification criteria are fulfilled, the diagnosis should be revised if new symptoms emerge or if the recommended treatment options are failing.\n\nIn our patient, a variety of steroid-sparing agents with different mechanisms of action have been employed with limited or no clinical success. Some of these agents were used in line with current treatment recommendations, but many were used based on anecdotal reports [24–28]. Finally, due to signs of systemic inflammation characterized by increased inflammatory markers (CRP and ESR) and cytokines (IL-6 and TNF-alfa), which is indicative for the activation of JAK/STAT pathway, treatment with tofacitinib, a first generation JAK inhibitor, was initiated with a good clinical response. Several clinical trials in adults with rheumatoid and psoriatic arthritis have given solid evidence about the use of tofacitinib, while the results of a phase 3 randomized double blind placebo controlled withdrawal study in patients with polyarticular JIA showed improvement in symptoms, less disease flares and improved functional ability, together with a clinical amelioration of disease activity [29, 30]. Moreover, tofacitinib is an oral agent, and the challenge of using biologics requiring injection or infusion for an extended length of time, especially in children, should not be overlooked.\n\nAlong with the various treatment modalities, the different diagnosis was constantly being considered in our patient. Firstly, due to persistent contracture in some joints with little or no signs of swelling, LSDs such as mucopolysaccharidosis type I, Gaucher disease type I and Fabry disease were investigated. Besides, other inflammatory causes like systemic lupus erythematosus were also excluded. Lastly, the diagnosis of Leri Weill syndrome characterized by deletions in SHOX gene and Madelung deformity was established. This painful deformity of the wrist was first described in 1878 by the German surgeon Otto Madelung in adolescents between the ages 8 and 14 [12]. Although initially asymptomatic, the patients often went on to develop pain, loss of grip strength and reduced mobility, which were the symptoms present in our patient even after the inflammation was tackled with tofacitinib. Moreover, the features of Leri Weill syndrome include the short stature, which was also one of the dominant finding in the presented patient. Yet, the growth deficit caused by SHOX haploinsufficiency in Leri Weill syndrome is around 2 standard deviation scores (SDS) [31], while our patient had a SDS of -5,5. Besides, due to a prolonged use of GC, our patient had a full blown Cushingoid appearance, low bone density, delayed puberty and growth retardation. Therefore, the possible explanation for the short stature and growth delay in our patient includes multifactorial aetiology. Firstly, it is well known that extended GC treatment leads to a defect in bone turnover (and formation) due to impaired osteoblastogenesis and osteoclastogenesis, and may have direct effects on the growth plate [32]. Additionally, higher prepubertal glucocorticoid level appears to delay early and late pubertal timing of healthy girls, particularly the onset of pubertal growth spurt and menarche [33]. Moreover, it has been shown that girls with polyarticular juvenile idiopathic arthritis are significantly more likely to present with short stature even 6 months after stopping the steroid therapy [34]. Finally, the product of SHOX gene is implicated in bone development and regulation of chondrocyte differentiation, which clarifies the association of SHOX gene haploinsufficiency with idiopathic short stature, as well as short stature in Turner syndrome and Leri Weill dyschondrosteosis [31].\n\nIn the presented case, the diagnosis of the Madelung deformity and Leri Weill syndrome was delayed due to the concomitant active inflammation caused by JIA taking the focus from other possible causes of pain in the wrists. However, as subsequent analysis by experienced musculoskeletal radiologist has shown, the characteristic signs of the Madelung deformity were present few years before the final diagnosis was reached, emphasizing once again the importance of multidisciplinary approach and close collaboration of many subspecialists in the care of children with rheumatic diseases. Nevertheless, this lag probably did not influence the therapeutic management in our particular patient; although positive effect on final height was observed with growth hormone therapy in patients with Leri Weill syndrome, due to the matching influence of GC and lack of agreement with her parents, this treatment option was avoided in our patient [35].\n\nIn conclusion, this case report emphasizes the difficulties and challenges in management of patient with long-standing polyarticular JIA refractory to wide range of treatment modalities. Although many high-quality guidelines are available for treatment of JIA patients, there is still need for individual reports of difficult to treat cases, especially when additional diagnosis are involved. While Leri Weill syndrome is extensively reported in the literature, to the best of our knowledge, our case report describes it for the first time along with JIA. Taking all these into account, we strongly encourage the aggregation of similar patients and establishment of the common ground that will help clinician to decide upon the introduction of treatment options outside of the contemporary guidelines.\n\nAbbreviations\nJIAJuvenile idiopathic arthritis\n\nLSDLysosomal storage disease\n\nMPSMucopolysaccharidosis\n\nNSAIDNonsteroidal anti-inflammatory drug\n\ncDMARDConventional disease modifying anti-rheumatic drug\n\nbDMARDBiologic disease modifying anti-rheumatic drug\n\nIAGIIntraarticular glucocorticoid injection\n\nGCGlucocorticoids\n\nMASMacrophage activation syndrome\n\nTNFiTumor necrosis factor inhibitor\n\nT2TTreat-to-target\n\nRFRheumatoid factor\n\nESRErythrocyte sedimentation rate\n\nCRPC-reactive protein\n\nANAAntinuclear antibody\n\nMTXMethotrexate\n\nSLESystemic lupus erythematosus\n\nTNFαTumor necrosis factor alpha\n\nanti-IL-6Anti-interleukin-6\n\nMMFMycophenolate mofetil\n\nMCPMetacarpophalangeal\n\nPIPProximal interphalangeal\n\nDIPDistal interphalangeal\n\nJAKJanus kinase\n\nMRIMagnetic resonance imaging\n\nSHOXShort-stature homeobox\n\nJAK/STATJanus kinase/signal transducer and activator of transcription proteins\n\nSDSStandard deviation score\n\nGnRHGonadotropin-releasing hormone\n\nHPGHypothalamic-pituitary-gonadal\n\nIFXInfliximab\n\nADAAdalimumab\n\nTOCTocilizumab\n\nETCEtanercept\n\nCFMCyclophosphamide\n\nRTXRituximab\n\nMTFMetformin\n\nCYCCyclosporine\n\nTFATofacitinib\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nAcknowledgements\nWe thank parents for availability of publishing medical history of their daughter.\n\nAuthors’ contributions\nVV and AS have equally contributed to the paper. VV: medical charts review, literature search, creation of figures and tables and manuscript draft preparation. AS: medical charts review, literature search, creation of figures and tables and manuscript draft preparation RV: radiographic images interpretation, manuscript draft preparation. MV: clinical care and the final revision of the manuscript. MH: clinical care and the final revision of the manuscript. LL: clinical care, medical charts review, literature search, creation of figures and tables, manuscript draft preparation, final revision of the manuscript. All authors read and approved the final manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nData sharing is not applicable to this article as no datasets were generated or analysed during the current study. / Not applicable.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the parents for publication of this case report and any accompanying images.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n==== Refs\nReferences\n1. Prakken B Albani S Martini A Juvenile idiopathic arthritis Lancet 2011 377 2138 49 10.1016/S0140-6736(11)60244-4 21684384 \n2. Manger B Mengel E Schaefer RM Rheumatologic aspects of lysosomal storage diseases Clin Rheumatol 2007 26 335 41 10.1007/s10067-006-0299-x 16680390 \n3. Paira SO Roverano S Iribas JL Barceló HA Joint manifestations of Fabry’s disease Clin Rheumatol 1992 11 562 5 10.1007/BF02283120 1486752 \n4. Rosa Neto NS Bento JCDB Pereira RMR Higher rate of rheumatic manifestations and delay in diagnosis in Brazilian Fabry disease patients Adv Rheumatol 2020 60 1 8 10.1186/s42358-019-0111-7 \n5. Michels H Mengel E Lysosomal storage diseases as differential diagnoses to rheumatic disorders Curr Opin Rheumatol 2008 20 76 81 10.1097/BOR.0b013e3282f169fe 18281861 \n6. Politei J Remondino G Heguilen R Wallace E Durand C Schenone A When arthralgia is not arthritis Eur J Rheumatol 2017 3 182 4 10.5152/eurjrheum.2016.15073 \n7. Mahoney D. Lysosomal Storage Disorders: Awareness, Early Action Are Key. Rheumatol News. 7:17. doi:10.1016/S1541-9800(08)70584-2.\n8. James RA Singh-Grewal D Lee SJ McGill J Adib N Lysosomal storage disorders: A review of the musculoskeletal features J Paediatr Child Health 2016 52 262 71 10.1111/jpc.13122 27124840 \n9. Moiseev S Karovaikina E Novikov PI Ismailova D Moiseev A Bulanov N What rheumatologist should know about Fabry disease Ann Rheum Dis 2019 79 6 7 \n10. 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A, Received: Juvenile Idiopathic Arthritis: Diagnosis and Treatment Rheumatol Ther 2016 3 187 207 10.1007/s40744-016-0040-4 27747582 \n15. Ringold S Angeles-Han ST Beukelman T Lovell D Cuello CA Becker ML 2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis Arthritis Care Res 2019 71 717 34 10.1002/acr.23870 \n16. Batu ED Glucocorticoid treatment in juvenile idiopathic arthritis Rheumatol Int 2019 39 13 27 10.1007/s00296-018-4168-0 30276425 \n17. Giancane G Alongi A Rosina S Tibaldi J Consolaro A Ravelli A Recent therapeutic advances in juvenile idiopathic arthritis Best Pract Res Clin Rheumatol 2017 31 476 87 10.1016/j.berh.2018.01.001 29773268 \n18. Blazina Š Markelj G Avramovič MZ Toplak N Avčin T Management of Juvenile Idiopathic Arthritis: A Clinical Guide Pediatr Drugs 2016 18 397 412 10.1007/s40272-016-0186-0 \n19. 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Radiotriquetral Ligament in Madelung’s Deformity Associated with Leri-Weill’s Dyschondrosteosis. Cureus. 2020;12.\n24. Sakamoto AP Pinheiro MM Barbosa CMPL Fraga MM Len CA Terreri MT Uso de rituximabe em adultos jovens com diagnóstico de artrite idiopática juvenil refratária ao tratamento convencional: relato de 6 casos Rev Bras Reumatol 2015 55 536 41 10.1016/j.rbr.2014.12.015 26066294 \n25. Berrada K Abourazzak FE Mezouar I El, Lazrak F Aradoini N Tahiri L A successful treatment of juvenile idiopathic arthritis with rituximab: A report of two cases Eur J Rheumatol 2014 1 164 6 10.5152/eurjrheumatol.2014.140049 27708906 \n26. Monteiro de Castro TC Terreri MT Len C Esteves Hilário MO Treatment of refractory juvenile idiopathic arthritis via pulse therapy using methylprednisolone and cyclophosphamide Sao Paulo Med J 2003 121 117 20 10.1590/S1516-31802003000300006 12920473 \n27. Ishikawa S, Tasaki M, Kuroda T, Kobayashi D, Saito K, Nakagawa Y, et al. Management of Juvenile Idiopathic Arthritis in ABO-incompatible Kidney Transplantation: A Case Report. Transplant Proc. 2018;50:869–72. doi:10.1016/j.transproceed.2017.12.052.\n28. Semo Oz R Tesher MS Arthritis in children with LRBA deficiency - Case report and literature review Pediatr Rheumatol 2019 17 1 6 10.1186/s12969-019-0388-4 \n29. Kerrigan SA, Mcinnes IB. JAK Inhibitors in Rheumatology: Implications for Paediatric Syndromes ? 2018;:1–9.\n30. Brunner HI. Tofacitinib for the treatment of polyarticular course juvenile idiopathic arthritis: results of a Phase 3 randomized, double-blind, placebo-controlled withdrawal study Disclosures (continued). 2019;:1–14.\n31. Leka SK, Kitsiou-tzeli S, Kalpini-mavrou A, Kanavakis E. Short stature and dysmorphology associated with defects in the SHOX gene. 2006;5:107–18.\n32. Weinstein RS Jilka RL Michael Parfitt A Manolagas SC Inhibition of osteoblastogenesis and promotion of apoptosis of osteoblasts end osteocytes by glucocorticoids potential mechanisms of their deleterious effects on bone J Clin Invest 1998 102 274 82 10.1172/JCI2799 9664068 \n33. Shi L Wudy SA Buyken AE Maser-Gluth C Hartmann MF Remer T Prepubertal glucocorticoid status and pubertal timing J Clin Endocrinol Metab 2011 96 891 8 10.1210/jc.2010-2935 \n34. Machado SH Xavier RM Lora PS Gonçalves LMK Trindade LR Marostica PJC Height and sexual maturation in girls with juvenile idiopathic arthritis J Pediatr (Rio J) 2020 96 100 7 10.1016/j.jped.2018.07.015 30339783 \n35. Benabbad I Rosilio M Child CJ Carel JC Ross JL Deal CL Safety Outcomes and Near-Adult Height Gain of Growth Hormone-Treated Children with SHOX Deficiency: Data from an Observational Study and a Clinical Trial Horm Res Paediatr 2017 87 42 50 10.1159/000452973 28002818\n\n",
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"keywords": "Case report; Juvenile idiopathic arthritis; Leri Weill syndrome; Madelung deformity; Tofacitinib.",
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"title": "Beyond the guidelines management of juvenile idiopathic arthritis: a case report of a girl with polyarticular disease refractory to multiple treatment options and Leri Weill syndrome.",
"title_normalized": "beyond the guidelines management of juvenile idiopathic arthritis a case report of a girl with polyarticular disease refractory to multiple treatment options and leri weill syndrome"
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"abstract": "Cartilage hair hypoplasia (CHH) is a rare autosomal recessive ribosomopathy characterised by skeletal and integumentary system manifestations. It may also present with varied forms and intensities of haematopoietic and/or immune disorders. We report a 27-year-old female who presented a picture of combined immunodeficiency after receiving an adriamycin-based chemotherapy regimen followed by autologous stem cell transplantation. Her medical history indicated neonatal dwarfism, recurrent ear, nose and throat and respiratory infections, and hypogammaglobulinaemia, which were suggestive of a primary minor B-cell immune deficiency. Taken together, the diagnosis of cartilage hair hypoplasia was suspected and confirmed by means of molecular biological analysis. Here, we discuss the causal relationship and molecular mechanisms existing between both primary immunodeficiency and lymphoma conditions and between chemotherapy cytotoxicity and aggravation of the immune system and associated hematopoietic dysfunction, considering the role of all these components in light of the initially undiagnosed cartilage hair hypoplasia. Finally, this case highlights the importance of screening for primary immunodeficiencies in the setting of a diagnosis of lymphoma and/or dwarfism; moreover, CHH must be distinguished from other causes of small size; its diagnosis and complete check-up must include the molecular characterisation, and its management must be global in collaboration with haematologists, immunologists and internists.",
"affiliations": "CHU de Caen, Department of Internal Medicine and Clinical Immunology, Caen, France.;CHU de Caen, Department of Internal Medicine and Clinical Immunology, Caen, France.;CHU de Caen, Department of Internal Medicine and Clinical Immunology, Caen, France.;CHU de Caen, Department of Clinical Haematology, Caen, France.;CHU de Caen, Department of Internal Medicine and Clinical Immunology, Caen, France.",
"authors": "Nguyen|Alexandre|A|;Martin Silva|Nicolas|N|;de Boysson|Hubert|H|;Damaj|Gandhi|G|;Aouba|Achille|A|",
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"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000328:Adult; D002356:Cartilage; D004358:Drug Therapy; D004392:Dwarfism; D005260:Female; D006197:Hair; D018380:Hematopoietic Stem Cell Transplantation; D006627:Hirschsprung Disease; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D016403:Lymphoma, Large B-Cell, Diffuse; D010009:Osteochondrodysplasias; D000081207:Primary Immunodeficiency Diseases; D013557:Switzerland",
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"title": "Diffuse large B-cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia.",
"title_normalized": "diffuse large b cell lymphoma chemotherapy reveals a combined immunodeficiency syndrome in cartilage hair hypoplasia"
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"drugadditional":... |
{
"abstract": "BACKGROUND\nChronic graft-versus-host disease (cGVHD) is the most important cause of late non-relapse mortality after allogeneic hematopoietic stem cell transplantation. Sclerodermatous cGVHD is usually steroid refractory and remains a therapeutic challenge. Activating antibodies against the PDGFR have been reported in patients with sclerodermatous cGVHD. These antibodies induce PDGFR phosphorylation and lead to fibrosis. There is increasing evidence of successful treatment of sclerodermatous cGVHD with imatinib, a tyrosine kinase inhibitor.\n\n\nOBJECTIVE\nTo evaluate the response of cutaneous sclerodermatous cGVHD to imatinib.\n\n\nMETHODS\nRetrospective study of 18 patients with sclerodermatous cGVHD refractory to immunosuppressants treated with imatinib in a single center. Evaluation of treatment response was performed by clinicians' assessment and patients' subjective response at one, 3, 6, 9, 12 and 18 months after initiation of imatinib. Response was assessed as complete, partial, significant, no change or progression. Tapper off steroids was complete, partial or not possible.\n\n\nRESULTS\nIn our series, 4 (22%) patients achieved complete response, 9 (50%) patients partial response, 2 (11%) patients significant response, 2 (11%) patients had no change and one (6%) patient progressive disease at last follow-up. Mean time from initiation of imatinib to any degree of response was 2,75 months (range 1-9 months).\n\n\nCONCLUSIONS\nThis study provides further evidence of the role of imatinib for the treatment of steroid refractory sclerodermatous cGVHD.",
"affiliations": "Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Instituto de Investigación Sanitaria La Fe, Valencia, España. Electronic address: paula.moles@gmail.com.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Grupo de Investigación en Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Valencia, España.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Instituto de Investigación Sanitaria La Fe, Valencia, España; Grupo de Investigación Clínica y Traslacional del Cáncer, Hospital Universitario y Politécnico La Fe, Valencia, España.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Grupo de Investigación en Hematología y Hemoterapia, Hospital Universitario y Politécnico La Fe, Valencia, España.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Instituto de Investigación Sanitaria La Fe, Valencia, España; Grupo de Investigación de Dermatología y Regeneración Tisular, Hospital Universitario y Politécnico La Fe, Valencia, España.;Unidad de Dermatología, Hospital Universitario y Politécnico La Fe, Valencia, España; Grupo de Investigación de Dermatología y Regeneración Tisular, Hospital Universitario y Politécnico La Fe, Valencia, España.",
"authors": "Molés-Poveda|P|P|;Montesinos|P|P|;Sanz-Caballer|J|J|;de Unamuno|B|B|;Piñana|J L|JL|;Sahuquillo|A|A|;Botella-Estrada|R|R|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D000068877:Imatinib Mesylate",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.ad.2017.11.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5778",
"issue": "109(3)",
"journal": "Actas dermo-sifiliograficas",
"keywords": "Chronic sclerodermatous graft versus host disease; Cutaneous graft versus host disease; Enfermedad de injerto contra huésped; Enfermedad de injerto contra huésped crónica esclerodermiforme; Enfermedad de injerto contra huésped cutánea; Graft-versus-host disease; Imatinib; Platelet-derived growth factor receptor; Receptor del factor de crecimiento derivado de plaquetas; Tratamiento; Treatment",
"medline_ta": "Actas Dermosifiliogr (Engl Ed)",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002908:Chronic Disease; D005260:Female; D006086:Graft vs Host Disease; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D047428:Protein Kinase Inhibitors; D012189:Retrospective Studies; D012594:Scleroderma, Localized; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101777537",
"other_id": null,
"pages": "241-247",
"pmc": null,
"pmid": "29254596",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Sclerodermatous Chronic Graft-versus-Host Disease Treated With Imatinib: A Dermatological Perspective.",
"title_normalized": "sclerodermatous chronic graft versus host disease treated with imatinib a dermatological perspective"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1018420",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Heparin-induced thrombocytopenia and thrombosis (HITT) is an under-recognized cause of deep venous thrombosis treatment failure and of complications during catheter-directed thrombolysis. After a review of HITT pathophysiology, diagnosis, and management, three different cases are presented in this article. Each case highlights subtleties and challenges of HITT diagnosis and management. An example of a practical approach to the diagnosis of HITT is presented.",
"affiliations": "Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.;Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.;Department of Radiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.",
"authors": "Wannamaker|Eric|E|;Kondo|Kimi|K|;Johnson|D Thor|DT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1055/s-0037-1608864",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0739-9529",
"issue": "34(4)",
"journal": "Seminars in interventional radiology",
"keywords": "HITT; catheter-directed thrombolysis; hypercoagulability workup; interventional radiology; venous thrombosis",
"medline_ta": "Semin Intervent Radiol",
"mesh_terms": null,
"nlm_unique_id": "8510974",
"other_id": null,
"pages": "409-414",
"pmc": null,
"pmid": "29249865",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "20008202;26368591;21788317;17258119;25588983;21633576;16634744;26261772;24360929;18291250;22641378;26036229;24750676;17823223;12871282",
"title": "Heparin-Induced Thrombocytopenia and Thrombosis: Preventing your Thrombolysis Practice from Taking a HITT.",
"title_normalized": "heparin induced thrombocytopenia and thrombosis preventing your thrombolysis practice from taking a hitt"
} | [
{
"companynumb": "US-TEVA-2018-US-853780",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "1",
... |
{
"abstract": "According to the literature, only 20-30% of patients are screened for osteoporosis after a hip fracture. Osteoporosis treatment may have a potential protective effect on the 5-year mortality rate. Our results demonstrated that 5-year survival is higher in patients who received osteoporosis treatment after hemiarthroplasty for hip fracture compared with those who did not.\n\n\n\nThis study aims to investigate the status of osteoporosis treatment in patients who underwent hemiarthroplasty for an osteoporotic hip fracture and to compare subsequent fractures and the 5-year survival rates of these patients with those who did not receive the osteoporosis treatment.\n\n\n\nPatients > 65 years of age who underwent hemiarthroplasty for an osteoporotic hip fracture were included in this retrospective multicenter study. Patients who died within 12 months postoperative, who were lost to follow-up, and those with malignancy and secondary osteoporosis were excluded. Group I comprised patients who had no postoperative osteoporosis screening and treatment, and Group II comprised those who received the screening and treatment.\n\n\n\nA total of 460 of 562 patients (82%) did not receive osteoporosis treatment after hip fracture. No significant difference was observed between the groups in terms of subsequent fracture numbers and fracture sites (p = 0.296 and 0.240, respectively). Mean 5-year survival rate was significantly higher in Group II (p = 0.002).\n\n\n\nAccording to our results, elderly patients who underwent hemiarthroplasty for an osteoporotic hip fracture were not commonly screened or treated for osteoporosis. Our results demonstrated no significant difference between the groups in terms of subsequent fracture. However, we observed a significant high 5-year survival rate among patients who received the osteoporosis treatment.",
"affiliations": "Department of Orthopaedics and Traumatology, Ministry of Health Kayseri City Hospital, Kayseri, Turkey.;Department of Otorhinolaryngology, Ministry of Health Kayseri City Hospital, Kayseri, Turkey.;Department of Orthopaedics and Traumatology, Erzincan Binali Yildirim University Faculty of Medicine, Basbaglar Mahallesi, 24100, Erzincan, Turkey. yalkin.camurcu@gmail.com.;Department of Orthopaedics and Traumatology, Erzincan Binali Yildirim University Faculty of Medicine, Basbaglar Mahallesi, 24100, Erzincan, Turkey.;Department of Orthopaedics and Traumatology, Selahaddin Eyyubi State Hospital, Diyarbakir, Turkey.;Department of Orthopaedics and Traumatology, Altinbas University Bahcelievler Medicalpark Hospital, Istanbul, Turkey.",
"authors": "Cobden|Adem|A|http://orcid.org/0000-0002-1020-3333;Cobden|Serap Bulut|SB|http://orcid.org/0000-0002-4471-1934;Camurcu|Yalkin|Y|http://orcid.org/0000-0002-3900-5162;Ucpunar|Hanifi|H|http://orcid.org/0000-0001-8394-0708;Duman|Serda|S|http://orcid.org/0000-0001-6629-9189;Sofu|Hakan|H|http://orcid.org/0000-0003-0415-4245",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1007/s11657-019-0657-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "14(1)",
"journal": "Archives of osteoporosis",
"keywords": "Hemiarthroplasty; Hip fracture; Mortality; Osteoporosis; Survival",
"medline_ta": "Arch Osteoporos",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D062785:Hemiarthroplasty; D006620:Hip Fractures; D006801:Humans; D008297:Male; D010024:Osteoporosis; D058866:Osteoporotic Fractures; D011183:Postoperative Complications; D011184:Postoperative Period; D012008:Recurrence; D012189:Retrospective Studies; D015996:Survival Rate; D014421:Turkey",
"nlm_unique_id": "101318988",
"other_id": null,
"pages": "100",
"pmc": null,
"pmid": "31628566",
"pubdate": "2019-10-18",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Effects of postoperative osteoporosis treatment on subsequent fracture and the 5-year survival rates after hemiarthroplasty for hip fracture.",
"title_normalized": "effects of postoperative osteoporosis treatment on subsequent fracture and the 5 year survival rates after hemiarthroplasty for hip fracture"
} | [
{
"companynumb": "TR-AMGEN-TURSP2019188866",
"fulfillexpeditecriteria": "2",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IBANDRONATE SODIUM"
},
"drugadditional": null... |
{
"abstract": "OBJECTIVE\nFluoroquinolone-induced immune-mediated thrombocytopenia is uncommon, and no reports of cross-reactivity among fluoroquinolones exist. Here, we describe a case of ciprofloxacin-induced immune thrombocytopenia with no cross-reactivity with gemifloxacin.\n\n\nMETHODS\nA 77-year-old woman showed profound thrombocytopenia immediately after two ciprofloxacin injections for pneumonia. Platelet counts recovered rapidly after ciprofloxacin discontinuation. She had experienced thrombocytopenia after ciprofloxacin administration 4 years earlier, which was assumed to be ciprofloxacin-induced immune-related. Interestingly, no thrombocytopenia occurred following the subsequent exposure to another fluoroquinolone, gemifloxacin.\n\n\nCONCLUSIONS\nNo cross-reactivity occurred between ciprofloxacin and gemifloxacin in this fluoroquinolone-induced immune thrombocytopenia case.",
"affiliations": "Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Division of Allergy, Asthma and Clinical Immunology, Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.",
"authors": "Sim|D W|DW|http://orcid.org/0000-0002-9723-0720;Yu|J E|JE|;Jeong|J|J|;Koh|Y-I|YI|",
"chemical_list": "D000890:Anti-Infective Agents; D024841:Fluoroquinolones; D009287:Naphthyridines; D002939:Ciprofloxacin; D000077735:Gemifloxacin",
"country": "England",
"delete": false,
"doi": "10.1111/jcpt.12596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0269-4727",
"issue": "43(1)",
"journal": "Journal of clinical pharmacy and therapeutics",
"keywords": "ciprofloxacin; cross-reactivity; drug-induced immune thrombocytopenia; gemifloxacin",
"medline_ta": "J Clin Pharm Ther",
"mesh_terms": "D000368:Aged; D000890:Anti-Infective Agents; D002939:Ciprofloxacin; D005260:Female; D024841:Fluoroquinolones; D000077735:Gemifloxacin; D006801:Humans; D009287:Naphthyridines; D011014:Pneumonia; D013921:Thrombocytopenia",
"nlm_unique_id": "8704308",
"other_id": null,
"pages": "134-136",
"pmc": null,
"pmid": "28791716",
"pubdate": "2018-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Ciprofloxacin-induced immune-mediated thrombocytopenia: No cross-reactivity with gemifloxacin.",
"title_normalized": "ciprofloxacin induced immune mediated thrombocytopenia no cross reactivity with gemifloxacin"
} | [
{
"companynumb": "KR-PFIZER INC-2018026826",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN HYDROCHLORIDE"
},
"drugadditiona... |
{
"abstract": "OBJECTIVE\nTo describe a unique case of drug-induced transient myopia with angle-closure glaucoma in a patient being treated with zolmitriptan for migraines.\n\n\nMETHODS\nA 42-year-old woman who had been using increasing amounts of zolmitriptan over the previous 12 months presented with an acute myopic shift and raised intraocular pressures (IOP) with anterior chamber shallowing. Clinical examination findings at presentation and at follow-up visits were reviewed.\n\n\nRESULTS\nInitial examination revealed unaided visual acuities of 20/100 in the right eye and 20/125 in the left, with IOP measuring 34 mm Hg bilaterally. Zolmitriptan was ceased and the patient was commenced on topical antiglaucoma medication. Within 2 weeks, IOP had normalized, with deepening of the anterior chambers and complete resolution of her myopia. Her final recorded unaided visual acuities were 20/12.5 in the right eye and 20/16 in the left. When topical antiglaucoma medication was ceased the patient developed pressure-related headaches and selective laser trabeculoplasty was performed to minimize the need for long-term topical medication use.\n\n\nCONCLUSIONS\nIdiosyncratic drug reactions resulting in ciliochoroidal effusion, secondary angle closure, and transient myopia are well described, but they have not been previously reported with zolmitriptan use. An awareness of the various potential causative agents is important, as findings are generally reversible if recognized early and if the offending drug is discontinued.",
"affiliations": "*Department of Ophthalmology, The Alfred Hospital ‡Departments of Ophthalmology and Surgery, Royal Melbourne Hospital, University of Melbourne §Royal Victorian Eye and Ear Hospital, Melbourne †Discipline of Ophthalmology, University of Sydney, Sydney, Australia.",
"authors": "Lee|Jonathan Tak Loong|JTL|;Skalicky|Simon Edward|SE|;Lin|Ming-Lee|ML|",
"chemical_list": "D023303:Oxazolidinones; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines; C089750:zolmitriptan",
"country": "United States",
"delete": false,
"doi": "10.1097/IJG.0000000000000742",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1057-0829",
"issue": "26(10)",
"journal": "Journal of glaucoma",
"keywords": null,
"medline_ta": "J Glaucoma",
"mesh_terms": "D000328:Adult; D005260:Female; D015812:Glaucoma, Angle-Closure; D006801:Humans; D008881:Migraine Disorders; D009216:Myopia; D023303:Oxazolidinones; D058825:Serotonin 5-HT1 Receptor Agonists; D014363:Tryptamines",
"nlm_unique_id": "9300903",
"other_id": null,
"pages": "954-956",
"pmc": null,
"pmid": "28858962",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced Myopia and Bilateral Angle Closure Secondary to Zolmitriptan.",
"title_normalized": "drug induced myopia and bilateral angle closure secondary to zolmitriptan"
} | [
{
"companynumb": "AU-GLENMARK PHARMACEUTICALS-2018GMK030886",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLMITRIPTAN"
},
"drugadditio... |
{
"abstract": "Muscle relaxants are commonly prescribed in the United States but may have deleterious side effects that are unrecognized by physicians. Here, we report a 55-year-old Caucasian man who developed pancreatitis and a subsequent hyperosmolar hyperglycemic state after being prescribed tizanidine. The patient had untreated hypertriglyceridemia, unbeknownst to the prescribing physician. While hypertriglyceridemia is a widely understood risk factor for pancreatitis, its incidence with tizanidine is not. As an alpha-2 agonist, tizanidine slows gastrointestinal motility by inhibiting gastrointestinal smooth muscle contraction, which could lead to ileus which occurred in this patient. Alpha-2 agonists further contract the hepato-pancreatic sphincter, which may result in obstruction of pancreatic enzyme flow via the pancreatic duct. This patient's case of pancreatitis was precipitated by 2 factors: (i) his use of tizanidine and (ii) hypertriglyceridemia. This case demonstrates that patients presenting with severe hypertriglyceridemia, or other potential risk factors for pancreatitis, should not be prescribed tizanidine.",
"affiliations": "Department of Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA.;Department of Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA.;Brown University Alpert School of Medicine, Providence, USA.;Department of Biomedical Engineering, McKelvey School of Engineering and Applied Science, Washington University, St. Louis, USA.;Department of Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA.;Department of Medicine, University of Missouri-Kansas City School of Medicine, Kansas City, USA.;Little Rock Diagnostic Clinic, CHI St. Vincent, Little Rock, USA.",
"authors": "Bao|Yicheng K|YK|0000-0002-4354-7271;Ganesan|Vishwanath C|VC|;Jiang|Winston|W|;Lin|Lydia|L|;Brown|Norwood R|NR|;Steigerwalt|Kristy E|KE|;Yu|Amy Z|AZ|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/omcr/omz012",
"fulltext": "\n==== Front\nOxf Med Case ReportsOxf Med Case ReportsomcrOxford Medical Case Reports2053-8855Oxford University Press 10.1093/omcr/omz012omz012Case ReportMuscle relaxant induced pancreatitis leading to hyperosmolar hyperglycemic state http://orcid.org/0000-0002-4354-7271Bao Yicheng K 1Ganesan Vishwanath C 1Jiang Winston 2Lin Lydia 3Brown Norwood R 1Steigerwalt Kristy E 1Yu Amy Z 41 Department of Medicine, University of Missouri–Kansas City School of Medicine, Kansas City, USA2 Brown University Alpert School of Medicine, Providence, USA3 Department of Biomedical Engineering, McKelvey School of Engineering and Applied Science, Washington University, St. Louis, USA4 Little Rock Diagnostic Clinic, CHI St. Vincent, Little Rock, USACorrespondence address. University of Missouri–Kansas City School of Medicine, 2411 Holmes Street, Kansas City, MO 64108, USA. Tel: +1-501-349-7721; E-mail: ybao@umkc.edu3 2019 29 3 2019 29 3 2019 2019 3 omz01218 9 2018 26 11 2018 25 1 2019 © The Author(s) 2019. Published by Oxford University Press.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nMuscle relaxants are commonly prescribed in the United States but may have deleterious side effects that are unrecognized by physicians. Here, we report a 55-year-old Caucasian man who developed pancreatitis and a subsequent hyperosmolar hyperglycemic state after being prescribed tizanidine. The patient had untreated hypertriglyceridemia, unbeknownst to the prescribing physician. While hypertriglyceridemia is a widely understood risk factor for pancreatitis, its incidence with tizanidine is not. As an alpha-2 agonist, tizanidine slows gastrointestinal motility by inhibiting gastrointestinal smooth muscle contraction, which could lead to ileus which occurred in this patient. Alpha-2 agonists further contract the hepato-pancreatic sphincter, which may result in obstruction of pancreatic enzyme flow via the pancreatic duct. This patient’s case of pancreatitis was precipitated by 2 factors: (i) his use of tizanidine and (ii) hypertriglyceridemia. This case demonstrates that patients presenting with severe hypertriglyceridemia, or other potential risk factors for pancreatitis, should not be prescribed tizanidine.\n\nNIH/NIDDKT32DK007120\n==== Body\nCASE REPORT\nA 55-year-old Caucasian male with a past medical history of hypertension and hyperlipidemia presented to the emergency department with nausea, vomiting and mental status changes. Patient history revealed an injury to his back after lifting heavy objects a few days prior. This injury prompted a visit to his primary care physician who prescribed the muscle relaxant tizanidine hydrochloride (Zanaflex®), without baseline laboratory testing. Preceding this visit, he had not followed up with his primary care provider for 2 years, was taking no medications for his hypertension or hyperlipidemia, nor was he taking any additional prescribed medications or over the counter supplements. After ingesting tizanidine, the patient became excessively drowsy. The following day, he became delirious, could not be roused by his family, and was subsequently brought to the emergency department.\n\nOn review of systems, the patient reported that he had been recently experiencing fatigue, polyuria and polydipsia, as well as 20 pound weight loss over the past 3 months. On physical examination, he was comatose, febrile at 101.2 °F, and his systolic blood pressure was 60 mmHg. Laboratory data is displayed in Table 1. Notably, labs showed glucose was 1811 mg/dL (80–107 mg/dL), creatinine 2.0 mg/dL (0.6–1.2 mg/dL), and WBC count 9300 with a left shift. Alanine aminotransferase (ALT) (10–40 U/L) and aspartate aminotransferase (AST) (8–48 U/L) were elevated at 418 and 975 U/L, respectively; lipase 106 U/L (8–78 U/L) and amylase 339 U/L (25–125 U/L) were as well. Alkaline phosphatase was 92 U/L (80–150 U/L). The metabolic panel included hyponatremia, hyperkalemia, hypochloridemia, hyperkalcemia, elevated creatinine, hypophosphatemia, etc. pH was 7.396 (7.350–7.450), pO2 74.0 mmHg (80–100 mmHg), pCO2 29.9 mmHg (35–45 mmHg) and HCO3 17.9 mEq/L (22–26 mEq/dL). A fasting lipid profile obtained 2 years prior by the primary care provider indicated a history of hyperlipidemia: total cholesterol 196 mg/dL (0–200 mg/dL), triglycerides 352 mg/dL (0–150 mg/dL), HDL 38 mg/dL (15–100 mg/dL) and LDL 88 mg/dL (<99 mg/dL). A lipid profile obtained in the emergency department indicated hyperlipidemia: total cholesterol 380 mg/dL, triglycerides 1125 mg/dL and HDL 9 mg/dL. Abdominal CT showed proximal small bowel thickening with mesenteric edema. In addition, there was increased fluid signal, and swelling of the pancreatic head with fluid in the pararenal spaces. No peripancreatic pseudocyst was identified. His liver showed significant steatosis. Due to his severely increased liver enzymes and acute pancreatitis, MRI ERCP was performed the next day. No evidence of cholelithiasis or choledocholithiasis was found, nor were biliary stones or masses visible.\nTable 1: Laboratory findings for this patient\n\nLaboratory test\tSerum levels\t\nGlucose (80–107 mg/dL)\t1811 mg/dL\t\nNa+ (136–146 mg/dL)\t129.2 mEq/L\t\nK+ (3.50–5.50 mEq/L)\t6.86 mEq/L\t\nCl− (98–107 mEq/L)\t94.09 mEq/L\t\nCreatinine (0.6–1.2 mg/dL)\t2.0 mg/dL\t\nCa2+ (8.2–10.8 mg/dL)\t11.2 mg/dL\t\nPhosphate (2.3–4.7 mg/dL)\t0.7 mg/dL\t\nMg (1.56–2.52 mg/dL)\t1.86 mg/dL\t\nAlanine aminotransferase (10–40 U/L)\t418 U/L\t\nAspartate aminotransferase (8–48 U/L)\t975 U/L\t\nLipase (8–78 U/L)\t106 U/L\t\nAmylase (25–125 U/L)\t339 U/L\t\nAlkaline phosphatase (80–150 U/L)\t92 U/L\t\npH (7.350–7.450)\t7.396\t\npO2 (80–100 mmHg)\t74.00 mmHg\t\npCO2 (25–45 mmHg)\t29.9 mmHg\t\nHCO3 (22–26 mEq/L)\t17.9 mEq/L\t\nTotal cholesterol (0–200 mg/dL)\t196 mg/dL\t\nTriglycerides (0–150 mg/dL)\t352 mg/dL\t\nHDL (15–100 mg/dL)\t38 mg/dL\t\nLDL (<99 mg/dL)\t88 mg/dL\t\n\n\nThe patient was intubated for airway protection, treated with insulin drip, intravenous fluids and required vasopressor support. Tizanidine was discontinued. The patient’s osmolar status resolved and he regained consciousness 2 days after discontinuation. After three days of intravenous fluid, insulin drip and fasting, the patient’s hypertriglyceridemia decreased to 437 mg/dL. The patient was then extubated. He was discharged on Day 7 with normalized electrolytes. His diabetes was initially managed with insulin.\n\nOn follow-up, his diabetes was under moderate control with Metformin 1 g two times a day, and insulin was discontinued. Triglycerides were below 300 mg/dL following a regimen of diet and exercise. He was started on Atorvastatin 20 mg daily for his cholesterol and Lisinopril 10 mg daily for his hypertension. He had no complaints of pancreatitis. His liver enzymes were slightly elevated due to persistent fatty liver. He was subsequently able to follow a low-carbohydrate, low-fat diet which resulted in continued weight loss.\n\nDISCUSSION\nIn summary, this patient presented with undiagnosed type 2 diabetes, severe hypertriglyceridemia, and oral tizanidine use which we suspect caused acute pancreatitis and mental status changes. Acute pancreatitis further precipitated a hyperglycemic hyperosmolar event that resulted in this patient’s comatose state.\n\nThis episode of acute pancreatitis was potentially precipitated by two factors: (i) use of tizanidine and (ii) hypertriglyceridemia. Tizanidine, an alpha-2 adrenergic agonist [1], is a commonly used muscle relaxant that is used to treat muscle tightness, cramping and spasms. While many complications of this drug are well documented, the effects of using this drug in patients with severe hypertriglyceridemia, to our knowledge, have not been reported in the literature.\n\nHypertriglyceridemia is a well-documented cause of acute pancreatitis [2]. Chylomicrons are the largest transporter of triglycerides, up to 600 nm in width [3]; it is postulated that these large particles obstruct the pancreatic vasculature and cause ischemia and infarction distal to the blockage, leading to acute pancreatitis. Additionally, lipase within the pancreas may be exposed to fatty acid contained within the chylomicron, resulting in excess fatty acid release, which ultimately may trigger activation of pancreatic lipases.\n\nAlpha-2 agonists are commonly prescribed in the USA as muscle relaxants. Tizanidine is an alpha-2 receptor agonist which potentially influenced this patient’s episode of acute pancreatitis. The alpha-2 adrenergic receptor is a G-protein coupled receptor (GPCR) present in a wide variety of tissues, such as vascular smooth muscle, coronary arteries, salivary glands and the gastrointestinal tract. Its specific actions on the gastrointestinal tract include contraction of sphincters and decreased motility of the smooth muscle within the gastrointestinal tract [4, 5]. Activation of the alpha-2 receptor causes contraction of the hepato-pancreatic sphincter (sphincter of oddi), leading to obstruction of pancreatic enzyme flow via the pancreatic duct, resulting in acute pancreatitis. Furthermore, alpha-2 adrenergic agonists like tizanidine slow gastrointestinal motility by inhibiting gastrointestinal smooth muscle contraction, leading to ileus, which occurred in this patient. Consequently, backing up the pressure in the biliary tract likely exacerbated this episode of acute pancreatitis. Although hypertriglyceridemia was likely the major contributor to acute pancreatitis in this case because the serum values were more than twice normal, the concomitant use of tizanidine likely precipitated this attack.\n\nPreviously, one case of tizanidine causing pancreatitis was reported in the literature [6]. The United States Food and Drug Administration Adverse Events Reporting System (FAERS) lists nineteen cases of reported pancreatitis since 2003 in patients taking tizanidine [7]. It is possible that tizanidine’s effects on GI tract motility lead to the development of pancreatitis in these patients. Further cases of pancreatitis may occur without reporting to the FAERS due to unknown pathophysiology.\n\nIn summary, patients with severe hypertriglyceridemia, or other potential risk factors for pancreatitis should not be prescribed tizanidine. In addition, tizanidine may need to be stopped in patients presenting with severe hypertriglyceridemia.\n\nCONFLICT OF INTEREST STATEMENT\nNone to report for any author.\n\nFUNDING\nUMKC School of Medicine Sarah Morrison Research Award (YKB, VCG).\n\nConsent\nWritten patient consent was obtained.\n==== Refs\nReferences\n1 \nCoward DM \nTizanidine: neuropharmacology and mechanism of action . Neurology 1994 ;44 :S6 –10 ; discussion S10–11.\n2 \nKasper DL , Fauci AS , Hauser SL , Longo DL , Jameson JL , Loscalzo J. \nHarrison’s Principles of Internal Medicine 19/E (Vol.1 & Vol.2) (ebook) . New York: McGraw-hill , 2015 .\n3 \nMartins IJ , Mortimer BC , Miller J , Redgrave TG \nEffects of particle size and number on the plasma clearance of chylomicrons and remnants . J Lipid Res 1996 ;37 :2696 –705 .9017520 \n4 \nSagrada A , Fargeas MJ , Bueno L \nInvolvement of alpha-1 and alpha-2 adrenoceptors in the postlaparotomy intestinal motor disturbances in the rat . Gut 1987 ;28 :955 –9 .2889649 \n5 \nCoelho JC , Gouma DJ , Moody FG , Li YF , Weisbrodt NW \nInfluence of autonomic drugs on the motility of the sphincter of Oddi in the opossum . Surg Gynecol Obstet 1986 ;163 :209 –14 .3750175 \n6 \nNewman PM , Nogues M , Newman PK , Weightman D , Hudgson P \nTizanidine in the treatment of spasticity . Eur J Clin Pharmacol 1982 ;23 :31 –5 . 10.1007/BF01061374 .6751834 \n7 \nUS Food and Drug Administration \nFDA Adverse Events Reporting System (FAERS)\nhttps://fis.fda.gov/sense/app/d10be6bb-494e-4cd2-82e4−0135608ddc13/sheet/7a47a261-d58b-4203-a8aa-6d3021737452/state/analysis. Updated June 30, 2018. (24 July 2018, date last accessed).\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2053-8855",
"issue": "2019(3)",
"journal": "Oxford medical case reports",
"keywords": null,
"medline_ta": "Oxf Med Case Reports",
"mesh_terms": null,
"nlm_unique_id": "101642070",
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"pmid": "30949350",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports",
"references": "2889649;3750175;6751834;7970012;9017520",
"title": "Muscle relaxant induced pancreatitis leading to hyperosmolar hyperglycemic state.",
"title_normalized": "muscle relaxant induced pancreatitis leading to hyperosmolar hyperglycemic state"
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"abstract": "Ibuprofen, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), is one of the most commonly prescribed analgesics for managing musculoskeletal, orofacial, and postoperative pain after periodontal therapy. Although considered as one of the safest analgesic agents, the onset of adverse drug reactions after ibuprofen intake has been recently observed. The present report aims to highlight the development of localized swellings in the temporal and frontal forehead following intake of 200 mg of ibuprofen after routine oral prophylaxis. This is the first case report to document the development of an adverse drug reaction with ibuprofen in a patient following a routine dental procedure. The article also aim to comprehensively describe the most appropriate and effective method to diagnose, manage, and prevent NSAIDs-induced adverse drug reactions in routine dental practice.",
"affiliations": "Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.;Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.;Department of Prosthodontics, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India.",
"authors": "Chopra|Aditi|A|;Pappu|Rachana|R|;Sivaraman|Karthik|K|",
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"doi": "10.4103/jisp.jisp_119_19",
"fulltext": "\n==== Front\nJ Indian Soc Periodontol\nJ Indian Soc Periodontol\nJISP\nJournal of Indian Society of Periodontology\n0972-124X 0975-1580 Wolters Kluwer - Medknow India \n\nJISP-24-178\n10.4103/jisp.jisp_119_19\nCase Report\nIbuprofen-induced localized frontal and temporal forehead swellings: A rare case report\nChopra Aditi Pappu Rachana Sivaraman Karthik 1 Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India\n1 Department of Prosthodontics, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India\nAddress for correspondence: Dr. Aditi Chopra, Department of Periodontology, Manipal College of Dental Sciences, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India. E-mail: draditichopra@gmail.com\nMar-Apr 2020 \n02 3 2020 \n24 2 178 181\n26 2 2019 01 9 2019 28 10 2019 Copyright: © 2020 Journal of Indian Society of Periodontology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Ibuprofen, nonselective nonsteroidal anti-inflammatory drugs (NSAIDs), is one of the most commonly prescribed analgesics for managing musculoskeletal, orofacial, and postoperative pain after periodontal therapy. Although considered as one of the safest analgesic agents, the onset of adverse drug reactions after ibuprofen intake has been recently observed. The present report aims to highlight the development of localized swellings in the temporal and frontal forehead following intake of 200 mg of ibuprofen after routine oral prophylaxis. This is the first case report to document the development of an adverse drug reaction with ibuprofen in a patient following a routine dental procedure. The article also aim to comprehensively describe the most appropriate and effective method to diagnose, manage, and prevent NSAIDs-induced adverse drug reactions in routine dental practice.\n\nKey words:\nAngioedemahypersensitivity reactionsibuprofennonsteroidal anti-inflammatory drugs\n==== Body\nINTRODUCTION\nIbuprofen, organically known as (2RS)-1 (4-[2-methyl propyl]) phenyl, is a commonly prescribed analgesic with good anti-inflammatory and antipyretic properties. It is a propionic acid derivative that belongs to the category of non-selective nonsteroidal anti-inflammatory drug (NSAID).[12] Ibuprofen is one of the most commonly prescribed analgesics for managing mild to moderate musculoskeletal and orofacial pain such as migraine, osteoarthritis, rheumatoid arthritis, soft-tissue disorders, and postoperative pain following various dental and periodontal procedures. Although considered to be one of the safest analgesics with minimal side effects, few adverse drug reactions have been reported recently in the literature.[2] This case highlights the development of localized swelling and angioedema on the frontal and temporal forehead in a 57-year-old systemically healthy male on the intake of a single dose of ibuprofen following routine oral prophylaxis.\n\nCASE REPORT\nA 57-year-old male patient (weight: 62 kg) reported with a chief complaint of bleeding gums from the upper back tooth region for 1 month. On examination, a generalized probing depth of 6–7 mm with the moderate horizontal bone loss was observed. The oral hygiene of the patient was fair with a moderate amount of supragingival and subgingival deposits. The patient was systemically healthy with no history of any cutaneous skin lesions, drug intake, or allergic reaction to any medication or irritant. A nonsurgical phase one therapy comprising of full mouth oral prophylaxis and root surface debridement was initiated. Ibuprofen 200 mg was prescribed post-treatment in case any pain or discomfort was experienced. The patient was recalled after 2 weeks for re-evaluation and follow-up. However, the patient reported back within 1 h, with the development of a sudden, localized, soft, edematous, non-fluctuant, and nonmovable lobular swelling on the frontal and temporal part of his forehead. The swelling was tender on palpation with slight erythema on its outer surface [Figure 1]. The patient also reported the development of a mild rise in body temperature, lassitude, and malaise.\n\nFigure 1 Angioedema on the frontal and temporal part of the forehead after consuming a single dose of 200 mg of Ibuprofen\n\nBased on the patient's history and the timing of onset of allergic response, ibuprofen-induced hypersensitivity reaction was suspected. The patient was questioned regarding the onset of any similar incidents in the past. The patient then reported the onset of a similar swelling a few years back (etiology unknown). The patient was immediately referred to a physician, and blood was withdrawn to check for the total and differential blood count delete was done. The blood reports showed increases in the eosinophils (absolute eosinophils count = 9.67 × 103/μL (H); differential cell count = 16.5%) suggestive of an allergic reaction [Table 1]. A local prick skin test with ibuprofen was also performed to confirm the hypersensitivity reaction [Figure 2]. To exclude the cross-reactivity and tolerance to other chemically unrelated NSAIDS, an oral challenge with other COX 1 inhibitors (aspirin) was done. The patient was immediately administered 10–20 mg intravenous injection of pheniramine maleate to control the reaction. A drastic reduction in the temporal swelling was observed within 24 h. The patient was kept under observation and was prescribed 10 mg of pheniramine maleate twice a day for 3 days. The patient was instructed not be take any nonselective NSAIDs in the future. The complete resolution of the swelling and urticaria was observed within 72 h.\n\nTable 1 Complete blood profile of the patient immediately after the allergic reaction\n\nTest\tResults\tMethods\t\nComplete blood count\t\t\t\n Hemoglobin\t15.3 g/dL\tPhotometric\t\n Hematocrit\t43.9%\tCalculated\t\n RBC count\t5.31 × 106/µL\tImpedance\t\n Total WBC count\t4.1 × 103/µL\tImpedance\t\nDifferential count\t\t\t\n Neutrophil\t50.4%\tVSC\ntechnology/lightmicroscopy\t\n Lymphocyte\t26.5%\t\n Monocyte\t6.0%\t\n Eosinophil\t16.5% (H)\t\n Basophils\t0.6% (L)\t\nAbsolute eosinophil count\t9.67 × 103/µL (H)\tCalculated\t\nAbsolute neutrophil count\t0.2 × 103/µL\t\nErythrocyte sedimentation rate\t23 mm/h\t\t\nRBC – Red blood cell; WBC – White blood cell; VSC – volume, conductivity, and light scatter\n\nFigure 2 Schematic representation of a skin prick test for testing the allergic response to Ibuprofen\n\nSince the allergic response to ibuprofen was immediately observed in the absence of any previous history of cutaneous lesion, bronchial asthma, respiratory disorders along with cross-reactivity to two or more NSAIDs, a diagnosis of NSAID-induced urticaria/angioedema (NIUA) was established based on the European Academy of Allergy and Clinical Immunology)/WAO nomenclature [Figure 3].[234]\n\nFigure 3 Classification of adverse drug reactions to nonsteroidal anti.in.ammatory drugs\n\nDISCUSSION\nThe localized frontal and temporal angioedema following ibuprofen intake is a rare manifestation of NSAIDs-induced adverse drug reaction. The onset of this unique response confirmed the complex and varied nature of NSAIDs-induced hypersensitivity reactions and is a fertile area for further research. NSAIDs are the most frequent cause of drug hypersensitivity with NIUA being the most common phenotypic characteristics.[56] The main mechanisms of such non-immunological reactions are the inhibition of the cyclooxygenase enzyme of the arachidonic acid pathways and activation of lipoxygenase pathways.[34567] According to the “cyclooxygenase hypothesis,” the inhibition of COX-1 receptors by aspirin or other related NSAIDs such as ibuprofen metabolizes the arachidonic acid to inhibits the release of various proinflammatory cytokines such as prostaglandins, thromboxanes, and prostacyclin. This release of the proinflammatory mediators from the inflammatory cells deviates the arachidonic acid pathway toward the 5-lipoxygenase pathway. The activation of lipoxygenase eventually releases a large amount of cysteinyl leukotrienes (Cys-LTs 5 LTC4, LTD4, and LTE4) both locally and systemically in the systemic circulation. Cys-LTs are 100 times more potent than histamine in inducing hypersensitivity reactions. Recent studies have confirmed elevated levels of urinary LTE4 on aspirin administration in patients with chronic urticaria, NSAID intolerance, and aspirin-exacerbated respiratory disease.[6789101112] The severity of NSAIDs-induced hypersensitivity reaction also shows temporary fluctuations related to the nature and potency of the offending drug to inhibit the COX receptors, cross-reactivity among NSAIDs, and the presence of underlying chronic systemic and cutaneous disease.[10] The heteroaryl acetic acid group of NSAIDs such as naproxen, diclofenac, and ibuprofen has shown a higher risk for anaphylactic or immediate hypersensitivity reactions.[8] In patients with pyrazolone-induced drug hypersensitivity, a strong association between human leukocyte antigen (HLA)-DQ and HLA-DR gene loci and severity of allergic response has been documented.[11] In addition, it has also been observed that NIUA patients may develop tolerance to NSAIDs over time, a process that seems to be influenced by atopy and type of clinical reaction.[6]\n\nThus, it is important to promptly identify and sequential manage such an allergic response to avoid untoward complications [Figure 4].[345] A detailed clinical history highlighting the timing of onset of the allergic event along with the name, dose, brand, route of the administration of the culprit drug; pattern and chronology of the allergy response; the time interval between the last dose and onset of symptoms and the time of disappearance of symptoms after drug withdrawal should be recorded.[56711] The name and doses of the previously tolerated NSAIDs, history of underlying chronic disorders such as bronchial asthma, chronic rhinosinusitis, nasal polyps, and chronic spontaneous urticaria/angioedema should also be recorded.[91314] In vitro skin testing techniques such as intradermal patch tests, oral challenge test, and/or drug provocation test with the suspected and alternative drugs should also be done to confirm the etiology of such adverse drug reactions.[1314151617] It is important not to carry out any provocation testing if the adverse drug reaction has resulted in a life-threatening reaction or anaphylaxis.[4813141516] In case the causative drug is aspirin, the patient can be tested with another strong COX-1 inhibitor to confirm the cross-reactive type of hypersensitivity. An inhaled route of provocation with lysine aspirin can also be used in patients with a history of bronchial asthma and related respiratory symptoms.[1316] Moreover, skin testing should be avoided for immediate hypersensitivity reactions such as type III serum sickness reactions, Stevens–Johnson syndrome, toxic epidermal necrolysis, and drug reaction/rash with severe eosinophilia and systemic symptoms.[6]\n\nFigure 4 Stepwise approach in the diagnosis and management of nonsteroidal anti-in?ammatory drugs-induced hypersensitivity reactions\n\nCONCLUSION\nNSAID, such as ibuprofen, should be considered as a potential and common etiological agent for hypersensitivity reactions in dental clinics. NSAIDs-induced adverse drug reactions can be a complex and intimidating situation if not managed appropriately. Therefore, a comprehensive knowledge and understanding of the complex pathogenic mechanisms that govern such an allergic response would help clinicians to arrive at a correct and timely diagnosis and provide appropriate treatment. Furthermore, additional research analyzing the pharmacokinetics and pharmacodynamics of the ibuprofen that is related to the various adverse drug reactions should be explored. Moreover, it is important to understand the mechanism by NSAIDs such as ibuprofen interact with the body to develop novel therapeutic modalities by which NSAIDs-induced adverse drug reactions can be prevented.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgement\nWe would like to thank Dr. Mansi Mahendra for a schematic representation of the diagrams.\n==== Refs\nREFERENCES\n1 Ritter JM Lewis L Mant TG Analgesics and the control of pain A Text Book of Clinical Pharmacology 1999 4th ed London Arnold 216 \n2 Caimmi S Caimmi D Bousquet PJ Demoly P How can we better classify NSAID hypersensitivity reactions.– Validation from a large database? Int Arch Allergy Immunol 2012 159 306 12 22739440 \n3 Kowalski ML Asero R Bavbek S Blanca M Blanca-Lopez N Bochenek G Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs Allergy 2013 68 1219 32 24117484 \n4 Kowalski ML Makowska JS Blanca M Bavbek S Bochenek G Bousquet J Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) – Classification, diagnosis and management: Review of the EAACI/ENDA(#) and GA2LEN/HANNA* Allergy 2011 66 818 29 21631520 \n5 De Weck A Szczeklik A Brockow K Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) – Classification, diagnosis, and management: A review of the EAACI/ENDA(#) and GA2LEN/HANNA* Allergy 2011 66 818 29 21631520 \n6 Doña I Barrionuevo E Salas M Cornejo-García JA Perkins JR Bogas G Natural evolution in patients with nonsteroidal anti-inflammatory drug-induced urticaria/angioedema Allergy 2017 72 1346 55 28226401 \n7 Kanaoka Y Boyce JA Cysteinyl leukotrienes and their receptors; emerging concepts Allergy Asthma Immunol Res 2014 6 288 95 24991451 \n8 Mastalerz L Setkowicz M Sanak M Szczeklik A Hypersensitivity to aspirin: Common eicosanoid alterations in urticaria and asthma J Allergy Clin Immunol 2004 113 771 5 15100686 \n9 Jenkins C Costello J Hodge L Systematic review of prevalence of aspirin induced asthma and its implications for clinical practice BMJ 2004 328 434 14976098 \n10 Doña I Blanca-López N Torres MJ García-Campos J García-Núñez I Gómez F Drug hypersensitivity reactions: Response patterns, drug involved, and temporal variations in a large series of patients J Investig Allergol Clin Immunol 2012 22 363 71 \n11 Kowalski ML Woszczek G Bienkiewicz B Mis M Association of pyrazolone drug hypersensitivity with HLA-DQ and DR antigens Clin Exp Allergy 1998 28 1153 8 9761020 \n12 Blanca-Lopez N J Torres M Doña I Campo P Rondón C Seoane Reula ME Value of the clinical history in the diagnosis of urticaria/angioedema induced by NSAIDs with cross-intolerance Clin Exp Allergy 2013 43 85 91 23278883 \n13 Dursun AB Woessner KA Simon RA Karasoy D Stevenson DD Predicting outcomes of oral aspirin challenges in patients with asthma, nasal polyps, and chronic sinusitis Ann Allergy Asthma Immunol 2008 100 420 5 18517072 \n14 Barbaud A Gonçalo M Bruynzeel D Bircher A European Society of Contact Dermatitis. Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions Contact Dermatitis 2001 45 321 8 11846746 \n15 Aberer W Bircher A Romano A Blanca M Campi P Fernandez J Drug provocation testing in the diagnosis of drug hypersensitivity reactions: General considerations Allergy 2003 58 854 63 12911412 \n16 Defrance C Bousquet PJ Demoly P Evaluating the negative predictive value of provocation tests with nonsteroidal anti-inflammatory drugs Allergy 2011 66 1410 4 21722141 \n17 Nizankowska E Bestyńska-Krypel A Cmiel A Szczeklik A Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma Eur Respir J 2000 15 863 9 10853850\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-124X",
"issue": "24(2)",
"journal": "Journal of Indian Society of Periodontology",
"keywords": "Angioedema; hypersensitivity reactions; ibuprofen; nonsteroidal anti-inflammatory drugs",
"medline_ta": "J Indian Soc Periodontol",
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"nlm_unique_id": "101499342",
"other_id": null,
"pages": "178-181",
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"pubdate": "2020",
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"title": "Ibuprofen-induced localized frontal and temporal forehead swellings: A rare case report.",
"title_normalized": "ibuprofen induced localized frontal and temporal forehead swellings a rare case report"
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"abstract": "Anabolic Androgenic Steroids (AAS) is an hormone family whose use has considerably increased among body-builders during the last decades. The AAS abuse, especially associated with other drugs or nutritional supplements and protein loads, may cause a variety of pathologies to several organs with a mechanism related to dosage, timing and substance. The kidney is the main metabolizer of these drugs and it can be acutely or chronically damaged with ESKD. The literature reports some cases of Focal Segmental Glomerulosclerosis (FSGS) in body-builders who abused of AAS. However, the link is not well understood and limited to some case-studies. In this paper, we report the case of a young body-builder who developed a FSGS collapsing variant with ESKD after prolonged abuse of AAS and a strongly hyperproteic diet and other dietary supplements. The patient underwent a genetic test because of the rapid and irreversibile onset of ESKD. The test showed a gene mutation of ACTN4, predisposing and causal of some genetic forms of FSGS. It was a very complex case, caused by several factors. The mutant protein of ACTN4 gene makes most vulnerable the cytoskeleton of the podocytes to external disturbances. That would explain why in those patients where the mutation has occurred, only those patients subject to \"unfavorable environmental conditions\", like the abuse of AAS, can develop a disease.",
"affiliations": "UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.;UO Nefrologia Dialisi e Trapianto Policlinico S. Orsola-Malpighi Bologna.;SSD di Diagnostica Istopatologica e Molecolare degli Organi solidi e del relativo Trapianto Policlinico S. Orsola-Malpighi Bologna.;UO Nefrologia Dialisi e Trapianto Policlinico S. Orsola-Malpighi Bologna.;UO Nefrologia e Dialisi AUSL Romagna Ospedale Infermi Rimini.",
"authors": "Flachi|Marta|M|;Menghi|Viola|V|;Moschella|Maria Rita|MR|;De Giovanni|Paola|P|;Montevecchi|Marcello|M|;Cerretani|Davide|D|;Grimaldi|Daniela|D|;Baraldi|Olga|O|;Fabbrizio|Benedetta|B|;La Manna|Gaetano|G|;Rigotti|Angelo|A|",
"chemical_list": "D004044:Dietary Proteins; D045165:Testosterone Congeners; D007052:Ibuprofen",
"country": "Italy",
"delete": false,
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"issue": "35(6)",
"journal": "Giornale italiano di nefrologia : organo ufficiale della Societa italiana di nefrologia",
"keywords": "AAS; ESKD; anabolic androgenic steroids; end stage kidney disease; focal segmental glomerulosclerosis collapsing variant",
"medline_ta": "G Ital Nefrol",
"mesh_terms": "D000328:Adult; D006332:Cardiomegaly; D004044:Dietary Proteins; D005923:Glomerulosclerosis, Focal Segmental; D006801:Humans; D017379:Hypertrophy, Left Ventricular; D007052:Ibuprofen; D007676:Kidney Failure, Chronic; D007678:Kidney Glomerulus; D008297:Male; D064797:Physical Conditioning, Human; D050199:Podocytes; D019966:Substance-Related Disorders; D045165:Testosterone Congeners",
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"references": null,
"title": "FSGS collapsing variant during anabolic steroid abuse: Case Report.",
"title_normalized": "fsgs collapsing variant during anabolic steroid abuse case report"
} | [
{
"companynumb": "IT-TEVA-2019-IT-1083953",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
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"activesubstance": {
"activesubstancename": "IBUPROFEN"
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"abstract": "Pial arteriovenous fistulae (AVFs) are rare vascular abnormalities that are distinct from arteriovenous malformations and dural AVFs. These vascular lesions have been linked with trauma, ischemic syndromes, venous thrombotic diseases, and intracranial surgical procedures. In this report we describe a case of an intracranial ruptured pial AVF immediately following uneventful spinal surgery in an elderly patient with subsequent spontaneous resolution. He was a previous heavy smoker with a 60-pack-year history and alcohol abuse. His examination was positive for morbid obesity and mild weakness of the anterior tibialis and gastrocnemius muscles bilaterally. He underwent uneventful spinal surgery, suffering a generalized seizure shortly after extubation. Imaging studies demonstrated acute subarachnoid hemorrhage and cerebral angiography identified a pial AVF. He was stabilized medically and follow-up angiography demonstrated spontaneous resolution of the pial AVF. This case highlights a rare vascular malformation with rupture following uneventful spinal surgery.",
"affiliations": "Mayo Clinic in Arizona, USA.;Mayo Clinic in Arizona, USA.;Mayo Clinic in Arizona, USA.;Mayo Clinic in Arizona, USA.;Mayo Clinic in Arizona, USA.",
"authors": "Lyons|Mark K|MK|;Hoxworth|Joseph M|JM|;McClendon|Jamal|J|;Krishna|Chandan X|CX|;Patel|Naresh P|NP|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1177/1971400916689576",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1971-4009",
"issue": "30(2)",
"journal": "The neuroradiology journal",
"keywords": "Pial arteriovenous fistula; spine surgery; subarachnoid hemorrhage",
"medline_ta": "Neuroradiol J",
"mesh_terms": "D000368:Aged; D017542:Aneurysm, Ruptured; D020785:Central Nervous System Vascular Malformations; D002533:Cerebral Angiography; D006801:Humans; D008297:Male; D019635:Neurosurgical Procedures; D010841:Pia Mater; D011183:Postoperative Complications; D013122:Spinal Diseases; D015898:Tomography Scanners, X-Ray Computed",
"nlm_unique_id": "101295103",
"other_id": null,
"pages": "175-179",
"pmc": null,
"pmid": "28151094",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "2505503;23346547;14978926;2034363;24097086;8009411;11981628;21501060;2838360;18159139;831316;11846934;22120267;10548689;9555640",
"title": "Spontaneous resolution of ruptured intracranial pial arteriovenous fistula following spinal surgery.",
"title_normalized": "spontaneous resolution of ruptured intracranial pial arteriovenous fistula following spinal surgery"
} | [
{
"companynumb": "US-UCBSA-2017021915",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PROPOFOL"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We present, to our knowledge, the first case of fatal fulminant liver failure associated with hepatitis E virus infection, autoimmune hepatitis, and excessive paracetamol intake, which occurred in a 77-year-old woman. Hepatitis E testing should be performed in severe acute liver failure cases, even when another cause has been identified.",
"affiliations": "Hôpital Saint-Joseph, Service de Médecine Interne, Marseille, France.",
"authors": "Doudier|Barbara|B|;Vencatassin|Hugues|H|;Aherfi|Sarah|S|;Colson|Philippe|P|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D012367:RNA, Viral; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1128/JCM.03372-13",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0095-1137",
"issue": "52(4)",
"journal": "Journal of clinical microbiology",
"keywords": null,
"medline_ta": "J Clin Microbiol",
"mesh_terms": "D000082:Acetaminophen; D000368:Aged; D018712:Analgesics, Non-Narcotic; D016000:Cluster Analysis; D017809:Fatal Outcome; D005260:Female; D005602:France; D016751:Hepatitis E; D016752:Hepatitis E virus; D019693:Hepatitis, Autoimmune; D006801:Humans; D017093:Liver Failure; D008969:Molecular Sequence Data; D010802:Phylogeny; D012367:RNA, Viral; D017422:Sequence Analysis, DNA",
"nlm_unique_id": "7505564",
"other_id": null,
"pages": "1294-7",
"pmc": null,
"pmid": "24478416",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "18346187;18821593;18486561;18360913;22121109;19656710;19401616;17439518;22099089;21855518;16482537;18617784;23556050;16801899;20695795;22273541;22647825;21764632;23343760;14686743;15674089;22733353;19804658;21281681;18094741;17434400;24462173;17125878;21320558;23303497;18992406;24465537;24099020;17850420;20638564;20494538;23054435;16801900;19638731;22592074;18192058;22499295;20695796;23200774;21837786;22549046;19116067",
"title": "Fatal fulminant hepatitis E associated with autoimmune hepatitis and excessive paracetamol intake in Southeastern France.",
"title_normalized": "fatal fulminant hepatitis e associated with autoimmune hepatitis and excessive paracetamol intake in southeastern france"
} | [
{
"companynumb": "PHHY2015FR016923",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM\\MISOPROSTOL"
},
"drugadditional": n... |
{
"abstract": "An 80-year-old male was referred to our department for prolonged APTT (activated partial thromboplastin time) and subcutaneous hemorrhage. His medical history comprised alcoholic liver cirrhosis, hepatocellular carcinoma (HCC), and peripheral artery disease (PAD). For refractory HCC, he had received transcatheter arterial chemoembolization and was followed up regularly at our hospital. He underwent percutaneous transluminal angioplasty for PAD 10 months ago, and dual antiplatelet therapy with clopidogrel and cilostazol was initiated. Cilostazol was discontinued owing to subcutaneous hemorrhage 6 months ago. The prolonged APTT level, inhibitor pattern by cross-mixing test, and the presence of the inhibitor against factor VIII (449 Bethesda unit/ml) corroborated acquired hemophilia A (AHA). Thus, clopidogrel was discontinued for possible drug-induced AHA. After 4-week oral corticosteroid therapy, the APTT level recovered to normal. This case highlights two distinct features as follows: (1) possible relation to clopidogrel; and (2) despite extremely high titer of factor VIII inhibitor, his bleeding episodes were managed without antihemorrhagic agents. Here we present a case of clopidogrel-related AHA. Further accumulation of such cases is warranted to determine the potential correlation with clopidogrel and AHA.",
"affiliations": "Kyoto University Hospital, Department of Hematology.;Nara Medical University Hospital, Department of Pediatrics.;Osaka Red Cross Hospital, Department of Hematology.;Osaka Red Cross Hospital, Department of Hematology.",
"authors": "Shimizu|Takuya|T|;Nogami|Keiji|K|;Mizutani|Chisato|C|;Imada|Kazunori|K|",
"chemical_list": "D005169:Factor VIII; D000077144:Clopidogrel",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.291",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0485-1439",
"issue": "60(4)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Acquired hemophilia A; Clopidogrel; Hepatocellular carcinoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular; D016461:Chemoembolization, Therapeutic; D000077144:Clopidogrel; D005169:Factor VIII; D006467:Hemophilia A; D006801:Humans; D008113:Liver Neoplasms; D008297:Male",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "291-295",
"pmc": null,
"pmid": "31068558",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acquired hemophilia A with high-titer factor VIII inhibitor developing subsequent to clopidogrel administration.",
"title_normalized": "acquired hemophilia a with high titer factor viii inhibitor developing subsequent to clopidogrel administration"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2019RR-221358",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BENIDIPINE"
},
"dru... |
{
"abstract": "The impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).\n\n\n\nA woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On second postpartum day, the mother was in good condition and was switched to oral steroid therapy. On third postpartum day she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.\n\n\n\nWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.",
"affiliations": "Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Unit of Obstetrics and Gynecology, Department of Woman, Child and Neonate, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Neonatology and Neonatal Intensive Care Unit (NICU), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.;Neonatology and Neonatal Intensive Care Unit (NICU), Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.;Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.;Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.",
"authors": "Giavoli|Claudia|C|;Iurlaro|Enrico|E|;Morelli|Valentina|V|;Rodari|Giulia|G|;Ronchi|Andrea|A|;Pietrasanta|Carlo|C|;Pugni|Lorenza|L|;Tubiolo|Daniela|D|;Properzi|Paolo|P|;Pesenti|Antonio|A|;Mantovani|Giovanna|G|;Ferrazzi|Enrico|E|;Arosio|Maura|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fendo.2020.602535",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392 Frontiers Media S.A. \n\n10.3389/fendo.2020.602535\nEndocrinology\nCase Report\nCase Report: Late-Onset Congenital Adrenal Hyperplasia and Acute Covid-19 Infection in a Pregnant Woman: Multidisciplinary Management\nGiavoli Claudia 12* Iurlaro Enrico 3 Morelli Valentina 1 Rodari Giulia 12 Ronchi Andrea 4 Pietrasanta Carlo 24 Pugni Lorenza 4 Tubiolo Daniela 5 Properzi Paolo 5 Pesenti Antonio 56 Mantovani Giovanna 12 Ferrazzi Enrico 23 Arosio Maura 12 1Endocrinology Unit, Fondazione Istituto di Ricerca e Cura a Carattere Scientifico (IRCCS) Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy\n2Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy\n3Unit of Obstetrics and Gynecology, Department of Woman, Child and Neonate, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy\n4Neonatology and Neonatal Intensive Care Unit (NICU), Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy\n5Department of Anesthesia, Critical Care and Emergency, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy\n6Department of Pathophysiology and Transplantation, University of Milan, Milan, Italy\nEdited by: Riccarda Granata, University of Turin, Italy\n\nReviewed by: Svetlana Lajic, Karolinska Institutet (KI), Sweden; Jesús Devesa, University of Santiago de Compostela, Spain\n\n*Correspondence: Claudia Giavoli, claudia.giavoli@unimi.itThis article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology\n\n\n15 1 2021 \n2020 \n15 1 2021 \n11 60253503 9 2020 02 12 2020 Copyright © 2021 Giavoli, Iurlaro, Morelli, Rodari, Ronchi, Pietrasanta, Pugni, Tubiolo, Properzi, Pesenti, Mantovani, Ferrazzi and Arosio2021Giavoli, Iurlaro, Morelli, Rodari, Ronchi, Pietrasanta, Pugni, Tubiolo, Properzi, Pesenti, Mantovani, Ferrazzi and ArosioThis 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.Background\nThe impact of the Covid-19 infection on patients with chronic endocrine disease is not fully known. We describe here the first case of a pregnant woman with Covid-19 acute infection and non-classical congenital adrenal hyperplasia (NCAH).\n\nCase description\nA woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). Her medical history was positive for NCAH on chronic steroid replacement till the age of 17 years (cortisone acetate and dexamethasone, both in the morning). At admission, her naso-oro-pharyngeal swab resulted positive for SARS-CoV-2. Due to hyperpyrexia and late preterm PROM, cesarean section was planned, and she was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h. A female neonate in good clinical condition and with a negative nasopharyngeal Covid-19 swab was delivered. On second postpartum day, the mother was in good condition and was switched to oral steroid therapy. On third postpartum day she worsened, with radiological signs of acute pulmonary embolism. Oro-tracheal intubation and mechanical ventilation were started, and she was switched back to intravenous steroid therapy. On April 30, pulmonary embolism was resolved, and on May 13th she was discharged in good condition.\n\nConclusions\nWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement. The management of the patient in a reference center with early involvement of a multidisciplinary team granted prompt care and adequate protection for all the involved sanitary operators.\n\npregnancyCovid-19congenital adrenal hyperplasiaadrenalsteroid replacement\n==== Body\nBackground\nIn Italy, Lombardy was one of the first and worst hit regions by the novel coronavirus disease (Covid-19). Here we describe the first case of acute Covid-19 infection in a pregnant woman affected with late-onset congenital adrenal hyperplasia.\n\nCase Description\nOn April 6, 2020, a 39 years-old pregnant woman at 36 weeks of gestation was referred to our Maternity Hospital for premature rupture of membranes (PROM). In the previous days, she had suffered from hyperpyrexia up to 38.6°C, easily managed by paracetamol. Prior to admission, the naso-oro-pharyngeal swab performed in the emergency room resulted positive for SARS-CoV-2 at rRT-PCR assay. She weighed 97 kg, her height was 166 cm, blood pressure was 128/74 mmHg, O2sat was 100%, and respiratory rate was 16 bpm. Medical history was positive for late onset congenital adrenal hyperplasia due to 21-hydroxilase deficiency (NCAH) diagnosed at the age of 17 because of elevated basal 17-hydroxyprogesterone (17OHP) concentrations at the investigations performed for hyperandrogenism and alopecia. Since then, she was on steroid replacement therapy (cortisone acetate 12.5 mg plus dexamethasone 0.75 mg per day, both in the morning). She had two previous pregnancies, one six years earlier, delivered at term and one first trimester miscarriage. Glucocorticoid dosage had never been adjusted. Cesarean section was planned due to persisting hyperpyrexia and late preterm PROM. She was started on a 100 mg-bolus of hydrocortisone, followed by continuous infusion of 200 mg/24 h as indicated to avoid adrenal crisis in surgical intervention of chronic adrenal insufficient patients (1–3). She was delivered by cesarean section under spinal anesthesia, provided its positive influence on cardiopulmonary function (4).\n\nAt 36 weeks of gestational age, a female neonate was delivered. She was in good clinical condition, and her nasopharyngeal swab for SARS-CoV-2 by rRT-PCR was negative.\n\nOn second postpartum day, the mother was in good condition and was switched from intravenous to oral supra-physiological steroid therapy (cortisone acetate 25 + 12.5 + 12.5 mg/day); at that time since her temperature was 37.5°C, she was started on full dose low molecular weight heparin. On the third day her clinical conditions progressively worsened, with fever >39°C associated with respiratory symptoms requiring O2 support. Thus, therapy with hydroxychloroquine and azithromycin was started. Accordingly, cortisone acetate was increased to overall 75 mg/day. A Chest Computed Tomography (CT) showed signs of acute pulmonary embolism, along with extensive ground-glass opacifications involving both the lung parenchyma (Figure 1) and laboratory tests showed high D-Dimer (4,136 µg/L, nv <500 µg/L) and CRP (11.22 mg/dl, nv < 0.05 mg/dl). Her conditions rapidly worsened so she was moved to the Intensive Care Unit (ICU); orotracheal intubation along with mechanical ventilation were started, and she was promptly switched back to intravenous steroid therapy (Hydrocortisone, 50 mg every 6 h iv).\n\nFigure 1 Chest CT showing signs of acute pulmonary embolism, along with extensive ground-glass opacifications involving both the lung parenchyma.\n\nThis aggressive respiratory and medical support allowed her to recover and, after the first week, to improve significantly her general condition. On April 30, pulmonary embolism was completely resolved at CT scans. Finally, on May 13th, she was discharged in good condition.\n\nAt the beginning of May, hydrocortisone was progressively reduced and switched to oral route (cortisone acetate 12.5 + 12.5 + 6.25 mg) to continue monitoring at our tertiary outpatient’s clinics.\n\nDiscussion\nWe report the first case of Covid-19 acute infection that occurred in late-pregnancy in a woman with NCAH on chronic steroid replacement.\n\nNon-classic congenital adrenal hyperplasia is an autosomal recessive disorder due to a deficiency of 21-hydroxylase, an essential enzyme for the adrenal synthesis of cortisol and aldosterone. NCAH patients typically have 20–70% residual enzyme activity, enough to maintain a normal electrolyte homeostasis by aldosterone, but with a variable deficiency of cortisol, reduced pituitary feed-back, and increased ACTH and adrenal androgen production. By suppressing ACTH production, glucocorticoids can normalise the excessive androgen production and can be used in symptomatic patients to increase fertility and during pregnancy (3, 5–7). However, during pregnancy and especially in NCAH, most experts do not recommend dexamethasone, a category C drug that passes the placenta and has potential adverse effects on both mother and fetus (3, 6, 8).\n\nIn the absence of data about her native adrenal function, we managed successfully the patient as adrenal insufficient according to the current Guidelines (1–3). Definitely, this could be assumed at least as resulting from long-term (more than 20 years) high dose steroid treatment.\n\nThe COVID-19 infection, in this case probably of familiar origin, affected many young women between March and April in Lombardy, where about 9% of cases occurred in women between 30 and 39 years (9). However, the disease was particularly severe in our patient requiring a long recovery in ICU with a particularly challenging management, since the infection spread in late pregnancy.\n\nIndeed, a systematic review including 538 pregnant women with Covid-19 infection reported approximately the same rate of ICU admission as in the non-pregnant population, but an increased risk of preterm and cesarean delivery (10).\n\nTo frame the situation, in the period between March 1st and April 30th, 852 women delivered in Mangiagalli Obstetrics Unit, a high-risk maternity center in Milan, and one of the six Covid-19 hubs identified in Lombardy to centralize care of pregnant patients affected by SARS Co-v 2 infection (11). Among these, 25 had confirmed COVID-19 infection (3%). In the Covid-19 group, 11 (44%) women delivered by cesarean and 14 (56%) vaginally. Only two women were admitted to the ICU and one in the sub-intensive Unit. The patient here described was the only one requiring mechanical ventilation.\n\nIt is possible to hypothesize that the long-term steroid therapy may have contributed to cause either a major risk of infection or a greater clinical picture severity. Concordant to this hypothesis, a recent paper reported an increased risk of lower respiratory tract infections in CAH patients on chronic glucocorticoids therapy, not only compared to general population, but also to CAH patients not treated with glucocorticoids, thus enlightening that non-physiological delivery of glucocorticoid replacement may represents a risk factor for infections development (12). Moreover, as in other critical illnesses, Covid-19 pneumonia can affect residual adrenal function through cytokine release, not only worsening the outcome but also raising the risk either of medical complications as well as of progressing to worse critical stages (13). Few data on Covid-19 infection spread and course in patients with adrenal disorders are available so far. A recent survey published by our group reported a similar rate and severity of Covid-related symptoms in adrenal insufficient patients and in controls (14). In this study CAH patients were excluded because of the possible detrimental role both of androgen excess and of not fully physiological steroid therapy.\n\nWhile present report was under review, a first case of SARS-CoV-2 infection in a 5-week-old infant with adrenal insufficiency secondary to CAH was published (15). The authors underline the positive clinical course of SARS-CoV-2, even in the presence of underlying adrenal insufficiency and suggest that even though hydrocortisone was started to treat adrenal insufficiency, it may have also contributed to improve response to SARS-CoV-2 infection.\n\nSimilarly, in the woman here reported, hydrocortisone 200 mg/die (1) has been sufficient not only to prevent acute adrenal crisis but also to reach disease remission (16).\n\nFrom the pandemic outspread up to now, plenty of literature has tried to widen the knowledge of this novel Coronavirus, and the medical approach is continuously evolving.\n\nFor instance, considering the latest data about the use of dexamethasone (17, 18), it is possible to hypothesize that an earlier use of higher corticosteroid dose might have prevented the worsening of her clinical conditions.\n\nSimilarly, even though no consensus is still available, more recent case series or reports about postpartum patients with Covid-19 infection tend to support the benefits of thromboprophylaxis (19). Moreover, in the last few months the role of immune response on the pathogenesis of Covid-19 complications pointed out the possible benefit of immune-modulators as adjuvant therapy (20). In this context, reports about the use of melatonin suggest its possible beneficial effects in anti-inflammation, anti-oxidation, immune response regulation, as demonstrated in respiratory disorder models induced by infections. Thus, even though the direct evidence of melatonin application in Covid-19 is not fully clear, given also its high safety profile, these suggestions may prompt its use in Covid-19 patients (21).\n\nTreating an acute Covid-19 infection, spread in late pregnancy and at the beginning of Covid-19 pandemic, was particularly challenging not only for the adrenal condition, but also for all the uncertainties on best therapeutic approaches.\n\nUndoubtedly, the management of the patient and the neonate in a reference center with early involvement of a multidisciplinary team, through application of the best medical knowledges available at that time, granted prompt care for them and adequate protection for all the involved sanitary operators.\n\nData Availability Statement\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nCG, EI, VM, CP, AR, CP, LP, DT, and PP performed treatment and follow-up of the patients and the newborn. CG, VM, and GR collected clinical data and prepared the manuscript. AP, GM, EF, and MA performed the critical revision of the manuscript. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n1 \nWoodcock T Barker P Daniel S Fletcher S Wass JAH Tomlinson JW \nGuidelines for the management of glucocorticoids during the peri-operative period for patients with adrenal insufficiency\n. Anaesthesia (2020 ) 75 :654–63. 10.1111/anae.14963 \n\n2 \nBornstein SR Allolio B Arlt W Barthel A Don-Wauchope A Hammer GD \nDiagnosis and Treatment of Primary Adrenal Insufficiency: An Endocrine Society Clinical Practice Guideline\n. J Clin Endocrinol Metab (2016 ) 101 :364–89. 10.1210/jc.2015-1710 \n\n3 \nSpeiser PW Arlt W Auchus RJ Baskin LS Conway GS Merke DP \nCongenital Adrenal Hyperplasia due to Steroid 21-Hydroxylase Deficiency: An Endocrine Society Clinical Practice Guideline\n. J Clin Endocrinol Metab (2018 ) 103 :4043–88. 10.1210/jc.2018-01865 \n\n4 \nPeng PWH Ho P-L Hota SS \nOutbreak of a new coronavirus: what anaesthetists should know\n. Br J Anaesth (2020 ) 124 :497 –501\n. 10.1016/j.bja.2020.02.008 \n32115186 \n5 \nNordenstrom A Falhammar H \nMANAGEMENT OF ENDOCRINE DISEASE: Diagnosis and Management of the Patient with Non-Classic CAH Due to 21-hydroxylase Deficiency\n. Eur J Endocrinol Metab (2019 ) 180 :R127–45. 10.1530/EJE-18-0712 \n\n6 \nvan’t Westeinde A Karlsson L Nordenström A Padilla N Lajic S \nFirst-Trimester prenatal Dexamethasone Treatment is Associated with Alterations in Brain Structure at Adult Age\n. J Clin Endocrinol Metab (2020 ) 105 :1 –12\n. 10.1210/clinem/dgaa340 \n\n7 \nParsa AA New MI \nSteroid 21-hydroxylase Deficiency in Congenital Adrenal Hyperplasia\n. J Steroid Biochem Mol Biol (2017 ) 165 :2 –11\n. 10.1016/j.jsbmb.2016.06.015 \n27380651 \n8 \nBothou C Anand G Li D Kienitz T Seejore K Simeoli C \nCurrent management and outcome of pregnancies in women with adrenal insufficiency: experience from a multi-center survey\n. Clin Endocrinol Metab (2020 ). 10.1210/clinem/dgaa266 \n\n9 \nIstituto Superiore di Sanità \nCoronavirus\n(2020 ). Available at: https://www.epicentro.iss.it/coronavirus/ (Accessed May 20, 2020).\n\n10 \nHuntely BJ Huntley ES Di Mascio D Chen T Berghella V Chauhan SP \nRates of Maternal and Perinatal Mortality and Vertical Transmission in Pregnancies Complicated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-Co-V-2) Infection: A Systematic Review\n. Obstet Gynecol (2020 ). 10.1097/AOG.0000000000004010 \n\n11 \nFerrazzi EM Frigerio L Cetin I Vergani P Spinillo A Prefumo F \nCOVID-19 Obstetrics Task Force, Lombardy, Italy: Executive management summary and short report of outcome\n. Int J Gynaecol Obstet (2020 ) 149 :377–8. 10.1002/ijgo.13162 \n\n12 \nTresoldi AS Sumilo D Perrins M Toulis KA Prete A Reddy N \nIncreased Infection Risk in Addison’s Disease and Congenital Adrenal Hyperplasia\n. J Clin Endocrinol Metab (2020 ) 105 :418–29. 10.1210/clinem/dgz006 \n\n13 \nTeblick A Peeters B Langouche L Van den Berghe G \nAdrenal function and dysfunction in critically ill patients\n. Nat Rev Endocrinol (2019 ) 15 :417–27. 10.1038/s41574-019-0185-7 \n\n14 \nCarosi G Morelli V Del Sindaco G Serban AL Cremaschi A Frigerio S \nAdrenal insufficiency at the time of COVID-19: a retrospective study in patients referring to a tertiary centre\n. J Clin Endocrinol Metab (2020 ). 10.1210/clinem/dgaa793 \n\n15 \nAzouz H Gerrits P Surhigh J Kalladi Puthanpurayil SK \nCOVID-19 in an Infant with Congenital Adrenal Hyperplasia: A Case Report\n. Global Pediatr Health (2020 ) 7 :1 –3\n. 10.1177/2333794X20958933 \n\n16 \nIsidori AM Arnaldi G Boscaro M Falorni A Giordano C Giordano R \nCOVID−19 infection and glucocorticoids: update from the Italian Society of Endocrinology Expert Opinion on steroid replacement in adrenal insufficiency\n. J Endocrinol Invest (2020 ). 10.1007/s40618-020-01266-w \n\n17 \nJohnson RM Vinetz JM \nDexamethasone in the management of Covid -19\n. BMJ (2020 ) 370 :m2648. 10.1136/bmj.m2648 \n32620554 \n18 \nMukhtar H Ahmed MH Hassan A \nDexamethasone for the Treatment of Coronavirus Disease (COVID-19): a Review\n. SN Compr Clin Med (2020 ). 10.1007/s42399-020-00610-8 \n\n19 \nBenhamou D Keita H Ducloy-Bouthors AS CARO working group \nCoagulation changes and thromboembolic risk in COVID-19 obstetric patients\n. Anaesth Crit Care Pain Med (2020 ) 39 :351–3. 10.1016/j.accpm.2020.05.003 \n\n20 \nMoghadam SO \nReview on currently available potential therapeutic options for COVID-19\n. Int J Gen Med (2020 ) 13 :443–67. 10.2147/IJGM.S263666 \n\n21 \nGarcía Garcia I Rodriguez-Rubio M Rodríguez Mariblanca A Martínez de Soto L Díaz García L Monserrat Villatoro J \nA randomized multicenter clinical trial to evaluate the efficacy of melatonin in the prophylaxis of SARS-CoV-2 infection in high-risk contacts (MeCOVID Trial): A structured summary of a study protocol for a randomised controlled trial\n. Trials (2020 ) 21 (1 ):46 . 10.1186/s13063-020-04436-6 \n31915043\n\n",
"fulltext_license": "CC BY",
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"keywords": "Covid-19; adrenal; congenital adrenal hyperplasia; pregnancy; steroid replacement",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": "D000312:Adrenal Hyperplasia, Congenital; D000328:Adult; D017668:Age of Onset; D000086382:COVID-19; D002585:Cesarean Section; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D037841:Pregnant Women; D011379:Prognosis; D000086402:SARS-CoV-2",
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"title": "Case Report: Late-Onset Congenital Adrenal Hyperplasia and Acute Covid-19 Infection in a Pregnant Woman: Multidisciplinary Management.",
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"abstract": "Clozapine has been widely used as an antipsychotic drug for the treatment of refractory schizophrenia. Unfortunately, a wide range of blood dyscrasias have been reported as adverse effects of this drug. Agranulocytosis has gotten the most clinical vigilance; however, there are substantial reports of other blood dyscrasias associated with Clozapine some more serious than others. Of relevance, there have been previous claims of Clozapine-associated leukocytosis and acute myeloid leukemia. We report the case of a 31-year-old patient who developed Acute lymphoblastic leukemia shortly after starting treatment with Clozapine for refractory schizophrenia. We suggest Clozapine may play a causal role in the development of leukemias in patients taking this medication and we encourage vigilance for such correlation.",
"affiliations": "Department of Internal medicine, St Joseph's University Medical Center, Paterson, NJ, United States of America.;Department of Internal medicine, St Joseph's University Medical Center, Paterson, NJ, United States of America.",
"authors": "Augustin|Neslyne B|NB|;Maroules|Michael|M|",
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"fulltext": "\n==== Front\nLeuk Res Rep\nLeuk Res Rep\nLeukemia Research Reports\n2213-0489\nElsevier\n\nS2213-0489(21)00020-0\n10.1016/j.lrr.2021.100253\n100253\nArticle\nHyperleukocytosis during clozapine treatment: A rare presentation of B-cell Acute lymphoblastic leukemia\nAugustin Neslyne B neslyne.b.augustin@gmail.com\na⁎\nMaroules Michael ab\na Department of Internal medicine, St Joseph's University Medical Center, Paterson, NJ, United States of America\nb Division of Hematology and Oncology, St Joseph's University Medical Center, Paterson, NJ, United States of America\n⁎ Corrresponding author. neslyne.b.augustin@gmail.com\n31 5 2021\n2021\n31 5 2021\n15 10025316 10 2020\n22 3 2021\n23 5 2021\n© 2021 The Author(s). Published by Elsevier Ltd.\n2021\n\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).\nClozapine has been widely used as an antipsychotic drug for the treatment of refractory schizophrenia. Unfortunately, a wide range of blood dyscrasias have been reported as adverse effects of this drug. Agranulocytosis has gotten the most clinical vigilance; however, there are substantial reports of other blood dyscrasias associated with Clozapine some more serious than others. Of relevance, there have been previous claims of Clozapine-associated leukocytosis and acute myeloid leukemia. We report the case of a 31-year-old patient who developed Acute lymphoblastic leukemia shortly after starting treatment with Clozapine for refractory schizophrenia. We suggest Clozapine may play a causal role in the development of leukemias in patients taking this medication and we encourage vigilance for such correlation.\n\nKeywords\n\nB-cell Acute lymphoblastic leukemia\nClozapine toxicity\nHyperleukocytosis\nSchizophrenia\n==== Body\n1 Background\n\nAcute lymphoblastic leukemia (ALL) is known to have a bimodal distribution with occurrence in children and in adults in the fifth decade of life. Incidence is twice as high in the children population than in the latter [5]. Studies of the adult population affected by ALL show a higher incidence in males and in Hispanics [9]. ALL is subcategorized into B-cell ALL or T-cell ALL depending on progenitor cells characteristics. B cell ALL (B-ALL) is a subtype of ALL that involves a dysregulation of B cell lymphoid progenitor cells. B-ALL is more common than the T cell subtype [5].\n\nClozapine is an atypical antipsychotic drug that has been shown to be superior to other drugs in the same class in patients with medication-resistant schizophrenia [10]. Agranulocytosis is a well-established side effect of this drug and is routinely monitored in patients taking this medication. Other blood dyscrasias get limited attention during Clozapine treatment [1].\n\nThere has been increasing evidence of cytotoxicity of Clozapine. More specifically, the metabolite N-desmethyl clozapine has been identified as toxic to myeloid precursor cells [4]. This raises the possibility of this metabolite being toxic to a more primitive stem cell precursor of both myeloid and lymphoid stem cells. Both Clozapine and N-desmethyl Clozapine were shown to be toxic to CD34+ progenitor cells. A study using the Danish register found an eight-fold increased risk of developing acute myeloid leukemia (AML) in patients treated with Clozapine versus patients not receiving clozapine [8]. In fact, cases of malignancies in patients receiving Clozapine for treatment-resistant schizophrenia have been substantial enough to generate ample literature discussion about the continuation of this medication during chemotherapy in that population [3]. Nonetheless, few of those investigations considered Clozapine as the potential carcinogenic agent. Association of clozapine with lymphoma has also been reported [7]. Toxicity has been reported in other organs; we cite clozapine-associated myocarditis [6] and parenchymal lung disease [2]. The latter is potentially conflicting with the finding of lower incidence of lung cancer among patients taking clozapine [11]. Studies on both sides do agree that Clozapine has considerate cellular effects commendable for further study.\n\nWe report the case of a patient with medication-resistant Schizophrenia who developed B-ALL shortly after starting Clozapine treatment.\n\n2 Case presentation\n\nThe case is about a 31-year-old Hispanic male with Schizophrenia diagnosed at age 29. The patient had been treated with multiple medication regimens without much success to control his psychotic outbreaks. The patient was most recently started on clozapine by his psychiatrist and was subsequently scheduled for regular blood monitoring. The patient had been taking Clozapine for a total of 8 months. Routine complete blood count (CBC) was repeated every two weeks. White blood cells (WBC) trended from 6.9 x10³/μL to 21.2 x10³/μL in two weeks. On the next routine CBC, WBC spiked to 104x10³/μL. (See Table 1) This prompted the psychiatrist to send the patient to Emergency department for further evaluation.Table 1 Ten-week trend CBC with differentials.\n\nTable 1\tDOA*\t2-wks\t4-wks\t6-wks\t8-wks\t10-wks\t\nWBC (x10³/μL)\t104.0\t21.2\t6.9\t5.2\t4.3\t5.8\t\nNeutrophils (%)\t4\t2\t20\t29\t41\t43\t\nBands (%)\t2\t3\t3\t0\t1\t3\t\nLymphocytes (%)\t10\t65\t48\t70\t50\t51\t\nMonocytes (%)\t1\t1\t3\t1\t8\t2\t\nEosinophils (%)\t2\t0\t0\t\t\t\t\nBasophils (%)\t0\t0\t0\t\t\t1\t\nMetalymphocytes (%)\t0\t1\t1\t\t\t\t\nBlast (%)\t3\t15\t7\t\t\t\t\nAtypical lymphocytes (%)\t78\t13\t19\t\t\t\t\nHemoglobin (g/dL)\t12.1\t14.4\t15.1\t14.9\t14.5\t14.6\t\nPlatelets (x 10³/μL)\t104\t132\t190\t263\t273\t289\t\n-wks: weeks before DOA.\n\n⁎ DOA: day of admission.\n\nUpon admission, review of systems was positive only for vague generalized weakness and fatigue for the past “few” months. Patient denied any fever, chills, night sweats, weight loss, sore throat, cough, chest pain, SOB, abdominal pain, nausea, vomiting, or changes in bowel movements. He also denied any rash or bleeding from his gums. There is no family history of malignancy. Physical exam was significant only for obesity and tender cervical lymphadenopathy noted on the right.\n\nLaboratory was significant for hyperleukocytosis with WBC 104x10³/μL (normal range: 4.5–11x10³/μL). Differentials were 78% atypical lymphocytes, 10% lymphocytes, 3% blasts (Figure 1), 4% neutrophils, 2% bands, 1% monocytes, 2% eosinophils (See Table 1 for 10-week trend). Laboratory was also significant for mildly elevated LDH 289 unit/L (normal range: 140-271 unit/L) and new-onset thrombocytopenia and normocytic anemia. HIV was negative. Peripheral blood Flow cytometry analysis showed 85% of the cells consisting of TdT+, CD34+ B cell lymphoblasts; consistent with the diagnosis of B cell ALL (See Table 2).Table 2 Peripheral blood flow cytometry analysis.\n\nTable 2Viability & Abnormal Cells\t\nViability\t89%\t\nAnormal Cells\tYes\t\n% Abnormal Cells\t85%\t\nCell Size\tLarge\t\nCell Distribution\t\nLymphocyte gate\t7.67%\t\nBlast Gate\t90.47%\t\nMonocyte Gate\t0.48%\t\nGranulocyte/Myeloid gate\t1.24%\t\nErythroid/Plasma Cell Gate\t0.00%\t\nB-lymhoblasts (TdT+, CD79a+, CD34+, CD19+, CD20dim+, CD22+) with co-expression of CD10 and HLA-DR.\n\nThe mature B-cells (1.1% of total) appear polytypic.\n\nThe T-cells (4.4% of total) show no pan T-cell antigenic deletion.\n\nCD4: CD8 T-cell ratio is 1:1.\n\n3 Treatment\n\nSoon after medication review during admission, Clozapine was discontinued. Patient was placed on a pediatric-inspired protocol given his age and poor prognostic feature including WBC>30x10³/μL . He received induction with Hyper-CVAD regimen. He was positive for minimal residual disease (MRD). Patient later relapsed and was then started on Inotuzumab after which he achieved remission.\n\n4 Discussion\n\nThis case offers the peculiar development of hyperleukocytosis during Clozapine treatment which is paradoxical to the more commonly anticipated agranulocytosis. This possibly explains the delay in clinical investigation even after the CBC revealed WBC 21 x10³/μL two weeks prior to admission; such high values were already within investigative range. Also significant with these values were 15% blasts and 13% atypical lymphocytes.\n\nWe should point this patient's age of 31 falls outside the more common population of the bimodal distribution of ALL. On the other hand, his Hispanic origin places him in the high-risk lifetime incidence population.\n\nOur case support previous claim that Clozapine may increase the risk of hematologic malignancies. We also believe correlation of clozapine with such malignancies may have been missed. We encourage report of similar cases for improve awareness during usage of this drug.\n==== Refs\nReference\n\n1 Alvir, Jose M.J. Lieberman Allan ZS Schwimmer Jeffrey L Schaaf John A Clozapine-induced Agrnulocytosis - Incidence and risk factors in the United States N. Engl. J. Med. 329 1993 162 167 8515788\n2 Bugge E. Nissen T. Wynn R. Probable clozapine-induced parenchymal lung disease and perimyocarditis: a case report BMC Psychiatry 16 1 2016 438 Dec 8 27931201\n3 Cunningham N.T. Dennis N. Dattilo W. Hunt M. Bradford D.W. Continuation of clozapine during chemotherapy: a case report and review of literature Psychosomatics 55 6 2014 673 679 10.1016/j.psym.2014.05.007 25497505\n4 Deliliers G.L. Servida F. Lamorte G. Quirici N. Soligo D. In vitro effect of clozapine on hemopoietic progenitor cells Haematologica 83 10 1998 882 889 9830796\n5 Jabbour E. O’Brien S. Konopleva M. Kantarjian H. New insights into the pathophysiology and therapy of adult acute lymphoblastic leukemia Cancer 121 2015 2517 2528 10.1002/cncr.29383 25891003\n6 Layland J.J. Liew D. Prior D.L. Clozapine-induced cardiotoxicity: a clinical update Med. J. Aust. 190 4 2009 190 192 19220183\n7 Leung J.G. Barreto J.N. Thompson C.A. Lymphoma following clozapine exposure: more information needed Schizophr. Res. 199 2018 420 421 10.1016/j.schres.2017.12.019 29329822\n8 Nielsen J. Boysen A. Clozapine treatment associated with increased risk of acute myeloid leukemia (AML) Schizophr. Res. 2010 123 2–3 2010 270 272 10.1016/j.schres.2010.08.035\n9 Pullarkat S.T. Danley K. Bernstein L. Brynes R.K. Cozen W. High lifetime incidence of adult acute lymphoblastic leukemia among Hispanics in California Cancer Epidemiol. Biomark. Prev. 18 2 2009 611 615 10.1158/1055-9965.EPI-07-2949\n10 Raguraman J. Vijay Sagar K.J. Chandrasekaran R Effectiveness of clozapine in treatment-resistant schizophrenia Indian J. Psychiatry 47 2 2005 102 105 10.4103/0019-5545.55955 20711291\n11 Yin Y.C. Lin C.C. Chen T.T. Clozapine induces autophagic cell death in non-small cell lung cancer cells Cell Physiol. Biochem. 35 3 2015 945 956 10.1159/000369751 25659606\n\n",
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"title": "Hyperleukocytosis during clozapine treatment: A rare presentation of B-cell Acute lymphoblastic leukemia.",
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"abstract": "Acyclovir produces neurologic symptoms that resemble extension of viral infection into the central nervous system. We discuss our observations in the cases of two patients with acyclovir neurotoxicity and review the findings of all previous reports in the English language literature. Systemic disease, most commonly renal dysfunction, preceded all 30 reported cases of acyclovir neurotoxicity. The most common symptoms were mental status disorder and involuntary movements. Measurement of serum acyclovir levels substantiated the diagnosis in only a subset of patients. Although all patients recovered, hemodialysis hastened the rate of recovery.",
"affiliations": "Department of Neurology, Shands Hospital, University of Florida, Gainesville 32610.",
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"abstract": "Bullous systemic lupus erythematosus (BSLE) is a blistering skin condition occurring in lupus patients. Although cutaneous manifestations are common in lupus (59-85%), BSLE is rare, affecting <5% of lupus patients with very few reported cases among Africans. Dapsone is effective in mild to moderate cases, but off-label standard-dose rituximab (1,000 mg 2 weeks apart) has led to good outcomes in refractory cases. We report the case of a 39-yearold African lady with BSLE, who was successfully treated with low-dose rituximab (500 mg 2 weeks apart), healing her skin lesions at one year post-treatment. Low-dose rituximab may be as effective as standard dosing for the treatment of severe bullous SLE and is recommended in low resource settings.",
"affiliations": "Internal Medicine Department, University of Uyo Teaching Hospital, Uyo. petersakpabio@yahoo.com.;Internal Medicine Department, University of Port Harcourt Teaching Hospital, Port-Harcourt, Rivers State. bolajio_o@yahoo.com.",
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"title": "Severe bullous systemic lupus erythematosus successfully treated with low dose rituximab: a case report from sub-Saharan Africa.",
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"abstract": "OBJECTIVE\nThe purpose of this article is to describe the imaging features of proximal femoral insufficiency fractures in patients on long-term bisphosphonate therapy.\n\n\nCONCLUSIONS\nThe imaging findings of bisphosphonate-related femoral insufficiency fractures, which include a typical proximal diaphyseal location and transverse liner radiolucency through localized thickening of the lateral cortex, allow a specific diagnosis.",
"affiliations": "Department of Radiology, University of Arizona, 1501 N Campbell Ave, Tucson, AZ 85724, USA.",
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "The shortage of deceased donors led to an increase of living related renal transplant performed in the presence of donor-specific antibodies (DSAs) or ABO incompatibilities. There are various desensitization protocols that have been proposed. Here, we describe the outcome of these sensitized patients. This is a prospective cohort study recruiting all kidney transplant recipients from August 2016 until June 2018. Deceased donations, ABO incompatible patients, and sensitized patients who were not prescribed on our desensitization protocol were excluded. Recipients were screened for the presence of HLA-antibodies 1 month before transplant. Those with positive DSA will undergo flow cytometry (risk stratification). We are using a protocol that consisted of intravenous rituximab 200 mg (day -14), intravenous antithymocyte globulin 5mg/kg (day 0-4), plasma exchange post transplant for patients with mean fluorescent intensity (MFI) < 3000, and negative flow cytometry. Those patients with MFI ≥ 3000 or positive flow cytometry need extra cycles pretransplant. A total of 40 patients were recruited, and 20 were sensitized patients. Among the sensitized group 4 of 20 had flow cytometry crossmatch positive, while all had preformed HLA-DSA. A total of 8 of 20 had class I HLA-DSA, 11 of 20 had class II HLA-DSA, and 1of 20 was positive for both class I and II HLA-DSA. Mean immunodominant MFI was 2133.4 (standard deviation [SD], 4451.24) and 1383.7 (SD, 2979.02) for class I and class II, respectively. At 1 year, mean serum creatinine was 108.90 (SD, 25.95) and 118.42 (SD, 31.68) in sensitized and unsensitized patients, respectively. One of 20 unsensitized patients had Banff 1B rejection at 3 months, and there was no significant rejection in sensitized patients at 6 months and 1 year. There was no difference in the occurrence of de novo HLA-DSA between the groups. Desensitization protocols may help to overcome incompatibility barriers in living donor renal transplant. The combination of low-dose rituximab, antithymocyte globulin, and judicious use of plasma exchange has worked well for our cohort.",
"affiliations": "Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia. Electronic address: mai_jalal@yahoo.com.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Renal Unit, Faculty of Medicine, Universiti Teknologi MARA, Sungai Buloh, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.;Division of Nephrology, Department of Medicine, University Malaya Medical Centre, Kuala Lumpur, Malaysia.",
"authors": "Jalalonmuhali|Maisarah|M|;Ng|Kok Peng|KP|;Mohd Shariff|Nur Hidayati|NH|;Lee|Yee Wan|YW|;Wong|Albert Hing|AH|;Gan|Chye Chung|CC|;Lim|Soo Kun|SK|",
"chemical_list": "D000906:Antibodies; D000961:Antilymphocyte Serum; D006680:HLA Antigens; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.02.140",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D000917:Antibody Formation; D000961:Antilymphocyte Serum; D015331:Cohort Studies; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D006085:Graft Survival; D006680:HLA Antigens; D006650:Histocompatibility Testing; D006801:Humans; D016030:Kidney Transplantation; D019520:Living Donors; D008296:Malaysia; D008297:Male; D008875:Middle Aged; D010956:Plasmapheresis; D057234:Preoperative Period; D011446:Prospective Studies; D000069283:Rituximab; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1718-1722",
"pmc": null,
"pmid": "32448671",
"pubdate": "2020",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "One-Year Outcomes of Living Related Kidney Transplant in Patients With Preformed HLA Donor-Specific Antibodies: A Single-Center Experience in Malaysia.",
"title_normalized": "one year outcomes of living related kidney transplant in patients with preformed hla donor specific antibodies a single center experience in malaysia"
} | [
{
"companynumb": "NVSC2020MY147726",
"fulfillexpeditecriteria": "1",
"occurcountry": "MY",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"druga... |
{
"abstract": "We report a case of an 83-year-old woman who developed tumor lysis syndrome (TLS) 5 days after FOLFIRI+cetuximab (Cmab) therapy. A huge ascending colon cancer measuring 10 cm in diameter and with peritoneal dissemination was diagnosed. Following successful therapy with FOLFIRI alone, FOLFIRI+Cmab was administered. On day 5, TLS was diagnosed with hyperuricemia, hyperkalemia, hyperphosphatemia, and an increase in serum creatinine. Intravenous furosemide, volume loading, and glucose-insulin therapy resulted in improvement of laboratory data in 2 days. However, she died on the 34th day due to multiple organ failure caused by aspiration pneumonia following small intestine functional ileus. Although TLS is a rare complication in colon cancer, its onset must be taken into consideration. Also, risk assessment and preventive therapy for TLS should be performed before cancer treatment.",
"affiliations": "Department of Surgery, Shimada Hospital.",
"authors": "Matsuyama|Satoru|S|;Kuramoto|Takako|T|;Tanaka|Ryosuke|R|;Hashiguchi|Kazutoshi|K|",
"chemical_list": "D000970:Antineoplastic Agents; D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "Japan",
"delete": false,
"doi": "10.11405/nisshoshi.112.714",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0446-6586",
"issue": "112(4)",
"journal": "Nihon Shokakibyo Gakkai zasshi = The Japanese journal of gastro-enterology",
"keywords": null,
"medline_ta": "Nihon Shokakibyo Gakkai Zasshi",
"mesh_terms": "D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D000068818:Cetuximab; D044682:Colon, Ascending; D003110:Colonic Neoplasms; D005260:Female; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D015275:Tumor Lysis Syndrome",
"nlm_unique_id": "2984683R",
"other_id": null,
"pages": "714-20",
"pmc": null,
"pmid": "25843460",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Tumor lysis syndrome after FOLFIRI+cetuximab for ascending colon cancer.",
"title_normalized": "tumor lysis syndrome after folfiri cetuximab for ascending colon cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2017M1001573",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CETUXIMAB"
},
"drugadditional": "3",
... |
{
"abstract": "Methotrexate (MTX)-associated lymphoproliferative disorders (MTX-LPDs) that occur in rheumatoid arthritis patients who were administered MTX for long periods are well known. However, studies on their pathology in forming hepatic tumors are rare. An approach using diagnostic imaging modalities, mainly computed tomography (CT), is considered a very useful tool for the differential diagnosis of various hepatic tumors. In the present study, detailed findings of dynamic CT, magnetic resonance (MR) imaging, and contrast-enhanced ultrasonography of a hepatic tumor that was confirmed as infected by Epstein-Barr virus, in a rheumatoid arthritis patient administered MTX are presented.",
"affiliations": "Department of Radiology, UBE INDUSTRIES, LTD. Central Hospital, 750 Nishikiwa, Ube, Yamaguchi 755-0151, Japan. Electronic address: r34tfuji@solid.ocn.ne.jp.",
"authors": "Fujita|Takeshi|T|;Tanabe|Masahiro|M|;Iida|Etsushi|E|;Okimoto|Tomoaki|T|;Matsunaga|Naofumi|N|",
"chemical_list": "D018501:Antirheumatic Agents; D007166:Immunosuppressive Agents; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-7071",
"issue": "37(5)",
"journal": "Clinical imaging",
"keywords": "Epstein-Barr virus; Hepatic tumor; Methotrexate; computed tomography",
"medline_ta": "Clin Imaging",
"mesh_terms": "D000368:Aged; D018501:Antirheumatic Agents; D001172:Arthritis, Rheumatoid; D003937:Diagnosis, Differential; D020031:Epstein-Barr Virus Infections; D004854:Herpesvirus 4, Human; D006801:Humans; D007166:Immunosuppressive Agents; D008113:Liver Neoplasms; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D064847:Multimodal Imaging",
"nlm_unique_id": "8911831",
"other_id": null,
"pages": "962-4",
"pmc": null,
"pmid": "23849101",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Multi-modality imaging findings of methotrexate-related Epstein-Barr virus-associated hepatic tumor.",
"title_normalized": "multi modality imaging findings of methotrexate related epstein barr virus associated hepatic tumor"
} | [
{
"companynumb": "PHHY2013JP114269",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
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