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"abstract": "Maternal folic acid (FA) intake before and during early pregnancy reduces the risk for neural tube defects (NTDs); evidence suggests it may also reduce the risk for oral clefts, urinary defects, and cardiac defects. We sought to re-examine the use of drugs, which affect folate metabolism, dihydrofolate reductase inhibiting (DHFRI) medications, and anti-epileptic drugs (AEDs), in data collected in the post-FA fortification era (1998+) in the Slone Birth Defects Study.\n\n\n\nWe assessed maternal DHFRI and AED use and risk for NTDs, oral clefts, and urinary and cardiac defects. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) using logistic regression. We assessed daily average FA intake of ≥400 mcg as a potential effect modifier.\n\n\n\nWe analyzed data from 10,209 control and 9,625 case mothers. Among controls, the prevalence of exposure to DHFRI medications was 0.3% and to AEDs was 0.5%. Maternal use of AEDs was associated with increased risks for NTDs (OR: 3.4; 95% CI: 1.5, 7.5), oral clefts (OR: 2.3; 95% CI: 1.3, 4.0), urinary defects (OR: 1.6; 95% CI: 1.0, 2.7), and cardiac defects (OR: 1.6; 95% CI: 1.1, 2.3); similar or further increased risks were found among those with FA intake ≥400 mcg per day. DHFRI use was rare and relative risk estimates were imprecise and consistent with the null.\n\n\n\nSimilar to our previous analyses, we observed associations between AED use and these defects. For DHFRI exposure, we found no evidence for increased risk of these defects. Though statistical power to examine FA effect modification was low, we found no evidence of further protection among those with FA intake ≥400 mcg, with some associations somewhat stronger in this group.",
"affiliations": "Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.;Department of Epidemiology, Boston University, Boston, Massachusetts, USA.;Slone Epidemiology Center at Boston University, Boston, Massachusetts, USA.;Centers for Disease Control and Prevention, National Center on Birth Defects and Developmental Disabilities, Atlanta, Georgia, USA.;Department of Epidemiology, Boston University, Boston, Massachusetts, USA.",
"authors": "Kerr|Stephen M|SM|0000-0001-9442-9737;Parker|Samantha E|SE|;Mitchell|Allen A|AA|;Tinker|Sarah C|SC|0000-0002-7610-6288;Werler|Martha M|MM|",
"chemical_list": "D005493:Folic Acid Antagonists; D005492:Folic Acid",
"country": "United States",
"delete": false,
"doi": "10.1002/bdr2.1789",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "112(18)",
"journal": "Birth defects research",
"keywords": "anti-epileptic drugs; birth defects; folic acid; folic acid antagonists; pregnancy",
"medline_ta": "Birth Defects Res",
"mesh_terms": "D016022:Case-Control Studies; D005260:Female; D005492:Folic Acid; D005493:Folic Acid Antagonists; D006801:Humans; D009436:Neural Tube Defects; D016017:Odds Ratio; D011247:Pregnancy",
"nlm_unique_id": "101701004",
"other_id": null,
"pages": "1526-1540",
"pmc": null,
"pmid": "32875745",
"pubdate": "2020-11",
"publication_types": "D016428:Journal Article; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": null,
"title": "Folic acid antagonist use before and during pregnancy and risk for selected birth defects.",
"title_normalized": "folic acid antagonist use before and during pregnancy and risk for selected birth defects"
} | [
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"companynumb": "US-UCBSA-2020049164",
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"abstract": "A 17-year-old male with ADHD who was treated with sertraline and lisdexamfetamine presented with transient episodes of speech impairment and right-sided hemiparesis preceded by headaches. Magnetic resonance imaging revealed three cerebral ischaemic lesions. Treatment was initiated with aspirin and discontinued with lisdexamfetamine. In the literature a causal relationship between treatment with central stimulants and the development of cerebrovascular events has not been substantiated. Vasospasm and paroxystic tachycardia may be associated with the event, but lisdexamfetamine and sertraline cannot be ruled out as risk factors.",
"affiliations": "malenemar@gmail.com.",
"authors": "Martinussen|Malene|M|;Debes|Nanette Mol|NM|;Christensen|Catrine|C|;Leth|Gabriele|G|;Pagsberg|Anne Katrine|AK|;Kruuse|Christina|C|",
"chemical_list": "D000697:Central Nervous System Stimulants; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline; D000069478:Lisdexamfetamine Dimesylate",
"country": "Denmark",
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"issn_linking": "0041-5782",
"issue": "178(45)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000293:Adolescent; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002544:Cerebral Infarction; D003866:Depressive Disorder; D038524:Diffusion Magnetic Resonance Imaging; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D017367:Serotonin Uptake Inhibitors; D020280:Sertraline",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27855771",
"pubdate": "2016-11-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Development of cerebral infarcts in a 17-year-old male treated with sertraline and lisdexamfetamine.",
"title_normalized": "development of cerebral infarcts in a 17 year old male treated with sertraline and lisdexamfetamine"
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"companynumb": "DK-ACCORD-046255",
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"abstract": "Invasive fungal infection is a complication seen in immunocompromised patients. A disseminated fungal infection has a high rate of mortality. Although disseminated infection is known to be seen in most organs, thyroid involvement is rarely reported. Hence, we report a fatal case of thyroid mucormycosis which resulted into laryngeal nerve paralysis and death of a renal allograft recipient.",
"affiliations": "Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Microbiology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Pathology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Pathology, SGPGIMS, Lucknow, Uttar Pradesh, India.;Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India.",
"authors": "Prasad|N|N|;Manjunath|R|R|;Bhadauria|D|D|;Marak|R S K|RSK|;Sharma|R K|RK|;Agarwal|V|V|;Jain|M|M|;Gupta|A|A|",
"chemical_list": null,
"country": "India",
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"doi": "10.4103/ijn.IJN_192_17",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-28-23210.4103/ijn.IJN_192_17Case ReportMucormycosis of the Thyroid Gland: A Cataclysmic Event in Renal Allograft Recipient Prasad N. Manjunath R. Bhadauria D. Marak R. S. K. 1Sharma R. K. Agarwal V. 2Jain M. 2Gupta A. Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India1 Department of Microbiology, SGPGIMS, Lucknow, Uttar Pradesh, India2 Department of Pathology, SGPGIMS, Lucknow, Uttar Pradesh, IndiaAddress for correspondence: Dr. N. Prasad, Department of Nephrology, SGPGIMS, Lucknow, Uttar Pradesh, India. E-mail: narayan.nephro@gmail.comMay-Jun 2018 28 3 232 235 Copyright: © 2018 Indian Journal of Nephrology2018This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Invasive fungal infection is a complication seen in immunocompromised patients. A disseminated fungal infection has a high rate of mortality. Although disseminated infection is known to be seen in most organs, thyroid involvement is rarely reported. Hence, we report a fatal case of thyroid mucormycosis which resulted into laryngeal nerve paralysis and death of a renal allograft recipient.\n\nAirwaymucormycosisrenal allograftthyroid\n==== Body\nIntroduction\nImmunocompromised patients are prone to various types of infections. This group of patients is especially prone for atypical manifestations of common infections, opportunistic infections, atypical sites of infections, and occult infections, all leading to a missed or a delayed diagnosis. Invasive fungal infection (IFI) has been increasing in incidence in this group of patients as more intensive chemotherapy/immunosuppressive therapy is used in expectation for a cure or finer control of the disease.[1] We report a renal allograft recipient who had recurrence of focal segmental glomerulosclerosis (FSGS) and developed acute fungal thyroiditis caused by mucormycosis. He subsequently died because of bilateral vocal cord palsy due to bilateral laryngeal nerve involvement.\n\nCase Report\nA 52-year-old male, renal allograft recipient, presented to the transplant clinic with complaints of fever, nonproductive cough, and throat pain for 2 days. His brief pretransplant course suggested native kidney disease as chronic glomerulonephritis as he had a history of significant proteinuria and hypertension in the past. He underwent living donor renal transplant with his haploidentical brother as donor with basiliximab induction and triple immunosuppressant (prednisolone, tacrolimus, and mycophenolate mofetil) in February 2013. On the postoperative day 8, he had an increase in serum creatinine from 1.2 to 1.8 mg/dl and graft biopsy revealed borderline rejection. He was treated with intravenous methylprednisolone. He was discharged on maintenance immunosuppression (prednisolone, tacrolimus, and mycophenolate mofetil) with a baseline serum creatinine of 1.2 mg/dl. On the 62nd day, he presented to the transplant clinic with new onset edema. Evaluation revealed graft dysfunction (serum creatinine: 2.1 mg/dl) and a proteinuria of 26 g/day/1.73 m2. His second allograft biopsy revealed FSGS [Figure 1] without any deposit of immunoglobulin and complement on immunofluorescence, and electron microscopy showed diffuse foot process effacement. With FSGS presumed to be the native kidney disease, he was considered to have recurrence of FSGS. He was started on 3 times per week plasmapheresis. His proteinuria decreased to 14 g/day and serum creatinine remained stable at 1.5–1.8 mg/dl. He was given 4 doses of rituximab at 500 mg per week and switched over to once a week plasmapheresis. His serum creatinine remained stable (1.45–1.7 mg/dl) and proteinuria decreased (3.9–4.1 g/day). Maintenance immunosuppression was changed from tacrolimus to cyclosporine, along with mycophenolate and prednisolone. The reason of changing from tacrolimus to cyclosporine was few literature evidence of better response of recurrence of FSGS with cyclosporine.[2] Every time, his serum creatinine increased to 1.68–1.9 mg/dl preplasmapheresis, only to decrease after plasmapheresis to 1.19–1.32 mg/dl. He remained plasmapheresis dependent. The patient was noncompliant and was on 1 plasmapheresis in 2 weeks. In February 2014, he had a creeping increase in serum creatinine (peak value: 3.2 mg/dl) and proteinuria increased from baseline of 4.1 to 7.5 g. He underwent third allograft biopsy and was opined as FSGS. As there was only mild interstitial fibrosis and tubular atrophy in the present biopsy, his plasmapheresis dose was escalated to 3 per week. However, his graft dysfunction persisted. With the 3rd graft biopsy being CD80 positive, he received 2 doses of abatacept 500 mg each at 3-week interval. His right radiocephalic arteriovenous fistula (AVF) had thrombosis and high radial AVF was made, with interim plasmapheresis done through femoral access, to resume later from the right high radial AVF. He was on maintenance plasmapheresis twice a month, until this admission in July 2014 (with serum creatinine at 1.9–2.2 mg/dl with 3.6–4.0 g/day proteinuria).\n\nFigure 1 Light microscopy of renal allograft showing synechiae formation (thin arrow) and segmental sclerosis (thick arrow) (Periodic acid–Schiff, ×200)\n\nAt the office visit for his fever and cough, he was given symptomatic medications along with amoxicillin and clavulanate potassium. He reported back next day for indoor admission in view of no improvement. His clinical examination was unremarkable except for temperature of 101.8°F. Oropharyngeal examination did not show any membrane or thrush. No lymph node enlargement was noted. His urine and blood cultures were sterile. Computed tomography (CT) of the chest and paranasal sinuses was normal. He was started on intravenous amoxicillin and clavulanate potassium. On day 3, the patient complained of swelling in the neck. Examination showed swelling which moved with deglutition. Ultrasound showed heterogeneous echotexture of bilateral lower part of thyroid and isthmus and multiple hypoechoic lesion [Figure 2a and b]. Ultrasound guided fine-needle aspiration was done and cytology revealed thyroid tissue with lymphocytic infiltration. On day 4, he developed hoarseness of voice. Immediate repeat ultrasound did not show any increase in the swelling size or hematoma. Laryngoscopy showed right vocal cord palsy [Figure 2c]. The patient had no complaints of dyspnea or any choking sensation. After 6 h, the patient had a sudden onset stridor and dyspnea. Examination showed bilateral vocal cord palsy and mild laryngeal edema. An urgent tracheostomy and ventilation was planned. He developed cardiac arrest during the same and could not be revived from it. The family consented for a postmortem biopsy of the thyroid gland. Biopsy showed mucormycosis of thyroid gland with severe angioinvasion [Figure 3].\n\nFigure 2 (a and b) Ultrasonogram of thyroid with hypoechoic lesions and (c) laryngoscopy picture showing paramedian-fixed right vocal cord indicating vocal cord palsy\n\nFigure 3 Section from postmortem thyroid biopsy shows coagulative necrosis of thyroid parenchyma with presence of angioinvasive mucormycosis showing nonseptate hyaline fungal hyphae occluding the blood vessel (a: H and E, ×200; b: Periodic acid Schiff, ×400)\n\nDiscussion\nIn this case report, we observed that a renal transplant recipient had recurrence of FSGS who responded partially with plasmapheresis and multiple immunosuppressants, rituximab, intravenous immunoglobulin, and abatacept; however, the patient died because of mucormycosis of thyroid gland. This emphasizes that there should be critical balance between immunosuppression and infection for success of transplantation.\n\nIFI is known to complicate the course of many immunocompromised patients, like patients with uncontrolled diabetics, with leukemia, lymphoma, AIDS, and use of immunosuppressive therapy. IFIs after renal transplantation are uncommon, incidence ranging from 1% to 14% in renal transplant recipients, with mucormycosis representing only in 0.2%–1.2% of cases.[1] IFI is reported to involve most of the organs; however, fungal invasion of thyroid is very rare. The possible explanation of less thyroid involvement as compared to that of other organs could be its rich blood supply and lymphatic drainage. It is also separated from other structures by its fibrous capsule and fascias of the neck. Iodine in the thyroid gland could also act as an antimicrobial agent; however, it is less likely to be a factor as the concentration of 3 μg/g of thyroid is not proven to have antimicrobial activity.[34]\n\nMoreover, the thyroid involvement could be because of hematogenous or lymphatic spread. Usually, the thyroid involvement is a part of disseminated involvement. However, rarely isolated thyroid involvement is reported with histoplasmosis, Aspergillus, coccidioidomycosis, and pneumocystis infection.[4] Infection without systemic involvement could be attributed to seeding during transient periods of fungemia. In our case, the focus of the dissemination remains obscure. Clinical examination and the CT scan of the chest and sinuses were normal. We presume that thyroid was seeded during fungemia, akin to the description in patients with isolated allograft mucormycosis.[5] However, his blood culture was sterile. The other possible route could be direct invasion through skin injury in thyroid region during shaving, a very remote possibility; however, the patient had denied any such history of injury.\n\nRarely, candida, cryptococcal, coccidioidal, and histoplasma thyroiditis is reported as a part of disseminated disease. A recent review by Goldani et al.[6] revealed Aspergillus as one of the most common fungal infections of the thyroid. Cases of aspergillus thyroiditis after dissemination,[7] fatal aspergillus thyroiditis with tracheal involvement,[8] and esophageal involvement with stenosis and obstruction[9] have been reported in nontransplant recipients.[789] A rapid onset of hoarseness, compressive symptoms, and dyspnea at rest due to aspergillus thyroiditis has also been reported in renal transplant recipients who required urgent tracheostomy.[10]\n\nThyroid involvement by mucormycosis is rarely reported particularly in renal transplant recipients. Recent review reports only 10 cases of thyroid involvement and only 1 among them was a renal allograft recipient.[11] He had a disseminated mucormycosis and died due to sepsis.[211] The rhinocerebral, pulmonary, and gastrointestinal forms are the common forms of mucormycosis. It can also involve the liver, genitourinary system, and the skin. Clinically, local signs and symptoms of fungal thyroiditis are indistinguishable from other infectious thyroiditis. Disseminated infection is defined as infection at two or more noncontiguous sites. In the patients with solid organ transplant, disseminated disease occurs in 9%–26% of cases, with the highest incidence among liver transplant recipients (26%–55%) and lowest in kidney transplant recipients (9%–13%).[1213] Reason for this disparity among different organ transplant groups is not known. In mucormycosis, about 50% of patients with pulmonary infection, 38% with gastrointestinal infection, and 20% with cutaneous infections suffered from dissemination. Disseminated infection in immunocompromised patients can be asymptomatic in the initial period. Nearly half of the patients with thyroid involvement remained asymptomatic even when autopsy reveals significant areas of fungal infiltration and necrosis.[12] In addition to sparse case reports, thyroid involvement by fungal infection is reported in many autopsy series of immunocompromised patients. In an autopsy series of 21 patients with disseminated Cunninghamella bertholletiae infection, thyroid gland involvement was seen in 19%. Among 9 cases of disseminated Rhizomucor pusillus infection, thyroid involvement was seen in 22%. Hence, this may be indicative of a missed antemortem diagnosis as many of them may have remained asymptomatic.[1415] Our patient was unique in the sense that he did not reveal any evidences of mucor infections at common site such as rhinocerebral and pulmonary involvement. He had initially unilateral vocal cord paralysis and fine-needle aspiration cytology of the thyroid did not reveal any microorganisms but lymphocytic thyroiditis.\n\nOur patient was highly immunosuppressed with plasmapheresis, rituximab, and abatacept in the past to treat recurrence of FSGS, only with partial benefit. Abatacept was recently reported to be beneficial in recurrence of FSGS in CD80-positive patients.[16] These immunosuppression might have predisposed him to this infection. However, the cause of death in our case remains obscure. When the patient was tried for endotracheal intubation, he was noted to have bilateral vocal cord palsy and laryngeal edema, so he underwent urgent tracheostomy. Mucormycosis is an angioinvasive fungus. The biopsy [Figure 1] shows the fungal ball in the blood vessel. The patient had unilateral vocal cord palsy, and within 6 h, he had bilateral palsy. Rapid blood vessel invasion could have led to bilateral recurrent laryngeal nerve involvement with vocal cord palsy and death.\n\nConclusion\nMucor infection to thyroid may cause rapid vasoinvasion and laryngeal nerve palsy leading to death of the patient. A simple fine-needle aspiration may miss the diagnosis. A strong suspicion and Trucut biopsy is required to diagnose this unusual site of dissemination.\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 Einollahi B Lessan-Pezeshki M Aslani J Nemati E Rostami Z Hosseini MJ Two decades of experience in mucormycosis after kidney transplantation Ann Transplant 2011 16 44 8 21959509 \n2 Raafat RH Kalia A Travis LB Diven SC High-dose oral cyclosporin therapy for recurrent focal segmental glomerulosclerosis in children Am J Kidney Dis 2004 44 50 6 15211437 \n3 Murillo M Carrión N Quintana M Sanabria G Ríos M Duarte L Determination of selenium and iodine in human thyroids J Trace Elem Med Biol 2005 19 23 7 16240668 \n4 Saikia UN Jain D Joshi K Lal A Sakhuja V Disseminated zygomycosis presenting as thyroid abscess in a renal allograft recipient Nephrol Dial Transplant 2007 22 641 4 17000732 \n5 Stas KJ Louwagie PG Van Damme BJ Coosemans W Waer M Vanrenterghem YF Isolated zygomycosis in a bought living unrelated kidney transplant Transpl Int 1996 9 600 2 8914243 \n6 Goldani LZ Zavascki AP Maia AL Fungal thyroiditis: An overview Mycopathologia 2006 161 129 39 16482384 \n7 Kishi Y Negishi M Kami M Hamaki T Miyakoshi S Ueyama J Fatal airway obstruction caused by invasive aspergillosis of the thyroid gland Leuk Lymphoma 2002 43 669 71 12002779 \n8 Bula G Trompeta J Niemiec A Truchanowski W Gawrychowski J Purulent thyroiditis - A clinical study of 5 cases Acta Chir Belg 2009 109 618 9 27377315 \n9 Sion ML Armenaka MC Georgiadis I Paraskevopoulos G Nikolaidis I Aspergillus fumigatus abscesses of the thyroid with obstruction of the esophagus Thyroid 2004 14 786 8 15361267 \n10 Cornet M Ugo V Lefort E Molina T James JM Vekhoff A A case of disseminated aspergillosis with thyroid involvement Eur J Clin Microbiol Infect Dis 2001 20 358 9 11453600 \n11 Irga N Kosiak W Jaworski R Komarnicka J Birkholz D Hyperthyroidism secondary to disseminated mucormycosis in a child with acute lymphoblastic leukemia: Case report and a review of published reports Mycopathologia 2013 175 123 7 23007613 \n12 Nguyen J Manera R Minutti C Aspergillus thyroiditis: A review of the literature to highlight clinical challenges Eur J Clin Microbiol Infect Dis 2012 31 3259 64 22843285 \n13 Hamdi T Karthikeyan V Alangaden GJ Mucormycosis in a renal transplant recipient: Case report and comprehensive review of literature Int J Nephrol 2014 2014 950643 \n14 Vogeser M Haas A Aust D Ruckdeschel G Postmortem analysis of invasive aspergillosis in a tertiary care hospital Eur J Clin Microbiol Infect Dis 1997 16 1 6 9063664 \n15 Gomes MZ Lewis RE Kontoyiannis DP Mucormycosis caused by unusual mucormycetes, non-Rhizopus , -Mucor , and -Lichtheimia species Clin Microbiol Rev 2011 24 411 45 21482731 \n16 Yu CC Fornoni A Weins A Hakroush S Maiguel D Sageshima J Abatacept in B7-1-positive proteinuric kidney disease N Engl J Med 2013 369 2416 23 24206430\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "28(3)",
"journal": "Indian journal of nephrology",
"keywords": "Airway; mucormycosis; renal allograft; thyroid",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "232-235",
"pmc": null,
"pmid": "29962676",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "15361267;16240668;21959509;16482384;23007613;8914243;11453600;27377315;21482731;9063664;22843285;12002779;17000732;15211437;24688793;24206430",
"title": "Mucormycosis of the Thyroid Gland: A Cataclysmic Event in Renal Allograft Recipient.",
"title_normalized": "mucormycosis of the thyroid gland a cataclysmic event in renal allograft recipient"
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"abstract": "Congenital or acquired severe aplastic anaemia (SAA) is cured by bone marrow transplantation (BMT) from a histocompatible leukocyte antigen- (HLA-) identical sibling. The best conditioning regimen is cyclophosphamide (CTX) with or without antithymocyte globulin (ATG), followed by short-term methotrexate (MTX) and cyclosporine A (CsA) to prevent graft-versus-host disease (GvHD). In our pediatric oncology-hematology unit, a 5-year-old girl with SAA was treated with two BMT from the same HLA-identical sibling donor. Severe CsA-induced adverse events (severe hypertension and PRES) after the first BMT led necessarily to CSA withdrawal. Alternative immunosuppressive treatment for GvHD prevention as tacrolimus and mycophenolate were not tolerated by our patient because toxicity > grade II. For this reason we decided to administrate sirolimus alone as GvHD prophylaxis and to prevent disease relapse after the rescue BMT. Here we report the successful use of sirolimus alone for GvHD prophylaxis after the second transplant in a pediatric BMT setting for SAA.",
"affiliations": "Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.;Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy.",
"authors": "Perruccio|Katia|K|0000-0003-0431-3197;Mastrodicasa|Elena|E|;Arcioni|Francesco|F|;Capolsini|Ilaria|I|;Cerri|Carla|C|;Gurdo|Grazia|G|;Caniglia|Maurizio|M|",
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"doi": "10.1155/2015/321602",
"fulltext": "\n==== Front\nCase Rep HematolCase Rep HematolCRIHEMCase Reports in Hematology2090-65602090-6579Hindawi Publishing Corporation 10.1155/2015/321602Case ReportSirolimus-Based Immunosuppression as GvHD Prophylaxis after Bone Marrow Transplantation for Severe Aplastic Anaemia: A Case Report and Review of the Literature http://orcid.org/0000-0003-0431-3197Perruccio Katia \n*\nMastrodicasa Elena Arcioni Francesco Capolsini Ilaria Cerri Carla Gurdo Grazia Caniglia Maurizio Pediatric Oncology Hematology Unit, Perugia General Hospital, Località Sant'Andrea delle Fratte, 06156 Perugia, Italy*Katia Perruccio: katia.perruccio@ospedale.perugia.itAcademic Editor: Panayiotis Tsirigotis\n\n2015 5 1 2015 2015 32160226 9 2014 10 12 2014 11 12 2014 Copyright © 2015 Katia Perruccio et al.2015This 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.Congenital or acquired severe aplastic anaemia (SAA) is cured by bone marrow transplantation (BMT) from a histocompatible leukocyte antigen- (HLA-) identical sibling. The best conditioning regimen is cyclophosphamide (CTX) with or without antithymocyte globulin (ATG), followed by short-term methotrexate (MTX) and cyclosporine A (CsA) to prevent graft-versus-host disease (GvHD). In our pediatric oncology-hematology unit, a 5-year-old girl with SAA was treated with two BMT from the same HLA-identical sibling donor. Severe CsA-induced adverse events (severe hypertension and PRES) after the first BMT led necessarily to CSA withdrawal. Alternative immunosuppressive treatment for GvHD prevention as tacrolimus and mycophenolate were not tolerated by our patient because toxicity > grade II. For this reason we decided to administrate sirolimus alone as GvHD prophylaxis and to prevent disease relapse after the rescue BMT. Here we report the successful use of sirolimus alone for GvHD prophylaxis after the second transplant in a pediatric BMT setting for SAA.\n==== Body\n1. Introduction\nCongenital or acquired severe aplastic anemia (SAA) is a life-threatening bone marrow failure disorder whose hallmarks are pancytopenia and a hypocellular bone marrow. Mortality ensues from complications of pancytopenia [1–3], but survival has greatly improved since the advent of BMT. In fact, decision-making on therapy is guided by availability of a matched sibling donor for transplantation with ATG in the conditioning regimen and CsA as prophylaxis for GvHD [1–4]. Transplantation from alternative donors is a last resort when patients relapse or do not respond to immunosuppressive therapy.\n\nStandard immunosuppressive therapy is a combination of horse ATG and CSA [1–3] as outcomes are not improved by adding other immunosuppressive agents like MMF [4] or sirolimus [5–9]. Few data are available on use of tacrolimus, sirolimus, and mycophenolate mofetil (MMF) as prophylaxis of graft-versus-host disease (GvHD) after BMT in SAA patients [10]. Although sirolimus was used in combination with other immunosuppressive agents for preventing GvHD after allogeneic hematopoietic stem cell transplantation (HSCT) for haematological malignancies, no data are available about its use alone or in association with other immunosuppressive agents to prevent GvHD after BMT for SAA. Here we report the case of a child with SAA who received two BMT from one HLA-identical sibling donor in whom sirolimus alone successfully prevented GvHD after the second.\n\n2. Case Report\nA 5-year-old girl had been affected by SAA from the age of 2, without cytogenetic abnormalities and with a bone marrow (BM) parvovirus B19 positivity, as detected by polymerase chain reaction (PCR) [11, 12]. She received a BMT from a HLA-identical sister after a conditioning regimen based on fludarabine 30 mg/m2/day for 4 days, CTX 300 mg/m2/day for 4 days, and ATG 10 mg/Kg/day for 3 days. As GvHD prophylaxis, 3 mg/Kg/day CsA from day 2 onwards and MTX (8 mg/m2/day on days +2, +4, and +8) were used. Engraftment occurred on day +16 after bone marrow infusion, remaining stable with 15% of host chimerism.\n\nIn the immediate posttransplant period, the patient developed hypertension, which was refractory to intravenous labetalol and infectious pneumonia which required broad-spectrum antibiotic therapy. On the following days, the onset of neurological symptoms led to the hypothesis of a posterior reversible encephalopathy syndrome (PRES). A CT scan of the skull showed hypodense lesions in the basal ganglia. Although CsA was suspended immediately, the child's clinical condition rapidly worsened. After repeated desaturation episodes she was transferred to the intensive care unit for assisted ventilation, dialysis, and treatment with vasoactive amines to ensure blood perfusion. MRI of the brain and spinal cord showed several anoxic-ischemic lesions in the basal ganglia, thalamus, right perirolandic region, and cervicodorsal tract of the spinal cord, indicating PRES. After flaccid paralysis for approximately one month, the patient gradually improved and slowly recovered almost all neurological functions. During this period, as GvHD prophylaxis she received mycophenolate and then tacrolimus, both of which were poorly tolerated (grade III bone marrow toxicity due to mycophenolate and grade III-IV nausea, vomiting, and weight loss due to tacrolimus). Five months after bone marrow transplant (BMT) we observed a gradual worsening of blood counts (WBC < 1,000/cmm and platelets <10,000/cmm) which reached 47% of host chimerism as shown in Figure 1. To counteract relapse the patient was given another BMT. Horse ATG 40 mg/Kg/die for 4 days was followed by infusion of cryopreserved BM stem cells from the same donor. Sirolimus replaced tacrolimus as GvHD prophylaxis because of gastrointestinal toxicity and risk of triggering PRES again.\n\nThe patient slowly and stably recovered blood counts, achieving 10–15% host chimerism. Sirolimus therapy continued as GvHD prophylaxis, modulating the dosage according to plasma levels. There was no toxicity. At present in more than 18 months after the rescue BMT, the patient is in a generally good clinical condition, with almost no neurological deficit. Blood counts are normal without transfusion. Sirolimus therapy continues to prevent GvHD and relapse of severe aplastic anaemia.\n\n3. Discussion\nHere we report the first case of a child with SAA who relapsed after BMT and CsA withdrawal, in whom sirolimus alone successfully prevented GvHD after a second rescue BMT. Control of GvHD was good with no toxicity. Haematological reconstitution was stable at more than one year after the second transplant.\n\nThe differential diagnosis of SAA in our young patient was between congenital and acquired SAA which share common features such as bone marrow failure and response to immunosuppressive treatments. In our patient cytogenetics were normal, thus ruling out congenital forms of AA and Fanconi's anaemia. Parvovirus positivity, the only abnormality, was eliminated by high-dose immunoglobulins before BMT. CsA had to be withdrawn because of severe PRES. Tacrolimus, the best alternative to CsA, was not tolerated by our patient because it is also a calcineurin inhibitor and caused gastrointestinal toxicity and hypertension which could have led to PRES. Therapy with MMF was not feasible during the second BMT because its myelosuppression could have interfered with engraftment and caused cytopenia. The only other option was sirolimus (a m-TOR inhibitor) which was well tolerated and successfully prevented acute and chronic GvHD, as well as relapse and graft failure.\n\nThis is the first use of sirolimus, a macrocyclic antibiotic, alone in pediatric SAA as it is commonly used in association with CsA. The synergism of sirolimus combined with CsA was established in in vitro experiments and in the clinical setting of solid organ transplantation [12]. CsA binds to calcineurin, inhibits calcium-stimulated serine/threonine phosphatase activity, and blocks T-cell activation while sirolimus blocks the multifunctional serine-threonine kinase, which is the mammalian target of rapamicine (mTOR). It also blocks CsA-resistant and calcium-independent pathways late in the T-cell cycle [12, 13] and complements CsA activity by inhibiting autoreactive cells which may escape inhibition through calcium-independent (or CsA-resistant) pathways [12].\n\nIn SAA use of sirolimus was explored by Scheinberg et al. [6] who, in a randomized study, added it to horse ATG and CsA (the standard SAA immunosuppressive treatment) in an unsuccessful attempt to elicit a better response rate. On the other hand, Young et al. reported two cases of aplastic anemia (AA) which relapsed after a CsA and ATG treatment but were successfully treated with a combination of CsA and sirolimus [11].\n\nIn the present case study since sirolimus alone has successfully prevented GvHD and SAA relapse to date, it might be a feasible alternative in SAA patients who do not tolerate CsA.\n\nAcknowledgment\nThe authors acknowledge Dr. Geraldine A. Boyd Boyd for editorial assistance.\n\nConflict of Interests \nThe authors declare that there is no conflict of interests.\n\nFigure 1 Haematological reconstitution in a 5 year old girl with SAA after first BMT (time 0) and second (22 weeks later). Black line = white blood cell counts; red line platelet counts. Coloured bars = immunosuppressive agents to prevent GvHD. Green = cyclosporine; Yellow = tacrolimus; Light blue = mycophenolate and Purple = sirolimus.\n==== Refs\n1 Scheinberg P. Young N. S. How I treat acquired aplastic anemia Blood 2012 120 6 1185 1196 10.1182/blood-2011-12-274019 2-s2.0-84865195880 22517900 \n2 Scheinberg P. Aplastic anemia: therapeutic updates in immunosuppression and transplantation Hematology 2012 2012 292 300 10.1182/asheducation-2012.1.292 2-s2.0-84878012622 23233595 \n3 Kurre P. Johnson F. L. Deeg H. J. Diagnosis and treatment of children with aplastic anemia Pediatric Blood and Cancer 2005 45 6 770 780 10.1002/pbc.20322 2-s2.0-26244459630 15706582 \n4 Locatelli F. Bruno B. Zecca M. Cyclosporin A and short-term methotrexate versus cyclosporin A as graft versus host disease prophylaxis in patients with severe aplastic anemia given allogeneic bone marrow transplantation from an HLA-identical sibling: Results of a GITMO/EBMT randomized trial Blood 2000 96 5 1690 1697 2-s2.0-0034284306 10961865 \n5 Scheinberg P. Nunez O. Wu C. Young N. S. Treatment of severe aplastic anaemia with combined immunosuppression: anti-thymocyte globulin, ciclosporin and mycophenolate mofetil British Journal of Haematology 2006 133 6 606 611 10.1111/j.1365-2141.2006.06085.x 2-s2.0-33646688643 16704434 \n6 Scheinberg P. Wu C. O. Nunez O. Boss C. Sloand E. M. Young N. S. Treatment of severe aplastic anemia with a combination of horse antithymocyte globulin and cyclosporine, with or without sirolimus: a prospective randomized study Haematologica 2009 94 3 348 354 10.3324/haematol.13829 2-s2.0-62949210719 19181786 \n7 Young N. S. Calado R. T. Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia Blood 2006 108 8 2509 2519 2-s2.0-33750628439 10.1182/blood-2006-03-010777 16778145 \n8 Marsh J. C. W. Ball S. E. Cavenagh J. Guidelines for the diagnosis and management of aplastic anaemia British Journal of Haematology 2009 147 1 43 70 10.1111/j.1365-2141.2009.07842.x 2-s2.0-70349213313 19673883 \n9 Cutler C. Logan B. Nakamura R. Tacrolimus/sirolimus vs tacrolimus/methotrexate as GvHD prophylaxis after matched, related donor allogeneic HCT Blood 2014 124 8 1372 1377 10.1182/blood-2014-04-567164 24982504 \n10 Ostronoff F. Ostronoff M. Souto-Maior A. P. Prospective trial of mycophenolate mofetil-cyclosporine A prophylaxis for acute GVHD after G-CSF stimulated allogeneic bone marrow transplantation with HLA-identical sibling donors in patients with severe aplastic anemia and hematological malignancies Clinical Transplantation 2009 23 1 33 38 10.1111/j.1399-0012.2008.00894.x 2-s2.0-63349095025 \n11 Young N. S. Bacigalupo A. Marsh J. C. W. Aplastic anemia: pathophysiology and treatment Biology of Blood and Marrow Transplantation 2010 16 1, supplement S119 S125 10.1016/j.bbmt.2009.09.013 2-s2.0-77953078209 19782144 \n12 Young N. S. Maciejewski J. P. Aplastic Anemia in Hoffman Basic Principles and Practice 2009 Philadelphia, Pa, USA Churchill Livingston Elsevier \n13 Solomon S. R. Sanacore M. Zhang X. Calcineurin inhibitor—free graft-versus-host disease prophylaxis with post-transplantation cyclophosphamide and brief-course sirolimus following reduced-intensity peripheral blood stem cell transplantation Biology of Blood and Marrow Transplantation 2014 20 11 1828 1834 10.1016/j.bbmt.2014.07.020 25064745\n\n",
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"title": "Sirolimus-based immunosuppression as GVHD prophylaxis after bone marrow transplantation for severe aplastic anaemia: a case report and review of the literature.",
"title_normalized": "sirolimus based immunosuppression as gvhd prophylaxis after bone marrow transplantation for severe aplastic anaemia a case report and review of the literature"
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"abstract": "Immune checkpoint inhibitors (ICI) are transforming the field of oncology, leading to tumor regression in multiple advanced cancers. With this case series, we review the ultrasound imaging findings in a series of patients with ICI-induced inflammatory arthritis (IA), a novel rheumatic disease that is caused by cancer immunotherapy.\nWe identified patients with rheumatologist-diagnosed, ICI-induced IA who had musculoskeletal ultrasound performed for clinical care. A retrospective chart review was done to obtain demographics, oncologic history, clinical presentation, imaging, and synovial fluid results. Ultrasound images were reviewed and scored for synovial and tendon pathology, presence of Doppler, and bony erosion.\nNine patients were included in this study with a total of 18 joint regions assessed. The knees were the most commonly imaged joint followed by the hands, wrists, feet, and ankles. Synovitis was seen in 12 of the 18 joints with active Doppler in 50% of the cases. Tendon involvement was also frequently seen (13 of 18 joints) with tenosynovitis, tendinitis, and enthesophytes. Erosions were less frequent and seen in only three cases but were also an early finding.\nPatients with ICI-induced IA had a wide range of pathology affecting the synovium, tendons, and bones on musculoskeletal ultrasound. Further systematic study with imaging is needed for this group of diseases.",
"affiliations": "Johns Hopkins University School of Medicine Baltimore Maryland.;Johns Hopkins University School of Medicine Baltimore Maryland.;Johns Hopkins University School of Medicine Baltimore Maryland.;Johns Hopkins University School of Medicine Baltimore Maryland.;Johns Hopkins University School of Medicine Baltimore Maryland.",
"authors": "Albayda|Jemima|J|https://orcid.org/0000-0002-8030-9504;Dein|Eric|E|;Shah|Ami A|AA|;Bingham|Clifton O|CO|;Cappelli|Laura|L|",
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"doi": "10.1002/acr2.1026",
"fulltext": "\n==== Front\nACR Open RheumatolACR Open Rheumatol10.1002/(ISSN)2578-5745ACR2Acr Open Rheumatology2578-5745John Wiley and Sons Inc. Hoboken 10.1002/acr2.1026ACR21026Brief ReportBrief ReportSonographic Findings in Inflammatory Arthritis Secondary to Immune Checkpoint Inhibition: A Case Series ULTRASOUND IN IMMUNE CHECKPOINT INHIBITOR‐INDUCED ARTHRITISALBAYDA ET ALAlbayda Jemima MDhttps://orcid.org/0000-0002-8030-9504\n1\njalbayd1@jhmi.edu Dein Eric MD\n1\nShah Ami A. MD, MHS\n1\nBingham Clifton O. IIIMD\n1\nCappelli Laura MD, MHS\n1\n\n1 \nJohns Hopkins University School of Medicine\nBaltimore\nMaryland\n* Address correspondence to Jemima Albayda, MD, 5200 Eastern Avenue, Mason F. Lord Center Tower, Suite 4100 434c, Baltimore, MD 21224. E‐mail: jalbayd1@jhmi.edu12 6 2019 7 2019 1 5 10.1002/acr2.v1.5303 307 © 2019 The Authors. ACR Open Rheumatology published by Wiley Periodicals, Inc. on behalf of American College of RheumatologyThis 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.Objective\nImmune checkpoint inhibitors (ICI) are transforming the field of oncology, leading to tumor regression in multiple advanced cancers. With this case series, we review the ultrasound imaging findings in a series of patients with ICI‐induced inflammatory arthritis (IA), a novel rheumatic disease that is caused by cancer immunotherapy.\n\nMethods\nWe identified patients with rheumatologist‐diagnosed, ICI‐induced IA who had musculoskeletal ultrasound performed for clinical care. A retrospective chart review was done to obtain demographics, oncologic history, clinical presentation, imaging, and synovial fluid results. Ultrasound images were reviewed and scored for synovial and tendon pathology, presence of Doppler, and bony erosion.\n\nResults\nNine patients were included in this study with a total of 18 joint regions assessed. The knees were the most commonly imaged joint followed by the hands, wrists, feet, and ankles. Synovitis was seen in 12 of the 18 joints with active Doppler in 50% of the cases. Tendon involvement was also frequently seen (13 of 18 joints) with tenosynovitis, tendinitis, and enthesophytes. Erosions were less frequent and seen in only three cases but were also an early finding.\n\nConclusion\nPatients with ICI‐induced IA had a wide range of pathology affecting the synovium, tendons, and bones on musculoskeletal ultrasound. Further systematic study with imaging is needed for this group of diseases.\n\nNational Institutes of Arthritis and Musculoskeletal and Skin DiseasesP30AR070254R01AR073208Jerome L. Greene Foundation source-schema-version-number2.0cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.2 mode:remove_FC converted:15.11.2019This work was supported by the National Institutes of Arthritis and Musculoskeletal and Skin Diseases (P30‐ AR070254 to Drs. Albayda, Bingham, Shah, Cappelli; R01‐AR073208 to Dr. Shah) as well as the Jerome L. Greene Foundation (Drs. Albayda and Cappelli). The funders had no role in study design, data collection, analysis, decision to publish, or preparation of the manuscript.\n\nDr. Bingham has served as a consultant to and received research funding from Bristol Myers Squibb. Dr. Cappelli has received research funding from bristol Myers Squibb. Dr. Shah has served on a Pan Tumour Rheumatology Advisory Board for Bristol Myers Squibb. No other disclosures relevant to this article were reported.\n==== Body\nIntroduction\nThe expansion of immunotherapies has introduced new treatment options for patients with advanced cancer. Immune checkpoint inhibitors (ICIs) target the inhibitory costimulatory molecules on T cells and their ligands, including cytotoxic T‐lymphocyte antigen‐4 (CTLA‐4), programmed cell death‐1 (PD‐1), and programmed death ligand 1 (PD‐L1) 1, 2. Inhibition of these checkpoints by monoclonal antibodies permits nonspecific T‐cell activation and can result in a dramatic antitumor response.\n\nAs ICI use increases for a wider variety of cancers, immune‐related adverse effects (irAEs) are increasingly recognized as significant toxicities 3, 4. IrAEs manifest in a variety of organs, including skin rashes, colitis, myositis, sicca syndrome, and inflammatory arthritis (IA) 5, 6. IA appears to be the most common rheumatic irAE and can become chronic, persisting after ICI cessation 7. ICI‐induced IA shows notable clinical differences from “usual” rheumatoid arthritis. Most patients are seronegative for rheumatoid factor and anti‐cyclic citrullinated peptide (CCP) antibodies, many do not respond to low to moderate doses of corticosteroids, and there are several potential clinical subgroups, including small‐joint polyarthritis, reactive arthritis‐like disease, and large‐joint oligoarthritis with or without axial disease 8. The mechanism behind ICI‐induced IA is not well elucidated and may be due to direct T‐cell effects and/or downstream effects of T‐cell activation, like inflammation that is due to cytokines and effectors cells. The clinical response of ICI‐induced IA to tumor necrosis factor–inhibitor and IL‐6R inhibitors also suggests the importance of these cytokines 8, 9\n\n\nUltrasonography has become an important modality for the diagnosis and monitoring of IA, able to identify not only inflammatory features of synovitis, effusions, and tendonitis but also structural damage like bone erosions 10. There has been no systematic study using musculoskeletal ultrasound to evaluate patients with ICI‐induced IA and describe the imaging features of this condition. We describe ten cases of ICI‐induced IA evaluated with ultrasonography to highlight notable presentations and pathologic changes seen.\n\nMaterials and Methods\nThis is a retrospective case series of patients with ICI‐induced IA who were evaluated and treated at the Johns Hopkins Division of Rheumatology from October 2015 to January 2018. We identified and reviewed the medical records of those patients with ICI‐induced IA who had available sonographic imaging of their joints. The study was approved by the Johns Hopkins Institutional Review Board (IRB #00144789).\n\nUltrasound assessments\nSymptomatic joints were assessed in each patient based on clinical need. Studies were carried out using a GE Logiq e (GE Healthcare), which had a 12L linear phased array transducer or hockey stick probe, by one examiner (JA), a rheumatologist with 6 years of musculoskeletal ultrasound experience. For each joint region scanned, orthogonal views of symptomatic areas were obtained. The images were then reviewed, assessing for the presence/absence of joint pathology (synovial hypertrophy, Doppler signal, effusion), tendon pathology (tenosynovitis, enthesopathy), and bone changes (erosion). Definitions for ultrasound pathology are as described by the Outcome Measures in Rheumatology (OMERACT) network 11. For enthesopathy, findings of thickening or hypoechoic irregularity of the tendons and presence of Doppler signal were specified. The presence of enthesophytes was also recorded for more granularity. A semiquantitative scoring system for synovial hypertrophy and Doppler assessments was used according to the EULAR/OMERACT score 12. The most severe finding/grade was recorded for each section. For all other pathology, presence or absence was recorded as either positive (+) or negative (−).\n\nResults\nDemographics\nNine patients with IA due to ICIs were included in this study (Table 1). They ranged in age from 47 to 81 (mean 61.6) and less than half were female (Table 1). Underlying cancer diagnoses included lung cancer (n = 4), melanoma (n = 2), basal cell carcinoma (n = 1), prostate cancer (n = 1), and colorectal cancer (n = 1). Five of nine patients (55%) received combination therapy with ipilumimab and nivolumab; four received a PD‐1 inhibitor as single agent (nivolumab or pembrolizumab). Four of the nine patients (44%) had other irAE symptoms preceding, including colitis, sicca syndrome, and pancreatitis. Patients developed symptoms of IA anywhere from 1 to 23 months after starting ICI therapy (average 7.8 months).\n\nTable 1 Patient demographics and clinical variables\n\nPt\tAge\tSex\tCancer Dx\tTx\tDuration of Symptoms Before US (mos)\tIS at Time of US\tPrednisone (mg) dose\tOther IS prior to US\tOther irAE\t\n1\t48\tF\tMelanoma\tN/Ip\t20\tM/E\t…\tI/Pr\tC, S, Th\t\n2*\n\t69\tM\tProstate cancer\tN/Ip\t2\tPr\t5\t…\tC\t\n3\t59\tF\tNSCLC\tN\t2\t…\t…\t…\t…\t\n4\t59\tM\tBasal cell carcinoma\tN/Ip\t0\tPr\t20\t…\t…\t\n5\t62\tM\tNSCLC\tN/Ip\t3\tPr\t5\t…\t…\t\n6\t56\tF\tColon cancer\tP\t0\t…\t…\t…\tPa\t\n7\t47\tF\tNSCLC\tN\t12\t…\t…\tPr\t…\t\n8\t74\tM\tNSCLC\tN/Ip\t0.5\t…\t…\t…\t…\t\n9\t81\tM\tMelanoma\tN\t2\tPr\t40\t…\tC\t\nAbbreviation: C, colitis; Dx, diagnosis; E, etanercept; Ip, ipilumimab; irAE, immune‐related adverse event; IS, immunosuppression; I, infliximab; M, methotrexate; N, nivolumab; NSCLC, non–small cell lung cancer; Pa, pancreatitis; Pe, pembrolizumab; Pr, prednisone; S, sicca; Th, thyroid disease; Tx, treatment; US, ultrasound.\n\n*Correction added after online publication 11 July 2019: the patients in Table 1 have been renumbered.\n\nJohn Wiley & Sons, LtdClinically affected joints\nThree patients presented with an inflammatory monoarthritis that affected the knee; all other patients (n = 6) had at least three joints involved over their clinical course. Most patients with polyarthritis had both upper and lower extremities involved (n = 7), with one patient having only upper extremity involvement (wrists, fingers, shoulders) and another having only lower extremity involvement (knees, metatarsophalangeal joints).\n\nUltrasound findings\nThe most frequently imaged joint was the knee, with seven out of nine patients undergoing an ultrasound of this joint (Table 2) because of their symptoms. In order of decreasing frequency, the other joints assessed included the hands, wrists, ankles, elbows, and feet.\n\nTable 2 Ultrasound findings\n\nPatient\tLocation\tJoint\tTendon\tBone\t\nGS \tD\tEf\tTS\tEn\tEnp\tEr\t\n1\tElbow\t2\t1\t+\t−\t−\t−\t+\t\nHand\t1\t0\t+\t−\t−\t−\t‐\t\n2\tWrist\t2\t2\t−\t+ (Wrist extensors comp 3/4)\t−\t−\t‐\t\nKnee\t2\t1\t+\t−\t+ (Thickening of distal P)\t−\t‐\t\n3\tKnee\t1\t1\t+\t−\t+ (Thickening of Q/proximal and distal P)\t+ At Q and proximal P)\t+\t\n4\tKnee\t1 \t2\t+\t−\t+ (Thickening of Q insertion with doppler)\t−\t‐\t\nHand\t0\t0\t−\t−\t+ (Thickening of extensor tendon at PIP)\t−\t‐\t\nFoot\t2\t1\t−\t+ (MTP extensor tendon)\t−\t−\t‐\t\nAnkle\t0\t0\t+\t+ (Peroneus tendons)\t−\t−\t+\t\n5 \tElbow\na\n\n\t*\t*\t+\t*\t*\t*\t*\t\nKnee\t0\t0\t−\t \t+ (Thickening of Q insertion)\t+ (At distal P)\t‐\t\n6\tKnee\t2\t3\t+\t−\t+ (Hypoechoic proximal P)\t−\t‐\t\n7 \tKnee\t0\t0\t−\t−\t+ (Hypoechoic Q/distal P)\t−\t‐\t\nAnkle\t0\t0\t+\t+ (Peroneus tendons)\t−\t−\t‐\t\nFoot\t2\t0\t+\t−\t−\t−\t‐\t\n8\tHand \t1\t0\t+\t+ (Flexor tendons at MCPs)\t−\t+ (At extensor tendon at PIP)\t‐\t\nWrist\t2\t1\t−\t−\t−\t−\t‐\t\n9 \tKnee\t2\t2\t+\t−\t+ (Thickening of Q) \t+ (At Q/proximal P)\t‐\t\nAbbreviation: D, Doppler; Ef, effusion; En, enthesopathy; Enp, enthesophyte; Er, erosion or bone irregularity; GS, gray scale synovial hypertrophy; MCP, metacarpophalangeal joint; MTP, metatarsophalangeal joint; P, patellar tendon; Q, quadriceps tendon; TS, tenosynovitis.\n\na Note that asterisks (*) indicate metastasis.\n\nJohn Wiley & Sons, LtdOut of 18 joint regions assessed, 12 were found to have synovitis, with active Doppler signal in 9 of those joints (one example: Figure 1A and 1G). Effusions were most commonly seen in the knees and ankles (Figure 1B) but were also noted in elbows and hands. Tendon involvement with either tenosynovitis (Figure 1A, 1E, and 1F) or enthesopathy was seen in 13 of the joint regions and spanned the range of both large and small joints. Enthesophytes were noted most commonly at knee tendons (Figure 1H) but were also seen at an extensor tendon of the finger (Figure 1C and 1D). Erosions and bony cortical irregularities were only seen in three joints but were noted even in cases with a symptom duration of only 2‐3 months. Metastatic joint involvement was found in one case at an elbow, as previously described 13.\n\nFigure 1 Transverse view of wrist extensors with tenosynovitis (*) and Doppler signal (A); effusion at the tibiotalar joint of the ankle ( ● ) (B); orthogonal dorsal views of a third PIP showing enthesophyte (arrows (C, D); synovitis with grade 3 Doppler signal at the knee (E); and bulky enthesophytes at proximal insertion of patellar tendon of knee (arrowhead) (F).\n\nSynovial studies\nFluid aspiration was performed for six knees to rule out alternative etiologies to irAE. All knee aspirates were sent for bacterial culture and resulted in no positive cultures. Five aspirates were also sent for cell count and crystal evaluation. One case showed the presence of monosodium urate crystals so colchicine was initiated for therapy, which yielded minimal clinical response; prednisone, and ultimately methotrexate, were effective for this patient's ICI‐induced IA. The white blood cell count of the crystalline‐negative aspirates ranged from 49 to 11 400 cells/cu mm (mean 5037). Two of the six patients were on prednisone (5 and 40 mg, respectively) at the time of joint aspiration, with white blood cell counts of 4900 and 3800, respectively. The patient with a low white blood cell count (n = 49) had received intra‐articular corticosteroids several weeks before the aspiration.\n\nDiscussion\nRheumatic complications of ICI therapy have been increasingly recognized in the last few years, with IA being one of the more common manifestations. ICI‐induced IA can be a complex entity, with varied presentations and some similarities with primary rheumatic diseases. An additional layer of difficulty is posed by its occurrence in the background of active malignancy, requiring a quick and judicious response from the evaluating clinician as to whether the manifestation is an irAE or cancer progression. Imaging provides an important additive assessment to the clinical examination, allowing for objective characterization of the anatomic and inflammatory nature of the process that can help guide management.\n\nIn studies detailing the occurrence of joint‐related complications from ICIs, a spectrum of findings has been described, including synovitis, tenosynovitis, and enthesitis 3, 14, 15, 16. In our study, we show that the most common findings were synovial hypertrophy with or without Doppler signal, as well as tendon involvement. The tendon involvement was one of the more interesting findings. It spanned the range of the more classic tenosynovitis seen with IA, to tendinopathy with only decreased echogenicity and thickening of the involved tendon, which could be interpreted as mechanically induced in a different clinical setting. However, a more unusual presentation was that of enthesophytes, such as at extensor tendons in the small joints of the hands and bulky ones at the knee tendons. Like bone erosions, enthesophytes are considered structural changes, indicative of damage and are usually seen in more long‐standing disease. Hence, finding enthesophytes and erosions in these early cases (symptom duration between 2‐20 months) raises further questions about underlying mechanisms, particularly in terms of the potential impact of ICIs on bone.\n\nThe retrospective nature of our study and targeted ultrasound assessments pose limitations on potential conclusions. Unfortunately, some patients were already on steroids by the time of sonographic evaluation, and this may have already affected changes, such as decreasing the amount of Doppler signal and inflammatory synovial or tendon changes seen. In one case, the elbow involvement was later determined to be due to metastatic disease, hence other findings in the elbow (like tendon abnormalities or effusions) were not counted toward ICI‐induced IA as has been described elsewhere 13.\n\nThere is much more to understand about ICI‐induced IA. Ultrasound imaging may help further define clinically relevant subgroups of ICI‐induced IA, and differences in affected structures might reflect differences in pathogenesis. Musculoskeletal ultrasound can also evaluate for alternate causes of joint pain and has the added advantage of bedside availability, allowing evaluation of as many joints as desired, which makes it suitable for the assessment of this novel rheumatic disease.\n\nIn summary, musculoskeletal ultrasound showed a variety of pathology involving the synovium, tendons, and bones in patients who develop IA because of ICIs. Further systematic studies are needed to fully characterize the imaging features of this disease and to direct guidelines for the use of ultrasound in diagnosis and monitoring of response to therapy.\n\nAuthor Contributions\nDrs. Albayda and Capelli drafted the article. Drs. Dein, Shah, and Bingham were responsible for article revision.\n\nStudy conception and design\nAlbayda, Cappelli.\n\nAcquisition of data\nAlbayda, Dein, Cappelli.\n\nAnalysis and interpretation of data\nShah, Bingham.\n==== Refs\nReferences\n1 \n\nPardoll \nDM \n. The blockade of immune checkpoints in cancer immunotherapy . Nat Rev Cancer \n2012 ;12 :252 –64 .22437870 \n2 \n\nTopalian \nSL \n, \nDrake \nCG \n, \nPardoll \nDM \n. Immune checkpoint blockade: a common denominator approach to cancer therapy . Cancer Cell \n2015 ;27 :450 –61 .25858804 \n3 \n\nCalabrese \nC \n, \nKirchner \nE \n, \nKontzias \nK \n, \nVelcheti \nV \n, \nCalabrese \nLH \n. Rheumatic immune‐related adverse events of checkpoint therapy for cancer: case series of a new nosological entity . RMD Open \n2017 ;3 :e000412 .28405474 \n4 \n\nCappelli \nLC \n, \nGutierrez \nAK \n, \nBingham \nCO \nIII\n, \nShah \nAA \n. Rheumatic and musculoskeletal immune‐related adverse events due to immune checkpoint inhibitors: a systematic review of the literature . Arthritis Care Res (Hoboken) \n2017 ;69 :1751 –63 .27998041 \n5 \n\nFriedman \nCF \n, \nProverbs‐Singh \nTA \n, \nPostow \nMA \n. Treatment of the immune‐related adverse effects of immune checkpoint inhibitors: a review . JAMA Oncol \n2016 ;2 :1346 –53 .27367787 \n6 \n\nLidar \nM \n, \nGiat \nE \n, \nGarelick \nD \n, \nHorowitz \nY \n, \nAmital \nH \n, \nSteinberg‐Silman \nY \n, et al. Rheumatic manifestations among cancer patients treated with immune checkpoint inhibitors . Autoimmun Rev \n2018 ;17 :284 –9 .29341936 \n7 \n\nCappelli \nLC \n, \nGutierrez \nAK \n, \nBaer \nAN \n, \nAlbayda \nJ \n, \nManno \nRL \n, \nHaque \nU \n, et al. Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab . Ann Rheum Dis \n2017 ;76 :43 –50 .27307501 \n8 \n\nCappelli \nLC \n, \nBrahmer \nJR \n, \nForde \nPM \n, \nLe \nDT \n, \nLipson \nEJ \n, \nNaidoo \nJ \n, et al. Clinical presentation of immune checkpoint inhibitor‐induced inflammatory arthritis differs by immunotherapy regimen . Semin Arthritis Rheum \n2018 ;48 :553 –7 .29573850 \n9 \n\nKim \nST \n, \nTayar \nJ \n, \nTrinh \nVA \n, \nSuarez‐Almazor \nM \n, \nGarcia \nS \n, \nHwu \nP \n, et al. Successful treatment of arthritis induced by checkpoint inhibitors with tocilizumab: a case series . Ann Rheum Dis \n2017 ;76 :2061 –4 .28830882 \n10 \n\nSudoł‐Szopińska \nI \n, \nSchueller‐Weidekamm \nC \n, \nPlagou \nA \n, \nTeh \nJ \n. Ultrasound in arthritis . Radiol Clin North Am \n2017 ;55 :985 –96 .28774458 \n11 \n\nWakefield \nRJ \n, \nBalint \nPV \n, \nSzkudlarek \nM \n, \nFilippucci \nE \n, \nBackhaus \nM \n, \nD'Agostino \nMA \n, et al. Musculoskeletal ultrasound including definitions for ultrasonographic pathology . J Rheumatol \n2005 ;32 :2485 –7 .16331793 \n12 \n\nD'Agostino \nMA \n, \nTerslev \nL \n, \nAegerter \nP \n, \nBackhaus \nM \n, \nBalint \nP \n, \nBruyn \nGA \n, et al. Scoring ultrasound synovitis in rheumatoid arthritis: a EULAR‐OMERACT ultrasound taskforce – part 1: definition and development of a standardised, consensus‐based scoring system . RMD Open \n2017 ;3 :e000428 .28948983 \n13 \n\nAlbayda \nJ \n, \nBingham \nCO \nIII\n, \nShah \nAA \n, \nKelly \nRJ \n, \nCappelli \nL \n. Metastatic joint involvement or inflammatory arthritis? A conundrum with immune checkpoint inhibitor‐related adverse events . Rheumatology (Oxford) \n2018 ;57 :760 –2 .29342300 \n14 \n\nChan \nMM \n, \nKefford \nRF \n, \nCarlino \nM \n, \nClements \nA \n, \nManolios \nN \n. Arthritis and tenosynovitis associated with the anti‐PD1 antibody pembrolizumab in metastatic melanoma . J Immunother \n2015 ;38 :37 –9 .25415286 \n15 \n\nInamo \nJ \n, \nKaneko \nY \n, \nTakeuchi \nT \n. Inflammatory tenosynovitis and enthesitis induced by immune checkpoint inhibitor treatment . Clin Rheumatol \n2018 ;37 :1107 –10 .29455266 \n16 \n\nMekki \nA \n, \nDercle \nL \n, \nLichtenstein \nP \n, \nMarabelle \nA \n, \nMichot \nJ‐M \n, \nLambotte \nO \n, et al. Detection of immune‐related adverse events by medical imaging in patients treated with anti‐programmed cell death 1 . Eur J Cancer \n2018 ;96 :91 –104 .29698933\n\n",
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"title": "Sonographic Findings in Inflammatory Arthritis Secondary to Immune Checkpoint Inhibition: A Case Series.",
"title_normalized": "sonographic findings in inflammatory arthritis secondary to immune checkpoint inhibition a case series"
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"abstract": "BACKGROUND\nThe right and left lung anatomy are similar but asymmetrical. The right lung consists of three lobes, and the left lung consists of two lobes. Our study is unique because of discovering a very rare morphological feature of the left lung which has not been reported yet. By the way, we compared two different available chemical agents for pleurodesis (talc and bleomycin) according to side effects, complications, and pneumothorax recurrence.\n\n\nMETHODS\nWe reported a case of bilateral primary spontaneous pneumothorax, who underwent talc slurry and bleomycin pleurodesis at right and left side retrospectively, and then complicate with left-sided recurrent spontaneous pneumothorax, so underwent open thoracotomy and was surprisingly and accidentally found to have 4 lobes and 3 fissures in left lung.\n\n\nCONCLUSIONS\nIn our case report, there were one main oblique fissure and two accessory fissures which divided the lung into 4 separated lobes, and this discovery in human's and other animals' lung anatomy has not been previously reported. In our case study, the talc slurry was more effective in preventing spontaneous pneumothorax recurrence, but with more side effects than bleomycin. We could hypothesize that the morphological variation of the lung might affect spontaneous pneumothorax development and recurrence.",
"affiliations": "Department of General Surgery, Shahid Beheshti Hospital, Yasuj University of Medical Sciences, Yasuj, Iran.;Stem Cells Technology Research Center, Stem Cells Research Institute, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of General Surgery, Shahid Beheshti Hospital, Yasuj University of Medical Sciences, Yasuj, Iran.;Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran.;Department of General Surgery, Shahid Beheshti Hospital, Yasuj University of Medical Sciences, Yasuj, Iran. mj.yavari.barhaghtalab@gmail.com.",
"authors": "Mehrabi|Saadat|S|;Tanideh|Nader|N|;Hosseinpour|Reza|R|;Irajie|Cambyz|C|;Yavari Barhaghtalabi|Mohammad Javad|MJ|http://orcid.org/0000-0002-2859-044X",
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"fulltext": "\n==== Front\nJ Cardiothorac Surg\nJ Cardiothorac Surg\nJournal of Cardiothoracic Surgery\n1749-8090\nBioMed Central London\n\n1651\n10.1186/s13019-021-01651-3\nCase Report\nA left lung with four lobes: a new discovery during the thoracotomy for recurrent primary spontaneous pneumothorax\nMehrabi Saadat 1\nTanideh Nader 2\nHosseinpour Reza 1\nIrajie Cambyz 3\nhttp://orcid.org/0000-0002-2859-044X\nYavari Barhaghtalabi Mohammad Javad mj.yavari.barhaghtalab@gmail.com\nmj.yavari.barhaghtalab@yums.ac.ir\n\n1\n1 grid.413020.4 0000 0004 0384 8939 Department of General Surgery, Shahid Beheshti Hospital, Yasuj University of Medical Sciences, Yasuj, Iran\n2 grid.412571.4 0000 0000 8819 4698 Stem Cells Technology Research Center, Stem Cells Research Institute, Shiraz University of Medical Sciences, Shiraz, Iran\n3 grid.412571.4 0000 0000 8819 4698 Department of Medical Biotechnology, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran\n28 9 2021\n28 9 2021\n2021\n16 27612 5 2021\n14 9 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\nThe right and left lung anatomy are similar but asymmetrical. The right lung consists of three lobes, and the left lung consists of two lobes. Our study is unique because of discovering a very rare morphological feature of the left lung which has not been reported yet. By the way, we compared two different available chemical agents for pleurodesis (talc and bleomycin) according to side effects, complications, and pneumothorax recurrence.\n\nCase presentation\n\nWe reported a case of bilateral primary spontaneous pneumothorax, who underwent talc slurry and bleomycin pleurodesis at right and left side retrospectively, and then complicate with left-sided recurrent spontaneous pneumothorax, so underwent open thoracotomy and was surprisingly and accidentally found to have 4 lobes and 3 fissures in left lung.\n\nConclusion\n\nIn our case report, there were one main oblique fissure and two accessory fissures which divided the lung into 4 separated lobes, and this discovery in human’s and other animals’ lung anatomy has not been previously reported. In our case study, the talc slurry was more effective in preventing spontaneous pneumothorax recurrence, but with more side effects than bleomycin. We could hypothesize that the morphological variation of the lung might affect spontaneous pneumothorax development and recurrence.\n\nKeywords\n\nPrimary spontaneous pneumothorax\nLeft lung\nThoracotomy\nFour lobes\nNew discovery\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcIntroduction\n\nThe right and left lung anatomy are similar but asymmetrical. The right lung consists of three lobes: the right upper lobe (RUL), the right middle lobe (RML), and the right lower lobe (RLL). The right lobe is divided by an oblique and horizontal fissure, where the horizontal fissure divides the upper and middle lobe, and the oblique fissure divides the middle and lower lobes. The left lung consists of two lobes: the left upper lobe (LUL) and the left lower lobe (LLL). In the left lobe, there is only an oblique fissure that separates the upper and lower lobe [1].\n\nLobation varies greatly among species. Table 1 compares the lung lobes in different species of animals [2–11].Table 1 Interspecies comparison of Lung lobes\n\n\tNumber of right lung lobes\tDescription of right lung lobes\tNumber of left lung lobes\tDescription of left lung lobes\t\nHuman (1, 2)\t3\t–\t2\t–\t\nDog (2, 3)\t4\tCranial, middle, caudal, and accessory lobes\t2 or 3\tApical, middle, and diaphragmatic lobes, left apical and middle lobes are partially fused, being separated only by an incomplete (cranial) fissure\t\nCat (2, 4)\t4\tCranial, middle, caudal and accessory lobes\t2 or 3\tApical (cranial), middle (cardiac), and diaphragmatic (caudal) lobes (3 lobes theory) versus apical (cranial) and diaphragmatic (caudal) lobes (2 lobes theory)\t\nBovine (5)\t4\tCranial, middle, caudal and accessory lobes\t2\tCranial and caudal lobes\t\nHorse (2, 6)\t1\tCranial, middle, caudal and accessory lobular divisions are united to form 1 lobe\t1\tCranial, middle, caudal and accessory lobular divisions are united to form 1 lobe\t\nRaccoon (2)\t4\t–\t3\t–\t\nEquine (7)\t3\tcranial, caudal and accessory lobes\t2\tCranial and caudal lobes\t\nMouse (2, 9, 10)\t4\tCranial, middle, caudal, and accessory lobes\t1\tNo division\t\nRat (2, 10, 11)\t4\tUpper, middle, accessory and lower lobes\t1\tThe upper and accessory lobes are lost. The middle and lower lobes are united to form one lobe\t\nHamster (11)\t5\tcranial, middle, caudal, intermediate, accessory\t1\tSingle lobe\t\n\nSpontaneous pneumothorax occurs secondary to intrinsic abnormalities of the lung without any preceding trauma or obvious precipitating causes, and can be classified as primary and secondary. Primary spontaneous pneumothorax is defined as a spontaneous pneumothorax without underlying lung disease, while secondary spontaneous pneumothorax refers to those that develop in the presence of an underlying lung disease such as emphysema (rupture of a bleb or bulla), cystic fibrosis, acquired immunodeficiency syndrome (AIDS), metastatic cancer (especially sarcoma), asthma, lung abscess, occasionally lung cancer, and Catamenial pneumothorax [12, 13]. Apical subpleural bleb rupture is the most common cause. The cause of these blebs is unknown, but they occur more frequently in smokers and young post-adolescent males with a tall thin body habitus. Treatment is generally chest tube insertion with water seal [12].\n\nIt has been demonstrated that 32% of patients will develop a recurrence, with most of the risk in the first year. Recurrence rates did not differ based on the initial intervention for primary spontaneous pneumothorax. Female sex, lower body mass index (BMI), smoking cessation and radiological evidence of dystrophic lung lesions (evaluated with computed tomography (CT) scan according to the pulmonary dystrophic lesions score (number and size of blebs and bullae)), are factors which are associated with a higher risk of recurrence [14, 15].\n\nOther than emptying air from the pleural cavity by simple aspiration or chest tube drainage, the management of spontaneous pneumothorax also focused on the stopping of the air leak and avoiding the recurrence by surgical intervention or chemical pleurodesis. Making symphysis between the two layers of pleura by sclerosing agents is called chemical pleurodesis. Sclerosing agents which could be used for chemical pleurodesis are talc, tetracycline, minocycline, bleomycin, autologous blood patch, OK-432 (Picibanil), and Iodopovidone [16].\n\nSurgery is specified to disease process and may involve surgical pleurectomy, pleurodesis, bullectomy, and lung resection through video-assisted thoracoscopic surgery (VATS), axillary mini-thoracotomy (AMT) and formal anterolateral or posterolateral thoracotomy [12, 17].\n\nIn this study, we reported a case of bilateral primary spontaneous pneumothorax, who underwent talc slurry and bleomycin pleurodesis at right and left side respectively, and then complicated with left sided recurrent spontaneous pneumothorax, so underwent open thoracotomy and was surprisingly and accidentally found to have 4 lobes and 3 fissures in left lung. Our study is unique because of discovering a very rare morphological feature of left lung which has not been reported yet. By the way, we compared two different available chemical agents for pleurodesis (talc and bleomycin) according to side effects, complications, and pneumothorax recurrence.\n\nCase presentation\n\nThe patient was a 47-year-old man who was brought to the emergency department of Shahid Beheshti hospital with chief complaints of dyspnea and dry cough but no respiratory distress for two days before the admission. The patient had an amputated left leg and knee due to the previous trauma since childhood and was a heavy smoker (1 pack-year) and had inhalational opium addiction for more than 20 and 10 years respectively. The patient had no family history of any specific disease. The patient’s upright chest radiography and Chest spiral CT scan revealed bilateral primary spontaneous pneumothorax (Figs. 1, 2), and the patient underwent bilateral chest tube insertion (After local anesthesia, a conventional large-bore chest tube (32 French) was placed into the pleural space in the bilateral 5th-6th intercostal space in the posterior axillary line (Fig. 3).Fig. 1 Chest radiography (1st admission), bilateral primary spontaneous pneumothorax\n\nFig. 2 Spiral chest CT scan without contrast (1st admission), bilateral primary spontaneous pneumothorax, a mediastinal axial view, b lung window axial view, c lung window coronal view\n\nFig. 3 Spiral chest CT scan without contrast (1st admission), inserted bilateral chest tubes, a mediastinal axial view, b lung window axial view, c mediastinal coronal view\n\nTwo days after the insertion of the chest tubes, as there was no development of bullae within the lung parenchyma as the bullous lung disease, and after obtaining an informed consent from the patient, the patient underwent chemical pleurodesis with talc slurry at the right side, and on the next day chemical pleurodesis with bleomycin was done at the left side (Bilateral pleurodesis was done in two consecutive days). For talc slurry and bleomycin pleurodesis, 2 g of talc and 60 units of bleomycin were dissolved in 50 ml sodium chloride 0.9% respectively and were shacked to ensure the thorough mixing before flushing it with a 50 ml syringe into the chest tube and then the intercostal tube was clamped for 4 to 6 h. During this time, the patient was told to rotate to prone supine and left and right lateral decubitus positions for every 20 min to make sure good spread of the talc slurry or bleomycin in the pleural cavity, and then the chest tube was unclamped, and was removed within 48 h. The patient received heart monitoring and pulse oximetry during and after the administration of talc or bleomycin until the chest tube was removed. The patient was discharged and was followed afterward. He developed again with severe dyspnea and respiratory distress 14 month after the first presentation of the disease, so was admitted and the patient’s upright chest radiography revealed recurrent left-sided spontaneous pneumothorax (Fig. 4). In Table 2, comparing of talc slurry and bleomycin pleurodesis is shown according to the side effects, complications, and pneumothorax recurrence. Left sided chest tube was inserted again for him, but unfortunately the lung was not expanded afterward, moreover, the patient intervention adherence and tolerability in using incentive spirometry was very poor, so the patient was candidate for surgery. Figures 5 and 6 show that the pneumothorax didn’t resolve.Fig. 4 Chest radiography (2nd admission), left sided recurrent spontaneous pneumothorax\n\nTable 2 Comparing of talc slurry and bleomycin according to side effects, complications, and pneumothorax recurrence\n\nEffect on pneumothorax, Side Effects, complications, and recurrence\tTalc, right side\tBleomycin, left side\t\nPain (pleuritic chest pain)\t++\t+\t\nNausea\t+\t−\t\nFever\t++\t+\t\nTachycardia\t+\t−\t\nHypotension\t−\t−\t\nBreathlessness and dyspnea\t+\t−\t\nCough\t+\t−\t\nRespiratory distress\t−\t−\t\nDecreased O2 saturation\t−\t−\t\nHypersensitivity to the drug\t−\t−\t\nRecurrent pneumothorax\t−\t+\t\nPethidine use\t++\t+\t\nPleural effusion\t−\t−\t\nPneumonia\t−\t−\t\nHemothorax\t−\t−\t\nPneumothorax recurrence\t−\t+\t\n\nFig. 5 Chest radiography (2nd admission), not-resolved left sided pneumothorax after the chest tube insertion\n\nFig. 6 Spiral chest CT scan without contrast (2nd admission), not-resolved left sided pneumothorax after the chest tube insertion, a mediastinal axial view, b lung window axial view\n\nThe patient underwent posterolateral thoracotomy, pneumolysis, and wedge resection of apical segment of left upper lobe (bullectomy), apical pleurectomy, and scarification. We found an accidental and surprising finding in left lung during thoracotomy and that was that the left lung had 4 lobes with 3 developed fissures (Fig. 7). Figure 8 shows chest radiography after the operation.Fig. 7 Left posterolateral thoracotomy, A left lung with 4 lobes and 3 developed fissures\n\nFig. 8 Chest radiography (2nd admission), after the operation showing two chest tubes, and resolved pneumothorax\n\nThe patient was then discharged with a good recovery after 7 days. Figure 9 shows the chest radiography on the time of discharge from the hospital. There was no report of the recurrence afterward in follow-up visits.Fig. 9 Chest radiography (2nd admission), at the time of discharge from the hospital showing discontinued chest tube, and resolved pneumothorax\n\nDiscussion\n\nIn our study, using talc suspension (slurry) was resulted in pain (pleuritic chest pain), nausea, fever, tachycardia, breathlessness or dyspnea, and cough; and using bleomycin was resulted in pain (pleuritic chest pain), fever, and recurrent spontaneous pneumothorax. Fever and pain were the side effects of pleurodesis seen in usage of both talc and bleomycin. Pethidine was used more often in talc than the bleomycin pleurodesis.\n\nOur results were compatible with the results of other studies according to the talc effects [16, 18]. Talc poudrage and slurry were supposed to be more effective, but were associated with more complications, including respiratory failure [18]. There are at least 32 cases in the literature in whom acute respiratory distress syndrome was developed after administration of talc [19], but in our study, the patient didn’t develop respiratory distress after talc pleurodesis.\n\nAn animal model showed that the intrapleural injection of bleomycin was ineffective in creating pleural fibrosis, and that the bleomycin is expensive and relatively ineffective compared with other sclerosing agents; therefore, it is not suggested to be used as a pleural sclerosant in patients with non-neoplastic pleural disease (like pneumothorax) [16, 20, 21]. Our results for the administration of bleomycin was compatible with the results from other studies mentioned above, as the pneumothorax occurred again at the side in which bleomycin was administered before.\n\nUpper and a lower lobes divide the left lung by the means of the oblique fissure [1, 22]. The left lung does not have a middle lobe in contrast to the right lung, however it does have a projection of the upper lobe called lingula. The lingula on the left lung is as the same as the middle lobe in the right lung. In a study done on the Nepalese cadavers showed two left lungs with lingula appearing as a separate lobe [22]. In another study done on the Indian cadavers showed that from 73 left lungs, there were two (2.73%) lungs with 2 fissures (one of them considered to be an accessary fissure) and they divided the left lung in to 3 lobes instead of 2 lobes [23], and this result shows that just the three lobes in the left lung has the highest number of lobes which has been reported in the literature in the human studies. In the other animals, as was described in Table 1, no separated 4 lobes have been identified. In our case report, there were one main oblique fissure and two accessory fissures which divided the lung into 4 separated lobes, and this discovery in human’s and other animals’ lung anatomy has not been previously reported. (Fig. 6).\n\nConclusion\n\nIn our case study, the talc slurry was more effective in preventing spontaneous pneumothorax recurrence, but with more side effects than bleomycin. We could hypothesize that the morphological variation of the lung might affect spontaneous pneumothorax development and recurrence. Variations in the number and pattern of lobes in both human lungs is obscure, and there is little knowledge about the association of some lung diseases like spontaneous pneumothorax with these morphological variations, so some relevant future studies are needed to prove this claim.\n\nAbbreviations\n\nRUL Right upper lobe\n\nRML Right middle lobe\n\nRLL Right lower lobe\n\nLUL Left upper lobe\n\nLLL Left lower lobe\n\nCT scan Computed Tomography scan\n\nAcknowledgements\n\nWe all express our gratitude to the patient who kindly gave consent for this case to be presented in this paper.\n\nAuthors' contributions\n\nSM is a professor of thoracic surgery; he evaluated the patient clinically, operated the patient (main surgeon), and read and revised the manuscript. NT is a professor of the veterinary surgery; he read and revised the manuscript according to the other animals’ lung anatomy. RH is a professor of general surgery; he read and revised the manuscript. CI is a professor of biotechnology and read and revised the manuscript. MJYB is a general surgery resident; he evaluated the patient clinically, helped to operate the patient (co-surgeon), prepared the first draft, and revised the manuscript. All the authors have read and approved the manuscript.\n\nFunding\n\nNot received.\n\nAvailability of data and materials\n\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nWritten informed consent was obtained from the patient for participation in this case report. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\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 of this manuscript declare no competing of 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. Chaudhry R, Bordoni B. Anatomy, Thorax, Lungs. [Updated 2021 Jul 31]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan. https://www.ncbi.nlm.nih.gov/books/NBK470197/\n2. Wanda MH, Colin GR, Matthew AW. Chapter 6—respiratory system. In: Wanda MH, Colin GR, Matthew AW, editors, Fundamentals of toxicologic pathology (Second Edition), Academic Press. 2010, pp 93–133. ISBN 9780123704696. 10.1016/B978-0-12-370469-6.00006-4\n3. Ishaq M A morphological study of the lungs and bronchial tree of the dog: with a suggested system of nomenclature for bronchi J Anat 1980 131 Pt 4 589 610 7216900\n4. OLIVEIRA, Fabrício Singaretti, BORGES, Edson Moreira, MACHADO, Márcia Rita Fernandes, CANOLA, Júlio Carlos, & RIBEIRO, Antonio Augusto Coppi Maciel. Anatomicosurgical arterial segmentation of the cat lungs (Felis catus domesticus, L., 1758). Brazilian Journal of Veterinary Research and Animal Science. 2001; 38(6): 253–257. 10.1590/S1413-95962001000600001\n5. Prohl A Ostermann C Lohr M Reinhold P The bovine lung in biomedical research: visually guided bronchoscopy, intrabronchial inoculation and in vivo sampling techniques J Vis Exp 2014 89 51557 10.3791/51557\n6. Nakakuki S The bronchial tree and lobular division of the horse lung J Vet Med Sci 1993 55 3 435 438 10.1292/jvms.55.435 8357916\n7. Smith BL Aguilera-Tejero E Tyler WS Jones JH Hornof WJ Pascoe JR Endoscopic anatomy and map of the equine bronchial tree Equine Vet J 1994 4 283 290 10.1111/j.2042-3306.1994.tb04388.x\n8. Miller LA Royer CM Pinkerton KE Schelegle ES Nonhuman primate models of respiratory disease: past, present, and future ILAR J 2017 58 2 269 280 10.1093/ilar/ilx030 29216343\n9. Sato S Bartolák-Suki E Parameswaran H Hamakawa H Suki B Scale dependence of structure-function relationship in the emphysematous mouse lung Front Physiol 2015 6 146 10.3389/fphys.2015.00146 26029115\n10. Kling MA A review of respiratory system anatomy, physiology, and disease in the mouse, rat, hamster, and gerbil Vet Clin North Am Exot Anim Pract 2011 14 2 287 337 10.1016/j.cvex.2011.03.007 21601816\n11. Nakakuki S The bronchial tree and blood vessels of the rat lung Anat Anz 1983 154 4 305 312 6660544\n12. Katie S. Nason, Rose B. Ganim, James D. Luketich. Chest Wall, Lung, Mediastinum, and Pleura. Chapter 19, In: F. Charles Brunicardi, Dana K. Andersen, Timothy R. Billiar, David L. Dunn, Lillian S. Kao, John G. Hunter, Jeffrey B. Matthews, Raphael E. Pollock Schwartz’s Principles of Surgery, Eleventh Edition, by McGraw-Hill Education, 2019\n13. Tulay CM, Özsoy IE. Spontaneous pneumothorax recurrence and surgery. Indian J Surg. 2015; 77 (Suppl 2):463–465. 10.1007/s12262-013-0876-6\n14. Walker SP, Bibby AC, Halford P, Stadon L, White P, Maskell NA. Recurrence rates in primary spontaneous pneumothorax: a systematic review and meta-analysis. Eur Respir J. 2018; 52(3):1800864. 10.1183/13993003.00864-2018\n15. Ouanes-Besbes L, Golli M, Knani J, et al. Prediction of recurrent spontaneous pneumothorax: CT scan findings versus management features. Respir Med. 2007; 101(2):230–236.10.1016/j.rmed.2006.05.016\n16. How CH, Hsu HH, Chen JS. Chemical pleurodesis for spontaneous pneumothorax. J Formosan Med Assoc Taiwan yi zhi. 2013; 112(12):749–755. 10.1016/j.jfma.2013.10.016.\n17. Foroulis CN Surgery for primary spontaneous pneumothorax J Thorac Dis 2016 8 12 E1743 E1745 10.21037/jtd.2016.12.31 28149629\n18. Lee YC Baumann MH Maskell NA Pleurodesis practice for malignant pleural effusions in five English-speaking countries: survey of pulmonologists Chest 2003 124 6 2229 2238 10.1378/chest.124.6.2229 14665505\n19. Light RW Diseases of the pleura: the use of talc for pleurodesis Curr Opin Pulm Med 2000 6 4 255 258 10.1097/00063198-200007000-00001 10912629\n20. Vargas FS Wang NS Lee HM Gruer SE Sassoon CS Light RW Effectiveness of bleomycin in comparison to tetracycline as pleural sclerosing agent in rabbits Chest 1993 104 5 1582 1584 10.1378/chest.104.5.1582 7693399\n21. Dikensoy O Light RW Alternative widely available, inexpensive agents for pleurodesis Curr Opin Pulm Med 2005 11 4 340 344 10.1097/01.mcp.0000166587.24127.91 15928503\n22. Kc S Shrestha P Shah AK Jha AK Variations in human pulmonary fissures and lobes: a study conducted in nepalese cadavers Anat Cell Biol 2018 51 2 85 92 10.5115/acb.2018.51.2.85 29984052\n23. George BM Nayak SB Marpalli S Morphological variations of the lungs: a study conducted on Indian cadavers Anat Cell Biol. 2014 47 4 253 258 10.5115/acb.2014.47.4.253 25548723\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1749-8090",
"issue": "16(1)",
"journal": "Journal of cardiothoracic surgery",
"keywords": "Four lobes; Left lung; New discovery; Primary spontaneous pneumothorax; Thoracotomy",
"medline_ta": "J Cardiothorac Surg",
"mesh_terms": "D006801:Humans; D008168:Lung; D018700:Pleurodesis; D011030:Pneumothorax; D012008:Recurrence; D012189:Retrospective Studies; D013627:Talc; D013908:Thoracotomy",
"nlm_unique_id": "101265113",
"other_id": null,
"pages": "276",
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"pmid": "34583735",
"pubdate": "2021-09-28",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "29984052;25046445;14665505;25548723;26730046;10912629;24268613;8575395;29216343;15928503;7216900;6660544;7693399;16844363;21601816;28149629;26029115;30002105;8357916",
"title": "A left lung with four lobes: a new discovery during the thoracotomy for recurrent primary spontaneous pneumothorax.",
"title_normalized": "a left lung with four lobes a new discovery during the thoracotomy for recurrent primary spontaneous pneumothorax"
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"abstract": "Anesthesia for pulmonary endarterectomy (PEA) has always been one of the challenges of anesthesia. As one of the leading cardiothoracic institutions in Southeast Asia, our hospital has vast interest in this subject. A local multidisciplinary team was deployed to an expert center in the United Kingdom (UK), and the experience was then integrated to the care of our patients. We present a case series of ten patients undergoing anesthesia for PEA, a first for our institution, and discuss techniques as well as potential complications.\n\n\n\nPatients with chronic thromboembolic pulmonary hypertension were reviewed by a multidisciplinary team, and those who were suitable for surgical intervention subsequently underwent PEA. A total of ten patients were identified and operated on. The perioperative management and conduction of anesthesia for all patients followed a protocol adapted from the expert center in the UK, with revisions to cater to our Asian population.\n\n\n\nIn the ten patients operated on, eight of them were successfully extubated on the first postoperative day. Apart from one incident of prolonged ventilator usage due to reperfusion lung injury and pneumonia, there were no major respiratory or hemodynamic complications. Certainly, six of the ten patients developed subdural hemorrhage after the commencement of enoxaparin, although none of them sustained any permanent neurological deficits.\n\n\n\nWe have demonstrated that with careful planning and a well-outlined protocol, anesthesia for PEA in an Asian population can be achieved with favorable outcomes. Further fine-tuning of the protocol is still required based on local expertise.",
"affiliations": "Department of Anesthesiology, Singapore General Hospital, Singapore.;Department of Anesthesiology, Singapore General Hospital, Singapore.;Department of Anesthesiology, Singapore General Hospital, Singapore.;Department of Anesthesiology, Singapore General Hospital, Singapore.",
"authors": "Chen|Yufan|Y|;Tan|Zihui|Z|;Shah|Shitalkumar S|SS|;T Loh|Kenny W|KW|",
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"country": "India",
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"doi": "10.4103/aca.ACA_63_18",
"fulltext": "\n==== Front\nAnn Card AnaesthAnn Card AnaesthACAAnnals of Cardiac Anaesthesia0971-97840974-5181Wolters Kluwer - Medknow India 30971599ACA-22-16910.4103/aca.ACA_63_18Original ArticlePerioperative Anesthesia Management for Pulmonary Endarterectomy: Adopting an Established European Protocol for the Asian Population Chen Yufan Tan Zihui Shah Shitalkumar S Loh Kenny WT Department of Anesthesiology, Singapore General Hospital, SingaporeAddress for correspondence: Dr. Yufan Chen, Department of Anaesthesiology, Singapore General Hospital, Outram Road, Singapore 169608, Singapore. E-mail: chen.yufan@singhealth.com.sgApr-Jun 2019 22 2 169 176 Copyright: © 2019 Annals of Cardiac Anaesthesia2019This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.Background:\nAnesthesia for pulmonary endarterectomy (PEA) has always been one of the challenges of anesthesia. As one of the leading cardiothoracic institutions in Southeast Asia, our hospital has vast interest in this subject. A local multidisciplinary team was deployed to an expert center in the United Kingdom (UK), and the experience was then integrated to the care of our patients. We present a case series of ten patients undergoing anesthesia for PEA, a first for our institution, and discuss techniques as well as potential complications.\n\nMethods:\nPatients with chronic thromboembolic pulmonary hypertension were reviewed by a multidisciplinary team, and those who were suitable for surgical intervention subsequently underwent PEA. A total of ten patients were identified and operated on. The perioperative management and conduction of anesthesia for all patients followed a protocol adapted from the expert center in the UK, with revisions to cater to our Asian population.\n\nResults:\nIn the ten patients operated on, eight of them were successfully extubated on the first postoperative day. Apart from one incident of prolonged ventilator usage due to reperfusion lung injury and pneumonia, there were no major respiratory or hemodynamic complications. Certainly, six of the ten patients developed subdural hemorrhage after the commencement of enoxaparin, although none of them sustained any permanent neurological deficits.\n\nConclusion:\nWe have demonstrated that with careful planning and a well-outlined protocol, anesthesia for PEA in an Asian population can be achieved with favorable outcomes. Further fine-tuning of the protocol is still required based on local expertise.\n\nAnesthesiaAsian populationchronic thromboembolic pulmonary hypertensionpulmonary endarterectomy\n==== Body\nIntroduction\nAnesthesia for pulmonary endarterectomy (PEA) has always been one of the challenges of anesthesia. Epidemiological studies have shown vastly different rates of chronic thromboembolic pulmonary hypertension (CTEPH) being diagnosed in an Asian versus Caucasian populations, possibly due to the lower incidences of acute pulmonary embolism in Asian populations.[12] This has resulted in less operative exposure to such cases in Asian centers.[2] With PEA being the treatment of choice for CTEPH and a rising number of such surgeries performed, it is imperative that anesthesiologists are well equipped to manage patients for surgeries with their potential complications.[3] The prevalence of CTEPH in Singapore is currently unknown, but as one of the leading cardiothoracic institutions in Southeast Asia, our hospital has vast interest in this subject. A local multidisciplinary team was deployed to an expert center in the United Kingdom (UK), with over 1200 operations under their belts, and the experience was then integrated to the care of our patients.[4] We present a case series of ten patients undergoing anesthesia for PEA, a first for our institution, and discuss techniques as well as potential complications.\n\nMethods\nPatients with CTEPH were reviewed by a multidisciplinary team and those who were suitable for surgical intervention subsequently underwent PEA from November 2017 to August 2018. A total of ten patients were identified and operated on. All ten patients underwent a complete diagnostic workup including preoperative echocardiography, pulmonary angiography, right heart catheterization, isotope ventilation/perfusion scans, and computed tomography (CT) scan. Functional assessments such as the 6-min walk test and lung function tests were also performed. The patients selected for surgery all had Jamieson type 1 or 2 proximal disease. All ten surgeries were supervised by a senior surgeon from the UK institution. The perioperative management and conduction of anesthesia for all patients followed a protocol adapted from the expert center in UK as well, with revisions to cater to our Asian population. Preoperative and postoperative cardiac output (CO) measurements were documented. Any complications which arose during surgery and the postoperative period were also duly noted and further discussed at multidisciplinary meetings.\n\nCase details and results\nTable 1 shows a compilation of patient demographics, operative and anesthesia details, and intraoperative complications.\n\nTable 1 Patient demographics, operative and anesthesia details, and intraoperative complications\n\nPatient\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\tCase 8\tCase 9\tCase 10\t\nAge (years)\t45\t63\t55\t56\t67\t55\t55\t61\t52\t57\t\nGender\tFemale\tFemale\tMale\tFemale\tFemale\tFemale\tFemale\tFemale\tFemale\tMale\t\nRace\tIndian\tChinese\tChinese\tChinese Obstructive sleep apnea\tChinese\tChinese\tSikh\tIndian\tChinese\tChinese\t\nPast medical history\tAnti - phospholipid syndrome\tHTN\tCTEPH\tHTN\tEndometrial polypoid\tHTN\tDiabetes\tHTN\tSmoker\t\nHLD\t\t\tHLD\ttumor\tHLD\tHTN\tAsthma\tPUD\t\nDVT\t\t\t\tPUD\tLeft temporal – parietal infarct\tHLD\tDysfunctional uterine bleeding\tIschemic heart disease\t\n\t\n\t\t\tDVT\tVogt – Koyanagi - Harada disease\t\tTabes dorsalis\t\nNYHA class preoperation\tIII\tII\tII\tIII\tII\tI\tII\tII\tII\tII\t\nNYHA class postoperation\tI\tI-II\tI\tI-II\tI\tI\tII-III\tII\tI\tI\t\n6-min walk test preoperation (m)\t319\t330\t460\t420\t354\t397\t90\t390\t481\tNone†\t\n6-min walk test postoperation (m)\t409\t410\tNone‡\t386\t310\tNone‡\tNone‡\t405\tNone‡\tNone†\t\nPreoperative saturations on room air (%)\t98\t97\t97\t98\t95\t98\t86\t94\t96\t96\t\nPostoperative saturations on room air (%)\t99\t97\t97\t99\t97\t98\t93\t98\t98\t100\t\nOperation performed\tPEA\tPEA\tPEA\tPEA\tPEA\tPEA\tPEA, CABG 1 graft*\tPEA\tPEA\tPEA, CABG 3 grafts*\t\nTotal CBP time (min)\t303\t320\t381\t279\t356\t263\t319\t230\t311\t283\t\nTotal AXC time (min)\t79\t81\t117\t85\t89\t63\t110\t20\t79\t119\t\nTotal DHCA sessions\t3\t3\t4\t3\t3\t2\t3\t1\t2\t2\t\nLength of individual DHCA sessions (min)\t20, 20, 7\t22, 12, 8\t20, 20, 20, 9\t22, 10, 18\t20, 18, 20\t19, 20\t20, 14, 20\t14\t21, 21\t17, 19\t\nSurgical complications\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\t\nAnesthesia complications\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\tNil\t\nAdditional inotropic support required (apart from dopamine)\tNone\tNone\tNone\tNone\tNone\tNone\tNone\tNoradre - naline\tNone\tNone\t\nAdditional blood products required\tNone\tNone\tNone\tNone\tNone\tNone\tNone\tNone\tNone\tNone\t\nOral vasodilator use before PEA\tYes\tYes\tYes\tNo\tYes\tNo\tYes\tYes\tNo\tNo\t\nOral vasodilator use after PEA\tNo\tYes\tNo\tNo\tYes\tNo\tYes\tYes\tNo\tNo\t\n*Operation times not prolonged as CABG performed while waiting for adequate rewarming, †Patient’s mobility was impaired by history of tabes dorsalis, ‡6 mine walk test performed usually at 3–6 months after surgery; some patients have not undergone testing yet. DVT: Deep vein thrombosis, HTN: Hypertension, HLD: Hyperlipidemia, PUD: Peptic ulcer disease, IHD: Ischemic heart disease, PEA: Pulmonary endarterectomy, NYHA: New York Heart Association, CABG: Coronary bypass graft surgery, AXC: Aortic cross-clamp, DHCA: Deep hypothermic circulatory arrest\n\nTable 2 shows the individual patients’ preoperative and postoperative CO measurements, major postoperative complications, and length of hospital stay.\n\nTable 2 Individual patients’ preoperative and postoperative cardiac output measurements, operative times, initiation of anticoagulation, major postoperative complications, and length of hospital stay\n\nPatient\tCase 1\tCase 2\tCase 3\tCase 4\tCase 5\tCase 6\tCase 7\tCase 8\tCase 9\tCase 10\t\nPreoperative 2DE results\tEF 50%, PASP 55\tEF 58%,\tEF 65%,\tEF 72%, PASP 72\tEF 54%, PASP 82\tEF 69%,\tEF 70%, PASP 67\tEF 65%, PASP 99\tEF 51%, PASP 44\tEF 53%, PASP 20\t\nTAPSE 1.3\tPASP 89\tPASP 57\tTAPSE 1.8\tTAPSE 1.5\tPASP 39\tTAPSE 1.3\tTAPSE 1.4\tTAPSE 1.4\tTAPSE 1.8\t\nTAPSE 1.8\tTAPSE 2.1\t\t\tTAPSE 2.0\t\t\t\t\t\nPostoperative 2DE results at 3-6 months\tEF 54%, PASP 13\tEF 65%, PASP\tEF 67%, PASP\tEF 67%, PASP 42\tEF 62%, PASP 16\tEF 66%, PASP\tEF 65%, PASP 33\tEF 58%, PASP 46\tEF 48%, PASP 20\tEF 55%, PASP 21\t\nTAPSE 1.7\t32\t26\tTAPSE 1.7\tTAPSE 1.7\t23\tTAPSE 2.0\tTAPSE 1.2\tTAPSE 2.2\tTAPSE 1.7\t\n\tTAPSE 1.8\tTAPSE 1.9\t\t\tTAPSE 1.8\t\t\t\t\t\nPre- CBP cardiac output measurements\tCO 4.2, CI 2.5, MAP 70, MPAP 54, CVP 22, SVR 914, SVRI 1513, PVR 838, PVRI 1387\tCO 3.4, CI 2.3, MAP 80, MPAP 45, CVP 10, SVR 1671, SVRI 2457, PVR 836, PVRI 1228\tCO 4.5, CI 2.43, MAP 115, MPAP 48, CVP 7, SVR 1912, SVRI 3552, PVR 672, 1250\tCO 3.0, CI 2, MAP 77, MPAP 46, CVP 7, SVR 1803, SVRI 2861, PVR 927, PVRI 1471\tCO 3.3, CI 2.1, MAP 76, MPAP 49, CVP 15, SVR 1479, SVRI 2278, PVR 945, PVRI 1456\tCO 4.8, CI 3.1, MAP 69, MPAP 35, CVP 12, SVR 953, SVRI 1469, PVR 418, PVRI 644\tCO 3.3, CI 2.8, MAP 88, MPAP 71, CVP 13, SVR 1813, SVRI 3340, PVR 1479, PVRI 1741\tCO 2.3, CI 1.6, MAP 68, MPAP 40, CVP 7, SVR 2105, SVRI 3085, PVR 1043, PVRI 1517\tCO 3.6, CI 2.1, MAP 105, MPAP 42, CVP 14, SVR 2022, SVRI 3444, PVR 711, PVRI 1211\tCO 3.5, CI 2.0, MAP 86, MPAP 46, CVP 12 SVR 1713, SVRI 3033, PVR 833, PVRI 1476\t\nPost-CBP cardiac output measurements\tCO 4.3, CI 2.6, MAP 67, MPAP 24, CVP 9, SVR 1079, SVRI 1786, PVR 260, PVRI 431\tCO 3, CI 2, MAP 76, MPAP 27, CVP 8, SVR 1813, SVRI 2666, PVR 453, PVRI 666\tCO 4.7, CI 2.6, MAP 64, MPAP 31, CVP 15, SVR 834, SVRI 1534, PVR 357, PVRI 658\tCO 4.1, CI 2.6, MAP 65, MPAP 26, CVP 8, SVR 1124, SVRI 1783, PVR 315, PVRI 501\tCO 4.0, CI 2.6, MAP 85, MPAP 37, CVP 16, SVR 1380, SVRI 2126, PVR 540, PVRI 832\tCO 5.4, CI 3.5, MAP 75, MPAP 26, CVP 11, SVR 949, SVRI 1461, PVR 237, PVRI 365\tCO 5.0, CI 2.7, MAP 71, MPAP 43, CVP 10, SVR 981, SVRI 1807, PVR 531, PVRI 978\tCO 2.3, CI 1.6, MAP 56, MPAP 35, CVP 17, SVR 1362, SVRI 1997, PVR 873, PVRI 1280\tCO 4.7, CI 2.8, MAP 74, MPAP 27, CVP 14, SVR 1021, SVRI 1739, PVR 289, PVRI 493\tCO 5.1, CI 2.9, MAP 69, MPAP 26, CVP 10, SVR 932, SVRI 1650, PVR 253, PVRI 447\t\nPOD 1 cardiac output measurements\tCO 4.0, CI 2.3, MPAP 24\tCO 3.8, CI 2.4, MPAP 26\tCO 3.6, CI 2.0, MPAP 21\tCO 3.9, CI 2.6, MPAP 25\tCO 2.7, CI 1.8, MPAP 21\tCO 4.1, CI 2.7, MPAP 23\tCO 4.2, CI 2.2, MPAP 43\tCO 2.5, CI 2.0, MPAP 32\tCO 4.6, CI 2.7, MPAP 22\tCO 3.7, CI 2.1, MPAP 25\t\nDay of extubation\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 12\tPOD 1\tPOD 1\tPOD 1\t\nInitiation of enoxaparin\tPOD 0 (Antipho - spholipid syndro-me)\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\tPOD 1\t\nMajor postoperative complications\tAcute SDH\tNil\tNil\tPneumot - horax\tAcute- on- chronic SDH\tNil\tAcute renal impairment\tAccident-al fall with acute- on- chronic SDH\tAcute SDH\tAcute SDH\t\nAtrial fibrillation\tReperfusion lung injury\t\nPneumonia\t\nAcute- on - chronic SDH\t\nTiming of SDH diagnosis\tPOD 4\tN/A\tN/A\tN/A\tPOD 8\tN/A\tPOD 8\tPOD 5\tPOD 7\tPOD 6\t\nSymptoms of SDH\tHeadache\tN/A\tN/A\tN/A\tHeadache\tN/A\tDelirium\tAsymptomatic\tAsymptomatic\tAsymptomatic\t\nIntervention for SDH\tBurrhole and craniectomy\tN/A\tN/A\tN/A\tConservative*\tN/A\tConservative*\tConservative*\tConservative*\tConservative*\t\nResidual neurological deficits\tNil\tN/A\tN/A\tN/A\tNil\tN/A\tNil\tNil\tNil\tNil\t\nLength of hospital stay (days)\t35\t15\t14\t14\t20\t15\t37\t38\t16\t21\t\n*Conservative management of SDH include cessation of antiplatelets and/or anticoagulation, administration of reversal such as protamine, Vitamin K, and/or fresh frozen plasma. Units: Pulmonary artery systolic pressure (mmHg), tricuspid annular plane systolic excursion (cm), cardiac output (L/min), cardiac index (L/min/m2), mean pulmonary arterial pressure (mmHg), central venous pressure (mmHg), systemic vascular resistance (dn/s/cm5), systemic vascular resistance index (dn/s/m2/cm5), pulmonary vascular resistance (dn/s/cm5), pulmonary vascular resistance index (dn/s/m2/cm5). PAWP assumed to be 10 mmHg for calculations. 2DE: Two-dimensional echocardiography, CBP: Cardiopulmonary bypass, EF: Ejection fraction; left ventricular, PASP: Pulmonary artery systolic pressure, TAPSE: Tricuspid annular plane systolic excursion, CO: Cardiac output, CI: Cardiac index, MPAP: Mean pulmonary arterial pressure, CVP: Central venous pressure, SVR: Systemic vascular resistance, SVRI: Systemic vascular resistance index, PVR: Pulmonary vascular resistance, PVRI: Pulmonary vascular resistance index, SDH: Subdural hemorrhage, POD: Postoperative day\n\nDiscussion\nThe success of PEA surgeries is largely contingent on a multidisciplinary team-based approach. Cardiologists, respiratory physicians, cardiothoracic surgeons, perfusionists, and anesthesiologists work together to ensure optimal care before, during, and after the operations.\n\nSpecifically, anesthesia for patients undergoing PEA has always posed certain challenges to anesthesiologists. This patient population generally has a degree of right ventricular (RV) failure, and the goal of surgery is to ameliorate RV compromise as much as possible. This, however, means a certain degree of hemodynamic compromise as well as possible cardiopulmonary collapse during anesthesia. Cardiopulmonary bypass and deep hypothermic circulatory arrest (DHCA) have specific requirements with regard to cooling and cerebral protection/oxygen monitoring. Postbypass, anesthesiologists also have to be prepared to deal with potential complications such as residual pulmonary hypertension, RV failure, reperfusion pulmonary edema, and pulmonary hemorrhage.[56] We discuss our technique for anesthesia adapted from the UK institution and the perioperative care of these patients.\n\nPremedications\nPatients who are on direct oral anticoagulants (DOAC) have them stopped 48 h preoperatively unless renal clearance is impaired. For patients on warfarin, it is stopped 5 days preoperatively and a therapeutic dose of enoxaparin is started 4 days preoperatively and continued till 24 h before surgery. Oral prednisolone of 1 mg/kg bodyweight is served at 2200 h night before surgery. All sedatives are avoided due to their potential for respiratory depression with subsequent hypercarbia and acidosis leading to increased pulmonary vascular resistance (PVR). In the very anxious patient, a small dose of midazolam 0.5–1 mg is administered before setting of lines to avoid overt sympathetic activation which may also lead to increased PVR. Special consideration is paid to patients with high baseline central venous pressure (CVP) or right atrial (RA) pressures. We are considering more aggressive diuresis preoperatively to lower the RA pressures in the hope of lowering the risk of subdural hemorrhages (SDH).\n\nEquipment, monitoring, and invasive lines\nInvasive lines include a wide bore peripheral cannula, a radial 20G arterial line, a triple lumen central venous catheter, and 7 Fr swan sheath placed in the right internal jugular vein if possible. The pulmonary artery (PA) catheter is docked but not floated. Head-down position during insertion of lines is avoided. A 16G femoral arterial line is inserted by surgeons postinduction as prolonged bypass times with DHCA have been shown to dampen the radial arterial pressures.\n\nThe standard monitoring devices are applied. A transesophageal echocardiography (TEE) probe is inserted postinduction, and the PA catheter is then floated through under TEE guidance, this PA catheter is temporarily removed from the surgical field by surgeons to aid with visualization after accessing the PA (it is then repositioned before closing of the pulmonary artery). Continuous CO monitoring is obtained with CO, cardiac index (CI), PA pressures, PVR, and systemic vascular resistance (SVR) recorded. The PA catheter can be wedged at baseline to obtain the PA wedge pressure (PAWP), or alternatively and more commonly, the PAWP is assumed to be 10 mmHg in the calculation of PVR. In addition, bispectral index (BIS) and near infra-red spectroscopy are utilized for cerebral monitoring and cerebral oximetry during periods of DHCA. Esophageal and bladder (incorporated into urinary catheter) temperature probes are inserted to ensure even cooling and warming. Patients lie on both a warming mattress and underbody Bair-hugger™. ROTEM™ is available for postbypass coagulation indices if required.\n\nInduction\nPatients are induced in the operating theater with a combination of midazolam, etomidate or propofol, and fentanyl after thorough preoxygenation. An additional dose of fentanyl 500 mcg is given before sternotomy. Pancuronium is the muscle relaxant of choice. Dopamine is started at 5 mcg/kg/min, titrated, and continued for the duration of the surgery till transfer to the Intensive Care Unit (ICU). Additional inotropic agents may be prepared at the discretion of the anesthesiologist. Maintenance of adequate SVR is important as it determines the RV perfusion pressures. Boluses of phenylephrine can be administered for rapid titration of SVR.\n\nMethylprednisolone 1 g is administered postinduction. Antibiotic prophylaxis is achieved with cefazolin 2 g or vancomycin 1 g (to run as an infusion) if the patient is methicillin-resistant Staphylococcus aureus positive unless otherwise indicated. A tranexamic acid bolus of 1 g is given followed by a continuous infusion of 500 mg/h maintained till ICU admission. Baseline arterial blood gas (ABG) is obtained and an insulin infusion is commenced if necessary to maintain blood sugars between 4 and 9 mg/dL. Baseline activated clotting time (ACT) is also recorded.\n\nVentilation is achieved with pressure control or pressure-controlled ventilation-volume guaranteed at FiO2 of 0.3, tidal volume (TV) of 4 ml/kg, peak end-expiratory pressure (PEEP) 6 cmH2O, and respiratory rate (RR) of 12. Care is taken to avoid hypoxia, hypercarbia, and acidosis which will further increase PVR.\n\nPositioning\nPatients are in the supine position with their hands tucked in. Overt neck extension is not recommended as it may impede cerebral perfusion. In our Asian population, due to the smaller sizes of the patients, sometimes, a shoulder roll is still required to elevate the chest for surgical exposure.\n\nBefore cardiopulmonary bypass\nCO measurements are taken before initiation of CBP; these include: CO, CI, mean arterial pressure (MAP), mean PA pressure, CVP, SVR, SVR index, PVR, and PVR index, with PAWP assumed to be 10 mmHg. These measurements are repeated after patients are weaned off CBP.\n\nHeparin of 4 IU/kg is given to patient to achieve an ACT of >400 s. The bypass pump is primed as per normal to other procedures. The only change is that the priming solution is now replaced by albumin 5% instead of crystalloids or gelafundin.\n\nCardiopulmonary bypass\nPropofol is infused for maintenance of anesthesia at the start of CBP, titrated as per BIS monitoring. Patients with CTEPH and chronic hypoxemia are usually polycythemic. At the initiation of CBP, one to two autologous units of blood is obtained depending on the starting hemoglobin (Hb) concentration and size of the patient, targeting a hematocrit of not <22% and Hb of 7–9 g/dL during bypass. The blood is stored in OT for a maximum of 8 h and transfused back to the patient at various stages “on-pump” and when coming off bypass to reach target Hb. The hemodilution of blood with autologous donation leads to decreased blood viscosity which aids with tissue oxygen delivery and promotes uniform cooling in preparation for DHCA. In addition, autologous blood contains factors and platelets, replacing those lost and diluted by bypass.[6] Carbon dioxide is also given at low flow during bypass to promote cerebral vasodilatation and increase cerebral oxygenation before DHCA.\n\nDeep hypothermic circulatory arrest\nPatients are cooled gradually to a core temperature of 20°C or 18° C before circulatory arrest is initiated. We use ice packs wrapped around the head with a towel instead of cooling caps for head cooling; the effects seem to be acceptable. DHCA is continued for a maximum of 20 min if cooled to 20°C, 25 min if cooled to 18°C, or when cerebral oximetry drops below 40%. Bypass is then resumed for 10 min before another round of DCHA is performed as required. Maintenance of cerebral perfusion was not employed in any of our cases as the PEACOG trial performed at an expert center showed no significant impairment in cognitive function between antegrade cerebral perfusion and DHCA, and DHCA is recommended as the optimum modality.[7]\n\nRewarming\nRewarming is achieved gradually to ensure uniformity. Esophageal temperatures should not exceed 37°C and the gradient between esophageal and bladder temperatures should not exceed 5° at any point. Ice packs are removed from the head together with the change of jelly doughnut head rings as they tend to remain cold. Ventilation is resumed initially at FiO2 of 0.25–0.3, TV 4–5 ml/kg, PEEP of 6, and RR 12 with an ICU ventilator. TVs are adjusted to 8 ml/kg, and FiO2 increased to 0.6%–0.8% when weaning off bypass. ABGs are repeated to ensure normal pH and electrolyte balances, with serum potassium targeted at no <5 mmol/L. Atrial-ventricular pacing is usually commenced at a rate of 80–90 beats/min if required to maintain CO. The aim is to wean off bypass with the patient relatively underfilled: CVP half of prebypass values.\n\nAfter cardiopulmonary bypass\nAdditional inotropic support may be started if required, usually adrenaline or noradrenaline. The postbypass CO measurements are recorded again. Should the MAP be borderline when coming off bypass, CO should be guided by cerebral oximetry as a surrogate marker instead of MAP, aiming for levels obtained when on full flow on bypass. Once the patient is hemodynamically stable, protamine is administered to achieve prebypass values. A target Hb of 10 g/dL is desired, additional donor blood may be required. Rotem™ is performed after reversal with protamine to guide with the replacement of blood products if there is a question of coagulopathy. RR is adjusted to achieve normocapnia. As much as possible, no additional opiates are administered.\n\nAfter surgery\nPatients are transferred to the ICU with the ICU ventilator and last ventilator setup in OT. This is to avoid disconnecting the endotracheal tube from the ventilator to maintain PEEP as these patients are prone to reperfusion lung injury. Dopamine infusion is typically continued overnight to maintain CI and perfusion pressures at appropriate levels. Pacing is continued from OT if needed. The PA catheter position is checked, and the balloon inflation device disabled to prevent further use in ICU. Mean PA pressure, CO, and CI are documented till the first postoperative day. Patients are kept intubated overnight for lung protection with the aim for extubation after 24 h. Fluids are kept at a minimum to maintain “dry lungs,” with the aim of a negative 1–1.5 L fluid balance by the first postoperative day. Prophylactic enoxaparin is started at 40 mg/day (dose adjustment needed for renal impairment) 24 h after surgery if bleeding is <25 ml/h for two consecutive hours. This is escalated to a therapeutic dose of enoxaparin at 0.75 mg/kg twice a day (dose adjustment needed for renal impairment) 48–72 h postsurgery if there are no contraindications. Warfarin may be resumed with enoxaparin overlap if there are no contraindications; usually after the postoperative day 2. For those previously on DOAC, this can be resumed the morning or evening before discharge (depending on the frequency of dosing). The enoxaparin is to be discontinued once DOAC is commenced.\n\nComplications\nThree major complications associated with PEA are pulmonary hemorrhage, reperfusion pulmonary edema, and residual pulmonary hypertension with RV failure.[568] Only one out of the ten patients operated on suffered from such complications in this case series, but we briefly discuss the planned management should such issues arise.\n\nPulmonary hemorrhage, if detected intraoperatively, can be repaired primarily if surgery is possible. Depending on the severity of bleed, conservative management consisting of PEEP, lung isolation of segment bleeding with bronchial blockade, reversal of heparin, application of a topical vasoconstrictor (vasopressin or phenylephrine), and correction of coagulopathies is also an alternative if the bleed is small.[9] If surgical access is difficult, and the surgical field is obstructed by bleeding, lung isolation strategies may be insufficient. Bypass is resumed to reduce PA blood flow and bleeding and then switched to central venous-arterial extracorporeal membrane oxygenation (ECMO) should RV function be compromised or venous-venous ECMO if biventricular function is preserved. Heparin is fully reversed with protamine, and the patient is brought to the ICU with chest open and central ECMO in situ.[69] Heparin is withheld for the first 24 h.[10] After 24–48 h, a bronchoscopy is performed to assess for bleeding. Should the bleeding abate, ECMO is weaned off and the chest is then closed. Lung isolation may be used in conjunction with ECMO to prevent bleeding into other lung segments.\n\nReperfusion pulmonary edema is one of the most common complication after pulmonary endarterectomies and typically occurs within 48-h postsurgery.[11] It is characterized by high permeability edema and new radiological opacities in areas of the lungs that have been reperfused.[1213] Prevention starts with protective lung strategies; (1) protective lung ventilation with reduced TVs and maintenance of PEEP and (2) maintenance of “dry lungs” by minimizing fluid overload, coming off bypass with a low CVP. For management of reperfusion pulmonary edema, the treatment is mainly supportive with diuresis, minimizing FiO2, and avoidance of high CO.[56] In refractory cases, ECMO can be initiated and may be lifesaving.[14]\n\nResidual pulmonary hypertension may present with concurrent RV failure and failure to wean off CBP. These patients often require inotropic support and attention is paid to optimizing RV preload.[6815] They may have to be commenced on ECMO if the hemodynamics are unstable.[15] Pharmacological therapy may be helpful in some cases. Inhaled nitric oxide or iloprost will help to reduce PVR.[161718] If the residual pulmonary hypertension is significant, pulmonary antihypertensive agents such as prostacyclin analogs and phosphodiesterase-5 inhibitors should be continued.[6819]\n\nFor our institution, the most common complication seems to be SDH with 60% of patients affected. Subdural hemorrhage is one of the less common, but potential complications after PEA surgery. Current literature yields little on its incidence; a study conducted by Papworth Hospital from 2000 to 2013 showed that 6 out of 42 patients (14%) undergoing PEA for CTEPH sustained SDH.[4] In comparison, our complication rate is fourfold despite adherence to protocol. Several postulations have been made with regard to this increased rate. First, to maintain “dry lungs” in the postoperative period, patients are diuresed aggressively (from mannitol in the pump solution and mannitol and frusemide given postoperatively), causing rapid fluid shifts. Second, DHCA with subsequent rewarming causes marked changes in cerebral perfusion with repeated vasoconstrictive, then vasodilatory episodes. A combination of these two factors, together with reduced RV afterload and improved CO, may lead to increased shearing forces between bridging veins of the two meningeal layers, resulting in SDH. Another factor could be that Asians are more prone to development of intracranial bleeds as compared to the Western population.[2021] As half of the patients who sustained SDH did not have overt neurological symptoms (three out of six), there is a possibility that rates of SDH after PEA could have been underreported previously. Our institution is currently looking at several strategies toward prevention, these include: (1) More aggressive preoperative diuresis for patients with baseline high CVP/RA pressures to lower them, (2) Gentler postoperative diuresis, (3) routine screening with postoperative CT brains and resumption of anticoagulation only if there is no evidence of intracranial bleeds.\n\nConclusion\nThis case series is a first of its kind for our hospital. In the ten patients operated on, eight of them were successfully extubated on the first postoperative day. Apart from one incident of prolonged ventilator usage due to reperfusion lung injury and pneumonia, there were no major respiratory or hemodynamic complications. Certainly, six of the ten patients developed SDH after the commencement of enoxaparin. Only one of them required surgical intervention, the rest were managed conservatively. All cases of SDH were promptly picked up and none of the patients sustained any permanent neurological deficits. We are presently in the midst of revising our protocol as mentioned above in the hope of decreasing such incidences.\n\nIn this series, we have demonstrated that with careful planning and a well-outlined protocol, anesthesia for PEA in an Asian population can be achieved with favorable outcomes. There are definitely variations due to different patient demographics and further fine-tuning of the protocol is still required based on local expertise. Although this surgery is associated with a high risk of mortality and morbidity, with increased experience and further research, we hope to achieve higher success rates and promote awareness around the region.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgment\nWe would like to thank the Royal Papworth Hospital UK Anesthesia department and Dr. D Jenkins for their invaluable help and contribution of technical expertise toward the success of our case series.\n==== Refs\n1 Gall H Hoeper MM Richter MJ Cacheris W Hinzmann B Mayer E An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan Eur Respir Rev 2017 26 pii: 160121 \n2 Luo WC Huang SC Lin YH Lai HS Kuo SW Pan SC Pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension – A single-center experience in Taiwan J Formos Med Assoc 2015 114 1197 203 25267092 \n3 Lewczuk J Piszko P Jagas J Porada A Wójciak S Sobkowicz B Prognostic factors in medically treated patients with chronic pulmonary embolism Chest 2001 119 818 23 11243963 \n4 Taboada D Pepke-Zaba J Jenkins DP Berman M Treacy CM Cannon JE Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease Eur Respir J 2014 44 1635 45 25234805 \n5 Manecke GR Jr Anesthesia for pulmonary endarterectomy Semin Thorac Cardiovasc Surg 2006 18 236 42 17185186 \n6 Banks DA Pretorius GV Kerr KM Manecke GR Pulmonary endarterectomy: Part II. Operation, anesthetic management, and postoperative care Semin Cardiothorac Vasc Anesth 2014 18 331 40 25005856 \n7 Vuylsteke A Sharples L Charman G Kneeshaw J Tsui S Dunning J Circulatory arrest versus cerebral perfusion during pulmonary endarterectomy surgery (PEACOG): A randomised controlled trial Lancet 2011 378 1379 87 22000135 \n8 Jenkins DP Madani M Mayer E Kerr K Kim N Klepetko W Surgical treatment of chronic thromboembolic pulmonary hypertension Eur Respir J 2013 41 735 42 23143539 \n9 Manecke GR Jr Kotzur A Atkins G Fedullo PF Auger WR Kapelanski DP Massive pulmonary hemorrhage after pulmonary thromboendarterectomy Anesth Analg 2004 99 672 5 15333391 \n10 Cronin B Maus T Pretorius V Nguyen L Johnson D Ovando J Case 13–2014: Management of pulmonary hemorrhage after pulmonary endarterectomy with venovenous extracorporeal membrane oxygenation without systemic anticoagulation J Cardiothorac Vasc Anesth 2014 28 1667 76 25440651 \n11 Duwe BV Kerr KM Fedullo PF Kim NH Test VJ Auger WR Clinical impact of reperfusion lung injury on patients undergoing pulmonary thromboendarterectomy Am J Respir Crit Care Med 2009 179 A4628 \n12 Levinson RM Shure D Moser KM Reperfusion pulmonary edema after pulmonary artery thromboendarterectomy Am Rev Respir Dis 1986 134 1241 5 3789523 \n13 Kerr KM Auger WR Marsh JJ Comito RM Fedullo RL Smits GJ The use of cylexin (CY-1503) in prevention of reperfusion lung injury in patients undergoing pulmonary thromboendarterectomy Am J Respir Crit Care Med 2000 162 14 20 10903213 \n14 Edemskiy A Chernyavskiy M Tarkova A Chernyavskiy A Central extracorporeal membrane oxygenation for treatment of reperfusion oedema following pulmonary thromboendarterectomy: A case report J Cardiothorac Surg 2016 11 76 27145866 \n15 Mayer E Surgical and post-operative treatment of chronic thromboembolic pulmonary hypertension Eur Respir Rev 2010 19 64 7 20956168 \n16 Kramm T Eberle B Guth S Mayer E Inhaled iloprost to control residual pulmonary hypertension following pulmonary endarterectomy Eur J Cardiothorac Surg 2005 28 882 8 16242948 \n17 Flondor M Merkel M Hofstetter C Irlbeck M Frey L Zwissler B The effect of inhaled nitric oxide and inhaled iloprost on hypoxaemia in a patient with pulmonary hypertension after pulmonary thrombarterectomy Anaesthesia 2006 61 1200 3 17090242 \n18 Imanaka H Miyano H Takeuchi M Kumon K Ando M Effects of nitric oxide inhalation after pulmonary thromboendarterectomy for chronic pulmonary thromboembolism Chest 2000 118 39 46 10893357 \n19 Piazza G Goldhaber SZ Chronic thromboembolic pulmonary hypertension N Engl J Med 2011 364 351 60 21268727 \n20 Shen AY Yao JF Brar SS Jorgensen MB Chen W Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation J Am Coll Cardiol 2007 50 309 15 17659197 \n21 van Asch CJ Luitse MJ Rinkel GJ van der Tweel I Algra A Klijn CJ Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: A systematic review and meta-analysis Lancet Neurol 2010 9 167 76 20056489\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-9784",
"issue": "22(2)",
"journal": "Annals of cardiac anaesthesia",
"keywords": "Anesthesia; Asian population; chronic thromboembolic pulmonary hypertension; pulmonary endarterectomy",
"medline_ta": "Ann Card Anaesth",
"mesh_terms": "D000368:Aged; D000758:Anesthesia; D001210:Asia, Southeastern; D002985:Clinical Protocols; D004691:Endarterectomy; D005060:Europe; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D008875:Middle Aged; D019990:Perioperative Care; D011651:Pulmonary Artery; D016896:Treatment Outcome; D006113:United Kingdom",
"nlm_unique_id": "9815987",
"other_id": null,
"pages": "169-176",
"pmc": null,
"pmid": "30971599",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "27145866;25005856;25234805;25440651;17659197;28356407;11243963;10893357;20956168;21268727;17090242;15333391;23143539;16242948;17185186;3789523;10903213;25267092;20056489;22000135",
"title": "Perioperative anesthesia management for pulmonary endarterectomy: Adopting an established European Protocol for the Asian Population.",
"title_normalized": "perioperative anesthesia management for pulmonary endarterectomy adopting an established european protocol for the asian population"
} | [
{
"companynumb": "SG-SA-2019SA112530",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOPAMINE\\DOPAMINE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "Clozapine is often the drug of choice within patients suffering from treatment-resistant paranoid schizophrenia. It has a complex side effects profile which includes potentially fatal agranulocytosis. Clozapine has also become increasingly associated with a range of other side effects including constipation and pneumonia. We report on a case of clozapine-induced severe constipation leading to a silent presentation of pneumonia with a subsequent respiratory arrest. To our knowledge, this is the first case report of pneumonia secondary to severe constipation occurring in the absence of respiratory aspiration of feculent vomitus. We suggest a new pathological mechanism by way of severe constipation leading to diaphragmatic dysfunction and subsequent clozapine-induced pneumonia. In addition, implications for clinical practice are outlined.",
"affiliations": "St Andrew's Healthcare, Birmingham, UK.",
"authors": "Galappathie|Nuwan|N|;Khan|Sobia|S|",
"chemical_list": "D014150:Antipsychotic Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1177/0025802413497708",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-8024",
"issue": "54(2)",
"journal": "Medicine, science, and the law",
"keywords": "clozapine; constipation; pneumonia; respiratory arrest; schizophrenia",
"medline_ta": "Med Sci Law",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D003248:Constipation; D005244:Fecal Impaction; D006801:Humans; D008297:Male; D011014:Pneumonia; D012131:Respiratory Insufficiency; D012563:Schizophrenia, Paranoid; D012812:Sigmoidoscopy",
"nlm_unique_id": "0400721",
"other_id": null,
"pages": "105-9",
"pmc": null,
"pmid": "24052002",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clozapine-associated pneumonia and respiratory arrest secondary to severe constipation.",
"title_normalized": "clozapine associated pneumonia and respiratory arrest secondary to severe constipation"
} | [
{
"companynumb": "PHHY2014GB086059",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": null,
"druga... |
{
"abstract": "BACKGROUND\nDopamine agonists (DAs) represent the first-line treatment in restless legs syndrome (RLS); however, in the long term, a substantial proportion of patients will develop augmentation, which is a severe drug-related exacerbation of symptoms and the main reason for late DA withdrawal. Polysomnographic features and mechanisms underlining augmentation are unknown. No practice guidelines for management of augmentation are available.\n\n\nMETHODS\nA clinical case series of 24 consecutive outpatients affected by RLS with clinically significant augmentation during treatment with immediate-release DA was performed. All patients underwent a full-night polysomnographic recording during augmentation. A switchover from immediate-release DAs (l-dopa, pramipexole, ropinirole, rotigotine) to the long-acting, extended-release formula of pramipexole was performed.\n\n\nRESULTS\nFifty percent of patients presented more than 15 periodic limb movements per hour of sleep during augmentation, showing longer sleep latency and shorter total sleep time than subjects without periodic limb movements. In all patients, resolution of augmentation was observed within two to four weeks during which immediate-release dopamine agonists could be completely withdrawn. Treatment efficacy of extended-release pramipexole has persisted, thus far, over a mean follow-up interval of 13 months.\n\n\nCONCLUSIONS\nPramipexole extended release could be an easy, safe, and fast pharmacological option to treat augmentation in patients with restless legs syndrome. As such it warrants further prospective and controlled investigations. This observation supports the hypothesis that the duration of action of the drug plays a key role in the mechanism of augmentation.",
"affiliations": "Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;Sleep Disorders Centre, Department of Clinical Neurosciences, San Raffaele Scientific Institute, Milan, Italy.;Sleep Disorders Centre, Department of Clinical Neurosciences, San Raffaele Scientific Institute, Milan, Italy.;Sleep Disorders Centre, Department of Clinical Neurosciences, San Raffaele Scientific Institute, Milan, Italy.;Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland.;University Department of Neurology, Inselspital, Bern, Switzerland.;Sleep and Epilepsy Center, Neurocenter of the Southern Switzerland, Civic Hospital of Lugano, Lugano, Switzerland. Electronic address: mauro.manconi@eoc.ch.",
"authors": "Maestri|Michelangelo|M|;Fulda|Stephany|S|;Ferini-Strambi|Luigi|L|;Zucconi|Marco|M|;Marelli|Sara|S|;Staedler|Claudio|C|;Bassetti|Claudio L|CL|;Manconi|Mauro|M|",
"chemical_list": "D052160:Benzothiazoles; D003692:Delayed-Action Preparations; D018491:Dopamine Agonists; D007211:Indoles; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; C046649:ropinirole; D007980:Levodopa; D000077487:Pramipexole; C047508:rotigotine",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-9457",
"issue": "15(5)",
"journal": "Sleep medicine",
"keywords": "Augmentation; Dopamine; Periodic limb movements; Restless legs syndrome; Sleep; Therapy",
"medline_ta": "Sleep Med",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D052160:Benzothiazoles; D003692:Delayed-Action Preparations; D018491:Dopamine Agonists; D005260:Female; D006801:Humans; D007211:Indoles; D007980:Levodopa; D008297:Male; D008875:Middle Aged; D017286:Polysomnography; D000077487:Pramipexole; D012148:Restless Legs Syndrome; D012894:Sleep Stages; D013764:Tetrahydronaphthalenes; D013876:Thiophenes; D016896:Treatment Outcome",
"nlm_unique_id": "100898759",
"other_id": null,
"pages": "570-5",
"pmc": null,
"pmid": "24767724",
"pubdate": "2014-05",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Polysomnographic record and successful management of augmentation in restless legs syndrome/Willis-Ekbom disease.",
"title_normalized": "polysomnographic record and successful management of augmentation in restless legs syndrome willis ekbom disease"
} | [
{
"companynumb": "CH-MYLANLABS-2015M1010309",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"drugadditional": null,
... |
{
"abstract": "Severe drug hypersensitivity reactions to antibiotics are rare but trimethoprim-sulfamethoxazole (TMP-SMX) is uniquely associated with numerous and varied manifestations including a reaction resembling septic shock, first observed in human immunodeficiency virus (HIV)/AIDS patients. Over the past 25 years about 20 cases have been reported and an association with the virus and related immune system dysregulation was assumed. However, recent reports in adults have recognized similar shock-like reactions in non-HIV infected individuals. Here we review severe TMP-SMX hypersensitivity reactions and within the context of these known reactions, describe three non-HIV infected adolescent patients with shock-like reactions to TMP-SMX observed in one institution over 1.5 years.",
"affiliations": "Division of Infectious Disease, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.;Division of Infectious Disease, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.;Division of Infectious Disease, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington, USA.",
"authors": "Rathe|Jennifer A|JA|;Poole|Nicole|N|;Melvin|Ann|A|",
"chemical_list": "D000900:Anti-Bacterial Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "England",
"delete": false,
"doi": "10.1093/jpids/piaa100",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2048-7193",
"issue": "10(3)",
"journal": "Journal of the Pediatric Infectious Diseases Society",
"keywords": "adolescents; drug allergy; hypersensitivity reactions; shock; trimethoprim-sulfamethoxazole",
"medline_ta": "J Pediatric Infect Dis Soc",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000900:Anti-Bacterial Agents; D004342:Drug Hypersensitivity; D015658:HIV Infections; D006801:Humans; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "101586049",
"other_id": null,
"pages": "382-385",
"pmc": null,
"pmid": "32955095",
"pubdate": "2021-04-03",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Atypical Severe Shock-like Reactions in Adolescents After Trimethoprim-Sulfamethoxazole Therapy.",
"title_normalized": "atypical severe shock like reactions in adolescents after trimethoprim sulfamethoxazole therapy"
} | [
{
"companynumb": "US-VISTA PHARMACEUTICALS INC.-2096164",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
... |
{
"abstract": "Atherosclerotic cardiovascular disease (ASCVD) events are the most common cause of death in the United States and for most individuals who experience these events, may be predicted by risk identification tools. ASCVD risk calculators enable a clinician-patient discussion and the presence of risk-enhancing factors may further inform decision-making with respect to preventive pharmacotherapy, especially statin prescription. In cases where the decision of whether to treat with medicine is unclear, coronary artery calcium scoring by computed tomography offers enhanced risk stratification and may allow both clinicians and patients to feel more at ease with the decision to withhold statin therapy. Despite this thoughtful approach, individual risk may still be underestimated. We present a case of a woman whose family history suggested increased short- and long-term ASCVD risk due to intracranial atherosclerosis, but whose tests suggested a more equivocal indication for treatment. Neither she nor her clinician appreciated the presence of significant enough risk to persevere through minor statin side effects for primary prevention, but she was lucky to have survived without appreciable harm from an acute cerebrovascular event and is now able to pursue an appropriate secondary preventive strategy. We discuss how exceptional characteristics may mislead clinicians, including misperception about lower risk due to gender, East Asian predisposition to intracranial more than coronary atherosclerosis, high levels of high density lipoprotein cholesterol (HDL-C), and CACS = 0.",
"affiliations": "Perelman School of Medicine at the University of Pennsylvania.;Perelman School of Medicine at the University of Pennsylvania.;Perelman School of Medicine at the University of Pennsylvania.;Perelman School of Medicine at the University of Pennsylvania.;Perelman School of Medicine at the University of Pennsylvania. Electronic address: Daniel.soffer@pennmedicine.upenn.edu.",
"authors": "Gong|Jan|J|;Asher|Stephanie Byers|SB|;Cucchiara|Brett|B|;Cuchel|Marina|M|;Soffer|Daniel|D|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.jacl.2021.01.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1876-4789",
"issue": "15(2)",
"journal": "Journal of clinical lipidology",
"keywords": "Atherosclerotic cardiovascular disease (ASCVD); Coronary artery calcium score (CACS); High density lipoprotein-cholesterol (HDL-C); Intracranial stenosis; Precision medicine; Scavenger receptor binding protein type 1 (SCARB1 genotype); Stroke",
"medline_ta": "J Clin Lipidol",
"mesh_terms": null,
"nlm_unique_id": "101300157",
"other_id": null,
"pages": "248-254",
"pmc": null,
"pmid": "33573892",
"pubdate": "2021",
"publication_types": "D016428:Journal Article; D002363:Case Reports",
"references": null,
"title": "Case report: 68 yo Chinese-American woman with high HDL-C and ischemic stroke attributed to intracranial atherosclerotic stenosis.",
"title_normalized": "case report 68 yo chinese american woman with high hdl c and ischemic stroke attributed to intracranial atherosclerotic stenosis"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/20/0128080",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ATORVASTATIN"
},
"drugadditional": "1",
... |
{
"abstract": "Methylphenidate is a central nervous system stimulant medicinally used in the treatment of attention-deficit disorder with or without hyperactivity (ADD/ADHD). Data on its use in human pregnancy are limited. The primary objective of the study was to evaluate the risk of major congenital anomalies after pregnancy exposure to methylphenidate for medical indications.\n\n\n\nIn a prospective, comparative, multicenter observational study performed in 4 participating Teratology Information Services (in Jerusalem, Berlin, Newcastle upon Tyne, and Toronto) between 1996 and 2013, methylphenidate-exposed pregnancies were compared with pregnancies counseled for nonteratogenic exposure (NTE) after matching by maternal age, gestational age, and year at initial contact.\n\n\n\n382 methylphenidate-exposed pregnancies (89.5% in the first trimester) were followed up. The overall rate of major congenital anomalies was similar between the groups (10/309 = 3.2% [methylphenidate] vs 13/358 = 3.6% [NTE], P = .780). The rates of major congenital anomalies (6/247 = 2.4% [methylphenidate] vs 12/358 = 3.4% [NTE], P = .511) and cardiovascular anomalies (2/247 = 0.8% [methylphenidate] vs 3/358 = 0.8% [NTE], P = .970) were also similar after exclusion of genetic or cytogenetic anomalies and limiting methylphenidate exposure to the period of organogenesis (weeks 4-13 after the last menstrual period). There was a higher rate of miscarriages and elective terminations of pregnancy in the methylphenidate group. Significant predictors for the miscarriages using Cox proportional hazards model were methylphenidate exposure (adjusted hazard ratio [HR] = 1.98; 95% CI, 1.23-3.20; P = .005) and past miscarriage (adjusted HR = 1.35; 95% CI, 1.18-1.55; P < .001).\n\n\n\nThe present study suggests that methylphenidate does not seem to increase the risk for major malformations. Further studies are required to establish its pregnancy safety and its possible association with miscarriages.",
"affiliations": "The Israeli Teratology Information Service, Israel Ministry of Health, PO Box 1176, Jerusalem, 9446724, Israel. orna.diav-citrin@moh.gov.il.;The Israeli Teratology Information Service, Jerusalem, Israel Ministry of Health.;The Israeli Teratology Information Service, Jerusalem, Israel Ministry of Health.;The Israeli Teratology Information Service, Jerusalem, Israel Ministry of Health.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Berlin, Germany.;Berlin Institute for Clinical Teratology and Drug Risk Assessment in Pregnancy, Berlin, Germany.;The United Kingdom Teratology Information Service, Newcastle upon Tyne, England.;The Motherisk Program, The Hospital for Sick Children, Toronto, Canada.;The Motherisk Program, The Hospital for Sick Children, Toronto, Canada.;The Israeli Teratology Information Service, Jerusalem, Israel Ministry of Health.",
"authors": "Diav-Citrin|Orna|O|;Shechtman|Svetlana|S|;Arnon|Judy|J|;Wajnberg|Rebecka|R|;Borisch|Cornelia|C|;Beck|Evelin|E|;Richardson|Jonathan Luke|JL|;Bozzo|Pina|P|;Nulman|Irena|I|;Ornoy|Asher|A|",
"chemical_list": "D000697:Central Nervous System Stimulants; D008774:Methylphenidate",
"country": "United States",
"delete": false,
"doi": "10.4088/JCP.15m10083",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0160-6689",
"issue": "77(9)",
"journal": "The Journal of clinical psychiatry",
"keywords": null,
"medline_ta": "J Clin Psychiatry",
"mesh_terms": "D000014:Abnormalities, Drug-Induced; D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D018376:Cardiovascular Abnormalities; D000697:Central Nervous System Stimulants; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008774:Methylphenidate; D011247:Pregnancy; D011248:Pregnancy Complications; D012306:Risk",
"nlm_unique_id": "7801243",
"other_id": null,
"pages": "1176-1181",
"pmc": null,
"pmid": "27232650",
"pubdate": "2016-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Methylphenidate in Pregnancy: A Multicenter, Prospective, Comparative, Observational Study.",
"title_normalized": "methylphenidate in pregnancy a multicenter prospective comparative observational study"
} | [
{
"companynumb": "IL-JNJFOC-20161022321",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPHENIDATE HYDROCHLORIDE"
},
"drugadditional... |
{
"abstract": "An increasing percentage of potential organ donors are infected with hepatitis C virus (HCV). After transplantation from an infected donor, establishment of HCV infection in uninfected recipients is near-universal, with the requirement for post-transplant antiviral treatment. The aim of this study was to determine if antiviral drugs combined with an HCV entry blocker given before and for 7 days after transplant would be safe and reduce the likelihood of HCV infection in recipients of organs from HCV-infected donors.\n\n\n\nHCV-uninfected organ recipients without pre-existing liver disease were treated with ezetimibe (10 mg; an HCV entry inhibitor) and glecaprevir-pibrentasvir (300 mg/120 mg) before and after transplantation from HCV-infected donors aged younger than 70 years without co-infection with HIV, hepatitis B virus, or human T-cell leukaemia virus 1 or 2. Recipients received a single dose 6-12 h before transplant and once a day for 7 days after surgery (eight doses in total). HCV RNA was assessed once a day for 14 days and then once a week until 12 weeks post-transplant. The primary endpoint was prevention of chronic HCV infection, as evidenced by undetectable serum HCV RNA at 12 weeks after transplant, and assessed in the intention-to-treat population. Safety monitoring was according to routine post-transplant practice. 12-week data are reported for the first 30 patients. The trial is registered on ClinicalTrials.gov, NCT04017338. The trial is closed to recruitment but follow-up is ongoing.\n\n\n\n30 patients (23 men and seven women; median age 61 years (IQR 48-66) received transplants (13 lung, ten kidney, six heart, and one kidney-pancreas) from 18 HCV-infected donors. The median donor viral load was 5·11 log10IU/mL (IQR 4·55-5·63) and at least three HCV genotypes were represented (nine [50%] donors with genotype 1, two [11%] with genotype 2, five [28%] with genotype 3, and two [11%] with unknown genotype). All 30 (100%) transplant recipients met the primary endpoint of undetectable HCV RNA at 12 weeks post-transplant, and were HCV RNA-negative at last follow-up (median 36 weeks post-transplant [IQR 25-47]). Low-level viraemia was transiently detectable in 21 (67%) of 30 recipients in the early post-transplant period but not after day 14. Treatment was well tolerated with no dose reductions or treatment discontinuations; 32 serious adverse events occurred in 20 (67%) recipients, with one grade 3 elevation in alanine aminotransferase (ALT) possibly related to treatment. Non-serious transient elevations in ALT and creatine kinase during the study dosing period resolved with treatment completion. Among the serious adverse events were two recipient deaths due to causes unrelated to study drug treatment (sepsis at 49 days and subarachnoid haemorrhage at 109 days post-transplant), with neither patient ever being viraemic for HCV.\n\n\n\nEzetimibe combined with glecaprevir-pibrentasvir given one dose before and for 7 days after transplant prevented the establishment of chronic HCV infection in recipients of different organs from HCV-infected donors. This study shows that an ultra-short course of direct-acting antivirals and ezetimibe can prevent the establishment of chronic HCV infection in the recipient, alleviating many of the concerns with transplanting organs from HCV-infected donors.\n\n\n\nCanadian Institutes of Health Research; the Organ Transplant Program, University Health Network.",
"affiliations": "Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: Jordan.feld@uhn.ca.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Program for Experimental and Theoretical Modeling, Division of Hepatology, Department of Medicine, Loyola University Chicago, Chicago, IL, USA.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto Centre for Liver Disease, Toronto, ON, Canada; Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada; Soham and Shaila Ajmera Family Transplant Centre, University Health Network, University of Toronto, Toronto, ON, Canada.",
"authors": "Feld|Jordan J|JJ|;Cypel|Marcelo|M|;Kumar|Deepali|D|;Dahari|Harel|H|;Pinto Ribeiro|Rafaela Vanin|RV|;Marks|Nikki|N|;Kamkar|Nellie|N|;Bahinskaya|Ilona|I|;Onofrio|Fernanda Q|FQ|;Zahoor|Mohamed A|MA|;Cerrochi|Orlando|O|;Tinckam|Kathryn|K|;Kim|S Joseph|SJ|;Schiff|Jeffrey|J|;Reichman|Trevor W|TW|;McDonald|Michael|M|;Alba|Carolina|C|;Waddell|Thomas K|TK|;Sapisochin|Gonzalo|G|;Selzner|Markus|M|;Keshavjee|Shaf|S|;Janssen|Harry L A|HLA|;Hansen|Bettina E|BE|;Singer|Lianne G|LG|;Humar|Atul|A|",
"chemical_list": "D000924:Anticholesteremic Agents; D000998:Antiviral Agents; D001562:Benzimidazoles; D004338:Drug Combinations; D011759:Pyrrolidines; D011810:Quinoxalines; D013449:Sulfonamides; C000654128:glecaprevir and pibrentasvir; D000069438:Ezetimibe",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2468-1253(20)30081-9",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "5(7)",
"journal": "The lancet. Gastroenterology & hepatology",
"keywords": null,
"medline_ta": "Lancet Gastroenterol Hepatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000924:Anticholesteremic Agents; D000998:Antiviral Agents; D001562:Benzimidazoles; D002170:Canada; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D000069438:Ezetimibe; D005260:Female; D005838:Genotype; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011759:Pyrrolidines; D011810:Quinoxalines; D012328:RNA Viruses; D013449:Sulfonamides; D014019:Tissue Donors; D066027:Transplant Recipients; D019737:Transplants; D019562:Viral Load",
"nlm_unique_id": "101690683",
"other_id": null,
"pages": "649-657",
"pmc": null,
"pmid": "32389183",
"pubdate": "2020-07",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "24990994;21488765;14715313;19182773;30861340;28459186;31353243;26575258;31448549;30040178;30480869;31306549;26571066;29710288;29507971;30946553;29365309;30696822;17325668;26535533;26111063;25591505;28818546;31652392;28556422;31606437;29020583;9794763;30083748;22231557",
"title": "Short-course, direct-acting antivirals and ezetimibe to prevent HCV infection in recipients of organs from HCV-infected donors: a phase 3, single-centre, open-label study.",
"title_normalized": "short course direct acting antivirals and ezetimibe to prevent hcv infection in recipients of organs from hcv infected donors a phase 3 single centre open label study"
} | [
{
"companynumb": "CA-ALKEM LABORATORIES LIMITED-CA-ALKEM-2020-03670",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GLECAPREVIR\\PIBRENTASVIR"
},
... |
{
"abstract": "There is little information about pregnancy outcomes in patients with active membranous nephropathy (MN), especially those with circulating autoantibodies to M-type phospholipase A₂receptor (PLA₂R), the major autoantigen in primary MN. We present what we believe to be the first known case of successful pregnancy in a 39-year-old woman with PLA₂R-associated MN. In the year prior to pregnancy, the patient developed anasarca, hypoalbuminemia (albumin, 1.3-2.2g/dL), and proteinuria (protein excretion, 29.2 g/d). Kidney biopsy revealed MN with staining for PLA₂R, and the patient was seropositive for anti-PLA₂R autoantibodies. She did not respond to conservative therapy and was treated with intravenous rituximab (2 doses of 1 g each). Several weeks after presentation, she was found to be 6 weeks pregnant and was closely followed up without further immunosuppressive treatment. Proteinuria remained with protein excretion in the 8- to 12-g/d range. Circulating anti-PLA₂R levels declined but were still detectable. At 38 weeks, a healthy baby girl was born, without proteinuria at birth or at her subsequent 6-month postnatal visit. At the time of delivery, the mother still had detectable circulating anti-PLA₂R of immunoglobulin G1 (IgG1), IgG3, and IgG4 subclasses, although at low titers. Only trace amounts of IgG4 anti-PLA₂R were found in cord blood. Potential reasons for the discrepancy between anti-PLA₂R levels in the maternal and fetal circulation are discussed.",
"affiliations": "Department of Medicine, Renal Section, Boston University Medical Center, Boston, MA.;Department of Medicine, Renal Section, Boston University Medical Center, Boston, MA.;Department of Medicine, Renal Section, Boston University Medical Center, Boston, MA.;Department of Obstetrics and Gynecology, Boston University Medical Center, Boston, MA.;Department of Pediatrics, Boston University Medical Center, Boston, MA.;Department of Pathology and Laboratory Medicine, Boston University Medical Center, Boston, MA.;Department of Medicine, Renal Section, Boston University Medical Center, Boston, MA.;Department of Medicine, Renal Section, Boston University Medical Center, Boston, MA. Electronic address: lhbeckjr@bu.edu.",
"authors": "Al-Rabadi|Laith|L|;Ayalon|Rivka|R|;Bonegio|Ramon G|RG|;Ballard|Jennifer E|JE|;Fujii|Alan M|AM|;Henderson|Joel M|JM|;Salant|David J|DJ|;Beck|Laurence H|LH|",
"chemical_list": "D001323:Autoantibodies; D007166:Immunosuppressive Agents; D054507:Receptors, Phospholipase A2; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0272-6386",
"issue": "67(5)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "M-type phospholipase A(2) receptor (PLA(2)R); Membranous nephropathy (MN); autoantibody; immunoglobulin G (Ig G) subclass; nephrotic syndrome; placenta; pregnancy; rituximab",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D005260:Female; D015433:Glomerulonephritis, Membranous; D006801:Humans; D007166:Immunosuppressive Agents; D011247:Pregnancy; D011248:Pregnancy Complications; D054507:Receptors, Phospholipase A2; D000069283:Rituximab",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "775-8",
"pmc": null,
"pmid": "26744127",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "25613900;25288605;25565308;25766759;2188203;6390081;6226590;956658;1607681;1695559;2397175;12087141;22390840;22233329;7721806;10357095;19571279",
"title": "Pregnancy in a Patient With Primary Membranous Nephropathy and Circulating Anti-PLA2R Antibodies: A Case Report.",
"title_normalized": "pregnancy in a patient with primary membranous nephropathy and circulating anti pla2r antibodies a case report"
} | [
{
"companynumb": "US-BRISTOL-MYERS SQUIBB COMPANY-BMS-2017-057367",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TORSEMIDE"
},
"drugaddi... |
{
"abstract": "BACKGROUND\nIn recent years, combination antiretroviral therapy has substantially improved the prognosis of human immunodeficiency virus type-1 (HIV-1) infection. However, at present, information regarding the effects of these regimens during pregnancy is limited.\n\n\nMETHODS\nSide-effects, vertical transmission rate and neonatal outcome associated with different combination therapies were evaluated retrospectively in a consecutive series of 100 women who attended the II Department of Obstetrics and Gynecology for the management of HIV-1 infection in pregnancy.\n\n\nRESULTS\nAntiretroviral treatment was initiated at a median of 16 weeks gestation with a range from pre-pregnancy until 31 weeks gestation. Twentythree women continued their pre-pregnancy therapy during the first trimester of gestation. Protease inhibitors were incorporated in 23 of the final therapeutic regimens. Twentyfive women did not receive zidovudine. Most women (97) delivered by Caesarean section and none breast-fed. Prematurity rate for the entire series was 19%. When women who actively used illicit drugs were excluded, only seven of 69 (10%) women were found to deliver prematurely. The use of protease inhibitors was limited by an elevated frequency of severe gastrointestinal disturbances. The rate of congenital malformations did not appear to differ significantly from that reported in the literature for the general population. Only one of 102 live newborns was found to be HIV-1-infected (1.0%, 95% confidence interval; 0.3-4.6%).\n\n\nCONCLUSIONS\nThe present findings confirm the remarkable efficacy of combination antiretroviral therapy, Caesarean section and refraining from breast-feeding in lowering the rate of vertical HIV-1 transmission. Moreover, they are suggestive that combination antiretroviral therapy may not be related to major neonatal toxicity. The necessity to discontinue the therapy during the first trimester of pregnancy and to systematically incorporate zidovudine into combination regimens is discussed.",
"affiliations": "II Department of Obstetrics and Gynecology, University of Milan, Milano, Italy. dadosomigliana@yahoo.it",
"authors": "Bucceri|A M|AM|;Somigliana|E|E|;Matrone|R|R|;Ferraris|G|G|;Rossi|G|G|;Grossi|E|E|;Vignali|M|M|",
"chemical_list": "D019380:Anti-HIV Agents; D011480:Protease Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1093/humrep/17.2.436",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0268-1161",
"issue": "17(2)",
"journal": "Human reproduction (Oxford, England)",
"keywords": null,
"medline_ta": "Hum Reprod",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D001903:Bottle Feeding; D002585:Cesarean Section; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D015497:HIV-1; D006801:Humans; D015994:Incidence; D018445:Infectious Disease Transmission, Vertical; D007752:Obstetric Labor, Premature; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011480:Protease Inhibitors",
"nlm_unique_id": "8701199",
"other_id": null,
"pages": "436-41",
"pmc": null,
"pmid": "11821291",
"pubdate": "2002-02",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Combination antiretroviral therapy in 100 HIV-1-infected pregnant women.",
"title_normalized": "combination antiretroviral therapy in 100 hiv 1 infected pregnant women"
} | [
{
"companynumb": "IT-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-059357",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"... |
{
"abstract": "We present a case of Mycobacterium fortuitum ventriculoperitoneal shunt infection in a 26-year-old immunocompromised woman. The patient was treated with revision and replacement of her peritoneal shunt and prolonged combination antimicrobial therapy. There are no established guidelines for the treatment of VP shunt infections due to M. fortuitum. We review the literature and provide treatment recommendations.",
"affiliations": "Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA.;Infectious Disease, Sarasota Memorial Hospital, Sarasota, FL, USA.",
"authors": "Lattanzio|Natalia|N|;Bell|Stephen|S|;Campdesuner|Victoria|V|;George|Justin|J|;Alkayali|Talal|T|;Rodriguez|Yorlenis|Y|;Wiese-Rometsch|Wilhelmine|W|;Kraitman|Natan|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2020.e00995",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509 Elsevier \n\nS2214-2509(20)30303-6\n10.1016/j.idcr.2020.e00995\ne00995\nArticle\nMycobacterium fortuitum ventriculoperitoneal shunt infection in an immunocompromised patient: A case report\nLattanzio Natalia Natalia-Lattanzio@smh.coma⁎ Bell Stephen a Campdesuner Victoria a George Justin a Alkayali Talal a Rodriguez Yorlenis a Wiese-Rometsch Wilhelmine a Kraitman Natan b a Internal Medicine, Sarasota Memorial Hospital, Sarasota, FL, USA\nb Infectious Disease, Sarasota Memorial Hospital, Sarasota, FL, USA\n⁎ Corresponding author at: Internal Medicine, Sarasota Memorial Hospital, 1700 S Tamiami Trail, Sarasota, FL 34239, USA. Natalia-Lattanzio@smh.com\n23 10 2020 \n2020 \n23 10 2020 \n22 e0099519 7 2020 11 10 2020 14 10 2020 © 2020 The Authors2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We present a case of Mycobacterium fortuitum ventriculoperitoneal shunt infection in a 26-year-old immunocompromised woman. The patient was treated with revision and replacement of her peritoneal shunt and prolonged combination antimicrobial therapy. There are no established guidelines for the treatment of VP shunt infections due to M. fortuitum. We review the literature and provide treatment recommendations.\n\nAbbreviations\nVP, ventriculoperitoneal shuntCNS, central nervous systemCT, computed tomographyKeywords\nMycobacterium fortuitumVentriculoperitoneal shuntRapidly growing mycobacteria\n==== Body\nIntroduction\nMycobacterium fortuitum is a bacterium commonly found in the environment, more specifically in water, soil and dust [3]. This bacterium is classified as a rapidly growing mycobacteria, as it can be isolated and identified within the first week of incubation [2]. Infections in the central nervous system (CNS) are usually secondary to surgical site, catheter or shunt contamination as this mycobacterium has the ability to form biofilms and colonize foreign bodies. Disseminated infection with M. fortuitum is most commonly seen in immunocompromised patients and this warrants an extended course of antimicrobial therapy. Currently, there are still no established guidelines for the treatment of M. fortuitum, as infections with nontuberculous mycobacterium are uncommon and difficult to treat [2]. We present a case of a ventriculoperitoneal (VP) shunt infection caused by M. fortuitum in a 26-year-old immunocompromised woman with reported allergies to several antimicrobial therapies. Recommendations regarding treatment are described based on this case and pertinent literature review.\n\nCase\nA 26-year-old woman with a past medical history of endometriosis with prior abdominal surgeries, Crohn’s disease on prednisone and ustekinumab, and pseudotumor cerebri, initially presented with progressive loss of vision and headaches and subsequently underwent optic nerve fenestration and VP shunt placement. Her headaches dramatically improved but she developed abdominal pain with drainage from her incision site. Computed tomography (CT) of the abdomen showed the peritoneal catheter was in the subcutaneous tissue. She underwent two laparoscopic revisions and placement of a distal shunt catheter tip. Following surgery, she experienced significant improvement in her abdominal pain and had resolution of incision site drainage. Her headaches also improved. Ten days following surgery, she developed worsening headaches, erythema and swelling along the shunt on the right side of her neck and erythema of the abdomen over the operative scar. She subsequently presented to the emergency department for further evaluation.\n\nAt presentation, vitals were all within normal limits. Physical examination was significant for a right VP shunt incision scar with surrounding erythema, but no drainage or tenderness was appreciated. Laboratory findings were significant for leukocytosis of 14,400 cells/μL with a left shift. The patient reported anaphylactic reactions to azithromycin, trimethoprim-sulfamethoxazole, doxycycline and amoxicillin. Therefore, empiric therapy with intravenous (IV) cefepime 2gm every 8 h, vancomycin 1500 mg every 8 h and metronidazole 500 mg every 8 h were initiated. The patient started to experience worsening headaches and myalgias. Subsequent physical examination was significant for facial flushing and pain with flexion of the neck. The patient started to spike fevers (Fig. 1) and develop right neck tenderness along the shunt path. She underwent VP shunt removal. CT abdomen was obtained, which showed a small superficial fluid collection around her incision. She underwent lumbar puncture (Table 1) and percutaneous drainage of 20cc of cloudy abdominal fluid collection remarkable for 7475 cells/uL of white blood cells with 91 % neutrophils. At this stage, the patient had been treated with metronidazole 500 mg IV every 8 h, cefepime 2gm IV every 8 h, meropenem 1000 mg IV every 8 h, fluconazole 400 mg IV daily and vancomycin 1250 mg IV every 8 h. The patient was soon after started on imipenem 500 mg IV every 6 h, amikacin 1250 mg IV daily and tedizolid 200 mg orally daily as cultures from the abdominal fluid and the VP shunt itself were concerning for a rapid-growing mycobacterium.Fig. 1 Hospitalization temperature curve of the patient in °F.\n\nFig. 1Table 1 Spinal fluid analysis performed after lumbar puncture.\n\nTable 1Spinal Fluid Analysis\t\n\tMeasure Values [Reference Value]\t\nTotal Volume\t40 mL\t\nAppearance\tHazy [Clear]\t\nRed Cells\t22 [0 cells/uL]\t\nWhite Cells\t284 [0−5 cells/uL]\t\nPolys\t59 [0−5%]\t\nMonos\t41 [5−100%]\t\nTotal Cell Counted\t100\t\nGlucose\t40 [40−76 mg/dL]\t\nProtein\t65 [11−45 mg/dL]\t\n\n\nM. fortuitum was identified from the VP shunt and abdominal fluid collection eleven days after shunt removal and five days following drainage. As a result of this, the patient underwent incision and drainage of the abdominal fluid collection. Surgical findings were significant for necrotic material with encapsulated pus. Surgical cultures were also positive for M. fortuitum. The patient underwent azithromycin desentization and completed twelve days of treatment intravenously. Antimicrobials were adjusted to imipenem 1000 mg IV every 8 h, amikacin 1250 mg IV once a day and levofloxacin 750 mg orally once a day after susceptibility profile returned and showed resistance to azithromycin. The patient was discharged home with a planned two month of intravenous combination antimicrobial therapy, followed by ten months of oral antimicrobial therapy with levofloxacin 750 mg once a day. Upon outpatient follow up, the patient complained of ringing of the ears, possibly secondary to amikacin. The patient was briefly hospitalized to undergo doxycycline desentization. Her planned course of therapy was ten months of antimicrobial therapy with imipenem 1 g IV every 8 h, levofloxacin 750 mg orally once a day and doxycycline 100 mg oral every 12 h.\n\nDiscussion\nInfections of permanent shunts tend to be most commonly caused by gram-positive organisms [8]. Permanent shunt infections with atypical mycobacterium are rare but should be considered in immunocompromised patients given the high risk for dissemination and worse outcomes. M. fortuitum postoperative wound infections are uncommon [1]. The patients tend to present with non-specific symptoms which typically include fever, headache, signs concerning for meningitis, mental status changes, nausea and vomiting [8]. In order to correctly identify this organism as the cause of infection, it is crucial that acid-fast smear and cultures are sent on all samples including those obtained from removed hardware. Polymerase chain reaction may also aid in the diagnosis.\n\nTreatment of M. fortuitum consists of source control via surgical debridement and removal of the foreign body as well as a combination of antimicrobial therapy aggressively dosed guided by in vitro sensitivity tests. This bacterium is known to be resistant to antituberculosis medications and macrolides but has been found to respond effectively to antimicrobials including amikacin, linezolid, imipenem, sulfonamides, cephalosporins, fluoroquinolones and tetracyclines [8]. Prolonged antimicrobial treatment is necessary in order to prevent relapse, which usually occurs within two months after discontinuation of treatment [7]. Failure to respond to treatment has been attributed to the failure to remove the foreign body, inadequate surgical drainage, a low serum antimicrobial level or poor penetration of antimicrobials [3]. In the case of CNS infections, the blood-brain barrier adds a challenge to the successful treatment of this bacterium.\n\nWe performed a literature review using MEDLINE with search terms including “ventriculoperitoneal shunt”, “Mycobacterium fortuitum” and “treatment”. Only four cases, excluding ours, have been reported pertaining to ventriculoperitoneal or ventriculoatrial shunt infection by Mycobacterium fortuitum.\n\nChan et al. reported a case of a 60-year-old who develop a ventriculoatrial shunt infection after insertion. Treatment included removal of the shunt as well as administration of IV amikacin with oral ofloxacin. Due to poor penetration of the blood brain barrier by amikacin, amikacin was administered intraventricularly via a Rickham reservoir. The patient underwent ten weeks of continuous intravenous and intrathecal treatment with no relapse seen during one year of follow up [3].\n\nMidani and Rathore reported a case of VP shunt infection by M. fortuitum in a 13-year-old girl with spina bifida [4]. The patient continued to experience fevers with deterioration of her mental status despite completion of antimicrobial therapy. She underwent removal of her shunt and cultures became positive with M. fortuitum after 72 h. The patient was successfully treated with a six-week course of IV amikacin and oral trimethoprim-sulfamethoxazole followed by six months of trimethoprim-sulfamethoxazole monotherapy [5].\n\nViswanathan et al. describe a case of a 60-year-old man with traumatic brain injury complicated by hydrocephalus requiring placement of VP shunt. He presented with fever and signs concerning for pneumonia six weeks later. The pneumonia was initially treated with a combination of amoxycillin-clavulanic acid but despite clearance of the infection, fevers persisted. He underwent VP shunt removal, and shunt cultures on Lowenstein Jensen’s medium eventually grew M. fortuitum. Sensitivity testing showed resistance to isoniazid, rifampin, streptomycin, ethambutol, pyrazinamide, ofloxacin, amikacin, and sparfloxacin, but susceptibility to kanamycin and ciprofloxacin. He was treated for two months with intramuscular kanamycin and for three weeks with ciprofloxacin IV followed by six weeks of oral ciprofloxacin [6].\n\nCadena et al. describe a case of a 14-year-old boy who developed postoperative VP shunt infection with M. fortuitum. The patient initially failed broad-spectrum antimicrobials consisting of ceftriaxone and vancomycin. Cultures obtained from the CSF and shunt eventually grew M. fortuitum. He underwent shunt removal and was treated with three months of IV meropenem and six months of oral moxifloxacin and trimethoprim-sulfamethoxazole. The patient was symptom free after nine months of antimicrobial therapy [2].\n\nBased on our case and review of the related literature, we recommend that in the event of severe CNS infection or disseminated disease, specifically in an immunocompromised patient, initial treatment should consist of two or more IV antimicrobials for a minimum of two months. This should be followed by at least two to twelve months of oral antimicrobial therapy. Antimicrobials which have been found to be effective include amikacin, fluoroquinolones, sulfonamides, doxycycline and imipenem. Antimicrobial spectrum should be guided based on in vitro susceptibility studies.\n\nConclusion\nIn immunocompromised patient and in patients with VP shunts in place, clinicians should have a high index of suspicion for atypical mycobacteria infections, especially in the event of negative cultures. Typical signs and symptoms include unremitting fevers, headache, persistent signs of wound infection or signs concerning for meningeal irritation. Once identified, infection with M. fortuitum can be successfully managed with removal of the foreign body along with a prolonged course of combined antimicrobials.\n\nFounding sources\nThe authors report no founding sources.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal on request.\n\nAuthor contribution\nAll authors listed have contributed equally to the making of this manuscript.\n\nDeclaration of Competing Interest\nThe authors report no declarations of interest.\n\nAcknowledgement\nThank you to the Libraries at Florida State University for granting this manuscript the Open Access Grant which covered the cost for publication.\n==== Refs\nReferences\n1 Aliabadi H. Osenbach R.K. Intrathecal drug delivery device infection and meningitis due to Mycobacterium fortuitum : a case report Neuromodulation 11 4 2008 311 314 10.1111/j.1525-1403.2008.00181.x 22151146 \n2 Cadena G. Wiedeman J. Boggan J.E. Ventriculoperitoneal shunt infection with Mycobacterium fortuitum : a rare offending organism J Neurosurg Pediatr 14 6 2014 704 707 10.3171/2014.8.PEDS13677 25325413 \n3 Chan K.H. Mann K.S. Seto W.H. Infection of a shunt by Mycobacterium fortuitum : case report Neurosurgery 29 3 1991 472 474 10.1097/00006123-199109000-00028 1922723 \n4 Midani S. Rathore M.H. Mycobacterium fortuitum infection of ventriculoperitoneal shunt South Med J 92 7 1999 705 707 10.1097/00007611-199907000-00009 10414479 \n5 Levy Z.D. Du V. Chiluwal A. Chalif D.J. Ledoux D.E. Ventriculoperitoneal shunt infection with Mycobacterium abscessus : a rare cause of ventriculitis World Neurosurg 86 2016 10.1016/j.wneu.2015.10.068 510.e1–510.e5104 \n6 Viswanathan R. Bhagwati S.N. Iyer V. Newalkar P. Ventriculo-peritoneal shunt infection by Mycobacterium fortuitum in an adult Neurol India 52 3 2004 393 394 \n7 Wallace R.J. Jr Swenson J.M. Silcox V.A. Bullen M.G. Treatment of nonpulmonary infections due to Mycobacterium fortuitum and Mycobacterium chelonei on the basis of in vitro susceptibilities J Infect Dis 152 3 1985 500 514 10.1093/infdis/152.3.500 3875667 \n8 Zakrzewski J. Hu K. Neisewander B.L. Mycobacterium fortuitum meningitis: approach to lumboperitoneal shunt infection South Med J 112 4 2019 217 221 10.14423/SMJ.0000000000000955 30943540\n\n",
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"issn_linking": "2214-2509",
"issue": "22()",
"journal": "IDCases",
"keywords": "CNS, central nervous system; CT, computed tomography; Mycobacterium fortuitum; Rapidly growing mycobacteria; VP, ventriculoperitoneal shunt; Ventriculoperitoneal shunt",
"medline_ta": "IDCases",
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"pages": "e00995",
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"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "25325413;26546993;30943540;3875667;10414479;15472442;1922723;22151146",
"title": "Mycobacterium fortuitum ventriculoperitoneal shunt infection in an immunocompromised patient: A case report.",
"title_normalized": "mycobacterium fortuitum ventriculoperitoneal shunt infection in an immunocompromised patient a case report"
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"abstract": "Opioid agonist therapy (OAT) has been implemented for the treatment of individuals with opioid use disorders in Lebanon since 2011, but has not been evaluated yet. The aim of the study is to describe the implementation of the first pilot OAT program in Lebanon from the users' perspective.\n\n\n\nData collectors gathered data from male participants during June 2016-July 2016. Eighty-one out of 94 patients agreed to participate in the study. Data regarding access to treatment, satisfaction with the treatment protocol and treatment outcomes, patient-provider relationship, and misuse and diversion was collected through semi-structured qualitative interviews. Data saturation was reached after 81 interviews; once no new themes were reported.\n\n\n\nFindings showed inequalities in access to treatment and showed that OAT improved mental and social wellbeing among users who had financial access and complied with the program protocols. Registering in the program protected users from arrest and reduced their economic burden. Among the main encountered challenges were fear of dependence to buprenorphine, restricted geographical access to treatment, misuse and diversion of buprenorphine.\n\n\n\nResults implicate inequalities in access to OAT as one important gap to be tackled in the management of OAT in Lebanon. Further research should be done in order to understand the challenges in the implementation of the program from the providers' perspectives.",
"affiliations": "Department of Biomedical Sciences, Lebanese International University, Beirut, Lebanon. ali.ghaddar@liu.edu.lb.;Department of Biomedical Sciences, Lebanese International University, Beirut, Lebanon.;Department of Narcotics, Ministry of Public Health, Beirut, Lebanon.",
"authors": "Ghaddar|Ali|A|;Khandaqji|Sanaa|S|;Abbass|Zeinab|Z|",
"chemical_list": "D002047:Buprenorphine; D008691:Methadone",
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"doi": "10.1186/s13011-018-0151-8",
"fulltext": "\n==== Front\nSubst Abuse Treat Prev PolicySubst Abuse Treat Prev PolicySubstance Abuse Treatment, Prevention, and Policy1747-597XBioMed Central London 15110.1186/s13011-018-0151-8ResearchChallenges in implementing opioid agonist therapy in Lebanon: a qualitative study from a user’s perspective Ghaddar Ali ali.ghaddar@liu.edu.lb 12Khandaqji Sanaa 12Abbass Zeinab 341 0000 0004 0417 6142grid.444421.3Department of Biomedical Sciences, Lebanese International University, Beirut, Lebanon 2 Observatory of Public Policies and Health, Beirut, Lebanon 3 Department of Narcotics, Ministry of Public Health, Beirut, Lebanon 4 0000 0004 0417 6142grid.444421.3School of Pharmacy, Lebanese International University, Beirut, Lebanon 19 4 2018 19 4 2018 2018 13 1410 11 2017 13 4 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nOpioid agonist therapy (OAT) has been implemented for the treatment of individuals with opioid use disorders in Lebanon since 2011, but has not been evaluated yet. The aim of the study is to describe the implementation of the first pilot OAT program in Lebanon from the users’ perspective.\n\nMethods\nData collectors gathered data from male participants during June 2016-July 2016. Eighty-one out of 94 patients agreed to participate in the study. Data regarding access to treatment, satisfaction with the treatment protocol and treatment outcomes, patient-provider relationship, and misuse and diversion was collected through semi-structured qualitative interviews. Data saturation was reached after 81 interviews; once no new themes were reported.\n\nResults\nFindings showed inequalities in access to treatment and showed that OAT improved mental and social wellbeing among users who had financial access and complied with the program protocols. Registering in the program protected users from arrest and reduced their economic burden. Among the main encountered challenges were fear of dependence to buprenorphine, restricted geographical access to treatment, misuse and diversion of buprenorphine.\n\nConclusion\nResults implicate inequalities in access to OAT as one important gap to be tackled in the management of OAT in Lebanon. Further research should be done in order to understand the challenges in the implementation of the program from the providers’ perspectives.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13011-018-0151-8) contains supplementary material, which is available to authorized users.\n\nKeywords\nBuprenorphineQualitativeOpioid substitution therapyLebanonissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe use of buprenorphine for opioid agonist therapy (OAT) was officially approved in Lebanon in 2011. A small-scale take-home pilot OAT program has been in implementation ever since, with around 1800 enrolled patients (800 of which are currently active). The national guidelines adopt take-home buprenorphine prescribed by authorized psychiatrists with weekly monitoring for adherence and response to treatment in clinical settings.\n\nBuprenorphine is a mixed opioid agonist/antagonist used for opioid detoxification, and as a substitution therapy to prevent withdrawal symptoms in inpatient and outpatient settings [1]. With lower abuse potential than other full opioid agonists, office-based treatment is considered an effective and safe agent to use in OAT [2]. Due to its mode of action as a partial agonist, limited respiratory depression, and its ceiling effect, buprenorphine is highly effective in reducing overdose [3]. In France, overdose incidence decreased by 79% since the introduction of buprenorphine [4]. High-dose buprenorphine is also effective in suppressing illicit opioid use [5]. Compared with observed induction, take-home buprenorphine has advantages in terms of its feasibility, comparable safety, and fewer logistic barriers [6, 7].\n\nNevertheless, emerging evidence revealed certain problematic issues related to buprenorphine, including its potential diversion and misuse through injection [8]. In Australia, buprenorphine diversion showed 10 times higher than methadone [9]. Buprenorphine represents the most commonly abused drug in several countries such as Finland [10], and is illicitly used (mainly intravenously) in a wide variety of settings, including France [4], Sweden [11], Norway [12], Ireland [13], and Spain [14]. Illicit use of buprenorphine raised concerns in India, being the most commonly injected drug after heroin [15] and being the initiating injecting drug for many IDUs [16]. Diversion of buprenorphine is also widespread in South Asia [17].\n\nThe qualitative assessment of patient’s perception about the received care in addiction treatment services is frequently used as an indicator of the quality of care and of the use and the benefits of the treatment [18–20]. Moreover, user’s satisfaction in addiction treatment programs has been also related to positive treatment outcomes and better retention in the treatment [21, 22].\n\nSix years have passed since the start of implementation of the pilot OAT program in Lebanon. In this program, patients diagnosed with opioid use disorder according to DSM-V criteria are registered, and receive weekly take-home buprenorphine from the centralized dispensing unit of the Ministry of Health. The monthly cost of treatment ranges from 85 to 250 USD. Registered patients are followed-up on a weekly basis by multidisciplinary teams of treatment providers, comprising of a psychiatrist, psychologist, social worker and a nurse, all experienced to work with drug users. The weekly follow-up visits to the treatment centers involve psychosocial support and monitoring for misuse and stability of response.\n\nA quantitative evaluation of the OAT program in Lebanon has recently been conducted [23]. Although the program produced positive outcomes on quality of life, mental and social wellbeing and reduction of risky behavior among users, very low retention rates has been observed. The same study pointed out to possible information bias related to overestimation of the outcomes and finally called for the importance of exploring the predictors of adherence using qualitative assessment.\n\nOn the other hand, there has been no independent evaluation of the challenges related to the program’s setup and its implementation and to its degree of adaptation to the needs and culture of persons seeking treatment from opioid dependence disorder in Lebanon.\n\nThe objective of the study is to provide a qualitative assessment of the OAT program in Lebanon from a user’s perspective, and to describe how inequalities in the access to treatment could shape users’ compliance and perceptions about the treatment outcomes.\n\nMethods\nStudy design\nThis qualitative study was conducted at one of the two OAT dispensaries in Beirut, Lebanon. Female participants were not included, as most of the OAT users in Lebanon are males. Also, participants registered in the program for less than 3 months were excluded. All patients who were found in the dispensary were included in the study. Only male patients were included as most of OAT users in Lebanon are males. Participants with less than 3 months in therapy were excluded.\n\nEighty-one (86%) out of 94 approached patients agreed to participate. Non-respondents were offered to be interviewed at a different time, one accepted and was interviewed the following week, and the others excused for having no time.\n\nEthical consideration\nEthical approval was obtained from the Institutional Review Board of the Lebanese International University (ethical approval: Ref: LIUCRE-140320-1). Verbal informed consent was obtained from all participants. All interviews were audio-recorded except four, as participants had refused to be audio-recorded. In this case, written notes were taken instead.\n\nData collection\nData was collected during 15 consecutive days between June 2016 and July 2016. by three data collectors experienced in qualitative research. The majority of interviews conducted with OAT patients were done by two data collectors (first and second authors). They approached participants in the alley outside the dispensary, to avoid any direct contact between them and the healthcare providers. Patients were asked to participate in the study after being briefed about its objectives. The third data collector (AT) was an OAT patient specially trained for the study purpose. He interviewed patients outside the hospital, as some of them were not officially registered and were self-treating with diverted buprenorphine. Interviews were done using a semi-structured guideline and lasted around 20 min. Information was gathered anonymously about access to treatment, satisfaction with treatment rules, patient-provider relationship, perceived benefits and side effects of the drug, and misuse and diversion (guideline as online supplement). Questions included: In general, are you satisfied with your achieved outcomes regarding family relations, self-image, social functioning, avoiding arrest and reducing financial burden? Have you sold or given buprenorphine to peers? Which part of the treatment/ rules do you find hardest to meet?\n\nData analysis\nThe theoretical sampling method with selective coding was used in this study in order to formulate new emerging theories from collected data [24]. Selective coding took into consideration the concepts found in previous studies related to the topic. The grounded theory with constant comparison was adopted in order to develop a theory as it emerges [25]. As codes were developed during reviewing the transcripts for relevant emergent themes, data was simultaneously analyzed in order to decide what data to collect in the next step. Themes were identified from the codes drawn out from the transcripts, reviewed and analyzed in order to identify structures that helped construct the theoretical model. The theory induced from the data analysis was then applied to existing data in order to assess their validity.\n\nData saturation was reached after 81 interviews when no new facts or ideas were likely to appear in any of the categories, the categories are well developed in terms of their properties, dimensions and variation, and the relationship between categories are well established and validated [24, 26, 27].\n\nThe socio-demographic characteristics of the participants are summarized in Table 1. Participants were males with average age 29.1 years (range: 20–56 years). The majority were single and had no stable income. The average time spent in treatment was 2.40 years (range: 1 month - 6 years). More than half of the participants (58.0%) had ever injected drugs and 45.7% ever injected buprenorphine. 12.3% were currently injecting buprenorphine and 37.0% mixed buprenorphine with other drugs.Table 1 Socio-demographic characteristics of the participants\n\n\nAge (years)\n\tn (%)\t\n18-25\t36 (44.4%)\t\n26-30\t22 (27.2%)\t\n31-35\t9 (11.1%)\t\n36+\t14 (17.2%)\t\n\nEducational level\n\t\nPrimary school education\t38 (46.9%)\t\nSecondary school education\t43 (53.2%)\t\n\nCurrently employed\n\t\nYes\t33 (40.7%)\t\nNo\t48 (59.3)\t\n\nStable income\n\t\nYes\t49 (60.4%)\t\nNo\t32 (39.6%)\t\n\nMarital status\n\t\nSingle\t67 (82.7%)\t\nMarried\t14 (17.3%)\t\n\n\nResults\nFindings revealed the existence of inequalities in the access to treatment that shaped users’ compliance to therapy and their satisfaction with its outcomes. Two different views regarding the outcomes of therapy emerged. The first group of participants (G1) did not express major financial or logistic concerns in their access to therapy. All 52 participants who belonged to this group were OAT registered users who have been in therapy for at least one year. The majority of them were not using illicit drugs along with buprenorphine and none reported current injecting drugs. The other group (G2) (29 participants) had clear financial barriers to access therapy. Almost all of them were unemployed and unregistered users who occasionally got access to diverted buprenorphine form the black market. Others were officially registered users in the OAT program who had to interrupt their therapy for being unable to afford its cost or for deciding to self-treat their addiction without medical supervision. All participants who belonged to this group currently use illicit drugs together with buprenorphine and many of them currently injected buprenorphine.\n\nPerceived benefits\nSome participants reported improvements in different domains of mental and social wellbeing during therapy and others expressed concerns and challenges related to therapy (Table 2).Table 2 Main reported dimensions of improvements and concerns related to therapy\n\n\t\nUsers with good access to therapy (G1) (N = 52)\n\t\nUsers with limited access to therapy (G2) (N = 29)\n\t\n\nReported improvements\n\t\nn (%)\n\t\nn (%)\n\t\nPhysical health\t37 (71.2%)\t8 (27.6%)\t\nMental health\t39 (75.0%)\t11 (37.9%)\t\nReducing drug cravings\t41 (78.9%)\t4 (13.8%)\t\nAbstinence from other drugs\t33 (63.5%)\t2 (6.9%)\t\nSocial functioning\t42 (80.8%)\t12 (41.4%)\t\nFamily relations\t34 (65.4%)\t14 (48.3%)\t\nSelf-image and confidence\t44 (84.6%)\t11 (37.9%)\t\nAvoiding arrest\t47 (90.4%)\t26 (89.7%)\t\nReducing financial burden\t50 (96.2%)\t20 (69.0%)\t\n\nReported concerns\n\t\nn (%)\n\t\nn (%)\n\t\nDependence to buprenorphine\t29 (55.8%)\t21 (72.4%)\t\nTreatment side-effects\t9 (17.3%)\t19 (65.5%)\t\nGeographical access\t7 (13.5%)\t4 (13.8%)\t\nTime and other logistic constraints\t11 (21.2%)\t8 (27.6%)\t\nTreatment cost\t6 (11.5%)\t27 (93.1%)\t\nDifficulty to adhere to treatment protocol\t13 (25.0%)\t19 (65.5%)\t\n\n\nMost participants who belonged to G1 (37 participants) were generally satisfied with the impact of the treatment on physical and mental wellbeing. They considered that OAT is effective in reducing illicit opioid use and its associated craving:–“It does not make you nostalgic…under heroin, I need to inject every few hours, but now, the morning tablet and that’s it. Many people I know managed to quit and stood back on their feet, this encouraged me. After the tablet, you have no desire to take anything else. Before, I took everything available”– (M3, 35 y/o, G1)\n\n\n\nInterviews revealed the importance of OAT in sustaining users’ social inclusion, especially among participants of G1. They considered that OAT enhanced their self-confidence, their workability and their image in society. Several quotes were selected to illustrate this perspective:–“Before therapy I was excluded from society; I did not wear decent clothes, I dressed like an addict and didn’t shower. All I cared about was how to obtain H [heroin]. Now, I feel respected at work and in society…”– (M1, 32 y/o, G1)\n\n–“I don’t have to lie to them anymore… nobody trusted me before, although I wanted to behave good and loved my fiancée, I frequently forgot everything about her when my friends called me to inject”– (M5, 32 y/o, G1)\n\n–“At least you don’t have needle marks… I can wear short sleeves. I feel more energetic, I can concentrate at work” – (M27, 24 y/o, G1).\n\n\n\nIt was also obvious from interviews with participants of G1 that OAT helped users avoid drug scenes and the negative influence from peers. Some quotes were selected to explain this idea:–“It takes you out of the street… before, I was always searching for H in neighborhoods… they [drug dealers] are always there, offering you H and you cannot refuse” – (M16, 20 y/o, G1)\n\n–“We decided to register in order not to remain on the street with the bunch of heroin addict hooligans”– (Father of M7, 19 y/o, G1)\n\n–“Instead of waiting all day for drug sellers in the streets, I can just come here to take my drug” – (M9, 28 y/o, G1)\n\n\n\nFurthermore, it appeared that in G1, the treatment promoted family acceptance and strengthened family support. The following quotes support this viewpoint:–“It is completely different; my family supports me financially to get the drug and I feel more protected”– (M16, 20 y/o, G1)\n\n–“I am no family enemy anymore, my parents stopped insulting me and making me feel undesired. They believe in me and we now do things together”– (M34, 25 y/o, G1).\n\nOn the other hand, participants who belonged to G2 experienced constant withdrawal symptoms and had important concerns related to the benefits of OAT.\n\nPerceived concerns\nDependence to buprenorphine\nBoth groups of users (with and without good access to OAT) were concerned about the long-term nature of the therapy and about its social acceptance. Participants of G1 perceived OAT as “switching from one type of addiction to another” upon realizing their unexpected prolonged time duration of the therapy. Apparently, many initially saw in the OAT program a way out of their addiction. More than half (62%) declared not having been explicitly briefed about the long duration of maintenance therapy upon joining the program and expected a better outcome and shorter duration of therapy. The following quotes elaborate this point:–“What is the point, they sell us this legal drug, and people get attached to it… I mean until when I will keep buying this drug? I need a solution”– (M11, 29 y/o, G1).\n\n–“I was enthusiastic at first, believing that this is the ultimate solution, but I realized it is not possible to quit… I tried; you just can’t”– (M48, 31 y/o, G1)\n\n– “When you get registered, they just recommend this therapy as an option, and you get to register without really being explained that it will last forever, nobody tells you that from the beginning” – (M4, 26 y/o, G1)\n\n\n\nThey clearly viewed the long-term use of buprenorphine as socially unacceptable and had concerns about dependence. Some of the below quotes illustrate this perspective:–“I cannot imagine my life going to the dispensary and all the complications for my entire life. Imagine my kids asking me what is this drug … it is difficult to explain” – (M2, 27 y/o, G1)\n\n–“People will still look at you as an addict, it will chase you for your entire life. The only difference is that now I take a legal drug whereas I had to search for H in the streets”– (M39, 28 y/o, G1)\n\n\n\nThe majority of participants who belonged to G2 (72.4%) expressed the same concerns related to dependence on buprenorphine, especially after experiencing the severe associated withdrawal symptoms. Those were completely convinced that stopping buprenorphine is just impossible, as described by the following quotes:–“You cannot stop a single day, you feel extremely exhausted. The consequences are more awful than the brown [heroin]… I get feelings of knives stabbing inside my stomach… you cannot walk, you have to drag your legs…”– (M54, 27 y/o, G2)\n\n–“It just takes you from one problem to another, from the dependence on heroin to the dependence on buprenorphine”– (M60, 32 y/o, G2)\n\n–“We will die taking the drug…it is like blood pressure drugs”– (M73, 40 y/o, G2)\n\n–“Had I known previous to starting this program that it will be forever, I wouldn’t have registered” – (M54, 27 y/o, G2)\n\n\n\nSome expressed serious concerns about this issue, especially when they have trouble securing the treatment cost. One participant explained:–“The treatment is temporary, and when the time comes and I cannot afford it, I will go back to the streets” – (M65, 25 y/o, G2)\n\n\n\nFinancial and geographical access to treatment\nAlmost all participants in G1 (93.8%) agreed that their engagement in the therapy lowered their financial burden:–“Before, I needed to pay $50-100/day for a couple of grams of heroin, while now it costs me just $3/day for my 2 tablets of buprenorphine, you see” – (M23, 21 y/o, G1)\n\n–“I lost all $50,000 in two years when I was using heroin, now I can easily afford to pay for the tablets” – (M37, 22 y/o, G1)\n\n\n\nHowever, participants who belonged to G2 had difficulties in securing the weekly therapy cost, especially when the majority of them were unemployed. One participant expressed briefly the concerns of others:–“When you are not working, it is not easy. The pressure on me is huge, the LBP 70,000/week (around $50) for buprenorphine, transportation, and laboratory tests …many times I beg friends for money” – (M58, 42 y/o,, G2)\n\n\n\nLiving outside Beirut appeared to be an important barrier to access therapy. Almost all participants lived in Beirut and its suburbs. The two interviewees from North Lebanon (85 km away from Beirut) had private cars but mentioned that numerous of their peers have no means to reach the dispensaries (one located in Beirut center and the other 15 km Northern Beirut). Many participants residing in Beirut also considered transportation a barrier to access:–“I feel sorry each time my father has to leave work to take me get the drug”- (M54, 27 y/o, G2)\n\n\n\nAvoiding arrest is a main motivation to register\nPerhaps one of the most commonly reported treatment benefit is the fact that it reduced the risk of arrest:–“We do not fear police anymore, with prescription papers, you feel secure when going out”– (M18, 32 y/o, G1)\n\n\n\nThe discourse revealed that many participants in G2 hide behind their prescriptions and do not refrain from using illicit drugs:–“All those people you see [pointing out to the direction of registered patients at the OAT dispensary] share their tablets for the exchange of a bit of heroin. Not only me, many still use heroin at least twice a week. We just register to be on the safe side, not to run out of drugs, to avoid trouble with the police. But it is quite impossible to quit, this substance is crazy” –(M84, 28 y/o, G2)\n\n–“Buprenorphine is legal heroin”– (M61, 31 y/o, G2)\n\n–“Before, every other week I had to take the bus to Baalbek [North Lebanon] to get heroin, and on the way I got arrested twice…the road is too risky, they wait to arrest you”– (M67, 26 y/o, G2)\n\n\n\nInjecting drugs and buprenorphine misuse\nMaintenance therapy reduced injecting behavior. The percentage of participants reporting injecting drugs reduced from 58% to 12% after therapy. This discussion led to the emergence of a new theme about the misuse of buprenorphine mainly by injecting in both G1 and G2. 45.7% of the participants reported having previously injected buprenorphine and 12.3% reported current injection:–“The moment I do my urine test I have my heroin equipment ready to inject”– (M18, 32 y/o, G1)\n\n–“Every time I stop and see my sister injecting heroin I try again”– M76, 30 y/o, G2)\n\n\n\nHowever, almost all participants mentioned that most of their peers currently inject buprenorphine:–“99% of people in the program are hitting buprenorphine”– (M90, 38 y/o, G2)\n\n\n\nThe discourses suggested that injecting buprenorphine is the preferred mode of administration for many participants. The following quotes elaborate this perspective:–“It gives a sweeter effect and it lasts longer and so I mean why not inject? This is the first time I hear that it is harmful…” – (M88, 35 y/o, G2)\n\n–“Injecting buprenorphine makes more sense”– (M21, 27 y/o, G1)\n\n–“When you hit, it makes you contain yourself. With only half a tablet, you need nothing else until the next day” – (M49, 22 y/o, G1)\n\n–“It is so difficult to cease injecting. It is a virus inside”– (M18, 32 y/o, G1)\n\n–“My brother died at hospital after his leg inflamed, I knew it was due to injecting…I know it is evil, still I prefer to inject buprenorphine, there is no other way that keeps me standing” – (M49, 22 y/o, G1)\n\n\n\nDiversion\nParticipants who were unregistered in OAT program (15%) were at the dispensary site for trying to obtain diverted buprenorphine from registered peers. The below discussion highlight the context of diversion of buprenorphine in the black market:\n–Interviewer: “I can’t figure out why someone would sell his medication?”\n\n\n\n–Participant (M75): “some of them need money to buy their medications and thus they share”\n\n\n\n–Interviewer: “but then the therapy might not work well, if they don’t adhere as prescribed, right?”\n\n\n\n–Participant: “what else to do, you can manage with one tablet- I myself sold half of my tablets”\n\n\n\n–Interviewer: “and you were fine? Why did you unregister in the program?”\n\n\n\n–Participant: “if you need the money you will sell, you have to manage at the end, they unregistered me because I always had difficulties, the visits and all the strict control”\n\n\n\n–Interviewer: “so you mixed other drugs during the treatment?”\n\n\n\n–Participant: “when I am out of Bup. I searched for heroin from time to time, but I was Ok”.\n\n\n\n\nFurther accounts confirmed that prescribed buprenorphine was diverted:–“I can do with one tablet/day and sell the rest to secure the cost of buprenorphine. Some indifferent people sell the tablet (for around $15-20) to buy other drugs” – (M93, 38 y/o , G2)\n\n\n\nParticipants generally did not acknowledge diverting buprenorphine (only 14% reported diversion). However most of them declared having been frequently requested to share or sell their tablets:–“Right outside the dispensary, they tire me out ‘man, please’, and all that… how much do you want for it?’ and ‘just one tablet’, but I don’t sell at all, I need it more than anyone else does” – (M32, 30 y/o , G1)\n\n\n\nOne participant highlighted the main reason that made him refrain from registration, and is instead using diverted buprenorphine:–“I cannot register in the treatment because I work and I do not want my employer to know. I do not want to get fired”– (M59, 28 y/o, G2)\n\n\n\nAnother explained the logistic barriers supposed by engaging in the program:–“I prefer not to register because it is practically impossible to drive up to the NGO every week to do urine tests”– (M78, 30 y/o, G2)\n\n\n\nIt is important to note, however, that a few of them had previously registered in the program, but had failed to adhere to the treatment protocol for financial or logistic reasons:–“The program is not flexible” and\n\n–“I was excluded for missing three consecutive follow-up sessions”– (M51, 27 y/o, G2)\n\nThese patients found a way to get access buprenorphine without registering in the treatment:–“Buprenorphine is a savior when short of money to buy heroin”– (M70, 32 y/o, G2)\n\n\n\nDiscussion\nThis study aimed to provide a qualitative assessment of the pilot OAT program in Lebanon from the perspective of the users. Results revealed inequalities in the access to treatment and showed that OAT generally improved mental and social wellbeing among users who had financial means to access the program and managed to comply with the treatment protocols. Registering in the program protected users from arrest and reduced their financial burden. Challenges include fear of dependence, restricted access to treatment and misuse and diversion of buprenorphine.\n\nResults provide several indications to improve patient-provider relationship. Firstly, the common observed concern about dependence on buprenorphine could be resolved through providing patients with adequate briefing about the long-term nature of buprenorphine treatment and its properties that allow gradual withdrawal without big discomfort in comparison to methadone [28]. In fact, promoting transparent communication between providers and patients shape patients’ believes and expectations, and in turn influence patient satisfaction and the achievement of positive treatment outcomes [29].\n\nResults replicate those found in previous studies and identified the main motivations for diversion and illicit use of buprenorphine as self-detoxification and lack of financial means to formally register in the treatment [12, 30]. The fact mentioned by one interviewee that “many of us register in the program because buprenorphine is less expensive than heroin” has been reflected upon in a previous study in Australia [31]. In fact, buprenorphine diversion has been partly attributed to its feasible access to IDUs with limited income [14]. However, this fact has not been contrasted in middle and low development settings. Buprenorphine diversion, though frequently previously reported in various contexts, raises concerns for its potential of use by individuals initiating opioids and/or injecting drugs, as indicated in previous studies [12, 17, 32]. Injecting buprenorphine is also not new and intravenous use represents the most efficient route of administration in terms of bioavailability where euphoric effects could be obtained with relatively small doses [33]. The motivation to engage in OAT as a way to avoid arrest and police harassment has also been mentioned in previous studies [34].\n\nLimitations, strengths and future research\nIt is worth mentioning that data of OAT patients from all clinics that provide OAT in Lebanon are connected through a central network to a central database in the Ministry of Health. This system has the advantage of tracking patients IDs in order to prevent duplication of services and doctor shopping, a phenomena common in other contexts [35]. The study has certain limitations related to the sample. Results do not reflect the opinion of female OAT patients. Moreover, it would have been interesting to include patients from the other OAT hospital dispensary to compare findings.\n\nThe current study also has several strengths. It actually provides the first qualitative overview about the opinion of users about the OAT program in the Middle East and North Africa (MENA) countries, excluding Iran. Moreover, participants were selected from one of the only two available dispensary centers in the country. Information bias was also reduced through coding data by two different researchers who discussed disagreements whenever present. During analysis, results were validated with other research team members including previous IDUs. Results were consistent with those presented in previous studies and support their transferability to other MENA countries.\n\nFuture research is warranted to understand the reasons of injecting buprenorphine from a social perspective rather than clinical pharmacological effect evaluation. The public health and economic implications of injecting buprenorphine should be explored rather than understanding the pharmacological effects of the drug mode of administration. Future research should be done in order to understand the challenges in the implementation of the program from the providers’ perspectives.\n\nConclusion\nResults revealed that the OAT program in Lebanon should be supported and highlighted certain gaps that should be tackled to improve its implementation. Results highlighted the importance of continuing the efforts to advocate for better social tolerability of OAT in Lebanon, strengthening the outreach and awareness activities to cover unregistered opioid-dependent participants and to achieve a better communication between providers and users. Finally, the observed inequalities in the access to treatment call for the need to scale-up the program and widen geographical access to districts other than the capital Beirut and to the most marginalized population groups with low socio-economic status.\n\nAdditional file\n\nAdditional file 1: GUIDELINE_Patients. (DOCX 24 kb)\n\n \n\n\nElectronic supplementary material\n\nThe online version of this article (10.1186/s13011-018-0151-8) contains supplementary material, which is available to authorized users.\n\nAcknowledgements\nThe authors would like to acknowledge Dr. Alaa Fawaz for her efforts in revising the article.\n\nFunding\nThis study was not funded by any institution or body.\n\nAvailability of data and materials\nAll data generated or analysed during this study are included in this published article [and its Additional file 1].\n\nAuthors’ contributions\nAG developed the study design, performed data collection, and drafted the manuscript. SK performed data collection and transcribed the audio-records of the interviews. ZA performed literature review and reviewed the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent: Informed consent was obtained from all individual participants included in the study.\n\nConsent for publication\nAll authors declare that they have consented to the publication of this study, and all of the participants the study was conducted on have also consented to participation and publication of this study.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Mattick RP Breen C Lawrance A Batey R Salmelainen P Comparing overdose mortality associated with methadone and buprenorphine treatment Drug Alcohol Depend 2009 104 1-2 73 77 10.1016/j.drugalcdep.2009.03.020 19443138 \n6. Lee J Vocci F Fiellin D Unobserved “home” induction onto buprenorphine J Addict Med 2014 8 5 299 308 10.1097/ADM.0000000000000059 25254667 \n7. Wolff K Substance misuse: substitution drugs (methadone and buprenorphine): methadone and buprenorphine. Encyclopedia of Forensic & Legal Medicine 2005 Oxford Elsevier BV \n8. Lofwall MR Walsh SL A review of buprenorphine diversion and misuse: the current evidence base and experiences from around the world J Addict Med 2014 8 5 315 326 10.1097/ADM.0000000000000045 25221984 \n9. Winstock AR Lea T Sheridan J Prevalence of diversion and injection of methadone and buprenorphine among clients receiving opioid treatment at community pharmacies in new South Wales, Australia Int J Drug Policy. 2008 9 6 450 458 10.1016/j.drugpo.2007.03.002 \n10. Aalto M Halme J Visapää J Salaspuro M Buprenorphine misuse in Finland Substance Use Misuse 2007 42 6 1027 1028 10.1080/10826080701434857 17613961 \n11. Hakansson A Medvedeo A Andersson M Berglund M Buprenorphine misuse among heroin and amphetamine users in Malmo, Sweden: purpose of misuse and route of administration Eur Addict Res 2007 13 4 207 215 10.1159/000104883 17851242 \n12. Mounteney J Haugland S Earlier warning: a multi-indicator approach to monitoring trends in the illicit use of medicines Int J Drug Policy. 2009 20 2 161 169 10.1016/j.drugpo.2007.09.006 18032012 \n13. 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Pradel V Frauger E Thirion X Ronfle E Lapierre V Masut A Impact of a prescription monitoring program on doctor-shopping for high dosage buprenorphine Pharmacoepidemiol Drug Saf 2009 18 1 36 43 10.1002/pds.1681 19040199\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1747-597X",
"issue": "13(1)",
"journal": "Substance abuse treatment, prevention, and policy",
"keywords": "Buprenorphine; Lebanon; Opioid substitution therapy; Qualitative",
"medline_ta": "Subst Abuse Treat Prev Policy",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D002047:Buprenorphine; D055030:Drug Users; D007722:Health Knowledge, Attitudes, Practice; D006297:Health Services Accessibility; D006801:Humans; D007861:Lebanon; D008297:Male; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D036301:Qualitative Research; D055815:Young Adult",
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"other_id": null,
"pages": "14",
"pmc": null,
"pmid": "29673369",
"pubdate": "2018-04-19",
"publication_types": "D016428:Journal Article",
"references": "18032012;16930865;20141452;15851908;21417558;20465372;18584580;21565452;29216892;17613961;19040199;26374128;19443138;18552728;21844833;18420772;18264882;8181201;15204673;25221984;25254667;10699546;19887803;18359216;3265643;25228817;19378450;15204675;8251871;17851242",
"title": "Challenges in implementing opioid agonist therapy in Lebanon: a qualitative study from a user's perspective.",
"title_normalized": "challenges in implementing opioid agonist therapy in lebanon a qualitative study from a user s perspective"
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"abstract": "Background and Objectives: Demodex species are common obligatory parasites and normally present in low number in human beings. Immunosuppression was suggested to be associated with increased density of Demodex mites. Systemic glucocorticoids, cyclosporine, methotrexate, and azathioprine are commonly used immunosuppressive agents. We aim to determine the pre- and post-treatment Demodex densities in patients receiving immunosuppressive therapy and compare with those of healthy subjects. Materials and Methods: Demodex density was investigated at the beginning, first, and third months of the immunosuppressive therapy in 45 patients who received methotrexate, cyclosporine, systemic steroid, or azathioprine treatments and in 45 healthy subjects at the same time as the patients. Five standardized skin surface biopsies were taken from cheeks, forehead, nose, and chin of the patients and control group. The presence of five or more parasites in 1 cm2 area was considered as positive. Results: Demodex test was negative at the beginning of the treatment in all patients. Demodex test was positive in one patient in the first and third months of treatment and in three patients only in the third month of treatment. In the control group, Demodex test was determined as positive in just one healthy individual at the beginning, first and third months of the study. When the patient and control groups were evaluated in terms of Demodex number, there was a statistically significant difference in Demodex density in patients treated with immunosuppressive treatment in the first and third months when compared with the control group (p < 0.05). Conclusion: Immunosuppressive treatment might increase the number of Demodex mites and demodicidosis should be kept in mind in patients on immunosuppressive treatment.",
"affiliations": "Dermatology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55139, Turkey.;Dermatology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55139, Turkey.;Dermatology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55139, Turkey.;Dermatology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55139, Turkey.",
"authors": "Keles|Hacer|H|;Pancar Yuksel|Esra|E|0000-0003-1233-5556;Aydin|Fatma|F|;Senturk|Nilgun|N|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Switzerland",
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"doi": "10.3390/medicina56030107",
"fulltext": "\n==== Front\nMedicina (Kaunas)\nmedicina\nMedicina\n1010-660X 1648-9144 MDPI \n\n10.3390/medicina56030107\nmedicina-56-00107\nArticle\nPre-Treatment and Post-Treatment Demodex Densities in Patients under Immunosuppressive Treatments\nKeles Hacer https://orcid.org/0000-0003-1233-5556Pancar Yuksel Esra * Aydin Fatma Senturk Nilgun Dermatology Department, Faculty of Medicine, Ondokuz Mayıs University, Samsun 55139, Turkey; dr.hacer_keles@hotmail.com (H.K.); bennet@mynet.com (F.A.); nilsenturk@yahoo.com (N.S.)\n* Correspondence: esrapancar@yahoo.com; Tel.: +90-362-312-1919 (ext. 3222); Fax: +90-362-457-6071\n03 3 2020 \n3 2020 \n56 3 10705 2 2020 27 2 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background and Objectives: Demodex species are common obligatory parasites and normally present in low number in human beings. Immunosuppression was suggested to be associated with increased density of Demodex mites. Systemic glucocorticoids, cyclosporine, methotrexate, and azathioprine are commonly used immunosuppressive agents. We aim to determine the pre- and post-treatment Demodex densities in patients receiving immunosuppressive therapy and compare with those of healthy subjects. Materials and Methods: Demodex density was investigated at the beginning, first, and third months of the immunosuppressive therapy in 45 patients who received methotrexate, cyclosporine, systemic steroid, or azathioprine treatments and in 45 healthy subjects at the same time as the patients. Five standardized skin surface biopsies were taken from cheeks, forehead, nose, and chin of the patients and control group. The presence of five or more parasites in 1 cm2 area was considered as positive. Results: Demodex test was negative at the beginning of the treatment in all patients. Demodex test was positive in one patient in the first and third months of treatment and in three patients only in the third month of treatment. In the control group, Demodex test was determined as positive in just one healthy individual at the beginning, first and third months of the study. When the patient and control groups were evaluated in terms of Demodex number, there was a statistically significant difference in Demodex density in patients treated with immunosuppressive treatment in the first and third months when compared with the control group (p < 0.05). Conclusion: Immunosuppressive treatment might increase the number of Demodex mites and demodicidosis should be kept in mind in patients on immunosuppressive treatment.\n\nazathioprinecorticosteroidscyclosporinedemodeximmunosuppressive treatmentmethotrexate\n==== Body\n1. Introduction \nThe two Demodex species Demodex folliculorum and Demodex brevis are common obligatory parasites of the pilosebaceous units in human beings. Demodex folliculorum is usually found in the infundibulum of hair follicle and Demodex brevis in the sebaceous glands and ducts [1,2]. The two Demodex species were reported to be present worldwide with an incidence ranging from 25% to 93% [3]. They can appear anywhere on the face but mainly on forehead, cheeks, nose, nasolabial folds and, normally present less than 5 parasites/cm2. But when their number increases, they might be the cause of dermatoses with chronic inflammatory eruptions [4,5,6]. Rosacea is the prominent dermatological disorder in which an association was defined between disease development and infestation with Demodex mites. Demodex folliculorum density was reported to be increased in patients with rosacea [7,8].\n\nImmunosuppression was suggested as one of the causes of increased density of Demodex mites. Tacrolimus ointment was thought to be the possible cause of overgrowth of Demodex folliculorum because of the immunosuppressive properties. Immunocompromised patients with acquired immunodeficiency syndrome developed facial lesions of demodicidosis. Leukemia and lymphoma patients receiving chemotherapy were also found to have increased number of mites [9,10,11,12]. Since immunosuppressive agents are also frequently used for inflammatory or autoimmune skin diseases, we aimed to determine the number of Demodex mites before and after the immunosuppressive treatment in patients with dermatological disorders in this study. \n\n2. Materials and Methods\n2.1. Patients Examined\nThis study included 45 patients (21 male, 24 female; mean age 42.6 ± 16 years) who were admitted to the Dermatology Clinic and were treated with immunosuppressive therapies for psoriasis vulgaris, pemphigus vulgaris, alopecia areata, or lichen planus. Patients with facial lesions were excluded from the study. The control group consisted of 45 healthy subjects (17 male, 28 female; mean age 34.6 ± 15 years). The study protocol was approved by the Ondokuz Mayıs University, Clinical Research Ethics Committee with code number OMU-KAEK-2014-805 on 25.09.2014.\n\n2.2. Testing for Demodex\nFive standardized skin surface biopsies were taken from the cheeks, forehead, nose, and chin of the patients at the beginning, first, and third months of the immunosuppressive treatment. Five standardized skin surface biopsies were also taken from the same regions of control subjects at the same time with the patients. For standardized skin surface biopsy, a drop of cyanoacrylate adhesive was put on 1 cm2 pen-marked area of a microscope slide. The adhesive-bearing surface of the slide is pressed over the skin for about 30 s. Then the slide was gently detached from the skin, clarified with 2–3 drops of glycerin, and covered with a coverslip. The slides were assessed for parasites by light microscope at magnifications of ×10. Determination of five or more parasites in 1 cm2 area was considered as positive [13]. \n\n2.3. Statistical Analysis\nAll statistical analyses were performed using the SPSS version 15 (SPSS Inc, Chicago, IL, USA). The Kolmogorov-Smirnov/Shapiro–Wilk tests were used to analyze the normal distribution. Frequency tables were used for ordinal variables and they were evaluated by chi-square test, Mann–Whitney U-test, Friedman test, Wilcoxon test. A p-value < 0.05 was considered statistically significant.\n\n3. Results\nOf all the patients 29 (64%) were psoriasis vulgaris, 7 (16%) were pemphigus vulgaris, 5 (11%) were alopecia areata, and 4 (9%) were lichen planus. When the patients were examined in terms of treatment, fifteen patients were treated with cyclosporine, fifteen patients were treated with methotrexate, nine patients were treated with only corticosteroids, and six patients were treated with both corticosteroids and azathioprine.\n\nDemodex test was negative at the beginning in all patients. However, Demodex test was positive in one patient in the first and third months of treatment and in three patients in the third month of treatment. The patient whose Demodex test was positive at the first and third months was a female pemphigus vulgaris patient and treated with systemic steroid and azathioprine. Two of the patients, whose Demodex tests were negative at the first month but positive at the third month, were also female pemphigus vulgaris patients under systemic steroid and azathioprine. The other patient, whose Demodex test was negative at the first month but positive at the third month, was a male psoriasis vulgaris patient receiving methotrexate.\n\nIn the control group, Demodex test was determined as positive in only one healthy individual at the beginning, first and third months of the study. The rest of the individuals in the control group had negative Demodex test at the beginning, first and third months.\n\nConsidering the number of mites, Demodex mites were observed in 16 patients at the beginning, in 28 patients in the first month and in 27 patients in the third month. \n\nThe number of healthy individuals in which Demodex mites observed was 12 at the beginning, 11 at the first month, and 14 at the third month of the study in the control group. Demodex densities of patient and control groups were presented in Table 1.\n\nWhen the patient and control groups were evaluated in terms of Demodex density, no statistically significant difference was found in the Demodex density at the beginning of the treatment. On the other hand there was a statistically significant difference in Demodex density in patients treated with immunosuppressive therapy in the first and third months when compared with the control group (p < 0.05).\n\n4. Discussion\nAlthough Demodex mites might be seen in healthy people, density remains low. They are acquired shortly after birth by the mother to infant transmission and increase in number with sebaceous gland proliferation during puberty. They become pathogenic when they multiply and reach to the density of >5 mites/cm2 of skin [2,6]. However factors affecting the density of Demodex mites are still not known exactly. Some local or systemic factors may induce the proliferation of mites. Immune deficiency was suggested to be the possible cause of overgrowth of mites [10,11]. \n\nDemodicidosis was observed in immunocompromised patients. It was described as an opportunistic infection of the skin in immunocompromised children who were receiving chemotherapy with the diagnosis of acute lymphoblastic leukemia. A pruritic, papulopustular facial eruption was described in those patients [12,13,14,15]. Similarly demodicidosis was also described in adult leukemia and lymphoma patients. The acute myelocytic leukemia patients receiving treatment of cytosine arabinoside, daunorubicin, hydroxyurea, and mitozantrone were reported with the highest Demodex density. Demodicidosis was suggested in the differential diagnosis of facial eruptions in patients with hematological malignancies on chemotherapy [6]. Another group of immunocompromised patients who were also reported to be predisposed to Demodicidosis was patients with acquired immunodeficiency syndrome. Erythematous papulopustules were described in those patients but just one had an unusual manifestation of Demodex infestation with ivory-white, poorly defined, indurated area. Alterations in humoral and cell-mediated immunity may allow the proliferation of Demodex and so the pathogenic role of it [16,17,18]. \n\nPatients with chronic renal failure were reported to have defective host defenses [19]. Uremia causes alterations in different aspects of immune response such as impaired oxidative response of neutrophils and abnormal function of lymphocytes [19]. Therefore, proliferation of the normally commensal mites might be allowed by host immune dysfunction. This was shown in the study investigating the incidence of Demodex folliculorum in end stage renal failure patients, the number of mite was found to be increased and the mean number of Demodex folliculorum was reported as 6.12/cm2 in those patients. Presence of more than five Demodex in a 1 cm2 area was found in 27 patients among 67 end stage renal failure patients. [20]. Similarly Duzgun et al. [21] also reported higher mean mite density in hemodialysis patients than controls. \n\nTacrolimus an immunosuppressive macrolide inhibits cytokine transcription and activation of T cells [9]. Rosaceiform dermatitis as a complication of treatment with tacrolimus ointment was reported. Increased Demodex mites determined by biopsy in two of the patients treated with tacrolimus ointment and proliferation of Demodex was suggested as the result of local immunosuppression caused by topical tacrolimus treatment [22]. Rosaceiform dermatitis with follicular Demodex was also reported by Lübbe et al. [23] with pimecrolimus 1% cream. Malignancy and the malnutrition were the other known immune deficiency states. Both conditions were found to be associated with increased Demodex [24]. In the study analyzing the frequency of Demodex folliculorum infestation in patients with urological cancers, possible relationship between the cancer as the immunosuppressive state, and the increased Demodex folliculorum incidence was detected [25]. Demodex mites were also reported to be isolated from eyelashes and associated with blepharitis [26,27,28].\n\nSome systemic agents have the property of causing immune dysregulation. Systemic glucocorticoids increase susceptibility to many bacterial, viral, fungal, and parasitic infections while reducing the activation and proliferation of effector T cells and also B cell function [29]. Cyclosporine reduces CD4+ and CD8+ T cells in the epidermis, methotrexate inhibits DNA synthesis in immunologically active cells and causes pancytopenia, and azathioprine suppresses T-cell function, B-cell antibody production, and ability of Langerhans cells to present antigens [30]. In this study, we investigated the density of Demodex in patients receiving these agents. The combination treatment such as systemic glucocorticoid and azathioprine caused the prominent increase in Demodex density in our study compared to monotherapy. \n\nThe results of our study suggest that there is an association between immunosuppressive treatment and the number of Demodex mites. Patients receiving immunosuppressive therapy showed statistically significant difference in Demodex density when compared with the control group. These results are consistent with the literature. However we did not find any facial eruption in our patients. We evaluated the patients just one and three months after the initiation of the treatment. This duration may not be enough to increase mites further. So if the patients had been evaluated after a longer period of time, greater number of Demodex and provoked abnormal immunologic reaction of the skin to the parasites with the appearance of cutaneous lesions might be observed. \n\n5. Conclusions\nDemodex density was higher than the control group at the first and third months of the immunosuppressive therapy and this difference was statistically significant. So, immunologic deficiency might increase the number of mites and demodicidosis should be kept in mind in patients on immunosuppressive treatment.\n\nAcknowledgments\nNone.\n\nAuthor Contributions\nConceptualization: E.P.Y., Data curation: H.K., E.P.Y. Formal analysis: H.K., Investigation: H.K., E.P.Y., F.A., N.S., Methodology: E.P.Y., Resources: H.K., E.P.Y., Supervision: P.Y.E., Validation: H.K., E.P.Y., F.A., N.S., Visualization: E.P.Y. Writing original draft: H.K., E.P.Y., Writing, review and editing: H.K., E.P.Y., F.A., N.S. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding.\n\nConflicts of Interest\nThe authors declare no conflict of interest.\n\nmedicina-56-00107-t001_Table 1Table 1 Demodex densities of patient and control groups at the initiation, first, and third months of therapy.\n\n\n\tInitiation of Treatment\tFirst Month of Treatment\tThird Month of Treatment\t\nMean Demodex Density\tMinimum, Maximum Demodex Number\tMean Demodex Density\tMinimum, Maximum Demodex Number\tMean Demodex Density\tMinimum, Maximum Demodex Number\t\nDisease group\t0.44 ± 0.65\t0/2\t1.15 ± 1.39\t0/8\t1.84 ± 2.29\t0/10\t\nControl group\t0.48 ± 1.05\t0/6\t0.51 ± 1.1\t0/6\t0.71 ± 1.39\t0/8\n==== Refs\nReferences\n1. Elston C.A. Elston D.M. Demodex mites Clin Dermatol 2014 32 739 743 10.1016/j.clindermatol.2014.02.012 25441466 \n2. Baima B. Sticherling M. Demodicidosis revisited Acta Derm. Venereol. 2002 82 3 6 10.1080/000155502753600795 12013194 \n3. Rufli T. Mumcuoglu Y. The hair follicle mites Demodex folliculorum and Demodex brevis: biology and medical importance. A review Dermatologica 1981 162 1 11 10.1159/000250228 6453029 \n4. Akilov O.E. Mumcuoglu K.Y. Immune response in demodicosis. J. Eur. Acad. Dermatol Venereol 2004 18 440 444 10.1111/j.1468-3083.2004.00964.x \n5. Hsu C.K. Hsu M.M. Lee J.Y. Demodicosis: a clinicopathological study J. Am. Acad. Dermatol. 2009 60 453 462 10.1016/j.jaad.2008.10.058 19231642 \n6. Seyhan M.E. Karincaoğlu Y. Bayram N. Aycan O. Kuku I. Density of Demodex folliculorum in haematological malignancies J. Int. Med. Res. 2004 32 411 415 10.1177/147323000403200410 15303773 \n7. Chang Y.S. Huang Y.C. Role of Demodex mite infestation in rosacea: A systematic Review and meta-analysis J. Am. Acad. Dermatol. 2017 77 441 447.e6 10.1016/j.jaad.2017.03.040 28711190 \n8. Lacey N. Ní Raghallaigh S. Powell F.C. Demodex mites--commensals, parasites or Mutualistic organisms? Dermatology 2011 222 128 130 10.1159/000323009 21228556 \n9. Fujiwara S. Okubo Y. Irisawa R. Tsuboi R. Rosaceiform dermatitis associated with topical tacrolimus treatment J. Am. Acad. Dermatol. 2010 62 1050 1052 10.1016/j.jaad.2009.01.029 20466178 \n10. Aydingöz I.E. Dervent B. Güney O. Demodex folliculorum in pregnancy Int. J. Dermatol. 2000 39 743 745 10.1046/j.1365-4362.2000.00013.x 11095192 \n11. Jansen T. Kastner U. Kreuter A. Altmeyer P. Rosacea-like demodicidosis associated with acquired immunodeficiency syndrome Br. J. Dermatol. 2001 144 139 142 10.1046/j.1365-2133.2001.03794.x 11167695 \n12. Sahn E.E. Sheridan D.M. Demodicidosis in a child with leukemia J. Am. Acad. Dermatol. 1992 27 799 801 10.1016/0190-9622(92)70250-J 1469129 \n13. Ivy S.P. Mackall C.L. Gore L. Gress R.E. Hartley A.H. Demodicidosis in childhood acute lymphoblastic leukemia; an opportunistic infection occurring with immunosuppression J. Pediatr. 1995 127 751 754 10.1016/S0022-3476(95)70168-0 7472831 \n14. Castanet J. Monpoux F. Mariani R. Ortonne J.P. Lacour J.P. Demodicidosis in an immunodeficient child Pediatr. Dermatol. 1997 14 219 220 10.1111/j.1525-1470.1997.tb00242.x 9192417 \n15. Morrás P.G. Santos S.P. Imedio I.L. Echeverria M.L. Hermosa J.M. Rosacea-like demodicidosis in an immunocompromised child Pediatr. Dermatol. 2003 20 28 30 10.1046/j.1525-1470.2003.03006.x 12558842 \n16. Dominey A. Rosen T. Tschen J. Papulonodular demodicidosis associated with acquired immunodeficiency syndrome J. Am. Acad. Dermatol. 1989 20 197 201 10.1016/S0190-9622(89)70021-9 2915054 \n17. Redondo Mateo J. Soto Guzmán O. Fernández Rubio E. Dominguez Franjo F. Demodex-attributed rosacea-like lesions in AIDS Acta Derm. Venereol. 1993 73 437 10.2340/0001555573437 7906456 \n18. Sarro R.A. Hong J.J. Elgart M.L. An unusual demodicidosis manifestation in a patient with AIDS J. Am. Acad. Dermatol. 1998 38 120 121 10.1016/S0190-9622(98)70554-7 9448221 \n19. Pesanti E.L. Immunologic defects and vaccination in patients with chronic renal failure Infect. Dis. Clin. North. Am. 2001 15 813 832 10.1016/S0891-5520(05)70174-4 11570143 \n20. Karincaoglu Y. Esrefoglu Seyhan M. Bayram N. Aycan O. Taskapan H. Incidence of Demodex folliculorum in patients with end stage chronic renal failure Ren. Fail. 2005 27 495 499 10.1080/08860220500198037 16152985 \n21. Yagdiran Düzgün O. Aytekin S. Comparison of Demodex folliculorum density in haemodialysis patients with a control group J. Eur. Acad. Dermatol. Venereol. 2007 21 480 483 10.1111/j.1468-3083.2007.01926.x 17373974 \n22. Antille C. Saurat J.H. Lübbe J. Induction of rosaceiform dermatitis during treatment of facial inflammatory dermatoses with tacrolimus ointment Arch. Dermatol. 2004 140 457 460 10.1001/archderm.140.4.457 15096374 \n23. Lübbe J. Stucky L. Saurat J.H. Rosaceiform dermatitis with follicular Demodex after treatment of facial atopic dermatitis with 1% pimecrolimus cream Dermatology 2003 207 204 205 10.1159/000071800 \n24. Kaya S. Selimoglu M.A. Kaya O.A. Ozgen U. Prevalence of Demodex folliculorum and Demodex brevis in childhood malnutrition and malignancy Pediatr. Int. 2013 55 85 89 10.1111/j.1442-200X.2012.03740.x 23039878 \n25. Inci M. Kaya O.A. Inci M. Yula E. Gökçe H. Rifaioğlu M.M. Demirtaş O. Yengil E. Investigating Demodex folliculorum in patients with urological cancer. Turkiye Parazitol. Derg. 2012 36 208 210 10.5152/tpd.2012.50 23339940 \n26. Szkaradkiewicz A. Chudzicka-Strugała I. Karpiński T.M. Goślińska-Pawłowska O. Tułecka T. Chudzicki W. Szkaradkiewicz A.K. Zaba R. Bacillus oleronius and Demodex mite infestation in patients with chronic blepharitis Clin. Microbiol. Infect. 2012 18 1020 1025 10.1111/j.1469-0691.2011.03704.x 22114987 \n27. Biernat M.M. Rusiecka-Ziółkowska J. Piątkowska E. Helemejko I. Biernat P. Gościniak G. Occurrence of Demodex species in patients with blepharitis and in healthy individuals: a 10-year observational study Jpn. J. Ophthalmol. 2018 62 628 633 10.1007/s10384-018-0624-3 30255395 \n28. Navel V. Mulliez A. Benoist d’Azy C. Baker J.S. Malecaze J. Chiambaretta F. Dutheil F. Efficacy of treatments for Demodex blepharitis: A systematic review and meta-analysis Ocul. Surf. 2019 17 655 669 10.1016/j.jtos.2019.06.004 31229586 \n29. Schadt C.R. Jackson S.M. Dermatology Bolognia J.L. Schaffer J.V. Cerroni L. Elsevier Saunders Philadelphia, PA, USA 2018 Volume 2 Chapter 125 2186 2199 \n30. Maiberger M.P. Nunley J.R. Wolverton S.E. Dermatology Bolognia J.L. Schaffer J.V. Cerroni L. Elsevier Saunders Philadelphia, PA, USA 2018 Volume 2 Chapter 130 2278 2295\n\n",
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"issue": "56(3)",
"journal": "Medicina (Kaunas, Lithuania)",
"keywords": "azathioprine; corticosteroids; cyclosporine; demodex; immunosuppressive treatment; methotrexate",
"medline_ta": "Medicina (Kaunas)",
"mesh_terms": "D000328:Adult; D000818:Animals; D005145:Face; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D008924:Mite Infestations; D008925:Mites; D059208:Parasite Load; D055815:Young Adult",
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"title": "Pre-Treatment and Post-Treatment Demodex Densities in Patients under Immunosuppressive Treatments.",
"title_normalized": "pre treatment and post treatment demodex densities in patients under immunosuppressive treatments"
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"abstract": ": The current gold standard for contemporary treatment of rectal cancer is total mesorectal excision (TME), achieving excellent local disease control and low recurrence rates. However, TME may be associated with postoperative mortality and quality of life deterioration. Therefore, the need to develop less radical treatment strategies has emerged. Transanal minimally invasive surgery (TAMIS) is currently indicated only for early rectal cancer. However, local excision following chemoradiation has yielded promising clinical outcomes in selected cases with more advanced disease. : We describe three cases of patients with advanced rectal cancer, who were managed with TAMIS, either due to patients' unwillingness to tolerate permanent colostomy or due to significant comorbidities. : Two of the three patients who also received adjuvant chemoradiation are still in remission for 18 and 15 months respectively. The third patient died early after hospital release due to unrelated causes. : Local excision utilizing minimally invasive techniques, alongside with chemoradiotherapy and close follow up can be a viable alternative in carefully selected rectal cancer patients with advanced disease who deny permanent colostomy or are ineligible for major operations.",
"affiliations": "a National and Kapodistrian University of Athens, Faculty of Medicine, Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;a National and Kapodistrian University of Athens, Faculty of Medicine, Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;b National and Kapodistrian University of Athens, Faculty of Medicine , Department of Clinical Therapeutics , Vasilissis Sofias 80, 11528, Alexandra Hospital , Athens , Greece.;c Assistant Professor of Surgery, National and Kapodistrian University of Athens , Faculty of Medicine, Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;d National and Kapodistrian University of Athens, Faculty of Medicine , Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;a National and Kapodistrian University of Athens, Faculty of Medicine, Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;e Associate Professor of Surgical Critical Care, National and Kapodistrian University of Athens, Faculty of Medicine, Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;f Professor of Surgery, National and Kapodistrian University of Athens, Faculty of Medicine , Second Department of Surgery , Aretaieion University Hospital , Vasilissis Sofias 76, 11528, Athens , Greece.;g Associate Professor of Surgery, National and Kapodistrian University of Athens, Faculty of Medicine , Second Department of Surgery, Aretaieion University Hospital , Vasilissis Sofias 76, 11528 , Athens , Greece.",
"authors": "Giannoulopoulos|Dimitrios|D|http://orcid.org/0000-0003-4033-5211;Nastos|Constantinos|C|;Gavriatopoulou|Maria|M|;Vezakis|Antonios|A|;Dellaportas|Dionysios|D|;Sotirova|Ira|I|;Giokas|Georgios|G|;Polymeneas|Georgios|G|;Theodosopoulos|Theodosios|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1080/08941939.2017.1418462",
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"issn_linking": "0894-1939",
"issue": "32(4)",
"journal": "Journal of investigative surgery : the official journal of the Academy of Surgical Research",
"keywords": "TAMIS; TME; advanced disease; rectal cancer",
"medline_ta": "J Invest Surg",
"mesh_terms": "D001003:Anal Canal; D006801:Humans; D019060:Minimally Invasive Surgical Procedures; D009364:Neoplasm Recurrence, Local; D011788:Quality of Life; D012004:Rectal Neoplasms; D000067368:Transanal Endoscopic Surgery",
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"pages": "371-376",
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"pmid": "29313396",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016420:Comment",
"references": null,
"title": "The Role of TAMIS (Transanal Minimally Invasive Surgery) in the Management of Advanced Rectal Cancer - One Shared Story of Three Exceptional Cases.",
"title_normalized": "the role of tamis transanal minimally invasive surgery in the management of advanced rectal cancer one shared story of three exceptional cases"
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"abstract": "BACKGROUND\nAnti-thrombosis therapy for atrial fibrillation (AF) management and stroke prevention is an important aspect of disease management. Novel oral anticoagulants (NOACs) are recommended by guidelines for AF management. However, if one can switch one NOAC to another when the former showed a poor effect has not been fully determined.\nA 52-year-old man was admitted to our center for heart failure and AF with a thrombus in the left atrium.\nCardiomyopathy was diagnosed by cardiac magnetic resonance (CMR) and echocardiography.\n\n\nMETHODS\nHe was prescribed rivaroxaban (20 mg daily) as treatment, and dabigatran (150 mg twice daily) was used when the thrombus was found to be non-response to rivaroxaban.\n\n\nRESULTS\nThe rivaroxaban did not diminish the atrial thrombus, and dabigatran was given instead which finally eliminated the thrombus.\n\n\nCONCLUSIONS\nIndividualized responsiveness to NOACs should be considered and paid more attention to during clinical practice.",
"affiliations": "Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Radiology Department.;Department of Exercise Sciences, University of Toronto, Toronto, Canada.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Ultrasound Department, China-Japan Union Hospital of Jilin University, Changchun, China.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.;Cardiology Department, China-Japan Union Hospital of Jilin University.",
"authors": "Sun|Huan|H|;Zhao|Qini|Q|;Wang|Yanjing|Y|;Lakin|Robert|R|;Liu|Xueyan|X|;Yu|Ming|M|;Yang|Hongliang|H|;Gao|Dongmei|D|;Chen|Weiwei|W|;Gao|Guangyuan|G|;Yan|Mengjie|M|;He|Yuquan|Y|;Yang|Ping|P|",
"chemical_list": "D000991:Antithrombins; D000069552:Rivaroxaban; D000069604:Dabigatran",
"country": "United States",
"delete": false,
"doi": "10.1097/MD.0000000000013623",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 30572474MD-D-18-0549910.1097/MD.0000000000013623136233400Research ArticleClinical Case ReportDabigatran as an alternative for atrial thrombosis resistant to rivaroxaban A case reportSun Huan MD, PhDabcZhao Qini MDabcWang Yanjing MDdLakin Robert PhDeLiu Xueyan MD, PhDabcYu Ming MDabcYang Hongliang MDabcGao Dongmei MDfChen Weiwei MDabcGao Guangyuan MDabcYan Mengjie MD, PhDabcHe Yuquan MD, PhDabc∗Yang Ping MD, PhDabcNA. a Cardiology Department, China-Japan Union Hospital of Jilin Universityb Jilin Provincial Cardiovascular Research Institutec Jilin Provincial Key Laboratory for Genetic Diagnosis of Cardiovascular Diseased Radiology Departmente Department of Exercise Sciences, University of Toronto, Toronto, Canadaf Ultrasound Department, China-Japan Union Hospital of Jilin University, Changchun, China.∗ Correspondence: Yuquan He, Cardiology Department, China-Japan Union Hospital of Jilin University, 126 Xiantai Street, Changchun 130033, China (e-mail: hyq2@sina.com).12 2018 21 12 2018 97 51 e1362310 8 2018 19 11 2018 Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc.2018This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nAnti-thrombosis therapy for atrial fibrillation (AF) management and stroke prevention is an important aspect of disease management. Novel oral anticoagulants (NOACs) are recommended by guidelines for AF management. However, if one can switch one NOAC to another when the former showed a poor effect has not been fully determined.\n\nPatient concerns:\nA 52-year-old man was admitted to our center for heart failure and AF with a thrombus in the left atrium.\n\nDiagnoses:\nCardiomyopathy was diagnosed by cardiac magnetic resonance (CMR) and echocardiography.\n\nInterventions:\nHe was prescribed rivaroxaban (20 mg daily) as treatment, and dabigatran (150 mg twice daily) was used when the thrombus was found to be non-response to rivaroxaban.\n\nOutcomes:\nThe rivaroxaban did not diminish the atrial thrombus, and dabigatran was given instead which finally eliminated the thrombus.\n\nLessons:\nIndividualized responsiveness to NOACs should be considered and paid more attention to during clinical practice.\n\nKeywords\nanticoagulationdabigatrannovel oral anticoagulantsrivaroxabanthrombusOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nAtrial fibrillation (AF) is the most common clinical arrhythmia worldwide.[1,2] Anti-thrombosis therapy for AF management and stroke prevention is an important aspect of disease management,[3] with non-vitamin K antagonist oral anticoagulants (NOACs) having been reported to be both safe and effective for preventing thrombus formation and stroke in AF patients.[4]\n\nHowever, whether different NOACs are equally effective in AF treatment among patients has yet to be determined. In addition, equal recommendation of both factor IIa (i.e., Dabigatran) and factor Xa (i.e., Rivaroxaban) inhibitors among therapeutic guidelines[3] further complicates optimal and individualized NOAC treatment approaches. In the present case report, we present an AF patient whose left atrial thrombus was resistant to one anticoagulant therapy but sensitive to another, which may have implications for how NOACs are prescribed in the future.\n\n2 Informed consent and ethical statement\nThe patient signed an informed consent. The whole report meets the requirements from the institution ethical committee.\n\n3 Case presentation\nA 52-year-old man was admitted to our center in late September 2017 presenting with shortness of breath as well as facial and lower limb edema. The patient was diabetic (10-year diagnosis), and was found to have had a stroke 3 months prior to his admission, resulting in slight dullness of speech. His electrocardiogram showed persistent AF (CHA2DS2-VASc score: 4). Renal function serum album levels were within normal. However, his echocardiography showed an enlarged left atrium (55 mm × 70 mm), reduced ejection fraction (44.9%), and a suspected mass (8.0 mm × 8.4 mm) in the left atrium (Fig. 1A).\n\nFigure 1 Evidence of a thrombus in the left atrium and its response to non-vitamin K antagonist oral anticoagulant (NOAC) therapy using echocardiography. (A) Transthoracic echocardiography (TTE) showed a thrombus (black arrow) in the left atrium upon initial presentation. (B) TTE imaging after 1-month rivaroxaban treatment revealed the thrombus had increased in size (black arrow). TEE imaging (C) and 3D imaging (D) further confirmed the presence of a left atrial thrombus. (E) TTE imaging showed dabigatran treatment reduced the size of the thrombus, with a later TEE examination revealing complete elimination of the thrombus (F).\n\nUpon further evaluation, a normal coronary artery angiography (CAG) made the diagnosis of coronary heart disease unlikely. Subsequently, a cardiac magnetic resonance (CMR) evaluation confirmed an enlarged left atrium, with evidence of diffuse late gadolinium enhancement (LGE) in the left ventricle (Fig. 2) and a left atrial thrombus.\n\nFigure 2 Representative cardiac magnetic resonance (CMR) image showing diffuse late gadolinium enhancement (LGE) in the left ventricle (red arrows), which implied diffuse myocardial damage in the patient.\n\nBased on the clinical presentation, we prescribed diuretics (furosemide 20 mg bid), ACEI (Ramipril 2.5 mg Qd), a β-blocker (metorol 49.5 mg Qd) as well as a NOAC, rivaroxaban (20 mg daily). In response to treatment, the patient's shortness of breath and edema quickly improved. After approximately 1 month (early November 2017), we performed a follow-up transthoracic echocardiography (TTE) examination that showed that the mass within the left atrium had increased in size (8.09 mm × 8.36 mm), which was further confirmed by transesophageal echocardiography (TEE). In response, we started treatment of the thrombus with a different NOAC, dabigatran (150 mg bid). During a follow-up examination in December 2017, both TTE and TEE examinations confirmed that the thrombus had decreased in size (4.36 mm × 6.02 mm) and had completely vanished in January 2018 (as shown in Fig. 1), after which AF ablation was performed to safely restore sinus rhythm. In response to its successful treatment of the thrombolytic mass, dabigatran (110 mg bid) was prescribed to this patient as a long-term strategy for stroke prevention. Following up with the patient over the next 4 months, he was free of ischemia or bleeding events.\n\n4 Discussion\nAs thrombosis is a major complication of AF, anticoagulation therapy is essential to reduce the risk of stroke in AF patients.[5,6] Previously, the RELY study[7] and ROCKET-AF study[8] demonstrated the efficacy of the NOACs dabigatran and rivaroxaban, respectively, for thrombosis treatment related to AF. Moreover, Lip et al[9] recently reported that rivaroxaban can resolve atrial thrombi in up to 62.5% of the AF patients. Moreover, NOACs have proven to be as efficacious as warfarin in stroke prevention in AF patients, requiring less frequent monitoring of the coagulation index or adjustment of dose and making their use more convenient for physicians.[8] In spite of the established benefits of NOAC treatment, it is unknown whether differences in the efficacy of these medications exist among AF patients, which would have clinical implications for the prescription and treatment success.\n\nIn the current case study, our patient initially had an unclear pathology given the lack of results of myocardial biopsy, though a diagnosis of an underlying cardiomyopathy could be made based on the CMR results. It was determined that the patient's history of diabetes was the likely cause of his myocardial injury and morphology. At this point, anticoagulation therapy and treatment for heart failure are necessary, regardless of the exact underlying pathogenesis.\n\nIt has been previously reported that rivaroxaban (10 mg daily) resolved left ventricular thrombus,[10] demonstrating the high efficiency of this oral factor Xa inhibitor for thrombus treatment. By contrast, the present case demonstrated an opposite effect, with the left atrial thrombus showing evidence of enlargement after 1-month of rivaroxaban treatment. Specifically, we used rivaroxaban, at a daily dose of 20 mg, as the first choice for anticoagulation, but the evidence of thrombus enlargement led us to change our therapeutic strategy from the Xa inhibitor to dabigatran, a factor IIa inhibitor. Unexpectedly, dabigatran showed a greater efficacy in our patient, resolving the thrombus in about 1 month and proving to be superior to the Xa inhibitor in this given case. To the best of our knowledge, this is the first report to demonstrate successful thrombus breakdown with dabigatran in a patient presenting with thrombus resistance to full-dose rivaroxaban. These findings align with a recent report that showed the factor IIa inhibitor was effective at treating an atrial thrombus resistant to reduced-dose (15 mg) rivaroxaban in aged-patients.[11] The reasons for the disparate responses to the NOACs used in the current study are unclear and may not be easily determined. Specifically, in spite of an overall linear dose–effect relationship for NOACs and their anticoagulant effects, this relationship may be unique for each patient, which will require an individualized approach to ensure that “super-responders” and “non-responders” are permanently identified.[12] The underlying mechanism is unclear, but variability in the sensitivity of the target molecular (factor Xa and factor IIa) to specific NOACs and individualized pharmacokinetics might explain these findings, which warrants further exploration.\n\nIt should be noted that our findings do not prove that dabigatran is a superior NOAC to rivaroxaban or a Xa inhibitor in every patient presenting with a cardiac thrombus. Moreover, in support of patients showing different sensitivities to NOACs, a previous case presented a patient in which a different Xa inhibitor, apixaban, eliminated a thrombus resistant to both warfarin and dabigatran.[13] Therefore, our case provides support for heterogeneity in patient responses to NOACs, which requires more attention from clinicians.\n\nWe did not perform coagulation tests for either rivaroxaban or dabigatran in our patient, which would have provided insight into the individual anticoagulation strength prior to treatment; however, this is the normal approach for NOACs prescription in AF patients. As we mentioned previously, our clinic did not perform the biopsy on this patient, which prevented us from determining the underlying pathogenesis of the patient's cardiomyopathy. In many AF patients, dabigatran or rivaroxaban may both prove to be efficacious in thrombus prevention and treatment. However, some patients may show resistance to NOAC treatment, requiring an alternative therapeutic strategy. While the factors mediating the heterogeneous responsiveness to NOACs are currently unclear, it has important implications for individualized NOAC therapy for thrombus treatment and prevention that warrants further consideration.\n\nAuthor contributions\nConceptualization: Huan Sun, Qini Zhao, Robert Lakin, Mengjie Yan.\n\nData curation: Xueyan Liu, Ming Yu.\n\nFunding acquisition: Yuquan He, Ping Yang.\n\nInvestigation: Huan Sun, Dongmei Gao, Mengjie Yan.\n\nMethodology: Qini Zhao, Yanjing Wang, Dongmei Gao.\n\nResources: Xueyan Liu, Ming Yu, Hongliang Yang, Guangyuan Gao.\n\nSoftware: Qini Zhao, Yanjing Wang, Hongliang Yang, Guangyuan Gao.\n\nSupervision: Yuquan He, Ping Yang.\n\nValidation: Robert Lakin, Weiwei Chen, Yuquan He.\n\nVisualization: Yanjing Wang.\n\nWriting – original draft: Huan Sun.\n\nWriting – review & editing: Robert Lakin, Guangyuan Gao, Mengjie Yan.\n\nAbbreviations: AF = atrial fibrillation, NOACs = novel oral anticoagulants.\n\nHS and QZ have contributed equally to this article.\n\nThis work is funded by the Project of Science and Technology of Jilin Province (20180414042GH) and Project of Yangzi River Pharmocological Group.\n\nThe authors have no conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Chugh SS Havmoeller R Narayanan K \nWorldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study . Circulation \n2014 ;129 :837–47 .24345399 \n[2] Colilla S Crow A Petkun W \nEstimates of current and future incidence and prevalence of atrial fibrillation in the U.S. adult population . Am J Cardiol \n2013 ;112 :1142–7 .23831166 \n[3] Kirchhof P Benussi S Kotecha D \n2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS . Europace \n2016 ;18 :1609–78 .27567465 \n[4] Steffel J Verhamme P Potpara TS \nThe 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation . Eur Heart J \n2018 ;39 :1330–93 .29562325 \n[5] Hart RG Pearce LA Aguilar MI \nMeta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation . Ann Intern Med \n2007 ;146 :857–67 .17577005 \n[6] Ruff CT Giugliano RP Braunwald E \nComparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials . Lancet \n2014 ;383 :955–62 .24315724 \n[7] Connolly SJ Ezekowitz MD Yusuf S \nDabigatran versus warfarin in patients with atrial fibrillation . N Engl J Med \n2009 ;361 :1139–51 .19717844 \n[8] Patel MR Mahaffey KW Garg J \nRivaroxaban versus warfarin in nonvalvular atrial fibrillation . N Engl J Med \n2011 ;365 :883–91 .21830957 \n[9] Lip GY Hammerstingl C Marin F \nLeft atrial thrombus resolution in atrial fibrillation or flutter: results of a prospective study with rivaroxaban (X-TRA) and a retrospective observational registry providing baseline data (CLOT-AF) . Am Heart J \n2016 ;178 :126–34 .27502860 \n[10] Sun H Zhao Q Wang Y \nDaily 10 mg rivaroxaban as a therapy for ventricular thrombus related to left ventricular non-compaction cardiomyopathy: a case report . Medicine \n2018 ;97 :e9670.29369185 \n[11] Watanabe T Shinoda Y Ikeoka K \nDabigatran therapy resulting in the resolution of rivaroxaban-resistant left atrial appendage thrombi in patients with atrial fibrillation . Intern Med \n2017 ;56 :1977–80 .28768967 \n[12] Ezekowitz MD Reilly PA Nehmiz G \nDabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study) . Am J Cardiol \n2007 ;100 :1419–26 .17950801 \n[13] Miwa Y Minamishima T Sato T \nResolution of a warfarin and dabigatran-resistant left atrial appendage thrombus with apixaban . J Arrhythm \n2016 ;32 :233–5 .27354873\n\n",
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"title": "Dabigatran as an alternative for atrial thrombosis resistant to rivaroxaban: A case report.",
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"abstract": "Clostridioides (Clostridium) difficile infection manifests as intestinal infections, namely pseudomembranous colitis. The occurrence of extra-intestinal disease is thought to be rare with a rate of 1.08% of 2034 isolates of C. difficile and an incidence of 4/100,000 admissions. C. difficile had been rarely associated with osteomyelitis. Here, we report the occurrence of C. difficile osteomyelitiin a patient with sickle cell disease. The patient had multiple surgeries and a prolonged antimicrobial therapy to achieve a cure. The patient had C. difficile infection of native bone and of a prosthetic joint. The patient received prolonged therapy with amoxicillin-clavulanic acid and metronidazole and she remained free of C. difficile infection for 3 years off antibiotics.",
"affiliations": "Specialty Internal Medicine and Quality Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia; Indiana University School of Medicine, Indianapolis, Indiana, USA; Johns Hopkins University School of Medicine, Baltimore, MD, USA; General Internal Medicine Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia. Electronic address: jaffar.tawfiq@aramco.com.;Specialty Internal Medicine and Quality Department, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia; Johns Hopkins University School of Medicine, Baltimore, MD, USA; General Internal Medicine Unit, Johns Hopkins Aramco Healthcare, Dhahran, Saudi Arabia.",
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"title": "Multi-focal Clostridioides (Clostridium) difficile osteomyelitis in a patient with sickle cell anemia: case presentation and literature review.",
"title_normalized": "multi focal clostridioides clostridium difficile osteomyelitis in a patient with sickle cell anemia case presentation and literature review"
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"abstract": "Primitive neuroectodermal tumor (PNET) is most commonly encountered in the soft tissue or bone in children and young adults, and its involvement in the intestines is exceedingly rare. To the best of our knowledge, eighteen cases have been reported to date. The present study reports three cases of PNET arising in the mesentery and ileocecum in 59- and 22-year-old males and a 36-year-old female. Computed tomography revealed a solid mass in the lower abdomen, with areas of cystic changes. Microscopically, the tumors were composed of small round cells arranged in sheets and rosettes with scant cytoplasm, hyperchromatic nuclei and a high mitotic rate. The tumor cells were immunopositive for CD99 and FLI1. EWS/FLI1 translocations were detected in all cases. Case 1 and case 2 underwent tumor resection without any preoperative radiotherapy, chemotherapy or biological therapy. Case 3 underwent tumor resection and received eight cycles of IAP chemotherapy (2.0 mg ifosfamide, 80 mg epirubicin, 30 mg cisplatin 30mg). Case 3 was followed up for 34 months until they succumbed to peritoneal recurrence, whereas the other cases were not followed up. The incidence of these small round-cell tumors in the intestinal system, their clinical and pathological features and differential diagnosis are discussed with a review of the literature.",
"affiliations": "Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, Jiangsu 210002, P.R. China.;Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, Jiangsu 210002, P.R. China.;Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, Jiangsu 210002, P.R. China.;Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, Jiangsu 210002, P.R. China.",
"authors": "Peng|Libo|L|;Yang|Limin|L|;Wu|Nan|N|;Wu|B O|BO|",
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"fulltext": "\n==== Front\nExp Ther MedExp Ther MedETMExperimental and Therapeutic Medicine1792-09811792-1015D.A. Spandidos 10.3892/etm.2015.2242etm-09-04-1299ArticlesPrimary primitive neuroectodermal tumor arising in the mesentery and ileocecum: A report of three cases and review of the literature PENG LIBO YANG LIMIN WU NAN WU BO Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, Nanjing, Jiangsu 210002, P.R. ChinaCorrespondence to: Professor Bo Wu, Department of Pathology, Jinling Hospital, Clinical Medical School of Southern Medical University, 305 East Zhongshan Road, Nanjing, Jiangsu 210002, P.R. China, E-mail: wubojlh@163.com4 2015 30 1 2015 30 1 2015 9 4 1299 1303 07 5 2014 04 12 2014 Copyright © 2015, Spandidos Publications2015This is an open-access article licensed under a Creative Commons Attribution-NonCommercial 3.0 Unported License. The article may be redistributed, reproduced, and reused for non-commercial purposes, provided the original source is properly cited.Primitive neuroectodermal tumor (PNET) is most commonly encountered in the soft tissue or bone in children and young adults, and its involvement in the intestines is exceedingly rare. To the best of our knowledge, eighteen cases have been reported to date. The present study reports three cases of PNET arising in the mesentery and ileocecum in 59- and 22-year-old males and a 36-year-old female. Computed tomography revealed a solid mass in the lower abdomen, with areas of cystic changes. Microscopically, the tumors were composed of small round cells arranged in sheets and rosettes with scant cytoplasm, hyperchromatic nuclei and a high mitotic rate. The tumor cells were immunopositive for CD99 and FLI1. EWS/FLI1 translocations were detected in all cases. Case 1 and case 2 underwent tumor resection without any preoperative radiotherapy, chemotherapy or biological therapy. Case 3 underwent tumor resection and received eight cycles of IAP chemotherapy (2.0 mg ifosfamide, 80 mg epirubicin, 30 mg cisplatin 30mg). Case 3 was followed up for 34 months until they succumbed to peritoneal recurrence, whereas the other cases were not followed up. The incidence of these small round-cell tumors in the intestinal system, their clinical and pathological features and differential diagnosis are discussed with a review of the literature.\n\nprimitive neuroectodermal tumormesenteryileocecal\n==== Body\nIntroduction\nPrimitive neuroectodermal tumor (PNET) is a rare aggressive malignant small round cell tumour, which is most common in children and young adults (1). PNET belongs to the Ewing’s sarcoma family tumors (ESFT), due to its specific chromosomal translocation: t(11;22)(q24;q12) (2). It is thought to be of neural crest origin and is most commonly encountered in the soft tissue or bone (3). Reports of cases arising in the intestines are extremely rare. To the best of our knowledge, there are 18 cases in the literature (4–21). The present study reports three unusual cases of PNET arising from the mesentery and ileocecum and describes the presenting symptoms, imaging findings, pathological features and molecular genetics of the tumors.\n\nCase reports\nEthics\nThe present study was conducted in accordance with the Declaration of Helsinki and was approved by the Institutional Review Board of Jingling Hospital (Nanjing, China). Furthermore, informed consent was obtained from the relatives of each participating patient.\n\nCase 1\nIn June 2005, a previously healthy 59-year-old male presented to the Department of Pathology, Nanjing Jinling Hospital (Nanjing, China) following 20 days of lower quadrant pain. Computed tomography (CT) scanning revealed a 5×6 cm mass in the lower quadrant. Tumor markers, such as carcinoembryonic antigen and carbohydrate antigen 19–9, were normal. Explorative laparotomy revealed a 6×5×3 cm mass in the mesentery of the terminal ileum, without any macroscopic spread elsewhere in the abdomen. Microscopically, the sections revealed the proliferation of small round cells in nests with a finely distributed chromatin pattern and rosette formation, hyperchromatic nuclei and scant cytoplasm, and the rosettes were diffusely infiltrated with fat. The tumor cells were positive for CD99, FLI1 and EMA, but negative for CD3, CgA, CD20, CKpan, S100 and HMB45. As no other foci were detected in extensive clinical and radiological investigations, the tumor was considered to be primary. Molecular testing demonstrated the expression of EWS/FLI1 fusion transcripts corresponding to the t(11;22)(q24;q12) translocation. Based on the above clinicopathological and genetic findings, a histopathological diagnosis of PNET developing from the mesentery of the terminal ileum was made. The patient was surgically treated for the tumor and administered with adjuvant chemotherapy.\n\nCase 2\nIn September 2005, a 22-year-old male presented with abdominal intermittent abdominal pain of 20 days duration. Physical examination revealed the presence in the lower abdomen of a ~10×8 cm mass, with an uneven surface and no tenderness. Abdominal CT showed a mass (10×11 cm) in the lower abdomen and pelvis; it also revealed multiple areas of intrahepatic cystic density. Explorative laparotomy revealed that the mass adhered tightly to the sigmoid colon, rectum and omentum. The left lateral lobe and right lobe of the liver could touch two obvious nodules, 6 and 8 cm in diameter, respectively. Due to massive intraoperative blood loss and hypotension, the patient did not undergo liver tumor resection. Macroscopic examination revealed a grayish-brown, soft tissue mass, with varicose veins on the surface and areas of cystic changes. Microscopically, the tumor featured a uniform, sheet-like proliferation of small round tumor cells with high mitosis. Focally the tumor cells also formed ribbon-like or rosette-like structures, with areas of hemorrhage and necrosis, and infiltration into adipose tissue. The mesenteric lymph nodes were free. Immunohistochemically, the tumor cells showed diffuse membrane positivity for CD99, Syn and FLI1. There was a punctate pattern of positive staining for S100 and negativity for CKpan, CD3, CD34, SMA, HMB45, MelanA and CgA. EWS/FLI1 fusion gene translocation demonstrated the translocation t(11;22)(q24;q12). The final diagnosis was intestinal PNET with liver metastases. Postoperative adjuvant chemotherapy was not administered.\n\nCase 3\nIn January 2009, a 36-year-old female was admitted to hospital with abdominal pain and an abdominal mass. On physical examination, a large and firm mass was evident in the right abdomen. Laboratory evaluation showed a CA125 level of 57.41 IU/ml (normal, 35 IU/ml), whereas the CA199 levels were within normal limits. Magnetic resonance imaging confirmed a large mass in the pelvis (Fig. 1). A provisional diagnosis of right accessory malignancy was made. Exploratory laparotomy revealed that the mass was localized in the ileocecal region and adhered to the sigmoid colon, with no adhesion to the uterus or fallopian tubes. There was also a large quantity (~500 ml) of bloody, jelly-like liquid within the abdominal cavity. On gross examination, a huge mass in the ileocecum, measuring 15×15×13 cm, with a cauliflower-like appearance was found. The mass was grayish-black in color with a hard texture. Histologically, the tumor consisted of small round cells arranged in diffuse sheets with uniform rosette formation, large and round nuclei, hyperchromatic nuclei and scant cytoplasm. Large areas of necrosis were also present. Immunohistochemistry demonstrated diffuse membrane positivity of the tumor cells for vimentin, FLI1 and CD99 and negativity for CKpan, CgA, Syn, CD117, HMB45, S100, CD20 and CD3 (Fig. 2). The EWS/FLI1 fusion transcript of the t(11,22)(q24;q12) translocation was also detected by fluorescence in situ hybridization (FISH; Fig. 3). Due to the unusual location of the tumor in the mesentery, the patient succumbed from peritoneal recurrence 34 months after the surgery.\n\nDiscussion\nPNET is a rare aggressive malignant small round cell tumor most commonly arising in the central nervous system, soft tissues or bones, which was first recognized by Stout in 1918 (22). The progenitor cells are possibly neural crest cells (1). PNET is usually seen along the central axis, particularly in the soft tissue or bone in children and young adults. This rare and aggressive tumor has been described in the kidney (23), uterine cervix (24) and pancreas (25). Regardless of the point of origin, these tumors are highly aggressive, often quickly metastasizing to the lung and bone. To the best of our knowledge, 18 cases of intestinal PNET have been reported previously (Table I). The cases were eight males and 10 females, with an average age at presentation of 29 years (range, 9–63 years); 12 cases were aged ≤40 years. Its incidence in older individuals, as in case 1 in the present study, is quite rare. The small bowel, and its mesentery, is the most common site (15 cases); others occurred in the duodenum and mesocolon. The present study describes another unusual location, namely the ileocecum (case 3).\n\nIn the current study, all cases were primary to the mesentery and ileocecum, with no evidence of the PNET arising elsewhere. The maximum tumor diameter was 6–15 cm. The histologic appearance of the tumor typically comprised round-to-ovoid hyperchromatic cells with minimal cytoplasm, arranged in nests with variable rosette formation. Immunohistological examinations usually revealed CD99 and FLI1 positivity. FISH analysis indicated the presence of EWSR1 gene rearrangement in these three patients.\n\nMaking an accurate diagnosis is critical for optimal patient management and prognostication. Physical examination often reveals an abdominal or pelvic mass with recurrent abdominal pain. Imaging examination such as CT scanning is able to provide important information regarding the size of the mass, the involvement of adjacent structures and the presence of metastasis. There are no suggestive blood markers that can be used to diagnose PNET. Mhawech-Fauceglia et al (26) demonstrated that the most sensitive and specific test panel for the diagnosis of Ewing’s sarcoma/PNET is a combination of CD99 and FLI1. Recently, Yoshida et al (27) reported that the NKX2.2 gene, as an important target of EWS-FLI1, is a valuable marker for PNET, with a sensitivity of 93% and a specificity of 89%. The genetic hallmark is the presence of a specific translocation t(11;22)(q24;q12), which is expressed in 90–95% of patients (28).\n\nIt is difficult to differentiate PNET from other small round-cell tumors. However, immunohistochemical examinations with myogenic, neurogenic, and lymphoid cell markers can rule out many of these tumors. In gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), histological examination reveals a trabecular or solid arrangement and immunohistochemical analysis reveals the expression of neuroendocrine markers (Syn and CgA) (29). In type II enteropathy-associated T-cell lymphoma, histological examination of the lymphoma cells reveals full-thickness infiltration of the intestinal wall. A notable difference from PNET is the presence of villous atrophy, cryptal hyperplasia and intraepithelial lymphocytosis. The tumor cells express CD3, CD43 and CD8 (30). Metastatic carcinoma has a high incidence in older patients and often has a definite primary lesion, good adhesion between cells, nested or irregular glandular structure, cellular atypia and mitotic activity. In addition, specific immune markers suggestive of tissue origin are positive. For metastatic malignant melanoma, the majority of cases have an antecedent history of melanoma (skin and mucous membrane), morphological diversity is observed, and lipofuscin granules are visible in the cytoplasm. Malignant melanoma often has diffuse positivity for S-100 protein as well as possible positivity for melanocytic markers, including HMB45 and MelanA (31).\n\nThere is no established treatment modality for intestinal PNET. Surgical excision when complete offers the best chance for survival and adjuvant radiotherapy may reduce local recurrence (32). Combination chemotherapy has traditionally included vincristine, doxorubicin, cyclophosphamide and dactinomycin. The addition of ifosfamide and etoposide to a standard regimen significantly improves the outcome for patients with nonmetastatic Ewing’s sarcoma (33). The prognosis of mesenteric PNET is better compared with that of other sites and is not associated with the size of the tumor. The 5-year disease-free survival rate of patients without metastatic disease is >60% compared with 35% for patients who present with metastatic disease (6). In reviewing the literature, it was observed that two patients succumbed due to recurrence, one succumbed to acute respiratory failure, and two survived with no evidence of disease. The duration of follow-up ranged from 6 to 20 months. The average survival time was 12 months. In the patients of the present study, case 3 was followed up for 34 months and succumbed due to peritoneal recurrence. However, cases 1 and 2 were not followed up.\n\nIn conclusion, the present study reviewed 18 known cases of PNET arising from the intestine and mesentery and reported three additional cases. Immunohistochemical examination and molecular characterization are beneficial for differentiating PNET from other small round-cell tumors.\n\nAcknowledgements\nThis study was supported in part by the National Natural Science Foundation of China (81371611, 81171391, 81372743) and the National Basic Research Priorities Program 973 Project (2014CB744504) from the Ministry of Science and Technology of China.\n\nFigure 1 Case 3. MRI scan of the abdomen and pelvis showing a large, heterogeneous and enhanced right lower quadrant mass. (A) Parietal image. (B) Horizontal image. MRI, magnetic resonance imaging.\n\nFigure 2 Case 3. (A) Tumor infiltrating the bowel wall starting from the deep layer of the mucosa. (B) High power view of the tumor cells showing uniform small round blue cells with scant cytoplasm, uniform nuclei and stippled chromatin, with areas of hemorrhage and necrosis. (C) CD99 was diffusely expressed with strong membranous staining. (D) Strong nuclear immunoreactivity was demonstrated for FLI1. Hematoxylin-eosin; magnification, ×200.\n\nFigure 3 Case 3. Nuclei exhibited positive signals for EWS gene translocations (one integrated, one red and one green signal; fluorescence in situ hybridization method). Magnification, ×1,000).\n\nTable I Clinical features of previously reported cases with PNET arising from the intestine and mesentery.\n\nAuthors (ref.)\tAge (years)/gender\tLocation\tTumor size and/or weight\tPositive immunomarker\tFollow-up\t\n1 Balasubramanian et al (4)\t53/F\tSmall bowel mesentery\t25×26×17.5 cm; 2.6 kg\tMIC-2 and PGP9.5 strongly\tNM\t\n2 Sethi and Smith (5)\t44/M\tSmall bowel\t120 mm diameter\tMIC-2 strongly and NSE weakly\tSuccumbed with recurrence, 13 mo\t\n3 Bala et al (6)\t57/F\tSmall bowel mesentery\t12 cm diameter\tVimentin, NSE, O-13, c-Kit, FLI\tNED, 8 mo\t\n4 Horie and Kato (7)\t40/M\tSmall bowel mesentery\t11×8 cm\tCD99, NSE, syn and vimentin.\tSuccumbed with recurrence, 5 mo\t\n5 Tokudome et al (8)\t24/F\tTransverse colonic mesentery\t12×10×7 cm, 590 g\tNSE and Mic-2\tNED, 20 mo\t\n6 Maisonnette et al (9)\t56/F\tMesocolon\t12×14×12 cm\tCD99 and FLI1\tSuccumbed to acute respiratory failure, 13 mo\t\n7 Adair et al (10)\t21/F\tDuodenum\tNM\tCD99 and CK\t10 mo DFS\t\n8 Rodarte-Shade et al (11)\t32/M\tSmall bowel\t12×8 cm\tCD99 and FLI1\t6 mo DFS\t\n9 Sarangarajan et al (12)\t13/M\tJejunum\tNM\tCD99 and CK\t12 mo DFS\t\n10 Graham et al (13)\t14/M\tSmall bowel and mesentery\t6×3.5×3 cm\tCD99 and CK\t10 mo DFS\t\n11 Vignali et al (14)\t15/F\tIleum\t12×9×8 cm\tNM\tNM\t\n12 Kim et al (15)\t63/M\tSmall bowel\tNM\tCD99 and CD117\tNM\t\n13 Shek et al (16)\t9/F\tSmall bowel and mesentery\tNM\tCD99\t18 mo DFS\t\n14 Boehm et al (17)\t18/M\tIleum\tNM\tNM\tNM\t\n15 Kie et al (18)\t20/F\tDuodenum\tNM\tCD99\t18 mo DFS\t\n16 Prasertvit and Stoikes (19)\t28/F\tSmall intestine\tNM\tNM\tNM\t\n17 Turkyilmaz et al (20)\t15/F\tMesocolon\t10×10×12 cm\tVimentin and CD99\tNM\t\n18 Kim et al (21)\t23/M\tMesentery of jejunum\t12×8×7.5 cm\tCD99, CD57 and NSE\tNM\t\nPNET, primitive neuroectodermal tumor; NM, not mentioned; DFS, disease-free survival; NED, no evidence of disease; Mo, months; ref, reference.\n==== Refs\nReferences\n1 Dehner LP Primitive neuroectodermal tumor and Ewing’s sarcoma Am J Surg Pathol 17 1 13 1993 10.1097/00000478-199301000-00001 8383465 \n2 Folpe AL Goldblum JR Rubin BP Morphologic and immunophenotypic diversity in Ewing family tumors: a study of 66 genetically confirmed cases Am J Surg Pathol 29 1025 1033 2005 16006796 \n3 Burchill SA Ewing’s sarcoma: diagnostic, prognostic, and therapeutic implications of molecular abnormalities J Clin Pathol 56 96 102 2003 10.1136/jcp.56.2.96 12560386 \n4 Balasubramanian B Dinakarababu E Molyneux AJ Primary primitive neuroectodermal tumour of the small bowel mesentery: case report Eur J Surg Oncol 28 197 198 2002 10.1053/ejso.2001.1155 11884059 \n5 Sethi B Smith GT Primary primitive neuroectodermal tumour arising in the small bowel Histopathology 50 665 666 2007 10.1111/j.1365-2559.2007.02631.x 17394505 \n6 Bala M Maly A Remo N Peripheral primitive neuroectodermal tumor of bowel mesentery in adults Isr Med Assoc J 8 515 516 2006 16889176 \n7 Horie Y Kato M Peripheral primitive neuroectodermal tumor of the small bowel mesentery: a case showing perforation at onset Pathol Int 50 398 403 2000 10.1046/j.1440-1827.2000.01045.x 10849329 \n8 Tokudome N Tanaka K Kai MH Primitive neuroectodermal tumor of the transverse colonic mesentery defined by the presence of EWS-FLI1 chimeric mRNA in a Japanese woman J Gastroenterol 37 543 549 2002 10.1007/s005350200084 12162413 \n9 Maisonnette F Roux ET Abita T Ewing sarcoma of the mesocolon Gastroenterol Clin Biol 31 552 554 2007 (In French) 10.1016/S0399-8320(07)89427-9 17541349 \n10 Adair A Harris SA Coppen MJ Hurley PR Extraskeletal Ewings sarcoma of the small bowel: case report and literature review J R Coll Surg Edinb 46 372 374 2001 11768578 \n11 Rodarte-Shade M Palomo-Hoil R Vazquez J Primitive neuroectodermal tumor (PNET) of the small bowel in a young adult with lower gastrointestinal bleeding J Gastrointest Cancer 4 2012 \n12 Sarangarajan R Hill DA Humphrey PA Primitive neuroectodermal tumors of the biliary and gastrointestinal tracts: clinicopathologic and molecular diagnostic study of two cases Pediatr Dev Pathol 4 185 191 2001 10.1007/s100240010141 11178636 \n13 Graham DK Stork LC Wei Q Molecular genetic analysis of a small bowel primitive neuroectodermal tumor Pediatr Dev Pathol 5 86 90 2002 10.1007/s10024-001-0192-1 11815873 \n14 Vignali M Zacchè MM Messori P Ewing’s sarcoma of the small intestine misdiagnosed as a voluminous pedunculated uterine leiomyoma Eur J Obstet Gynecol Reprod Biol 162 234 235 2012 10.1016/j.ejogrb.2012.02.009 22410473 \n15 Kim DW Chang HJ Jeong JY Ewing’s sarcoma/primitive neuroectodermal tumor (ES/PNET) of the small bowel: a rare cause of intestinal obstruction Int J Colorectal Dis 22 1137 1138 2007 10.1007/s00384-006-0142-5 16683104 \n16 Shek TW Chan GC Khong PL Ewing sarcoma of the small intestine J Pediatr Hematol Oncol 23 530 532 2001 10.1097/00043426-200111000-00013 11878783 \n17 Boehm R Till H Landes J Ileoileal intussusception caused by a Ewing sarcoma tumour. An unusual case report Eur J Pediatr Surg 13 272 275 2003 10.1055/s-2003-42234 13680499 \n18 Kie JH Lee MK Kim CJ Primary Ewing’s sarcoma of the duodenum: a case report Int J Surg Pathol 11 331 337 2003 10.1177/106689690301100416 14615834 \n19 Prasertvit S Stoikes N A rare case of ewing’s sarcoma of the small intestine Am Surg 79 E78 E79 2013 23336641 \n20 Turkyilmaz Z Sonmez K Karabulut R Extraskeletal Ewing sarcoma of the mesocolon in a child J Pediatr Surg 47 E1 E3 2012 10.1016/j.jpedsurg.2012.04.009 22974628 \n21 Kim JM Chu YC Choi CH Peripheral primitive neuroectodermal tumor with osseous component of the small bowel mesentery: a case study Korean J Pathol 47 77 81 2013 10.4132/KoreanJPathol.2013.47.1.77 23482293 \n22 Stout AP A tumor of the ulnar nerve Proc NY Pathol Soc 18 2 12 1914 \n23 Risi E Iacovelli R Altavilla A Clinical and pathological features of primary neuroectodermal tumor/ewing sarcoma of the kidney Urology 82 382 386 2013 10.1016/j.urology.2013.04.015 23800653 \n24 Malpica A Moran CA Primitive neuroectodermal tumor of the cervix: a clinicopathologic and immunohistochemical study of two cases Ann Diagn Pathol 6 281 287 2002 10.1053/adpa.2002.35739 12376920 \n25 Shi L Guo Z Wu X Primary pulmonary primitive neuroectodermal tumor metastasis to the pancreas: a rare case with seven-year follow-up Diagn Pathol 8 51 2013 10.1186/1746-1596-8-51 23537038 \n26 Mhawech-Fauceglia P Herrmann F Penetrante R Diagnostic utility of FLI-1 monoclonal antibody and dual-colour, break-apart probe fluorescence in situ (FISH) analysis in Ewing’s sarcoma/primitive neuroectodermal tumour (EWS/PNET). A comparative study with CD99 and FLI-1 polyclonal antibodies Histopathology 49 569 575 2006 10.1111/j.1365-2559.2006.02535.x 17163841 \n27 Yoshida A Sekine S Tsuta K NKX2.2 is a useful immunohistochemical marker for Ewing sarcoma Am J Surg Pathol 36 993 999 2012 10.1097/PAS.0b013e31824ee43c 22446943 \n28 Saxena R Sait S Mhawech-Fauceglia P Ewing sarcoma/primitive neuroectodermal tumor of the kidney: a case report. Diagnosed by immunohistochemistry and molecular analysis Ann Diagn Pathol 10 363 366 2006 10.1016/j.anndiagpath.2005.11.001 17126256 \n29 Lindholm DP Oberg K Biomarkers and molecular imaging in gastroenteropancreatic neuroendocrine tumors Horm Metab Res 43 832 837 2011 10.1055/s-0031-1287794 22009449 \n30 Chan JK Chan AC Cheuk W Type II enteropathy-associated T-cell lymphoma: a distinct aggressive lymphoma with frequent γδ T-cell receptor expression Am J Surg Pathol 35 1557 1569 2011 10.1097/PAS.0b013e318222dfcd 21921780 \n31 McCluggage WG Ovarian neoplasms composed of small round cells: a review Adv Anat Pathol 11 288 296 2004 10.1097/01.pap.0000138146.357376.1e 15505529 \n32 Marec-Bérard P Chotel F Claude L PNET/Ewing tumours: current treatments and future perspectives Bull Cancer 97 707 713 2010 (In French) 20497910 \n33 Grier HE Krailo MD Tarbell NJ Addition of ifosfamide and etoposide to standard chemotherapy for Ewing’s sarcoma and primitive neuroectodermal tumor of bone N Engl J Med 348 694 701 2003 10.1056/NEJMoa020890 12594313\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1792-0981",
"issue": "9(4)",
"journal": "Experimental and therapeutic medicine",
"keywords": "ileocecal; mesentery; primitive neuroectodermal tumor",
"medline_ta": "Exp Ther Med",
"mesh_terms": null,
"nlm_unique_id": "101531947",
"other_id": null,
"pages": "1299-1303",
"pmc": null,
"pmid": "25780425",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article",
"references": "23482293;23537038;16006796;13680499;17163841;23336641;23800653;22974628;12376920;22760712;22446943;16889176;12594313;8383465;10849329;11768578;22410473;11878783;17394505;12560386;17541349;16683104;21921780;14615834;11178636;15505529;22009449;20497910;12162413;17126256;11815873;11884059",
"title": "Primary primitive neuroectodermal tumor arising in the mesentery and ileocecum: A report of three cases and review of the literature.",
"title_normalized": "primary primitive neuroectodermal tumor arising in the mesentery and ileocecum a report of three cases and review of the literature"
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"abstract": "OBJECTIVE\nInterferon-alfa (IFN)-related cytopenias are common and may be dose-limiting. We performed a genome wide association study on a well-characterized genotype 1 HCV cohort to identify genetic determinants of peginterferon-α (pegIFN)-related thrombocytopenia, neutropenia, and leukopenia.\n\n\nMETHODS\n1604/3070 patients in the IDEAL study consented to genetic testing. Trial inclusion criteria included a platelet (Pl) count ≥80×10(9)/L and an absolute neutrophil count (ANC) ≥1500/mm(3). Samples were genotyped using the Illumina Human610-quad BeadChip. The primary analyses focused on the genetic determinants of quantitative change in cell counts (Pl, ANC, lymphocytes, monocytes, eosinophils, and basophils) at week 4 in patients >80% adherent to therapy (n=1294).\n\n\nRESULTS\n6 SNPs on chromosome 20 were positively associated with Pl reduction (top SNP rs965469, p=10(-10)). These tag SNPs are in high linkage disequilibrium with 2 functional variants in the ITPA gene, rs1127354 and rs7270101, that cause ITPase deficiency and protect against ribavirin (RBV)-induced hemolytic anemia (HA). rs1127354 and rs7270101 showed strong independent associations with Pl reduction (p=10(-12), p=10(-7)) and entirely explained the genome-wide significant associations. We believe this is an example of an indirect genetic association due to a reactive thrombocytosis to RBV-induced anemia: Hb decline was inversely correlated with Pl reduction (r=-0.28, p=10(-17)) and Hb change largely attenuated the association between the ITPA variants and Pl reduction in regression models. No common genetic variants were associated with pegIFN-induced neutropenia or leucopenia.\n\n\nCONCLUSIONS\nTwo ITPA variants were associated with thrombocytopenia; this was largely explained by a thrombocytotic response to RBV-induced HA attenuating IFN-related thrombocytopenia. No genetic determinants of pegIFN-induced neutropenia were identified.",
"affiliations": "Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701, USA.",
"authors": "Thompson|Alexander J|AJ|;Clark|Paul J|PJ|;Singh|Abanish|A|;Ge|Dongliang|D|;Fellay|Jacques|J|;Zhu|Mingfu|M|;Zhu|Qianqian|Q|;Urban|Thomas J|TJ|;Patel|Keyur|K|;Tillmann|Hans L|HL|;Naggie|Susanna|S|;Afdhal|Nezam H|NH|;Jacobson|Ira M|IM|;Esteban|Rafael|R|;Poordad|Fred|F|;Lawitz|Eric J|EJ|;McCone|Jonathan|J|;Shiffman|Mitchell L|ML|;Galler|Greg W|GW|;King|John W|JW|;Kwo|Paul Y|PY|;Shianna|Kevin V|KV|;Noviello|Stephanie|S|;Pedicone|Lisa D|LD|;Brass|Clifford A|CA|;Albrecht|Janice K|JK|;Sulkowski|Mark S|MS|;Goldstein|David B|DB|;McHutchison|John G|JG|;Muir|Andrew J|AJ|",
"chemical_list": "D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; D012254:Ribavirin; D011755:Pyrophosphatases; C511829:ITPA protein, human; C417083:peginterferon alfa-2b; C100416:peginterferon alfa-2a",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jhep.2011.04.021",
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"issn_linking": "0168-8278",
"issue": "56(2)",
"journal": "Journal of hepatology",
"keywords": null,
"medline_ta": "J Hepatol",
"mesh_terms": "D000328:Adult; D000998:Antiviral Agents; D005260:Female; D055106:Genome-Wide Association Study; D019698:Hepatitis C, Chronic; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D007970:Leukopenia; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009503:Neutropenia; D011092:Polyethylene Glycols; D020641:Polymorphism, Single Nucleotide; D011755:Pyrophosphatases; D011994:Recombinant Proteins; D012254:Ribavirin; D013921:Thrombocytopenia",
"nlm_unique_id": "8503886",
"other_id": null,
"pages": "313-9",
"pmc": null,
"pmid": "21703177",
"pubdate": "2012-02",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "9819447;20434452;19684573;15946879;15028825;20547162;9253112;9807989;12324553;12360468;19749757;17006906;21199653;19749758;20173735;12384777;15163776;19180233;11583749;20564352;19625712;7535585;16384889;19759533;18369468;19166653;17304144;10385477;19207969;17701901;20399780;16135132;20931559;16862161",
"title": "Genome-wide association study of interferon-related cytopenia in chronic hepatitis C patients.",
"title_normalized": "genome wide association study of interferon related cytopenia in chronic hepatitis c patients"
} | [
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"companynumb": "US-ROCHE-650763",
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"activesubstancename": "PEGINTERFERON ALFA-2B"
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"abstract": "A young patient had unexpected and prolonged postoperative delirium apparently associated with morphine-induced biliary colic. Naloxone had no therapeutic effect, but a small dose of pethidine produced a dramatic return to lucidity. Unrecognized biliary spasm should be considered as a cause of agitation in the recovery room in postoperative patients who have received morphine.",
"affiliations": "Department of Anaesthesia, Royal Perth Hospital, Western Australia.",
"authors": "McLoughlin|P D|PD|",
"chemical_list": "D000701:Analgesics, Opioid; D009292:Narcotic Antagonists; D009270:Naloxone; D009020:Morphine; D008614:Meperidine",
"country": "United States",
"delete": false,
"doi": "10.1177/0310057X0002800311",
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"mesh_terms": "D000293:Adolescent; D017109:Akathisia, Drug-Induced; D000701:Analgesics, Opioid; D000762:Anesthesia Recovery Period; D001660:Biliary Tract Diseases; D003085:Colic; D003693:Delirium; D006801:Humans; D008297:Male; D008614:Meperidine; D009020:Morphine; D009270:Naloxone; D009292:Narcotic Antagonists; D011997:Recovery Room",
"nlm_unique_id": "0342017",
"other_id": null,
"pages": "311-2",
"pmc": null,
"pmid": "10853216",
"pubdate": "2000-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pethidine reverses morphine-induced delirium.",
"title_normalized": "pethidine reverses morphine induced delirium"
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"companynumb": "AU-PFIZER INC-2020491120",
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"activesubstancename": "MORPHINE SULFATE"
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"abstract": "This case report describes the successful use of granulocyte and macrophage colony-stimulating factor as salvage therapy and an alternative to hematopoietic stem cell transplantation in a 14-year-old adolescent with metamizole (dipyrone)-induced agranulocytosis and severe septic shock.",
"affiliations": "Division of Neonatology and Pediatric Intensive Care Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.;Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.;Division of Neonatology and Pediatric Intensive Care Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.;Division of Pediatric Surgery Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.;Division of Pediatric Hematology and Oncology Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.;Division of Neonatology and Pediatric Intensive Care Department of Pediatrics and Adolescent Medicine Medical University of Greifswald Greifswald Germany.",
"authors": "Winkler|Annegret|A|;Kietz|Silke|S|;Bahlmann|Hagen|H|;Jafarzade|Gunel|G|;Lode|Holger N|HN|;Heckmann|Matthias|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.616",
"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.616CCR3616Case ReportCase Reports\nGM‐CSF as successful salvage therapy of metamizole (dipyrone)‐induced agranulocytosis with Fournier's gangrene and severe septic shock in an adolescent A. Winkler et al.Winkler Annegret \n1\nKietz Silke \n2\nBahlmann Hagen \n1\nJafarzade Gunel \n3\nLode Holger N. \n2\nHeckmann Matthias \n1\n1 Division of Neonatology and Pediatric Intensive CareDepartment of Pediatrics and Adolescent MedicineMedical University of GreifswaldGreifswaldGermany2 Division of Pediatric Hematology and OncologyDepartment of Pediatrics and Adolescent MedicineMedical University of GreifswaldGreifswaldGermany3 Division of Pediatric SurgeryDepartment of Pediatrics and Adolescent MedicineMedical University of GreifswaldGreifswaldGermany* Correspondence\n\nAnnegret Winkler, Division of Neonatology and Pediatric Intensive Care, Department of Pediatrics and Adolescent Medicine, Medical University of Greifswald, Ferdinand‐Sauerbruch‐Straße, 17475 Greifswald, Germany. Tel: +49‐3834‐866421; Fax: +49‐3834‐866422; E‐mail: annegret.winkler@uni-greifswald.de\n20 7 2016 8 2016 4 8 10.1111/ccr3.2016.4.issue-8816 819 21 7 2015 13 4 2016 17 5 2016 © 2016 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Key Clinical Message\nThis case report describes the successful use of granulocyte and macrophage colony‐stimulating factor as salvage therapy and an alternative to hematopoietic stem cell transplantation in a 14‐year‐old adolescent with metamizole (dipyrone)‐induced agranulocytosis and severe septic shock.\n\nAgranulocytosisfilgrastimmetamizole (dipyrone)sargramostimseptic shock source-schema-version-number2.0component-idccr3616cover-dateAugust 2016details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:4.9.4 mode:remove_FC converted:05.08.2016\n==== Body\nIntroduction\nMetamizole (dipyrone)‐induced agranulocytosis (neutrophil granulocytes <0.5 × 109/L) is a rare severe adverse reaction (<1/10,000) 1, 2. In Europe, 10 per 1 million inhabitants per year are affected by drug‐induced agranulocytosis, and metamizole‐induced agranulocytosis represents only part of this incidence 1. However, if agranulocytosis is associated with severe sepsis and necrotic wounds, an adequate level of neutrophil granulocytes is crucial. Due to the rare occurrence, there are no common treatment guidelines regarding how to best re‐establish granulopoiesis. Available treatment interventions include recombinant human growth factors and blood stem cell transplantation as a last resort 3. Here, we report a case where granulocyte and macrophage colony‐stimulating factor (GM‐CSF) was successfully used as a second‐line treatment to re‐establish bone marrow function.\n\nCase Report\nA 14‐year‐old adolescent in severe septic shock was admitted to the hospital by ambulance. She had undergone an elective resection of a pilonidal fistula 4 weeks previously and was then treated with analgesic metamizole (dipyrone) frequently with 3 g/day (40 mg/kg body weight in three single doses, maximum 5 g/day) for pain due to progressive wound healing failure.\n\nUpon arrival, the adolescent presented with hypotension (60/30 mmHg), tachycardia, acute renal failure (serum creatinine 238 μmol/L), liver failure with cholestasis and dysfunctional plasma coagulation (Quick 29%, INR 2.4), and signs of systemic inflammation (CRP max. 155 mg/L). She was drowsy, but fully oriented. Although fluid was administered (40 mL/kg in 1 h), dopamine (up to 17.5 μg/kg/min) was required to maintain blood pressure. There were extensive necrotic areas and purulent lesions in the sacral and genital areas (Fig. 1). The wound swab and blood culture identified a mixture of aerobes and anaerobes, including Pseudomonas aeruginosa.\n\nFigure 1 Intraoperative findings on day 1. Left – the vulva and inguinal region after first debridement, right – sacral area with a lesion (10 cm × 5 cm × 5 cm) that extends down to the sacrum.\n\nWe initiated broad‐spectrum antibiotic therapy with meropenem (3 g/day), clindamycin (20 mg/kg/day), and metronidazole (30 mg/kg/day), and surgical infectious source control. The adolescent was intubated straightly before the first surgery, ventilator settings were PIP 26 cmH2O, Peep 12 cmH2O, maximum FiO2 0.45 after surgery.\n\nThe initial blood counts were leukocytes 0.6 × 109/L with absolute neutropenia (0.01 × 109/L) and moderate lymphopenia (0.56 × 109/L), normal platelets (150 × 109/L), decreased erythrocytes (2.5 × 1012/L), and anemia with a hemoglobin level of 4.2 mmol/L. The bone marrow was characterized by a complete absence of granulopoiesis with no myeloid progenitor cells, consistent with the diagnosis of a metamizole‐induced agranulocytosis. Due to the severe sepsis and extensive necrotic areas, we started therapy with granulocyte colony‐stimulating factor (G‐CSF, filgrastim, Neupogen®: Hexal AG, Holzkirchen, Germany) at a dose up to 18 μg/kg/day for 8 days. Neutrophil granulocytes did not increase with G‐CSF treatment. Between days 10 and 17, the patient received four granulocyte concentrates, which provided the bridging during the switch from G‐CSF to GM‐CSF. Granulocyte concentrates (containing a total of >1 × 1010) were collected from two different ABO blood donors after stimulation with G‐CSF at a dose of 5 μg/kg body weight 4. Tissue typing was performed to initiate the search for a matched, unrelated blood stem cell donor. The patient's treatment was changed to GM‐CSF (sargramostim, Leukine®: Sanofi Aventis, Bridgewater, New Jersey, USA), 250 μg/day for 7 days. Neutrophil granulocytes increased (after 6 days: 0.11 × 109/L, after 7 days: 1.19 × 109/L), as well as the monocyte count (Fig. 2).\n\nFigure 2 The counts of neutrophil granulocytes and monocytes over time in a 14‐year‐old adolescent with metamizole‐induced agranulocytosis and severe septic shock, treated with granulopoiesis‐stimulating factors.\n\nOnce granulopoiesis was restored, the patient's overall condition improved over time. Inotropic support was stopped on day 14. The patient was weaned from mechanical ventilation on day 17 and then received respiratory support with a high‐flow nasal cannula, which was applied for 3 weeks (flow 25 L/min, FiO2 around 0.30). The wound healing improved slowly with repetitive surgeries which include debridements and vacuum‐assisted closure therapy (a total of 41 surgeries). Clearly visible granulation tissue was reported by the surgeon 11 days after starting GM‐CSF. Discharge from the hospital was possible after 5 months.\n\nWhile in the hospital, a second episode of agranulocytosis occurred due to an accidental application of metamizole during surgery. Administration of GM‐CSF was able to restore neutrophil granulocytes again (Fig. 2).\n\nDiscussion\nOur patient presented with life‐threatening, severe septic shock, induced by Pseudomonas spp., as a result of isolated agranulocytosis in the blood and bone marrow following a 4‐week exposure to a high dose of metamizole (dipyrone). The options to treat the underlying problem are limited and include the use of growth factors and blood stem cell transplantation. Given the septic condition of this patient, blood stem cell transplantation would have been associated with extremely high treatment‐related mortality. Even if a genoidentical sibling donor is available, the aplasia during pre‐ and posttransplantation period would make the survival highly unlikely. Therefore, the first choice treatment was to use granulopoiesis stimulating factors. Both G‐CSF and GM‐CSF are known to stimulate granulopoiesis to approximately the same extent, and are equally used for this purpose 1, 5. One prospective study showed neutrophils recovered 1 day faster with G‐CSF compared with GM‐CSF after chemotherapy‐induced neutropenia 6. However, in acute leukemia for example there are no real benefits reported regarding the reduction in incidence and severity of infections and overall survival with less time in neutropenia. 7. Both agents have been used for the same indications in different countries, based on country‐specific drug approval conditions. Both agents were also reported to successfully treat agranulocytosis induced by drugs others than chemotherapy 8. For this indication too, a reduction in the duration of agranulocytosis, antibiotic therapy, and length of hospital stay is reported, whereas clear data on the reduction of mortality is lacking 1. Reports comparing both agents in metamizole‐induced agranulocytosis are not available. Furthermore, dose‐dependent side effects of GM‐CSF like hypoxia and hypotension as a first‐dose reaction following doses above 10 μg/kg should be taken into account particularly in the critical care setting 9. In our patient, a dose of 5 μg/kg (250 μg/day) was effective and well tolerated.\n\nIn Germany, G‐CSF is approved for chemotherapy‐induced neutropenia; therefore, we first selected G‐CSF. After 5 days without a response, granulocytes were transfused to rescue the critical situation. Three days later, the G‐CSF was switched to GM‐CSF. The monocytes increased after 3 days followed by neutrophils after two more days (Fig. 2). The GM‐CSF was well tolerated and no acute side effects were noted 10. However, both the neuroprotective and neurotoxic properties of GM‐CSF were reported in animal experiments 11, 12. The selection of GM‐CSF was also based on its broader effect, compared with G‐CSF, on the stimulation of myelopoiesis. GM‐CSF acts on more immature myeloid progenitor cells and it stimulates the monocyte/macrophage compartment; in contrast, G‐CSF stimulates the proliferation and differentiation of neutrophils 13. We cannot prove that the failure of G‐CSF in our patient was overcome by using GM‐CSF. However, G‐CSF did not restore granulopoiesis within the expected response time. In contrast, administration of GM‐CSF, with its broader spectrum of activity and recruitment of primitive hematopoietic progenitors, resulted in an immediate response. Therefore, GM‐CSF should be started directly in such a patient in whom a delay of 8 days of ineffective therapy might be life threatening. Furthermore, as outlined before, stem cell transplantation in such a critical patient is highly questionable.\n\nThe fact that the patient is an adolescent is probably one of the main reasons for the favorable outcome. The young, 14 years old patient was healthy without any pre‐existing conditions, before she became septic. Fournier's gangrene is rare in adolescents. Epidemiologic data and scoring systems are only available for adults, especially older male patients with pre‐existing diseases. However, age seemed to be an important factor as shown in the population‐based study by Sorensen et al. 14. They found an increasing mortality with higher age of the patient (odds ratio 4.0 until 15.0) compared to patients <40 years. Furthermore, young patients are probably better responders to growth factors compared to elderly patients 15.\n\nConclusion\nWe report successful rescue of myelopoiesis with second‐line GM‐CSF therapy in an adolescent with metamizole (dipyrone)‐induced agranulocytosis. This provides a new treatment option for patients who fail to respond to G‐CSF to avoid hematopoietic stem cell transplantation.\n\nEthics Statement\nInformed consent has been documented.\n\nConflict of Interest\nNone declared.\n\nAcknowledgment\nWe especially thank Prof. Tamam Bakchoul for the information about preparation of granulocyte concentrates.\n==== Refs\nReferences\n1 \n\nAndrès , E. \n, \nF. \nMaloisel \n, and \nJ. \nZimmer \n. 2010 \nThe role of haematopoietic growth factors granulocyte colony‐stimulating factor and granulocyte‐macrophage colony‐stimulating factor in the management of drug‐induced agranulocytosis . Br. J. Haematol. \n150 :3 –8 .20151980 \n2 \nProduct instruction Novalgin® (metamizole), product instruction service Germany Available at http://www.fachinfo.de/suche/fi/014708. Published May 2014, (accessed April 17, 2015).\n3 \n\nBeauchesne , M.‐F. \n, and \nS. J. \nShalansky \n. 1999 \nNonchemotherapy drug‐induced agranulocytosis: a review of 118 patients treated with colony‐stimulating factors . Pharmacotherapy \n19 :299 –305 .10221368 \n4 \n\nPrice , T. H. \n, \nM. \nBoeckh \n, \nR. W. \nHarrison \n, \nJ. \nMcCullough \n, \nP. M. \nNess \n, \nR. G. \nStrauss \n, et al. 2015 \nEfficacy of transfusions with granulocytes from GCSF/dexamethasone treated donors in neutropenic patients with infection . Blood \n126 :2153 –2161 .26333778 \n5 \n\nGarbe , E. \n\n2007 \nNon‐chemotherapy drug‐induced agranulocytosis . Expert. Opin. Drug Saf. \n6 :323 –335 .17480181 \n6 \n\nBeveridge , R. A. \n, \nJ. A. \nMiller \n, \nA. N. \nKales \n, \nR. A. \nBinder \n, \nN. J. \nRobert \n, \nJ. H. \nHarvey \n, et al. 1998 \nA comparison of sargramostim (yeast‐derived RhuGM‐CSF) and filgrastim (bacteria‐derived RhuG‐CSF) in the therapeutic setting of chemotherapy‐induced myelosuppression . Cancer Invest. \n16 :366 –373 .9679526 \n7 \n\nWadleigh , M. \n, and \nR. M. \nStone \n. 2009 \nThe role of myeloid growth factors in acute leukemia . J. Natl. Compr. Canc. Netw. \n7 :84 –91 .19176208 \n8 \n\nAndersohn , F. \n, \nC. \nKonzen \n, and \nE. \nGarbe \n. 2007 \nSystematic review: agranulocytosis induced by nonchemotherapy drugs . Ann. Intern. Med. \n146 :657 –665 .17470834 \n9 \n\nStern , A. C. \n, and \nT. C. \nJones \n. 1992 \nThe side‐effect profile of GM‐CSF . Infection \n20 (Suppl. 2 ):S124 –S127 .1493936 \n10 \n\nVial , T. \n, and \nJ. \nDescotes \n. 1995 \nClinical toxicity of cytokines used as haemopoietic growth factors . Drug Saf. \n13 :371 –406 .8652081 \n11 \n\nFranzen , R. \n, \nD. \nBouhy \n, and \nJ. \nSchoenen \n. 2004 \nNervous system injury: focus on the inflammatory cytokine ‘granulocyte‐macrophage colony stimulating factor’ . Neurosci. Lett. \n361 :76 –78 .15135897 \n12 \n\nZhu , F. \n, \nY. \nLiu \n, \nJ. \nZhao \n, and \nY. \nZheng \n. 2014 \nMinocycline alleviates behavioral deficits and inhibits microglial activation induced by intrahippocampal administration of granulocyte‐macrophage colony stimulating factor in adult rats . Neuroscience \n266 :275 –281 .24486961 \n13 \n\nBarreda , D. R. \n, \nP. C. \nHanington \n, and \nM. \nBelosevic \n. 2004 \nRegulation of myeloid development and function by colony stimulating factors . Dev. Comp. Immunol. \n28 :509 –554 .15062647 \n14 \n\nSorensen , M. D. \n, \nJ. N. \nKrieger \n, \nF. P. \nRivara \n, \nM. B. \nKlein \n, and \nH. \nWessells \n. 2009 \nFournier′s gangrene: management and mortality predictors in a population based study . J. Urol. \n182 :2742 –2747 .19837424 \n15 \n\nTortorella , C. \n, \nO. \nSimone \n, \nG. \nPiazzolla \n, \nI. \nStella \n, and \nS. \nAntonaci \n. 2007 \nAge‐related impairment of GM‐CSF‐induced signaling in neutrophils: role of SHP‐1 and SOCS proteins . Ageing Res. Rev. \n6 :81 –93 .17142110\n\n",
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"keywords": "Agranulocytosis; filgrastim; metamizole (dipyrone); sargramostim; septic shock",
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"title": "GM-CSF as successful salvage therapy of metamizole (dipyrone)-induced agranulocytosis with Fournier's gangrene and severe septic shock in an adolescent.",
"title_normalized": "gm csf as successful salvage therapy of metamizole dipyrone induced agranulocytosis with fournier s gangrene and severe septic shock in an adolescent"
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"abstract": "We present a case of recurrent, platinum-refractory undifferentiated carcinoma of the parotid which was treated with checkpoint inhibitor, Pembrolizumab, and achieved a complete response to therapy. We review the literature of checkpoint inhibitor use in undifferentiated carcinoma of the parotid.",
"affiliations": "Tripler Army Medical Center, 1 Jarrett White Road, DHCK-DM, Honolulu, HI 96859, USA.;Tripler Army Medical Center, 1 Jarrett White Road, DHCK-DM, Honolulu, HI 96859, USA.;Tripler Army Medical Center, 1 Jarrett White Road, DHCK-DM, Honolulu, HI 96859, USA.",
"authors": "Wiggins|Amanda|A|0000-0001-5561-9546;Arter|Zhaohui|Z|;Kerns|Tamie|T|0000-0001-7669-6428",
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"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2019/2305315Case ReportThe Three P's: Parotid, PD-L1, and Pembrolizumab http://orcid.org/0000-0001-5561-9546Wiggins Amanda amanda.keith8@gmail.comArter Zhaohui http://orcid.org/0000-0001-7669-6428Kerns Tamie Tripler Army Medical Center, 1 Jarrett White Road, DHCK-DM, Honolulu, HI 96859, USAAcademic Editor: Francesco A. Mauri\n\n2019 11 6 2019 2019 230531531 12 2018 28 5 2019 Copyright © 2019 Amanda Wiggins et al.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We present a case of recurrent, platinum-refractory undifferentiated carcinoma of the parotid which was treated with checkpoint inhibitor, Pembrolizumab, and achieved a complete response to therapy. We review the literature of checkpoint inhibitor use in undifferentiated carcinoma of the parotid.\n==== Body\n1. Introduction\nImmunologic therapy is an emerging treatment modality in oncology, which may provide prolonged survival in numerous malignancies [1]. PD-L1 expression has been found to have both prognostic and treatment utility in the management of metastatic malignancies [2]. We present a patient with one hundred percent PD-L1 expression in an undifferentiated, EBV positive, metastatic carcinoma of parotid origin with near complete remission after treatment with Pembrolizumab.\n\n2. Case Presentation\nA previously healthy 52-year-old Samoan woman initially presented to her primary care provider with complaints of otalgia and swelling in the left side of her face for three weeks. She reported no facial weakness, trismus, dysphagia, odynophagia, dental pain, fevers, chills, weight loss, and fatigue. On initial physical exam, a 6 cm nontender, subcutaneous, cystic mass was palpated in the left parotid. The oral cavity showed no deformities or evidence of abnormalities. There was no lymphadenopathy of the anterior or posterior cervical chain, supraclavicular, or axillary lymph nodes. At that time, she was prescribed with antibiotics for presumed sialadenitis with no effect on her symptoms. On the next follow-up visit, she was referred to otolaryngology for further evaluation.\n\nA neck and chest computer topography (CT) scan demonstrated two necrotic left parotid masses measuring 2.5 × 2.8 cm and 2.7 × 2.8 cm, respectively, multiple ipsilateral lymph nodes measuring up to 1.9 cm in diameter, and an asymmetrically enhancing left nasopharynx. A fine needle aspiration (FNA) of an involved local lymph node revealed a nonkeratinizing, undifferentiated carcinoma composed of pleomorphic cells positive for Epstein-Barr virus (EBV). The differential diagnosis based on FNA findings includes primary parotid carcinoma, lymphoepithelial carcinoma, or metastatic nasopharyngeal carcinoma. Blind biopsies of the nasopharynx were negative. PET/CT revealed hypermetabolic activity in the left parotid gland and several local nodes, highly suggestive of a primary parotid neoplasm. Excisional biopsy revealed a nonkeratinizing, undifferentiated carcinoma composed of pleomorphic cells, positive for Epstein-Barr virus (EBV). The results of subsequent excisional biopsy of the parotid gland masses were consistent with previous FNA findings.\n\nThe patient was staged as Stage IVa (cT3N2bM0) per AJCC 7th ed. Due to the extension of the parotid disease toward the main trunk of cranial nerve (CN) VII, there was a concern for postoperative CN VII palsy with surgical management. Surgery was therefore deferred, and definitive cisplatin-based concurrent/chemoradiation treatment was initiated. On first surveillance PET/CT, at 12 weeks postconcurrent chemoradiation treatment, she was found to have PET-avid hepatic and bone lesions (Figure 1). A CT-guided portacaval lymph node biopsy confirmed a metastatic disease (Figure 2). IHC staining of the portal cava lymph node demonstrated 100% PD-L1 expression. Next Generation Sequencing was negative for additional mutations. Pembrolizumab monotherapy resulted in a near complete resolution of her hepatic metastasis and complete metabolic resolution of the left parotid mass, cervical adenopathy, and skeletal lesions on PET/CT following four cycles (Figure 3). Follow-up PET/CT scan found a progression of disease per RECIST v1.1 criteria after seven months of treatment.\n\n3. Discussion\nSalivary gland malignancies are uncommon, accounting for 3-6.5% of all head and neck cancers [3]. Undifferentiated salivary gland malignancies, however, are exceedingly rare. Less than 1% of all salivary gland tumors are lymphoepithelial or undifferentiated carcinoma, carrying a poor prognosis [4]. The reported incidence of undifferentiated carcinoma ranged from 1 to 5.5% in all parotid gland malignancies [5]. A literature search for undifferentiated parotid carcinoma returned seldom results; most of these reports were small case series [6–8]. Furthermore, this patient with poorly differentiated parotid carcinoma behaved more like a nasopharyngeal carcinoma (NPC). Traditionally, salivary gland malignancies are slow growing and become metastatic late in the disease process [1]. Conversely, our patient developed metastatic disease early in her course following cytotoxic chemotherapy and local radiation.\n\nMany features of our patient's case mirror previously reported characteristics of NPC, which may suggest a relationship between NPC, salivary carcinomas, and other EBV-associated malignancies. First, ninety-five percent of primary nasopharyngeal carcinomas are poorly differentiated or undifferentiated, nonkeratinizing carcinomas, with the highest incidence in the Asian and Pacific islands [9]. NPC is also well known to be an EBV-associated malignancy and characteristically causes lymphocytic infiltrates surrounding tumors [9]. Finally, the upregulation of PD-L1 expression has been documented in multiple EBV-associated malignancies. While the exact mechanism of PD-L1 upregulation is not well understood, it is suspected to be due to constitutively activated oncogenic pathways [9–11]. In one study, all patients with high tumor PD-L1 expression (PD-L1 expressed in 90-100% of malignant cells) were positive for EBV, similar to our patient [11]. There is conflicting data on the prognostic value of PD-L1 expression in NPC; however, recent studies seem to suggest that a high percentage of PD-L1 expression may be associated with a poor prognosis [12]. Likewise, in other salivary gland malignancies, higher PD-L1 expression has been associated with a more aggressive cancer [13]. In this patient, the similarities between her histology and disease progression bears a striking resemblance to that seen in NPC, suggesting a similar pathophysiology of malignant transformation in undifferentiated primary parotid carcinoma and aggressive behavior.\n\nTargeted immunologic chemotherapy is emerging as a treatment for metastatic malignancies. Research regarding the use of PD-L1 inhibitors in multiple malignancies such as metastatic renal cell carcinoma, lymphoma, breast, colorectal cancer, nonsmall cell lung cancer (NSCLC), urothelial carcinoma, head and neck squamous cell, and melanoma is currently ongoing [10, 14–17]. These studies continue to elucidate the place of Pembrolizumab in various malignancies. For the treatment of recurrent or metastatic head and neck squamous cell cancers, Pembrolizumab was only recently approved in 2016 by the Food and Drug Administration [2]. Published last year, the KEYNOTE-028 was a multicohort, nonrandomized, phase Ib study of advanced salivary gland tumors with PD-L1 expression undergoing treatment with Pembrolizumab [1]. In this study, 46% of patients experienced stable disease with similar adverse events as reported in prior studies.\n\nAdditional trials investigating immunotherapy in recurrent and refractory head and neck cancer are now recruiting, for example, a phase-IIb study by Hsu et al. assessing benefit of using PD-L1 inhibitors for treatment of recurrent or metastatic NPC, which was published after the initiation of this patient's treatment [18]. In the 27 patients treated with Pembrolizumab, there was a promising outcome with an objective response rate of 25% per the RESIST v1.1 [18]; however, they could only confidently say that Pembrolizumab would be safe in this population given low power. It is important to note the growing use of targeted therapy has largely been oncologist driven with patients who have poor prognosis and limited therapeutic options, as seen in this case.\n\nAs immunotherapies continue to improve and provide significantly longer progression free and overall survival benefit, genetic sequencing and IHC staining should be incorporated into the work-up of a recurrent or metastatic head and neck malignancies.\n\nStill, additional research is needed to fully understand the role of immunotherapies in rare disease types.\n\nAcknowledgments\nPeer reviewed internally by Dr. Berenberg, Dr. Murphy, and Dr. Guess. Images were provided by Dr. Kao, MD Tripler radiology.\n\nConsent\nConsent was verbally obtained from the next of kin.\n\nDisclosure\nThe views expressed in this abstract/manuscript are those of the authors and do not reflect the official policy or position of the Department of the Army, Department of Defense, or the US Government.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interests.\n\nFigure 1 PET/CT image prior to immunotherapy.\n\nFigure 2 Biopsy of metastatic lesion involving the portacaval lymph node.\n\nFigure 3 PET/CT after 4 cycles of Pembrolizumab.\n==== Refs\n1 Cohen R. B. Delord J. P. Doi T. Pembrolizumab for the treatment of advanced salivary gland carcinoma: findings of the phase 1b KEYNOTE-028 study American Journal of Clinical Oncology 2018 41 11 1083 1088 10.1097/coc.0000000000000429 2-s2.0-85051226841 \n2 Larkins E. Blumenthal G. M. Yuan W. FDA approval summary: pembrolizumab for the treatment of recurrent or metastatic head and neck squamous cell carcinoma with disease progression on or after platinum-containing chemotherapy Oncologist 2017 22 7 873 878 10.1634/theoncologist.2016-0496 2-s2.0-85024126015 28533473 \n3 Harada K. Ferdous T. Ueyama Y. PD-L1 expression in malignant salivary gland tumors BMC Cancer 2018 18 1 p. 156 10.1186/s12885-018-4069-3 2-s2.0-85041409952 29409471 \n4 Kumar V. Abbas A. K. Aster J. C. Robbins and Cotran Pathologic Basis of Disease 2015 9th Philadelphia, PA, USA Elsevier/Saunders \n5 Hatta C. Terada T. Okita J. Kakibuchi M. Kubota A. Sakagami M. Clinicopathological study of undifferentiated carcinoma of the parotid gland Auris Nasus Larynx 2003 30 3 273 277 10.1016/S0385-8146(03)00096-8 2-s2.0-0043032824 12927291 \n6 Hui K. K. Luna M. A. Batsakis J. G. Ordóñez N. G. Weber R. Undifferentiated carcinomas of the major salivary glands Oral Surgery, Oral Medicine, Oral Pathology 1990 69 1 76 83 10.1016/0030-4220(90)90271-S 2-s2.0-0025138664 \n7 Stewart C. J. R. MacKenzie K. McGarry G. W. Mowat A. Fine-needle aspiration cytology of salivary gland: a review of 341 cases Diagnostic Cytopathology 2000 22 3 139 146 10.1002/(sici)1097-0339(20000301)22:3<139::aid-dc2>3.0.co;2-a 10679992 \n8 Moore J. G. Bocklage T. Fine-needle aspiration biopsy of large-cell undifferentiated carcinoma of the salivary glands: presentation of two cases, literature review, and differential cytodiagnosis of high-grade salivary gland malignancies Diagnostic Cytopathology 1998 19 1 44 50 10.1002/(SICI)1097-0339(199807)19:1<44::AID-DC9>3.0.CO;2-O 9664183 \n9 Fang W. Zhang J. Hong S. EBV-driven LMP1 and IFN-γ up-regulate PD-L1 in nasopharyngeal carcinoma: implications for oncotargeted therapy Oncotarget 2014 5 23 12189 12202 10.18632/oncotarget.2608 2-s2.0-84920031403 25361008 \n10 Chen B. J. Chapuy B. Ouyang J. PD-L1 expression is characteristic of a subset of aggressive B- cell lymphomas and virus-associated malignancies Clinical Cancer Research 2013 19 13 3462 3473 10.1158/1078-0432.CCR-13-0855 2-s2.0-84879866976 23674495 \n11 Chang A. M. V. Chiosea S. I. Altman A. Pagdanganan H. A. Ma C. Programmed death-ligand 1 expression, microsatellite instability, Epstein-Barr virus, and human papillomavirus in nasopharyngeal carcinomas of patients from the Philippines Head and Neck Pathology 2017 11 2 203 211 10.1007/s12105-016-0765-y 2-s2.0-84994223613 27807760 \n12 Li Y. F. Ding J. W. Liao L. M. Expression of programmed death ligand-1 predicts poor outcome in nasopharyngeal carcinoma Molecular and Clinical Oncology 2017 7 3 378 382 10.3892/mco.2017.1318 28781814 \n13 Mukaigawa T. Hayashi R. Hashimoto K. Ugumori T. Hato N. Fujii S. Programmed death ligand-1 expression is associated with poor disease free survival in salivary gland carcinomas Journal of Surgical Oncology 2016 114 1 36 43 10.1002/jso.24266 2-s2.0-84976576922 27111278 \n14 Toh J. W. T. de Souza P. Lim S. H. The potential value of immunotherapy in colorectal cancers: review of the evidence for programmed death-1 inhibitor therapy Clinical Colorectal Cancer 2016 15 4 285 291 10.1016/j.clcc.2016.07.007 2-s2.0-84996445447 27553906 \n15 Reck M. Rodríguez-Abreu D. Robinson A. G. Pembrolizumab versus chemotherapy for PD-L1-positive non- small-cell lung cancer The New England Journal of Medicine 2016 375 19 1823 1833 10.1056/NEJMoa1606774 2-s2.0-84994802263 27718847 \n16 Ribas A. Puzanov I. Dummer R. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial The Lancet Oncology 2015 16 8 908 918 10.1016/S1470-2045(15)00083-2 2-s2.0-84938205998 26115796 \n17 Roper E. Lum T. Palme C. E. PD-L1 expression predicts longer disease free survival in high risk head and neck cutaneous squamous cell carcinoma Pathology 2017 49 5 499 505 10.1016/j.pathol.2017.04.004 2-s2.0-85021733996 28666643 \n18 Hsu C. Lee S. H. Ejadi S. Safety and antitumor activity of pembrolizumab in patients with programmed death-ligand 1–positive nasopharyngeal carcinoma: results of the KEYNOTE-028 study Journal of Clinical Oncology 2017 35 36 4050 4056 10.1200/JCO.2017.73.3675 2-s2.0-85038381568 28837405\n\n",
"fulltext_license": "CC BY",
"issn_linking": null,
"issue": "2019()",
"journal": "Case reports in oncological medicine",
"keywords": null,
"medline_ta": "Case Rep Oncol Med",
"mesh_terms": null,
"nlm_unique_id": "101581035",
"other_id": null,
"pages": "2305315",
"pmc": null,
"pmid": "31308983",
"pubdate": "2019",
"publication_types": "D002363:Case Reports",
"references": "10679992;12927291;2296451;23674495;25361008;26115796;27111278;27553906;27718847;27807760;28533473;28666643;28781814;28837405;29409471;29462123;9664183",
"title": "The Three P's: Parotid, PD-L1, and Pembrolizumab.",
"title_normalized": "the three p s parotid pd l1 and pembrolizumab"
} | [
{
"companynumb": "US-009507513-1909USA002414",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PEMBROLIZUMAB"
},
"drugadditional": null,
... |
{
"abstract": "Based on a clinical case, the authors consider the problem of the optimal choice of an antidepressant, taking into account not only the psychopathological structure of depression, the severity and characteristics of its triad, but also the presence of somatic symptoms. This determines the need for a comprehensive analysis of the pharmacological profile of prescribed antidepressants, their psychotropic and somatotropic effects. The switch of the patient to brintellix, which has polymodal neuroreceptor activity, at a dose of 20 mg per day, made it possible to achieve remission and reduce adverse reactions caused by SSRIs.",
"affiliations": "Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia.;Pavlov First Saint Petersburg State Medical University, St. Petersburg, Russia.",
"authors": "Krylov|V I|VI|0000-0002-7372-2384;Butylin|D Yu|DY|0000-0001-7055-0065",
"chemical_list": "D000928:Antidepressive Agents; D017367:Serotonin Uptake Inhibitors",
"country": "Russia (Federation)",
"delete": false,
"doi": "10.17116/jnevro2021121052116",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1997-7298",
"issue": "121(5. Vyp. 2)",
"journal": "Zhurnal nevrologii i psikhiatrii imeni S.S. Korsakova",
"keywords": "antidepressants; depression; side-effects",
"medline_ta": "Zh Nevrol Psikhiatr Im S S Korsakova",
"mesh_terms": "D000928:Antidepressive Agents; D003863:Depression; D006801:Humans; D017367:Serotonin Uptake Inhibitors",
"nlm_unique_id": "9712194",
"other_id": null,
"pages": "116-121",
"pmc": null,
"pmid": "34405667",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Selecting the optimal treatment for depression taking into account the psychotropic and somatotropic effects of the antidepressant.",
"title_normalized": "selecting the optimal treatment for depression taking into account the psychotropic and somatotropic effects of the antidepressant"
} | [
{
"companynumb": "RU-LUPIN PHARMACEUTICALS INC.-2022-02495",
"fulfillexpeditecriteria": "2",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PAROXETINE"
},
"drugadditional... |
{
"abstract": "BackgroundReduced gastrointestinal motility can alter the toxicokinetics of acetaminophen poisoning. We report a case of altered acetaminophen toxicokinetics due to delayed gastrointestinal absorption, likely secondary to intestinal trauma/surgery. Case ReportA 37-year-old woman ingested an unknown amount of acetaminophen and ethanol then stabbed herself in the abdomen. The initial acetaminophen was 1,285.9 μmol/L and the time of ingestion was not known. Intravenous acetylcysteine protocol was started. She developed an ileus post-surgery for the stab wounds. At 31 hours post-presentation, the acetaminophen returned undetectable, and the transaminases were normal. After the resolution of the ileus, repeated acetaminophen peaked at 363.3 μmol/L 52 hours post-admission. At 76 hours post-admission, the acetaminophen was undetectable, and transaminases and coagulation parameters were normal. ConclusionsReduction in gastrointestinal motility secondary to trauma and/or surgery must be considered when determining when to initiate or discontinue treatment as well as how long to monitor acetaminophen concentrations.",
"affiliations": null,
"authors": "Alyahya|B|B|;Tamur|S|S|;Aljenedil|S|S|;Larocuque|A|A|;Holody|E|E|;Gosselin|S|S|",
"chemical_list": "C539025:Per1 protein, Xenopus; D056950:Period Circadian Proteins; D029867:Xenopus Proteins; D000082:Acetaminophen; D000431:Ethanol; D000111:Acetylcysteine",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2561-8741",
"issue": "23(2)",
"journal": "Journal of population therapeutics and clinical pharmacology = Journal de la therapeutique des populations et de la pharmacologie clinique",
"keywords": null,
"medline_ta": "J Popul Ther Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000328:Adult; D000431:Ethanol; D005260:Female; D006801:Humans; D007422:Intestines; D056950:Period Circadian Proteins; D014951:Wounds, Stab; D029867:Xenopus Proteins",
"nlm_unique_id": "101530023",
"other_id": null,
"pages": "e142-4",
"pmc": null,
"pmid": "27463118",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Double-peaked Acetaminophen Concentration Secondary to Intestinal Trauma.",
"title_normalized": "double peaked acetaminophen concentration secondary to intestinal trauma"
} | [
{
"companynumb": "CA-MYLANLABS-2016M1050423",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ACETYLCYSTEINE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nHematopoietic cell transplantation (HCT) is curative in patients with severe aplastic anemia (SAA). HCT is considered at presentation when a HLA-matched related donor (MRD) is available and has a high success rate. Unrelated donor (URD) transplants are typically undertaken if immunosuppressive therapy fails. Increased toxicity and graft rejection are often encountered in this setting.\n\n\nMETHODS\nWe report a prospective multi-center trial of HCT in 17 children with SAA following novel reduced intensity conditioning with alemtuzumab, fludarabine and melphalan, and the best available donor. Nine were URD transplants matched at 7-8/8 loci, and performed following failure of immune suppression. Median follow up was 61 months (range 6-128).\n\n\nRESULTS\nAll patients engrafted. Estimated 5 year event-free and overall-survival was 88% (95%CI 65.7-96.7). Five year overall survival for MRD and URD transplants was 100% and 78% (95%CI 45-93.6) respectively. Median times to neutrophil and platelet engraftment was 14 (range 10-27) and 23.5 (range 11-65) days respectively. Treatment related mortality was 12%. The incidence of grade II-IV and III-IV acute graft-versus-host disease was 29% and 18% respectively. At two years, all but one patient discontinued immunosuppression successfully. Laboratory measures of immune reconstitution normalized at one year and infection rates were low in the latter part of the first year.\n\n\nCONCLUSIONS\nHCT using this RIC approach was well tolerated and successful in achieving donor engraftment and early immune reconstitution with good quality of life free of immune suppression. Children with SAA can be successfully transplanted using alemtuzumab based conditioning.",
"affiliations": "Department of Pediatrics, Washington University in St. Louis, Missouri.;Department of Pediatrics, Washington University in St. Louis, Missouri.;Department of Pediatrics, Washington University in St. Louis, Missouri.;Blood/Marrow Transplantation and Immunology, Children's National Medical Center, District of Columbia.;Department of Pediatrics, Children's Mercy Hospital, Kansas City, Missouri.;Department of Pediatrics, University of Chapel Hill, North Carolina.;Department of Pediatrics, Washington University in St. Louis, Missouri.",
"authors": "Ngwube|Alexander|A|;Hayashi|Robert J|RJ|;Murray|Lisa|L|;Loechelt|Brett|B|;Dalal|Jignesh|J|;Jaroscak|Jennifer|J|;Shenoy|Shalini|S|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D000074323:Alemtuzumab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25458",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "62(7)",
"journal": "Pediatric blood & cancer",
"keywords": "aplastic anemia; children; reduced intensity transplants",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000074323:Alemtuzumab; D000741:Anemia, Aplastic; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D008297:Male; D011379:Prognosis; D011446:Prospective Studies; D011788:Quality of Life; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D061349:Unrelated Donors",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "1270-6",
"pmc": null,
"pmid": "25755151",
"pubdate": "2015-07",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia.",
"title_normalized": "alemtuzumab based reduced intensity transplantation for pediatric severe aplastic anemia"
} | [
{
"companynumb": "US-SA-2015SA082413",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Preclinical studies in small cell lung cancer (SCLC) have shown that hyaluronic acid (HA) can be effectively used to deliver chemotherapy and selectively decrease CD44 expressing (stem cell-like) tumour cells. The current study aimed to replicate these findings and obtain data on safety and activity of HA-irinotecan (HA-IR). Eligible patients with extensive stage SCLC were consented. A safety cohort (n = 5) was treated with HA-IR and Carboplatin (C). Subsequently, the patients were randomised 1:1 to receive experimental (HA-IR + C) or standard (IR + C) treatment, to a maximum of 6 cycles. The second line patients were added to the study and treated with open label HA-IR + C. Tumour response was measured after every 2 cycles. Baseline tumour specimens were stained for CD44s and CD44v6 expression. Circulating tumour cells (CTCs) were enumerated before each treatment cycle. Out of 39 patients screened, 34 were evaluable for the study. The median age was 66 (range 39-83). The overall response rates were 69% and 75% for experimental and standard arms respectively. Median progression free survival was 42 and 28 weeks, respectively (p = 0.892). The treatments were well tolerated. The incidence of grade III/IV diarrhea was more common in the standard arm, while anaemia was more common in the experimental arm. IHC analysis suggested that the patients with CD44s positive tumours may gain survival benefit from HA-IR. HA-IR is well tolerated and active in ES-SCLC. The effect of HA-IR on CD44s + cancer stem-like cells provide an early hint towards a potential novel target.",
"affiliations": "Department of Medical Oncology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, 3168, Australia. alamgeer.muhammad@hudson.org.au.;The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, NSW, 2010, Australia.;Monash University, Wellington Road, Clayton, VIC, 3168, Australia.;Department of Pathology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, Australia.;Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, 3168, Australia.;Department of Medical Oncology, Monash Medical Centre, 246 Clayton Road, Clayton, VIC, 3168, Australia.;Centre for Cancer Research, Hudson Institute of Medical Research, 27-31 Wright Street, Clayton, VIC, 3168, Australia.",
"authors": "Alamgeer|Muhammad|M|0000-0002-6443-2350;Neil Watkins|D|D|;Banakh|Ilia|I|;Kumar|Beena|B|;Gough|Daniel J|DJ|;Markman|Ben|B|;Ganju|Vinod|V|",
"chemical_list": "C497483:CD44 protein, human; C112697:CD44v6 antigen; D018960:Hyaluronan Receptors; D000077146:Irinotecan; D006820:Hyaluronic Acid",
"country": "United States",
"delete": false,
"doi": "10.1007/s10637-017-0555-8",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-6997",
"issue": "36(2)",
"journal": "Investigational new drugs",
"keywords": "CD44; Cancer stem cells; Hyaluronic acid; Small cell lung cancer",
"medline_ta": "Invest New Drugs",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004339:Drug Compounding; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D000077146:Irinotecan; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009360:Neoplastic Cells, Circulating; D055752:Small Cell Lung Carcinoma; D016896:Treatment Outcome",
"nlm_unique_id": "8309330",
"other_id": null,
"pages": "288-298",
"pmc": null,
"pmid": "29277856",
"pubdate": "2018-04",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase IIa study of HA-irinotecan, formulation of hyaluronic acid and irinotecan targeting CD44 in extensive-stage small cell lung cancer.",
"title_normalized": "a phase iia study of ha irinotecan formulation of hyaluronic acid and irinotecan targeting cd44 in extensive stage small cell lung cancer"
} | [
{
"companynumb": "AU-CIPLA (EU) LIMITED-2018AU17850",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3"... |
{
"abstract": "BACKGROUND\nRecent evidence shows that use of anthracycline and taxane adjuvant chemotherapy and dose-dense regimens, consisting of more frequent administration of the drugs, have improved outcomes for breast cancer patients. In this study, we evaluated administration of an epirubicin-based regimen with paclitaxel in a sequential, dose-dense schedule as adjuvant treatment for patients with high-risk primary breast cancer.\n\n\nMETHODS\nIn a phase II Simon two-stage design study, we evaluated the feasibility of a modified fluorouracil, epirubicin, and cyclophosphamide (FEC) regimen at high dose intensity (fluorouracil 500 mg/m(2) i.v. on days 1 and 4, epirubicin 60 mg/m(2) i.v. on days 1 and 4, and cyclophosphamide 500 mg/m(2) i.v. on days 1 and 4; all drugs were administered every 14 days for 3 cycles) with granulocyte colony-stimulating factor support followed by dose-intense weekly paclitaxel 100 mg/m(2) for 8 cycles. In 11 patients with breast cancer following quadrantectomy (n = 8) or modified radical mastectomy (n = 3), any grade 3 (G3) or higher nonhematologic toxicity (excluding alopecia, nausea or vomiting, and bone pain, which might be a consequence of the administration of filgrastim) and adherence to the scheduled dose-dense treatment (deliverability) were monitored with the purpose of enrolling an additional 27 patients in the case of a satisfying toxicity profile and deliverability of the planned treatment (at least 7 patients completing the treatment).\n\n\nRESULTS\nFive of 11 patients experienced G3 or higher nonhematologic toxicity during the FEC regimen. We did not observe G3 or higher nonhematologic toxicity related to paclitaxel treatment. In particular, three patients experienced G3 fatigue, one patient had G3 oral mucositis, three patients had G3 hypokalemia, one patient had G3 syncope, one patient had G3 transaminitis (alanine aminotransferase), one patient experienced G4 pulmonary thromboembolism, and 1 patient had a G3 breast infection. Four of 11 patients received the regimen with a 25% dose reduction of day 1 and 4 administrations of FEC. Seven of 11 patients required FEC delay ≥7 days in at least 1 cycle, regardless of dose intensity. Two patients failed to complete the FEC regimen. Two of the remaining 9 patients were treated with paclitaxel delay ≥7 days in at least one cycle. After a median follow-up of 28 months, 9 patients were continuously disease free.\n\n\nCONCLUSIONS\nThe tolerability rate of a dose-density regimen with FEC followed by weekly paclitaxel was considered not promising for completing the accrual of this study.",
"affiliations": "Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy.;Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola, Italy ugo.degiorgi@irst.emr.it.",
"authors": "Pietri|Elisabetta|E|;Andreis|Daniele|D|;Fabbri|Francesca|F|;Menna|Cecilia|C|;Schirone|Alessio|A|;Kopf|Barbara|B|;Rocca|Andrea|A|;Amadori|Dino|D|;De Giorgi|Ugo|U|",
"chemical_list": "D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D015251:Epirubicin; D003520:Cyclophosphamide; D017239:Paclitaxel; D000069585:Filgrastim; D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.1634/theoncologist.2014-0326",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1083-7159",
"issue": "20(3)",
"journal": "The oncologist",
"keywords": null,
"medline_ta": "Oncologist",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D004305:Dose-Response Relationship, Drug; D015251:Epirubicin; D005260:Female; D000069585:Filgrastim; D005472:Fluorouracil; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D017239:Paclitaxel; D011994:Recombinant Proteins; D016019:Survival Analysis; D016896:Treatment Outcome",
"nlm_unique_id": "9607837",
"other_id": null,
"pages": "239-40",
"pmc": null,
"pmid": "25637379",
"pubdate": "2015-03",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": null,
"title": "A phase II study of a dose-density regimen with fluorouracil, epirubicin, and cyclophosphamide on days 1 and 4 every 14 days with filgrastim support followed by weekly paclitaxel in women with primary breast cancer.",
"title_normalized": "a phase ii study of a dose density regimen with fluorouracil epirubicin and cyclophosphamide on days 1 and 4 every 14 days with filgrastim support followed by weekly paclitaxel in women with primary breast cancer"
} | [
{
"companynumb": "IT-CIPLA LTD.-2015IT03032",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nMetastatic colorectal cancer (mCRC) in pregnancy and post-partum is rare, but represents significant diagnostic and therapeutic challenges for clinicians. A multidisciplinary team (MDT) approach is essential. This study reports the first series in the Australasian literature, describing our experience with and management of pregnant and post-partum patients diagnosed with synchronous colorectal liver metastases (sCRLM).\n\n\nMETHODS\nA retrospective review of prospectively collected data for patients with sCRLM diagnosed during pregnancy or post-partum, presenting to a tertiary referral hospital between 2009 and 2014, was performed. Data regarding patient presentation, imaging, management, histopathology and survival were analysed. Patient characteristics and outcomes were reviewed, including age, presenting complaint and median survival.\n\n\nRESULTS\nFive patients were identified with sCRLM: three patients were diagnosed antepartum and two post-partum. Median age was 31 years (range 26-34). All patients were diagnosed with colorectal primary and synchronous liver lesions. All patients received folinic acid, fluorouracil, oxaliplatin chemotherapy, two intrapartum. One patient had both the primary lesion and liver metastases excised early post-partum. Second-line chemotherapy with folinic acid, fluorouracil, irinotecan and other biological agents was used in some cases post-partum. One patient suffered a fetal loss, while the other four had uncomplicated live births. Median survival was 7.6 months, with two patients dying shortly after delivery.\n\n\nCONCLUSIONS\nThe diagnosis of mCRC in pregnancy is challenging and survival is poor. A MDT approach to management is essential. Chemotherapy remains the mainstay of treatment from the second trimester. Rapid confirmation of diagnosis and early chemotherapy, followed by post-partum colorectal and liver resection may improve survival.",
"affiliations": "Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia.;Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia.;Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia.;Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia.;Hepatopancreatobiliary Unit, Department of General Surgery, Royal Brisbane Hospital, Brisbane, Queensland, Australia.",
"authors": "Robson|Danielle E|DE|;Lewin|Joel|J|;Cheng|Anthony W|AW|;O'Rourke|Nicholas A|NA|;Cavallucci|David J|DJ|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/ans.13196",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1445-1433",
"issue": "87(10)",
"journal": "ANZ journal of surgery",
"keywords": "colorectal cancer; metastatic; post-partum; pregnancy",
"medline_ta": "ANZ J Surg",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001315:Australia; D015179:Colorectal Neoplasms; D005260:Female; D006801:Humans; D008099:Liver; D008113:Liver Neoplasms; D009378:Neoplasms, Multiple Primary; D049590:Postpartum Period; D011247:Pregnancy; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101086634",
"other_id": null,
"pages": "800-804",
"pmc": null,
"pmid": "26072664",
"pubdate": "2017-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
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"abstract": "In order to break through drug resistance in platinum-refractory ovarian cancer, augmented drug exposure was administered to the abdomen by means of an isolated perfusion system. Four cycles of isolated hypoxic abdominal perfusion with cisplatin, adriamycin, and mitomycin were conducted in 4-week intervals. Cisplatin and adriamycin were chosen because of their increased cytotoxicity under hypoxic conditions. Chemofiltration was performed for prophylaxis of cumulative toxicity of adriamycin and mitomycin. The study included 45 patients with recurrent epithelial ovarian cancer who had prior platinum containing therapies (3, stage Federation of Gynecology and Obstetrics (FIGO) IIIB; 20, stage FIGO IIIC; 22; stage FIGO IV). The median survival rate in stage FIGO IIIBC was 12 months, and in stage IV was 10 months. The tumor marker decreased to complete response or partial response at 17.8% and 55.6% of the patients. CT or MRI visualization showed complete response in 4.1%, and partial response was in 54.1%. Complete resolution of ascites was noted in 30% of cases and substantial reduction in another 43%. Toxicity was generally low. Quality of life was improved in the majority of cases. Bone-marrow suppression ranged between WHO grade 1 and 2, and in patients with previous third- or fourth-line chemotherapy, it was WHO grade 3. Isolated hypoxic abdominal perfusion with chemofiltration for patients with progressive and platinum-refractory stage III and IV ovarian cancer is an effective therapy, breaking through chemoresistance and offering comparably long survival at good quality of life.",
"affiliations": "Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany.;Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany.;Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany.;Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany.",
"authors": "Aigner|Karl Reinhard|KR|0000-0003-2952-6180;Selak|Emir|E|;Gailhofer|Sabine|S|;Aigner|Kornelia|K|",
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"doi": "10.1007/s13193-019-00922-9",
"fulltext": "\n==== Front\nIndian J Surg Oncol\nIndian J Surg Oncol\nIndian Journal of Surgical Oncology\n0975-7651 0976-6952 Springer India New Delhi \n\n31496601\n922\n10.1007/s13193-019-00922-9\nOriginal Article\nHypoxic Isolated Abdominal Perfusion (HAP) chemotherapy for non-operable advanced staged ovarian cancer with peritoneal carcinosis: an experience in 45 platinum-refractory ovarian cancer patients\nhttp://orcid.org/0000-0003-2952-6180Aigner Karl Reinhard info@prof-aigner.de Selak Emir e.selak@medias-klinikum.de Gailhofer Sabine s.gailhofer@medias-klinikum.de Aigner Kornelia kornelia.aigner@medias-klinikum.de grid.473689.7Department of Surgical Oncology, Medias Klinikum GmbH & Co KG, Krankenhausstr. 3a, 84489 Burghausen, Germany \n16 4 2019 \n16 4 2019 \n9 2019 \n10 3 506 514\n18 1 2019 2 4 2019 © The Author(s) 2019Open Access This 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.In order to break through drug resistance in platinum-refractory ovarian cancer, augmented drug exposure was administered to the abdomen by means of an isolated perfusion system. Four cycles of isolated hypoxic abdominal perfusion with cisplatin, adriamycin, and mitomycin were conducted in 4-week intervals. Cisplatin and adriamycin were chosen because of their increased cytotoxicity under hypoxic conditions. Chemofiltration was performed for prophylaxis of cumulative toxicity of adriamycin and mitomycin. The study included 45 patients with recurrent epithelial ovarian cancer who had prior platinum containing therapies (3, stage Federation of Gynecology and Obstetrics (FIGO) IIIB; 20, stage FIGO IIIC; 22; stage FIGO IV). The median survival rate in stage FIGO IIIBC was 12 months, and in stage IV was 10 months. The tumor marker decreased to complete response or partial response at 17.8% and 55.6% of the patients. CT or MRI visualization showed complete response in 4.1%, and partial response was in 54.1%. Complete resolution of ascites was noted in 30% of cases and substantial reduction in another 43%. Toxicity was generally low. Quality of life was improved in the majority of cases. Bone-marrow suppression ranged between WHO grade 1 and 2, and in patients with previous third- or fourth-line chemotherapy, it was WHO grade 3. Isolated hypoxic abdominal perfusion with chemofiltration for patients with progressive and platinum-refractory stage III and IV ovarian cancer is an effective therapy, breaking through chemoresistance and offering comparably long survival at good quality of life.\n\nKeywords\nOvarian cancerQuality of lifeChemoresistanceIsolated abdominal perfusionIntra-arterial chemotherapyissue-copyright-statement© Indian Association of Surgical Oncology 2019\n==== Body\nBackground\nOvarian cancer is the leading cause of death among all gynecological cancers. The standard therapy option is still complete cytoreduction when possible, combined with chemotherapy [1–3]. Despite initial response rates of 70–80% to platinum-based combination chemotherapies with taxanes, platinum-resistant recurrences occur very frequently within 2 years. The shorter the recurrence-free interval, the lower the prospect of a renewed response to chemotherapy [4–6]. While increased drug exposure could theoretically lead to a renewed response, they are not universally administered due to increased toxicity [7–15]. Even high-dose or modified combination therapy did not result in any real progress [16–19]. Only recently two randomized studies showed that the addition of HIPEC to cytoreductive surgery resulted in longer recurrence-free and overall survival than cytoreductive surgery alone [20, 21].\n\nAlternatively, consideration may be given to new drugs or targeted substances [22–24]. As the response behavior rises sharply with an increased dose or concentration of active agents, we surmised that an isolated extracorporeal perfusion would increase local exposure and break through any existing cytostatic resistance. In order to limit systemic toxicity, which could adversely affect quality of life, chemofiltration for detoxification was carried out, following the isolated perfusion procedure [26, 27]. A case series of 45 heavily pretreated patients with ovarian cancer treated with hypoxic abdominal perfusion is herein reported. It has been applied in patients with advanced and recurrent tumors, resistant to platinum-containing combination therapies.\n\nMethods\nPatients\nThe study included 45 patients at the clinical stages of Federation of Gynecology and Obstetrics (FIGO) IIIB, IIIC, and IV (n = 3, 20, and 22, respectively) treated in one institution between 2006 and 2017. All patients were progressive after systemic chemotherapy and had received at least two lines of platinum-containing combinations; three had undergone third-line and one patient fourth-line therapies. Previously given drugs contained combinations of cisplatin or carboplatin with paclitaxel, caelyx, treosulfan, or bevacizumab. The minimum chemotherapy-free interval before the start of abdominal perfusion therapy was 4 weeks. Performance status was ECOG 1 (7 patients), ECOG 2 (13 patients), and ECOG 3 (25 patients). Forty one patients (91%) had peritoneal carcinosis and according to MRI, four patients had no evidence of peritoneal carcinosis. Progression of peritoneal carcinosis was classified by the affection of either two quadrants (11 patients, 24%) or four quadrants (30 patients, 67%). Seventeen patients had additional liver metastases, and three patients had metastases on the spleen. Lymphatic metastases were detected in 13 patients; one of them was inguinal, and in one case was mediastinal. Median number of metastatic locations (peritoneum considered as one location) was two. Surgery as a primary measure after progression was considered as unfeasible in all cases.\n\nInvestigations were performed in compliance with the principles of good clinical practice outlined in the Declaration of Helsinki and federal guidelines, and had approval by the Institutional Review Committee. Informed consent was obtained from each participant or participant’s guardian. Patients were required to be > 18 years of age and have an ECOG performance status ≤ 3. Exclusion criteria included cardiovascular diseases, as well as uncontrolled diabetes or serious infectious diseases. The leucocyte count had to be no less than 2500/μl, but more importantly should not show a declining trend before start of the therapy. The same applied to the thrombocyte count, with a threshold of no less than 100,000/μl.\n\nIsolated Hypoxic Abdominal Perfusion\nUnder general anesthetic, the arteria and vena femoralis were exposed and tied with tourniquets. An arterial stop-flow catheter (PfM, Cologne, Germany and Dispomedica, Hamburg, Germany) was placed over the arterial transverse incision under X-ray monitoring, with the balloon above the diaphragm. The venous stop-flow catheter was secured with a purse-string suture and inserted through a stab incision. The balloon was placed in the inferior vena cava above the confluence of the right hepatic vein and below the right atrium. After blocking the balloons and checking the position with contrast medium, the balloons were unblocked again and both thighs were initially blocked with pneumatic cuffs. Under temporary hyperoxygenation, the chemotherapeutic agents were then applied through the aortal catheter as a bolus and both balloon catheters were immediately blocked again (Fig. 1). It is mandatory to inject the drugs under prior hyperoxygenation directly before balloon-blocking. The subsequent therapy was conducted for 15 min under hypoxic conditions in which mitomycin and adriamycin unlike other chemotherapeutics produce increased tumor toxicity [28]. Only the effect of cisplatin is not influenced by the pH value. Leakage monitoring of the isolated abdominal perfusion segment was not required; as after 15 min of hypoxic perfusion, the stop-flow balloon catheters and femoral pressure cuffs were unblocked and the systemic chemofiltration started immediately. Chemofiltration is maintained up to a substitution volume of at least 4 l of filtrate. After completing chemofiltration, the catheters were removed and the artery and vein sutured successively.Fig. 1 Isolated hypoxic abdominal perfusion via a femoral access. The balloon catheters are positioned beneath the diaphragm and connected with an extracorporeal roller pump\n\n\n\nTreatment and Drug Regimen\nThe isolated abdominal hypoxic perfusion was conducted in 4 cycles at 4-week intervals. The cytostatic drugs used were cisplatin, adriamycin, and mitomycin. Using a bolus injection in the abdominal aorta at the diaphragm level, the maximum intra-arterial total dose of CDDP was 70 mg at one shot. For ADM, the maximum dose was 50 mg and for MMC 20 mg at one shot. For a patient of 70 ± 5 kg, the overall dose of CDDP was 60 mg, ADM 40 mg, and MMC 20 mg. Due to their intra-aortal administration, the cytostatic drugs were not dosed by body weight for extremely obese patients.\n\nLeucocytes and thrombocytes were monitored weekly after every treatment; while decreasing close to the lowest nadir, checks were carried out every 2 days until the blood count started to reemerge.\n\nResponse Evaluation and Statistical Analysis\nThe main endpoint of the trial was quality of life, overall survival, and clinical response rates. Tumor responses were visualized and assessed in accordance with Response Evaluation Criteria in Solid Tumors (RECIST version 1.1) at 2 to 4 weeks after every second treatment cycle. Responses were evaluated by CT, magnetic resonance imaging (MRI), and positron emission tomography (PET). Plasma levels of the tumor marker CA 12-5 were determined before any treatment. The extent of residual disease, the degree of response in ascites, as well as the course of the tumor marker CA 12-5 were evaluated and compared. A reliable pain relief was noted if pain was controlled by < 50% analgesic administration 20 days after treatment. Adverse events were assessed according to the common terminology criteria for adverse events of the National Cancer Institute. Quality of life was evaluated by a patient questionnaire according to RCT institutional QOL approvement and compared to questionnaires regarding previous systemic chemotherapy treatments. Statistics have been calculated with 95% confidence limits, or as specified, survival times were estimated using the Kaplan–Meier product limit estimator. Survival times were stratified according to clinical variables that may affect survival, and log-rank tests were used to verify significance. Statistical analyses were performed by using the institutional research software, version 28.5.14.\n\nBlood Sampling for Cisplatin and Mitomycin C Plasma Concentration Measurements\nA series of cisplatin (CDDP) and Mitomycin C (MMC) plasma concentration measurements have been investigated. Blood samples derive from a patient with ovarian cancer and peritoneal carcinosis during and after hypoxic abdominal perfusion with CDDP and MMC. Arterial and venous drug concentrations, originating from the tumor region, were measured at minute 1, 2, and 3, respectively, following measurements at 2-min intervals.\n\nResults\nResponse and Survival Rates\nThe median progression-free survival (PFS) of all 45 patients was 6.9 months; the median overall survival was 11.3 months. The median survival rate of pretreated platinum-refractory patients at FIGO stage IIIB/C was 12.3 months, and at stage IV was 9.8 months (Fig. 2) (p < 0.05). Overall survival in FIGO III and IV together is 37.8% at 1 year, 18.3% at 2 years, stays 18.3% at 3 years, and 9.2% at 4 years. Time measurements started after completing multiple lines of standard chemotherapy, diagnosis of recurrent or progressive disease, and start treatment with hypoxic abdominal perfusion therapy. According to tumor marker 12-5, complete response and partial response have been achieved in 17.8% and 55.6% of all patients, respectively. CT or MRI visualization showed complete response and partial response in 4.1 and 54.1% of the cases (Fig. 3), respectively.Fig. 2 Observational survival rates of 45 advanced staged, heavily pretreated, recurrent ovarian cancer patients on hypoxic abdominal perfusion chemotherapy. Three patients were staged FIGO IIIB, 20 patients were stage IIIC, and 22 patients were staged IV. Survival times were estimated using the Kaplan–Meier product limit estimator, and follow-up for surviving patients was minimum 18 months; median follow-up was 26 months\n\nFig. 3 Response rates of 45 advanced staged, heavily pretreated, recurrent metastatic ovarian cancer patients on hypoxic abdominal perfusion chemotherapy. Response classification was complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD). Responses of a clinical benefit (CR, PR, SD) endured at least 8 weeks\n\n\n\nArterial and Venous Concentrations of CDDP and MMC\nDuring and after 15 min of hypoxic abdominal perfusion, drug concentrations were measured from plasma deriving from the inferior vena cava and from the aorta, both inside the perfusion area, and additionally from a peripheral vein outside the perfusion area (Fig. 4).Fig. 4 Drug concentration levels of cisplatin (a) and MMC (b) in the tumor supplying arteria (violet), the tumor draining vein (blue), and the peripheral vein (green) during and after a hypoxic abdominal perfusion. Measurements inside the perfusion circuit (arterial and venous) have been made at minute 1, 2, and 3, and then every 2 min until 35 min after drug injection. Drug levels in the peripheral vein have been measured at minute 1, 5, and after releasing of perfusion balloons at minute 15. Given drug regimen was 50 mg cisplatin and 20 mg mitomycin as a bolus injection. Both charts derive from the same perfusion event\n\n\n\nToxicity\nBone-marrow suppression was low for 43 patients and ranged between WHO grade 1 and 2. Two patients in poor general condition following third- and fourth-line chemotherapy had leucopenia and thrombocytopenia WHO grade 3. Neutropenic fever at WHO grade 4 toxicity was never observed. Fatigue syndrome never occurred before the third day post-therapy and, if it occurred, it was always associated with an increase in both LDH and the tumor marker CA 12-5. Hypodense areas seen simultaneously in CT scans were identified as an expression of post-therapeutic tumor necrosis. All of these syndromes were observed during the first week after isolated perfusion. Mild renal toxicity with slight transient elevation of creatinine was observed in seven (15.6%) patients. Neuropathy in terms of hand–foot syndrome was never observed after isolated perfusion with chemofiltration.\n\nQuality of Life\nComplete or partial response on clinical symptoms was noted among 36.3% of all patients in stages IIIB/C and IV. Stable disease was achieved in 51.1% of patients. Complete disappearance of ascites was observed in 30% of patients after only two perfusions; 43% of patients reported a substantial reduction of abdominal pressure and fluid volume and a considerable improvement in general wellbeing. As shown in Fig. 5, patients perceived hypoxic abdominal perfusion (HAP) therapy less stressful than conventional chemotherapy. A patient questionnaire showed decrease in adverse events for the symptoms nausea, hair loss, diarrhea, mucositis, fatigue, exhaustion, weight loss, and anorexia. The mean decrease over all collected data for HAP was 1.86 (confidence interval, with 91% CI 0.5). A definite decrease in pain, which was controlled by < 50% analgesic administration 20 days after treatment, is reported for 30% of patients with advanced ovarian carcinoma.Fig. 5 Adverse effects after systemic chemotherapy (green) and hypoxic abdominal perfusion (HAP blue). Ovarian cancer patients filled in a questionnaire about adverse effects after chemotherapy. Each possible adverse effect is scaled on a spectrum from 1 to 6 for increasing severeness of side effects. Mean reduction of adverse events was 1.86 points for hypoxic abdominal perfusion compared to systemic chemotherapy, that patients perceived at an earlier treatment period (confidence interval for 1.86 (with 91% CI 0.5)\n\n\n\nDiscussion\nThe limiting factor of augmented systemic drug exposure always had been the increasing toxicity such as neuropathy with hand–foot syndrome, neutropenia, or fatigue to the point of exhaustion [9–15]. Since mortality rates of ovarian cancer remain high and have hardly changed in the last three decades, more recent treatment options are being tested in the context of molecular biology research. Based on the angiogenetic properties of ovarian cancer with induction of vascularization, there has been an expectation that targeted treatments could achieve a restriction of tumor blood supply, higher response rates, and improved survival times, while sparing healthy tissue [24]. Apart from prolonging PFS in ovarian cancer, targeted antiangiogenic therapies occasionally cause severe collateral damage in terms of high blood pressure, hemorrhages, protein urea, cardiotoxicity, and gastrointestinal toxicity with spontaneous perforations [23]. In a trial on 32 patients pretreated with multiple chemotherapy regimens, positive results were achieved with bevacizumab [24]. The median survival time was 6.9 months, with a median PFS of 5.5 months. With the limitation that the patient groups are not necessarily exactly comparable, these data do not reach the median survival time of 11.3 months at a PFS of 6.9 months reported here, following hypoxic isolated abdominal perfusion.\n\nProlonging life while maintaining or improving quality of life should be the basic requirement for any cancer treatment. No other fundamental necessity for any treatment to be recommended should actually apply [25]. In a comparative study, we looked at patients who were in progression following systemic chemotherapy and were then treated with regional chemotherapy [29]. Patients were asked to complete a questionnaire on the severity of the most common side effects, comparing their previous systemic therapy and the regional chemotherapy. Results showed that regional chemotherapy resulted in side effects that were perceived as less severe than the ones derived from systemic chemotherapy.\n\nSurgical tumor debulking with the aim of complete cytoreduction is intended to prolong progression-free survival even in the case of advanced diseases, but it is ultimately limited to early stages, in which the desired curative removal of all lesions is still possible [30, 31]. At clinical stage IV, there is no difference in overall survival, no matter what treatment, chemotherapy, or primary cytoreductive surgery (PCS) was used. The administration of hyperthermic intra-peritoneal chemotherapy (HIPEC) has been considered another option of regional chemotherapy. The rationale behind is that after exposure of all peritoneal surfaces, the direct contact with hyperthermic chemotherapy generates a higher tissue uptake in residual tumors which is usually limited down to a depth of 1 to 2-mm tumor thickness [32]. In contrast, the depth of penetration with intra-arterial therapy is homogenous throughout the entire tumor tissue, depending on the blood supply of the tumor. Metastases from ovarian cancer are well-vascularized and usually respond even in case of bulky lesions. So far, there have been studies with HIPEC for ovarian cancer in therapy for primary and for recurrent disease [33]. Particularly because of high morbidity and side effects, HIPEC was not recommended as a standard therapy for ovarian cancer [34, 35]. Only recently, however, two randomized studies showed that the addition of HIPEC to cytoreductive surgery resulted in longer survival than surgery alone. Hypoxic abdominal perfusion on the other hand is not associated with relevant toxicity, and quality of life is not impaired. It is not primarily performed in operable cases, appropriate for cytoreduction, but in systemically pretreated, advanced non-operable patients.\n\nPresumably, advances in the treatment of various types of cancer such as ovarian, colorectal, or testicular carcinoma correlate extensively with the chemoresistance of tumor stem cells. While in the recent past, the cure rates of testicular carcinoma and even stage III colorectal carcinoma have increased significantly; the cure rates or clinical progress of ovarian carcinoma have remained unchanged, at between approx. 12% and 14% [36]. This may be related to the low response rate of epithelial ovarian carcinoma stem cells. An increase in overall survival in tumors in general may be due to suppression of the non-stem cell proportion of the tumor. It could also explain why further chemotherapy following recurrences brings about renewed remission and may even prolong life. Due to the existence of the problem of chemoresistant stem cells, these patients have limited therapeutic options and limited prospects for an improvement in prognosis.\n\nIsolated perfusion therapy for bulky disease provides an option to a limited group of patients with advanced bulky disease, to achieve downsizing with operability, in the form of radical cytoreduction. In addition to stage IIIC, this would also apply to stage IV, where conventionally, primary cytoreductive surgery (PCS) has not provided any advantages in the past. The basic principle for increasing the cytostatic effect in the target area is the primary passage through the arterial blood supply with high cytostatic drug concentration, to increase the area under the curve (AUC). A high-concentration passage of the cytostatic in the form of a protracted bolus over 4 to 7 min results in an enhanced first-pass extraction, and based on experience, generate increased tumor necrosis even within the first few days after treatment [37–40]. In order to increase the local cytotoxicity without a significant increase in the overall dosage, the chemotherapeutic agent mitomycin (MMC) and adriamycin (ADM) were selected for perfusion under hypoxic conditions, which, as BA. Teicher described for the first time, produce multiple degrees of their normal cytotoxicity under hypoxic conditions [28]. Thus, the totally administered bone-marrow toxic dose can be kept low. Cisplatin (CDDP) activity is independent of oxygen conditions. Due to the increased cytostatic exposure with isolated perfusion techniques, it is possible to break through chemoresistance in platinum-refractory tumors. The extent to which this applies to tumor stem cells is unknown, but it could apply to initially well-advanced G3 tumors in the case of a few long-term surviving patients following regional chemotherapy. It is particularly remarkable that the survival curves, both in the chemoresistant stage IIIBC as well as IV, do not end abruptly after the median but show a survival rate of 18% and 9% even 3 years after therapy. “A focus on the tail of the survival curves, yields a distinct perspective on the benefit of anticancer therapies and prioritizes therapies with potential to profoundly alter the natural history of disease, even if uncommonly” [41]. This is an important aspect with a selective cohort of patients lifting the “tail” of the survival curve and thus enlarging the area under the curve.\n\nAnother important aspect in locally highly concentrated chemotherapy is the lowering of systemic cytostatic exposure by simultaneous chemofiltration [26]. Further improvement in quality of life is achieved in addition to systemic detoxification, through the rapid and high percentage decline in ascites. Seventy three percent of patients reported dramatic relief of their abdominal pain and discomfort. Quality of life should be a priority factor in tumor treatment, especially because newer treatment options, despite some advances, often only lead to slight increases in PFS or overall survival, at the expense of considerable toxicity [42]. As such, the approach of hypoxic abdominal perfusion warrants further investigation in selected patients with ovarian cancer not amenable to surgical resection. In the present situation, there was no control group of heavily pretreated patients available for repeated conventional chemotherapy. Therefore, the pretreated patients receiving isolated perfusion therapy, which is well tolerated due to chemofiltration, serve as their own control. A phase-III study, which investigates HAP versus systemic chemotherapy in non-pretreated patients, could provide information about future treatment options to be adopted.\n\nConclusion\nIsolated abdominal perfusion under hypoxic conditions for advanced, recurrent, and platinum-refractory ovarian cancer can be an option for multiply pretreated, recurrent ovarian cancer with peritoneal carcinosis, even if drug resistance is existent. Profit in terms of high response rates is achieved by increased tumor toxicity of adriamycin and mitomycin under hypoxic conditions. Due to subsequent chemofiltration, systemic drug exposure is reduced and toxic side effects kept low. Quality of life generally is reported mostly unaffected.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nThe authors wish to acknowledge Giuseppe Zavattieri and Rita Schlaf for their help and assistance in preparing the manuscript and statistics used in this report.\n\nCompliance with Ethical Standards\nConflict of Interest\nThe authors declare that they have no conflict of interest.\n\nEthical Approval\nAll procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\n\nInformed Consent\nInformed consent was obtained from all individual participants included in the study.\n\nAbbreviations\nECOGEastern Cooperative Oncology Group\n\nCTcomputed tomography\n\nFIGOFédération Internationale de Gynécologie et d’Obstétrique\n\nCACarbohydrate antigen\n\nMMCmitomycin C\n\nCDDPCisplatin\n\nPFSProgression-free survival\n\nWHOWorld Health Organization\n\nOSOverall survival\n\nLDHLactate dehydrogenase\n\nPCSPrimary cytoreductive surgery\n\nNACTNeoadjuvant chemotherapy\n\nHIPECHyperthermic intra-peritoneal chemotherapy\n\nAUCArea under the curve\n\nTUMTumor marker\n\nADMAdriamycin\n==== Refs\nReferences\n1. 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Fung MF Johnston ME Eisenhauer EA Chemotherapy for recurrent epithelial ovarian cancer previously treated with platinum – a systematic review of the evidence from randomized trials Eur J Gynaecol Oncol 2002 23 104 110 12013102 \n19. du Bois A Weber B Rochon J Meier W Goupil A Olbricht S Barats JC Kuhn W Orfeuvre H Wagner U Richter B Lueck HJ Pfisterer J Costa S Schroeder W Kimmig R Pujade-Lauraine E Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group Groupe d'Investigateurs Nationaux pour l'Etude des Cancers Ovariens Addition of epirubicin as a third drug to carboplatin-paclitaxel in first-line treatment of advanced ovarian cancer: a prospectively randomized gynecologic cancer intergroup trial by the Arbeitsgemeinschaft Gynaekologische Onkologie Ovarian Cancer Study Group and the Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens J Clin Oncol 2006 24 1127 1135 10.1200/JCO.2005.03.2938 16505432 \n20. Spiliotis J Halkia E Lianos E Kalantzi N Grivas A Efstathiou E Giassas S Cytoreductive surgery and HIPEC in recurrent epithelial ovarian cancer: a prospective randomized phase III study Ann Surg Oncol 2015 22 1570 1575 10.1245/s10434-014-4157-9 25391263 \n21. van Driel WJ Koole SN Sikorska K Schagen van Leeuwen JH Schreuder HWR Hermans RHM de Hingh IHJT van der Velden J Arts HJ Massuger LFAG Aalbers AGJ Verwaal VJ Kieffer JM van de Vijver KK van Tinteren H Aaronson NK Sonke GS Hyperthermic intraperitoneal chemotherapy in ovarian cancer N Engl J Med 2018 378 230 240 10.1056/NEJMoa1708618 29342393 \n22. Yi S Zeng L Kuan Y Antiangiogenic drugs used with chemotherapy for patients with recurrent ovarian cancer: a meta-analysis Onco Targets Ther 2017 10 973 984 10.2147/OTT.S119879 28255243 \n23. Stone RL Sood AK Coleman RL Collateral damage: toxic effects of targeted antiangiogenic therapies in ovarian cancer Lancet Oncol 2010 11 465 475 10.1016/S1470-2045(09)70362-6 20226736 \n24. Monk BJ Han E Joseph-Cowen CA Salvage bevacizumab (rhuMABVEGF)-based therapy after multiple prior cytotoxics regimens in advanced refractory epithelial ovarian cancer Gynecol Oncol 2006 102 140 144 10.1016/j.ygyno.2006.05.006 16790264 \n25. Cannistra SA The ethics of early stopping rules: who is protecting whom? J Clin Oncol 2004 22 1542 1545 10.1200/JCO.2004.02.150 15117977 \n26. Aigner KR Gailhofer S High dose MMC: aortic stopflow infusion (ASI) with versus without chemofiltration: a comparison of toxic side effects (abstract) Reg Cancer Treat 1993 6 Suppl 1 3 4 \n27. Aigner KR Tonn JC Hechtel R Die intraarterielle Zytostatikatherapie mit venöser Filtration im halboffenen System Onkologie 1983 6 74 76 6346193 \n28. Teicher BA Lazo JS Sartorelli A Classification of antineoplastic agents by their selective toxicities toward oxygenated and hypoxic tumor cells Cancer Res 1981 41 73 81 7448778 \n29. Aigner KR Knapp N Aigner KR Stephens FO Toxicity profiles with systemic vs. regional chemotherapy Induction chemotherapy – systemic and locoregional 2016 Second Berlin Springer Verlag 497 506 \n30. Crawford SC Vasey PA Paul J Hay A Davis JA Kaye SB Does aggressive surgery only benefit patients with less advanced ovarian cancer? Results from an international comparison within the SCOTROC-1 trial J Clin Oncol 2005 23 8802 8811 10.1200/JCO.2005.02.1287 16314640 \n31. Kehoes S Hook J Nankivell M Primary chemotherapy versus primary surgery for newly diagnosed advanced ovarian cancer (CHORUS): an open-label randomized, controlled, non-inferiority trial Lancet 2015 386 249 257 10.1016/S0140-6736(14)62223-6 26002111 \n32. van de Vaart PJ van der Vange N Zoetmulder FA Intraperitoneal cisplatin with regional hyperthermia in advanced ovarian cancer: pharmacokinetics and cisplatin-DNA adduct formation in patients and ovarian cancer cell lines Eur J Cancer 1998 34 148 154 10.1016/S0959-8049(97)00370-5 9624250 \n33. Bijelic L Jonson A Sugarbaker PH Systematic review of cytoreductive surgery and heated intraoperative intraperitoneal chemotherapy for treatment of peritoneal carcinomatosis in primary and recurrent ovarian cancer Ann Oncol 2007 18 1943 1950 10.1093/annonc/mdm137 17496308 \n34. Gore M du Bois A Vergote I Intraperitoneal chemotherapy in ovarian cancer remains experimental J Clin Oncol 2006 24 4528 4530 10.1200/JCO.2006.06.0376 17008689 \n35. Harter P Heitz F du Bois A Surgery for relapsed ovarian cancer: when should it be offered? Curr Oncol Rep 2012 14 6 539 543 10.1007/s11912-012-0260-x 22918696 \n36. Lan H Cronin KA Johnson KA Improved survival time: what can survival cure models tell us about population-based survival improvements in late-stage colorectal, ovarian, and testicular cancer? Cancer 2010 112 2289 2300 \n37. Stephens FO Harker GJS Crea P The intra-arterial infusion of chemotherapeutic agents as “basal” treatment of cancer: evidence of increased drug activity in regionally infused tissues Aust NZ J Surg 1980 50 597 602 10.1111/j.1445-2197.1980.tb04205.x \n38. Stephens FO Why use regional chemotherapy? Principles and pharmacokinetics Reg Cancer Treat 1988 1 4 10 \n39. Guadagni S Clementi M Valenti M Fiorentini G Cantore M Kanavos E Caterino GP di Giuro G Amicucci G Hypoxic abdominal stop-flow perfusion in the treatment of advanced pancreatic cancer: a phase II evaluational trial Eur J Surg Oncol 2007 33 72 7840 10.1016/j.ejso.2006.10.042 17166688 \n40. Stephens FO Induction (neo-adjuvant) chemotherapy: the place and techniques of using chemotherapy to downgrade aggressive or advanced localised cancers to make them potentially more curable by surgery and/or radiotherapy Eur J Surg Oncol 2001 27 627 688 10.1053/ejso.2001.1158 \n41. Hellmann M Kris MG Rudin CM Medians and milestones in describing the path to cancer cures: telling “tails” JAMA Oncol 2016 2 167 168 10.1001/jamaoncol.2015.4345 26583516 \n42. Aigner KR, Stephens FO (2012) Guidelines and evidence-based medicine – evidence of what? EJCMO 4:(3). Available at: http://www.slmoncology.com/Guidelines_and_Evidence_Based_Medicine_Evidence_of_What_,1,272.html. Accessed Sept 2012\n\n",
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"journal": "Indian journal of surgical oncology",
"keywords": "Chemoresistance; Intra-arterial chemotherapy; Isolated abdominal perfusion; Ovarian cancer; Quality of life",
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"title": "Hypoxic Isolated Abdominal Perfusion (HAP) chemotherapy for non-operable advanced staged ovarian cancer with peritoneal carcinosis: an experience in 45 platinum-refractory ovarian cancer patients.",
"title_normalized": "hypoxic isolated abdominal perfusion hap chemotherapy for non operable advanced staged ovarian cancer with peritoneal carcinosis an experience in 45 platinum refractory ovarian cancer patients"
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"abstract": "Hyponatraemia is the most common electrolyte anomaly and is associated with significant morbidity and mortality. Patients with severe hyponatraemia often present to acute medical units with non-specific symptoms which can progress to overt neurological manifestations. There are many causes of hyponatriaemia, the most common being drug-induced causes, particularly thiazide diuretics, and the Syndrome of Inappropriate ADH Secretion (SIADH). Initial assessment should include a careful evaluation of the patient's volume status, which helps to identify the most likely cause. This article utilises a recent case which presented to our AMU to illustrate the importance of a careful and systematic assessment of patients presenting to hospital with hyponatraemia. The new vasopressin receptor antagonists are explored as an option for the management of severe hyponatraemia.",
"affiliations": "FY1 Trainee, The Royal Wolverhampton Hospitals NHS Trust, Wolverhampton, West Midlands.;CT1 in General Medicine, Alexandra Hospital, Redditch, West Midlands.;Consultant Physician in Acute and Renal Medicine, Walsall Hospitals NHS Trust, Walsall, West Midlands.;Consultant Physician in acute and General Medicine, Walsall Hospitals NHS Trust, Walsall, West Midlands.",
"authors": "Saeed|M|M|;Ahmad|S|S|;Hayat|A|A|;Saeed|S|S|",
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"issue": "13(2)",
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"mesh_terms": "D000368:Aged; D003937:Diagnosis, Differential; D005260:Female; D005440:Fluid Therapy; D006801:Humans; D007010:Hyponatremia; D007177:Inappropriate ADH Syndrome; D012964:Sodium; D049993:Sodium Chloride Symporter Inhibitors",
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"title": "Problem based review: the patient presenting with hyponatraemia.",
"title_normalized": "problem based review the patient presenting with hyponatraemia"
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"abstract": "BACKGROUND\nThe relevance of oncology trial results to clinical practice depends on whether the trial participants are similar to the actual population of patients receiving treatment for the malignancy and whether the patients are treated similarly in both circumstances. Chemotherapy treatments may be more toxic in patients of advanced age and poor performance status-patients typically excluded from clinical trials.\n\n\nMETHODS\nIn a retrospective chart review that included all non-trial patients with metastatic colorectal cancer treated with irinotecan-based chemotherapy from January 2004 to September 2006 at our institution, we quantified and subsequently compared the toxicity rates of the irinotecan regimens in clinical practice with published toxicity rates from corresponding phase iii clinical trials. The primary endpoint was the incidence of grades 3 and 4 diarrhea.\n\n\nRESULTS\nThe study included 203 patients, and the irinotecan regimens considered included FOLFIRI [irinotecan, leucovorin, 5-fluorouracil (5fu)],IFL (bevacizumab, irinotecan, 5FU, leucovorin),XELIRI (capecitabine, 3-weekly irinotecan), andirinotecan monotherapy. The rates of grades 3 and 4 diarrhea for FOLFIRI, IFL, XELIRI, and irinotecan monotherapy in clinical practice were 10%, 15%, 17%, and 21% as compared with 10%, 23%, 20%, and 31% respectively in clinical trials. When only patients meeting trial performance status and age criteria were analyzed, the rates of grades 3 and 4 diarrhea by regimen were 11%, 20%, 19%, and 26% respectively.\n\n\nCONCLUSIONS\nOverall, the toxicity rates for FOLFIRI and irinotecan monotherapy in non-trial patients were not statistically different from the rates quoted in published clinical trials.",
"affiliations": "Department of Medicine, McMaster University, Hamilton, ON.",
"authors": "Tam|V C|VC|;Rask|S|S|;Koru-Sengul|T|T|;Dhesy-Thind|S|S|",
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"doi": "10.3747/co.v16i6.426",
"fulltext": "\n==== Front\nCurr OncolCOCurrent Oncology1198-00521718-7729Multimed Inc. 66 Martin St. Milton, ON, Canada L9T 2R2 20016742co16-6-413E-Manuscript Article SummaryMedical OncologyGeneralizability of toxicity data from oncology clinical trials to clinical practice: toxicity of irinotecan-based regimens in patients with metastatic colorectal cancer Tam V.C. MD BSc (HON)*Rask S. MD BSc†Koru–Sengul T. MHS MA PhD†Dhesy–Thind S. MD MSc‡* Department of Medicine, McMaster University, Hamilton, ON† Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON‡ Department of Oncology, McMaster University, Juravinski Cancer Centre, Hamilton, ONCorrespondence to: Sukhbinder Dhesy–Thind, Juravinski Cancer Centre, 699 Concession Street, Hamilton, Ontario L8V 5C2. E-mail:bindi.dhesy@jcc.hhsc.ca12 2009 16 6 13 20 2009 Multimed Inc.This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nThe relevance of oncology trial results to clinical practice depends on whether the trial participants are similar to the actual population of patients receiving treatment for the malignancy and whether the patients are treated similarly in both circumstances. Chemotherapy treatments may be more toxic in patients of advanced age and poor performance status—patients typically excluded from clinical trials.\n\nMethods\nIn a retrospective chart review that included all non-trial patients with metastatic colorectal cancer treated with irinotecan-based chemotherapy from January 2004 to September 2006 at our institution, we quantified and subsequently compared the toxicity rates of the irinotecan regimens in clinical practice with published toxicity rates from corresponding phase iii clinical trials. The primary endpoint was the incidence of grades 3 and 4 diarrhea.\n\nResults\nThe study included 203 patients, and the irinotecan regimens considered included\n\n\nfolfiri [irinotecan, leucovorin, 5-fluorouracil (5fu)],\n\nifl (bevacizumab, irinotecan, 5fu, leucovorin),\n\nxeliri (capecitabine, 3-weekly irinotecan), and\n\nirinotecan monotherapy.\n\n\n\nThe rates of grades 3 and 4 diarrhea for folfiri, ifl, xeliri, and irinotecan monotherapy in clinical practice were 10%, 15%, 17%, and 21% as compared with 10%, 23%, 20%, and 31% respectively in clinical trials. When only patients meeting trial performance status and age criteria were analyzed, the rates of grades 3 and 4 diarrhea by regimen were 11%, 20%, 19%, and 26% respectively.\n\nConclusions\nOverall, the toxicity rates for folfiri and irinotecan monotherapy in non-trial patients were not statistically different from the rates quoted in published clinical trials.\n\nColorectal neoplasmsdrug therapydrug toxicityclinical trials\n==== Body\n1. INTRODUCTION\nDespite that fact that colorectal cancers tend to occur in elderly people, oncology clinical trials have tended to exclude elderly patients in favour of patients who are younger and who have fewer comorbidities and a better performance status 1,2. These population effects—that is, the differences between clinical trial and non-trial patient populations—have led to a general belief that patients enrolled in clinical trials have outcomes that are superior compared with those in patients who are not included 3–5. Trial effects—such as increased frequency of medical imaging, more frequent follow-up visits, and additional attention by clinical trials staff during treatment—may lead to additional benefit for cancer patients participating in clinical trials.\n\nDespite these assumptions, a systematic review has shown that the evidence is insufficient to support a claim of improved outcomes for cancer patients who participate in clinical trials as compared with patients who are not trial participants 6. However, all of the studies included in that review focused on efficacy endpoints such as overall survival and response to treatment; few reported on toxicity.\n\nIrinotecan-based chemotherapy regimens are frequently used in the treatment of metastatic colon cancer, and they have extended the median survival of patients with this disease to 20 months 7. However, this survival benefit is not without risk, because irinotecan regimens are associated with high rates of severe diarrhea 8–10. Although the toxicity rates for folfiri [irinotecan, leucovorin, 5-fluorouracil (5fu)], ifl (bevacizumab, irinotecan, 5fu, leucovorin), xeliri (capecitabine, 3-weekly irinotecan), and irinotecan monotherapy are well documented in publications of phase ii and iii clinical trials, we are unaware of any studies that document the toxicity of these regimens in clinical practice. The objective of the present study was to determine whether chemotherapy toxicity rates in non-trial patients are similar to those quoted in published clinical trials.\n\n2. PATIENTS AND METHODS\n2.1 Study Design\nIn a retrospective single-institution chart review, the incidence of irinotecan-based chemotherapy toxicity in the palliative treatment of patients with metastatic colorectal cancer was characterized. Toxicity rates in clinical practice were compared with those described in the largest phase iii clinical trial published to date for each regimen. The primary endpoint was the incidence of grades 3 and 4 diarrhea. Secondary endpoints included the incidence of other grade 3 or 4 toxicities, hospital admissions for toxicity related to chemotherapy, dose reductions or delays because of toxicity, discontinuation of chemotherapy secondary to toxicity, and chemotherapy-related mortality.\n\nPatients with metastatic colorectal adenocarcinoma treated with folfiri, ifl, xeliri, or irinotecan monotherapy (Table I) between January 1, 2004, and September 30, 2006, at the Juravinski Cancer Centre (jcc) in Hamilton, Ontario, Canada, were included in the study. Patients were excluded if they received the chemotherapy of interest in a clinical trial, if their pathology was not adenocarcinoma, if they lacked documented metastatic sites, and if they received the chemotherapy of interest at an institution other than the jcc. Charts of the included patients were reviewed for demographic, pathology, treatment, and toxicity data. Two investigators (VCT, SR) completed the data abstraction. Ten percent of the charts were evaluated by both investigators to determine inter-observer variability. Differences in data abstraction were resolved by consensus. The remaining 90% of the charts were then randomly divided between the two investigators for data abstraction.\n\nToxicities were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0. If a toxicity grade was not clearly stated in the patient’s chart, the two physician investigators abstracting the data determined a grade based on the information available in each chart according to the previously stated criteria. Toxicity rates observed in patients treated at the jcc were compared with rates from a clinical trial that delivered the identical irinotecan regimen. A separate analysis was conducted to compare younger patients (70 years of age or younger) with elderly patients (older than 70 years of age). A similar comparison was attempted for patients having a good or fair performance status [Eastern Cooperative Oncology Group (ecog) 0–2] with those having a poor performance status (ecog 3–4).\n\nFor each regimen included in the study, a representative comparator was chosen from the literature. Where possible, the selected comparator was the largest phase iii trial that used the dose regimen also used at our institution. Our main comparator for folfiri toxicity was the phase iii clinical trial conducted by Colucci et al. 11 The toxicity rates for ifl and irinotecan monotherapy were compared with the phase iii trial data published by Saltz et al. 9 Unfortunately, phase iii toxicity data were not available for xeliri at the time of our data analysis. The chosen comparator was therefore a phase ii study by Patt et al. 12, which was the clinical trial with the largest sample size published up to the time of our data analysis.\n\n2.2 Statistical Analysis\nData were recorded and organized using a Microsoft Excel spreadsheet (Redmond, WA, U.S.A.). Statistical analysis was performed using SAS for Windows (version 9.1: SAS Institute, Cary, NC, U.S.A.). Inter-observer variability in data abstraction was assessed by calculating percentage agreement and kappa statistics. Unadjusted and adjusted analyses were both performed. The unadjusted analysis included all non-trial patients; it describes any benefit derived from the combination of population and trial effects. The adjusted analysis excluded all non-trial patients who did not meet the clinical trial age and performance status criteria described in the corresponding comparator trials, effectively eliminating population effects and focusing on trial effects. Tabulations and descriptive statistics were used to analyze the toxicity data. Two-sided hypothesis tests for proportions were performed using the chi-square test or the Fisher exact test when appropriate. A p value less than or equal to 0.05 was considered significant.\n\n3. RESULTS\n3.1 Patient Characteristics\nFigure 1 outlines the patient selection process. The study included 203 patients in the unadjusted analysis. Of the 203 patients, 137 (67%) met the age and performance status criteria of their respective comparator clinical trials, and they were used in the adjusted analysis.\n\nTable II outlines the characteristics of the 203 patients. Fifty patients were over the age of 70 years, and 34 of those patients received irinotecan monotherapy. An ecog performance status at the time of therapy was not recorded for 29% of the patients. Of the patients with a clearly described ecog performance status, 95% were classified as better than or equal to 2. At the time of cancer diagnosis, 64% of the patients presented with metastatic disease. Upon initiation of irinotecan treatment, 64% of the patients had two or more metastatic sites. Liver metastases were present in 78% of the patients.\n\nFor the charts reviewed in duplicate, agreement was 100% (κ = 1.0) between the two investigators for most of the abstracted data. The exceptions were dose reductions and dose delays. Agreement for the number of dose reductions was 96% (κ = 0.93), and for dose delays, it was 85% (κ = 0.72).\n\n3.2 Rates of Toxicity in the Unadjusted Analysis\nTable III outlines rates of common toxicities encountered by non-trial patients during treatment with irinotecan regimens. Overall, diarrhea was the most common adverse event, occurring in 61% of all non-trial patients. Grades 3 and 4 diarrhea were reported in 10% of patients receiving folfiri, in 15% receiving ifl, in 17% receiving xeliri, and in 21% receiving irinotecan monotherapy. There was no statistically significant difference in the rates of grades 3 and 4 diarrhea observed in non-trial patients treated with the four irinotecan regimens as compared with the rates observed in patients treated in the comparator clinical trials.\n\nNeutropenia was the second most common toxicity, occurring in 54% of the patients. Grades 3 and 4 neutropenia were reported in 22% of patients receiving folfiri, in 15% receiving ifl, in 11% receiving xeliri, and in 19% receiving irinotecan monotherapy. The rate of grades 3 and 4 neutropenia was significantly higher in the non-trial patients treated with folfiri than in the patients in the study by Colucci et al. (p < 0.01). For ifl and irinotecan monotherapy, the rates of grades 3 and 4 neutropenia were significantly lower in the non-trial patients than in the patients in the published comparator studies (p = 0.01 and p = 0.02 respectively). A significantly lower rate of grades 3 and 4 vomiting was also observed for non-trial patients treated with irinotecan monotherapy as compared with patients in the clinical trial by Saltz et al. (p = 0.05).\n\nOnly 9 patients developed febrile neutropenia during the study period. Grade 3 febrile neutropenia was observed in 5% of patients receiving folfiri, 8% receiving ifl, 6% receiving xeliri, and 3% receiving irinotecan monotherapy. No reports of grade 4 febrile neutropenia were found for the patients included in the present study.\n\n3.3 Rates of Toxicity in the Adjusted Analysis\nTable III also shows toxicity rates resulting from the adjusted analysis. Grades 3 and 4 diarrhea were reported in 11% of patients receiving folfiri, in 20% receiving ifl, in 19% receiving xeliri, and in 26% receiving irinotecan monotherapy. Again, there was no statistically significant difference between the rates of grades 3 and 4 diarrhea observed with the four irinotecan regimens in the non-trial patients and the rates observed in the relevant published clinical trial data.\n\nWith the exclusion of non-trial patients who failed to meet the age and performance criteria in the comparator clinical trials, no significant changes in the toxicity rates occurred. For folfiri in the non-trial population, the rates of mucositis and vomiting of any grade remained significantly lower and the rates of neutropenia of any grade and grades 3 and 4 neutropenia remained significantly higher than the rates reported in the clinical trial results. The rates of grades 3 and 4 neutropenia with ifl, vomiting of any grade with xeliri, and grades 3 and 4 vomiting with irinotecan monotherapy remained significantly lower in non-trial patients. The lower rate of grades 3 and 4 neutropenia for non-trial patients treated with irinotecan monotherapy was no longer statistically significant in the adjusted analysis (p = 0.12).\n\n3.4 Consequences of Chemotherapy Toxicity\nTable IV shows the clinical consequences of toxicities from treatment with the four irinotecan regimens. Only selected consequences of chemotherapy toxicity were reported in the publications of the comparator trials, and therefore a systematic comparison was not possible. With the information provided by the comparator clinical trial publications, we found several statistically significant differences. In the unadjusted analysis, the rate of premature discontinuation of ifl treatment secondary to toxicity was 31% in the non-trial patients as compared with 8% in the trial patients (p = 0.02). For non-trial patients treated with irinotecan monotherapy, the rate of premature discontinuation of irinotecan chemotherapy in the non-trial patients secondary to toxicity was in the range 24%–26%, which was significantly higher than the 6% quoted in the comparator trial (p < 0.01). A similar trend was observed for deaths related to irinotecan monotherapy toxicity, which showed a death rate in non-trial patients of 4%–7% as compared with 1% in the comparator trial (p = 0.03).\n\nOverall, there was no clear trend toward an increase or decrease in the rates of toxicity consequences when comparing the unadjusted and adjusted analyses. The highest rates of hospital admission, dose delays, premature discontinuation of irinotecan chemotherapy, and deaths related to irinotecan chemotherapy were seen with ifl as compared with the other three irinotecan regimens. The rate of overall death while on irinotecan chemotherapy was also highest in patients treated with ifl (15%).\n\n3.5 Comparison of Toxicity According to Age\nThe analysis of irinotecan toxicity in younger patients as compared with elderly patients (older than 70 years) showed no significant differences in the rates of diarrhea, mucositis, vomiting, neutropenia, and febrile neutropenia between the two groups. However, admissions for chemotherapy side effects were significantly more frequent in the elderly patients as compared with the younger patients (26% vs. 10%, p = 0.02). The incidence of premature discontinuation of irinotecan chemotherapy was also significantly higher in the elderly patients (30% vs. 14%, p = 0.02).\n\n3.6 Comparison of Toxicity According to Performance Status\nIn 145 patients, a performance status was clearly defined; data regarding performance status were unavailable in the remaining patient records. Irinotecan toxicity for patients with a good or fair performance status (ecog 0–2) was compared with that for patients with a poor performance status (ecog 3–4). However, only 7 non-trial patients had a poor performance status, and the sample size was therefore too small for any meaningful comparisons to be made.\n\n4. DISCUSSION\nAs compared with patients in published clinical trials, non-trial patients with metastatic colorectal cancer do not appear to experience increased rates of toxicity when treated with irinotecan chemotherapy. The only exception is a higher rate of grades 3 and 4 neutropenia in non-trial patients treated with folfiri: 22% versus 10% in a comparator study (p < 0.01). However, that finding might be explained by the abnormally low rate of grades 3 and 4 neutropenia reported in the study by Colucci et al. The combined incidence of grades 3 and 4 neutropenia in phase iii clinical trials of folfiri has been noted to be 24%, which is nearly equivalent to the rate in our study population 7.\n\nThe rates of several toxicities were actually significantly lower in our non-trial patients, as in the case of vomiting of any grade in the folfiri group and of grades 3 and 4 neutropenia in the ifl group. One possible explanation for these differences is that the documentation of toxicities is poor in the chart notes of non-trial patients as compared with patients on clinical trials. Some of the significantly lower toxicity rates may also be a result of chance, because multiple comparisons were made and sample sizes were small in some groups—particularly for ifl, which is now seldom used in clinical practice, and for xeliri, which is a relatively new regimen.\n\nPeppercorn et al. published a systematic review of studies comparing outcomes between trial and non-trial cancer patients 6. In unadjusted analyses, 13 of 21 studies (62%) showed some evidence of improved outcomes in trial patients. In adjusted analyses, where confounding factors were accounted for, 11 of 17 studies (65%) showed better outcomes in the trial patients. However, the overall conclusion by those authors was that the evidence is insufficient to prove that enrolment in cancer clinical trials leads to improved outcomes. It should be noted that nearly all the outcomes examined by studies in the systematic review were efficacy endpoints such as survival and response rate. Because treatment decisions are based both on efficacy and on toxicity of a chemotherapy regimen, our study provides oncologists with important evidence supporting the generalizability of clinical trial toxicity rates to non-trial patients.\n\nSpecific age and performance status criteria are prominent in the inclusion criteria for many clinical trials. These factors are important in the analysis of irinotecan toxicity, because age older than 70 years and ecog performance status less than 2 have generally been regarded as risk factors for developing irinotecan toxicity. As a result, several large clinical trials of irinotecan regimens have used an initial dose reduction for all elderly patients 13–15.\n\nWith respect to age, it is well documented that patients enrolled in clinical trials tend to be younger than non-trial patients and also younger than the overall population of patients with the malignancy 1,2,4. Differences in age are theoretically important, because medications have different pharmacokinetics in elderly people, who tend to have decreased renal and liver function, lower total body water, and higher amounts of adipose tissue 16,17. In addition, elderly people are generally perceived as having multiple comorbid conditions, limited socioeconomic support, and reduced cognition, which may limit the potential benefit from systemic cancer therapy 17. Despite these theoretic risks, we did not find any significant increase in grades 3 and 4 toxicity rates in non-trial patients older than 70 years. Our findings are supported by several studies that have found irinotecan regimens to be well tolerated in fit elderly patients 18–21. Thus, the current general consensus is that elderly patients fit enough to enrol in clinical trials can be treated with chemotherapy. Frail elderly patients are more likely to suffer adverse outcomes when faced with stressors, and they should not receive systemic chemotherapy. Unfortunately, because of the underrepresentation of elderly patients in cancer clinical trials, the evidence is insufficient to support or oppose the use of chemotherapy in the preponderance of elderly patients who have an intermediate performance status 22.\n\nIt has been well established that patients with a poor performance status have a worse prognosis and that they may have reduced response to chemotherapy treatment and increased rates of toxicity 23. As a result, these patients are almost always excluded from clinical trials. Of patients in the present study with a clearly defined performance status, the proportion that were ecog 0 or 1 was 82% among non-trial folfiri patients as compared with 98% among patients in the Colucci et al. comparator study. Also, of our non-trial folfiri patients with a clearly determined performance status, 5% had an ecog performance status of 3 and would have been ineligible for the comparator trial. That ineligible proportion may have been even greater, given that performance status was not documented for 26% of the folfiri patients.\n\nThe present study has several limitations. Because of the retrospective design, we were unable to mandate rigorous documentation of toxicities for the non-trial patients, possibly leading to underestimation of toxicity rates. Although we attempted to adjust the analysis for the inclusion criteria of the clinical trials, only age and performance status were accounted for. The four comparator trials used numerous exclusion criteria that varied between them, preventing a practical accounting for those criteria in the non-trial population.\n\n5. CONCLUSIONS\nThe folfiri and irinotecan monotherapy regimens do not appear to cause higher rates of toxicity in non-trial patients than in patients treated in clinical trials. However, we advise caution in generalizing clinical trial toxicity data to patients who fail to meet trial inclusion criteria.\n\n6. CONFLICT OF INTEREST DISCLOSURE\nThis study received no funding support.\n\nFigure 1 Method of patient selection. jcc = Juravinski Cancer Centre; capiri = capecitabine–irinotecan.\n\nTABLE I Chemotherapy regimens\n\nRegimen name\tChemotherapy agents\tStarting dose\tSchedule per cycle\t\nfolfiri\tIrinotecan\t180 mg/m2\tOnce every 2 weeks\t\n\t5-Fluorouracil\t2400 mg/m2 24-h intravenous infusion\tWith irinotecan\t\n\tLeucovorin\t400 mg/m2\tWith irinotecan\t\nifl\tIrinotecan\t80–125 mg/m2 or 180 mg/m2\tOnce weekly for 4–6 weeks \nOnce every 2 weeks\t\n\t5-Fluorouracil\t2400 mg/m2 intravenous bolus\tWith irinotecan\t\n\tLeucovorin\t400 mg/m2\tWith irinotecan\t\nxeliri\tIrinotecan\t250 mg/m2\tOnce every 3 weeks\t\n\tCapecitabine\t1000 mg/m2 orally\tTwice daily for 14 days\t\nIrinotecan monotherapy\tIrinotecan\t80 mg/m2 or 125 mg/m2\tOnce weekly for 4 weeks \nOnce weekly for 4 weeks\t\nTABLE II Patient characteristics\n\nCharacteristic\tRegimen group\t\n\tfolfiri (n=102)\tifl (n=13)\txeliri (n=18)\tIrinotecan monotherapy (n=70)\t\nAge (years)a\t\n Mean ± standard deviation\t59±10\t59±11\t58±14\t68±9\t\n Median\t61\t54\t60\t70\t\n Range\t29–84\t46–83\t19–73\t44–84\t\nAge > 70 years [n (%)]\t10 (10)\t2 (15)\t4 (22)\t34 (49)\t\nSex [n (%)]\t\n Female\t46 (45)\t6 (46)\t8 (44)\t25 (36)\t\n Male\t56 (55)\t7 (54)\t10 (56)\t45 (64)\t\necog performance status [n (%)]\t\n 0\t35 (34)\t3 (23)\t9 (50)\t21 (30)\t\n 1\t26 (26)\t2 (15)\t6 (33)\t15 (21)\t\n 2\t10 (10)\t0 (0)\t1 (6)\t10 (14)\t\n 3\t4 (4)\t0 (0)\t0 (0)\t3 (4)\t\n Not available\t27 (26)\t8 (62)\t2 (11)\t21 (30)\t\nSite of primary tumour [n (%)]\t\n Colon\t62 (61)\t7 (54)\t14 (78)\t39 (56)\t\n Rectum\t37 (36)\t5 (38)\t4 (22)\t31 (44)\t\n Not available\t3 (3)\t0 (0)\t0 (0)\t0 (0)\t\nMetastatic at diagnosis [n (%)]\t\n Yes\t60 (59)\t9 (69)\t13 (72)\t47 (67)\t\n No\t42 (41)\t4 (31)\t5 (28)\t23 (33)\t\nPathology [n (%)]\t\n Well differentiated\t7 (7)\t1 (8)\t0 (0)\t2 (3)\t\n Moderately differentiated\t73 (72)\t9 (69)\t15 (83)\t45 (64)\t\n Poorly differentiated\t20 (20)\t0 (0)\t1 (6)\t17 (24)\t\n Undifferentiated\t0 (0)\t0 (0)\t1 (6)\t0 (0)\t\n Not available\t2 (2)\t3 (23)\t1 (6)\t6 (9)\t\nMetastatic sites [n (%)]\t\n 1\t31 (30)\t6 (46)\t6 (33)\t27 (39)\t\n 2\t40 (39)\t4 (31)\t7 (39)\t28 (40)\t\n >2\t31 (30)\t3 (23)\t5 (28)\t15 (21)\t\nLiver involvement [n (%)]\t\n Yes\t77 (76)\t9 (69)\t15 (83)\t57 (81)\t\n No\t25 (24)\t4 (31)\t3 (17)\t13 (19)\t\na At date of first irinotecan treatment.\n\nfolfiri = irinotecan, leucovorin, 5-fluorouracil; ifl = bevacizumab, irinotecan, 5-fluorouracil, leucovorin; xeliri = capecitabine, 3-weekly irinotecan; ecog = Eastern Cooperative Oncology Group.\n\nTABLE III Toxicity comparisons by regimen\n\nRegimen and toxicity\tUnadjusted analysis\tAdjusted analysis\t\n\tTrial pts [n (%)]\tNon-trial pts [n (%)]\tp Value\tNon-trial pts [n (%)]\tp Value\t\nfolfiri\t(n=178)a\t(n=102)\t\t(n=70)\t\t\n Diarrhea\t\n Any grade\t113 (63)\t55 (54)\t0.07\t39 (56)\t0.26\t\n Grades 3 and 4\t18 (10)\t10 (10)\t1.00\t8 (11)\t0.80\t\n Mucositis\t\n Any grade\t63 (35)\t22 (22)\t<0.01\t16 (23)\t0.04\t\n Grades 3 and 4\t2 (1)\t1 (1)\t1.00\t1 (1)\t1.00\t\n Vomiting\t\n Any grade\t128 (71)\t26 (26)\t<0.01\t19 (27)\t<0.01\t\n Grades 3 and 4\t8 (4)\t3 (3)\t1.00\t2 (3)\t0.93\t\n Neutropenia\t\n Any grade\t80 (45)\t57 (56)\t<0.01\t43 (61)\t<0.01\t\n Grades 3 and 4\t17 (10)\t23 (22)\t<0.01\t16 (23)\t<0.01\t\n Febrile neutropenia\t\n Any grade\tna\t5 (5)\t—\t4 (6)\t—\t\n Grades 3 and 4\tna\t5 (5)\t—\t4 (6)\t—\t\nifl\t(n=225)b\t(n=13)\t\t(n=5)\t\t\n Diarrhea\t\n Any grade\tna\t8 (62)\t—\t4 (80)\t—\t\n Grades 3 and 4\tna (23)\t2 (15)\t0.81\t1 (20)\t1.00\t\n Mucositis\t\n Any grade\tna\t3 (23)\t—\t1 (20)\t—\t\n Grades 3 and 4\tna (2)\t0 (0)\t1.00\t0 (0)\t1.00\t\n Vomiting\t\n Any grade\tna\t2 (15)\t—\t1 (20)\t—\t\n Grades 3 and 4\tna (10)\t0 (0)\t0.53\t0 (0)\t1.00\t\n Neutropenia\t\n Any grade\tna\t9 (69)\t—\t4 (80)\t—\t\n Grades 3 and 4\tna (54)\t2 (15)\t0.01\t0 (0)\t0.04\t\n Febrile neutropenia\t\n Any grade\tna (7)\t1 (8)\t1.00\t1 (20)\t0.61\t\n Grades 3 and 4\tna\t1 (8)\t—\t1 (20)\t—\t\nxeliri\t(n=51)c\t(n=18)\t\t(n=16)\t\t\n Diarrhea\t\n Any grade\tna (78)\t14 (78)\t1.00\t12 (75)\t0.96\t\n Grades 3 and 4\tna (20)\t3 (17)\t1.00\t3 (19)\t1.00\t\n Mucositis\t\n Any grade\tna\t1 (6)\t—\t1 (6)\t—\t\n Grades 3 and 4\tna\t0 (0)\t—\t0 (0)\t—\t\n Vomiting\t\n Any grade\tna (61)\t6 (33)\t0.03\t5 (31)\t0.03\t\n Grades 3 and 4\tna (17)\t0 (0)\t0.07\t0 (0)\t0.10\t\n Neutropenia\t\n Any grade\tna (37)\t6 (33)\t0.98\t5 (31)\t0.85\t\n Grades 3 and 4\tna (25)\t2 (11)\t0.27\t2 (12)\t0.39\t\n Febrile neutropenia\t\n Any grade\tna\t1 (6)\t—\t1 (6)\t—\t\n Grades 3 and 4\tna\t1 (6)\t—\t1 (6)\t—\t\nIrinotecan monotherapy\t(n=223)b\t(n=70)\t\t(n=46)\t\t\n Diarrhea\t\n Any grade\tna\t46 (66)\t—\t31 (67)\t—\t\n Grades 3 and 4\tna (31)\t15 (21)\t0.10\t12 (26)\t0.58\t\n Mucositis\t\n Any grade\tna\t5 (7)\t—\t3 (6)\t—\t\n Grades 3 and 4\tna (2)\t1 (1)\t1.00\t1 (2)\t1.00\t\n Vomiting\t\n Any grade\tna\t19 (27)\t—\t12 (26)\t—\t\n Grades 3 and 4\tna (12)\t3 (4)\t0.05\t1 (2)\t0.04\t\n Neutropenia\t\n Any grade\tna\t38 (54)\t—\t29 (63)\t—\t\n Grades 3 and 4\tna (31)\t13 (19)\t0.02\t9 (19)\t0.12\t\n Febrile neutropenia\t\n Any grade\tna (6)\t2 (3)\t0.44\t2 (4)\t0.94\t\n Grades 3 and 4\tna\t2 (3)\t—\t2 (4)\t—\t\na Colucci et al. 11\n\nb Saltz et al. 9\n\nc Patt et al. 13\n\nna = not available from published clinical trial article.\n\nTABLE IV Consequences of chemotherapy toxicity\n\nConsequence of toxicity\tPatients [n (%)]\t\nfolfiri\tifl\txeliri\tIrinotecan monotherapy\t\nAdjusted\tAdjusted\tAdjusted\tAdjusted\t\nNo (n=102)\tYes (n=70)\tNo (n=13)\tYes (n=5)\tNo (n=18)\tYes (n=16)\tNo (n=70)\tYes (n=46)\t\nOne or more admissions for irinotecan chemo-therapy side effects\t11 (11)\t8 (11)\t3 (23)\t1 (20)\t1 (6)\t1 (6)\t13 (19)\t10 (22)\t\nDose delays secondary to irinotecan toxicity\t43 (42)\t31 (44)\t9 (69)\t4 (80)\t6 (33)\t6 (38)\t30 (43)\t18 (39)\t\nDose reductions secondary to irinotecan toxicity\t40 (39)\t29 (41)\t3 (23)\t1 (20)\t8 (44)\t7 (44)\t35 (50)\t23 (50)\t\nPremature discontinuation of irinotecan chemo- therapy secondary to toxicity\t12 (12)\t9 (13)\t4 (31)\t2 (40)\t3 (17)\t2 (12)\t17 (24)\t12 (26)\t\nDeaths while still on irinotecan chemotherapy\t9 (9)\t4 (6)\t2 (15)\t0 (0)\t0 (0)\t0 (0)\t6 (9)\t3 (7)\t\nDeaths related to irinotecan chemotherapy toxicity\t0 (0)\t0 (0)\t1 (8)\t0 (0)\t0 (0)\t0 (0)\t3 (4)\t3 (7)\n==== Refs\n7. REFERENCES\n1 Elting LS Cooksley C Bekele BN Generalizability of cancer clinical trial results: prognostic differences between participants, and nonparticipants Cancer 2006 106 2452 8 16639738 \n2 Hori A Shibata T Kami M Age disparity between a cancer population and participants in clinical trials submitted as a new drug application of anticancer drugs in Japan Cancer 2007 109 2541 6 17477381 \n3 Mayers C Panzarella T Tannock IF Analysis of prognostic effects of inclusion in clinical trial and of myelosuppression on survival after adjuvant chemotherapy for breast carcinoma Cancer 2001 91 2246 57 11413512 \n4 Cottin V Arpin D Lasset C Small-cell lung cancer: patients included in clinical trials are not representative of the patient population as a whole Ann Oncol 1999 10 809 15 10470428 \n5 Fossa SD Skovlund E Selection of patients may limit generalizability of results from cancer clinical trials Acta Oncol 2002 41 131 7 12102156 \n6 Peppercorn JM Weeks JC Cook EF Joffe S Comparison of outcomes in cancer patients treated within, and outside clinical trials: conceptual framework, and structured review Lancet 2004 363 263 70 14751698 \n7 Kelly H Goldberg RM Systemic therapy for metastatic colorectal cancer: current options, current evidence J Clin Oncol 2005 23 4553 60 16002847 \n8 Douillard JY Cunningham D Roth AD Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial Lancet 2000 355 1041 7 10744089 \n9 Saltz LB Cox JV Blanke C Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer N Engl J Med 2000 343 905 14 11006366 \n10 Köhne CH van Cutsem E Wils J Phase iii study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986 J Clin Oncol 2005 23 4856 65 15939923 \n11 Colucci G Vittorio G Paoletti G Phase iii randomized trial of folfiri versus folfox4 in the treatment of advanced colorectal cancer: a multicenter study of the Gruppo Oncologico Dell’Italia Meridionale J Clin Oncol 2005 23 4866 75 15939922 \n12 Patt YZ Lee FC Liebmann JE Capecitabine plus 3-weekly irinotecan (xeliri regimen) as first-line chemotherapy for metastatic colorectal cancer: phase ii trial results Am J Clin Oncol 2007 30 350 7 17762434 \n13 Cunningham D Pyrhonen S James RD Randomised trial of irinotecan plus supportive care versus supportive care alone after fluorouracil failure for patients with metastatic colorectal cancer Lancet 1998 352 1413 18 9807987 \n14 Rougier P Van Cutsem E Bajetta E Randomised trial of irinotecan versus fluorouracil by continuous infusion after fluorouracil failure in patients with metastatic colorectal cancer Lancet 1998 352 1407 12 9807986 \n15 Fuchs CS Moore MR Harker G Villa L Rinaldi D Hecht JR Phase iii comparison of two irinotecan dosing regimens in second-line therapy of metastatic colorectal cancer J Clin Oncol 2003 21 807 14 12610178 \n16 Repetto L Greater risks of chemotherapy toxicity in elderly patients with cancer J Support Oncol 2003 1 suppl 2 18 24 15346996 \n17 Balducci L Extermann M Cancer chemotherapy in the older patient: what the medical oncologist needs to know Cancer 1997 80 1317 22 9317185 \n18 Chau I Norman AR Cunningham D Elderly patients with fluoropyrimidine and thymidylate synthase inhibitor–resistant advanced colorectal cancer derive similar benefit without excessive toxicity when treated with irinotecan monotherapy Br J Cancer 2004 91 1453 8 15365570 \n19 Fata F Mirza A Craig Wood G Efficacy, and toxicity of adjuvant chemotherapy in elderly patients with colon carcinoma: a 10-year experience of the Geisinger Medical Center Cancer 2002 94 1931 8 11932894 \n20 Sastre J Marcuello E Masutti B Irinotecan in combination with fluorouracil in a 48-hour continuous infusion as first-line chemotherapy for elderly patients with metastatic colorectal cancer: a Spanish Cooperative Group for the Treatment of Digestive Tumors study J Clin Oncol 2005 23 3545 51 15908665 \n21 Souglakos J Pallis A Kakolyris S Combination of irinotecan (cpt-11) plus 5-fluorouracil, and leucovorin (folfiri regimen) as first line treatment for elderly patients with metastatic colorectal cancer: a phase ii trial Oncology 2005 69 384 90 16319509 \n22 Lewis JH Kilgore ML Goldman DP Participation of patients 65 years of age or older in cancer clinical trials J Clin Oncol 2003 21 1383 9 12663731 \n23 Miller RJ The role of chemotherapy in the hospice patient: a problem of definition Am J Hosp Palliat Care 1989 6 19 26\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1198-0052",
"issue": "16(6)",
"journal": "Current oncology (Toronto, Ont.)",
"keywords": "Colorectal neoplasms; clinical trials; drug therapy; drug toxicity",
"medline_ta": "Curr Oncol",
"mesh_terms": null,
"nlm_unique_id": "9502503",
"other_id": null,
"pages": "13-20",
"pmc": null,
"pmid": "20016742",
"pubdate": "2009-12",
"publication_types": "D016428:Journal Article",
"references": "16002847;12610178;10470428;11413512;12663731;9807986;15346996;15939923;15908665;16319509;10744089;11932894;16639738;9807987;17762434;14751698;2481479;12102156;15939922;9317185;15365570;17477381;11006366",
"title": "Generalizability of toxicity data from oncology clinical trials to clinical practice: toxicity of irinotecan-based regimens in patients with metastatic colorectal cancer.",
"title_normalized": "generalizability of toxicity data from oncology clinical trials to clinical practice toxicity of irinotecan based regimens in patients with metastatic colorectal cancer"
} | [
{
"companynumb": "CA-PFIZER INC-2019258077",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IRINOTECAN HYDROCHLORIDE"
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"drugadditional":... |
{
"abstract": "Vedolizumab is an IgG1 anti-α4β7 integrin antibody approved for the treatment of inflammatory bowel diseases [IBD], but without clear safety data during conception, pregnancy and nursing. Animal studies showed that mucosal vascular addressin cell adhesion molecule 1 [MAdCAM-1] is expressed by maternal vessels in the placenta and recruits α4β7-expressing cells that are considered important for maternal/fetal tolerance. Blocking this interaction by vedolizumab might affect this process. We aimed to evaluate pregnancy outcomes in vedolizumab-treated female IBD patients.\nWe conducted a retrospective, multicentre Belgian observational study. Details on disease activity, prenatal complications, delivery and neonatal outcome were collected through a case report form.\nTwenty-four pregnancies were reported. Five women had active disease at conception and one patient flared during pregnancy. There were 23 live births. Complications were observed in 25% of pregnancies [premature rupture of membranes, pre-eclampsia, miscarriage, elective termination and stillbirth] and in 35% of infants [prematurity, intra-uterine growth retardation, small for gestational age and congenital malformations including hip dysplasia, pulmonary valve stenosis and Hirschprung's disease]. Vedolizumab was continued throughout pregnancy in two females and stopped in the 1st and 2nd trimester in five and 16 patients, respectively. For live born children, the median [interquartile range] gestational age, weight and Apgar score 5 min after birth were 39 [37-39.6] weeks, 3270 [3080-3585] grams and 10 [9-10], respectively.\nAlthough several complications were observed, both in mothers and in newborns, no firm conclusions can be drawn. Awaiting prospective and controlled registries, vigilance and strict follow-up of pregnant patients treated with vedolizumab seems mandatory.",
"affiliations": "Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.;Department of Chronic Diseases, Metabolism and Ageing, KU Leuven, Leuven, Belgium.;Department of Gastroenterology, Ziekenhuis Oost-Limburg - Campus Sint-Jan, Genk, Belgium.;Deparment of Gastroenterology, CHU UCL Namur, Université catholique de Louvain, Yvoir, Belgium.;Department of Gastroenterology, Imeldaziekenhuis, Bonheiden, Belgium.;Department of Gastroenterology, Mariaziekenhuis Noord-Limburg, Overpelt, Belgium.;Department of Gastroenterology, Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium.;Department of Gastroenterology, Universiteit ziekenhuis Antwerpen, UZA, Antwerp, Belgium.;Department of Gastroenterology, Sint-Trudo Ziekenhuis, Sint-Truiden, Belgium.;Department of Gastroenterology, AZ Vesalius, Tongeren, Belgium.;Department of Gastroenterology, AZ Sint-Lucas, Gent, Belgium.;Department of Gastroenterology, AZ Klina, Brasschaat, Belgium.;Department of Gastroenterology, AZ Groeninge, Kortrijk, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.;Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium.",
"authors": "Moens|Annick|A|;van Hoeve|Karen|K|;Humblet|Evelien|E|;Rahier|Jean-François|JF|;Bossuyt|Peter|P|;Dewit|Sophie|S|;Franchimont|Denis|D|;Macken|Elisabeth|E|;Nijs|Jochen|J|;Posen|Annelies|A|;Strubbe|Beatrijs|B|;Van Hootegem|Anneleen|A|;Van Moerkercke|Wouter|W|;Vermeire|Séverine|S|;Ferrante|Marc|M|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D005765:Gastrointestinal Agents; C543529:vedolizumab",
"country": "England",
"delete": false,
"doi": "10.1093/ecco-jcc/jjy142",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1873-9946",
"issue": "13(1)",
"journal": "Journal of Crohn's & colitis",
"keywords": null,
"medline_ta": "J Crohns Colitis",
"mesh_terms": "D000022:Abortion, Spontaneous; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D001034:Apgar Score; D001530:Belgium; D001724:Birth Weight; D000013:Congenital Abnormalities; D005260:Female; D005317:Fetal Growth Retardation; D005765:Gastrointestinal Agents; D005865:Gestational Age; D006801:Humans; D007231:Infant, Newborn; D007236:Infant, Small for Gestational Age; D015212:Inflammatory Bowel Diseases; D050498:Live Birth; D011247:Pregnancy; D011248:Pregnancy Complications; D011256:Pregnancy Outcome; D047928:Premature Birth; D012189:Retrospective Studies; D012720:Severity of Illness Index; D050497:Stillbirth; D055815:Young Adult",
"nlm_unique_id": "101318676",
"other_id": null,
"pages": "12-18",
"pmc": null,
"pmid": "30281093",
"pubdate": "2019-01-01",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Outcome of Pregnancies in Female Patients With Inflammatory Bowel Diseases Treated With Vedolizumab.",
"title_normalized": "outcome of pregnancies in female patients with inflammatory bowel diseases treated with vedolizumab"
} | [
{
"companynumb": "BE-TAKEDA-2019TJP012759AA",
"fulfillexpeditecriteria": "1",
"occurcountry": "BE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VEDOLIZUMAB"
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"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo summarize and analyze the clinical characteristics, treatment and prognosis of acute lung injury in patients with diffuse large B-cell lymphoma (DLBCL) after chemotherapy with rituximab chemotherapy, so as to improve the understanding of the disease and guide the clinical treatment.\n\n\nMETHODS\nTwenty-Six patients with DLBCL were treated with rituximab chemotherapy and developed to acute lung injury in Third Hospital of Peking University from January 2013 to September 2018 were selected. The clinical features, imaging findings, chemotherapy course, therapeutic effect and prognosis were analyzed.\n\n\nRESULTS\nThe main clinical symptoms of patients were fever, cough and chest tightness, among which 12 patients showed hypoxia and 3 patients showed respiratory failure type I. The mainly manifested chest CT was diffusive glass grinding in both lungs, and some patients were complicated with a small amount of pleural effusion. The onset chemotherapy time was mainly distributed in 2 to 4 courses, the time between the onset of symptoms and the infusion of rituximab was 8 to 49 days. 25 patients shows no obvious limitation in daily life after effective treatment, and 1 patient died of ineffective treatment.\n\n\nCONCLUSIONS\nThere are no typical clinical symptoms in the early stage of acute lung injury after rituximab chemotherapy in DLBCL. Early detection and early hormone therapy are very important to achieve good therapeutic effect.",
"affiliations": "Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China.;Department of Hematology, The Third Hospital of Peking University, Beijing 100191, China E-mail: xiaoyank@yahoo.com.",
"authors": "Zheng|Dong|D|;Dong|Fei|F|;Pang|Meng|M|;Zhao|Wei|W|;Tian|Lei|L|;Wang|Jing|J|;Ke|Xiao-Yan|XY|",
"chemical_list": "D000069283:Rituximab; D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "China",
"delete": false,
"doi": "10.19746/j.cnki.issn.1009-2137.2020.06.021",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1009-2137",
"issue": "28(6)",
"journal": "Zhongguo shi yan xue ye xue za zhi",
"keywords": null,
"medline_ta": "Zhongguo Shi Yan Xue Ye Xue Za Zhi",
"mesh_terms": "D055371:Acute Lung Injury; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D016403:Lymphoma, Large B-Cell, Diffuse; D011379:Prognosis; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine",
"nlm_unique_id": "101084424",
"other_id": null,
"pages": "1919-1922",
"pmc": null,
"pmid": "33283720",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Clinical Analysis of Acute Lung Injury in 26 Cases of Diffuse Large B-Cell Lymphoma Treated with Rituximab Chemotherapy.",
"title_normalized": "clinical analysis of acute lung injury in 26 cases of diffuse large b cell lymphoma treated with rituximab chemotherapy"
} | [
{
"companynumb": "CN-ROCHE-2746436",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "BRAF inhibitors (BRAFi), a targeted therapy, are used to treat metastatic late-stage melanomas harbouring the BRAF-V600 mutation (found in about 50% of melanomas). The targeted therapy is generally maintained until tumour progression or major toxicity occurs, although responses are often limited in time. It is unknown whether melanoma patients achieving a complete response with targeted therapy can safely discontinue treatment. We retrospectively observed the clinical course of patients with metastatic melanoma who discontinued BRAFi therapy after achieving a complete response and those with an incomplete response combined with surgical removal of the remaining tumours. We also evaluated the effectiveness of BRAFi in these patients after recurrence. In 11 patients, the best response was diagnosed after a median BRAFi treatment duration of 105 (29-341) days. The median follow-up after BRAFi initiation was 769 (435-1765) days. Recurrence was observed in all 11 patients (100%), median: 82 (27-322) days. Five patients achieved a complete response, with a median progression-free survival after cessation of 136.5 (34-322) days versus 82 (27-144) days for six patients with an incomplete response combined with surgical removal of remaining tumours. Baseline characteristics and time to best response and to discontinuation did not influence the rate of relapse. Subsequently, eight patients were rechallenged with a BRAFi. The median progression-free survival time after BRAFi rechallenge was 222.5 (15-425) days. The three remaining patients received treatments other than BRAFi. Our findings may be valuable with respect to ongoing clinical trials of combinations of targeted therapies and immunomodulatory antibodies.",
"affiliations": "aDepartment of Dermatology, Lille University Hospital, Claude Huriez Hospital bLille University cDepartment of Biostatistics, Univ. Lille, CHU Lille, EA 2694 - Santé publique: épidémiologie et qualité des soins dINSERM U1189 ONCO-THAI, F-59000 Lille, France.",
"authors": "Desvignes|Céline|C|;Abi Rached|Henry|H|;Templier|Carole|C|;Drumez|Elodie|E|;Lepesant|Pauline|P|;Desmedt|Eve|E|;Mortier|Laurent|L|",
"chemical_list": "D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000350",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "27(3)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009364:Neoplasm Recurrence, Local; D011379:Prognosis; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D012074:Remission Induction; D019233:Retreatment; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "281-287",
"pmc": null,
"pmid": "28240681",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "BRAF inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response.",
"title_normalized": "braf inhibitor discontinuation and rechallenge in advanced melanoma patients with a complete initial treatment response"
} | [
{
"companynumb": "FR-ROCHE-1941822",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "We conducted a retrospective analysis of patients younger than 60 years (N = 10, median age 54.5) with newly diagnosed primary central nervous system lymphoma (PCNSL) at the University of Tsukuba Hospital from January 2008 to November 2016. All the patients were scheduled to receive a single regimen without registration to any clinical trials. This was based on a phase 2 study by Memorial Sloan-Kettering Cancer Center (MSKCC); induction chemotherapy with rituximab, methotrexate, procarbazine, and vincristine (R-MPV) (five to seven cycles), followed by whole-brain radiotherapy (rd-WBRT) (23.4 Gy) and two high-dose cytarabine (HD-AC) cycles as a consolidation. The median age was 54.5 years, and median follow up duration was 33.1 months. The 3-year overall survival (OS) and progression-free survival (PFS) were 69% (95% CI 31-89%) and 56% (95% CI 20-81%). The median OS and PFS were not reached, respectively. Acute and delayed toxicities were manageable. In particular, OS and PFS of seven patients who achieved CR by the R-MPV induction chemotherapy were significantly superb (3-year OS, 100%; 3-year PFS, 80%), implying that a large proportion of patients in CR after the completion of this treatment may achieve durable disease control. On the other hand, all of the three patients who had progressive disease during this treatment died of disease progression within 1 year after diagnosis without achieving CR. Identifying the patients having a risk of failure in the R-MPV induction chemotherapy is important, and may allow us to consider a potentially more effective regimen.",
"affiliations": "Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Ibaraki Clinical Education and Training Center, University of Tsukuba Hospital; Department of Hematology, Ibaraki Prefectural Central Hospital.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba.;Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba.;Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba.;Department of Neurosurgery, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.;Department of Clinical and Experimental Hematology, Institute of Clinical Medicine, University of Tsukuba.",
"authors": "Hattori|Keiichiro|K|;Sakata-Yanagimoto|Mamiko|M|;Okoshi|Yasushi|Y|;Kato|Takayasu|T|;Kurita|Naoki|N|;Yokoyama|Yasuhisa|Y|;Obara|Naoshi|N|;Takano|Shingo|S|;Ishikawa|Eiichi|E|;Yamamoto|Tetsuya|T|;Matsumura|Akira|A|;Hasegawa|Yuichi|Y|;Chiba|Shigeru|S|",
"chemical_list": "D003561:Cytarabine; D011344:Procarbazine; D000069283:Rituximab; D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.3960/jslrt.17012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1346-4280",
"issue": "57(2)",
"journal": "Journal of clinical and experimental hematopathology : JCEH",
"keywords": "CR after completion of treatment; R-MPV induction therapy followed by consolidation rdWBRT and HD-AC; primary central nervous system lymphoma",
"medline_ta": "J Clin Exp Hematop",
"mesh_terms": "D000359:Aftercare; D000971:Antineoplastic Combined Chemotherapy Protocols; D016543:Central Nervous System Neoplasms; D059248:Chemoradiotherapy; D003561:Cytarabine; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008223:Lymphoma; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D011344:Procarbazine; D000069283:Rituximab; D015996:Survival Rate",
"nlm_unique_id": "101141257",
"other_id": null,
"pages": "41-46",
"pmc": null,
"pmid": "28781291",
"pubdate": "2017-10-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": "12525518;1572835;17116938;17947720;18166803;19060176;20511181;21303800;21383331;22228634;22734565;23208313;23963042;24101038;24265352;24928128;25138297;25527263;25568347;25853747;26193343;26239089;27161435;27641927",
"title": "A single institutional retrospective evaluation for younger patients with primary central nervous lymphomas on a modified R-MPV regimen followed by radiotherapy and high dose cytarabine.",
"title_normalized": "a single institutional retrospective evaluation for younger patients with primary central nervous lymphomas on a modified r mpv regimen followed by radiotherapy and high dose cytarabine"
} | [
{
"companynumb": "JP-PFIZER INC-2017472299",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Cytomegalovirus (CMV) infection is latent in the majority of adult humans. The reactivation of CMV causes pneumonia and gastrointestinal disease in severely immunosuppressed patients, who consequently suffer very high mortality due to CMV central nervous system disease. We report here a case involving a 28-year-old female patient with mycosis fungoides who underwent umbilical cord blood transplantation three times and developed CMV ventriculoencephalitis. The patient's CMV viremia was successfully preempted with ganciclovir (GCV) as indicated by undetectable CMV antigenemia; despite this successful treatment, the patient developed CMV ventriculoencephalitis. Foscarnet (FCV) therapy led to a temporary recovery, after which CMV ventriculoencephalitis recurred, and the patient died after receiving combination GCV and FCV therapy. Autopsy samples revealed CMV ventriculoencephalitis, as indicated by numerous inclusion-bearing cells (Owl's eye). It is likely that this patient harbored a GCV-resistant CMV strain; however, it was not possible to obtain nucleic acids suitable for use in assessing this possibility.",
"affiliations": "Stem Cell Transplantation Center, Hokkaido University Hospital, Kita-14, Nishi-5, Kita-ku, Sapporo, Hokkaido, 060-8638, Japan. t-matsukawa@med.hokudai.ac.jp",
"authors": "Matsukawa|Toshihiro|T|;Goto|Hideki|H|;Takahashi|Kenta|K|;Asanuma|Shinsuke|S|;Yasumoto|Atsushi|A|;Takahata|Mutsumi|M|;Shigematsu|Akio|A|;Endo|Tomoyuki|T|;Tanaka|Junji|J|;Hashino|Satoshi|S|;Tanaka|Shinya|S|;Imamura|Masahiro|M|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-012-1003-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "95(2)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D036101:Cord Blood Stem Cell Transplantation; D003586:Cytomegalovirus Infections; D018792:Encephalitis, Viral; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging; D009182:Mycosis Fungoides; D014775:Virus Activation",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "217-22",
"pmc": null,
"pmid": "22262140",
"pubdate": "2012-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "7991550;12508158;12535263;1652311;8585743;20358010;12873880;17313468;21849359;9265682;20190836;3010685;18647960;9864186;11994020;12393485;19067913;8239583;14716290;7826299;21617009;20930070;16421783;20487415;15319096;11577375;10881242;3017630",
"title": "A fatal case of cytomegalovirus ventriculoencephalitis in a mycosis fungoides patient who received multiple umbilical cord blood cell transplantations.",
"title_normalized": "a fatal case of cytomegalovirus ventriculoencephalitis in a mycosis fungoides patient who received multiple umbilical cord blood cell transplantations"
} | [
{
"companynumb": "JP-CLINIGEN GROUP PLC/ CLINIGEN HEALTHCARE LTD-E2B_00005595",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": null,
"drugadditional": null,
"drugadministratio... |
{
"abstract": "A 12-year-old girl with normal neurodevelopment and narcolepsy type 1 presented with unexpected central apneas in response to sodium oxybate (SO). The patient underwent overnight polysomnography on SO (2.75 + 2.5 grams) which showed an apnea-hypopnea index of 4.3 events/h, and all the events were central apneas. A majority of central apneas clustered at about 1.5 hours after the first dose of SO. Remarkably, after a second dose of SO that was 0.25 grams smaller, she did not exhibit clusters of central sleep apneas. However, she did experience similar but milder breathing abnormalities that did not meet criteria to be scored as central apneas or hypopneas. Based on this observation, there may be an association between SO treatment and the development of central apnea. Further polysomnographic research on pediatric patients taking SO would help determine if there is a significant association between SO treatment and the development of central apnea in the pediatric population.",
"affiliations": "Columbia University Medical Center, New York, New York.",
"authors": "Heshmati|Arezou|A|",
"chemical_list": "D012978:Sodium Oxybate",
"country": "United States",
"delete": false,
"doi": "10.5664/jcsm.7690",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1550-9389",
"issue": "15(3)",
"journal": "Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine",
"keywords": "central sleep apnea; narcolepsy type 1; pediatric narcolepsy; sodium oxybate",
"medline_ta": "J Clin Sleep Med",
"mesh_terms": "D002648:Child; D005260:Female; D006801:Humans; D009290:Narcolepsy; D017286:Polysomnography; D020182:Sleep Apnea, Central; D012978:Sodium Oxybate",
"nlm_unique_id": "101231977",
"other_id": null,
"pages": "515-517",
"pmc": null,
"pmid": "30853045",
"pubdate": "2019-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19941084;19897413;19626356;18226949;20082240;19269893;23834969;22445591;29512449",
"title": "Central Sleep Apnea With Sodium Oxybate in a Pediatric Patient.",
"title_normalized": "central sleep apnea with sodium oxybate in a pediatric patient"
} | [
{
"companynumb": "US-JAZZ-2018-US-010156",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SODIUM OXYBATE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nTo describe a case of bilateral macular edema appearing after treatment with rituximab.\n\n\nMETHODS\nThis is a case report describing macular edema after rituximab infusions. The information was collected retrospectively through chart review.\n\n\nRESULTS\nA 53-year-old patient known for IgG4-related disease of the face and sinuses presented with bilateral decreased visual acuity from cystoid macular edema shortly after undergoing two rituximab infusions. Laboratory workup did not reveal any underlying systemic etiology. Treatment with topical and oral corticosteroids as well as with anti-vascular endothelial growth factor injections led to mild improvement. Treatment with intraocular triamcinolone resulted in complete resolution of the edema, although accompanied by an increase in intraocular pressure.\n\n\nCONCLUSIONS\nRituximab has been previously associated with macular edema. Macular edema causing visual loss shortly after receiving rituximab may respond to discontinuation of the rituximab and local steroid injection.",
"affiliations": "Department of Ophthalmology, Rush University Medical Center, Chicago, Illinois.;Department of Ophthalmology, Rush University Medical Center, Chicago, Illinois.",
"authors": "Gilca|Marina|M|;Merrill|Pauline T|PT|",
"chemical_list": "D007155:Immunologic Factors; D000069283:Rituximab",
"country": "United States",
"delete": false,
"doi": "10.1097/ICB.0000000000000556",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1935-1089",
"issue": "13(2)",
"journal": "Retinal cases & brief reports",
"keywords": null,
"medline_ta": "Retin Cases Brief Rep",
"mesh_terms": "D005260:Female; D006801:Humans; D000077733:Immunoglobulin G4-Related Disease; D007155:Immunologic Factors; D008269:Macular Edema; D008875:Middle Aged; D000069283:Rituximab; D014786:Vision Disorders",
"nlm_unique_id": "101298744",
"other_id": null,
"pages": "111-114",
"pmc": null,
"pmid": "28267110",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "CYSTOID MACULAR EDEMA SECONDARY TO RITUXIMAB.",
"title_normalized": "cystoid macular edema secondary to rituximab"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-03512",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE ACETONIDE"
},
... |
{
"abstract": "Breakage of an epidural catheter occurs rarely dur- ing the insertion or removal procedures. In previous reports, the broken epidural catheter fragment need not be removed in asymptomatic patients. However, late-onset neurological symptoms might occur. This is a case of delayed onset subdural hematoma due to a broken epidural catheter retained in the body for 18 years. We considered that the catheter fragment might induce chronic inflammation and vascular fragil- ity around the catheter. Antiplatelet therapy might lead to the hematoma because this patient took an aspirin (antiplatelet drug) for over 9 years. Antiplatelet and anticoagulant therapies are likely to be a risk of hematoma. Thus, even without neurological symptoms, it is necessary to consider the removal of the epidural catheter fragment in patients on anti- platelet and anticoagulant therapy.",
"affiliations": null,
"authors": "Fujii|Tasuku|T|;Suzuki|Katsunao|K|;Shibata|Yasuyuki|Y|;Nishiwaki|Kimitoshi|K|",
"chemical_list": "D000925:Anticoagulants; D010975:Platelet Aggregation Inhibitors; D001241:Aspirin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0021-4892",
"issue": "66(1)",
"journal": "Masui. The Japanese journal of anesthesiology",
"keywords": null,
"medline_ta": "Masui",
"mesh_terms": "D000767:Anesthesia, Epidural; D000925:Anticoagulants; D001241:Aspirin; D005260:Female; D020199:Hematoma, Subdural, Acute; D006801:Humans; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors",
"nlm_unique_id": "0413707",
"other_id": null,
"pages": "65-69",
"pmc": null,
"pmid": "30380259",
"pubdate": "2017-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Subdural Hematoma due to the Breakage of an Epidural Catheter Left for a Long Time.",
"title_normalized": "acute subdural hematoma due to the breakage of an epidural catheter left for a long time"
} | [
{
"companynumb": "JP-DSJP-DSJ-2017-102522",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARVEDILOL"
},
"drugadditional": "3",
... |
{
"abstract": "We reviewed all cases of Nocardia infection in cystic fibrosis patients at 2 centers. Eight of 200 patients had Nocardia in sputum. Four developed severe lung disease, including 3 with associated allergic bronchopulmonary aspergillosis; 4 remained clinically stable. Nocardia is often associated with significant lung disease in cystic fibrosis, possibly associated with allergic bronchopulmonary aspergillosis or steroids.",
"affiliations": "From the *The Kathy and Lee Graub Cystic Fibrosis Center, Pulmonary Institute, Schneider Children's Medical Center of Israel, Petah Tikva, Israel; †Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel; and ‡Pediatric Pulmonology Unit, Meyer Children's Hospital, Rambam Medical Center, The Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel.",
"authors": "Mei-Zahav|Meir|M|;Livnat|Galit|G|;Bentur|Lea|L|;Mussaffi|Huda|H|;Prais|Dario|D|;Stafler|Patrick|P|;Bar-On|Ophir|O|;Steuer|Guy|G|;Blau|Hannah|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000759",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "34(8)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001229:Aspergillosis, Allergic Bronchopulmonary; D002648:Child; D003550:Cystic Fibrosis; D005260:Female; D006801:Humans; D007557:Israel; D016040:Lung Transplantation; D008297:Male; D008875:Middle Aged; D009615:Nocardia; D009617:Nocardia Infections; D012189:Retrospective Studies; D013183:Sputum",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "909-11",
"pmc": null,
"pmid": "25973994",
"pubdate": "2015-08",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Spectrum of Nocardia Lung Disease in Cystic Fibrosis.",
"title_normalized": "the spectrum of nocardia lung disease in cystic fibrosis"
} | [
{
"companynumb": "PHHY2015IL098543",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LINEZOLID"
},
"drugadditional": null,
"druga... |
{
"abstract": "This study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (PwMS).\n\n\n\nWe retrospectively collected data of PwMS with suspected or confirmed COVID-19. All the patients had complete follow-up to death or recovery. Severe COVID-19 was defined by a 3-level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID-19 by multivariate and propensity score (PS)-weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.\n\n\n\nOf 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID-19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty-eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized. After adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti-CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18-4.74, p = 0.015) with increased risk of severe COVID-19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20-12.53, p = 0.001). Results were confirmed by the PS-weighted analysis and by all the sensitivity analyses.\n\n\n\nThis study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID-19 pandemic persists. ANN NEUROL 2021;89:780-789.",
"affiliations": "Department of Health Sciences, University of Genoa, Genoa, Italy.;Centro Sclerosi Multipla ASST Spedali Civili di Brescia, Montichiari, Italy.;Department of Health Sciences, University of Genoa, Genoa, Italy.;Department of Health Sciences, University of Genoa, Genoa, Italy.;Centro Sclerosi Multipla ASST Spedali Civili di Brescia, Montichiari, Italy.;Department of Neurology, Multiple Sclerosis Center, IRCCS Ospedale San Raffaele, Milan, Italy.;Department of Neurology and Multiple Sclerosis Center, ASST Papa Giovanni XXIII, Bergamo, Italy.;Multiple Sclerosis Center, Ospedale Guglielmo da Saliceto, Piacenza, Italy.;Department of Neurology, Regional Referral Multiple Sclerosis Center, University Hospital San Luigi, Orbassano, Torino, Italy.;Department of Basic Medical Sciences, Neurosciences, and Sense Organs, University of Bari, Bari, Italy.;Research Department, Italian Multiple Sclerosis Foundation, Genoa, Italy.;Department of Advanced Medical and Surgical Sciences, University of Campania, Naples, Italy.;Institute of Experimental Neurology, IRCCS Ospedale San Raffaele, Milan, Italy.;Research Department, Italian Multiple Sclerosis Foundation, Genoa, Italy.;Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia, University of Catania, Catania, Italy.;Department of Neuroscience, Mental Health, and Sensory Organs, Sapienza University of Rome, Rome, Italy.",
"authors": "Sormani|Maria P|MP|0000-0001-6892-104X;De Rossi|Nicola|N|;Schiavetti|Irene|I|;Carmisciano|Luca|L|;Cordioli|Cinzia|C|;Moiola|Lucia|L|;Radaelli|Marta|M|;Immovilli|Paolo|P|;Capobianco|Marco|M|;Trojano|Maria|M|;Zaratin|Paola|P|;Tedeschi|Gioacchino|G|;Comi|Giancarlo|G|0000-0002-6989-1054;Battaglia|Mario A|MA|;Patti|Francesco|F|0000-0002-6923-0846;Salvetti|Marco|M|;|||",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D000069442:Natalizumab; D007372:Interferons; C533411:ocrelizumab; D000069462:Dimethyl Fumarate; D000068876:Fingolimod Hydrochloride",
"country": "United States",
"delete": false,
"doi": "10.1002/ana.26028",
"fulltext": "\n==== Front\nAnn Neurol\nAnn Neurol\n10.1002/(ISSN)1531-8249\nANA\nAnnals of Neurology\n0364-5134\n1531-8249\nJohn Wiley & Sons, Inc. Hoboken, USA\n\n33480077\n10.1002/ana.26028\nANA26028\nResearch Article\nResearch Articles\nDisease‐Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis\nDMTs and COVID‐19 in MS\nSormani et al\nSormani Maria P. PhD https://orcid.org/0000-0001-6892-104X\n1 2\nDe Rossi Nicola MD 3\nSchiavetti Irene PhD 1\nCarmisciano Luca MD 1\nCordioli Cinzia MD 3\nMoiola Lucia MD 4\nRadaelli Marta MD 5\nImmovilli Paolo MD 6\nCapobianco Marco MD 7\nTrojano Maria MD 8\nZaratin Paola PhD 9\nTedeschi Gioacchino MD 10\nComi Giancarlo MD https://orcid.org/0000-0002-6989-1054\n11\nBattaglia Mario A. MD 9 12\nPatti Francesco MD https://orcid.org/0000-0002-6923-0846\n13 14\nSalvetti Marco MD 15 16 marco.salvetti@uniroma1.it\n\nthe Musc‐19 Study GroupNozzolillo Agostino\nBellacosa Alessandra\nProtti Alessandra\nDi Sapio Alessia\nSignori Alessio\nPetrone Alfredo\nBisecco Alvino\nIovino Aniello\nDutto Anna\nRepice Anna Maria\nConte Antonella\nBertolotto Antonio\nBosco Antonio\nGallo Antonio\nZito Antonio\nSartori Arianna\nGiometto Bruno\nTortorella Carla\nAntozzi Carlo\nPozzilli Carlo\nMancinelli Chiara Rosa\nZanetta Chiara\nCordano Christian\nCordioli Cinzia\nScandellari Cinzia\nGuaschino Clara\nGasperini Claudio\nSolaro Claudio\nFioretti Cristina\nBezzini Daiana\nMarastoni Damiano\nPaolicelli Damiano\nVecchio Domizia\nLandi Doriana\nBucciantini Elisabetta\nPedrazzoli Elisabetta\nSignoriello Elisabetta\nSbragia Elvira\nSusani Emanuela Laura\nCurti Erica\nMilano Eva\nMarinelli Fabiana\nCamilli Federico\nBoneschi Filippo Martinelli\nGovone Flora\nBovis Francesca\nCalabria Francesca\nCaleri Francesca\nRinaldi Francesca\nVitetta Francesca\nCorea Francesco\nCrescenzo Francesco\nPatti Francesco\nTeatini Francesco\nTabiadon Giulietta\nGranella Franco\nBoffa Giacomo\nLus Giacomo\nBrichetto Giampaolo\nComi Giancarlo\nTedeschi Gioacchino\nManiscalco Giorgia Teresa\nBorriello Giovanna\nDe Luca Giovanna\nKonrad Giovanna\nVaula Giovanna\nMarfia Girolama Alessandra\nMallucci Giulia\nLiberatore Giuseppe\nSalemi Giuseppe\nMiele Giuseppina\nSibilia Grazia\nPesci Ilaria\nSchiavetti Irene\nBrambilla Laura\nLopiano Leonardo\nSinisi Leonardo\nPasquali Livia\nSaraceno Lorenzo\nCarmisciano Luca\nChiveri Luca\nMancinelli Luca\nMoiola Lucia\nGrimaldi Luigi M.E.\nCaniatti Luisa Maria\nCapobianco Marco\nCava Marco Della\nOnofrj Marco\nRovaris Marco\nSalvetti Marco\nVercellino Marco\nBragadin Margherita Monti\nBuccafusca Maria\nBuscarinu Maria Chiara\nCelani Maria Grazia\nGrasso Maria Grazia\nStromillo Maria Laura\nPetracca Maria\nAmato Maria Pia\nSormani Maria Pia\nL'Episcopo Maria Rita\nSessa Maria\nFerrò Maria Teresa\nTrojano Maria\nErcolani Maria Vittoria\nBianco Mariangela\nRe Marianna Lo\nVianello Marika\nClerico Marinella\nBattaglia Mario Alberto\ndi Napoli Mario\nPonzano Marta\nRadaelli Marta\nConti Marta Zaffira\nCalabrese Massimiliano\nMirabella Massimiliano\nFilippi Massimo\nInglese Matilde\nLucchini Matteo\nPozzato Matteo\nDanni Maura Chiara\nZaffaroni Mauro\nZampolini Mauro\nPonzio Michela\nDe Riz Milena\nDe Rossi Nicola\nDe Stefano Nicola\nCavalla Paola\nDe Mitri Paola\nGrossi Paola\nZaratin Paola\nConfalonieri Paolo\nGallo Paolo\nImmovilli Paolo\nRagonese Paolo\nSola Patrizia\nAnnovazzi Pietro\nIaffaldano Pietro\nNardone Raffaele\nCerqua Raffaella\nClerici Raffaella\nLanzillo Roberta\nMotta Roberta\nBalgera Roberto\nBergamaschi Roberto\nTotaro Rocco\nIodice Rosa\nCapra Ruggero\nMarangoni Sabrina\nRealmuto Sabrina\nCottone Salvatore\nMontepietra Sara\nRasia Sarah\nArena Sebastiano\nBucello Sebastiano\nBanfi Silvia\nBonavita Simona\nMalucchi Simona\nTonietti Simone\nVollaro Stefano\nCordera Susanna\nAguglia Umberto\nClerici Valentina Torri\nBarcella Valeria\nBergamaschi Valeria\nMorra Vincenzo Brescia\nDattola Vincenzo\nMantero Vittorio\n\n1 Department of Health Sciences University of Genoa Genoa Italy\n2 IRCCS Ospedale Policlinico San Martino Genoa Italy\n3 Centro Sclerosi Multipla ASST Spedali Civili di Brescia Montichiari Italy\n4 Department of Neurology Multiple Sclerosis Center, IRCCS Ospedale San Raffaele Milan Italy\n5 Department of Neurology and Multiple Sclerosis Center ASST Papa Giovanni XXIII Bergamo Italy\n6 Multiple Sclerosis Center Ospedale Guglielmo da Saliceto Piacenza Italy\n7 Department of Neurology, Regional Referral Multiple Sclerosis Center University Hospital San Luigi Orbassano Torino Italy\n8 Department of Basic Medical Sciences, Neurosciences, and Sense Organs University of Bari Bari Italy\n9 Research Department Italian Multiple Sclerosis Foundation Genoa Italy\n10 Department of Advanced Medical and Surgical Sciences University of Campania Naples Italy\n11 Institute of Experimental Neurology, IRCCS Ospedale San Raffaele Milan Italy\n12 Department of Life Sciences University of Siena Siena Italy\n13 Department of Medical and Surgical Sciences and Advanced Technologies, GF Ingrassia University of Catania Catania Italy\n14 Centro Sclerosi Multipla Policlinico Catania, University of Catania Catania Italy\n15 Department of Neuroscience, Mental Health, and Sensory Organs Sapienza University of Rome Rome Italy\n16 Unit of Neurology, IRCCS Neuromed Pozzilli Italy\n* Address correspondence to Dr Salvetti, Dipartimento di Neuroscienze, Salute Mentale e Organi di Senso, AOU S. Andrea, via di Grottarossa 1035‐1039, 00189‐Rome, Italy. E‐mail: marco.salvetti@uniroma1.it\n\n09 2 2021\n4 2021\n89 4 10.1002/ana.v89.4 780789\n18 1 2021\n11 11 2020\n18 1 2021\n© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.\nThis is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.\n\nObjective\n\nThis study was undertaken to assess the impact of immunosuppressive and immunomodulatory therapies on the severity of coronavirus disease 2019 (COVID‐19) in people with multiple sclerosis (PwMS).\n\nMethods\n\nWe retrospectively collected data of PwMS with suspected or confirmed COVID‐19. All the patients had complete follow‐up to death or recovery. Severe COVID‐19 was defined by a 3‐level variable: mild disease not requiring hospitalization versus pneumonia or hospitalization versus intensive care unit (ICU) admission or death. We evaluated baseline characteristics and MS therapies associated with severe COVID‐19 by multivariate and propensity score (PS)‐weighted ordinal logistic models. Sensitivity analyses were run to confirm the results.\n\nResults\n\nOf 844 PwMS with suspected (n = 565) or confirmed (n = 279) COVID‐19, 13 (1.54%) died; 11 of them were in a progressive MS phase, and 8 were without any therapy. Thirty‐eight (4.5%) were admitted to an ICU; 99 (11.7%) had radiologically documented pneumonia; 96 (11.4%) were hospitalized.\n\nAfter adjusting for region, age, sex, progressive MS course, Expanded Disability Status Scale, disease duration, body mass index, comorbidities, and recent methylprednisolone use, therapy with an anti‐CD20 agent (ocrelizumab or rituximab) was significantly associated (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.18–4.74, p = 0.015) with increased risk of severe COVID‐19. Recent use (<1 month) of methylprednisolone was also associated with a worse outcome (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). Results were confirmed by the PS‐weighted analysis and by all the sensitivity analyses.\n\nInterpretation\n\nThis study showed an acceptable level of safety of therapies with a broad array of mechanisms of action. However, some specific elements of risk emerged. These will need to be considered while the COVID‐19 pandemic persists. ANN NEUROL 2021;89:780–789\n\nF. Hoffmann‐La Roche 10.13039/100007013 donating the web‐based platform for data collectio source-schema-version-number2.0\ncover-dateApril 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:01.04.2021\nThe members of the Musc‐19 Study Group are identified in a supplementary table.\n==== Body\nThe COVID‐19 pandemic and the many questions about the postpandemic period complicate the management of patients who need therapies that impact on the immune system. Data available so far are overall reassuring, excluding major safety issues. 1 , 2 , 3 , 4 However, the robustness of results is not optimal due to the relatively small samples, collected in a situation of urgency. Furthermore, for most of the autoimmune diseases, many possible therapies are available, thus increasing the heterogeneity of the datasets. It is therefore necessary to rely on larger and better characterized case series to improve data quality and relevance. The results will inform clinical decisions that will have a long‐term impact, given the chronicity of the diseases, the duration of therapies, and the long‐lasting effects of some treatments.\n\nMultiple sclerosis (MS) is the major cause of neurological disability in young adults, with approximately 2.3 million people affected worldwide. 5 Up to 70% of people with MS (PwMS) are treated with disease‐modifying therapies (DMTs) that impact on the immune response and may carry an increased probability of infection. 6 This risk must be balanced against the consequences of poorly controlled MS. Hence, reliably assessing the risk of coronavirus disease 2019 (COVID‐19) in these patients is an important public health issue, and more data are needed to guide clinical practice, as pointed out in recent reviews. 7 So far, the largest study based on data is the paper on the French cohort, 3 but the sample size did not allow drawing conclusions about the association of DMTs and COVID‐19 severity.\n\nWe present the results of an observational study on PwMS with a confirmed or suspected COVID‐19 infection, based on clinician‐reported data. The study was conducted in Italy, a high‐prevalence area for MS 8 that was the first European country to suffer the effects of the pandemic. The results are presented after the preplanned sample size needed to reach conclusions on the effect of DMTs on COVID‐19 severity was reached.\n\nPatients and Methods\n\nData Sources\n\nWe obtained clinician‐reported demographic and clinical data on PwMS with a confirmed or suspected COVID‐19 infection from 85 Italian MS centers (Supplementary Table S2). We used a common web‐based electronic case report form (eCRF) to collect the data and a unified protocol to analyze them. Data were obtained after data‐sharing agreements between the Italian MS Society, the Italian Neurological Society, the University of Genoa, and all the MS centers involved. Demographic, MS history, COVID‐19 infection, and follow‐up data were collected. The study was approved by the regional ethics committee of Liguria (University of Genoa; n 130/2020–DB id 10433) and at a national level by the Italian Medicines Agency.\n\nStudy Population\n\nWe included adult MS patients who had been in contact with their neurologist because of a confirmed or suspected infection by severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) during the observation period (January 15 to September 10, 2020). The confirmed cases were those with a positive test (reverse transcriptase polymerase chain reaction on nasal and pharyngeal swabs) for SARS‐CoV‐2 or a positive serological test obtained at any point during the observation period; the suspected cases were those who had radiological findings or symptoms highly suggestive of SARS‐CoV‐2 infection, according to medical judgment (cough, fever, shortness of breath, sudden onset of anosmia, ageusia, dysgeusia), and/or had close contact with a confirmed COVID‐19 case in the 14 days prior to the onset of symptoms. Data were collected retrospectively from the first contact until an outcome (death or recovery), taking as baseline the day of symptoms appearance. The first contact was a hospital visit, a phone call, or a web‐based visit, upon patients' or clinicians' request. Clinicians collected data by reviewing patients' clinical charts.\n\nVariables Assessed\n\nCollected data are detailed in the eCRF. We collected demographic data, including age, sex, body mass index (BMI), patient‐reported race and ethnic group, work status, number of cohabitants and number of cohabitants positive for SARS‐CoV‐2 infection, patient‐reported smoking and drinking status, and comorbidities; MS history data, including type of MS (relapsing–remitting MS [RRMS], primary progressive, or secondary progressive), disease onset date, Expanded Disability Status Scale (EDSS), DMTs at the date of symptoms start, and date of last treatment dose; and COVID‐19 infection data, including suspected geographic area of infection, symptoms, laboratory and radiological data, hospitalization, pneumonia and severity of pneumonia according to radiological examinations and ventilation support, therapies for COVID‐19, intensive care unit (ICU) admission, and recovery or death.\n\nEach week a query for follow up update was sent to all centers, until they filled the outcome report (death or recovery).\n\nEnd Points\n\nWe run 2 main analyses on the following primary endpoints: (1) observed number of deaths over the whole follow‐up; and (2) severe COVID‐19 characterized by a 3‐level variable; the highest severity level was death or ICU admission, the intermediate severity level was diagnosis of pneumonia or hospitalization, and the lowest severity level was a milder disease with no need for hospitalization or documented diagnosis of pneumonia.\n\nStatistical Analysis\n\nThe web‐based data collection started on March 1, 2020 and closed for the analysis on September 10, 2020. The first date of symptom appearance retrospectively reported was January 15, 2020. All the patients had complete follow‐up to death or recovery.\n\nFor the sample size calculations, we determined that 800 patients were needed, assuming a rate of severe outcomes (death, ICU admission, pneumonia, or hospitalization) of 20% in the reference group and a comparison group made of 15% of the full cohort, to have a power of 90% to detect an increased risk of severe outcome in the comparison group quantified by an odds ratio (OR) = 2.0 at a confidence level of 0.05.\n\nTo make efficient use of the available data, we used multiple imputation of missing values for missing baseline data. Imputation was performed using chained equations, 9 where each incomplete variable is imputed by a separate model and implemented trough the \"mice\" R package. Continuous variables (age, height, weight, BMI, and disease duration) were parameterized as numeric data and imputed with the predictive mean matching method, whereas polytomous logistic regression was used for the unordered categorical variables (such as MS phenotype). EDSS and disease duration were used to impute the MS phenotype; age and MS phenotype were used to impute disease duration; age, height, or weight was used to impute BMI.\n\nTo assess risk factors at symptoms onset for a severe disease course, we ran a multivariate ordinal logistic regression assuming proportional ORs with severe outcome (defined as a 3‐level factor) as the dependent variable, after assessing that the assumptions of proportional odds were satisfied. The ORs reflect the multiplicative change in the odds of being at a higher level of the dependent variable for every one‐unit increase of the independent variable. The multivariate model included age, sex, BMI, EDSS, disease duration, MS disease phase (RRMS vs progressive), presence of comorbidities, methylprednisolone use within 1 month since COVID‐19 symptoms onset, and DMT class as independent variables, stratified by macroregion (defined as Lombardy; Northern Italy, including Piedmont, Veneto, Emilia‐Romagna, and Liguria; and the rest of Italy). DMT class was coded as an 8‐level variable as no therapy, interferon, glatiramer‐acetate, teriflunomide, dimethyl fumarate, natalizumab, anti‐CD20 (rituximab or ocrelizumab), or other. Alemtuzumab and cladribine were grouped in the “other” group, because the number of patients in these two therapeutic arms was too low to draw meaningful conclusions. “No therapy” was used as the reference category. We also ran the same ordinal logistic analysis after a multinomial propensity score (PS) weighting, as an alternative method to balance the differences of baseline characteristics among patients treated with different DMTs. The weights were calculated using an iterative robust approach based on the Generalized Boosted Model (GBM). 10 The balance among treatment groups was defined by the standardized mean difference, and the optimal GBM iteration was found by minimizing this quantity.\n\nResults were also presented taking dimethyl fumarate, which is the most frequently used therapy in Italy, as the reference therapy group (Supplementary Appendix). Additional analyses were focused on the anti‐CD20 therapies using the same multivariate ordinal logistic model adjusted for all the baseline variables; we investigated the effect of being on anti‐CD20 versus not being on anti‐CD20, the effect of the distance from last infusion (0–3 months, >3 months), and the effect of the time since therapy start (<6 months, 6–12 months, >12 months).\n\nSensitivity analyses were run by repeating all the analyses on the subgroup of confirmed cases only, in the subgroup of patients with a RRMS course, in a model including only patients with complete baseline data with no imputation and using a leave one out procedure rerunning the analysis excluding one of the 3 major centers (Brescia, Bergamo, Milan) at a time (Supplementary Appendix).\n\nRole of the Funding Source\n\nRoche donated the web‐based platform for data collection. Roche did not have any role in study design; in analysis and interpretation of data; in the writing of the report; or in the decision to submit the paper for publication.\n\nResults\n\nPatients Characteristics\n\nOn September 10, 844 PwMS with complete follow‐up from first contact to the outcome (recovery or death) from 85 centers were included in the dataset (Supplementary Appendix). Thirty‐four percent (286/844) of patients were from 3 centers in Lombardy (ASST Spedali Civili, Brescia‐Montichiari; Papa Giovanni XXIII Hospital, Bergamo; and San Raffaele Hospital, Milan); the distribution of patients by region is shown in Supplementary Table S3.\n\nTable 1 reports the baseline demographic and clinical characteristics of the cohort. The mean age was 45 years (range = 18–82), the percentage of females was 70.3%, the median EDSS was 2 (interquartile range [IQR] = 1.50–4), and the proportion of progressive patients was 16%. Six hundred ninety‐three (82%) patients were treated with a DMT at the time of COVID‐19 presumed symptoms onset.\n\nTABLE 1 Baseline Demographic and Clinical Characteristics of Included Patients\n\nCharacteristic\tOverall, N = 844\tSuspected, n = 565\tConfirmed, n = 279\t\nAge, n (%)\t\t\t\t\n<40 yr\t279 (33.1)\t203 (35.9)\t76 (27.2)\t\n40–59 yr\t471 (55.8)\t312 (55.2)\t159 (57.0)\t\n60–79 yr\t92 (10.9)\t50 (8.8)\t42 (15.1)\t\n≥80 yr\t2 (0.2)\t0 (0.0)\t2 (0.7)\t\nFemale sex, n (%)\t593 (70.3)\t410 (72.6)\t183 (65.6)\t\nBMI, mean (SD)\t23.82 (4.37)\t23.61 (4.37)\t24.28 (4.37)\t\nComorbidities, n (%)\t188 (22.3)\t115 (20.4)\t73 (26.2)\t\nMS phenotype, n (%)\t\t\t\t\nPrimary progressive\t44 (5.2)\t24 (4.2)\t20 (7.2)\t\nRelapsing–remitting\t676 (80.1)\t469 (83.0)\t207 (74.2)\t\nSecondary progressive\t91 (10.8)\t46 (8.1)\t45 (16.1)\t\nMissing data\t33 (3.9)\t26 (4.6)\t7 (2.5)\t\nMS disease duration, median (IQR)\t10.2 (4.7–17.1)\t9.6 (4.3–16.2)\t11.8 (5.4–18.5)\t\nEDSS, median (IQR)\t2 (1.50–4)\t2 (1.50–3.50)\t2 (1.50–4)\t\nMS treatment, n (%)\t\t\t\t\nDimethyl fumarate\t174 (20.6)\t131 (23.2)\t43 (15.4)\t\nFingolimod\t94 (11.1)\t59 (10.4)\t35 (12.5)\t\nOcrelizumab\t89 (10.5)\t58 (10.3)\t31 (11.1)\t\nNatalizumab\t85 (10.1)\t51 (9.0)\t34 (12.2)\t\nInterferon\t73 (8.6)\t52 (9.2)\t21 (7.5)\t\nCopaxone\t70 (8.3)\t52 (9.2)\t18 (6.5)\t\nTeriflunomide\t64 (7.6)\t37 (6.5)\t27 (9.7)\t\nAlemtuzumab\t14 (1.7)\t11 (1.9)\t3 (1.1)\t\nCladribine\t11 (1.3)\t7 (1.2)\t4 (1.4)\t\nAzathioprine\t10 (1.2)\t4 (0.7)\t6 (2.2)\t\nRituximab\t5 (0.6)\t4 (0.7)\t1 (0.4)\t\nMethotrexate\t1 (0.1)\t1 (0.2)\t0 (0.0)\t\nMitoxantrone\t1 (0.1)\t1 (0.2)\t0 (0.0)\t\nOther\t2 (0.2)\t2 (0.4)\t0 (0.0)\t\nNone\t151 (17.9)\t95 (16.8)\t56 (20.1)\t\nPrevious methylprednisolone, n (%)\t26 (3.1)\t16 (2.8)\t10 (3.6)\t\nBMI = body mass index; EDSS = Expanded Disability Status Scale; IQR = interquartile range; MS = multiple sclerosis; SD = standard deviation.\n\nThree hundred eighty‐four patients (45.5%) had at least one laboratory test executed for the COVID‐19 diagnosis; 307 (36.4%) patients were tested in the active phase with a swab and 127 (15.0%) had a serological test after recovery. Overall, 279 (33.1%) were classified as confirmed cases. Because the test during the pandemic peak was done only in the most severe patients, confirmed cases are expected to be more severe than suspected cases. In the confirmed cases subgroup, there was a higher proportion of older subjects than in the suspected cases subgroup (>60 years = 16% vs 9%) and more patients in the progressive MS phase (23% vs 12%).\n\nThe baseline characteristics of the cohort according to DMT received are reported in Table 2; patients with no therapy were older (mean age = 53.4 years), with a higher EDSS (mean EDSS = 5.5) and with a higher proportion of progressive patients (45.7%) than patients treated with DMTs. Among treated patients, those treated with interferon, glatiramer‐acetate, or teriflunomide were older than those in other DMT groups, and patients treated with anti‐CD20 had a higher EDSS (mean EDSS = 3) and a larger portion of progressive patients (25.6%) than those treated with other DMTs, but not larger than the untreated group.\n\nTABLE 2 Baseline Demographic and Clinical Characteristics of Included Patients according to Disease‐Modifying Therapy Received\n\nCharacteristic\tNo Therapy, n = 151\tIFN, n = 73\tGA, n = 70\tTeri, n = 64\tDMF, n = 174\tFTY, n = 94\tNat, n = 85\tAnti‐CD20, n = 94 a\tOther, n = 39\t\nAge, mean (SD)\t53.4 (13.4)\t47.5 (10.5)\t45.7 (11.3)\t49.1 (9.4)\t41.4 (10.9)\t44.2 (9.5)\t37.9 (9.8)\t42.0 (10.0)\t42.2 (13.8)\t\nFemale sex, n (%)\t104 (68.9)\t53 (72.6)\t48 (68.6)\t44 (68.8)\t114 (65.5)\t74 (78.7)\t64 (75.3)\t64 (68.1)\t28 (71.8)\t\nBMI, mean (SD)\t24.6 (4.6)\t24.3 (2.7)\t25.2 (5.0)\t24.7 (4.5)\t23.3 (4.1)\t23.9 (5.2)\t22.7 (4.1)\t22.6 (3.7)\t23.2 (3.8)\t\nMS phenotype, n (%)\t\t\t\t\t\t\t\t\t\t\nPrimary progressive\t22 (14.6)\t0 (0.0)\t1 (1.4)\t0 (0.0)\t0 (0.0)\t2 (2.1)\t1 (1.2)\t16 (17.0)\t2 (5.1)\t\nRelapsing–remitting\t65 (43.0)\t65 (89.0)\t64 (91.4)\t59 (92.2)\t165 (94.8)\t81 (86.2)\t83 (97.6)\t67 (71.3)\t27 (69.2)\t\nSecondary progressive\t47 (31.1)\t6 (8.2)\t2 (2.9)\t3 (4.7)\t5 (2.9)\t9 (9.6)\t0 (0.0)\t9 (9.6)\t10 (25.6)\t\nMissing data\t17 (11.3)\t2 (2.7)\t3 (4.3)\t2 (3.1)\t4 (2.3)\t2 (2.1)\t1 (1.2)\t2 (2.1)\t0 (0.0)\t\nMS disease duration, median yr (IQR)\t16.2 (8–23)\t12.0 (6–19)\t10.1 (5–17)\t11.4 (6–15)\t5.5 (3–13)\t11.8 (7–18)\t9.1 (5–15)\t8.2 (4–13)\t12.9 (5–18)\t\nEDSS, median (IQR)\t5.5 (2–7)\t1.5 (1–2.5)\t1.5 (1–2)\t2.0 (1.5–3)\t1.5 (1–2)\t2.0 (1.5–3)\t2.0 (1.5–3)\t3.0 (1.5–4.5)\t3.0 (1.5–6)\t\nMethylprednisolone, b n (%)\t9 (6.0)\t2 (2.7)\t1 (1.4)\t2 (3.1)\t4 (2.3)\t4 (4.3)\t1 (1.2)\t1 (1.1)\t2 (5.1)\t\na Ocrelizumab or rituximab.\n\nb One month before symptoms onset.\n\nBMI = body mass index; DMF = dimethyl fumarate; EDSS = Expanded Disability Status Scale; FTY = fingolimod; GA = glatiramer‐acetate; IFN = interferon; IQR = interquartile range; MS = multiple sclerosis; Nat = natalizumab; SD = standard deviation; Teri = teriflunomide.\n\nThirteen (1.54%) patients died, and their characteristics are described in Table 3; 8 of them were PwMS with no therapy, all in a progressive disease phase (1 primary progressive MS, 7 secondary progressive MS). Five of them were treated (rituximab, ocrelizumab, natalizumab, glatiramer‐acetate, dimethyl fumarate), and only 2 of them were in a RRMS phase (glatiramer‐acetate and natalizumab). The mean time from symptoms to death was 18 days (range = 5–54 days).\n\nTABLE 3 Characteristics of Deceased Patients\n\nSex, Age, yr\tDisease Duration\tDisease Phase\tEDSS\tTherapy\tComorbidities\t\nM, 63\t33\tSPMS\t7\tNo therapy\tDiabetes\t\nM, 67\t2\tPPMS\t7.5\tNo therapy\tCHD, hypertension, HBV\t\nM, 68\t21\tSPMS\t6\tDimethyl fumarate\tCerebrovascular disease, hypertension, depression, TBC\t\nF, 57\t20\tSPMS\t9\tNo therapy\tNo\t\nM, 76\t17\tSPMS\t6.5\tNo therapy\tCHD, hypertension, depression, dyslipidemia\t\nF, 52\t1\tRRMS\t5\tNatalizumab\tNo\t\nF, 50\t27\tSPMS\t6\tOcrelizumab\tNo\t\nM, 59\t33\tSPMS\t9\tNo therapy\tNo\t\nF, 68\t19\tSPMS\t5.5\tNo therapy\tNo\t\nF, 54\t20\tSPMS\t7\tRituximab\tNo\t\nM, 64\t10\tRRMS\t2\tGlatiramer‐acetate\tNo\t\nM, 63\t33\tSPMS\t6.5\tNo therapy\tDiabetes, bipolar disorder\t\nM, 60\t30\tSPMS\t9\tNo therapy\tHypertension, cerebrovascular disease, CHD\t\nCHD = coronary heart disease; F = female; HBV = hepatitis B virus; M = male; PPMS = primary progressive multiple sclerosis; RRMS = relapsing–remitting multiple sclerosis; SPMS = secondary progressive multiple sclerosis; TBC = tuberculosis.\n\nRisk Factors for a Severe COVID‐19 Outcome\n\nThirty‐eight (4.5%) patients were admitted to an ICU (7 of them died); 99 cases (11.7%) of radiologically documented pneumonia were reported; 96 patients (11.4%) were hospitalized. Forty‐four patients (5.2%) were in the highest severity class (death or ICU admission), and 92 patients (10.9%) were in the intermediate severity class (pneumonia or hospitalization). Twenty‐six patients (3.1%) received methylprednisolone in the month preceding the first symptoms of COVID‐19.\n\nRisk factors for severe COVID‐19 in univariate, multivariate, and PS‐weighted analysis are reported in Table 4. The assumptions of proportional odds were satisfied. Older age, male sex, higher EDSS, longer MS duration, presence of comorbidities, and progressive MS course were all risk factors for a more severe disease in univariate analysis. Methylprednisolone use within 1 month before COVID‐19 symptoms onset was associated with increased risk (OR = 3.38, 95% confidence interval [CI] = 1.49–7.67, p = 0.004). Taking no therapy as the reference category indicated a reduced risk for all the DMTs, with OR ranging from 0.34 to 0.50, except for the anti‐CD20 therapies (ocrelizumab/rituximab, OR = 0.94). When adjusting the OR in the multivariate model, the risk factors with a significant impact on COVID‐19 severity were age, sex, EDSS, recent use of methylprednisolone, and anti‐CD20 therapy. Age and EDSS fully explained the apparent risk associated with no therapy as compared to the other DMTs, and the only treatment associated with a higher risk of a severe COVID‐19 disease was anti‐CD20 therapy (OR = 2.37, 95% CI = 1.18–4.74, p = 0.015). Also, the increased risk associated with the use of recent methylprednisolone was confirmed (OR = 5.24, 95% CI = 2.20–12.53, p = 0.001). The PS‐weighted characteristics of patients according to the different DMTs received are reported in Supplementary Table S11. The DMT effects on COVID‐19 severity are replicated by the PS‐weighted analysis. The OR for anti‐CD20 therapy was 3.91 (95% CI = 1.71–8.91, p = 0.001).\n\nTABLE 4 Univariate, Multivariate, and PS‐Weighted Ordinal Logistic Regression Models Evaluating Risk Factors for Severe Coronavirus Disease 2019 a\n\n\tUnivariate Analysis, n = 844 b\tMultivariate Analysis, n = 844 b\tPS Analysis, n = 844 b\t\nVariable\tOR (95% CI)\tp\tOR (95% CI)\tp\tOR (95% CI)\tp\t\nAge, yr\t1.06 (1.04–1.08)\t<0.001\t1.06 (1.03–1.08)\t<0.001\t1.06 (1.03–1.10)\t0.001\t\nSex, F vs M\t0.64 (0.40–1.03)\t0.068\t0.69 (0.45–1.04)\t0.076\t0.83 (0.50–1.39)\t0.49\t\nProgressive vs RRMS\t4.14 (2.70–6.35)\t<0.001\t1.59 (0.81–3.01)\t0.18\t1.76 (0.70–4.40)\t0.23\t\nEDSS\t1.33 (1.22–1.45)\t<0.001\t1.07 (0.93–1.22)\t0.40\t1.08 (0.86–1.35)\t0.50\t\nDisease duration, yr\t1.04 (1.02–1.06)\t<0.011\t1.00 (0.98–1.03)\t0.99\t0.99 (0.96–1.02)\t0.57\t\nBMI\t1.01 (0.97–1.05)\t0.53\t0.98 (0.94–1.02)\t0.44\t0.99 (0.93–1.02)\t0.74\t\nComorbidities, yes\t1.70 (1.13–2.56)\t0.012\t0.93 (0.58–1.47)\t0.74\t0.82 (0.48–1.42)\t0.48\t\nMethylprednisolone c\t3.38 (1.49–7.67)\t0.004\t5.24 (2.20–12.53)\t0.001\t2.51 (0.99–6.44)\t0.05\t\nDMT\t\t\t\t\t\t\t\nNo therapy d\t1 (ref)\t\t1 (ref)\t\t1 (ref)\t\t\nInterferon\t0.35 (0.15–0.79)\t0.012\t0.67 (0.28–1.65)\t0.39\t0.71 (0.29–1.78)\t0.48\t\nGlatiramer‐acetate\t0.34 (0.14–0.81)\t0.015\t0.77 (0.29–2.00)\t0.59\t1.19 (0.30–4.87)\t0.80\t\nTeriflunomide\t0.48 (0.21–1.07)\t0.07\t0.86 (0.36–2.08)\t0.74\t1.17 (0.41–3.63)\t0.76\t\nDimethyl fumarate\t0.38 (0.20–0.70)\t0.002\t1.12 (0.55–2.30)\t0.75\t1.29 (0.58–2.87)\t0.62\t\nNatalizumab\t0.35 (0.16–0.76)\t0.009\t1.30 (0.53–3.22)\t0.57\t1.77 (0.61–5.07)\t0.29\t\nFingolimod\t0.50 (0.26–0.98)\t0.04\t1.19 (0.57–2.52)\t0.64\t1.48 (0.66–3.34)\t0.34\t\nAnti‐CD20 e\t0.94 (0.52–1.08)\t0.85\t2.37 (1.18–4.74)\t0.015\t3.91 (1.71–8.91)\t0.001\t\nOther\t0.38 (0.14–1.04)\t0.06\t0.71 (0.28–2.65)\t0.39\t1.50 (0.40–5.71)\t0.55\t\na Intensive care unit or death vs hospitalization or pneumonia vs milder symptoms not requiring hospitalization and no documented pneumonia.\n\nb All the analyses are adjusted for macroregion (Lombardy; Northern Italy, including Veneto, Emilia‐Romagna, Piedmont, and Liguria; and the rest of Italy).\n\nc One month before symptoms onset.\n\nd No therapy was chosen as the reference class.\n\ne Ocrelizumab or rituximab.\n\nBMI = body mass index; CI = confidence interval; DMT = disease‐modifying therapy; EDSS = Expanded Disability Status Scale; F = female; M = male; OR = odds ratio; PS = propensity score; RRMS = relapsing–remitting multiple sclerosis.\n\nThe results taking dimethyl fumarate as the reference category are reported in the Supplementary Appendix and are in line with the above results. All the sensitivity analyses confirmed these findings; the anti‐CD20–treated patients had an OR = 2.62 (p = 0.05) in the subgroup of confirmed cases, an OR = 2.87 (p = 0.03) in the subgroup of RRMS patients, and an OR = 2.69 (p = 0.026) using only complete baseline data with no imputation (Supplementary Appendix).\n\nA further result that deserves attention is the risk reduction observed in patients treated with interferon (OR = 0.67); however, this does not reach a statistical significance. Among the 73 patients on interferon, no ICU admissions or deaths were recorded.\n\nTo give an idea of the absolute risk of severe COVID‐19 according to DMT, Figure 1 reports the percentage of patients with severe events (pneumonia, hospitalization, ICU, or death) in the group treated with anti‐CD20, in the untreated group, and in the group treated with other DMTs. To adjust these values for the confounding factors, the figure was restricted to patients <65 years old and with EDSS < 6.5 (n = 733), and presented separately for the RRMS (n = 675) and progressive MS (n = 58) groups. The percentage of subjects with severe events was higher in the group of patients treated with anti‐CD20 both in the RRMS and in the progressive MS patients; in the RRMS group, the proportion of patients deceased or admitted to ICU in the anti‐CD20 group was 6.1%, versus 4.2% in the untreated and 2.2% in the other DMTs group. In the progressive MS group, it was 12.5% in the anti‐CD20 group, 10.5% in the untreated group, and 4.3% in the other DMTs group. The percentage of patients with an intermediate severity (pneumonia or hospitalization) had the same trend of increase in the anti‐CD20 group.\n\nFIGURE 1 Percentage of patients with pneumonia/hospitalization and intensive care unit (ICU)/death in the subgroup of subjects with age < 65 years and Expanded Disability Status Scale < 6.5, according to multiple sclerosis (MS) phenotype (relapsing–remitting vs progressive MS), in the anti‐CD20, no therapy, and other therapies groups. DMT = disease‐modifying therapy.\n\nThe increase of risk associated with anti‐CD20 was maintained on hard end points (death or ICU admission), even if the small number of events did not allow this to reach statistical significance (Supplementary Appendix).\n\nThe adjusted OR for anti‐CD20 therapy versus all the other therapies was 2.37 (95% CI = 1.36–4.12, p = 0.002). Exploratory analyses revealed no association between COVID‐19 severity and the time passed since the last anti‐CD20 infusion (OR = 2.77, 95% CI = 1.31–5.89, p = 0.012 for last infusion within 3 months and OR = 2.05, 95% CI = 0.97–4.28, p = 0.023 for last infusion before 3 months), whereas there was a trend with therapy duration; as compared to PwMS treated with other therapies, patients on anti‐CD20 therapy for <6 months had an OR = 1.65 (95% CI = 0.56–4.90, p = 0.36), patients on anti‐CD20 therapy for 6–12 months had an OR = 2.24 (95% CI = 0.91–5.55, p = 0.08), and patients on anti‐CD20 therapy for >12 months had an OR = 2.98 (95% CI = 1.37–6.46, p = 0.006; Supplementary Appendix).\n\nNo severe outcomes (no pneumonia, hospitalization, ICU, or death) were observed in the 11 patients treated with cladribine or in the 14 patients treated with alemtuzumab.\n\nDiscussion\n\nThis study shows an acceptable level of safety of immunomodulatory and immunosuppressive therapies in MS during the COVID‐19 pandemic. However, two results deserve attention.\n\nFirst, 11 of 13 deaths occurred in persons with advanced disease and disability (median EDSS = 7). The median age of people who died was 63 years versus a median age of 45 years for those who recovered. Higher EDSS was associated in multivariate analysis with COVID‐19 severity also in the French MS population. 3 These findings strengthen the need to enforce prevention strategies for people with advanced disability and older age during the pandemic. 11\n\nSecond, we observed an increased frequency of a severe COVID‐19 in people treated with anti‐CD20 therapies compared to other DMTs. Smaller case series suggested an increased susceptibility to COVID‐19 in PwMS taking B‐cell–depleting monoclonal antibodies, 12 , 13 , 14 without major effects on the severity of COVID‐19. 13 , 14 , 15 In the largest study published so far (the French study), DMT exposure was not included in the multivariate model. The results of the univariate analysis are very similar to those presented here. 3 It will be informative to evaluate the OR for the impact of DMTs on severity in the French cohort in the multivariate model, to check the size of effect, irrespective of the statistical significance. Data are available about the general risk of infections during DMTs for MS; a nationwide Swedish cohort examined the infection risks in PwMS treated with DMTs. 16 In that study, rituximab was associated with the highest rate of serious infections. However, the use of herpes antivirals was lower with rituximab compared to fingolimod and natalizumab; ocrelizumab clinical trials reported an increased risk of respiratory tract infections, 17 , 18 and safety issues emerged in diseases other than MS. 19 With respect to the association with treatment duration, it has been shown that long‐term anti‐CD20 treatment is associated with the risk of hypogammaglobulinemia in neuromyelitis optica‐spectrum disorder. 20 A protracted treatment may impact on the protective, anti–SARS‐CoV‐2 humoral response 21 and on a pre‐existing humoral and cellular immune repertoire, recently described in unexposed individuals. 22 , 23\n\nWe did not observe a link between time to last infusion of ocrelizumab and COVID‐19 risk. This preliminary result needs to be confirmed, but it is consistent with the idea that the immunological effects of ocrelizumab may last longer than 6 months. Reducing the frequency of dosing, or adjusting it according to the monitoring of B‐cell repopulation kinetics in individual patients, 20 may maintain efficacy while limiting the risk of infection. 24 A similar strategy deserves attention also in view of future vaccinations. 25 However, it may not be without risks linked to the re‐expansion of autoreactive B cells. 26\n\nThe role of interferon treatment and the severity of COVID‐19 is of high interest. Our data indicated a decrease of risk associated with interferon, even if it did not reach statistical significance. The majority of laboratory studies are in line with this preliminary observation, suggesting that supplementing type I interferons may circumvent a defective response that, in people with severe COVID‐19, may depend on various mechanisms including the presence of anti‐interferon autoantibodies, 27 a genetically defective type I interferon response, 28 , 29 or the ability of SARS‐CoV‐2 to neutralize the antiviral effects of type I interferons. 30 A recent clinical trial of interferon beta‐1b and lopinavir–ritonavir in Middle East respiratory syndrome 31 supports this hypothesis, but a negative trial of interferon beta‐1b, alone or in combination with lopinavir, does not. 32 It is possible that timing in the administration of type I interferons is crucial, as early therapy is associated with favorable clinical responses. 33 This is in accord with our observation in patients who are already under interferon beta therapy when they develop COVID‐19.\n\nImportantly, methylprednisolone in the month preceding the first symptoms of COVID‐19 was significantly associated with a worse outcome. This aspect was not considered in previous reports, is in agreement with data in other autoimmune diseases, 34 and is relevant in assessing the risk of DMTs (ie, COVID‐19 risk vs steroid‐sparing potential).\n\nThis study has limitations that must be considered when evaluating the results. First, we included in the study not only confirmed but also suspected cases. For this reason, we cannot exclude that the suspected cases suffered from infections other than COVID‐19. We took the decision of including suspected cases because, during the pandemic peak in Italy, only the most severe cases (often after hospitalization) were tested. Hence, including only confirmed cases would have limited the representativeness of our sample. The inclusion of patients suffering from non–COVID‐19 infections might have diluted the effect of the detected association, resulting in a conservative approach. Furthermore, we reran all the main analyses on the subgroup of confirmed cases, obtaining similar and even stronger results, despite the smaller sample size. A second relevant bias might derive from differences in awareness and expectations of risks in patients receiving therapies with stronger immunosuppressive effect. This might have favored more frequent contacts with treating neurologists, resulting in increased attention to ocrelizumab or rituximab patients. However, the same should have been true also for other intravenous therapies. Finally, although the multivariate analysis adjusts the effect of DMTs on COVID‐19 severity for the main confounding factors, we cannot exclude that some residual confounding can partly explain the observed associations.\n\nOverall, this study shows an acceptable safety profile of DMTs in MS during the COVID‐19 pandemic. The differences that emerged among the various DMTs are in agreement with previous knowledge about infections in PwMS. The results are also plausible based on current biological knowledge, although the exact mechanisms that affect the risk of COVID‐19 remain uncertain. It will be important to look at other ongoing studies 35 to verify whether they confirm our findings and to compare the new clinical insight in other autoimmune diseases. This may stimulate new laboratory research and shed new light on the biology of SARS‐CoV‐2 infection and on the pathophysiology of the different autoimmune diseases.\n\nAuthor Contributions\n\nAll authors contributed to the conception and design of the study; the Musc‐19 Study Group contributed to the acquisition and analysis of data; M.P.S., I.S., L.C., and M.S. contributed to drafting the text and preparing the figures.\n\nPotential Conflicts of Interest\n\nM.P.S. reports a grant from Roche to cover data management of this study; Roche makes ocrelizumab, which is one of the DMTs assessed in this study. The remaining authors have nothing to report.\n\nSupporting information\n\nAPPENDIX S1. Supporting Information\n\nClick here for additional data file.\n\nAcknowledgments\n\nThe Musc‐19 Study Group thanks Roche for donating the web‐based platform for data collection and the Department of Informatics, Bioengineering, Robotics, and Systems Engineering, University of Genoa, for its help in installing the platform.\n==== Refs\nReferences\n\n1 Haberman R , Axelrad J , Chen A , et al. Covid‐19 in immune‐mediated inflammatory diseases—case series from New York. N Engl J Med 2020;383 :85–88.32348641\n2 Sormani MP . Italian Study Group on COVID‐19 Infection in Multiple Sclerosis. An Italian programme for COVID‐19 infection in multiple sclerosis. Lancet Neurol 2020;19 :481–482; erratum Lancet Neurol 2020;19:e6.32359409\n3 Louapre C , Collongues N , Stankoff B , et al. Clinical characteristics and outcomes in patients with coronavirus disease 2019 and multiple sclerosis. JAMA Neurol 2020;77 :1079–1088.32589189\n4 Hughes R , Pedotti R , Koendgen H . COVID‐19 in persons with multiple sclerosis treated with ocrelizumab—a pharmacovigilance case series. Mult Scler Relat Disord 2020;42 :102192.32570202\n5 Browne P , Chandraratna D , Angood C , et al. Atlas of multiple sclerosis 2013: a growing global problem with widespread inequity. Neurology 2014;83 :1022–1024.25200713\n6 Winkelmann A , Loebermann M , Reisinger EC , et al. Disease‐modifying therapies and infectious risks in multiple sclerosis. Nat Rev Neurol 2016;12 :217–233.26943779\n7 Amor S , Baker D , Khoury SJ , et al. SARS‐CoV‐2 and multiple sclerosis: not all immune depleting DMTs are equal or bad. Ann Neurol 2020;87 :794–797.32383812\n8 Battaglia MA , Bezzini D . Estimated prevalence of multiple sclerosis in Italy in 2015. Neurol Sci 2017;38 :473–479.28040843\n9 Van Buuren S , Groothuis‐Oudshoorn K . mice: multivariate imputation by chained equations in R. J Stat Software 2011;45 :1–67.\n10 Mccaffrey DF , Griffin BA , Almirall D , et al. A tutorial on propensity score estimation for multiple treatments using generalized boosted models. Stat Med 2013;32 :3388–3414.23508673\n11 Rubin EJ , Baden LR , Morrissey S . Audio interview: Lessons from Covid‐19 hotspots. N Engl J Med 2020;382 :e35.32242382\n12 Sahraian MA , Azimi A , Navardi S , et al. Evaluation of the rate of COVID‐19 infection, hospitalization and death among Iranian patients with multiple sclerosis. Mult Scler Relat Disord 2020;46 :102472.32890817\n13 Safavi F , Nourbakhsh B , Azimi AR . B‐cell depleting therapies may affect susceptibility to acute respiratory illness among patients with multiple sclerosis during the early COVID‐19 epidemic in Iran. Mult Scler Relat Disord 2020;43 :102195.32460086\n14 Parrotta E , Kister I , Charvet L , et al. COVID‐19 outcomes in MS: Observational study of early experience from NYU Multiple Sclerosis Comprehensive Care Center. Neurol Neuroimmunol Neuroinflamm. 2020;7:e835. 10.1212/NXI.0000000000000835.\n15 Montero‐Escribano P , Matías‐Guiu J , Gómez‐Iglesias P , et al. Anti‐CD20 and COVID‐19 in multiple sclerosis and related disorders: a case series of 60 patients from Madrid, Spain. Mult Scler Relat Disord 2020;42 :102185.32408147\n16 Luna G , Alping P , Burman J , et al. Infection risks among patients with multiple sclerosis treated with fingolimod, natalizumab, rituximab, and injectable therapies. JAMA Neurol 2020;77 :184–191.31589278\n17 Hauser SL , Bar‐Or A , Comi G , et al. Ocrelizumab versus interferon beta‐1a in relapsing multiple sclerosis. N Engl J Med 2017;376 :221–234.28002679\n18 Montalban X , Hauser SL , Kappos L , et al. Ocrelizumab versus placebo in primary progressive multiple sclerosis. N Engl J Med 2017;376 :209–220.28002688\n19 Emery P , Rigby W , Tak PP , et al. Safety with ocrelizumab in rheumatoid arthritis: results from the ocrelizumab phase III program. PLoS One 2014;9 :e87379.24498318\n20 Schweitzer F , Laurent S , Fink GR , et al. Effects of disease‐modifying therapy on peripheral leukocytes in patients with multiple sclerosis. J Neurol 2020. 10.1007/s00415-019-09690-6. (Online ahead of print).\n21 Ren L , Zhang L , Chang D , et al. The kinetics of humoral response and its relationship with the disease severity in Covid‐19. Commun Biol 2020;3 :780.33311543\n22 Díez JM , Romero C , Vergara‐Alert J , et al. Cross‐neutralization activity against SARS‐CoV‐2 is present in currently available intravenous immunoglobulins. Immunotherapy 2020;12 :1247–1255.32900263\n23 Guthmiller JJ , Wilson PC . Remembering seasonal coronaviruses. Science 2020;370 :1272–1273.33303605\n24 Baker D , Pryce G , James LK , et al. The ocrelizumab phase II extension trial suggests the potential to improve the risk: benefit balance in multiple sclerosis. Mult Scler Relat Disord 2020;44 :102279.32645640\n25 Bar‐Or A , Calkwood JC , Chognot C , et al. Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: the VELOCE study. Neurology 2020;95 :e1999–e2008.32727835\n26 Rommer PS , Milo R , Han MH , et al. Immunological aspects of approved MS therapeutics. Front Immunol 2019;10 :1564.31354720\n27 Bastard P , Rosen LB , Zhang Q , et al. Autoantibodies against type I IFNs in patients with life‐threatening Covid‐19. Science 2020;370 :eebd4585.\n28 Zhang Q , Bastard P , Liu Z , et al. Inborn errors of type I IFN immunity in patients with life‐threatening Covid‐19. Science 2020;370 :eebd4570.\n29 Pairo‐Castineira E , Clohisey S , Klaric L , et al. Genetic mechanisms of critical illness in Covid‐19. Nature. 2020. 10.1038/s41586-020-03065-y. (Online ahead of print).\n30 Blanco‐Melo D , Nilsson‐Payant BE , Liu WC , et al. Imbalanced host response to SARS‐CoV‐2 drives development of COVID‐19. Cell 2020;181 :1036–1045.e9.32416070\n31 Arabi YM , Asiri AY , Assiri AM , et al. Interferon beta‐1b and lopinavir‐ritonavir for Middle East respiratory syndrome. N Engl J Med 2020;383 :1645–1656.33026741\n32 WHO Solidarity Trial Consortium , Pan H , Peto R , et al. Repurposed antiviral drugs for Covid‐19—interim WHO Solidarity Trial results. N Engl J Med 2020. 10.1056/NEJMoa2023184. (Online ahead of print).\n33 Wang N , Zhan Y , Zhu L , et al. Retrospective multicenter cohort study shows early interferon therapy is associated with favorable clinical responses in Covid‐19 patients. Cell Host Microbe 2020;28 :455–464.e2. (Online ahead of print).32707096\n34 Gianfrancesco M , Hyrich KL , Al‐Adely S , et al. Characteristics associated with hospitalisation for COVID‐19 in people with rheumatic disease: data from the COVID‐19 Global Rheumatology Alliance physician‐reported registry. Ann Rheum Dis 2020;79 :859–866.32471903\n35 Peeters LM , Parciak T , Walton C , et al. COVID‐19 in people with multiple sclerosis: a global data sharing initiative. Mult Scler 2020;26 :1157–1162.32662757\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0364-5134",
"issue": "89(4)",
"journal": "Annals of neurology",
"keywords": null,
"medline_ta": "Ann Neurol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000086382:COVID-19; D000069462:Dimethyl Fumarate; D005260:Female; D000068876:Fingolimod Hydrochloride; D006760:Hospitalization; D006801:Humans; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D007362:Intensive Care Units; D007372:Interferons; D008297:Male; D008875:Middle Aged; D009026:Mortality; D009103:Multiple Sclerosis; D000069442:Natalizumab; D000086402:SARS-CoV-2; D012720:Severity of Illness Index; D055815:Young Adult",
"nlm_unique_id": "7707449",
"other_id": null,
"pages": "780-789",
"pmc": null,
"pmid": "33480077",
"pubdate": "2021-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "32242382;25200713;32972995;31354720;33303605;32645640;32383812;32471903;32348641;26943779;32589189;33264556;32890817;32359409;32662757;32036423;32646885;24498318;32570202;33307546;32900263;23508673;33026741;32972996;32707096;28040843;32416070;32460086;32727835;28002688;33311543;28002679;32408147;31589278",
"title": "Disease-Modifying Therapies and Coronavirus Disease 2019 Severity in Multiple Sclerosis.",
"title_normalized": "disease modifying therapies and coronavirus disease 2019 severity in multiple sclerosis"
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"activesubstancename": "GLATIRAMER ACETATE"
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"abstract": "Aortic pseudoaneurysm formation subsequent to concurrent chemoradiotherapy (CCRT) for esophageal cancer patient with esophageal metallic stent insertion is a rare condition.A 52-year-old man with esophageal cancer, cT4N1M0, stage IIIC, was treated with concurrent weekly cisplatin (30 mg/m) and 5-Fluorouracil (500 mg/m) as well as radiotherapy (50.4 Gy in 28 fractions) for 6 weeks. An esophageal metallic stent was inserted for dysphagia 1 week after initiation of CCRT. During the treatment regimen, the platelet count dropped to less than 200 × 10 /μL. One month after the completion of CCRT, chest CT revealed the presence of an aortic pseudoaneurysm as well as aortoesophageal fistulas. A thoracic aortic endografting was performed and the patient responded well to surgery. However, the patient died 2 months later due to a nosocomial infection.Multimodality treatment for esophageal cancer comprising cisplatin-based CCRT and esophageal metallic stent placement near a great vessel may increase the risk of pseudoaneurysm formation.",
"affiliations": "From the Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City (P-YH, P-WS, C-HH); Department of Medicine (C-JT, C-HH); Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei (C-HH); Division of Oncology and Hematology, Department of Medicine, Far Eastern Memorial Hospital, New Taipei City (C-JT); Institute of Public Health, National Yang-Ming University, Taipei (C-JT); Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City (C-SC); College of Medicine, Fu Jen Catholic University, New Taipei City (C-SC); Department of Thoracic surgery, Far Eastern Memorial Hospital, New Taipei City (C-YL); Department of Medical Imaging, Far Eastern Memorial Hospital, New Taipei City (C-CH); Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City (M-HC); Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (P-WS).",
"authors": "Hou|Pei-Yu|PY|;Teng|Chung-Jen|CJ|;Chung|Chen-Shuan|CS|;Liu|Chao-Yu|CY|;Huang|Chun-Chieh|CC|;Chang|Miu-Hsiang|MH|;Shueng|Pei-Wei|PW|;Hsieh|Chen-Hsi|CH|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D002945:Cisplatin; D005472:Fluorouracil",
"country": "United States",
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"doi": "10.1097/MD.0000000000000862",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 2599706410.1097/MD.0000000000000862008625700ArticleClinical Case ReportAortic Pseudoaneurysm Formation Following Concurrent Chemoradiotherapy And Metallic Stent Insertion in a Patient With Esophageal Cancer Hou Pei-Yu MDTeng Chung-Jen MDChung Chen-Shuan MDLiu Chao-Yu MDHuang Chun-Chieh MDChang Miu-Hsiang MDShueng Pei-Wei MDHsieh Chen-Hsi MD, PhDDurante. Alessandro From the Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, New Taipei City (P-YH, P-WS, C-HH); Department of Medicine (C-JT, C-HH); Institute of Traditional Medicine, School of Medicine, National Yang-Ming University, Taipei (C-HH); Division of Oncology and Hematology, Department of Medicine, Far Eastern Memorial Hospital, New Taipei City (C-JT); Institute of Public Health, National Yang-Ming University, Taipei (C-JT); Department of Internal Medicine, Far Eastern Memorial Hospital, New Taipei City (C-SC); College of Medicine, Fu Jen Catholic University, New Taipei City (C-SC); Department of Thoracic surgery, Far Eastern Memorial Hospital, New Taipei City (C-YL); Department of Medical Imaging, Far Eastern Memorial Hospital, New Taipei City (C-CH); Department of Anatomical Pathology, Far Eastern Memorial Hospital, New Taipei City (M-HC); Department of Radiology, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (P-WS).Correspondence: Chen-Hsi Hsieh, Division of Radiation Oncology, Department of Radiology, Far Eastern Memorial Hospital, 21 Sec 2, Nanya S Road, Banciao District, New Taipei City 220, Taiwan (e-mail: chenciab@gmail.com).5 2015 22 5 2015 94 20 e8622 2 2015 25 3 2015 14 4 2015 Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.2015This is an open access article distributed under the Creative Commons Attribution License 4.0, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nAortic pseudoaneurysm formation subsequent to concurrent chemoradiotherapy (CCRT) for esophageal cancer patient with esophageal metallic stent insertion is a rare condition.\n\nA 52-year-old man with esophageal cancer, cT4N1M0, stage IIIC, was treated with concurrent weekly cisplatin (30 mg/m2) and 5-Fluorouracil (500 mg/m2) as well as radiotherapy (50.4 Gy in 28 fractions) for 6 weeks. An esophageal metallic stent was inserted for dysphagia 1 week after initiation of CCRT. During the treatment regimen, the platelet count dropped to less than 200 × 103 /μL. One month after the completion of CCRT, chest CT revealed the presence of an aortic pseudoaneurysm as well as aortoesophageal fistulas. A thoracic aortic endografting was performed and the patient responded well to surgery. However, the patient died 2 months later due to a nosocomial infection.\n\nMultimodality treatment for esophageal cancer comprising cisplatin-based CCRT and esophageal metallic stent placement near a great vessel may increase the risk of pseudoaneurysm formation.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nTreatment options for patients with esophageal cancer and malignant dysphagia include endoluminal stenting, surgery, radiotherapy, brachytherapy, chemotherapy, and chemoradiotherapy (concurrent chemoradiotherapy, CCRT).1,2 Eldeeb and El-Hadaad3 showed that radiotherapy combined with stenting offers a survival advantage. However, metallic stents have been shown to cause irradiation dose perturbation between the stent and surrounding tissues, resulting in intimal thickening, proteoglycan deposition and increased inflammatory cell content, thereby increasing the risk of vascular disease development in cancer patients who undergo RT.4,5\n\nCisplatin (CDDP) and 5-Fluorouracil (5-FU) are reported to be the most active chemotherapeutic regimens for patients with esophageal cancer.6 Both drugs are radiosensitizors that enhance the cytotoxic effect of irradiation.7,8 Additionally, they also cause the damage of the arterial endothelium.9,10\n\nAortic arch pseudoaneurysm is a rare condition but carries a high risk of rupture. Neoadjuvant chemoradiotherapy followed by esophagectomy caused aortic fistula and related to sudden death for esophageal carcinoma had been reported.11 However, pseudoaneurysm development as a result of intraluminal stenting and CCRT in patients with esophageal cancer has never been reported. Herein, we present a case of aortic pseudoaneurysm development in a patient who underwent CCRT for esophageal cancer and metallic stent placement for cancer-induced dysphagia.\n\nCASE REPORT\nA 52-year-old man, with history of hypertension, was diagnosed with stage IIIC (cT4N1M0, American Joint Committee on Cancer, 7th Edition) squamous cell carcinoma at the middle third of the esophagus (Figures 1A and 2) underwent neoadjuvant CCRT comprising concurrent weekly CDDP (30 mg/m2) and 5-FU (500 mg/m2) as well as radiotherapy (50.4 Gy in 28 fractions) for 6 weeks (Figure 3). The regimen in the clinical trial of Cancer and Leukemia Group B (CALGB 9781) was 4-weekly schedule of chemotherapy.6 However, the regimen would be modified to be weekly regimen12 for patients who could not be treated in hospitalization or with poor compliance. Therefore, 4-weekly and weekly schedule both were the standard CCRT protocols in our hospital for esophageal cancer patients. Retrospective data were collected with the approval of the Institutional Review Board of Far Eastern Memorial Hospital (FEMH-IRB-103174-C). Approximately 1 week after beginning the CCRT regimen, however, the patient reported having difficulty swallowing semi-liquid food. A WallFlex™ esophageal stent (18 mm × 123 mm, Boston Scientific Corporation, MA) with metallic radiopaque material that is formed into a cylindrical mesh and was partially covered with a translucent silicone polymer to restrict tumor ingrowth through the wire mesh. After the stent was inserted, the CCRT regimen was continued. Platelet count at the time of stent insertion was 234 × 103/μL. In the following weeks, the platelet counts ranged from 91 × 103 to 153 × 103/μL. One month after completion of the CCRT regimen, histopathologic analysis of biopsy specimens of the esophageal tumor revealed inflammation with ulceration change (Figure 1B) and positron emission tomography (PET)–computed tomography (CT) showed a residual esophageal tumor and persistently enlarged lymph nodes with intact aortic vessel (Figure 4A). However, a few days after the PET-CT study the patient developed midthoracic pain and a hemorrhagic cough. Chest CT at the emergency department revealed a pseudoaneurysm arising from the medial aspect of the proximal descending aorta (Figure 4B). Massive hematemesis was subsequently noted. Emergency surgery was performed to repair the pseudoaneurysm. During the surgery, aorto-esophageal fistulas with active bleeding located about 2 cm distal to the left subclavian artery orifice were noted. Aortography revealed no evidence of rupture at the descending aorta. A thoracic aortic endografting with an aortic stent (8.7 cm in length) was performed and the patient responded well to surgery. One month later, he received adjuvant chemotherapy with CDDP (70 mg/m2) and 5-FU (1000 mg/m2) for residual esophageal cancer (Figure 4A). However, the patient developed symptoms of fever and cough with leukocytosis. The chest X-ray revealed increased infiltrations over left lower lung. Hospital-acquired pneumonia was impressed, and empirical antibiotics were prescribed firstly. The culture of sputum and blood were negative findings, respectively. Unfortunately, progressive pneumonia with septic shock and respiratory failure was noted even through aggressive treatment. Patient expired 2 months after the thoracic aortic endografting. Autopsy was suggested. However, patient's families want to maintain the patient's body completely without surgery procedure especially after patient expired. To obey the wish of family, autopsy was not conducted for determining the reason of the patient's death.\n\nFIGURE 1 (A) Histopathologic analysis revealed predominantly small blue round cells with invasive nests that had grown beyond the mucosa (hematoxylin and eosin stain, magnification ×100), findings suggestive of squamous cell carcinoma. (B) Representative hematoxylin eosin staining after chemoradiation therapy (magnification ×100). Note the large number of leukocytes, the marked accumulation of eosinophilic nucleoli, mixed inflammation, and debris in the mucosal layer.\n\nFIGURE 2 Chest computed tomography (CT) shows an esophageal tumor with obstruction at the middle third portion of the esophagus invading the adventitia. Also note the enlarged lymph node between the esophagus and the distal trachea.\n\nFIGURE 3 The dose distribution in the tumor and surrounding tissues. The high-dose regions with radiation dose of 53.2 Gy are adjacent to the wall of the aorta.\n\nFIGURE 4 (A) Follow-up positron emission tomography scan 1 month after the completion of concurrent chemoradiotherapy revealed a residual esophageal tumor and enlarged lymph nodes with intact aortic vessel. (B) Chest CT shows a pseudoaneurysm arising from the medial aspect of the proximal descending aorta.\n\nDISCUSSION\nA pseudoaneurysm is an outpouching of a vessel involving a defect of the tunica intima and media that contains a hematoma.13 Numerous causes of pseudoaneurysm formation have been reported, including infection, traumatic reaction, iatrogenic injury, suture dehiscence or loosening, infiltrating neoplasms, tissue necrosis, and a low platelet count (<200 × 103 /μL).14–16\n\nRadiotherapy is a well-known cause of vascular disease especially when vessels are exposed to radiation doses ranging from 25 to 40 Gy.17 In our patient, the aortic pseudoaneurysm developed in a region that received a total radiation dose of 53.2 Gy (Figures 3 and 4B). The metallic stent irradiated that could result in an overdose of 14% to 21% at a depth of 0.5 mm in the esophageal wall.18 Nevertheless, the dose perturbation caused by the backscatter of WallFlex™ esophageal stent ranges from 6% to 13%,4 resulting in an effective dose of 56.5–60.3 Gy for the patient reported here. These influences might contribute to better tumor eradication but increases the probability of vascular changes.\n\nRadiotherapy also increases the production of free radicals and oxidative stress, processes that upregulate numerous pathways pertinent to vascular disease, including matrix metalloproteinases (MMP), adhesion molecules, pro-inflammatory cytokines, and smooth muscle cell proliferation and apoptosis, while inactivating vasculoprotective nitric oxide (NO).19 Furthermore, fractionated doses increase the adhesiveness of aortic endothelial cells through chemokine-dependent signaling from endothelial cells to leukocytes and significantly increase intercellular adhesion molecule 1 (ICAM-1) mRNA and endothelial adhesiveness, which also accelerate vascular inflammation.20,21\n\nInterestingly, neutrophils localized at inflammatory sites can potentially degrade collagen by releasing members of the MMP family.22 Moreover, histological examination has shown that radiotherapy can induce intimal thickening and inflammatory cell infiltrates.5 Histologic examination of biopsy specimens from our patient also disclosed neutrophil accumulation and mixed inflammation in the mucosal layer after CCRT (Figure 1B). Papalambros et al23 found that the concentration of MMP-9 in the arterial wall correlates positively with aneurysm size and radiotherapy has been shown to increase the expression of MMP-9.24 Wilson et al25 found that the concentration of MMP-8 is increased at the site of abdominal aortic aneurysm rupture, and radiotherapy also enhances the expression of MMP-8, which modulates the pharmacokinetics of anticancer drugs.26\n\nCDDP and 5-FU are radiosensitizors that enhance the cytotoxic effects of radiotherapy.7,8 Although CCRT is more effective at tumor eradication than radiotherapy alone, the combined use of CDDP, 5-FU, and radiotherapy can cause unpredictable localized and systemic vascular inflammation with a higher incidence of atherosclerotic disease, coronary artery disease, and myocardial infarction.9,10 A previous study showed that CDDP results in a decrease in NO production and the upregulation of ICAM-1 expression in endothelial cells that accelerate vascular inflammation.20,21,27 Furthermore, an experimental study in rabbits showed that damage to the intima caused by 5-FU occasionally results in thrombus formation.10 Cwikiel et al28 found that the severity of endothelial injury was proportional to the incidence of thrombus formation. It could be reasonably hypothesized that CDDP-based regimens concurrent with radiotherapy not only sensitize the treatment effects of radiotherapy but also synchronize endothelial injury.\n\nAortic degeneration and atherosclerosis are the major causes of aotic aneurysms.29 Hypertension is a well-known predisposing factor for vascular degeneration and atherosclerosis. Vardulaki et al30 found that hypertension was an important risk factor for the development of abdominal aortic aneurysm, which increased the risk by 30% to 40%. Also, the prevalence of hypertension was over 60% in populations with thoracic aortic aneurysm.31 The degradation of extracellular matrix proteins by proteases like MMP has the primary role for vascular degeneration and atherosclerosis, and will weaken the aortic wall.29 Combined with the increased concentration and enhanced expression of MMP by RT, and vascular inflammation correlated to the radiosensitizors of CDDP and 5-FU, the underlying hypertension of our patient may accentuate the impairment of aortic wall, and probably increase the incidence of aneurysms formation.\n\nThe insertional procedure of metallic stent might contribute to the traumatic injury of aortic and esophageal walls to form the fistula. Schweigert et al32 found that among 17 patients with anastomotic leakage after esophagectomy who underwent endoscopic esophageal stent implantation, 18% developed aortic erosion followed by aortoesophageal fistula. Homann et al33 revealed that patients with esophageal metallic stent implantation experienced esophageal wall and respiratory tract impairment, and the incidence of delayed complications of esophagorespiratory fistula was 9%.\n\nA platelet count below 200 × 103/μL has been shown to be a predictor of iatrogenic pseudoaneurysm after percutaneous endovascular procedures.15 In our patient, platelet counts ranged from 91 to 153 × 103/μL 2 weeks after initiation of CCRT that perhaps increased the incidences of iatrogenic psuedoaneurysm also.\n\nCONCLUSION\nMultimodality treatment for esophageal cancer comprising CDDP-based CCRT and esophageal metallic stent placement near a great vessel may increase the risk of pseudoaneurysm formation.\n\nAbbreviations: CCRT = concurrent chemoradiotherapy, CDDP = Cisplatin, CT = computed tomography, 5-FU = 5-Fluorouracil, ICAM-1 = intercellular adhesion molecule 1, MMP = matrix metalloproteinases, NO = nitric oxide, PET = positron emission tomography.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nREFERENCES\n1. Weigel TL Frumiento C Gaumintz E \nEndoluminal palliation for dysphagia secondary to esophageal carcinoma . Surg Clin North Am \n2002 ; 82 :747 –761 .12472128 \n2. Allum WH Griffin SM Watson A \nGuidelines for the management of oesophageal and gastric cancer . Gut \n2002 ; 50 :v1 –v23 .12049068 \n3. Eldeeb H El-Hadaad HA \nRadiotherapy versus stenting in treating malignant dysphagia . J Gastrointest Oncol \n2012 ; 3 :322 –325 .23205308 \n4. Atwood TF Hsu A Ogara MM \nRadiotherapy dose perturbation of esophageal stents examined in an experimental model . Int J Radiat Oncol Biol Phys \n2012 ; 82 :1659 –1664 .21514064 \n5. Russell NS Hoving S Heeneman S \nNovel insights into pathological changes in muscular arteries of radiotherapy patients . Radiother Oncol \n2009 ; 92 :477 –483 .19541382 \n6. Tepper J Krasna MJ Niedzwiecki D \nPhase III trial of trimodality therapy with cisplatin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781 . J Clin Oncol \n2008 ; 26 :1086 –1092 .18309943 \n7. Dewit L \nCombined treatment of radiation and cisdiamminedichloroplatinum (II): a review of experimental and clinical data . Int J Radiat Oncol Biol Phys \n1987 ; 13 :403 –426 .3549645 \n8. Pu AT Robertson JM Lawrence TS \nCurrent status of radiation sensitization by fluoropyrimidines . Oncology (Williston Park) \n1995 ; 9 :707 –714 .discussion 714, 717–708, 721 .7577371 \n9. Wang YC Hsieh TC Chen SW \nConcurrent chemo-radiotherapy potentiates vascular inflammation: increased FDG uptake in head and neck cancer patients . JACC Cardiovasc Imaging \n2013 ; 6 :512 –514 .23579012 \n10. Cwikiel M Zhang B Eskilsson J \nThe influence of 5-fluorouracil on the endothelium in small arteries. An electron microscopic study in rabbits . Scanning Microsc \n1995 ; 9 :561 –576 .8714749 \n11. Egan C Szontagh-Kishazi P Flavin R \nAortic fistula after neoadjuvant chemoradiotherapy and esophagectomy for esophageal carcinoma: an unusual cause of sudden death . Am J Forensic Med Pathol \n2012 ; 33 :270 –272 .22854882 \n12. Zhang WW Zhu YJ Yang H \nConcurrent radiotherapy and weekly chemotherapy of 5-fluorouracil and platinum agents for postoperative locoregional recurrence of oesophageal squamous cell carcinoma . Sci Rep \n2015 ; 5 :8071 .25627119 \n13. Katz ME Perlman JM Tack ED \nNeonatal umbilical artery pseudoaneurysm: sonographic evaluation (case report) . AJR Am J Roentgenol \n1986 ; 147 :322 –324 .3524162 \n14. Albuquerque FC Krasna MJ McLaughlin JS \nChronic, traumatic pseudoaneurysm of the ascending aorta . Ann Thorac Surg \n1992 ; 54 :980 –982 .1417297 \n15. Mlekusch W Haumer M Mlekusch I \nPrediction of iatrogenic pseudoaneurysm after percutaneous endovascular procedures . Radiology \n2006 ; 240 :597 –602 .16864680 \n16. Byard RW \nLethal aorto-oesophageal fistula – characteristic features and aetiology . J Forensic Leg Med \n2013 ; 20 :164 –168 .23472796 \n17. Lindsay S Kohn HI Dakin RL \nAortic arteriosclerosis in the dog after localized aortic x-irradiation . Circ Res \n1962 ; 10 :51 –60 .14465540 \n18. Li XA Chibani O Greenwald B \nRadiotherapy dose perturbation of metallic esophageal stents . Int J Radiat Oncol Biol Phys \n2002 ; 54 :1276 –1285 .12419457 \n19. Weintraub NL Jones WK Manka D \nUnderstanding radiation-induced vascular disease . J Am Coll Cardiol \n2010 ; 55 :1237 –1239 .20298931 \n20. Khaled S Gupta KB Kucik DF \nIonizing radiation increases adhesiveness of human aortic endothelial cells via a chemokine-dependent mechanism . Radiat Res \n2012 ; 177 :594 –601 .22087741 \n21. Cervelli T Panetta D Navarra T \nEffects of single and fractionated low-dose irradiation on vascular endothelial cells . Atherosclerosis \n2014 ; 235 :510 –518 .24953491 \n22. Weiss SJ Peppin G Ortiz X \nOxidative autoactivation of latent collagenase by human neutrophils . Science \n1985 ; 227 :747 –749 .2982211 \n23. Papalambros E Sigala F Georgopoulos S \nImmunohistochemical expression of metalloproteinases MMP-2 and MMP-9 in abdominal aortic aneurysms: correlation with symptoms and aortic diameter . Int J Mol Med \n2003 ; 12 :965 –968 .14612975 \n24. Asuthkar S Velpula KK Nalla AK \nIrradiation-induced angiogenesis is associated with an MMP-9-miR-494-syndecan-1 regulatory loop in medulloblastoma cells . Oncogene \n2014 ; 33 :1922 –1933 .23728345 \n25. Wilson WR Anderton M Schwalbe EC \nMatrix metalloproteinase-8 and -9 are increased at the site of abdominal aortic aneurysm rupture . Circulation \n2006 ; 113 :438 –445 .16432074 \n26. Hsieh CH Liu CY Hsieh YJ \nMatrix metalloproteinase-8 mediates the unfavorable systemic impact of local irradiation on pharmacokinetics of anti-cancer drug 5-Fluorouracil . PloS One \n2011 ; 6 :e21000 .21695264 \n27. Zhu M Chen J Yin H \nPropofol protects human umbilical vein endothelial cells from cisplatin-induced injury . Vascul Pharmacol \n2014 ; 61 :72 –79 .24732179 \n28. Cwikiel M Eskilsson J Wieslander JB \nThe appearance of endothelium in small arteries after treatment with 5-fluorouracil. An electron microscopic study of late effects in rabbits . Scanning Microsc \n1996 ; 10 :805 –818 .discussion 819 .9813641 \n29. Isselbacher EM \nThoracic and abdominal aortic aneurysms . Circulation \n2005 ; 111 :816 –828 .15710776 \n30. Vardulaki KA Walker NM Day NE \nQuantifying the risks of hypertension, age, sex and smoking in patients with abdominal aortic aneurysm . Br J Surg \n2000 ; 87 :195 –200 .10671927 \n31. Bickerstaff LK Pairolero PC Hollier LH \nThoracic aortic aneurysms: a population-based study . Surgery \n1982 ; 92 :1103 –1108 .7147188 \n32. Schweigert M Dubecz A Stadlhuber RJ \nRisk of stent-related aortic erosion after endoscopic stent insertion for intrathoracic anastomotic leaks after esophagectomy . Ann Thorac Surg \n2011 ; 92 :513 –518 .21592460 \n33. Homann N Noftz MR Klingenberg-Noftz RD \nDelayed complications after placement of self-expanding stents in malignant esophageal obstruction: treatment strategies and survival rate . Dig Dis Sci \n2008 ; 53 :334 –340 .17597412\n\n",
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"mesh_terms": "D017541:Aneurysm, False; D000964:Antimetabolites, Antineoplastic; D000970:Antineoplastic Agents; D001018:Aortic Diseases; D059248:Chemoradiotherapy; D002945:Cisplatin; D003131:Combined Modality Therapy; D004938:Esophageal Neoplasms; D017809:Fatal Outcome; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D015607:Stents",
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"title": "Aortic pseudoaneurysm formation following concurrent chemoradiotherapy and metallic stent insertion in a patient with esophageal cancer.",
"title_normalized": "aortic pseudoaneurysm formation following concurrent chemoradiotherapy and metallic stent insertion in a patient with esophageal cancer"
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"abstract": "OBJECTIVE\nImmune checkpoint inhibitors (ICIs) targeting cytotoxic T-lymphocyte-associated protein 4 and programmed cell death protein 1 (PD-1) have demonstrated improved survival for multiple cancers. However, these new drug classes have led to increased immune-related adverse events (IrAE). Rheumatic IrAEs have not been well described in clinical trials. We report here cases of rheumatoid arthritis (RA) and polymyalgia rheumatica (PMR) occurring after ICI treatment.\n\n\nMETHODS\nThis was a retrospective study of patients receiving an ICI in whom symptoms of arthritis or arthralgia developed and revealed a diagnosis of RA or PMR.\n\n\nRESULTS\nIn 10 patients who received ICI therapy (all anti-PD-1 or anti-PDL1 antibodies), RA or PMR developed at a median of 1 month (1 to 9) after exposure. No patient had pre-existing rheumatic or autoimmune disease. RA developed in six patients; all six were positive for anti-cyclic citrullinated peptide (anti-CCP) antibodies and four for rheumatoid factor. Anti-CCP antibodies were detected in two out of three patients tested before immunotherapy. Disease-modifying antirheumatic drugs were needed for three patients; the three others received corticosteroids or non-steroid anti-inflammatory drugs. PMR was diagnosed in four patients, all responded to corticosteroids. Despite these IrAEs, immunotherapy was pursued for all but one patient until cancer progression.\n\n\nCONCLUSIONS\nThis is the first description of RA occurring after ICI therapy for cancer. PMR can also occur after ICI, particularly after anti-PD-1 therapy. All cases responded to corticosteroids or with immunosuppressive therapy. Collaboration between rheumatologists and oncologists is crucial and could lead to better recognition and care of these patients.",
"affiliations": "Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.;AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Immunologie clinique, Le Kremlin-Bicêtre, France.;Service de rhumatologie et médecine interne, Centre Hospitalier du Pays d'Aix, Aix-en-Provence, France.;Département d'Innovation Thérapeutique et Essais Précoces (DITEP), Gustave Roussy Cancer Campus, France.;Département d'Innovation Thérapeutique et Essais Précoces (DITEP), Gustave Roussy Cancer Campus, France.;Gustave Roussy Cancer Campus, Villejuif; Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.;Gustave Roussy Cancer Campus, Villejuif; Univ. Paris-Sud, Université Paris-Saclay, Villejuif, France.;Institut Gustave Roussy, Unité Fonctionnelle de Pharmacovigilance, Villejuif, France.;Service de médecine nucléaire, Centre Hospitalier de Saint Brieuc, 22000 Saint Brieuc, France.;AP-HP, université Paris-Descartes, hôpital Cochin, centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France.;Rheumatology Department, René Dubos Hospital, Pontoise, France.;Rheumatology Department, Lapeyronie Hospital and &EA 2415, Montpellier, France.;AP-HP, Service de Médecine Interne, Hôpital Saint-Antoine, Université Paris, France.;AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Immunologie clinique, Le Kremlin-Bicêtre, France.;Rheumatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre, France.",
"authors": "Belkhir|Rakiba|R|;Burel|Sébastien Le|SL|;Dunogeant|Laetitia|L|;Marabelle|Aurélien|A|;Hollebecque|Antoine|A|;Besse|Benjamin|B|;Leary|Alexandra|A|;Voisin|Anne-Laure|AL|;Pontoizeau|Clémence|C|;Coutte|Laetitia|L|;Pertuiset|Edouard|E|;Mouterde|Gaël|G|;Fain|Olivier|O|;Lambotte|Olivier|O|;Mariette|Xavier|X|",
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"country": "England",
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"doi": "10.1136/annrheumdis-2017-211216",
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"issue": "76(10)",
"journal": "Annals of the rheumatic diseases",
"keywords": "immune-checkpoint inhibitors; polymyalgia rheumatica; rheumatoid arthritis",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D001172:Arthritis, Rheumatoid; D060890:B7-H1 Antigen; D060908:CTLA-4 Antigen; D005260:Female; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D000077594:Nivolumab; D010456:Peptides, Cyclic; D011111:Polymyalgia Rheumatica; D061026:Programmed Cell Death 1 Receptor; D012189:Retrospective Studies",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1747-1750",
"pmc": null,
"pmid": "28600350",
"pubdate": "2017-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment.",
"title_normalized": "rheumatoid arthritis and polymyalgia rheumatica occurring after immune checkpoint inhibitor treatment"
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{
"abstract": "BACKGROUND\nInfants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors.\n\n\nMETHODS\nTwenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy. Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered.\n\n\nRESULTS\nAll 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5-5.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, event-free, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable.\n\n\nCONCLUSIONS\nOur results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT.",
"affiliations": "Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. kwsped@skku.edu.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Ma|Youngeun|Y|https://orcid.org/0000-0002-5862-6319;Lim|Do Hoon|DH|https://orcid.org/0000-0002-5426-0604;Cho|Heewon|H|https://orcid.org/0000-0002-0440-645X;Lee|Ji Won|JW|https://orcid.org/0000-0003-0084-1304;Sung|Ki Woong|KW|https://orcid.org/0000-0001-5989-4772;Yoo|Keon Hee|KH|https://orcid.org/0000-0002-5980-7912;Koo|Hong Hoe|HH|https://orcid.org/0000-0001-8082-1412;Shin|Hyung Jin|HJ|https://orcid.org/0000-0003-0856-7098;Suh|Yeon Lim|YL|https://orcid.org/0000-0001-5809-2401",
"chemical_list": "D005047:Etoposide; D013852:Thiotepa; D016190:Carboplatin",
"country": "Korea (South)",
"delete": false,
"doi": "10.3346/jkms.2020.35.e405",
"fulltext": "\n==== Front\nJ Korean Med Sci\nJ Korean Med Sci\nJKMS\nJournal of Korean Medical Science\n1011-8934 1598-6357 The Korean Academy of Medical Sciences \n\n10.3346/jkms.2020.35.e405\nOriginal Article\nPediatrics\nTandem High-dose Chemotherapy without Craniospinal Irradiation in Treatment of Non-metastatic Malignant Brain Tumors in Very Young Children\nhttps://orcid.org/0000-0002-5862-6319Ma Youngeun 1* https://orcid.org/0000-0002-5426-0604Lim Do Hoon 2* https://orcid.org/0000-0002-0440-645XCho Heewon 3 https://orcid.org/0000-0003-0084-1304Lee Ji Won 3 https://orcid.org/0000-0001-5989-4772Sung Ki Woong 3 https://orcid.org/0000-0002-5980-7912Yoo Keon Hee 3 https://orcid.org/0000-0001-8082-1412Koo Hong Hoe 3 https://orcid.org/0000-0003-0856-7098Shin Hyung Jin 4 https://orcid.org/0000-0001-5809-2401Suh Yeon-Lim 5 1 Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Korea.\n2 Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.\n3 Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.\n4 Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.\n5 Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.\nAddress for Correspondence: Ki Woong Sung, MD, PhD. Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea. kwsped@skku.edu*Youngeun Ma and Do Hoon Lim contributed equally to this work.\n\n\n17 11 2020 \n14 12 2020 \n35 48 e40519 6 2020 05 10 2020 © 2020 The Korean Academy of Medical Sciences.2020The Korean Academy of Medical SciencesThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nInfants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors.\n\nMethods\nTwenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy. Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered.\n\nResults\nAll 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5−15.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, event-free, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable.\n\nConclusion\nOur results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT.\n\nGraphical Abstract\n\n\nBrain TumorHigh-dose ChemotherapyRadiation TherapyChildrenMinistry of Health and Welfarehttps://doi.org/10.13039/5011000036250520300\n==== Body\nINTRODUCTION\nTreatment of malignant brain tumors in very young children is challenging because radiotherapy (RT), and particularly craniospinal radiotherapy (CSRT), should be used minimally due to the risk of functional impairment of the developing brain and late adverse effects, which include global reduction in intelligence quotient, cognitive deficits, and neuroendocrine dysfunction.1 In an effort to minimize the adverse effects of RT, most institutions and national groups have adopted chemotherapy-based strategies to avoid or delay RT; however, the outcomes of these approaches have been largely unsatisfactory.234\n\nA strategy using high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) to improve the prognosis of patients with high-risk solid tumors has been explored.567 Following success in high-risk neuroblastoma, studies have investigated the effectiveness of HDCT/auto-SCT in improving the prognosis of high-risk brain tumors and/or to avoid or minimize RT.89101112 Recently, it has been demonstrated that further dose intensification by tandem HDCT/auto-SCT may further improve outcomes in patients with high-risk brain tumors.1314\n\nPreviously, we reported the early results of a single-arm pilot trial using tandem HDCT/auto-SCT to minimize RT dose and volume in very young children with malignant brain tumors.1 The results suggested that it was possible to avoid or defer RT until 3 years of age while improving survival rates. However, the results were not confirmative because the number of patients was small, and the short follow-up prevented determination of long-term effects. Therefore, the study has been extended. Here, we report the results of the study with a larger cohort of patients and a longer follow-up duration. In the present study, we focused on very young children with non-metastatic malignant brain tumors.\n\nMETHODS\nPatients\nChildren younger than 3 years who were diagnosed with non-metastatic malignant brain tumors between September 2004 and November 2017 were eligible for the study. A pediatric neuropathologist reviewed all cases according to the WHO criteria. Past diagnosis based on the 2007 WHO classification was revised using the 2016 WHO classification if a tumor sample was available. Immunohistochemistry and/or next-generation sequencing using a targeted panel (PedSCAN™) were performed. For molecular subgrouping of medulloblastoma, nanoString-based RNA assays were also performed.15 The extent of disease at the time of diagnosis was assessed using brain and spinal magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) cytology.\n\nInduction chemotherapy\nFig. 1 shows the treatment scheme used in this study. Surgery was the primary treatment for all resectable tumors. Second-look surgery was performed whenever possible. Prior to HDCT/auto-SCT, six cycles of induction chemotherapy were administered consisting of alternating CECV (cisplatin + etoposide + cyclophosphamide + vincristine) and CEIV (carboplatin + etoposide + ifosfamide + vincristine) regimens. Induction chemotherapy cycles were scheduled 4 weeks apart, but some delays were permitted to allow recovery of absolute neutrophil count (ANC) and platelet count to 1,000/µL and 100,000/µL, respectively. Peripheral blood stem cells (PBSCs) were collected during the recovery phase of the first chemotherapy cycle. For patients with atypical teratoid/rhabdoid tumor (ATRT) or primitive neuroectodermal tumor (PNET), intrathecal methotrexate (6 mg for age < 1 year, 8 mg for age 1–2 years, 10 mg for age 2–3 years) was administered on day 0 of each induction chemotherapy starting in September 2015.\n\nFig. 1 Treatment scheme.\nCT = chemotherapy, HDCT = high-dose chemotherapy, L-RT = local radiotherapy, CSRT = craniospinal radiotherapy, ATRT = atypical teratoid/rhabdoid tumor, PNET = primitive neuroectodermal tumor, R = post-operative gross residual tumor, M = metastases.\n\nTandem HDCT/auto-SCT\nCTE (carboplatin + thiotepa + etoposide) and CyM (cyclophosphamide + melphalan) regimens were used for the first and second HDCT/auto-SCT, respectively (Fig. 1). We allowed an approximately 12-week interval between the first and second HDCT/auto-SCT to minimize toxicity. Approximately half of the PBSCs collected during a single round of leukapheresis was infused for bone marrow rescue during each HDCT/auto-SCT session.\n\nRT\nRT was administered with 3-dimensional photon beams until December 2015, after which patients were treated with proton beams. Proton beam doses were same as photon therapy with a relative biologic effectiveness of 1.1. Local RT (L-RT, 30.6 Gy) with 1–2 cm margins from surgical defects was administered after the patient reached 3 years of age only if gross residual tumor (> 1.5 cm2) remained after initial or second-look surgery. Otherwise, no RT was given if the patient remained progression-free. However, immediate RT was administered if the patient experienced relapse or progression. For patients who experienced metastatic relapse, both CSRT (23.4 Gy) and L-RT (30.6 Gy) were administered. The daily fraction size was 1.8 Gy. Because the outcome of patients with ATRT or PNET was disappointing due to early progression in the early phase of the study,1 early post-operative L-RT was administered starting in September 2015; patients without residual tumors received 41.4 Gy, and patients with residual tumors received 56.2 Gy. During early L-RT, the dose of concomitant chemotherapy was reduced to 75% of the full dose.\n\nResponse and toxicity criteria\nTreatment response was evaluated by brain and spinal MRI and CSF cytology after every 2 cycles of induction chemotherapy, between the first and second HDCT/auto-SCT, every 3 months for the first year after the second HDCT/auto-SCT, every 4 months for the second year, every 6 months for the third year, and every 12 months thereafter. Tumor size was estimated by MRI as the product of the greatest diameter and the longest perpendicular diameter. Treatment responses were categorized as follows: complete response (CR), complete disappearance of all previously measurable tumor; partial response (PR), greater than 50% decrease in tumor size; minor response (MR), 25% to 50% decrease in tumor size; stable disease (SD), less than 25% change in tumor size; and progressive disease (PD), greater than 25% increase in tumor size or appearance of a new area of tumor. Toxicities were graded using the National Cancer Institute's Common Terminology Criteria (version 4.0).\n\nEvaluation of late adverse effects\nLate adverse effects were evaluated yearly after completion of the second HDCT/auto-SCT. Neuroendocrine, cardiac, pulmonary, renal, auditory, ophthalmologic, and cognitive functions were evaluated. Thyroid hormones (T3 and free T4), thyroid stimulating hormone, morning cortisol and ACTH, insulin like growth factor-1, bone age, gonadotropin (FSH, LH), sex hormones (testosterone or estradiol), blood lipid profile, hemoglobin A1c, insulin and C-peptide were checked to screen for neuroendocrine dysfunction. Cardiac evaluation was performed by two-dimensional echocardiography and electrocardiography. The respiratory system was evaluated using pulmonary function test and computed tomography scan. Renal function was evaluated using the serum and urine biomarkers. Auditory evaluation including pure tone and speech audiometry was performed by the otolaryngologist. An ophthalmic examination by an ophthalmologist was also performed. Cognitive function was evaluated using the Korean-Wechsler Preschool and Primary Scale of Intelligence and the Korean-Wechsler Intelligence Scale for Children-IV.\n\nStatistics\nEvent-free survival (EFS) was calculated from the date of diagnosis until the date of relapse, progression, secondary malignancy or death from any cause, whichever occurred first. Overall survival (OS) was calculated from the date of diagnosis until death from any cause. CSRT-free survival was calculated from the date of diagnosis until initiation of CSRT or death from any cause. Survival rates and standard errors were estimated using the Kaplan–Meier method. Differences in survival rates between the two groups were compared using the log-rank test. P values less than 0.05 were considered significant.\n\nEthics statement\nThe Samsung Medical Center Institutional Review Board (IRB) approved this study (IRB 2004-12-009), and informed consent was obtained from all parents or guardians.\n\nRESULTS\nPatient characteristics\nPatient characteristics are listed in Table 1. During the study period, 20 consecutive patients (15 boys and 5 girls) with various malignant brain tumors (anaplastic ependymoma in four, medulloblastoma in four, choroid plexus carcinoma in three, high-grade glioma in two, PNET in four, immature teratoma in one, malignant fibrous histiocytoma in one, and ATRT in one) were enrolled. The median age at diagnosis was 1.5 (range, 0.2−3.0) years, and 17 patients were younger than 2 years at diagnosis. The tumor was located at the posterior fossa in six patients and supratentorially in 14 patients. Gross residual tumor (> 1.5 cm2) remained after surgery in eight patients. After revision of the diagnoses according to the WHO 2016 classification, the diagnosis of PNET was changed to anaplastic ependymoma in two patients, embryonal tumor with multilayered rosette C19MC-altered in one patient, and pineoblastoma in one patient. One anaplastic glioneuronal tumor was also reclassified as embryonal tumor, NOS. Among four medulloblastoma cases, we could identify a molecular subgroup in three: all were SHH-activated and TP53-wild type medulloblastoma.\n\nTable 1 Patient characteristics\nNo.\tSex/age, yr\tInitial Dx\tRevised Dx\tTumor site\tResidual tumor, > 1.5 cm2\tResponse after induction\tResponse after HDCT1\tResponse after HDCT2\tL-RT, Gy\tCSRT, Gy\tAge at RT, yr\tReason for RT\tFinal outcome (follow-up from Dx)\t\n1\tM/1.5\tMB-U\tMB-SHH+/TP53-\t4th V\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t15.7 yr, alive, disease free\t\n2\tF/1.9\tPNET\tAEa\tT, BG\tYes\tPR\tCR\tPD\t30.6\t23.4\t2.9\tRelapse after HDCT2\t15.6 yr, alive, relapse at 0.9 yr\t\n3\tM/1.3\tAE\tN/A\tFP\tNob\tCR\tCR\tCR\t0\t0\t-\t-\t14.1 yr, alive, disease free\t\n4\tF/1.5\tMB-A\tMB-SHH+/TP53-\t4th V\tYes\tCR\tCR\tCR\t30.6\t23.4\t3.2\tRelapse after HDCT2\t13.8 yr, alive, relapse at 1.6 yr\t\n5\tM/1.3\tAE\tN/A\tLat V\tYes\tPR\tPRc\tCR\t30.6\t0\t3.3\tAs scheduled\t12.0 yr, alive, disease free\t\n6\tM/0.2\tMFH\t-\tT\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t12.0 yr, alive, disease free\t\n7\tM/0.3\tGM\tN/A\tP\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t9.9 yr, alive, disease free\t\n8\tM/1.4\tIMT\t-\tPG\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t9.1 yr, alive, disease free\t\n9\tM/1.7\tAE\tAE\t4th V\tYes\tPR2\tPR2\tCR\t30.6\t0\t1.9\tPD during induction\t7.8 yr, alive, PD at 0.2 yr\t\n10\tF/1.7\tMB-C\tN/A\t4th V\tNo\tCR\tCR\tTRM\t-\t-\t-\t-\t0.7 yr, dead, TRM at 0.7 yr\t\n11\tM/1.4\tPNET\tETMR\tF\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t6.8 yr, alive, disease free\t\n12\tM/3.0\tCPC\t-\tTP\tYes\tCR\tCR\tCR\t30.6\t0\t4.2\tAs scheduled\t6.5 yr, alive, disease free\t\n13\tM/0.6\tAGNT\tET\tTPO\tYes\tPR\tPR\tTRM\t-\t-\t-\t-\t1.1 yr, dead, TRM at 1.1 yr\t\n14\tM/1.1\tCPC\t-\tLat V\tNo\tCR\tCR\t-\t0\t0\t-\t-\t4.0 yr, alive, disease free\t\n15\tM/1.6\tAE\tN/A\t4th V\tYes\tCR\tCR\tCR\t30.6\t0\t3.0\tAs scheduled\t3.6 yr, alive, disease free\t\n16\tM/1.0\tCPC\t-\tLat V\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t3.6 yr, alive, disease free\t\n17\tF/2.2\tMB-DN\tMB-SHH+/TP53-\t4th V\tNo\tCR\tCR\tCR\t0\t0\t-\t-\t2.7 yr, alive, disease free\t\n18d\tM/1.8\tPNET\tAE\tP\tNo\tCR\tCR\tCR\t41.4\t0\t1.9\tAs scheduled\t4.8 yr, alive, disease free\t\n19d\tM/2.6\tPNET\tPineoblastoma\tPG\tYes\tPR\tPD\t-\t56.2\t0\t2.8\tAs scheduled\t1.0 yr, dead, PD at 1.0 yr\t\n20d\tF/1.5\tATRT\t-\tBG, P\tNo\tCR\tCR\tCR\t41.4\t0\t1.6\tAs scheduled\t2.5 yr, alive, disease free\t\nDx = diagnosis, HDCT1 = first high-dose chemotherapy, HDCT2 = second HDCT, L-RT = local radiotherapy, CSRT = craniospinal RT, N/A = not available, MB-U = medulloblastoma of unknown pathology, MB-SHH+/TP53- = medulloblastoma, SHH-activated and TP53-wildtype, PNET = primitive neuroectodermal tumor, AE = anaplastic ependymoma, MB-A = anaplastic medulloblastoma, MFH = malignant fibrous histiocytoma, GM = glioblastoma multiforme, IMT = immature teratoma, MB-C = classic medulloblastoma, CPC = Choroid plexus carcinoma, AGNT = anaplastic glioneuronal tumor, MB-DN = desmoplastic/nodular medulloblastoma, ATRT = atypical teratoid/rhabdoid tumor, ETMR = embryonal tumor with multilayered rosette, C19MC-altered, ET = embryonal tumor, NOS, 4th V = 4th ventricle, T = temporal lobe, BG = basal ganglia, FP = fronto-parietal lobe, Lat V = lateral ventricle, P = parietal lobe, PG = pineal gland, F = frontal lobe, TP = temporo-parietal lobe, TPO = temporo-parieto-occipital lobe, CR = complete response, PR = partial response, PR2 = second PR, PD = progressive disease, TRM = treatment-related mortality, VOD = hepatic veno-occlusive disease.\n\naL1CAM-positive tumor, however, we could not check RELA fusion because of the insufficient tumor sample; bNo residual tumor remained after second-look surgery; cNear total resection was possible after first HDCT/auto-SCT; dBecause these patients were diagnosed with PNET or ATRT after September 2015, early local RT before 3 years old were administered.\n\nInduction treatment\nFig. 2 shows the flow of patients. All patients experienced neutropenic fever during induction chemotherapy; however, non-hematologic toxicity was not common. In one patient (No. 3), gross total resection was possible during second-look surgery after six cycles of induction chemotherapy. Another patient (No. 9) experienced local progression at the primary tumor site and received L-RT with concomitant chemotherapy. Otherwise, all patients remained progression-free during induction chemotherapy. Tumor status at the end of induction treatment was CR in 15 patients, PR in four, and second PR in one. The median number of CD34+ cells collected during a median of 3 (range, 2−10) leukapheresis events was 68.6 (range, 3.8−223.0) × 106 cells/kg.\n\nFig. 2 Flow of patients.\nHDCT1= first high-dose chemotherapy, HDCT2 = second HDCT, CR = complete response, CCR = continuous CR, PR = partial response, PD = progressive disease, REL = relapse, TRM = treatment-related mortality, off-Tx = off treatment, RT = radiotherapy, MB = medulloblastoma, AE = anaplastic ependymoma, CPC = Choroid plexus carcinoma, ATRT = atypical teratoid/rhabdoid tumor, ETMR = embryonal tumor with multilayered rosette, C19MC-altered, GM = glioblastoma multiforme, IMT = immature teratoma, MFH = malignant fibrous histiocytoma, ET = embryonal tumor, NOS.\n\nTandem HDCT/auto-SCT\nAll 20 patients, including a patient (No. 9) who experienced progression during induction chemotherapy, underwent the first HDCT/auto-SCT. The median age at the time of the first HDCT/auto-SCT was 2.1 (range, 0.8−3.6) years. In one patient (No. 5) who was still in PR after the first HDCT/auto-SCT, near total resection of the tumor was performed prior to the second HDCT/auto-SCT. In another patient (No. 14), who was in CR after the first HDCT/auto-SCT, parents refused the second HDCT/auto-SCT. In another patient (No.19), who experienced progression after the first HDCT/auto-SCT, parents refused further treatment. Consequently, a total of 18 patients proceeded to the second HDCT/auto-SCT. The median interval between the first auto-SCT and initiation of the second HDCT was 83 (range, 75−122) days. Table 2 shows the toxicities observed during tandem HDCT/auto-SCT. Hematologic recovery was rapid in both the first and second HDCT/auto-SCT. Frequent grade 3/4 toxicity included fever, stomatitis, diarrhea, elevation of liver enzymes, and hypokalemia. No treatment-related mortality (TRM) occurred during the first HDCT/auto-SCT; however, two patients died from toxicities (asphyxia and hepatic veno-occlusive disease) during the second HDCT/auto-SCT.\n\nTable 2 Grade 3/4 toxicities during tandem HDCT/auto-SCT\nParameters\tFirst HDCT/auto-SCT (n = 20)\tSecond HDCT/auto-SCT (n = 18)\t\nHematologic toxicity\t\t\t\n\tCD34+ cells, × 106/kg\t21.4 (1.4–131.3)\t18.7 (1.8–86.5)\t\n\tTime (days) to reach an ANC 0.5 × 109/La\t9 (7–11)\t9 (7–12)\t\n\tTime (days) to reach a PLT count 20 × 109/La,b\t19 (7–66)\t20 (13–77)\t\n\tDays of BT ≥ 38.0°C\t4 (0–13)\t2 (0–9)\t\n\tPositive blood culture\t1 (5.0)\t2 (11.1)\t\nNon-hematologic toxicity\t\t\t\n\tStomatitis\t10 (50.0)\t0 (0)\t\n\tVomiting\t2 (10.0)\t3 (16.7)\t\n\tDiarrhea\t10 (50.0)\t10 (55.6)\t\n\tElevation of liver enzymes\t15 (75.0)\t1 (5.6)\t\n\tHyperbilirubinemia\t0 (0)\t0 (0)\t\n\tRenal insufficiency\t0 (0)\t1 (5.6)\t\n\tHypokalemia\t4 (20.0)\t3 (16.7)\t\n\tHyperkalemia\t0 (0)\t3 (16.7)\t\n\tHyponatremia\t0 (0)\t0 (0)\t\n\tHypernatremia\t0 (0)\t1 (5.6)\t\n\tSeizure\t3 (15.0)\t0 (0)\t\n\tHepatic VOD\t2 (10.0)\t2 (11.1)\t\n\tMyocarditis\t0 (0)\t0 (0)\t\n\tTreatment-related mortality\t0 (0)\t2 (11.1)\t\nData are presented as median (range) or number (%).\n\nANC = absolute neutrophil count, PLT = platelet, BT = body temperature, VOD = hepatic veno-occlusive disease.\n\naThe first day when ANC exceeded 0.5 × 109/L for 3 consecutive days; bThe first day when PLT count exceeded 20 × 109/L without transfusion for 7 days.\n\nRT\nOf 12 patients without gross residual tumor after surgery, all but one (No. 10, who died from asphyxia during the second HDCT/auto-SCT) remained event-free and did not receive RT except two patients who received early L-RT. Of eight patients with gross residual tumor, three remained event-free and received L-RT alone as scheduled. One patient died from hepatic veno-occlusive disease during the second HDCT/auto-SCT. The remaining four patients experienced relapse/progression. A patient (No. 9) with anaplastic ependymoma who experienced local progression during induction treatment received L-RT (30.6 Gy) after progression. Two patients with anaplastic ependymoma (No. 2) and medulloblastoma (No. 4) who experienced metastatic relapse after tandem HDCT/auto-SCT received both CSRT (23.4 Gy) and L-RT (30.6 Gy). The remaining patient (No. 19) with pineoblastoma received early L-RT during induction chemotherapy; however, metastatic relapse occurred after the first HDCT/auto-SCT, and the patient died without further treatment. Proton beam was used in three patients. Collectively, among 17 survivors, nine received no RT, six received L-RT alone, and two received both CSRT and L-RT. The median age at initiation of RT was 2.9 (range, 1.6–4.2) years, and five patients received RT at younger than 3 years.\n\nSurvival\nOf four patients who experienced relapse/progression, three remain alive after salvage treatment including RT. The remaining patient (No. 19) died without salvage treatment. Two patients died from toxicities during the second HDCT/auto-SCT. Therefore, a total of 17 patients remain alive at a median follow-up of 7.8 (range, 2.5−15.7) years from diagnosis. The 5-year OS and EFS rates were 85.0% ± 8.0% and 70.0% ± 10.2%, respectively (Fig. 3A). The 5-year CSRT-free survival rate was 75.0% ± 9.7% (Fig. 3B). The EFS was lower in patients with gross residual tumor than in those without (37.5% ± 17.1% versus 91.7% ± 8.0%, P = 0.012) (Fig. 3C). There was no difference in EFS between embryonal and non-embryonal tumors (Fig. 3D). All six patients with anaplastic ependymoma remain alive although two of them experienced relapse/progression. In addition, there were no differences in survival rates according to other clinical factors such as primary tumor site or age at diagnosis.\n\nFig. 3 Survival rates. (A) The 5-year OS and EFS rates were 85.0% ± 8.0% and 70.0% ± 10.2%, respectively. (B) The 5-year CSRT-free survival was 75.0% ± 9.7%. (C) The EFS was lower in patients with gross residual tumor than in those without (37.5% ± 17.1% versus 91.7% ± 8.0%, P = 0.012). (D) There was no difference in EFS between embryonal and non-embryonal tumors.\nOS = overall survival, EFS = event-free survival, CSRT = craniospinal radiotherapy, GTR = gross total resection.\n\nLate adverse effects\nTable 3 shows late adverse effects observed 5 years after the second HDCT/auto-SCT in 11 patients, two of whom received both CSRT and L-RT. Frequent late adverse effects included hypothyroidism, growth hormone deficiency, sensory neural hearing loss, and renal tubulopathy; however, except in one patient with grade 4 hearing loss, all adverse effects were grade 1 or 2. Until 4 years after tandem HDCT/auto-SCT, continuous deceleration in vertical growth was observed (Fig. 4). The median height at 5 years after the second HDCT/auto-SCT was –2.2 (range, 0.2 to –3.2) standard deviations from mean for patient age. The median value for full-scale intelligence quotient evaluated at 5 years after the second HDCT/auto-SCT was 81 (range, 43–99).\n\nTable 3 Late adverse effects 5 years after tandem HDCT/auto-SCT\nVariables\tValues (n = 11)a\t\nEndocrine dysfunction\t\t\n\tHypothyroidism\t3 (27.3)\t\n\tGrowth hormone deficiency\t5 (45.5)\t\n\tGlucocorticoid deficiency\t0 (0)\t\nHearing loss\t7 (63.6)b\t\nCataracts\t0 (0)\t\nChronic lung disease\t0 (0)\t\nRenal dysfunction\t\t\n\tGlomerulopathy\t0 (0)\t\n\tTubulopathy\t2 (18.2)\t\nCardiac dysfunction\t0 (0)\t\nSecond malignancy\t1 (9.1)\t\nFull-scale intelligence quotient\t81 (43–99)\t\nAll but one adverse effects were grade 1 or 2. Data are presented as number (%) or median (range).\n\naTwo of 11 patients received CSRT; bGrade 4 in one patient.\n\nFig. 4 Vertical growth during follow-up.\nDx = diagnosis, Off-Tx = off treatment, GH = growth hormone.\n\nDISCUSSION\nThe adverse effects of RT vary according to dose/volume and age at the time of RT, with late neurocognitive deficits being more pronounced in children treated before 3 years of age.16 Several studies using HDCT/auto-SCT to minimize RT, including Head Start I-III and CCG 99703, have reported encouraging outcomes in very young patients with malignant brain tumors.891011121314 Previously, we also reported encouraging preliminary results of a single-arm trial using tandem HDCT/auto-SCT in very young children with malignant brain tumors. However, the number of enrolled patients was small, and the short follow-up duration prevented analysis of long-term late effects. In the present study, we report the long-term follow-up results of an extended study, focusing on very young children with non-metastatic malignant brain tumors. Fifteen of 17 survivors did not receive CSRT, and nine of them did not receive RT. The results suggest that tandem HDCT/auto-SCT may improve the survival rates of patients with non-metastatic brain tumors while minimizing RT, particularly CSRT, and that late adverse effects were generally acceptable.\n\nOne of the most interesting observations in the present study is that all 12 patients without gross residual tumor remain progression-free, although one died from toxicity. In contrast, four of eight patients with gross residual tumor experienced relapse/progression (metastatic relapse in three). Tumors relapsed/progressed before scheduled RT in three of the patients, although they remain alive after salvage treatment including RT. These findings suggest that early L-RT might improve the outcome in patients with gross residual tumor. In the results of the Children's Oncology Group study P9934 by Ashley et al.,17 addition of conformal RT to the posterior fossa and tumor bed after induction chemotherapy increased EFS compared with use of chemotherapy alone, and neurodevelopmental assessments did not show a decline in cognitive or motor function. Another therapeutic option to prevent relapse/progression in very young children might be use of intrathecal or intraventricular chemotherapy. A previous report of the HIT 2000 trial demonstrated the efficacy of intraventricular methotrexate with acceptable toxicity.18 Recently, researchers have reported that administration of intrathecal topotecan is an effective strategy for treatment of various relapsed tumors.1920 During the late period of this study, early L-RT and intrathecal chemotherapy were administered to three patients with ATRT or PNET. Although one patient with residual tumor experienced metastatic relapse, two patients remain event-free. To evaluate the effectiveness of this treatment strategy, further study with a longer follow-up in a larger cohort is needed.\n\nTandem HDCT/auto-SCT is associated with greater toxicity and a higher TRM rate than single HDCT/auto-SCT, particularly during the second HDCT/auto-SCT.21 In the present study, two patients younger than 2 years of age died from TRM in the second HDCT/auto-SCT. This finding is consistent with the results of our previous report evaluating toxicities during tandem HDCT/auto-SCT in patients with brain tumors.21 The study suggests that dose intensity during the second HDCT/auto-SCT might be relatively higher in younger children than in older children, and dose reduction might reduce the TRM rate during the second HDCT/auto-SCT in younger children. However, dose reduction should be weighed against a probable increase in relapse rate. Therefore, further study is needed to determine the optimal dose in very young children with malignant brain tumors.\n\nLate adverse effects were generally acceptable, and all but one of the adverse late effects observed at 5 years after the second HDCT/auto-SCT were grade 1 or 2. However, patients who did not receive CSRT also showed substantial late adverse effects. These late effects might be associated with dose-intense tandem HDCT/auto-SCT. Further dose escalation and addition of more drugs during tandem HDCT/auto-SCT might be associated with more significant late adverse effects compared with single HDCT/auto-SCT. Therefore, longer follow-up is needed to assess whether the probable survival benefits from tandem HDCT/auto-SCT will ultimately outweigh the overall late adverse effects.\n\nRisk stratification and choice of RT in the present study were based on conventional clinical parameters (age, presence/absence of metastasis, and significant post-operative residual tumor). Tumor type might be important when determining treatment strategies including RT in very young children with malignant brain tumors. Other than early L-RT given to ATRT/PNET patients starting in September 2015, all patients in the present study received uniform treatment regardless of tumor type. In addition, recent efforts at stratifying brain tumors on the basis of their molecular/genetic features have subdivided brain tumors into various distinct subgroups characterized by disparate genetic and clinical features. For example, prognosis is quite variable with medulloblastomas according to molecular/genetic subtype.2223 Moreover, with the emergence of molecular/genetic characteristics as an important factor, molecular/genetic parameters are now used to establish brain tumor diagnoses in the revised 2016 WHO classification.24 In three of our patients, diagnosis according to the 2016 WHO classification was SHH-activated and TP53-wild type medulloblastoma. It is not clear whether our treatment strategy is appropriate for these patients. In the next phase of clinical trials using HDCT/auto-SCT, selection of patients will also be based on these molecular/genetic stratification data, potentially avoiding an intensive treatment regimen in some patients previously considered high risk.\n\nOne of the important limitations of this study is that it included patients with heterogeneous diagnoses. The role of chemotherapy is well established in embryonal tumors, however, it is controversial in other tumors such as immature teratomas and ependymomas. Due to the rarity of immature teratomas, standard treatment have not been established. In several research groups, patients with immature teratomas were enrolled in nongerminomatous germ cell tumor trials and treated with protocols including chemotherapy.25 While there have been some reports that chemotherapy may benefit patients with immature teratomas, several reports have shown that chemotherapy does not significantly affect survival.2526272829 Therefore, the efficacy of tandem HDCT/auto-SCT in patients with immature teratomas could be highly controversial. Despite controversies about the effectiveness of chemotherapy in ependymomas,3031 some studies have suggested that chemotherapy may be beneficial for ependymomas that are not completely resected,32 making it possible to either delay RT without compromising survival3133 or facilitate resection of residual tumors.34 This potential beneficial effects of chemotherapy are expected to be more prominent in anaplastic ependymomas. Our previous reports suggests that multimodal treatment including tandem HDCT/auto-SCT could be a feasible option for improving survival in children, particularly very young children, with anaplastic ependymomas.13536 However, Rajagopal et al.37 suggested that treatment with induction chemotherapy and HDCT/auto-SCT is less likely to hold the remission status without RT. And recent Children’s Oncology Group ACNS0121 trial showed that conformal RT without chemotherapy can be an alternative option for very young pediatric patients with completely resected anaplastic ependymoma.38 In this study, all six patients with anaplastic ependymoma remain alive although two of them experienced relapse/progression. In the future, optimal treatment based on the molecular classification of ependymomas will be investigated.\n\nThe limitations of small patient number (various pathologies in a few patients) and study design (single-arm study) due to the rarity of malignant brain tumors in very young children at a single center make it difficult to draw a robust conclusion regarding the applicability of our treatment strategy in very young children with malignant brain tumors. Therefore, multi-center, prospective, randomized, controlled studies with a larger cohort of patients are needed to compare the efficacy and toxicity among treatment strategies, including ours.\n\nIn conclusion, the results of our single-arm study suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal treatment including tandem HDCT/auto-SCT while minimizing RT, particularly CSRT. However, further study with a larger cohort of patients is needed to confirm these findings.\n\nFunding: This study was supported by a grant from the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (No. 0520300).\n\nDisclosure: The authors have no potential conflicts of interest to disclose.\n\nAuthor Contributions:\nConceptualization: Ma Y, Lim DH, Cho HW, Lee JW, Sung KW, Yoo KH, Koo HH, Shin HJ, Suh YL.\n\nData curation: Ma Y, Lim DH, Cho HW, Lee JW, Sung KW.\n\nFormal analysis: Ma Y, Lim DH, Cho HW, Lee JW.\n\nInvestigation: Ma Y, Lim DH.\n\nWriting - original draft: Ma Y, Lim DH, Sung KW.\n\nWriting - review & editing: Ma Y, Lim DH, Yoo KH, Sung KW, Koo HH, Shin HJ, Suh YL.\n==== Refs\n1 Sung KW Lim DH Lee SH Yoo KH Koo HH Kim JH Tandem high-dose chemotherapy and auto-SCT for malignant brain tumors in children under 3 years of age Bone Marrow Transplant 2013 48 7 932 938 23318534 \n2 Duffner PK Horowitz ME Krischer JP Friedman HS Burger PC Cohen ME Postoperative chemotherapy and delayed radiation in children less than three years of age with malignant brain tumors N Engl J Med 1993 328 24 1725 1731 8388548 \n3 Geyer JR Zeltzer PM Boyett JM Rorke LB Stanley P Albright AL Survival of infants with primitive neuroectodermal tumors or malignant ependymomas of the CNS treated with eight drugs in 1 day: a report from the Childrens Cancer Group J Clin Oncol 1994 12 8 1607 1615 8040673 \n4 Grill J Sainte-Rose C Jouvet A Gentet JC Lejars O Frappaz D Treatment of medulloblastoma with postoperative chemotherapy alone: an SFOP prospective trial in young children Lancet Oncol 2005 6 8 573 580 16054568 \n5 Berthold F Boos J Burdach S Erttmann R Henze G Hermann J Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial Lancet Oncol 2005 6 9 649 658 16129365 \n6 Marachelian A Butturini A Finlay J Myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for childhood central nervous system tumors Bone Marrow Transplant 2008 41 2 167 172 18176620 \n7 Matthay KK Reynolds CP Seeger RC Shimada H Adkins ES Haas-Kogan D Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children’s oncology group study J Clin Oncol 2009 27 7 1007 1013 19171716 \n8 Mason WP Grovas A Halpern S Dunkel IJ Garvin J Heller G Intensive chemotherapy and bone marrow rescue for young children with newly diagnosed malignant brain tumors J Clin Oncol 1998 16 1 210 221 9440745 \n9 Chi SN Gardner SL Levy AS Knopp EA Miller DC Wisoff JH Feasibility and response to induction chemotherapy intensified with high-dose methotrexate for young children with newly diagnosed high-risk disseminated medulloblastoma J Clin Oncol 2004 22 24 4881 4887 15611503 \n10 Dhall G Grodman H Ji L Sands S Gardner S Dunkel IJ Outcome of children less than three years old at diagnosis with non-metastatic medulloblastoma treated with chemotherapy on the “Head Start” I and II protocols Pediatr Blood Cancer 2008 50 6 1169 1175 18293379 \n11 Zaky W Dhall G Khatua S Brown RJ Ginn KF Gardner SL Choroid plexus carcinoma in children: the Head Start experience Pediatr Blood Cancer 2015 62 5 784 789 25662896 \n12 Espinoza JC Haley K Patel N Dhall G Gardner S Allen J Outcome of young children with high-grade glioma treated with irradiation-avoiding intensive chemotherapy regimens: final report of the Head Start II and III trials Pediatr Blood Cancer 2016 63 10 1806 1813 27332770 \n13 Cohen BH Geyer JR Miller DC Curran JG Zhou T Holmes E Pilot study of intensive chemotherapy with peripheral hematopoietic cell support for children less than 3 years of age with malignant brain tumors, the CCG-99703 phase I/II study. A report from the Children's Oncology Group Pediatr Neurol 2015 53 1 31 46 26092413 \n14 Lafay-Cousin L Smith A Chi SN Wells E Madden J Margol A Clinical, pathological, and molecular characterization of infant medulloblastomas treated with sequential high-dose chemotherapy Pediatr Blood Cancer 2016 63 9 1527 1534 27145464 \n15 Northcott PA Shih DJ Remke M Cho YJ Kool M Hawkins C Rapid, reliable, and reproducible molecular sub-grouping of clinical medulloblastoma samples Acta Neuropathol 2012 123 4 615 626 22057785 \n16 Raleigh DR Tomlin B Buono BD Roddy E Sear K Byer L Survival after chemotherapy and stem cell transplant followed by delayed craniospinal irradiation is comparable to upfront craniospinal irradiation in pediatric embryonal brain tumor patients J Neurooncol 2017 131 2 359 368 27778212 \n17 Ashley DM Merchant TE Strother D Zhou T Duffner P Burger PC Induction chemotherapy and conformal radiation therapy for very young children with nonmetastatic medulloblastoma: Children's Oncology Group study P9934 J Clin Oncol 2012 30 26 3181 3186 22851568 \n18 Pompe RS von Bueren AO Mynarek M von Hoff K Friedrich C Kwiecien R Intraventricular methotrexate as part of primary therapy for children with infant and/or metastatic medulloblastoma: feasibility, acute toxicity and evidence for efficacy Eur J Cancer 2015 51 17 2634 2642 26346136 \n19 Blaney SM Tagen M Onar-Thomas A Berg SL Gururangan S Scorsone K A phase-1 pharmacokinetic optimal dosing study of intraventricular topotecan for children with neoplastic meningitis: a Pediatric Brain Tumor Consortium study Pediatr Blood Cancer 2013 60 4 627 632 23002039 \n20 Yamada A Moritake H Kamimura S Yamashita S Takeshima H Nunoi H Proposed strategy for the use of high-dose chemotherapy with stem cell rescue and intrathecal topotecan without whole-brain irradiation for infantile classic medulloblastoma Pediatr Blood Cancer 2014 61 12 2316 2318 25174961 \n21 Lee SH Son MH Sung KW Choi YB Lee NH Yoo KH Toxicity of tandem high-dose chemotherapy and autologous stem cell transplantation using carboplatin-thiotepa-etoposide and cyclophosphamide-melphalan regimens for malignant brain tumors in children and young adults J Neurooncol 2014 120 3 507 513 25108776 \n22 von Bueren AO von Hoff K Pietsch T Gerber NU Warmuth-Metz M Deinlein F Treatment of young children with localized medulloblastoma by chemotherapy alone: results of the prospective, multicenter trial HIT 2000 confirming the prognostic impact of histology Neuro-oncol 2011 13 6 669 679 21636711 \n23 AbdelBaki MS Boué DR Finlay JL Kieran MW Desmoplastic nodular medulloblastoma in young children: a management dilemma Neuro-oncol 2018 20 8 1026 1033 29156007 \n24 Louis DN Perry A Reifenberger G von Deimling A Figarella-Branger D Cavenee WK The 2016 World Health Organization Classification of tumors of the central nervous system: a summary Acta Neuropathol 2016 131 6 803 820 27157931 \n25 Abu Arja MH Bouffet E Finlay JL AbdelBaki MS Critical review of the management of primary central nervous nongerminomatous germ cell tumors Pediatr Blood Cancer 2019 66 6 e27658 30767415 \n26 Ogawa K Toita T Nakamura K Uno T Onishi H Itami J Treatment and prognosis of patients with intracranial nongerminomatous malignant germ cell tumors: a multiinstitutional retrospective analysis of 41 patients Cancer 2003 98 2 369 376 12872359 \n27 Lee YH Park EK Park YS Shim KW Choi JU Kim DS Treatment and outcomes of primary intracranial teratoma Childs Nerv Syst 2009 25 12 1581 1587 19693515 \n28 Phi JH Kim SK Park SH Hong SH Wang KC Cho BK Immature teratomas of the central nervous system: is adjuvant therapy mandatory? J Neurosurg 2005 103 6 Suppl 524 530 16383251 \n29 Huang X Zhang R Zhou LF Diagnosis and treatment of intracranial immature teratoma Pediatr Neurosurg 2009 45 5 354 360 19907199 \n30 Grill J Le Deley MC Gambarelli D Raquin MA Couanet D Pierre-Kahn A Postoperative chemotherapy without irradiation for ependymoma in children under 5 years of age: a multicenter trial of the French Society of Pediatric Oncology J Clin Oncol 2001 19 5 1288 1296 11230470 \n31 Grundy RG Wilne SA Weston CL Robinson K Lashford LS Ironside J Primary postoperative chemotherapy without radiotherapy for intracranial ependymoma in children: the UKCCSG/SIOP prospective study Lancet Oncol 2007 8 8 696 705 17644039 \n32 Needle MN Goldwein JW Grass J Cnaan A Bergman I Molloy P Adjuvant chemotherapy for the treatment of intracranial ependymoma of childhood Cancer 1997 80 2 341 347 9217048 \n33 Geyer JR Sposto R Jennings M Boyett JM Axtell RA Breiger D Multiagent chemotherapy and deferred radiotherapy in infants with malignant brain tumors: a report from the Children's Cancer Group J Clin Oncol 2005 23 30 7621 7631 16234523 \n34 Foreman NK Love S Gill SS Coakham HB Second-look surgery for incompletely resected fourth ventricle ependymomas: technical case report Neurosurgery 1997 40 4 856 860 9092863 \n35 Lee JW Lim DH Sung KW Lee HJ Yi ES Yoo KH Multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation in children with anaplastic ependymomas Pediatr Transplant 2018 22 3 e13127 29453811 \n36 Sung KW Lim DH Lee SH Yoo KH Koo HH Kim JH Tandem high-dose chemotherapy and autologous stem cell transplantation for anaplastic ependymoma in children younger than 3 years of age J Neurooncol 2012 107 2 335 342 22081297 \n37 Rajagopal R Foo JC Jawin V Qaddoumi I Bouffet E High-dose chemotherapy with autologous stem cell transplantation in infants and young children with ependymoma: a 10-year experience with the Head Start II protocol Pediatr Transplant 2019 23 4 e13421 31012212 \n38 Merchant TE Bendel AE Sabin ND Burger PC Shaw DW Chang E Conformal radiation therapy for pediatric ependymoma, chemotherapy for incompletely resected ependymoma, and observation for completely resected, supratentorial ependymoma J Clin Oncol 2019 37 12 974 983 30811284\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1011-8934",
"issue": "35(48)",
"journal": "Journal of Korean medical science",
"keywords": "Brain Tumor; Children; High-dose Chemotherapy; Radiation Therapy",
"medline_ta": "J Korean Med Sci",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D016190:Carboplatin; D002675:Child, Preschool; D061888:Craniospinal Irradiation; D005047:Etoposide; D005260:Female; D034381:Hearing Loss; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D060828:Induction Chemotherapy; D007223:Infant; D008297:Male; D009364:Neoplasm Recurrence, Local; D000077982:Progression-Free Survival; D012307:Risk Factors; D016879:Salvage Therapy; D015996:Survival Rate; D013852:Thiotepa; D014182:Transplantation, Autologous",
"nlm_unique_id": "8703518",
"other_id": null,
"pages": "e405",
"pmc": null,
"pmid": "33316857",
"pubdate": "2020-12-14",
"publication_types": "D016428:Journal Article",
"references": "16234523;22057785;26092413;26346136;27332770;23002039;16054568;16129365;12872359;27145464;27157931;8388548;17644039;16383251;30767415;27778212;19907199;18176620;11230470;25174961;15611503;8040673;18293379;9440745;29156007;31012212;19171716;22851568;29453811;25108776;21636711;19693515;22081297;9092863;25662896;23318534;9217048;30811284",
"title": "Tandem High-dose Chemotherapy without Craniospinal Irradiation in Treatment of Non-metastatic Malignant Brain Tumors in Very Young Children.",
"title_normalized": "tandem high dose chemotherapy without craniospinal irradiation in treatment of non metastatic malignant brain tumors in very young children"
} | [
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"companynumb": "KR-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-325730",
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"actiondrug": "5",
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"activesubstancename": "MELPHALAN"
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"abstract": "BACKGROUND\nEncapsulating peritoneal sclerosis (EPS) is a rare but serious complication of peritoneal dialysis (PD). EPS almost exclusively occurs in patients treated longer than 3-5 years on PD. The more severe clinical features of EPS may develop if PD is discontinued (patient transferred to hemodialysis or transplanted).\n\n\nMETHODS\nAll PD patients diagnosed with EPS after transplantation were identified, and their data were compared with those of non-EPS PD patients transplanted in our unit between 1994 and 2010.\n\n\nRESULTS\nFour EPS cases were diagnosed among 157 transplanted PD patients. Mean renal replacement therapy and PD-only duration were 103.8 and 83.5 months in EPS and 26.5 and 22.2 months in non-EPS patients, respectively. All EPS patients (n = 4) required high-volume dialysis, 2 received icodextrin, 3 were high transporters, 1 had recurrent intraperitoneal bleeding, 4 received beta-blockers and 3 had peritonitis incidents. All required surgical intervention within 1-3 months after kidney transplantation (KT). Diagnosis of EPS was based on clinical symptoms, surgery, radiologic and histopathology findings. Treatment consisted of adhesiolysis (all), parenteral nutrition (PN) (3/4) and tamoxifen (all). One patient died 49 months after EPS diagnosis.\n\n\nCONCLUSIONS\nFirst, bowel obstruction symptoms in long-term PD patients undergoing KT may suggest EPS. Second, long-term PD patients showing features of technique failure are at high risk of EPS after KT. Third, adhesiolysis, PN and tamoxifen are the available treatment options in EPS patients post KT. And finally, referral of eligible patients to a transplant waiting list early after starting PD may contribute significantly to EPS prevention in clinical practice.",
"affiliations": "Department of Nephrology, Transplantation and Internal Medicine, Medical University in Gdansk, Gdansk - Poland.",
"authors": "Dębska-Ślizien|Alicja|A|;Konopa|Joanna|J|;Januszko-Giergielewicz|Beata|B|;Wołyniec|Zuzanna|Z|;Wołyniec|Wojciech|W|;Chamienia|Andrzej|A|;Rutkowski|Bolesław|B|",
"chemical_list": "D013629:Tamoxifen",
"country": "Italy",
"delete": false,
"doi": "10.5301/jn.5000230",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1121-8428",
"issue": "26(5)",
"journal": "Journal of nephrology",
"keywords": null,
"medline_ta": "J Nephrol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D010288:Parenteral Nutrition; D010530:Peritoneal Dialysis; D056627:Peritoneal Fibrosis; D012086:Reoperation; D012307:Risk Factors; D013629:Tamoxifen; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9012268",
"other_id": null,
"pages": "906-11",
"pmc": null,
"pmid": "23065918",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Posttransplant encapsulating peritoneal sclerosis: presentation of cases and review of the literature.",
"title_normalized": "posttransplant encapsulating peritoneal sclerosis presentation of cases and review of the literature"
} | [
{
"companynumb": "PL-WATSON-2015-12495",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
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"drugadditional": null,... |
{
"abstract": "Recently, definitive chemoradiotherapy (dCRT) has become one of the essential treatment strategies for esophageal squamous cell carcinoma (ESCC) and has been especially gaining prevalence for cervical ESCC to preserve the larynx. Our department recently introduced dCRT concomitant with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for treating advanced cervical ESCC. This study aims to assess the safety and outcomes of DCF-R in patients with advanced cervical ESCC.\n\n\n\nWe retrospectively assessed 11 patients with advanced cervical ESCC (clinical stage: II-IV, including T4b and/or M1 lymph node) who received DCF-R as the first-line treatment between December 2010 and February 2015.\n\n\n\nOur patient cohort comprised 8 males and 3 females (median age 68 years; range 54-76 years). The pretreatment clinical stage included stage II (1), stage III (7), and stage IV (3) cases [including 3 patients with T4b (2 trachea and 1 thyroid) and 3 patients with M1 lymph node]. We attained complete response (CR) in 10 patients and stable disease in 1 patient. Of 10 patients with CR, 5 experienced recurrence and 5 continued exhibiting CR. Furthermore, grade 3 or more adverse events included leucopenia (91%), neutropenia (91%), febrile neutropenia (45%), and pharyngeal pain (55%). While the 2-year overall survival rate was 72%, the 2-year recurrent-free survival rate was 64%, respectively.\n\n\n\nDCF-R treatment for advanced cervical esophageal cancer could be completed by the careful administration; although a strong blood toxicity might occur, this treatment may provide the chance to obtain favorable prognosis with larynx preservation.",
"affiliations": "Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan. hi-ok-0531@med.tohoku.ac.jp.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.;Department of Gastroenterological Surgery, Graduate School of Medicine, Tohoku University, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan.",
"authors": "Okamoto|Hiroshi|H|0000-0002-9042-7096;Taniyama|Yusuke|Y|;Sakurai|Tadashi|T|;Heishi|Takahiro|T|;Teshima|Jin|J|;Sato|Chiaki|C|;Maruyama|Shota|S|;Ito|Ken|K|;Onodera|Yu|Y|;Konno-Kumagai|Takuro|T|;Ishida|Hirotaka|H|;Kamei|Takashi|T|",
"chemical_list": "D000077143:Docetaxel; D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10388-018-0627-7",
"fulltext": null,
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"issn_linking": "1612-9059",
"issue": "15(4)",
"journal": "Esophagus : official journal of the Japan Esophageal Society",
"keywords": "5-Fluorouracil; Chemoradiotherapy; Cisplatin; Docetaxel; Esophageal squamous cell carcinoma",
"medline_ta": "Esophagus",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002945:Cisplatin; D000077143:Docetaxel; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D005472:Fluorouracil; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009503:Neutropenia; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "101206627",
"other_id": null,
"pages": "281-285",
"pmc": null,
"pmid": "29948480",
"pubdate": "2018-10",
"publication_types": "D016428:Journal Article",
"references": "25544126;26233590;28960561;17227304;25922724;28870931;20932658;24347470;24867539;12144188;18789828;24147973;11585510;17443746;16615159;29294022;17118849;25716773;27745985;27629865;29346536;28423530;10680872;19735862",
"title": "Definitive chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil (DCF-R) for advanced cervical esophageal cancer.",
"title_normalized": "definitive chemoradiotherapy with docetaxel cisplatin and 5 fluorouracil dcf r for advanced cervical esophageal cancer"
} | [
{
"companynumb": "JP-SA-2018SA175774",
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"activesubstancename": "DOCETAXEL"
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{
"abstract": "The voltage-gated sodium channel NaV1.7, encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in epileptogenesis. Previous studies have identified an increasing number of SCN9A mutations in patients with variable epilepsy phenotypes. Phenotypes of SCN9A mutations include febrile seizures (FS), genetic epilepsy with febrile seizures plus (GEFS+), and Dravet syndrome (DS), which pose challenges in clinical treatment. Here, we identified a heterozygous SCN9A mutation (c.980G > A chr2:167149868 p.G327E) from two twin sisters with Rolandic epilepsy by whole-exome sequencing. The patient became seizure free with a combination of levetiracetam and clonazepam. Identification of this mutation is also helpful for advancing our understanding of the role of SCN9A in epilepsy and provides deeper insights for SCN9A mutations associated with broad clinical spectrum of seizures.",
"affiliations": "Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China.;Department of pediatrics, Southern Medical University Affiliated Maternal & Child Health Hospital of Foshan, 11 Renminxi Road, Foshan, 528000, Guangdong, China. fsgaopm666@126.com.",
"authors": "Liu|Zhigang|Z|;Ye|Xingguang|X|;Qiao|Peixiu|P|;Luo|Weiyao|W|;Wu|Yanling|Y|;He|Yun|Y|;Gao|Pingming|P|http://orcid.org/0000-0003-3091-2417",
"chemical_list": "D000927:Anticonvulsants; D062556:NAV1.7 Voltage-Gated Sodium Channel; C486866:SCN9A protein, human",
"country": "Italy",
"delete": false,
"doi": "10.1007/s10072-019-03752-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-1874",
"issue": "40(7)",
"journal": "Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology",
"keywords": "Epilepsy; Heterozygous mutation; Rolandic spikes; SCN9A",
"medline_ta": "Neurol Sci",
"mesh_terms": "D000927:Anticonvulsants; D002648:Child; D004200:Diseases in Twins; D019305:Epilepsy, Rolandic; D005260:Female; D006579:Heterozygote; D006801:Humans; D009154:Mutation; D062556:NAV1.7 Voltage-Gated Sodium Channel; D010641:Phenotype",
"nlm_unique_id": "100959175",
"other_id": null,
"pages": "1457-1460",
"pmc": null,
"pmid": "30834459",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "17167466;17508172;18060017;18625963;19763161;20095983;23895530;23933819;25741868;28074849;28704742;29500686",
"title": "G327E mutation in SCN9A gene causes idiopathic focal epilepsy with Rolandic spikes: a case report of twin sisters.",
"title_normalized": "g327e mutation in scn9a gene causes idiopathic focal epilepsy with rolandic spikes a case report of twin sisters"
} | [
{
"companynumb": "CN-UCBSA-2019012892",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
... |
{
"abstract": "Background. During hypertensive therapy for post-subarachnoid hemorrhage (SAH) symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI) post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140-150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130-140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.",
"affiliations": "Section of Neurosurgery, University of Manitoba, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9.;Section of Neurosurgery, University of Manitoba, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9.;Section of Neurosurgery, University of Manitoba, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9.;Section of Critical Care, Department of Medicine, University of Manitoba, Room GC425, 820 Sherbrook Street, Winnipeg, MB, Canada R3T 2N2.;Section of Neurosurgery, University of Manitoba, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R9.",
"authors": "Zeiler|F A|FA|;Silvaggio|J|J|;Kaufmann|A M|AM|;Gillman|L M|LM|;West|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2014/630970",
"fulltext": "\n==== Front\nCase Rep Crit CareCase Rep Crit CareCRICCCase Reports in Critical Care2090-64202090-6439Hindawi Publishing Corporation 10.1155/2014/630970Case ReportNorepinephrine as a Potential Aggravator of Symptomatic Cerebral Vasospasm: Two Cases and Argument for Milrinone Therapy Zeiler F. A. \n1\n\n*\nSilvaggio J. \n1\nKaufmann A. M. \n1\nGillman L. M. \n2\nWest M. \n1\n1Section of Neurosurgery, University of Manitoba, GB-1 820 Sherbrook Street, Winnipeg, MB, Canada R3A 1R92Section of Critical Care, Department of Medicine, University of Manitoba, Room GC425, 820 Sherbrook Street, Winnipeg, MB, Canada R3T 2N2*F. A. Zeiler: umzeiler@cc.umanitoba.caAcademic Editor: Kurt Lenz\n\n2014 9 11 2014 2014 6309702 9 2014 20 10 2014 21 10 2014 Copyright © 2014 F. A. Zeiler et al.2014This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground. During hypertensive therapy for post-subarachnoid hemorrhage (SAH) symptomatic vasospasm, norepinephrine is commonly used to reach target blood pressures. Concerns over aggravation of vasospasm with norepinephrine exist. Objective. To describe norepinephrine temporally related deterioration in neurological examination of two post-SAH patients in vasospasm. Methods. We retrospectively reviewed two charts of patients with delayed cerebral ischemia (DCI) post-SAH who deteriorated with norepinephrine infusions. Results. We identified two patients with DCI post-SAH who deteriorated during hypertensive therapy with norepinephrine. The first, a 43-year-old male presented to hospital with DCI, failed MABP directed therapy with rapid deterioration in exam with high dose norepinephrine and MABP of 140–150 mm Hg. His exam improved on continuous milrinone and discontinuation of norepinephrine. The second, a 39-year-old female who developed DCI on postbleed day 8 responded to milrinone therapy upfront. During further deterioration and after angioplasty, norepinephrine was utilized to drive MABP to 130–140 mm Hg. Progressive deterioration in examination occurred after angioplasty as norepinephrine doses escalated. After discontinuation of norepinephrine and continuation of milrinone, function dramatically returned but not to baseline. Conclusions. The potential exists for worsening of DCI post-SAH with hypertensive therapy directed by norepinephrine. A potential role exists for vasodilation and inotropic directed therapy with milrinone in the setting of DCI post-SAH.\n==== Body\n1. Introduction\nDelayed cerebral ischemia (DCI) post-subarachnoid hemorrhage (SAH) poses significant challenges to the treating physician. Current standard therapy consists of hypertensive directed measures in order to ensure preservation of cerebral blood flow to risk territories and is titrated typically to the neurological examination [1–3]. In addition to this, maintenance of euvolemia is also a cornerstone of therapy [2]. In order to achieve the desired level of hypertension, a variety of inotropic and vasoconstrictive vasopressors have been utilized in the literature.\n\nDespite our best attempts at preservation of cerebral blood flow with hypertensive therapy, some patients progress to develop cerebral infarcts with a range of morbidity and mortality depending on infarct location and extent [3].\n\nDespite maximal therapy, some patients will fail hypertensive direct therapy for DCI post-SAH. However, with the use of peripheral vasoconstrictive substances to achieve desired mean arterial blood pressure (MABP) goals, one could question their effect on aggravating the cerebral vasoconstriction and having a negative impact on the neurological exam. To date, animal literature points towards cerebral vasoconstriction with the administration of norepinephrine [4–6]. Autopsy evidence suggests a dose dependant vasoconstrictive effect on proximal cerebral vessels with norepinephrine administration [7]. Furthermore, norepinephrine levels are known to be elevated in the cerebral spinal fluid of SAH patients and have been postulated as a potential mediator of cerebral vasospasm post-SAH [8]. Similarly, healthy human controls have displayed cerebral vasospasm via transcranial Dopplers (TCDs) when given intravenous norepinephrine [9]. Thus, norepinephrine may not be a safe choice for MABP directed therapy in post-SAH symptomatic cerebral vasospasm.\n\nWithin this paper we describe two cases of DCI post-SAH with worsening neurological examination temporally related to elevation of norepinephrine doses during hypertensive therapy. These effects were ameliorated via discontinuation of norepinephrine and continuing intravenous phosphodiesterase inhibitor (PDEI) based therapy with milrinone.\n\n2. Case Presentations\n2.1. Case 1\nA 43-year-old male with no significant past medical history presents to hospital with a 4-day history of headache, lethargy, and diplopia. Computed tomography (CT) of the brain demonstrated a Fisher grade 4 SAH; clinically he was Hunt and Hess grade 2 SAH. CT-angiography displayed a left posterior communicating artery aneurysm and left middle cerebral artery (MCA) vasospasm.\n\nClinically he had a partial oculomotor nerve palsy on the left and a significant headache. He was admitted, with plans for clipping of the aneurysm in the morning. Nimodipine prophylaxis was started. On postbleed day 5, he was seen on morning rounds neurologically unchanged, awaiting surgery. Within 30 minutes he developed progressive dysphasia, both receptive and expressive, with right hemineglect. Repeat CT head failed to display signs of aneurysmal rebleed. He received 2.5 liters of crystalloid and was transferred to the intensive care unit (ICU) for hypertensive therapy prior to going to the operative room (OR). Norepinephrine was started at 0.02 mcg/kg/min and titrated to 0.16 mcg/kg/min to achieve MABP of 130 mm Hg, as measured with the arterial line transducer zeroed at the tragus. Significant deterioration followed this titration of norepinephrine, progressing to right hemiplegia and aphasia.\n\nThe patient was then taken to the OR and the aneurysm was clipped successfully. Intraoperatively significant left MCA vasospasm was noted. The vessels were wiped with papaverine soaked gel foam. Mean arterial pressures were maintained between 130 and 140 mm Hg intraoperatively, with no hypotensive episodes noted in the anesthesia records.\n\nPostoperatively in the ICU, the patient awoke with right hemiplegia, right homonymous hemianopsia, and aphasia while achieving the target MABP of 150 mm Hg with norepinephrine at 0.68 mcg/kg/min. It was elected to stop norepinephrine and start intravenous milrinone therapy 45 minutes after emergence from his general anesthetic. A 5 mg bolus of milrinone over 10 minutes was given, followed by a continuous infusion of 0.75 mcg/kg/min. Within 30 minutes of discontinuing the norepinephrine and starting milrinone all deficits, except the third nerve palsy, resolved. His MABP at this time was 95 mm Hg.\n\nOn postbleed day 6, after 24 hours of milrinone therapy and a stable neurological examination, he developed acute sensory extinction on the right side and hemianopsia. Milrinone was rebolused, and the infusion was increased to 1.5 mcg/kg/min with partial improvement in symptoms within 40 minutes. Mean arterial pressures at this time were 120 mm Hg. Given only a partial response to milrinone escalation, norepinephrine was restarted with a goal MABP of 140 mm Hg, and interventional neuroradiology was called for angioplasty. While waiting for angioplasty, the norepinephrine was titrated to 0.46 mcg/kg/min with progressive deterioration in the neurological examination leading to hemiplegia.\n\nThe angioplasty of a severely spastic left proximal MCA and anterior cerebral artery (ACA) was conducted without incident. The degree of spasm in these arterial segments was noted to be worse compared to previous CT-angiography. Distal small vessel spasm in the left MCA territory was noted as well during angioplasty.\n\nAfter angioplasty he remained hemiparetic, with hemianopia and dysphasia, while the norepinephrine remained infusing with the goal of achieving MABP of 140 mm Hg. With no improvement in the next 48 hours, the norepinephrine was discontinued, while milrinone was continued at 1.5 mcg/kg/min with MABP around 90 to 110 mm Hg. The patient improved over the following hours after discontinuation of norepinephrine. Milrinone was then titrated down by 0.25 mcg/kg/day increments.\n\nCurrently, on postbleed day 25 he only has a partial third cranial nerve palsy and mild expressive language issues. Euvolemia was targeted throughout his entire course. No cardiac output monitoring was conducted throughout the patient's ICU stay.\n\n2.2. Case 2\nA 39-year-old female with a past medical history significant for polio, leaving her wheelchair bound secondary to lower extremity involvement, was admitted for a history of acute onset headache and mild confusion. She had a CT of the brain demonstrating a Fisher grade 4 SAH; clinically she was Hunt and Hess grade 2 SAH. Her CT-angiography demonstrated a right MCA aneurysm. She was taken to the OR for microsurgical clipping of the aneurysm and external ventricular drain (EVD) placement.\n\nPostoperatively the patient did initially well. No focal deficits were noted postoperatively other than a partial left abducens palsy related to fluctuations in intracranial pressure (ICP).\n\nOn postbleed day 7 a follow-up CT-angiogram was performed displaying right MCA and ACA vasospasm, but the patient was clinically unaffected at that time. On postbleed day 8, significant diuresis and cerebral salt wasting were noted. On postbleed day 9 the patient developed left upper motor neuron (UMN) facial weakness and left arm paresis. She was taken to ICU for management of her DCI.\n\nMilrinone therapy was initiated. Five milligrams of milrinone was bolused over 10 minutes, followed by a continuous infusion at 0.75 mcg/kg/min. She improved within 20 minutes to baseline. On postbleed day 11 she deteriorated again in a similar fashion. Milrinone was then rebolused, and the infusion was increased to 1.5 mcg/kg/min, leading to neurological improvement with minor residual pronator drift.\n\nOn postbleed day 13, neurological deterioration occurred again with now left UMN facial weakness and left arm paresis. Norepinephrine was started at 0.02 mcg/kg/min to target MABP of 140 mm Hg and interventional radiology was called for angioplasty. The proximal MCA and ACA were noted to be severely spastic and were the targets of angioplasty. These vessels appear as narrowed, compared to preangioplasty CT-angiography. Distal small vessel spasm was unchanged. The angioplasty occurred without incident and a good angiographic result was obtained.\n\nNeurologically after angioplasty the patient's left arm was plegic. Norepinephrine was increased to 0.22 mcg/kg/min to target MABP of 150 mm Hg. Occasional episodes of improvement were seen in the left arm but not sustained. Episodes of symptomatic pulmonary edema began to develop during this phase of her treatment. An MRI was conducted displaying watershed diffusion weighted changes in the ACA/MCA and MCA/posterior cerebral artery (PCA) territories. There was some perfusion/diffusion mismatch noted, and thus aggressive MABP therapy was continued for these potentially salvageable areas. No improvement occurred over the following 72 hours.\n\nNorepinephrine was then discontinued on postbleed day 16, with milrinone therapy running at 1.5 mcg/kg/min. The norepinephrine was discontinued given concerns over potential aggravation of cerebral vasoconstriction and the presence of maintained MABP goals on milrinone alone. No cardiac output monitoring was conducted during the patient's ICU stay. Within 12 hours of discontinuing norepinephrine, the patients left arm went from plegic to 4/5 strength in biceps, with 2-3/5 strength throughout the other muscles. Her left UMN facial weakness almost completely resolved during this time frame. Milrinone was then titrated off over the following day, as described in the first case.\n\nCurrently, on postbleed day 22 the patient has the same examination with mild left UMN facial weakness and the paretic left arm.\n\n3. Discussion\nCerebral vessels are known to be innervated by nerves containing norepinephrine and 5-hydroxytryptamine (5-HT) [4]. Norepinephrine has been demonstrated in both animal and human autopsy specimens, to induce a dose mediated vasoconstrictive effect on cerebral vasculature [7].\n\nNorepinephrine mediates vasoconstriction of cerebral vessels via two mechanisms. First, at low serum concentrations the alpha adrenergic mediated effects of norepinephrine lead to vasoconstriction. Second, at high concentrations, low-affinity sites [7] or gamma adrenoreceptor [8, 9] may be stimulated by norepinephrine leading to a much more pronounced cerebral vasoconstriction. These effects are seen in the proximal large cerebral vessels greater than in the smaller distal vessels [7].\n\nIn the setting of aneurysmal SAH, both serum and CSF norepinephrine levels have been demonstrated to be elevated [10, 11]. These serum [11] and CSF levels [10] seem to rise correlating with the severity of SAH and may be related to symptomatic cerebral vasospasm or just a marker of disease severity.\n\nDuring hypertensive therapy for DCI post-SAH, a variety of vasopressors have been utilized, with norepinephrine displaying the most predictable hemodynamic response in traumatic brain injury as identified in recent literature [12–14]. However there are concerns of cerebral vasoconstriction with norepinephrine administration, as outlined above. Within the two cases described, we were able to temporally relate worsening of the neurological examination with escalating norepinephrine doses during the treatment of their DCI. Though no objective radiographic markers of worsening cerebral vasospasm were identified (other than during angioplasty in Case 1), the deterioration of the neurological examination was dramatic and partially/entirely reversible with discontinuation of the norepinephrine infusions. With the absence of cardiac output monitoring and objective measures of cerebral blood flow, we can only suggest the temporally related decompensation was potentially related to norepinephrine induced vasoconstriction. Furthermore, the potential utility of the PDEI milrinone via continuous intravenous infusions was displayed in both of these cases.\n\nA few important points can be taken from both of these cases. First, MABP directed therapy for DCI postaneurysmal SAH can be challenging. It is not uncommon, as seen in both cases, that there exists a balancing act between symptomatic improvement with pharmacological alterations in cerebral blood flow and inducing systemic hemodynamic complications, such as pulmonary edema. Second, there seemed to be a norepinephrine dose related temporal change in both patients' neurological examinations. One patient displayed this deterioration with escalating norepinephrine both on and off milrinone therapy. The second patient displayed this effect while being on milrinone. Caution should be taken however, since the deteriorations seen may reflect either failure of hypertensive therapy (i.e., refractory DCI) or hypertension induced posterior reversible encephalopathy syndrome (PRES) related to escalating norepinephrine doses. Given the temporal relation between deterioration/improvement and norepinephrine doses, with neuroimaging failing to demonstrate features of PRES, we feel medication induced vasoconstriction is a real possibility. Third, this potential norepinephrine mediated deterioration is seemingly reversible to some extent, as seen when both patients had improvement in their neurological examination with discontinuation of norepinephrine. However, this improvement is clouded by the fact that both were on high dose intravenous infusions of milrinone at the time. Finally, the role of vasodilator therapy utilizing PDEI, such as milrinone, via continuous intravenous infusions is still undefined, though, in the two cases described and in existing literature [15], continuous infusions of milrinone have been shown to lead to neurological improvement in DCI post-SAH. The concerns over aggravation of cerebral vasospasm do not exist with milrinone, as they do with norepinephrine. Thus, maybe vasodilator therapies should be the front line for DCI post-SAH. Further study in this area is warranted.\n\nThere are significant limitations to our study. First, we only have two cases and this hardly is proof of concept that norepinephrine leads to worsening of DCI in SAH. This is further exemplified by the numerous other cases treated at both our institution and others, utilizing MABP directed therapy with norepinephrine, which have failed to display this response. This raises the point of a potential genetic driver of cerebrovascular response to particular vasopressors. Genetic polymorphisms within adrenoreceptors have been increasingly linked to hypertension and cardiovascular disease [16]. For example, the alpha 2B adrenergic insertion/deletion polymorphism has demonstrated greater degrees of peripheral vasoconstriction when stimulated with an alpha 2 agonist, dexmedetomidine, compared to controls [17]. Furthermore, this polymorphism has been linked to sudden cardiac death, presumably related to coronary vasospasm [18]. Similarly, alterations in the beta 2 adrenoreceptor have been linked to refractory hypertension, related to impaired vasodilatory effects when stimulated. Endothelin-1, angiotensin II, and nitric oxide-cGMP pathway polymorphisms have also been linked to altered adrenergic vascular reactivity and are associated with hypertension [16]. All of the mentioned polymorphisms could contribute to undesired cerebrovascular reactivity to adrenergic stimulation with vasopressor agents. However, insufficient data exists in the literature to date to make further comments on this. Second, the only data that we have to implicate norepinephrine in worsening cerebral vasospasm is the direct temporal relationship between administration of this drug and deterioration of the neurological examination. Only during angioplasty in Case 1 was the potential for worsening of proximal vasospasm, compared to CT-angiography, made. Though we suspect that this deterioration is related to worsening vasospasm, given the outlined mechanisms of action of norepinephrine on cerebral vasculature, we have no objective imaging evidence of this. The deterioration in these two cases could very well be a demonstration of failure of norepinephrine therapy in DCI or PRES (as previously mentioned), as opposed to worsening vasoconstriction related to norepinephrine. Potentially functional MRI or even Xenon enhanced CT would have shed more light on the matter. Similarly, cerebral microdialysis and cerebral blood flow catheters may have added some useful information about local metabolic changes with alterations in norepinephrine dosing. Finally, even though the response to intravenous PDEI therapy in these two cases was dramatic, it in no way proves superiority or equivalency to standard hypertensive therapy for DCI postaneurysmal SAH. Furthermore, with the absence of cardiac output monitoring during milrinone therapy in these cases, our goal with treatment was to titrate the medication doses to clinical improvement in the neurological examination, as per previously described protocols [15]. It is unknown what the particular hemodynamic changes were during this therapy, which may shed light on more objective targets with milrinone based therapy. Further prospective study with invasive/noninvasive determination of cardiac index during milrinone therapy for DCI is required.\n\nIn the setting of DCI post-SAH, hypertensive therapy with norepinephrine may lead to deterioration related to failure of therapy or medication induced vasoconstriction. Overall, we believe that norepinephrine carries the potential for aggravating DCI in certain patients. Prospective studies utilizing genetic profiling, multimodal intracranial monitoring, and neuroimaging need to be conducted in order to determine the effects of various vasopressors on cerebral metabolism and blood flow in post-SAH vasospasm. The role of milrinone in such cases, and for post-SAH vasospasm in general, carries potential and but has yet to be fully determined.\n\n4. Conclusions\nHypertensive directed therapy for DCI post-SAH may not lead to symptomatic improvement and potentially may lead to neurological deterioration. Genetic drivers of cerebrovascular response to vasopressors may dictate potential neurological improvement during hypertensive therapy, and further prospective study is warranted utilizing genotyping, multimodal monitoring, and advanced neuroimaging. The role for intravenous vasodilators in post-SAH vasospasm has yet to be determined but is promising.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nAuthors’ Contribution\nJ. Silvaggio, A. M. Kaufmann, and L. M. Gillman contributed equally to this work.\n==== Refs\n1 Diringer M. N. Management of aneurysmal subarachnoid hemorrhage Critical Care Medicine 2009 37 2 432 440 10.1097/CCM.0b013e318195865a 2-s2.0-67650392042 19114880 \n2 Diringer M. N. Axelrod Y. Hemodynamic manipulation in the neuro-intensive care unit: cerebral perfusion pressure therapy in head injury and hemodynamic augmentation for cerebral vasospasm Current Opinion in Critical Care 2007 13 2 156 162 10.1097/MCC.0b013e32807f2aa5 2-s2.0-33847328310 17327736 \n3 Bauer A. M. Rasmussen P. A. Treatment of intracranial vasospasm following subarachnoid hemorrhage Frontiers in Neurology 2014 5, article 72 \n4 Lincoln J. Innervation of cerebral arteries by nerves containing 5-hydroxytryptamine and noradrenaline Pharmacology & Therapeutics 1995 68 3 473 501 10.1016/0163-7258(95)02017-9 2-s2.0-0029621905 8788567 \n5 Liu Y. Yang X. Gong H. Jiang B. Wang H. Xu G. Deng Y. Assessing the effects of norepinephrine on single cerebral microvessels using optical-resolution photoacoustic microscope Journal of Biomedical Optics 2013 18 7 076007 10.1117/1.JBO.18.7.076007 2-s2.0-84885460287 \n6 Lobato R. D. Marin J. Salaices M. Rivilla F. Burgos J. Cerebrovascular reactivity to noradrenaline and serotonin following experimental subarachnoid hemorrhage Journal of Neurosurgery 1980 53 4 480 485 10.3171/jns.1980.53.4.0480 2-s2.0-0018953620 7420169 \n7 Duckworth J. W. Wellman G. C. Walters C. L. Bevan J. A. Aminergic histofluorescence and contractile responses to transmural electrical field stimulation and norepinephrine of human middle cerebral arteries obtained promptly after death Circulation Research 1989 65 2 316 324 10.1161/01.RES.65.2.316 2-s2.0-0024320567 2752543 \n8 Hirst G. D. S. Neild T. O. Evidence for two populations of excitatory receptors for noradrenaline on arteriolar smooth muscle Nature 1980 283 5749 767 768 10.1038/283767a0 2-s2.0-0018866682 6243746 \n9 Hirst G. D. S. Neild T. O. Localization of specialized noradrenaline receptors at neuromuscular junctions on arterioles of the guinea-pig Journal of Physiology 1981 313 343 350 2-s2.0-0019391107 7277224 \n10 Shigeno T. Norepinephrine in cerebrospinal fluid of patients with cerebral vasospasm Journal of Neurosurgery 1982 56 3 344 349 10.3171/jns.1982.56.3.0344 2-s2.0-0019949445 7057232 \n11 Loach A. B. Benedict C. R. Plasma catecholamine concentrations associated with cerebral vasospasm Journal of the Neurological Sciences 1980 45 2-3 261 271 10.1016/0022-510X(80)90170-7 2-s2.0-0018841499 7365503 \n12 Pfister D. Strebel S. P. Steiner L. A. Effects of catecholamines on cerebral blood vessels in patients with traumatic brain injury European Journal of Anaesthesiology 2008 25 42 98 103 10.1017/S0265021507003407 2-s2.0-43149096698 \n13 Steiner L. A. Johnston A. J. Czosnyka M. Chatfield D. A. Salvador R. Coles J. P. Gupta A. K. Pickard J. D. Menon D. K. Direct comparison of cerebrovascular effects of norepinephrine and dopamine in head-injured patients Critical Care Medicine 2004 32 4 1049 1054 10.1097/01.CCM.0000120054.32845.A6 2-s2.0-1842738358 15071400 \n14 Kroppenstedt S.-N. Thomale U.-W. Griebenow M. Sakowitz O. W. Schaser K.-D. Mayr P. S. Unterberg A. W. Stover J. F. Effects of early and late intravenous norepinephrine infusion on cerebral perfusion, microcirculation, brain-tissue oxygenation, and edema formation in brain-injured rats Critical Care Medicine 2003 31 8 2211 2221 10.1097/01.CCM.0000080482.06856.62 2-s2.0-0042944273 12973182 \n15 Lannes M. Teitelbaum J. del Pilar Cortés M. Cardoso M. Angle M. Milrinone and homeostasis to treat cerebral vasospasm associated with subarachnoid hemorrhage: the Montreal Neurological Hospital protocol Neurocritical Care 2012 16 3 354 362 10.1007/s12028-012-9701-5 2-s2.0-84873021700 22528278 \n16 Henrion D. Benessiano J. Iglarz M. Philip I. Levy B. I. Genetic determinants of vascular reactivity Current Hypertension Reports 2002 4 1 41 48 10.1007/s11906-002-0052-z 2-s2.0-0036484092 11790291 \n17 Talke P. Stapelfeldt C. Lobo E. Brown R. Scheinin M. Snapir A. Alpha-2B adrenoceptor polymorphism and peripheral vasoconstriction Pharmacogenetics and Genomics 2005 15 5 357 363 10.1097/01213011-200505000-00012 2-s2.0-18744368473 15864138 \n18 Laukkanen J. A. Mäkikallio T. H. Kauhanen J. Kurl S. Insertion/deletion polymorphism in α \n2 -adrenergic receptor gene is a genetic risk factor for sudden cardiac death American Heart Journal 2009 158 4 615 621 10.1016/j.ahj.2009.07.023 2-s2.0-70349220902 19781422\n\n",
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"title": "Norepinephrine as a potential aggravator of symptomatic cerebral vasospasm: two cases and argument for milrinone therapy.",
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"abstract": "Takotsubo cardiomyopathy is a form of transient, reversible left ventricular dysfunction that can mimic an acute coronary event. However, cardiac catheterization often reveals normal coronary arteries. Patients are often postmenopausal women who experience acute physical or emotional distress. The prognosis for this entity is quite favorable. In this report, we present three cases of Takotsubo cardiomyopathy in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management.",
"affiliations": "Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA. ejh3@columbia.edu.",
"authors": "Littlejohn|F Craig|FC|;Syed|Omar|O|;Ornstein|Eugene|E|;Connolly|E Sander|ES|;Heyer|Eric J|EJ|",
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"fulltext": "\n==== Front\nCases JCases Journal1757-1626BioMed Central 1757-1626-1-2271884214310.1186/1757-1626-1-227Case ReportTakotsubo cardiomyopathy associated with anesthesia: three case reports Littlejohn F Craig 1fcl2105@columbia.eduSyed Omar 2ons2101@columbia.eduOrnstein Eugene 1eo4@columbia.eduConnolly E Sander 23esc5@columbia.eduHeyer Eric J 13ejh3@columbia.edu1 Department of Anesthesiology, Columbia University Medical Center, New York, NY, USA2 Neurological Surgery, Columbia University Medical Center, New York, NY, USA3 Neurology, Columbia University Medical Center, New York, NY, USA2008 8 10 2008 1 227 227 19 9 2008 8 10 2008 Copyright © 2008 Littlejohn et al; licensee BioMed Central Ltd.2008Littlejohn et al; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\n\nTakotsubo cardiomyopathy is a form of transient, reversible left ventricular dysfunction that can mimic an acute coronary event. However, cardiac catheterization often reveals normal coronary arteries. Patients are often postmenopausal women who experience acute physical or emotional distress. The prognosis for this entity is quite favorable. In this report, we present three cases of Takotsubo cardiomyopathy in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management.\n==== Body\nBackground\nTakotsubo cardiomyopathy, also known as the 'transient left ventricular apical ballooning syndrome', is an uncommon phenomenon originally described in the Japanese population in 1991. [1] Sufferers are typically postmenopausal women who experience acute physical or emotional stress and subsequently develop chest pain and dyspnea. [2] The pathophysiological mechanism is likely catecholamine overload. [3]\n\nVentriculography typically reveals LV apical akinesis/hypokinesis and basal hypercontractility. [4] This gives the characteristic \"takotsubo,\" or octopus trap appearance. Ejection fraction is typically near 30% [3]. Coronary angiography is typically unremarkable, as most patients have no coronary artery disease, or non-obstructive disease [4]. Prognosis is generally favorable, as in-hospital mortality was 1.1%, and recurrence 3.5% in a review of multiple studies. [5] We present three cases of Takotsubo cardiomyopathy occurring at our institution in the past six months in patients having procedures involving anesthesia. Each case illustrates a different etiology for the syndrome: Patient, procedure, and anesthetic management.\n\nCase presentation\nCase 1\nA 71 year-old woman with a history of depression, refractory to medical management, presented with a major depressive episode for electroconvulsive therapy (ECT).\n\nShe had an uneventful ECT series four years prior, consisting of approximately 10 sessions. Her past medical history was significant only for hypertension. Her medications included daily quetiapine 300 mg, nortriptyline 25 mg, metoprolol succinate 100 mg, amlodipine 5 mg, and ativan 0.5 mg. She was also taking a four-day course of cefuroxime for a urinary tract infection. She had no allergies, and no family history of heart disease. Her electrocardiogram one day prior to ECT revealed normal sinus rhythm, at 97 beats per minute, with no ST or T abnormalities, or Q waves.\n\nAnesthesia was induced with 50 mg of methohexitol, and 50 mg of succinylcholine. After unilateral ECT was delivered to the right side of the head, a generalized seizure was initiated. The patient remained hemodynamically stable, resumed spontaneous respirations, and emerged rapidly.\n\nThree to four hours following the procedure she complained of chest pain. Her ECG revealed T wave flattening in AVL, and poor precordial R wave progression. A troponin level performed at that time was 3.28 ng/mL. Cardiac catheterization revealed non-obstructive coronary artery disease. Echocardiography demonstrated LV dysfunction with an ejection fraction of 20%, and a large apical aneurysm. A follow up echocardiogram one day later revealed improved LV function, and an EF of 45%. The troponin levels decreased over seven days to 0.18 ng/mL. Based on these results, the consulting cardiologist diagnosed Takotsubo cardiomyopathy. Subsequently, this patient's blood pressure regimen was modified with the addition of an angiotensin converting enzyme inhibitor. Follow-up echocardiography four months later revealed normal ejection fraction. Since that episode, the patient has had nineteen uneventful follow-up ECT treatments. These follow-up ECT treatments were performed with the addition of nicardipine, esmolol, and/or labetolol for blood pressure management, and cardioprotection.\n\nCase 2\nA 34 year-old woman with a history of asthma, hypercholesterolemia, pregnancy associated hypertension, obesity, and migraine headaches presented with a two week episode of post-prandial nausea, vomiting, and right-upper quadrant pain. Cholelithiasis was diagnosed, and the patient was scheduled for elective cholecystectomy. Her medications included daily hydrochlorothiazide 25 mg, rosuvastatin, montelukast sodium 10 mg, twice-daily fluticasone/salmeterol 500/50, and a rarely used albuterol metered-dose inhaler. She recently started celecoxib for her abdominal pain. She had an allergy to simvastatin, which was associated with a rash. She used no alcohol, tobacco, or other drugs. Her family history was significant only for hypertension.\n\nBaseline vital signs included blood pressure 130/74, heart rate 67, respiratory rate 16, and room air oxygen saturation 98%. Exercise tolerance was not limited by chest pain or dyspnea. Her physical exam was significant for obesity, and tenderness to deep palpation of the right upper quadrant, without guarding, or rebound. Preoperative ECG revealed normal sinus rhythm at 64 bpm, normal axis, T inversion in II, III, and AVF, V3-6, with T flattening in V1-2, ST depression of 1 mm in II, II, F, V3-6. A bedside transthoracic echocardiogram was performed in the preoperative area, and was normal. The cardiologist performing the exam felt that the patient was at very low risk for a coronary event, despite the abnormal ECG, and insisted that the patient was in optimal condition for the procedure.\n\nIn the operating room, the patient was given intravenous midazolam 1 mg, and fentanyl 50 mcg, and pre-oxygenation. Minutes later she developed pressure-like, non-radiating, substernal chest pain, and dyspnea. She was noted to be diaphoretic, tachypneic, and hypoxic, with an oxygen saturation of 80–90%. Her first non-invasive blood pressure reading was 213/141, with a heart rate in the 140s. Large ST elevations were noted on the 5-lead ECG monitor in leads I, and AVL. Metoprolol 1 mg was given, and the heart rate slowed to the 70s, with an unobtainable blood pressure. Phenylephrine was given, an arterial line was placed, and the initial blood pressure was 90/50. A 12-lead ECG was obtained and revealed new ST elevations in I and AVL, and ST depressions in V4-6.\n\nSurgery was cancelled, and the patient was transferred to the intensive care unit. The initial troponin level was 0.4 ng/mL, and peaked at 9.0 within six hours. The patient received oral aspirin 325 mg, clopidogrel 600 mg, and an intravenous heparin drip. A repeat echocardiogram revealed posterior wall akinesis, inferior wall hypokinesis, and an EF of 35–40%. Cardiac catheterization was performed the following day and revealed normal coronary anatomy. Ventriculography showed findings consistent with the preceding echocardiogram.\n\nAfter an extensive workup, the patient was diagnosed with Takotsubo cardiomyopathy, with the 0 possibility of vasospastic angina.\n\nA follow-up echocardiogram at one month revealed normal LV size, function, EF, and no wall motion abnormalities. Three months later, the patient had an uneventful laparoscopic cholecystectomy, having started atenolol prior to the procedure.\n\nCase 3\nAn 83 year-old woman with bilateral carotid stenosis presented for elective right carotid endarterectomy. Her past medical history included hypertension, hypercholesterolemia, polymyalgia rheumatica, pernicious anemia, and peptic ulcer disease treated with a Billroth 2 gastrectomy. Her preoperative medications included olmesartan, alendronate, rosuvastatin, and aspirin, which had been stopped seven days prior to surgery. Of note, the patient took olmesartan, an angiotensin receptor blocker, the morning of surgery. She had no allergies, no history of smoking, alcohol consumption, or other drug use, and no family history of heart disease.\n\nHer preoperative ECG was significant for low-voltage QRS. Her preoperative blood pressure was 97/58, heart rate 93, respirations 15, and room air oxygen saturation 97%. Her chest was clear to auscultation bilaterally, heart tones were normal, and there was no JVD. No medications were given in the preoperative area.\n\nIn the operating room, an IV and radial arterial line were placed, and the patient was sedated with midazolam and fentanyl. Anesthesia induction and intubation were facilitated with lidocaine, etomidate, and vecuronium. Prior to induction, a phenylephrine drip had been started at 25 mcg/min to maintain systolic blood pressure greater than 150 mm Hg, a target requested by the neurosurgical attending. During intubation, blood pressure briefly rose to 220/100 with a heart rate of 100. Subsequently, during dissection of the carotid sheath, blood pressure was noted to be poorly responsive to phenylephrine boluses, however ephedrine was effective. At one point during dissection an episode of bradycardia and hypotension occurred that was treated with 0.2 mg glycopyrrolate, 10 mg ephedrine, and 80 mcg phenylephrine simultaneously as the surgeon's released manual pressure on the carotid sinus. The heart rate quickly normalized, with recovery of blood pressure to previous levels (SBP 140s).\n\nDuring the following hour, maintaining the target blood pressure became increasingly difficult, and was punctuated by a series of transient precipitous drops, followed by recovery with treatment. Vasopressin was given in two 0.5 unit boluses, with a 2 unit/hr infusion, followed by several boluses of norepinephrine ranging from 8–32 mcg. The phenylephrine infusion started at the beginning of the case was titrated as high as 75 mcg/min, but was safely discontinued upon release of the carotid cross clamp. The procedure was nearing completion by the end of the hour, and pink frothy fluid was noted in the gas sampling line. Breath sounds were coarse, but not crackly. Oxygen saturation fell to 95% at one point, but recovered to 97% following suctioning of the endotracheal tube. The patient was deemed stable for extubation, and was transported to the PACU on a 100% non-rebreather mask.\n\nIn the PACU, the patient complained of dull, non-radiating, substernal chest pain. The ECG revealed a low-voltage QRS, but was essentially unchanged from baseline. A chest x-ray revealed pulmonary edema. The troponin level was 5.19 ng/mL. Cardiac catheterization revealed normal coronary anatomy, ventriculography revealed severe anterolateral hypokinesis, and severe apical septal hypokinesis, with a left-ventricular ejection fraction of 25%. Of note, pulmonary capillary wedge pressure was 25 cm H2O. An intra-aortic counterpulsation balloon pump was placed for cardiogenic shock. The patient recovered in coronary care unit (CCU), and was discharged one week later. Follow-up studies cardiac studies were said to have returned to normal.\n\nDiscussion\nTakotsubo cardiomyopathy is most commonly associated with acute physical or emotional stress. [2] Our cases are unusual in that they were all associated with different forms of iatrogenic stress related to medical procedures.\n\nFirst, during the course of ECT treatment, it is common for blood pressure and heart rate to increase because of endogenous catecholamine release. Elevated catecholamine levels are found within one minute and frequently last 10–15 minutes [6,7]. However, there have been only a few case reports of Takotsubo cardiomyopathy associated with ECT [8].\n\nSecond, while it is difficult to determine precisely the etiology and sequence of pathological events in our second case, the patient experienced an acutely stressful event, and developed Takotsubo cardiomyopathy. Given this history of migraine headaches, and sudden onset of the episode, we feel it is most likely that this patient experienced severe coronary vasospasm, which may have resulted in ischemia, leading to myocardial dysfunction.\n\nAlternatively, the emotional and physical stress of the coronary vasospasm may have caused a surge in endogenous catecholamines that was directly responsible for inducing Takotsubo cardiomyopathy, as diagnosed by the cardiologist.\n\nThird, the catecholamine excess that led to Takotsubo cardiomyopathy was iatrogenic. To optimize collateral circulation to the brain during carotid cross-clamping, anesthesiologists frequently induce hypertension. Our patient was particularly resistant to the usual doses of phenylephrine, a pure alpha-1 vasoconstrictor. We attributed this to preoperative treatment of her hypertension with an angiotensin receptor blocker (ARB), which has been associated with enhanced and potentially severe hypotension during anesthesia. [6,7] Her blood pressure did respond to ephedrine, an indirect inotrope-vasoconstrictor. She received a total of 50 mg ephedrine over the first hour of surgery. The phenylephrine, ephedrine, norepinephrine and vasopressin likely all contributed to the patient developing Takotsubo cardiomyopathy, and ultimately heart failure. The most effective treatment for anesthesia-induced ARB/ACE-I hypotension is terlipressin. [8,9] In this case, vasopressin was given in two small boluses, and an infusion was started. At the same time, several boluses of norepinephrine were given. These treatments were minimally effective, because she was likely already in heart failure.\n\nTakotsubo cardiomyopathy is an increasingly reported phenomenon that may occur not only in settings of acute physical or emotional stress, but also iatrogenic stress related to common medical procedures. Physicians participating in these procedures would be well advised to consider the risk factors inherent in the patient, procedure, and anesthetic management for developing this syndrome, in order to better anticipate and potentially prevent this outcome.\n\nConsent\nA telephone informed consent including witness in accordance with the author's local institutional guidelines was obtained from each patient for publication of this case report. A copy of this consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nFCL and ONS prepared the manuscript. EO and EJH were the anesthesiologists caring for these patients. ESC was the neurosurgeon involved for patient three. Collectively, EO EJH, and ESC analyzed the data and provided critical assessment for the final manuscript. All authors read and approved the final manuscript.\n\nAcknowledgements\nFinancial Support:E.J.H. was supported in part by a grant from the NIA (RO1 AG17604).\n==== Refs\nDote K Sato H Tateishi H Uchida T Ishihara M [Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases] J Cardiol 1991 21 203 14 1841907 \nSharkey SW Lesser JR Zenovich AG Maron MS Lindberg J Longe TF Acute and reversible cardiomyopathy provoked by stress in women from the United States Circulation 2005 111 472 9 15687136 10.1161/01.CIR.0000153801.51470.EB \nWittstein IS Thiemann DR Lima JA Baughman KL Schulman SP Gerstenblith G Neurohumoral features of myocardial stunning due to sudden emotional stress N Engl J Med 2005 352 539 48 15703419 10.1056/NEJMoa043046 \nBybee KA Kara T Prasad A Lerman A Barsness GW Wright RS Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction Ann Intern Med 2004 141 858 65 15583228 \nGianni M Dentali F Grandi AM Sumner G Hiralal R Lonn E Apical ballooning syndrome or takotsubo cardiomyopathy: a systematic review Eur Heart J 2006 27 1523 9 16720686 10.1093/eurheartj/ehl032 \nColson P Ryckwaert F Coriat P Renin angiotensin system antagonists and anesthesia Anesth Analg 1999 89 1143 55 10553825 10.1097/00000539-199911000-00012 \nColson P Saussine M Seguin JR Cuchet D Chaptal PA Roquefeuil B Hemodynamic effects of anesthesia in patients chronically treated with angiotensin-converting enzyme inhibitors Anesth Analg 1992 74 805 8 1595911 10.1213/00000539-199206000-00005 \nMorelli A Tritapepe L Rocco M Conti G Orecchioni A De Gaetano A Terlipressin versus norepinephrine to counteract anesthesia-induced hypotension in patients treated with renin-angiotensin system inhibitors: effects on systemic and regional hemodynamics Anesthesiology 2005 102 12 9 15618781 10.1097/00000542-200501000-00006 \nBoccara G Ouattara A Godet G Dufresne E Bertrand M Riou B Terlipressin versus norepinephrine to correct refractory arterial hypotension after general anesthesia in patients chronically treated with renin-angiotensin system inhibitors Anesthesiology 2003 98 1338 44 12766641 10.1097/00000542-200306000-00007\n\n",
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"title": "Takotsubo cardiomyopathy associated with anesthesia: three case reports.",
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"abstract": "Ruxolitinib has become a new therapeutic option for steroid refractory graft-versus-host disease (srGVHD), with a substantial remission rate. Its anti-inflammatory properties by blocking interleukin pathways have made it a novel therapeutic approach to inflammatory disease processes, such as GVHD. The long-term use of ruxolitinib has not been explicitly studied outside the context in the treatment of multiple myeloma. With current clinical trials underway for the use of ruxolitinib in srGVHD, there are still no current guidelines or protocols for long-term clinical use. Of the available literature showing ruxolitinib utilization for srGVHD, most cases lead to resolution and eventual discontinuation. We present a case of a 32-year-old male on ruxolitinib with GVHD status postmatched unrelated donor stem cell transplant (MUD SCT) for acute myeloid leukemia (AML) with FLT3 mutation currently on ruxolitinib for 5 years who is not able to tolerate reduction in dosage due to flare-ups. We discuss the clinical implications and nuance of therapy with ruxolitinib with unknown long-term effects and weigh the risks and benefits.",
"affiliations": "Internal Medicine, White River Health System, Batesville, AR, USA.;Medical Oncology, Augusta University, Augusta, GA, USA.;Medical Oncology, Augusta University, Augusta, GA, USA.",
"authors": "Sobash|Philip T|PT|;Guddati|Achuta K|AK|https://orcid.org/0000-0002-9390-0424;Kota|Vamsi|V|https://orcid.org/0000-0002-5290-9289",
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"fulltext": "\n==== Front\nCase Rep Oncol Med\nCase Rep Oncol Med\nCRIONM\nCase Reports in Oncological Medicine\n2090-6706 2090-6714 Hindawi \n\n10.1155/2020/4936846\nCase Report\nLong-Term Use of Ruxolitinib in an AML Patient with Posttransplant Steroid Refractory GVHD\nSobash Philip T. \n1\n https://orcid.org/0000-0002-9390-0424Guddati Achuta K. \n2\n https://orcid.org/0000-0002-5290-9289Kota Vamsi vkota@augusta.edu\n2\n \n1Internal Medicine, White River Health System, Batesville, AR, USA\n\n2Medical Oncology, Augusta University, Augusta, GA, USA\nAcademic Editor: Ossama W. Tawfik\n\n\n2020 \n6 4 2020 \n2020 493684617 9 2019 3 3 2020 26 3 2020 Copyright © 2020 Philip T. Sobash et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Ruxolitinib has become a new therapeutic option for steroid refractory graft-versus-host disease (srGVHD), with a substantial remission rate. Its anti-inflammatory properties by blocking interleukin pathways have made it a novel therapeutic approach to inflammatory disease processes, such as GVHD. The long-term use of ruxolitinib has not been explicitly studied outside the context in the treatment of multiple myeloma. With current clinical trials underway for the use of ruxolitinib in srGVHD, there are still no current guidelines or protocols for long-term clinical use. Of the available literature showing ruxolitinib utilization for srGVHD, most cases lead to resolution and eventual discontinuation. We present a case of a 32-year-old male on ruxolitinib with GVHD status postmatched unrelated donor stem cell transplant (MUD SCT) for acute myeloid leukemia (AML) with FLT3 mutation currently on ruxolitinib for 5 years who is not able to tolerate reduction in dosage due to flare-ups. We discuss the clinical implications and nuance of therapy with ruxolitinib with unknown long-term effects and weigh the risks and benefits.\n==== Body\n1. Introduction\nSteroid refractory GVHD (srGVHD) has a poor prognosis, with survival rates between 5 and 30% [1]. Ruxolitinib has been shown to reduce side effects from srGVHD, in both acute and chronic settings, with some studies showing 81.5% overall response in an acute state and 46.3% in a chronic state [2]. Responses have been shown to occur mostly early in treatment with a 68% discontinuation rate and 21% reduction in steroid use [3]. Multiple centers have noted the promising effects [2, 3] along with clinical trials underway [4, 5].\n\nMany of the best available treatments for srGVHD with current immunomodulatory drugs have side effects including lymphoproliferative disorders, relapse of disease, cancer, and opportunistic infections. While there have been reports of cytomegalovirus infection and pancytopenias on ruxolitinib [2, 6], others did not show these effects [3]. As dosages and treatments were similar, it is hard to speculate why there was a discrepancy between data sets. It is potentially due to the differing use of steroids and other immunosuppressive agents in conjunction with ruxolitinib. Further studies with sole administration of ruxolitinib are needed to determine if it is a causative agent for side effects or if there are other confounding variables.\n\nTo the authors' knowledge, no studies have assessed the use of ruxolitinib in terms of long-term sequela. Many effects have been noted in the treatment of sr-acute GVHD, but less for sr-chronic GVHD due to lack of necessity for further therapy with reduction of symptoms. Prolonged use of therapy due to inability to taper has not been specifically studied. This is due in part to the high percentage of patients who respond and ultimately are discontinued from therapy. Herein, we report our experience with a patient who responded to ruxolitinib and has been on the drug for 6 years with flare-ups despite prolonged taper schedule.\n\n2. Presentation\nA 26-year-old patient presented to an outside facility in late 2013 with a WBC count of 260,000, subsequently diagnosed with AML with FLT-3 mutation, and started on emergent treatment. He was initially treated with 2 rounds of induction therapy with 7 + 3 regimen, but his disease state remained persistent. Given his young age and previous history of mucositis, pneumonia with sepsis, and a decreased ejection fraction due to previous therapy, he was given a course of high-dose cytarabine 1500 mg/m2 with sorafenib. Ultimately, he did receive a MUD SCT with fludarabine/busulfan (4)/antithymocyte globulin regimen in November 2013. Immunosuppressive regimen consisted of tacrolimus and methotrexate. The patient began displaying mild aGVHD after transplant and received topical steroids. Bone marrow biopsy 30 days from transplant showed minimal residual disease (MRD) and FLT3 positivity on PCR. The patient was then started on sorafenib 200 mg BID and azacytidine and continued on GM-CSF to help with GVHD with plans to rebiopsy in one month. At this time, a second transplant was discussed but ultimately decided to not be an option due to organ problems prior to the transplant. A repeat bone marrow biopsy in February/2014 showed no activity of disease indicating hematological and morphological remission. Patient received azacytidine for 4 days at 75 mg/m2 and was given a donor lymphocyte infusion (DLI) in March/2014. Although he continued to be in remission since that DLI, he had a flare-up of GVHD post-DLI. He presented with severe chronic GVHD involving the skin, eyes, and lungs in May 2014. Skin manifestations included rapidly progressing sclerotic appearance typically seen in the chronic GVHD setting and involving more than 50% of his body surface. Lung GVHD was diagnosed with follow-up pulmonary function tests where his DLCO dropped to 20% of predicted. His immunosuppression at the time of his presentation consisted of tacrolimus alone with levels being between 5 and 7 ng/ml as it was being tapered slowly and levels kept lower due to his high risk of relapse.\n\nHe initiated therapy with prednisone at 2 mg/kg given his severe GVHD (NIH severity 4) in addition to increase in tacrolimus dosing to achieve levels in the 7-10 ng/ml range. He did have a response to the high-dose steroids but rapidly developed complications of steroids therapy most notably, steroid myopathy (CTCAE v4.03, grade 3) involving both the upper and lower limbs in the typical proximal muscle distribution seen with steroids. On high-dose steroids, his GVHD symptoms did improve with skin GVHD having a partial response and improvement in his DLCO to 40%. Attempts to taper to below 20 mg resulted in a flare-up of skin GVHD as well as worsening of lung function. He also started having progressive skin symptoms despite being on steroids, and mycophenolate mofetil (MMF) was added to his immunosuppressive regimen. He did not have any benefit in terms of either clinical improvement of GVHD or reduction in steroid dose, and so MMF was discontinued and he had an increase in steroid dose. Ruxolitinib 5 mg PO BID was started in 2014, when steroid therapy proved to be ineffective, and he had an excellent rapid response to symptoms. His skin GVHD was controlled with improvement appearing within the first month of initiation of therapy. His lung function also stabilized with DLCO in the 35-45 range. He was weaned off of other immunosuppressants quickly at the patient discretion but did not have a flare-up despite a rapid taper of steroids. His myopathy resolved as expected within the first month after discontinuation of steroids. At present time, his cGVHD is under control with ruxolitinib alone. Attempts to wean off of his current dosage of ruxolitinib have proved unsuccessful as cGVHD flares up and symptoms worsen. His weaning attempts initially were per standard recommendations with the dose tapered to 5 mg once a day and plans for discontinuation. He was never off ruxolitinib for prolonged periods as his symptoms flared up within a week and had to restart therapy. His GVHD did respond to restarting the ruxolitinib at 5 mg twice a day. Patient seemingly tolerates the treatment with ruxolitinib, and he has had no identifiable issues or side effects from long-term use. Of note, he did have one admission to the hospital for community-acquired pneumonia in 2018 which resolved with appropriate antibiotic therapy. The current prospective treatment plan involves a taper attempt every 3-4 months with 2.5 mg every two months to wean off therapy as tolerated. The clinical question then becomes if a patient is seemingly gaining benefit from ruxolitinib therapy, does the risk of the unknown long-term therapy use outweigh the benefits of current stability of suppressing cGVHD.\n\n3. Discussion\nGiven the relatively recent utilization of ruxolitinib for srGVHD and the varying responses, the proper management of patients on long-term therapy in the absence of clinical guidelines is unclear. To date, no long-term toxicities have been noted, although some infections and viral reactivations have been seen as noted earlier. In our experience with this patient, we have only identified one potential negative event in terms of infection in an event of pneumonia. Even then, this could be due to multiple factors and not directly attributed to ruxolitinib, although this cannot be determined. The authors of this paper speculate though that like any long-term immunosuppressive, clinical judgement should be used to determine a risk/benefit analysis. In our specific case, tapering causes severe GVHD flare-ups and hence the reason for continued use. With no seemingly therapeutic consequences of long-term use, we argue that there may be no reason not to continue our patient on therapy and monitor closely as with other immunosuppressive therapies.\n\nAnother consideration is the mechanism of action of ruxolitinib versus other immunomodulating drugs. While both are acting on regulation and proliferation of T-cells, ruxolitnib acts on the Jak1/2 kinase pathways. The exact impact on T-cell regulation and proliferation is still poorly understood [7]. For example, in some studies, ruxolitinib decreased regulatory T-cells while in others, it increased [8]. There may be more of an involvement in reduction of inflammatory cytokines rather than absolute T-cell numbers compared to calcineurin inhibitors.\n\nThere have been multiple studies highlighting the long-term use of ruxolitinib in individuals with myelofibrosis with side effects including pancytopenias, viral reactivation, and infections. Liver toxicity with longer-term use in patients with myelofibrotic disorders has been reported [9]. While many studies were a different disease state, much of the length of therapy overlaps with our patient to some extent. It is reasonable then to state that the length of therapy in regard to our patient is in line with that in other uses for ruxolitinib in the context of long-term side effects. A final thought is that increased doses may harbor an unforeseen effect on the sr-cGVHD process. Most studies that have gone by the dosing parameters outlined by Zeiser et al. [2]. Our experience thus far has not shown any increased overall morbidity or mortality due to long-term ruxolitinib use. More studies and cases are needed to assess long-term outcomes of ruxolitinib use and if there are any side effects in the long-term, other than reported, to be weighed into management decisions.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n==== Refs\n1 Martin P. J. Rizzo J. D. Wingard J. R. First- and second-line systemic treatment of acute graft-versus-host disease: recommendations of the American Society of Blood and Marrow Transplantation Biology of Blood and Marrow Transplantation 2012 18 8 1150 1163 10.1016/j.bbmt.2012.04.005 2-s2.0-84862137300 22510384 \n2 Zeiser R. Burchert A. Lengerke C. Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell transplantation: a multicenter survey Leukemia 2015 29 10 2062 2068 10.1038/leu.2015.212 2-s2.0-84943582032 26228813 \n3 Khoury H. J. Langston A. A. Kota V. K. Ruxolitinib: a steroid sparing agent in chronic graft-versus-host disease Bone Marrow Transplantation 2018 53 7 826 831 10.1038/s41409-017-0081-5 2-s2.0-85040911317 29367708 \n4 Jagasia M. Zeiser R. Arbushites M. Delaite P. Gadbaw B. Bubnoff N. . Ruxolitinib for the treatment of patients with steroid-refractory GVHD: an introduction to the REACH trials Immunotherapy 2018 10 5 391 402 10.2217/imt-2017-0156 2-s2.0-85042681852 29316837 \n5 von Bubnoff N. Ihorst G. Grishina O. Ruxolitinib in GvHD (RIG) study: a multicenter, randomized phase 2 trial to determine the response rate of ruxolitinib and best available treatment (BAT) versus BAT in steroid-refractory acute graft-versus-host disease (aGvHD) (NCT02396628) BMC Cancer 2018 18 1 p. 1132 10.1186/s12885-018-5045-7 2-s2.0-85056740412 30453910 \n6 Abedin S. McKenna E. Chhabra S. Efficacy, toxicity, and infectious complications in ruxolitinib-treated patients with corticosteroid-refractory graft-versus-host disease after hematopoietic cell transplantation Biology of Blood and Marrow Transplantation 2019 25 8 1689 1694 10.1016/j.bbmt.2019.04.003 2-s2.0-85065022222 30965140 \n7 Seif F. Khoshmirsafa M. Aazami H. Mohsenzadegan M. Sedighi G. Bahar M. The role of JAK-STAT signaling pathway and its regulators in the fate of T helper cells Cell Communication and Signaling: CCS 2017 15 1 p. 23 10.1186/s12964-017-0177-y 2-s2.0-85021101177 28637459 \n8 González Vicent M. Molina B. González de Pablo J. Castillo A. Díaz M. Á. Ruxolitinib treatment for steroid refractory acute and chronic graft vs host disease in children: clinical and immunological results American Journal of Hematology 2019 94 3 319 326 10.1002/ajh.25376 2-s2.0-85059008742 30536806 \n9 Tremblay D. Putra J. Vogel A. The implications of liver biopsy results in patients with myeloproliferative neoplasms being treated with ruxolitinib Case Reports in Hematology 2019 2019 3 10.1155/2019/3294046 30723558\n\n",
"fulltext_license": "CC BY",
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"title": "Long-Term Use of Ruxolitinib in an AML Patient with Posttransplant Steroid Refractory GVHD.",
"title_normalized": "long term use of ruxolitinib in an aml patient with posttransplant steroid refractory gvhd"
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"abstract": "Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare brain-capillary leak syndrome, characterized by clinical symptoms of headache, visual loss, seizures and altered mental functioning. This syndrome is usually reversible and is associated with hypertension, nephropathy, and use of immunosuppressive medication and cytotoxic agents. We describe two rare cases of RPLS occurring in colorectal cancer, both of which presented with coma, that we believe can be directly attributed to bevacizumab, a monoclonal antibody that inhibits the angiogenesis of tumours by specifically blocking vascular endothelial growth factor. We analysed the clinical features, risk factors and outcomes of RPLS in these two patients, and although no typical finding was identified on imaging examination, we found that inadequate blood pressure control was one of the risk factors leading to RPLS and that supportive treatment including intensive blood pressure control improved outcomes. Due to the increasing use of bevacizumab in colorectal cancer, clinicians should be aware of this potential complication.",
"affiliations": "Wei Wang, Li-Rong Zhao, Xiu-Qiang Lin, Fen Feng, Department of Gastroenterology, Foshan First People's Hospital, Foshan 520800, Guangdong Province, China.;Wei Wang, Li-Rong Zhao, Xiu-Qiang Lin, Fen Feng, Department of Gastroenterology, Foshan First People's Hospital, Foshan 520800, Guangdong Province, China.;Wei Wang, Li-Rong Zhao, Xiu-Qiang Lin, Fen Feng, Department of Gastroenterology, Foshan First People's Hospital, Foshan 520800, Guangdong Province, China.;Wei Wang, Li-Rong Zhao, Xiu-Qiang Lin, Fen Feng, Department of Gastroenterology, Foshan First People's Hospital, Foshan 520800, Guangdong Province, China.",
"authors": "Wang|Wei|W|;Zhao|Li-Rong|LR|;Lin|Xiu-Qiang|XQ|;Feng|Fen|F|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v20.i21.6691",
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"issn_linking": "1007-9327",
"issue": "20(21)",
"journal": "World journal of gastroenterology",
"keywords": "Bevacizumab; Colorectal cancer; Coma; Hypertension; Reversible posterior leukoencephalopathy syndrome",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D015746:Abdominal Pain; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D015179:Colorectal Neoplasms; D003128:Coma; D005260:Female; D006801:Humans; D006973:Hypertension; D007166:Immunosuppressive Agents; D008279:Magnetic Resonance Imaging; D008875:Middle Aged; D009362:Neoplasm Metastasis; D054038:Posterior Leukoencephalopathy Syndrome; D012307:Risk Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "100883448",
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"pages": "6691-7",
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"pmid": "24914397",
"pubdate": "2014-06-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19451611;184880;18470563;1637134;17030665;21768795;17145522;16510760;18290962;21111130;18235136;18421054;8559202;16177780;15307110",
"title": "Reversible posterior leukoencephalopathy syndrome induced by bevacizumab plus chemotherapy in colorectal cancer.",
"title_normalized": "reversible posterior leukoencephalopathy syndrome induced by bevacizumab plus chemotherapy in colorectal cancer"
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"companynumb": "CN-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-119143",
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"abstract": "Histoplasmosis is a systemic mycosis caused by the dimorphous fungus Histoplasma capsulatum (H. capsulatum). The fungus enters the body through the respiratory tract in the form of microconidia, which are transformed into intracellular yeast-like structures in the lungs before disseminating hematogenously. Primary infection is usually asymptomatic and self-resolving. Some patients develop severe disease with acute or chronic respiratory involvement. Immunosuppressed patients, mainly those with altered cellular immunity, may have disseminated disease with variable mucocutaneous involvement characterized by papules, nodules, gummas, or ulcers with a granulomatous base. We report the case of 3 HIV-negative patients infected by H capsulatum in whom diagnosis based on the skin lesions proved essential for early initiation of treatment.",
"affiliations": "Servicio de Dermatología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina. Electronic address: leidy.gomez@hospitalitaliano.org.ar.;Servicio de Dermatología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Dermatología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Anatomía Patológica, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Infectología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.;Servicio de Dermatología, Hospital Italiano de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.",
"authors": "Gómez-Santana|L V|LV|;Torre|A C|AC|;Hernández|B A|BA|;Volonteri|V I|VI|;Laura|B|B|;Luis-Galimberti|R|R|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.ad.2017.08.006",
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"issue": "109(4)",
"journal": "Actas dermo-sifiliograficas",
"keywords": "Cutaneous histoplasmosis; Disseminated histoplasmosis; Histoplasmosis cutánea; Histoplasmosis diseminada; Immunosuppression; Inmunosupresión; Itraconazol; Itraconazole",
"medline_ta": "Actas Dermosifiliogr (Engl Ed)",
"mesh_terms": "D000368:Aged; D042241:Early Diagnosis; D005148:Facial Dermatoses; D018023:HIV Seronegativity; D016027:Heart Transplantation; D006658:Histoplasma; D006660:Histoplasmosis; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D019226:Oral Ulcer; D011183:Postoperative Complications",
"nlm_unique_id": "101777537",
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"pmid": "29429549",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mucocutaneous Manifestations of Infection by Histoplasma capsulatum in HIV-Negative Immunosuppressed Patients.",
"title_normalized": "mucocutaneous manifestations of infection by histoplasma capsulatum in hiv negative immunosuppressed patients"
} | [
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"companynumb": "AR-ASTELLAS-2018US024761",
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"activesubstancename": "TACROLIMUS"
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"abstract": "A 54-year-old male was diagnosed with follicular lymphoma in September 2003. Despite multiple chemotherapies, including autologous hematopoietic stem cell transplantation (HSCT) with high-dose chemotherapy, the disease eventually relapsed. Additionally, bone marrow analysis revealed the co-emergence of therapy-related myelodysplastic syndrome (t-MDS) in February 2012. In March 2012, we performed related allogeneic HSCT for the treatment of both malignancies. This strategy was successful and the patient has remained free from both malignancies for 23 months. Allogeneic HSCT is a potent curative therapeutic option for both t-MDS and refractory follicular lymphoma.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan ; Division of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan ; Division of Hematology, Department of Medicine, Kyoto First Red Cross Hospital, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan ; Department of Hematology, Matsushita Memorial Hospital, Osaka, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Shimura|Yuji|Y|;Kuroda|Junya|J|;Sasaki|Nana|N|;Uchiyama|Hitoji|H|;Ohshiro|Muneo|M|;Matsumura|Yayoi|Y|;Nagoshi|Hisao|H|;Mizutani|Shinsuke|S|;Kobayashi|Tsutomu|T|;Matsumoto|Yosuke|Y|;Horiike|Shigeo|S|;Taniwaki|Masafumi|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000360905",
"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000360905cro-0007-0188Published online: March, 2014Reduced-Intensity Allogeneic Stem Cell Transplantation for Co-Emergence of Chemotherapy-Refractory Follicular Lymphoma and Therapy-Related Myelodysplastic Syndrome Shimura Yuji a*Kuroda Junya aSasaki Nana aUchiyama Hitoji abOhshiro Muneo acMatsumura Yayoi adNagoshi Hisao aMizutani Shinsuke aKobayashi Tsutomu aMatsumoto Yosuke aHoriike Shigeo aTaniwaki Masafumi aaDivision of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, JapanbDivision of Hematology, Department of Medicine, Kyoto Second Red Cross Hospital, Kyoto, JapancDivision of Hematology, Department of Medicine, Kyoto First Red Cross Hospital, Kyoto, JapandDepartment of Hematology, Matsushita Memorial Hospital, Osaka, Japan*Yuji Shimura, MD, PhD, Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyo-ku, Kyoto 602-8566 (Japan), E-Mail yshimura@koto.kpu-m.ac.jpJan-Apr 2014 13 3 2014 13 3 2014 7 1 188 194 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.A 54-year-old male was diagnosed with follicular lymphoma in September 2003. Despite multiple chemotherapies, including autologous hematopoietic stem cell transplantation (HSCT) with high-dose chemotherapy, the disease eventually relapsed. Additionally, bone marrow analysis revealed the co-emergence of therapy-related myelodysplastic syndrome (t-MDS) in February 2012. In March 2012, we performed related allogeneic HSCT for the treatment of both malignancies. This strategy was successful and the patient has remained free from both malignancies for 23 months. Allogeneic HSCT is a potent curative therapeutic option for both t-MDS and refractory follicular lymphoma.\n\nKey words\nTherapy-related myelodysplastic syndromeFollicular lymphomaAllogeneic transplantation\n==== Body\nIntroduction\nTherapy-related myelodysplastic syndromes and acute myelogenous leukemia (t-MDS/AML) constitute the most serious late-onset complications caused by chemotherapy and/or radiotherapy. Recent advances in anticancer chemotherapy using various classical and novel anticancer agents have led to a higher rate of treatment success and longer survival for patients with cancerous diseases, including hematologic malignancies, so that the number of the so-called cancer survivors has increased during the past decade. This was also accompanied by an increase in the number of patients suffering from t-MDS/AML [1]. Because of chemorefractoriness due to frequent poor-risk cytogenetics and therapy-related organ damage caused by previous use of cytotoxic therapies, the treatment outcome for t-MDS/AML has remained dismal. The median survival for t-MDS/AML has been reported to be 6–8 months when treated by conventional chemotherapy, which is significantly shorter than that for de novo MDS and AML [2]. While allogeneic hematopoietic stem cell transplantation (HSCT) remains the only curative therapeutic strategy for t-MDA/AML, this strategy cannot be used for all patients due to the high frequency of therapy-related mortality [3, 4]. In particular, for patients exhibiting co-emergence of relapsed disease and t-MDS/AML, the life expectancy has been unfavorable due to the lack of a promising therapeutic modality [4].\n\nThe therapeutic outcome of non-Hodgkin lymphomas (NHLs) has been greatly improved over the past two decades as a result of the development of immunochemotherapy. While these advances in therapeutic strategies have greatly enhanced the cure rate for aggressive NHLs, such as diffuse large B-cell lymphoma, it remains difficult to achieve a cure for indolent lymphomas, such as follicular lymphoma (FL), even though survival has been prolonged. The repeated use of various kinds of immunochemotherapies over a long period has been generally required for patients with FL. The increase in anticancer agents and the longer survival period are associated with a higher occurrence rate of t-MDS/AML in FL [5]. Therefore, current and future topics regarding the treatment of FL include the therapeutic strategy for refractory/relapsed disease complicated by t-MDS/AML.\n\nIn this report, we describe the case of a patient with FL who relapsed after a series of treatments with a variety of chemotherapeutic agents. In addition, his condition was eventually complicated by the co-emergence of t-MDS.\n\nCase Report\nA 54-year-old male was admitted to hospital in September 2003 with systemic lymphadenopathy, fatigue and night sweating. Computed tomography scans confirmed cervical, axillary, mediastinal, para-aortic, mesenteric and inguinal lymphadenopathies. Laboratory tests showed an elevated soluble interleukin-2 receptor (14,800 U/ml) and elevated WBC (113.3 × 109/l), comprised of 89% of abnormal lymphoid cells. The bone marrow (BM) was also massively invaded by abnormal lymphoid cells. Biopsy of the cervical lymph node disclosed the diagnosis of FL grade 3A. In immunohistochemical examinations, lymphoma cells were positive for CD10, Bcl-2, and CD20, and t(14;18)(q32;q21) translocation was detected by fluorescence in situ hybridization. Eight cycles of R-CHOP consisting of rituximab, cyclophosphamide, adriamycin, vincristine and prednisolone and subsequent maintenance therapy with rituximab for 8 months induced complete remission (CR), but the disease relapsed 8 months after the cessation of rituximab. Salvage chemotherapy consisting of rituximab and fludarabine induced a partial response, but the disease relapsed again after 14 months. For the second salvage therapy, the patient was enrolled in a clinical trial for treatment with everolimus, a new inhibitor of mammalian target of rapamycin. The drug induced CR, which sustained for 23 months, but lymphoma eventually relapsed (fig. 1a). A second biopsy of the cervical lymph node confirmed the diagnosis of relapsed FL without the evidence of transformation into a more aggressive lymphoma. Then, the patient underwent intensified chemotherapy using cyclophosphamide, high-dose Ara-C, dexamethasone, and etoposide (CHASE), radioimmunotherapy with 90Y ibritumomab tiuxetan and myeloablative chemotherapy with melphalan, cyclophosphamide, etoposide, and dexamethasone (LEED) supported by autologous HSCT. The patient achieved CR, which was confirmed by 18F-FDG-PET (PET) examination and BM analysis (no invasion and normal karyotype). However, 7 months after the transplantation, PET examination revealed generalized lymphadenopathy and uptake in the bilateral femoral nerve (suspected to be neurolymphomatosis). BM infiltration with abnormal lymphoid cells was also identified.\n\nAt this time, 81 months from the initial diagnosis of FL, we planned allogeneic HSCT using reduced-intensity conditioning (RIC). To reduce the tumor burden prior to RIC-HSCT, we administered three cycles of salvage therapy, comprised of rituximab and bendamustine, after which only minor cervical lymphadenopathy was identifiable by PET examination. However, myelosuppression accompanied by grade 4 neutropenia lasted for several weeks after the last dose of bendamustine, and BM analysis revealed hypocellularity with an increase in myeloblasts (5.2% of all nucleated cells) and multilineage dysplastic changes, which was documented in this case for the first time (fig. 2a). Chromosomal analysis revealed the presence of complex karyotypic abnormalities, including chromosome 7 deletion (fig. 2b). From these results, the diagnosis of t-MDS, refractory anemia with excess blasts-1, was made [6]. Regarding the MDS International Prognostic Scoring System, the patient was classified as intermediate-2 risk category [7]. Furthermore, the patient's condition was complicated by cytomegalovirus retinitis and required antiviral therapy for 4 weeks.\n\nFor simultaneous treatment of both chemotherapy-resistant FL and t-MDS, we performed RIC-HSCT with peripheral hematopoietic stem cells from his HLA-matched sibling (sister) 4 weeks after the diagnosis of t-MDS. At this time, the FL remained in partial remission. The conditioning regimen consisted of fludarabine (25 mg/m2 × 5 days), melphalan (80 mg/m2 × 1 day) and 4 Gy of total body irradiation (TBI). Cyclosporine A and short-term methotrexate were utilized as prophylaxis against graft-versus-host disease (GVHD). Neutrophil engraftment was confirmed on day 14 and platelet engraftment on day 22. There was no acute GVHD, and infectious complications, such as febrile neutropenia, Clostridium difficile-associated colitis, and reactivated cytomegalovirus retinitis, were treated successfully with antibiotics and antiviral agents. BM analysis on day 30 showed complete donor chimerism with a normal karyotype and without any myelodysplastic changes. The patient was discharged on day 56 and his condition was later complicated by chronic GVHD of the hepatic type that was alleviated successfully by re-dosing with cyclosporine A. PET examination on day 80 also showed no abnormal uptake (fig. 1b). Since then, CR of both FL and t-MDS has been maintained for 672 days at the timing of writing.\n\nDiscussion\nAccording to the WHO classification, t-MDS is classified as one of the therapy-related myeloid neoplasms (t-MN) that can occur subsequent to exposure to cytotoxic agents or irradiation [6]. The latency period from first exposure to the development of t-MN varies by the dose intensity and the type of cytotoxic agents. For example, alkylating agents or radiation therapies typically cause t-MDS 5–7 years after the exposure, and often manifest as complex chromosomal abnormalities, including monosomy 5 or 7. Topoisomerase II inhibitors are other leukemogenic agents that are potent inducers of t-AML, with 11q23 or 21q22 abnormalities occurring months to 3 years after the use. However, because most patients receive multiple drugs within the course of several years, it is difficult to determine the drug responsible for leukemogenesis in individuals [1, 6].\n\nFludarabine is a purine analog (antimetabolite) that is highly effective in the treatment of indolent malignant lymphoma or chronic lymphocytic leukemia. Fludarabine impairs DNA repair and induces cytopenia (lymphopenia), which can account for the increase of the incidence of secondary malignancy. Indeed, treatment with fludarabine, especially in combination with another cytotoxic drug, has been reported to increase the risk of t-MN [8]. High-dose chemotherapy supported by autologous HSCT may also contribute to the increased occurrence of t-MN [9]. In our case, various alkylating agents, topoisomerase II inhibitors and fludarabine were administered and high-dose chemotherapy was also administered within a short period. Thus, it is impossible to determine the drug or regimen responsible for the development of t-MDS.\n\nBendamustine is one of the promising cytotoxic agents among the alkylating agents that has been widely used for the treatment of indolent lymphoma. The drug has both alkylating and antimetabolite properties, and it has demonstrated significant efficacy for patients with indolent lymphoma [10]. Considering its mechanisms of action, bendamustine could be a more powerful inducer for the emergence of t-MN. However, there is no evidence for any relationship between administration of this drug and the development of leukemogenesis. We administered bendamustine 8 months after autologous HSCT, and the possible association between bendamustine and t-MDS could not be refuted in our case.\n\nThe therapeutic options for t-MDS/AML have been limited. Recently, the hypomethylating agents 5-azacitidine and decitabine have demonstrated equivalent efficacy for t-MDS and de novo MDS in terms of hematologic responses and have improved the overall survival for t-MDS. However, the overall survival for t-MDS still remains shorter than that for de novo MDS because of the poor preexisting risk factor, i.e., poor performance status, complex karyotypic abnormalities, or chemoresistance [11]. Thus, allogeneic RIC-HSCT is a potential curative treatment option. t-MDS patients who have received more than two chemotherapeutic regimens or have undergone allograft more than 6 months after the diagnosis showed a significantly higher nonrelapse mortality [3, 4]. Thus, an earlier decision for the choice of therapies with allogeneic HSCT is necessary, once the diagnosis of t-MDS is made.\n\nFL is the most common indolent NHL of the germinal center B cells. Progress in immunochemotherapy using the anti-CD20 antibody rituximab combined with conventional and/or new cytotoxic agents, including bendamustine or fludarabine, has produced significant improvements in the response rate and survival [12, 13, 14]. However, most patients with FL eventually relapse and require subsequent therapies. The use of autologous or allogeneic HSCT for FL has not proven to have any significant survival advantage over chemotherapy alone [12]. However, for selected patients, especially those who relapse shortly after immunochemotherapy or those with histologic transformation to a more aggressive lymphoma, high-dose chemotherapy followed by autologous HSCT has prolonged the progression-free survival in cases of chemosensitive relapse [15]. Allogeneic HSCT holds promise for the cure of advanced stage FL, but has been associated with relatively high treatment-related mortality. Therefore, the indication of FL for allogeneic HSCT is further restricted and is generally considered at relapse after autologous HSCT. As a preparative regimen for allogeneic transplantation, RIC has been increasing because of its feasibility for elderly or heavily pretreated patients. Through retrospective analysis, prolonged overall survival and lower treatment-related mortality have been reported with RIC for allogeneic HSCT. Thomson et al. [16] reported the outcome of related or unrelated allogeneic HSCT for FL with a conditioning regimen of fludarabine, melphalan, and alemtuzumab. With a median follow-up of 43 months, nonrelapse mortality and progression-free survival at 4 years were 15 and 76%, respectively.\n\nCombing these, in our case with concurrent t-MDS and refractory FL, allogeneic HSCT was the only curative therapeutic strategy, despite the fact that the clinical outcome of allogeneic transplantation for patients with concurrent MDS and lymphoid malignancy remains quite unfavorable [17]. In our case, the less toxic RIC-HSCT from an HLA-matched sibling donor, the effective disease control of FL by bendamustine just before HSCT, and the short time between the diagnosis of t-MDS and allo-HSCT might all contribute to the success of the treatment.\n\nSince there is no established common conditioning regimen that is effective for both malignant lymphoma and MDS, we used the RIC regimen, consisting of fludarabine, melphalan, and low-dose TBI, in consideration of the superior clinical results from Thomson et al. [16] and Yuji et al. [18]. In the previous reports and our experience, this regimen is most likely to be feasible and safe, even for the elderly or those who have previously received multiple chemotherapies, including high-dose chemotherapy, when efficacy sufficient to eradicate residual disease is warranted. The addition of TBI in the conditioning regimen might contribute to lowering the relapse rate [19].\n\nIn summary, t-MN is impairing instead of improving the clinical outcome with the advance of therapies for hematological malignancies. Therefore, the number of patients simultaneously suffering from t-MN and lymphoid malignancy will inevitably increase. Intervention with allogeneic HSCT should be considered as early as possible in such situations.\n\nFig. 1 18F-FDG-PET images at relapse (a) and 507 days after RIC-HSCT (b). Multiple indications of abnormal 18F-FDG uptake (a) disappeared after RIC-HSCT.\n\nFig. 2 Wright-Giemsa staining (a) and cytogenetic analysis (G banding) (b) of BM cells at the onset of t-MDS. Typical dysplastic hematopoietic cells, i.e., hypogranular neutrophils (arrowheads) and a micromegakaryocyte (arrow) were identified (a), and complex cytogenetic alterations, including chromosome 7 deletion, were detected (b).\n==== Refs\nReferences\n1 Leone G Fianchi L Voso MT Therapy-related myeloid neoplasms Curr Opin Oncol 2011 23 672 680 21918440 \n2 Smith SM Le Beau MM Huo D Karrison T Sobecks RM Anastasi J Vardiman JW Rowley JD Larson RA Clinical-cytogenetic associations in 306 patients with therapy-related myelodysplasia and myeloid leukemia: the University of Chicago series Blood 2003 102 43 52 12623843 \n3 Spina F Alessandrino PE Milani R Bonifazi F Bernardi M Luksch R Fagioli F Formica C Farina L Allogeneic stem cell transplantation in therapy-related acute myeloid leukemia and myelodysplastic syndromes: impact of patient characteristics and timing of transplant Leuk Lymphoma 2012 53 96 102 21740299 \n4 Litzow MR Tarima S Pérez WS Bolwell BJ Cairo MS Camitta BM Cutler CS de Lima M DiPersio JF Gale RP Keating A Lazarus HM Luger S Marks DI Maziarz RT McCarthy PL Pasquini MC Phillips GL Rizzo JD Sierra J Tallman MS Weisdorf DJ Allogeneic transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia Blood 2010 115 1850 1857 20032503 \n5 Morton LM Dores GM Tucker MA Kim CJ Onel K Gilbert ES Fraumeni JF Curtis RE Evolving risk of therapy-related acute myeloid leukemia following cancer chemotherapy among adults in the United States, 1975–2008 Blood 2013 121 2996 3004 23412096 \n6 Vardiman JW Thiele J Arber DA Brunning RD Borowitz MJ Porwit A Harris NL Le Beau MM Hellstrom-Lindberg E Tefferi A Bloomfield CD The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes Blood 2009 114 937 951 19357394 \n7 Greenberg P Cox C LeBeau MM Fenaux P Morel P Sanz G Sanz M Vallespi T Hamblin T Oscier D Ohyashiki K Toyama K Aul C Mufti G Bennett J International scoring system for evaluating prognosis in myelodysplastic syndromes Blood 1997 89 2079 2088 9058730 \n8 Carney DA Westerman DA Tam CS Milner A Prince HM Kenealy M Wolf M Januszewicz EH Ritchie D Came N Seymour JF Therapy-related myelodysplastic syndrome and acute myeloid leukemia following fludarabine combination chemotherapy Leukemia 2010 24 2056 2062 20962860 \n9 Tarella C Passera R Magni M Benedetti F Rossi A Gueli A Patti C Parvis G Ciceri F Gallamini A Cortelazzo S Zoli V Corradini P Carobbio A Mulé A Bosa M Barbui A Di Nicola M Sorio M Caracciolo D Gianni AM Rambaldi A Risk factors for the development of secondary malignancy after high-dose chemotherapy and autograft, with or without rituximab: a 20-year retrospective follow-up study in patients with lymphoma J Clin Oncol 2011 29 814 824 21189387 \n10 Cheson BD Rummel MJ Bendamustine: rebirth of an old drug J Clin Oncol 2009 27 1492 1501 19224851 \n11 Duong VH Lancet JE Alrawi E Al-Ali NH Perkins J Field T Epling-Burnette PK Zhang L List AF Komrokji RS Outcome of azacitidine treatment in patients with therapy-related myeloid neoplasms with assessment of prognostic risk stratification models Leuk Res 2013 37 510 515 23332452 \n12 Freedman A Follicular lymphoma: 2012 update on diagnosis and management Am J Hematol 2012 87 988 995 23001911 \n13 Rummel MJ Niederle N Maschmeyer G Banat GA Grünhagen von U Losem C Kofahl-Krause D Heil G Welslau M Balser C Kaiser U Weidmann E Dürk H Ballo H Stauch M Roller F Barth J Hoelzer D Hinke A Brugger W Study group indolent Lymphomas (StiL) Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial Lancet 2013 381 1203 1210 23433739 \n14 Tobinai K Ishizawa K Ogura M Itoh K Morishima Y Ando K Taniwaki M Watanabe T Yamamoto J Uchida T Nakata M Terauchi T Nawano S Matsusako M Hayashi M Hotta T Phase II study of oral fludarabine in combination with rituximab for relapsed indolent B-cell non-Hodgkin lymphoma Cancer Sci 2009 100 1951 1956 19594547 \n15 Montoto S Corradini P Dreyling M Ghielmini M Kimby E López-Guillermo A Mackinnon S Marcus RE Salles G Schouten HC Sureda A Dreger P Indications for hematopoietic stem cell transplantation in patients with follicular lymphoma: a consensus project of the EBMT-lymphoma working party Haematologica 2013 98 1014 1021 23813647 \n16 Thomson KJ Morris EC Milligan D Parker AN Hunter AE Cook G Bloor AJC Clark F Kazmi M Linch DC Chakraverty R Peggs KS Mackinnon S T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma J Clin Oncol 2010 28 3695 3700 20606089 \n17 Zimmerman Z Scott BL Gopal AK Sandmaier BM Maloney DG Deeg HJ Allogeneic hematopoietic cell transplantation in patients with myelodysplastic syndrome and concurrent lymphoid malignancy Bone Marrow Transplant 2012 47 804 809 21909142 \n18 Yuji K Miyakoshi S Kato D Miura Y Myojo T Murashige N Kishi Y Kobayashi K Kusumi E Narimatsu H Hamaki T Matsumura T Kami M Fukuda T Masuo S Masuoka K Wake A Ueyama J Yoneyama A Miyamoto K Nagoshi H Matsuzaki M Morinaga S Muto Y Takeue Y Taniguchi S Reduced-intensity unrelated cord blood transplantation for patients with advanced malignant lymphoma Biol Blood Marrow Transplant 2005 11 314 318 15812397 \n19 Russell JA Irish W Balogh A Chaudhry MA Savoie ML Turner AR Larratt L Storek J Bahlis NJ Brown CB Quinlan D Geddes M Zacarias N Daly A Duggan P Stewart DA The addition of 400 cGY total body irradiation to a regimen incorporating once-daily intravenous busulfan, fludarabine, and antithymocyte globulin reduces relapse without affecting nonrelapse mortality in acute myelogenous leukemia Biol Blood Marrow Transplant 2010 16 509 514 19948235\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "7(1)",
"journal": "Case reports in oncology",
"keywords": "Allogeneic transplantation; Follicular lymphoma; Therapy-related myelodysplastic syndrome",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "188-94",
"pmc": null,
"pmid": "24748869",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports",
"references": "19948235;19224851;15812397;21189387;12623843;21909142;20962860;21740299;23433739;21918440;9058730;20606089;23332452;20032503;23412096;23001911;19357394;23813647;19594547",
"title": "Reduced-intensity allogeneic stem cell transplantation for co-emergence of chemotherapy-refractory follicular lymphoma and therapy-related myelodysplastic syndrome.",
"title_normalized": "reduced intensity allogeneic stem cell transplantation for co emergence of chemotherapy refractory follicular lymphoma and therapy related myelodysplastic syndrome"
} | [
{
"companynumb": "JP-TEVA-551296ISR",
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"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": null,
"d... |
{
"abstract": "Suicidal suffocation by forced oxygen depletion (environmental hypoxia) with carbon dioxide (CO2) and with propane is discussed in two cases. No toxicologic proof was available with the former and circumstantial evidence weighed heavily. The latter case demonstrated inhaled propane by an on-scene transthoracic aspirate; all other toxicology specimens, including brain, liver, blood, kidney, fat, and vitreous, did not contain hydrocarbons. This second fatality was complicated by multi-agent overdose, including diphenhydramine, fluoxetine (Prozac), and nordiazepam. The designation of these deaths as due to oxygen depletion involved careful scrutiny of the autopsy, toxicologic, and scene findings. Complete analysis of all factors surrounding these rarely encountered suffocation deaths is stressed.",
"affiliations": "Charleston County Medical Examiner's Office, South Carolina.",
"authors": "Downs|J C|JC|;Conradi|S E|SE|;Nichols|C A|CA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/00000433-199409000-00008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0195-7910",
"issue": "15(3)",
"journal": "The American journal of forensic medicine and pathology",
"keywords": null,
"medline_ta": "Am J Forensic Med Pathol",
"mesh_terms": "D000328:Adult; D001237:Asphyxia; D006801:Humans; D000860:Hypoxia; D008297:Male; D013405:Suicide",
"nlm_unique_id": "8108948",
"other_id": null,
"pages": "216-23",
"pmc": null,
"pmid": "7825552",
"pubdate": "1994-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Suicide by environmental hypoxia (forced depletion of oxygen).",
"title_normalized": "suicide by environmental hypoxia forced depletion of oxygen"
} | [
{
"companynumb": "US-SA-2020SA361977",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "NORDAZEPAM"
},
"drugadditional": null,
"dr... |
{
"abstract": "Myeloablative treatment and peripheral blood progenitor cell (PBPC) transplantation are increasingly used for lymphomas and leukemias. We have sought to optimize conditions for priming, collection, and engraftment of the leukapheresis product. Fifty-four consecutive adult patients were eligible, 31 with high-grade non-Hodgkin's lymphoma of poor prognosis, 12 with Hodgkin's disease in chemosensitive relapse, and 11 with poor prognosis acute lymphoblastic leukemia. Filgrastim was administered after routine chemotherapy with VAPEC-B or HiCCOM to mobilize PBPC. A rapidly increasing white blood cell count was used to predict the time of peak PBPC release and plan leukapheresis. Forty-five patients underwent leukapheresis. A median of 14 L of blood was processed at a single apheresis. A median of 2.4 x 10(8)/kg mononuclear cells (MNCs), 1.04 x 10(6)/kg granulocyte-macrophage colony-forming cells (GM-CFCs), and 10.6 x 10(6)/kg CD34+ cells were obtained. Slightly fewer MNCs were obtained from the heavily pretreated Hodgkin's disease group. There were no other significant differences in the size or composition of the leukapheresis harvest in the three patient groups. Forty patients underwent high-dose therapy and PBPC transplantation. Filgrastim was administered by daily subcutaneous injection until the absolute neutrophil count was > or = 1 x 10(9)/L for 2 consecutive days. Rapid and sustained hematopoietic engraftment occurred in all patients. The median time to achieve a neutrophil count > or = 0.5 x 10(9)/L was 9 days (range, 8 to 16 days); to achieve a platelet count > or = 20 x 10(9)/L was 10 days (range, 6 to 88 days); and to achieve a platelet count > or = 50 x 10(9)/L was 15.5 days (range, 10 to 100 days). Neutrophil recovery was faster than that of a historical control group treated with autologous bone marrow transplantation and filgrastim, but platelet recovery times were halved in the PBPC group. There was no secondary engraftment failure. Requirements for blood and platelet transfusions, antibiotic use, and parenteral nutrition were similar in the three patient groups. The median number of days in the hospital was 13 (range, 10 to 55) in the PBPC patients, compared with 19 (range, 14 to 51) in the historical controls. Leukapheresis yields (MNC, GM-CFC, and CD34+ cell numbers) were not useful for predicting the times to engraftment. We have shown that sufficient PBPC for transplantation can be obtained at a single leukapheresis after mobilization with routine chemotherapy and filgrastim in patients with non-Hodgkin's lymphoma, Hodgkin's disease, and acute lymphoblastic leukemia, even those heavily pretreated.(ABSTRACT TRUNCATED AT 400 WORDS)",
"affiliations": "CRC Department of Medical Oncology, Christie Hospital NHS Trust, Manchester, UK.",
"authors": "Pettengell|R|R|;Morgenstern|G R|GR|;Woll|P J|PJ|;Chang|J|J|;Rowlands|M|M|;Young|R|R|;Radford|J A|JA|;Scarffe|J H|JH|;Testa|N G|NG|;Crowther|D|D|",
"chemical_list": "D003561:Cytarabine; D001761:Bleomycin; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D008727:Methotrexate",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "82(12)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001761:Bleomycin; D003114:Colony-Forming Units Assay; D003131:Combined Modality Therapy; D003520:Cyclophosphamide; D003561:Cytarabine; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D007902:Length of Stay; D007937:Leukapheresis; D008223:Lymphoma; D008228:Lymphoma, Non-Hodgkin; D008297:Male; D008727:Methotrexate; D008875:Middle Aged; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D014750:Vincristine",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3770-7",
"pmc": null,
"pmid": "7505124",
"pubdate": "1993-12-15",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Peripheral blood progenitor cell transplantation in lymphoma and leukemia using a single apheresis.",
"title_normalized": "peripheral blood progenitor cell transplantation in lymphoma and leukemia using a single apheresis"
} | [
{
"companynumb": "GB-AMGEN-GBRSP2020201902",
"fulfillexpeditecriteria": "2",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": null,... |
{
"abstract": "BACKGROUND\nTreatment options for drug-resistant tuberculosis (DR-TB) are limited. Linezolid has been successfully used to treat DR-TB in adults, but there are few case reports of its use in children for TB. The reported rate of adverse events in adults is high.\n\n\nMETHODS\nWe conducted a retrospective review of children with DR-TB treated with linezolid-containing regimens from February 2007 to March 2012 at two South African hospitals.\n\n\nRESULTS\nSeven children (three human immunodeficiency virus [HIV] infected) received a linezolid-containing regimen. All had culture-confirmed DR-TB; five had previously failed second-line anti-tuberculosis treatment. Four children were cured and three were still receiving anti-tuberculosis treatment, but had culture converted. None of the non-HIV-infected children experienced adverse events while receiving linezolid. Three HIV-infected children had adverse events, one of which was life-threatening; linezolid was permanently discontinued in this case. Adverse events included lactic acidosis (n = 1), pancreatitis (n = 2), peripheral neuropathy (n = 1) and asymptomatic bone marrow hypoplasia (n = 1).\n\n\nCONCLUSIONS\nLinezolid-containing regimens can be effective in treating children with DR-TB even after failing second-line treatment. Adverse events should be monitored, especially in combination with medications that have similar adverse effects. Linezolid remains costly, and a reduced dosage and duration may result in fewer adverse events and lower cost.",
"affiliations": "Desmond Tutu TB Centre, Department of Paediatrics and Child Health, Faculty of Health Sciences, Stellenbosch University, Cape Town, Tygerberg, South Africa. pcrose@sun.ac.za",
"authors": "Rose|P C|PC|;Hallbauer|U M|UM|;Seddon|J A|JA|;Hesseling|A C|AC|;Schaaf|H S|HS|",
"chemical_list": "D000081:Acetamides; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "France",
"delete": false,
"doi": "10.5588/ijtld.12.0322",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1027-3719",
"issue": "16(12)",
"journal": "The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease",
"keywords": null,
"medline_ta": "Int J Tuberc Lung Dis",
"mesh_terms": "D000081:Acetamides; D000293:Adolescent; D000367:Age Factors; D019380:Anti-HIV Agents; D000995:Antitubercular Agents; D002648:Child; D002675:Child, Preschool; D060085:Coinfection; D017046:Cost Savings; D016527:Drug Costs; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D054908:Extensively Drug-Resistant Tuberculosis; D005260:Female; D015658:HIV Infections; D006801:Humans; D007223:Infant; D000069349:Linezolid; D008297:Male; D009169:Mycobacterium tuberculosis; D023303:Oxazolidinones; D012189:Retrospective Studies; D013019:South Africa; D013183:Sputum; D013997:Time Factors; D016896:Treatment Outcome; D018088:Tuberculosis, Multidrug-Resistant; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9706389",
"other_id": null,
"pages": "1588-93",
"pmc": null,
"pmid": "23032215",
"pubdate": "2012-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children.",
"title_normalized": "linezolid containing regimens for the treatment of drug resistant tuberculosis in south african children"
} | [
{
"companynumb": "ZA-ALKEM LABORATORIES LIMITED-ZA-ALKEM-2018-03718",
"fulfillexpeditecriteria": "1",
"occurcountry": "ZA",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ISONIAZID"
},
"drugad... |
{
"abstract": "OBJECTIVE\nSince the introduction of combination antiretroviral therapy (cART) as the standard of care for HIV disease, there has been a precipitous decline in the death rate due to HIV/ AIDS. The purpose of this study was to report the prevalence of metabolic syndrome in HIV infected patients.\n\n\nMETHODS\nRetrospective, cross-sectional, observational study of 259 patients with HIV infection treated with cART from an urban community hospital. Metabolic syndrome prevalence was defined using the International Diabetes Federation (IDF) and the U.S. National Cholesterol Education Program Adult Treatment Panel III (ATP III) criteria. Study patients were included regardless of the duration of cART.\n\n\nRESULTS\nThe prevalence of metabolic syndrome was 27% using IDF criteria and 26% using ATP III criteria. Logistic regression analysis found an association between treatment with the protease inhibitor darunavir and metabolic syndrome. (OR 3.32 with 95% confidence interval between 1.54 and 7.15).\n\n\nCONCLUSIONS\nThere is a high prevalence of metabolic syndrome and obesity in HIV patients treated with cART, especially those taking the protease inhibitor darunavir.",
"affiliations": null,
"authors": "Lombo|Bernardo|B|;Alkhalil|Imran|I|;Golden|Marjorie P|MP|;Fotjadhi|Irma|I|;Ravi|Sreedhar|S|;Virata|Michael|M|;Lievano|Marta|M|;Diez|Jose|J|;Ghantous|Andre|A|;Donohue|Thomas|T|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0010-6178",
"issue": "79(5)",
"journal": "Connecticut medicine",
"keywords": null,
"medline_ta": "Conn Med",
"mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D015897:Comorbidity; D003430:Cross-Sectional Studies; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D024821:Metabolic Syndrome; D008875:Middle Aged; D009765:Obesity; D015995:Prevalence; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0372745",
"other_id": null,
"pages": "277-81",
"pmc": null,
"pmid": "26245015",
"pubdate": "2015-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Prevalence of Metabolic Syndrome in Patients with HIV in the Era of Highly Active Antiretroviral Therapy.",
"title_normalized": "prevalence of metabolic syndrome in patients with hiv in the era of highly active antiretroviral therapy"
} | [
{
"companynumb": "US-JNJFOC-20140517453",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DARUNAVIR"
},
"drugadditional": null,
"... |
{
"abstract": "BACKGROUND\nThe outcome for patients with relapsed and refractory pediatric sarcomas remains dismal. Novel agents are needed to improve overall survival in these patients.\n\n\nMETHODS\nWe present 3 patients with relapsed/refractory sarcomas treated with gemcitabine, docetaxel, and bevacizumab in 3-week cycles. The combination was well tolerated with minimal toxicity. Two patients had a partial response and the third patient had stable disease for >6 months.\n\n\nCONCLUSIONS\nThese results are limited by small patient numbers but this strategy should be evaluated in prospective clinical trials.",
"affiliations": "Division of Hematology, Phoenix Children's Hospital, Phoenix, AZ 85016, USA. phingorani@phoenixchildrens.com",
"authors": "Hingorani|Pooja|P|;Eshun|Francis|F|;White-Collins|Andrea|A|;Watanabe|Masayo|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A; D003841:Deoxycytidine; D000077143:Docetaxel; D000068258:Bevacizumab; C056507:gemcitabine",
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0b013e31826b9d25",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "34(7)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D003841:Deoxycytidine; D000077143:Docetaxel; D005260:Female; D006801:Humans; D008297:Male; D012509:Sarcoma; D043823:Taxoids; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "524-7",
"pmc": null,
"pmid": "23007339",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Gemcitabine, docetaxel, and bevacizumab in relapsed and refractory pediatric sarcomas.",
"title_normalized": "gemcitabine docetaxel and bevacizumab in relapsed and refractory pediatric sarcomas"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-13SUNGE05P",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
"drugad... |
{
"abstract": "Giant cell hepatitis (GCH) is a rare diagnosis in adults that is found in 0.25% of liver biopsies. GCH has been associated with multiple causes including drugs (6-mercaptopurine, methotrexate), toxins, viruses and autoimmune. GCH has been described in few patients with chronic lymphocytic leukemia (CLL). Here we describe three patients diagnosed with GCH thought to be related to underlying CLL and its management. All of our patients were treated with a combination of immunosuppression as well as CLL-directed therapy to address CLL and concomitant liver disease. GCH is a rare manifestation of active CLL and should be ruled out with prompt liver biopsy in patients with CLL with persistent transaminitis without another attributable cause. Prompt treatment of GCH with immunosuppression is required to prevent long-term liver toxicity. If transaminitis does not improve with immunosuppression alone, the addition of CLL directed therapy should be considered in patients who carry this diagnosis to prevent long-term liver toxicity.",
"affiliations": "a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;b Department of Pathology , University of Pennsylvania , Philadelphia , PA , USA.;a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;a Lymphoma Program, Abramson Cancer Center , University of Pennsylvania , Philadelphia , PA , USA.;c CLL Program, Leukemia Service , Memorial Sloan- Kettering Cancer Center , New York , NY , USA.",
"authors": "Rhodes|Joanna M|JM|0000-0002-5068-9040;Schuster|Stephen J|SJ|;Furth|Emma E|EE|;Kennard|Kaitlin|K|;Nasta|Sunita Dwivedy|SD|;Svoboda|Jakub|J|;Porter|David L|DL|;Mato|Anthony R|AR|",
"chemical_list": "D015415:Biomarkers; D016756:Immunoglobulins, Intravenous",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2019.1598763",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "20(8)",
"journal": "Cancer biology & therapy",
"keywords": "Chronic lymphocytic leukemia; autoimmune hepatitis; giant cell hepatitis; ibrutinib; transaminitis",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D001706:Biopsy; D005260:Female; D006432:Hemochromatosis; D006801:Humans; D016756:Immunoglobulins, Intravenous; D007150:Immunohistochemistry; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008111:Liver Function Tests; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "1136-1140",
"pmc": null,
"pmid": "31091174",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "10710079;12702915;18682418;18687640;1988831;20871223;21043007;21119537;22812631;22892492;25201797;26147671;26377300;30248210;8878001;9762216;9772058",
"title": "Management of giant cell hepatitis associated with chronic lymphocytic leukemia - a case series and review of the literature.",
"title_normalized": "management of giant cell hepatitis associated with chronic lymphocytic leukemia a case series and review of the literature"
} | [
{
"companynumb": "US-MEDAC PHARMA, INC.-2068039",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "1",
... |
{
"abstract": "OBJECTIVE\nIdentifying the nerve of origin in head and neck schwannomas is a diagnostic challenge. Surgical management leads to a risk of permanent deficit. Accurate identification of the nerve would improve operative planning and patient counselling.\n\n\nMETHODS\nThree patients with head and neck schwannomas underwent a diagnostic procedure hypothesised to identify the nerve of origin. The masses were infiltrated with 1 per cent lidocaine solution, and the patients were observed for neurological deficits.\n\n\nRESULTS\nAll three patients experienced temporary loss of nerve function after lidocaine injection. Facial nerve palsy, voice changes with documented unilateral same-side vocal fold paralysis, and numbness in the distribution of the maxillary nerve (V2), respectively, led to a likely identification of the nerve of origin.\n\n\nCONCLUSIONS\nInjection of lidocaine into a schwannoma is a safe, in-office procedure that produces a temporary nerve deficit, which may enable accurate identification of the nerve of origin of a schwannoma. Identifying the nerve of origin enhances operative planning and patient counselling.",
"affiliations": "Department of Otolaryngology - Head and Neck Surgery,University of Nevada Las Vegas School of Medicine,USA.;Department of Otolaryngology - Head and Neck Surgery,University of Nevada Las Vegas School of Medicine,USA.;Department of Otolaryngology - Head and Neck Surgery,University of Nevada Las Vegas School of Medicine,USA.;Department of Otolaryngology - Head and Neck Surgery,University of Nevada Las Vegas School of Medicine,USA.",
"authors": "Ching|H H|HH|;Spinner|A G|AG|;Reeve|N H|NH|;Wang|R C|RC|",
"chemical_list": "D000779:Anesthetics, Local; D008012:Lidocaine",
"country": "England",
"delete": false,
"doi": "10.1017/S0022215118000567",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-2151",
"issue": "132(5)",
"journal": "The Journal of laryngology and otology",
"keywords": "Head; Neck; Neurilemmoma; Schwannoma",
"medline_ta": "J Laryngol Otol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000779:Anesthetics, Local; D003390:Cranial Nerve Neoplasms; D003391:Cranial Nerves; D003943:Diagnostic Techniques, Neurological; D005260:Female; D006258:Head and Neck Neoplasms; D006801:Humans; D008012:Lidocaine; D008297:Male; D008442:Maxillary Nerve; D008875:Middle Aged; D009442:Neurilemmoma; D014826:Vocal Cord Paralysis; D014831:Voice",
"nlm_unique_id": "8706896",
"other_id": null,
"pages": "452-456",
"pmc": null,
"pmid": "29665890",
"pubdate": "2018-05",
"publication_types": "D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "A novel technique to identify the nerve of origin in head and neck schwannomas.",
"title_normalized": "a novel technique to identify the nerve of origin in head and neck schwannomas"
} | [
{
"companynumb": "US-MYLANLABS-2018M1048232",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LIDOCAINE"
},
"drugadditional": "1",
... |
{
"abstract": "Antiepileptic drugs (AEDs) can cause hypersensitivity reactions during childhood. Studies report a wide clinical spectrum of reactions with AED use, ranging from a mild rash to severe cutaneous reactions.\n\n\n\nTo determine the prevalence and clinical features of AED hypersensitivity reactions during childhood.\n\n\n\nPatients in our pediatric neurology clinic who were prescribed an AED for the first time between November 2015 and November 2016 were monitored and those who developed skin rash during this period were evaluated.\n\n\n\nA total of 570 patients were evaluated. The median age of the patients was 8.86 (interquartile range, 4.2-13.7) years, and 55.8% (318) of patients were male. The most frequently used AEDs were valproic acid (42%, n = 285) and carbamazepine (20.4%, n = 116). Hypersensitivity reactions to AEDs developed in 5.4% of patients. Of these patients, 71% (29) had cutaneous drug reactions and 29% (9) had severe cutaneous drug reactions; 61.3% (19) were using aromatic AEDs, and the leading suspected AED was carbamazepine (45.2%). Comparison of patients who did and did not develop AED hypersensitivity showed that hypersensitivity was more frequent among patients who were younger than 12 years, who used aromatic AEDs, or who used multiple AEDs. In addition, according to regression analysis results, aromatic AED use significantly increased the risk of AED hypersensitivity (P < .001).\n\n\n\nAlthough allergic reactions to AEDs are rare, they are of significance because they can cause life-threatening severe cutaneous drug reactions. Therefore, patients receiving AEDs, especially aromatic AEDs, must be monitored closely.",
"affiliations": "Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Allergy and Immunology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Neurology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Department of Pediatric Neurology, Ankara Child Health and Diseases Hematology Oncology Training and Research Hospital, University of Health Sciences, Ankara, Turkey.;Division of Pediatric Allergy and Immunology, Department of Children's Health and Diseases, Faculty of Medicine, Mugla Sitki Kocman University, Mugla, Turkey. Electronic address: cankocabas@yahoo.com.",
"authors": "Guvenir|Hakan|H|;Dibek Misirlioglu|Emine|E|;Civelek|Ersoy|E|;Toyran|Muge|M|;Buyuktiryaki|Betul|B|;Ginis|Tayfur|T|;Capanoglu|Murat|M|;Gurkas|Esra|E|;Guven|Alev|A|;Kocabas|Can Naci|CN|",
"chemical_list": "D000485:Allergens; D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jaip.2018.02.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "6(6)",
"journal": "The journal of allergy and clinical immunology. In practice",
"keywords": "Antiepileptic drugs; Child; DRESS; Epilepsy; Hypersensitivity; Patch test; SJS",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000293:Adolescent; D000485:Allergens; D000927:Anticonvulsants; D002220:Carbamazepine; D002648:Child; D002675:Child, Preschool; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D008297:Male; D015995:Prevalence; D011446:Prospective Studies; D012867:Skin; D014421:Turkey; D014635:Valproic Acid",
"nlm_unique_id": "101597220",
"other_id": null,
"pages": "2043-2050",
"pmc": null,
"pmid": "29501520",
"pubdate": "2018",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Frequency and Clinical Features of Hypersensitivity Reactions to Antiepileptic Drugs in Children: A Prospective Study.",
"title_normalized": "the frequency and clinical features of hypersensitivity reactions to antiepileptic drugs in children a prospective study"
} | [
{
"companynumb": "TR-ACCORD-065513",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": null,
"d... |
{
"abstract": "BACKGROUND\nWomen are more likely than men to experience adverse cardiac events after ST-elevation myocardial (STEMI). Whether differences in infarct size or reperfusion contribute to sex differences in outcomes is unknown.\n\n\nMETHODS\nWe compared baseline and procedural characteristics, angiographic and electrocardiographic indices of reperfusion, microvascular obstruction, infarct size, and clinical outcomes in 118 women and 334 men with anterior STEMI enrolled in the INFUSE-AMI randomized trial of intralesion abciximab and aspiration thrombectomy (NCT00976521). Infarct size was assessed by cardiac magnetic resonance imaging at 30 days, and clinical end points were adjudicated by an independent committee.\n\n\nRESULTS\nWomen were older, were more commonly affected by hypertension and renal impairment, and had a 50.5-minute longer delay to reperfusion. There were no differences in infarct size, microvascular obstruction, or reperfusion success. At 30 days, major adverse cardiac events (MACE), defined as death, reinfarction, new-onset severe heart failure, or rehospitalization for heart failure, were more common in women (11.1% vs 5.4%, hazard ratio 2.09, 95% CI 1.03-4.27, P = .04). After multivariable adjustment, age, but not sex or time to reperfusion, was an independent predictor of MACE.\n\n\nCONCLUSIONS\nIn the INFUSE-AMI randomized trial, women with anterior STEMI experienced a higher rate of MACE, attributable to older age. Despite longer delay from symptom onset to reperfusion therapy, there was no difference between women and men in infarct size or reperfusion success.",
"affiliations": "The Icahn School of Medicine at Mount Sinai, New York, NY.;The Icahn School of Medicine at Mount Sinai, New York, NY; Cardiovascular Research Foundation, New York, NY. Electronic address: roxana.mehran@mountsinai.org.;Cardiovascular Research Foundation, New York, NY; New York Methodist Hospital, Brooklyn, NY.;Cardiovascular Research Foundation, New York, NY; Columbia University Medical Center, New York, NY.;Charité Campus Benjamin Franklin, Berlin, Germany.;Columbia University Medical Center, New York, NY.;Manchester Heart Centre, Manchester, United Kingdom.;Cardiovascular Research Foundation, New York, NY.;Beth Israel Deaconess Medical Center-Harvard Medical School, Boston, MA.;Cardiovascular Research Foundation, New York, NY; Columbia University Medical Center, New York, NY.",
"authors": "Tomey|Matthew I|MI|;Mehran|Roxana|R|;Brener|Sorin J|SJ|;Maehara|Akiko|A|;Witzenbichler|Bernhard|B|;Dizon|José M|JM|;El-Omar|Magdi|M|;Xu|Ke|K|;Gibson|C Michael|CM|;Stone|Gregg W|GW|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007140:Immunoglobulin Fab Fragments; D010975:Platelet Aggregation Inhibitors; D000077284:Abciximab",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-8703",
"issue": "169(1)",
"journal": "American heart journal",
"keywords": null,
"medline_ta": "Am Heart J",
"mesh_terms": "D000077284:Abciximab; D000368:Aged; D056988:Anterior Wall Myocardial Infarction; D000911:Antibodies, Monoclonal; D017023:Coronary Angiography; D005260:Female; D006333:Heart Failure; D006760:Hospitalization; D006801:Humans; D007140:Immunoglobulin Fab Fragments; D008297:Male; D008875:Middle Aged; D062645:Percutaneous Coronary Intervention; D010975:Platelet Aggregation Inhibitors; D012008:Recurrence; D012737:Sex Factors; D017131:Thrombectomy; D016896:Treatment Outcome",
"nlm_unique_id": "0370465",
"other_id": null,
"pages": "86-93",
"pmc": null,
"pmid": "25497252",
"pubdate": "2015-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Sex, adverse cardiac events, and infarct size in anterior myocardial infarction: an analysis of intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction (INFUSE-AMI).",
"title_normalized": "sex adverse cardiac events and infarct size in anterior myocardial infarction an analysis of intracoronary abciximab and aspiration thrombectomy in patients with large anterior myocardial infarction infuse ami"
} | [
{
"companynumb": "US-JNJFOC-20141219649",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABCIXIMAB"
},
"drugadditional": null,
"... |
{
"abstract": "Antibiotics reduce the commensal flora in the gut, thereby facilitating the overgrowth of undesirable microorganisms such as Candida albicans. Here, we report the case of a 48-year-old woman with a history of obstructive uropathy consecutive to a radiation therapy, in whom both indwelling ureteral stents were rapidly occluded by fungal mycelia, resulting in a rapidly progressive kidney failure. Ascendant infection by C albicans had occurred after a 2- week course of antibiotics, prescribed for a perforative peritonitis also due to radiation-induced colitis. As shown by iterative CT scans made before (at the time of the diagnosis of peritonitis) and after the antibiotic course, kidney failure was explained by a sudden and bilateral pyelocaliceal dilation, due to the obstruction of the ureteral stents. Fungal mycelia were objectivised during the replacement procedure. Intravenous fluconazole was started, and renal function recovered ad integrum with the relief of the obstruction.",
"affiliations": "Urgences Néphrologiques et Transplantation Rénale, APHP, Hopital Tenon, Paris, France.",
"authors": "Dubert|Marie|M|;Loi|Valeria|V|;Tligui|Mohamed|M|;Hertig|Alexandre|A|",
"chemical_list": "D000935:Antifungal Agents; D015725:Fluconazole",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2012()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000935:Antifungal Agents; D002176:Candida albicans; D002177:Candidiasis; D005260:Female; D015725:Fluconazole; D006801:Humans; D008875:Middle Aged; D011475:Prosthesis Failure; D051437:Renal Insufficiency; D015607:Stents; D014517:Ureteral Obstruction",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "23242091",
"pubdate": "2012-12-14",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12686883;9796660;21358662;8011831;16859469;18339499;10619726;8896509;16148461;3259374;18468666;19187507;16903942;19191635;1736766;21394104;20409771;920677;21666985",
"title": "Rapidly progressive kidney failure induced by fungal mycelia obstructing indwelling ureteral stents.",
"title_normalized": "rapidly progressive kidney failure induced by fungal mycelia obstructing indwelling ureteral stents"
} | [
{
"companynumb": "PHHY2014FR133222",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": null,
"drug... |
{
"abstract": "Oncogene amplification resulting in aberrant expression, although common in solid tumors, is rare in acute myeloid leukemia (AML) and is mostly associated with amplification of MYC, RUNX1, and MLL genes. Retinoic acid receptor alpha (RARA) and other target sequences at 17p11.2 often represent the amplicons expressed in breast cancer, not in AML. We present a unique case of a 59-year-old female with a history of breast cancer, now presenting with pancytopenia and bilateral infiltration with effusion in nodules of the right upper lobe of the lung. She was diagnosed with AML-M5. Chromosome analysis demonstrated a hypodiploid clone with complex numerical/structural abnormalities including 5q deletion, monosomy 7, as well as structurally rearranged chromosome 11 and several marker chromosomes. Fluorescence in situ hybridization (FISH) analysis showed amplification of RARA, loss of 7q, monosomy 7, loss of DEK (6p23), and additional copies of NUP214 (9q34) and MLL (11q23). Additional FISH studies showed both ERBB2 and TOP2A genes, which were co-amplified on one of the marker chromosomes. The follow-up bone marrow did not yield any metaphases, but FISH was normal for all probes, including RARA. After a short remission, the patient relapsed and showed clonal evolution. Additional case reports are necessary to assess whether RARA amplification in hematologic malignancies serves as an independent prognostic factor.",
"affiliations": "Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55906, USA.",
"authors": "Asleson|Anna D|AD|;Morgan|Vickie|V|;Smith|Stephen|S|;Velagaleti|Gopalrao V N|GV|",
"chemical_list": "C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cancergencyto.2010.06.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0165-4608",
"issue": "202(1)",
"journal": "Cancer genetics and cytogenetics",
"keywords": null,
"medline_ta": "Cancer Genet Cytogenet",
"mesh_terms": "D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11; D005260:Female; D005434:Flow Cytometry; D005784:Gene Amplification; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007621:Karyotyping; D015470:Leukemia, Myeloid, Acute; D008875:Middle Aged; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha",
"nlm_unique_id": "7909240",
"other_id": null,
"pages": "33-7",
"pmc": null,
"pmid": "20804918",
"pubdate": "2010-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Amplification of the RARA gene in acute myeloid leukemia: significant finding or coincidental observation?",
"title_normalized": "amplification of the rara gene in acute myeloid leukemia significant finding or coincidental observation"
} | [
{
"companynumb": "US-PFIZER INC-2018254407",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TAMOXIFEN"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nThere is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose. Objective. To determine if reported dose predicts the need for N-acetylcysteine (NAC).\n\n\nMETHODS\nData were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line.\n\n\nRESULTS\nThere were 1571 admissions in 1303 patients, with a median age of 27 years (12-96 years) and 1140 (73%) were females. The median dose was 10 g (1-100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4-7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6-9 g, a 10% chance of requiring NAC at a dose of 13-16 g, a 50% chance of requiring NAC at a dose of 30-34 g and a 90% chance for needing NAC at 48-50 g.\n\n\nCONCLUSIONS\nReported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.",
"affiliations": "School of Pharmacy, University of Otago , Dunedin , New Zealand.",
"authors": "Duffull|S B|SB|;Isbister|G K|GK|",
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"fulltext": "\n==== Front\nClin Toxicol (Phila)Clin Toxicol (Phila)CTXClinical Toxicology (Philadelphia, Pa.)1556-36501556-9519Informa Healthcare 10.3109/15563650.2013.830733Critical CarePredicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose Duffull S. B. \n1\nIsbister G. K. \n2\n\n3\n1School of Pharmacy, University of Otago, Dunedin, New Zealand2Discipline of Clinical Pharmacology, University of Newcastle, Newcastle NSW, Australia3Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Waratah NSW, AustraliaAddress correspondence to Geoffrey K. Isbister, c/o Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Edith Street, Waratah NSW 2298, Australia. Tel: + 612 4921 1211. Fax: + 612 4921 1870. E-mail: geoff.isbister@gmail.com9 2013 22 8 2013 51 8 772 776 29 5 2013 26 7 2013 © 2013 Informa Healthcare USA, Inc.2013Informa Healthcare USA, Inc.This is an open-access article distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the source is credited.Context\n There is contention over whether reported dose correlates with toxicity in paracetamol poisoning and risk assessment is currently based on serum paracetamol concentration compared to a nomogram, irrespective of reported dose.\n\nObjective\nTo determine if reported dose predicts the need for N-acetylcysteine (NAC).\n\nMethods\nData were taken from paracetamol overdoses presenting to a tertiary toxicology service. Age, sex, reported dose, ingestion time, timed paracetamol concentrations between 4 and 16 h, hepatotoxicity (peak alanine transaminase > 1000 U/L) and treatment (single dose-activated charcoal [SDAC] and NAC) were analysed. Data were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The primary outcome was administration of NAC, which was determined based on a serum paracetamol concentration greater than the nomogram line.\n\nResult\nThere were 1571 admissions in 1303 patients, with a median age of 27 years (12–96 years) and 1140 (73%) were females. The median dose was 10 g (1–100 g). The paracetamol concentration was above the nomogram line in 337 of 1571 (22%) patients. Patients presenting later (first paracetamol concentration between 7 and 16 h post-overdose) compared to those presenting earlier (4–7 h post-overdose) were more likely to have hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), have a toxic paracetamol concentration (34% vs. 18%; p < 0.0001) and receive NAC (48% vs. 23%; p < 0.0001). SDAC reduced the probability of the paracetamol concentration being above the nomogram. Based on SDAC not being administered there was a 5% probability of requiring NAC at a dose of 6–9 g, a 10% chance of requiring NAC at a dose of 13–16 g, a 50% chance of requiring NAC at a dose of 30–34 g and a 90% chance for needing NAC at 48–50 g.\n\nConclusion\nReported dose was a good predictor of a toxic paracetamol concentration and SDAC reduced the probability of the concentration being above the nomogram. These predictions may assist in determining which patients could be started on NAC immediately.\n\nParacetamol overdoseLogistric regressionAcetylcysteineRisk assessmentReported doseHepatotoxicity\n==== Body\nIntroduction\nParacetamol overdose remains one of the most important common poisonings in many parts of the world1,2 and an increasing problem in many developing and resource poor nations.3 N-acetylcysteine (NAC) is an effective treatment in the vast majority of cases if given early.4–6 The decision to give NAC is usually based on a paracetamol concentration measured at least 4 h after ingestion or later if the patient presents to hospital after this time.7 Although dose is recognised as a predictor of toxicity, reported dose is rarely used to define treatment if a paracetamol concentration is available.8\n\n\nIt remains unclear what the toxic dose of paracetamol is and in the majority of cases patients will have a serum paracetamol concentration measured irrespective of the reported dose taken. Toxic dose is defined empirically as a dose that is known to cause toxicity. Various guidelines suggest different toxic doses. Australian and most international guidelines recommend 200 mg/kg or 10 g as a toxic dose.1,2 However, despite this being defined as a toxic dose the majority of patients will have a serum paracetamol concentration measured, even if they have ingested less than this amount. A comparison of the reported and toxic dose is only used in cases where a serum paracetamol concentration is not available (i.e. late presentations) or in resource poor settings where laboratory services are not available.3 Although previous studies have shown that reported dose is an independent predictor of hepatotoxicity,9 this has not influenced risk assessment in paracetamol poisoning.8\n\n\nIf reported dose was a strong predictor of hepatotoxicity, then its use would potentially allow early initiation of NAC in large overdoses or conversely avoid waiting for paracetamol concentrations for non-toxic doses. This is already done in some cases with massive ingestions, but this is based on anecdotal evidence. Currently, the practice of a single serum paracetamol concentration being above the nomogram between 4 and 24 h from ingestion remains the gold standard for starting NAC therapy.1,6 Starting NAC prior to measuring a paracetamol concentration has been suggested as a potential approach in paracetamol poisoning because it allows for slower administration rates, that is the loading dose to be given over a longer duration.10 However, it would be best if NAC was only given to patients with a high probability of requiring NAC. Therefore, predicting whether the paracetamol concentration will be above the nomogram line based on reported dose is of significance.\n\nThe primary aim of this study was to determine whether reported paracetamol dose was predictive of the need for NAC. In addition, we will investigate whether a minimal dose could be defined below which treatment may not be required (e.g. < 10%) and a maximum dose above which the probability of requiring NAC was greater than 90%.\n\nMethods\nThis study included dosing and drug concentration data from single acute paracetamol overdoses recorded in a prospective database. The use of the database and de-identified patient information has been granted exemption as an audit by the local Human Research Ethics Committee.\n\nInformation for all presentations to a large regional toxicology centre was collected prospectively using a standardised data collection form that is completed at the time of presentation by the treating doctor. This information and any additional data from the medical record were entered into a relational database by trained research assistants. This included demographic information, details of the overdose/exposure (time of overdose and reported dose ingested), clinical information, laboratory investigations and treatment.\n\nAll paracetamol overdoses (single acute ingestions > 1 g) presenting to the toxicology service between January 1997 and December 2011 were extracted from the database. Cases were only included if there was a serum paracetamol concentration measured between 4 and 16 h after ingestion, and both the time of ingestion and the amount ingested were reported and recorded in the database. We used reported dose to represent the dose that the treating clinicians believe the patient took. The reported dose was based on the patient history which was confirmed on multiple occasions and cross checked with any collateral history from the family, friends or pre-hospital services (e.g. ambulance). Note the actual dose remains unknown and the perceived discrepancy between actual and reported dose is often perceived as the basis for uncertainty in the decision about treatment.\n\nThe following data were extracted from the database: age, sex, reported dose ingested, time of ingestion, paracetamol concentration and the time of the paracetamol concentration (between 4 and 16 h), peak alanine transaminase (ALT) and treatment (single dose activated-charcoal [SDAC] and NAC). Patients were further divided into two groups based on the time of their first paracetamol concentration. Early presenters were defined a priori as those that had their first paracetamol concentration between 4 and 7 h and could have NAC started within 8 h. Late presenters were defined as those that had their first level between 7 and 16 h post-overdose and were commenced on NAC on admission. Seven hours was chosen as the cut-off because this meant that NAC could be commenced within 8 h. Hepatotoxicity was defined as an ALT > 1000 U/L.\n\nData analysis\nFor ease of interpretation continuous variables are presented as medians with interquartile ranges (IQR). Dichotomous outcomes were compared using Fisher's exact test or Chi-square test.\n\nData extracted from the database were analysed within a repeated measures logistic regression framework using NONMEM (ver 7.2). The data were presented as 0 if the serum paracetamol concentration was below the line of the nomogram and hence no dose of NAC would usually be given and 1 if the concentration was above the nomogram. The nomogram used started from 150 mg/L (1000 μM) at 4 h and decreased with a half-life of 4 h. Factors that were considered were age, sex, reported paracetamol dose and SDAC. Model building was based on the likelihood ratio test where a decrease in the difference of two objective functions (proportional to twice the negative log-likehood) were assumed to be chi-squared distributed with the degrees of freedom equivalent to the difference in the number of parameter values for nested models. Interaction terms were also considered. The general form of the linear model was:\n\n with additional terms being added for other effects (e.g. SDAC) as required. Following transformation, the probability that NAC would be administered:\n\n The probability that the serum paracetamol concentration is greater than the value on the nomogram was the primary measure in the study but is considered to be a surrogate marker of the probability that NAC would have been administered.\n\nResults\nFrom a total of 2990 paracetamol poisoning admissions there were 1571 acute paracetamol overdoses with a reported dose, known time of ingestion and a paracetamol concentration performed between 4 and 16 h post-overdose. The reasons for exclusion were no known time of ingestion (385), no reported dose (94), dose less than 1 g (26) and no paracetamol concentration between 4 and 16 (914). The 1571 admissions were in 1303 patients, 1173 patients presented on one occasion and 130 on two or more occasions. The median age was 27 years (range: 12–96 years; IQR: 20–39 years) and 1140 (72.6%) were females. The median dose ingested was 10 g (range: 1–100 g; IQR: 6–16 g). The treatment and clinical outcome data for all admissions are included in Table 1. The paracetamol concentration was above the 150/1000 nomogram line in 337 of 1571 (21.5%) and 300 of these received NAC. An additional 143 patients received NAC who did not have a paracetamol concentration above the nomogram.\n\nTable 1. Comparison of patients with an early (4–7 h) first paracetamol concentration to patients with a late (7–16 h) first paracetamol concentration.\n\nMedian and IQR; percentage\tAll admissions\tEarly admissions\tLate admissions\t\nNumber of cases\t1571\t1241\t330\t\nSex (Female)\t1140a (72.6%)\t919a (74.1%)\t221a (67.0%)\t\nAge (years)b\n\t26 (20–39)\t26 (20–38)\t29 (20–42)\t\nDose (g)b\n\t10 (6–16)\t10 (6–15)\t11 (6–18)\t\nTime of paracetamol concentration (hours)b\n\t4.5 (4–6.6)\t4.25 (4–5)\t10 (8.5–12.3)\t\nParacetamol concentration (micromol/L)b\n\t288 (102–655)\t315 (123–697)\t173 (57–451)\t\nSDAC\t314 (20.0%)\t314 (25.3%)\t0\t\nTime of SDAC (hours)b\n\t2 (1.33–3)\t2 (1.33–3)\t\t\nNAC treatment\t443 (28.2%)\t286 (23.0%)\t157 (47.6%)\t\nAlanine transaminase (ALT; I/U)b\n\t60 (45–90)\t56 (43–80)\t70 (49–346)\t\nHepatotoxicity (ALT > 1000)\t23 (1.5%)\t5 (0.4%)\t18 (5.5%)\t\nAbove nomogram line\t337 (21.5%)\t226 (18.2%)\t111 (33.6%)\t\na Number.\n\nb IQR (interquartile range).\n\n\nTable 1 compares patients who presented early (had a serum paracetamol concentration taken between 4 and 7 h post-overdose), to those who presented late (with a serum paracetamol concentration between 7 and 16 h). Patients who presented later had a higher rate of hepatotoxicity (5.5% vs. 0.4%; p < 0.0001), were more likely to have a paracetamol concentration above the nomogram (33.6% vs. 18.2%; p < 0.0001) and more likely to receive NAC (47.6% vs. 23.0%; p < 0.0001).\n\nThe final model included paracetamol reported dose, age, sex and use of SDAC. The data were not able to support a random effect on either the baseline or the influence of reported dose on the probability of the serum paracetamol concentration being above the nomogram line. There was no interaction between the use of SDAC and ingested dose, age or sex.\n\nThe probability of the paracetamol concentration being above the nomogram line based on the dose given is shown in Fig. 1 for 30-year-old females and males. The probability of being above the nomogram line was lower for males at a similar dose compared to that for females. The influence of the ingested overdose dose on the adjusted probability of being above the nomogram line is given by the solid line. The probability based on dose is adjusted for the influence of SDAC (dashed line), age of the patient and sex of the patient. It is seen that SDAC reduces the probability of being above the nomogram line, shown by the dashed lines in Fig. 1. SDAC reduces the probability of NAC by up to 14% at 28 g and less than 10% at either doses lower than 19 g or doses greater than 37 g.\n\nFig. 1. Probability of the paracetamol concentration being above the nomogram line versus dose (a) for a 30-year-old female with (dashed line) and without (solid line) SDAC; and (b) for a 30-year- old male (solid line) compared to a 30-year-old female (dashed line).\n\nBased on SDAC not being administered then there was a 5% probability of being above the nomogram line at a dose of 6–9 g, a 10% probability of being above the nomogram line at a dose of 13–16 g, a 50% probability of being above the nomogram line at a dose of 30–34 g and a 90% probability of being above the nomogram line at 48–50 g.\n\nDiscussion\nThis study demonstrates that reported dose is a strong predictor of patients having paracetamol concentrations above the nomogram line. It has also shown that patient age, sex and the administration of SDAC influences this probability. The relationship between reported dose and toxic paracetamol concentration can potentially be used to allow early intervention in large overdoses. The study also confirmed that patients presenting 7 h or more after ingestion, who were therefore not administered NAC within 8 h, were more likely to receive NAC and develop an abnormal alanine transaminase. This supports current practice of commencing NAC prior to getting a paracetamol concentration in all patients presenting after 8 h and then ceasing it if the paracetamol concentration is below the nomogram line.\n\nMost guidelines recommend that patients presenting within 8 h have a serum paracetamol concentration measured prior to commencing NAC – “wait and see approach”. The results of this study suggest that if the reported dose is greater than 50 g then more than 90% of patients require treatment so NAC could potentially be commenced earlier in these patients. An alternate approach has been to commence NAC early and stop it if the paracetamol concentration is non-toxic. For this approach, reported doses associated with a low probability of requiring NAC could be used to define a group of patients where NAC should not be commenced prior to a paracetamol concentration being determined. In other words, a reported dose cut-off could be used to determine patients where a “wait and see approach” is followed (< cut-off dose) or an approach to commence NAC prior to obtaining a paracetamol concentration (> cut-off dose) and then revisit the use of NAC once a paracetamol concentration is available. For instance, if a reported dose of 10 g was used this would prevent half of all paracetamol overdose patients (in this study) being started on NAC early (i.e. if all patients are initially commenced on NAC prior to a paracetamol concentration), with the associated small risk of adverse reactions. Patients ingesting 10 g only have a 5–7% probability of being above the nomogram line and therefore requiring NAC.\n\nThis study confirms a previous study (data prior to 1997) at the same toxicology unit which demonstrated that the administration of SDAC reduces the probability of requiring NAC. This would support the early administration of activated charcoal in cooperative patients11 to reduce the number of patients requiring NAC and therefore reduce the length of stay. The study suggests that there is the greatest benefit of SDAC for doses greater than 28 g. However, although SDAC is a low risk intervention it could not be given as a duty of care in these patients because NAC is an effective antidote.\n\nThere are a number of limitations to the study including the retrospective extraction and review of the data. However, this is unlikely to affect the primary aim of the study which was based on the reported dose and the measured serum paracetamol concentration. Previous studies have demonstrated that reported dose is a good estimate of the true ingested dose and that patient history is reliable in the majority of cases12,13 although this remains a point of controversy in the literature.14–17 Another problem was that a large number of patients (47%) were excluded which may introduce selection bias. However, the majority (31%) were because a paracetamol concentration was not done between 4 and 16 h and includes late presenters, staggered, supratherapeutic and chronic paracetamol ingestions, where risk assessment is generally not based on a single paracetamol concentration plotted on the nomogram.\n\nAnother limitation was that SDAC was administered according to the emergency department doctor or treating clinical toxicologist and was not randomised. This may have meant that patients ingesting larger doses were more likely to receive SDAC. However, there was no interaction between dose and SDAC in the logistic regression model suggesting that this was unlikely to be the case.\n\nThere were a number of patients with paracetamol concentrations above the nomogram who did not receive NAC. This is most likely to be patients between the 150 and 200 mg/L nomogram lines who were not treated since this was prior to the change in Australia from the 200 mg/L nomogram line to the 150 mg/L nomogram line.\n\nIn addition to dose and SDAC, the final logistic regression model included both age and sex as significant covariates. Figure 1 shows that there was a greater probability of the serum paracetamol being above the line in females compared to males. This may be because females on average weigh less than males and weight was not included in the model because it was not available in the majority of patients.\n\nThe study shows that reported dose can be used as an early predictor of patients who require NAC. This may improve the risk assessment in patients with paracetamol poisoning allowing the earlier administration in large overdoses or more targeted use of NAC in early and late presenters.\n\nAcknowledgements\nWe acknowledge the assistance of the medical and nursing staff who contribute to the Hunter Area Toxicology Service clinical database.\n\nDeclaration of interest\nThe authors report no declarations of interest. The authors alone are responsible for the content and writing of the paper.\n\nFunding\nGeoff Isbister is funded by an NHMRC Clinical Career Development Award ID 605817.\n==== Refs\nReferences\n1. Daly FF Fountain JS Murray L Graudins A Buckley NA Panel of Australian and New Zealand clinical toxicologists Guidelines for the management of paracetamol poisoning in Australia and New Zealand–explanation and elaboration. A consensus statement from clinical toxicologists consulting to the Australasian poisons information centres Med J Aust 2008 296 301 18312195 \n2. Dart RC Erdman AR Olson KR Christianson G Manoguerra AS Chyka PA et al Acetaminophen poisoning: an evidence-based consensus guideline for out-of-hospital management Clin Toxicol (Phila) 2006 44 1 18 \n3. Senarathna SM Sri Ranganathan S Buckley N et al A cost effectiveness analysis of the preferred antidotes for acute paracetamol poisoning patients in Sri Lanka BMC Clin Pharmacol 2012 12 6 22353666 \n4. Buckley NA Whyte IM O’Connell DL Dawson AH Oral or intravenous N-acetylcysteine: which is the treatment of choice for acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 1999 37 759 767 10584588 \n5. Prescott LF Illingworth RN Critchley JA Proudfoot AT Intravenous N-acetylcysteine: the treatment of choice for paracetamol poisoning Br Med J 1979 2 1097 1100 519312 \n6. Bateman DN Controversies in the use of N-acetylcysteine as an antidote J Toxicol Clin Toxicol 2003 41 434 435 \n7. Buckley N Eddleston M Paracetamol (acetaminophen) poisoning Clin Evid 2005 (14) 1738 1744 16620471 \n8. Buckley NA Whyte IM O’Connell DL Dawson AH Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose J Toxicol Clin Toxicol 1999 37 753 757 10584587 \n9. Schmidt LE Dalhoff K Poulsen HE Acute versus chronic alcohol consumption in acetaminophen-induced hepatotoxicity Hepatology 2002 35 876 882 11915034 \n10. Shen F Coulter CV Isbister GK Duffull SB A dosing regimen for immediate N-acetylcysteine treatment for acute paracetamol overdose Clin Toxicol (Phila) 2011 49 643 647 21854081 \n11. Isbister GK Kumar VV Indications for single-dose activated charcoal administration in acute overdose Curr Opin Crit Care 2011 17 351 357 21716104 \n12. Isbister GK How do we use drug concentration data to improve the treatment of overdose patients? Ther Drug Monit 2010 32 300 304 20431510 \n13. Friberg LE Isbister GK Hackett LP Duffull SB The population pharmacokinetics of citalopram after deliberate self-poisoning: a bayesian approach J Pharmacokinet Pharmacodyn 2005 32 571 605 16307209 \n14. Manini A Smith S Moskovitz J Nelson L In response to Isbister et al.: Application of pharmacokinetic-pharmacodynamic modeling in management of QT abnormalities after citalopram overdose Intensive Care Med 2007 33 738 17279361 \n15. Lugassy DM Hoffman RS Chessex N In response to van Gorp F. et al. Escitalopram overdose Ann Emerg Med 2010 55 128 129 20116020 \n16. Isbister GK Friberg LE Duffull SB Application of pharmacokinetic-pharmacodynamic modelling in management of QT abnormalities after citalopram overdose Intensive Care Med 2006 32 1060 1065 16791669 \n17. van Gorp F Whyte IM Isbister GK Clinical and ECG effects of escitalopram overdose Ann Emerg Med 2009 54 404 408 19556032\n\n",
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"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018712:Analgesics, Non-Narcotic; D000931:Antidotes; D002606:Charcoal; D056486:Chemical and Drug Induced Liver Injury; D002648:Child; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D062787:Drug Overdose; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D049451:Nomograms; D017711:Nonlinear Dynamics; D011446:Prospective Studies; D012189:Retrospective Studies; D018570:Risk Assessment; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
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"title": "Predicting the requirement for N-acetylcysteine in paracetamol poisoning from reported dose.",
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"abstract": "We present a case of fulminant myocarditis in a preterm neonate born to a SARS-CoV-2-infected mother with COVID-19 disease. Despite complete separation after birth, cardiogenic decompensation initiated on day of life 7. Although the neonate tested negative for SARS-CoV-2, enterovirus viremia accompanied cardiac dysfunction, multiorgan failure, and neonatal death within 36 hours.",
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"authors": "Fick|Tyler A|TA|0000-0002-3755-6059;Morris|Shaine A|SA|;Tume|Sebastian C|SC|;Stafford|Tiffany D|TD|;Aagaard|Kjersti|K|;Schady|Deborah|D|;Molossi|Silvana|S|",
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"mesh_terms": "D000086382:COVID-19; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D009205:Myocarditis; D000086402:SARS-CoV-2",
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"title": "Fulminant Enteroviral Myocarditis in a Newborn Accompanying Maternal SARS-CoV-2 Infection.",
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"abstract": "Thymic large cell neuroendocrine carcinomas (LCNECs) are rare, and the optimal regimen for second and subsequent lines of chemotherapy for the treatment of LCNECs remains unknown. In the present case study, a 59-year-old male with post-operative recurrent thymic LCNEC was treated with nab-paclitaxel and carboplatin every 4 weeks as third-line chemotherapy, and a partial response was achieved following 4 cycles of this regimen. The patient developed grade 4 neutropenia and grade 3 leukopenia, but none of the other toxicities, including peripheral neuropathy, were severe. Therefore, the patient was able to tolerate this salvage chemotherapy. To the best of our knowledge, the present study is the first case demonstrating clinically meaningful antitumor activity by combination chemotherapy with carboplatin and nab-paclitaxel, resulting in a positive response in a patient with thymic LCNEC.",
"affiliations": "Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Pathology, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Research and Development Center for New Medical Frontiers, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Thoracic Surgery, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.;Department of Respiratory Medicine, Kitasato University School of Medicine, Sagamihara, Kanagawa 252-0374, Japan.",
"authors": "Igawa|Satoshi|S|;Yanagisawa|Nobuyuki|N|;Niwa|Hideyuki|H|;Ishihara|Mikiko|M|;Hiyoshi|Yasuhiro|Y|;Otani|Sakiko|S|;Katono|Ken|K|;Sasaki|Jiichiro|J|;Satoh|Yukitoshi|Y|;Masuda|Noriyuki|N|",
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"title": "Successful chemotherapy with carboplatin and nab-paclitaxel for thymic large cell neuroendocrine carcinoma: A case report.",
"title_normalized": "successful chemotherapy with carboplatin and nab paclitaxel for thymic large cell neuroendocrine carcinoma a case report"
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"companynumb": "JP-WATSON-2016-09394",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nGemcitabine is one of the most active drugs against non-small-cell lung cancer (NSCLC). Preclinical data suggested that gemcitabine efficacy could be improved by increasing the dose or by increasing the infusion duration. This study has been designed in order to explore two different approaches of gemcitabine dose intensification in patients with advanced NSCLC.\n\n\nMETHODS\nA total of 121 chemonaive patients with locally advanced or metastatic NSCLC not suitable for a platinum-based chemotherapy were randomly allocated to chemotherapy with gemcitabine 1500 mg/m2 on days 1 and 8 every 3 weeks by standard 30 min intravenous infusion (arm A), or gemcitabine 10 mg/m2/min for 150 min on days 1 and 8 every 3 weeks by intravenous infusion at fixed dose rate (arm B).\n\n\nRESULTS\nOne hundred and seventeen patients were fully analyzed. No difference in response rate (16.1% versus 9.9%, p=0.28), median time to disease progression (4 months versus 4.5 months, p=0.34) median survival (9.8 months in both arms), and 1-year survival (42.6% versus 39.0% p=0.98) was detected in arms A and B, respectively. No treatment-related deaths occurred. Main hematological toxicities were grade 3-4 neutropenia observed in 17.9% of patients in group A and in 49.2% of individuals in group B (p=0.0002). The incidence of febrile neutropenia was 3.3% in arm A and 0% in arm B (p=0.17). Grade 3-4 thrombocytopenia was more frequently observed in arm B patients (9.9% versus 1.8%, p=0.057). Non-hematological toxicity was similar in both arms, and consisted in grade 1-2 gastrointestinal toxicity observed in 48.2% of patients in arm A and 41.0% in arm B.\n\n\nCONCLUSIONS\nIntensification of standard doses or prolonged infusion schedule did not result in efficacy improvement. Gemcitabine infusion duration does not warrant further investigation in patients with advanced NSCLC.",
"affiliations": "Division of Medical Oncology, Bellaria Hospital, Bologna, Via Altura 3, 40139 Bologna, Italy. federico.cappuzzo@ausl.bo.it",
"authors": "Cappuzzo|F|F|;Novello|S|S|;De Marinis|F|F|;Selvaggi|G|G|;Scagliotti|G V|GV|;Barbieri|F|F|;Maur|M|M|;Papi|M|M|;Pasquini|E|E|;Bartolini|S|S|;Marini|L|L|;Crinò|L|L|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine; D002945:Cisplatin",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2006.03.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "52(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": null,
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic; D002289:Carcinoma, Non-Small-Cell Lung; D002945:Cisplatin; D003841:Deoxycytidine; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015996:Survival Rate",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "319-25",
"pmc": null,
"pmid": "16630670",
"pubdate": "2006-06",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "A randomized phase II trial evaluating standard (50 mg/min) versus low (10 mg/min) infusion duration of gemcitabine as first-line treatment in advanced non-small-cell lung cancer patients who are not eligible for platinum-based chemotherapy.",
"title_normalized": "a randomized phase ii trial evaluating standard 50 mg min versus low 10 mg min infusion duration of gemcitabine as first line treatment in advanced non small cell lung cancer patients who are not eligible for platinum based chemotherapy"
} | [
{
"companynumb": "IT-PFIZER INC-2020437826",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional"... |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy and tolerability of long-term treatment with Everolimus (EVO) in patients with tuberous sclerosis complex (TSC) and therapy-resistant epilepsy in a compassionate use trial.\n\n\nMETHODS\nAfter a 3-month baseline, patients were treated with EVO. Treatment was divided into treatment phases each lasting at least 9 months. Patients started with one of three target serum levels. In case of insufficient seizure control, subsequent treatment phases with other target serum levels followed. The accompanying antiseizure medication (ASM) remained stable during the baseline phase and for at least the initial three treatment phases. We evaluated changes in seizure frequency and seizure-free days compared to baseline for each patient (Cox-Stuart-test).\n\n\nRESULTS\nFifteen patients were followed up for up to 10 years (minimum 0.6 years, median 5.8 years). Twelve patients (80%) experienced a significant reduction in seizure frequency or an increase in seizure-free days: Six (40%) patients became seizure-free and four patients (26.7%) remained seizure free for > 7 years, of which three required no additional ASM. All participants reported at least one adverse effect, the vast majority (92.5%) of which were mild or moderate.\n\n\nCONCLUSIONS\nLong-term treatment with EVO was highly efficacious, safe and well tolerated. While EVO can be a therapeutic option for therapy-resistant epilepsy in TSC, it can take a long time for seizure relief to manifest.",
"affiliations": "Department of Pediatric and Adolescent Medicine II (Neuropediatrics, Social Pediatrics), University Medical Centre Schleswig-Holstein, Kiel, Germany; Neuropediatrics Section of the Department of Pediatrics, Asklepios Clinic Hamburg Nord-Heidberg, Hamburg, Germany. Electronic address: g.wiegand@asklepios.com.;Ev. Klinikum Bethel, v. Bodelschwinghsche Stiftungen Bethel, Bielefeld, Germany.;Department of Pediatric and Adolescent Medicine II (Neuropediatrics, Social Pediatrics), University Medical Centre Schleswig-Holstein, Kiel, Germany.;Department of Pediatric and Adolescent Medicine II (Neuropediatrics, Social Pediatrics), University Medical Centre Schleswig-Holstein, Kiel, Germany.;Department of Pediatric and Adolescent Medicine II (Neuropediatrics, Social Pediatrics), University Medical Centre Schleswig-Holstein, Kiel, Germany; Institute of Medical Psychology and Medical Sociology, University Medical Centre Schleswig- Holstein, Kiel, Germany.",
"authors": "Wiegand|Gert|G|;May|Theodor W|TW|;Lehmann|Irene|I|;Stephani|Ulrich|U|;Kadish|Navah E|NE|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1016/j.seizure.2021.10.011",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1059-1311",
"issue": "93()",
"journal": "Seizure",
"keywords": "Children; Epilepsy; Long-term treatment; Tuberous sclerosis complex (TSC); mTOR, Everolimus",
"medline_ta": "Seizure",
"mesh_terms": null,
"nlm_unique_id": "9306979",
"other_id": null,
"pages": "111-119",
"pmc": null,
"pmid": "34740140",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Long-term treatment with everolimus in TSC-associated therapy-resistant epilepsies.",
"title_normalized": "long term treatment with everolimus in tsc associated therapy resistant epilepsies"
} | [
{
"companynumb": "DE-SUN PHARMACEUTICAL INDUSTRIES LTD-2022RR-324064",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"d... |
{
"abstract": "Survival for patients with multiple myeloma has increased. Both melphalan and lenalidomide are associated with subsequent development of myelodysplasia. We reviewed the cases of all patients with multiple myeloma who had subsequent development of myelodysplastic syndrome (MDS) or acute non-lymphoblastic leukemia (ANLL) during a 12-year period in three centers. Of 55 patients identified, two received only lenalidomide before myelodysplasia developed. The median time between the diagnoses of multiple myeloma and MDS/ANLL was 52.7 months. Median survival after the diagnosis of MDS or ANLL was 6.7 months. Treatment of MDS comprised allogeneic stem cell transplant in eight patients (median survival, 219 days; one patient alive at 624 days) and a hypomethylating agent in 21 patients (response of stable or better in five patients). Myelodysplasia remains a devastating complication of therapy for multiple myeloma, with short survival and poor response rates to available modalities.",
"affiliations": "Division of Hematology.",
"authors": "Gertz|Morie A|MA|;Terpos|Evangelos|E|;Dispenzieri|Angela|A|;Kumar|Shaji|S|;Shah|Rupin A|RA|;Orlowski|Robert|R|;Kastritis|Efstathios|E|;Dimopoulos|Meletios A|MA|;Shah|Jatin|J|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D013792:Thalidomide; D000069286:Bortezomib; D000077269:Lenalidomide",
"country": "United States",
"delete": false,
"doi": "10.3109/10428194.2014.970543",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "56(6)",
"journal": "Leukemia & lymphoma",
"keywords": "Acute leukemia; hypomethylating agents; lenalidomide; multiple myeloma; myelodysplasia; stem cell transplant",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000069286:Bortezomib; D005260:Female; D006801:Humans; D000077269:Lenalidomide; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D009190:Myelodysplastic Syndromes; D033581:Stem Cell Transplantation; D013792:Thalidomide; D014182:Transplantation, Autologous",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "1723-6",
"pmc": null,
"pmid": "25284489",
"pubdate": "2015-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Therapy-related myelodysplastic syndrome/acute leukemia after multiple myeloma in the era of novel agents.",
"title_normalized": "therapy related myelodysplastic syndrome acute leukemia after multiple myeloma in the era of novel agents"
} | [
{
"companynumb": "US-CELGENE-USA-2014110825",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "Vancomycin-induced thrombocytopenia is a rare adverse reaction that may be overlooked because no specific diagnostic test is currently available. We herein report a patient with vancomycin-induced immune thrombocytopenia who was diagnosed by the detection of vancomycin-dependent anti-platelet antibody with flow cytometry. An IgG antibody in the patient's serum reacted with platelets only in the presence of vancomycin. Severe thrombocytopenia gave rise to life-threatening gastrointestinal bleeding, which was quickly resolved after effective platelet transfusion following the cessation of vancomycin administration. This report suggests that the flow cytometric test is useful for the differential diagnosis of thrombocytopenia and platelet transfusion should be performed after the cessation of vancomycin administration.",
"affiliations": "Departments of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Japan.",
"authors": "Yamanouchi|Jun|J|;Hato|Takaaki|T|;Shiraishi|Sanshiro|S|;Takeuchi|Kazuto|K|;Yakushijin|Yoshihiro|Y|;Yasukawa|Masaki|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007074:Immunoglobulin G; D014640:Vancomycin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.55.6902",
"fulltext": "\n==== Front\nIntern MedIntern. Med10.2169/internalmedicine.55.6902Internal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 27746445Case ReportVancomycin-induced Immune Thrombocytopenia Proven by the Detection of Vancomycin-dependent Anti-platelet Antibody with Flow Cytometry Yamanouchi Jun 1Hato Takaaki 2Shiraishi Sanshiro 3Takeuchi Kazuto 4Yakushijin Yoshihiro 4Yasukawa Masaki 11 Departments of Hematology, Clinical Immunology and Infectious Diseases, Ehime University Graduate School of Medicine, Japan2 Division of Blood Transfusion and Cell Therapy, Ehime University Graduate School of Medicine, Japan3 Department of Internal Medicine, Shiraishi Hospital, Japan4 Cancer Center, Ehime University Graduate School of Medicine, JapanCorrespondence to Dr. Jun Yamanouchi, yamanouc@m.ehime-u.ac.jp\n\n15 10 2016 55 20 3035 3038 27 11 2015 24 2 2016 The 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/).Vancomycin-induced thrombocytopenia is a rare adverse reaction that may be overlooked because no specific diagnostic test is currently available. We herein report a patient with vancomycin-induced immune thrombocytopenia who was diagnosed by the detection of vancomycin-dependent anti-platelet antibody with flow cytometry. An IgG antibody in the patient's serum reacted with platelets only in the presence of vancomycin. Severe thrombocytopenia gave rise to life-threatening gastrointestinal bleeding, which was quickly resolved after effective platelet transfusion following the cessation of vancomycin administration. This report suggests that the flow cytometric test is useful for the differential diagnosis of thrombocytopenia and platelet transfusion should be performed after the cessation of vancomycin administration. \n\nvancomycinthrombocytopeniaanti-platelet antibody\n==== Body\nIntroduction\nVancomycin, a glycopeptide antibiotic, is widely used to treat infection with resistant Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus (MRSA). It is well known that vancomycin has several adverse reactions including nephrotoxicity, ototoxicity, and red man syndrome (1-4). Vancomycin-induced thrombocytopenia is a rare adverse reaction, however, it may be underestimated because of the lack of a specific diagnostic test (5-7). Von Drygalski et al. recently demonstrated that vancomycin-induced thrombocytopenia was induced by drug-dependent anti-platelet antibodies that could be detected by flow cytometry (8). We herein present a case of vancomycin-induced immune thrombocytopenia followed by life-threating gastrointestinal bleeding that quickly recovered after discontinuation of the drug. Using flow cytometry, we identified a vancomycin-dependent anti-platelet antibody in the patient's serum and accordingly made a diagnosis of vancomycin-induced immune thrombocytopenia.\n\nCase Report\nA 72-year-old woman with a history of hypertension was admitted for dyspnea and edema. Laboratory studies showed the following results: hemoglobin, 7.5 g/dL; white blood cells, 1.4×104/μL; platelets, 27.3×104/μL; creatinine, 13.1 mg/dL; blood urea nitrogen, 137.7 mg/dL; Na, 133 mEq/L; K, 6.1 mEq/L; Cl, 103 mEq/L; total protein, 6.3 g/dL; C-reactive protein, 15.3 mg/dL; and brain natriuretic peptide(BNP), 5,930 pg/mL (Table). Chest radiography revealed an enlarged heart shadow and infiltrative shadow in the right upper lung field. Therefore, the patient was diagnosed with pneumonia, acute heart failure, and acute renal failure. Renal failure was considered to result from an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis because tests for anti-myeloperoxidase antibodies (MPO-ANCA) were strongly positive.\n\nTable. Laboratory Data on Admission.\n\nWBC\t14,000\t/µL\tT. Pro\t6.3\tg/dL\tCRP\t15.30\tmg/dL\t\nNe\t87.1\t%\tT. Bil\t0.7\tmg/dL\tBNP\t5930\tpg/mL\t\nLy\t7.7\t%\tAST\t65\tIU/L\t\t\t\t\nMo\t5.0\t%\tALT\t37\tIU/L\t\t\t\t\nEo\t0.1\t%\tLD\t497\tIU/L\t\t\t\t\nBa\t0.1\t%\tg-GTP\t25\tIU/L\t\t\t\t\nRBC\t260\tx104/µL\tALP\t413\tIU/L\t\t\t\t\nHb\t7.5\tg/dL\tBUN\t137.7\tmg/dL\t\t\t\t\nHt\t22.5\t%\tUA\t12.0\tmg/dL\t\t\t\t\nPLT\t27.3\tx104/µL\tCr\t13.1\tmg/dL\t\t\t\t\n\t\t\tNa\t133\tmEq/L\t\t\t\t\n\t\t\tK\t6.1\tmEq/L\t\t\t\t\n\t\t\tCl\t103\tmEq/L\t\t\t\t\nSteroid therapy, carbapenem, mechanical ventilation, and continuous hemodiafiltration (CHDF) were subsequently initiated. MRSA was ultimately isolated from the sputum, and vancomycin was administered at 1,000 mg intravenously (IV) on the first day and at 500 mg IV every 24 hours after the second day. Ten days after initiating vancomycin therapy, the patient developed massive melena followed by hypovolemic shock. At that time, her platelet count was 0.6×104/μL. Her D-dimer and fibrinogen levels were normal. According to the sudden onset of thrombocytopenia without coagulopathy, drug-induced thrombocytopenia was suspected. Because she received heparin for CHDF, we initially suspected heparin-induced thrombocytopenia (HIT) and switched from heparin to nafamostat mesilate. However, visible blood clotting in the hemodialysis circuit, the most prominent feature of HIT in dialysis patients, was not observed, and the test for HIT antibody was negative, suggesting a decreased possibility of HIT. The administration of other drugs including vancomycin and meropenem, which might be responsible for drug-induced thrombocytopenia, was discontinued. On the next day after the cessation of the administered drugs, the patient received platelet transfusion, which increased her platelet count from 0.2×104/μL to 3.4×104/μL. Her platelet count gradually increased and was 13.3×104/μL at 8 days after drug discontinuation (Fig. 1). Her melena resolved as her platelet count increased. This rapid recovery of the platelet count after cessation of the administrated drugs was consistent with drug-induced thrombocytopenia. Although the causative drug remained unknown, the clinical course of this patient was quite similar to that of patients with vancomycin-induced thrombocytopenia regarding the period between drug initiation and the onset of thrombocytopenia, severe thrombocytopenia with life-threatening bleeding, and rapid recovery after drug discontinuation (8).\n\nFigure 1. Clinical course.\n\nDetection of vancomycin-dependent anti-platelet antibody\nWe attempted to identify vancomycin-dependent anti-platelet antibody, which is responsible for vancomycin-induced immune thrombocytopenia. This antibody can bind to platelets only in the presence of vancomycin (8). The patient's serum was incubated for 40 minutes at room temperature with normal washed platelets in the presence or absence of 0.3 mg/mL of vancomycin. After a wash in buffer, each sample was incubated with Alexa Fluor 488-conjugated goat F(ab')2 anti-human IgG or FITC-conjugated goat F(ab')2 anti-human IgM (Invitrogen) for 20 minutes at room temperature. Platelet-bound fluorescein signals were detected by flow cytometry. A positive reaction was defined as a 2-fold or greater increase in the mean fluorescence intensity of platelets compared with control serum samples.\n\nThe result of the flow cytometric analysis is shown in Fig. 2. The patient had an anti-platelet IgG antibody that was detected only in the presence of vancomycin. No IgM antibody was detected (data not shown). The antibody titer (mean fluorescence intensity) was decreased after cessation of vancomycin and undetectable as the platelet count raised (Fig. 1).\n\nFigure 2. Histograms of fluorescence intensities of platelet-bound IgG antibody. Black: The patient's serum was tested against normal washed platelets in the absence of vancomycin. White: The patient's serum was tested against normal washed platelets in the presence of vancomycin. Gray: Normal serum was tested against normal washed platelets in the presence of vancomycin as a negative control.\n\nThe platelet antigen recognized by this antibody was further examined using an ELISA assay (PakAuto assay, Immucor GTI Diagnostics, Waukesha, USA). The patient or normal serum was added to wells immobilized with platelet membrane glycoprotein (GP) IIb/IIIa, Ib/IX, and Ia/IIa, allowing antibody, if present, to bind. Following incubation for 30 minutes at 37℃, unbound immunoglobulins were washed away, and an alkaline phosphatase-labeled anti-human Ig antibody was added to the wells, followed by the enzymatic substrate p-nitrophenyl phosphate. The reaction was evaluated by reading the optical density of the wells at an absorbance of 405 nm. We found that the antibody in the patient's serum specifically recognized GPIb/IX (Fig. 3).\n\nFigure 3. platelet antigen recognized by vancomycin-dependent antibody. Antibody binding in the patient's serum and normal serum to each platelet glycoprotein was measured using a pakAuto assay kit. Specific binding was expressed as % of control calculated using the following formula: % of control (%)=(sample – negative control) / (positive control – negative control)×100. Negative and positive controls were included in the kit.\n\nDiscussion\nThis report described a patient with vancomycin-induced immune thrombocytopenia associated with life-threating gastrointestinal bleeding. Drug-induced thrombocytopenia was suspected from her clinical course and the diagnosis was confirmed by the detection of vancomycin-dependent anti-platelet antibody with flow cytometry. This flow cytometric test made it possible to definitively diagnose vancomycin-induced immune thrombocytopenia, and our case showed the diagnostic value of this test.\n\nThe clinical features of vancomycin-induced thrombocytopenia have been reported in detail (8,9). Patients are typically administered vancomycin for at least six days, and the platelet counts decrease by a mean of 93% from the pre-treatment values. Nadir counts averaging 1.36×104/μL are reached approximately eight days after vancomycin treatments (ranging from 1 to 27 days). The platelet counts return to the pre-treatment values after discontinuation of the drug, and the median time required for the platelet level to return to at least 15×104/μL is 7.5 days (ranging from 4 to 17 days). One-third of the patients have extensive ecchymosis and severe mucous hemorrhaging that may be life-threatening.\n\nVon Drygalski et al. (8) reported that vancomycin-dependent antibody was detected in about 20% of patients who were referred for vancomycin-dependent, platelet-reactive antibody testing because of the clinical suspicion of vancomycin-induced thrombocytopenia. The majority of vancomycin-induced antibodies detected were the IgG type, with 2% of antibodies being the IgM type. No vancomycin-dependent antibodies were detected in 25 patients who had normal platelet counts after receiving vancomycin or another drug. The antibody was detected in only 1 of 451 normal subjects. These findings suggest that vancomycin-dependent antibody detected by flow cytometry is highly specific for patients with vancomycin-induced thrombocytopenia.\n\nWe identified that the antibody in the present patient recognized GPIb/IX. Previous studies have reported that vancomycin-dependent antibodies recognized either or both GPIIb/IIIa and GPIb/IX (10). This epitope profile is quite similar to that of antibodies in patients with quinine and other drug-induced thrombocytopenia (11,12). It is therefore suggested that drug-dependent antibodies responsible for severe thrombocytopenia are directed against the common antigens GPIIb/IIIa and/or GPIb/IX.\n\nIt remains to be determined whether the vancomycin-dependent antibody exists for a limited period or permanently. A previous study reported a patient in whom the second episode of thrombocytopenia was induced by re-administration of vancomycin 6 months after the first episode (8). In our patient, the antibody was detected only for several days. However, it is possible that an undetectable level of the antibody persists in the serum. Re-administration of vancomycin may induce an anamnestic immune response and cause thrombocytopenia. Accidental re-administration of vancomycin should be avoided irrespective of the detection of the antibody.\n\nPlatelet transfusion in patients with vancomycin-induced thrombocytopenia is likely to be ineffective because of immune destruction of platelets. The failure of platelet transfusion during vancomycin administration has been reported in previous studies (5,8,13,14). A recent study reported that platelet transfusion failed to elevate the platelet counts in 11 of 14 patients (8). However, platelet transfusion was effective in our case. This may be explained by the biological feature of the anti-platelet antibody to react with platelets only in the presence of vancomycin. In our case, platelet transfusion was performed after discontinuation of vancomycin. Similar to our case, successful platelet transfusion was reported in a patient after discontinuation of vancomycin (15). It should be noted that platelet transfusion must be performed after discontinuation of vancomycin.\n\nVancomycin is a mainstay in the treatment of MRSA infection in hospitalized patients. Such patients may have many comorbidities and take many drugs, which precipitate thrombocytopenia. The flow cytometric test for vancomycin-dependent antibody may be useful in the differential diagnosis of thrombocytopenia in these patients and lead to successful treatment of patients with potentially life-threatening bleeding.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Falcone M , Russo A , Venditti M \nOptimizing antibiotic therapy of bacteremia and endocarditis due to staphylococci and enterococci: new insights and evidence from the literature . J Infect Chemother \n21 : 330 -339 , 2015 .25813608 \n2. Carreno JJ , Kenney RM , Lomaestro B \nVancomycin-associated renal dysfunction: where are we now? \nPharmacotherapy \n34 : 1259 -1268 , 2014 .25220436 \n3. Rubinstein E , Keynan Y \nVancomycin revisited: 60 years later . Front Public Health \n2 : 217 , 2014 .25401098 \n4. Marsot A , Boulamery A , Bruquerolle B , Simon N \nVancomycin: a review of population pharmacokinetic analyses . Clin Pharmacokinet \n51 : 1 -13 , 2012 .22149255 \n5. Marraffa J , Guharoy R , Duggan D , Rose F , Nazeer S \nVancomycin-induced thrombocytopenia: a case proven with rechallenge . Pharmacotherapy \n23 : 1195 -1198 , 2003 .14524652 \n6. Kuruppu JC , Le TP , Tuazon CU \nVancomycin-associated thrombocytopenia: case report and review of the literature . Am J Hematol \n60 : 249 -250 , 1999 .\n7. Christie DJ , van Buren N , Lennon SS , Putnam JL \nVancomycin-dependent antibodies associated with thrombocytopenia and refractoriness to platelet transfusion in patients with leukemia . Blood \n75 : 518 -523 , 1990 .2295006 \n8. Von Drygalski A , Curtis BR , Bougie DW , et al \nVancomycin-induced immune thrombocytopenia . N Engl J Med \n356 : 904 -910 , 2007 .17329697 \n9. Warkentin T \nDrug-induced immune-mediateded thrombocytopenia: from purpura to thrombosis . N Engl J Med \n356 : 891 -893 , 2007 .17329695 \n10. Ganly P , Downing J , Stiven P , Frizelle F , Badami K \nClinical and serological diagnoses of a patient with vancomycin-induced thrombocytopenia . Transfus Med \n21 : 137 -139 , 2011 .21083776 \n11. Visentin GP , Newman PJ , Aster RH \nCharacteristics of quinine- and quinidine-induced antibodies specific for platelet glycoproteins IIb and IIIa . Blood \n77 : 2668 -2676 , 1991 .1710517 \n12. Aster RH \nDrug-induced immune cytopenias . Toxicology \n209 : 149 -153 , 2005 .15767027 \n13. Mizon P , Kiefel V , Mannessier L , Muller-Eckhardt C , Goudemand J \nThrombocytopenia induced by vancomycin-dependent platelet antibody . Vox Sang \n73 : 49 -51 , 1997 .9269071 \n14. Govindarajan R , Baxter D , Wilson C , Zent C \nVancomycin-induced thrombocytopenia . Am J Hematol \n62 : 122 -123 , 1999 .\n15. Shah RA , Musthaq A , Khardori N \nVancomycin-induced thrombocytopenia in a 60-year-old man: a case report . J Med Case Rep \n3 : 7290 , 2009 .19830166\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "55(20)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D001792:Blood Platelets; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007074:Immunoglobulin G; D017713:Platelet Transfusion; D016553:Purpura, Thrombocytopenic, Idiopathic; D014640:Vancomycin",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3035-3038",
"pmc": null,
"pmid": "27746445",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25220436;25813608;1710517;21083776;9269071;14524652;10509053;17329695;10072125;19830166;2295006;22149255;17329697;15767027;25401098",
"title": "Vancomycin-induced Immune Thrombocytopenia Proven by the Detection of Vancomycin-dependent Anti-platelet Antibody with Flow Cytometry.",
"title_normalized": "vancomycin induced immune thrombocytopenia proven by the detection of vancomycin dependent anti platelet antibody with flow cytometry"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK201609080",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "A 59-year-old male presented with methicillin-resistantStaphylococcus aureus bacteraemia from a prostatic abscess and was treated with vancomycin. Two weeks into his treatment course, he developed severe joint pains, abdominal pain with bloody, mucinous stools and a diffuse palpable purpuric rash on his extremities. Biopsy of the rash showed IgA immune-complex deposition consistent with Henoch-Schönlein purpura. After treatment with glucocorticoids, his symptoms resolved completely. Vancomycin is an extremely commonly used antibiotic with certain well-known adverse effects. Henoch-Schönlein purpura, a vasculitis involving abdominal pain, arthralgias and palpable purpura, is a much less common side effect, as seen in this patient. Given that vancomycin is widely used internationally, clinicians should be aware of the risks entailed by its use.",
"affiliations": "Internal Medicine, University of Florida, Gainesville, Florida, USA.;Internal Medicine, University of Florida, Gainesville, Florida, USA.;Internal Medicine, Malcom Randall Veterans Affairs Medical Center, Gainesville, Florida, USA.",
"authors": "Shah|Nikhil H|NH|;Kline|Kristopher P|KP|;Shukla|Manas K|MK|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005938:Glucocorticoids; D007070:Immunoglobulin A; D014640:Vancomycin; D010100:Oxygen; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219988",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Dermatology; Drugs: Infectious Diseases; Immunology; Musculoskeletal And Joint Disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000900:Anti-Bacterial Agents; D016470:Bacteremia; D004864:Equipment and Supplies; D005938:Glucocorticoids; D006801:Humans; D011695:IgA Vasculitis; D007070:Immunoglobulin A; D008297:Male; D055624:Methicillin-Resistant Staphylococcus aureus; D008875:Middle Aged; D010100:Oxygen; D011241:Prednisone; D014640:Vancomycin",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28637844",
"pubdate": "2017-06-20",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10499071;11341123;12401245;16113386;16431201;17382810;19967009;22235302;22490390;27681233;2984637;3605234;9645421",
"title": "A dirty cause of vancomycin-mediated Henoch-Schonlein purpura: oxygen tubing is not a foley.",
"title_normalized": "a dirty cause of vancomycin mediated henoch schonlein purpura oxygen tubing is not a foley"
} | [
{
"companynumb": "US-BAXTER-2018BAX013121",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional": "1",
... |
{
"abstract": "Here we describe the case of a 19-year-old woman, in her 29th week of gestation, who was from Llumpe (Ancash, Peru) and had a history of traveling to Chanchamayo (Junín, Peru) and Rinconada (Ancash, Peru). The patient presented at Chacas Hospital (Chacas, Ancash, Peru) with general malaise, dehydration, respiratory distress, jaundice, the sensation of thermal rise, and abdominal pain. Analysis of blood smears revealed 60% hemoparasites. She was transferred to Ramos Guardia Hospital (Huaraz, Peru) where she presented increasing respiratory distress, choluria, hematuria, and decreased urine output, moreover she was positive for Plasmodium. From there she was transferred to Cayetano Heredia Hospital (Lima, Peru), where she was admitted to the intensive care unit (ICU) with multiple organ failure, stillbirth, and leading to death. She underwent mechanical ventilation, was administered clindamycin, and was prescribed quinine, which she did not received due a lack by availability. The evolution of the illness was torpid, and she ultimately developed multiple organ failure and died. Plasmodium vivax infection was confirmed. Accordingly, we emphasize the importance of improving our diagnostic capabilities and management techniques to enable clinicians to provide adequate and timely treatment.",
"affiliations": null,
"authors": "Arróspide|Nancy|N|;Espinoza|Máximo Manuel|MM|;Miranda-Choque|Edwin|E|;Mayta-Tristán|Percy|P|;Legua|Pedro|P|;Cabezas|César|C|",
"chemical_list": null,
"country": "Peru",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1726-4634",
"issue": "33(2)",
"journal": "Revista peruana de medicina experimental y salud publica",
"keywords": null,
"medline_ta": "Rev Peru Med Exp Salud Publica",
"mesh_terms": "D000328:Adult; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D008288:Malaria; D016780:Malaria, Vivax; D063130:Maternal Death; D010568:Peru; D010966:Plasmodium vivax; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D055815:Young Adult",
"nlm_unique_id": "101227566",
"other_id": null,
"pages": "368-72",
"pmc": null,
"pmid": "27656940",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Maternal death from severe malaria due to Plasmodium vivax.",
"title_normalized": "maternal death from severe malaria due to plasmodium vivax"
} | [
{
"companynumb": "PE-MYLANLABS-2016M1040317",
"fulfillexpeditecriteria": "1",
"occurcountry": "PE",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "A 72-year-old woman with end-stage kidney disease due to recurrent urinary tract infections and obstructive uropathy of a solitary kidney presented to our hospital for renal transplantation. She underwent successful transplantation of a deceased donor allograft, but developed acute mental status deterioration on the fifth postoperative day. Her serum ammonia was found to be markedly elevated to 447 μmol/L in the setting of normal hepatic function. She was treated with emergent dialysis and empiric antibiotics targeting urea-splitting organisms, and ultimately made a full neurologic recovery with stable renal allograft function. Noncirrhotic hyperammonemia (NCH) is an exceedingly rare clinical entity but seems to have a predilection for patients who have undergone solid organ transplantation. This report emphasizes the importance of rapid diagnosis and initiation of treatment for NCH, which is associated with a high rate of mortality and irreversible neurological morbidity. We outline the successful workup and management approach for this patient.",
"affiliations": "Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Medicine, Renal Division, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Surgery, Brigham and Women's Hospital, Boston, Massachusetts.;Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, Massachusetts.",
"authors": "Li|George Z|GZ|0000-0002-4588-7667;Tio|Maria C|MC|;Pak|Linda M|LM|;Krier|Joel|J|;Seifter|Julian L|JL|;Tullius|Stefan G|SG|;Riella|Leonardo V|LV|0000-0002-7636-3196;Malek|Sayeed K|SK|;Stergachis|Andrew B|AB|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.15545",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "19(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "clinical research/practice; encephalopathy; genetics; infection and infectious agents - bacterial; infectious disease; kidney disease; kidney transplantation/nephrology; metabolism/metabolite",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D003643:Death; D005260:Female; D006801:Humans; D022124:Hyperammonemia; D007676:Kidney Failure, Chronic; D016030:Kidney Transplantation; D011379:Prognosis; D014019:Tissue Donors; D014184:Transplantation, Homologous",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "3197-3201",
"pmc": null,
"pmid": "31347272",
"pubdate": "2019-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "17673917;8807124;25754921;20620562;9313001;697227;17250553;25573265;17538087;25904745;27537683;6798491;9178720",
"title": "Noncirrhotic hyperammonemia after deceased donor kidney transplantation: A case report.",
"title_normalized": "noncirrhotic hyperammonemia after deceased donor kidney transplantation a case report"
} | [
{
"companynumb": "US-ACCORD-169038",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VALGANCICLOVIR"
},
"drugadditional": "3",
"d... |
{
"abstract": "Lichen planus (LP) is an inflammatory disease affecting both adults and children that may present with numerous rare morphologies. LP and its many subtypes can prove difficult to treat and often leave patients with dyspigmentation. Additionally, pruritus associated with LP can be distressing to patients. The aim of this report is to highlight an uncommon subtype, annular atrophic lichen planus, which uniquely presented in a child, to emphasize the importance of early disease recognition and finally, to demonstrate successful treatment with topical monotherapy with clobetasol propionate ointment.",
"affiliations": "Division of Dermatology, Department of Internal Medicine, University of Louisville School of Medicine, Louisville, KY, USA.;University of Louisville School of Medicine, Louisville, KY, USA.;Division of Dermatology, Department of Internal Medicine, University of Louisville School of Medicine, Louisville, KY, USA.;Division of Pediatric Dermatology, Department of Pediatrics, University of Louisville School of Medicine, Louisville, KY, USA.",
"authors": "Sears|Samantha|S|;Daftary|Karishma|K|https://orcid.org/0000-0002-8759-6366;Burch|Andrea|A|;Todd|Patricia|P|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14812",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "38(5)",
"journal": "Pediatric dermatology",
"keywords": "dermatopathology; dyspigmentation; inflammatory disorders; pruritus; topical therapy",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000328:Adult; D002648:Child; D006801:Humans; D008010:Lichen Planus",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "1283-1287",
"pmc": null,
"pmid": "34561910",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016454:Review",
"references": null,
"title": "A case of annular atrophic lichen planus in a child and review of the literature.",
"title_normalized": "a case of annular atrophic lichen planus in a child and review of the literature"
} | [
{
"companynumb": "US-TOLMAR, INC.-21US030781",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOBETASOL PROPIONATE"
},
"drugadditional": ... |
{
"abstract": "OBJECTIVE\nRandomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99).\n\n\nRESULTS\nEighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections.\n\n\nCONCLUSIONS\nThe small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.",
"affiliations": "Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.;Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.;Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.;Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilian-University Munich, Munich, Germany.;Munich Leukemia Laboratory (MLL), Munich, Germany.;Department of Medicine A, Hematology-Oncology, University of Muenster, Muenster, Germany.;Department I of Internal Medicine, University at Cologne, Cologne, Germany.;Community Hospital Barmherzige Brüder, Regensburg, Germany.;Department of Medicine A, Hematology-Oncology, University of Muenster, Muenster, Germany.;Catholic Hospital, Hagen, Germany.;University of Kiel, Kiel, Germany.;Community Hospital München-Harlaching, Munich, Germany.;Community Hospital Düren, Düren, Germany.;Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.;Munich Leukemia Laboratory (MLL), Munich, Germany.;Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilian-University Munich, Munich, Germany.;Department of Hematology and Oncology, Charité University Medicine Berlin, Berlin, Germany.;Department of Hematology and Oncology, University Hospital Mannheim, Mannheim, Germany.;Department of Medicine A, Hematology-Oncology, University of Muenster, Muenster, Germany.;Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.;Institute of Biostatistics and Clinical Research, University of Muenster, Muenster, Germany.;Department of Medicine A, Hematology-Oncology, University of Muenster, Muenster, Germany.;Internal Medicine III, University Hospital Grosshadern, Ludwig-Maximilian-University Munich, Munich, Germany.",
"authors": "Lengfelder|Eva|E|http://orcid.org/0000-0002-2785-8168;Görlich|Dennis|D|;Nowak|Daniel|D|;Spiekermann|Karsten|K|;Haferlach|Claudia|C|;Krug|Utz|U|;Kreuzer|Karl-Anton|KA|;Braess|Jan|J|;Schliemann|Christoph|C|;Lindemann|Hans-Walter|HW|;Horst|Heinz A|HA|;Schiel|Xaver|X|;Flasshove|Michael|M|;Hecht|Anna|A|;Schnittger|Susanne|S|;Schneider|Stephanie|S|;Wörmann|Bernhard|B|;Hofmann|Wolf-Karsten|WK|;Berdel|Wolfgang E|WE|;Bormann|Eike|E|;Sauerland|Cristina|C|;Büchner|Thomas|T|;Hiddemann|Wolfgang|W|;|||",
"chemical_list": "D018943:Anthracyclines; D015415:Biomarkers; D003561:Cytarabine; D014212:Tretinoin",
"country": "England",
"delete": false,
"doi": "10.1111/ejh.12994",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0902-4441",
"issue": "100(2)",
"journal": "European journal of haematology",
"keywords": "acute promyelocytic leukemia; early death; high-dose cytosine arabinoside; high-risk APL; minimal residual disease; relapse",
"medline_ta": "Eur J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D015415:Biomarkers; D060830:Consolidation Chemotherapy; D003561:Cytarabine; D020732:Cytogenetic Analysis; D005260:Female; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute; D008297:Male; D008875:Middle Aged; D018365:Neoplasm, Residual; D012008:Recurrence; D012074:Remission Induction; D016019:Survival Analysis; D016896:Treatment Outcome; D014212:Tretinoin; D055815:Young Adult",
"nlm_unique_id": "8703985",
"other_id": null,
"pages": "154-162",
"pmc": null,
"pmid": "29114972",
"pubdate": "2018-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Frontline therapy of acute promyelocytic leukemia: Randomized comparison of ATRA and intensified chemotherapy versus ATRA and anthracyclines.",
"title_normalized": "frontline therapy of acute promyelocytic leukemia randomized comparison of atra and intensified chemotherapy versus atra and anthracyclines"
} | [
{
"companynumb": "DE-PFIZER INC-2017547848",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IDARUBICIN HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "Hypertrophic cardiomyopathy (HCM) is the most common inherited disease, with a prevalence of 1:200 worldwide. The cause of HCM usually presents with an autosomal dominant mutation in the genes encoding one of more than 20 sarcomeric proteins, incomplete penetrance, and variable expressivity. HCM classically manifests as an unexplained thickness of the interventricular septum (IVS) and left ventricular (LV) walls, with or without the obstruction of the LV outflow tract (LVOT), and variable cardiac arrhythmias. Here, we present a rare case of mixed cardiomyopathy (cardiac hypertrophy and dilation) and erythrocytosis in a young patient. A 27-year-old man was admitted to the clinic due to biventricular heart failure (HF) NYHA class III. Personal medical records included a diagnosis of dilated cardiomyopathy (DCM) since the age of 4 years and were, at the time, considered an outcome of myocarditis. Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis. The combination of non-obstructive LV hypertrophy (LV walls up to 15 mm), LV dilatation, decreased contractility (LV EF 24%), and LV apical thrombosis were seen. Cardiac MRI showed a complex pattern of late gadolinium enhancement (LGE). Endomyocardial biopsy (EMB) revealed primary cardiomyopathy with intravascular coagulation and an inflammatory response. No viral genome was detected in the plasma or EMB samples. Whole exome sequencing (WES) revealed a homozygous in-frame deletion p.2711_2737del in the MyBPC3 gene. The clinically unaffected mother was a heterozygous carrier of this deletion, and the father was unavailable for clinical and genetic testing. Essential erythrocytosis remains unexplained. No significant improvement was achieved by conventional treatment, including prednisolone 40 mg therapy. ICD was implanted due to sustained VT and high risk of SCD. Orthotopic heart transplantation (HTx) was considered optimal. Early manifestation combined hypertrophic and dilated phenotype, and progression may reflect a complex genotype with more than one pathogenic allele and/or a combination of genetic diseases in one patient.",
"affiliations": "Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia.;Medical Genetics Laboratory, Petrovsky National Research Centre of Surgery, Moscow, Russia.;Department of Bioinformatics, Centre of Genetics and Reproductive Medicine \"Genetico\", Moscow, Russia.;Medical Genetics Laboratory, Petrovsky National Research Centre of Surgery, Moscow, Russia.",
"authors": "Blagova|Olga|O|;Alieva|Indira|I|;Kogan|Eugenia|E|;Zaytsev|Alexander|A|;Sedov|Vsevolod|V|;Chernyavskiy|S|S|;Surikova|Yulia|Y|;Kotov|Ilya|I|;Zaklyazminskaya|Elena V|EV|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fphar.2020.579450",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812 Frontiers Media S.A. \n\n10.3389/fphar.2020.579450\nPharmacology\nCase Report\nMixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the MyBPC3 Gene Treated as Myocarditis for a Long Time\nBlagova Olga 1 Alieva Indira 1 Kogan Eugenia 1 Zaytsev Alexander 1 Sedov Vsevolod 1 Chernyavskiy S. 1 Surikova Yulia 2 Kotov Ilya 3 Zaklyazminskaya Elena V. 2* 1Sechenov First Moscow State Medical University, Sechenov University, Moscow, Russia\n2Medical Genetics Laboratory, Petrovsky National Research Centre of Surgery, Moscow, Russia\n3Department of Bioinformatics, Centre of Genetics and Reproductive Medicine “Genetico”, Moscow, Russia\nEdited by: Ya Liu, Army Medical University, China\n\nReviewed by: Tamer M. A. Mohamed, University of Louisville, United States; Thomas Seidel, University of Erlangen Nuremberg, Germany\n\n*Correspondence: Elena V. Zaklyazminskaya, zhelene@mail.ruThis article was submitted to Cardiovascular and Smooth Muscle Pharmacology, a section of the journal Frontiers in Pharmacology\n\n\n25 9 2020 \n2020 \n11 57945002 7 2020 09 9 2020 Copyright © 2020 Blagova, Alieva, Kogan, Zaytsev, Sedov, Chernyavskiy, Surikova, Kotov and Zaklyazminskaya2020Blagova, Alieva, Kogan, Zaytsev, Sedov, Chernyavskiy, Surikova, Kotov and ZaklyazminskayaThis 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.Hypertrophic cardiomyopathy (HCM) is the most common inherited disease, with a prevalence of 1:200 worldwide. The cause of HCM usually presents with an autosomal dominant mutation in the genes encoding one of more than 20 sarcomeric proteins, incomplete penetrance, and variable expressivity. HCM classically manifests as an unexplained thickness of the interventricular septum (IVS) and left ventricular (LV) walls, with or without the obstruction of the LV outflow tract (LVOT), and variable cardiac arrhythmias. Here, we present a rare case of mixed cardiomyopathy (cardiac hypertrophy and dilation) and erythrocytosis in a young patient. A 27-year-old man was admitted to the clinic due to biventricular heart failure (HF) NYHA class III. Personal medical records included a diagnosis of dilated cardiomyopathy (DCM) since the age of 4 years and were, at the time, considered an outcome of myocarditis. Severe respiratory infection led to circulatory decompensation and acute femoral thrombosis. The combination of non-obstructive LV hypertrophy (LV walls up to 15 mm), LV dilatation, decreased contractility (LV EF 24%), and LV apical thrombosis were seen. Cardiac MRI showed a complex pattern of late gadolinium enhancement (LGE). Endomyocardial biopsy (EMB) revealed primary cardiomyopathy with intravascular coagulation and an inflammatory response. No viral genome was detected in the plasma or EMB samples. Whole exome sequencing (WES) revealed a homozygous in-frame deletion p.2711_2737del in the MyBPC3 gene. The clinically unaffected mother was a heterozygous carrier of this deletion, and the father was unavailable for clinical and genetic testing. Essential erythrocytosis remains unexplained. No significant improvement was achieved by conventional treatment, including prednisolone 40 mg therapy. ICD was implanted due to sustained VT and high risk of SCD. Orthotopic heart transplantation (HTx) was considered optimal. Early manifestation combined hypertrophic and dilated phenotype, and progression may reflect a complex genotype with more than one pathogenic allele and/or a combination of genetic diseases in one patient.\n\nhypertrophic cardiomyopathydilated cardiomyopathyMyBPC3 geneheart failure progressionbi-allelic mutationsmyocarditisendomyocardial biopsyRussian Science Foundation10.13039/501100006769\n==== Body\nIntroduction\nPrimary myocardial diseases are one of the most difficult to diagnose and treat in cardiology. The most common inherited disease of the myocardium is hypertrophic cardiomyopathy (HCM), with an overall prevalence of approximately 1:200 worldwide (Maron et al., 2018). The disease is characterized by cardiac hypertrophy unexplained by pressure or volume overload, non-dilated left ventricle, and preserved or increased ejection fraction (Marian and Braunwald, 2017). HCM classically manifests as an unexplained thickness of the interventricular septum (IVS) and left ventricular (LV) walls with or without obstruction of the left ventricular outflow tract (LVOT), and variable arrhythmias (Marian and Braunwald, 2017). The cause of HCM is usually an autosomal dominant mutation in the genes encoding one of more than 20 sarcomeric proteins, incomplete penetrance, and variable expressivity (Kuusisto, 2020). The most common findings are causative variants of the MYH7 and MyBPC3 genes (Marian and Braunwald, 2017; Maron et al., 2018; Kuusisto, 2020). Generally, 5% to 7% of HCM index cases have two or more presumably damaging variants in the genes of interest; such patients have earlier manifestations, more pronounced cardiac hypertrophy, higher risk of sudden cardiac death, and increased risk of heart failure (Wang et al., 2014; Marian and Braunwald, 2017).\n\nMulti-systemic disorders, which can mimic “sarcomeric” HCM and progress to heart failure, account for up to 40% of all unexplained myocardial hypertrophy (Authors/Task Force members et al., 2014). These phenocopies have rather different genetic origins, molecular pathogenesis, and natural course of disease. Precise etiological diagnosis is significant because the short-term and long-term prognosis may widely differ, and some of these phenocopies have gene-specific targets available for therapy (Fabry disease, TTR-amyloidosis, etc.). Various epigenetic factors and mechanisms may also significantly modulate the clinical course of the disease and prognosis; an important factor being inflammation. The driving role of inflammation is widely discussed in dilated cardiomyopathy, but there are few studies discussing the role of myocarditis in the progression and de-compensation in patients with HCM (Frustaci et al., 2007). We suggest that myocarditis should always be taken into consideration in cases of unexplained deterioration of cardiomyopathy. The mixed phenotype of cardiomyopathy makes the search for more than one cause, especially relevant.\n\nHere, we present a case of progressive mixed hypertrophic and dilated cardiomyopathy in a young patient with a rare genetic cause: bi-allelic mutations in the MyBPC3 gene.\n\nCase Description\nA 27-year-old man was admitted to the cardiology department with symptoms of biventricular heart failure (NYHA class III), excessive sweating, and pain in the postoperative wound area at the site of thrombectomy 6 months prior to hospitalization.\n\nHis family history was unremarkable. Parents were not consanguineous. The father died at the age of 35, in a traumatic accident, and to the best of the patient’s knowledge, had no cardiac complaints. At the time of the first hospitalization, the mother was 56 years old and had no complaints. The proband had a sister who died at 15 days of age due to a congenital heart disease (transposition of the great arteries). No other relative was diagnosed with cardiomyopathy of other cardiac disease before 50 years of age. External risk factors: smoking average of three cigarettes/day for 7 years. No alcohol abuse or other toxic factors were mentioned.\n\nPersonal medical history with main milestones and medications taken (when possible) was reconstructed from the available medical records (Figure 1).\n\nFigure 1 The main milestones of the proband’s medical history. Reconstructed by the patient’s reports and medical records.\n\nThe patient had an average height (174 cm) and weight of 79 kg for his age, BMI 26.1 kg/m2, and normal arterial blood pressure (120/80 mmHg). Edema of the leg and slight serous discharge from the wound in the right groin area were found on the initial physical examination.\n\nDiagnostic Assessment\nHeadings Instrumental Investigations (ECG, EchoCG, Cardiac CT, and MRI With Gadolinium Enhancement)\nResting ECG showed HR 98 bpm, sinus tachycardia, signs of hypertrophy of both atria and ventricles, and low R waves in standard leads (Figure 2). Holter 24-h ECG monitoring revealed 289 PVBs of two morphologies and two episodes of non-sustained ventricular tachycardia of 4–7 beats 104–227 bpm. Echocardiography had shown (Figure 3) enlarged LA (110 ml) and RA (69 ml), dilated LV (end-diastolic diameter 6.4 cm, end-diastolic volume 236 ml, end-systolic volume 192 ml) with decreased contractility (LV EF 20%), and an enlarged RV (end-diastolic diameter 3.1 cm). LV diastolic function was significantly impaired (E, 35 cm/s; A, 23 cm/s; E/A, 1.5; DecT, 70 ms; Emed, 2.2 cm/s; E/Emed 15.8, 5 cm/s). Diffuse cardiac hypertrophy was revealed (IVS 14–16 mm, LV posterior wall 15–16 mm, RV walls 7–11 mm), with LV myocardial mass at 554.84 g. In the region of the apex, a fixed parietal thrombus was detected. Mild mitral, tricuspid, and pulmonary regurgitation were noted. The systolic pressure in the pulmonary artery was 36 mmHg.\n\nFigure 2 Resting ECG. HR 98 bpm, sinus tachycardia, signs of hypertrophy of both atria and ventricles, and decreased votage of the R waves in standard leads.\n\nFigure 3 Eсhocardiography. On the left—a severe decrease in left ventricular EF (at this measurement of 9%); in the center—a lining clot in the apex of the left ventricle with dimensions of 4 mm × 18 mm; on the right—hypertrophy of the left ventricular wall to 15–16 mm.\n\nCardiac CT revealed dilation of the LV chamber (69 mm) with a parietal clot spreading from the middle segment of the anterior wall to the apex (5 mm × 19 mm × 90 mm), and LV myocardial hypertrophy (up to 16 mm). In the delayed phase of LV myocardial contrast, it was diffusely heterogeneous. No definite late contrast enhancement or significant coronary stenosis was detected.\n\nOn cardiac MRI, the LV was spherical and severely dilated (EDD 71 mm, EDV 120 ml/m2) (Supplementary Figure 1). The wall thickness of the LV was 14 mm. Increased trabeculation of the LV was found but did not meet the criteria of the LVNC. A decrease in LV contractility with LV EF of 21% was confirmed. Several LGE sites were identified: transmural along the lower wall, subendocardial (up to 60%) in the apex of LV and apical segment of the anterior septum, and extended intra-ventricular LGE (“strip”) in the middle and apical segments of the septum. The apex of the LV was lined with a flat linear thrombus of 3.5 mm across it.\n\nLaboratory Blood Tests\nInitial blood tests revealed erythrocytosis (RBC, 6.85 mcL) and high white blood cell count (WBC, 27.8 × 10U3/ul). Platelet count was normal. Clinical chemistry showed a high hemoglobin level (193 g/L), increased hematocrit (65.8%), elevated erythropoietin (81.3 U/ml), slightly elevated creatinine (119.5 μmol/L), fibrinogen 4.67 g/L, and INR 5.85.\n\nHigh levels of anti-heart antibodies against cardiomyocytes’ nuclear antigens, endothelial antigens, cardiomyocyte antigens, conduction system fibers, and smooth muscle antigens were detected. No viral genome was detected by virus-specific PCR in the blood.\n\nEndomyocardial and Bone Marrow Biopsy\nA right ventricular endomyocardial biopsy was performed to verify the diagnosis of myocarditis. A combination of pathologically altered cardiomyocytes, productive vasculitis with thrombosis of individual vessels, and small perivascular lymphocytic-macrophage infiltrates (less than 14 cells) was detected (Figure 4). Morphological changes were specific for primary cardiomyopathies in combination with disseminated intravascular coagulation and secondary inflammatory reactions. The genomes of herpes virus, adenovirus, and parvovirus B19 were not detected by PCR in the myocardial biopsy sample.\n\nFigure 4 The endomyocardial biopsy of the right ventricle (10–50 micron scale). Hematoxylin eosin staining showed: the endocardium is thin. Cardiomyocytes with foci of enlightenment in the perinuclear zone, disarray, with homogenization of the cytoplasm. In individual cardiomyocytes, there are foci of myolysis with the formation of voids in the cytoplasm. Microvessels with red blood cell sludge phenomenon, sclerosed walls, proliferation of endothelial cells, stenosis of the lumen and single perivascular lymphohistiocytic cells. There are minor hemorrhages, mild sclerosis. Staining of congo red (in non-polarized and polarized light), Perls reaction, the PAS reaction are a negative.\n\nA bone marrow trepanobiopsy was performed to clarify the origin of erythrocytosis, but no evidence of myeloproliferative disease was found.\n\nGenetic Analysis\nWhole exome sequencing (WES) for the proband’s DNA was performed using a TruSeq Exome library preparation kit (IDT-Illumina) followed by next-generation sequencing on an Illumina system. Reads were aligned to the human genome build GRCh37/UCSC hg19 and analyzed for sequence variants using a custom-developed bioinformatics pipeline. The proband’s WES identified the homozygous deletion chr11:g.47357432_47357458del (ENST00000545968.1: c.2711_2737del) in the MyBPC3 gene p.2711_2737del. This variant was confirmed in the proband’s DNA in the homozygous state, and in his mother’s DNA in a heterozygous state. In-frame 27 bp deletion leads to the shortening of cardiac myosin binding protein for nine amino acids in the fibronectin III 2 (C7) domain (Supplementary Figure 2). This variant was classified as likely pathogenic (Class IV) based on the ACMG (2015) criteria (Richards et al., 2015). No additional pathogenic, likely pathogenic variants nor unique variant of unknown clinical significance was found in the genes responsible for cardiomyopathies or any other storage disorders. Thus, we suggest that bi-allelic deletion in the MyBPC3 gene might be sufficient explanation of the progressive cardiomyopathy in this patient. But, presence of additional variant in the less studied genomic area cannot be completely excluded. Strictly speaking there is an alternative explanation of the NGS and Sanger results for this patient. In theory, it might be a combination of hemizygous deletion due to the whole/partial deletion of the paternal allele (inherited or de novo). But, we have no any prove for it and for the best of our knowledge proband’s father had no complaints until he died in car accident at his 35.\n\nNo known pathogenic mutations or rare variants were found in the EPOR or other genes responsible for the familial erythrocytosis. No unique or known variants with proven clinical significance were found in the genes associated with inherited thrombophilia.\n\nThe combination of data from complex evaluation results in the following diagnosis: 1. Familial sarcomeric cardiomyopathy (homozygous deletion p.2711_2737del in the MyBPC3 gene), mixed phenotype (diffuse hypertrophic, dilated). 2. Ischemic cardiomyopathy due to impaired microcirculation with secondary inflammation. 3. Erythrocytosis of unknown origin\n\nSupportive therapy was prescribed: prednisolone 5 mg, bisoprolol 2.5 mg, amiodarone 200 mg, perindopril 2.5 mg, furosemide 40 mg, spironolactone 50 mg, warfarin, acetylsalicylic acid 100 mg, and omeprazole 20 mg. The patient’s condition remains relatively stable for 6 months of follow-up but transient edema, palpitations, sweating, dyspnea at the level of NYHA class 2–3 persisted. Hemoglobin levels returned to normal, but LV dysfunction (LV EF 19%) remained after a temporary improvement (LV EF 28%).\n\nSix months later, the patient experienced another acute thrombosis of the right posterior tibial artery without flotation, and conservative treatment was administered. Due to the development of thyrotoxicosis, amiodarone was replaced with sotalol. Therapy with prednisolone 5 mg per day was continued. In the next 6 months, ICD was implanted. No appropriate shocks were noted. The patient was included in the waiting list for heart transplantation. Unfortunately, despite the normalization of erythrocyte levels and two-component antithrombotic therapy, no improvement in myocardial contractility was noted. Prolonged therapy with prednisolone (at an initial dose of 40 mg per day) and standard cardiotropic therapy had no effect. Heart transplantation appears to be the optimal treatment option.\n\nDiscussion\nThis clinical case was unusual and challenging in many respects. The combination of severe systolic dysfunction with dilatation of all heart chambers and evident diffuse myocardial hypertrophy is a rare clinical observation. Dilatation of the spherical changed LV with a markedly reduced EF can be a manifestation of both primary DCM and severe myocarditis. At the same time, dilated cardiomyopathy might represent the decompensating stage of any cardiomyopathy.\n\nThe wall thickness of the LV met the criteria for HCM. Typical cardiomyocyte disarray found in myocardial biopsy samples was a particular feature of the primary HCM, and the patient had no obvious reason for pressure overload. However, the anatomical variant of cardiac remodeling with diffused, generalized LV walls and right ventricular involvement is more typical for phenocopies of HCM, especially for storage disorders. Among the storage diseases, the earliest decompensation is typical of Danon disease. Therefore, in one of the last studies, unfavorable outcomes (death/transplantation) were noted in one-third of men, with an average age of 21 years (Brambatti et al., 2019). However, the degree of myocardial hypertrophy in our patient was unusually low for Danon disease in men. In addition, he had no typical systemic manifestations of Danon disease, as well as other storage diseases involving the heart (Fabry’s disease, for example). No data was obtained for storage disease in myocardial biopsy after special staining (periodic Acid-Schiff and Congo red in polarized light). Finally, no pathogenic/likely pathogenic genetic variant was found in the genes responsible for the known storage disorders after whole-exome sequencing.\n\nProlonged undulating course of the disease from 4 years with periods of persistent improvement, possible effects of steroid therapy in the past, the association of rapid deterioration at 26 years with influenza, LV apex thrombosis, preservation of elevated titers of anti-heart antibodies, and mild signs of inflammation in myocardial biopsy despite steroid therapy, might provide evidence of myocarditis. Steroid therapy was started before the patient came to the clinic, which made it difficult to interpret the biopsy data. However, no clinical effect of the steroid prescription was observed despite the absence of viruses in the myocardium.\n\nInefficiency of steroids and early debut of the disease may have been evidence of primary DCM. However, there was no explanation for diffuse myocardial hypertrophy. The presence of increased trabeculation of the myocardium according to MRI is more typical for sarcomeric cardiomyopathy. Mixed and severe phenotypes have also been reported. Some authors have even proposed the concept of a continuum of sarcomeric cardiomyopathies (Baldi et al., 2010). The cause of rapid decompensation in a previously stable course (myocardial embolic infarct? myocarditis)? was unclear in this case. The pattern of LGE according to MRI could reflect both inflammation and myocardial necrosis. In addition, there were signs of fibrosis, typical of primary myocardial hypertrophy. The diagnosis of isolated sarcomeric HCM was inconsistent with the early manifestation of the DCM phenotype.\n\nAccording to a large multicenter cohort study, the average age of decompensation for patients with sarcomeric HCM was 45 years (Biagini et al., 2014). The earliest (41 years on average) appearance of final stage of HCM developed in patients with mutations in gene MYH7 and multiple mutations. However, only adult patients were included in the study. According to the data from the Mayo Clinic, out of 2,073 patients with HCM, only eight had EF below 50%, (Killu et al., 2018). Their average age was 44 years. Only five patients underwent LVAD implantation and cardiac heart transplantation 15 years prior to HCM diagnosis. All this data indicated that our case was atypical for an isolated sarcomeric HCM.\n\nThe most likely, therefore, was the primary (genetically determined) nature of cardiomyopathy in our patient. One could think of a combination of two or more mutations in the genes of interest for HCM, and we found a bi-allelic mutation in the MyBPC3 gene. Deletion of nine amino acids raised in the highly conservative C7 FnIII domain (Supplementary Figure 2) framed with amino acids from 872 to 967 (Karsai et al., 2011). Several missense mutations (for example, p.Pro873Leu, p. Pro873His, p.Asn948Thr, p. Thr957Ser, p.Thr958Ile) leading to HCM, DCM and LV non-compaction were described in this region (Daehmlow et al., 2002; Nanni et al., 2003; Lekanne Deprez et al., 2006; Ehlermann et al., 2008; Probst et al., 2011). It’s remarkable that most of them were discussed in patients with rapid progression of HCM to a dilated phase even in mono-allelic state (Daehmlow et al., 2002; Nanni et al., 2003; Lekanne Deprez et al., 2006; Ehlermann et al., 2008; Probst et al., 2011). There is no large randomized study regarding the natural course of HCM in patients carrying more than one pathogenic or likely pathogenic allele. However, many particular clinical cases, case-control and observational studies have pointed out that the role of a second genetic hit can be crucial in the age of HCM manifestation (Wessels et al., 2015; Dzemeshkevich et al., 2018; Kissopoulou et al., 2018). Prospective genetic counseling was also challenging. Despite well-accepted autosomal dominant nature of HCM and severe phenotype in our patient, the prognosis for off-springs seems to be favorable. We based it on the fact that his parents were asymptomatic (mother, confirmed carrier, is asymptomatic at 57 y.o.; and father, presumed carrier, was asymptomatic at 35 y.o. when died in accident). Thus, we hypothesize that this deletion p.2711_2737del in mono-allelic state is highly tolerated. But, in the absence of direct confirmation of the health status and genotype of the father, we cannot claim it confidently.\n\nThe role of associated myocarditis in the development of rapid decompensation cannot be excluded. However, a mild inflammatory reaction detected in the biopsy may have developed secondary to primary myocardial damage. In any case, there were no indications for aggressive treatment of inflammation.\n\nFinally, it was necessary to exclude polycythemia vera as a cause of erythrocytosis, which can aggravate myocardial dysfunction due to microcirculation disorders. Even cases of massive myocardial infarcts in patients with polycythemia and normal coronary arteries are described (Nahler et al., 2017). Myocardial biopsy data confirmed this mechanism to be dysfunctional. There were no strong data to support primary erythrocytosis. No mutations in the genes of interest were identified based on wide genetic screening, and no signs of myeloproliferative disease in bone marrow biopsy were found. Elevated erythropoietin levels could indicate a compensatory mechanism of erythrocytosis due to hypoxia.\n\nAmong epigenetic mechanisms, decompensation may influence a lot of the clinical appearance and disease progression. However, we believe chronic microcirculation disorder (sludge, microthrombosis, hemorrhage with cardiomyocyte death) and secondary inflammatory response are responsible for the myocardial damage. It is also impossible to rule out embolic infarction of the lower wall of the left ventricle or necrosis due to intravascular clogging.\n\nCorrect diagnosis influence a lot the treatment strategy, long-term prognosis, life style modifications, and reproductive strategy. Information about primary nature of disease is usually stressful what raises many questions regarding risk of transmission and health perspectives and may affect quality of life. Communicating the genetic risk information to maximize understanding and promote health is increasingly important given the rapidly expanding availability and capabilities of genomic and reproductive technologies (Lautenbach et al., 2013). In this clinical case, the prognosis for offspring is favorable provided that second partner in the couple has no HCM. This information was very important for our patient. Currently, there are no options of intervention in primary genetic cardiomyopathy. But, currently, several gene therapy approaches have been developed to rescue genetic defects in “sarcomeric” genes, and, especially, in the MyBPC3 (Prondzynski et al., 2019). We believe that accumulation of information about natural course of HCM caused by particular mutations and their combinations may provide important insights of new treatment strategies.\n\nConclusion\nHere, we present a rare case of mixed hypertrophic and dilated cardiomyopathy in a young patient complicated by myocarditis, erythrocytosis, and recurrent thrombi. Disease progression was more severe than usual in classic HCM patients, but relatively long lasting for pediatric DCM first diagnosed at 4 years. Etiological diagnosis was challenging. It required a differential diagnosis between primary, inflammatory, and ischemic myocardial damage. Whole exome sequencing revealed bi-allelic deletion in the MyBPC3 gene, but erythrocytosis remained unexplained. This observation supports the hypothesis that the co-existence of the genetic causes and additional external factors (thrombosis, inflammation, etc.) contribute significantly to the phenotype and HF progression, and it is important to reveal all of them. Successful diagnostic search and optimal management is only possible with a multidisciplinary team and a whole spectrum of investigations from cardiac imaging and myocardial biopsy to deep genotyping. Experimental research including iPS-CMs studies are needed for the detailed evaluation of the effect of the p.2711_2737del variant in hetero- and homozygous state on myosin-binding protein C3 functioning, and for further insight on molecular mechanisms of cardiomyopathy.\n\nPatient Perspective\n“I have many concerns regarding my future. I’ve thought about heart transplantation and came to the referred Centre. I need to live close to this Centre but I don’t have any opportunity to live in Moscow continiously. I would get on the waiting list but have many concerns about risks related to the operation by itself and subsequent immunosupression. So the question is still open. Well, how to say, I will live as long as I can, and how long it left. I think it will get worse, and I sometimes feel it, but I’m not telling anyone in my city what the condition is now, not to relatives nor my doctor from my city. I don’t think it makes sense if no one can really change the course of genetic disease, right?”\n\nData Availability Statement\nThe raw clinical and genetic data supporting this article cannot be placed in public repository due to ethical reason (personal data protection) but it will be available by the corresponding author (ZE, zhelene@mail.ru) upon reasonable request.\n\nEthics Statement\nInformed written consent was obtained from the patient for this clinical case publication, and all data and figures included in this article.\n\nAuthor Contributions\nOB, IA, AZ, and SC participated in the diagnosis and treatment of the patient. EK and VS performed histopathological and instrumental investigations. YS and IK performed wet and bioinformatic genetic investigation. EZ performed genetic counseling of the family. OB and ZE prepared the draft of the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\nThis work was funded by Russian Science Foundation (Grant № 16-15-10421).\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\nAcknowledgments\nWe thank our patient for his kind permission to present this clinical case and sharing his personal perception of disease and its genetic nature.\n\nSupplementary Material\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020.579450/full#supplementary-material\n\nSupplementary Figure 1 Cardiac MRI with gadolinium enchamcement. LV was spherical, severely dilated (EDD 71 mm, EDV 120 ml/m2), with increased thickness (14 mm) and trabeculae. LV EF of 21%. Several LGE sites: transmural along the lower wall, subendocardial (up to 60%) in the apex of LV and apical segment of the anterior septum, and extended intra-ventricular LGE (“strip”) in the middle and apical segments of the septum. The apex of the LV was lined with a flat linear thrombus of 3.5 mm across it.\n\nClick here for additional data file.\n\n Supplementary Figure 2 Schematic representation of deletion of the 27 bp (chr11:g.47357432_47357458del (ENST00000545968.1: c.2711_2737del) in the MyBPC3 gene found in proband in homozygous state at the DNA, mRNA, and protein level.\n\nClick here for additional data file.\n==== Refs\nReferences\n\nAuthors/Task Force members Elliott P. M. Anastasakis A. Borger M. A. Borggrefe M. Cecchi F. (2014 ). ESC Guidelines on diagnosis and management of hypertrophic cardiomyopathy: the Task Force for the Diagnosis and Management of Hypertrophic Cardiomyopathy of the European Society of Cardiology (ESC)\n. Eur. 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"fulltext_license": "CC BY",
"issn_linking": "1663-9812",
"issue": "11()",
"journal": "Frontiers in pharmacology",
"keywords": "MyBPC3 gene; bi-allelic mutations; dilated cardiomyopathy; endomyocardial biopsy; heart failure progression; hypertrophic cardiomyopathy; myocarditis",
"medline_ta": "Front Pharmacol",
"mesh_terms": null,
"nlm_unique_id": "101548923",
"other_id": null,
"pages": "579450",
"pmc": null,
"pmid": "33101033",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "22004751;29663722;20860157;16679492;25741868;25132132;25173338;21551322;25037680;25335496;28912181;17309901;18957093;30857840;32546508;24003856;29971600;12379228;29315424;28148580;29724362;12951062",
"title": "Mixed Hypertrophic and Dilated Phenotype of Cardiomyopathy in a Patient With Homozygous In-Frame Deletion in the MyBPC3 Gene Treated as Myocarditis for a Long Time.",
"title_normalized": "mixed hypertrophic and dilated phenotype of cardiomyopathy in a patient with homozygous in frame deletion in the mybpc3 gene treated as myocarditis for a long time"
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"abstract": "We investigated the therapeutic potential of the interleukin-6 receptor inhibitor tocilizumab in 7 patients with new onset refractory status epilepticus (NORSE) who remained refractory to conventional immunotherapy with rituximab (n = 5) or without rituximab (n = 2). Status epilepticus (SE) was terminated after 1 or 2 doses of tocilizumab in 6 patients with a median interval of 3 days from the initiation. They had no recurrence of SE during the observation. However, 2 patients experienced severe adverse events related to infection during the tocilizumab therapy. Further prospective controlled studies are warranted to validate the efficacy and safety of tocilizumab in patients with NORSE. Ann Neurol 2018;84:940-945.",
"affiliations": "Department of Neurology, School of Medicine, Kyungpook National University, Kyungpook National University Chilgok Hospital, Daegu, South Korea.;Department of Neurology, Seoul National University Hospital, Seoul, South Korea.;Department of Neurology, Seoul National University Hospital, Seoul, South Korea.;Department of Neurology, Seoul National University Hospital, Seoul, South Korea.;Department of Neurology, Seoul National University Hospital, Seoul, South Korea.",
"authors": "Jun|Jin-Sun|JS|;Lee|Soon-Tae|ST|0000-0003-4767-7564;Kim|Ryul|R|;Chu|Kon|K|0000-0001-5863-0302;Lee|Sang Kun|SK|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D016207:Cytokines; D007155:Immunologic Factors; C502936:tocilizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/ana.25374",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0364-5134",
"issue": "84(6)",
"journal": "Annals of neurology",
"keywords": null,
"medline_ta": "Ann Neurol",
"mesh_terms": "D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D015331:Cohort Studies; D016207:Cytokines; D000069279:Drug Resistant Epilepsy; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D013226:Status Epilepticus; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7707449",
"other_id": null,
"pages": "940-945",
"pmc": null,
"pmid": "30408233",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Tocilizumab treatment for new onset refractory status epilepticus.",
"title_normalized": "tocilizumab treatment for new onset refractory status epilepticus"
} | [
{
"companynumb": "KR-CHUGAI-2021023774",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"... |
{
"abstract": "BACKGROUND\nSignal transducer and activator 1 (STAT-1) mutations are rare and have been implicated in combined immunodeficiency, enhanced tumorigenesis, and vascular defects.\n\n\nMETHODS\nA 60-year-old woman with a novel STAT-1 mutation and resulting immunodeficiency, squamous cell carcinoma, and vascular disease presented with profuse epistaxis secondary to rupture of an aberrant artery that she developed in part because of this mutation. After unsuccessful posterior packing, embolization was initiated but subsequently aborted because of a bovine origin carotid artery and a history of multiple carotid dissections.\n\n\nRESULTS\nAfter repeat posterior packing, hemostasis was achieved. No additional episodes of epistaxis occurred in the subsequent 13 months.\n\n\nCONCLUSIONS\nVascular anomalies can present challenges in epistaxis management. In patients with conditions known to cause vascular anomalies, it is critical to obtain vascular imaging before intervention.",
"affiliations": "Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut.;Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut.;Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut.;Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut.;Department of Surgery, Section of Otolaryngology, Yale University School of Medicine, New Haven, Connecticut.",
"authors": "Chang|Michael T|MT|;Schwam|Zachary G|ZG|;Hajek|Michael A|MA|;Paskhover|Boris|B|;Judson|Benjamin L|BL|",
"chemical_list": "D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human",
"country": "United States",
"delete": false,
"doi": "10.1002/hed.24165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "38(3)",
"journal": "Head & neck",
"keywords": "carcinoma; epistaxis; immunologic deficiency syndromes; signal transducer and activator 1 (STAT-1) transcription factor; squamous cell carcinoma of the head and neck; vascular diseases",
"medline_ta": "Head Neck",
"mesh_terms": "D002294:Carcinoma, Squamous Cell; D002339:Carotid Arteries; D002340:Carotid Artery Diseases; D000072226:Computed Tomography Angiography; D004844:Epistaxis; D005260:Female; D006801:Humans; D008875:Middle Aged; D009062:Mouth Neoplasms; D009154:Mutation; D027383:Papillomaviridae; D030361:Papillomavirus Infections; D050794:STAT1 Transcription Factor",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E68-70",
"pmc": null,
"pmid": "26445901",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Severe epistaxis due to aberrant vasculature in a patient with STAT-1 mutation.",
"title_normalized": "severe epistaxis due to aberrant vasculature in a patient with stat 1 mutation"
} | [
{
"companynumb": "US-BAYER-2016-049383",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
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"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
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"drugadditional": null,
"dr... |
{
"abstract": "While being treated with azathioprine and dexamethasone, a 21-year old man with myasthenia gravis suddenly developed rapidly progressing brown macules, predominantly on the trunk, palms and soles. We made a diagnosis of eruptive melanocytic nevi (EMN). This rare entity can appear after blistering skin diseases, in immunocompromised patients, and, in particular, during immunosuppressive therapy for autoimmune diseases. Since therapeutic regimens including azathioprine have been frequently reported in association with EMN, we recommended to our patient a treatment switch to mycophenolic acid to prevent the development of more nevi.",
"affiliations": "Hautklinik, Universitätsklinikum Düsseldorf, Moorenstr. 5, 40225, Düsseldorf, Deutschland.",
"authors": "Braun|S A|SA|;Helbig|D|D|;Frank|J|J|;Hanneken|S|S|",
"chemical_list": "D007166:Immunosuppressive Agents; D001379:Azathioprine",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00105-012-2440-x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0017-8470",
"issue": "63(10)",
"journal": "Der Hautarzt; Zeitschrift fur Dermatologie, Venerologie, und verwandte Gebiete",
"keywords": null,
"medline_ta": "Hautarzt",
"mesh_terms": "D001379:Azathioprine; D003875:Drug Eruptions; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D009157:Myasthenia Gravis; D009508:Nevus, Pigmented; D012878:Skin Neoplasms; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0372755",
"other_id": null,
"pages": "756-9",
"pmc": null,
"pmid": "23008007",
"pubdate": "2012-10",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": "14639379;15858520;20644052;16634890;19194340;15811090;22402255",
"title": "Eruptive melanocytic nevi during azathioprine therapy in myasthenia gravis.",
"title_normalized": "eruptive melanocytic nevi during azathioprine therapy in myasthenia gravis"
} | [
{
"companynumb": "DE-BAUSCH-BL-2019-000551",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "Infectious keratitis in contact lens wearers Infectious keratitis is a sight-threatening complication in contact lens wearers. The infection is most frequently caused by bacteria (Pseudomonas aeruginosa). However, fungi or Acanthamoeba are found in increasing frequency. Three cases illustrate a characteristic course: patient A (11-year-old male) was treated for three weeks before the characteristic aspect of Acanthamoeba keratitis was recognized and confirmed. Patient B (45-year-old female) developed a severe corneal ulcer within 4 days; microbiological diagnostics confirmed Pseudomonas aeruginosa keratitis. Examination of patient C (27-year-old female) showed an infiltrate with satellites, typical of fungal keratitis. It is important to check the use of contact lenses in patients with keratitis. Referral to the ophthalmologist is mandatory: immediate in cases with an infiltrate. A dentritiform epithelial lesion in a contact lens wearer is indicative of Acanthamoeba keratitis, whereas fungal keratitis shows satellites or feathering edges. Steroids may only be prescribed by an ophthalmologist after confirmation of the causative agent.",
"affiliations": "Radboudumc, afd. Oogheelkunde, Nijmegen.;Radboudumc, afd. Medische Microbiologie, Nijmegen.;Het Oogziekenhuis Rotterdam, Rotterdam.;UMC Groningen, afd. Oogheelkunde, Groningen.",
"authors": "Eggink|Cathrien A|CA|;Oliveira Dos Santos|Claudy|C|;Randag|Anna C|AC|;Wijdh|Robert Jan|RJ|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "163()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000048:Acanthamoeba; D015823:Acanthamoeba Keratitis; D002648:Child; D003261:Contact Lenses; D005260:Female; D006801:Humans; D007634:Keratitis; D008297:Male; D008875:Middle Aged; D011552:Pseudomonas Infections; D011550:Pseudomonas aeruginosa",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "31120209",
"pubdate": "2019-05-16",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Infectious keratitis in contact lens wearers.",
"title_normalized": "infectious keratitis in contact lens wearers"
} | [
{
"companynumb": "NL-ALLERGAN-2028408US",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "UNSPECIFIED INGREDIENT"
},
"drugadditional": "1",... |
{
"abstract": "Pregnancy in acromegaly is rare and generally safe, but tumour expansion may occur. Managing tumour expansion during pregnancy is complex, due to the potential complications of surgery and side effects of anti-tumoural medication. A 32-year-old woman was diagnosed with acromegaly at 11-week gestation. She had a large macroadenoma invading the suprasellar cistern. She developed bitemporal hemianopia at 20-week gestation. She declined surgery and was commenced on 100 µg subcutaneous octreotide tds, with normalisation of her visual fields after 2 weeks of therapy. She had a further deterioration in her visual fields at 24-week gestation, which responded to an increase in subcutaneous octreotide to 150 µg tds. Her vision remained stable for the remainder of the pregnancy. She was diagnosed with gestational diabetes at 14/40 and was commenced on basal bolus insulin regimen at 22/40 gestation. She otherwise had no obstetric complications. Foetal growth continued along the 50th centile throughout pregnancy. She underwent an elective caesarean section at 34/40, foetal weight was 3.2 kg at birth with an APGAR score of 9. The neonate was examined by an experienced neonatologist and there were no congenital abnormalities identified. She opted not to breastfeed and she is menstruating regularly post-partum. She was commenced on octreotide LAR 40 mg and referred for surgery. At last follow-up, 2 years post-partum, the infant has been developing normally. In conclusion, our case describes a first presentation of acromegaly in pregnancy and rescue of visual field loss with somatostatin analogue therapy. Learning points: Tumour expansion may occur in acromegaly during pregnancy. Treatment options for tumour expansion in pregnancy include both medical and surgical options. Somatostatin analogues may be a viable medical alternative to surgery in patients with tumour expansion during pregnancy.",
"affiliations": "Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland.;Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland.;Departments of Neurosurgery, Cork University Hospital, Cork, Ireland.;Department of Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK.;Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, Ireland.;Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, Ireland.;Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland.",
"authors": "Hannon|Anne Marie|AM|;Frizelle|Isolda|I|;Kaar|George|G|;Hunter|Steven J|SJ|;Sherlock|Mark|M|;Thompson|Christopher J|CJ|;O'Halloran|Domhnall J|DJ|;|||",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nEndocrinol Diabetes Metab Case RepEndocrinol Diabetes Metab Case RepEDMEndocrinology, Diabetes & Metabolism Case Reports2052-0573Bioscientifica Ltd Bristol 10.1530/EDM-19-0019EDM190019Novel TreatmentOctreotide use for rescue of vision in a pregnant patient with acromegaly A M Hannon and othersOctreotide in pregnancy and acromegalyHannon Anne Marie 1Frizelle Isolda 1Kaar George 2Hunter Steven J 3Sherlock Mark 4Thompson Christopher J 4O’Halloran Domhnall J 1the Irish Pituitary Database Group 1 Departments of Endocrinology and Diabetes, Cork University Hospital, Cork, Ireland2 Departments of Neurosurgery, Cork University Hospital, Cork, Ireland3 Department of Endocrinology and Diabetes, Royal Victoria Hospital, Belfast, UK4 Department of Endocrinology and Diabetes, Beaumont Hospital, Dublin, IrelandCorrespondence should be addressed to A M Hannon; Email: annemarie_hannon@hotmail.com20 5 2019 2019 2019 19-001929 3 2019 08 4 2019 © 2019 The authors2019The authors This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License..Summary\nPregnancy in acromegaly is rare and generally safe, but tumour expansion may occur. Managing tumour expansion during pregnancy is complex, due to the potential complications of surgery and side effects of anti-tumoural medication. A 32-year-old woman was diagnosed with acromegaly at 11-week gestation. She had a large macroadenoma invading the suprasellar cistern. She developed bitemporal hemianopia at 20-week gestation. She declined surgery and was commenced on 100 µg subcutaneous octreotide tds, with normalisation of her visual fields after 2 weeks of therapy. She had a further deterioration in her visual fields at 24-week gestation, which responded to an increase in subcutaneous octreotide to 150 µg tds. Her vision remained stable for the remainder of the pregnancy. She was diagnosed with gestational diabetes at 14/40 and was commenced on basal bolus insulin regimen at 22/40 gestation. She otherwise had no obstetric complications. Foetal growth continued along the 50th centile throughout pregnancy. She underwent an elective caesarean section at 34/40, foetal weight was 3.2 kg at birth with an APGAR score of 9. The neonate was examined by an experienced neonatologist and there were no congenital abnormalities identified. She opted not to breastfeed and she is menstruating regularly post-partum. She was commenced on octreotide LAR 40 mg and referred for surgery. At last follow-up, 2 years post-partum, the infant has been developing normally. In conclusion, our case describes a first presentation of acromegaly in pregnancy and rescue of visual field loss with somatostatin analogue therapy.\n\nLearning points:\nTumour expansion may occur in acromegaly during pregnancy.\n\nTreatment options for tumour expansion in pregnancy include both medical and surgical options.\n\nSomatostatin analogues may be a viable medical alternative to surgery in patients with tumour expansion during pregnancy.\n==== Body\nBackground\nAcromegaly is a rare disease characterised by excessive growth hormone production. Subfertility is common in acromegaly and has various aetiologies, both as a result of the pituitary adenoma and also due to the treatments involved to treat the disease resulting in hypogonadism.\n\nPregnancy in acromegaly has been reported to be generally safe (1, 2, 3); however, rarely tumour expansion may occur. As this is a rare occurrence, little is known regarding the optimum management of these patients during pregnancy. Here, we present the first case of resolution of a visual field defect with the use of somatostatin analogues during pregnancy.\n\nCase presentation\nA 32-year-old woman presented at 11-week gestation of a planned pregnancy to her local hospital with headaches. She had a past medical history of asthma and depression. A CT scan of the brain was performed due to claustrophobia and a pituitary lesion was identified. She was referred to her regional pituitary centre and was noted to have enlarged hands, prognathism and increased inter-dentate spacing. She denied any visual disturbance and formal visual field testing confirmed intact fields. She had no family history of pituitary disease.\n\nInvestigation\nMRI of her pituitary gland without contrast confirmed a 3.0 × 2.6 × 2.6 cm mass with significant distortion of the infundibulum and optic chiasm (Fig. 1A). Her plasma GH concentration was significantly elevated at 65 μg/L following a glucose load at 12 weeks. Her plasma glucose concentrations were in the normal range, her prolactin was 827 mU/L (reference value in non-pregnant females:102–496 mU/L – ) and her plasma IGF-1 concentration (IDS-iSYS) was also elevated at 82 nmol/L (normal range: 9–33 nmol/L). Her plasma GH concentration was measured using the IDS-iSYS assay, which is specific for 22 kDa pituitary GH.Figure 1 (A) T2 pituitary MRI at 12/40 – macroadenoma extending upwards into the suprasellar region causing distortion of the optic chiasm at 12 weeks’ gestation. (B) T2 pituitary MRI at 20/40 3.2 × 2.7 × 2.8 cm macroadenoma extending upwards into the suprasellar region causing compression of the optic chiasm at 20 weeks’ gestation.\n\n\n\n\nHer morning cortisol was 116 nmol/L and due to difficulty with interpreting ACTH axis testing during pregnancy, it was deemed safest she commence replacement dose glucocorticoid treatment for presumptive ACTH deficiency. Biweekly visual field testing was arranged to monitor for tumour expansion. Her baseline blood results are summarised in Table 1.\nTable 1 Baseline endocrine laboratory evaluations.\n\n\tResults at 12/40\tPost-partum\tNormal range\t\nT4 (pmol/L)\t17.6\t17.1\t12–22\t\nTSH (mIU/L)\t0.7\t0.63\t0.4–3.8\t\nIGF-1 (nmol/L)\t82\t60\t9–33\t\nProlactin (mU/L)\t827\t557\t102–496\t\nGH (μg/L)\t65\t9.81\t\t\nRandom cortisol (nmol/L)\t116\t99\t\t\n\n\n\nTreatment\nAt 20/40 gestation she was reviewed in the pituitary clinic and complained of increased headaches. Repeat non-contrast MRI showed a slight increase in the size of the adenoma at 3.2 × 2.7 × 2.8 cm with significant compression of the infundibulum and optic chiasm (Fig. 1B). Formal perimetry testing revealed bitemporal hemianopia (Fig. 2). Surgical and medical options were discussed with the patient. The patient declined surgical intervention and opted for medical therapy. Both cabergoline and octreotide therapies were considered, however, in view of the superior anti-tumour effects of octreotide, she was initiated on 100 µg octreotide subcutaneously tds. Her visual field deficit completely recovered on repeat visual field testing after 2 weeks. At 24/40 gestation there was a further deterioration in her visual fields and her octreotide dose was increased to 150 µg tds. She once again had a resolution of her visual field defect to normal within 2 weeks. Her vision remained stable for the remainder of pregnancy on the increased dose.Figure 2 Formal perimetry testing throughout pregnancy – demonstrating a dramatic improvement in bitemporal hemianopia following the introduction of octreotide . LE, left eye; RE, right eye.\n\n\n\n\nOutcome and follow-up\nShe was diagnosed with gestational diabetes when screened at 14/40. She was initially treated with dietary modifications, but was commenced on basal bolus insulin regimen at 22/40 due to elevated fasting capillary glucose readings. She remained normotensive throughout pregnancy.\n\nFoetal growth continued along the 50th centile throughout pregnancy. She underwent an elective caesarean section at 34/40, foetal weight was 3.2 kg at birth with an APGAR score of 9. The neonate was examined by an experienced neonatologist and no congenital abnormalities were identified. She opted not to breastfeed and she is menstruating regularly post-partum. Her biochemical assessment post-partum showed a mildly elevated serum prolactin concentration of 557 mU/L (102–496) and normal thyroid function (Table 1). Her random GH and plasma IGF-1 concentrations were significantly elevated at 9.81 μg/L and 60 nmol/L (normal range: 9–33) respectively.\n\nPost-partum, she discontinued all medication for diabetes mellitus, her repeat OGTT showed impaired glucose tolerance and her HbA1c was controlled at 44 mol/mol with no medication. Her ACTH axis was normal when it was evaluated in the post-partum period, she had a peak cortisol of 527 nmol/L on an insulin tolerance test. She was commenced on octreotide LAR 40 mg and referred for surgery. Immunohistochemical analysis of her adenoma showed a sparsely granulated tumour which stained positively for GH and sparse staining of prolactin. The adenoma did not stain for FSH, LH, TSH or ACTH.\n\nShe had persistent hyper-secretion post-operatively and monthly octreotide LAR was restarted. She has not yet been screened for an AIP mutation. At last follow-up, the infant has been developing normally at age 2 years.\n\nDiscussion\nAcromegaly is a low prevalence disease characterised by growth hormone hyper-secretion. Subfertility is common in acromegaly and has numerous aetiologies, both as a result of the pituitary adenoma but also the treatments involved to treat the disease resulting in hypogonadism. Therefore, pregnancy in acromegaly is rare with less than 200 cases reported in the literature. The limited data that are available suggest that pregnancy in acromegaly is generally safe (1, 3, 4); however, there have been case reports of tumour expansion and the development of visual field deficits during pregnancy (5).\n\nThe largest series of pregnancy in acromegaly is derived from the French acromegaly registry, which published pregnancy outcomes in 59 pregnancies in 46 women. Four of 59 pregnancies in this cohort were complicated by clinically apparent tumour expansion; 3 of these were women who were diagnosed with acromegaly whilst pregnant. None of these four women were treated with a somatostatin analogue, one received glucocorticoids, two received glucocorticoid therapy and bromocriptine and one had surgical intervention in the second trimester (1). However, other case series have not demonstrated any visual field deficits in spite of the withdrawal of medical therapy (6). As tumour expansion during pregnancy is rare, the approach to the pregnant acromegaly patient with tumour expansion is guided only by available case reports.\n\nThe goals of management of acromegaly shift during pregnancy. Both maternal and foetal perspectives need to be considered. The Endocrine Society Guidelines recommend withdrawing medical treatment before pregnancy and monitoring visual fields in each trimester (7). In exceptional cases where tumour expansion occurs, the options for treatment include both medical and surgical approaches. In this case, our patient declined surgery and was therefore offered medical therapy as an alternative to preserve her visual fields.\n\nDuring normal pregnancy, placental GH, which bears significant homology with 22 kDa pituitary GH, is released in increasing amounts throughout the pregnancy. Some assays may cross-react with placental GH, therefore, when interpreting GH results during pregnancy, one needs to consider the specificity of the assay used (8). Furthermore, routine measurement of GH concentrations during pregnancy is not usually indicated as it will not change the management of the patient.\n\nMedical therapy for tumour shrinkage in acromegaly consists of dopamine agonists and somatostatin analogues (9). However, neither cabergoline nor somatostatin analogues are licenced in pregnancy, and the risk/benefit profile should be carefully examined before deciding on a therapy. The little data available regarding the safety of somatostatin analogue therapy during pregnancy are from isolated case reports and small case series. The main concern with the use of somatostatin analogues in pregnancy is the risk of foetal growth restriction which was noted in case reports of women continuing medication during pregnancy (1). Somatostatin analogues have been shown to cross the placenta by passive diffusion (10) and there is evidence that short-acting octreotide produces a reversible reduction in uterine artery blood flow on Doppler flow analysis, which may explain the case reports of growth restriction in foetuses exposed to somatostatin analogues (11).\n\nTrans-sphenoidal surgery during pregnancy is rare. The French series had one second trimester surgery in 59 pregnancies (1). Jallad et al. reported outcomes in 27 pregnancies with acromegaly, 3 patients in this cohort underwent surgery in the second trimester due to visual field loss. One of these three pregnancies miscarried shortly after surgery, the other two delivered healthy babies at term (3). Other case reports have reported surgery in the second trimester due to increased intracranial pressure (12), apoplexy (13) and visual loss (1, 14, 15). Surgery during pregnancy is typically performed in the second trimester. However, there are inherent surgical and anaesthetic risks that need to be considered before undergoing the procedure and surgery in the second trimester is associated with increased rate of foetal loss (16). It is crucial therefore that these patients are managed by a multi-disciplinary team including an endocrinologist, neurosurgeon, neuro-radiologist and ophthalmologist to ensure optimal outcomes for both the mother and the foetus.\n\nWhilst there are reports of patients who had rescue of visual fields with dopamine agonist therapy during pregnancy (17), this is the first case report of resolution of visual field compromise with somatostatin analogues that we, the authors are aware of. This case report would suggest that somatostatin analogue therapy may be an alternative option to surgery for patients with symptomatic tumour growth during pregnancy.\n\nDeclaration of interest\nThe authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.\n\nFunding\nThis research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.\n\nPatient consent\nWritten informed consent has been obtained from the patient for publication of the submitted article and accompanying images.\n\nAuthor contribution statement\nA M Hannon wrote the first draft. I F, G K and D O H provided direct care for the patient. All authors contributed to editing of the manuscript.\n==== Refs\nReferences\n1 Caron P Broussaud S Bertherat J Borson-Chazot F Brue T Cortet-Rudelli C Chanson P \nAcromegaly and pregnancy: a retrospective multicenter study of 59 pregnancies in 46 women . Journal of Clinical Endocrinology and Metabolism \n2010 \n95 \n4680 –4687 . (10.1210/jc.2009-2331 )20660047 \n2 Cheng V Faiman C Kennedy L Khoury F Hatipoglu B Weil R Hamrahian A \nPregnancy and acromegaly: a review . Pituitary \n2012 \n15 \n59 –63 . (10.1007/s11102-011-0330-3 )21789529 \n3 Jallad RS Shimon I Fraenkel M Medvedovsky V Akirov A Duarte FH Bronstein MD \nOutcome of pregnancies in a large cohort of women with acromegaly . Clinical Endocrinology \n2018 \n88 \n896 –907 . (10.1111/cen.13599 )29574986 \n4 Hannon AM O’Shea T Thompson CA Hannon MJ Dineen R Khattak AK Gibney J O’Halloran DJ Hunter S Thompson CJ , \nPregnancy in acromegaly is safe and is associated with improvements in GH/IGF-1 concentrations . European Journal of Endocrinology \n2019 \n180 \nK21 –K29 . (10.1530/EJE-18-0688 )30620709 \n5 Kasuki L Neto LV Takiya CM Gadelha MR \nGrowth of an aggressive tumor during pregnancy in an acromegalic patient . Endocrine Journal \n2012 \n59 \n313 –319 . (10.1507/endocrj.EJ11-0306 )22240890 \n6 Dias M Boguszewski C Gadelha M Kasuki L Musolino N Vieira JG Abucham J \nAcromegaly and pregnancy: a prospective study . European Journal of Endocrinology \n2014 \n170 \n301 –310 . (10.1530/EJE-13-0460 )24247731 \n7 Katznelson L Laws ER JrMelmed S Molitch ME Murad MH Utz A Wass JA & Endocrine Society . Acromegaly: an endocrine society clinical practice guideline . Journal of Clinical Endocrinology and Metabolism \n2014 \n99 \n3933 –3951 . (10.1210/jc.2014-2700 )25356808 \n8 Junnila RK Strasburger CJ Bidlingmaier M \nPitfalls of insulin-like growth factor-I and growth hormone assays . Endocrinology and Metabolism Clinics of North America \n2015 \n44 \n27 –34 . (10.1016/j.ecl.2014.10.003 )25732639 \n9 Bevan JS Atkin SL Atkinson AB Bouloux PM Hanna F Harris PE James RA McConnell M Roberts GA Scanlon MF , \nPrimary medical therapy for acromegaly: an open, prospective, multicenter study of the effects of subcutaneous and intramuscular slow-release octreotide on growth hormone, insulin-like growth factor-I, and tumor size . Journal of Clinical Endocrinology and Metabolism \n2002 \n87 \n4554 –4563 . (10.1210/jc.2001-012012 )12364434 \n10 Caron P Gerbeau C Pradayrol L \nMaternal-fetal transfer of octreotide . New England Journal of Medicine \n1995 \n333 \n601 –602 . (10.1056/NEJM199508313330918 )7623921 \n11 Maffei P Tamagno G Nardelli GB Videau C Menegazzo C Milan G Calcagno A Martini C Vettor R Epelbaum J , \nEffects of octreotide exposure during pregnancy in acromegaly . Clinical Endocrinology \n2010 \n72 \n668 –677 . (10.1111/j.1365-2265.2009.03706.x )19769624 \n12 Montini M Pagani G Gianola D Pagani MD Piolini R Camboni MG \nAcromegaly and primary amenorrhea: ovulation and pregnancy induced by SMS 201-995 and bromocriptine . Journal of Endocrinological Investigation \n1990 \n13 \n193 (10.1007/BF03349537 )2329262 \n13 Atmaca A Dagdelen S Erbas T \nFollow-up of pregnancy in acromegalic women: different presentations and outcomes . Experimental and Clinical Endocrinology and Diabetes \n2006 \n114 \n135 –139 . (10.1055/s-2005-873004 )16636980 \n14 Guven S Durukan T Berker M Basaran A Saygan-Karamursel B Palaoglu S \nA case of acromegaly in pregnancy: concomitant transsphenoidal adenomectomy and cesarean section . Journal of Maternal-Fetal and Neonatal Medicine \n2006 \n19 \n69 –71 . (10.1080/14767050500434021 )16492596 \n15 Mozas J Ocon E Lopez de la Torre M Suarez AM Miranda JA Herruzo AJ \nSuccessful pregnancy in a woman with acromegaly treated with somatostatin analog (octreotide) prior to surgical resection . International Journal of Gynecology and Obstetrics \n1999 \n65 \n71 –73 . (10.1016/S0020-7292(98)00221-5 )10390105 \n16 Cohen-Kerem R Railton C Oren D Lishner M Koren G \nPregnancy outcome following non-obstetric surgical intervention . American Journal of Surgery \n2005 \n190 \n467 –473 . (10.1016/j.amjsurg.2005.03.033 )16105538 \n17 Yap AS Clouston WM Mortimer RH Drake RF \nAcromegaly first diagnosed in pregnancy: the role of bromocriptine therapy . American Journal of Obstetrics and Gynecology \n1990 \n163 \n477 –478 . (10.1016/0002-9378(90)91178-F )2386133\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-0573",
"issue": "2019()",
"journal": "Endocrinology, diabetes & metabolism case reports",
"keywords": "2019; Acromegaly; CT scan; Caesarean section; Cortisol; Cortisol (9am); Diabetes insipidus - gestational; Diet; Female; GH; Glucose (blood, fasting); Haemoglobin A1c; Hands - enlargement; Headache; Hemianopia; IGF1; Insulin; Ireland; MRI; May; Novel treatment; Octreotide; Pituitary; Pituitary adenoma; Pregnant adult; Prognathism; Prolactin; Somatostatin analogues; TSH; Teeth gapping; Thyroid function; Thyroxine (T4); Total T4; Visual field defect; White",
"medline_ta": "Endocrinol Diabetes Metab Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101618943",
"other_id": null,
"pages": null,
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"pmid": "31117051",
"pubdate": "2019-05-20",
"publication_types": "D016428:Journal Article",
"references": "10390105;12364434;16105538;16492596;16636980;19769624;20660047;21789529;22240890;2329262;2386133;24247731;25356808;25732639;29574986;30620709;7623921",
"title": "Octreotide use for rescue of vision in a pregnant patient with acromegaly.",
"title_normalized": "octreotide use for rescue of vision in a pregnant patient with acromegaly"
} | [
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"abstract": "Pazopanib is an orally bioavailable tyrosine kinase inhibitor anticancer drug approved worldwide for the treatment of metastatic renal cell carcinoma and advanced soft tissue sarcoma. Here we report the case of a patient whose recurrent retroperitoneal soft tissue sarcoma showed a drastic reduction immediately after pazopanib administration accompanied by severe liver dysfunction. His liver function was restored conservatively by giving him hepatoprotectors and having him stop taking pazopanib. The recurrent tumor disappeared but by 4 months later had regrown.",
"affiliations": "Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.;Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.;Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.;Department of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan.",
"authors": "Okubo|Kazuki|K|;Horiguchi|Akio|A|;Ito|Keiichi|K|;Asano|Tomohiko|T|",
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"country": "United States",
"delete": false,
"doi": "10.1016/j.eucr.2018.05.018",
"fulltext": "\n==== Front\nUrol Case RepUrol Case RepUrology Case Reports2214-4420Elsevier S2214-4420(18)30154-210.1016/j.eucr.2018.05.018OncologyRecurrent retroperitoneal soft tissue sarcoma showing drastic reduction after pazopanib administration accompanied by severe liver dysfunction Okubo Kazuki otti1104@gmail.com∗Horiguchi Akio impreza@cb3.so-net.ne.jpIto Keiichi itok@ndmc.ac.jpAsano Tomohiko tomasano@ndmc.ac.jpDepartment of Urology, National Defense Medical College, 3-2 Namiki, Tokorozawa, Saitama, 359-8513, Japan∗ Corresponding author. otti1104@gmail.com06 6 2018 9 2018 06 6 2018 20 22 24 7 5 2018 23 5 2018 © 2018 The Authors. Published by Elsevier Inc.2018This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Pazopanib is an orally bioavailable tyrosine kinase inhibitor anticancer drug approved worldwide for the treatment of metastatic renal cell carcinoma and advanced soft tissue sarcoma. Here we report the case of a patient whose recurrent retroperitoneal soft tissue sarcoma showed a drastic reduction immediately after pazopanib administration accompanied by severe liver dysfunction. His liver function was restored conservatively by giving him hepatoprotectors and having him stop taking pazopanib. The recurrent tumor disappeared but by 4 months later had regrown.\n\nKeywords\nLiver toxicityPazopanibRecurrent soft tissue sarcoma\n==== Body\nIntroduction\nSoft tissue sarcomas (STSs) are rare malignant tumors of mesenchymal origin found in fat, blood vessels, lymphatic tissue, muscles, and nerves. Pazopanib is an orally available receptor tyrosine kinase inhibitor targeting the vascular endothelial growth factor receptors (VEGFRs) 1–3, and c-kit and also targeting platelet-derived growth factor receptors (PDGFRs) alpha and beta, and it is effective in the treatment of soft tissue sarcoma.\n\nHere we report a patient whose recurrent STS showed drastic reduction after a short pazopanib treatment that was accompanied by severe liver dysfunction.\n\nCase presentation\nA 75-year-old male who six years ago underwent surgical resection of a retroperitoneal tumor surrounding the right kidney, the histological diagnosis of which was undifferentiated/unclassified sarcoma, came to our hospital for annual follow up. Magnetic resonance imaging (MRI) showed a high-intensity lesion in the right iliopsoas muscle (Fig. 1A). The lesion was highly suggestive of recurrent STS, so he was started on a course of oral pazopanib at 800 mg per day. Two weeks later he showed signs of liver dysfunction (elevated serum levels of liver enzymes) appeared and the pazopanib treatment was stopped (Fig. 2). After 1 week he was restarted on pazopanib at a reduced dosage, 400 mg per day. Six days later he visited our hospital complaining of fever, general malaise, fatigue, and appetite loss. Biochemical examination of his blood showed severe liver dysfunction (elevated liver enzymes and bilirubin) (Fig. 2), so he was admitted to our hospital immediately and treated by giving him hepatoprotectors and stopping his pazopanib. Liver biopsy confirmed drug-induced hepatitis, and he was additionally treated with prednisolone. After administration of these drugs, he recovered from drug-induced hepatitis and was discharged from the hospital. MRI performed during his hospital stay showed that the tumor had completely disappeared (Fig. 1B). Four months later, however, MRI showed a small high-intensity lesion in the right iliopsoas muscle, suggesting tumor regrowth (Fig. 1C). We recommended anthracycline chemotherapy, but he chose not to receive any further anticancer treatment and instead be followed up serially.Fig. 1 MRI before and after treatment. T2-weighted MR images showing recurrent tumor before and after treatment with pazopanib. Pretreatment image shows a mass with heterogenous intensity in right iliopsoas muscle (A, arrows). Image 2 months after administration of pazopanib shows no tumor (B). Image 4 months after cessation of pazopanib shows that the tumor reappeared (C).\n\nFig. 2 Clinical course of biochemical examinations. Sequential changes of liver enzymes and total bilirubin during pazopanib treatment. *1: 800 mg per day. *2: 400 mg per day.\n\n\n\nDiscussion\nMalignant fibrous histiocytoma is the most common type of STS and is now classified as undifferentiated/unclassified sarcoma.1 Surgical resection remains the mainstay of the treatment of STSs and it is important for clinical outcome to obtain negative margins by excising the tumor and surrounding tissues. But with retroperitoneal tumors it is very difficult to obtain negative margins because of the many critical organs around them. The 5-year survival rate of patients with unresectable tumors is <10%.2 New agents for treating recurrent STSs systemically have therefore been needed.\n\nPazopanib is an oral thyrosine kinase and has approved as the 1st line therapy for advanced and metastatic RCC, and it has also been approved for recurrent and/or metastatic STSs treatment according to the multicenter phase 3 trial conducted by the European Organization for Research and Treatment of Cancer (EORTC), the EORTC 62072—PALETTE study.3 The PALETTE study included only patients who had previously received at least one regimen of chemotherapy containing anthracycline and had received no more than four previous lines of chemotherapy. The histopathological diagnosis of the primary site in the present case was undifferentiated/unclassified sarcoma, which in the PALETTE study was classified as “other sarcoma.” To the best of our knowledge, this is the first report of recurrent STS that showed complete response after administration of pazopanib for only 2 weeks. One of the reasons for the prompt response to pazopanib in our case might be that the patient had previously taken no other anticancer drug.\n\nDespite the marked antitumor effect in this case, the patient had to stop taking pazopanib due to severe hepatotoxicity. Some studies based on the clinical trials have demonstrated that pazopanib is associated with a significantly increased risk of liver toxicity.4 Liver toxicity has also been associated with other tyrosine kinase inhibitors such as sunitinib, sorafenib, and axitinib, but it is clear that the rate of high-grade liver toxicity is significantly higher with pazopanib.4 The different liver toxicities of different tyrosine kinase inhibitors may be due to different receptor affinities, liver metabolisms, and target differences. It has been suggested that the occurrence of adverse events such as hypertension and/or hypothyroidism after taking tyrosine kinase inhibitors is associated with improved antitumor efficacy and that these events might be markers of a drug's antitumor activity.5 The association between liver toxicity and antitumor activity remains unclear and clinical meta-analysis will be needed to elucidate their association.\n\nIn the present case, we also proposed to the patient surgical resection of the recurrent tumor before taking pazopanib. He chose to receive pazopanib and forgo surgical resection because of the risk of post-surgical complications such as walking disorder due to intraoperative nerve injury and the risk of incomplete resection. This case suggests that pazopanib is effective against STSs but that we must pay attention to the risk of liver toxicity with it. Awareness of this risk could lead to appropriate intervention reducing the morbidity and mortality due to pazopanib's liver toxicity, thereby leading to a more beneficial effect of pazopanib.\n\nConclusion\nWe experienced a case in which recurrent STS showed drastic reduction after a short pazopanib treatment that was accompanied by severe liver dysfunction.\n\nConflicts of interest\nWe have no conflict of interest to declare.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report.\n==== Refs\nReferences\n1 Jo V.Y. Fletcher C.D. WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition Pathology 46 2014 95 104 24378391 \n2 Sherman K.L. Wayne J.D. Chung J. Assessment of multimodality therapy use for extremity sarcoma in the United States J Surg Oncol 109 2014 395 404 24375444 \n3 Van der Graaf W.T. Blay J.Y. Chawla S.P. Pazopanib for metastatic soft-tissue sarcoma (PALETTE): a randomised, double-blind, placebo-controlled phase 3 trial Lancet 379 2012 1879 1886 22595799 \n4 Kapadia S. Hapani S. Choueiri T.K. Wu S. Risk of liver toxicity with the angiogenesis inhibitor pazopanib in cancer patients Acta Oncol 52 2013 1202 1212 23594201 \n5 Ravaud A. Schmidinger M. Clinical biomarkers of response in advanced renal cell carcinoma Ann Oncol 24 2013 2935 2942 23925998\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2214-4420",
"issue": "20()",
"journal": "Urology case reports",
"keywords": "Liver toxicity; Pazopanib; Recurrent soft tissue sarcoma",
"medline_ta": "Urol Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101626357",
"other_id": null,
"pages": "22-24",
"pmc": null,
"pmid": "30003043",
"pubdate": "2018-09",
"publication_types": "D002363:Case Reports",
"references": "22595799;23594201;24378391;24375444;23925998",
"title": "Recurrent retroperitoneal soft tissue sarcoma showing drastic reduction after pazopanib administration accompanied by severe liver dysfunction.",
"title_normalized": "recurrent retroperitoneal soft tissue sarcoma showing drastic reduction after pazopanib administration accompanied by severe liver dysfunction"
} | [
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{
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"activesubstancename": "PAZOPANIB"
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{
"abstract": "A reset osmostat as a cause of hyponatremia can be found in a variety of clinical settings, including pulmonary and neurologic diseases, as well as in physiologic circumstances such as pregnancy. This teaching case describes a 72-year-old white man with a long-standing history of self-medicating with desmopressin acetate (DDAVP) who presented with profound hyponatremia. On discontinuation of DDAVP treatment, he was found to have a reset osmostat. The mild hyponatremia persisted on follow-up. We theorize that the reset osmostat may have developed secondary to long-standing DDAVP use.",
"affiliations": "Section of Nephrology, Division of Nephrology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL.;Section of Nephrology, Division of Nephrology, Department of Internal Medicine, Rush University Medical Center, Chicago, IL. Electronic address: william_whittier@rush.edu.",
"authors": "Andreoli|Daniel C|DC|;Whittier|William L|WL|",
"chemical_list": "D050034:Antidiuretic Agents; D003894:Deamino Arginine Vasopressin",
"country": "United States",
"delete": false,
"doi": "10.1053/j.ajkd.2016.12.009",
"fulltext": null,
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"issn_linking": "0272-6386",
"issue": "69(6)",
"journal": "American journal of kidney diseases : the official journal of the National Kidney Foundation",
"keywords": "Reset osmostat; desmopressin acetate (DDAVP); hyponatremia; osmolality; osmolality homeostasis; serum sodium; vasopressin",
"medline_ta": "Am J Kidney Dis",
"mesh_terms": "D000368:Aged; D050034:Antidiuretic Agents; D001281:Atrial Fibrillation; D003894:Deamino Arginine Vasopressin; D006801:Humans; D007010:Hyponatremia; D007031:Hypothalamus; D008297:Male; D009994:Osmolar Concentration; D011141:Polyuria; D012651:Self Medication; D016482:Urinalysis",
"nlm_unique_id": "8110075",
"other_id": null,
"pages": "853-857",
"pmc": null,
"pmid": "28223002",
"pubdate": "2017-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Reset Osmostat: The Result of Chronic Desmopressin Abuse?",
"title_normalized": "reset osmostat the result of chronic desmopressin abuse"
} | [
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"companynumb": "US-MYLANLABS-2017M1057476",
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"activesubstance": {
"activesubstancename": "PROPAFENONE"
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"abstract": "Traumatic head injury is a very rare cause of secondary tic disorders. We add another case by describing, for the first time, the response to tetrabenazine in a blinded video assessment. Our patient had a severe traumatic head injury and subsequently developed tics refractory to various agents including neuroleptics. We assessed tetrabenazine treatment by virtue of patient's impression, the treating neurologist's non-blinded (Yale Global Tic Severity Scale) and a second neurologist's blinded assessment (modified Rush Video Scale). The Yale Global Tic Severity Score improved by 24% on 12.5 mg twice daily and 45% on 12.5 mg thrice daily. Subjective improvement was 50% and 70%, respectively. The modified Rush Video scores improved by 21% and 28.5%, respectively. Post-traumatic tourettism can respond to tetrabenazine. The magnitude of benefit though, may be overestimated with open-label observations, thus there is a need for studies examining objectively the effect of tetrabenazine in tic disorders.",
"affiliations": "Department of Neurology, University of Vermont, Bangor, Maine, USA.",
"authors": "Poulopoulos|Markos|M|;Hajjar|Mirna|M|",
"chemical_list": "D018759:Adrenergic Uptake Inhibitors; D013747:Tetrabenazine",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2013()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000063:Accidents, Traffic; D018759:Adrenergic Uptake Inhibitors; D006259:Craniocerebral Trauma; D006801:Humans; D008297:Male; D012720:Severity of Illness Index; D013747:Tetrabenazine; D005879:Tourette Syndrome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24311459",
"pubdate": "2013-12-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": "2325689;10811697;8139600;10348478;2768151;9040721;9380066;2682216;11642235;17133512;7148581",
"title": "Post-traumatic tics and tetrabenazine treatment: a blinded video assessment.",
"title_normalized": "post traumatic tics and tetrabenazine treatment a blinded video assessment"
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"companynumb": "US-JNJFOC-20140115465",
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"actiondrug": "5",
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"activesubstancename": "SERTRALINE HYDROCHLORIDE"
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"abstract": "We compared serious early and late events experienced by 2726 bone marrow (BM) and 6768 peripheral blood stem cell (PBSC) donors who underwent collection of PBSC or BM between 2004 and 2009 as part of a prospective study through the National Marrow Donor Program. Standardized FDA definitions for serious adverse events (SAEs) were used, and all events were reviewed by an independent physician panel. BM donors had an increased risk for SAEs (2.38% for BM vs 0.56% for PBSC; odds ratio [OR], 4.13; P < .001), and women were twice as likely to experience an SAE (OR for men, 0.50; P = .005). Restricting the analysis to life-threatening, unexpected, or chronic/disabling events, BM donors maintained an increased risk for SAEs (0.99% for BM vs 0.31% for PBSC; OR, 3.20; P < .001). Notably, the incidence of cancer, autoimmune illness, and thrombosis after donation was similar in BM vs PBSC donors. In addition, cancer incidence in PBSC donors was less than that reported in the general population (Surveillance, Epidemiology, and End Results Program database). In conclusion, SAEs after donation are rare but more often occurred in BM donors and women. In addition, there was no evidence of increased risk for cancer, autoimmune illness, and stroke in donors receiving granulocyte colony-stimulating factor during this period of observation.",
"affiliations": "University of Utah School of Medicine, Primary Children's Hospital, Salt Lake City, UT;;Center for International Blood and Marrow Transplant Research, Minneapolis, MN;;Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, Milwaukee, WI;;Center for International Blood and Marrow Transplant Research, Minneapolis, MN; National Marrow Donor Program, Minneapolis, MN;;The University of Michigan, Ann Arbor, MI;;National Marrow Donor Program, Minneapolis, MN;;Anthony Nolan Research Institute, London, United Kingdom;;Fred Hutchinson Cancer Research Center, Seattle, WA; and.;Center for International Blood and Marrow Transplant Research, Minneapolis, MN; Cleveland Clinic, Cleveland, OH.;Center for International Blood and Marrow Transplant Research, Minneapolis, MN; National Marrow Donor Program, Minneapolis, MN;",
"authors": "Pulsipher|Michael A|MA|;Chitphakdithai|Pintip|P|;Logan|Brent R|BR|;Navarro|Willis H|WH|;Levine|John E|JE|;Miller|John P|JP|;Shaw|Bronwen E|BE|;O'Donnell|Paul V|PV|;Majhail|Navneet S|NS|;Confer|Dennis L|DL|",
"chemical_list": "D016179:Granulocyte Colony-Stimulating Factor",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2013-12-542464",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "123(23)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D001853:Bone Marrow; D016026:Bone Marrow Transplantation; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D036102:Peripheral Blood Stem Cell Transplantation; D011183:Postoperative Complications; D012307:Risk Factors; D012720:Severity of Illness Index; D014019:Tissue Donors; D020858:Tissue and Organ Harvesting; D055815:Young Adult",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "3655-63",
"pmc": null,
"pmid": "24735965",
"pubdate": "2014-06-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.; D013487:Research Support, U.S. Gov't, P.H.S.",
"references": "19666868;6380620;19190248;20173787;23109243;21120643;21170092;14647251;8461478;14716337;17054431;8647235;21719598;17563736;18387976;20190845;9242518;24076552;12420204;24184336;18721778;10654020;11360107;14725909;19059940;17284714;8704701;12555210",
"title": "Lower risk for serious adverse events and no increased risk for cancer after PBSC vs BM donation.",
"title_normalized": "lower risk for serious adverse events and no increased risk for cancer after pbsc vs bm donation"
} | [
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"companynumb": "US-AMGEN-USASP2021021300",
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"activesubstance": {
"activesubstancename": "FILGRASTIM"
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{
"abstract": "A 9-year-old girl accidentally injected her right thumb with an adult dose of epinephrine through an auto-injector syringe, delivering 0.3 mg of 1:1000 epinephrine. This injection caused immediate ischemic changes in the digit. This is the first reported case of accidental self injection by a child of an adult dose of epinephrine and its successful treatment with low-dose phentolamine simultaneously infiltrated directly into the puncture area and along the course of the digital artery. The use of phentolamine as a specific competitive alpha-adrenergic antagonist to epinephrine has been well documented in adults and animal models. This report compares the management of a pediatric case to that of all reported adult cases of accidental subcutaneous epinephrine injections. This case suggests a pattern of infiltration with low-dose phentolamine that may be the most effective form of treatment for this condition in a patient of any age.",
"affiliations": null,
"authors": "Sellens|C|C|;Morrison|L|L|",
"chemical_list": null,
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"delete": false,
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"nlm_unique_id": "100893237",
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"pages": "34-6",
"pmc": null,
"pmid": "17659099",
"pubdate": "1999-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Accidental injection of epinephrine by a child: a unique approach to treatment.",
"title_normalized": "accidental injection of epinephrine by a child a unique approach to treatment"
} | [
{
"companynumb": "CA-PFIZER INC-2017120389",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "EPINEPHRINE"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nIn recent years, herpes simplex encephalitis (HSE) has been reported with increasing frequency in settings of immunosuppression, such as acquired immunodeficiency, transplantation and cancer. As observed, in immunocompromised individuals HSE presents peculiar clinical and paraclinical features, and poorer prognosis.\n\n\nMETHODS\nHere we describe a retrospective series of seven cases of HSE in patients with high-grade glioma (HGG), collected among three institutions in a 5-year period (during this time, a total of 1750 patients with HGG were treated).\n\n\nRESULTS\nDiagnosis of the condition was particularly challenging due to the confounding clinical presentation and the atypical biological findings. As a result, antiviral treatment was started with a sharp delay compared with immunocompetent hosts. Prognosis was poor, with high short-term mortality and severe residual disability in survivors.\n\n\nCONCLUSIONS\nThe substantial incidence of HSE observed in our centres together with the difficulty in diagnosing the condition suggest that the incidence of this complication may be highly underestimated. The aim of our report is to strengthen the observation of HSE in patients with HGG and outline the key elements that may allow its diagnosis.",
"affiliations": "C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino, Pavia, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.;AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Service de Neurologie 2, Paris, France.;Neuro-oncology Unit, C. Besta Neurological Institute, Milan, Italy.;Neuro-oncology Unit, C. Besta Neurological Institute, Milan, Italy.;Neuro-oncology Unit, C. Besta Neurological Institute, Milan, Italy SC Neurologia, Ospedale A. Manzoni, Lecco, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy Neuroscience Consortium, University of Pavia, Monza Policlinico and Pavia Mondino, Pavia, Italy.;Molecular Virology Unit, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy Department of Neuroscience, University of Pavia, Pavia, Italy.;C. Mondino National Institute of Neurology Foundation, IRCCS, Pavia, Italy.",
"authors": "Berzero|Giulia|G|;Di Stefano|Anna Luisa|AL|;Dehais|Caroline|C|;Sanson|Marc|M|;Gaviani|Paola|P|;Silvani|Antonio|A|;Salmaggi|Andrea|A|;Vitali|Paolo|P|;Diamanti|Luca|L|;Baldanti|Fausto|F|;Farina|Lisa Maria|LM|;Ceroni|Mauro|M|;Marchioni|Enrico|E|",
"chemical_list": "D000998:Antiviral Agents",
"country": "England",
"delete": false,
"doi": "10.1136/jnnp-2013-307198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-3050",
"issue": "86(4)",
"journal": "Journal of neurology, neurosurgery, and psychiatry",
"keywords": "Clinical Neurology; Infectious Diseases; Neurooncology; Neurovirology; Radiotherapy",
"medline_ta": "J Neurol Neurosurg Psychiatry",
"mesh_terms": "D000328:Adult; D000368:Aged; D000998:Antiviral Agents; D001932:Brain Neoplasms; D003072:Cognition Disorders; D020803:Encephalitis, Herpes Simplex; D005260:Female; D005910:Glioma; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D012189:Retrospective Studies; D016019:Survival Analysis",
"nlm_unique_id": "2985191R",
"other_id": null,
"pages": "374-7",
"pmc": null,
"pmid": "24876188",
"pubdate": "2015-04",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Herpes simplex encephalitis in glioma patients: a challenging diagnosis.",
"title_normalized": "herpes simplex encephalitis in glioma patients a challenging diagnosis"
} | [
{
"companynumb": "IT-TEVA-681907ACC",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drug... |
{
"abstract": "Drug-induced subacute cutaneous lupus erythematosus (DI-SCLE) has been associated with numerous drugs, but there are limited reports of its association with aromatase inhibitor anastrozole. We report the case of a patient undergoing treatment with anastrozole for breast cancer who presented with clinical, serological, and histological evidence consistent with DI-SCLE. Her condition quickly began to improve after the use of anastrozole was discontinued and hydroxychloroquine therapy was initiated. Cases such as ours as well as several others that implicate antiestrogen drugs in association with DI-SCLE seem to be contradictory to studies looking at the usefulness of treating systemic lupus erythematosus (SLE) with antiestrogen therapy. Further research on this relationship is warranted.",
"affiliations": "Department of Dermatology, SUNY Downstate Medical Center, Brooklyn, New York, USA.;Department of Dermatology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA.;Department of Dermatology, Metropolitan Hospital Center, New York, New York, USA.;Northwell Department of Dermatology, Hofstra-Northwell School of Medicine, Hempstead, New York, USA.",
"authors": "Fisher|Juliya|J|;Patel|Mital|M|;Miller|Michael|M|;Burris|Katy|K|",
"chemical_list": "D000974:Antibodies, Antinuclear; D047072:Aromatase Inhibitors; D009570:Nitriles; C035356:SS-A antibodies; D014230:Triazoles; D000077384:Anastrozole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0011-4162",
"issue": "98(2)",
"journal": "Cutis",
"keywords": null,
"medline_ta": "Cutis",
"mesh_terms": "D000368:Aged; D000077384:Anastrozole; D000974:Antibodies, Antinuclear; D001132:Arm; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D008178:Lupus Erythematosus, Cutaneous; D009570:Nitriles; D013909:Thorax; D014230:Triazoles",
"nlm_unique_id": "0006440",
"other_id": null,
"pages": "E22-6",
"pmc": null,
"pmid": "27622265",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Anastrozole-induced subacute cutaneous lupus erythematosus.",
"title_normalized": "anastrozole induced subacute cutaneous lupus erythematosus"
} | [
{
"companynumb": "US-DRREDDYS-USA/USA/16/0083930",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ANASTROZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "The randomized \"Testicular cancer and Aerobic and Strength Training trial\" (TAST-trial) aimed to evaluate the effect of high-intensity interval training (HIIT) on cardiorespiratory fitness during cisplatin-based chemotherapy (CBCT) for testicular cancer (TC). Here, we report on an unexpected high number of thromboembolic (TE) events among patients randomized to the intervention arm, and on a review of the literature on TE events in TC patients undergoing CBCT. Patients aged 18 to 60 years with a diagnosis of metastatic germ cell TC, planned for 3 to 4 CBCT cycles, were randomized to a 9 to 12 weeks exercise intervention, or to a single lifestyle counseling session. The exercise intervention included two weekly HIIT sessions, each with 2 to 4 intervals of 2 to 4 minutes at 85% to 95% of peak heart rate. The study was prematurely discontinued after inclusion of 19 of the planned 94 patients, with nine patients randomized to the intervention arm and 10 to the control arm. Three patients in the intervention arm developed TE complications; two with pulmonary embolism and one with myocardial infarction. All three patients had clinical stage IIA TC. No TE complications were observed among patients in the control arm. Our observations indicate that high-intensity aerobic training during CBCT might increase the risk of TE events in TC patients, leading to premature closure of the TAST-trial.",
"affiliations": "National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway.;Department of Oncology, University Hospital of North Norway, Tromsø, Norway.;National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway.;Department of Oncology and Medical Physics, Haukeland University Hospital, Bergen, Norway.;Clinic of Oncology, St. Olavs Hospital, Trondheim, Norway.;Institute of Clinical Medicine, University of Tromsø - The Arctic University, Tromsø, Norway.;National Advisory Unit on Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway.;Department of Pulmonary Medicine, Oslo University Hospital, Oslo, Norway.;Department of Pulmonary Medicine, Oslo University Hospital, Oslo, Norway.;Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;Institute of Clinical Medicine, University of Oslo, Oslo, Norway.;Department of Physical Performance, Norwegian School of Sports Sciences, Oslo, Norway.;Department of Oncology, Oslo University Hospital, Oslo, Norway.",
"authors": "Thorsen|Lene|L|0000-0002-7857-5475;Haugnes|Hege S|HS|;Fosså|Sophie D|SD|;Brydøy|Marianne|M|;Tandstad|Torgrim|T|;Wisløff|Torbjørn|T|;Gjerset|Gunhild M|GM|;Edvardsen|Elisabeth|E|;Larsen|Karl-Otto|KO|;Sandset|Per Morten|PM|;Henriksson|Carola E|CE|;Raastad|Truls|T|;Negaard|Helene F S|HFS|",
"chemical_list": "D002945:Cisplatin",
"country": "United States",
"delete": false,
"doi": "10.1002/ijc.33151",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-7136",
"issue": "147(11)",
"journal": "International journal of cancer",
"keywords": "cisplatin-based chemotherapy; high-intensity training; testicular cancer; thromboembolic events",
"medline_ta": "Int J Cancer",
"mesh_terms": "D000328:Adult; D000072599:Cardiorespiratory Fitness; D002945:Cisplatin; D003376:Counseling; D000072696:High-Intensity Interval Training; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009373:Neoplasms, Germ Cell and Embryonal; D016032:Randomized Controlled Trials as Topic; D013736:Testicular Neoplasms; D013923:Thromboembolism; D055815:Young Adult",
"nlm_unique_id": "0042124",
"other_id": null,
"pages": "3189-3198",
"pmc": null,
"pmid": "32525564",
"pubdate": "2020-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Thromboembolic events after high-intensity training during cisplatin-based chemotherapy for testicular cancer: Case reports and review of the literature.",
"title_normalized": "thromboembolic events after high intensity training during cisplatin based chemotherapy for testicular cancer case reports and review of the literature"
} | [
{
"companynumb": "NO-MYLANLABS-2020M1103671",
"fulfillexpeditecriteria": "1",
"occurcountry": "NO",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BLEOMYCIN SULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "The bacterium Alcaligenes xylosoxidans is known to cause several nosocomial infections; however, it rarely causes endocarditis, which has a very high mortality rate. Early isolation of the infection source and prompt identification of the patient's antibiotic sensitivities are paramount if the infection is to be treated adequately. We present what is apparently only the second documented case of the successful eradication of bioprosthetic valve endocarditis that was caused by pacemaker lead infection with Alcaligenes xylosoxidans. A 62-year-old woman with multiple comorbidities presented with endocarditis of a recently placed bioprosthetic aortic valve. The infection was secondary to pacemaker lead infection. She underwent antibiotic therapy, but an unusual pattern of antibiotic resistance developed. Despite initially adequate therapy, the infection recurred because of virulence induced by antibiotic resistance. Emergent, high-risk surgical treatment involved excising the infected valve and removing the source of the infection (the pacemaker leads). The patient eventually recovered after prolonged antibiotic therapy and close vigilance for recurrent infection. In addition to the patient's case, we discuss the features of this bacteremia and the challenges in its diagnosis.",
"affiliations": "Department of Internal Medicine, Community Regional Medical Center, Fresno, California 93701, USA. acsawant@gmail.com",
"authors": "Sawant|Abhishek C|AC|;Srivatsa|Sanjay S|SS|;Castro|Luis J|LJ|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0730-2347",
"issue": "40(1)",
"journal": "Texas Heart Institute journal",
"keywords": "Alcaligenes/drug effects; anti-bacterial agents/therapeutic use; bacteremia/complications/diagnosis/drug therapy/etiology; endocarditis, bacterial/diagnosis/ultrasonography; gram-negative bacterial infections/complications/etiology; heart valve prosthesis; opportunistic infections/epidemiology; pacemaker, artificial/microbiology; treatment outcome",
"medline_ta": "Tex Heart Inst J",
"mesh_terms": "D000421:Alcaligenes; D000900:Anti-Bacterial Agents; D020878:Device Removal; D024881:Drug Resistance, Bacterial; D017548:Echocardiography, Transesophageal; D004697:Endocarditis, Bacterial; D005260:Female; D016905:Gram-Negative Bacterial Infections; D006350:Heart Valve Prosthesis; D006801:Humans; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D010138:Pacemaker, Artificial; D016459:Prosthesis-Related Infections; D012008:Recurrence; D012086:Reoperation; D016896:Treatment Outcome; D014774:Virulence",
"nlm_unique_id": "8214622",
"other_id": null,
"pages": "95-8",
"pmc": null,
"pmid": "23466992",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8655217;19281752;10770721;15389476;8879782;15082906;3667915;12750959;6699141;5316576;3163242;9495677;11100967",
"title": "Alcaligenes xylosoxidans endocarditis of a prosthetic valve and pacemaker in a 62-year-old woman.",
"title_normalized": "alcaligenes xylosoxidans endocarditis of a prosthetic valve and pacemaker in a 62 year old woman"
} | [
{
"companynumb": "US-AUROBINDO-AUR-APL-2021-040957",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PIPERACILLIN SODIUM\\TAZOBACTAM SODIUM"
},
... |
{
"abstract": "is missing (Short communication).",
"affiliations": "Department of Dermatology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, NL-9700 RB Groningen, The Netherlands. E-mail: m.a.lamberts@umcg.nl.",
"authors": "Lamberts|Aniek|A|;Diercks|Gilles F H|GFH|;Pas|Hendri H|HH|;Horváth|Barbara|B|",
"chemical_list": "D005938:Glucocorticoids; D007166:Immunosuppressive Agents",
"country": "Sweden",
"delete": false,
"doi": "10.2340/00015555-3523",
"fulltext": "\n==== Front\nActa Derm Venereol\nActa Derm Venereol\nActaDV\nActa Dermato-Venereologica\n0001-5555\n1651-2057\nActa Dermato-Venereologica\n\n32424432\nActaDV-100-10-5778\n10.2340/00015555-3523\nShort Communication\nNon-bullous Lichen Planus Pemphigoides: A Case Report\nLAMBERTS Aniek *\nDIERCKS Gilles F. H.\nPAS Hendri H.\nHORVÁTH Barbara\nDepartment of Dermatology, University of Groningen, Center for Blistering Diseases, University Medical Center Groningen, Hanzeplein 1, NL-9700 RB Groningen, The Netherlands\nE-mail: m.a.lamberts@umcg.nl\n\n29 5 2020\n2020\n100 10 577811 5 2020\n© 2020 Acta Dermato-Venereologica\n2020\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license\n==== Body\npmcLichen planus pemphigoides (LPP) is a rare disease combining clinical and immunological features of lichen planus and bullous pemphigoid (BP) (1). Patients clinically present with intense pruritus, lichenoid papules and plaques, and tense blisters that occur on and outside of lichenoid lesions. Histopathology of a lichenoid lesion shows typical features of lichen planus, such as a band-like lymphocytic infiltrate, focal hyperkeratosis, hypergranulosis, and interface dermatitis with vacuolar changes at the basement membrane zone (BMZ) (2). In contrast, histopathology of skin taken at the edge of a blister reveals a subepithelial split, and perivascular infiltrate commonly including eosinophils and lymphocytes, compatible with a diagnosis of BP (3). Positive direct immunofluorescence (DIF) microscopy is a requirement for the diagnosis LPP, and shows skin-bound immunoglobulin (Ig)G, IgA or C3c in a linear pattern along the BMZ (3). Serum autoantibodies against BP180 and its non-collagenous 16A domain can be identified in the majority of patients with LPP, but also BP230 reactivity has been reported (1). These anti-BP180 and anti-BP230 autoantibodies can also be detected in serum and skin of patients with non-bullous pemphigoid, a pemphigoid variant that clinically lacks skin blisters (4). We report here a case of LPP without blisters, and introduce the term non-bullous LPP.\n\nCASE REPORT\n\nA 62-year-old man with a history of chronic obstructive pulmonary disease (COPD) and type II diabetes mellitus was referred to our tertiary centre with intense generalized pruritus, causing sleep deprivation in the last 2 years. The onset of pruritus was possibly related to the start of metformin. Skin examination showed nummular erythematous hyperkeratotic plaques with secondary excoriations, located mainly on both lower legs and, less extensively, at the upper legs. Moreover, we observed polygonal flat erythematous papules distributed over the whole body except the face (Fig. 1A,B).\n\nFig. 1 (A) Livid erythematous polygonal papules on the dorsal side of the hand. (B) Hyperkeratotic papules and plaques on the back of the left calf. (C) Immunoglobulin A (IgA) deposits linear along the basement membrane zone by direct immunofluorescence microscopy. White bar: 500 μm. (D) Reduction of hyperkeratotic lesions on the left calf after whole-body application of super potent corticosteroids for one month.\n\nThe hyperkeratotic plaques on the lower extremities were suggestive of a diagnosis of lichen planus, while the intense pruritic erythematous papules over the whole body suggested a diagnosis of non-bullous pemphigoid. Therefore, one lesional biopsy was taken for histopathology, and one perilesional biopsy for DIF microscopy.\n\nHistopathological examination of a papule on the upper leg showed compact hyperkeratosis, a widened granular layer, and a band-shaped lymphocytic infiltrate resembling lichen planus. No microscopic blister formation was objectified. DIF microscopy demonstrated linear depositions of IgG (1+) and IgA (3+) in an n-serrated pattern along the BMZ (Fig. 1C). Serological tests detected circulating IgG against the non-collagenous 16A domain of BP180 (immunoblot 180 kDa positive; ELISA NC16A index 23 (MBL, Nagoya, Japan)). Based on these findings the diagnosis of non-bullous LPP was made.\n\nMetformin was discontinued and replaced by gliclazide. Lesional topical steroids were previously not effective; therefore, whole-body application of clobetasol 30 g per day was started according to the guideline for management of BP (5). Initially, there was a good and rapid response with regard to the pruritus and skin lesions (Fig. 1D). However, the pruritic symptoms relapsed during tape-ring of whole-body application of clobetasol. Systemic therapy with methotrexate, 7.5 mg/week, was prescribed, with an excellent response with complete remission. Despite discontinuation of methotrexate 9 months later, due to recurring pneumonia, the patient remained in complete remission off therapy.\n\nDISCUSSION\n\nLichenoid lesions, together with blisters, are considered the clinical hallmark of LPP, a disease linking pemphigoid and lichen planus (1). The current case report presents a patient with LPP lacking blisters, a disease termed non-bullous LPP. This entity was first published by Tan & Vaidya (6), describing a 42-year-old man with violaceous lichenoid papules located on both shins, possibly induced by venlafaxine (6). Remarkably, in both cases skin lesions were predominantly localized at the lower extremities, and the onset of symptoms were possibly related to the start of a new drug. Differences between the cases include the finding of a microscopic subepithelial split by Tan & Vaidya, which we did not observe. Moreover, Tan &Vaidya did not detect any circulating autoantibodies, while in the current case anti-BP180 autoantibodies were identified by immunoblot and ELISA.\n\nThe pathogenesis of LPP is not completely elucidated. In most reported cases lichenoid lesions precede blister formation (1). It is hypothesized that the T-cell driven lichenoid interface dermatitis by lichen planus “exposes” immunologically “hidden” epitopes to the immune system, provoking a B-cell driven autoimmune response (1, 7). This phenomenon is referred to as epitope spreading (8). LPP should not be mistaken with bullous lichen planus, in which blisters are exclusively located on lichenoid lesions (9). In bullous lichen planus, blisters are formed by extensive inflammation, causing degeneration of cells around the epidermal-dermal junction. Anti-BMZ autoantibodies in skin and serum are absent.\n\nIn our patient, the onset of disease was possibly related to the start metformin; however, cessation of the drug did not stop the pruritus. Several drug-induced cases of LPP have been published previously, with angiotensinconverting-enzyme inhibitors as the most reported culprit (10). Single reports on drug-induced LPP have also implicated psoralen, cinnarizine and simvastatin, but not metformin (10). Interestingly, one report describes metformin-induced lichen planus (11). In contrast, BP was associated with dipeptidyl peptidase IV inhibitors in several studies, but not with metformin monotherapy (12).\n\nThe exact prevalence of subepidermal auto-immune blistering diseases, such as cutaneous or mucous membrane pemphigoids, resembling or accompanying lichen planus is unknown. A recent case series describes 12 patients with mucous membrane pemphigoid, clinically and histologically resembling oral lichen planus (13). The diagnosis of such cases is greatly dependent on the performance of DIF by clinicians. This may also apply to non-bullous LPP, and more research is needed to determine its true incidence. Interestingly, mucosal lichen planus was previously associated with low titres of circulating anti-BP180 autoantibodies and, more recently, with reactivity of T helper 1 and T helper 17 cells against both desmoglein 3 and BP180 (1, 14, 15). Yet, the relevance of these findings and the likelihood that these patients develop pemphigoid remains unknown.\n\nThis case highlights that non-bullous LPP can be a cause of pruritus in patients with lichenoid lesions, and illustrates that systemic therapy might be required to achieve long-term remission. We advise clinicians to perform pemphigoid diagnostics in patients with pruritic lichenoid lesions refractory to topical steroids, in order to examine whether non-bullous LPP could be diagnosed.\n==== Refs\nREFERENCES\n\n1 Hubner F, Langan EA, Recke A. Lichen planus pemphigoides: from lichenoid inflammation to autoantibody-mediated blistering. Front Immunol 2019; 10 : 1389.31312198\n2 Gorouhi F, Davari P, Fazel N. Cutaneous and mucosal lichen planus: a comprehensive review of clinical subtypes, risk factors, diagnosis, and prognosis. ScientificWorldJournal 2014; 2014 : 742826.24672362\n3 Schmidt E, Zillikens D. Pemphigoid diseases. Lancet 2013; 381 : 320–332.23237497\n4 Lamberts A, Meijer JM, Pas HH, Diercks GFH, Horváth B, Jonkman MF. Nonbullous pemphigoid: insights in clinical and diagnostic findings, treatment responses and prognosis. J Am Acad Dermatol 2019; 81 : 355–363.31009674\n5 Feliciani C, Joly P, Jonkman MF, Zambruno G, Zillikens D, Ioannides D, et al . Management of bullous pemphigoid: the European Dermatology Forum consensus in collaboration with the European Academy of Dermatology and Venereology. Br J Dermatol 2015; 172 : 867–877.25827742\n6 Tan AJ, Vaidya S. Non-bullous lichen planus pemphigoides possibly induced by venlafaxine. Australas J Dermatol 2016; 57 :154–155.27124647\n7 Lodi G, Scully C, Carrozzo M, Griffiths M, Sugerman PB, Thongprasom K. Current controversies in oral lichen planus: report of an international consensus meeting. Part 1. Viral infections and etiopathogenesis. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2005; 100 : 40–51.15953916\n8 Chan LS, Vanderlugt CJ, Hashimoto T, Nishikawa T, Zone JJ, Black MM, et al . Epitope spreading: lessons from autoimmune skin diseases. J Invest Dermatol 1998; 110 : 103–109.9457902\n9 Liakopoulou A, Rallis E. Bullous lichen planus – a review. J Dermatol Case Rep 2017; 11 : 1–4.28539981\n10 Onprasert W, Chanprapaph K. Lichen planus pemphigoides induced by enalapril: a case report and a review of literature. Case Rep Dermatol 2017; 9 : 217–224.29282395\n11 Azzam H, Bergman R, Friedman-Birnbaum R. Lichen planus associated with metformin therapy. Dermatology 1997; 194 : 376.9252768\n12 Varpuluoma O, Försti AK, Jokelainen J, Turpeinen M, Timonen M, Huilaja L, Tasanen K. Vildagliptin significantly increases the risk of bullous pemphigoid: a Finnish nationwide registry study. J Invest Dermatol 2018; 138 : 1659–1661.29427585\n13 Benzaquen M, Suter VGA, Gschwend M, Feldmeyer L, Borradori L. Mucous membrane pemphigoid of the oral lichen type: a retrospective analysis of 16 cases. J Eur Acad Dermatol Venereol 2019; 33 : e205–e207.30720898\n14 Buijsrogge JJ, Hagel C, Duske U, Kromminga A, Vissink A, Kloosterhuis AJ, et al . IgG antibodies to BP180 in a subset of oral lichen planus patients. J Dermatol Sci 2007; 47 : 256–258.17604609\n15 Schmidt T, Solimani F, Pollmann R, Stein R, Schmidt A, Stulberg I, et al . TH1/TH17 cell recognition of desmoglein 3 and bullous pemphigoid antigen 180 in patients with lichen planus. J Allergy Clin Immunol 2018; 142 : 669–672.e7.29626572\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0001-5555",
"issue": "100(10)",
"journal": "Acta dermato-venereologica",
"keywords": " bullous pemphigoid; lichen planus pemphigoides; nonbullous pemphigoid; pemphigoid diseases; lichen planus",
"medline_ta": "Acta Derm Venereol",
"mesh_terms": "D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D008010:Lichen Planus; D008297:Male; D008875:Middle Aged; D010391:Pemphigoid, Bullous; D012074:Remission Induction; D012867:Skin; D009626:Terminology as Topic; D016896:Treatment Outcome",
"nlm_unique_id": "0370310",
"other_id": null,
"pages": "adv00156",
"pmc": null,
"pmid": "32424432",
"pubdate": "2020-05-28",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Non-bullous Lichen Planus Pemphigoides: A Case Report.",
"title_normalized": "non bullous lichen planus pemphigoides a case report"
} | [
{
"companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2020R1-258313",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Pressurized intraperitoneal aerosol chemotherapy (PIPAC) shows encouraging results for patients with unresectable peritoneal metastasis. Several reports demonstrated the safety of the procedure combined with systemic chemotherapy, with a low rate of complication. The aim of this study is to report severe hypersensitivity reactions to platinum compounds (SHRPC) during PIPAC procedures.\n\n\n\nAll patients who underwent PIPAC for non-resectable PC in Lyon Sud University hospital were included in a prospective institutional database. All patients who presented a SHRPC after PIPAC were included in our analysis.\n\n\n\nOne hundred and thirty-two patients underwent 383 PIPAC procedures between December 2015 and December 2017. oxaliplatin's and cisplatin-doxorubicin's protocols were used in 71 and 312 PIPAC, respectively. Four patients (3%) developed SHRPC; two patients (2.8%) after oxaliplatin and two patients (0.6%) after cisplatin-doxorubicin protocols. SHRPC occurred during the 6th PIPAC with cisplatin-doxorubicin protocol and during 2nd and 3rd PIPAC of the oxaliplatin protocol. Three events appeared within 15 min and one event occurred 50 min following nebulization. All the SHRPC have been managed successfully without any complication.\n\n\n\nThis is the first report of SHRPC after PIPAC. The physician must constantly keep this rare but life-threatening complication in mind, especially after repeated PIPAC administration or previous platinum-based systemic chemotherapy.",
"affiliations": "Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France. swar_ms@hotmail.com.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Service d'Allergologie et Immunologie Clinique, INSERM U851, Dufourt-5F. CHU Lyon-Sud, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.;Department of Surgical Oncology, Centre Hospitalier Lyon-Sud, Hospices Civils de Lyon, Pierre-Bénite, France.",
"authors": "Siebert|Matthieu|M|;Alyami|Mohammad|M|0000-0002-0040-8511;Mercier|Frederic|F|;Gallice|Colin|C|;Villeneuve|Laurent|L|;Bérard|Frédéric|F|;Glehen|Olivier|O|;Bakrin|Naoual|N|;Kepenekian|Vahan|V|",
"chemical_list": "D000336:Aerosols; D000077150:Oxaliplatin; D004317:Doxorubicin; D002945:Cisplatin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-018-3740-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "83(3)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Allergy; Cisplatin; Doxorubicin; HIPEC; Oxaliplatin; Peritoneal metastasis; SHRPC",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000328:Adult; D000336:Aerosols; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002945:Cisplatin; D004317:Doxorubicin; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D009330:Nebulizers and Vaporizers; D000077150:Oxaliplatin; D010534:Peritoneal Neoplasms; D011312:Pressure; D011446:Prospective Studies; D012720:Severity of Illness Index",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "425-430",
"pmc": null,
"pmid": "30511218",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Severe hypersensitivity reactions to platinum compounds post-pressurized intraperitoneal aerosol chemotherapy (PIPAC): first literature report.",
"title_normalized": "severe hypersensitivity reactions to platinum compounds post pressurized intraperitoneal aerosol chemotherapy pipac first literature report"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1057301",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Radioiodine ((131)I) has been widely used in the treatment of differentiated thyroid carcinoma (DTC). Since radiation can carry a known risk of mutagenic abnormalities, we decided to study the outcome of pregnancy in females with DTC and evaluate the genetic risks and health status of their offspring. We retrospectively studied the medical records of these patients in our Institute from 1999 to 2004. A total of 1110 women were hospitalized for treatment with high doses of (131)I, at least 3700MBq. During this period, 653 of these women were in their reproductive period. A hundred of them who had at least one pregnancy after (131)I treatment, were studied. These women had a total of 126 pregnancies (1-6 pregnancies each) after treatment and 101 pregnancies before treatment. We also reviewed the (131)I dose administered last, as well as the cumulative dose of (131)I. Our results show that the incidence of abortions before (131)I treatment was 16.83% (all were spontaneous abortions) and increased to 26.19% after (131)I treatment (15.87% induced and 10.3% spontaneous abortions). Spontaneous abortions were decreased. There was no significant difference between the mean last (131)I dose and the cumulative dose in patients with or without a history of abortions. Mean interval between the last dose of (131)I treatment and abortions versus the last dose and live child births showed a significant difference. All children had normal birth weight. Three congenital anomalies: Down's syndrome, cardiac abnormalities and macrocephaly were diagnosed. Three episodes of intrauterine death were also recorded. In conclusion, our findings indicate that in women with DTC, treated with high doses of(131)I: a) There was no evidence of increased spontaneous abortions, b) Increasing the interval between the last dose of (131)I treatment and time to pregnancy might be beneficial for decreasing the entire risk of abortions and c) It appears that (131)I treatment had no obvious adverse effects on the risk of congenital anomalies.",
"affiliations": "Research Institute for Nuclear Medicine, Shariati Hospital, Tehran, Iran.",
"authors": "Fard-Esfahani|Armaghan|A|;Hadifar|Mahsa|M|;Fallahi|Babak|B|;Beiki|Davood|D|;Eftekhari|Mohammad|M|;Saghari|Mohsen|M|;Takavar|Abbas|A|",
"chemical_list": "D007457:Iodine Radioisotopes; D019275:Radiopharmaceuticals",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1790-5427",
"issue": "12(1)",
"journal": "Hellenic journal of nuclear medicine",
"keywords": null,
"medline_ta": "Hell J Nucl Med",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D015897:Comorbidity; D000013:Congenital Abnormalities; D005260:Female; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007457:Iodine Radioisotopes; D007492:Iran; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011297:Prenatal Exposure Delayed Effects; D011832:Radiation Injuries; D019275:Radiopharmaceuticals; D011878:Radiotherapy; D018570:Risk Assessment; D012307:Risk Factors; D013964:Thyroid Neoplasms; D055815:Young Adult",
"nlm_unique_id": "101257471",
"other_id": null,
"pages": "37-40",
"pmc": null,
"pmid": "19330181",
"pubdate": "2009",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Radioiodine treatment complications to the mother and child in patients with differentiated thyroid carcinoma.",
"title_normalized": "radioiodine treatment complications to the mother and child in patients with differentiated thyroid carcinoma"
} | [
{
"companynumb": "IR-JUBILANT PHARMA LTD-2021IR000268",
"fulfillexpeditecriteria": "1",
"occurcountry": "IR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SODIUM IODIDE I-131"
},
"drugadditi... |
{
"abstract": "Traumatic experiences and sleep disturbances are both common in children and adolescents. Because of the reciprocal relationship between sleep complaints and trauma, a mental health evaluation should include not only an assessment of posttraumatic stress disorder and other trauma symptoms but also a specific evaluation of sleep-related complaints. Similarly, if a history of both trauma and sleep complaints is identified, an effective trauma-informed intervention, whether psychological, psychopharmacologic, or a combination of the two, should directly address sleep issues.",
"affiliations": "Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, Child Study Center, One Park Avenue, 7th Floor, New York City, NY 10016, USA. Electronic address: Veronica.fellman@nyulangone.org.;Department of Child and Adolescent Psychiatry, NYU Grossman School of Medicine, Child Study Center, One Park Avenue, 7th Floor, New York City, NY 10016, USA.;Psychiatry and Behavioral Health, NYC Administration for Children's Services, 150 William Street, 11th Floor, New York City, NY 10038, USA.",
"authors": "Fellman|Veronica|V|;Heppell|Patrick J|PJ|;Rao|Suchet|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.chc.2020.09.002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1056-4993",
"issue": "30(1)",
"journal": "Child and adolescent psychiatric clinics of North America",
"keywords": "Adolescents; Children; PTSD; Sleep disorders; Sleep treatment; Trauma; Trauma treatment",
"medline_ta": "Child Adolesc Psychiatr Clin N Am",
"mesh_terms": "D000293:Adolescent; D002648:Child; D006801:Humans; D012890:Sleep; D012893:Sleep Wake Disorders; D013313:Stress Disorders, Post-Traumatic; D011795:Surveys and Questionnaires; D014851:Wakefulness",
"nlm_unique_id": "9313451",
"other_id": null,
"pages": "225-249",
"pmc": null,
"pmid": "33223064",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Afraid and Awake: The Interaction Between Trauma and Sleep in Children and Adolescents.",
"title_normalized": "afraid and awake the interaction between trauma and sleep in children and adolescents"
} | [
{
"companynumb": "US-OTSUKA-2021_021601",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "This report describes a case of premature closure in utero of the ductus arteriosus (DA) diagnosed postnatally in a baby with hydrops and cardiac failure. An echocardiogram 6 h postnatally showed marked dilation of the right atrium and right ventricle with marked hypertrophy and impaired function, elevated pulmonary pressures, a small pericardial effusion, and no flow through the DA. The mother was unaware of her pregnancy until she presented in labor, and she had taken diclofenac medication in the preceding months. This case and the accompanying literature review illustrate the potential fetal and neonatal complications resulting from antenatal closure of the DA due to maternal diclofenac medication during pregnancy.",
"affiliations": "Neonatal Intensive Care Unit, Norfolk & Norwich University Hospitals NHS Foundation Trust, Colney Lane, Norwich, Norfolk, NR4 7UY, UK.",
"authors": "Shastri|Aravind T|AT|;Abdulkarim|Dalia|D|;Clarke|Paul|P|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac",
"country": "United States",
"delete": false,
"doi": "10.1007/s00246-012-0461-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0172-0643",
"issue": "34(8)",
"journal": "Pediatric cardiology",
"keywords": null,
"medline_ta": "Pediatr Cardiol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D004008:Diclofenac; D004373:Ductus Arteriosus; D015150:Echocardiography, Doppler; D005260:Female; D005318:Fetal Heart; D006801:Humans; D015160:Hydrops Fetalis; D007231:Infant, Newborn; D011247:Pregnancy; D011263:Pregnancy Trimester, Third; D016216:Ultrasonography, Prenatal",
"nlm_unique_id": "8003849",
"other_id": null,
"pages": "1925-7",
"pmc": null,
"pmid": "22872018",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19389789;9290437;15133806;8633660;3970083;21269413;1957039;15009583;8790048;16483966;10099762;10072645",
"title": "Maternal diclofenac medication in pregnancy causing in utero closure of the fetal ductus arteriosus and hydrops.",
"title_normalized": "maternal diclofenac medication in pregnancy causing in utero closure of the fetal ductus arteriosus and hydrops"
} | [
{
"companynumb": "GB-BAUSCH-BL-2014-003625",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": null,
... |
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