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"abstract": "There are no globally agreed upon treatment guidelines for patients with chronic hepatitis B virus (HBV) with multidrug resistance (MDR). We conducted a multicenter, prospective, real-world cohort study of effects of tenofovir disoproxyl fumarate (TDF) monotherapy and TDF-based combination therapy, as rescue therapy, in patients with multidrug-resistant chronic HBV infections.\n\n\n\nWe recruited patients with chronic HBV infection with resistance to antivirals from 8 tertiary hospitals in Korea. Patients (n=423) received rescue therapy with TDF monotherapy (n=174) or TDF-based combination therapy (n=249). The median follow-up period was 180 weeks. A virologic response was defined as a serum HBV DNA level of <20 IU/mL.\n\n\n\nCumulative rates of virologic response did not differ significantly between the groups that received TDF monotherapy vs combination therapy at 48 weeks (71.7% vs 68.9%), 96 weeks (85.1% vs 84.2%), 144 weeks (92.1% vs 92.7%), 192 weeks (93.4% vs 95.7%), or 240 weeks (97.7% vs 97.2%). Serum levels of HBV DNA below 4.0 log10 IU/mL (odds ratio, 2.478; 95% CI 1.959-3.135; P < .001) and the absence of mutations associated with resistance to adefovir (odds ratio, 1.570; 95% CI 1.279-1.926; P < .001) were associated with virologic response in patients with MDR. There was no significant difference of virologic response among patients of different ages, sex, patients with vs without cirrhosis, positivity for hepatitis B e antigen, or renal function (all P > .05).\n\n\n\nIn a multicenter, real-world cohort study, long-term use of TDF monotherapy showed non-inferior antiviral efficacy compared with that of TDF-based combination therapy in patients with MDR.",
"affiliations": "Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Inha University School of Medicine, Incheon, Republic of Korea.;Department of Internal Medicine, Pusan National University School of Medicine, Yangsan, Republic of Korea.;Department of Internal Medicine, Catholic University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, CHA University College of Medicine, Bundang, Republic of Korea.;Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Republic of Korea.;Department of Internal Medicine, Wonju College of Medicine, Yonsei University, Wonju, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.;Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea. Electronic address: ahnsh@yuhs.ac.",
"authors": "Lee|Hye Won|HW|;Park|Jun Yong|JY|;Lee|Jin Woo|JW|;Yoon|Ki Tae|KT|;Kim|Chang Wook|CW|;Park|Hana|H|;Kim|Young Seok|YS|;Paik|Soon Ku|SK|;Lee|Jung Il|JI|;Kim|Beom Kyung|BK|;Han|Kwang-Hyub|KH|;Ahn|Sang Hoon|SH|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; D006513:Hepatitis B e Antigens; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cgh.2018.10.037",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1542-3565",
"issue": "17(7)",
"journal": "Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association",
"keywords": "Antiviral Resistance; Hepatitis B; Rescue Therapy; Tenofovir",
"medline_ta": "Clin Gastroenterol Hepatol",
"mesh_terms": "D000998:Antiviral Agents; D004279:DNA, Viral; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral; D005260:Female; D005500:Follow-Up Studies; D006513:Hepatitis B e Antigens; D006515:Hepatitis B virus; D019694:Hepatitis B, Chronic; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D000068698:Tenofovir; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101160775",
"other_id": null,
"pages": "1348-1355.e2",
"pmc": null,
"pmid": "30613003",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Long-term Efficacy of Tenofovir Disoproxil Fumarate Monotherapy for Multidrug-Resistant Chronic HBV infection.",
"title_normalized": "long term efficacy of tenofovir disoproxil fumarate monotherapy for multidrug resistant chronic hbv infection"
} | [
{
"companynumb": "KR-GILEAD-2019-0384973",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
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"activesubstancename": "LAMIVUDINE"
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{
"abstract": "OBJECTIVE\nThe aim of this article is to evaluate the safety and efficacy of perimenstrual telcagepant, a CGRP receptor antagonist, for headache prophylaxis.\n\n\nMETHODS\nWe conducted a randomized, double-blind, placebo-controlled, six-month trial in women with migraine for ≥ 3 months who experienced perimenstrual headaches. Women were randomized to telcagepant 140 mg or placebo (2:1 ratio) for seven consecutive days perimenstrually. Safety was assessed by adverse events and laboratory tests. The primary efficacy endpoint was mean monthly headache days in the subset of women reporting perimenstrual migraine (-2 days to +3 days of menses onset) and ≥ 5 moderate or severe migraines per month prior to entering the trial.\n\n\nRESULTS\nTelcagepant was generally well tolerated: 66/2660 (2.5%) on telcagepant and 36/1326 (2.7%) on placebo discontinued because of a clinical adverse event. The percentages of patients with clinical adverse events, laboratory adverse events, or discontinuation because of a laboratory adverse event were also similar between treatments. Alanine aminotransferase elevations ≥ 3x normal occurred in 0.6% of women on telcagepant and 0.4% on placebo. Three women on telcagepant vs none on placebo had alanine aminotransferase elevations ≥ 8× normal. In the efficacy subset there was no significant effect of telcagepant (n = 887) vs placebo (n = 447) in mean monthly headache days (treatment difference -0.5 day (95% CI: -1.1, 0.1)). However, telcagepant was associated with a reduction in on-drug headache days (treatment difference -0.4 day (95% CI: -0.5, -0.2), nominal p < 0.001).\n\n\nCONCLUSIONS\nTelcagepant 140 mg taken perimenstrually for seven days was generally well tolerated, but was associated with transaminase elevations. Telcagepant did not reduce monthly headache frequency, but did reduce perimenstrual headaches.",
"affiliations": "Merck & Co. Inc, Department of Clinical Research, USA.;Merck & Co. Inc, Department of Clinical Research, USA.;Merck & Co. Inc, Department of Clinical Research, USA.;Merck & Co. Inc, Department of Clinical Research, USA.;Merck & Co. Inc, Department of Clinical Research, USA.;Barts Sexual Health Centre, St Bartholomew's Hospital, UK; Centre for Neuroscience and Trauma, Blizard Institute of Cell and Molecular Science, Barts and the London School of Medicine and Dentistry, UK.;Headache Associates, USA.;Leiden University Medical Center, the Netherlands.;Merck & Co. Inc, Department of Clinical Research, USA.;Merck & Co. Inc, Department of Clinical Research, USA.;Leiden University Medical Center, the Netherlands.;Merck & Co. Inc, Department of Clinical Research, USA david.michelson@merck.com.",
"authors": "Ho|Tony W|TW|;Ho|Andrew P|AP|;Ge|Yang Joy|YJ|;Assaid|Christopher|C|;Gottwald|Regina|R|;MacGregor|E Anne|EA|;Mannix|Lisa K|LK|;van Oosterhout|Willebrordus P J|WP|;Koppenhaver|Janelle|J|;Lines|Christopher|C|;Ferrari|Michel D|MD|;Michelson|David|D|",
"chemical_list": "D001381:Azepines; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D007093:Imidazoles; C525458:telcagepant; D000410:Alanine Transaminase; D015740:Calcitonin Gene-Related Peptide",
"country": "England",
"delete": false,
"doi": "10.1177/0333102415584308",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0333-1024",
"issue": "36(2)",
"journal": "Cephalalgia : an international journal of headache",
"keywords": "CGRP; Telcagepant; headache; menstrual; migraine; prophylaxis",
"medline_ta": "Cephalalgia",
"mesh_terms": "D000328:Adult; D000410:Alanine Transaminase; D001381:Azepines; D015740:Calcitonin Gene-Related Peptide; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007093:Imidazoles; D008881:Migraine Disorders; D011293:Premenstrual Syndrome",
"nlm_unique_id": "8200710",
"other_id": null,
"pages": "148-61",
"pmc": null,
"pmid": "25926620",
"pubdate": "2016-02",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Randomized controlled trial of the CGRP receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine.",
"title_normalized": "randomized controlled trial of the cgrp receptor antagonist telcagepant for prevention of headache in women with perimenstrual migraine"
} | [
{
"companynumb": "US-JNJFOC-20160621915",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TELCAGEPANT"
},
"drugadditional": "3",
... |
{
"abstract": "Medical treatment options for severe, steroid refractory ulcerative colitis (UC) include infliximab (IFX) or cyclosporine (CSA), but general consensus has been that both agents should not be used together or even successively. We report a case of a 17-year-old male with severe UC refractory to IV steroids with successful sequential salvage therapy guided by serum IFX level. After primary lack of response to IFX, an undetectable serum IFX level and elevated IFX antibodies were followed by immediate transition to IV CSA. This case demonstrates the possibility of therapeutic drug monitoring of IFX levels when calculating the risk/benefit ratio for patients with steroid-refractory UC failing primary salvage therapy.",
"affiliations": "Inflammatory Bowel Disease Center, University of Chicago Medical Center, Chicago, IL.;Inflammatory Bowel Disease Center, University of Chicago Medical Center, Chicago, IL.;Inflammatory Bowel Disease Center, University of Chicago Medical Center, Chicago, IL.;Inflammatory Bowel Disease Center, University of Chicago Medical Center, Chicago, IL.",
"authors": "Chapman|Christopher G|CG|;Bochenek|Ashley|A|;Stein|Adam C|AC|;Rubin|David T|DT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.2014.33",
"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2014.3310.14309/crj.2014.33Case ReportInflammatory Bowel DiseaseUse of Serum Infliximab Level Prior to Cyclosporine Salvage Therapy in Severe Ulcerative Colitis Chapman Christopher G. MDBochenek Ashley MSN, APN/FNP-BCStein Adam C. MDRubin David T. MDInflammatory Bowel Disease Center, University of Chicago Medical Center, Chicago, ILCorrespondence: Christopher G. Chapman, 5841 S. Maryland Avenue, Chicago, IL, 60647 (christopher.chapman@uchospitals.edu).4 2014 04 4 2014 1 3 148 150 03 11 2013 16 12 2013 Copyright © Chapman et al.2014This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/Medical treatment options for severe, steroid refractory ulcerative colitis (UC) include infliximab (IFX) or cyclosporine (CSA), but general consensus has been that both agents should not be used together or even successively. We report a case of a 17-year-old male with severe UC refractory to IV steroids with successful sequential salvage therapy guided by serum IFX level. After primary lack of response to IFX, an undetectable serum IFX level and elevated IFX antibodies were followed by immediate transition to IV CSA. This case demonstrates the possibility of therapeutic drug monitoring of IFX levels when calculating the risk/benefit ratio for patients with steroid-refractory UC failing primary salvage therapy.\n==== Body\nIntroduction\nBoth infliximab (IFX) and cyclosporine (CSA) are effective for the treatment of severe ulcerative colitis (UC) that is refractory to IV steroids,1,2 but general consensus has been that both agents should not be used together or even successively. A recent randomized trial of these agents in IV steroid-refractory patients found no difference in efficacy, but 40% of patients did not respond to the therapy in either arm.3 Case series have reported significant infectious events when the 2 agents are used for salvage therapy in close succession.4–7 We report a case of severe UC with successive salvage therapy guided by serum IFX level.\n\nCase Report\nA 17-year-old male with a 6-month history of pan-UC presented to our center. He had primary non-response to 8 weeks of mesalamine and continuous oral prednisone. He was started on combination therapy with azathioprine (AZA) 50 mg per day and IFX 5 mg/kg IV at 0 and 2 weeks, but due to lack of response, received 7.5 mg/kg IV at 6 weeks. Despite this approach, he was unable to wean from prednisone with persistent disease activity characterized by 6-8 bloody loose stools per day with associated severe urgency and nocturnal bowel movements. He received his next IFX at 7.5 mg/kg 6 weeks later. When this failed to control his colitis, he transferred care to our institution and was admitted. At that time (2 weeks after his last IFX dose) admission labs (Table 1) and serum IFX level and antibodies to IFX (ATI) were ordered (electrochemiluminescence immunoassay [ECLIA]; Esoterix Endocrinology, Calabasa Hills, CA).\n\nTable 1 Patient Laboratory Admission Values and Normal Values\n\nLaboratory Parameter\tAdmission Values\tNormal Values\t\nSodium, mEq/L\t140\t134-149\t\nPotassium, mEq/L\t4.0\t3.5-5.0\t\nChloride, mEq/L\t104\t95-108\t\nBicarbonate, mEq/L\t28\t23-30\t\nUrea nitrogen, mg/dL\t12\t7-20\t\nCreatinine, mg/dL\t0.9\t0.5-1.4\t\nGlucose, mg/dL\t85\t60-109\t\nCalcium, mg/dL\t8.9\t8.4-10.2\t\nTotal protein, g/dL\t6.6\t6.0-8.3\t\nAlbumin, g/dL\t3.7\t3.5-5.0\t\nTotal bilirubin, mg/dL\t0.1\t0.1-1.0\t\nAlkaline phosphatase, U/L\t67\t100-390\t\nAST, U/L\t17\t8-37\t\nALT, U/L\t34\t8-35\t\nWhite blood cells, K/uL\t19.0\t3.5-11\t\nHemoglobin, g/dL\t11.2\t13.5-17.5\t\nPlatelets, K/uL\t391\t150-450\t\nC-Reactive protein, mg/L\t27\t<5\t\nAST = aspartate aminotransferase; ALT = alanine transaminase\n\nHe was found to have Clostridium difficile (C. difficile) infection and was treated with oral vancomycin 125 mg 4 times daily, metronidazole 500 mg IV every 8 hours, and IV methylprednisolone 20 mg every 12 hours. He was maintained on dual therapy for C. difficile for 12 days with continuation of oral vancomycin monotherapy for an additional 18 days. Despite clearance of C. difficile (by negative PCR 7 days after initiating therapy), he continued to have frequent bloody stools and urgency. Colonoscopy confirmed the presence of diffuse moderate to-severe active colitis (Figure 1). Biopsies demonstrated no evidence of viral cytopathic change, and immunostains were negative for cytomegalovirus infection. Eight days after admission, IFX and ATI results showed that serum infliximab was undetectable, and ATI was 265 ng/mL (reference: <22 ng/mL). After discussion with the patient, we decided to pursue further medical management. CSA 2 mg/kg IV continuous infusion was started (goal serum level: 300-400 ng/mL)8 with standard antibiotic prophylaxis for Pneumocystis pneumonia with trimethoprim/sulfamethoxazole (TMP/SMZ) and continued IV steroids. After 4 days of CSA, the hemato-chezia had stopped and the diarrhea started to resolve. He was discharged from the hospital on oral CSA, prednisone, TMP/SMZ, and AZA (Figure 2). At the time of this report 9 months later, he remains in steroid-free remission only on AZA, and there were no adverse events.\n\nFigure 1 Moderate-to-severe active ulcerative colitis in the sigmoid colon confirmed via colonoscopy.\n\nFigure 2 Clinical course, with Simple Clinical Colitis Activity Index (SSCAI) and cyclosporine levels.\n\nDiscussion\nMedical options for hospitalized patients with severe, corticosteroid-refractory UC include IFX or CSA. Initial response rates for both CSA and IFX in this challenging patient population are similar, ranging from 62% to 83%,2,9–11 respectively, and 71% of patients at 3 months.1 A recent parallel, open label, randomized control trial comparing the 2 therapies found IV CSA and IFX to be no different for achieving short-term remission and colectomy-free survival, with similar rates of serious adverse events.3\n\nIn patients treated with either CSA or IFX who do not respond to therapy, options include colectomy or, in a selective cohort, successive salvage therapy with the other agent. Published experience with successive salvage medical therapy has been limited to several small case series. Manosa et al6 reported that 6 of 16 patients receiving IFX salvage after CSA (38%) required colectomy after a median follow-up time of 195 days, while in a similar cohort, Chaparro et al7 reported that 29% progressed to colectomy at 1 year. Maser et al4 reported a retrospective study of 19 patients with steroid-refractory UC who were treated with CSA or IFX within 30 days as sequential rescue therapy. At 1 year, 8 (42%) patients required colectomy; steroid-free remission was achieved in 40% of the IFX-salvage cohort and 33% in the CSA-salvage cohort without statistical difference between them. In the largest cohort published to date, Leblanc et al5 published a retrospective study of 86 patients in which 48 (56%) patients had a colectomy despite sequential salvage therapy at 1 year, while 22% of patients had steroid-free remission.\n\nThe decision to pursue sequential medical therapy must account for the risks of delaying surgical intervention and that dual immunosuppression raises the risk of infection. Maser et al reported 3 (16%) serious infectious adverse events, including 1 death from gram-negative sepsis in the IFX salvage group. Leblanc et al reported that their IFX salvage group suffered 9 (10.5%) serious infectious complications as well as 1 death due to post-colectomy pulmonary embolism, possibly related to delayed surgical intervention. Chaparro et al also reported an infection adverse event rate of 8.4%, including 1 death due to post-colectomy nosocomial pneumonia.\n\nThe significantly longer half-life for IFX (8-10 days) versus CSA (6-8 hours) has led some to suggest the use of CSA as a first approach to steroid-refractory UC; if CSA fails, a shorter wash-out period may allow for safer IFX use. A lack of experience with CSA by gastroenterologists has made this option impractical. There is increasing evidence that the primary non-response to IFX in severe colitis may be partially attributed to rapid metabolism or rapid clearance of the drug, with emerging reports of fecal elimination of the drug as a potential explanation.12,13\n\nThis is the first report of the use of therapeutic drug monitoring to minimize toxicity and guide IFX/CSA salvage therapy. We believe that this patient's lack of response to IFX was due to rapid clearance and anti-drug antibodies. We do not know if he was losing IFX through a protein-losing colopathy and this “pseudo-episodic” therapy resulted in immunogenicity against the drug, or if he already had ATI that neutralized the IFX. In either explanation, it was clear that the subtherapeutic drug level was contributing to his lack of response to this therapy. The undetectable IFX level provided reassurance for use of salvage CSA. We propose that therapeutic monitoring may be used in the assessment of salvage therapies for selected patients.\n\nA practical limitation to this approach is the time required to obtain IFX and ATI levels with currently available clinical assays, which delays clinical and therapeutic decisions for the patient. We believe that waiting for these results is worthwhile, considering the risks of surgery that may be averted. In the future, we hope “point of service” assays and improved turnaround times—driven by volume and demand—will reduce waiting time and make this approach more practical.\n\nDisclosures\nAuthor contributions: CG Chapman and AC Stein were involved with patient care and wrote the manuscript. A. Bo-chenek was involved with patient care. DT Rubin was involved with patient care, reviewed and revised the manuscript, and is the article guarantor.\n\nFinancial disclosure: No financial support was received, and the authors have no conflicts of interest to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Jarnerot G , Hertervig E , Friis-Liby I , et al. Infliximab as rescue therapy in severe to moderately severe ulcerative colitis: A randomized, placebo-controlled study . Gastroenterology . 2005 ;128 (7 ):1805 –11 .15940615 \n2 Lichtiger S , Present DH , Kornbluth A , et al. Cyclosporine in severe ulcerative colitis refractory to steroid therapy . N Engl J Med . 1994 ;330 (26 )1841 –5 .8196726 \n3 Laharie D , Bourreille A , Branche J , et al. Ciclosporin versus inflimab in patients with severe ulcerative colitis refractory to intravenous steroids: A parallel, open-label randomised controlled trial . Lancet . 2012 ;380 (9857 ):1909 –15 .23063316 \n4 Maser EA , Deconda D , Lichtiger S , et al. Cyclosporine and infliximab as rescue therapy for each other in patients with steroid-refractory ulcerative colitis . Clin Gastroenterol Hepatol . 2008 ;6 (10 ):1112 –6 .18928936 \n5 Leblanc S , Allez M , Seksik P , et al. Successive treatment with cyclosporine and infliximab in steroid-refractory ulcerative colitis . Am J Gastroenterol . 2011 ;106 (4 ):771 –7 .21386832 \n6 Mañosa M , López San Román A , Garcia-Planella E , et al. Infliximab rescue therapy after cyclosporin failure in steroid-refractory ulcerative colitis . Digestion . 2009 ;80 (1 ):30 –5 .19439969 \n7 Chaparro M , Burgueño P , Iglesias E , et al. Infliximab salvage therapy after failure of ciclosporin in corticosteroid-refractory ulcerative colitis: A multi-centre study . Aliment Pharmacol Ther . 2012 ;35 (2 ):275 –83 .22142227 \n8 Van Assche G , D'Haens G , Noman M , et al. Randomized, double-blind comparison of 4 mg/kg versus 2 mg/kg intravenous cyclosporine in severe ulcerative colitis . Gastroenterology . 2003 ;125 (4 ):1025 –31 .14517785 \n9 García-López S , Gomollón-García F , Pérez-Gisbert J \nCyclosporine in the treatment of severe attack of ulcerative colitis: A systematic review . Gastroenterol Hepatol . 2005 ;28 (10 ):607 –14 .16373009 \n10 Campbell S , Travis S , Jewell D \nCiclosporin use in acute ulcerative colitis: A long-term experience . Eur J Gastroenterol Hepatol . 2005 ;17 (1 ):79 –84 .15647646 \n11 Arts J , D'Haens G , Zeegers M , et al. Long-term outcome of treatment with intravenous cyclosporin in patients with severe ulcerative colitis . Inflamm Bowel Dis . 2004 ;10 (2 ):73 –8 .15168804 \n12 Brandse J , Wildenberg ME , Bruyn JR , et al. Fecal loss of infliximab as a cause of lack of response in severe inflammatory bowel disease . Presented at: Digestive Disease Week ; May 18 , 2013 ; Abstract 157 .\n13 Kevans D , Murthy S , Iacono A , et al. Accelerated clearance of serum infliximab during induction therapy for acute ulcerative colitis is associated with treatment failure . Gastroenterology . 2012 ;142 (suppl 1 ):S384 –S385 .\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2326-3253",
"issue": "1(3)",
"journal": "ACG case reports journal",
"keywords": null,
"medline_ta": "ACG Case Rep J",
"mesh_terms": null,
"nlm_unique_id": "101638398",
"other_id": null,
"pages": "148-50",
"pmc": null,
"pmid": "26157857",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports",
"references": "23063316;15647646;14517785;15168804;19439969;21386832;18928936;8196726;16373009;15940615;22142227",
"title": "Use of Serum Infliximab Level Prior to Cyclosporine Salvage Therapy in Severe Ulcerative Colitis.",
"title_normalized": "use of serum infliximab level prior to cyclosporine salvage therapy in severe ulcerative colitis"
} | [
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"companynumb": "US-JNJFOC-20131112292",
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"occurcountry": "US",
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"actiondrug": "3",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
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{
"abstract": "There has been considerable progress in treating malignant melanoma over the last few years. The immune-checkpoint-inhibitors nivolumab and pembrolizumab have been approved by the Food and Drug Administration in 2014 for the therapy of metastatic melanoma. Anti-programmed cell death-1-blocking antibodies are known to cause immune-related adverse events. Physicians should be aware of common and rare side effects and pay attention to new ones. We therefore report a severe and life-threatening side effect of anti-programmed cell death-1 immunotherapy with nivolumab that has not been previously reported: the development of a third-degree atrioventricular block. After a second infusion with nivolumab, our patient developed a troponin I-positive and autoantibody-positive myositis and a few days later a new-onset third-degree atrioventricular block. This is most likely because of an autoimmune-induced myositis with a cardiac impairment in terms of a myocarditis, which led to an impairment of the conduction of cardiac electrical stimuli.",
"affiliations": "Departments of aDermatology bCardiology, University Hospital Mainz, Johannes Gutenberg - Universität Mainz, Mainz, Germany.",
"authors": "Behling|Juliane|J|;Kaes|Joachim|J|;Münzel|Thomas|T|;Grabbe|Stephan|S|;Loquai|Carmen|C|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D000077594:Nivolumab",
"country": "England",
"delete": false,
"doi": "10.1097/CMR.0000000000000314",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0960-8931",
"issue": "27(2)",
"journal": "Melanoma research",
"keywords": null,
"medline_ta": "Melanoma Res",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D054537:Atrioventricular Block; D001327:Autoimmune Diseases; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D008545:Melanoma; D008875:Middle Aged; D009220:Myositis; D000077594:Nivolumab; D014604:Uveal Neoplasms",
"nlm_unique_id": "9109623",
"other_id": null,
"pages": "155-158",
"pmc": null,
"pmid": "27977496",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New-onset third-degree atrioventricular block because of autoimmune-induced myositis under treatment with anti-programmed cell death-1 (nivolumab) for metastatic melanoma.",
"title_normalized": "new onset third degree atrioventricular block because of autoimmune induced myositis under treatment with anti programmed cell death 1 nivolumab for metastatic melanoma"
} | [
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"companynumb": "DE-BAYER-2017-056145",
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"occurcountry": "DE",
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"actiondrug": "1",
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"activesubstancename": "SORAFENIB"
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"abstract": "Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.",
"affiliations": "Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Medicine, Saint Agnes Hospital, Baltimore, Maryland, USA.;Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.;Department of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.;Department of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA.",
"authors": "Thummalapalli|Rohit|R|;Heumann|Thatcher|T|;Stein|Julie|J|;Khan|Sarah|S|;Priemer|David S|DS|;Duffield|Amy S|AS|;Laterra|John|J|;Couzi|Rima|R|;Lim|Michael|M|;Holdhoff|Matthias|M|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000507281",
"fulltext": "\n==== Front\nCase Rep Oncol\nCase Rep Oncol\nCRO\nCase Reports in Oncology\n1662-6575 S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.com \n\n32518546\n10.1159/000507281\ncro-0013-0508\nCase Report\nHemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma\nThummalapalli Rohit a Heumann Thatcher a Stein Julie b Khan Sarah e Priemer David S. b Duffield Amy S. b Laterra John c Couzi Rima a Lim Michael d Holdhoff Matthias a* aDepartment of Oncology, The Johns Hopkins University School of Medicine and The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, USA\nbDepartment of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\ncDepartment of Neurology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\ndDepartment of Neurosurgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA\neDepartment of Medicine, Saint Agnes Hospital, Baltimore, Maryland, USA\n*Matthias Holdhoff, MD, PhD, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, 201 North Broadway, 9th floor, mailbox 3, Baltimore, MD 21287 (USA), mholdho1@jhmi.edu\nMay-Aug 2020 \n12 5 2020 \n12 5 2020 \n13 2 508 514\n12 3 2020 16 3 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Immune checkpoint inhibition (ICI)-based approaches have transformed the treatment landscape of numerous solid tumors. Glioblastoma (GBM) is an aggressive and almost universally fatal disease which is in need of novel treatment options, and combinations of immune checkpoint inhibitors, including dual agent therapy, are starting to be explored in refractory GBM. Growing adoption of ICI-based approaches in solid tumors has been met with improved understanding of immune-related adverse events (IRAEs), including primary hematologic adverse events. Although management guidelines for multiple hematologic IRAEs have been established, the emergence of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has only rarely been described, and its pathogenesis and optimal management are incompletely understood. We present the case of a 74-year-old male with a history of refractory GBM treated with PD-1 and indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibition who experienced acute liver injury, followed by progressive fevers, altered mental status, and cytopenias. Serum studies and examination of spleen and bone marrow pathology were consistent with HLH, which was refractory to steroids and ultimately resulted in his rapid clinical decline. Here, we review prior cases of HLH secondary to ICI therapy across solid tumors, and explore potential mechanisms contributing to the rapid onset and refractory nature of our patient's HLH syndrome. We hope to further highlight HLH as an emerging hematologic IRAE secondary to ICI therapy, and suggest that new practice guidelines begin to recognize HLH as a characteristic hematologic IRAE in patients treated with PD-1 and other immune checkpoint inhibitors.\n\nKeywords\nHemophagocytic lymphohistiocytosisProgrammed cell death receptor-1Indoleamine-pyrrole 2,3-dioxygenaseImmune checkpoint inhibitionImmune-related adverse eventsGlioblastoma\n==== Body\nBackground\nImmune checkpoint inhibition (ICI) can produce durable responses in subsets of solid tumor patients, and is therefore starting to be widely explored across cancers. Glioblastomas are the most common primary brain cancers in adults, and despite aggressive multimodal management, virtually all patients eventually face recurrence and die of their disease. In this setting, there has been a strong interest in exploring immunotherapeutic treatments for patients with glioblastomas. ICI therapy is classically associated with characteristic immune-related adverse events (IRAEs), including colitis, hepatitis, pneumonitis, and endocrinopathies [1]. However, the emergence of new and less common IRAEs, including hematologic toxicities, continues to be explored, particularly in the setting of dual ICI therapy and clinical trials of novel ICI agents. Management of hematologic IRAEs including autoimmune hemolytic anemia, acquired TTP/hemolytic uremic syndrome, aplastic anemia, immune thrombocytopenia, and acquired hemophilias have been described in recent practice guidelines [2]; however, the presentation and management of hemophagocytic lymphohistiocytosis (HLH) secondary to ICI therapy has yet to be rigorously explored or described in practice guidelines. Recently, several reports have described HLH in solid tumor patients treated with ICI [3, 4, 5, 6, 7, 8, 9, 10, 11]; these HLH syndromes varied in terms of method of diagnosis, onset, severity, and response to immunosuppressive modalities. In this case report, we describe a patient with recurrent glioblastoma who developed HLH while on a clinical trial with the PD-1 inhibitor nivolumab and a novel indoleamine-pyrrole 2,3-dioxygenase (IDO) inhibitor.\n\nCase Presentation\nA 74-year-old male with a history of glioblastoma, coronary artery disease, atrial fibrillation, hypertension, hyperlipidemia, and type 2 diabetes mellitus presented to our service with abnormal liver enzymes found at an outpatient clinic visit. Thirteen months prior to admission, he had developed aphasia resulting from a left temporal lobe enhancing mass found on imaging. Subsequent surgical resection revealed a BRAF V600E mutated, IDH1 wild type, MGMT promoter unmethylated glioblastoma. His disease progressed following 6 weeks of fractionated radiation with concurrent temozolomide and four cycles of monthly adjuvant temozolomide. He was then enrolled in a phase I trial of nivolumab and anti-IDO immunotherapy for patients with first glioblastoma recurrence (NCT03707457). He received a single infusion of nivolumab, and then was started on monthly nivolumab and once daily BMS-986205, an oral IDO1 inhibitor. On cycle 2, day 17 of nivolumab and BMS-986205, he was found to have an elevated AST of 832, ALT of 1,378, alkaline phosphatase of 152, and total bilirubin of 4.1, and was admitted to the inpatient service. Duplex liver ultrasound, CT imaging, and markers for autoimmune, infiltrative, and viral etiologies of liver injury proved unremarkable. As a result of this negative workup, he was treated for immune-mediated hepatitis, secondary to his anti-PD-1 and/or anti-IDO therapy, and was initiated on IV methylprednisolone. His liver enzymes continued to uptrend to a peak of AST 1,064, ALT 1,675 on day four of admission leading to an increase in steroid dosing followed by a liver biopsy. Pathology was significant for focal bile duct injury, mild portal inflammation, and minimal lymphocytic lobular infiltration. Overall, these findings were non-specific but possibly supportive of a resolving hepatitis. His transaminases began to downtrend and he was weaned to oral prednisone.\n\nOn day 8 of admission, he started to experience new fevers, progressively worsening mental status, new leukopenia to a total WBC of 460 per mm3, and new neutropenia to an absolute neutrophil count of 350 per mm3. His worsening mental status was not thought to be reflective of worsening liver dysfunction or steroid-related delirium, and was concerning for an infectious or inflammatory cause. He underwent a lumbar puncture which showed 18 WBCs per mm3 (95% lymphocytes), a normal glucose of 61 mg/dL, and a slightly elevated total protein of 74.4 mg/dL, which raised some concern for an autoimmune encephalitis that had been unresponsive to steroids. CSF was positive for malignant cells. A broad serum, urine, and CSF infectious workup was sent but was only significant for low level serum and urine BK virus, low level serum JC viremia, and negative JC virus in CSF; his clinical syndrome was not thought to be consistent with BKV meningoencephalitis. CT chest, abdomen, and pelvis showed mild duodenal and perinephric fat stranding, an irregular posterior bladder wall with a hyperattenuating nodule, and splenomegaly to 15.6 cm. Given the progressive neutropenia and fevers, he was broadly covered with IV vancomycin, ceftazidime, metronidazole, amphotericin B, acyclovir, and atovaquone.\n\nGiven the progressive cytopenias, fevers, altered mental status, splenomegaly, and continued bilirubin elevation without a clear alternate cause, the diagnosis of HLH was considered. Ferritin was elevated at 33,738 ng/mL (normal <400), IL-6 ELISA was elevated at 37.3 pg/mL (normal <5), and triglycerides were elevated at 843 mg/dL (normal <150). Whether this represented a true HLH process or simply reflected profound inflammation in the setting of severe hepatitis, undiagnosed infection, or other IRAE was unclear. Accounting for the patient's rapid clinical decline and lack of further safe treatment options, his family declined a bone marrow biopsy. He was ultimately transitioned to comfort measures, became progressively somnolent, and expired on day 15 of admission.\n\nPostmortem soluble IL-2 receptor was found to be significantly elevated at 28,985 pg/mL (normal 532–1,891). Postmortem autopsy was completed. Gross pathology was significant for generalized jaundice, hepatomegaly (2,350 g; reference range: 1,500–1,800 g), and splenomegaly (350 g; reference range: 150–200 g). Histologic examination of the spleen (Fig. 1) and bone marrow (Fig. 2) was supportive of HLH, showing scattered infiltration by foamy histiocytes which occasionally contained hematolymphoid cells and/or cell debris, consistent with hemophagocytosis. His final HScore was 239, reflecting a 98–99% probability of HLH. Histologic examination of the liver showed canalicular and intrahepatic cholestasis (Fig. 3). There was also centrilobular hepatocellular dropout, which was seen in coordination with scarring and/or distortion of the central veins. It was difficult to characterize the etiology of the central vein injury, but it may have represented the effects of a prior vasculitis. There was only mild mixed portal inflammation and rare foci of lobular inflammation, which was unconvincing for an antecedent ICI-induced autoimmune hepatitis, and there was no evidence of HLH in the liver (Fig. 3). Hence, the liver pathology was not consistent with either HLH or ICI-induced autoimmune hepatitis, and perhaps could have been secondary to sinusoidal congestion from drug-induced liver injury, or an incompletely characterized vasculitis.\n\nDiscussion/Conclusions\nHLH represents a rare, severe inflammatory reaction characterized by overstimulation of lymphocytes and macrophages, and is characterized by high levels of serum cytokines, the presence of hemophagocytosis in the reticuloendothelial and lymphoid systems, and often results in multi-organ failure, particularly of the liver and bone marrow [12]. HLH can be primary (genetic cause, usually presenting in childhood) or secondary to a number of causes including infections (particularly viral including EBV, as well as bacterial, and fungal), hematologic malignancies (particularly of T and NK lineages), autoimmune conditions (including SLE and adult-onset Still's disease), immunodeficient states (including chemotherapy or modes of immune suppression) [12], and is starting to be described in patients receiving ICI therapy.\n\nWe found a total of six pathology-proven cases of HLH in the setting of ICI for solid tumors, including nivolumab [3, 4], pembrolizumab [5, 6, 7], and combined ipilimumab and nivolumab [8] (Table 1). We also found an additional five cases [4, 9, 10, 11] which were diagnosed based on serum findings, including elevated ferritin, soluble IL-2 receptor, triglycerides, NK cell functional assays, and cytopenias (Table 1). The majority of patients were receiving ICI for melanoma or NSCLC (eight of 11 cases); no prior cases were described in patients with glioblastoma. All 11 patients received steroids. Three received additional immunosuppression, including two with mycophenolate mofetil [10, 11], and one with IVIG and anakinra [7]. One received etoposide according to HLH-2004 protocol [5]. In contrast to our patient, five of seven showed clinical improvement with steroids alone [3, 4, 6, 8, 9]; in addition, our patient experienced HLH earlier than all cases except two, with one case occurring after one dose of pembrolizumab [6] and another after one dose of avelumab [4]. Overall, this suggested that our patient may have had a particularly aggressive manifestation of the syndrome, and we wondered whether concurrent IDO1 inhibition could have contributed. Upregulation of the IDO pathway has been implicated as an escape mechanism to PD-1 blockade, and acts by metabolizing tryptophan to kynurenine, which can promote differentiation of T regulatory cells and induction of T cell tolerance [13]. However, patients with HLH have been shown to have high plasma kynurenine to tryptophan ratios [14], and IDO1 knockout murine models have not been shown to affect clinical outcome in secondary HLH models [15]. This suggested that PD-1 blockade was likely the main driver of our patient's immunotoxicity.\n\nConclusions\nTaken together, this case represents a particularly early and aggressive form of HLH secondary to combination ICI therapy, and the first described in a patient receiving combined PD-1 and IDO inhibition. As new ICI agents continue to be explored in the management of solid tumors, the increasing incidence of HLH as a possible severe IRAE should be considered, and practice guidelines should begin to recognize HLH is a more commonly observed hematologic IRAE.\n\nStatement of Ethics\nThe study (ClinicalTrials.gov ID: NCT03707457) was approved by the Institutional Review Board (IRB) of the Johns Hopkins Medical Institutions. Informed consent for participation in the clinical trial (ClinicalTrials.gov ID: NCT03707457) had been obtained by the patient. Consent for publication was obtained from the family.\n\nDisclosure Statement\nM.H. has consulted or served on an advisory board for Celgene, Abbvie, BTG International, and NewLink Genetics. M.L. has research support from Arbor, BMS, Accuray, DNAtrix, Tocagen, Biohaven, and Kyrin-Kyowa, and has consulted for Tocagen, SQZ Technologies, VBI, and Stryker. The authors declare that there are no competing interests.\n\nFunding Sources\nThis study was supported by the Sidney Kimmel Comprehensive Cancer Center Core Grant No. P30CA006973.\n\nAuthor Contributions\nR.T., T.H., S.K., R.C., J.L., R.C., M.L., and M.H. took clinical care of the patient. J.S., D.S.P., and A.S.D. provided pathology figures and interpreted pathology specimens. R.T. wrote the manuscript with input from all authors. All authors read and approved the final manuscript. M.H. reviewed and interpreted the data presented in this case report, coordinated this project, contributed to writing the manuscript, and has approved the final manuscript.\n\nAcknowledgement\nWe thank the patient's family for agreeing to the report of his case.\n\nFig. 1 Histologic examination of the spleen, showing infiltration of foamy histocytes containing occasional hematolymphoid cells.\n\nFig. 2 Histologic examination of the bone marrow, showing infiltration of foamy histocytes containing occasional hematolymphoid cells.\n\nFig. 3 Histologic examination of the liver, showing canalicular and intrahepatic cholestasis, centrilobular hepatocellular dropout, scarring of central veins, and mild mixed portal inflammation and foci of lobular inflammation.\n\nTable 1 List of prior cases of HLH secondary to ICI therapy\n\nReference\tType of ICI\tTiming/cycles of therapy\tPrimary malignancy\tMethod of diagnosis\tBM biopsy/pathology\tTreatment\tClinical outcome\t\nTakeshita et al., 2017 [3]\tNivolumab\t2 doses\tNSCLC\tBM biopsy\tBM biopsy + for HLH\tSteroids\tImprovement\t\n\t\nMalissen et al., 2017 (case 1) [4]\tNivolumab\t17 months\tMelanoma\tBM biopsy\tBM biopsy + for HLH\tSteroids\tDeath\t\n\t\nHonjo et al., 2019 [10]\tNivolumab\t4 doses\tNSCLC\tFerritin, soluble IL-2R, triglyceride elevation\tN/A\tSteroids, mycophenolate mofetil\tImprovement\t\n\t\nSadaat and Jang, 2018 [9]\tPembrolizumab\t6 doses\tMelanoma\tNK cell functional assay, soluble CD163 elevation\tN/A\tSteroids\tImprovement\t\n\t\nShah et al., 2017 [5]\tPembrolizumab\t9 months\tBladder cancer\tBM biopsy, NK cell functional assay, soluble IL-2R elevation\tBM biopsy + for HLH\tSteroids and etoposide (HLH 2004)\t?\t\n\t\nOkawa et al., 2019 [6]\tPembrolizumab\t1 dose\tNSCLC\tBM biopsy, soluble IL-2R, ferritin elevation\tBM biopsy + for HLH\tSteroids\tImprovement\t\n\t\nLaderian et al., 2019 [7]\tPembrolizumab\t12 months\tThymic cancer\tBM biopsy, liver biopsy, soluble IL-2R, ferritin elevation, cytopenias\tBM biopsy + for HLH\tSteroids, IVIG, anakinra\tDeath\t\n\t\nMalissen et al., 2017 (case 2) [4]\tIpilimumab\t1 dose of ipilimumab; prior history of 9 months of nivolumab\tMelanoma\tFerritin, triglyceride elevation, cytopenias\tBM biopsy negative for HLH\tSteroids\tImprovement\t\n\t\nMalissen et al., 2017 (case 3) [4]\tAvelumab\t1 dose\tMerkel cell carcinoma\tFerritin, triglyceride elevation, cytopenias\tN/A\tSteroids\tDeath\t\n\t\nHantel et al., 2018 [8]\tIpilimumab and nivolumab\t4 doses of ipilimumab, 1 dose of ipilimumab and nivolumab (3 weeks prior)\tMelanoma\tBM biopsy, soluble IL-2R elevation\tBM biopsy + for HLH\tSteroids\tImprovement\t\n\t\nSatzger et al., 2018 [11]\tIpilimumab and nivolumab\t4 doses\tMelanoma\tLiver biopsy, ferritin, triglyceride, soluble IL-2 elevation, cytopenias\tN/A\tSteroids, mycophenolate mofetil\tImprovement\n==== Refs\nReferences\n1 Topalian SL Hodi FS Brahmer JR Gettinger SN Smith DC McDermott DF Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 (26) 2443 54 22658127 \n2 Brahmer JR Lacchetti C Thompson JA Atkins MB Brassil KJ Caterino JM National Comprehensive Cancer Network Management of immune-related adverse events in patients treated with immune checkpoint inhibitor therapy: American society of clinical oncology clinical practice guideline summary J Oncol Pract 2018 14 (4) 247 9 29517954 \n3 Takeshita M Anai S Mishima S, Inoue K Coincidence of immunotherapy-associated hemophagocytic syndrome and rapid tumor regression Ann Oncol 2017 28 (1) 186 9 28043982 \n4 Malissen N Lacotte J Du-Thanh A Gaudy-Marqueste C Guillot B Grob JJ Macrophage activation syndrome: a new complication of checkpoint inhibitors Eur J Cancer 2017 77 88 9 28365531 \n5 Shah D Shrestha R Ramlal R Hatton J, Saeed H Pembrolizumab associated hemophagocytic lymphohistiocytosis Ann Oncol 2017 28 (6) 1403 28368439 \n6 Okawa S Kayatani H Fujiwara K Ozeki T Takada K Iwamoto Y Pembrolizumab-induced autoimmune hemolytic anemia and hemophagocytic lymphohistiocytosis in non-small cell lung cancer Intern Med 2019 58 (5) 699 702 30828042 \n7 Laderian B Koehn K Holman C Lyckholm L, Furqan M Association of hemophagocytic lymphohistiocytosis and programmed death 1 checkpoint inhibitors J Thorac Oncol 2019 14 (4) e77 8 30922584 \n8 Hantel A Gabster B Cheng JX Golomb H, Gajewski TF Severe hemophagocytic lymphohistiocytosis in a melanoma patient treated with ipilimumab + nivolumab J Immunother Cancer 2018 6 (1) 73 30012206 \n9 Sadaat M, Jang S Hemophagocytic lymphohistiocytosis with immunotherapy: brief review and case report J Immunother Cancer 2018 6 (1) 49 29871698 \n10 Honjo O Kubo T Sugaya F Nishizaka T Kato K Hirohashi Y Severe cytokine release syndrome resulting in purpura fulminans despite successful response to nivolumab therapy in a patient with pleomorphic carcinoma of the lung: a case report J Immunother Cancer 2019 7 (1) 97 30944043 \n11 Satzger I Ivanyi P Länger F Kreipe HH Schaper-Gerhardt K Beutel G Treatment-related hemophagocytic lymphohistiocytosis secondary to checkpoint inhibition with nivolumab plus ipilimumab Eur J Cancer 2018 93 150 3 29472154 \n12 Jordan MB Allen CE Weitzman S Filipovich AH, McClain KL How I treat hemophagocytic lymphohistiocytosis Blood 2011 118 (15) 4041 52 21828139 \n13 Moon YW Hajjar J Hwu P, Naing A Targeting the indoleamine 2,3-dioxygenase pathway in cancer J Immunother Cancer 2015 3 51 26674411 \n14 Put K Avau A Brisse E Mitera T Put S Proost P Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ Rheumatology (Oxford) 2015 54 (8) 1507 17 25767156 \n15 Put K Brisse E Avau A Imbrechts M Mitera T Janssens R Ido1 deficiency does not affect disease in mouse models of systemic juvenile idiopathic arthritis and secondary hemophagocytic lymphohistiocytosis PLoS ONE 2016 11 (2) e0150075 26914138\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "13(2)",
"journal": "Case reports in oncology",
"keywords": "Glioblastoma; Hemophagocytic lymphohistiocytosis; Immune checkpoint inhibition; Immune-related adverse events; Indoleamine-pyrrole 2,3-dioxygenase; Programmed cell death receptor-1",
"medline_ta": "Case Rep Oncol",
"mesh_terms": null,
"nlm_unique_id": "101517601",
"other_id": null,
"pages": "508-514",
"pmc": null,
"pmid": "32518546",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "30922584;25767156;30828042;29472154;28368439;28043982;29517954;26914138;28365531;22658127;30944043;30012206;29871698;21828139;26674411",
"title": "Hemophagocytic Lymphohistiocytosis Secondary to PD-1 and IDO Inhibition in a Patient with Refractory Glioblastoma.",
"title_normalized": "hemophagocytic lymphohistiocytosis secondary to pd 1 and ido inhibition in a patient with refractory glioblastoma"
} | [
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"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-20-05663",
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"occurcountry": "US",
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"activesubstancename": "VANCOMYCIN"
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"abstract": "OBJECTIVE\nTo report our institutional experience with treatment of primary genitourinary soft tissue sarcoma.\n\n\nMETHODS\nWe retrospectively reviewed the medical records of adult soft tissue sarcoma patients treated between March 2005 and May 2019. The primary tumor sites included the prostate, kidney, urinary bladder and the paratesticular structures.\n\n\nRESULTS\nA total of 19 patients - 16 men (84%) and three women (16%) - were enrolled in the study. The median age was 41 years (range 20-79 years). The most common primary site was the prostate (in eight patients; 42%), and prostatic sarcoma patients were younger than patients with sarcomas of other origins. The most common histological subtype was leiomyosarcoma (in five patients; 26%). The overall survival rates after 1, 3 and 5 years were 61.5%, 34.4% and 25.8%, respectively. The median survival time was 20.7 months (95% confidence interval 5.9-35.5 months). Univariate analysis showed that an absence of metastasis at diagnosis and complete surgical resection were predictive of favorable survival. In the chemotherapy group, the objective response rate was 20.5%. Pazopanib was administered to nine patients in the late-line setting, and the objective response rate was 11.1%; six grade ≥3 adverse events were observed in three patients.\n\n\nCONCLUSIONS\nInoperable metastatic genitourinary soft tissue sarcoma remains difficult to treat, as previously reported. Further investigation on this malignancy, including optimization of currently available antitumor drugs and the development of novel therapeutic agents, is required.",
"affiliations": "Departments of, Department of, Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Departments of, Department of, Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Departments of, Department of, Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Pathology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Department of, Urology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.;Departments of, Department of, Medical Oncology, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan.",
"authors": "Urasaki|Tetsuya|T|;Nakano|Kenji|K|;Tomomatsu|Junichi|J|;Komai|Yoshinobu|Y|;Yuasa|Takeshi|T|;Yamashita|Kyoko|K|;Takazawa|Yutaka|Y|;Yamamoto|Shinya|S|;Yonese|Junji|J|;Takahashi|Shunji|S|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Australia",
"delete": false,
"doi": "10.1111/iju.14417",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0919-8172",
"issue": "28(1)",
"journal": "International journal of urology : official journal of the Japanese Urological Association",
"keywords": "adult; drug therapy; sarcoma; survival; urogenital system",
"medline_ta": "Int J Urol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012509:Sarcoma; D012983:Soft Tissue Neoplasms; D015996:Survival Rate; D055815:Young Adult",
"nlm_unique_id": "9440237",
"other_id": null,
"pages": "91-97",
"pmc": null,
"pmid": "33169456",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adult genitourinary sarcoma: The era of optional chemotherapeutic agents for soft tissue sarcoma.",
"title_normalized": "adult genitourinary sarcoma the era of optional chemotherapeutic agents for soft tissue sarcoma"
} | [
{
"companynumb": "NVSC2020JP303200",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PAZOPANIB HYDROCHLORIDE"
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"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nStellate Ganglion Block (SGB) provides a blockade of sympathetic signals from the sympathetic chain and appears to be a promising method of controlling refractory ventricular arrhythmias, but there are scanty data in the literature.\nHerein, we describe a 59-year-old male patient with a history of non-ischemic cardiomyopathy and suffering from frequent VT episodes, who received ICD implantation and regular amiodarone medication control.\nMonomorphic VT refractory to standard medication control and focal extensive catheter ablation.\n\n\nMETHODS\nLeft Stellate Ganglion Block (LSGB) was performed under ultrasound-assisted injection at the C6 level using a 10 ml solution of 0.4% lidocaine and 0.5% bupivacaine.\n\n\nRESULTS\nIn our case, refractory VT subsided and sinus rhythm was retained immediately after LSGB. There were no VT episodes for at least 3 hours during the inter-hospital transfer, which did not involve any specific complications.\n\n\nCONCLUSIONS\nLSGB may provide effective VT control and play an important role in rescue and bridge therapy before catheter ablation.",
"affiliations": "Taichung Veterans General Hospital, Department of Anesthesiology, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan ROC.",
"authors": "Yang|Shih-Chieh|SC|;Wu|Chih-Cheng|CC|;Hsieh|Yun-Jui|YJ|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1097/MD.0000000000017790",
"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31689853MD-D-19-0000410.1097/MD.0000000000017790177903300Research ArticleClinical Case ReportLeft stellate ganglion block, a rescue treatment for ventricular arrhythmia refractory to radiofrequency catheter ablation A care-compliant case reportYang Shih-Chieh MDWu Chih-Cheng MD, PhDHsieh Yun-Jui MD∗NA. Taichung Veterans General Hospital, Department of Anesthesiology, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan ROC.∗ Correspondence: Yun-Jui Hsieh, Taichung Veterans General Hospital, Department of Anesthesiology, 1650 Taiwan Boulevard Sect. 4, Taichung 40705, Taiwan, ROC (e-mail: cipherhsieh@gmail.com).11 2019 01 11 2019 98 44 e1779029 1 2019 08 9 2019 03 10 2019 Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.2019This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nStellate Ganglion Block (SGB) provides a blockade of sympathetic signals from the sympathetic chain and appears to be a promising method of controlling refractory ventricular arrhythmias, but there are scanty data in the literature.\n\nPatient concerns:\nHerein, we describe a 59-year-old male patient with a history of non-ischemic cardiomyopathy and suffering from frequent VT episodes, who received ICD implantation and regular amiodarone medication control.\n\nDiagnoses:\nMonomorphic VT refractory to standard medication control and focal extensive catheter ablation.\n\nInterventions:\nLeft Stellate Ganglion Block (LSGB) was performed under ultrasound-assisted injection at the C6 level using a 10 ml solution of 0.4% lidocaine and 0.5% bupivacaine.\n\nOutcomes:\nIn our case, refractory VT subsided and sinus rhythm was retained immediately after LSGB. There were no VT episodes for at least 3 hours during the inter-hospital transfer, which did not involve any specific complications.\n\nLessons:\nLSGB may provide effective VT control and play an important role in rescue and bridge therapy before catheter ablation.\n\nKeywords\nautonomic nerve blockstellate ganglionventricular tachycardiaOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nStellate Ganglion Block (SGB) has been widely used in the treatment for various types of acute and chronic pain since it was first introduced in the 1930s.[1,2] It provides a blockade of sympathetic signals from the sympathetic chain. Despite not being part of mainstream treatment, a number of reports have revealed that SGB shows promising effects for controlling refractory ventricular arrhythmias. However, the mechanism by which it exerts its antiarrhythmic effect remains unclear.\n\nWe present the case of a patient with refractory ventricular arrhythmia which was controlled by left Stellate Ganglion Block (LSGB). Furthermore, we also review previous studies and discuss the possible pathophysiologies.\n\n2 Case report\nThis 59-year-old male had a history of non-ischemic cardiomyopathy, with chamber dilatation and an ejection fraction (EF) that was 35% as measured two years ago. Cardioversion and Implantable Cardioverter Defibrillator (ICD) implantation, along with amiodarone medication were administered due to frequent Ventricular Tachycardia (VT). Recently, frequent ICD therapy due to fast VT was noted, and the ICD VT detection threshold was adjusted. However, frequent Multifocal VT persisted. Two attempts using focal extensive ablation were performed resulting in limited improvement. The patient also had amiodarone-induced thyrotoxicosis while under Carbimazole treatment.\n\nHe was then admitted to hospital due to acute pulmonary edema which improved under diuretic therapy. However, several days later, hemodynamic instability was noted, and an Electrocardiogram (ECG) revealed monomorphic VT (Fig. 1). Emergent intubation and resuscitation were subsequently performed. Lugol's solution, an anti-hyperthyroid agent, and anti-arrhythmics, along with Bisoprolol, Propranolol, Xylocaine and Amiodarone, were administered, and anti-tachycardia pacing with ICD cardioversion were performed, however, VT persisted. Electrical Storm (ES) refractory to medication and defibrillation was suspected, so an interhospital transfer for the purpose of catheter ablation was implemented. Our pain management group was consulted for transient sympathetic blockade.\n\nFigure 1 Persistent monomorphic VT recorded by 12-lead ECG.\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images. Percutaneous LSGB under ultrasound-assisted intervention was then performed. The patient was placed in the supine position with his head tilted to the right side. After preparing a sterile environment, the stellate ganglion was localized and lidocaine was infused locally. Ultrasound-assisted needle insertion to the anterior longus coli fascia plane at the C6 level was performed using a 25-gauge, 1.5-inch needle, implementing the in-plane approach. After the negative aspiration of the syringe showed no air or blood, the LSGB using a 10 ml solution of 0.4% lidocaine and 0.05% bupivacaine was performed smoothly. Sinus rhythm was obtained 10 minutes after infusion. The patient who was in relatively stable condition, was then transferred. No VT episodes occurred during the 3-hour relocation process, and no arrhythmia episodes were observed before catheter ablation.\n\n3 Discussion and conclusions\nElectrical Storm (ES) refers to a state of cardiac electrical instability, characterized by two or more episodes in a patient without ICD, and three or more episode in a patient with ICD of hemodynamically unstable VT storm, or Ventricular fibrillation (VF) storm within 24 hours.[3] ES is an independent marker for subsequent death among ICD recipients, particularly within the first 3 months of its occurrence (relative risk 5.4).[4] To treat ES, correcting the underlying cause (e.g., acute myocardial infarction, heart failure), and stabilizing the hemodynamic status should be prioritized.\n\nCurrently, antiarrhythmic medications and catheter ablation remain the standard treatments for ES.[5] However, there are also other options including neuromodulation with thoracic epidural anesthesia, spinal cord stimulation, cardiac sympathetic denervation, and as in our case, SGB can provide a curative effect in certain situations when standard treatments are ineffective.[6,7]\n\nThe effect of SGB on heart rhythm was first evaluated in 1966. At the time, animal studies revealed that left stellate stimulation produces prolonged Q-T intervals in open-chested dogs,[8] while LSGB increases the electrophysiological stability of ventricular myocardium in rabbits.[9] These findings imply that the use of LSGB benefit patients with ventricular arrhythmias.\n\nSome case reports have described the effects of SGB on ES. Shrinivas et al treated ES via ultrasound-guided LSGB (0.25% Bupivacaine 6 ml), which resulted in an arrhythmia-free duration of 2 hours immediately after LSGB, and a reduction in the incidence of VT in the following 12 hours.[10] Nademanee et al revealed that in patients with ES treated by sympathetic blockade, 1-week mortality rate (22% vs 82%, P < .0001) and 1-year survival rate (67% vs 5%, P < .0001) were significantly superior compared with those in patient treated by the ACLS protocol.[11] In a systematic review of 3374 publications, it was found that SGB resulted in a significant decrease in both VA burden (12.4 ± 8.8 vs 1.04 ± 2.12 episodes/day, P < .001) and number of external and ICD shocks (10.0 ± 9.1 vs 0.05 ± 0.22 shocks/day, P < .01). Following SGB, 80.6% of patients survived through to discharge.[12]\n\nIn our case, it was necessary to conduct an inter-hospital transfer before catheter ablation, and therefore it was especially important to perform rescue therapy for VT refractory to medication control. As such, we successfully performed LSGB and sinus rhythm was retained immediately. There were no VT episodes for at least 3 hours during the inter-hospital transfer which did not involve any complications.\n\nIn conclusion, although it is not the mainstay treatment, LSGB may provide effective arrhythmia control and play an important role in rescue and bridge therapy, especially for the treatment of refractory ventricular arrhythmia before catheter ablation.\n\nAcknowledgments\nWe received no funding from any organizations or groups, and we declare no conflicts of interest in this or other relevant studies.\n\nAuthor contributions\nConceptualization: Yun-Jui Hsieh.\n\nInvestigation: Yun-Jui Hsieh.\n\nWriting – original draft: Yun-Jui Hsieh, Shih-Chieh Yang, Chih-Cheng Wu.\n\nWriting – review & editing: Yun-Jui Hsieh, Shih-Chieh Yang, Chih-Cheng Wu.\n\nYun-Jui Hsieh orcid: 0000-0003-1012-7227.\n\nAbbreviations: ECG = electrocardiogram, ES = electrical storm, ICD = implantable cardioverter defibrillator, LSGB = left stellate ganglion block, SGB = stellate ganglion block, VF = ventricular fibrillation, VT = ventricular tachycardia.\n\nHow to cite this article: Yang SC, Wu CC, Hsieh YJ. Left stellate ganglion block, a rescue treatment for ventricular arrhythmia refractory to radiofrequency catheter ablation. Medicine. 2019;98:44(e17790).\n\nInformed written consent was obtained from the patient for publication of this case report and accompanying images.\n\nThe authors report no conflicts of interest.\n==== Refs\nReferences\n[1] Kulkarni KR Kadam AI Namazi IJ \nEfficacy of stellate ganglion block with an adjuvant ketamine for peripheral vascular disease of the upper limbs . Indian J Anaesth \n2010 ;54 :546 –51 . doi:10.4103/0019-5049.72645 .21224973 \n[2] Serna-Gutiérrez J \nBloqueo ganglio estrellado guiado por ultrasonografia . Rev Colomb Anestesiol \n2015 ;43 :278 –82 . doi:10.1016/j.rcae.2014.09.004 .\n[3] Kowey PR \nAn overview of antiarrhythmic drug management of electrical storm . Can J Cardiol \n1996 ;12 Suppl B :3B .\n[4] Exner DV Pinski SL Wyse DG \nElectrical storm presages nonsudden death: The antiarrhythmics versus implantable defibrillators (AVID) trial . Circulation \n2001 ;103 :2066 –71 .11319196 \n[5] Zipes DP Camm AJ Borggrefe M \nACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death–executive summary: A report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) Developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society . J Am Coll Cardiol \n2006 ;48 :1064 –108 .\n[6] Blomberg S Ricksten SE \nThoracic epidural anaesthesia decreases the incidence of ventricular arrhythmias during acute myocardial ischaemia in the anaesthetized rat . Acta Anaesthesiol Scand \n1988 ;32 :173 –8 .3364144 \n[7] Kamibayashi T Hayashi Y Mammoto T \nThoracic epidural anesthesia attenuates halothane-induced myocardial sensitization to dysrhythmogenic effect of epinephrine in dogs . Anesthesiology \n1995 ;82 :129 –34 .7832294 \n[8] Yanowitz F Preston JB Abildskov JA \nFunctional distribution of right and left stellate innervation to the ventricles. Production of neurogenic electrocardiographic changes by unilateral alteration of sympathetic tone . Circ Res \n1966 ;18 :416 –28 .4952701 \n[9] Gu Y Wang L Wang X \nAssessment of ventricular electrophysiological characteristics at periinfarct zone of postmyocardial infarction in rabbits following stellate ganglion block . J Cardiovasc Electrophysiol \n2012 ;23 :S29 –35 .\n[10] Shrinivas G Rupa S Unnikrishnan M \nElectrical storm: Role of stellate ganglion blockade and anesthetic implications of left cardiac sympathetic denervation . Indian J Anaesth \n2013 ;57 :397 –400 .24163457 \n[11] Nademanee K Taylor R Bailey WE \nTreating electrical storm: Sympathetic blockade versus advanced cardiac life support-guided therapy . Circulation \n2000 ;102 :742 –7 .10942741 \n[12] Meng L Tseng CH Shivkumar K \nEfficacy of stellate ganglion blockade in managing electrical storm: a systematic review . JACC Clin Electrophysiol \n2017 ;3 :942 –9 . doi: 10.1016/j.jacep.2017.06.006 .29270467\n\n",
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"mesh_terms": "D001340:Autonomic Nerve Block; D009202:Cardiomyopathies; D006801:Humans; D008297:Male; D008875:Middle Aged; D013233:Stellate Ganglion; D017180:Tachycardia, Ventricular; D016896:Treatment Outcome",
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"title": "Left stellate ganglion block, a rescue treatment for ventricular arrhythmia refractory to radiofrequency catheter ablation: A care-compliant case report.",
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"abstract": "Disease progression during immunotherapy in colorectal cancer does not always indicate treatment failure. A case argues that carcinoembryonic antigen (CEA) may serve as an early marker to distinguish between pseudoprogression and real progression. Presentation of results from reintroduction of chemotherapy after progression on immunotherapy that suggest increased efficiency.",
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"authors": "Trabjerg|Natacha Dencker|ND|https://orcid.org/0000-0001-9282-9235;Rask|Christina|C|;Jensen|Lars Henrik|LH|https://orcid.org/0000-0002-0020-1537;Hansen|Torben Frøstrup|TF|https://orcid.org/0000-0001-7476-671X",
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.2262CCR32262Case ReportCase ReportsPseudoprogression during treatment with pembrolizumab followed by rechallenge with chemotherapy in metastatic colorectal cancer: A case report TRABJERG et al.Trabjerg Natacha Dencker https://orcid.org/0000-0001-9282-9235natacha.dencker.trabjerg2@rsyd.dk \n1\nRask Christina \n1\nJensen Lars Henrik https://orcid.org/0000-0002-0020-1537\n1\n\n2\nHansen Torben Frøstrup https://orcid.org/0000-0001-7476-671X\n1\n\n2\n\n1 \nDanish Colorectal Cancer Center South\nDepartment of Oncology\nVejle Hospital\nVejle\nDenmark\n\n2 \nInstitute of Regional Health Research\nUniversity of Southern Denmark\nOdense\nDenmark\n* Correspondence\n\nNatacha Dencker Trabjerg, Department of Oncology, Vejle Hospital, Beriderbakken 4, 7100 Vejle, Denmark.\n\nEmail: natacha.dencker.trabjerg2@rsyd.dk\n18 6 2019 7 2019 7 7 10.1002/ccr3.2019.7.issue-71445 1449 25 3 2019 07 5 2019 17 5 2019 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Abstract\nDisease progression during immunotherapy in colorectal cancer does not always indicate treatment failure. A case argues that carcinoembryonic antigen (CEA) may serve as an early marker to distinguish between pseudoprogression and real progression. Presentation of results from reintroduction of chemotherapy after progression on immunotherapy that suggest increased efficiency.\n\ncarcinoembryonic antigencolorectal cancerimmunotherapypseudoprogressionreintroducing chemotherapyThe Cancer FoundationRegional Strategic Council for Research in the Region of Southern Denmark source-schema-version-number2.0component-idccr32262cover-dateJuly 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.6.1 mode:remove_FC converted:18.07.2019\n\n\nTrabjerg \nND \n, \nRask \nC \n, \nJensen \nLH \n, \nHansen \nTF \n. Pseudoprogression during treatment with pembrolizumab followed by rechallenge with chemotherapy in metastatic colorectal cancer: A case report . Clin Case Rep . 2019 ;7 :1445 –1449 . 10.1002/ccr3.2262 \n\n\n\n\nFunding information\n\n\nThe Cancer Foundation and the Regional Strategic Council for Research in the Region of Southern Denmark.\n==== Body\n1 INTRODUCTION\nColorectal cancer (CRC) is the third most common solid malignancy in western countries.1 Around half of patients develop metastatic CRC (mCRC). Median overall survival of patients with mCRC has increased after the introduction of chemotherapy (5‐fluorouracil combined with oxaliplatin or irinotecan or both) and the targeting of the vascular endothelial growth factor and epidermal growth factor receptor systems.2 The recent introduction of immunotherapy has added a new layer of treatment opportunities for the minority of patients with mismatch repair deficient tumors (dMMR).3\n\n\nThe mismatch repair (MMR) system corrects errors that occur spontaneously during DNA replication. In dMMR tumors, DNA errors accumulate causing microsatellite length mutations, microsatellite instability (MSI),4 and truncated peptides with potential immune activation.5 Tumors with dMMR are rather common in localized colon cancer, approximately 15%, and these patients have an overall better stage‐adjusted survival and may respond differently to 5‐fluorouracil‐based chemotherapy.6, 7 The presence of tumors with a dMMR system in the metastatic setting is consequently less common, typically 4%‐5%.8\n\n\nThe high degree of “genetic noise” characteristic for dMMR tumors gives the theoretical basis for effect from immunotherapy. Pembrolizumab is a humanized antibody targeting the programmed cell death 1 (PD‐1) receptor on the lymphocytes. In 2017, it was approved for solid tumors harboring MSI.9 Pembrolizumab, along with other immune modulating drugs, is currently being investigated in multiple different settings in mCRC. The introduction of immunotherapy has also challenged our traditional way of interpreting treatment response.\n\nPseudoprogression is a phenomenon describing apparent progression on treatment followed by tumor regression. Pseudoprogression has been observed in patients treated with immunotherapy in various tumor types but the frequency and role of pseudoprogression in colon cancer, during immunotherapy, are largely unknown.10, 11\n\n\n2 CASE PRESENTATION\nA middle‐aged man diagnosed with mCRC and synchronous renal cell carcinoma. A low‐risk malignant melanoma was surgically removed from his back approximately one year before the diagnosis.\n\nThe patient was referred to the hospital because of difficulties in swallowing and with symptoms of anemia. A gastroscopy showed esophageal candidiasis. A computed tomography (CT) scan demonstrated a tumor in the colon ascendens, a synchronous tumor in the left kidney, and a solitary lever metastasis of 10 cm in addition to several nonspecific lung nodules. A biopsy from the primary tumor confirmed adenocarcinoma, staged T4N2M1 at a multidisciplinary team (MDT) conference. Mutation analysis revealed a BRAF mutation (Val600Glu) and immunohistochemistry loss of MLH1 and PMS2 protein expression. Additional analyses revealed methylation of the MLH1 promoter together with no familial history of bowel cancer in this case was considered sporadic.\n\nThe liver metastasis was deemed potentially resectable, and it was decided to treat the patient with neoadjuvant chemotherapy. Four cycles of folinic acid, 5‐fluorouracil and oxaliplatin (FOLFOX), and bevacizumab resulted in stable disease (SD). An additional biopsy from the left kidney revealed a renal cell carcinoma. After a further four cycles of FOLFOX and bevacizumab, CT scans showed regression in the liver and a liver biopsy confirmed adenocarcinoma from colorectal origin. The patient underwent right hemicolectomy with radical removal of the tumor in the colon after a total of nine cycles of FOLFOX + bevacizumab. A hemihepatectomy was planned, but the patient was deemed nonresectable due to the occurrence of peritoneal carcinomatoses and growth of, and new liver metastases.\n\nThe overall treatment strategy changed to a palliative focus and the patient received four cycles of FOLFIRI resulting in disease progression. After five cycles of capecitabine and bevacizumab, a CT scan again confirmed disease progression with growth of the peritoneal carcinomatoses. Pembrolizumab was then initiated after individual approval by the National Board of Health. The patient was hospitalized after only two days with fever and clinical symptoms of infection and abdominal pain. Performance status (PS) was now rapidly declining and the patient was totally confined to the bed and with limited ability to carry out self‐care during the following week (PS = 3). Progression of the peritoneal carcinomatoses was suspected, threatening to perforate the skin. Pseudoprogression was later documented by a CT scan after three cycles of pembrolizumab demonstrating progression of peritoneal carcinomatoses (primarily nontarget lesions) and multiple new lung metastases (Figure 1). Clinically, in contrast, PS was now improving to PS = 1 and CEA was dropping and we decided to continue treatment despite progressive disease (PD) as defined by RECIST1.1. Performance status normalized and the patient received an overall of 21 cycles of pembrolizumab (15 months) before PD was confirmed, again, and this time backed up by increasing CEA (Figure 2).\n\nFigure 1 Computer tomography scans of the thorax and abdomen before ignition of pembrolizumab (A + C) and at the first evaluation after two months of treatment (B + D). One of the new lung metastasis is identified by the small arrow (B). The longest diameter of the peritoneal carcinomatoses locus demonstrated increased from 6.2 cm at baseline (C) to 8.0 cm at the first evaluation (D)\n\nFigure 2 Changes in carcinoembryonic antigen (CEA, blue line) and total target lesion dimension (red line, according to RECIST 1.1) from initiation of pembrolizumab in March 2017 to progression in June 2018 and the following reintroducing of folinic acid, fluorouracil, and irinotecan (FOLFIRI). CEA was not measured in the sample drawn in March 2018\n\nAs the patient was unaffected, PS = 0, it was decided to reintroduce FOLFIRI. This has so far resulted in stable disease, and treatment is currently ongoing on its seventh month (Figure 2).\n\n3 DISCUSSION\nPseudoprogression is a rather new concept in clinical oncology. The growth of existing lesions (carcinomatoses) and the appearance of new metastases (multiple lung metastases) combined with clinical improvement of the patient let us to suspect pseudoprogression in this case. The phenomenon primarily reported for patients with malignant melanoma, lung cancer, and urothelial cancers is reported with a frequency of <10%.10 The incidence in mCRC is unknown, and we only encountered one case report published in 2017.11 The new lung metastases detected in the present case were actually confirmed on the following CT scan after an additional nine weeks of treatment but they did not increase in size. The decision to continue treatment after initial radiologic progression should, naturally, be supported by clinical benefit to the patient. Predisposing factors of pseudoprogression are still largely unknown but the combination of a high disease proliferation rate combined with slower cancer cell elimination may increase the likelihood. This case with a BRAF‐mutated dMMR mCRC treated with pembrolizumab may resemble such a combination.\n\nRelying on pseudoprogression, pose a new challenge, for example, risk of continuing a treatment that may not benefit the patient. This concern is real since most progressions are real progressions. The fear of terminating effective treatments, because of pseudoprogression, led to the introduction of several immune‐related response evaluation criteria (irRC, irRECIST, iRECIST) requiring confirmation of tumor progression after an additional four weeks. Hyperprogression during immunotherapy has made it even more important to discriminate between these two outcomes as early as possible. Based on this case, we propose CEA as an early marker. A rapid decline was identified early during the pseudoprogression phase followed by an increase when true progression was confirmed. Chae et al proposed that lactate dehydrogenase (LDH) may serve as a marker for discrimination. However, LDH increased during the initial tumor progression in their study. In this case, LDH remained within the normal range throughout the treatment. Recent reports have proposed quantification of circulating tumor DNA as a way to discriminate; however, in the setting of mCRC, the role of this strategy is largely unknown.12, 13 One may also argue that a routine assessment of CEA is less laborious and easier to interpret.\n\nHow to proceed after progression on immunotherapy in a patient with mCRC and unaffected PS? The answer may be obvious in patients treated with immunotherapy upfront but less obvious in patients that receives immunotherapy as a last line of treatment. The present case illustrates the last scenario and was furthermore complicated by persisting neuropathy from previous oxaliplatin exposure and a BRAF‐mutated disease. Reintroducing FOLFIRI thus seemed to be the only real option although PD was detected after only two months of treatment when the patient was first exposed. We hoped that the influence by pembrolizumab on the immune system might have altered the response to subsequent chemotherapy. The reintroduction led to a decrease in CEA, and the first CT evaluation after two months confirmed a SD with minor shrinkage of target and nontarget lesions. Due to an increase in CEA after three months of treatment with FOLFIRI, we decided to add Bevacizumab, although progression was not documented and even though the disease had also progressed on a bevacizumab containing regimen previosly. This strategy has now kept the disease stable for more than seven months after cessation of pembrolizumab. CEA is still stable, and the patient is doing well with no limitations (PS = 0). Increased efficiency of standard chemotherapy has been reported following immunotherapy in patients with lung cancer14 and malignant melanoma15 but we are not aware of any previous reports regarding patients with mCRC.\n\nThis rather unique observation adds speculations to the optimal handling of patients with mCRC and dMMR. Should we use all standard chemotherapy regimens first, then immunotherapy, and then rechallenge with standard chemotherapy again? We are planning to offer ipilimumab + nivolumab once the disease progresses again, to explore the potential benefit of a second intervention with immunotherapy.\n\n4 CONCLUSIONS\nTreatment beyond progression in patients with mCRC receiving immunotherapy may be indicated in patients with clinical benefit, and CEA may aid in discriminating pseudoprogression from real progression. Furthermore, immunotherapy may revert earlier resistance to chemotherapy and reintroduction of chemotherapy can be an option.\n\nCONFLICT OF INTEREST\nThe authors declare no conflict of interest.\n\nAUTHOR CONTRIBUTION\nNDT: identified the special learning points and conceived the idea for the case report, responsible for collection and assembly of data, drafted the primary manuscript, discussed the results, commented, and approved the final version of the manuscript. CR: identified the special learning points and conceived the idea for the case report, discussed the results, commented, and approved the final version of the manuscript. LHJ: identified the special learning points and conceived the idea for the case report, discussed the results, commented, and approved the final version of the manuscript. TFH: identified the special learning points and conceived the idea for the case report, responsible for collection and assembly of data, drafted the primary manuscript, discussed the results, commented, and approved the final version of the manuscript.\n\nACKNOWLEDGMENTS\nWe are very thankful for the willingness of the patient to share his history and for the linguistic editing provided by Karin Larsen. This study was supported by the Regional Strategic Council for Research in the Region of Southern Denmark, which had no influence on any part of the study.\n==== Refs\nREFERENCES\n1 \n\nFerlay \nJ \n, \nColombet \nM \n, \nSoerjomataram \nI \n, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods . Int J Cancer . 2019 ;144 :1941 ‐1953 .30350310 \n2 \n\nFakih \nMG \n. Metastatic colorectal cancer: current state and future directions . J Clin Oncol . 2015 ;33 :1809 ‐1824 .25918280 \n3 \n\nJeught \nK \n, \nXu \nH‐C \n, \nLi \nY‐J \n, \nLu \nX‐B \n, \nJi \nG \n. Drug resistance and new therapies in colorectal cancer . World J Gastroenterol . 2018 ;24 :3834 ‐3848 .30228778 \n4 \n\nLaporte \nGA \n, \nLeguisamo \nNM \n, \nKalil \nAN \n, \nSaffi \nJ \n. Clinical importance of DNA repair in sporadic colorectal cancer . Crit Rev Oncol Hematol . 2018 ;126 :168 ‐185 .29759559 \n5 \n\nViale \nG \n, \nTrapani \nD \n, \nCurigliano \nG \n. Mismatch repair deficiency as a predictive biomarker for immunotherapy efficacy . Biomed Res Int . 2017 ;2017 :4719194 .28770222 \n6 \n\nBertagnolli \nMM \n, \nRedston \nM \n, \nCompton \nCC \n, et al. Microsatellite instability and loss of heterozygosity at chromosomal location 18q: prospective evaluation of biomarkers for stages II and III colon cancer–a study of CALGB 9581 and 89803 . J Clin Oncol . 2011 ;29 :3153 ‐3162 .21747089 \n7 \n\nSinicrope \nFA \n, \nMahoney \nMR \n, \nSmyrk \nTC \n, et al. Prognostic impact of deficient DNA mismatch repair in patients with stage III colon cancer from a randomized trial of FOLFOX‐based adjuvant chemotherapy . J Clin Oncol . 2013 ;31 :3664 ‐3672 .24019539 \n8 \n\nVenderbosch \nS \n, \nNagtegaal \nID \n, \nMaughan \nTS \n, et al. Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies . Clin Cancer Res . 2014 ;20 :5322 ‐5330 .25139339 \n9 \n\nLemery \nS \n, \nKeegan \nP \n, \nPazdur \nR \n. First FDA approval agnostic of cancer site ‐ when a biomarker defines the indication . N Engl J Med . 2017 ;377 :1409 ‐1412 .29020592 \n10 \n\nBorcoman \nE \n, \nNandikolla \nA \n, \nLong \nG \n, \nGoel \nS \n, \nLe Tourneau \nC \n. Patterns of response and progression to immunotherapy . Am Soc Clin Oncol Educ Book:169–178 . 2018 .\n11 \n\nChae \nYK \n, \nWang \nSI \n, \nNimeiri \nH \n, \nKalyan \nA \n, \nGiles \nFJ \n. Pseudoprogression in microsatellite instability‐high colorectal cancer during treatment with combination T cell mediated immunotherapy: a case report and literature review . Oncotarget . 2017 ;8 :57889 ‐57897 .28915720 \n12 \n\nGray \nES \n, \nRizos \nH \n, \nReid \nAL \n, et al. Circulating tumor DNA to monitor treatment response and detect acquired resistance in patients with metastatic melanoma . Oncotarget . 2015 ;6 :42008 ‐42018 .26524482 \n13 \n\nWeiss \nGJ \n, \nBeck \nJ \n, \nBraun \nDP \n, et al. Tumor cell‐free DNA copy number instability predicts therapeutic response to immunotherapy . Clin Cancer Res . 2017 ;23 :5074 ‐5081 .28320758 \n14 \n\nSchvartsman \nG \n, \nPeng \nSA \n, \nBis \nG \n, et al. Response rates to single‐agent chemotherapy after exposure to immune checkpoint inhibitors in advanced non‐small cell lung cancer . Lung Cancer . 2017 ;112 :90 ‐95 .29191606 \n15 \n\nSimon \nA \n, \nKourie \nHR \n, \nKerger \nJ \n. Is there still a role for cytotoxic chemotherapy after targeted therapy and immunotherapy in metastatic melanoma? A case report and literature review . Chin J Cancer . 2017 ;36 :10 .28086948\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2050-0904",
"issue": "7(7)",
"journal": "Clinical case reports",
"keywords": "carcinoembryonic antigen; colorectal cancer; immunotherapy; pseudoprogression; reintroducing chemotherapy",
"medline_ta": "Clin Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101620385",
"other_id": null,
"pages": "1445-1449",
"pmc": null,
"pmid": "31360509",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports",
"references": "21747089;24019539;25139339;25918280;26524482;28086948;28320758;28770222;28915720;29020592;29191606;29759559;30228778;30231380;30350310",
"title": "Pseudoprogression during treatment with pembrolizumab followed by rechallenge with chemotherapy in metastatic colorectal cancer: A case report.",
"title_normalized": "pseudoprogression during treatment with pembrolizumab followed by rechallenge with chemotherapy in metastatic colorectal cancer a case report"
} | [
{
"companynumb": "DK-009507513-1908DNK001874",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "PEMBROLIZUMAB"
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{
"abstract": "Natalizumab treatment is associated with progressive multifocal leukoencephalopathy (PML) development. Treatment duration, prior immunosuppressant use, and JCV serostatus are currently used for risk stratification, but PML incidence stays high. Anti-JCV antibody index and L-selectin (CD62L) have been proposed as additional risk stratification parameters.\n\n\n\nThis study aimed at verifying and integrating both parameters into one algorithm for risk stratification.\n\n\n\nMulticentric, international cohorts of natalizumab-treated MS patients were assessed for JCV index (1921 control patients and nine pre-PML patients) and CD62L (1410 control patients and 17 pre-PML patients).\n\n\n\nCD62L values correlate with JCV serostatus, as well as JCV index values. Low CD62L in natalizumab-treated patients was confirmed and validated as a biomarker for PML risk with the risk factor \"CD62L low\" increasing a patient's relative risk 55-fold (p < 0.0001). Validation efforts established 86% sensitivity/91% specificity for CD62L and 100% sensitivity/59% specificity for JCV index as predictors of PML. Using both parameters identified 1.9% of natalizumab-treated patients in the reference center as the risk group.\n\n\n\nBoth JCV index and CD62L have merit for risk stratification and share a potential biological relationship with implications for general PML etiology. A risk algorithm incorporating both biomarkers could strongly reduce PML incidence.",
"affiliations": "Department of Neurology, University of Münster, Germany nicholas.schwab@ukmuenster.de heinz.wiendl@ukmuenster.de.;Department of Neurology, University of Münster, Germany.;Pole des Neurosciences Centre Hospitalier Universitaire Toulouse, CPTP INSERM UMR 1043 et Université de Toulouse, UPS, France.;Clinical Neurobiology Unit, Regional Referring Multiple Sclerosis Centre (CRESM), Neuroscience Institute Cavalieri Ottolenghi (NICO), University Hospital San Luigi Gonzaga, Orbassano, Italy.;Institute of Biostatistics and Clinical Research, University of Münster, Germany.;Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University Munich and Munich Cluster Systems Neurology (SyNergy), Germany.;Department of Neurology, Clinics Osnabrück, Germany.;Department of Neurology, Philipps University and University Clinics Gießen and Marburg, Germany.;Department of Neurology, University of Münster, Germany.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.;Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University Munich and Munich Cluster Systems Neurology (SyNergy), Germany.;Institute for Clinical Neuroimmunology, Ludwig-Maximilians-University Munich and Munich Cluster Systems Neurology (SyNergy), Germany.;Department of Neurology, University of Mainz, Germany.;Department of Neurology, University of Mainz, Germany.;Department of Neurology, University of Münster, Germany.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.;Department of Neurology, University of Münster, Germany.;Department of Neurology, University of Mainz, Germany.;Department of Neurology, Ruhr University Bochum, Germany.;Divisions of Immunology and Allergy and of Neurology, Centre Hospitalier Universitaire Vaudois, Switzerland.;Department of Neurology, University of Würzburg, Germany.;Division of Rheumatology and Clinical Immunology, University of Münster, Germany/Division of Rheumatology and Clinical Immunology, Brandenburg Medical School, Neuruppin, Germany.;Servei de Neurologia-Neuroimmunologia, Centre d'Esclerosi Múltiple de Catalunya (Cemcat), Institut de Recerca Vall d'Hebron (VHIR), Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain.;Clinical Neurobiology Unit, Regional Referring Multiple Sclerosis Centre (CRESM), Neuroscience Institute Cavalieri Ottolenghi (NICO), University Hospital San Luigi Gonzaga, Orbassano, Italy.;Pole des Neurosciences Centre Hospitalier Universitaire Toulouse, CPTP INSERM UMR 1043 et Université de Toulouse, UPS, France/David Brassat also represents the BioNAT study group.;Department of Neurology, University of Münster, Germany.",
"authors": "Schwab|Nicholas|N|;Schneider-Hohendorf|Tilman|T|;Pignolet|Béatrice|B|;Spadaro|Michela|M|;Görlich|Dennis|D|;Meinl|Ingrid|I|;Windhagen|Susanne|S|;Tackenberg|Björn|B|;Breuer|Johanna|J|;Cantó|Ester|E|;Kümpfel|Tania|T|;Hohlfeld|Reinhard|R|;Siffrin|Volker|V|;Luessi|Felix|F|;Posevitz-Fejfár|Anita|A|;Montalban|Xavier|X|;Meuth|Sven G|SG|;Zipp|Frauke|F|;Gold|Ralf|R|;Du Pasquier|Renaud A|RA|;Kleinschnitz|Christoph|C|;Jacobi|Annett|A|;Comabella|Manuel|M|;Bertolotto|Antonio|A|;Brassat|David|D|;Wiendl|Heinz|H|",
"chemical_list": "D000914:Antibodies, Viral; D015415:Biomarkers; D000069442:Natalizumab; C546935:SELL protein, human; D019041:L-Selectin",
"country": "England",
"delete": false,
"doi": "10.1177/1352458515607651",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1352-4585",
"issue": "22(8)",
"journal": "Multiple sclerosis (Houndmills, Basingstoke, England)",
"keywords": "CD62L; JCV index; L-selectin; Natalizumab; PML; risk stratification",
"medline_ta": "Mult Scler",
"mesh_terms": "D000465:Algorithms; D000914:Antibodies, Viral; D015415:Biomarkers; D005060:Europe; D006801:Humans; D016867:Immunocompromised Host; D007577:JC Virus; D019041:L-Selectin; D007968:Leukoencephalopathy, Progressive Multifocal; D009103:Multiple Sclerosis; D000069442:Natalizumab; D009894:Opportunistic Infections; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012698:Serologic Tests; D016896:Treatment Outcome",
"nlm_unique_id": "9509185",
"other_id": null,
"pages": "1048-60",
"pmc": null,
"pmid": "26432858",
"pubdate": "2016-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "PML risk stratification using anti-JCV antibody index and L-selectin.",
"title_normalized": "pml risk stratification using anti jcv antibody index and l selectin"
} | [
{
"companynumb": "DE-BIOGENIDEC-2015BI147030",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NATALIZUMAB"
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"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe purpose of this study was to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics and preliminary activity of TH-302, a hypoxia-activated prodrug, in combination with doxorubicin in patients with advanced soft tissue sarcoma.\n\n\nMETHODS\nTH-302 was administered intravenously on days 1 and 8 and doxorubicin 75 mg/m² on day 1 (2 h after TH-302) of every 3-week cycle. TH-302 starting dose was 240 mg/m² with a classic 3 + 3 dose escalation. Pharmacokinetics were assessed on days 1 and 8 of cycle 1. Tumor assessments were performed after every second cycle.\n\n\nRESULTS\nSixteen patients enrolled. Prophylactic growth factor support was added due to grade 4 neutropenia. The MTD was 300 mg/m². DLTs at 340 mg/m² were neutropenia-associated infection and grade 4 thrombocytopenia. Common adverse events included fatigue, nausea and skin rash. There was no evidence of pharmacokinetic interaction between TH-302 and doxorubicin. Five of 15 (33%) evaluable patients had a partial response by RECIST (Response Evaluation Criteria in Solid Tumors) criteria.\n\n\nCONCLUSIONS\nThe hematologic toxicity of doxorubicin is increased when combined with TH-302. This can be mitigated by prophylactic growth factor support. Toxicities were manageable and there was evidence of antitumor activity.",
"affiliations": "Stanford University Medical Center, Stanford, Calif., USA. kganjoo@stanford.edu",
"authors": "Ganjoo|Kristen N|KN|;Cranmer|Lee D|LD|;Butrynski|James E|JE|;Rushing|Daniel|D|;Adkins|Douglas|D|;Okuno|Scott H|SH|;Lorente|Gustavo|G|;Kroll|Stew|S|;Langmuir|Virginia K|VK|;Chawla|Sant P|SP|",
"chemical_list": "D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; C552526:TH 302; D016179:Granulocyte Colony-Stimulating Factor; D004317:Doxorubicin; C010013:adriamycinol",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000327739",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0030-2414",
"issue": "80(1-2)",
"journal": "Oncology",
"keywords": null,
"medline_ta": "Oncology",
"mesh_terms": "D000038:Abscess; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000971:Antineoplastic Combined Chemotherapy Protocols; D002481:Cellulitis; D018572:Disease-Free Survival; D004317:Doxorubicin; D003875:Drug Eruptions; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D008231:Lymphopenia; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009503:Neutropenia; D009593:Nitroimidazoles; D010752:Phosphoramide Mustards; D012509:Sarcoma; D013280:Stomatitis; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "0135054",
"other_id": null,
"pages": "50-6",
"pmc": null,
"pmid": "21625179",
"pubdate": "2011",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase I study of the safety and pharmacokinetics of the hypoxia-activated prodrug TH-302 in combination with doxorubicin in patients with advanced soft tissue sarcoma.",
"title_normalized": "a phase i study of the safety and pharmacokinetics of the hypoxia activated prodrug th 302 in combination with doxorubicin in patients with advanced soft tissue sarcoma"
} | [
{
"companynumb": "US-JNJFOC-20140819767",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EVOFOSFAMIDE"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of disseminated Cladophialophora bantiana phaeohyphomycosis with cerebral and pulmonary disease in a 69-year-old renal transplant recipient. The patient presented with confusion, low-grade fever and progressed quickly to a comatose state. Imaging revealed multiple small brain abscesses and a right pulmonary nodule. Cultures of bronchial washings and biopsy of the right pulmonary nodule grew C. bantiana, a highly neurotropic fungus with a high mortality rate. He was treated with Isavuconazonium sulfate (Isavuconazole) and Liposomal Amphotericin B along with reduction immunosuppressive therapy. His neurologic status remained unimproved despite treatment with dual antifungal therapy for two months. The patient eventually died from respiratory failure 79 days after his initial presentation, C. bantiana has been reported in both immunocompetent and immunocompromised patients. Its neurotropism has been reported and described in the literature with C. bantiana responsible for 50 % of the reported cases of fungal brain abscess. However, reports of pulmonary and cerebral involvement are exceedingly rare. Our patient was immunocompromised and succumbed to cerebral involvement.",
"affiliations": "Division of Infectious Disease, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United States.;Division of Infectious Disease, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United States.",
"authors": "Hernandez|Claudia|C|;Lawal|Folake|F|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.idcr.2021.e01240",
"fulltext": "\n==== Front\nIDCases\nIDCases\nIDCases\n2214-2509\nElsevier\n\nS2214-2509(21)00196-7\n10.1016/j.idcr.2021.e01240\ne01240\nCase Report\nCerebral and pulmonary phaeohyphomycosis due Cladophialophora bantiana in an immunocompromised patient\nHernandez Claudia\nLawal Folake http://berkeley.edu\n⁎\nDivision of Infectious Disease, Department of Internal Medicine, Medical College of Georgia at Augusta University, Augusta, GA, United States\n⁎ Corresponding author at: 1120 15th St, AE- 3024, Augusta, GA, 30912, United States. http://berkeley.edu\n26 7 2021\n2021\n26 7 2021\n25 e0124025 5 2021\n23 7 2021\n24 7 2021\n© 2021 The Author(s)\n2021\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nWe report a case of disseminated Cladophialophora bantiana phaeohyphomycosis with cerebral and pulmonary disease in a 69-year-old renal transplant recipient. The patient presented with confusion, low-grade fever and progressed quickly to a comatose state. Imaging revealed multiple small brain abscesses and a right pulmonary nodule. Cultures of bronchial washings and biopsy of the right pulmonary nodule grew C. bantiana, a highly neurotropic fungus with a high mortality rate. He was treated with Isavuconazonium sulfate (Isavuconazole) and Liposomal Amphotericin B along with reduction immunosuppressive therapy. His neurologic status remained unimproved despite treatment with dual antifungal therapy for two months. The patient eventually died from respiratory failure 79 days after his initial presentation, C. bantiana has been reported in both immunocompetent and immunocompromised patients. Its neurotropism has been reported and described in the literature with C. bantiana responsible for 50 % of the reported cases of fungal brain abscess. However, reports of pulmonary and cerebral involvement are exceedingly rare. Our patient was immunocompromised and succumbed to cerebral involvement.\n\nKeywords\n\nCerebral abscess\nCladophialophora bantiana\nDematiaceous fungi\nPhaeohyphomycosis\nPulmonary phaeohyphomycosis\n==== Body\nIntroduction\n\nAn identifying feature of all Dematiaceous fungi is their dark pigmentation attributed to melanin in their cell wall. They are distributed worldwide and generally found in soil or associated with plants. Cladophialophora bantiana is the most neurotropic of the dematiaceous fungi and has been associated with brain abscesses in both immunocompetent and immunocompromised hosts with higher mortalities reported in the latter group [1,2]. Here we report a case of disseminated phaeohyphomycosis due to C. bantiana in an immunocompromised renal transplant patient.\n\nCase\n\nA 69-year-old man transferred to our facility for continued management of dematiaceous fungal infection of the lung with presumed dissemination to the brain. The patient had a history of end stage renal disease (ESRD)for which he received a deceased donor renal transplant 3 years prior to presentation. Since his transplant, he had been maintained on Mycophenolate Mofetil 750 mg twice daily and Prednisone 10 mg daily for immunosuppression. He first presented to the initial hospital on 01/20/2020 with complaints of generalized malaise, cough, and confusion of one-month duration. A CT Chest (Image 1 ) revealed a 1.5 cm nodule in the posterior segment of his right upper lobe and multiple less than 5 mm soft tissue nodules scattered throughout the right lung and minimally in the left lung. Magnetic Resonance Imaging (MRI) of the brain (Image 2 ) showed multifocal bilateral supratentorial and bilateral subependymal and deep periventricular white matter irregularly shaped enhancing lesions concerning for brain abscess. CT guided right lung nodule biopsy demonstrated necrotic granulomatous inflammation with darkly pigmented organisms in hyphae form on Gomori Methanamine Stain (GMS), concerning for dematiaceous mold/phaeohyphomycosis. He was started on Voriconazole and Liposomal Amphotericin B (L-AmB) within one week of his initial presentation. His mental status continued to deteriorate throughout the hospital course, and he was then transferred to Augusta University Medical Center (AUMC) on 02/17/2020, 28 days after his initial presentation to an outside hospital. Infectious Disease was consulted and evaluated patient on same day of arrival. Patient was somnolent, minimally arousable with Glasgow Coma Scale of 6. He was promptly intubated and bronchoalveolar lavage was done, bronchial washings and biopsy were sent for cultures. Repeat bronchoscopy was done on second day of admission at AUMC and lung biopsy obtained were also sent for cultures.Image 1 CT scan of thorax without contrast, coronal view.\n\nNumerous soft tissue density nodules throughout both lungs largest measuring 1.5x 1.3 cm in the periphery of the right upper lobe (orange arrow) and additional numerous sub-centimeter pulmonary nodules.\n\nImage 1\n\nImage 2 MRI Brain performed at AUMC on 02/22/2020.\n\nCompared with the MRI exam on 01/20/2020, This Axial view, T1Weighted image with contrast shows a Left parietal periventricular lesion along the posterior body of left lateral ventricle that is now demonstrating more cystic appearance with central diffusion restriction, likely small abscess measuring approximately 1.1 cm AP by 0.8 cm transverse, previously this measured approximately 1.2 × 0.9 cm.\n\nImage 2\n\nUsing fluoroscopic guidance, lumbar puncture was performed on 02/18/2021 with opening pressure of 26 cmH2O, analysis of Cerebrospinal fluid (CSF) obtained revealed elevated protein of 220 mg/dL, a normal glucose of 66 mg/dL, leukocytosis at 228 WBC/mm3, 55 % segmented cells, 29 % lymphocytes, 16 % monocytes and 5950 RBC/mm3. CSF culture, gram stain, and cryptococcal antigen test were negative, brain biopsy showed neuroglial tissue with reactive astrocytes and microglia. Fungal cultures from bronchial washings grew Cladophialophora bantiana. Initial identification was after five days in culture, as a dematiaceous fungus, followed by species identification of Cladophialophora after 13 days in culture and final identification as Cladophialophora (Xylohypha) bantiana was obtained after 33 days in culture. This was consistent with the findings from a repeat right lung nodule biopsy taken at AUMC, the day after admission, that grew Cladophialophora species. After 7 days on admission at AUMC, Voriconazole was changed to Intravenous Isavuconazole for better side effect profile, mycophenolate mofetil was discontinued and Prednisone reduced to 5 mg daily on day 8, to minimize immune suppression and increase the chances of survival. He developed new persistent fevers on day 12 at AUMC, approximately five days after reducing immunosuppressant doses suggestive of abscess formation. Repeat MRI of the brain on day 19 at AUMC, demonstrated progression of current abscesses, new lesions and vasogenic edema shown in Image 2 . He underwent a tracheostomy on day 15 at AUMC and PEG tube placement on day 17. He remained stable on dual fungal therapy with Isavuconazole and L-AmB over the following 2 months. Despite the subsiding fever, his mental status remained poor with grimace only to pain. He was scheduled to be transferred to long term acute care hospital on Isavuconazole to be continued for at least 6 months with interval evaluation for clinical improvement. On day 51 at AUMC, the patient was pronounced dead due to respiratory failure, 79 days after his initial presentation at outside hospital.\n\nDiscussion\n\nCladophialophora Bantiana is a highly neurotropic dematiaceous fungi associated with high mortality even when antifungal treatments are administered. Although a rare disease, it is responsible for about 50 % of the reported cases of fungal brain abscess due to dematiaceous molds [1]. C. bantiana cerebral infections are associated with poor prognosis with a reported mortality rate of 65.0 % regardless of the individual’s immune status [1]. Microscopic features of C. bantiana include hyaline-to-brown, septate hyphae arranged in long branched chains [3]. Melanin is a virulence factor for all the pigmented molds as it is thought to scavenge free radical, and hypochlorite produced by phagocytic cells in the oxidative burst thus preventing killing of the organism [4]. This feature, combined with a thermotolerance above 40 °C are considered two significant virulence factors that make it easier for this fungus to survive in brain tissue [5]. Treatment has been generally unsuccessful in most cases, this likely attributed to its virulence factors and poor penetration of the antifungal drugs through meninges and the abscesses wall [5].\n\nThe mode of central nervous system penetration of C. bantiana has yet to be clearly defined. As the lesions have been recorded in many parts of the brain with no known predilection for a particular region, it is likely that the agent possibly gains access through bloodstream from an innocuous site of infection in the lung or subcutaneous traumatic inoculation site which may be facilitated by immunosuppressive therapy [6].\n\nThe rarity and lack of specific symptoms and signs of the disease pose a significant barrier to obtaining early diagnosis. Imaging modalities such as CT or MRI do not show findings specific to C. bantiana and lesions may appear similar to bacterial or tuberculous abscess [7]. Therefore, a specimen sample, direct microscopy and culture are considered essential for diagnosis [1].\n\nCases in which C. bantiana presents with both lung and cerebral involvement are extremely rare and certainly more complicated to treat. In a recent systematic review of 120 case reports, lung infection along with cerebral involvement was documented only in three of the 120 cases [5]. Although the data on therapeutics and prognosis is limited, no single antifungal or combination of antifungals has proven to be effective. Surgical resection in combination with utilization of antifungals with good CSF penetration were associated with better survival [[8], [9], [10], [11]]. In this case, the patients’ multiple small abscesses excluded the feasibility of surgical intervention and he received medical treatment alone. Further investigations into the in vivo antifungal susceptibility of the strain of C. bantiana would be of great value to developing future therapeutic recommendations.\n\nDeclaration of Competing Interest\n\nThe authors report no declarations of interest.\n\nFunding\n\nNo research funding, no sponsor.\n\nConsent\n\nConsent N/A for index case report. No identifying information included.\n\nAuthors contribution\n\nClaudia Hernandez – case report design, data collection, writing.\n\nFolake Lawal – case report design, review, edit, proofread.\n==== Refs\nReferences\n\n1 Revankar S.G. Sutton D.A. Rinaldi M.G. Primary central nervous system phaeohyphomycosis: a review of 101 cases Clin Infect Dis 38 2004 206 216 10.1086/380635 14699452\n2 Revankar S.G. Baddley J.W. Chen S.C.A. Kauffman C.A. Slavin M. Vazquez J.A. A mycoses study group international prospective study of phaeohyphomycosis: an analysis of 99 proven/probable cases Open Forum Infect Dis 4 2017 10.1093/ofid/ofx200\n3 Badali H. Gueidan C. Najafzadeh M.J. Bonifaz A. Gerrits van den Ende A.H.G. de Hoog G.S. Biodiversity of the genus cladophialophora Stud Mycol 61 2008 175 191 10.3114/sim.2008.61.18 19287540\n4 Jacobson E.S. Pathogenic roles for fungal melanins Clin Microbiol Rev 13 2000 708 717 10.1128/CMR.13.4.708-717.2000 11023965\n5 Kantarcioglu A.S. Guarro J. de Hoog S. Apaydin H. Kiraz N. An updated comprehensive systematic review of Cladophialophora bantiana and analysis of epidemiology, clinical characteristics, and outcome of cerebral cases Med Mycol 55 2017 579 604 10.1093/mmy/myw124 28007938\n6 Chakrabarti A. Kaur H. Rudramurthy S.M. Appannanavar S.B. Patel A. Mukherjee K.K. Brain abscess due to Cladophialophora bantiana: a review of 124 cases Med Mycol 54 2016 111 119 10.1093/mmy/myv091 26483430\n7 Aljuboori Z. Hruska R. Yaseen A. Arnold F. Wojda B. Nauta H. Fungal brain abscess caused by “Black Mold” (Cladophialophora bantiana) – a case report of successful treatment with an emphasis on how fungal brain abscess may be different from bacterial brain abscess Surg Neurol Int 8 2017 10.4103/sni.sni_448_16\n8 Garzoni C. Markham L. Bijlenga P. Garbino J. Cladophialophora bantiana: a rare cause of fungal brain abscess. Clinical aspects and new therapeutic options Med Mycol 46 2008 481 486 10.1080/13693780801914906 18608882\n9 Garg N. Devi I. Vajramani G. Nagarathna S. Sampath S. Chandramouli B. Central nervous system cladosporiosis: an account of ten culture-proven cases Neurol India 55 2007 282 288 10.4103/0028-3886.35690 17921658\n10 Gopalakrishnan R. Sethuraman N. Madhumitha R. Sukhwani K. Bansal N. Poojary I. Cladophialophora bantiana brain abscess: a report of two cases treated with voriconazole Indian J Med Microbiol 35 2017 620 622 10.4103/ijmm.IJMM_17_72 29405163\n11 Levin T.P. Baty D.E. Fekete T. Truant A.L. Suh B. Cladophialophora bantiana brain abscess in a solid-organ transplant recipient: case report and review of the literature J Clin Microbiol 42 2004 4374 4378 10.1128/JCM.42.9.4374-4378.2004 15365048\n\n",
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"keywords": "Cerebral abscess; Cladophialophora bantiana; Dematiaceous fungi; Phaeohyphomycosis; Pulmonary phaeohyphomycosis",
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"title": "Cerebral and pulmonary phaeohyphomycosis due Cladophialophora bantiana in an immunocompromised patient.",
"title_normalized": "cerebral and pulmonary phaeohyphomycosis due cladophialophora bantiana in an immunocompromised patient"
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"abstract": "BACKGROUND\nThere has been a 291% relative increase in congenital syphilis (CS) cases in the United States from 2015 to 2019. Although the majority of affected fetuses/infants are stillborn or are asymptomatic, a subset is born with severe clinical illness. We describe a series of severe CS cases in the neonatal intensive care unit.\n\n\nMETHODS\nRetrospective review of infants with CS, admitted to the Duke Intensive Care Nursery from June 2016 to February 2020. We recorded birthweight, gestational age, medications, procedures, diagnoses, laboratory data and outcomes. Severe symptoms included: birth depression, hypoxic ischemic encephalopathy (HIE), disseminated intravascular coagulopathy and/or persistent pulmonary hypertension (PPHN).\n\n\nRESULTS\nSeven infants with CS were identified and 5 with severe presentations were included. Median gestational age was 35.1 weeks (range: 29-37 weeks, median: 35 weeks). All infants required intubation at birth, 2 required chest compressions and epinephrine in the delivery room. One had hydrops fetalis and died in the delivery room. All 4 surviving infants had HIE, severe PPHN, hepatitis and seizures. All infants had a positive rapid plasma reagin, and were treated with penicillin G. Maternal rapid plasma reagin was pending for 3 of 5 infants at delivery, and later returned positive; 2 were positive during pregnancy but not treated. Other infectious work-up was negative. Three infants survived to discharge.\n\n\nCONCLUSIONS\nCS can be associated with HIE, PPHN and disseminated intravascular coagulopathy in affected infants. Clinicians should have a high index of suspicion and include CS in their differential diagnoses. This study also highlights the importance of adequate treatment of identified cases and screening during the third trimester and at delivery.",
"affiliations": "From the Department of Pediatrics, Duke University Duke Clinical Research Institute Department of Obstetrics and Gynecology, Duke University, Durham Department of Obstetrics and Gynecology, Wake Forest Baptist Health, Winston-Salem, North Carolina.",
"authors": "Aleem|Samia|S|;Walker|LaShawndra S|LS|;Hornik|Chi D|CD|;Smith|Michael J|MJ|;Grotegut|Chad A|CA|;Weimer|Kristin E D|KED|",
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"title": "Severe Congenital Syphilis in the Neonatal Intensive Care Unit: A Retrospective Case Series.",
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"abstract": "Sporotrichosis is an infection caused by the fungus of the Sporothrix schenckii complex and can be particularly harmful in immunocompromised patients. We report the case of a 26-year-old male patient with a previous history of pulmonary infection who underwent a liver transplant for Budd-Chiari syndrome. After the procedure, he presented with persistent fever and leukocytosis. On the 13th post-operative day, he was diagnosed with thrombosis of the hepatic artery and underwent a second liver transplant 15 days after the first procedure. After the retransplant, he presented daily episodes of fever, even after the use of several antimicrobial, antiviral, and antifungal agents. A number of negative cultures from different sites were obtained. After an acute episode of mental confusion, the growth of S schenckii was observed in cultures from cerebrospinal fluid and ascites obtained from a diagnostic paracentesis. Treatment with amphotericin B was started but the patient died on the fourth day of antifungal treatment, from a massive gastrointestinal hemorrhage. We found no previous report in the literature of spontaneous dissemination of S schenckii to the abdominal cavity causing peritonitis.",
"affiliations": "Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil. Electronic address: arantesferreira@yahoo.com.br.;Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil.;Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil.;Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil.;Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil.;Liver Transplantation Division, Federal District Institute of Cardiology, Brasília, Brazil.;Medical School, Chatolic University of Brasilia, Brasília, Brazil.;Medical School, Chatolic University of Brasilia, Brasília, Brazil.",
"authors": "Arantes Ferreira|G S|GS|;Watanabe|A L C|ALC|;Trevizoli|N C|NC|;Jorge|F M F|FMF|;Cajá|G O N|GON|;Diaz|L G G|LGG|;Meireles|L P|LP|;Araújo|M C C L|MCCL|",
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"issue": "51(5)",
"journal": "Transplantation proceedings",
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"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D006502:Budd-Chiari Syndrome; D017809:Fatal Outcome; D006801:Humans; D016867:Immunocompromised Host; D016031:Liver Transplantation; D008297:Male; D010538:Peritonitis; D013174:Sporotrichosis",
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"title": "Disseminated Sporotrichosis in a Liver Transplant Patient: A Case Report.",
"title_normalized": "disseminated sporotrichosis in a liver transplant patient a case report"
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"abstract": "A presumptive diagnosis of bone metastasis can be easily made when a patient with a history of colorectal cancer develops bone lesions that are seen on follow-up imaging. In this case report, we describe a patient whose multiple bone lesions were wrongly attributed to a recurrence of rectal cancer rather than being identified as multiple myeloma lesions. When clinicians detect new, abnormal, bony lesions in a patient with a previous history of cancer, they should consider diseases such as multiple myeloma in their differential diagnosis.",
"affiliations": "Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.;Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.",
"authors": "Kim|Im-Kyung|IK|;Kang|Jeonghyun|J|;Kim|Yu Ri|YR|;Jeon|Tae Joo|TJ|;Baik|Seung Hyuk|SH|;Sohn|Seung-Kook|SK|",
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"fulltext": "\n==== Front\nAnn ColoproctolAnn ColoproctolACAnnals of Coloproctology2287-97142287-9722The Korean Society of Coloproctology 10.3393/ac.2017.33.2.70Case ReportMultiple Myeloma Mimics Bone Metastasis From a Rectal Adenocarcinoma Kim Im-Kyung Kang Jeonghyun Kim Yu Ri 1Jeon Tae Joo 2Baik Seung Hyuk Sohn Seung-Kook Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.1 Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.2 Department of Nuclear Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea.Correspondence to: Jeonghyun Kang, M.D. Department of Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea. Tel: +82-2-2019-3369, Fax: +82-2-3462-5994, ravic@naver.com4 2017 28 4 2017 33 2 70 73 27 10 2016 02 1 2017 © 2017 The Korean Society of Coloproctology2017This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.A presumptive diagnosis of bone metastasis can be easily made when a patient with a history of colorectal cancer develops bone lesions that are seen on follow-up imaging. In this case report, we describe a patient whose multiple bone lesions were wrongly attributed to a recurrence of rectal cancer rather than being identified as multiple myeloma lesions. When clinicians detect new, abnormal, bony lesions in a patient with a previous history of cancer, they should consider diseases such as multiple myeloma in their differential diagnosis.\n\nMultiple myelomaBone metastasisRectal neoplasms\n==== Body\nINTRODUCTION\nSkeletal bone is a frequent site of distant metastasis in patients with advanced solid cancers, such as breast, prostate, and lung cancers [1]. In contrast, primary colorectal cancer rarely metastasizes to the bone late in its course [23]. Regardless, a presumptive diagnosis of bone metastasis can be easily made when a patient with a history of colorectal cancer develops bone lesions that are seen on follow-up imaging.\n\nMultiple myeloma (MM) is a malignant neoplasm of plasma cells and mainly involves the bone marrow; it accounts for approximately 10% of hematologic malignancies [4]. The overall survival of patients with MM has improved significantly in the last decade with the emergence of thalidomide, bortezomib, lenalidomide, and hematopoietic stem-cell transplantation [4]. Although plain radiographs of the skeleton are routinely used to assess the extent of bone involvement, positron emission tomography/computed tomography (PET/CT) and magnetic resonance imaging (MRI) are frequently added to increase the sensitivity or specificity of the diagnosis [45].\n\nThe coexistence of MM and colon cancer has rarely been reported in the literature [6789]. Because of their distinct treatment modalities, the ability of clinicians to distinguish MM from bone metastasis secondary to colorectal cancer is important. However, previous reports have demonstrated that despite advanced imaging studies, discrimination between MM and bone metastasis from colon cancer is difficult [89]. For that reason, this case report describes a patient whose multiple bone lesions were wrongly attributed to a recurrence of rectal cancer rather than being identified as MM lesions. This misunderstanding resulted in a delay of appropriate treatment.\n\nCASE REPORT\nA 69-year-old male patient visited an outpatient clinic for his fifth annual follow-up. He had a history of rectal cancer for which he had undergone a long course of preoperative chemoradiotherapy, followed by a low anterior resection with colo-anal anastomosis. The pathology of the surgical specimen revealed proper muscle invasion without any regional or distant metastases (ypT2N0M0; yp stage I). Adjuvant chemotherapy, based on a regimen containing 5-fluorouracil (FU), was given 4 times.\n\nAt the fifth annual follow-up, the following tests were performed: serum carcinoembryonic antigen (CEA), colonoscopy, pelvic MRI, and PET/CT. The colonoscopy showed no evidence of local recurrence. The patient's CEA level was 1.5 ng/mL. However, pelvic MRI revealed multiple, newly developed, small nodules in the pelvic bones that were suggestive of bony metastases (Fig. 1). The PET/CT scan also showed multiple hypermetabolic foci in the bilateral humerus, femurs, scapulae, ribs, spine and pelvic bones (Fig. 2). Further study using Tc-99m methylene diphosphonate (MDP) whole-body bone images showed increased uptake in the right anterior sixth rib, the spinous process of T9, and the upper portion of the bilateral sacroiliac joints (Fig. 3).\n\nUnder a presumptive diagnosis of bone metastases from rectal cancer, palliative chemotherapy with the XELOX regimen (capecitabine, 5-FU and oxaliplatin) was planned. However, chemotherapy was delayed for approximately five weeks due to abnormal laboratory findings, including anemia, leukocytopenia and mildly-elevated serum creatinine (Cr). After the first dose of XELOX chemotherapy, the patient was noted to have pancytopenia and a gradually-rising serum Cr level. The patient also suffered from poor oral intake and nausea. These clinical manifestations and abnormal laboratory findings were attributed to the adverse effects of XELOX chemotherapy. Therefore, further chemotherapy could not be given. The pancytopenia and the elevated serum Cr persisted for 2 months after the last chemotherapy dose. The patient was transferred to the Department of Nephrology to evaluate his elevated Cr levels. Initially, the patient was suspected to have contrast-induced acute kidney injury or chemotherapy-induced chronic renal disease. A 24-hour urine study detected a large amount of protein. Urinary immunoelectrophoresis demonstrated a monoclonal gammopathy with an M spike. Furthermore, urinary immunofixation electrophoresis revealed an abnormal band in the kappa lane. Serum protein electrophoresis showed hypogammaglobulinemia (680 mg/dL) with an elevated free kappa light chain (6,090 mg/L).\n\nThe above results led us to perform a bone marrow biopsy for suspected MM. The biopsy revealed hypercellular marrow particles with marked plasmacytosis (88.3% of absolute neutrophil counts). Based on these results, a final diagnosis of MM (kappa type) was made. Chemotherapy was initiated with a combined regimen of bortezomib, melphalan and prednisone (VMP regimen) every 35 days. A 50% reduction of in the recommended dose of mephalan and prednisone were initially administered due to chronic renal failure. During the first cycle of the VMP regimen, we reduced the dose of bortezomib by an additional 75% because the patient experienced severe diarrhea. After the fifth cycle of chemotherapy, the hypogammaglobulinemia (720 mg/dL) with free kappa light chain elevation (587 mg/L) improved, suggestive of a partial response. Eight cycles of the VMP regimen were completed. The patient was offered an additional 12 cycles of cyclophosphamide, thalidomide and dexamethasone (CTD regimen). However, the disease had progressed. Unfortunately, the patient could not tolerate further chemotherapy (including low dose dexamethasone with lenalidomide) and was lost to follow up.\n\nDISCUSSION\nA few prior studies have reported the coexistence of MM and colon cancer [6789]. However, to the best of our knowledge, this is the first case of MM mimicking bone metastases from rectal cancer. In this case, a presumptive diagnosis was made based on the patient's history of rectal cancer and the presence of multiple bony lesions on imaging.\n\nMM causes approximately 1% of all malignancies and is increasing in prevalence annually. Most patients undergo an asymptomatic period, defined as monoclonal gammopathy of undetermined significance (MGUS). At a rate of approximately 1% per year, MGUS progresses to myeloma [4]. MM may present with the following signs of end-organ damage: hypercalcemia, renal insufficiency, anemia, and bone lesions (including lytic lesions and osteopenia) [5]. Although the patient described here had thrombocytopenia and elevated serum Cr, these abnormal laboratory findings are not specific to MM. Furthermore, the prolonged pancytopenia and elevated Cr were thought to have resulted from the first cycle of XELOX chemotherapy. These clinical situations resulted in a delay in the proper diagnosis and management.\n\nRecent reports have demonstrated that most patients with bone metastasis from colorectal cancer have initially advanced stages (stage III or IV), high levels of CEA at the time of diagnosis, and a median time interval to bone metastasis of 10–11 months [23]. In addition, isolated bony metastases without the involvement of another organ, such as the liver or the lungs, are rare [210]. In this case, the patient had stage I rectal cancer postoperatively, with no elevation of the CEA level (2.1 when rectal cancer was diagnosed, and 1.5 when MM was diagnosed). No other metastatic lesions, except those in the bone, were present. Furthermore, almost 5 years had elapsed between the initial resection of the primary tumor and the detection of possible recurrence. If the bony lesions were truly metastases from rectal cancer, the patient's presentation would be considered extremely rare and inconsistent with each subcategory of bone metastasis from colorectal cancer. Even though, the clinician, depending on a thorough review of radiologic imaging and multidisciplinary discussion, considered bone metastasis as a priority of diagnosis.\n\nIn the diagnosis of MM, whole body X-ray (WBXR), CT, MRI, radionuclide imaging, and PET/CT are currently used. That Tc-99m MDP may not detect all lesions in MM is well known [11]. PET/CT or PET is useful in the detection of occult lesions that are invisible in Tc-99m MDP. When the Durie-Salmon PLUS staging system is used, PET/CT or PET imaging is required [5]. Although PET scans have a superior detection rate for bone lesions compared to WBXR, the superiority of PET/CT in comparison to MRI has not yet been established [5]. Shortt et al. [12] reported that when PET and whole-body MRI were used in combination with concordant results, the positive predictive value was 100%.\n\nHowever, data addressing the sensitivity or the specificity of diagnostic modalities in discriminating MM from bone metastasis are limited, potentially given its rarity. The incidence of bone metastases from primary colorectal cancer is relatively low (less than 10%) compared to that of other solid tumors. The most common sites for skeletal metastases are the vertebral column, particularly the lumbar and the sacral portions, followed by the pelvic bones and ribs [231314]. The radiologic findings usually demonstrate osteolytic or mixed osteolytic-osteoblastic patterns, resembling the patterns described in our case. For this reason, previous case reports have also demonstrated that distinguishing between MM and bone metastasis, even with the addition of PET/CT scans, is difficult [89]. Considering the diagnostic challenges, this case emphasized the importance of considering MM as a potential diagnosis in the assessment of rectal cancer patients with bone lesions. This is particularly true in patients with somewhat unusual clinical presentations.\n\nIn conclusion, this case highlights the rarity of detecting MM on routine annual follow-ups for rectal cancer, in contrast to the relatively frequent diagnosis of bone metastasis from rectal cancer. When clinicians detect new abnormal bony lesions in a patient with a previous history of cancer, they should consider diseases such as MM in their differential diagnosis.\n\nCONFLICT OF INTEREST: No potential conflict of interest relevant to this article was reported.\n\nFig. 1 Pelvic magnetic resonance imaging revealed newly developed, multiple, small, nodular lesions in the pelvic bone (white arrowheads).\nFig. 2 Positron emission tomography/computed tomography scans demonstrated newly developed, multiple, hypermetabolic foci in the bilateral humerus, femurs, scapulae, ribs, spine and pelvic bones (black arrows).\nFig. 3 Tc-99m methylene diphosphonate showed increased uptakes in the right anterior sixth rib (black arrow), spinous process of T9 (white arrowhead), and upper portion of the bilateral Sacroiliac joints (black arrowhead).\n==== Refs\n1 Coleman RE Rubens RD The clinical course of bone metastases from breast cancer Br J Cancer 1987 55 61 66 3814476 \n2 Baek SJ Hur H Min BS Baik SH Lee KY Kim NK The characteristics of bone metastasis in patients with colorectal cancer: a long-term report from a single institution World J Surg 2016 40 982 986 26541868 \n3 Santini D Tampellini M Vincenzi B Ibrahim T Ortega C Virzi V Natural history of bone metastasis in colorectal cancer: final results of a large Italian bone metastases study Ann Oncol 2012 23 2072 2077 22219016 \n4 Rajkumar SV Multiple myeloma: 2013 update on diagnosis, risk-stratification, and management Am J Hematol 2013 88 226 235 23440663 \n5 Mihailovic J Goldsmith SJ Multiple myeloma: 18F-FDG-PET/CT and diagnostic imaging Semin Nucl Med 2015 45 16 31 25475376 \n6 Shanbrom E Multiple myeloma and coexistent carcinoma of the sigmoid colon Am J Clin Pathol 1963 40 67 71 13988425 \n7 Yermiahu T Peiser J Benharroch D Ovnat A Aggressive behavior of carcinoma of the colon associated with nonsecreting plasma cell myeloma: a case report J Clin Gastroenterol 1989 11 565 567 2794435 \n8 Chang CY Peng YJ Shen DH Huang WS Cherng SC Detection of multiple myeloma by PET/CT in a patient with colon cancer Clin Nucl Med 2008 33 367 370 18431161 \n9 Zhang H Lv J Lv C Zhang H Presentation of multiple myeloma mimicking bone metastasis from colon adenocarcinoma: a case report and literature review Mol Clin Oncol 2016 4 31 34 26870352 \n10 Roth ES Fetzer DT Barron BJ Joseph UA Gayed IW Wan DQ Does colon cancer ever metastasize to bone first? a temporal analysis of colorectal cancer progression BMC Cancer 2009 9 274 19664211 \n11 Wang K Allen L Fung E Chan CC Chan JC Griffith JF Bone scintigraphy in common tumors with osteolytic components Clin Nucl Med 2005 30 655 671 16166837 \n12 Shortt CP Gleeson TG Breen KA McHugh J O'Connell MJ O'Gorman PJ Whole-Body MRI versus PET in assessment of multiple myeloma disease activity AJR Am J Roentgenol 2009 192 980 986 19304704 \n13 Onesti JK Mascarenhas CR Chung MH Davis AT Isolated metastasis of colon cancer to the scapula: is surgical resection warranted? World J Surg Oncol 2011 9 137 22029634 \n14 Kanthan R Loewy J Kanthan SC Skeletal metastases in colorectal carcinomas: a Saskatchewan profile Dis Colon Rectum 1999 42 1592 1597 10613479\n\n",
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"title": "Multiple Myeloma Mimics Bone Metastasis From a Rectal Adenocarcinoma.",
"title_normalized": "multiple myeloma mimics bone metastasis from a rectal adenocarcinoma"
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"abstract": "A severe course of infectious mononucleosis should always lead up to the suspicion of a primary immunodeficiency. We describe the case of a boy with severe mononucleosis accompanied by the development of hemophagocytic lymphohistiocytosis and lymphoma. By whole exome sequencing, we identified a mutation of uncertain significance in CTPS2, a gene closely related to CTPS1, which is involved in a primary immune deficiency with susceptibility to herpesviruses. We discuss the challenge of a correct interpretation of data from whole exome sequencing, questioning whether the CTPS2 variant found in our patient is just an incidental finding or a mutation with variable penetrance.",
"affiliations": "Departments of Pediatrics.;Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health, IRCCS Burlo Garofolo.;Departments of Pediatrics.;Departments of Pediatrics.;Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health, IRCCS Burlo Garofolo.;Department of Medical Surgical and Health Sciences, University of Trieste, Trieste, Italy.;Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health, IRCCS Burlo Garofolo.;Departments of Pediatrics.;Advanced Diagnostic and Clinical Trials, Institute for Maternal and Child Health, IRCCS Burlo Garofolo.",
"authors": "Verzegnassi|Federico|F|;Valencic|Erica|E|;Kiren|Valentina|V|;Giurici|Nagua|N|;Bianco|Anna Monica|AM|;Marcuzzi|Annalisa|A|;Vozzi|Diego|D|;Tommasini|Alberto|A|;Faletra|Flavio|F|",
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"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "The Challenge of Next Generation Sequencing in a Boy With Severe Mononucleosis and EBV-related Lymphoma.",
"title_normalized": "the challenge of next generation sequencing in a boy with severe mononucleosis and ebv related lymphoma"
} | [
{
"companynumb": "IT-PFIZER INC-2018328797",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Glucagon-like peptide-1 (GLP-1) receptor agonists and sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce glycaemia and weight, and improve cardiovascular risk factors via different mechanisms. We aimed to compare the efficacy and safety of co-initiation of the GLP-1 receptor agonist exenatide and the SGLT2 inhibitor dapagliflozin with exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled by metformin.\n\n\n\nDURATION-8 was a 28 week, multicentre, double-blind, randomised, active-controlled phase 3 trial done at 109 sites in six countries. Adults (aged ≥18 years) with type 2 diabetes and inadequate glycaemic control (HbA1c 8-12% [64-108 mmol/mol]) despite stable metformin monotherapy (≥1500 mg/day) were randomly assigned (1:1:1), via an interactive voice and web-response system, to receive once-weekly exenatide 2 mg by subcutaneous injection plus once-daily dapagliflozin 10 mg oral tablets, exenatide with dapagliflozin-matched oral placebo, or dapagliflozin with exenatide-matched placebo injections. Randomisation was stratified by baseline HbA1c (<9·0% vs ≥9·0% [<75 mmol/mol vs ≥75 mmol/mol]). The primary endpoint was change in HbA1c from baseline to week 28. Secondary endpoints were the change from baseline in fasting plasma glucose at week 2 and week 28, and 2 h postprandial glucose at week 28; the proportion of patients with an HbA1c less than 7·0% (<53 mmol/mol) at week 28; change in weight at week 28; the proportion of patients with weight loss of 5% or more at week 28; and change in systolic blood pressure at week 28. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT02229396.\n\n\n\nBetween Sept 4, 2014, and Oct 15, 2015, we randomly assigned 695 patients to receive exenatide plus dapagliflozin (n=231), exenatide alone (n=231; n=1 untreated), or dapagliflozin alone (n=233). The intention-to-treat population comprised 685 participants (mean HbA1c 9·3% [SD 1·1]; 78 mmol/mol [12]), of whom 611 (88%) completed the study. After 28 weeks, the change in baseline HbA1c was -2·0% (95% CI -2·1 to -1·8) in the exenatide plus dapagliflozin group, -1·6% (-1·8 to -1·4) in the exenatide group, and -1·4% (-1·6 to -1·2) in the dapagliflozin group. Exenatide plus dapagliflozin significantly reduced HbA1c from baseline to week 28 compared with exenatide alone (-0·4% [95% CI -0·6 to -0·1]; p=0·004) or dapagliflozin alone (-0·6% [-0·8 to -0·3]; p<0·001). Exenatide plus dapagliflozin was significantly superior to either drug alone for all secondary efficacy endpoints, with greater reductions in fasting plasma and postprandial glucose, more patients with an HbA1c less than 7·0% (<53 mmol/mol), greater weight loss, a greater proportion of patients with weight loss of 5% or more, and greater reductions in systolic blood pressure (all p≤0·025). Adverse events were recorded in 131 (57%) of 231 patients in the exenatide plus dapagliflozin group, 124 (54%) of 230 patients in the exenatide group, and 121 (52%) of 233 patients in the dapagliflozin group. The most common adverse events (≥5% of patients in any group) were diarrhoea, injection-site nodules, nausea, and urinary tract infections. No episodes of major hypoglycaemia or minor hypoglycaemia were reported.\n\n\n\nCo-initiation of exenatide and dapagliflozin improved various glycaemic measures and cardiovascular risk factors in patients with type 2 diabetes inadequately controlled by metformin monotherapy. The dual treatment regimen was well tolerated, with the expected safety profile for this combination. Additional data from an ongoing study (eg, AWARD-10; NCT02597049) will further inform the use of these drug classes in combination.\n\n\n\nAstraZeneca.",
"affiliations": "National Research Institute, Los Angeles, CA, USA. Electronic address: juan.frias@nritrials.com.;Department of Diabetes, Nutrition and Metabolic Diseases, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania; 1st Clinic of Diabetes, N Paulescu National Institute of Diabetes, Nutrition and Metabolic Diseases, Bucharest, Romania.;AstraZeneca, Gaithersburg, MD, USA.;Apex Medical Research, Chicago, IL, USA; John H Stroger Jr Hospital, Chicago, IL, USA; Rush University Medical Center, Chicago, IL, USA.;AstraZeneca, Gaithersburg, MD, USA.;AstraZeneca, Gaithersburg, MD, USA.;Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College of Thomas Jefferson University, Philadelphia, PA, USA.",
"authors": "Frías|Juan P|JP|;Guja|Cristian|C|;Hardy|Elise|E|;Ahmed|Azazuddin|A|;Dong|Fang|F|;Öhman|Peter|P|;Jabbour|Serge A|SA|",
"chemical_list": "D001559:Benzhydryl Compounds; D005960:Glucosides; D007004:Hypoglycemic Agents; D010455:Peptides; D014688:Venoms; C529054:dapagliflozin; D008687:Metformin; D000077270:Exenatide",
"country": "England",
"delete": false,
"doi": "10.1016/S2213-8587(16)30267-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2213-8587",
"issue": "4(12)",
"journal": "The lancet. Diabetes & endocrinology",
"keywords": null,
"medline_ta": "Lancet Diabetes Endocrinol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001559:Benzhydryl Compounds; D003924:Diabetes Mellitus, Type 2; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000077270:Exenatide; D005260:Female; D005960:Glucosides; D006801:Humans; D007004:Hypoglycemic Agents; D008297:Male; D008687:Metformin; D008875:Middle Aged; D010455:Peptides; D017211:Treatment Failure; D014688:Venoms",
"nlm_unique_id": "101618821",
"other_id": null,
"pages": "1004-1016",
"pmc": null,
"pmid": "27651331",
"pubdate": "2016-12",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy (DURATION-8): a 28 week, multicentre, double-blind, phase 3, randomised controlled trial.",
"title_normalized": "exenatide once weekly plus dapagliflozin once daily versus exenatide or dapagliflozin alone in patients with type 2 diabetes inadequately controlled with metformin monotherapy duration 8 a 28 week multicentre double blind phase 3 randomised controlled trial"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2019-10333",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "We describe a case of Strongyloides stercoralis hyperinfection in a liver allograft recipient 2.5 months after transplantation. The patient lives in Spain, which is not considered an endemic country for strongyloidiasis, and denied prior residence or travel to any known endemic area. The initial symptoms were fever and vomiting, and he subsequently developed a severe respiratory disease. An endoscopic biopsy of ulcerative lesions of the duodenum revealed massive mucosa infiltration by larvae and adult worms, which were also found in respiratory samples. The patient was successfully treated with combined therapy with albendazole and ivermectin. The strongyloides infection was transmitted by the liver allograft. The donor was from Ecuador and, retrospectively, his serum tested positive for S. stercoralis IgG antibodies. Additionally, the pancreas-left kidney allograft recipient from the same donor later developed an intestinal strongyloidiasis without hyperinfection syndrome. To our knowledge, this is the first confirmed case of S. stercoralis infection transmission from the same donor to two solid allograft recipients.",
"affiliations": "Department of Infectious Diseases, Hospital Virgen del Rocío, Sevilla, Spain. lfvgmjrh1@yahoo.es",
"authors": "Rodriguez-Hernandez|M J|MJ|;Ruiz-Perez-Pipaon|M|M|;Cañas|E|E|;Bernal|C|C|;Gavilan|F|F|",
"chemical_list": "D000871:Anthelmintics; D000977:Antiparasitic Agents; D007559:Ivermectin; D015766:Albendazole",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1600-6143.2009.02828.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1600-6135",
"issue": "9(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D015766:Albendazole; D000818:Animals; D000871:Anthelmintics; D000977:Antiparasitic Agents; D006801:Humans; D007559:Ivermectin; D016031:Liver Transplantation; D008297:Male; D011183:Postoperative Complications; D017171:Strongyloides stercoralis; D013322:Strongyloidiasis; D014184:Transplantation, Homologous",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2637-40",
"pmc": null,
"pmid": "19843038",
"pubdate": "2009-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Strongyloides stercoralis hyperinfection transmitted by liver allograft in a transplant recipient.",
"title_normalized": "strongyloides stercoralis hyperinfection transmitted by liver allograft in a transplant recipient"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-03503",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"druga... |
{
"abstract": "To analyse the pooled safety data of intravitreal ziv-aflibercept (IVZ) therapy for various retinal conditions.\n\n\n\nThis was a retrospective, observational study which included patients from 14 participating centres who received IVZ. The medical records of patients who received IVZ from March 2015 through October 2017 were evaluated. Patient demographics and ocular details were compiled. Ocular and systemic adverse events that occurred within 1 month of IVZ injections were recorded and defined as either procedure-related or drug-related.\n\n\n\nA total of 1704 eyes of 1562 patients received 5914 IVZ injections (mean±SD: 3.73±3.94) during a period of 2.5 years. The age of patients was 60.6±12.8 years (mean±SD) and included diverse chorioretinal pathologies. Both ocular (one case of endophthalmitis, three cases of intraocular inflammation, and one case each of conjunctival thinning/necrosis and scleral nodule) and systemic adverse events (two cases of myocardial infarction, one case of stroke and two deaths) were infrequent.\n\n\n\nThis constitutes the largest pooled safety report on IVZ use and includes patients from 14 centres distributed across the globe. It shows that IVZ has an acceptable ocular and systemic safety profile with incidences of adverse events similar to those of other vascular endothelial growth factor inhibitory drugs. The analysis supports the continued use of IVZ in various retinal disorders.",
"affiliations": "Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India.;Department of Ophthalmology, Mayo Clinic, Jacksonville, Florida, USA.;Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India.;Department of Ophthalmology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt.;Department of Ophthalmology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt.;Department of Ophthalmology, Alexandria Faculty of Medicine, Alexandria University, Alexandria, Egypt.;Foresight Eye Clinic, New Delhi, India.;Banker's Retina Clinic and Laser Centre, Ahmedabad, India.;Department of Ophthalmology, American University of Beirut, Beirut, Lebanon.;Marashi Eye Clinic, Aleppo, Syria.;Shivam Eye Foundation, Navi Mumbai, Maharashtra, India.;Department of Surgery, School of Medicine and Dentistry, University of Ghana, Accra, Ghana.;Ophthalmic Research Center, Labbafinejad Medical Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Ophthalmic Research Center, Labbafinejad Medical Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Ophthalmic Research Center, Labbafinejad Medical Center, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.;Department of Ophthalmology, Federal University of São Paulo - Paulista Medical School (UNIFESP/EPM), São Paulo, Brazil.;Department of Ophthalmology, Federal University of São Paulo - Paulista Medical School (UNIFESP/EPM), São Paulo, Brazil.;Department of Ophthalmology, Federal University of São Paulo - Paulista Medical School (UNIFESP/EPM), São Paulo, Brazil.;Department of Ophthalmology, Federal University of São Paulo - Paulista Medical School (UNIFESP/EPM), São Paulo, Brazil.;Department of Ophthalmology, Federal University of São Paulo - Paulista Medical School (UNIFESP/EPM), São Paulo, Brazil.;Banker's Retina Clinic and Laser Centre, Ahmedabad, India.;Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India jay.chhablani@gmail.com.",
"authors": "Singh|Sumit Randhir|SR|;Stewart|Michael W|MW|;Chattannavar|Goura|G|;Ashraf|Mohammed|M|0000-0003-4231-2566;Souka|Ahmed|A|0000-0002-1664-704X;ElDardeery|Mazen|M|;Wadhwa|Neeraj|N|;Sarvaiya|Chintan|C|;Mansour|Ahmad M|AM|;Marashi|Ameen|A|;Ramchandani|Suresh|S|;Braimah|Imoro Zeba|IZ|;Jabbarpoor Bonyadi|Mohammad Hossein|MH|;Ramezani|Alireza|A|;Soheilian|Masoud|M|;de Oliveira Dias|João Rafael|JR|;de Andrade|Gabriel Costa|GC|;Maia|André|A|;Rodrigues|Eduardo Büchele|EB|;Farah|Michel Eid|ME|;Banker|Alay|A|;Chhablani|Jay|J|;|||",
"chemical_list": "D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "England",
"delete": false,
"doi": "10.1136/bjophthalmol-2018-312453",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-1161",
"issue": "103(6)",
"journal": "The British journal of ophthalmology",
"keywords": "diabetic macular edema (DME); intravitreal ziv-aflibercept (IVZ); neovascular age related macular degeneration (n-AMD); retinal venous occlusion (RVO); ziv-aflibercept",
"medline_ta": "Br J Ophthalmol",
"mesh_terms": "D004305:Dose-Response Relationship, Drug; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D008875:Middle Aged; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D012160:Retina; D012164:Retinal Diseases; D012189:Retrospective Studies; D013997:Time Factors; D041623:Tomography, Optical Coherence; D016896:Treatment Outcome; D014792:Visual Acuity",
"nlm_unique_id": "0421041",
"other_id": null,
"pages": "805-810",
"pmc": null,
"pmid": "30099379",
"pubdate": "2019-06",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study",
"references": null,
"title": "Safety of 5914 intravitreal ziv-aflibercept injections.",
"title_normalized": "safety of 5914 intravitreal ziv aflibercept injections"
} | [
{
"companynumb": "IN-SA-2019SA207820",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "AFLIBERCEPT"
},
"drugadditional": null,
"d... |
{
"abstract": "OBJECTIVE\nTo illustrate the anatomical and pathophysiological risks of epidural hematoma formation, other than direct needle trauma, after lumbar transforaminal epidural steroid injection in the setting of severe central canal stenosis.\n\n\nMETHODS\nThis case report presents the development of an epidural hematoma after lumbar transforaminal epidural steroid injection in a patient who has anatomical risk factor of severe lumbar spinal stenosis. The anatomic location of epidural hematoma was at the injected level, but on the contralateral side of the dura at a distance from the needle path. Epidural vascular anatomy and the potential mechanisms of bleeding in the epidural space in the absence of direct needle trauma, including the importance of injection pressures are discussed.\n\n\nCONCLUSIONS\nThis is the first reported case of an epidural hematoma on the contralateral side of the dura at a distance from the needle tip location, in the setting of severe central canal stenosis.",
"affiliations": "Division of Pain Medicine, Department of Anesthesiology, Hospital for Special Surgery, Weill Cornell Medical College, NY, USA.;Department of Psychiatry, Hofstra Northwell Health, Staten Island University Hospital, NY, USA.",
"authors": "Gungor|Semih|S|;Aiyer|Rohit|R|",
"chemical_list": "D013256:Steroids",
"country": "England",
"delete": false,
"doi": "10.2217/pmt-2017-0012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1758-1869",
"issue": "7(5)",
"journal": "Pain management",
"keywords": "bleeding; celecoxib; contralateral; epidural injection; hematoma; spinal stenosis; steroid; transforaminal",
"medline_ta": "Pain Manag",
"mesh_terms": "D046748:Hematoma, Epidural, Spinal; D006801:Humans; D007268:Injections, Epidural; D008875:Middle Aged; D013130:Spinal Stenosis; D013256:Steroids",
"nlm_unique_id": "101555934",
"other_id": null,
"pages": "367-375",
"pmc": null,
"pmid": "28936912",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epidural hematoma development contralateral to dura after lumbar transforaminal epidural steroid injection.",
"title_normalized": "epidural hematoma development contralateral to dura after lumbar transforaminal epidural steroid injection"
} | [
{
"companynumb": "US-009507513-1710USA005905",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CELECOXIB"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nChronic spontaneous urticaria (CSU) is a frequent mast cell-driven disease that affects approximately 0.5-1% of the population. Antihistamines are currently the drugs of choice in patients with CSU. Omalizumab has been shown to be very effective in CSU and has been recently approved as second-line therapy. However, although its introduction has markedly improved the therapeutic possibilities for CSU, there is still a hard core of patients who do not respond and require effective treatment.\n\n\nMETHODS\nWe report the case of a patient who achieved an 8-month remission of refractory CSU following the use of rituximab, and perform a review of the literature regarding the use of rituximab in CSU.\n\n\nRESULTS\nThere was a remarkable improvement in her CSU after the administration of rituximab maintained over time.\n\n\nCONCLUSIONS\nRituximab is a chimeric murine/human monoclonal antibody directed against CD20, which depletes memory B-lymphocytes that are necessary for autoantibody production. The abrogation of the autoantibody production is the proposed mechanism by which it may alleviate the symptoms of CSU.",
"affiliations": "Dermatology Unit, Hospital Clinic de Barcelona, Barcelona, Spain.;Internal Medicine Unit, Hospital Clinic de Barcelona, Barcelona, Spain.;Internal Medicine Unit, Hospital Clinic de Barcelona, Barcelona, Spain.;Dermatology Unit, Hospital Clinic de Barcelona, Barcelona, Spain.",
"authors": "Combalia|Andrea|A|;Losno|Ricardo A|RA|;Prieto-González|Sergio|S|;Mascaró|J Manuel|JM|",
"chemical_list": "D001323:Autoantibodies; D007155:Immunologic Factors; D000069283:Rituximab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000487402",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1660-5527",
"issue": "31(4)",
"journal": "Skin pharmacology and physiology",
"keywords": "Chronic spontaneous urticaria; Omalizumab; Rituximab; Urticaria",
"medline_ta": "Skin Pharmacol Physiol",
"mesh_terms": "D000328:Adult; D001323:Autoantibodies; D002908:Chronic Disease; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D000069283:Rituximab; D016896:Treatment Outcome; D014581:Urticaria",
"nlm_unique_id": "101188418",
"other_id": null,
"pages": "184-187",
"pmc": null,
"pmid": "29649806",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rituximab in Refractory Chronic Spontaneous Urticaria: An Encouraging Therapeutic Approach.",
"title_normalized": "rituximab in refractory chronic spontaneous urticaria an encouraging therapeutic approach"
} | [
{
"companynumb": "ES-ASTELLAS-2018US033199",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
... |
{
"abstract": "Interdigitating dendritic cell sarcoma is an extremely rare tumor. The diagnosis is difficult and is based on clinical, pathological and immunohistochemical evaluation. Differential diagnosis includes melanoma, mesenchymal and hematological malignancies. The mainstay of treatment is surgery for limited disease and different chemotherapy combinations have been tested for advanced disease. No evidence from prospective trials is currently available. We report the case of a 59 year-old male patient who experienced axillary lymphadenopathy with initial diagnosis of large-cell lung cancer on tumor biopsy. He underwent surgical resection with radical intent. Pathological diagnosis of interdigitating dendritic cell sarcoma was obtained on surgical samples. Nine months after radical surgery, he experienced systemic recurrence of disease and underwent chemotherapy with epirubicin and ifosfamide for 4 courses. During chemotherapy, he developed brain disease progression and underwent whole-brain radiotherapy. Systemic progression was then observed and molecular characterization was performed. B-RAF evaluation resulted positive for V600E mutation and the patient was treated with Vemurafenib according to molecular findings. He thus obtained initial clinical benefit but eventually died of brain hemorrhage. In conclusion, we report a case of B-RAF mutation detected in an interdigitating dendritic cell sarcoma patient treated with targeted therapy. B-RAF pathway could have a role in pathogenesis and evolution of this rare disease and could open new perspectives of treatment.",
"affiliations": "a Medical Oncology 2 ; Istituto Oncologico Veneto IRCCS ; Padova , Italy.",
"authors": "Di Liso|Elisabetta|E|;Pennelli|Natale|N|;Lodovichetti|Gigliola|G|;Ghiotto|Cristina|C|;Dei Tos|Angelo Paolo|AP|;Conte|PierFranco|P|;Bonanno|Laura|L|",
"chemical_list": "D007211:Indoles; D013449:Sulfonamides; D000077484:Vemurafenib; D015251:Epirubicin; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1080/15384047.2015.1057359",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "16(8)",
"journal": "Cancer biology & therapy",
"keywords": "18FDG- PET-CT, 18fluorodeoxyglucose-positron emission tomography-computed tomography; ALK, anaplastic lymphoma kinase; ATP, adenosine triphosphate; B-RAF; BCL2, B-cell lymphoma 2; CD, cluster of differentiation; CT, computed tomography; CTCAE, common terminology criteria for adverse events; ECG, electrocardiogram; ECOG, eastern cooperative oncology group; EMA, ephitelial membrane antigen; H3Ac, acetylated histone H3; HLA, human leukocyte antigen; Ig, immunoglobulin; IgH, heavy immunoglobulin; MHC, Major Histocompatibility Complex; MRI, magnetic resonance imaging; NSE, neuron specific enolase; PS, performance status; QTc, corrected QT interval; SUV, standardized uptake value; TCR, t cell receptor; TIM, T cell immunoglobulin mucin; Vemurafenib; WHO, world health organization; differential diagnosis; interdigitating dendritic cell sarcoma",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001932:Brain Neoplasms; D054739:Dendritic Cell Sarcoma, Interdigitating; D015251:Epirubicin; D006801:Humans; D007069:Ifosfamide; D007211:Indoles; D008297:Male; D008875:Middle Aged; D058990:Molecular Targeted Therapy; D009154:Mutation; D048493:Proto-Oncogene Proteins B-raf; D013449:Sulfonamides; D000077484:Vemurafenib",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "1128-35",
"pmc": null,
"pmid": "26047060",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "23755890;9766802;24863690;22859608;8311662;12121233;20519626;20439325;11914634;12068308;6270876;19926586;6750114;9606805;11422494;25722315;22879539;8555475;17636477;4281966;2158241;2692887;17169812;12153170;10208672;21639808;15945093;3891942;11293908;25787243;2471772;3985124;15806378;25992240;8690042;3081423;17455317;25815361;17658269;22506009;20656318;9010103;24720374",
"title": "Braf mutation in interdigitating dendritic cell sarcoma: a case report and review of the literature.",
"title_normalized": "braf mutation in interdigitating dendritic cell sarcoma a case report and review of the literature"
} | [
{
"companynumb": "IT-ROCHE-1760141",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VEMURAFENIB"
},
"drugadditional": null,
"dru... |
{
"abstract": "BACKGROUND\nAspergillosis in patients with impaired immunity usually presents with invasive pulmonary infection and dissemination to a variety of organs via hematogenous spread. Aspergilloma in the retroperitoneal cavity is a rare disease with only a few cases reported in the literature. To the best of our knowledge, the present case of a retroperitoneal aspergilloma with no surgical history is only the second report in the literature.\n\n\nMETHODS\nA 65 year-old man, who had been receiving immunosuppressive treatment for rheumatoid arthritis with vasculitis for 9 years, was referred to the Urology Department with a retroperitoneal mass. This was confirmed by computed tomography performed during treatment for pulmonary aspergilloma. Because it was not possible to rule out malignant disease (e.g., liposarcoma), surgical exploration was performed. Pathological examination revealed aspergillus hyphae with fat necrosis, and retroperitoneal aspergilloma was diagnosed and appropriately treated. The tumor did not recur subsequently.\n\n\nCONCLUSIONS\nOur present case emphasizes that pharmacological treatments for aspergilloma in the retroperitoneal cavity have poor drug transitivity, so the relative effectiveness of pharmacological response is not useful for differentiating retroperitoneal aspergilloma from malignant disease.",
"affiliations": "Department of Urology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Urology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Pathology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Pathology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan.;Department of Urology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa, Japan. kohirai2002@yahoo.co.jp.",
"authors": "Shinoki|Risa|R|;Takeshima|Teppei|T|;Horie|Koichiro|K|;Matsui|Toshihiro|T|;Horita|Ayako|A|;Saito|Ikuo|I|;Hirai|Kotaro|K|http://orcid.org/0000-0002-4120-9340",
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"fulltext": "\n==== Front\nBMC UrolBMC UrolBMC Urology1471-2490BioMed Central London 38110.1186/s12894-018-0381-0Case ReportCase report: retroperitoneal aspergilloma in a patient with rheumatoid arthritis presenting as malignant tumor Shinoki Risa rbpwg562@gmail.com 1Takeshima Teppei teppeitalia@gmail.com 1Horie Koichiro horie@sagamihara-hosp.gr.jp 2Matsui Toshihiro matslci@tmd.ac.jp 2Horita Ayako a-horita@sagamihara-hosp.gr.jp 3Saito Ikuo i-saitou@sagamihara-hosp.gr.jp 3http://orcid.org/0000-0002-4120-9340Hirai Kotaro +81-45-851-2621kohirai2002@yahoo.co.jp 141 0000 0004 0642 7451grid.415689.7Department of Urology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa Japan 2 0000 0004 0642 7451grid.415689.7Department of Rheumatology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa Japan 3 0000 0004 0642 7451grid.415689.7Department of Pathology, National Hospital Organization Sagamihara National Hospital, Sagamihara, Kanagawa Japan 4 Department of Urology, National Hospital Organization Yokohama Medical Center, Yokohama, Kanagawa Japan 31 7 2018 31 7 2018 2018 18 673 3 2017 23 7 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\nAspergillosis in patients with impaired immunity usually presents with invasive pulmonary infection and dissemination to a variety of organs via hematogenous spread. Aspergilloma in the retroperitoneal cavity is a rare disease with only a few cases reported in the literature. To the best of our knowledge, the present case of a retroperitoneal aspergilloma with no surgical history is only the second report in the literature.\n\nCase presentation\nA 65 year-old man, who had been receiving immunosuppressive treatment for rheumatoid arthritis with vasculitis for 9 years, was referred to the Urology Department with a retroperitoneal mass. This was confirmed by computed tomography performed during treatment for pulmonary aspergilloma. Because it was not possible to rule out malignant disease (e.g., liposarcoma), surgical exploration was performed. Pathological examination revealed aspergillus hyphae with fat necrosis, and retroperitoneal aspergilloma was diagnosed and appropriately treated. The tumor did not recur subsequently.\n\nConclusion\nOur present case emphasizes that pharmacological treatments for aspergilloma in the retroperitoneal cavity have poor drug transitivity, so the relative effectiveness of pharmacological response is not useful for differentiating retroperitoneal aspergilloma from malignant disease.\n\nKeywords\nAspergillomaImmunocompromised hostRheumatoid arthritis with vasculitisRetroperitoneumSurgical resectionissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nAspergillosis, alongside candidiasis, is one of the most common deep-seated mycoses. The increased number of immunocompromised patient resulting from the use of immunosuppressive drugs for organ transplantation and other indications, as well as the effects of anticancer chemotherapy, has resulted in an increased incidence of opportunistic aspergillosis [1, 2]. Aspergillomas are most commonly found in the lungs, where Aspergillus colonizes a cyst or existing cavernous lesion and multiplies, forming a fungus ball. Long-term ingestion of antifungal agents is necessary to treat pulmonary aspergilloma and surgical resection may be indicated for isolated lesions when they are refractory to antifungal treatment.\n\nHere, we report a rare case of retroperitoneal aspergilloma successfully treated by surgical resection after pharmacological therapy.\n\nCase presentation\nA retroperitoneal mass on the left side was found in a 65-year-old-man who was then referred to the Urology Department. He had been receiving methylprednisolone and cyclosporine as treatment for rheumatoid arthritis with vasculitis in the Rheumatology Department of the same hospital. He complained of exertional dyspnea and was hospitalized on suspicion of atypical pneumonia. Blood tested positive for both β-D-glucan and aspergillus antigen. A diffuse nodular shadow across both lungs was seen on chest computed tomography (CT) and a diagnosis of pulmonary aspergilloma was made. Treatment with voriconazole (200 mg twice a daily) was initiated.\n\nOn subsequent CT 8 months thereafter, the nodular shadow in the lungs appeared smaller, but a mass in the left retroperitoneum was now seen. Consequently, he was referred to the Urology Department. His past medical history included rheumatoid arthritis with vasculitis, steroid-induced diabetes, hyperlipidemia, and compression fracture of the lumbar vertebrae. He had been receiving methylprednisolone and cyclosporine treatment for 8 years. In addition, he received bezafibrate and his diabetes was controlled with hypodermic insulin and oral sitagliptin. He had no notable family history. The patient’s physical findings were normal, except for chest and joint symptoms related to rheumatoid arthritis with vasculitis.\n\nBlood test results on admission were as follows: white blood cells, 11830/μL; C-reactive protein, 2.16 mg/dL; glucose, 250 mg/dL; total-cholesterol, 230 mg/dL; triglyceride, 642 mg/dL. There was no apparent liver or kidney dysfunction. The aspergillus antigen level was 0.7 (positive, > 0.5) and the β-D glucan level was 240 pg/ml (> 11.0). The frequent occurrence of a diffuse nodular shadow across both lungs on a simple CT image of the chest was noted. Thus, intravenous voriconazole was commenced. On subsequent CT 3 weeks later, a reduction in the pulmonary nodular shadow and improvement of the previous pneumonia was identified (Fig. 1). The voriconazole dose was altered for oral application (200 mg/day). He was then referred to the Urology Department once more because a 35-mm mass was found in the retroperitoneal cavity on CT (Fig. 2).Fig. 1 Hollow nodules seen on chest CT\n\nFig. 2 Abdominal CT image showing a 30 mm × 35 mm mass in the left retroperitoneal cavity\n\n\n\nThe tumor did not exhibit any internal contrast uptake and a film-like layer of contrast was seen around the border on abdominal contrast-enhanced CT. As a result, we believed that the tumor was not a renal angiomyolipoma; however, it was considered possible that it was a lipoma, liposarcoma, or teratoma. We recognized the mixed heterogeneous nature of the high-low signal on abdominal magnetic resonance imaging in both the T2 and T1-weighted images, with signal strength decreasing on the T1 fat suppression images. As liposarcoma could not be ruled out, a left retroperitoneal tumor resection was performed (Fig. 3).Fig. 3 MRI of the abdomen and pelvis: a axial T2. b Fat suppression axial T1 images. The mixed heterogeneous signal of the high-low signal in both the T2 and T1-weighted images, and signal strength, decreased with T1 fat suppression\n\n\n\nWe performed a lumbar incision under the left 12th rib with the patient in the jackknife posture during surgery. The mass did not adhere to the surrounding tissues, so there was a small amount of blood loss.\n\nHistological examination identified the contents of tumor as adipose tissue and necrotic debris that were encapsulated by fibrous connective tissue, with a large number of fungal hyphae in the tumor. A blood vessel cavity that passed through the necrotic tissue was identified as the origin (Fig. 4). Because the origin showed a Y-shaped divergence with the form of the constituent part, the histopathological diagnosis was aspergilloma. The postoperative course was uneventful and the patient was discharged 10 days after surgery. Thereafter, he continued antifungal therapy and no recurrence was seen on follow-up CT. In the tenth month after the operation, he developed pancytopenia, thought to be related to bone marrow suppression, with Cytomegalovirus infection. He suffered respiratory failure and succumbed.Fig. 4 Microscopic findings (hematoxylin and eosin stain). a Tumor identified as adipose tissue and necrotic debris encapsulated by fibrous connective tissue. b Large number of fungi in the mass\n\n\n\nDiscussion and conclusion\nAspergilloma is one of the clinical manifestations of aspergillosis, with pulmonary aspergilloma being the main presentation. In an aspergilloma, Aspergillus forms a ball of fungus in an existing lung cavity. Aspergilloma formation in an abdominal organ is rare. Several examples have been reported elsewhere, including the paranasal sinus and central nervous system, as well as formation of a fungus ball in the abdominal cavity after abdominal surgery. To the best of our knowledge, our case of an aspergilloma that formed in the retroperitoneal cavity in a patient with no surgical history is the second case globally [3–5]. Mycobacterial infectious disease often occurs in the abdominal cavity of immune-deficient patients, such as diabetics and long-term steroid users, both the case for the patient described here [5, 6]. Because pharmacological treatments for aspergilloma, such as micafungin or voriconazole, have poor drug transitivity in cavities, surgical resection is an option in cases refractory to antifungals. The failure of antifungal treatment could have been due to a difference of the blood concentration at each lesion.\n\nThe reason why aspergillus organisms located in the retroperitoneal space survive longer remains unclear. Aspergilloma mainly affects people with underlying cavitary lung diseases such as tuberculosis, sarcoidosis, bronchiectasis, cystic fibrosis and systemic immunodeficiency. The fungus colonizes a cavity and is able to grow free of interference because critical elements of the immune system as well as anti-fungal agents are unable to penetrate into the cavity. Following colonization, angioinvasion and dissemination could be occurring in immunocompromised patients. These considerations suggest the possibility of prior retroperitoneal infection such as with bacillus tuberculosis, which more commonly form abscesses in the retroperitoneal cavity.\n\nThe reason that aspergilloma mimicked liposarcoma may be that the tumor contained heterogeneous mixtures of adipose tissue and necrotic debris, appearing similar to some liposarcomas (e.g. myxoid liposarcoma).\n\nIn this case, even though the patient had already received voriconazole treatment previously which had reduced the pulmonary lesion, the retroperitoneal lesion appeared to be increasing in size. The disease course did not allow us to rule out a retroperitoneal malignant tumor for which the treatment of choice is surgical resection, as same as previous reports. This led to the appropriate treatment for this patient despite an erroneous indication. We have presented a very rare case of retroperitoneal aspergilloma, thought to be only the second in the literature. Thus, physicians should bear in mind the possibility of failure of anti-mycotic treatment when diagnosing such immuno-deficient patients, and should select appropriate treatment.\n\nAbbreviation\nCTComputed tomography\n\nAcknowledgements\nH. Goto gives insightful comments and suggestions about the rationale of aspergillus infection in the immune-compromized patient.\n\nAuthors’ contributions\nRS, KH participated in the case diagnosis and management, preparation of the case report and literature review, draft of the manuscript. TM, KH participated in the case management, preparation of the case details and review of the manuscript draft TT participated in the in case management, performed the surgery and review of the manuscript draft AH, IS participated in case diagnosis, review of the manuscript draft. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the family of this patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editorial team of this journal.\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. Ando T Moriya A Shibuya K Aspergillosis Nihon Rinsho 2008 12 2345 2349 \n2. Maesaki S. Aspergillosis. Med Mycol J. 2011; 10.3314/jjmm.52.97.\n3. Butros SR, Tierce ML 4th, Marks A, Rongkavilit C, Joshi A. Retroperitoneal aspergilloma. Pediatr Radiol. 2013:886–9. 10.1007/s00247-013-2629-x.\n4. Stevens DA Kan VL Judson MA Practice guidelines for diseases caused by Aspergillus. Infectious Diseases Society of America Clin Infect Dis 2000 30 696 709 10.1086/313756 10770732 \n5. Kobayashi E Iwamiya T Masaki H Postoperative abdominal aspergilloma mimicking cervical cancer recurrence and diagnostic imaging, including F-fluorodeoxyglucose positron emission tomography, with false-positive findings Obstet Gynaecol Res 2009 4 808 811 10.1111/j.1447-0756.2009.01019.x \n6. Nafady-Hego H Elgendy H Moghazy WE Pattern of bacterial and fungal infections in the first 3 months after pediatric living donor liver transplantation: an 11-year single-center experience Liver Transpl 2011 17 976 984 10.1002/lt.22278 21786404\n\n",
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"mesh_terms": "D000368:Aged; D001172:Arthritis, Rheumatoid; D001228:Aspergillosis; D001232:Aspergillus fumigatus; D003937:Diagnosis, Differential; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D009369:Neoplasms; D012187:Retroperitoneal Space; D014057:Tomography, X-Ray Computed",
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"title": "Case report: retroperitoneal aspergilloma in a patient with rheumatoid arthritis presenting as malignant tumor.",
"title_normalized": "case report retroperitoneal aspergilloma in a patient with rheumatoid arthritis presenting as malignant tumor"
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"abstract": "Sinonasal intestinal-type adenocarcinomas (SNS-ITAC) are very rare tumors that resemble colorectal cancer in many of their pathological and molecular characteristics. Indeed, in most published series, 10%-14% of SNS-ITAC harbor mutations in KRAS. There is no standard systemic treatment in recurrent or metastatic SNS-ITAC, and there is no evidence of the use of any targeted agent in this entity. We present the case of a recurrent nasoethmoidal ITAC informed as RAS and BRAF wild-type by standard real-time polymerase chain reaction methods and treated with first-line cetuximab and irinotecan without response. Circulating tumor cells coupled to highly sensitive DNA analyses unveiled a mutation in KRAS exon 2 codon 12. Subsequent studies in the primary tumor using BEAMing detected a mutation in the same codon, confirming the KRAS mutated status of the tumor, and possibly explaining the absence of treatment response. This case exemplifies how liquid biopsy can aid in the correct and real-time molecular characterization of tumors even in a rare nonmetastatic cancer of the head and neck. KEY POINTS: Sinonasal intestinal type adenocarcinomas (SNS-ITAC) are rare tumors that commonly develop after a prolonged exposure to organic dusts (wood, leather, etc.), and that resemble colorectal cancer in some of their morphological and molecular characteristics.KRAS mutations have been described in 10%-14% in most series. However, its predictive value for guiding treatment decisions with targeted therapies (i.e., anti-epidermal growth factor receptor [EGFR] therapy) has not been defined.The first case of an SNS-ITAC treated with anti-EGFR therapy (cetuximab) is reported. Analysis of DNA from circulating tumor cells (CTCs) unveiled a mutation in KRAS not detected by standard methods in the primary tumor. However, RAS analysis using BEAMing detected a mutation in the primary tumor in the same codon of KRAS originally detected in CTCs, altogether possibly explaining the lack of treatment response.Liquid biopsy may allow for an accurate molecular diagnosis in rare, organ-confined tumors where few therapeutic options exist. Highly sensitive molecular diagnostics may aid in better characterizing rare entities harboring potentially druggable targets.",
"affiliations": "Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain santicc81@gmail.com.;CTC Unit, Molecular Oncology Laboratory, Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico Universitario San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;Molecular Oncology Laboratory, Medical Oncology Department, Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;CTC Unit, Molecular Oncology Laboratory, Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico Universitario San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;Pathology Department, Hospital Clínico Universitario San Carlos, Madrid, Spain.;Molecular Oncology Laboratory, Medical Oncology Department, Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;Molecular Oncology Laboratory, Medical Oncology Department, Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;Radiology Department, Hospital Clínico Universitario San Carlos, Madrid, Spain.;Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.;Medical Oncology Department, Instituto de Investigación Sanitaria San Carlos (IdISSC), Hospital Clínico Universitario San Carlos, Centro de Investigación Biomédica en Red de Cancer (CIBERONC), Madrid, Spain.",
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"references": "26830399;26976150;15611505;29205085;24151533;28963820;22722830;26477319;25274616;24935016;16721785;16258065;23791006;26299074;25088940;25605843;25115304;11177030;29356178;23459231;22722843;24338245;22270724;26255226;22459936;22426079;26662311;23055340;27207888;25326804;18289366;28778958;27224655;19213595;12673679;24687833;18176354;21836482;10421261;25937522;28596308;28368441;19679400;16906516;21113138",
"title": "Nasoethmoidal Intestinal-Type Adenocarcinoma Treated with Cetuximab: Role of Liquid Biopsy and BEAMing in Predicting Response to Anti-Epidermal Growth Factor Receptor Therapy.",
"title_normalized": "nasoethmoidal intestinal type adenocarcinoma treated with cetuximab role of liquid biopsy and beaming in predicting response to anti epidermal growth factor receptor therapy"
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"abstract": "BACKGROUND\nThere is a limited evidence base for the treatment of cutaneous sarcoidosis.\n\n\nOBJECTIVE\nTo describe treatment modalities and responses in patients with predominantly cutaneous sarcoidosis, in addition to clinical characteristics and prevalence of systemic disease.\n\n\nMETHODS\nData were prospectively collected over a 6-year period. The Cutaneous Sarcoidosis Activity and Morphology Index was used to assess treatment effectiveness.\n\n\nRESULTS\nIn total, 47 patients with biopsy-confirmed cutaneous sarcoidosis were identified. Morphologically, the most common lesions were papules (49%) and plaques (42.6%). The most commonly affected sites were the head and neck (79%); 89.4% had systemic as well as cutaneous disease; 77% received systemic corticosteroid therapy, while 87% required further steroid-sparing treatment; 40% achieved clinical remission with hydroxychloroquine (HCQ) and 88% achieved clinical remission with methotrexate (MTX). OR of achieving remission on MTX compared with HCQ was 9.8 (95% CI 2.4-40.4, P = 0.001). MTX was superior to both azathioprine (AZA) (OR = 22; 95% CI 1.7-285.9; P = 0.02) and mycophenolate mofetil (MMF) (OR = 22; 95% CI 1.7-285.9; P = 0.02) in achieving remission.\n\n\nCONCLUSIONS\nHCQ is effective and well-tolerated. MTX was associated with significantly increased probability of achieving clinical remission compared with AZA and MMF.",
"affiliations": "Departments of, Dermatology, King's College Hospital, London, UK.;Rheumatology, King's College Hospital, London, UK.;Respiratory Medicine, King's College Hospital, London, UK.;Neurology, King's College Hospital, London, UK.;Ophthalmology, King's College Hospital, London, UK.;Respiratory Medicine, King's College Hospital, London, UK.;Cardiology, King's College Hospital, London, UK.;Cardiology, King's College Hospital, London, UK.;Departments of, Dermatology, King's College Hospital, London, UK.",
"authors": "Paolino|A|A|https://orcid.org/0000-0003-1894-8396;Galloway|J|J|;Birring|S|S|;Brex|P|P|;Larkin|G|G|;Patel|A|A|;Sado|D|D|;Murgatroyd|F|F|;Walsh|S|S|https://orcid.org/0000-0002-8279-0506",
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"title": "Clinical phenotypes and therapeutic responses in cutaneous-predominant sarcoidosis: 6-year experience in a tertiary referral service.",
"title_normalized": "clinical phenotypes and therapeutic responses in cutaneous predominant sarcoidosis 6 year experience in a tertiary referral service"
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"abstract": "Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.",
"affiliations": "Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA.;Paratek Pharmaceuticals, Inc., King of Prussia, Pennsylvania, USA ken.tanaka@paratekpharma.com.;Paratek Pharmaceuticals, Inc., King of Prussia, Pennsylvania, USA.",
"authors": "Kovacs|Steven J|SJ|;Ting|Lillian|L|;Praestgaard|Jens|J|;Sunkara|Gangadhar|G|;Sun|Haiying|H|;Stein|Daniel S|DS|;Tanaka|S Ken|SK|;Villano|Stephen|S|",
"chemical_list": "D013754:Tetracyclines; C000591640:omadacycline",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01650-20",
"fulltext": "\n==== Front\nAntimicrob Agents Chemother\nAntimicrob Agents Chemother\naac\naac\nAAC\nAntimicrobial Agents and Chemotherapy\n0066-4804 1098-6596 American Society for Microbiology 1752 N St., N.W., Washington, DC \n\n01650-20\n10.1128/AAC.01650-20\nPharmacology\nAn Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline\nPharmacokinetics of Omadacycline in Hepatic ImpairmentKovacs et al.Kovacs Steven J. a Ting Lillian a* Praestgaard Jens a Sunkara Gangadhar a Sun Haiying a Stein Daniel S. a* Tanaka S. Ken b Villano Stephen b a Novartis Institute for BioMedical Research, Novartis Pharmaceuticals, East Hanover, New Jersey, USA\nb Paratek Pharmaceuticals, Inc., King of Prussia, Pennsylvania, USA\nAddress correspondence to S. Ken Tanaka, ken.tanaka@paratekpharma.com.* Present address: Lillian Ting, Merck & Co., Inc., Kenilworth, New Jersey, USA; Daniel S. Stein, Insmed, Inc., Bridgewater, New Jersey, USA.\n\nCitation Kovacs SJ, Ting L, Praestgaard J, Sunkara G, Sun H, Stein DS, Tanaka SK, Villano S. 2020. An open-label study of the impact of hepatic impairment on the pharmacokinetics and safety of single oral and intravenous doses of omadacycline. Antimicrob Agents Chemother 64:e01650-20. https://doi.org/10.1128/AAC.01650-20.\n\n\n24 8 2020 \n20 10 2020 \n11 2020 \n20 10 2020 \n64 11 e01650-2029 7 2020 31 7 2020 Copyright © 2020 Kovacs et al.2020Kovacs et al.This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.Omadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment.\n\nABSTRACT\nOmadacycline is a once-daily oral or intravenous (i.v.) aminomethylcycline antibiotic approved in the United States for the treatment of community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults. Omadacycline pharmacokinetics were characterized in 18 patients with hepatic impairment and 12 matched healthy subjects. Patients with hepatic impairment received i.v. omadacycline at 100 mg (mild hepatic impairment) or 50 mg (moderate and severe hepatic impairment) and oral omadacycline at 300 mg (mild hepatic impairment) or 150 mg (moderate hepatic impairment); oral omadacycline was not evaluated in those with severe hepatic impairment. Safety monitoring included the collection of adverse events (AEs), performance of laboratory tests, determination of vital signs, and performance of electrocardiograms. Omadacycline exposures were similar in patients with hepatic impairment and healthy subjects following i.v. or oral administration, with the geometric mean ratios for the area under the concentration-time curve and the maximum drug concentration ranging from 0.79 to 1.42. Omadacycline was safe and well tolerated. Overall, 13/30 (43.3%) participants experienced an AE; those occurring in more than 1 participant included headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%), with no differences based on the degree of hepatic impairment or the route of administration. Asymptomatic increases in heart rate were observed; none was considered an AE. These findings suggest that no omadacycline dose adjustment is warranted in patients with hepatic impairment.\n\nKEYWORDS\naminomethylcyclineomadacyclinehepatic impairmentpharmacokineticsParatek Pharmaceuticals, Inc.Tanaka S. Ken Villano Stephen Novartis Pharmaceuticals Corporation (NPC)https://doi.org/10.13039/100008272Sun Haiying Praestgaard Jens Sunkara Gangadhar Kovacs Steven J. Ting Lillian Stein Daniel S. cover-dateNovember 2020\n==== Body\nINTRODUCTION\nContemporary antibiotics often require dose adjustment for patients with some degree of hepatic impairment in order to maintain exposure largely within the range expected for the same dose given to patients who do not have hepatic impairment. Tigecycline, a glycylcycline tetracycline derivative, requires a dosage reduction by 50% in patients with severe hepatic impairment (1). Intravenous (i.v.) lefamulin, a pleuromutilin, requires a dosage reduction in patients with severe hepatic impairment; oral lefamulin has not been studied and is not recommended for patients with moderate or severe hepatic impairment (2). Among other antibiotic classes, oritavancin (a lipoglycopeptide) has not been evaluated in those with severe impairment (3); linezolid (an oxazolidinone) may require dosage adjustment in those with severe impairment (4); and clarithromycin (a macrolide), tedizolid (an oxazolidinone), and delafloxacin (a fluoroquinolone) require no dosage adjustment in patients with hepatic impairment (5). For drugs with hepatic elimination, increased systemic exposure from reduced hepatic clearance may lead to safety risks; therefore, clinical investigation of the effect of various degrees of hepatic impairment on pharmacokinetics (PK) is required to determine the need for dose adjustment (6).\n\nOmadacycline is a once-daily oral or i.v. aminomethylcycline antibiotic that is approved in the United States for the treatment of adults with community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) (7). Omadacycline has activity against Gram-positive and Gram-negative aerobic bacteria, anaerobes, and atypical organisms (8, 9). In phase I studies of healthy adults, a 300-mg oral dose of omadacycline produced peak plasma concentrations exceeding 500 ng/ml and had an elimination half-life (t1/2) of approximately 17 h, thus supporting once-daily dosing (10). Oral bioavailability is 34.5% (10). Protein binding is approximately 21% in human serum (11). In phase III studies, omadacycline has shown efficacy as a once-daily oral and i.v. treatment for CABP and ABSSSI (12–14). Nonclinical data revealed that omadacycline is cleared hepatically (i.e., by biliary excretion) and renally (15). Clinical investigations indicate that no adjustment of the omadacycline dose is needed in patients with impaired renal function (16). The purpose of this study was to determine whether dose adjustment may be necessary for omadacycline in patients with hepatic impairment.\n\nRESULTS\nEighteen patients with mild (group 1), moderate (group 2), or severe (group 3) hepatic impairment and 12 healthy subjects were enrolled. Hepatic impairment was classified according to the Child-Turcotte-Pugh scoring method (17). Healthy subjects were matched to patients in either group 1 or group 2 (Table 1). All 30 participants were included in the safety analysis, and 29 (96.7%) completed the study; 1 patient in the mild impairment group discontinued due to an adverse event (AE) of rash after the i.v. dose in period 1 and did not receive the oral dose in period 2. Twenty-eight participants were included in the PK analysis set; 1 patient each in the mild and severe impairment groups was excluded because PK results were not reliable due to bioanalytical interference. A total of 23 participants received both the single i.v. dose and the single oral dose of omadacycline in the separate study periods, as planned. Per protocol, the 6 patients with severe hepatic impairment received a single i.v. dose of omadacycline only. At baseline, patients with hepatic impairment and healthy subjects were comparable for demographic characteristics (Table 2). All enrolled participants were white, the overall age (mean ± standard deviation) was 54.7 ± 5.4 years, and 26 (86.7%) participants were male.\n\nTABLE 1 Treatment groups and assigned omadacycline dosesd\n\nTreatment group\tPeriod 1, single i.v. dose (mg)\tPeriod 2, single oral dose (mg)\t\nGroup 1, mild hepatic impairment (CTP class Aa)\t100\t300\t\nGroup 2, moderate hepatic impairment (CTP class Bb)\t50\t150\t\nGroup 3, severe hepatic impairment (CTP class Cc)\t50\t\t\nGroup 4, healthy subject matched to group 1\t100\t300\t\nGroup 5, healthy subject matched to group 2\t50\t150\t\na Class A corresponds to a Child-Turcotte-Pugh score of 5 to 6.\n\nb Class B corresponds to a Child-Turcotte-Pugh score of 7 to 9.\n\nc Class C corresponds to a Child-Turcotte-Pugh score of 10 to 15.\n\nd Each group had six subjects. One subject in group 1 (Child-Turcotte-Pugh class A) discontinued due to an adverse event of a rash after the i.v. dose in period 1 and did not receive the oral dose in period 2. CTP, Child-Turcotte-Pugh; i.v., intravenous.\n\nTABLE 2 Baseline demographic characteristics\n\nCharacteristic\tValue for the following subjects:\t\nHepatic impairment\tHealthy (n = 12)\t\nMild (n = 6)\tModerate (n = 6)\tSevere (n = 6)\t\nAge (yr)\t\t\t\t\t\n Mean ± SD\t54.0 ± 5.3\t57.0 ± 6.2\t56.2 ± 3.7\t53.1 ± 5.8\t\n Range\t47–60\t47–64\t51–62\t46–64\t\nNo. (%) of male subjects\t5 (83.3)\t6 (100)\t4 (66.7)\t11 (91.7)\t\nHt (cm)\t\t\t\t\t\n Mean ± SD\t171.3 ± 3.8\t174.7 ± 7.8\t169.8 ± 11.1\t174.0 ± 5.7\t\n Range\t165–175\t166–188\t152–182\t166–184\t\nWt (kg)\t\t\t\t\t\n Mean ± SD\t81.7 ± 13.9\t80.6 ± 7.6\t82.6 ± 21.6\t80.5 ± 9.8\t\n Range\t63–102\t71–93\t63–118\t64–94\t\nBMIa\n (kg/m2)\t\t\t\t\t\n Mean ± SD\t27.9 ± 4.8\t26.4 ± 1.2\t28.4 ± 5.6\t26.6 ± 2.9\t\n Range\t20.6–35.1\t24.5–27.7\t22.7–35.6\t23.0–32.5\t\nNo. (%) of subjects of the following race/ethnicity\t\t\t\t\t\n Hispanic/Latino\t2 (33.3)\t4 (66.7)\t3 (50.0)\t7 (58.3)\t\n White\t6 (100)\t6 (100)\t6 (100)\t12 (100)\t\na BMI, body mass index.\n\nPharmacokinetics.\nA comparison of plasma PK parameters for each group showed the expected dose-related differences in exposure for both the i.v. and oral routes of administration (Table 3). Generally, intersubject variability in exposure was higher following oral dosing than following the i.v. infusion. The median time to reach the peak concentration following drug administration (Tmax) ranged from 0.25 to 0.5 h with i.v. doses and from 1.5 to 2.0 h with oral doses. Similar clearance was observed across the groups: the mean total body clearance following i.v. administration (CL) ranged from 9.1 to 14.2 liters/h, and the mean apparent total body clearance following oral administration (CL/F) ranged from 48.4 to 72.1 liters/h. The terminal elimination half-life (t1/2) was relatively consistent and ranged from 8 to 16 h across the groups, with no apparent trend relative to the degree of hepatic impairment.\n\nTABLE 3 Plasma pharmacokinetic parameters for omadacycline by treatment groupa\n\nParameter\tValue (no. of subjects) for:\t\nPatients with hepatic impairment\tHealthy matched controls\t\nMild (group 1)\tModerate (group 2)\tSevere (group 3), 50 mg i.v.\tMatched to mild (group 4)\tMatched to moderate (group 5)\t\n100 mg i.v.\t300 mg oral\t50 mg i.v.\t150 mg oral\t100 mg i.v.\t300 mg oral\t50 mg i.v.\t150 mg oral\t\nAUClast (ng · h/ml)\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\nAUCinf (ng · h/ml)\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\nCmax (ng/ml)\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\nTmax (h)b\n\t9,734–1,943 (5)\t5,839–2,765 (4)\t3,542–397 (6)\t3,213–828 (6)\t4,484–531 (5)\t10,851–2,595 (6)\t6,533–1,665 (6)\t4,199–721 (6)\t3,162–1,033 (6)\t\nt1/2 (h)\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\nCL or CL/F (liters/h)c\n\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\nVz or Vz/F (liters)c\n\t9,734 ± 1,943 (5)\t5,839 ± 2,765 (4)\t3,542 ± 397 (6)\t3,213 ± 828 (6)\t4,484 ± 531 (5)\t10,851 ± 2,595 (6)\t6,533 ± 1,665 (6)\t4,199 ± 721 (6)\t3,162 ± 1,033 (6)\t\na Data are for 28 subjects. Values are the mean ± standard deviation unless otherwise stated. AUCinf, area under the concentration-time curve from time zero to infinity; AUClast, area under the concentration-time curve from time zero to the last quantifiable concentration point; CL, mean total body clearance following intravenous administration; CL/F, apparent total body clearance following oral administration; Cmax, maximum drug concentration; i.v., intravenous; t1/2, terminal elimination half-life; Tmax, time to reach peak concentration following drug administration; Vz, apparent volume of distribution (beta method) following i.v. administration; Vz/F, apparent volume of distribution (beta method) following oral administration.\n\nb Tmax is reported as the median (range).\n\nc CL and Vz for i.v. infusion; CL/F and Vz/F for oral administration.\n\nOverall, the geometric mean ratios for the comparison of patients with hepatic impairment to the matched healthy control subjects showed that omadacycline exposure was similar regardless of the severity of hepatic impairment (Table 4). Following single oral and i.v. doses of omadacycline, the area under the concentration-time curve (AUC) from time zero to infinity (AUCinf), the area under the concentration-time curve from time zero to the last quantifiable concentration point (AUClast), and the maximum drug concentration (Cmax) in patients with hepatic impairment were comparable to those in healthy subjects (Table 4). While a somewhat higher Cmax was observed following i.v. dosing of 100 mg in patients with mild hepatic impairment than in the matched controls, this trend was not observed in patients with moderate or severe hepatic impairment.\n\nTABLE 4 Geometric mean ratio for primary pharmacokinetic parameters after i.v. or oral omadacycline in patients with hepatic impairment versus healthy subjectsd\n\nParameter\tGeometric mean ratio (90% confidence interval) for:\t\nGroup 1 (mild hepatic impairment)a\n\tGroup 2 (moderate hepatic impairment)b\n\tGroup 3 (severe hepatic impairment)c\t\n100 mg i.v.\t300 mg oral\t50 mg i.v.\t150 mg oral\t50 mg i.v.\t\nAUClast (ng · h/ml)\t0.90 (0.73, 1.11)\t0.79 (0.50, 1.24)\t0.85 (0.75, 0.97)\t1.02 (0.75, 1.40)\t1.08 (0.91, 1.27)\t\nAUCinf (ng · h/ml)\t0.86 (0.69, 1.07)\t0.79 (0.50, 1.24)\t0.88 (0.78, 0.99)\t1.02 (0.75, 1.40)\t1.08 (0.91, 1.27)\t\nCmax (ng/ml)\t1.42 (1.10, 1.84)\t0.96 (0.64, 1.42)\t1.02 (0.84, 1.25)\t1.24 (0.94, 1.65)\t1.08 (0.89, 1.31)\t\na Group 1, mild hepatic impairment versus matched healthy subjects.\n\nb Group 2, moderate hepatic impairment versus matched healthy subjects.\n\nc Group 3, severe hepatic impairment versus healthy subjects matched to group 2 receiving omadacycline at 50 mg i.v.\n\nd AUCinf, area under the concentration-time curve from time zero to infinity; AUClast, area under the concentration-time curve from time zero to the last quantifiable concentration point; Cmax, maximum drug concentration in plasma; i.v., intravenous.\n\nThe mean plasma concentration-time profiles for i.v. omadacycline at 50 and 100 mg and oral omadacycline at 150 and 300 mg were comparable for patients with mild, moderate, or severe hepatic impairment and the matched healthy subjects (Fig. 1). The dose-normalized AUClast and Cmax following i.v. omadacycline demonstrated no relationship (the R2 correlation values for regression analysis were approximately 0) between exposure to omadacycline and the severity of hepatic impairment (Fig. 2).\n\nFIG 1 Plasma concentration-time profiles for omadacycline following i.v. (A and B) and oral (C and D) administration in patients with hepatic impairment versus healthy subjects. Data are shown as the mean ± standard deviation. IV, intravenous.\n\nFIG 2 Dose-normalized AUClast (A) and Cmax (B) versus Child-Turcotte-Pugh score following an intravenous infusion of omadacycline (healthy subjects were assigned a score of 0). AUClast, area under the concentration-time curve from time zero to the last quantifiable concentration point; Cmax, maximum drug concentration.\n\nSafety/tolerability.\nOverall, 13 (43.3%) participants experienced at least 1 AE. AE rates were similar between patients with hepatic impairment and healthy subjects. The most commonly reported AEs were headache (13.3%), nausea (6.7%), infusion-site pain (6.7%), contusion (6.7%), and dizziness (6.7%). All other AEs were reported in only 1 participant. One patient, a 47-year-old male with moderate hepatic impairment, experienced serious AEs of alcohol intoxication with angina pectoris, hypocalcemia, hypotension, and rhabdomyolysis; these occurred 8 days after receiving oral omadacycline at 150 mg. He had previously received i.v. omadacycline at 50 mg, which he tolerated well. This patient had a history of alcoholic cirrhosis, hepatitis C, hypertension, and diabetes mellitus, among other conditions. The events resolved after supportive care in the hospital; none of these events was considered related to omadacycline. One patient with mild hepatic impairment discontinued the study due to a mild facial rash, which occurred several hours after receiving i.v. omadacycline at 100 mg. This event was considered related to omadacycline; the rash was treated with diphenhydramine and resolved after approximately 4 days. Other than the laboratory findings in the patient with the serious AEs described above, there were no clinically relevant changes in serum chemistry, hematology, or physical examination findings during the study.\n\nParticipants in all treatment groups experienced a mean maximum increase in heart rate (from predose to any postdose measurement) that ranged from 3 to 19 beats per minute. Mean maximum increases in systolic and diastolic blood pressure ranged from 8 to 13 mm Hg and 3 to 10 mm Hg, respectively. Increases in heart rate and blood pressure were transient; they typically occurred within 6 to 12 h after dosing, returned to normal levels by 24 h after the dose, and were not reported as AEs. Electrocardiogram (ECG) data reflected the heart rate changes but showed no other notable findings. There were no apparent differences in these effects between the patients with hepatic impairment and the healthy subjects; heart rate changes tended to occur earlier following i.v. administration than following oral administration.\n\nDISCUSSION\nOmadacycline is incompletely absorbed from the gastrointestinal tract, resulting in an oral bioavailability of about 35%. Systemically available omadacycline undergoes negligible biotransformation and is eliminated largely unchanged in feces and urine (15). Following oral administration, excretion of unabsorbed drug in feces is the predominant route of elimination of omadacycline, with approximately 14% of the total dose and 40% of the absorbed dose being excreted in urine (15, 16). The results of this study suggest that hepatic impairment does not have a clinically relevant impact on the PK of omadacycline following oral or i.v. administration. The dose-normalized AUC and Cmax across all study groups after i.v. administration showed no association between exposure to omadacycline and the Child-Turcotte-Pugh score. Different degrees of hepatic impairment had no clinically relevant effect on the systemic clearance of i.v. omadacycline.\n\nAlthough it was unexpected that hepatic impairment had only a small effect on the clearance of omadacycline, such an effect is not unprecedented. For example, in an open-label, parallel-group, PK study, the metabolism of oseltamivir was not compromised in subjects with moderate hepatic impairment (18). In addition, in 2 open-label, single-dose studies investigating the effect of hepatic or renal impairment on the PK of aripiprazole, no meaningful differences in aripiprazole PK were found between groups of subjects with normal hepatic or renal function and those with hepatic or renal impairment (19). We can only speculate as to why the PK of omadacycline were not substantially affected in hepatically impaired subjects across the Child-Turcotte-Pugh score classes. It is possible that a lower hepatic clearance of omadacycline in these subjects was compensated for by an increase in renal clearance. However, urine samples were not taken in the study to determine renal clearance. Another possible explanation is that the levels of hepatic impairment in these individuals did not affect the biliary transport functions to such an extent to affect the overall clearance of omadacycline. At this time, it is not known how omadacycline is taken up by hepatocytes or secreted across the biliary canalicular membranes. Omadacycline has been shown in vitro not to be a substrate of several known biliary and renal transporters, such as OATP1B1, OATP1B3, MRP2, and BCRP (20).\n\nSingle doses of omadacycline were safe and well tolerated, with no apparent differences between healthy subjects and patients with hepatic impairment, although the sample sizes were small. The only AE that occurred in more than 2 study participants was headache (which occurred in 4 participants [13%]). Modest, asymptomatic increases in heart rate were observed for several hours after dose administration, but no increase was considered to be an AE or associated with ECG abnormalities. Asymptomatic increases in heart rate have also been observed in other phase I clinical studies of omadacycline (10, 21), which is thought to be due to a vagolytic effect (omadacycline does not bind to adrenergic receptors and has no direct effect on the sinoatrial node) (21). To date, this finding has not been associated with cardiac arrhythmia or other clinically significant cardiovascular toxicity in clinical studies (21).\n\nA possible limitation of this study is that oral omadacycline was not administered to patients with severe hepatic impairment. If a drug is to be administered by more than 1 route, only the route that provides the most information about the impact of hepatic impairment on the drug’s elimination needs to be studied (6). Omadacycline is neither extensively metabolized nor protein bound, and the results of this study revealed no relevant impact of any degree of hepatic impairment on omadacycline elimination following i.v. administration. The results of this study, however, cannot address the potential impact, if any, of severe hepatic impairment on absorption following oral administration because it was not specifically investigated.\n\nOlder antibiotics in the tetracycline class (e.g., tetracycline, oxytetracycline, minocycline, and doxycycline) have generally not been studied or specifically labeled for use in patients with hepatic impairment (22–24). Data on the PK of tigecycline in patients with hepatic impairment are available (1). No clinically relevant difference in PK was observed between healthy subjects and patients with mild hepatic impairment, but the total exposure AUC increased by 50% and 105% in those with moderate and severe hepatic impairment, respectively, necessitating a recommendation for a tigecycline dose reduction in those with severe impairment (1).\n\nWith respect to nontetracycline antibiotics, reduced doses of i.v. lefamulin (a pleuromutilin antibacterial) are required in patients with severe hepatic impairment (2). Lefamulin tablets have not been studied in patients with moderate or severe hepatic impairment and are not recommended (2). The antimycobacterial agent rifampicin is contraindicated in patients with hepatic dysfunction (25).\n\nThe potential for hepatotoxicity is well documented with some antibiotics, including tetracyclines, clavulanic acid, macrolides, sulfonamides, and linezolid; however, hepatotoxicity is rare for most other classes of antibiotics (26). The risk for hepatotoxicity is an additional consideration that can be independent from dose selection to achieve similar systemic exposures. An integrated analysis of safety for 3 phase III clinical trials of omadacycline showed that the rate of occurrence of treatment-associated liver-related AEs (5.4%) was comparable to that seen with linezolid (4.9%) and moxifloxacin (7.2%) (27). Moreover, the observed changes from baseline for the transaminases associated with exposure to omadacycline were not considered clinically significant. The absence of a signal for possibly different safety across the different hepatic impairment classes in this small study is consistent with the findings of the integrated safety analyses and the prior clinical experience with omadacycline. The results of this study suggest that systemic omadacycline exposures following i.v. administration of 100 mg or oral administration of 300 mg—the bioequivalent therapeutic doses for treatment of CABP and ABSSSI—can be expected to be similar in those with and those without liver disease.\n\nThe availability of once-daily oral and i.v. dosing and the lack of a need for dosage adjustment with omadacycline in populations with liver disease offer simplicity and possible advantages for its use in the treatment of common bacterial infectious diseases.\n\nMATERIALS AND METHODS\nThe study was conducted at 2 centers in the United States (the Orlando Clinical Research Center and the University of Miami) according to the ethical principles of the Declaration of Helsinki and good clinical practice. The study protocol, consent form, and all amendments were reviewed and approved by an independent ethics committee or institutional review board for each center (Independent Investigational Review Board, Inc., and the University of Miami Human Subjects Research Office). Written informed consent was obtained from each study participant prior to enrollment.\n\nStudy design.\nThis was an open-label, fixed-sequence study in adult patients with hepatic impairment and healthy adult subjects. The degree of hepatic impairment was classified according to the Child-Turcotte-Pugh scoring method (17). Two separate groups of healthy subjects were matched to patients with mild or moderate hepatic impairment by age (±10 years), sex, weight (±10 kg), and smoking status (Table 1).\n\nThe study consisted of a screening period that did not exceed 28 days, a baseline period, and 2 treatment periods. During period 1, patients with mild hepatic impairment (group 1) received a single i.v. dose of omadacycline at 100 mg, and those with moderate and severe hepatic impairment (groups 2 and 3) received a single i.v. dose of omadacycline at 50 mg; omadacycline was administered as a 30-min i.v. infusion. A washout period of at least 7 days separated periods 1 and 2. During period 2, groups 1 and 2 received a single oral dose of omadacycline at 300 mg or 150 mg, respectively; they were required to fast for 10 h before and 4 h after the dose. In both periods, healthy subjects matched to groups 1 and 2 received the same doses as the subjects in their respective hepatic impairment groups (Table 1). An end-of-study evaluation was performed approximately 1 week after dosing in period 2. Lower doses of omadacycline were administered to patients in groups 2 and 3 as a precaution, given that the biliary excretion of unchanged drug is the major component of elimination and that the clearance of tigecycline (a compound that is also derived from tetracyclines) is reduced and requires a dose reduction in patients with severe hepatic impairment (1).\n\nSubject selection.\nHealthy control subjects were eligible if they were aged 18 to 70 years, weighed at least 50 kg (body mass index, 18 to 36 kg/m2), had normal vital signs with no orthostatic changes, and were in good health generally. Patients with hepatic impairment had to meet the same criteria for age, weight, and vital signs; they also had to have a Child-Turcotte-Pugh score of at least 5 and to have been in a stable condition for at least 3 months prior to enrollment. In all groups, the following exclusion criteria were applied: tobacco use (>10 cigarettes per day), recent blood donation or a hemoglobin concentration of <10 g/dl, a history of hypersensitivity to omadacycline or similar drugs (tetracyclines), a history of malignancy, and a history of any medical condition that could interfere with the conduct of the study. Pregnant or lactating women were excluded, and women of childbearing potential had to use an acceptable form of contraception. Healthy control subjects were also excluded for the following reasons: clinically significant ECG abnormalities; a history or presence of impaired renal function; and the use of other prescription medications, herbal supplements, over-the-counter drugs, or investigational drugs. Patients with hepatic impairment were also excluded for a calculated creatinine clearance of <50 ml/min or the use of investigational drugs; these patients could receive their routine prescription or over-the-counter medications, but drugs such as antacids, calcium-containing supplements, sucralfate, lactulose, and binding resins could not be taken for at least 12 h before and after the administration of omadacycline.\n\nStudy assessments.\nPeripheral blood samples (4 ml each), obtained by direct venipuncture or an indwelling cannula inserted in a forearm vein, were collected prior to dose administration and at 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24, 48, 72, and 96 h after dose administration in tubes containing sodium heparin. The samples were centrifuged for 10 min within 30 min of collection. The resulting plasma was transferred to polypropylene screw-cap tubes and placed on dry ice. The tubes were kept frozen at −70°C or colder until analysis. The plasma concentrations of omadacycline were measured using a validated liquid chromatography-mass spectrometry/mass spectrometry assay having a lower limit of quantitation of approximately 20 ng/ml. Calibration standard responses were linear over the range of 20 to 2,000 ng/ml. In plasma, the interday assay accuracy, expressed as percent relative error for quality control (QC) concentrations (20, 60, 758, and 1,520 ng/ml), ranged from −5.3% to 2.0% bias in QC samples. Assay precision, expressed as the interday percent coefficients of variation of the mean estimated concentrations of the QC samples, ranged from 3.1% to 4.5%. The extraction efficiency ranged from 87.0% to 93.5% across the QC samples. The overall mean matrix effect at 60, 758, and 1,520 ng/ml was 1.8%.\n\nAt screening and baseline (the day prior to dosing), the study participants underwent a physical examination; determination of vital signs (temperature, blood pressure, and heart rate), height (at screening only), and body weight; a serum or urine pregnancy test; and tests for alcohol and drugs. Blood pressure and heart rate were measured at screening, baseline, and predose, as well as at multiple time points on the day of dosing and at the end-of-study visit. A urinalysis was performed at screening, as were hepatitis virus and HIV tests. A 12-lead ECG was obtained at screening and baseline; at 2, 12, and 24 h after dosing; and at the end-of-study visit. Serum chemistry and hematology testing were carried out at screening and baseline, at 24 and 48 h after dosing, and at the end-of-study visit. Safety assessments consisted of collecting all AEs and serious AEs, noting their severity and relationship to the study drug.\n\nPharmacokinetic analysis.\nThe plasma concentrations of omadacycline are reported in nanograms per milliliter. Except for the predose samples, concentrations below the limit of quantitation were excluded from the calculation of the PK parameters. Plasma concentration-time data were analyzed using standard noncompartmental methods incorporating SAS programs validated with WinNonlin software (Certara USA, Inc., Princeton, NJ). PK parameters included AUClast and AUCinf, each of which was calculated by the linear trapezoidal linear interpolation method; Cmax; CL; apparent total body clearance following oral administration (CL/F); apparent volume of distribution (beta method) following i.v. administration (Vz); apparent volume of distribution (beta method) following oral administration (Vz/F); Tmax; and t1/2, calculated from the PK program that included a minimum of 3 terminal time points.\n\nStatistical analysis.\nThe primary PK analysis variables were AUClast, AUCinf, and Cmax. Secondary variables were Tmax, CL or CL/F, Vz or Vz/F, and t1/2. The numerical Child-Turcotte-Pugh score (17) was used to correlate liver function with the dose-normalized PK exposure.\n\nAUC and Cmax were analyzed for patients with mild and moderate hepatic impairment and their matched healthy controls, with a fixed effect of hepatic function (mild impairment or normal) and a random effect for matching block or impaired subject/healthy subject pair. The 90% confidence intervals were calculated for the ratio of PK parameters for impaired versus healthy subjects. All analyses were done on the logarithmic scale and back-transformed for reporting. Analysis was performed separately for the i.v. and oral dose parameters. Dose-normalized AUC values after a single i.v. infusion were pooled across all study groups, and the relationship to the Child-Turcotte-Pugh score was investigated by exploratory regression. Various linear and polynomial regressions were explored to find a well-fitting statistical model for this relationship.\n\nData availability.\nParatek Pharmaceuticals, Inc., has a commitment to ensure that access to clinical trial data is available to regulators, researchers, and trial participants, when permitted, feasible, and appropriate. Requests for deidentified patient-level data may be submitted to medinfo@paratekpharma.com for review.\n\nACKNOWLEDGMENTS\nWe thank the investigators, study staff, and study participants at the Orlando Clinical Research Center and the University of Miami, FL. Editorial assistance and medical writing support in the preparation of the manuscript were provided by Richard S. Perry and Theresa Singleton, respectively, of Innovative Strategic Communications, LLC, Milford, PA.\n\nThis work was supported by the Novartis Institute for Biomedical Research, Novartis Pharmaceuticals, East Hanover, NJ, and Paratek Pharmaceuticals, Inc., King of Prussia, PA.\n\nS.J.K., L.T., J.P., G.S., H.S., and D.S.S. were employees of Novartis Pharmaceuticals at the time that this work was completed. S.K.T. was a consultant to and is currently an employee of Paratek Pharmaceuticals, Inc. S.V. is a consultant to Paratek Pharmaceuticals, Inc. L.T. is currently an employee of Merck & Co., Inc. D.S.S. is currently an employee of Insmed, Inc.\n\nS.J.K., S.K.T., and S.V.: conceptualization, methodology, investigation. L.T., J.P., G.S., H.S., and D.S.S.: conceptualization, investigation. All authors were involved in manuscript review and editing and approved the final version for submission.\n==== Refs\nREFERENCES\n1. Korth-Bradley JM , Baird-Bellaire SJ , Patat AA , Troy SM , Bohmer GM , Gleiter CH , Buecheler R , Morgan MY \n2011 \nPharmacokinetics and safety of a single intravenous dose of the antibiotic tigecycline in patients with cirrhosis\n. J Clin Pharmacol \n51 :93 –101\n. doi:10.1177/0091270010363477 .20308689 \n2. Nabriva Therapeutics, USA, Inc . 2019 \nXenleta (lefamulin injection and tablets) prescribing information\n. Revised August 2019 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2019/211672s000,211673s000lbl.pdf. Accessed 3 April 2020.\n3. Rubino CM , Bhavnani SM , Moeck G , Bellibas SE , Ambrose PG \n2015 \nPopulation pharmacokinetic analysis for a single 1,200-milligram dose of oritavancin using data from two pivotal phase 3 clinical trials\n. Antimicrob Agents Chemother \n59 :3365 –3372\n. doi:10.1128/AAC.00176-15 .25824211 \n4. MacGowan AP \n2003 \nPharmacokinetic and pharmacodynamic profile of linezolid in healthy volunteers and patients with Gram-positive infections\n. J Antimicrob Chemother \n51 (Suppl 2 ):ii17 –ii25\n. doi:10.1093/jac/dkg248 .12730139 \n5. Flanagan S , Minassian SL , Morris D , Ponnuraj R , Marbury TC , Alcorn HW , Fang E , Prokocimer P \n2014 \nPharmacokinetics of tedizolid in subjects with renal or hepatic impairment\n. Antimicrob Agents Chemother \n58 :6471 –6476\n. doi:10.1128/AAC.03431-14 .25136024 \n6. Food and Drug Administration . 2003 \nGuidance for industry: pharmacokinetics in patients with impaired liver function: study design, data analysis, and impact on dosing and labeling . Center for Biologics Evaluation and Research, Food and Drug Administration , Rockville, MD .\n7. Paratek Pharmaceuticals, Inc . 2019 \nNuzyra (omadacycline) prescribing information\n. Revised June 2019 \nhttps://www.nuzyra.com/nuzyra-pi.pdf. Accessed 13 January 2020.\n8. Draper MP , Weir S , Macone A , Donatelli J , Trieber CA , Tanaka SK , Levy SB \n2014 \nMechanism of action of the novel aminomethylcycline antibiotic omadacycline\n. Antimicrob Agents Chemother \n58 :1279 –1283\n. doi:10.1128/AAC.01066-13 .24041885 \n9. Macone AB , Caruso BK , Leahy RG , Donatelli J , Weir S , Draper MP , Tanaka SK , Levy SB \n2014 \nIn vitro and in vivo antibacterial activities of omadacycline, a novel aminomethylcycline\n. Antimicrob Agents Chemother \n58 :1127 –1135\n. doi:10.1128/AAC.01242-13 .24295985 \n10. Sun H , Ting L , Machineni S , Praestgaard J , Kuemmell A , Stein DS , Sunkara G , Kovacs SJ , Villano S , Tanaka SK \n2016 \nRandomized, open-label study of the pharmacokinetics and safety of oral and intravenous administration of omadacycline to healthy subjects\n. Antimicrob Agents Chemother \n60 :7431 –7435\n. doi:10.1128/AAC.01393-16 .27736760 \n11. Lin W , Flarakos J , Du Y , Hu W , He H , Mangold J , Tanaka SK , Villano S \n2017 \nPharmacokinetics, distribution, metabolism, and excretion of omadacycline following a single intravenous or oral dose of 14C-omadacycline in rats\n. Antimicrob Agents Chemother \n61 :e01784-16. doi:10.1128/AAC.01784-16 .27821446 \n12. O'Riordan W , Green S , Overcash JS , Puljiz I , Metallidis S , Gardovskis J , Garrity-Ryan L , Das AF , Tzanis E , Eckburg PB , Manley A , Villano SA , Steenbergen JN , Loh E \n2019 \nOmadacycline for acute bacterial skin and skin-structure infections\n. N Engl J Med \n380 :528 –538\n. doi:10.1056/NEJMoa1800170 .30726689 \n13. Stets R , Popescu M , Gonong JR , Mitha I , Nseir W , Madej A , Kirsch C , Das AF , Garrity-Ryan L , Steenbergen JN , Manley A , Eckburg PB , Tzanis E , McGovern PC , Loh E \n2019 \nOmadacycline for community-acquired bacterial pneumonia\n. N Engl J Med \n380 :517 –527\n. doi:10.1056/NEJMoa1800201 .30726692 \n14. O'Riordan W , Cardenas C , Shin E , Sirbu A , Garrity-Ryan L , Das AF , Eckburg PB , Manley A , Steenbergen JN , Tzanis E , McGovern PC , Loh E , OASIS-2 Investigators . 2019 \nOnce-daily oral omadacycline versus twice-daily oral linezolid for acute bacterial skin and skin structure infections (OASIS-2): a phase 3, double-blind, multicentre, randomised, controlled, non-inferiority trial\n. Lancet Infect Dis \n19 :1080 –1090\n. doi:10.1016/S1473-3099(19)30275-0 .31474458 \n15. Flarakos J , Du Y , Gu H , Wang L , Einolf HJ , Chun DY , Zhu B , Alexander N , Natrillo A , Hanna I , Ting L , Zhou W , Dole K , Sun H , Kovacs SJ , Stein DS , Tanaka SK , Villano S , Mangold JB \n2017 \nClinical disposition, metabolism and in vitro drug-drug interaction properties of omadacycline\n. Xenobiotica \n47 :682 –696\n. doi:10.1080/00498254.2016.1213465 .27499331 \n16. Berg J , Tzanis E , Garrity-Ryan L , Bai S , Chitra S , Manley A , Villano S \n2017 \nPharmacokinetics and safety of the aminomethylcycline antibiotic omadacycline in subjects with impaired renal function\n. Antimicrob Agents Chemother \n62 :e02057-17. doi:10.1128/AAC.02057-17 .\n17. Pugh RN , Murray-Lyon IM , Dawson JL , Pietroni MC , Williams R \n1973 \nTransection of the oesophagus for bleeding oesophageal varices\n. Br J Surg \n60 :646 –649\n. doi:10.1002/bjs.1800600817 .4541913 \n18. Snell P , Dave N , Wilson K , Rowell L , Weil A , Galitz L , Robson R \n2005 \nLack of effect of moderate hepatic impairment on the pharmacokinetics of oral oseltamivir and its metabolite oseltamivir carboxylate\n. Br J Clin Pharmacol \n59 :598 –601\n. doi:10.1111/j.1365-2125.2005.02340.x .15842560 \n19. Mallikaarjun S , Shoaf SE , Boulton DW , Bramer SL \n2008 \nEffects of hepatic or renal impairment on the pharmacokinetics of aripiprazole\n. Clin Pharmacokinet \n47 :533 –542\n. doi:10.2165/00003088-200847080-00003 .18611062 \n20. Rodvold KA , Pai MP \n2019 \nPharmacokinetics and pharmacodynamics of oral and intravenous omadacycline\n. Clin Infect Dis \n69 :S16 –S22\n. doi:10.1093/cid/ciz309 .31367744 \n21. Tanaka SK , Villano S \n2016 \nIn vitro and in vivo assessments of cardiovascular effects with omadacycline\n. Antimicrob Agents Chemother \n60 :5247 –5253\n. doi:10.1128/AAC.00320-16 .27324778 \n22. Warner Chilcott . 2008 \nDoryx (doxycycline delayed-release tablets) prescribing information\n. Revised June 2008 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2008/050795s005lbl.pdf. Accessed 14 February 2020.\n23. Medicis Pharmaceutical Corporation . 2019 \nSolodyn (minocycline extended release tablets) prescribing information\n. Revised March 2019 \nhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2011/050808s014lbl.pdf. Accessed 14 February 2020.\n24. Agwuh KN , MacGowan A \n2006 \nPharmacokinetics and pharmacodynamics of the tetracyclines including glycylcyclines\n. J Antimicrob Chemother \n58 :256 –265\n. doi:10.1093/jac/dkl224 .16816396 \n25. World Health Organization . 1991 \nWHO model prescribing information: drugs used in mycobacterial diseases\n. WHO , Geneva, Switzerland \nhttps://apps.who.int/iris/handle/10665/37585.\n26. Andrade RJ , Tulkens PM \n2011 \nHepatic safety of antibiotics used in primary care\n. J Antimicrob Chemother \n66 :1431 –1446\n. doi:10.1093/jac/dkr159 .21586591 \n27. Opal S , File TM , van der Poll T , Tzanis E , Chitra S , McGovern PC \n2019 \nAn integrated safety summary of omadacycline, a novel aminomethylcycline antibiotic\n. Clin Infect Dis \n69 :S40 –S47\n. doi:10.1093/cid/ciz398 .31367740\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0066-4804",
"issue": "64(11)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "aminomethylcycline; hepatic impairment; omadacycline; pharmacokinetics",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D061605:Administration, Intravenous; D000284:Administration, Oral; D000328:Adult; D019540:Area Under Curve; D017714:Community-Acquired Infections; D006801:Humans; D008107:Liver Diseases; D013754:Tetracyclines",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32839218",
"pubdate": "2020-10-20",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "24295985;27499331;27736760;31474458;25136024;16816396;24041885;4541913;18611062;21586591;25824211;29158281;27324778;31367744;30726689;31367740;27821446;30726692;12730139;15842560;20308689",
"title": "An Open-Label Study of the Impact of Hepatic Impairment on the Pharmacokinetics and Safety of Single Oral and Intravenous Doses of Omadacycline.",
"title_normalized": "an open label study of the impact of hepatic impairment on the pharmacokinetics and safety of single oral and intravenous doses of omadacycline"
} | [
{
"companynumb": "US-OTSUKA-2020_032584",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ARIPIPRAZOLE"
},
"drugadditional": "3",
... |
{
"abstract": "Rheumatoid vasculitis (RV) is one of the most serious extra-articular complications of rheumatoid arthritis (RA), generally treated with a high dose of immunosuppressive drugs. Recently, we encountered two cases of ulcerative vasculitis in methotrexate (MTX)-prescribed RA patients, which simulated RV; however, Epstein-Barr virus (EBV)-encoded RNA in situ hybridization on their skin biopsies revealed many EBV-positive lymphocytes (over 50 cells/high-power field) within the vessel walls and perivascular stroma, which led us to the diagnosis of EBV-related vasculitis instead of RV. Subsequently, both ulcers regressed after the discontinuation of MTX and no recurrence was noted during the follow-up period. To prevent unnecessary treatment, EBV-positive vasculitis should be added in the differential diagnosis of lymphocytic vasculitis observed in MTX-administered RA patients.",
"affiliations": "Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.;Department of Dermatology, Kyoto University Hospital, Kyoto, Japan.;Department of Rheumatology and Clinical Immunology, Kyoto University Hospital, Kyoto, Japan.;Department of Rheumatology and Clinical Immunology, Kyoto University Hospital, Kyoto, Japan.;Department of Rheumatology and Clinical Immunology, Kyoto University Hospital, Kyoto, Japan.;Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.;Department of Rheumatology and Clinical Immunology, Kyoto University Hospital, Kyoto, Japan.;Department of Dermatology, Kyoto University Hospital, Kyoto, Japan.;Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.",
"authors": "Fujimoto|Masakazu|M|;Kaku|Yo|Y|;Yamakawa|Noriyuki|N|;Kawabata|Daisuke|D|;Ohmura|Koichiro|K|;Koyanagi|Itsuko|I|;Mimori|Tsuneyo|T|;Kabashima|Kenji|K|;Haga|Hironori|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1111/cup.12690",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0303-6987",
"issue": "43(6)",
"journal": "Journal of cutaneous pathology",
"keywords": "Epstein-Barr virus (EBV); methotrexate (MTX); rheumatoid vasculitis; skin",
"medline_ta": "J Cutan Pathol",
"mesh_terms": null,
"nlm_unique_id": "0425124",
"other_id": null,
"pages": "520-525",
"pmc": null,
"pmid": "26955985",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Methotrexate-associated EBV-positive vasculitis in the skin: a report of two cases simulating rheumatoid vasculitis.",
"title_normalized": "methotrexate associated ebv positive vasculitis in the skin a report of two cases simulating rheumatoid vasculitis"
} | [
{
"companynumb": "JP-ACCORD-039049",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": null,
"dr... |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy, safety, and pharmacokinetics of infliximab (IFX) in Japanese patients with active ankylosing spondylitis (AS).\n\n\nMETHODS\nIn this multicenter open-label study, IFX was infused at 5 mg/kg to 33 Japanese patients with active AS using or intolerable to non-steroidal anti-inflammatory drugs (NSAIDs) at Weeks 0, 2, and 6, and then every six weeks for approximately three years (mean: 149.5 weeks).\n\n\nRESULTS\nAssessment in Ankylosing Spondylitis (ASAS) 20 response at Week 24 (primary endpoint) was 97.0% (32/33) and was thereafter maintained at approximately 90% over the three-year study period. Improvements in range of motion, physical function, inflammatory parameters, and quality of life (QOL) were all maintained throughout the three-year study period. A serum IFX level of ≥5 μg/mL was maintained with six-week infusion intervals, and only two patients (6.1%) developed antibodies to IFX. Specific adverse events in AS patients were not observed.\n\n\nCONCLUSIONS\nThese findings suggest that a 5 mg/kg administration of IFX at six-week intervals to Japanese patients with active AS is safe, effective and provides long-term therapeutic benefits.",
"affiliations": "a Division of Rheumatology, Department of Internal Medicine , Juntendo University Koshigaya Hospital , Koshigaya , Japan and.;b Sohyaku Innovative Research Division , Mitsubishi Tanabe Pharma Corporation , Tokyo , Japan.",
"authors": "Kobayashi|Shigeto|S|;Yoshinari|Toru|T|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": "10.1080/14397595.2016.1176635",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1439-7595",
"issue": "27(1)",
"journal": "Modern rheumatology",
"keywords": "Ankylosing spondylitis; Anti-TNFα monoclonal antibody; Clinical trial; Infliximab; Japan",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D018501:Antirheumatic Agents; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D000069285:Infliximab; D008137:Longitudinal Studies; D008297:Male; D011788:Quality of Life; D013167:Spondylitis, Ankylosing; D016896:Treatment Outcome",
"nlm_unique_id": "100959226",
"other_id": null,
"pages": "142-149",
"pmc": null,
"pmid": "27299733",
"pubdate": "2017-01",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "A multicenter, open-label, long-term study of three-year infliximab administration in Japanese patients with ankylosing spondylitis.",
"title_normalized": "a multicenter open label long term study of three year infliximab administration in japanese patients with ankylosing spondylitis"
} | [
{
"companynumb": "JP-JNJFOC-20170110773",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "We report a case of aortic dissection masquerading as acute ischemic stroke followed by intravenous thrombolysis. A 59-year-old man presented with dizziness. After examination, the patient had a seizure with bilateral Babinski signs. Soon after identifying multiple acute infarctions in both hemispheres on diffusion-weighted brain magnetic resonance (MR) imaging, tissue plasminogen activator (t-PA) was administered. Both common carotid arteries were invisible on MR angiography, and subsequent chest computed tomography revealed an aortic dissection. The emergency operation was delayed for 13 hours due to t-PA administration. The patient died of massive bleeding.",
"affiliations": "Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.;Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.;Department of Cardiology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.;Department of Thoracic Surgery, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.;Department of Thoracic Surgery, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.;Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine.",
"authors": "Choi|Nari|N|;Yoon|Jee-Eun|JE|;Park|Byoung-Won|BW|;Chang|Won-Ho|WH|;Kim|Hyun-Jo|HJ|;Lee|Kyung Bok|KB|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.5090/kjtcs.2016.49.5.392",
"fulltext": "\n==== Front\nKorean J Thorac Cardiovasc SurgKorean J Thorac Cardiovasc SurgThe Korean Journal of Thoracic and Cardiovascular Surgery2233-601X2093-6516The Korean Society for Thoracic and Cardiovascular Surgery 10.5090/kjtcs.2016.49.5.392kjtcv-49-392Case ReportDelayed Surgery for Aortic Dissection after Intravenous Thrombolysis in Acute Ischemic Stroke Choi Nari M.D.1Yoon Jee-Eun M.D.1Park Byoung-Won M.D.2Chang Won-Ho M.D.3Kim Hyun-Jo M.D.3Lee Kyung Bok M.D.11 Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine2 Department of Cardiology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine3 Department of Thoracic Surgery, Soonchunhyang University Hospital, Soonchunhyang University School of MedicineCorresponding author: Kyung Bok Lee, Department of Neurology, Soonchunhyang University Hospital, Soonchunhyang University School of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul 04401, Korea, (Tel) 82-2-709-9026 (Fax) 82-2-709-9226 (E-mail) kblee@schmc.ac.kr10 2016 05 10 2016 49 5 392 396 20 1 2016 26 4 2016 26 4 2016 Copyright © 2016 by The Korean Society for Thoracic and Cardiovascular Surgery. All rights Reserved.2016This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.We report a case of aortic dissection masquerading as acute ischemic stroke followed by intravenous thrombolysis. A 59-year-old man presented with dizziness. After examination, the patient had a seizure with bilateral Babinski signs. Soon after identifying multiple acute infarctions in both hemispheres on diffusion-weighted brain magnetic resonance (MR) imaging, tissue plasminogen activator (t-PA) was administered. Both common carotid arteries were invisible on MR angiography, and subsequent chest computed tomography revealed an aortic dissection. The emergency operation was delayed for 13 hours due to t-PA administration. The patient died of massive bleeding.\n\nAortic dissectionStrokeThrombolysis\n==== Body\nCase report\nA 59-year-old male patient visited emergency room of Soonchunhyang University Seoul Hospital for slight uneasiness in the chest and vertigo. He was fully conscious and no neurological findings were observed. The patient’s blood pressure was 77/66 mmHg, which was quite low; however, it recovered to 102/65 mmHg with a heart rate of 40 beats per minute with fluid therapy. Second-degree atrioventricular block was observed in the electrocardiogram. No abnormalities were observed in myocardial enzyme levels or in a standard blood examination. The department of emergency medicine collaborated with the department of cardiology to treat this patient. The patient was scheduled to be hospitalized in the cardiology ward for coronary angiography because Mobitz type II atrioventricular block and unstable angina were suspected.\n\nThe patient had a sudden convulsive seizure while waiting to be hospitalized. The seizure did not stop for more than 5 minutes, during which lorazepam was administered. The patient did not have a history of seizure, heavy drinking, or trauma. After the seizure, while in a semicoma, quadriplegia and the Babinski sign were observed. In order to determine whether the convulsive seizure was accompanied by an acute stroke, diffusion-weighted magnetic resonance imaging was performed. Multiple cerebral infarctions were found in both the frontal and temporal lobes (Fig. 1A, B). Tissue plasminogen activator (t-PA) was administered promptly (within 90 minutes after symptom occurrence), and magnetic resonance angiography (MRA) was conducted while intravenous thrombolysis was performed. Forty minutes after t-PA administration, the common carotid arteries on bilateral sides showed no contrast on the MRA (i.e., the arteries were invisible on the scan), and aortic dissection was suspected (Fig. 1C).\n\nStanford type A aortic dissection, which requires an immediate emergency operation, was observed on chest computed tomography (CT) (Fig. 2). However, the operation was postponed due to the high bleeding risk caused by the thrombolytic agent; the operation was finally conducted 13 hours later. The patient expired 4 hours after the termination of the operation due to excessive bleeding.\n\nDiscussion\nAortic dissection generally presents with sudden and severe pain. In the case where the aortic dissection invades the ascending aorta, mortality may be as high as 40%–50% if appropriate emergency medical treatment is not obtained promptly [1]. In an aortic dissection, various abnormal neurological findings can occur, and ischemic cerebral infarction is the most frequently observed such finding. However, 10%–55% of all aortic dissection cases are painless. When a patient seeks care for mental deterioration or language disturbance, the diagnosis of an aortic dissection can be quite difficult.\n\nThrombolysis, conducted to treat acute cerebral infarction, may sometimes be applied without understanding the secondary cause of cerebral infarction due to limited time. The effects of thrombolysis on aortic dissection patients have not been reported widely [2].\n\nCarotid or vertebral dissection is not an absolute contraindication for intravenous thrombolysis. Intracranial hemorrhage and recurrent infarction in patients with carotid dissection were found to occur approximately as frequently as in patients without carotid dissection [3]. The Safe Implementation of Thrombolysis in Stroke-Monitoring Study also reported that the occurrence of adverse effects was similar with or without intravenous thrombolysis in patients with cerebral infarction caused by carotid or vertebral dissection [4].\n\nMyocardial infarction in patients with an aortic dissection is a contraindication for intravenous thrombolysis. In previous studies, it was reported that thrombolysis could cause hemopericardium or cardiac tamponade by aortic rupture [5]. Thrombolysis could reduce the patient’s possibility of survival by leading to the postponement of an emergency operation to treat a Stanford Type A aortic dissection [4].\n\nAntiplatelet or anticoagulant agents, which have lower bleeding risks than t-PA, can have higher bleeding risks during aortic surgery. In the case of cardiac procedures such as coronary artery bypass grafting, the amount of bleeding and transfusion volume were higher in patients who continued antiplatelet medication than in those who had discontinued medication 7 days prior to the procedure [3]. The amount of bleeding during aortic surgery can be massive; usage of t-PA before surgery is likely to significantly increase hemorrhagic complications and mortality.\n\nHowever, few reports have been published concerning cerebral infarction caused by aortic dissection. Cases in which intravenous thrombolysis were conducted without knowing that aortic dissection was present in patients with acute cerebral infarction are summarized in Table 1. Although many patients exhibit a tendency for increased bleeding, no consensus exists regarding the optimal timing for major cardiac surgery after the administration of t-PA. T-PA was administrated to a total of 7 patients prior to diagnosis with an aortic dissection. Complete doses of t-PA were infused in 2 patients and administration ceased in 5 patients because they were diagnosed with an aortic dissection. Of the 2 patients who received full dosages of t-PA, 1 of them underwent surgery within 3 days and recovered to independent ambulation (modified Rankin Score [mRS], 3 points). However, the other patient died without undergoing surgery. Among the 5 patients who received partial doses of t-PA, emergency operations were conducted for 3 patients, while 1 patient underwent surgery after 24 hours. The other patient did not undergo surgery due to the caregiver’s refusal. The 3 patients who underwent surgery had a mRS of 0, 3, and 4 points, respectively, and the patient who underwent surgery after 24 hours recovered to a nearly normal status. Therefore, unlike previous cases that had a relatively positive prognosis, this case represents the first case in which a patient expired after aortic surgery and t-PA administration. Since a total dose of 63 mg of t-PA was applied, the operation was delayed for 13 hours, and excessive hemorrhage following the operation was the cause of death. Despite the fact that the half-life of t-PA in blood is short, it is possible that a tendency for increased bleeding persists for an additional 1–2 days. In this case, however, the increased size of the hemopericardium and the enlarged extent of the cerebral infarction made an emergency operation inevitable. All doses of t-PA were administrated to this patient, and it is thought that the reduced time delay before the operation increased the patient’s bleeding risk. Henceforth, t-PA usage in patients with cerebral infarction accompanied with an aortic dissection will not be recommended in treatment guidelines.\n\nIn an aortic dissection, cerebral infarctions can be caused by mechanical occlusion of the common carotid artery and vertebral artery, or by relatively low cerebral perfusion. Approximately 1 out of 3 patients who have neurologic symptoms from an aortic dissection do not feel chest pain [6]. A cerebral infarction caused by an aortic dissection usually occurs in the right hemisphere through infiltration into the right common carotid artery; however, it can also occur in both sides (as in this case) [7]. In order to diagnose an aortic dissection without symptoms in patients with acute cerebral infarctions, the pulse difference between both radial arteries should be confirmed, physical examinations including heart murmur auscultation should be performed, and observations such as a ST segment increase in echocardiography and expanded mediastinum in simple chest radiography should be confirmed [8]. In cases of aortic dissection seen in practice, the pulse disappeared in only 15% of patients, a heart murmur was present in 31% of patients, and electrocardiography was normal in 31% of patients [1]. In addition, chest X-rays show ed a bnormal findings in 50% of patients [9]; thus, it is difficult to rely on simple examinations alone when diagnosing aortic dissection. Chest angiography using CT or magnetic resonance can acquire and confirm images around the aorta directly, and may be the only useful method for diagnosis if atypical symptoms are observed [10]. We initially performed transthoracic echocardiography on this patient with symptoms of dizziness in the emergency room, and we did not check the suprasternal view or carotid artery to rule out aortic dissection. We should have suspected aortic dissection during the first echocardiography.\n\nIn some cases, an intimal fragment is observed in the extracranial MRA in aortic dissection [10], and it is also possible that the bilateral sides of the common carotid artery are not seen simultaneously (as in this case). Findings such as these are rare in cardiac embolism or atherosclerosis. If there is a finding of occlusion of the common carotid artery along with multiple cerebral infarctions in both hemispheres, the physician must consider the possibility of aortic disease [7]. Additionally, the right side of the aorta tends to be more severely infiltrated. Aortic dissection should be suspected if a cerebral infarction is significantly more severe in the right hemisphere than in the left hemisphere.\n\nIt is difficult to diagnose an aortic dissection before the administration of t-PA if the patient exhibits neither typical chest pains nor abnormal findings in laboratory tests. No consensus exists regarding the optimal timing of major cardiac surgery after thrombolysis. We recommend that emergency operations should be postponed for at least 24 hours after t-PA administration. Cardiac diseases such as aortic dissection must be ruled out before emergency thrombolysis is performed to treat acute ischemic stroke.\n\nWe report a case in which we encountered difficulties during emergency surgery. Aortic dissection was diagnosed after intravenous thrombolysis in a patient who presented to the emergency room for convulsive seizure and multiple cerebral infarctions without typical severe chest pain.\n\nConflict of interest\n\nNo potential conflict of interest relevant to this article was reported.\n\nFig. 1 (A, B) Diffusion-weighted imaging revealed multiple acute infarctions in the bilateral frontal and temporal lobes, especially in the territory of the in whole territory of the right middle cerebral artery. (C) On magnetic resonance angiography, both common carotid arteries were invisible.\n\nFig. 2 A Stanford type A aortic dissection documented on (A) a coronal and (B) an axial chest computed tomography scan.\n\nTable 1 Summary of cases where intravenous thrombolysis without knowledge that an aortic dissection was present\n\nAge (yr)/sex\tInitial symptom\tNIHSS\tTissue plasminogen activator dose\tSurgery\tOutcome\tReference\t\n44/M\tLt. hemiparesis\t18\tLoading dose\tEmergency operation\tmRS 3\tChua et al. [11] (2005)\t\n56/F\tLt. hemiparesis\t16\tLoading dose, 5 mg\tEmergency operation\tmRS 4\tUchino et al. [12] (2005)\t\n81/F\tLt. hemiparesis\t22\tTotal dose\tDelayed operation (3 days)\tmRS 3\tNoel [13] (2010)\t\n80/F\tDecreased level of consciousness\t16\t15 mg\tRefused\tDeath\tRodríguez-Luna et al. [14] (2011)\t\n54/M\tRight hemiparesis\t-\tTotal dose, 72 mg\t(−)a)\tDeathb)\tFessler and Alberts [15] (2000)\t\n69/F\tLost consciousness\t6\t60% of total dose\tEmergency operation\tNIHSS 0\tHong et al. [16] (2009)\t\n38/M\tLt. hemiparesis\t13\tLoading dose\tDelayed operation (24 hours)\tNear total recovery\tChinchure et al. [17] (2013)\t\nNIHSS, National Institute of Health Stroke Scale; M, male; Lt., left; mRS, modified Rankin Score; F, female.\n\na) The patient was a poor surgical candidate due to being in a comatose state.\n\nb) In accordance with the family’s wishes, the patient was extubated and died 6 days after admission.\n==== Refs\nReferences\n1 Hagan PG Nienaber CA Isselbacher EM The International Registry of Acute Aortic Dissection (IRAD): new insights into an old disease JAMA 2000 283 897 903 10.1001/jama.283.7.897 10685714 \n2 Grupper M Eran A Shifrin A Ischemic stroke, aortic dissection, and thrombolytic therapy: the importance of basic clinical skills J Gen Intern Med 2007 22 1370 2 10.1007/s11606-007-0269-2 17619933 \n3 Badreldin A Kroener A Kamiya H Lichtenberg A Hekmat K Effect of clopidogrel on perioperative blood loss and transfusion in coronary artery bypass graft surgery Interact Cardiovasc Thorac Surg 2010 10 48 52 10.1510/icvts.2009.211805 19850596 \n4 Tsivgoulis G Safouris A Alexandrov AV Safety of intravenous thrombolysis for acute ischemic stroke in specific conditions Expert Opin Drug Saf 2015 14 845 64 10.1517/14740338.2015.1032242 25845759 \n5 Marian AJ Harris SL Pickett JD Campbell E Fromm RE Inadvertent administration of rtPA to a patient with type 1 aortic dissection and subsequent cardiac tamponade Am J Emerg Med 1993 11 613 5 10.1016/0735-6757(93)90015-4 8240566 \n6 Gaul C Dietrich W Friedrich I Sirch J Erbguth FJ Neurological symptoms in type A aortic dissections Stroke 2007 38 292 7 10.1161/01.STR.0000254594.33408.b1 17194878 \n7 Gaul C Dietrich W Erbguth FJ Neurological symptoms in aortic dissection: a challenge for neurologists Cerebrovasc Dis 2008 26 1 8 10.1159/000135646 18511865 \n8 Hiratzka LF Bakris GL Beckman JA 2010 ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM Guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine J Am Coll Cardiol 2010 55 e27 e129 10.1016/j.jacc.2010.02.015 20359588 \n9 Khan IA Nair CK Clinical, diagnostic, and management perspectives of aortic dissection Chest 2002 122 311 28 10.1378/chest.122.1.311 12114376 \n10 Hyland MH Holloway RG Pearls & Oy-sters: a stroke of luck: detecting type A aortic dissection by MRA Neurology 2011 76 e31 3 10.1212/WNL.0b013e31820d6271 21339492 \n11 Chua CH Lien LM Lin CH Hung CR Emergency surgical intervention in a patient with delayed diagnosis of aortic dissection presenting with acute ischemic stroke and undergoing thrombolytic therapy J Thorac Cardiovasc Surg 2005 130 1222 4 10.1016/j.jtcvs.2005.06.023 16214555 \n12 Uchino K Estrera A Calleja S Alexandrov AV Garami Z Aortic dissection presenting as an acute ischemic stroke for thrombolysis J Neuroimaging 2005 15 281 3 10.1111/j.1552-6569.2005.tb00323.x 15951413 \n13 Noel M Short J Farooq MU Thrombolytic therapy in a patient with acute ischemic stroke caused by aortic dissection Clin Neurol Neurosurg 2010 112 695 6 10.1016/j.clineuro.2010.03.021 20427122 \n14 Rodríguez-Luna D Vilar RM Peinazo M del Villar A Claramonte B Vilar C Geffner D Intravenous thrombolysis in an elderly patient with acute ischemic stroke masking aortic dissection J Stroke Cerebrovasc Dis 2011 20 559 61 10.1016/j.jstrokecerebrovasdis.2010.02.023 20833084 \n15 Fessler AJ Alberts MJ Stroke treatment with tissue plasminogen activator in the setting of aortic dissection Neurology 2000 54 1010 10.1212/WNL.54.4.1010 10691010 \n16 Hong KS Park SY Whang SI Seo SY Lee DH Kim HJ Cho JY Cho YJ Jang WI Kim CY Intravenous recombinant tissue plasminogen activator thrombolysis in a patient with acute ischemic stroke secondary to aortic dissection J Clin Neurol 2009 5 49 52 10.3988/jcn.2009.5.1.49 19513335 \n17 Chinchure SD Goel G Gupta V Bansal AR Singh D Garg A Jha AN Aortic dissection presenting as acute stroke: Careful selection of patients for intravenous thrombolysis Neurol India 2013 61 76 7 10.4103/0028-3886.108017 23466846\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2233-601X",
"issue": "49(5)",
"journal": "The Korean journal of thoracic and cardiovascular surgery",
"keywords": "Aortic dissection; Stroke; Thrombolysis",
"medline_ta": "Korean J Thorac Cardiovasc Surg",
"mesh_terms": null,
"nlm_unique_id": "101563922",
"other_id": null,
"pages": "392-396",
"pmc": null,
"pmid": "27734002",
"pubdate": "2016-10",
"publication_types": "D002363:Case Reports",
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"title": "Delayed Surgery for Aortic Dissection after Intravenous Thrombolysis in Acute Ischemic Stroke.",
"title_normalized": "delayed surgery for aortic dissection after intravenous thrombolysis in acute ischemic stroke"
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"abstract": "We describe an unusual case of non-traumatic compartment syndrome in three compartments of the left lower limb in a 57-year-old male inpatient. He had recently been started on anticoagulation therapy for multiple pulmonary emboli and deep vein thrombosis of the left posterior tibial and peroneal veins. Three of the four osteofascial compartments had pressures above 70 mm Hg, hence four compartment fasciotomies were performed. Postoperatively, intravenous heparin therapy was started resulting in a significant blood loss, but he had no neurovascular deficit. At reoperation, for primary wound closure, his tissues looked healthy. Non-traumatic causes of acute compartment syndrome, including deep venous thrombosis and anticoagulation, are considered.",
"affiliations": "Department of General Surgery, North Bristol NHS Trust, Bristol, UK.",
"authors": "Newman|Peter Alexander|PA|;Deo|Sunny|S|",
"chemical_list": "D000925:Anticoagulants; D006493:Heparin",
"country": "England",
"delete": false,
"doi": null,
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"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000792:Angiography; D000925:Anticoagulants; D003161:Compartment Syndromes; D003937:Diagnosis, Differential; D005500:Follow-Up Studies; D006493:Heparin; D006801:Humans; D007275:Injections, Intravenous; D007866:Leg; D008297:Male; D008875:Middle Aged; D014057:Tomography, X-Ray Computed; D020246:Venous Thrombosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24443334",
"pubdate": "2014-01-17",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1011308;12639164;6830350;8436859;9768900;8070154;22674040;18794622;10229313;20663221;11370950;20103024;7358759;15446541;9253926;7989391;18993022;4350530;20859728;8672833;2105485;10645301;1493394;10755426;20670592;9875937;17582052;16503323;22132025;21410121;721868;1192678;8102413;7354364;2663286;19047984;15611553;7963391",
"title": "Non-traumatic compartment syndrome secondary to deep vein thrombosis and anticoagulation.",
"title_normalized": "non traumatic compartment syndrome secondary to deep vein thrombosis and anticoagulation"
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"companynumb": "GB-MYLANLABS-2014S1004956",
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"abstract": "OBJECTIVE\nTo report the first case and a new diagnostic sign of interface fluid collection following small incision lenticule extraction (SMILE).\n\n\nMETHODS\nCase report.\n\n\nRESULTS\nA 20-year-old man underwent SMILE for correction of compound myopic astigmatism. Postoperative follow-up examination included vision testing, slit-lamp examination, intraocular pressure measurement, corneal topography, and optical coherence tomography (OCT). The patient presented postoperatively with decreased vision in his right eye. Topography revealed an island of corneal steepening, the location of which kept shifting on successive visits. OCT revealed the presence of fluid pockets in the interface. The condition resolved with topical hypertonic saline and the uncorrected visual acuity recovered to 20/20. The intraocular pressure remained normal throughout.\n\n\nCONCLUSIONS\nThis is the first case report of interface fluid collection after SMILE. The report demonstrates shifting corneal \"ectasia\" (steepening) as a diagnostic sign of interface fluid collection. The authors recommend a new pathogenesis for this condition and suggest the use of topical hypertonic saline to treat this condition. [J Refract Surg. 2016;32(11):773-775.].",
"affiliations": null,
"authors": "Bansal|Aashish K|AK|;Murthy|Somasheila I|SI|;Maaz|Syed M|SM|;Sachdev|Mahipal S|MS|",
"chemical_list": "D009883:Ophthalmic Solutions; D012462:Saline Solution, Hypertonic",
"country": "United States",
"delete": false,
"doi": "10.3928/1081597X-20160721-02",
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"issue": "32(11)",
"journal": "Journal of refractive surgery (Thorofare, N.J. : 1995)",
"keywords": null,
"medline_ta": "J Refract Surg",
"mesh_terms": "D000287:Administration, Topical; D001251:Astigmatism; D003316:Corneal Diseases; D063171:Corneal Pachymetry; D003319:Corneal Stroma; D048988:Corneal Surgery, Laser; D019781:Corneal Topography; D004108:Dilatation, Pathologic; D045604:Extracellular Fluid; D006801:Humans; D057446:Hydrodynamics; D007429:Intraocular Pressure; D008297:Male; D009216:Myopia; D009883:Ophthalmic Solutions; D011183:Postoperative Complications; D012462:Saline Solution, Hypertonic; D041623:Tomography, Optical Coherence; D014792:Visual Acuity; D055815:Young Adult",
"nlm_unique_id": "9505927",
"other_id": null,
"pages": "773-775",
"pmc": null,
"pmid": "27824382",
"pubdate": "2016-11-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Shifting \"Ectasia\": Interface Fluid Collection After Small Incision Lenticule Extraction (SMILE).",
"title_normalized": "shifting ectasia interface fluid collection after small incision lenticule extraction smile"
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"abstract": "Case report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.",
"affiliations": "Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil.;Hospital Israelita Albert Einstein, São Paulo, SP, Brazil.",
"authors": "Giavina-Bianchi|Mara Huffenbaecher|MH|http://orcid.org/0000-0001-7059-4068;Giavina-Bianchi|Pedro|P|http://orcid.org/0000-0002-1034-7580;Rizzo|Luiz Vicente|LV|http://orcid.org/0000-0001-9949-9849",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C508598:IL4 protein, human; D007166:Immunosuppressive Agents; D018793:Interleukin-13; D015847:Interleukin-4; C582203:dupilumab",
"country": "Brazil",
"delete": false,
"doi": "10.31744/einstein_journal/2019RC4599",
"fulltext": "\n==== Front\nEinstein (Sao Paulo)Einstein (Sao Paulo)EINSEinstein1679-45082317-6385Instituto Israelita de Ensino e Pesquisa Albert Einstein 0050010.31744/einstein_journal/2019RC4599Case ReportDupilumab in the treatment of severe atopic dermatitis refractory to systemic immunosuppression: case report Dupilumabe no tratamento da dermatite atópica grave refratária à imunossupressão sistêmica: relato de caso http://orcid.org/0000-0001-7059-4068Giavina-Bianchi Mara Huffenbaecher \n1\nhttp://orcid.org/0000-0002-1034-7580Giavina-Bianchi Pedro \n1\nhttp://orcid.org/0000-0001-9949-9849Rizzo Luiz Vicente \n2\n\n1 Faculdade de Medicina, Universidade de São Paulo, São Paulo, SP, Brazil\n2 Hospital Israelita Albert Einstein, São Paulo, SP, BrazilCorresponding author: Mara Huffenbaecher Giavina-Bianchi, Avenida Brigadeiro Faria Lima, 2.894, conjunto 23 – Jardim Paulistano, Zip code: 01451-000 – São Paulo, SP, Brazil Phone: (5511) 3368-0857 E-mail: marahgbianchi@gmail.com28 6 2019 2019 17 4 eRC459916 7 2018 28 12 2018 This content is licensed under a Creative Commons Attribution 4.0 International License.ABSTRACT\nCase report of a patient with severe atopic dermatitis who showed a good response to dupilumab. She had already used two immunosuppressive agents, cyclosporine A and mycophenolate mofetil, for the treatment of atopic dermatitis with no proper control of the disease. She had also been taking all measures to control severe cases of the disease: bath and environmental controls, topical potent corticosteroids and emollients. She presented constant pruritus and skin lesions, frequent skin infections e poor quality of life. She also developed depression due to her disease. Recently, dupilumab, a new biological agent, was approved for the treatment of moderate/severe atopic dermatitis in many countries, including Brazil. Dupilumab is a monoclonal antibody with a common alpha chain of interleukin (IL) 4 and IL-13 receptors, two cytokines involved in the Th2 profile immune response that promote atopic inflammation. In a pioneer way in Brazil, the patient initiated the treatment with an attack dose of 600mg subcutaneous of dupilumab and 300mg subcutaneous every other week. Up to now, she has taken four applications, presenting a great improvement of the disease and her quality of life. There were no adverse effects, nor in the injection site nor of other kind. Patient and her family are very satisfied, and the medical team evaluates that the treatment is being well succeed. The case report described here subsidizes the use of dupilumab in the treatment of severe atopic dermatitis refractory to use of immunosuppressive agents.\n\nRESUMO\nRelatamos o caso de uma paciente com dermatite atópica grave, que mostrou boa resposta ao dupilumabe. Ela já tinha usado dois agentes imunossupressores, a ciclosporina A e o micofenolato de mofetila, para o tratamento da dermatite atópica, sem obter o controle adequado da doença. Ela também vinha fazendo uso de todas as medidas de controle para casos graves da doença: cuidados com o banho, controle ambiental, corticosteroides potentes tópicos e emolientes. Apresentava prurido e lesões cutâneas constantes, infeções de pele frequentes e qualidade de vida ruim. Passou a apresentar depressão devido à sua doença. Recentemente, o dupilumabe, um agente biológico novo, foi aprovado para o tratamento de dermatite atópica moderada a severa em muitos países, incluindo o Brasil. Dupilumabe é um anticorpo monoclonal cujo alvo é a cadeia alfa comum aos receptores da interleucina (IL) 4 e IL-13, duas citocinas envolvidas no perfil de resposta imune Th2, que promove inflamação atópica. De modo pioneiro no Brasil, a paciente iniciou o tratamento, com dose de ataque de 600mg por via subcutânea de dupilumabe e 300mg também por via subcutânea a cada 2 semanas. Até o momento deste relato, ela realizou quatro aplicações, apresentando grande melhora da doença e da qualidade de vida. Não houve efeitos adversos, nem no local da injeção e nem de outro tipo. A paciente e sua família estão muito satisfeitas, e os médicos que a tratam avaliam que a terapia está sendo bem-sucedida. Este relato de caso subsidia o uso de dupilumabe no tratamento da dermatite atópica grave refratária ao uso de imunossupressores.\n\nKeywords:\nDermatitis, atopic/drug therapyImmunosuppressive agents/therapeutic useSeverity of illness indexDescritores:\nDermatite atópica/tratamento farmacológicoImunossupressores/uso terapêuticoÍndice de gravidade de doença\n==== Body\nINTRODUCTION\nAtopic dermatitis (AD) is a chronic, relapsing, inflammatory skin disease, with intense pruritus and erythematous or vesicular maculopapular lesions, with scaling, accompanied by dry skin, crusts and/or lichenification. Superinfection by viruses or bacteria is a frequent finding. Its prevalence, which is approximately 15% in children and 5% in adults, is increasing.(\n\n1\n\n–\n\n3\n\n)\n\n\nDue to its chronic nature and frequent relapses, living with AD can be a burden, particularly for those requiring long-term, systemic treatment, since the drugs used can lead to serious toxicities. Pruritus and skin lesions can cause sleep disorders, anxiety, depression and low self-esteem, compromising the quality of life of patients and family.(\n\n4\n\n)\n\n\nAD pathogenesis includes changes in skin barrier function, in some cases associated with mutations in the filaggrin gene, increased colonization by Staphylococcus aureus, and exacerbated Th2 immune response, with sensitization to allergens, increased IgE levels, and blood eosinophilia. The most frequently used immunosuppressants for AD are cyclosporine, mycophenolate mofetil, azathioprine, and methotrexate.(\n\n5\n\n) New therapies based on AD pathogenesis have been developed, more effective and less detrimental, such as dupilumab, and will probably change the way we approach patients with moderate to severe AD.(\n\n5\n\n)\n\n\nCASE REPORT\nA female, 18-year-old, Caucasian patient, born and residing in São Paulo. The patient has AD since she was 2 years old, with aggravation for the past 4 years, on 250mg cyclosporine (150mg in the morning and 100mg in the afternoon: 3.2mg/kg/day), 5mg desloratadine (morning), and 25mg hydroxyzine (evening), moisturizing lotion twice-daily, and clobetasol propionate cream twice-daily. History of allergic rhinitis, hypothyroidism and metabolic syndrome, on levothyroxine sodium 50mg/day and metformin hydrochloride 500mg/day.\n\nThe patient referred previous hospitalization for infection secondary to the skin lesions in late 2015, and five other subsequent episodes, treated in the outpatient setting. In November 2017, she was started on agomelatine 25mg/day and buspirone 5mg/day, due to depression and insomnia.\n\nThe disease remained poorly controlled, and the patient had very poor quality of life. After being on cyclosporine for more than 2 years uninterruptedly, without achieving proper control of the disease, the patient was started on mycophenolate mofetil, 1g every 12 hours, in the end of 2017. Cyclosporine was gradually tapered, and eventually discontinued. After switching medications, there were some side effects such as 12kg weight loss over 2 months, menstrual changes and telogen effluvium, but the regimen was maintained. However, with no clinical improvement.\n\nThe skin exam showed extensive eczema affecting 90% of the skin tissue, along with very intense pruritus and dry skin, and a Score for Atopic Dermatitis (SCORAD) of 45. The SCORAD is a tool to assess the severity of AD using a signs and symptoms scale ranging from zero (no lesions and symptoms) to 103 (maximum score). Over 40, AD is considered severe.(\n\n6\n\n)\n\n\nAfter the dupilumab results were published and the monoclonal antibody was approved in different countries, including Brazil, it was indicated for this patient.(\n\n5\n\n) In March 2018, the patient received her first dose of 600mg dupilumab, subcutaneously. The loading dose was followed by 300mg every other week. Mycophenolate was discontinued one month after the biological agent was introduced. In the fifth dose, the patient was already showing considerable improvement. She is currently on 25mg hydroxyzine every evening. Desloratadine, the topical corticosteroid and the antidepressants have been discontinued. The skin exam showed major improvements, as well as dry skin and pruritus. The current SCORAD is 16. Figures 1A to 1C (pre-treatment) and 2A to 2C (after three applications) show the level of improvement achieved between the first and third doses.\n\nFigure 1 Atopic dermatitis lesions before dupilumab. (A) Lesions on the neck and upper torso, pre-treatment; (B) Lesions on upper limbs, pre-treatment; (C) Lesions on lower limbs, pre-treatment\nFigure 2 Atopic dermatitis lesions after dupilumab. (A) Lesions on the neck and upper torso after 3 applications; (B) Lesions on upper limbs after 3 applications; (C) Lesions on lower limbs after 3 applications\nDISCUSSION\nWe report the case of a patient with severe AD, poorly controlled, even with the most effective systemic therapies currently available in Brazil. The patient had used two systemic immunosuppressants, cyclosporine and mycophenolate mofetil, without achieving proper disease control. The patient had ongoing pruritus and skin lesions, in addition to greatly impaired quality of life, and depression.\n\nTraditionally, cyclosporine is the first choice of treatment, since it is approved in many countries and has rapid onset of action. It is a calcineurin inhibitor, which inhibits interleukin (IL) 2 and T-cell activation, reducing immunoreactivity.(\n\n7\n\n) The dose for adults is 3 to 5mg/kg/day, split in two (morning and evening). Mycophenolate mofetil is a prodrug of mycophenolic acid, derived from Penicillium echinulatum, and a metabolite that blocks T- and B-cell proliferation.(\n\n8\n\n) It is used for severe cases of AD in children or adults who do not respond to cyclosporine.(\n\n9\n\n) Its efficacy is comparable to that of cyclosporine and, despite its longer onset of action, results last longer. The dose ranges from 600 to 1.200mg/m2/day, or 40 to 50mg/kg/day in small children, 30 to 40mg/kg/day in adolescents, and 2g/day in adults.\n\nDupilumab is a fully humanized monoclonal antibody directly targeting the shared alpha chain of IL-4 and IL-13 receptors. These two cytokines are involved in Th2 immune response, inducing allergen sensitization, promoting atopic inflammation, and decreasing the skin barrier function and structure.(\n\n10\n\n) The antibody inhibits the action of these cytokines, and has been associated with gene expression changes in AD lesions, improving their molecular signature.(\n\n11\n\n) In a phase III clinical trial with 1,379 adult subjects with moderate to severe AD, poorly controlled with topical treatment, dupilumab was able to improve the signs and symptoms of the disease, including pruritus, anxiety, depression and quality of life. Skin infections were significantly less frequent in the treatment group versus placebo. The two regimens tested, 300mg subcutaneously every week or 300mg subcutaneously every other week for 16 weeks, were equally effective and safe. The most frequent side effects were injection site reactions and conjunctivitis.(\n\n12\n\n) It is considered a breakthrough therapy for moderate to severe AD in poorly controlled adults. There are new studies in progress in children.\n\nCONCLUSION\nWe report the first case in Brazil using dupilumab, a new class of drugs for controlling atopic dermatitis, in a patient with severe disease, poorly controlled by commonly used systemic therapies, who, to date, is evolving quite well, with no adverse effects. This case report supports the use of dupilumab in treating severe atopic dermatitis, refractory to the use of systemic immunosuppressants.\n==== Refs\nREFERENCES\n1 Kay J Gawkrodger DJ Mortimer MJ Jaron AG The prevalence of childhood atopic eczema in a general population J Am Acad Dermatol 1994 30 1 35 39 8277028 \n2 Silverberg JI Hanifin JM Adult eczema prevalence and associations with asthma and other health and demographic factors: a US population-based study J Allergy Clin Immunol 2013 132 5 1132 1138 24094544 \n3 Bieber T Atopic dermatitis N Engl J Med 2008 358 14 1483 1494 18385500 \n4 Wollenberg A Oranje A Deleuran M Simon D Szalai Z Kunz B Svensson A Barbarot S von Kobyletzki L Taieb A de Bruin-Weller M Werfel T Trzeciak M Vestergard C Ring J Darsow U European Task Force on Atopic Dermatitis/EADV Eczema Task Force. ETFAD/EADV Eczema task force 2015 position paper on diagnosis and treatment of atopic dermatitis in adult and paediatric patients J Eur Acad Dermatol Venereol 2016 30 5 729 747 27004560 \n5 Ring J Alomar A Bieber T Deleuran M Fink-Wagner A Gelmetti C Gieler U Lipozencic J Luger T Oranje AP Schäfer T Schwennesen T Seidenari S Simon D Ständer S Stingl G Szalai S Szepietowski JC Taïeb A Werfel T Wollenberg A Darsow U European Dermatology Forum; European Academy of Dermatology and Venereology; European Task Force on Atopic Dermatitis; European Federation of Allergy; European Society of Pediatric Dermatology; GlobalAllergy and Asthma European Network. Guidelines for treatment of atopic eczema (atopic dermatitis) Part II J Eur Acad Dermatol Venereol 2012 26 9 1176 1193 22813359 \n6 Megna M Napolitano M Patruno C Villani A Balato A Monfrecola G Systemic treatment of adult atopic dermatitis: a review Dermatol Ther (Heidelb) 2017 7 1 1 23 \n7 Sidbury R Davis DM Cohen DE Cordoro KM Berger TG Bergman JN Chamlin SL Cooper KD Feldman SR Hanifin JM Krol A Margolis DJ Paller AS Schwarzenberger K Silverman RA Simpson EL Tom WL Williams HC Elmets CA Block J Harrod CG Begolka WS Eichenfield LF AmericanAcademy of Dermatology. Guidelines of care for the management of atopic dermatitis: section 3. Management and treatment with phototherapy and systemic agents J Am Acad Dermatol 2014 71 2 327 349 24813298 \n8 Leung DY Boguniewicz M Howell MD Nomura I Hamid QA New insights into atopic dermatitis J Clin Invest 2004 113 5 651 657 14991059 \n9 Hamilton JD Suárez-Fariñas M Dhingra N Cardinale I Li X Kostic A Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis J Allergy Clin Immunol 2014 134 6 1293 1300 25482871 \n10 Simpson EL Akinlade B Ardeleanu M Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis N Engl J Med 2017 376 11 1090 1091 \n11 Hamilton JD Suárez-Fariñas M Dhingra N Cardinale I Li X Kostic A Dupilumab improves the molecular signature in skin of patients with moderate-to-severe atopic dermatitis J Allergy Clin Immunol 2014 134 6 1293 1300 25482871 \n12 Simpson EL Akinlade B Ardeleanu M Two Phase 3 Trials of Dupilumab versus Placebo in Atopic Dermatitis N Engl J Med 2017 376 11 1090 1091\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1679-4508",
"issue": "17(4)",
"journal": "Einstein (Sao Paulo, Brazil)",
"keywords": null,
"medline_ta": "Einstein (Sao Paulo)",
"mesh_terms": "D000293:Adolescent; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001938:Brazil; D003876:Dermatitis, Atopic; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents; D007279:Injections, Subcutaneous; D018793:Interleukin-13; D015847:Interleukin-4; D011788:Quality of Life; D012720:Severity of Illness Index",
"nlm_unique_id": "101281800",
"other_id": null,
"pages": "eRC4599",
"pmc": null,
"pmid": "31291386",
"pubdate": "2019-07-10",
"publication_types": "D002363:Case Reports",
"references": "14991059;18385500;22813359;24094544;24813298;25482871;27004560;28025775;28296614;8277028",
"title": "Dupilumab in the treatment of severe atopic dermatitis refractory to systemic immunosuppression: case report.",
"title_normalized": "dupilumab in the treatment of severe atopic dermatitis refractory to systemic immunosuppression case report"
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"abstract": "BACKGROUND\nAcetaminophen is one of the most common causes of poisoning among developed countries. The emergency department observation unit (EDOU) has been increasingly used in the management of various conditions to reduce hospitalisation but its efficacy in not well studied in management of poisoned patients. In this study, we aim to study the effectiveness of our EDOU in the management of acetaminophen overdosed patients.\n\n\nRESULTS\nMedical records of patients admitted from the emergency department from 2012 to 2016 for acetaminophen overdose were reviewed. One hundred ninety-five patients presenting with acetaminophen overdose were admitted to the EDOU while 184 were admitted to the general ward. Of these, 27 patients admitted to EDOU did not meet the admission criteria for it while 71 patients who met EDOU criteria were admitted to the ward instead. For patients who fulfilled EDOU admission criteria, median length of stay for EDOU patients was 23 h (IQR 19-24) while that for those admitted to the ward was 66 h (IQR 62.5-88.3).\n\n\nCONCLUSIONS\nThe EDOU is a safe alternative to hospitalisation for patients presenting with acetaminophen poisoning. It is also associated with a shorter length of stay for such patients. Further studies need to be done to assess the cost-effectiveness of EDOU for management of patients presenting with acetaminophen overdose.",
"affiliations": "Emergency Department, Tan Tock Seng Hospital, Emergency Department Level B1 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore. dilin_tang@ttsh.com.sg.;Emergency Department, Tan Tock Seng Hospital, Emergency Department Level B1 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.;Emergency Department, Tan Tock Seng Hospital, Emergency Department Level B1 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.",
"authors": "Tang|Dilin|D|http://orcid.org/0000-0003-1327-912X;Chan|Wui Ling|WL|;Phua|Dong Haur|DH|",
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"doi": "10.1186/s12245-018-0210-y",
"fulltext": "\n==== Front\nInt J Emerg MedInt J Emerg MedInternational Journal of Emergency Medicine1865-13721865-1380Springer Berlin Heidelberg Berlin/Heidelberg 21010.1186/s12245-018-0210-yOriginal ResearchPerformance of an emergency department observation unit protocol in reducing length of stay for acetaminophen overdose: a retrospective study http://orcid.org/0000-0003-1327-912XTang Dilin +6597536520dilin_tang@ttsh.com.sg Chan Wui Ling wuiling01@gmail.com Phua Dong Haur dong_haur_phua@ttsh.com.sg grid.240988.fEmergency Department, Tan Tock Seng Hospital, Emergency Department Level B1 11 Jalan Tan Tock Seng, Singapore, 308433 Singapore 16 11 2018 16 11 2018 2018 11 483 7 2018 30 10 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Introduction\nAcetaminophen is one of the most common causes of poisoning among developed countries. The emergency department observation unit (EDOU) has been increasingly used in the management of various conditions to reduce hospitalisation but its efficacy in not well studied in management of poisoned patients. In this study, we aim to study the effectiveness of our EDOU in the management of acetaminophen overdosed patients.\n\nResults\nMedical records of patients admitted from the emergency department from 2012 to 2016 for acetaminophen overdose were reviewed. One hundred ninety-five patients presenting with acetaminophen overdose were admitted to the EDOU while 184 were admitted to the general ward. Of these, 27 patients admitted to EDOU did not meet the admission criteria for it while 71 patients who met EDOU criteria were admitted to the ward instead. For patients who fulfilled EDOU admission criteria, median length of stay for EDOU patients was 23 h (IQR 19–24) while that for those admitted to the ward was 66 h (IQR 62.5–88.3).\n\nConclusion\nThe EDOU is a safe alternative to hospitalisation for patients presenting with acetaminophen poisoning. It is also associated with a shorter length of stay for such patients. Further studies need to be done to assess the cost-effectiveness of EDOU for management of patients presenting with acetaminophen overdose.\n\nKeywords\nEmergency medicine observation wardAcetaminophen overdoseLength of stayissue-copyright-statement© The Author(s) 2018\n==== Body\nIntroduction\nAcetaminophen is one of the most common causes of poisoning in developed countries [1, 2]. Similarly in Singapore, it is one of the most common drugs that is overdosed by both children and adults [3–5]. It is a common cause of liver failure in Europe and North America, which is associated with significant morbidity and mortality [6]. The mainstay of treatment is the timely administration of intravenous N-acetylcysteine (NAC) [7]. The standard treatment protocol for acetaminophen overdose is a 21-h course of intravenous (IV) NAC infusion. A previous study found that most general ward admissions secondary to drug overdose lasted 2 to 3 days only and were also largely managed for psychosocial rather than just medical issues [5].\n\nThe Emergency Department Observation Unit (EDOU) at our institution is a protocol-driven short-stay ward for patients with selected diagnoses to undergo further investigations and management for a defined time period up to 48 h. EDOUs are increasingly used to avoid hospital admissions in patients and may reduce the length of stay and cost of stay while providing high-quality healthcare [8–10]. Its role in management of poisoned patients is not well studied, but they may be used to extend the evaluation period for patients potentially needing inpatient admission; and also facilitate the administration of short-term interventions [11]. There is currently limited literature on the use of EDOU protocols for acetaminophen ingestion [12, 13].\n\nIn our institution, our emergency department (ED) developed a multi-disciplinary protocol for the treatment of acetaminophen in the EDOU. This protocol involves the emergency physicians (EP), toxicologists, nurses, psychiatrists, and medical social workers (MSWs). Together, they evaluate the patient for the appropriateness of 21-h IV NAC therapy and the progress under aforementioned therapy, as well as the results of further investigations, to determine the patient disposition to inpatient admission, further psychiatric workup or home discharge. The protocol provides different management strategies in terms of indications for IV NAC and evaluation of serum acetaminophen levels for single dose, staggered dose, sustained preparation, late presenter, and acetaminophen overdose of unknown timing.\n\nIn this study, we aim to describe our experience with our EDOU protocol over a 5-year period from 1 January 2012 till 31 December 2016 and assess its utilisation. We also aim to determine its effectiveness in terms of reducing hospital admissions and length of stay while providing the appropriate standard of care.\n\nMethods\nThis was a retrospective review of all patients admitted from the ED with a diagnosis of acute paracetamol poisoning from 1 January 2012 till 31 December 2016 to either the general ward or EDOU.\n\nSetting\nThe setting was that of a 1400-bed tertiary care hospital in Singapore. The EDOU is a 36-bed enclosed observation unit within the ED, staffed by two to three nurses and one doctor on each shift, under the oversight of an EP. Doctor rounds with the senior doctor are scheduled three times daily, to assess patients for further management or discharge. Serial investigations and treatment, including cardiac monitoring and laboratory testing, may be performed on the patients in the EDOU. The senior EP makes all decisions regarding admission to the EDOU and the patient’s final disposition.\n\nThe study was reviewed and approved by the Institutional Review Board (reference no: 2017/008700). Waver of patients’ consent was granted by the ethics board for this study due to minimal risk to patients.\n\nAcetaminophen overdose protocol\nThe protocol was implemented since 2010. All asymptomatic and hemodynamically stable patients were attended to and managed in the intermediate acuity care area of the ED by medical officer with oversight of a senior EP. A thorough history and physical examination was carried out for every patient. Important questions include the time of overdose, amount and type of drug, reason for overdose, as well as the presence of any other co-ingested substances or comorbidities were asked. Standard initial blood tests include a full blood count, renal panel, liver function test and coagulation studies and electrocardiogram were performed. For single ingestions, serum acetaminophen levels were taken at 4 h post-ingestion or as soon as possible thereafter and plotted on Rumack-Mathew nomogram that defines toxicity acetaminophen level as above 150 mg/dl at 4 h. For staggered ingestions, delayed presentations and unclear history time of ingestion, decision for antidote treatment is at the discretion of the supervising senior physician.\n\nAll supervising physicians have the option of admitting these patients to either the EDOU or a general ward under the medical discipline. The eligibility criteria for patients to be admitted to the EDOU acetaminophen overdose protocol is listed in Table 1.Table 1 Inclusion and exclusion criteria of EDOU pathway for acetaminophen poisoning\n\nInclusion criteria\t\n Clinically significant history for overdose\t\n Single overdose\t\n Staggered overdose\t\n Overdose with unknown time\t\n Sustained release formulation\t\n Overdose with gastro-motility delaying agents\t\n Late presenter (more than 24 h post-ingestion)\t\nExclusion criteria\t\n Unstable patients (symptoms, vital parameters and mental state)\t\n Children less than 16 years old\t\n Significant co-morbidities\t\n Significant co-ingestant\t\n Already has criteria to refer for transplant consideration\t\n\n\nStandard treatment in the protocol was a 21 h IV NAC infusion as well as management of any symptoms that the patient may have (e.g. vomiting, abdominal pain). For patients with intentional overdose, referral to psychiatry will be made upon admission to the EDOU. They will then be reviewed by psychiatry on the day of admission if admitted within office hours or the following morning if admitted after office hours. Patients are reviewed by psychiatry for continuing risk of self-harm and need for further psychiatric follow-up and care. For patients admitted to both ward and EDOU, those with high risk of further self-harm are then transferred to a psychiatric facility following completion of all medical treatment as decided by the psychiatric team.\n\nRepeat liver function tests, coagulation studies and serum acetaminophen levels were taken at the end of treatment to determine adequacy of treatment and disposition. As the ED observation unit only allows admission for up to 48 h with protocolised care, patients who develop other medical issues requiring subspecialty management will be transferred to the ward under the relevant medical discipline for further management. Also, patients admitted to both the emergency observation unit and ward with significant risk of self-harm will be transferred to the national psychiatric hospital upon resolution of their medical issues. While no routine follow-up visit is arranged for the patients discharged from EDOU, all patients are given a standard verbal and written discharge advice advising them to return if they feel unwell following the discharge.\n\nSelection of patients into study\nElectronic medical records of all patients who were admitted from the ED to either the general ward or the EDOU with a diagnosis of paracetamol/acetaminophen poisoning from 1 January 2012 till 31 December 2016 were reviewed. Patients who were admitted directly to the intensive care or high dependency unit, transferred to another hospital from the ED or discharged from the ED were excluded. Patients who fulfilled any exclusion criteria of the EDOU were also excluded from the final analysis. These included patients less than 16 years of age, pregnant patient, presence of other medical conditions that require inpatient management, agitated patients requiring sedation, unstable patients and patients already considered for transplant. Unstable patients were defined as having abnormal vital parameters (systolic blood pressure less than 90 mmHg, pulse oximetry less than 94% on room air) or depressed consciousness (Glasgow Coma score < =13).\n\nData collection\nPatient clinical data was abstracted from the hospital’s electronic record by a single investigator and recorded on a standard case report form. Cases are first reviewed for whether they meet the inclusion and/or exclusion criteria for EDOU admission under the acetaminophen treatment pathway (Table 2). Clinically significant acetaminophen overdose is defined as the ingestion of more than 150 mg/kg body weight acetaminophen tablets and/or require specific treatment for the overdose (i.e. N-acetylcysteine) based on clinician’s assessment.Table 2 Characteristics of patients admitted who fulfil EDOU criteria for acetaminophen poisoning (n = 219)\n\nVariables\tAdmitted EDOU (n = 153)\tAdmitted ward (n = 66)\t\nP\n\t\nMedian age, years (IQR)\t23 (19–32)\t29 (19.8–35.5)\t0.015\t\nGender\t\n Male, n (%)\t38 (24.8)\t27 (40.9)\t0.017\t\n Female, n (%)\t115 (75.2)\t39 (59.1)\t\t\nIngestion\t\n Single, n (%)\t121 (79.1)\t51 (77.3)\t0.76\t\nStaggered, n (%)\t32 (20.9)\t15 (22.7)\t\t\nMedian dose of paracetamol taken, g (IQR)\t10 (9–15)\t10.8 (8.6–15.8)\t0.28\t\nGiven IV NAC, n (%)\t124 (81.1)\t55 (83.3)\t0.69\t\nAcetaminophen-induced liver injury\t\n No liver injury, n (%)\t147 (96.0)\t60 (90.9)\t0.19\t\n Developed acute liver injurya, n (%)\t3 (2.0)\t2 (3.0)\t0.64\t\n Developed hepatotoxicityb, n (%)\t3 (2.0)\t4 (6.1)\t0.20\t\naAST/ALT double of initial value to at least 150 U/L\n\nbAST/ALT increased to 1000 U/L and above\n\n\n\nOther data abstracted include patient demographics, type of acetaminophen ingestion (single ingestion vs staggered ingestion), laboratory test results, whether N-acetylcysteine was given, final disposition from the hospital (discharge or transferred) and length of stay. Liver injury due to acetaminophen poisoning were defined into two categories—acute liver Injury is diagnosed if the aspartate aminotransferase (AST) or alanine aminotransferase (ALT) doubled from initial value to at least 150 U/L and hepatotoxicity is defined by the AST or ALT reaching 1000 U/L [14–16]. We also compared the length of stay in patients admitted to EDOU and ward who did not develop liver injury so as to adjust for the possible reason in the difference in length of stay that could be accounted by complications such as acute liver injury from acetaminophen poisoning.\n\nFor patients who were transferred from the EDOU to the inpatient medical unit, the case notes were reviewed for the reasons for the transfer. The electronic medical records of all patients included in the study were also reviewed for any return visits to the hospital within 7 days for any delayed complications arising from the overdose or treatment.\n\nOutcome measures\nThe primary outcome was the length of stay for the patients admitted to the EDOU and the general ward who fulfilled admission criteria for EDOU admission. Length of stay (LOS) was defined as the time from the admission of the patient to either the EDOU or the general ward until the discharge of the patient from the hospital. Thus, for patients admitted to EDOU and subsequently transferred to the ward, the length of stay includes their duration of stay in the wards till discharge from the hospital. Any differences in length of stay will therefore not be affected by bias arising from any administrative limitations on the length of stay in the EDOU.\n\nPatients who discharged against medical advice or absconded are excluded from this analysis. Other outcomes were the incorrect utilisation of the observation unit admission and the failure of the emergency observation protocol.\n\nIncorrect utilisation of the observation protocol comprise of two categories—over-utilisation and underutilisation. Over utilisation was defined as admission to the EDOU without either meeting the inclusion criteria or having one or more of the exclusion criteria. Underutilisation was defined as admission to the ward while meeting the admission criteria to the EDOU with no exclusion criteria. Failure of emergency observation protocol is defined as eventual admission of the patient to the general ward for further treatment after initial admission to the observation unit.\n\nData analysis\nThe data was analysed using SPSS 19 (IBM Corp. Released 2010. IBM SPSS Statistics for Windows, Version 19.0. Armonk, NY: IBM Corp). Categorical data is presented in frequency with proportion to the total number of patients. For continuous data, test of normality was done using Kolmogorov-Smirnov test. Parametric data were presented as means with standard deviation while non-parametric data were presented as median with interquartile range. For comparison between categorical values in each independent sample, chi-square or fisher’s exact test was used as appropriate. For comparison between non-parametric continuous variables, Man-Whitney U test is used.\n\nResults\nFrom 1 January 2012 till 31 December 2016, a total of 195 patients were admitted from the ED to the EDOU for acetaminophen poisoning and 184 patients were admitted to the general ward (Fig. 1).Fig. 1 Flow diagram of patient selection into study\n\n\n\nOf the 195 patients admitted to the EDOU for acetaminophen poisoning, 158 patients (81%) meets the admission criteria. Twenty-seven (13.8%) patients did not have significant paracetamol ingestion despite admission under the pathway. Of the 184 patients admitted to the general ward, 71 patients (38.6%) meets admission criteria to EDOU. Among these 229 patients who fulfilled the criteria for EDOU admission, eight patients (five in observation unit and three in the general ward) discharged against medical advice before treatment were completed. A further two patients were admitted to the high dependency ward for complications related to acetaminophen poisoning and these ten patients were excluded from the final analysis.\n\nThe characteristics of patients who fulfilled the EDOU criteria and admitted to either EDOU or ward are shown in Table 2. Majority of the patients admitted for acetaminophen poisoning in both groups are young with a median age of 24 years and majority are female at 70.3%. 18.9% and 16.7% of patients admitted to the EDOU and ward, respectively, did not require N-acetylcysteine based on serum paracetamol levels but were admitted for observation of symptoms. There are no significant differences between the two groups with regards to the number of patients who were given IV NAC and who developed liver injury or toxicity. Outcomes of both groups of patients are shown in Table 3. Median LOS for EDOU patients was 23 h (IQR 19 to 24) while that for patients admitted to the ward was 66 h (IQR 62.5 to 88.3) (Fig. 2).Table 3 Outcomes of patients who fulfil EDOU criteria for acetaminophen poisoning (n = 219)\n\nOutcomes\tAdmitted EDOU (n = 153)\tAdmitted ward (n = 66)\t\np\n\t\nMedian, length of stay in hospital, h (IQR)\t23 (19–24)\t66 (62.5–88.3)\t0.00\t\nTransferred from observation ward to the general ward, n (%)\t19 (12.4)\t\t\t\nTransferred to another hospital\t\n Psychiatric hospital, n (%)\t8 (5.2)\t7 (10.1)\t0.39\t\n Liver transplant unit, n (%)\t1 (0.7)\t0\t\t\nFig. 2 Length of stay for patients admitted for acetaminophen toxicity\n\n\n\nDuration of stay in EDOU is consistently shorter even when only patients without liver injury are considered. In this group of patients, median LOS for EDOU patients was 22 h (IQR 19 to 24) while that forward patients was 56.5 h (IQR 38.5 to 81) (Fig. 3).Fig. 3 Length of stay for patients admitted for acetaminophen who did not develop liver injury\n\n\n\nNine patients in the EDOU group (5.9%) and seven patients in the ward (10.1%) group were eventually transferred to another hospital. Most of the transfers were to a psychiatric facility due to high risk of suicide while one patient in the EDOU group was transferred to a hospital with transplant capability due to predicted poor prognosis. The patient eventually recovered without transplant. For the duration of hospital stay, 19 patients in the EDOU (12.4%) were transferred to the ward. The reasons for the transfer are shown in Table 4. Majority of the cases (52.6%) were transferred for further psychiatric monitoring and care. Among patients discharged from the EDOU there were no reattendance to the hospital within 7 days for any medical complications arising from the overdose or treatment while in hospital.Table 4 Reasons for conversion from EDOU to ward (n = 19)\n\nReasons\tNumber of patients (%)\t\nAbnormal laboratory tests (excluding liver Injury)\t2 (10.5)\t\nAcetaminophen induced liver injury\t5 (26.3)\t\nPsychiatric monitoring and care\t10 (52.6)\t\nSocial issues\t1 (5.3)\t\n\n\nLimitations\nThe main limitations of this study were related to this being a single-centre study and the inherent limitations of a retrospective design. There may also be bias due to the fact that one investigator extracted all the data; however, the variables used in this study are well defined and objective in nature. In the study clinical setting, the factors that the clinicians considered before determining if these patients should be admitted to EDOU or not were not documented in the case notes. These factors could be possible confounders that could have affected the length of stay. In this study, some clinical factors that may influence decision making and length of stay were eliminated by excluding patients who are unstable, mentally disturbed that require sedation or have other medical problems requiring intervention other than the overdose itself.\n\nAnother limitation of this study is that there were no follow-up arranged for the patients following discharge to ensure no adverse outcomes. However, all patients admitted to the EDOU were discharged with a standard discharge advice to return to the hospital if they feel unwell following discharge. The medical records were reviewed for any return visit to the hospital for complications related to the overdose or treatment. Despite this, any significant adverse events may be missed for patients who visited other hospitals or clinics subsequently.\n\nIn the study, patients admitted to the EDOU have early access to multi-disciplinary care including social work and psychiatric evaluation. All patients admitted to the ward and the EDOU that do not require further medical treatment but require psychiatric care are transferred to a separate psychiatric facility. That limits the applicability of this study to centres with such services.\n\nDiscussion\nThis study demonstrates that the EDOU is an effective strategy in reducing the of length of stay for stable patients presenting with acute acetaminophen poisoning. This finding is consistent with other studies on management of poisoned patients in the EDOU [13, 17, 18]. Despite a proportion of patients being transferred to the ward from the EDOU due to persistent psychiatric or medical issues, the overall length of stay for patients admitted initially to EDOU were still significantly shorter than those admitted to the ward. There are some factors that contribute to this. Management of the patients follows a standardised care path and this facilitates the use of evidence-based medicine in optimising outcomes and improving clinical efficiency. Several studies have demonstrated that standardised care can reduce length of stay in certain conditions [19, 20]. In the EDOU, ward rounds are performed three times a day including weekends by a senior physician from the ED. With a large proportion of poisoned patients presenting out-of-office hours [21], more frequent review of ward patients at such hours prevents delays in management and deposition of these patients. As part of the standardised care in the EDOU, patients admitted for intentional acetaminophen poisoning are referred early to the psychiatry and social services as part of a multi-disciplinary approach. Such multi-disciplinary approach had been shown to reduce the length of stay for some acute medical conditions [22].\n\nIn our study, 12.4% of patients admitted to the EDOU were eventually transferred to the general ward which represents the failure of EDOU care. More than half of these patients are transferred for continual psychiatric care. This rate of inpatient transfer was comparable to previous studies on the outcomes of toxicology patients in EDOU [13, 18]. However, a proportion of patients (15.8%) were transferred because of medical and social issues not related to acetaminophen overdose. Hence, there is a need to further determine any predictive factors responsible for this failure of EDOU management to help better refine the admission criteria and the treatment protocol further. As the decision to admit these patients to EDOU was determined by the reviewing senior EP, there was a significant number of over-utilisation of the pathway whereby patients who did not meet the criteria for EDOU were admitted there and underutilisation whereby patients who met the criteria were admitted to the ward instead. While the reasons to determine if these patients should be admitted to EDOU or to inpatient medical team were not stated in the case notes, one possible reason could be the lack of familiarity with capabilities of the EDOU and understanding of the admission criteria. There may be a need to clarify some of the admission criteria to improve compliance rate.\n\nFrom the study, medical treatment, i.e. IV NAC and development of hepatic injury, does not account for the differences in the length of stay between ward and EDOU as their frequency are similar in both groups of patients. In addition to the more frequent rounds and discharges in the EDOU, one possible factor in affecting the length of stay is the need for psychiatric care. The importance of psychiatric factors in affecting length of stay was also supported by the fact that majority of patients who failed EDOU treatment, as defined by transfer from EDOU to the inpatient ward, were for psychiatric care. Furthermore, most of the hospital transfers from the hospital were to a psychiatric facility due to persistent high risk of self-harm. Psychiatric disorders are prevalent in patients presenting with non-fatal self-harm, ranging from depression to substance misuse [23]. Zyoud et al. found that an acute depressed mood was an independent risk factor for a long length of stay in patients admitted for acetaminophen overdose [24]. Other studies have also shown an association between psychiatric comorbidity and increased length of stay for patients admitted for medical conditions [25, 26]. In the EDOU, the patients referred early upon admission to the psychiatric team and medical social workers as part of the multi-disciplinary approach and there was an arrangement with the psychiatric team for prioritisation of these patients for review to facilitate their disposition. Two studies had previously demonstrated that a proactive multi-disciplinary psychiatric consultation with close collaboration with the medical team for patients admitted for medical conditions is effective in decreasing the length of stay [27, 28]. A systemic review on consultation-liaison psychiatry services also suggests a shorter length of stay for medical patients with early referral to psychiatry [29].\n\nConclusion\nThe EDOU is an effective alternative to ward hospitalisation in the management of acetaminophen poisoning. Our study suggests that the EDOU protocol is associated with a shorter length of stay for patients presenting with acetaminophen overdose. No patients re-attended the hospital for any complications following discharge from EDOU as well. Further studies are needed to investigate the cost-effectiveness of the EDOU protocol.\n\nAbbreviations\nALTAlanine aminotransferase\n\nASTAspartate aminotransferase\n\nEDEmergency department\n\nEDOUEmergency Department Observation Unit\n\nEPEmergency physician\n\nIQRInterquartile range\n\nIVIntravenous\n\nLOSLength of stay\n\nNACN-Acetylcysteine\n\nAcknowledgements\nNot applicable.\n\nFunding\nNone declared.\n\nAvailability of data and materials\nPlease contact author for data requests.\n\nAuthor’s contributions\nDT and DHP conceived and designed the study. DT was responsible for the data collection. Both DT and DHP did the analysis. DT prepared the manuscript draft, with important input from WLC and DHP. All authors approved the final manuscript.\n\nEthics approval and consent to participate\nThe study was reviewed and approved by the Institutional Review Board, Singapore, provenance and peer review is not commissioned, externally peer reviewed (reference no: 2017/008700).\n\nConsent for publication\nNot applicable.\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. Bronstein AC Spyker DA Cantilena LR Jr Green JL Rumack BH Dart RC 2010 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 28th Annual Report Clin Toxicol (Phila) 2011 49 910 941 10.3109/15563650.2011.635149 22165864 \n2. Sivilotti ML Yarema MC Juurlink DN A risk quantification instrument for acute acetaminophen overdose patients treated with N-acetylcysteine Ann Emerg Med 2005 46 263 271 10.1016/j.annemergmed.2005.04.004 16126138 \n3. Ng KC Paracetamol ingestions at the children’s emergency department – a three-year series Singapore Med J 2003 44 79 83 14503781 \n4. Ponampalam R Tan HH Ng KC Lee WY Tan SC Demographics of toxic exposures presenting to three public hospital emergency departments in Singapore 2001-2003 Int J Emerg Med 2009 2 1 25 31 10.1007/s12245-008-0080-9 19390914 \n5. Chiu LQ Lim BL Vasu A Phua DH Goh HK Poison exposure in the emergency department: a Singaporean experience Hong Kong J Emerg Med 2011 18 4 197 203 10.1177/102490791101800402 \n6. Bernal W Wendon J Acute liver failure N Engl J Med 2013 369 26 2525 2534 10.1056/NEJMra1208937 24369077 \n7. Smilkstein MJ Knapp GL Kulig KW Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the National Multicentre Study (1976 to 1985) N Engl J Med 1988 319 1557 1562 10.1056/NEJM198812153192401 3059186 \n8. Damiani G Pinnarelli L Sommella L Vena V Magrini P Ricciardi W The short stay unit as a new option for hospitals: a review of the scientific literature Med Sci Monit 2011 17 6 SR15 SR19 10.12659/MSM.881791 21629205 \n9. McDermott MF Murphy DG Zalenski RJ Rydman RJ McCarren M Marder D Jovanovic B Kaur K Roberts RR Isola M Mensah E Rajendran R Kampe L A comparison between emergency diagnostic and treatment unit and inpatient care in the management of acute asthma Arch Intern Med 1997 157 18 2055 2062 10.1001/archinte.1997.00440390041006 9382660 \n10. Lateef F Anantharaman V The short-stay emergency EDOU is here to stay Am J Emerg Med 2000 18 5 629 634 10.1053/ajem.2000.9291 10999584 \n11. Calello DP Alpern ER McDaniel-Yakscoe M Garrett BL Shaw KN Osterhoudt KC Observation unit experience for pediatric poison exposures J Med Toxicol Mar 2009 5 1 15 19 10.1007/BF03160975 \n12. Sztajnkrycer MD Mell HK Melin GJ Development and implementation of an emergency department observation unit protocol for deliberate drug ingestion in adults—preliminary results Clin Toxicol (Phila) 2007 45 499 504 10.1080/15563650701354168 17503255 \n13. Beauchamp GA Hart KW Lindsell CJ Lyons MS Otten EJ Smith CL Ward MJ Wright SW Performance of a multi-disciplinary observation protocol for acetaminophen overdose J Med Toxicol 2013 9 235 241 10.1007/s13181-013-0310-2 23793935 \n14. Cairney DG Beckwith HK Al-Hourani K Eddleston M Bateman DN Dear JW Plasma paracetamol concentration at hospital presentation has a dose-dependent relationship with liver injury despite prompt treatment with intravenous acetylcysteine Clin Toxicol (Phila) 2016 54 5 405 410 10.3109/15563650.2016.1159309 27108714 \n15. Rumack BH Acetaminophen hepatotoxicity: the first 35 years J Toxicol Clin Toxicol 2002 40 1 3 20 10.1081/CLT-120002882 11990202 \n16. Smilkstein MJ Knapp GL Kulig KW Rumack BH Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. Analysis of the national multicenter study (1976 to 1985) N Engl J Med 1988 319 24 1557 1562 10.1056/NEJM198812153192401 3059186 \n17. Isoardi KZ Armitage MC Harris K Page CB Establishing a dedicated toxicology unit reduces length of stay of poisoned patients and saves hospital bed days Emerg Med Australas 2017 29 3 310 314 10.1111/1742-6723.12755 28266169 \n18. Mong R Arciaga GJ Tan HH Use of a 23-hour emergency department observation unit for the management of patients with toxic exposures Emerg Med J 2017 34 11 755 760 10.1136/emermed-2016-206531 28768699 \n19. Department of Health Fragility fractures: rehabilitation. Quality and productivity. Discher CL, Klein D, Pierce L, Levine AB and Levine TB (2003) ‘Heart failure disease management: impact on hospital care, length of stay, and reimbursement Congest Heart Fail 2009 9 77 83 \n20. Adamina M Kehlet H Tomlinson GA Senagore AJ Delaney CP Enhanced recovery pathways optimize health outcomes and resource utilization: a meta-analysis of randomized controlled trials in colorectal surgery Surgery 2011 149 6 830 8401 10.1016/j.surg.2010.11.003 21236454 \n21. Bailey G Wisniacki F One year of deliberate self-poisoning presentations at a West London emergency department The West London Med J 2014 6 1 33 44 \n22. Miani C Ball S Pitchforth E Organisational interventions to reduce length of stay in hospital: a rapid evidence assessment Heal Serv Deliv Res 2014 2 52 1 178 10.3310/hsdr02520 \n23. Hawton K Saunders K Topiwala A Haw C Psychiatric disorders in patients presenting to hospital following self-harm: a systematic review J Affect Disord 2013 151 3 821 830 10.1016/j.jad.2013.08.020 24091302 \n24. Zyoud SH Awang R Sulaiman SA Al-Jabi SW An analysis of the length of hospital stay after acetaminophen overdose Hum Exp Toxicol 2011 30 7 550 559 10.1177/0960327110377647 20630911 \n25. Bressi SK Marcus SC Solomon PL The impact of psychiatric comorbidity on general hospital length of stay Psychiatry Q 2006 77 203 209 10.1007/s11126-006-9007-x \n26. Furlanetto LM da Silva RV Bueno JR The impact of psychiatric comorbidity on length of stay of medical inpatients Gen Hosp Psychiatry 2003 25 14 19 10.1016/S0163-8343(02)00236-0 12583922 \n27. Sledge WH Gueorguieva R Desan P Bozzo JE Dorset J Lee HB Multidisciplinary proactive psychiatric consultation service: impact on length of stay for medical inpatients Psychother Psychosom 2015 84 4 208 216 10.1159/000379757. 26022134 \n28. Desan PH Zimbrean PC Weinstein AJ Bozzo JE Sledge WH Proactive psychiatric consultation services reduce length of stay for admissions to an inpatient medical team Psychosomatics 2011 52 6 513 520 10.1016/j.psym.2011.06.002 22054620 \n29. Wood R Wand APF The effectiveness of consultation-liaison psychiatry in the general hospital setting: a systematic review J Psychosom Res 2014 76 3 175 192 10.1016/j.jpsychores.2014.01.002 24529036\n\n",
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"journal": "International journal of emergency medicine",
"keywords": "Acetaminophen overdose; Emergency medicine observation ward; Length of stay",
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"title": "Performance of an emergency department observation unit protocol in reducing length of stay for acetaminophen overdose: a retrospective study.",
"title_normalized": "performance of an emergency department observation unit protocol in reducing length of stay for acetaminophen overdose a retrospective study"
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"abstract": "Background: Endobronchial and endotracheal metastases from extra-pulmonary solid tumors are rare. Patients and methods: We reported the case of a patient diagnosed with endobronchial and endotracheal metastases from rectal adenocarcinoma. Case report: Patient P.G., 62 years old, was diagnosed with a rectal tumor in 2011, for which, a surgical intervention was performed (pT3 pN2a M0, stage IIIB). Afterwards, she underwent adjuvant chemotherapy and concomitant radiochemotherapy. In September 2013, the chest CT showed 2 nodules for which, an incomplete surgical resection was done and which were histopathologically diagnosed as metastases from rectal cancer. The patient continued the treatment with chemotherapy associated with Bevacizumab and after 6 months only Bevacizumab for maintenance. In June 2015, the chest CT pointed out a nodule in the right upper lobe and the bronchoscopy highlighted a 4-5 mm lesion at the level of the right primary bronchus, whose biopsy proved the rectal origin. Afterwards, another surgical intervention was performed. Unfortunately, the postoperative chest CT revealed an intratracheal tissue mass (11/ 7mm) and multiple metastases in the right lung. The bronchoscopy showed 2 endotracheal lesions, out of which one was biopsied (histopathological result of metastasis from rectal cancer). Despite the fact that chemotherapy was continued, other endobronchial lesions appeared. All of them were removed and the patient started radiotherapy on the tracheal area. Afterwards, she refused to continue chemotherapy. The last bronchoscopy highlighted one endobronchial and two endotracheal secondary malignant lesions. Conclusion: Endobronchial and endotracheal metastases must be taken into consideration in all the patients with a history of extra-pulmonary cancer. Abbreviations: CT = computed tomography, MRI = magnetic resonance imaging, IMRT = intensity-modulated radiotherapy, ESMO = European Society for Medical Oncology, NCCN = National Comprehensive Cancer Network, iv = intravenous, PET - CT = Positron Emission Tomography - Computed Tomography.",
"affiliations": "Prof. Dr. Al. Trestioreanu\" Institute of Oncology, Bucharest, Romania.;\"Carol Davila'' University of Medicine and Pharmacy, Bucharest, Romania.",
"authors": "Serbanescu|G L|GL|;Anghel|R M|RM|",
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"fulltext": "\n==== Front\nJ Med LifeJ Med LifeJMedLifeJournal of Medicine and Life1844-122X1844-3117Carol Davila University Press Romania JMedLife-10-66Case PresentationsCan endobronchial or endotracheal metastases appear from rectal adenocarcinoma?\n Serbanescu GL *Anghel RM *** Prof. Dr. Al. Trestioreanu” Institute of Oncology, Bucharest, Romania;\n** “Carol Davila’’ University of Medicine and Pharmacy, Bucharest, Romania\nCorrespondence to: Luiza Serbanescu, MD, PhD student, Assistant Professor,\nClinical Department No. 8, “Carol Davila” University of Medicine and Pharmacy, Bucharest,\n“Prof. Dr. Al. Trestioreanu” Institute of Oncology\n252 Fundeni Street, Code: 22328, Bucharest, Romania,\nMobile phone: +40723 666 279, E-mail: luizaserbanescu@yahoo.com\nJan-Mar 2017 10 1 66 69 24 9 2016 07 12 2016 ©Carol Davila University Press\n2017This article is distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/3.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.Background: Endobronchial and endotracheal metastases from extra-pulmonary solid tumors are rare.\n\nPatients and methods: We reported the case of a patient diagnosed with endobronchial and endotracheal metastases from rectal adenocarcinoma.\n\nCase report: Patient P.G., 62 years old, was diagnosed with a rectal tumor in 2011, for which, a surgical intervention was performed (pT3 pN2a M0, stage IIIB). Afterwards, she underwent adjuvant chemotherapy and concomitant radiochemotherapy.\n\nIn September 2013, the chest CT showed 2 nodules for which, an incomplete surgical resection was done and which were histopathologically diagnosed as metastases from rectal cancer. The patient continued the treatment with chemotherapy associated with Bevacizumab and after 6 months only Bevacizumab for maintenance.\n\nIn June 2015, the chest CT pointed out a nodule in the right upper lobe and the bronchoscopy highlighted a 4-5 mm lesion at the level of the right primary bronchus, whose biopsy proved the rectal origin. Afterwards, another surgical intervention was performed. Unfortunately, the postoperative chest CT revealed an intratracheal tissue mass (11/ 7mm) and multiple metastases in the right lung. The bronchoscopy showed 2 endotracheal lesions, out of which one was biopsied (histopathological result of metastasis from rectal cancer). Despite the fact that chemotherapy was continued, other endobronchial lesions appeared. All of them were removed and the patient started radiotherapy on the tracheal area. Afterwards, she refused to continue chemotherapy. The last bronchoscopy highlighted one endobronchial and two endotracheal secondary malignant lesions.\n\nConclusion: Endobronchial and endotracheal metastases must be taken into consideration in all the patients with a history of extra-pulmonary cancer.\n\nAbbreviations: CT = computed tomography, MRI = magnetic resonance imaging, IMRT = intensity-modulated radiotherapy, ESMO = European Society for Medical Oncology, NCCN = National Comprehensive Cancer Network, iv = intravenous, PET – CT = Positron Emission Tomography – Computed Tomography\n\nrectal cancerendobronchial/ endotracheal metastasisradiotherapy\n==== Body\nIntroduction\nEndobronchial and endotracheal metastasis secondary to extra-pulmonary solid tumors or to primary lung tumors are rare, but can be life-threatening [1]. \n\nAmong the different localizations of the tracheobronchial tree, the trachea represents an extremely rare site for metastasis from solid extra-pulmonary cancers, being involved in only 5% of the cases [1]. The most frequent solid primary non pulmonary tumors which determine the appearance of endobronchial/ endotracheal metastasis are breast cancer, colorectal cancer, renal cell carcinoma and malignant melanoma [1,2].\n\nPatients and methods\nThe intrabronchial and intratracheal involvement were histopathologically proven as sites for metastasis from rectal cancer.\n\nCase report\nThe case of a 62-years-old Caucasian female patient, P.G., non-smoker, who denied alcohol beverages consumption, did not work in a toxic environment and who lived in the urban area, was presented. Personal physiologic antecedents were menarche at 12 years, one natural childbirth, and menopause at 50 years old. Family and personal pathologic history were without importance for the malignancy. The debut of the neoplasia was in 2011 with the rectal bleeding and lower abdominal pain for 2 to 3 months before she presented to the doctor. Colonoscopy showed an ulcerated non-obstructive tumor above 10 cm from the anal verge which was biopsied and whose histopathological result was uncertain (adenocarcinoma/ high-grade intraepithelial neoplasia). The patient underwent an abdominal and pelvic MRI with intravenous contrast which confirmed the presence of a rectal tumor (3/ 4,2 cm), which infiltrated the locoregional fat tissue and also showed infracentimetric locoregional lymph nodes. The chest CT showed no pathological changes. The CEA biological marker, the complete blood count, and the chemistry profile were within normal limits.\n\nIn September 2011, the surgical intervention was performed and consisted in a low anterior rectal resection. The histopathological result was of a well-differentiated adenocarcinoma with 20 resected lymph nodes from which 4 presented tumoral invasion (pT3pN2a, Ro).\n\nSo, in October 2011, the patient presented to “Prof. Dr. Al. Trestioreanu” Institute of Oncology in Bucharest with a good performance status (ECOG = 0) and the diagnosis of operated rectal adenocarcinoma stage IIIB. According to the NCCN and ESMO guidelines, she received adjuvant chemotherapy type FOLFOX6 (Oxaliplatin 85mg/ m2 iv day 1 + leucovorin 400mg/ m2 iv day 1 + 5-FU 400mg/ m2 iv bolus on day 1 and 5-FU 2400mg/ m2 over 46 hours iv continuous infusion, at every 2 weeks) for 6 months, which was well tolerated and in full dose. The imagistic tests and the level of CEA after 3 and 6 months of adjuvant chemotherapy (abdominal and pelvic CT with intravenous contrast) were within normal limits.\n\nAfterwards, according to the NCCN and ESMO guidelines, between June and July 2012, the patient underwent external beam radiotherapy up to a total dose of 50,4 Gy on the tumoral bed and locoregional pelvic lymph nodes (daily 1,8 Gy fractions, 5 days per week), concomitant with chemotherapy based on Capecitabine 825mg/ m2 twice a day, at 30 min after main meals, for 5 days per week. As side effects, we noticed diarrhea, grade 1 leucopenia and neutropenia in the last week of treatment.\n\nUntil September 2013, the follow-up consisted of a complete physical examination and CEA level determination at every 3 months, chest/ abdominal/ pelvic CT with intravenous contrast at every 6 months and colonoscopy every year. Then, the patient was asymptomatic, but the chest CT revealed 2 lung nodules localized in the right upper and right lower lobe, with dimensions of 12/ 11/ 11 mm, 6/ 7/ 7 mm respectively, for which, an incomplete resection was performed. The histopathological result was lung metastasis of adenocarcinoma with intestinal origin, without information about the resection margins. Therefore, immunochemistry interpretation was done and confirmed the result of a well-differentiated lung metastasis secondary to rectal cancer. The molecular analysis for mutation detection in exons 2, 3, 4 of the K-RAS and N-RAS oncogenes showed that the tumor carried a mutation in exon 2 codon 12 of K-RAS oncogene. The CEA level, the complete blood count, and the chemistry profile were within normal limits.\n\nThe oncological treatment was continued with chemotherapy type FOLFIRI (Irinotecan 180mg/ m2 iv day 1 + leucovorin 400mg/ m2 iv day 1 + 5-FU 400mg/ m2 iv bolus on day 1 and 5-FU 2400mg/ m2 over 46 hours iv continuous infusion, at every 2 weeks) in association with Bevacizumab 5mg/ kgc iv, day 1, at every 2 weeks for 6 months and afterwards only Bevacizumab for maintenance, very well tolerated.\n\nThe chest CT from June 2015 revealed a lung nodule localized in the right upper lobe with a suggestive aspect for metastasis. The bronchoscopy highlighted a lesion of 4-5 mm on the right primary bronchus, with a good vascularization, surrounded by normal mucosa and from which biopsy was taken. The histopathological result was metastasis of rectal adenocarcinoma. The sample was too small for immunochemistry tests. Further, the patient was investigated with a PET-CT which showed a metabolic activity for a lung nodule from the right upper lobe with a dimension of 2,9 cm and a max of 13,13 SUV; it did not offer any information about the tracheobronchial tree.\n\nThe patient was proposed for another surgical intervention, but she refused it. She returned in November 2015 with a CT scan and a bronchoscopy similar to those in June 2015. In December 2015, an upper right lobectomy with a resection of the primary bronchus and part of the intermediate bronchus was performed. The histopathological result confirmed that the resected pieces contained lesions of multifocal colon-like adenocarcinoma.\n\nFig. 1 November 2015 – Lesion localized in the right primary bronchus with suggestive aspect for metastasis\n\nAfter this complex surgical intervention, the patient presented a poor performance status and until February 2016 interrupted any oncological treatments. Then, the chest CT pointed out multiple secondary nodules in the right intermediate and lower lobes and an intratracheal mass with the dimension of 11/ 7mm. The CEA level was within normal values. Unfortunately, the patient presented intermittent nonproductive cough and stridor. The bronchoscopy highlighted 2 endotracheal lesions: one of 1,5 mm and the other one of 1 cm, which was biopsied and proved to be metastasis from rectal cancer. The patient continued chemotherapy with Oxaliplatin (85mg/ m2 iv) and Irinotecan (200mg/ m2) at every 3 weeks. In March 2016, through total anesthesia, one tracheal lesion was resected and for other three, local laser therapy was performed. In April 2016, the patient performed chest/ abdominal/ pelvic CT with intravenous contrast, which showed stable lung nodules localized in the right intermediate and lower lobes and no pathological information about the tracheobronchial tree. Therefore, she continued chemotherapy with Irinotecan and Oxaliplatin. As side effects, we remarked peripheral sensory neuropathy and grade 1-2 leucopenia and neutropenia. The bronchoscopy in May 2016 showed a right bronchial tree without alterations on the mucosa, but on the left one, 2 lesions of 3 mm and 2 mm, which were resected. \n\nBetween June and July 2016, the patient underwent external beam radiotherapy, using the IMRT technique, up to a total dose of 50,4 Gy to the tumoral bed with a conventional fractionation schedule. The treatment was well tolerated, with moderate dysphagia and the relief of the respiratory symptoms appeared.\n\nSince the end of radiotherapy, the patient refused to continue chemotherapy. \n\nHowever, at the end of October, the bronchoscopy showed 2 endotracheal lesions (of 5 and 8 mm) and one on the left primary bronchus with an aspect suspected for metastases, which were resected and their histopathological result proved the rectal origin.\n\nFig. 2 October 2016 - Intrabronchial lesion\n\nDiscussion\nThe particularity of this case was represented, firstly, by the fact that endobronchial and endotracheal metastases, which are a rare condition [1], have occurred in the evolution of a rectal adenocarcinoma. Usually, they appear late after the diagnosis of a primary tumor, at a median of 50 months, being associated with other metastases [1,3]. Our patient presented tracheobronchial tree metastases after 43 months from the diagnosis of a rectal cancer.\n\nIn this association with rectal cancer it is possible that they are underdiagnosed because bronchoscopy is the most important test through which the physician establishes the diagnosis of certitude, but it is not seldom used between the investigations that are done in a rectal cancer [4,5]. Through histopathology, it is very important to make the differential diagnosis with a primary lung cancer, because the treatment and prognosis differ [5-7]. As in the presented case, the symptoms that can appear in this condition can be life-threatening and are characteristic for an upper airway obstruction: cough, hemoptysis, dyspnea and stridor [3,4].\n\nRegarding the treatment of endobronchial and endotracheal metastasis, usually it is palliative [3,5,8]. It can relief the symptoms which are due to the upper airway obstruction and improve the quality of life [3,4,6]. It is represented by surgery, chemotherapy, external beam radiotherapy, cryotherapy, and brachytherapy [4]. \n\nIn the presented case, through surgery and chemotherapy the tracheobronchial metastasis continued to reappear very soon after their end. Radiotherapy succeeded in ameliorating the respiratory symptomatology and the interval between its end and the appearance of new lesions lasted longer.\n\nNeoadjuvant treatment (radiotherapy +/ - chemotherapy) represents the standard for locally advanced rectal cancers tumor (T3-4 N0 or Tany N+) [9]. The goals of neoadjuvant radiochemotherapy are to increase local control, pathologic complete response and the rate of sphincter preservation; in addition, it is less toxic than administered postoperative [9]. Maybe it would have been better for this patient, whose tumor was cT3 on the MRI performed in August 2011, to receive neoadjuvant radiochemotherapy and according to the postoperative pathological result, adjuvant treatment.\n\nConclusion\nThe tracheobronchial tree should be taken into consideration as a metastatic site for primary solid tumors localized extrapulmonary.\n\nSource of founding\n\nThis work received financial support through the project entitled “CERO – Career profile: Romanian Researcher”, grant number POSDRU/159/1.5/S/135760, co-financed by the European Social Fund for Sectoral Operational Programme Human Resources Development 2007-2013.\n\nDisclosures\n\nAuthors declare that there is no conflict of interest regarding the publication of this paper.\n==== Refs\n1 Sorensen JB Endobronchial metastases from extrapulmonary solid tumors Acta Oncol 2004 43 73 79 doi: 10.1080/02841860310018053 15068323 \n2 Galbis Caravajal JM Sales Badia JG Trescoli Serrano C Cordero Rodriguez P Jorda Aragon C Naval Sendra E Endotracheal metastases from colon adenocarcinoma Clin Transl Oncol 2008 10 676 678 18940751 \n3 Fournel C Bertoletti L Nguyen B Vergnon JM Endobronchial metastases from colorectal cancers: natural history and role of interventional bronchoscopy Respiration 2009 77 1 63 69 doi: 10.1159/000158487 18812690 \n4 Nair S Kumar P Ladas G Intratracheal metastasis secondary to soft tissue liposarcoma Singapore Med J 2007 48 3 e81 17342277 \n5 Kim AW Liptay MJ Saclarides TJ Warren WH Endobronchial colorectal metastasis versus primary lung cancer: a tale of two sleeve right upper lobectomies Interact Cardiovasc Thorac Surg 2009 8 9 2 379 381 doi: 10.1510/icvts.2009.207555 19429639 \n6 Katsimbri PP Bamias AT Froudarakis ME Peponis IA Constantopoulos SH Pavlidis NA Endobronchial metastases secondary to solid tumors: report of eight cases and review of the literature Lung Cancer 2000 5 28 2 163 170 10717334 \n7 Charpidou A Fotinou M Alamara C Kalkandi P Tiniakou D Alexopoulou K Merikas M Syrigos KN Report of two cases of endobronchial metastases secondary to colorectal cancer In Vivo 2007 Jan-Feb 21 1 133 136 17354626 \n8 Hye-kyung S Hyung-woo K Tae-Sung K Seok-ki K Endotracheal Metastasis Seen on FDG PET/ CT in a Patient with Previous Colorectal Cancer Nucl Med Mol Imaging 2010 12 44 4 294 296 doi: 10.1007/s13139-010-0050-z 24899967 \n9 Glimelius B Påhlman L Cervantes A Cancerul rectal: Ghidurile de pactica clinica ESMO pentru diagnostic, tratament si urmarire Journal of Radiotherapy & Medical Oncology 2014 20 Supplement 1 79 80\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1844-122X",
"issue": "10(1)",
"journal": "Journal of medicine and life",
"keywords": "endobronchial/ endotracheal metastasis; radiotherapy; rectal cancer",
"medline_ta": "J Med Life",
"mesh_terms": "D000230:Adenocarcinoma; D001984:Bronchial Neoplasms; D001999:Bronchoscopy; D005260:Female; D006801:Humans; D008875:Middle Aged; D012004:Rectal Neoplasms; D014057:Tomography, X-Ray Computed; D014134:Tracheal Neoplasms",
"nlm_unique_id": "101477617",
"other_id": null,
"pages": "66-69",
"pmc": null,
"pmid": "28255381",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "15068323;24899967;10717334;17354626;18812690;19429639;17342277;18940751",
"title": "Can endobronchial or endotracheal metastases appear from rectal adenocarcinoma?",
"title_normalized": "can endobronchial or endotracheal metastases appear from rectal adenocarcinoma"
} | [
{
"companynumb": "RO-FRESENIUS KABI-FK201702277",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IRINOTECAN"
},
"drugadditional": null,
... |
{
"abstract": "Lung cancer is the leading cause of cancer related death in men and the second cause in women worldwide. We describe a case of a 51- year old lady with small cell lung cancer who developed small bowel obstruction following chemotherapy with cisplatin and etoposide. Abdominal CT scan showed changes confined to the jejunum and proximal ileum with diffuse mural thickening and hyper-attenuation of the mucosa with sparing of the terminal ileum, caecum and colon. Her condition improved with conservative management and intravenous antibiotics.",
"affiliations": "Department of Medicine, Macclesfield District General Hospital, Macclesfield, Cheshire, UK.;Department of Respiratory Medicine, Macclesfield District General Hospital, Macclesfield, Cheshire, UK.;Department of Gastroenterology, Macclesfield District General Hospital, Macclesfield, Cheshire, UK; Department of Medicine, Faculty of Medicine, University of Khartoum, Khartoum, Sudan. Electronic address: hmudawi@hotmail.com.",
"authors": "Balu|Ashwin|A|;Nagarajan|Thapas|T|;Mudawi|Hatim|H|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Egypt",
"delete": false,
"doi": "10.1016/j.ajg.2021.07.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1687-1979",
"issue": "22(3)",
"journal": "Arab journal of gastroenterology : the official publication of the Pan-Arab Association of Gastroenterology",
"keywords": "Chemotherapy; Lung cancer; Small bowel obstruction",
"medline_ta": "Arab J Gastroenterol",
"mesh_terms": "D000970:Antineoplastic Agents; D000072700:Conservative Treatment; D005260:Female; D006801:Humans; D007415:Intestinal Obstruction; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101298363",
"other_id": null,
"pages": "246-248",
"pmc": null,
"pmid": "34531131",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chemotherapy induced small bowel obstruction in small cell lung cancer.",
"title_normalized": "chemotherapy induced small bowel obstruction in small cell lung cancer"
} | [
{
"companynumb": "GB-HQ SPECIALTY-GB-2021INT000213",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "There is increasing evidence that bioprosthetic valve thrombosis (BPVT) is more common than previously thought. However, there are very few cases describing the occurrence of BPVT on therapeutic anticoagulation, and no previous cases are available stating the occurrence of BPVT on direct oral anticoagulant therapy. We describe the case of surgically managed aortic BPVT that was diagnosed while the patient was on rivaroxaban.",
"affiliations": "Department of Cardiothoracic Surgery, Essex Cardiothoracic Centre, Basildon, Essex, UK.;Department of Cardiothoracic Surgery, Essex Cardiothoracic Centre, Basildon, Essex, UK.;Department of Cardiothoracic Surgery, Essex Cardiothoracic Centre, Basildon, Essex, UK.;Department of Cardiothoracic Surgery, Essex Cardiothoracic Centre, Basildon, Essex, UK.",
"authors": "Leatherby|Robert J|RJ|;Osman|Mohamed|M|;Birdi|Inderpaul|I|;Serino|Walter|W|",
"chemical_list": "D065427:Factor Xa Inhibitors; D000069552:Rivaroxaban",
"country": "Germany",
"delete": false,
"doi": "10.1093/ejcts/ezy341",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1010-7940",
"issue": "55(6)",
"journal": "European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery",
"keywords": "Aortic valve replacement; Bioprosthetic valve thrombosis; Direct oral anticoagulants",
"medline_ta": "Eur J Cardiothorac Surg",
"mesh_terms": "D000369:Aged, 80 and over; D001021:Aortic Valve; D001024:Aortic Valve Stenosis; D001705:Bioprosthesis; D017548:Echocardiography, Transesophageal; D065427:Factor Xa Inhibitors; D005260:Female; D006331:Heart Diseases; D006350:Heart Valve Prosthesis; D006352:Heart Ventricles; D006801:Humans; D011475:Prosthesis Failure; D000069552:Rivaroxaban; D013927:Thrombosis",
"nlm_unique_id": "8804069",
"other_id": null,
"pages": "1231-1233",
"pmc": null,
"pmid": "30445492",
"pubdate": "2019-06-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D059040:Video-Audio Media",
"references": null,
"title": "Early failure of a bioprosthetic aortic valve due to thrombus formation while on rivaroxaban.",
"title_normalized": "early failure of a bioprosthetic aortic valve due to thrombus formation while on rivaroxaban"
} | [
{
"companynumb": "GB-JNJFOC-20190624593",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": "1",
... |
{
"abstract": "Due to its low incidence, liposarcoma displays a limited number of therapeutic options. However, eribulin recently received approval for the treatment of advanced liposarcoma patients, progressing to at least two chemotherapy lines. We report herein the case of a man initially diagnosed with a leyomiosarcoma, subsequently reclassified as a dedifferentiated liposarcoma, who received eribulin after he failed several therapy lines. Eribulin provided our patient an 8-month disease control and a substantial clinical benefit with no relevant adverse effects, showing a good efficacy and safety profile despite its delayed employ. Additionally, this case strengthens the pivotal importance of molecular profiling in the management of soft tissue sarcomas.",
"affiliations": "Division of Medical Oncology, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy.;Division of Medical Oncology, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy.;Center of Experimental Oncology & Hematology, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy.;Center of Experimental Oncology & Hematology, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy.;Division of Medical Oncology, A.O.U. Policlinico-Vittorio Emanuele, Catania, Italy.",
"authors": "Martorana|Federica|F|https://orcid.org/0000-0001-5062-2914;Vigneri|Paolo|P|;Manzella|Livia|L|;Tirrò|Elena|E|;Soto Parra|Héctor J|HJ|",
"chemical_list": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D005663:Furans; D007659:Ketones; C490954:eribulin",
"country": "England",
"delete": false,
"doi": "10.2217/fon-2019-0596",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1479-6694",
"issue": "16(1s)",
"journal": "Future oncology (London, England)",
"keywords": "eribulin; liposarcoma; molecular profiling",
"medline_ta": "Future Oncol",
"mesh_terms": "D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D057210:Delayed Diagnosis; D003951:Diagnostic Errors; D005663:Furans; D014644:Genetic Variation; D006801:Humans; D007659:Ketones; D007890:Leiomyosarcoma; D008297:Male; D008875:Middle Aged; D019233:Retreatment; D061665:Time-to-Treatment; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101256629",
"other_id": null,
"pages": "9-13",
"pmc": null,
"pmid": "31916463",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Delayed use of eribulin in a heavily pretreated liposarcoma patient, previously misdiagnosed as leiomyosarcoma.",
"title_normalized": "delayed use of eribulin in a heavily pretreated liposarcoma patient previously misdiagnosed as leiomyosarcoma"
} | [
{
"companynumb": "ES-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-241529",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOCETAXEL"
},
"druga... |
{
"abstract": "Angioedema is an asymmetric non-pitting oedema on face, lips, tongue and mucous membranes; any delay in diagnosis and treatment can be fatal. Treatment with lisinopril as an angiotensin converting enzyme (ACE) inhibitor, can be a reason of angioedema. Here we report a case who developed oral-facial edema four years after using lisinopril/hydrochlorothiazide. Laryngeal oedema is a main cause of death in angioedema. The treatment of choice in angioedema including fresh frozen plasma, C1 inhibitor concentrations and BRK-2 antagonists (bradykinin B2 receptor antagonists) were used. In this case; a 77 years old female patient suffering from hypertension was considered. This patient was suffering two days from swelling on her face and neck. Non- allergic angioedema was distinguished in five major forms; acquired (AAO), hereditary (HAE), renin-angiotensin-aldosterone system (RAAS) blocker-dependent, pseudoallergic angioedema (PAS) and an idiopathic angioedema (IAO). She was admitted to our clinic with the diagnosis of hereditary angioedema. Patient had skin edema and life threatening laryngeal edema. In emergency department treatment was started using intravenous methylprednisolone, diphenydramine as well as inhaled and subcutaneous epinephrine simultaneously. Despite the initial treatment, the patient died due to the insufficient respiration and cardiac arrest. The patient has no history of kidney disease.",
"affiliations": "Department of Internal Medicine, Kafkas University Practice and Research Hospital, Kars, Turkey.;Department of Internal Medicine, Kafkas University Practice and Research Hospital, Kars, Turkey.;Kafkas University Practice and Reserch Hospital Emergency Department Kars, Turkey.;Department of Internal Medicine, Kafkas University Practice and Research Hospital, Kars, Turkey.;Department of Internal Medicine, Kafkas University Practice and Research Hospital, Kars, Turkey.;Department of Internal Medicine, Kafkas University Practice and Research Hospital, Kars, Turkey.;Medical University of Pleven, Faculty of Medicine Pleven, Bulgaria.",
"authors": "Atalay|Eray|E|;Özdemir|Mehmet Tamer|MT|;Çiğsar|Gülşen|G|;Omurca|Ferhat|F|;Aslan|Nurullah|N|;Yildiz|Mehmet|M|;Gey|Zehra Bahar|ZB|",
"chemical_list": "D000806:Angiotensin-Converting Enzyme Inhibitors",
"country": "Iran",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1735-1502",
"issue": "14(6)",
"journal": "Iranian journal of allergy, asthma, and immunology",
"keywords": "Angioedema; Angiotensin converting enzyme inhibitor; Lisinopril",
"medline_ta": "Iran J Allergy Asthma Immunol",
"mesh_terms": "D000368:Aged; D000799:Angioedema; D000806:Angiotensin-Converting Enzyme Inhibitors; D017809:Fatal Outcome; D005260:Female; D006801:Humans",
"nlm_unique_id": "101146178",
"other_id": null,
"pages": "642-5",
"pmc": null,
"pmid": "26725563",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Angiotensin Converting Enzyme Inhibitor-related Angioedema: A Case of an Unexpected Death.",
"title_normalized": "angiotensin converting enzyme inhibitor related angioedema a case of an unexpected death"
} | [
{
"companynumb": "TR-MYLANLABS-2016M1002689",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "HYDROCHLOROTHIAZIDE\\LISINOPRIL"
},
"drugaddi... |
{
"abstract": "Thionamides (such as thiamazole/methimazole) are a common first line treatment for Graves' disease. Common side effects include rash, urticaria, and arthralgia. However, thionamide treatment has also been associated with a variety of auto-immune syndromes. Here, we describe a patient presenting with mild arthritis after starting thiamazole. Although severe presentation warrants acute withdrawal of the causative agent, our case suggests that milder forms can be successfully treated with anti-inflammatory drugs alone. Recognition of the syndrome is key to warrant timely and effective treatment.",
"affiliations": "Department of Internal Medicine, Zuyderland Medical Centre, Sittard-Geleen, the Netherlands.",
"authors": "van Moorsel|D|D|;Tummers-de Lind van Wijngaarden|R F|RF|",
"chemical_list": "D013956:Antithyroid Agents; D008713:Methimazole",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "78(6)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D013956:Antithyroid Agents; D018771:Arthralgia; D006111:Graves Disease; D006801:Humans; D008713:Methimazole; D016896:Treatment Outcome",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "389-391",
"pmc": null,
"pmid": "33380538",
"pubdate": "2020-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "An uncommon side effect of thiamazole treatment in Graves' disease.",
"title_normalized": "an uncommon side effect of thiamazole treatment in graves disease"
} | [
{
"companynumb": "NL-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-292255",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHIMAZOLE"
},
"dru... |
{
"abstract": "Although most patients recover within several weeks after acute COVID-19, some of them develop long-lasting clinical symptoms. Renal transplant recipients have an increased mortality risk from COVID-19. We aimed to describe complications occurring after COVID-19 in this group of patients.\n\n\n\nA prospective single-center cohort study was conducted at University Hospital Centre Zagreb. Patients with two negative reverse transcriptase-polymerase chain reaction (RT-PCR) tests for SARS-CoV-2 after COVID-19 were eligible for further follow-up at our outpatient clinic. They underwent detailed clinical and laboratory assessments. The primary outcome was the development of complications after COVID-19.\n\n\n\nOnly 11.53% of renal transplant recipients who survived acute COVID-19 were symptomless and free from new-onset laboratory abnormalities during the median follow-up of 64 days (range: 50-76 days). Three patients died from sepsis after discharge from the hospital. In 47 patients (45.2%), clinical complications were present, while 74 patients (71.2%) had one or more laboratory abnormalities. The most common clinical complications included shortness of breath (19.2%), tiredness (11.5%), peripheral neuropathy (7.7%), self-reported cognitive impairments (5.7%), and dry cough (7.7%). Most common laboratory abnormalities included shortened activated partial thromboplastin time (50%), elevated D-dimers (36.5%), elevated fibrinogen (30.16%), and hypogammaglobulinemia (24%). Positive RT-PCR for cytomegalovirus (8.7%), Epstein-Barr virus (26%), or BK virus (16.3%). Multivariate analysis identified the history of diabetes mellitus and eGFR CKD-EPI as predictors for the development of post-COVID clinical complications. Six months after acute COVID-19, elevated D-dimers persisted with normalization of other laboratory parameters. Twenty-nine patients were hospitalized, mostly with several concomitant problems. However, initially reported clinical problems gradually improved in the majority of patients.\n\n\n\nPost-COVID-19 clinical and laboratory complications are frequent in the renal transplant population, in some of them associated with significant morbidity. All patients recovered from acute COVID-19 should undergo long-term monitoring for evaluation and treatment of complications.",
"affiliations": "Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Nephrology, Clinical Hospital Centre Split and Faculty of Medicine, University of Split, Zagreb, Croatia.;Department of Clinical and Molecular Microbiology, Zagreb, Croatia.;Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Zagreb, Croatia.;Department of Urology, Clinical Hospital Centre Zagreb, Zagreb, Croatia.",
"authors": "Basic-Jukic|Nikolina|N|0000-0002-0221-2758;Juric|Ivana|I|;Furic-Cunko|Vesna|V|;Katalinic|Lea|L|;Radic|Josipa|J|;Bosnjak|Zrinka|Z|;Jelakovic|Bojan|B|;Kastelan|Zeljko|Z|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/iid3.509",
"fulltext": "\n==== Front\nImmun Inflamm Dis\nImmun Inflamm Dis\n10.1002/(ISSN)2050-4527\nIID3\nImmunity, Inflammation and Disease\n2050-4527\nJohn Wiley and Sons Inc. Hoboken\n\n34414665\n10.1002/iid3.509\nIID3509\nOriginal Article\nOriginal Articles\nFollow‐up of renal transplant recipients after acute COVID‐19—A prospective cohort single‐center study\nBASIC‐JUKIC et al.\nBasic‐Jukic Nikolina http://orcid.org/0000-0002-0221-2758\n1 nbasic@kbc-zagreb.hr\n\nJuric Ivana 1\nFuric‐Cunko Vesna 1\nKatalinic Lea 1\nRadic Josipa 2\nBosnjak Zrinka 3\nJelakovic Bojan 1\nKastelan Zeljko 4\n1 Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine University of Zagreb Zagreb Croatia\n2 Department of Nephrology, Clinical Hospital Centre Split and Faculty of Medicine University of Split Zagreb Croatia\n3 Department of Clinical and Molecular Microbiology Zagreb Croatia\n4 Department of Urology Clinical Hospital Centre Zagreb Zagreb Croatia\n* Correspondence Nikolina Basic‐Jukic, MD, PhD, Department of Nephrology, Arterial Hypertension, Dialysis and Transplantation, Clinical Hospital Centre Zagreb and School of Medicine, University of Zagreb, Kispaticeva 12, 10000 Zagreb, Croatia.\nEmail: nbasic@kbc-zagreb.hr\n\n20 8 2021\n12 2021\n9 4 10.1002/iid3.v9.4 15631572\n22 6 2021\n29 7 2021\n© 2021 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.\nhttps://creativecommons.org/licenses/by/4.0/ This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.\n\nAbstract\n\nIntroduction\n\nAlthough most patients recover within several weeks after acute COVID‐19, some of them develop long‐lasting clinical symptoms. Renal transplant recipients have an increased mortality risk from COVID‐19. We aimed to describe complications occurring after COVID‐19 in this group of patients.\n\nMethods\n\nA prospective single‐center cohort study was conducted at University Hospital Centre Zagreb. Patients with two negative reverse transcriptase‐polymerase chain reaction (RT‐PCR) tests for SARS‐CoV‐2 after COVID‐19 were eligible for further follow‐up at our outpatient clinic. They underwent detailed clinical and laboratory assessments. The primary outcome was the development of complications after COVID‐19.\n\nResults\n\nOnly 11.53% of renal transplant recipients who survived acute COVID‐19 were symptomless and free from new‐onset laboratory abnormalities during the median follow‐up of 64 days (range: 50–76 days). Three patients died from sepsis after discharge from the hospital. In 47 patients (45.2%), clinical complications were present, while 74 patients (71.2%) had one or more laboratory abnormalities. The most common clinical complications included shortness of breath (19.2%), tiredness (11.5%), peripheral neuropathy (7.7%), self‐reported cognitive impairments (5.7%), and dry cough (7.7%). Most common laboratory abnormalities included shortened activated partial thromboplastin time (50%), elevated D‐dimers (36.5%), elevated fibrinogen (30.16%), and hypogammaglobulinemia (24%). Positive RT‐PCR for cytomegalovirus (8.7%), Epstein–Barr virus (26%), or BK virus (16.3%). Multivariate analysis identified the history of diabetes mellitus and eGFR CKD‐EPI as predictors for the development of post‐COVID clinical complications. Six months after acute COVID‐19, elevated D‐dimers persisted with normalization of other laboratory parameters. Twenty‐nine patients were hospitalized, mostly with several concomitant problems. However, initially reported clinical problems gradually improved in the majority of patients.\n\nConclusion\n\nPost‐COVID‐19 clinical and laboratory complications are frequent in the renal transplant population, in some of them associated with significant morbidity. All patients recovered from acute COVID‐19 should undergo long‐term monitoring for evaluation and treatment of complications.\n\nAlthough most patients recover within several weeks after acute COVID‐19, some of them develop chronic injury of different organs or have nonspecific long‐lasting clinical symptoms. Renal transplant recipients have clinical and laboratory complications after acute COVID‐19.\n\ncomplications\nlong‐COVID‐19\nmortality\npost‐COVID‐19\nrenal transplantation\nSARS‐CoV‐2\nsource-schema-version-number2.0\ncover-dateDecember 2021\ndetails-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:6.0.9 mode:remove_FC converted:12.11.2021\nBasic‐Jukic N , Juric I , Furic‐Cunko V , et al. Follow‐up of renal transplant recipients after acute COVID‐19—A prospective cohort single‐center study. Immun Inflamm Dis. 2021;9 :1563‐1572. 10.1002/iid3.509\n==== Body\npmc1 INTRODUCTION\n\nWhile still focused on acute SARS‐CoV‐2 infection, which spreads in waves worldwide, many subjects have lingering illness following acute COVID‐19. This condition is known as “post‐COVID‐19” or “long COVID‐19”. 1 , 2 , 3 , 4 Although most patients recover within several weeks, some develop chronic injury of different organs, including lungs, heart, kidneys, brain, and other organs and tissues, or develop nonspecific long‐lasting clinical symptoms. 1 , 2 , 3 , 4 , 5 Interestingly, some patients with severe COVID‐19 recover within a short period, while some with mild forms of the disease, or even asymptomatic, develop significant post‐COVID‐19 complications and require a long time for recovery. 6 A few studies focused on post‐COVID‐19 in the general population. 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8\n\nCurrent literature suggests that hospitalized kidney transplant recipients have a high risk of death from COVID‐19. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 Due to their numerous comorbidities and immunocompromised state, it seems reasonable to expect more complications and prolonged recovery from COVID‐19. Much less is known about COVID‐19 in ambulatory treated renal transplant recipients, and, to our knowledge, there is no data on post‐COVID‐19 in this patients' group.\n\nWe aimed to describe complications occurring after COVID‐19 in renal transplant recipients from our transplant center.\n\n2 METHODS\n\nBy the end of January 2021, we identified 140 adult kidney‐transplant patients with SARS‐CoV‐2 infection at University Hospital Centre Zagreb. Patients with two negative reverse transcriptase‐polymerase chain reaction (RT‐PCR) tests for SARS‐CoV‐2 were eligible for further follow‐up at our outpatient clinic. Patients followed in their local centers, and those with still positive RT‐PCR test for SARS‐CoV‐2 were excluded from the investigation.\n\nA prospective observational cohort study evaluated the outcomes of 104 patients after the initial diagnosis of the COVID‐19.\n\nA post‐COVID‐19 syndrome was defined as the presence of symptoms and laboratory abnormalities persisting beyond 8 weeks of the onset of acute COVID‐19 and not attributable to alternative diagnoses.\n\nTo assess clinical complications, patients were interviewed by a standardized survey by trained transplant nephrologists to recount symptoms during the acute illness and whether they persisted or some new occurred to assess clinical complications: fatigue, shortness of breath, cough, joint pain, headache, cognitive problems, intermittent fever, skin rash, hair loss or other specific problems.\n\nThey also underwent a detailed physical examination. Additional diagnostic methods were used individually (laboratory, radiologic). Data on immunosuppressive regimen and acute COVID‐19 characteristics were recorded. Venous blood samples were collected for complete blood count, biochemistry, coagulation examinations (prothrombin time (PT), activated partial thromboplastin time (APTT) and fibrinogen), D‐dimers, C3, C4, total complement, platelet aggregation with ADP (adenosine 5′‐diphosphate), serum electrophoresis, donor‐specific antibodies, and virology (molecular diagnostic detection for cytomegalovirus [CMV], Epstein–Barr virus [EBV], and BK virus [BKV]). Donor‐specific antibodies were determined by Luminex bead‐based technology (One lambda). Results were compared with historical values.\n\nWe had no data regarding the SARS‐CoV‐2 serology.\n\n2.1 Any laboratory finding outside the reference ranges not present in the patient before the acute COVID‐19 was considered a laboratory complication. Any new onset clinical problem diagnosed by a history taking, physical examination, or radiologic assessment was considered a clinical complication. Allograft dysfunction was defined as the new onset increase in serum creatinine by 25% or newly developed proteinuria.\n\nPatients have been in continuous follow‐up, with reassessment at six months after acute SARS‐CoV‐2 infection.\n\nThe primary outcomes included the presence of clinical complications or the occurrence of laboratory abnormalities.\n\nAbsolute and relative frequencies presented categorical data. The Shapiro–Wilk test tested the normality of the distribution of continuous variables. Continuous data were described by the median and the limits of the interquartile range (IQR). The Mann–Whitney U test was used to compare the median between two groups, while Fisher's exact test was used to analyze the differences between proportions. Logistic regression analysis was used to analyze the independent factors associated with clinical complications or laboratory abnormalities. A stepwise multivariable logistic regression was used to assess the association between potential risk factors and the development of laboratory or clinical complications, adjusting for known confounders. Variables assessed included demographic characteristics (i.e., age, gender, primary kidney disease), clinical characteristics (i.e., different comorbidities), acute COVID‐19 characteristics (i.e., presentation, need for hospitalization). Statistical significance in the univariate analysis was incorporated into the multivariate logistic regression model for in‐depth analysis. The level of significance was set at an α of .05. Considering the relatively small sample size and the possibility of overfitting in the multivariate logistic regression model, we adopted a stepwise forward method (probability for stepwise: entry, p < .05; removal, p < .1) for logistic regression analysis to reduce the number of independent variables entering the model. There was no substitution for the missing data. The statistical analysis was performed using MedCalc® Statistical Software version 19.6 (MedCalc Software Ltd.; https://www.medcalc.org; 2020) and the IBM SPSS Stat. 23 (IBM Corp., Released 2015, IBM SPSS Statistics for Windows, Version 23.0).\n\nThe study was approved by the University Hospital Centre Zagreb Ethics Committee.\n\n3 RESULTS\n\n3.1 Patients' characteristics\n\nFrom March 2020 to January 2021, 140 patients who received renal allograft at Clinical Hospital Centre Zagreb developed COVID‐19 proven by positive SARS‐CoV‐2 real‐time RT‐PCR on the nasopharyngeal swab and were potentially eligible for investigation. Seventy‐seven patients required hospitalization (49 in intensive care unit), and 63 were treated in our outpatient clinic. Twelve patients (8.57%) required mechanical ventilation. Treatment included immunosuppression modification in 71 patients (68.2%), remdesivir (24 patients [17.1%]), hydroxychloroquine (12 patients [8.57%]), prophylactic use of low‐molecular‐weight heparin, increased doses of glucocorticoids and antibiotics. Additionally, eight patients (5.7%) received intravenous immunoglobulins, four (2.8%) received convalescent plasma, and ten patients (7.1%) received hyperimmune anti‐CMV globulin (in exchange for convalescent plasma). Two patients (1.4%) were treated with tocilizumab. Ten patients received no treatment while were diagnosed locally with the mild form of the disease and did not inform us timely about the infection.\n\nOut of the initial cohort of 140 patients with acute COVID‐19, 104 patients had detailed clinical and laboratory investigations. Eleven patients died (three from the acute myocardial infarction, other from the sepsis), eight patients had positive SARS‐CoV‐2 RT‐PCR test and 17 have still not been assessed at our clinic (Figure 1).\n\nFigure 1 Flow‐chart of the study population\n\nPatients have been assessed at our transplant outpatient clinic a median of 64 days (range: 50–76 days) after the initial diagnosis of the COVID‐19. Their characteristics are presented in Table 1.\n\nTable 1 Patients' characteristics\n\nCharacteristic\t\tRange\t\nGender [n (%)]\t\t\t\nMale\t69 (66.3)\t\t\nPrimary kidney disease [n (%)]\t\t\t\nGlomerulonephritis\t32 (30.8)\t\t\nDiabetic nephropathy\t7 (6.7)\t\t\nADPKD\t15 (14.4)\t\t\nChronic pyelonephritis\t9 (8.7)\t\t\nNephroangiosclerosis\t9 (8.7)\t\t\nOther\t32 (30.8)\t\t\nAge (years) [median (IQR)]\t56 (45–65)\t24–80\t\nTime from transplantation (months) [median (IQR)]\t80 (42–126)\t5–204\t\neGFR CKD‐EPI (ml/min/1.73 m2)\t46 (34–61)\t18–133\t\nProteinuria (g/day)\t0.24 (0.13–0.5)\t0.2–2.62\t\nBMI (kg/m2)\t27.1 (24.2–30.2)\t18–45.8\t\nDiabetes mellitus [n (%)]\t21 (20.2)\t\t\nHypertension [n (%)]\t92 (88.5)\t\t\nNumber of antihypertensive drugs [median (IQR)]\t2 (1–3)\t0–5\t\nPrevious thrombosis [n (%)]\t7 (6.7)\t\t\nPrevious myocardial infarction or stroke [n (%)]\t11 (10.6)\t\t\nCOVID‐19 initial symptoms [n (%)]\t\t\t\nFebrility\t82 (78.8)\t\t\nDiarrhea\t25 (24)\t\t\nDyspnea\t65 (62.5)\t\t\nOther\t21 (20.2)\t\t\nAsymptomatic\t10 (9.6)\t\t\nCOVID‐19 initial complications\t\t\t\nHospitalization\t46 (44.2)\t\t\nPneumonia\t49 (47.1)\t\t\nMechanical ventilation\t1 (1)\t\t\nOther\t25 (24)\t\t\nInitial immunosuppression\t\t\t\nTac\t70 (67.3)\t\t\nCyA\t26 (25)\t\t\nMikofenolat\t94 (90.4)\t\t\nAza\t2 (1.9)\t\t\nEverolimus\t13 (12.5)\t\t\nDecortin (doza) [medijan (IQR)]\t5 (5–5)\t0–20\t\nAcute COVID‐19 treatment\t\t\t\nCessation of MMF/Aza\t35 (33.7)\t\t\nDecreasing MMF/Aza\t36 (34.6)\t\t\nCessation of Tac/CyA\t1 (1)\t\t\nDecreasing Tac/CyA\t19 (18.3)\t\t\nHyperimmune anti‐CMV globuline\t9 (8.7)\t\t\nIvlg\t4 (3.8)\t\t\nRemdesivir\t17 (16.3)\t\t\nHydroxychloroquine\t3 (2.8)\t\t\nAbbreviations: Aza, azathioprine; ADPKD, autosomal dominant polycystic kidney disease; BMI, body mass index; CMV, cytomegalovirus; CyA, cyclosporine A; eGFR CKD‐EPI, estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration; Ivig, intravenous immunoglobuline; tac, tacrolimus.\n\nJohn Wiley & Sons, Ltd.\n\n3.2 Post‐COVID‐19 clinical complications\n\nIn the short follow‐up, one or more rehospitalizations were necessary for 17 patients (16.3%) with one or more clinical problems (10 had recurrence of pneumonia (one with lung embolism, one with concomitant allograft dysfunction), five acute allograft dysfunction ± proteinuria, and two developed sepsis). Three patients died from sepsis during the post‐COVID‐19 follow‐up.\n\nClinical complications were present in 47 patients (45.2%) and included shortness of breath (20 patients [19.2%]), tiredness (12 patients [11.5%]), peripheral neuropathy (8 patients [7.7%]), self‐reported cognitive impairments (6 patients [5.7%]), dry cough (8 patients [7.7%]), worsening of hypertension (4 patients [3.8%]), deep venous thrombosis (3 patients [2.9%]), de novo diabetes mellitus (4 patients [3.8%]), skin changes (3 patients [2.9%]), hair loss (2 patients [1.9%]), dizziness (4 patients [3.8%]), costochondritis (2 patients [1.9%]) and anasarca (2 patients [1.9%]), while herpes zoster, lung embolism, paroxysmal atrial fibrillation, significant body weight loss (more than 10% of body mass), cardiorenal syndrome and spontaneous retroperitoneal bleeding were found in one patient each. Biopsy findings revealed borderline acute allograft rejection in one patient, while two had chronic active antibody‐mediated rejection. Most patients with long‐term post‐COVID‐19 symptoms had more than one clinical complication.\n\nThe bivariate analysis identified five significant predictors for the development of post‐COVID clinical complications. The strongest was hospitalization for acute disease, diabetes mellitus, and concomitant laboratory complications, while better allograft function estimated by CKD‐EPI decreased the probability of clinical complications. Stepwise multivariate regression analysis was used to examine the predictors significant for the prediction of clinical complications. Two predictors (diabetes mellitus and eGFR CKD‐EPI) had a unique statistically significant contribution to the model. The model was entirely statistically significant (χ 2 = 12.6, p = .002), and explained from 13.9% (according to Cox and Snell 20 ) to 18.5% (according to Negelkerke 21 ) variance in the presence of clinical complications, and correctly classified 60% of cases (Table 2).\n\nTable 2 Bivariate and multivariate analysis used to examine predictors of clinical complications\n\n\tβ\tWald\tp\tOR (95% CI)\t\nBivariate\t\t\t\t\t\nDiabetes mellitus\t1.24\t3.98\t.04\t3.44 (1.02–11.6)\t\nLaboratory complication\t1.48\t4.38\t.04\t4.4 (1.09–17.6)\t\nAllograft function (eGFR CKD‐EPI)\t−0.03\t6.1\t.01\t0.97 (0.94–0.99)\t\nHospitalization\t1.24\t7.02\t.008\t3.44 (1.38–8.58)\t\nFibrinogen\t0.52\t6.12\t.01\t1.69 (1.11–2.56)\t\nMultivariate\t\t\t\t\t\nDiabetes mellitus\t1.48\t4.76\t.03\t4.42 (1.16–16.8)\t\nAllograft function (eGFR CKD‐EPI)\t−0.03\t7.03\t.008\t0.97 (0.94–0.99)\t\nConstant\t1.54\t5.66\t.02\t\t\nAbbreviations: CI, confidence interval; eGFR CKD‐EPI, estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration; OR, odds ratio.\n\nJohn Wiley & Sons, Ltd.\n\nThe number of rehospitalizations has increased at 6 months post‐COVID‐19. Twenty‐nine patients were hospitalized, mostly with several concomitant problems (leucopenia, viral reactivation, sepsis, pneumonia, urinary tract infections, diabetes mellitus, rhabdomyolysis, psychotic reaction). Initially reported clinical problems gradually improved in the majority of patients. At 6 months, 4 patients (3.8%) still feel tired, 2 (1.9%) had peripheral neuropathy, 5 (4.8%) had diabetes requiring insulin treatment, and 4 (3.8%) complained of hair loss. Seven patients have still been followed by pulmologists with significant improvement of lung status both clinically and radiologically.\n\n3.3 Post‐COVID‐19 laboratory abnormalities\n\nAt the initial evaluation, one or more laboratory abnormalities were present in 74 patients (71.2%). Although allograft function remained stable after acute COVID‐19 in most patients, 8 had allograft dysfunction (7.7%), in 6 of them with proteinuria. One required temporary dialysis post‐COVID‐19 but returned to initial allograft function, and two patients remained dialysis‐dependent (1.9%).\n\nLaboratory abnormalities included increase in serum creatinine (8 patients [7.7%]), de novo development or worsening of proteinuria (6 patients [5.7%]), increased liver chemistries (2 patients (1.9%)), development of de novo DSA (6 patients [5.7%]), shortened APTT (52 patients [50%]), increased D‐dimers (38 patients [36.5%]; in 21 [20.2%] of them were 2× above the reference range), increased fibrinogen (29 patients [30.16%]), positive real‐time polymerase chain reaction for CMV (9 patients [8.7%]), EBV (27 patients [26%] patients) or BK virus (17 patients [16.3%], positive urine and/or blood test). Hypogammaglobulinemia was present in 25 patients (24%). C3 was decreased in 9 patients (8.65%), C4 elevated in one patient (0.9%), while total complement activity remained within the normal range in all patients. Platelet aggregation and prothrombin time were within normal range except for three patients treated with warfarin and had shortened PT. Anemia worsened in 17 patients (16.3%), eight patients (7.7%) had leukopenia, and nine thrombocytopenia (8.7%).\n\nSix months after acute COVID‐19, d‐dimers remained elevated in patients who presented after the initial infection with values 2× above the reference range (21 patient), indicating either ongoing inflammation, coagulopathy, or both. Acetilsalycil acid (75 mg) was introduced in their treatment at the initial visit. Patients with elevated d‐dimers had longer transplant vintage compared with patients with normal values (median 104 months [range: 62–154] vs. 72 months [range: 31–118], p = .04). Activated partial thromboplastin time remained shortened in only two patients.\n\nTwo months after acute COVID‐19, we have introduced erythropoiesis‐stimulating agents in patients with anemia, which resulted in improved serum hemoglobin levels.\n\nOver the observed period of 6 months, seven patients underwent indication biopsy, and one had allograft nephrectomy. One case of collapsing focal segmental glomerulosclerosis was recorded (the paper has been submitted for review). Two patients are dialysis‐dependent, and two have reached the preterminal stage of chronic allograft nephropathy without dialysis.\n\nViral reactivations remained a significant problem at six months post‐COVID‐19. Epstein Barr reactivation was recorded in 27% of patients and required decreasing the dosage of mycophenolate mofetil in 10 patients with a high number of copies (above 50,000/ml) and intravenous immunoglobulins (0.5 g/L) in 4 patients with a high number of copies accompanied with hypogammaglobulinemia. This group of patients is under close surveillance. CMV reactivation was severe in one patient with development of CMV colitis and resistance to ganciclovir and valganciclovir. She received foscarnet and continued with letermovir for secondary prophylaxis with hyperimmune anti‐CMV globulins. BK virus reactivations were more frequent in patients with lower C3 (median: 1.11 [interquartie range [IQR]: 0.93–1.33] vs. 1.37 (IQR: 1.1–1.44, p = .02) and C4 (median 0.21 [IQR: 0.16–0.25] vs. 0.27 [IQR: 0.2–0.3], p = .004).\n\nWe further investigated predictors for the development of laboratory abnormalities. Bivariate regression analysis recognized four significant predictors, the strongest being the existence of clinical complications. Decreasing the dose of tacrolimus during the acute SARS‐CoV‐2 infection had a protective effect (Table 3), remaining significant in the multivariate analysis.\n\nTable 3 Bivariate and multivariate analysis used to examine predictors of laboratory abnormalities after COVID‐19\n\n\tβ\tWald\tp\tOR (95% CI)\t\nBivariate\t\t\t\t\t\nAge\t0.05\t4.55\t.03\t1.05 (1.004–1.11)\t\neGFR CKD‐EPI\t−0.03\t4.24\t.04\t0.97 (0.95–0,99)\t\nDecreasing Tac dose\t−1.95\t7.92\t.005\t0.14 (0.04–0.55)\t\nClinical complication\t1.48\t4.39\t.04\t4.4 (1.09–17,6)\t\nMultivariate\t\t\t\t\t\nDecreasing Tac dose\t−1.92\t7.64\t.006\t0.15 (0.04– 0,57)\t\nConstant\t2.43\t27.2\t<.001\t\t\nAbbreviations: CI, confidence interval; eGFR CKD‐EPI, estimated glomerular filtration rate Chronic Kidney Disease Epidemiology Collaboration; OR, odds ratio; Tac, tacrolimus.\n\nJohn Wiley & Sons, Ltd.\n\n4 DISCUSSION\n\nPublished studies have focused on symptoms and outcomes of acute disease in renal transplant recipients with COVID‐19. 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 22 , 23 To our knowledge, this is the first study focused on the post‐COVID‐19 outcomes in this group of patients.\n\nWe found that only 11.53% of renal transplant recipients who survived acute COVID‐19 had no clinical symptoms or were free from any laboratory abnormality during the median follow‐up of 64 days (range: 50–76 days). Prolonged symptom duration and clinical complications were present in 47 patients (45.2%), while 74 patients (71.2%) had one or more laboratory abnormalities. An Italian study found that in the general population of patients who recovered from COVID‐19, only 12.6% were completely free of any COVID‐19‐related symptom 60 days after the onset of infection. 5 Delayed return to usual health 2 and decreased health‐related quality of life have been reported. 3 In the study of Huang et al., which included 1733 discharged patients with COVID‐19, the most common symptoms were fatigue or muscle weakness (63%) and sleep difficulties (26%). 4 Moradian et al. reported that 42% of their patients were symptom‐free, while fatigue persisted in 19.5%, followed by dyspnea (18.5%), weakness (18%), and activity intolerance (14.5%). 8\n\nThe proportion of patients reporting persistent symptoms in our study was similar or even lower than in other studies. 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 I may be due to the long‐term history of significant clinical problems present in the renal transplant population used to different complications (especially anemia‐related) and may underreport fatigue and dyspnea, the most common prolonged post‐COVID‐19 symptoms in the general population. However, our patients developed numerous severe complications, rare in the general population and maybe kidney transplant‐specific. Additionally, our analysis included both hospitalized and patients treated in the outpatient clinic, while most studies mainly focused on hospitalized patients. A few studies of patients who were not hospitalized for COVID‐19 exist for comparison. The major problem is a very diverse symptom evaluation after the acute disease that disables precise comparison between different studies. In line with this problem, Stavem et al. reported that 53% of nonhospitalized women and 67% of men were symptom‐free 1.5–6 months after the acute COVID‐19. The need for hospitalization during the acute COVID‐19 was a significant adverse risk factor for developing clinical complications in our cohort. Their cohort included a wide time frame after COVID‐19 33 with the expected decrease in occurrence and severity of post‐COVID‐19 symptoms.\n\nIn this study, hospitalization, diabetes mellitus, and renal allograft function estimated by eGFR CKD‐EPI, increased fibrinogen, and presence of any laboratory abnormality were predictors of clinical complications. In contrast, age, eGFR CKD‐EPI, and occurrence of clinical complications predicted the development of laboratory abnormalities. Published data indicates that people over age 50 and those with two or three chronic illnesses are more likely to develop the post‐COVID syndrome. Also, patients with very severe forms of acute disease were found to have an increased risk for post‐COVID. 1 Preexistent chronic renal disease was identified as a risk factor for acute kidney injury during the hospital stay. 34 , 35 , 36 , 37 We have also demonstrated that impaired renal allograft function presents a risk factor for developing post‐COVID‐19 complications in general. All except one patient with acute allograft dysfunction and/or development of proteinuria already had chronic allograft dysfunction. Sepsis, hypoperfusion, exposure to nephrotoxic drugs, and injury to other organs may contribute to the development of acute tubular injury, while immunologic reactions associated with the SARS‐CoV‐2 infection may trigger glomerular alterations.\n\nThe immunomodulatory capacity of different viruses has been shown. 38 , 39 While some patients from our cohort developed de novo donor‐specific antibodies and even allograft rejection, others reactivated either CMV, EBV, or BK virus. These findings may indicate possible immunomodulatory action of SARS‐CoV‐2, emphasizing prompt further investigations while may be associated with significant clinical consequences, including the development of malignancies or acute rejections. This problem may exist in the general population but has not been investigated so far.\n\nCoagulation abnormalities were frequent, most commonly shortened APTT and increased d‐dimers, while PT remained within the reference range. A normal PT with a shortened aPTT indicates the defect within the intrinsic pathway, with possible deficiency of factors VIII, IX, X, or XIII. In line with these findings, four patients developed thromboembolic complications. In contrast, one patient with a normal number of platelets developed spontaneous retroperitoneal bleeding. A growing body of evidence suggests that SARS‐CoV‐2 may induce different coagulation disorders associated with inferior outcomes. The most frequent pattern of coagulopathy in acute COVID‐19 patients includes increased levels of fibrinogen and D‐dimer, an increased PT and the aPTT, and a mild decrease in platelet count. 40 , 41 , 42 , 43 D‐dimer was most consistently associated with COVID‐19. 41 The phenomenon of prolonged post‐COVID‐19 procoagulant state found in our cohort may be present in the general population as well and needs to be examined. These findings may have implications for understanding the effects of COVID‐19 on the development of thromboembolic complications. While the mechanism of this association remains unclear, SARS‐CoV‐2 infection has been associated with numerous physiologic alterations, including cytokine storm, which may influence the coagulation system, 44 leading to venous thromboembolism. 45 Normal platelet counts with procoagulant state indicated by shortened APTT and increased d‐dimers frequently found in our population may justify the use of acetylsalicylic acid in prophylactic regimens. It remains to elucidate if selected patients require more aggressive anticoagulation. However, several cases of spontaneous bleeding reported to date 46 and one recorded in our group, highlighting the need for an individualized approach.\n\nThe complex interplay of the prothrombotic state caused by COVID‐19, anemia and the need to prevent cardiovascular complications required unprecedented treatment decisions. For this reason we were careful with introduction of erythropoiesis‐stimulating agents for treatment of anemia.\n\nDecreasing the dose of tacrolimus during the acute COVID‐19 had a protective effect on developing laboratory complications in our cohort. It may be in contrast with previous findings of the potentially protective role for tacrolimus during the acute‐COVID‐19. A TACROVID trial showed that methylprednisolone and tacrolimus might have a beneficial effect in COVID‐19 patients with severe pulmonary failure and systemic hyperinflammatory syndrome, probably due to the ability of tacrolimus to inhibit both the SARS‐CoV‐2 replication and the secondary cytokine storm. 47 A recently published meta‐analysis that included 202 solid organ transplant recipients concluded that receiving tacrolimus could benefit COVID‐19. However, their study included only 125 renal transplant recipients and was based generally on case reports or case series. 48 While possibly beneficial during the acute COVID‐19 due to the anti‐inflammatory effect, tacrolimus may be associated with an additional endothelial injury 49 , 50 induced by SARS‐CoV‐2. Further studies are needed to clarify these results.\n\nSix months after acute COVID‐19, most of our patients significantly improved and had no symptoms. However, many patients required rehospitalizations for severe complications. Some of them are hospital‐dependent, with complications arising one after the other. Reactivation of different viruses remains challenging. Longer follow‐up is needed to establish consequences, and those patients require close surveillance.\n\nLong‐term follow up by pulmologists is necessary for patients with more pronounced respiratory symptoms, although most recovered rapidly.\n\nThis study has several limitations. First, the visit schedule was determined by the recovery from acute COVID‐19. It meant that we did not have the same time point for a check‐up for every patient, impacting the results. Second, baseline EBV DNA expression was not available, which may have led to an overestimation of EBV reactivations. Third, we had no baseline serum electrophoresis which may overestimate hypogammaglobulinemia as the post‐COVID‐19 complication. Fourth, we had no details for all patients regarding the intrahospital laboratory findings and treatment during the acute COVID‐19. Fifth, we had no results of SARS‐CoV‐2 serology. Finally, this is a single‐center study conducted in a tertiary referral center. Together with a relatively small number of patients in the study, this may potentially limit the generalizability of our results. However, this is the first study focused on the problem of post‐COVID‐19 in renal transplant recipients. It included hospitalized and ambulatory patients giving essential insights into clinical problems that occur even in patients without any symptoms at the initial presentation.\n\nIn conclusion, recovery from acute COVID‐19 is associated with different clinical and laboratory complications in the renal transplant population, regardless of the age or severity of initial symptoms. Complications were more frequent in patients with decreased glomerular filtration and patients with diabetes mellitus. A better understanding of the post‐COVID‐19 clinical course in this population may help direct actions to prevent major complications and mortality. All patients recovered from COVID‐19 should undergo long‐term monitoring for evaluation and treatment of complications. Further studies with long‐term follow‐up are needed.\n\nAUTHOR CONTRIBUTIONS\n\nNikolina Basic‐Jukic initiated the study, participated in study planning, designed data collection tools, and questionnaire, monitored data collection, prepared the statistical analysis plan, and drafted and revised the paper. Ivana Juric, Vesna Furic‐Cunko, and Lea Katalinic contributed to study planning, administered and monitored data collection, and revised the paper. Zrinka Bosnjak and Bojan Jelakovic participated in study planning, analysis, and revising the paper. Zeljko Kastelan contributed to study conception, study planning, data collection and monitoring, analysis and revised the paper. All authors reviewed and approved the final version.\n\nDATA AVAILABILITY STATEMENT\n\nThe data that support the findings of this study are available from the corresponding author upon reasonable request.\n==== Refs\nREFERENCES\n\n1 Nalbandian A , Sehgal K , Gupta A , et al. Post‐acute COVID‐19 syndrome. Nat Med. 2021;27 :601‐615.33753937\n2 Tenforde MW , Kim SS , Lindsell CJ , et al. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID‐19 in a multistate health care systems network—United States, March‐June 2020. MMWR Morb Mortal Wkly Rep. 2020;69 (30 ):993‐998.32730238\n3 Garrigues E , Janvier P , Kherabi Y , et al. Post‐discharge persistent symptoms and health‐related quality of life after hospitalization for COVID‐19. J Infect. 2020 Dec;81 (6 ):e4‐e6.32853602\n4 Huang C , Huang L , Wang Y , et al. 6‐month consequences of COVID‐19 in patients discharged from hospital: a cohort study. Lancet. 2021;397 (10270 ):220‐232.33428867\n5 Carfì A , Bernabei R , Landi F , Gemelli Against COVID‐19 Post‐Acute Care Study Group . Persistent symptoms in patients after acute COVID‐19. JAMA. 2020;324 :603‐605.32644129\n6 Townsend L , Dowds J , O'Brien K , et al. Persistent poor health post‐COVID‐19 is not associated with respiratory complications or initial disease severity. Ann Am Thorac Soc. 2021;18 :1431‐1432.\n7 Goërtz YMJ , Van Herck M , Delbressine JM , et al. Persistent symptoms 3 months after a SARS‐CoV‐2 infection: the post‐COVID‐19 syndrome? ERJ Open Res. 2020;6 :542‐2020.\n8 Moradian ST , Parandeh A , Khalili R , Karimi L . Delayed symptoms in patients recovered from COVID‐19. Iran J Public Health. 2020;49 (11 ):2120‐2127.33708732\n9 Mahalingasivam V , Craik A , Tomlinson LA , et al. A systematic review of COVID‐19 and kidney transplantation. Kidney Int Rep. 2021;6 (1 ):24‐45.33163708\n10 Nair V , Jandovitz N , Hirsch JS , et al. COVID‐19 in kidney transplant recipients. Am J Transplant. 2020;20 (7 ):1819‐1825.32351040\n11 Pereira MR , Mohan S , Cohen DJ , et al. COVID‐19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant. 2020;20 (7 ):1800‐1808.32330343\n12 Hilbrands LB , Duivenvoorden R , Vart P , et al. COVID‐19‐related mortality in kidney transplant and dialysis patients: results of the ERACODA collaboration. Nephrol Dial Transplant. 2020;35 (11 ):1973‐1983.33151337\n13 Alfishawy M , Elbendary A , Mohamed M , Nassar M . COVID‐19 Mortality in Transplant Recipients. Int J Organ Transplant Med. 2020;11 (4 ):145‐162.33335696\n14 Ozturk S , Turgutalp K , Arici M , et al. Mortality analysis of COVID‐19 infection in chronic kidney disease, haemodialysis and renal transplant patients compared with patients without kidney disease: a nationwide analysis from Turkey. Nephrol Dial Transplant. 2020;35 (12 ):2083‐2095.33275763\n15 Adapa S , Chenna A , Balla M , et al. COVID‐19 pandemic causing acute kidney injury and impact on patients with chronic kidney disease and renal transplantation. J Clin Med Res. 2020;12 (6 ):352‐361.32587651\n16 Cravedi P , Mothi SS , Azzi Y , et al. COVID‐19 and kidney transplantation: results from the TANGO International Transplant Consortium. Am J Transplant. 2020;20 (11 ):3140‐3148.32649791\n17 Fernández‐Ruiz M , Andrés A , Loinaz C , et al. COVID‐19 in solid organ transplant recipients: a single‐center case series from Spain. Am J Transplant. 2020;20 (7 ):1849‐1858.32301155\n18 Kates OS , Haydel BM , Florman SS , et al. COVID‐19 in solid organ transplant: a multi‐center cohort study. Clin Infect Dis. 2020:ciaa1097.32766815\n19 Elias M , Pievani D , Randoux C , et al. COVID‐19 infection in kidney transplant recipients: disease incidence and clinical outcomes. J Am Soc Nephrol. 2020;31 (10 ):2413‐2423.32847984\n20 Cox DR & Snell EJ . Analysis of Binary Data. Vol 32. Monographs on Statistics and Applied Probability. London; 1989.\n21 Nagelkerke NJD . A note on a general definition of the coefficient of determination. Biometrika. 1991;78 :691‐692.\n22 Al‐Otaibi TM , Gheith OA , Abuelmagd MM , et al. Better outcome of COVID‐19 positive kidney transplant recipients during the unremitting stage with optimized anticoagulation and immunosuppression. Clin Transplant. 2021;25 :e14297.\n23 Akalin E , Azzi Y , Bartash R , et al. Covid‐19 and kidney transplantation. N Engl J Med. 2020;382 (25 ):2475‐2477.32329975\n24 Kamal M , Abo Omirah M , Hussein A , Saeed H . Assessment and characterisation of post‐COVID‐19 manifestations. Int J Clin Pract. 2020;75 :e13746.32991035\n25 Rudroff T , Fietsam AC , Deters JR , Bryant AD , Kamholz J . Post‐COVID‐19 fatigue: potential contributing factors. Brain Sci. 2020;10 (12 ):1012.\n26 Spruit MA , Holland AE , Singh SJ , Tonia T , Wilson KC , Troosters T . COVID‐19: Interim guidance on rehabilitation in the hospital and post‐hospital phase from a European Respiratory Society and American Thoracic Society‐coordinated International Task Force. Eur Respir J. 2020;56 (6 ):2002197.\n27 Torres‐Castro R , Solis‐Navarro L , Sitjà‐Rabert M , Vilaró J . Functional limitations Post‐COVID‐19: a comprehensive assessment strategy. Arch Bronconeumol. 2021;57 (suppl 1 ):7‐8.\n28 Wijeratne T , Crewther S . Post‐COVID 19 Neurological Syndrome (PCNS); a novel syndrome with challenges for the global neurology community. J Neurol Sci. 2020;419 :117179.33070003\n29 Mitrani RD , Dabas N , Goldberger JJ . COVID‐19 cardiac injury: implications for long‐term surveillance and outcomes in survivors. Heart Rhythm. 2020;17 (11 ):1984‐1990.32599178\n30 Ahmad Alhiyari M , Ata F , Islam Alghizzawi M , et al. Post COVID‐19 fibrosis, an emerging complication of SARS‐CoV‐2 infection. IDCases. 2020;23 :e01041.33425682\n31 Dani M , Dirksen A , Taraborrelli P , et al. Autonomic dysfunction in 'long COVID': rationale, physiology and management strategies. Clin Med. 2021;21 (1 ):e63‐e67.\n32 Woo MS , Malsy J , Pöttgen J , et al. Frequent neurocognitive deficits after recovery from mild COVID‐19. Brain Commun. 2020;2 (2 ):205.\n33 Stavem K , Ghanima W , Olsen MK , Gilboe HM , Einvik G . Persistent symptoms 1.5‐6 months after COVID‐19 in non‐hospitalised subjects: a population‐based cohort study. Thorax. 2020;76 (4 ):405‐407.33273028\n34 Xu C , Zhang T , Zhu N , Han M . Characteristics of COVID‐19 patients with preexisting CKD history. Int Urol Nephrol. 2021;5 :1‐9.\n35 ÖZtürk S , Turgutalp K , Arici M , et al. Impact of hospital‐acquired acute kidney injury on Covid‐19 outcomes in patients with and without chronic kidney disease: a multicentre, retrospective cohort study. Turk J Med Sci. 2021;51 :947‐961.33611868\n36 Dirim AB , Demir E , Yadigar S , et al. COVID‐19 in chronic kidney disease: a retrospective, propensity score‐matched cohort study. Int Urol Nephrol. 2021;6 :1‐9.\n37 Ronco C , Reis T , Husain‐Syed F . Management of acute kidney injury in patients with COVID‐19. Lancet Respir Med. 2020;8 (7 ):P738‐P742.\n38 Jackson SE , Redeker A , Arens R , et al. CMV immune evasion and manipulation of the immune system with aging. GeroScience. 2017;39 :273‐291.28647908\n39 Morales‐Sánchez A , Fuentes‐Panana EM . The immunomodulatory capacity of an Epstein‐Barr virus abortive lytic cycle: potential contribution to viral tumorigenesis. Cancers. 2018;10 (4 ):98.\n40 Connors JM , Levy JH . Thromboinflammation and the hypercoagulability of COVID‐19. J Thromb Haemost. 2020;18 :1559‐1561.32302453\n41 Tang N , Li D , Wang X , Sun Z . Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost. 2020;18 :844‐847.32073213\n42 Lippi G , Favaloro EJ . D‐dimer is associated with severity of coronavirus disease 2019: a pooled analysis. Thromb Haemost. 2020;120 :876‐878.32246450\n43 García‐Ortega A , de la Rosa D , Oscullo G , Castillo‐Villegas D , López‐Reyes R , Martínez‐García MÁ . Coagulation disorders and thromboembolic disease in COVID‐19: review of current evidence in search of a better approach. J Thorac Dis. 2021;13 (2 ):1239‐1255.33717596\n44 Jose RJ , Manuel A . COVID‐19 cytokine storm: the interplay between inflammation and coagulation. Lancet. 2020;8 (6 ):e46‐e47.\n45 Barnes GD , Burnett A , Allen A , et al. Thromboembolism and anticoagulant therapy during the COVID‐19 pandemic: interim clinical guidance from the anticoagulation forum. J Thromb Thrombolysis. 2020;50 (1 ):72‐81.32440883\n46 Vos CG , Gravendeel J , Keller BPJA . Three cases of spontaneous major bleeding in patients with a COVID‐19 infection. Acta Chir Belg. 2021;26 :1‐4.\n47 Solanich X , Antolí A , Padullés N , et al. Pragmatic, open‐label, single‐center, randomized, phase II clinical trial to evaluate the efficacy and safety of methylprednisolone pulses and tacrolimus in patients with severe pneumonia secondary to COVID‐19: the TACROVID trial protocol. Contemp Clin Trials Commun. 2021;21 :100716.33495742\n48 Karruli A , Spiezia S , Boccia F , et al. Effect of immunosuppression maintenance in solid organ transplant recipients with COVID‐19: systematic review and meta‐analysis. Transpl Infect Dis. 2021;28 :e13595.\n49 Eguchi R , Kubo S , Ohta T , et al. FK506 induces endothelial dysfunction through attenuation of Akt and ERK1/2 independently of calcineurin inhibition and the caspase pathway. Cell Signal. 2013;25 (9 ):1731‐1738.23707520\n50 Kidokoro K , Satoh M , Nagasu H , et al. Tacrolimus induces glomerular injury via endothelial dysfunction caused by reactive oxygen species and inflammatory change. Kidney Blood Press Res. 2012;35 (6 ):549‐557.22890154\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2050-4527",
"issue": "9(4)",
"journal": "Immunity, inflammation and disease",
"keywords": "SARS-CoV-2; complications; long-COVID-19; mortality; post-COVID-19; renal transplantation",
"medline_ta": "Immun Inflamm Dis",
"mesh_terms": "D000086382:COVID-19; D015331:Cohort Studies; D020031:Epstein-Barr Virus Infections; D005500:Follow-Up Studies; D004854:Herpesvirus 4, Human; D006801:Humans; D016030:Kidney Transplantation; D011446:Prospective Studies; D000086402:SARS-CoV-2",
"nlm_unique_id": "101635460",
"other_id": null,
"pages": "1563-1572",
"pmc": null,
"pmid": "34414665",
"pubdate": "2021-12",
"publication_types": "D016428:Journal Article",
"references": "33641202;33768630;32817258;23707520;32302453;32853602;32353251;33596163;33257910;33243837;32730238;32599178;32301155;32766815;29601503;33769205;33611868;32246450;33163708;28647908;34629627;33495742;32073213;32329975;33425682;33428867;33273028;32587651;32847984;33335696;32416769;22890154;33717596;33070003;32644129;33275763;33376990;33151337;34414665;33674950;33352638;32440883;33708732;32991035;33548044;32351040;33753937;32330343;32649791",
"title": "Follow-up of renal transplant recipients after acute COVID-19-A prospective cohort single-center study.",
"title_normalized": "follow up of renal transplant recipients after acute covid 19 a prospective cohort single center study"
} | [
{
"companynumb": "HR-ROCHE-2971875",
"fulfillexpeditecriteria": "1",
"occurcountry": null,
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TOCILIZUMAB"
},
"drugadditional": "3",
"drug... |
{
"abstract": "We report clinical findings of three patients presenting with thrombosis and thrombocytopaenia 10-16 days following the first dose of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2. All patients presented to a major university teaching hospital in the UK over a 5-day period and were found to have high-titre antibodies against platelet factor 4 (PF4) without previous exposure to heparin. All three patients presented with extensive venous thrombosis, significant thrombocytopaenia, elevated D-dimer and borderline low fibrinogen. Two had fatal intracerebral haemorrhage secondary to cavernous venous sinus thrombosis and one had PE. Reference laboratory testing of serum demonstrated anti-PF4 antibodies in all three patients. The clinical and laboratory findings confirmed vaccine-induced thrombotic thrombocytopaenia (VITT) which was poorly described at the time of presentation. We were able to manage successfully one patient with PE with intravenous immunoglobulin and corticosteroids.",
"affiliations": "Haematology, University Hospitals of North Staffordshire NHS Trust, Stoke-on-Trent, UK fehmida.bano@uhnm.nhs.uk.;Haematology, University Hospitals of North Staffordshire NHS Trust, Stoke-on-Trent, UK.;Haematology, University Hospitals of North Staffordshire NHS Trust, Stoke-on-Trent, UK.",
"authors": "Bano|Fehmida|F|http://orcid.org/0000-0001-8260-7604;Badugama|Buddikha|B|;Chandra|Deepak|D|",
"chemical_list": "D000086663:COVID-19 Vaccines; D000090985:ChAdOx1 nCoV-19",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2021-243894",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(7)",
"journal": "BMJ case reports",
"keywords": "vaccination/immunisation; venous thromboembolism",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000086382:COVID-19; D000086663:COVID-19 Vaccines; D000090985:ChAdOx1 nCoV-19; D006801:Humans; D000086402:SARS-CoV-2; D013921:Thrombocytopenia; D013927:Thrombosis; D006113:United Kingdom; D014611:Vaccination",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34257129",
"pubdate": "2021-07-13",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "33306989;17488345;33861525;28846826;33952445;16793681;33835769;33835768;33877737;28416511",
"title": "Thrombosis and thrombocytopaenia after ChAdOx1 nCoV-19 vaccination: a single UK centre experience.",
"title_normalized": "thrombosis and thrombocytopaenia after chadox1 ncov 19 vaccination a single uk centre experience"
} | [
{
"companynumb": "GB-TEVA-2021-GB-1963695",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTo describe a little-known therapy-related small-airway phenomenon presumably caused by mucosal irritation in patients undergoing allogeneic stem cell transplantation (allo-SCT).\n\n\nMETHODS\nRetrospective database search at our institution identified 739 hematologic patients who underwent chemotherapy + allo-SCT between September 2004 and March 2014. After infectious pulmonary complications were excluded, 75 patients (female = 24; male = 51; median age = 47 years) with signs of generalized bronchiolitis (GB) on chest high-resolution computed tomography were identified. Computed tomography (CT) was performed proximate to chemotherapy onset; 92% had follow-up CT (mean, 1.9 weeks). The presence of centrilobular nodules, bronchial wall thickening (BWT), tree-in-bud (distributed diffuse vs. focal), ground-glass opacity, airspace opacification, luminal impactions, and air trapping was correlated with occurrence and duration of oral mucositis and therapy characteristics. Intensity of tree-in-bud and centrilobular nodules was graded absent (grade = 0), moderate (grade = 1), or marked (grade = 2).\n\n\nRESULTS\nOverall incidence of GB among allo-SCT patients was 10.14%. GB was diagnosed at the time point of transplantation with a mean duration of CT findings of 4 weeks (±2.7). Tree-in-bud (17% [grade 2] and 83% [grade 1]) and BWT were present in 100% of the patients. Centrilobular nodules diffusely distributed were found in 45.5% of patients (20% [grade 2], 24% [grade 1], and 56% [none]). Air trapping and mosaic pattern were found in 13% and 16% of the patients, respectively. Resolution of GB was spontaneous. GB and its severity correlated with the temporal course and grade of oral mucositis; frequency and degree were not significantly influenced by the chemotherapy regimen. The incidence of GB in high-resolution computed tomography was statistically and significantly higher in patients with oral mucositis (P < 0.035).\n\n\nCONCLUSIONS\nGB is frequent during chemotherapy for allo-SCT and is characterized by an even distribution of tree-in-bud, BWT, centrilobular nodules, mild clinical symptoms, and spontaneous resolution.",
"affiliations": "Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany. Electronic address: christopher.kloth@med.uni-tuebingen.de.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.;Department of Internal Medicine II, Eberhard-Karls-University,72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.;Department of Internal Medicine II, Eberhard-Karls-University,72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.;Department of Diagnostic and Interventional Radiology, Eberhard-Karls-University, Hoppe-Seyler-Str. 3, 72076 Tübingen, Germany.",
"authors": "Kloth|C|C|;Grosse|U|U|;Wirths|S|S|;Gatidis|S|S|;Bethge|W|W|;Nikolaou|K|K|;Horger|M|M|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-6332",
"issue": "22(12)",
"journal": "Academic radiology",
"keywords": "Allogeneic stem cell transplantation (allo-SCT); Generalized bronchiolitis; HRCT; Mucositis",
"medline_ta": "Acad Radiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D001988:Bronchiolitis; D005260:Female; D006402:Hematologic Diseases; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D012141:Respiratory Tract Infections; D012189:Retrospective Studies; D013280:Stomatitis; D014057:Tomography, X-Ray Computed; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D055815:Young Adult",
"nlm_unique_id": "9440159",
"other_id": null,
"pages": "1546-54",
"pmc": null,
"pmid": "26482262",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Noninfectious Generalized Bronchiolitis in the Setting of Allogeneic Stem Cell Transplantation: A Potential Mimic of Lower Respiratory Tract Infection.",
"title_normalized": "noninfectious generalized bronchiolitis in the setting of allogeneic stem cell transplantation a potential mimic of lower respiratory tract infection"
} | [
{
"companynumb": "DE-FRESENIUS KABI-FK201701845",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
},
... |
{
"abstract": "OBJECTIVE\nAcute generalized exanthematous pustulosis (AGEP) is a rare and severe type of drug eruption. Dihydrocodeine phosphate is a semisynthetic opioid analgesic. Recently, recessive mutations in IL36RN have been identified in generalized pustular psoriasis (GPP). To date, 4 cases of AGEP and IL36RN mutation without previous history of psoriasis vulgaris (PV) have been reported.\n\n\nMETHODS\nA woman in her 60s with PV presented with diffuse erythema, nonfollicular pustules, and fever. She had been treated with dextromethorphan hydrobromide hydrate, amoxicillin hydrate, clarithromycin, dihydrocodeine phosphate, tipepidine hibenzate, and tulobuterol tape for a cough and common cold. Based on histopathologic results and a positive result in a drug provocation test with dihydrocodeine phosphate, she was diagnosed with AGEP. A heterozygous IL36RN mutation c.28C>T (p.Arg10X) was also confirmed by mutation analysis.\n\n\nCONCLUSIONS\nThis is the first report of dihydrocodeine phosphate-induced AGEP. In this case, helper T cells, type 17, might have been activated because of morphine and underlying PV, followed by increased production of interleukin (IL) 36. However, because of the IL36RN mutation, IL-36 signaling was uncontrolled, which might have resulted in the occurrence of AGEP. An IL36RN mutation might underlie several different pustular skin eruptions, including AGEP and GPP, and further accumulation of patient data is required.",
"affiliations": "Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.;Department of Dermatology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.",
"authors": "Nakai|Noriaki|N|;Sugiura|Kazumitsu|K|;Akiyama|Masashi|M|;Katoh|Norito|N|",
"chemical_list": "D000701:Analgesics, Opioid; C122187:IL36RN protein, human; D007378:Interleukins; C014481:dihydrocodeine; D003061:Codeine",
"country": "United States",
"delete": false,
"doi": "10.1001/jamadermatol.2014.3002",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2168-6068",
"issue": "151(3)",
"journal": "JAMA dermatology",
"keywords": null,
"medline_ta": "JAMA Dermatol",
"mesh_terms": "D056150:Acute Generalized Exanthematous Pustulosis; D000701:Analgesics, Opioid; D003061:Codeine; D005260:Female; D006579:Heterozygote; D006801:Humans; D007378:Interleukins; D008875:Middle Aged; D011565:Psoriasis",
"nlm_unique_id": "101589530",
"other_id": null,
"pages": "311-5",
"pmc": null,
"pmid": "25409173",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute generalized exanthematous pustulosis caused by dihydrocodeine phosphate in a patient with psoriasis vulgaris and a heterozygous IL36RN mutation.",
"title_normalized": "acute generalized exanthematous pustulosis caused by dihydrocodeine phosphate in a patient with psoriasis vulgaris and a heterozygous il36rn mutation"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-95493",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TIPEPIDINE HIBENZATE"
},
... |
{
"abstract": "The glucagon-like peptide-2 (GLP-2) analogue teduglutide is a medical treatment option for patients with short-bowel syndrome-associated chronic intestinal failure. Because studies in mice have shown that GLP-2 analogues may promote the growth of colonic neoplasms, surveillance colonoscopies before and during teduglutide therapy were recommended. The occurrence of small-intestinal neoplasms has not been reported so far, except for a recent report about de novo development of hamartomatous duodenal polyps. We report a case of de novo development of small-intestinal premalignant adenomatous polyps in both bulbar duodenum and distal jejunum in a patient treated with teduglutide for 41 months. Therefore, additional endoscopic surveillance of the upper gastrointestinal tract may be advised during teduglutide therapy for early detection and removal of potential small-bowel adenomas.",
"affiliations": "Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin, Institute of Health, Institute of Pathology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin, Institute of Health, Institute of Pathology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Medical Department, Division of Hepatology and Gastroenterology, Berlin, Germany.;Asklepios Klinik St. Georg, Department of Internal Medicine and Gastroenterology, Hamburg, Germany.",
"authors": "Pevny|Sophie|S|;Pape|Ulrich-Frank|UF|;Elezkurtaj|Sefer|S|;Rieger|Anja|A|;Jürgensen|Christian|C|;Blüthner|Elisabeth|E|0000-0002-7008-8795;Jochum|Christoph|C|;Tacke|Frank|F|;Maasberg|Sebastian|S|0000-0003-2321-4776",
"chemical_list": "D005765:Gastrointestinal Agents; D010455:Peptides; C494910:teduglutide",
"country": "United States",
"delete": false,
"doi": "10.1002/jpen.1982",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-6071",
"issue": "45(3)",
"journal": "JPEN. Journal of parenteral and enteral nutrition",
"keywords": "duodenal adenoma; endoscopy; glucagon-like peptide 2; intestinal failure; jejunal adenoma; parenteral nutrition; short bowel syndrome; teduglutide",
"medline_ta": "JPEN J Parenter Enteral Nutr",
"mesh_terms": "D000236:Adenoma; D005765:Gastrointestinal Agents; D006801:Humans; D007583:Jejunum; D010455:Peptides; D012778:Short Bowel Syndrome",
"nlm_unique_id": "7804134",
"other_id": null,
"pages": "652-656",
"pmc": null,
"pmid": "32740933",
"pubdate": "2021-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "De Novo Development of Distal Jejunal and Duodenal Adenomas After 41 Months of Teduglutide Treatment in a Patient With Short-Bowel Syndrome: A Case Report.",
"title_normalized": "de novo development of distal jejunal and duodenal adenomas after 41 months of teduglutide treatment in a patient with short bowel syndrome a case report"
} | [
{
"companynumb": "DE-TAKEDA-2021TUS024539",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TEDUGLUTIDE"
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"abstract": "Blockade of the immunological checkpoint programmed death 1 (PD-1) using monoclonal antibodies has shown robust anti-tumor activity across a broad range of solid and hematological malignancies including melanoma and renal cell carcinoma (RCC). Characteristic markers such as the presence of tumor infiltrating lymphocytes, PD-L1 status, and mutational load may be equally or even more important in predicting clinical benefit from PD-1 pathway blockade than tumor histology. This case of a patient with concurrent metastatic melanoma and metastatic RCC, both of which were controlled for more than a year after a single dose of the anti-PD-1 antibody pembrolizumab, illustrates the potential to simultaneously treat distinct immunogenic tumors with anti-PD-1 agents.",
"affiliations": "Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Imaging, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.;Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA USA.",
"authors": "Marmarelis|Melina E|ME|;Davis|Meredith R|MR|;Sethi|Nilay S|NS|;Krajewksi|Katherine M|KM|;McKay|Rana R|RR|;Choueiri|Toni K|TK|;Ott|Patrick A|PA|",
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"fulltext": "\n==== Front\nJ Immunother CancerJ Immunother CancerJournal for Immunotherapy of Cancer2051-1426BioMed Central London 12910.1186/s40425-016-0129-xCase ReportTumor control with PD-1 inhibition in a patient with concurrent metastatic melanoma and renal cell carcinoma Marmarelis Melina E. Melina_Marmarelis@dfci.harvard.edu Davis Meredith R. Meredith_Davis@dfci.harvard.edu Sethi Nilay S. Nilay_Sethi@dfci.harvard.edu Krajewksi Katherine M. kmkrajewski@partners.org McKay Rana R. Rana_McKay@dfci.harvard.edu Choueiri Toni K. Toni_Choueiri@dfci.harvard.edu Ott Patrick A. 617-582-9030Patrick_Ott@dfci.harvard.edu Department of Medical Oncology, Dana Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA USA Department of Imaging, Dana Farber Cancer Institute, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA USA 19 4 2016 19 4 2016 2016 4 2612 1 2016 4 4 2016 © Marmarelis et al. 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Blockade of the immunological checkpoint programmed death 1 (PD-1) using monoclonal antibodies has shown robust anti-tumor activity across a broad range of solid and hematological malignancies including melanoma and renal cell carcinoma (RCC). Characteristic markers such as the presence of tumor infiltrating lymphocytes, PD-L1 status, and mutational load may be equally or even more important in predicting clinical benefit from PD-1 pathway blockade than tumor histology. This case of a patient with concurrent metastatic melanoma and metastatic RCC, both of which were controlled for more than a year after a single dose of the anti-PD-1 antibody pembrolizumab, illustrates the potential to simultaneously treat distinct immunogenic tumors with anti-PD-1 agents.\n\nKeywords\nPD-1Immune checkpoint blockadeAntibody therapyMelanomaRenal cell cancerImmunotherapyConcurrent cancerissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nImmune checkpoint blockade using monoclonal antibodies directed against negative regulators such as cytotoxic lymphocyte antigen-4 (CTLA-4) and programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) has emerged as a powerful strategy in the treatment of different cancer types [1–3]. Both CTLA-4 and PD-1 are cell surface receptors that negatively regulate the immune response and their blockade can induce or enhance anti-tumor T cell activity. The anti-CTLA-4 monoclonal antibody ipilimumab demonstrated a survival benefit in Phase III studies for the first time in patients with advanced melanoma [2, 4], leading to approval in several countries. Durable tumor responses in patients with advanced melanoma being treated with ipilimumab yielded a plateau in the survival curve at 21 % 3 years out from study initiation [5]. Inhibition of the PD-1/PD-L1 pathway showed objective response rates of up to 40 % and superior overall survival when compared to ipilimumab in advanced melanoma [6]. Strikingly, as opposed to the relatively modest anti-tumor activity of ipilimumab outside of melanoma, PD-1 pathway inhibition is efficacious against a wide spectrum of solid and hematological malignancies including RCC, non-small cell lung cancer, bladder cancer, and Hodgkin’s lymphoma. There is evidence that tumor characteristics such as the presence of an immune cell infiltrate, expression of PD-L1 on tumor and/or immune cells, and an elevated mutational load with corresponding expression of neoantigens are predictive of anti-tumor activity with PD-1 pathway inhibition [7–10]. The broad anti-tumor activity of PD-1 pathway blockade suggests that it may be effective against different tumors present in one individual. These considerations may be critical in designing a treatment plan for a patient with metastases from different primary tumors, which poses a particular challenge in current cancer therapeutics. Here, we present a patient with concurrent metatstatic melanoma and RCC who achieved disease control of both malignancies after a single dose of the anti-PD-1 monoclonal antibody pembrolizumab.\n\nCase presentation\nA 73-year-old man was diagnosed with T1a melanoma arising from the right shoulder in 2009. He underwent a wide excision and sentinel lymph node biopsy. Pathology review revealed a 1.64 mm melanoma, anatomic level deep III/early IV, no ulceration, 1 mitosis/mm2. Four right axillary sentinel lymph nodes were negative for involvement with melanoma. In September 2013, after experiencing hematuria, the patient underwent a cystoscopy followed by transurethral resection of a bladder tumor (TURBT), which revealed a low-grade urothelial carcinoma with no evidence of bladder invasion. He is a lifelong non-smoker. A staging computerized tomography (CT) scan revealed two right lower lobe lung nodules (2.7 cm and <1 cm), and a 6.3 cm tumor in the left kidney. A positron emission tomography computerized tomography (PET/CT) in November 2013 (Fig. 1) showed enlarged mediastinal lymph nodes in addition to FDG uptake in the lung nodules and a complex left kidney mass. A mass in the thoracic spine (T3 vertebra) and a small focus of uptake in the right sacral ala were also noted (Fig. 2). A biopsy of the T3 vertebral lesion was performed and pathologic review demonstrated RCC. A core needle biopsy of one of the right lower lobe lung nodules was also performed and unexpectedly revealed recurrent metastatic melanoma (Fig. 3). In December 2013, a brain MRI showed a subcentimeter left temporal metastasis. The patient received radiation to the T3 vertebral metastasis and stereotactic radiosurgery to the brain metastasis.Fig. 1 Timeline of events and treatment. CT = computerized tomography. PET = positron emission tomography. RLL = right lower lobe. RCC = renal cell carcinoma\n\nFig. 2 \na PET CT demonstrating FDG uptake in an enlarged mediastinal lymph nodes, small right lower lobe lung nodule, exophytic heterogenous mass in left kidney and a 3.5 × 3.2 cm vertebral mass at T3 with SUV of 11.4. b Enhanced CT view of the T3 vertebral mass\n\nFig. 3 Pathology of T3 vertebral mass and right lower lobe lung lesions. Pathology of the T3 vertebral mass biopsy represents a metastasis from renal cell carcinoma, the lung lesion is consistent with a metastasis from melanoma. (1) Immunohistochemistry markers of the T3 vertebral mass and the right lower lobe (RLL) lung nodule. (2) T3 vertebral lesion: a. low power b. high power c. CAM5.2 d. Pax-8 (3) RLL lesion: a. high power b. Cytokeratin (CK7) c. S100 d. Melan-A e. HMB45\n\n\n\nWhile weighing the treatment options for these two cancers, although our initial thoughts were to focus on the more aggressive melanoma (BRAF and NRAS wild type), we were motivated to design a therapy regimen that could yield efficacious responses against both cancers. Bevacizumab, the anti-Vascular Endothelial Derived Growth Factor (VEGF) directed monoclonal antibody approved for use in renal cell carcinoma, has some efficacy in advanced melanoma and was found to be safe and potentially synergistic with ipilimumab [11, 12]. The urothelial cancer was not addressed therapeutically because of the metastatic melanoma and RCC taking precedence. Based on this data, the patient received one cycle of ipilimumab at the standard dose of 3 mg/kg. Following insurance approval, he then received a cycle of ipilimumab in combination with bevacizumab 15 mg/kg every 3 weeks. Shortly after receiving the combination, the patient presented with a left sided headache, blurred vision in the left eye, and left eyelid ptosis. A brain MRI revealed a subacute hemorrhage at the site of the previously irradiated left temporal metastasis. A temporal artery biopsy was negative for temporal arteritis. The remainder of ipilimumab therapy (3rd and 4th dose) was administered without concurrent Bevacizumab given the concern that VEGF inhibition may have possibly contributed to the brain hemorrhage. The ipilimumab treatment course was also complicated by immune-related hypophysitis resulting in adrenal insufficiency, which was successfully treated with hydrocortisone.\n\nSerial PET/CTs showed progressive disease in April 2014. Repeat PET/CT performed in July of 2014 once again revealed disease evolution with increased FDG avidity of a dominant right lower lobe lung mass, increased size and avidity of a right adrenal lesion, and increased FDG avidity of the left sided renal mass. Based on these results and the availability on an Expanded Access Program, treatment with the anti-PD-1 antibody pembrolizumab at 2 mg/kg every 3 weeks was initiated in July of 2014. After one dose, the patient developed grade 3 transaminitis (ALT > 7x ULN, AST >11x ULN, total bilirubin normal), prompting discontinuation of treatment due to presumed immune-related hepatitis. Intravenous solumedrol was administered for the treatment of immune-related hepatitis. A liver biopsy performed six days into the steroid taper (prednisone 80 mg BID for the six days prior to biopsy) showed pathological features compatible with but not diagnostic of immune-related hepatitis. Liver function tests normalized fifteen days after the initial diagnosis and remained within reference range after completion of a four-week prednisone taper.\n\nRestaging CTs of the chest, abdomen, and pelvis performed in September 2014 demonstrated dramatic reduction in size of several lung metastases, while others remained stable. The right adrenal lesion, several mesenteric nodules, and a subcutaneous nodule on the left anterior abdominal wall were all substantially smaller in size. The left renal mass remained stable. Serial CTs of the chest, abdomen, and pelvis in November 2014, February 2015, May 2015, and August 2014 showed continued decrease in tumor size consistent with a partial response to treatment for a duration of 14 months (Fig. 4). Most recently, a chest, abdomen, and pelvic CT in November of 2015 showed two new subcentimeter pulmonary lesions and a satellite nodule in the primary renal cell cancer. The patient is currently undergoing re-induction therapy with pembrolizumab.Fig. 4 \na PET CT images of the mediastinal mass, pulmonary lesion and renal mass. Left column: Pre- pembrolizumab; right column: 8 weeks after administration of one dose of pembrolizumab. There is near complete involution of the anterior mediastinal mass and a decrease in size of the pulmonary lesion. The size of the renal mass is unchanged. b Size (cm) on axial imaging (CT or PET/CT) of renal, mediastinal and dominant right pulmonary nodule over time. The last scan showed two new subcentimter pulmonary metastases and increased size of a soft tissue component of the left renal mass\n\n\n\nConclusion\nWe describe a patient with concurrent biopsy-proven metastatic melanoma and RCC who was treated with one dose of pembrolizumab that was complicated by immune-related hepatitis but nevertheless lead to a durable tumor response in both melanoma and RCC.\n\nWhile the presence of two distinct metastatic processes was established by biopsy (melanoma in the lung and RCC in the spine at level T3), the contribution of each tumor to the overall metastatic burden cannot be determined. However, since at least one (and likely more) lung lesion(s) represent melanoma and the left renal lesion represent RCC by imaging criteria, ongoing disease control of both cancers was evident on serial imaging. It is notable that the patient developed immune-related hepatitis after only one dose of pembrolizumab. Immune-related toxicity may be associated with a favorable outcome in patients treated with CTLA-4 and/or PD-1 inhibition [13].\n\nMultiple primary cancers, which is defined as the development of another primary cancer after diagnosis of an initial one (index cancer) in a given individual, is a relatively common occurrence. Interestingly, urinary bladder cancer is the most frequent index cancer in patients with multiple primary cancers (18 %), whereas 10 % of patients with RCC and melanoma, respectively develop a second primary [14]. No reliable data are available, to our knowledge, on frequencies of multiple primaries that have metastasized concurrently such as in our patient. It is interesting in this context that the patient’s diagnosis of a localized low grade urothelial carcinoma of the bladder immediately preceded the patient’s diagnosis of metastatic melanoma and RCC. While the non-muscle invasive bladder cancer lead to the diagnosis of melanoma and RCC in our patient, it appears unlikely that the bladder cancer contributed to the metastatic disease burden in this patient. Since bladder cancer has also been found to be responsive to PD-1 pathway inhibition, the possibility that a third solid tumor may also have been controlled by PD-1 blockade in our patient is nevertheless an intriguing consideration [8].\n\nPD-1 blockade reverts the PD-1 receptor-mediated dysfunctional state of effector memory T cells that have infiltrated the tumor into an active, functional state, thereby enabling tumor cell killing. These T cells are presumably endogenously primed and specific for antigens expressed on the respective tumor they traffic into. It therefore appears more likely that these T cells recognize tumor antigens that are distinct between the melanoma and the RCC rather than shared antigens. Although the immune response may be distinct in RCC and melanoma, a certain percentage of these tumors are immunogenic and therefore potentially responsive to immune checkpoint blockade [15]. This case illustrates that despite these distinct immune responses, PD-1 inhibition may be a suitable treatment option for patients with concurrent immune-responsive cancers.\n\nConsent\nClinical data for this case report were collected under institutional review board approval (Dana-Farber/Harvard Cancer Center #05-042).\n\nConsent to publish\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images.\n\nAbbreviations\nCTcomputerized tomography\n\nCTLA-4cytotoxic lymphocyte antigen-4\n\nMRIMagnetic Resonance Imaging\n\nPD-1immunological checkpoint programmed death\n\nPD-L1programmed death ligand 1\n\nPET/CTPositron emission tomography computerized tomography\n\nRCCrenal cell carcinoma\n\nTURBTtransurethral resection of a bladder tumor\n\nVEGFVascular Endothelial Derived Growth Factor\n\nCompeting interests\n\nTKC reports grants from Bristol-Myers Squibb, grants and personal fees from GlaxoSmithKline, grants and personal fees from Novartis, grants from Exelixis, Inc., grants and personal fees from Pfizer, grants and personal fees from Merck, grants from Roche, grants and personal fees from AstraZeneca, grants from TRACON Pharmaceuticals, grants from Peloton, personal fees from Bayer, personal fees from Prometheus outside the submitted work. PAO reports grants and personal fees from Bristol-Myers Squibb, personal fees from Amgen, and grants from Merck and AztraZeneca/MedImmune outside of the submitted work. All other authors have no conflicts to disclose.\n\nAuthors’ contributions\n\nAuthor MM drafted the manuscript. MD helped to draft the manuscript and participated in the care of the patient. NS helped to draft the manuscript and participated in the care of the patient. KMK provided and analyzed data and helped to draft the manuscript, RM helped to draft the manuscript and participated in the care of the patient. TKC helped to coordinate the care of the patient and helped to draft the manuscript. PAO conceived of the report, helped to draft the manuscript, and coordinated the care for the patient. All authors read and approved the manuscript.\n\nAcknowledgement\nWe thank Michelle Hirsch for providing pathology expertise and helpful discussions and Jonathan Nowak for providing the pathology images included in the paper.\n==== Refs\nReferences\n1. Sharma P Allison JP The future of immune checkpoint therapy Science 2015 348 6230 56 61 10.1126/science.aaa8172 25838373 \n2. Hodi FS Improved survival with ipilimumab in patients with metastatic melanoma N Engl J Med 2010 363 8 711 23 10.1056/NEJMoa1003466 20525992 \n3. Topalian SL Safety, activity, and immune correlates of anti-PD-1 antibody in cancer N Engl J Med 2012 366 26 2443 54 10.1056/NEJMoa1200690 22658127 \n4. Robert C Ipilimumab plus dacarbazine for previously untreated metastatic melanoma N Engl J Med 2011 364 26 2517 26 10.1056/NEJMoa1104621 21639810 \n5. Schadendorf D Pooled Analysis of Long-Term Survival Data From Phase II and Phase III Trials of Ipilimumab in Unresectable or Metastatic Melanoma J Clin Oncol 2015 33 17 1889 94 10.1200/JCO.2014.56.2736 25667295 \n6. Robert C Pembrolizumab versus Ipilimumab in Advanced Melanoma N Engl J Med 2015 372 26 2521 32 10.1056/NEJMoa1503093 25891173 \n7. Tumeh PC PD-1 blockade induces responses by inhibiting adaptive immune resistance Nature 2014 515 7528 568 71 10.1038/nature13954 25428505 \n8. Herbst RS Predictive correlates of response to the anti-PD-L1 antibody MPDL3280A in cancer patients Nature 2014 515 7528 563 7 10.1038/nature14011 25428504 \n9. Snyder A Wolchok JD Chan TA Genetic basis for clinical response to CTLA-4 blockade N Engl J Med 2015 372 8 783 10.1056/NEJMc1415938 25693024 \n10. Rizvi NA Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer Science 2015 348 6230 124 8 10.1126/science.aaa1348 25765070 \n11. Kim KB BEAM: a randomized phase II study evaluating the activity of bevacizumab in combination with carboplatin plus paclitaxel in patients with previously untreated advanced melanoma J Clin Oncol 2012 30 1 34 41 10.1200/JCO.2011.34.6270 22124101 \n12. Hodi FS Bevacizumab plus ipilimumab in patients with metastatic melanoma Cancer Immunol Res 2014 2 7 632 42 10.1158/2326-6066.CIR-14-0053 24838938 \n13. Postow MA Nivolumab and ipilimumab versus ipilimumab in untreated melanoma N Engl J Med 2015 372 21 2006 17 10.1056/NEJMoa1414428 25891304 \n14. Hayat MJ Cancer statistics, trends, and multiple primary cancer analyses from the Surveillance, Epidemiology, and End Results (SEER) Program Oncologist 2007 12 1 20 37 10.1634/theoncologist.12-1-20 17227898 \n15. McDermott DF Atezolizumab, an Anti-Programmed Death-Ligand 1 Antibody, in Metastatic Renal Cell Carcinoma: Long-Term Safety, Clinical Activity, and Immune Correlates From a Phase Ia Study J Clin Oncol 2016 34 8 833 42 10.1200/JCO.2015.63.7421 26755520\n\n",
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"keywords": "Antibody therapy; Concurrent cancer; Immune checkpoint blockade; Immunotherapy; Melanoma; PD-1; Renal cell cancer",
"medline_ta": "J Immunother Cancer",
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"title": "Tumor control with PD-1 inhibition in a patient with concurrent metastatic melanoma and renal cell carcinoma.",
"title_normalized": "tumor control with pd 1 inhibition in a patient with concurrent metastatic melanoma and renal cell carcinoma"
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"abstract": "BACKGROUND\nEncephalitozoon cuniculi, a microsporidial species most commonly recognized as a cause of renal, respiratory, and central nervous system infections in immunosuppressed patients, was identified as the cause of a temporally associated cluster of febrile illness among 3 solid organ transplant recipients from a common donor.\n\n\nOBJECTIVE\nTo confirm the source of the illness, assess donor and recipient risk factors, and provide therapy recommendations for ill recipients.\n\n\nMETHODS\nPublic health investigation.\n\n\nMETHODS\nTwo transplant hospitals and community interview with the deceased donor's family.\n\n\nMETHODS\nThree transplant recipients and the organ donor.\n\n\nMETHODS\nSpecimens were tested for microsporidia by using culture, immunofluorescent antibody, polymerase chain reaction,immunohistochemistry, and electron microscopy. Donor medical records were reviewed and a questionnaire was developed to assess for microsporidial infection.\n\n\nRESULTS\nKidneys and lungs were procured from the deceased donor and transplanted to 3 recipients who became ill with fever 7 to 10 weeks after the transplant. Results of urine culture, serologic,and polymerase chain reaction testing were positive for E. cuniculi of genotype III in each recipient; the organism was also identified in biopsy or autopsy specimens in all recipients. The donor had positive serologic test results for E. cuniculi. Surviving recipients received albendazole. Donor assessment did not identify factors for suspected E. cuniculi infection.\n\n\nCONCLUSIONS\nInability to detect organism by culture or polymerase chain reaction in donor due to lack of autopsy specimens.\n\n\nCONCLUSIONS\nMicrosporidiosis is now recognized as an emerging transplant-associated disease and should be considered in febrile transplant recipients when tests for routinely encountered agents are unrevealing. Donor-derived disease is critical to assess when multiple recipients from a common donor are ill.",
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"chemical_list": "D000935:Antifungal Agents; D015766:Albendazole",
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"mesh_terms": "D000328:Adult; D015766:Albendazole; D000935:Antifungal Agents; D009670:Encephalitozoon cuniculi; D016890:Encephalitozoonosis; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D007668:Kidney; D016030:Kidney Transplantation; D008168:Lung; D016040:Lung Transplantation; D008297:Male",
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"title": "Microsporidiosis acquired through solid organ transplantation: a public health investigation.",
"title_normalized": "microsporidiosis acquired through solid organ transplantation a public health investigation"
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"abstract": "We report the case of a woman supported by a left ventricular assist device (LVAD) who presented at 20 weeks of gestation and decided against recommendations to continue with her pregnancy. This was managed with well-developed plan for a multidisciplinary team approach. With close and regular follow-up and regular adjustment of the patient's medications and LVAD parameters, successful delivery and outcome for both the mother and the newborn were achieved.",
"affiliations": "Division of Cardiothoracic Surgery, Tampa General Hospital, Tampa, Florida. Electronic address: gmakdisi@hotmail.com.;Krannert Institute of Cardiology, Indiana University, Indianapolis, Indiana.;Maternal Fetal Medicine, Indiana University, Indianapolis, Indiana.;Division of Cardiovascular Surgery, Indiana University, Indianapolis, Indiana.;Krannert Institute of Cardiology, Indiana University, Indianapolis, Indiana.",
"authors": "Makdisi|George|G|;Jan|M Y|MY|;Dungy-Poythress|Lauren|L|;Wang|I-Wen|IW|;Caccamo|Marco A|MA|",
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"mesh_terms": "D000328:Adult; D036861:Delivery, Obstetric; D005260:Female; D006333:Heart Failure; D006353:Heart-Assist Devices; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D049168:Pregnancy, Unplanned",
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"title": "Successful Delivery in a Patient With Left Ventricular Assist Device and Unplanned Pregnancy.",
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"abstract": "Bisphosphonate compounds are used to treat osteoporosis and malignant bone metastasis. Despite the benefits related to use of these medications, osteonecrosis of the jaws is a significant complication in a subset of patients receiving these drugs. This complication occurs either spontaneously or after a simple dento-alveolar surgery. Recently there was a patient who showed the features of bisphosphonate related osteonecrosis of the jaws (BRONJ) in our hospital. This article reported one typical case of osteonecrosis of the maxilla treated with Zoledronic acid and reviewed the relevant literature related to pathogenesis, clinical presentation as well as management and prevention of this new complication.",
"affiliations": "Dental Center, Fifth Affiliated Hospital, Wenzhou Medical College, Central Hospital of Lishui City, Lishui 323000, Zhejiang Province, China. ywcls@sina.com",
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"title": "Bisphosphonate related osteonecrosis of the jaws: a case report and review of the literature.",
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"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ZOLEDRONIC ACID"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nHigh-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT.\n\n\nMETHODS\nThis phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen. The main objective was to determine the complete response rate.\n\n\nRESULTS\nForty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4-51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2-not reached] and 32 months (95% CI 4-49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32-67) and the 2-year OS was 66% (95% CI 44-81).\n\n\nCONCLUSIONS\nThe TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens.\n\n\nBACKGROUND\nNCT00231582.",
"affiliations": "Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris. Electronic address: frederic.selle@tnn.aphp.fr.;Department of Medicine, Institut Gustave Roussy, Villejuif.;Department of Medical Oncology, Centre Léon Bérard, Lyon.;Department of Medical Oncology, Institut Paoli Calmette, Marseille.;Department of Medicine, Institut Bergonié, Bordeaux.;Department of Medicine, Institut Bergonié, Bordeaux.;Department of Chemotherapy, Centre Paul Papin, Angers.;Department of Medicine, Centre Hospitalier Universitaire, Clermont-Ferrand.;Department of Medical Oncology, Centre Léon Bérard, Lyon.;Department of Medicine, Centre Alexis Vautrin, Nancy.;Department of Medicine, Centre Oscar Lambret, Lille.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris.;Department of Hematology, Hôpital D'Instruction des Armées Percy, Clamart.;Department of Medicine, Institut Gustave Roussy, Villejuif.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris.;Cytapheresis and Cell Therapy Unit, Hôpital St Louis (AP-HP), Paris.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris.;Statistic, 3ES-Cegedim Strategic Data, Boulogne, France.;Department of Internal Medicine, Brown University, Rhode Island Hospital, Providence, Rhode Island, USA.;Department of Clinical Research, Hôpital St Louis (AP-HP), Paris, France.;Department of Medical Oncology and Cellular Therapy, APREC (Alliance Pour la Recherche En Cancérologie), Hôpital Tenon (Hôpitaux Universitaires de l'Est-Parisien, AP-HP), Paris; Sorbonne Universités, Université Pierre et Marie Curie (UPMC Univ Paris 06), Paris.",
"authors": "Selle|F|F|;Wittnebel|S|S|;Biron|P|P|;Gravis|G|G|;Roubaud|G|G|;Bui|B N|BN|;Delva|R|R|;Bay|J O|JO|;Fléchon|A|A|;Geoffrois|L|L|;Caty|A|A|;Soares|D G|DG|;de Revel|T|T|;Fizazi|K|K|;Gligorov|J|J|;Micléa|J M|JM|;Dubot|C|C|;Provent|S|S|;Temby|I|I|;Gaulet|M|M|;Horn|E|E|;Brindel|I|I|;Lotz|J P|JP|",
"chemical_list": "D000970:Antineoplastic Agents; D015251:Epirubicin; D005047:Etoposide; D013852:Thiotepa; D016190:Carboplatin; D017239:Paclitaxel; D002945:Cisplatin; D007069:Ifosfamide",
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdu198",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0923-7534",
"issue": "25(9)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "TAXIF II trial; germ-cell tumors; hematopoietic stem-cell transplantation; high-dose chemotherapy; nonrefractory patients",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D018572:Disease-Free Survival; D015251:Epirubicin; D005047:Etoposide; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007069:Ifosfamide; D008297:Male; D008875:Middle Aged; D009373:Neoplasms, Germ Cell and Embryonal; D017239:Paclitaxel; D013852:Thiotepa; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "1775-1782",
"pmc": null,
"pmid": "24894084",
"pubdate": "2014-09",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study.",
"title_normalized": "a phase ii trial of high dose chemotherapy hdct supported by hematopoietic stem cell transplantation hsct in germ cell tumors gcts patients failing cisplatin based chemotherapy the multicentric taxif ii study"
} | [
{
"companynumb": "FR-CIPLA LTD.-2015FR05135",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "THIOTEPA"
},
"drugadditional": null,
... |
{
"abstract": "Delayed elimination of methotrexate was previously reported in 2 patients receiving concomitant levetiracetam.\n\n\n\nTo explore the potential interaction between methotrexate and levetiracetam in patients receiving high-dose methotrexate.\n\n\n\nThis retrospective study reviewed the records of 81 adults receiving 280 cycles of methotrexate to determine the effects of levetiracetam on methotrexate elimination. Institutional review board approval was obtained.\n\n\n\nLevetiracetam was administered in 33 (12%) cycles of methotrexate. Patients receiving levetiracetam had significantly lower 24-hour methotrexate concentrations compared with those not receiving levetiracetam (2.91 vs 7.37 µmol/L, P = 0.005). Despite this difference, concentrations at 48 and 72 hours were similar between groups. Times to nontoxic methotrexate concentration (<0.1 µmol/L) were the same regardless of the presence of levetiracetam. The frequency of delayed elimination at 24, 48, and 72 hours was similar in both groups as was the frequency of delayed elimination at any time point. Cox regression demonstrated that levetiracetam was not a significant predictor of time to nontoxic methotrexate concentration (P = 0.796; HR = 1.058; 95% CI = 0.692-1.617), and logistic regression demonstrated that levetiracetam was not a significant predictor of delayed elimination at any time point. Levetiracetam use was similar between groups when comparing patients experiencing delayed elimination at any time point with those without delayed elimination (13% vs 10%, respectively, P = 0.527).\n\n\n\nThis study does not support the previous reports of a significant interaction between levetiracetam and methotrexate. A clinically significant interaction is unlikely in those without additional risk factors for delayed elimination.",
"affiliations": "Butler University, Indianapolis, IN, USA dreeves@butler.edu.;Butler University, Indianapolis, IN, USA.;Butler University, Indianapolis, IN, USA.;Butler University, Indianapolis, IN, USA.;Butler University, Indianapolis, IN, USA.",
"authors": "Reeves|David|D|;DiDominick|Sarah|S|;Finn|Suzanne|S|;Kim|Hyeon Jin|HJ|;Shake|Amanda|A|",
"chemical_list": "D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D000077287:Levetiracetam; D008727:Methotrexate; D010889:Piracetam",
"country": "United States",
"delete": false,
"doi": "10.1177/1060028016661572",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1060-0280",
"issue": "50(12)",
"journal": "The Annals of pharmacotherapy",
"keywords": "drug interactions; drug monitoring; methotrexate; pharmacokinetics; seizures",
"medline_ta": "Ann Pharmacother",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000964:Antimetabolites, Antineoplastic; D004347:Drug Interactions; D005260:Female; D006801:Humans; D000077287:Levetiracetam; D016015:Logistic Models; D008297:Male; D008657:Metabolic Clearance Rate; D008727:Methotrexate; D008875:Middle Aged; D010889:Piracetam; D016016:Proportional Hazards Models; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "9203131",
"other_id": null,
"pages": "1016-1022",
"pmc": null,
"pmid": "27511814",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Methotrexate Elimination When Coadministered With Levetiracetam.",
"title_normalized": "methotrexate elimination when coadministered with levetiracetam"
} | [
{
"companynumb": "FR-CIPLA LTD.-2016US23292",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nThis case series is the first to describe divergence palsy as an adverse effect of antiepileptic drug use. Diplopia is a common adverse effect of antiepileptic drugs, but no explanatory motility deficit has ever been reported.\n\n\nMETHODS\nWe present 2 patients, 1 on oxcarbazepine and 1 on divalproex, each with a normal examination result between spells and divergency palsy when symptomatic.\n\n\nRESULTS\nDiscontinuation of the antiepileptic medication led to resolution of the episodes in both cases. Rechallenge with the offending agent after washout in one patient resulted in recurrence of diplopia and divergence palsy, both resolving after subsequent withdrawal of the antiepileptic.\n\n\nCONCLUSIONS\nAntiepileptic drugs may cause divergence palsy.",
"affiliations": "*Department of Ophthalmology, Division of Neuro-Ophthalmology, Massachusetts Eye and Ear Infirmary; †Department of Neurology; and ‡Department of Surgery, Division of Ophthalmology, Beth Israel Deaconess Medical Center, Boston, MA.",
"authors": "Bouffard|Marc Albert|MA|;Caplan|Louis R|LR|;Torun|Nurhan|N|",
"chemical_list": "D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D000078330:Oxcarbazepine",
"country": "United States",
"delete": false,
"doi": "10.1097/WNF.0000000000000210",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0362-5664",
"issue": "40(3)",
"journal": "Clinical neuropharmacology",
"keywords": null,
"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D000927:Anticonvulsants; D002220:Carbamazepine; D004172:Diplopia; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D020258:Neurotoxicity Syndromes; D015840:Oculomotor Nerve Diseases; D000078330:Oxcarbazepine; D016896:Treatment Outcome; D014635:Valproic Acid",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "154-155",
"pmc": null,
"pmid": "28277442",
"pubdate": "2017",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Divergence Palsy due to Divalproex and Oxcarbazepine.",
"title_normalized": "divergence palsy due to divalproex and oxcarbazepine"
} | [
{
"companynumb": "US-APOTEX-2017AP014736",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXCARBAZEPINE"
},
"drugadditional": "1",
... |
{
"abstract": "Direct antiviral agents (DAA) showed very good results in terms of efficacy and safety in clinical trials, but real-life data are still needed in order to confirm this profile.\n\n\n\nIn Romania, through a nationwide government-funded programme in 2015-2016, approx.5800 patients with virus C cirrhosis received fully reimbursed DAA therapy with OBV/PTV/r+DSV+RBV for 12 weeks. We analysed a national prospective cohort enrolling the first 2070 patients, all with genotype 1b. The only key inclusion criteria was advanced fibrosis (Metavir stage F4) confirmed by Fibromax testing (or liver biopsy/Fibroscan). Efficacy was assessed by the percentage of patients achieving SVR 12 weeks post-treatment (SVR12).\n\n\n\nForty patients stopped the treatment because of hepatic decompensation (1.9%), 21 stopped because of other adverse events and one was lost to follow-up. This cohort was 51% females, mean age 60 years (25÷82), 67% pretreated, 70% associated NASH, 67% with severe necro-inflammation (severity score 3-Fibromax), 37% with comorbidities, 10.4% with Child Pugh A6, 0.5% B7. The median MELD score was 8.09 (6 ÷ 22). SVR by intention-to-treat was reported in 1999/2070(96.6%), 55/2070 failed to respond. Liver decompensation was statistically associated in multivariate analysis with platelets< 105 /mm3 (P = .03), increased total bilirubin (P < .001), prolonged INR (P = .02), and albumin<3.5 g/dL (P = .03).\n\n\n\nOBV/PTV/r+DSV+RBV proved to be highly efficient in our population of cirrhotics with a 96.6% SVR. Serious adverse events related to therapy were reported in 61/2070(2.9%), most of them liver decompensation (1.9%), related to hepatic dysfunction, and lower platelet count.",
"affiliations": "UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF \"Carol Davila\" Virology Department, Victor Babes Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Internal Medicine Department, Colentina Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Internal Medicine Department, Colentina Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology Department, Emergency Universitary Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF Timisoara, Gastroenterology & Hepatology Department, Timisoara Emergency Hospital, Timisoara, Romania.;UMF Gr T Popa Iasi, Gastroenterology & Hepatology Department, Gastroenterology & Hepatology Institute, Iasi, Romania.;UMF I.Hatieganu Cluj, Gastroenterology & Hepatology Department, Medicala III, Cluj County Hospital, Cluj Napoca, Romania.;UMF I.Hatieganu Cluj, Gastroenterology & Hepatology Department, Medicala III, Cluj County Hospital, Cluj Napoca, Romania.;UMF \"Carol Davila\" Virology Department, Victor Babes Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF \"Carol Davila\" Virology Department, Victor Babes Hospital, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.;UMF \"Carol Davila\" Gastroenterology & Hepatology Department, Clinic Fundeni Institute, Bucharest, Romania.",
"authors": "Preda|Carmen M|CM|0000-0002-2675-7971;Popescu|Corneliu P|CP|;Baicus|Cristian|C|;Voiosu|Theodor A|TA|;Manuc|Mircea|M|;Pop|Corina Silvia|CS|;Gheorghe|Liana|L|;Sporea|Ioan|I|;Trifan|Anca|A|;Tantau|Marcel|M|;Tantau|Alina|A|;Ceausu|Emanoil|E|;Proca|Doina|D|;Constantinescu|Ileana|I|;Ruta|Simona M|SM|;Diculescu|Mircea M|MM|;Oproiu|Alexandru|A|",
"chemical_list": "D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D047029:Lactams, Macrocyclic; D047028:Macrocyclic Compounds; D013449:Sulfonamides; C586094:ombitasvir; D012254:Ribavirin; D014498:Uracil; D011392:Proline; D015081:2-Naphthylamine; C588260:dasabuvir; D014633:Valine; C585405:paritaprevir",
"country": "United States",
"delete": false,
"doi": "10.1111/liv.13550",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1478-3223",
"issue": "38(4)",
"journal": "Liver international : official journal of the International Association for the Study of the Liver",
"keywords": "cirrhosis; direct-acting antiviral agents; hepatitis C virus; paritaprevir/ombitasvir/ritonavir/dasabuvir+Ribavirin",
"medline_ta": "Liver Int",
"mesh_terms": "D015081:2-Naphthylamine; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000813:Anilides; D000998:Antiviral Agents; D002219:Carbamates; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D005260:Female; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D047029:Lactams, Macrocyclic; D008103:Liver Cirrhosis; D016015:Logistic Models; D047028:Macrocyclic Compounds; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D011392:Proline; D011446:Prospective Studies; D012254:Ribavirin; D012383:Romania; D013449:Sulfonamides; D000072230:Sustained Virologic Response; D014498:Uracil; D014633:Valine",
"nlm_unique_id": "101160857",
"other_id": null,
"pages": "602-610",
"pmc": null,
"pmid": "28816020",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Real-world efficacy and safety of ombitasvir, paritaprevir/r+dasabuvir+ribavirin in genotype 1b patients with hepatitis C virus cirrhosis.",
"title_normalized": "real world efficacy and safety of ombitasvir paritaprevir r dasabuvir ribavirin in genotype 1b patients with hepatitis c virus cirrhosis"
} | [
{
"companynumb": "RO-KADMON PHARMACEUTICALS, LLC-KAD201804-000225",
"fulfillexpeditecriteria": "1",
"occurcountry": "RO",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIBAVIRIN"
},
"drugaddi... |
{
"abstract": "Obsessive-compulsive disorder (OCD) is a widespread chronic neuropsychiatric disorder characterized by recurrent intrusive thoughts, images, or urges (obsessions) that typically cause anxiety or distress. Even when optimal treatment is provided, 10% of patients remain severely affected chronically. In some countries, deep brain stimulation (DBS) is an approved and effective therapy for patients suffering from treatment-resistant OCD. Hereafter, we report the case of a middle-aged man with a long history of treatment-resistant OCD spanning nearly a decade with Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores oscillating between 21 and 28. The patient underwent bilateral implantation of ventral striatum/ventral capsule DBS leads attached to a battery-operated implanted pulse generator. After a 3-month postimplantation period, the DBS protocol started. Three months after the onset of DBS treatment, the patient's Y-BOCS score had dropped to 3, and he became steadily asymptomatic. However, inadvertently, at this time, it was found out that the implanted pulse generator battery had discharged completely, interrupting brain stimulation. The medical team carried on with the original therapeutic and evaluation plan in the absence of active DBS current. After 12 additional months under off-DBS, the patient remained at a Y-BOCS score of 7 and asymptomatic. To our knowledge, this is the first report that provides an opportunity to discuss four different hypotheses of long-term recovery induced by DBS in a treatment-refractory OCD patient, notably: (1) A placebo effect; (2) Paradoxical improvements induced by micro-lesions generated by DBS probe implantation procedures; (3) Unexpected late spontaneous improvements; (4) Recovery driven by a combination of active DBS-induction, the effects of medication, and DBS-placebo effects.",
"affiliations": "Sorbonne Université, AP-HP, Service de psychiatrie adulte de la Pitié-Salpêtrière, Institut du Cerveau, ICM, Paris, France.;Groupe de Dynamiques Cérébrales, Plasticité et Rééducation and Frontlab Team, Institut du Cerveau (ICM), INSERM 1127, CNRS, UMR 7225 and Sorbonne Université (SO), Paris, France.;Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France.;Sorbonne Université, AP-HP, Service de psychiatrie adulte de la Pitié-Salpêtrière, Institut du Cerveau, ICM, Paris, France.;Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau (CRICM), UMR-S975, Paris, France.;Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau (CRICM), UMR-S975, Paris, France.;Sorbonne Université, AP-HP, Service de psychiatrie adulte de la Pitié-Salpêtrière, Institut du Cerveau, ICM, Paris, France.",
"authors": "Maatoug|Redwan|R|;Valero-Cabré|Antoni|A|;Duriez|Philibert|P|;Saudreau|Bertrand|B|;Fernández-Vidal|Sara|S|;Karachi|Carine|C|;Millet|Bruno|B|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fpsyt.2020.572059",
"fulltext": "\n==== Front\nFront Psychiatry\nFront Psychiatry\nFront. Psychiatry\nFrontiers in Psychiatry\n1664-0640 Frontiers Media S.A. \n\n10.3389/fpsyt.2020.572059\nPsychiatry\nCase Report\nSustained Recovery in a Treatment-Refractory Obsessive–Compulsive Disorder Patient After Deep Brain Stimulation Battery Failure\nMaatoug Redwan 1*† Valero-Cabré Antoni 2345† Duriez Philibert 67 Saudreau Bertrand 1 Fernández-Vidal Sara 891011 Karachi Carine 891012 Millet Bruno 1 1Sorbonne Université, AP-HP, Service de psychiatrie adulte de la Pitié-Salpêtrière, Institut du Cerveau, ICM, Paris, France\n2Groupe de Dynamiques Cérébrales, Plasticité et Rééducation and Frontlab Team, Institut du Cerveau (ICM), INSERM 1127, CNRS, UMR 7225 and Sorbonne Université (SO), Paris, France\n3Institut du Cerveau et de la Moelle Epinière (ICM), CNRS UMR 7225, INSERM U 1127, Sorbonne Université, Paris, France\n4Laboratory for Cerebral Dynamics Plasticity and Rehabilitation, Boston University, School of Medicine, Boston, MA, United States\n5Cognitive Neuroscience and Information Technology Research Program, Open University of Catalonia (UOC), Barcelona, Spain\n6Institute of Psychiatry and Neurosciences of Paris, Unité Mixte de Recherche en Santé (UMRS) 1266 Institut National de la Santé et de la Recherche Médicale (INSERM), University Paris Descartes, Paris, France\n7Clinique des Maladies Mentales et de l'Encéphale, Groupement Hospitalier Universitaire (GHU) Paris Psychiatry and Neuroscience, Sainte-Anne Hospital, Paris, France\n8Université Pierre et Marie Curie-Paris 6, Centre de Recherche de l'Institut du Cerveau (CRICM), UMR-S975, Paris, France\n9INSERM, U975, Paris, France\n10CNRS, UMR 7225, CR-ICM, Paris, France\n11Centre de Neuroimagerie de Recherche de l'Institut du Cerveau (CENIR ICM), Paris, France\n12Neurosurgery Department, APHP, Hôpitaux Universitaires Pitié-Salpêtrière/Charles Foix, Paris, France\nEdited by: Darin D. Dougherty, Massachusetts General Hospital and Harvard Medical School, United States\n\nReviewed by: Martijn Figee, Icahn School of Medicine at Mount Sinai, United States; Kiyotaka Nemoto, University of Tsukuba, Japan\n\n*Correspondence: Redwan Maatoug redwanmaatoug@gmail.comThis article was submitted to Neuroimaging and Stimulation, a section of the journal Frontiers in Psychiatry\n\n†These authors have contributed equally to this work\n\n\n13 11 2020 \n2020 \n11 57205912 6 2020 30 9 2020 Copyright © 2020 Maatoug, Valero-Cabré, Duriez, Saudreau, Fernández-Vidal, Karachi and Millet.2020Maatoug, Valero-Cabré, Duriez, Saudreau, Fernández-Vidal, Karachi and MilletThis 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.Obsessive-compulsive disorder (OCD) is a widespread chronic neuropsychiatric disorder characterized by recurrent intrusive thoughts, images, or urges (obsessions) that typically cause anxiety or distress. Even when optimal treatment is provided, 10% of patients remain severely affected chronically. In some countries, deep brain stimulation (DBS) is an approved and effective therapy for patients suffering from treatment-resistant OCD. Hereafter, we report the case of a middle-aged man with a long history of treatment-resistant OCD spanning nearly a decade with Yale–Brown Obsessive Compulsive Scale (Y-BOCS) scores oscillating between 21 and 28. The patient underwent bilateral implantation of ventral striatum/ventral capsule DBS leads attached to a battery-operated implanted pulse generator. After a 3-month postimplantation period, the DBS protocol started. Three months after the onset of DBS treatment, the patient's Y-BOCS score had dropped to 3, and he became steadily asymptomatic. However, inadvertently, at this time, it was found out that the implanted pulse generator battery had discharged completely, interrupting brain stimulation. The medical team carried on with the original therapeutic and evaluation plan in the absence of active DBS current. After 12 additional months under off-DBS, the patient remained at a Y-BOCS score of 7 and asymptomatic. To our knowledge, this is the first report that provides an opportunity to discuss four different hypotheses of long-term recovery induced by DBS in a treatment-refractory OCD patient, notably: (1) A placebo effect; (2) Paradoxical improvements induced by micro-lesions generated by DBS probe implantation procedures; (3) Unexpected late spontaneous improvements; (4) Recovery driven by a combination of active DBS-induction, the effects of medication, and DBS-placebo effects.\n\nobsessive compulsive disorderdeep brain stimulationtreatment refractorystimulation techniquesbattery failurecase-report\n==== Body\nPlain Language Summary\nDeep brain stimulation (DBS) is an approved, effective therapy for patients suffering from treatment-resistant obsessive–compulsive disorder (OCD). Here, we report the case of a middle-aged man with nearly a decade long history of treatment-refractory OCD who, in the context of a double-blind, randomized study, underwent bilateral implantation of DBS leads in the ventral striatum/ventral capsule region. After 3 months of DBS stimulation, the patient showed a dramatic drop of OCD severity score and became stable and asymptomatic. However, investigators found out that the battery of the stimulator had emptied completely, and brain stimulation had inadvertently turned off. Importantly, the patient remained symptom-free for an additional year, in the absence of any effective DBS treatment.\n\nBackground\nObsessive–compulsive disorder (OCD) is a widespread chronic neuropsychiatric disease characterized by recurrent intrusive thoughts, images, or urges (obsessions) that typically cause anxiety or distress. It is also associated with repetitive mental or behavioral acts (compulsions) that patients feel an urge to perform. OCD is considered the fourth most common mental disorder in developed countries, and according to the World Health Organization (WHO), represents the 10th leading cause of disability (1). Effective treatments for OCD include cognitive–behavioral therapy and serotonin reuptake inhibitors. Even when optimal treatment is provided, 10% of patients remain severely affected with treatment-resistant OCD (2). For the latter, deep brain stimulation (DBS) is the last available therapeutic option. Although the number of severe OCD treatment-resistant patients treated with DBS is still low and optimal targeting and stimulation parameters are still under debate, most studies (3) confirm that DBS constitutes an adequate treatment, with an acceptable profile of adverse effects and a global percentage of Yale–Brown Obsessive Compulsive Scale (Y-BOCS) reduction estimated at 45% and a global percentage of responders of 60%.\n\nDeep Brain Stimulation\nDBS involves the implantation of intracranial multielectrode leads with several contacts (also referred as electrodes) used to deliver trains of electrical pulses to specific brain locations such as the subthalamic nucleus (STN) or the ventral striatum/ventral capsule (VS/VC) by means of an implanted pulse generator (IPG) (4–6). The implantation of DBS leads and the delivery of electrical current do not cause major neural damage but require brief adjustments of stimulation parameters during the postoperative period and often lifelong maintenance involving battery replacement, the repair of hardware dysfunction, and, medically, the prevention of infections. Although shown effective in treating several disorders such as Parkinson's disease (7), dystonia (8), Tourette syndrome (9), and OCD (10), the underlying mechanisms leading to DBS-mediated improvements remain unknown. Moreover, the optimal locations where to implant electrodes and the best stimulation parameters (frequency, amplitude, and the number of pulses) are still debated.\n\nThe circuits connecting the orbitofrontal cortex (11, 12), the medial prefrontal cortex, the basal ganglia, and the thalamus are thought to be central to the pathophysiology and therapeutic response in OCD (13, 14). A widely accepted hypothesis is that the symptoms characterizing this condition are caused by an abnormally high-degree of hyperactivity in a cortico-striato-pallidal-thalamo-cortical (CSPTC) network (15, 16), which could be plausibly inhibited or functionally overridden with high-frequency DBS electrical patterns (11, 17, 18). To achieve the latter goal, DBS systems include three main components: an IPG, an intracranially implanted multielectrode lead with several contacts (or electrodes) along its bottom end, and a connection/extension cable linking the latter to the former. Electrical impulses are generated by the IPG, which is supplied in electricity by an embedded battery. This device is surgically implanted in the patient's chest subcutaneously. An extension cable running under the skin of the neck and the scalp, from the IPG through a burr hole in the skull, connects to the lead, which is implanted neurosurgically in a specific brain subcortical structure, such as the STN or the VS/VC region (see Figure 1 for details). The IPG used in DBS systems integrates a microchip, allowing neurostimulation parameters (current intensity, frequency, and pulse width) to be programmed and fine-tuned via an external portable appliance communicating wirelessly with it. Once multielectrode leads are implanted, the site of DBS neurostimulation can be further adjusted in the close vicinity of the implanted area by conveying electrical pulses to different contacts along with the lead, usually present in several 4, and activating them independently (19).\n\nFigure 1 Schematic drawing of a deep brain stimulation (DBS) multielectrode implanted lead and an implanted pulse generator (IPG) on OCD patients. Patterns of electrical activity and customized parameters of frequency, intensity, and pulse duration are delivered to improve the clinical symptoms of OCD. A multielectrode lead (Medtronic Model #3391) was inserted through the internal ventral capsule (VC) so that one of its contacts (3 mm long, 4 mm interelectrode distance) reach either the ventral striatum (VS) or the subthalamic nucleus (STN). VS, ventral striatum; GP, globus pallidus.\n\nAfter a quick initial coarse tuning of stimulation variables, further DBS parameter adjustment takes place on average between the first 3 and 6 months [see details in (10, 11)] guided by changes in symptom severity observed in patients and measured with clinical scores. Once established, DBS parameters remain effective for the following 12 months or even longer periods. Accordingly, stimulation parameters inducing clinical benefit shown in OCD by decreases of Y-BOCS scores are maintained until further notice and kept unchanged until the end of a clinical trial follow-up period. Typical stimulation parameters for DBS in OCD may vary within the following ranges (20): Pulse frequency between 130 and 185 Hz, current power between 1 and 10 V, and biphasic pulse width between 60 and 150 ms.\n\nCase Report\nIn 2007, a middle-aged man employed as a boilermaker was admitted into the hospital (Hôpital Pitié-Salpêtrière, Psychiatry Department, in Paris, France) after a work-related accident. His jacket caught fire while he was welding a metal piece. The patient was severely burned and underwent a skin grafting intervention. After this accident, the patient developed typical OCD symptoms, according to the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, with washing rituals, repetitive verifications, and fear of being contaminated. In 2011, his symptomatology started to increase in duration, impacting his life insidiously for ~7 h a day. In an attempt to control his symptoms, the patient was treated serially with monotherapy of fluoxetine (80 mg/day), then venlafaxine (375 mg/day), and ultimately clomipramine (225 mg/day). Nonetheless, pharmacological treatment failed to yield any sign of clinical improvement. During this period, CBT cognitive-behavioral therapy was also carried out unsuccessfully.\n\nIn 2012, the patient attempted suicide by voluntary drug poisoning. This event was explained by occupational inactivity, serious degradation of his quality of life caused by severe OCD symptoms, and increased alcohol consumption. At this time, new pharmacological therapies were attempted with a lower dose of risperidone (3 mg/day), aripiprazole (15 mg/day), and quetiapine (400 mg/day), once more, without clinical success. Subsequently, in 2015, a noninvasive transcranial brain neuromodulation treatment was also assayed via a regimen of 20 daily sessions of repetitive transcranial magnetic stimulation, delivering low-frequency patterns (1 Hz, intensity set at 120% of his resting motor threshold, for 20 min, 1,200 pulses per session) targeting the orbitofrontal cortex (21). Nonetheless, no major improvement was noticed either. Indeed, it should be noted that despite the treatments applied from 2007 to 2016, the patient's Y-BOCS remained relatively stable at high severity scores between 21 and 28 (out of a total of 40 points), a fact that attests the enduring and long-lasting nature of his OCD symptoms.\n\nIn 2016, the patient was included in a prospective randomized, double-blind DBS clinical trial. The design of the study included two arms; in one condition, two multielectrode leads were implanted bilaterally into the right and left VS/VC, whereas, in the other arm of the clinical trial, leads were also implanted bilaterally into the STN. Implanted multielectrodes were non-MRI compatible quadripolar stimulation leads (Model #3391, Medtronic, Minneapolis, MN, USA) made of four contacts (4.0-mm spacing between four 3.0-mm long electrodes). Target regions were identified using a combination of T1 (without and with gadolinium injection) and T2 MRI sequences and a validated three-dimensional histological and deformable YeB atlas of the basal ganglia (22). Neurosurgical trajectories were planned and selected to allow contacts in both the left and the right VS/VC regions. Implantations were performed using a Leksell frame (Elekta Instruments, Inc.) assisted intraoperatively with real-time X-ray guidance and microelectrode recordings. Implantations in our patient, targeted the right and left VS/VC site with the following Montreal Neurological Institute coordinates: right VS/VC: X = −8, Y = 34, Z = 4.5 (Leksell frame X = 91.5, Y = 118.5, Z = 113, A = 65, and B = 70) left VS/VC: X = 9.5 (Leksell frame Y = 33, Z = 4, X = 109, Y = 117, Z = 112.5, A = 120, B = 78). The final location of the four contacts at the bottom end of each multielectrode lead was semiautomatically detected on a postoperative O-Arm helical CT scan linearly registered to the preoperative T1-weighted MRI; the YeB atlas was co-registered to Figure 2 (23). As usually done in prior protocols, electrodes were left to settle for 3 months. By the end of the third month, and after a short period of parameter adjustment well-detailed elsewhere (10, 11), stimulation was set up at some fixed parameters (see later for details on stimulation parameters).\n\nFigure 2 Implanted multielectrode leads were visualized using a combination of a preimplantation T1 MRI volume (without and with gadolinium injection), a T2 MRI sequence, and a validated three-dimensional histological and deformable YeB atlas of the basal ganglia. Blue, caudale nucleus; dark green, putamen; purple, substantia nigra; Pink, limbic subthalamic nucleus; green, sensorimotor subthalamic nucleus.\n\nBy inclusion criteria, the patient had to attest to maintaining the same pharmacological treatment during 6 months preceding lead implantation neurosurgery and throughout his participation in the DBS trial, until the end of the follow-up. Hence, 6 months prior and throughout his participation in the DBS clinical trial, our patient was on fluoxetine 60 mg/day, aripiprazole 10 mg/day, and clomipramine 75 mg/day. No changes in medication were made during this period.\n\nAfter a postimplantation “off-stimulation” period of 3 months, stimulation with the IPG (Medtronic ActivaTM PC non-rechargeable neurostimulator) started. A set of parameters were implemented in a first stimulation protocol targeting bilaterally the VS/VC (130 Hz, 6 V, pulse width at 90 ms, delivered through lead contacts n° 3 and n° 11 for right and left stimulation, respectively). After a short period devoted to parameter adaptation and guided by short-term clinical responses, the former protocol was modified by adding the bilateral stimulation of the associative portion of the caudate nucleus. This modified stimulation protocol was then applied continuously for three additional months (130 Hz frequency, 3 V, and biphasic pulses of 120 ms width, delivered through lead contacts n° 2 and n° 10 for right and left stimulation, respectively).\n\nBefore DBS onset, by the end of the period that followed lead implantation, the patient's Y-BOCS score remained severely affected (Y-BOCS score of 22). Nonetheless, 3 months after the theoretical onset of DBS using the final set of fixed parameters reported earlier, the patient no longer complained of OCD symptoms, and his Y-BOCS fell to a score of 3. Clinically, he seemed soothed and did not feel the urge anymore for washing rituals, neither reported experiencing an insidious sense of contamination risk. The patient was euthymic; his personal interactive relationship skills had greatly improved; and he no longer consumed alcohol. Attesting such dramatic improvements, the patient even planned to resume his professional activity. Consequently, follow-up appointments were gradually spaced out, and 9 months post-lead implantation (hence after 6 months of DBS treatment), the patient was asymptomatic and stable, still with a low Y-BOCS score of 3. Nonetheless, at this time, during a routine check, the psychiatrist in charge of the study unexpectedly found out that the IPG was no longer operative because the battery had depleted completely long before. Unfortunately, we could not determine how long the battery might have been depleted by interrogating the IPG unit. The study blind was lifted, and investigators learned that the patient turned out to have been randomized to the VS/VC bilateral stimulation condition and treated with the last set of the earlier-reported parameters. In the absence of any specific complaint, and given the outstanding patient's recovery with consistent low Y-BOCS scores, in agreement with the patient, we decided not to replace the IPG. This decision was taken because it seemed unreasonable to operate the patient again considering: (1) the risk of infection or hemorrhage; (2) the risk of the anesthesia associated to the surgical procedure; (3) the risk of causing additional micro-lesions during implant removal; and (4) the risk of a recrudescence of OCD symptoms.\n\nMore regular medical consultations were, however, scheduled monthly, to follow the evolution of such an unexpected case. In January 2019, after a 12-month follow-up (Figure 3), the patient remained still stable and asymptomatic with a low Y-BOCS score of 7.\n\nFigure 3 Timeline of the symptoms history and their management.\n\nDiscussion\nTo the best of our knowledge, this is the first reported clinical case presenting evidence suggestive of DBS placebo recovery in a patient with severe OCD scores in the context of a stimulation regimen, halted inadvertently by battery depletion. Importantly, the patient had shown symptoms refractory to pharmacological and noninvasive brain stimulation treatments, spanning for nearly a decade. Hence, it is very unlikely that the achieved recovery might have been triggered “spontaneously” or could have occurred totally unrelated to the DBS procedures undergone as the ultimate therapeutic option.\n\nInterestingly, evidence from the National Institutes of Health OCD DBS patient cohort addressing the clinical consequences of IPG battery depletion and/or DBS device failures instead of OCD improvements reported increases in Y-BOCS scores and severe neuropsychiatric and mood symptoms, together with motor restless-like sensations (24). On this basis, either a very effective induction of after-effects after a short period of DBS stimulation or a DBS mediated placebo impact should be considered as potential recovery factors in this single patient OCD case. These findings are potentially promising because they could allow psychiatrists treating medication-resistant OCD patients with DBS to design stimulation regimens that operate during restricted periods instead of being delivered chronically, as it is most often the case. These alternative approaches could also significantly reduce the number of pulses and the duration of DBS regimens (hence, the total current delivered on a given brain area), limiting battery consumption in IPG systems.\n\nThe findings here reported are coherent with several clinical cases compiled in recent publications, reporting similar phenomena on other types of pharmaco-resistant disorders treated with DBS (23–25). More specifically, the case of a single patient with Tourette syndrome implanted bilaterally in the center median–parafascicular complex of the thalamus and the limbic territory of the internal portion of the globus pallidus revealed decreases of tic severity and self-injurious behavior, after implantation surgery and before stimulation was ever applied (23). Moreover, a systematic review studied the frequency and magnitude of placebo effects in a sample of 126 Parkinson's disease patients treated with DBS (25). Outcomes showed that active DBS was more effective when preceded by a sham-DBS block than in the absence thereof, estimating the contributions of placebo-DBS as accounting for 39% of the total recovery driven by active-DBS. Finally, a study in tremor-dominant Parkinson's disease treated with DBS to the STN showed that patient's expectations about stimulation therapy modulated motor and cognitive dysfunction outcomes (26). Indeed, positive expectations enhanced the clinical impact of STN-DBS by further decreasing the magnitude of patient's tremor, whereas in contrast, negative expectations counteracted its therapeutic benefit and exacerbated some of its adverse effects. Taken together, this evidence suggests that placebo effects and/or positive expectations tied to such may contribute to improvement in DBS patients enduring symptoms of treatment-resistant diseases (e.g., Tourette syndrome and Parkinson's disease), in the absence of effective stimulation. Our single case report extends these intriguing observations to a well-characterized psychiatric condition also treated with DBS such as OCD. Additionally, it suggests that DBS placebo effects, as those here hypothesized, may have boosted the impact of a short-lasting DBS protocol, extending its effects over very long periods of time, once stimulation was inadvertently discontinued due to battery depletion.\n\nWe here conclude that placebo effects could play a role either inducing and/or ensuring the maintenance of attained recovery levels in treatment-refractory OCD patients.\n\nOn such a basis, and as suggested by the outcomes of a meta-analysis by Schruers et al. (27), it is paramount to rule out unexpected placebo improvements when assessing the outcomes of randomized clinical DBS trials in OCD populations. It is, however, important to emphasize that several facts curtail our ability to fully confirm these explanatory hypotheses. First, even if unlikely, given the enduring and chronic nature of OCD symptoms in our patient, we cannot completely rule out late-acting spontaneous recovery triggered by uncontrolled behavioral factors the patient might have been exposed to but failed to report to clinicians. Second, we cannot totally discard either that a very short period of effective DBS stimulation during the brief time the IPG battery could have been operational may have driven enduring recovery, independently of placebo influences over longer-term recovery maintenance. Third, we cannot completely rule out either the possibility of a synergistic interaction between ongoing medication at the time our patient integrated the study and a short period of DBS during a period in which stimulation could have been effective (indeed, both factors insufficient to drive recovery per se but boosting their individual effects when combined). Last, four pieces of information highlight the atypicality of the patient's clinical history and may argue in favor of spontaneous recovery as the cause of clinical improvements: (1) An OCD condition that occurred in a middle-age patient (the average onset age of symptoms in OCD patients included in DBS studies is ~15 years old), hence which may be potentially influenced by a higher loading of environmental and neurological influences [see (28) for details]; (2) OCD symptoms that appeared after a traumatic event in relation to a work accident; (3) A halt in alcohol consumption (which was significantly increased since 2012), around the time of Y-BOCS recovery; (4) Finally, the very rapid fall of Y-BOCS scores (from 22 to 3) in only 3 months) during DBS treatment.\n\nAdditionally, recovery from essential tremor in Parkinson's disease (29–31) before the onset of a systematic DBS regimen has also been associated with structural micro-lesions in implanted gray matter sites along the trajectory of the multielectrode (32). Moreover, the existence of DBS micro-lesions has been questioned by a study in STN-stimulated Parkinsonian patients that failed to demonstrate lasting signs of microelectrode damage in positron emission tomography imaging (33). Unfortunately, in our current case, the lack of postimplantation high-resolution MRI (note that implanted leads contained paramagnetic materials) and the absence of a thorough search for collateral clinical symptoms, both essential to attest micro-damage, preclude confirming or ruling out any of these hypotheses. Similarly, we can only speculate on the potential mechanisms by which enduring severe OCD symptoms wore off persistently in our patient. These could be explained by self-training or self-learning processes and the long-term suppression of abnormally excited CSPTC loop activity induced by DBS. Nonetheless, none of these scenarios can be properly assessed, given the lack of direct measures (other than clinical assessments via Y-BOCS scores) able to follow structural and physiological changes subtending the recovery of our patient. Indeed, a large majority of European Union-certified DBS multielectrode leads approved for human use contain non-MRI-compatible components, preventing the recording of structural and functional MRI datasets of sufficient quality. Additionally, these leads are unsuited to record local electrical signals from stimulated regions.\n\nOptimizing multielectrode lead design would allow a better understanding of DBS modulation of brain systems. In fact, in OCD, this therapeutic approach hypothesizes frequency-specific effects along with a CSPTC network. These effects could be mediated via the modulation of local and network levels of activity and excitability and/or interregional synchrony. This is thus far difficult to be monitored jointly with high spatial and temporal resolution. The implantation of MRI compatible leads equipped with electrodes able to deliver current and also record intracranial electroencephalogram signals would enable precise localization of implanted brain sites and the identification of areas of damage at several intervals during a follow-up. Moreover, the coupling of the former with multimodal imaging (structural and functional MRI approaches, positron emission tomography–MRI technologies, and intracranial electroencephalogram/single-unit recordings) will grant new opportunities for monitoring hemodynamic, metabolic, and neurophysiological changes across DBS regimens and also assess the impact of micro-lesions caused by implanted multielectrode leads. Future OCD case studies similar to the one here reported, and controlled clinical trials implementing a new generation of leads coupled to imaging methods, will be in a better position to disambiguate sham DBS placebo effects from long-lasting clinical improvements induced by a short period of effective stimulation and/or sustained via placebo phenomena.\n\nData Availability Statement\nThe original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\nWritten informed consent was obtained from the [individual(s) AND/OR minor(s)' legal guardian/next of kin] for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\nBM, RM, and CK: Study concept and design. SF-V and BS:Data acquisition. RM, PD, and BS: Data analysis and interpretation. RM, AV-C, and BM: Drafting of the manuscript. RM and SF-V: Statistical analysis. All authors Critical revision of the manuscript for important intellectual content.\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\nWe are thankful to M. Bowen, for proof-reading this manuscript in English, and to Ms. Poinsel, for your help in drawing the figure.\n==== Refs\nReferences\n1. Kessler RC Chiu WT Demler O Walters EE . Prevalence, severity, and comorbidity of 12-month DSM-IV disorders in the National Comorbidity Survey Replication\n. Arch Gen Psychiatry. (2005 ) 62 :617 –27\n. 10.1001/archpsyc.62.6.617 15939839 \n2. Denys D . Pharmacotherapy of obsessive-compulsive disorder and obsessive-compulsive spectrum disorders\n. Psychiatr Clin N Am. (2006 ) 29 :553 –84\n. 10.1016/j.psc.2006.02.013 16650723 \n3. Alonso P Cuadras D Gabriëls L Denys D Goodman W Greenberg BD . Deep brain stimulation for obsessive-compulsive disorder: a meta-analysis of treatment outcome and predictors of response\n. PLOS One. (2015 ) 10 :e0133591 . 10.1371/journal.pone.0133591 26208305 \n4. de Koning PP Figee M van den Munckhof P Schuurman PR Denys D . Current status of deep brain stimulation for obsessive-compulsive disorder: a clinical review of different targets\n. Curr Psychiatry Rep. (2011 ) 13 :274 –82\n. 10.1007/s11920-011-0200-8 21505875 \n5. Nair G Evans A Bear RE Velakoulis D Bittar RG . The anteromedial GPi as a new target for deep brain stimulation in obsessive compulsive disorder\n. J Clin Neurosci. (2014 ) 21 :815 –21\n. 10.1016/j.jocn.2013.10.003 24524950 \n6. Coenen VA Schlaepfer TE Goll P Reinacher PC Voderholzer U Tebartz van Elst L . The medial forebrain bundle as a target for deep brain stimulation for obsessive-compulsive disorder\n. CNS Spectrums. (2017 ) 22 :282 –9\n. 10.1017/S1092852916000286 27268576 \n7. Fasano A Daniele A Albanese A . Treatment of motor and non-motor features of Parkinson's disease with deep brain stimulation\n. Lancet Neurol. (2012 ) 11 :429 –42\n. 10.1016/S1474-4422(12)70049-2 22516078 \n8. Bittar RG Yianni J Wang S Liu X Nandi D Joint C . Deep brain stimulation for generalised dystonia and spasmodic torticollis\n. J Clin Neurosci. (2005 ) 12 :12 –6\n. 10.1016/j.jocn.2004.03.025 15639404 \n9. Schrock LE Mink JW Woods DW Porta M Servello D Visser-Vandewalle V . Tourette syndrome deep brain stimulation: a review and updated recommendations: Tourette Syndrome DBS Guidelines\n. Mov Disord. (2015 ) 30 :448 –71\n. 10.1002/mds.26094 25476818 \n10. Mallet L Polosan M Jaafari N Baup N Welter M-L Fontaine D . Subthalamic nucleus stimulation in severe obsessive-compulsive disorder\n. N Engl J Med. (2008 ) 359 :2121 –34\n. 10.1056/NEJMoa0708514 19005196 \n11. Le Jeune F Vérin M N'Diaye K Drapier D Leray E Du Montcel ST . Decrease of prefrontal metabolism after subthalamic stimulation in obsessive-compulsive disorder: a positron emission tomography study\n. Biol Psychiatry. (2010 ) 68 :1016 –22\n. 10.1016/j.biopsych.2010.06.033 20951978 \n12. Nauczyciel C Le Jeune F Naudet F Douabin S Esquevin A Vérin M . Repetitive transcranial magnetic stimulation over the orbitofrontal cortex for obsessive-compulsive disorder: a double-blind, crossover study\n. Transl Psychiatry. (2014 ) 4 :e436 –e6\n. 10.1038/tp.2014.62 25203167 \n13. Greenberg BD Rauch SL Haber SN . Invasive circuitry-based neurotherapeutics: stereotactic ablation and deep brain stimulation for OCD\n. Neuropsychopharmacology. (2010 ) 35 :317 –36\n. 10.1038/npp.2009.128 19759530 \n14. Millet B Dondaine T Reymann J-M Bourguignon A Naudet F Jaafari N . Obsessive compulsive disorder networks: positron emission tomography and neuropsychology provide new insights\n. PLoS One. (2013 ) 8 :e53241 . 10.1371/journal.pone.0053241 23326403 \n15. Meissner W Leblois A Hansel D Bioulac B Gross CE Benazzouz A . Subthalamic high frequency stimulation resets subthalamic firing and reduces abnormal oscillations\n. Brain. (2005 ) 128 :2372 –82\n. 10.1093/brain/awh616 16123144 \n16. Maatoug R Goff BL Rotge J-Y Jaafari N Guillin O Millet B . Performance in delayed non-matching to sample task predicts the diagnosis of obsessive-compulsive disorder\n. Transl Psychiatry. (2019 ) 9 :338 . 10.1038/s41398-019-0667-3 31822655 \n17. McIntyre CC Hahn PJ . Network perspectives on the mechanisms of deep brain stimulation\n. Neurobiol Dis. (2010 ) 38 :329 –37\n. 10.1016/j.nbd.2009.09.022 19804831 \n18. Abelson JL Curtis GC Sagher O Albucher RC Harrigan M Taylor SF . Deep brain stimulation for refractory obsessive-compulsive disorder\n. Biol Psychiatry. (2005 ) 57 :510 –6\n. 10.1016/j.biopsych.2004.11.042 15737666 \n19. Denys D Mantione M Figee M Koerselman F Westenberg H Bosch A . Deep brain stimulation of the nucleus accumbens for treatment-refractory obsessive-compulsive disorder\n. Arch Gen Psychiatry. (2010 ) 67 :8 . 10.1001/archgenpsychiatry.2010.122 20921122 \n20. Nauczyciel C Robic S Dondaine T Verin M Robert G Drapier D . The nucleus accumbens: a target for deep brain stimulation in resistant major depressive disorder\n. J Mol Psychiatry. (2013 ) 1 :17 . 10.1186/2049-9256-1-17 26019865 \n21. Maatoug R Ekmen A Valero-Cabre A Millet B . Stimulation therapeutic approaches to better understand Obsessive Compulsive Disorder: the issue of 'where' to treat\n. L'Encéphale. (2019 ) 46 :399 –403\n. 10.1016/j.encep.2019.11.003 32014241 \n22. Yelnik J Bardinet E Dormont D Malandain G Ourselin S Tandé D . A three-dimensional, histological and deformable atlas of the human basal ganglia. I. Atlas construction based on immunohistochemical and MRI data\n. NeuroImage. (2007 ) 34 :618 –38\n. 10.1016/j.neuroimage.2006.09.026 17110133 \n23. Bardinet E Bhattacharjee M Dormont D Pidoux B Malandain G Schüpbach M . A three-dimensional histological atlas of the human basal ganglia. II. Atlas deformation strategy and evaluation in deep brain stimulation for Parkinson disease\n. JNS. (2009 ) 110 :208 –19\n. 10.3171/2008.3.17469 18976051 \n24. Vora AK Ward H Foote KD Goodman WK Okun MS . Rebound symptoms following battery depletion in the NIH OCD DBS cohort: Clinical and reimbursement issues\n. Brain Stimul. (2012 ) 5 :599 –604\n. 10.1016/j.brs.2011.10.004 22305344 \n25. de la Fuente-Fernández R . Uncovering the hidden placebo effect in deep-brain stimulation for Parkinson's disease\n. Parkinsonism Rel Disord. (2004 ) 10 :125 –7\n. 10.1016/j.parkreldis.2003.10.003 15036165 \n26. Keitel A Ferrea S Südmeyer M Schnitzler A Wojtecki L . Expectation modulates the effect of deep brain stimulation on motor and cognitive function in tremor-dominant Parkinson's disease\n. PLoS One. (2013 ) 8 :e81878 . 10.1371/journal.pone.0081878 24312596 \n27. Schruers K Baldi S van den Heuvel T Goossens L Luyten L Leentjens AlbertFG . The effects of deep-brain non-stimulation in severe obsessive-compulsive disorder: an individual patient data meta-analysis\n. Transl Psychiatry. (2019 ) 9 :183 . 10.1038/s41398-019-0522-6 31383848 \n28. Sharma E Reddy YC \nThe natural history of obsessive-compulsive disorder across the lifespan\n. In: Fontenelle LF Yucel M editors. A Transdiagnostic Approach to Obsessions, Compulsions and Related Phenomena . Cambridge : Cambridge University Press (2019 ). p. 144 –61\n.\n29. Pourfar M Tang C Lin T Dhawan V Kaplitt MG Eidelberg D \nAssessing the microlesion effect of subthalamic deep brain stimulation surgery with FDG PET\n. JNS. (2009 ) 110 :1278 –82\n. 10.3171/2008.12.JNS08991 \n30. Mann JM Foote KD Garvan CW Fernandez HH Jacobson CE Rodriguez RL \nBrain penetration effects of microelectrodes and DBS leads in STN or GPi\n. J Neurol Neurosurg Psychiatry. (2009 ) 80 :794 –8\n. 10.1136/jnnp.2008.159558 19237386 \n31. Tykocki T Nauman P Koziara H Mandat T . Microlesion effect as a predictor of the effectiveness of subthalamic deep brain stimulation for Parkinsons disease\n. Stereotact Funct Neurosurg . (2013 ) 91 :12 –7\n. 10.1159/000342161 23154788 \n32. Mestre TA Lang AE Okun MS . Factors influencing the outcome of deep brain stimulation: Placebo, nocebo, lessebo, and lesion effects: factors influencing deep brain stimulation outcome\n. Mov Disord. (2016 ) 31 :290 –8\n. 10.1002/mds.26500 26952118 \n33. Hilker R Voges J Weisenbach S Kalbe E Burghaus L Ghaemi M . Subthalamic nucleus stimulation restores glucose metabolism in associative and limbic cortices and in cerebellum: evidence from a FDG-PET study in advanced Parkinson's disease\n. J Cereb Blood Flow Metab. (2004 ) 24 :7 –16\n. 10.1097/01.WCB.0000092831.44769.09 14688612\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-0640",
"issue": "11()",
"journal": "Frontiers in psychiatry",
"keywords": "battery failure; case-report; deep brain stimulation; obsessive compulsive disorder; stimulation techniques; treatment refractory",
"medline_ta": "Front Psychiatry",
"mesh_terms": null,
"nlm_unique_id": "101545006",
"other_id": null,
"pages": "572059",
"pmc": null,
"pmid": "33281642",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": "22516078;21505875;20951978;15036165;31383848;16650723;16123144;22305344;14688612;24312596;26208305;26019865;17110133;19301972;31822655;19759530;15939839;27268576;19804831;26952118;25203167;20921122;18976051;23154788;23326403;32014241;15737666;15639404;19237386;19005196;25476818;24524950",
"title": "Sustained Recovery in a Treatment-Refractory Obsessive-Compulsive Disorder Patient After Deep Brain Stimulation Battery Failure.",
"title_normalized": "sustained recovery in a treatment refractory obsessive compulsive disorder patient after deep brain stimulation battery failure"
} | [
{
"companynumb": "FR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-290306",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUOXETINE HYDROCHLORIDE"
},
... |
{
"abstract": "FOLFOX (folinic acid, 5-fluorouracil and oxaliplatin) is the most commonly used chemotherapy regimen for the treatment of colorectal cancer. FOLFOX is administered in 14-day cycles, though toxicities frequently lead to unplanned delays. We report the incidence of unplanned delays among patients receiving FOLFOX and describe the reasons for delays.\nWe conducted a retrospective analysis of patients receiving FOLFOX chemotherapy for colorectal cancer. Patients were treated at one of two tertiary cancer centers between January 2012 and April 2016. Cycles 2-6 were assessed for delays, and treatments were considered delayed when the interval from prior treatment was >18 days. Reasons for unplanned delays were categorized based on review of clinical records.\nWe identified 214 patients receiving FOLFOX as standard-of-care therapy. The median age was 59 years, and 55% were female. Of 961 evaluable treatment cycles, 124 (13%) had unplanned delays, and 92 of 214 patients (43%) had one or more unplanned delays in cycles 2-6. Cytopenias (neutropenia and/or thrombocytopenia) were the most common cause of unplanned delays, affecting 34% of patients and accounting for 74 of 124 unplanned delays (60%).\nDelays are common during FOLFOX chemotherapy, with 43% of patients having at least one unplanned delay prior to completing cycle 6. Neutropenia and thrombocytopenia were the leading causes of unplanned delays. Our findings justify the development of systematic approaches for preventing unplanned delays, such as standardized laboratory treatment criteria and/or proactive dose adjustment strategies.",
"affiliations": "Department of Medicine, Rhode Island Hospital, Providence, RI, USA.;University of Colorado Cancer Center, Aurora, CO, USA.;Department of Medicine, Rhode Island Hospital, Providence, RI, USA.",
"authors": "Kogan|Lawrence G|LG|;Davis|S Lindsey|SL|;Brooks|Gabriel A|GA|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2019.07.03",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "10(5)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Treatment delay; chemotherapy; fluorouracil; neutropenia; oxaliplatin",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "841-846",
"pmc": null,
"pmid": "31602321",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": "23392240;26573078;27956539;19414665;26819636;26716401;23442307;28038865;20378503;26694717;15175436;29045513;26884581;28881381;25417044;30348537;25012517",
"title": "Treatment delays during FOLFOX chemotherapy in patients with colorectal cancer: a multicenter retrospective analysis.",
"title_normalized": "treatment delays during folfox chemotherapy in patients with colorectal cancer a multicenter retrospective analysis"
} | [
{
"companynumb": "US-AMGEN-USASP2019176923",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEUCOVORIN"
},
"drugadditional": null,
... |
{
"abstract": "Diphenhydramine, a first generation H1 histamine receptor antagonist, is a commonly used nonprescription medication that is used for the treatment of allergy, as a sleep aid, or combined with cough and cold remedies. Naproxen, a nonsteroidal anti-inflammatory drug (NSAID), is used commonly for analgesia. Although most cases of diphenhydramine or naproxen overdose require excellent supportive care only, meticulous attention should be given to cardiovascular and neurologic status.\n\n\n\nA 22-year-old woman presented with altered mental status secondary to intentional ingestion of 240 combination caplets of naproxen sodium 220 mg and diphenhydramine hydrochloride 25 mg. While in the emergency department, she manifested a wide-complex tachycardia in the setting of hypotension that required repeated administration of sodium bicarbonate to overcome the sodium channel blockade caused by diphenhydramine. Aggressive potassium repletion was performed simultaneously. Her clinical course was complicated by status-epilepticus that required intubation. Orogastric lavage was performed, which returned blue pill slurry consistent with the ingested caplets. The patient was extubated on hospital day 2 and transferred to psychiatry thereafter. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: In light of recent social media trends, such as the \"Benadryl challenge\" and its widespread availability, emergency providers should be familiar with diphenhydramine toxicity, especially the life-threatening neurologic consequences and risk of cardiovascular collapse. NSAIDs, such as naproxen, and other nonprescription analgesics are becoming more and more important in light of the current opioid crisis. There should be an emphasis on understanding these medications and their potential implications when taken in overdose.",
"affiliations": "Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York; St. John's University College of Pharmacy and Health Sciences, Jamaica, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York; Institute for Innovations in Medical Education, New York University Grossman School of Medicine, New York University Langone Health, New York, New York.;Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York, New York.",
"authors": "Mohan|Sanjay|S|;Backus|Timothy|T|;Furlano|Emma|E|;Howland|Mary Ann|MA|;Smith|Silas W|SW|;Su|Mark K|MK|",
"chemical_list": "D009288:Naproxen; D004155:Diphenhydramine; D017693:Sodium Bicarbonate",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jemermed.2021.04.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-4679",
"issue": "61(3)",
"journal": "The Journal of emergency medicine",
"keywords": "Bicarbonate; Diphenhydramine; Naproxen; Overdose; Physostigmine",
"medline_ta": "J Emerg Med",
"mesh_terms": "D000328:Adult; D004155:Diphenhydramine; D062787:Drug Overdose; D005260:Female; D006801:Humans; D009288:Naproxen; D017693:Sodium Bicarbonate; D013610:Tachycardia; D055815:Young Adult",
"nlm_unique_id": "8412174",
"other_id": null,
"pages": "259-264",
"pmc": null,
"pmid": "34148773",
"pubdate": "2021-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Massive Diphenhydramine and Naproxen Overdose.",
"title_normalized": "a case of massive diphenhydramine and naproxen overdose"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2021GMK066447",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NAPROXEN"
},
"drugadditional"... |
{
"abstract": "BACKGROUND\nStatus dystonicus (SD) is a life-threatening complication in which episodes of dystonic movements become increasingly frequent and severe, requiring urgent hospital admission, and can lead to respiratory, metabolic, and bulbar complications. Pharmacologic treatment has been the mainstay management for this complication; however, many refractory patients will still require further treatment. Deep brain stimulation (DBS) is an established therapeutic strategy that has been used for dystonia, and now it has been proposed to be used for SD.\n\n\nMETHODS\nIn this case series, we describe our experience with early DBS placement in 5 patients with SD to control symptoms that are refractory to pharmacologic therapy. In addition, we present a literature review of this therapy in the treatment of SD.\n\n\nRESULTS\nBefore discharge, symptomatic relief (decrease of dystonic movements and resolution of abnormal postures) was evidenced in all patients with a median of 3 days (interquartile range, 1-7) after surgery was performed. A follow-up Unified Dystonia Rating Scale score and Burke-Fahn-Marsden rating scale motor subscale score, at 6 months after hospital discharge with values being inferior to 20 and 30, respectively, for all cases. None of the patients had a recurrence of SD in the last follow-up period.\n\n\nCONCLUSIONS\nDBS surgery is a suitable, versatile, reversible and adequate therapy in the treatment of SD that is refractory to initial pharmacologic treatment.",
"affiliations": "Fundacion Valle del Lili, Cali, Colombia; Universidad Icesi, Cali, Colombia; Centro de Investigación Clinica, Cali, Colombia. Electronic address: jmlobatop@yahoo.com.;Fundacion Valle del Lili, Cali, Colombia; Universidad Icesi, Cali, Colombia.;Fundacion Valle del Lili, Cali, Colombia; Universidad Icesi, Cali, Colombia.;Fundacion Valle del Lili, Cali, Colombia; Universidad Icesi, Cali, Colombia; Centro de Investigación Clinica, Cali, Colombia.;Fundacion Valle del Lili, Cali, Colombia; Universidad Icesi, Cali, Colombia; Centro de Investigación Clinica, Cali, Colombia.;Fundacion Valle del Lili, Cali, Colombia; Centro de Investigación Clinica, Cali, Colombia.",
"authors": "Lobato-Polo|Javier|J|;Ospina-Delgado|Daniel|D|;Orrego-González|Eduardo|E|;Gómez-Castro|Juan F|JF|;Orozco|Jorge L|JL|;Enriquez-Marulanda|Alejandro|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.wneu.2018.03.129",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1878-8750",
"issue": "114()",
"journal": "World neurosurgery",
"keywords": "Deep brain stimulation; Dystonic crisis; Dystonic storm; Life-threatening dystonia; Severe dystonia; Status dystonicus",
"medline_ta": "World Neurosurg",
"mesh_terms": "D000328:Adult; D002648:Child; D046690:Deep Brain Stimulation; D020821:Dystonic Disorders; D005260:Female; D006801:Humans; D008297:Male; D011446:Prospective Studies; D012189:Retrospective Studies",
"nlm_unique_id": "101528275",
"other_id": null,
"pages": "e992-e1001",
"pmc": null,
"pmid": "29602003",
"pubdate": "2018-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Deep Brain Stimulation Surgery for Status Dystonicus: A Single-Center Experience and Literature Review.",
"title_normalized": "deep brain stimulation surgery for status dystonicus a single center experience and literature review"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-030146",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
... |
{
"abstract": "Infections and malignancies are among the most serious complications that follow organ or stem cell transplantation. They may have a mild course, and nonspecific and overlapping manifestations. The present article describes a case of symptomatic nodular pulmonary disease that complicated hematopoietic stem cell transplantation. It was diagnosed to be post-transplant lymphoproliferative disorder, a potential sequela of immunosuppression and a very difficult entity to treat in profoundly immunosuppressed patients.",
"affiliations": null,
"authors": "Salh|Omar S|OS|;Nadhem|Omar N|ON|;Thakore|Sanket R|SR|;Halloush|Ruba A|RA|;Khasawneh|Faisal A|FA|",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2015/132162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1198-2241",
"issue": "22(3)",
"journal": "Canadian respiratory journal",
"keywords": null,
"medline_ta": "Can Respir J",
"mesh_terms": "D020031:Epstein-Barr Virus Infections; D017809:Fatal Outcome; D018380:Hematopoietic Stem Cell Transplantation; D006689:Hodgkin Disease; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008297:Male; D008875:Middle Aged; D011014:Pneumonia",
"nlm_unique_id": "9433332",
"other_id": null,
"pages": "144-6",
"pmc": null,
"pmid": "26057372",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20732435;22173060;14751931;14564542;9787149;10084762;10498590;15596707;16303003;16594752;16254143;17468341;18645482;18516079;19264919;19474517",
"title": "A 47-year-old stem cell transplant recipient with fever, cough and chest pain.",
"title_normalized": "a 47 year old stem cell transplant recipient with fever cough and chest pain"
} | [
{
"companynumb": "US-FRESENIUS KABI-FK201602190",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
... |
{
"abstract": "We report a patient with non-ischemic dilated cardiomyopathy and low left ventricular systolic function (28%) presenting with an electrical storm originated in epicardial scar and ablated by radiofrequency. This case report suggests that a strategy of epicardial catheter ablation is reasonable for the patient presenting with electrical storm related to structural disease with a low left ventricular ejection fraction.",
"affiliations": "Electrophysiology Unit, Cardiovascular Department, \"Spirito Santo\" Hospital, ASL Pescara, Pescara, Italy.;Electrophysiology Unit, Cardiovascular Department, \"Spirito Santo\" Hospital, ASL Pescara, Pescara, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Italy.;Cardiovascular Department, ASL Lanciano-Vasto-Chieti, Italy.;Cardiovascular Department, ASL Lanciano-Vasto-Chieti, Italy.;Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Italy. Electronic address: carmine.pizzi@unibo.it.",
"authors": "Faustino|Massimiliano|M|;Agricola|Tullio|T|;Xyheri|Borejda|B|;Di Girolamo|Enrico|E|;Leonzio|Luigi|L|;Pizzi|Carmine|C|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.ihj.2016.01.010",
"fulltext": "\n==== Front\nIndian Heart JIndian Heart JIndian Heart Journal0019-4832Elsevier S0019-4832(16)00011-010.1016/j.ihj.2016.01.010Case ReportElectrical storm in dilated cardiomyopathy treated using epicardial radiofrequency ablation as a first line therapy Faustino Massimiliano aAgricola Tullio aXyheri Borejda bDi Girolamo Enrico cLeonzio Luigi cPizzi Carmine carmine.pizzi@unibo.itb⁎a Electrophysiology Unit, Cardiovascular Department, “Spirito Santo” Hospital, ASL Pescara, Pescara, Italyb Department of Specialized, Experimental and Diagnostic Medicine, University of Bologna, Italyc Cardiovascular Department, ASL Lanciano-Vasto-Chieti, Italy⁎ Corresponding author. carmine.pizzi@unibo.it9 2016 29 1 2016 68 Suppl 2 S218 S222 22 9 2015 10 1 2016 © 2016 Cardiological Society of India. Published by Elsevier B.V.2016Cardiological Society of IndiaThis is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).We report a patient with non-ischemic dilated cardiomyopathy and low left ventricular systolic function (28%) presenting with an electrical storm originated in epicardial scar and ablated by radiofrequency. This case report suggests that a strategy of epicardial catheter ablation is reasonable for the patient presenting with electrical storm related to structural disease with a low left ventricular ejection fraction.\n\nKeywords\nDilated cardiomyopathyVentricular arrhythmiasCatheter ablationEpicardial\n==== Body\n1 Introduction\nPatients with non-ischemic dilated cardiomyopathy (DCM) are at high risk for sudden cardiac death due to sustained ventricular tachycardia (VT) or ventricular fibrillation (VF).1 Randomized trials have proven the benefit of an implantable cardioverter-defibrillator (ICD) as compared with anti-arrhythmic drug therapy, and current guidelines recommend ICD therapy in both primary and secondary prevention.2, 3, 4, 5, 6, 7 Although ICDs improve overall survival, they do not eliminate the arrythmogenic substrate. Despite the presence of an ICD, the occurrence of a ventricular arrhythmia storm (≥3 hemodynamically destabilizing VTs in a 24-h period or the detection of ≥3 VTs in a 24-h period in ICD patients) may still lead to elevated mortality.8 According to the above-mentioned definition, the incidence of electrical storm (ES) ranges from 4%, over a 20.6-month period of follow-up in those studies in which ICD implantation was carried out for primary prevention, to 20% over a 31-month period of follow-up in secondary prevention ICD recipients.8\n\nIn patients experiencing ES, the key intervention is reduction of the sympathetic tone using beta-blockers, frequently combined with benzodiazepines; amiodarone intravenous infusion is also recommended while class I antiarrhythmic drugs are usually unsuccessful.8 The non-pharmacological therapeutic option for the recurrence of VT or VF is transcatheter ablation of ventricular arrhythmogenic foci.9, 10, 11, 12\n\nAlthough radiofrequency catheter ablation has an established role in the treatment of recurrent VT, its therapeutic role in patients with ES has been investigated only in selected populations with implanted ICDs. The current guidelines suggest that VT ablation intervention be used as an adjunctive therapy to ICD while radiofrequency ablation strategy alone has never been assessed in patients with structural heart disease and a low ejection fraction.\n\n2 Case report\nA 55-year-old man was admitted to the hospital due to a syncope episode preceded by palpitation. The patient had no cardiovascular risk factors, no familial history of sudden cardiac death, and no previous history of cardiovascular disorders, including syncope or palpitation episodes. During transport, the patient developed VT with hypotension and was defibrillated twice with 200 J from a biphasic defibrillator with standard anterior and lateral placement (one pad right parasternal and the second at the cardiac apex) obtaining temporary recovery of sinus rhythm with subsequent numerous subentrant episodes of VT. An IV infusion of amiodarone was immediately started and another 4 DC shocks were administered. While in the coronary care unit, by utilizing a conventional 12 lead surface electrocardiogram (ECG), sustained, wide complex tachycardia with a rate of 234 beats per minute with right bundle brunch and right-axis deviation morphology, and a pseudodelta wave in precordial leads were recorded. The tachycardia morphology was consistent with the diagnosis of VT originating from the left ventricle. The intravenous infusion of amiodarone, lidocaine, beta blockers, and magnesium sulfate was carried out with no resolution of the arrhythmia. After deep sedation and orotracheal intubation, sinus rhythm was restored by means of electrical cardioversion. Written informed consent for the cardiac catheterization and eventual electrophysiological study was obtained from the family of the patient. The patient underwent urgent cardiac catheterization, and coronary angiogram documented normal coronary vessels and diffuse left ventricular (LV) hypokinesia (left ventricular ejection fraction (LVEF) = 28%). The patient was referred for emergency electrophysiological study. Endocardial mapping did not identify any low-voltage areas suggestive of an arrhythmia focus. As the ECG-guided morphological analysis of the arrhythmia was coherent with an epicardial origin (pseudodelta wave) of the arrhythmia, a subxiphoid approach was undertaken to achieve pericardial access as described by Sosa et al.13 Epicardial LV mapping during sinus rhythm revealed a 1.6 cm2 scar at the posterolateral region of the basal segment of the LV epicardium with a voltage of 0.6 mV. After VT was induced (QRS morphology is identical to spontaneous ventricular arrhythmia), this isolated delayed potential became mid-diastolic and pre-systolic (180 ms before QRS complexes) (Fig. 1). One pulse radiofrequency current at this site interrupted VT after 4.5 s (maximum power, 45 W; maximum temperature, 42 °C). Several additional radiofrequency applications were placed in close proximity adjacent to this site on local abnormal ventricular activities (LAVA) potentials (Fig. 2). Coronary angiography was not performed before radiofrequency delivery because there was low possibility of damage of main coronary artery vessel. After the ablations were completed, VT could no longer be provoked.\n\nThe findings are consistent with a small, epicardial arrhythmogenetic scar area, possibly related to idiopathic cardiomyopathy. Endomyocardial biopsy had excluded inflammatory and non-inflammatory causes of idiopathic cardiomyopathy. Since we did not perform cardiac magnetic resonance, we cannot exclude a priori areas of myocardial inflammation or fibrosis near the site of epicardial ablation. During follow-up, no further ventricular arrhythmias were registered over a period of 30 days after ablation. Echocardiography showed severe LV systolic dysfunction with a LV ejection fraction of 28%. A dual chamber ICD was implanted for secondary prevention. At a 24-month follow-up, no further episodes of VT were recorded. No antiarrhythmic therapy was administered following the ablation.\n\n3 Discussion\nThis case report suggests that a strategy of epicardial catheter ablation is reasonable for a patient presenting with ES related to structural disease having a low LVEF (LVEF = 28%).\n\nRandomized controlled trials support the use of ICDs for the secondary prevention of sudden cardiac death. In patients with a history of cardiac arrest, an ICD is associated with clinically and statistically significant reductions in sudden death and total mortality as compared with antiarrhythmic drug therapy.1\n\nCatheter ablation (CA) has a well-established role in managing recurrent VT in order to reduce shocks in patients with ICDs. Many studies have demonstrated that, after CA, the frequency of VT was reduced by 50–67% at a 6-month follow-up. Della Bella et al. have demonstrated that the elevated success rate of CA is associated with a lower arrhythmia recurrence rate, also due to the systematic implementation of an ablation strategy, which focused on endocardial-epicardial substrate modification, independent of VT inducibility and tolerance. CA also improved the survival rate by 18–25% in a 1-year follow-up period.12\n\nTransthoracic epicardial radiofrequency has been demonstrated to be a safe, feasible, and effective alternative in patients undergoing unsuccessful endocardial ablation.13 Generally, an epicardial approach was performed in 17–19% of VT ablation procedures ranging from 6% in normal hearts to 16% for ischemic cardiomyopathy, 35% for DCM, and 41% for arrhythmogenic right ventricular cardiomyopathy.14 However, there are no reports in the literature regarding this procedure in patients before ICD implantation. Recently, Maury et al. reported that CA with a deferral of ICD implantation is reasonable for a patient presenting with well-tolerated sustained monomorphic VT related to structural disease having an LVEF > 30%.15 However, this ablation strategy has not been reported in patients with hemodynamically non-tolerated VTs and with severe altered left ventricular function as in our case report. We decided to implant an ICD after CA because a poor left ventricular ejection fraction and ES are independent predictors of VT recurrence, even if our patient had no arrhythmias in a 24-month follow up. Patients with VT ablation are more likely to remain at risk of sudden death and an ICD is usually warranted before hospital discharge.1\n\n4 Conclusion\nTo our knowledge, this is the first case reporting the efficacy of urgent VT ablation in a patient presenting with hemodynamically non-tolerated ES. Furthermore, we considered multiple factors in making our decision regarding this epicardial approach; this included ECG analysis of the clinical VT for features suggesting an epicardial source, history of previous failed endocardial ablation, and the presence of ES.\n\nConflicts of interest\nThe authors declare that they have no conflicts of interest.\n\nEthical standards\nThis is a case report.\n\nFig. 1 Electroanatomical mapping. Left ventricular posterior views of epicardial mapping (A) and endocardial/epircardial map (B). The earliest epicardial activation site during ventricular tachycardia (A, marked by a white arrow) shows the site where VT has been interrupted, and brown tags (A and C) indicate the ablation site on the LAVA potentials. A white circle (C) indicates voltage mapping during sinus rhythm (C) with isolated delayed potential around the ablation area.\n\nFig. 2 A twelve-lead ECG during ventricular tachycardia. Note the right bundle-branch morphology of the QRS complex (A). Findings during epicardial mapping during ventricular tachycardia show the presence of presystolic or mid-diastolic fragmentation (B). Panel (C) shows that the isolated potential in the epicardium occurs approximately 180 ms before the QRS complex during VT. Ablation at the epicardial site terminates ventricular tachycardia. In this area, during sinus rhythm it is possible to observe local abnormal ventricular activities (LAVA) potentials (white arrows). LAVA was defined as electrograms from poorly coupled surviving myocardial fibers with the following features: (1) sharp, high-frequency ventricular potentials distinct from the far-field ventricular electrogram; (2) occurring anytime during or, more frequently, after the far-field ventricular electrogram during sinus rhythm; and (3) sometimes displaying double or multiple high-frequency signals separated by very low-amplitude signals or an isoelectric interval. The complete elimination of LAVA would lead to a reduction in arrhythmia-free survival.\n==== Refs\nReferences\n1 European Heart Rhythm Association Heart Rhythm Society Zipes D.P. ACC/AHA/ESC 2006 guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: a report of the American College of Cardiology/American Heart Association Task Force and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Develop Guidelines for Management of Patients with Ventricular Arrhythmias and the Prevention of Sudden Cardiac Death) J Am Coll Cardiol 48 2006 e247 e346 16949478 \n2 A comparison of antiarrhythmic-drug therapy with implantable defibrillators in patients resuscitated from near-fatal ventricular arrhythmias. The Antiarrhythmics versus Implantable Defibrillators (AVID) Investigators N Engl J Med 337 1997 1576 1583 9411221 \n3 Wever E.F. Hauer R.N. van Capelle F.L. Randomized study of implantable defibrillator as first-choice therapy versus conventional strategy in postinfarct sudden death survivors Circulation 91 1995 2195 2203 7697849 \n4 Siebels J. Kuck K.H. Implantable cardioverter defibrillator compared with antiarrhythmic drug treatment in cardiac arrest survivors (the Cardiac Arrest Study Hamburg) Am Heart J 127 1994 1139 1144 8160593 \n5 Connolly S.J. Gent M. Roberts R.S. Canadian implantable defibrillator study (CIDS): a randomized trial of the implantable cardioverter defibrillator against amiodarone Circulation 101 2000 1297 1302 10725290 \n6 Kuck K.H. Cappato R. Siebels J. Ruppel R. Randomized comparison of antiarrhythmic drug therapy with implantable defibrillators in patients resuscitated from cardiac arrest: the Cardiac Arrest Study Hamburg (CASH) Circulation 102 2000 748 754 10942742 \n7 Connolly S.J. Hallstrom A.P. Cappato R. Meta-analysis of the implantable cardioverter defibrillator secondary prevention trials. AVID, CASH and CIDS studies. Antiarrhythmics vs Implantable Defibrillator study. Cardiac Arrest Study Hamburg. Canadian Implantable Defibrillator Study Eur Heart J 21 2000 2071 2078 11102258 \n8 Nayyar S. Ganesan A.N. Brooks A.G. Sullivan T. Roberts-Thomson K.C. Sanders P. Venturing into ventricular arrhythmia storm: a systematic review and meta-analysis Eur Heart J 34 2013 560 569 23264584 \n9 Bansch D. Oyang F. Antz M. Successful catheter ablation of electrical storm after myocardial infarction Circulation 108 2003 3011 3016 14662718 \n10 Della Bella P. Brugada J. Zeppenfeld K. Epicardial ablation for ventricular tachycardia: a European multicenter study Circ Arrhythm Electrophysiol 4 2011 653 659 21841191 \n11 Sternick E.B. Piorkowski C. Hindricks G. Dagres N. Sommer P. Electrical storm originating from a left ventricular epicardial scar in a patient with completely normal endocardial voltage Heart Vessels 26 2011 663 666 21274719 \n12 Della Bella P. Baratto F. Tsiachris D. Management of ventricular tachycardia in the setting of a dedicated unit for the treatment of complex ventricular arrhythmias: long-term outcome after ablation Circulation 127 2013 1359 1368 23439513 \n13 Sosa E. Scanavacca M. d’Avila A. Pilleggi F. A new technique to perform epicardial mapping in the electrophysiology laboratory J Cardiovasc Electrophysiol 7 1996 531 536 8743758 \n14 Boyle N.G. Shivkumar K. Epicardial interventions in electrophysiology Circulation 126 2012 1752 1769 23027811 \n15 Maury P. Baratto F. Zeppenfeld K. Radio-frequency ablation as primary management of well-tolerated sustained monomorphic ventricular tachycardia in patients with structural heart disease and left ventricular ejection fraction over 30% Eur Heart J 35 2014 1479 1485 24536081\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0019-4832",
"issue": "68 Suppl 2()",
"journal": "Indian heart journal",
"keywords": "Catheter ablation; Dilated cardiomyopathy; Epicardial; Ventricular arrhythmias",
"medline_ta": "Indian Heart J",
"mesh_terms": "D018780:Body Surface Potential Mapping; D002311:Cardiomyopathy, Dilated; D017115:Catheter Ablation; D006329:Heart Conduction System; D006339:Heart Rate; D006801:Humans; D008297:Male; D008875:Middle Aged; D010496:Pericardium; D017180:Tachycardia, Ventricular",
"nlm_unique_id": "0374675",
"other_id": null,
"pages": "S218-S222",
"pmc": null,
"pmid": "27751294",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10725290;8160593;9411221;10942742;24536081;7697849;8743758;23264584;14662718;23439513;16949478;21274719;11102258;21841191;23027811",
"title": "Electrical storm in dilated cardiomyopathy treated using epicardial radiofrequency ablation as a first line therapy.",
"title_normalized": "electrical storm in dilated cardiomyopathy treated using epicardial radiofrequency ablation as a first line therapy"
} | [
{
"companynumb": "IT-MYLANLABS-2016M1055938",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MAGNESIUM SULFATE"
},
"drugadditional": null,... |
{
"abstract": "Salvage regimens for patients with relapsed/refractory acute myeloid leukemia (rrAML) lack comparative data for superiority. Thus, we conducted a retrospective analysis of clofarabine-based (GCLAC; granulocyte colony-stimulating factor [filgrastim], clofarabine, high-dose cytarabine) versus cladribine-based (CLAG; cladribine, cytarabine, granulocyte colony-stimulating factor [filgrastim]) regimens in rrAML.\n\n\n\nWe identified 41 consecutive patients with rrAML who had received either GCLAC or CLAG from 2011 to 2014. The primary outcome measure was the complete remission (CR) rate defined according to the International Working Group criteria. The secondary outcomes included the proportion of patients who underwent allogenic stem cell transplantation and the rate of relapse-free survival and overall survival.\n\n\n\nWe found no significant differences in the baseline characteristics of the patients treated with GCLAC (n = 22) or CLAG (n = 19). The outcomes with these 2 regimens were not significantly different. Patients treated with GCLAC had a CR/CR with incomplete blood count recovery rate of 64% compared with 47% for the patients treated with CLAG (P = .36). Of the GCLAC patients, 45% underwent allogeneic stem cell transplantation compared with 26% of the CLAG patients (P = .32). The median relapse-free survival after GCLAC and CLAG was 1.59 years and 1.03 years, respectively (P = .75). The median overall survival after GCLAG and CLAG was 1.03 years and 0.70 years, respectively (P = .08). The drug costs were significantly different for GCLAC versus CLAG. Using an average wholesale price, the cost per patient per cycle was $60,821.60 for GCLAC and $4910.60 for CLAG.\n\n\n\nA single-institutional retrospective analysis found no significant differences in the outcomes between GCLAC and CLAG for rrAML patients, although formal comparisons should be performed in a randomized clinical trial. The cost of GCLAC was greater than that of CLAG, which should be considered when evaluating the choice for the salvage chemotherapy options.",
"affiliations": "Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC; University of North Carolina Eshelman School of Pharmacy, Chapel Hill, NC. Electronic address: bmuluneh@unch.unc.edu.;Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC.;Biostatistics and Clinical Data Management Core, University of North Carolina, Chapel Hill, NC.;Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Department of Medicine, University of North Carolina, Chapel Hill, NC.;Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Department of Medicine, University of North Carolina, Chapel Hill, NC.;Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC; Department of Medicine, University of North Carolina, Chapel Hill, NC.;Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, NC.;Department of Medicine, University of North Carolina, Chapel Hill, NC.",
"authors": "Muluneh|Benyam|B|;Buhlinger|Kaitlyn|K|;Deal|Allison M|AM|;Zeidner|Joshua F|JF|;Foster|Matthew C|MC|;Jamieson|Katarzyna Joanna|KJ|;Bates|Jill|J|;Van Deventer|Hendrik W|HW|",
"chemical_list": "D017338:Cladribine; D000077866:Clofarabine",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.09.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "18(1)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "AML; Cladribine; Clofarabine; GCSF; Relapsed/refractory",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D017338:Cladribine; D000077866:Clofarabine; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D016879:Salvage Therapy",
"nlm_unique_id": "101525386",
"other_id": null,
"pages": "e13-e18",
"pmc": null,
"pmid": "29100976",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "A Comparison of Clofarabine-based (GCLAC) and Cladribine-based (CLAG) Salvage Chemotherapy for Relapsed/Refractory AML.",
"title_normalized": "a comparison of clofarabine based gclac and cladribine based clag salvage chemotherapy for relapsed refractory aml"
} | [
{
"companynumb": "PHHY2018US015380",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "CYTARABINE"
},
"drugadditional": null,
"drug... |
{
"abstract": "BACKGROUND\nAnaphylaxis during general anaesthesia is a major concern. Early recognition and management of anaphylaxis, as well as its future prevention, remain a challenge for the anaesthetists, while for the allergists, the elucidation of the causal agents may be difficult. We aimed to describe our experience in our drug allergy clinic.\n\n\nMETHODS\nWe retrospectively reviewed 23 consecutive adult patients who presented with anaphylaxis during anaesthesia from March 1, 2005 to February 28, 2006.\n\n\nRESULTS\nOut of the 23 patients (12 females, 11 males) with mean age (+/- SD) of 53.1 +/- 15.8 years, 15 patients were found to have a positive skin test to at least one neuromuscular blocking agent (NMBA); all of them showed cross-sensitivity with one or more NMBA(s). Three patients had a positive skin test to opioids, two patients to gelofusine, two patients to penicillin, and one patient each to povidone-iodine and chlorhexidine. Two patients had negative test results to agents used during their anaesthesia. Four patients had double positive skin tests to different families of drugs/agents. 18 patients had severe reaction-grade 3, and 15 of them tested positive for NMBA(s). Serum tryptase levels were known in nine patients. We did not encounter any latex or hypnotics sensitisation.\n\n\nCONCLUSIONS\nNMBA was the commonest cause of anaphylaxis during general anaesthesia, occurring in 65% in our series.",
"affiliations": "Department of Rheumatology and Immunology, Singapore General Hospital, Outram Road, Singapore.",
"authors": "Chong|Y Y|YY|;Caballero|M R|MR|;Lukawska|J|J|;Dugué|P|P|",
"chemical_list": "D000701:Analgesics, Opioid; D009466:Neuromuscular Blocking Agents",
"country": "Singapore",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0037-5675",
"issue": "49(6)",
"journal": "Singapore medical journal",
"keywords": null,
"medline_ta": "Singapore Med J",
"mesh_terms": "D000328:Adult; D000368:Aged; D000701:Analgesics, Opioid; D000707:Anaphylaxis; D000768:Anesthesia, General; D004342:Drug Hypersensitivity; D005260:Female; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D009466:Neuromuscular Blocking Agents",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "483-7",
"pmc": null,
"pmid": "18581023",
"pubdate": "2008-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylaxis during general anaesthesia: one-year survey from a British allergy clinic.",
"title_normalized": "anaphylaxis during general anaesthesia one year survey from a british allergy clinic"
} | [
{
"companynumb": "SG-BECTON DICKINSON-2018BDN00323",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CHLORHEXIDINE"
},
"drugadditional": "3... |
{
"abstract": "We describe the case of a woman who developed a cutaneous leukocytoclastic vasculitis following a treatment with gabapentine.",
"affiliations": "Laboratoire de pharmacologie, Faculté de médecine, Sousse, Tunisie.;Laboratoire de pharmacologie, Faculté de médecine, Sousse, Tunisie.;Laboratoire de pharmacologie, Faculté de médecine, Sousse, Tunisie.;Service de dermatologie, Hôpital universitaire Farhat Hached, Sousse, Tunisie.;Service de dermatologie, Hôpital universitaire Farhat Hached, Sousse, Tunisie.;Laboratoire d'anatomie pathologique, Hôpital universitaire Farhat Hached, Sousse, Tunisie.;Laboratoire de pharmacologie, Faculté de médecine, Sousse, Tunisie.",
"authors": "Rached|Slaheddine|S|;Slim|Raoudha|R|;Fathallah|Neila|N|;Ghariani|Najet|N|;Nouira|Rafiaa|R|;Sriha|Badreddine|B|;Ben Salem|Chaker|C|",
"chemical_list": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin",
"country": "France",
"delete": false,
"doi": "10.2515/therapie/2014034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0040-5957",
"issue": "69(5)",
"journal": "Therapie",
"keywords": null,
"medline_ta": "Therapie",
"mesh_terms": "D000588:Amines; D000700:Analgesics; D003509:Cyclohexanecarboxylic Acids; D003924:Diabetes Mellitus, Type 2; D003929:Diabetic Neuropathies; D005260:Female; D000077206:Gabapentin; D006801:Humans; D008875:Middle Aged; D018366:Vasculitis, Leukocytoclastic, Cutaneous; D005680:gamma-Aminobutyric Acid",
"nlm_unique_id": "0420544",
"other_id": null,
"pages": "469-71",
"pmc": null,
"pmid": "25047672",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016422:Letter",
"references": null,
"title": "Gabapentin-induced cutaneous leukocytoclastic vasculitis.",
"title_normalized": "gabapentin induced cutaneous leukocytoclastic vasculitis"
} | [
{
"companynumb": "TN-ACTAVIS-2015-09647",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
... |
{
"abstract": "Minimal change disease (MCD) is the most common cause of nephrotic syndrome worldwide. For decades, the foundation of the treatment has been corticosteroids. However, relapse rate is high and up to 40% of patients develop frequent relapsing/steroid dependent course and one third become steroid resistant. This requires treatment with repeated courses of corticosteroids, and second and third line immunomodulators increasing the incidence of drug related adverse effects. More recently, there have been reports of a very small subset of Nephrotic Syndrome (NS) patients who are initially steroid sensitive and later become secondarily steroid resistant. The disease course in this small subset is often protracted leading ultimately to end stage kidney disease requiring dialysis or kidney transplantation. Unfortunately, patients with this disease course do not do well post transplantation because 80% of them will develop disease recurrence that will ultimately lead to graft failure. Few approaches have been tried over many years to reduce the frequency of relapses, and steroid dependence and there is absolutely no therapeutic intervention for patients who develop secondary steroid resistance. Nonetheless, their therapeutic index is low, evidencing the need of a safer complementary treatment. Several hypotheses, including an oxidative stress-mediated mechanism, and immune dysregulation have been proposed to date to explain the underlying mechanism of Minimal Change Disease (MCD) but its specific etiology remains elusive. Here, we report a case of a 54-year-old man with steroid and cyclosporine resistant MCD. The patient rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis. Intradialytic parenteral nutrition (IDPN), albumin infusion along with a proprietary dietary supplement, as part of the supportive therapy, led to kidney function recovery and complete remission of MCD without relapses.",
"affiliations": "Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States.;Division of Anatomic Pathology, Mayo Clinic, Department of Pathology, Rochester, MN, United States.;University of Rochester School of Medicine and Dentistry, Rochester, NY, United States.",
"authors": "Gbadegesin|Rasheed A|RA|;Hernandez|Loren P Herrera|LPH|;Brophy|Patrick D|PD|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fped.2021.614948",
"fulltext": "\n==== Front\nFront Pediatr\nFront Pediatr\nFront. Pediatr.\nFrontiers in Pediatrics\n2296-2360\nFrontiers Media S.A.\n\n10.3389/fped.2021.614948\nPediatrics\nCase Report\nCase Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease\nGbadegesin Rasheed A. 1\nHernandez Loren P. Herrera 2\nBrophy Patrick D. 3*\n\n1Division of Nephrology, Department of Pediatrics, Duke University School of Medicine, Durham, NC, United States\n2Division of Anatomic Pathology, Mayo Clinic, Department of Pathology, Rochester, MN, United States\n3University of Rochester School of Medicine and Dentistry, Rochester, NY, United States\nEdited by: Asha Moudgil, Children's National Hospital, United States\n\nReviewed by: Andrew Mallett, Royal Brisbane and Women's Hospital, Australia; Lyndsay Harshman, The University of Iowa, United States\n\n*Correspondence: Patrick D. Brophy pdbrophy@icloud.com\nThis article was submitted to Pediatric Nephrology, a section of the journal Frontiers in Pediatrics\n\n04 5 2021\n2021\n9 61494807 10 2020\n26 3 2021\nCopyright © 2021 Gbadegesin, Hernandez and Brophy.\n2021\nGbadegesin, Hernandez and Brophy\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nMinimal change disease (MCD) is the most common cause of nephrotic syndrome worldwide. For decades, the foundation of the treatment has been corticosteroids. However, relapse rate is high and up to 40% of patients develop frequent relapsing/steroid dependent course and one third become steroid resistant. This requires treatment with repeated courses of corticosteroids, and second and third line immunomodulators increasing the incidence of drug related adverse effects. More recently, there have been reports of a very small subset of Nephrotic Syndrome (NS) patients who are initially steroid sensitive and later become secondarily steroid resistant. The disease course in this small subset is often protracted leading ultimately to end stage kidney disease requiring dialysis or kidney transplantation. Unfortunately, patients with this disease course do not do well post transplantation because 80% of them will develop disease recurrence that will ultimately lead to graft failure. Few approaches have been tried over many years to reduce the frequency of relapses, and steroid dependence and there is absolutely no therapeutic intervention for patients who develop secondary steroid resistance. Nonetheless, their therapeutic index is low, evidencing the need of a safer complementary treatment. Several hypotheses, including an oxidative stress-mediated mechanism, and immune dysregulation have been proposed to date to explain the underlying mechanism of Minimal Change Disease (MCD) but its specific etiology remains elusive. Here, we report a case of a 54-year-old man with steroid and cyclosporine resistant MCD. The patient rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis. Intradialytic parenteral nutrition (IDPN), albumin infusion along with a proprietary dietary supplement, as part of the supportive therapy, led to kidney function recovery and complete remission of MCD without relapses.\n\nminimal change disease\nglycocalyx\nantioxidants\nkidney disease\nnephrotic syndrome\n==== Body\nIntroduction\n\nMinimal change disease (MCD) is the most common cause of nephrotic syndrome (NS) in children and accounts for the 15–25% of cases of NS in adults (1–5). The specific etiology has remained elusive and a variety of different hypotheses have been generated to date (6). In general, MCD and by extension focal segmental glomerular sclerosis (FSGS) are thought to be related to damage of the podocytes. Both of these are considered podocytopathies and in the case of FSGS the etiology has been linked to genetic abnormalities of the podocyte apparatus and disruption of the slit diaphragm (1). There is suggestion that MCD may lead to FSGS in treatment resistant patients and at times it may be difficult to adequately obtain a kidney biopsy sample that reflects the progression of MCD toward FSGS (due to potential biopsy sampling error) (1). Recent evidence from genetic association studies suggests that genetic variation in the adaptive immune response coupled with environmental factors may be very important risk factors for development of MCD (7–10). The animal model that most closely resembles MCD is the puromycin aminonucleoside nephrosis (PAN) in rats, which leads to the production of reactive oxygen species and direct DNA damage. This subsequently leads to the pathologic characteristics of MCD (i.e., alteration of the podocyte actin cytoskeleton, foot process effacement, and detachment from the glomerular basement membrane). These pathologic changes result in proteinuria. Interestingly, Angiopoietin-like 4 (Angptl4) is a secreted glycoprotein that is highly upregulated in the glomeruli of several models of podocyte injury in rats, including PAN, and in the human disease (1). This upregulation is specific to models of steroid-sensitive NS. Recently, it has been demonstrated that syndecan-1 level, a biomarker of endothelial glycocalyx damage, is increased in nephrotic patients with near-normal kidney function and it plays an important role in endothelial dysfunction (11). Angiopoietin-2 (ANGPT2) is an endothelial growth factor that promotes cell derangement (12). Indeed, the linkage between endothelial glycocalyx damage, proteinuria and systemic vascular dysfunction is becoming clearer (13). Therefore, loss of the endothelial surface layer appears to be a link between albuminuric kidney disease and systemic vascular dysfunction, providing a potential therapeutic target for proteinuric kidney disease. Besides glycoprotein dysregulation, immunologic hypotheses exist involving regulatory T-Cell and B cell immune dysregulation that have also been implicated in the pathophysiology of MCD (14).\n\nThe cornerstone of the treatment has been corticosteroids (e.g., prednisone). Although MCD in children is usually sensitive to corticosteroids, resulting in remission within few weeks, adults have delayed response to the treatment, sometimes requiring 24 weeks or more of treatment to enter remission. Moreover, relapse rate in adults may be up to 70%, with one third becoming frequent relapsing (15). This requires treatment with repeated courses of corticosteroids, increasing the incidence of drug related adverse effects, including weight gain, diabetes mellitus, infection, osteoporosis, vascular necrosis and gastrointestinal bleeding (16, 17).\n\nFew approaches have been tried over many years to reduce the frequency of relapses and/or permanently cure MCD, such as alkylating agents (e.g., cyclophosphamide) and calcineurin inhibitors (e.g., cyclosporine, tacrolimus). In particular, cyclosporine is frequently used in patients that are either frequent relapsing, steroid dependent or resistant. However, its therapeutic index is low. Therefore, patients undergoing long-term therapy with cyclosporine are susceptible to drug-related toxicity; including diabetes, hypertension, dermatologic complications, gastrointestinal, hepatic, neurological complications, hyperlipidemia, electrolyte abnormalities, neoplasia, and acute or chronic nephrotoxicity. In many instances, it is difficult to distinguish whether the chronic injuries are caused by cyclosporine or by the progression of the disease (18). Emma and colleagues present an excellent review of protocolized approaches to treatment in adults (1).\n\nAcute kidney injury (AKI) can occur and is not uncommon in adults with MCD, affecting up to 25% of patients, while progressive CKD in not common in adults with MCD; its occurrence is usually associated with underlying FSGS. Sometimes, AKI is severe enough to require dialysis. However, kidney function is usually recoverable within 14–21 days, although patients with AKI may progress to CKD due to residual kidney damage (19).\n\nIn certain circumstances, IDPN and albumin infusion have been used as supportive treatment for MCD and AKI. Nonetheless, their use remains controversial due to the risks associated with the treatment, their temporary effect, and the high cost. Interestingly, it is estimated that about 40% of patients with MCD may undergo spontaneous remission with supportive care (20, 21). However, that usually happens only after an unacceptable time of uncontrolled nephrotic syndrome, increasing the incidence of infection, thrombosis, malnutrition, and kidney injury.\n\nHere, we report a case of a previously healthy 54-year-old man with steroid and cyclosporine resistant MCD and nephrotic range proteinuria. The patient did not respond to standard therapy with diuretics, corticosteroids, and Calcineurin inhibitors (CNI) but rapidly progressed to end stage kidney disease requiring initiation of chronic dialysis and transplant work-up and listing. IDPN, albumin infusion and a proprietary dietary supplement [the supplement consists of a patent pending proprietary formula composed of 11 food grade supplements/ingredients in the proprietary formula that optimize the vascular system (see Appendix 1)] along with restoration of colloidal stability initiated by the patient himself, as part of the supportive therapy led to kidney function recovery and complete remission of MCD without relapses.\n\nCase Report\n\nOn October 2014, a 54-year-old male with no significant past medical history presented to the hospital with bilateral lower extremity edema and chest pain. A clinical, historical and imaging assessment revealed no evidence of a secondary cause of his clinical presentation. On admission his blood pressure was 157/93 mmHg. Laboratory tests revealed hypoalbuminemia (1.1 g/dl), elevated D-dimer (5,250 ng/ml), creatinine (1.4 mg/dl), BUN (19 mg/dl), low calcium (7.7 mg/dl), and proteinuria with random urine protein/creatinine ratio 5,139 mg/g. An ultrasound and a CT of the abdomen with IV contrast ruled out DVT in both extremities and any compressing mass or thrombus in the inferior vena cava, respectively. The patient was treated with furosemide 20 mg p.o. daily without improvement. Kidney biopsy was performed, revealing global effacement of the epithelial cell foot processes, unremarkable glomeruli on light microscopy, focal loss of fenestration of the endothelial cells and signs of injury with mild ectasia and slight vacuolization of the tubules consistent with minimal change disease (Figure 1).\n\nFigure 1 MCD electron microscopy. Black arrows denote podocyte effacement. Blue arrows denote podocyte subendothelial deposits.\n\nThe MCD was considered idiopathic and initially treated with mycophenolate and prednisone (80 mg p.o. daily) for 8 weeks without any improvement. In December 2014, the patient continued to have problems with anasarca and volume overload; he was given outpatient diuretics including furosemide, torsemide, and metolazone, and he initially lost weight. In January 2015, his 24-h urine protein went up to 12 g/day and he was started on cyclosporine 50 mg p.o. twice daily. After gaining 50 pounds through fluid retention, he was admitted to the hospital and treated with IV furosemide drip 20 mg/h along with IV albumin, metolazone, prednisone (40 mg) and cyclosporine (75 mg twice daily). The patient was also put on a low salt diet with fluid restriction and he lost 50 pounds of fluids during the 13 days of hospitalization. His serum albumin went up to 2.7 g/dl and creatinine improved to 1.0 mg/dl. However, proteinuria was not resolved. He was discharged with the following medications: cyclosporine (100 mg twice daily), prednisone (40 mg daily), and furosemide (80 mg daily).\n\nIn the following months, prednisone was tapered off and eventually discontinued while cyclosporine was increased to 125 mg twice daily. On a follow up visit in March 2015, laboratory tests revealed increased BUN (51 mg/dl) and creatinine (1.5 mg/dl), and low chloride (91 meq/l), potassium (3.1 meq/l), calcium (7.5 mg/dl), and albumin (1.5 g/dl). Subsequently, the patient lost his health insurance and discontinued cyclosporine. In June 2015, his BUN was 63 mg/dl and creatinine 2.0 mg/dl and he was treated with cyclosporine (200 mg twice daily), metolazone (5 mg daily) and torsemide (100 mg twice daily) for 30 days. The patient rapidly progressed to kidney failure (BUN 109 mg/dl and creatinine 6.27 mg/dl) and, in September, initiated hemodialysis thrice weekly given the patient's excess fluid overload and inability to control his metabolic status. The patient's daily ultrafiltration rate was up to 5 l/day. The patient continued to require significant fluid and electrolyte control and after 3 months on dialysis, was evaluated and listed for kidney transplantation and was placed on the waiting list. When the patient was placed on chronic dialysis, the patient (who has an extensive scientific engineering background) began to review the literature on MCD and proteinuria. Over time he developed a more comprehensive understanding of the pathophysiology of MCD and proteinuria. He developed a hypothesis and with a colleague who had access to a nutritional supplement process facility, began to evaluate possible treatment approaches. Together they developed and continue to produce this proprietary nutritional supplement (in a regulated sterile production facility). It was at this point that he, on his own began a supplement regimen to promote regrowth of the glycocalyx and prevent its degradation (Appendix 1) in the presence of a balanced colloid and electrolyte environment. Due to poor nutrition and at the request of the patient, at the beginning of January 2016, he initiated standard IDPN therapy together with hemodialysis. He responded to the improved nutritional delivery and intermittent hemodialysis and his kidney indices improved after 2 weeks of treatment (BUN 70 mg/dl and creatinine 3.45 mg/dl) and at the end of April BUN was 19 mg/dl and creatinine 1.4 mg/dl. Therefore, hemodialysis was discontinued. However, proteinuria was still present (random urine protein/creatinine ratio was 5,919 mg/g) and serum albumin was low (2.0 g/dl). The patient received supportive care consisting of IV albumin thrice weekly and His serum albumin increased up to 5.0 g/dl on July 2016 and IV albumin was discontinued. Proteinuria progressively decreased from June (random urine protein/creatinine ratio 2,458 mg/g) and almost completely resolved at his last follow up visit on September 2016 (random urine protein/creatinine ratio 280 mg/g). The patient continued to administer himself supplements and, as of today, he has had no further relapses. On May 2020, his urine protein/creatinine ratio was 159 mg/g, and his kidney function was stable (BUN 25 mg/dl and creatinine 1.41 mg/dl). Figure 2: Timeline for treatment and response. Figure 3 Chronic dialysis course.\n\nFigure 2 Disease course and treatment.\n\nFigure 3 Dialysis timeline and weights.\n\nDiscussion\n\nHere, we present the case of a previously health 54 yr old male who developed idiopathic biopsy proven MCD. Despite standardized treatment regimen he went on to develop progressive CKD and qualified for ESKD per KDIGO definition and was listed for kidney transplantation. While he met the KDIGO criteria, no biopsy was conducted and it is possible he had prolonged AKI which recovered with no ongoing indications of CKD, which in such a case would be unusual. During the course of his work up, he was assessed for possible infection related causes for initiation of his MCD. No etiologic agents (EBV, Hepatitis, HIV) were identified. He required IDPN and initiated a proprietary dietary supplement regimen based on his blood biomarkers. The goal of the proprietary dietary supplement regimen was to restore the glycocalyx along with the electrolyte balance to not only come off of chronic dialysis, but also to resolve his proteinuria and MCD. He has remained stable off all medication except for his daily supplement regimen. He has had no further relapses and has had resolution of his proteinuria. Importantly, the patient has tolerated the supplements without any notable deleterious side effects. Several components of the supplement included in the regimen are potent antioxidants. This case example furthers the association of antioxidants and their role in the treatment and prevention of proteinuric kidney disease and other vascular inflammatory states.\n\nMechanisms underlying the relation between kidney disease and systemic endothelial cell dysfunction remain incompletely understood, but a defect in the endothelial surface layer, which is common to all blood vessels, has been suggested as a mechanistic link between widespread vascular dysfunction and albuminuric kidney diseases leading to CKD and ESKD (22). The data for the value of antioxidant-based therapy in treating kidney and endovascular diseases are becoming clearer. Indeed, oxidative stress is regarded as a key mediator of endothelial dysfunction in kidney disease and contributes to development and progression of CKD (23). A Cochrane meta-analysis reviewed 10 randomized controlled (n = 1,979) trials investigating antioxidant use (vitamin E, co-enzyme Q, N-acetylcysteine, and human recombinant superoxide dismutase) in CKD (24). Data were pooled using the random effects model and expressed as either risk ratios (RR) or mean difference (MD) with 95% confidence intervals (CI) (24). The authors found that “compared with placebo, antioxidant therapy showed no clear overall effect on cardiovascular mortality (RR 0.95, 95% CI 0.70–1.27; P = 0.71); all-cause mortality (RR 0.93, 95% CI 0.76–1.14; P = 0.48); cardiovascular disease (RR 0.78, 95% CI 0.52–1.18; P = 0.24); coronary heart disease (RR 0.71, 95% CI 0.42–1.23; P = 0.22); cerebrovascular disease (RR 0.91, 95% CI 0.63–1.32; P = 0.63); or peripheral vascular disease (RR 0.54, 95% CI 0.26–1.12; P = 0.10)” (24). The authors concluded that while there was a potential benefit for the use of antioxidant supplementation in the prevention of progression from CKD to ESKD the studies lacked power to establish any definitive conclusions (24). It may be that a combinational therapeutic approach would give better results as antioxidants would prevent further ongoing damage in the face of restoration of the GCX and colloidal stability at the same time. Individuals with genetic susceptibility to oxidative stressors may be benefited from enhancing the anti-oxidant milieu present in their bodies, especially those anti-oxidants that target specific pathways. Increased oxidative stress is a major contributor to CKD progression and in patients undergoing chronic dialysis (25). In humans, a common deletion variant of the glutathione-S-transferase μ-1 (GSTM1) gene results in decreased GSTM1 enzymatic activity and is associated with elevated levels of oxidative stress factors (26). GSTM1 are antioxidant enzymes that are regulated by nuclear factor erythroid 2-related factor 2 (NRF2). In both the African American Study of Kidney Disease (AASK) trial and the Atherosclerosis Risk in Communities (ARIC) study participants GSTM1 null mutations were associated with enhanced CKD progression (25, 27). These findings have also been demonstrated in mouse Gstm1 knockout animals (28). Recently, glucoraphanin, a precursor of sulforaphane (found in broccoli and other like vegetables- brussels sprouts, cabbage) have been shown to have protective effects against oxidative damage through activation of NRF2 (27–29). Interestingly, the use of purified broccoli extract in Gstm1 knockout mice can reduce renal disease, a finding that correlates to a slowing of progression in GSTM1 null patients in the ARIC study that had high daily intake of cruciferous vegetables (27, 28). While genetic underpinnings have revealed the potential impact of dietary supplements on possible progression of renal disease, it remains unclear as to their effects on patients with other genotypes. There are now multiple studies examining the effects of purified broccoli powder as a supplement for mitigation and prevention of inflammatory states in a variety of diseases1. We speculate that the interplay between a triggered inflammatory/immune response leads to antioxidant depletion with subsequent glycocalyx defects and a loss of colloidal balance resulting in propagation of the disease state.\n\nDamage to the endothelial glycocalyx in response to factors in albuminuric plasma provides a novel concept in understanding endothelial dysfunction in disease states. In fact, albumin (which is dramatically lost in NS) is the most abundant and therefore main antioxidant (as it has a thiol group that can bind to ROS). Ghiggeri's group (30) has demonstrated the presence of massive oxidation of albumin associated with FSGS, implicating oxidative mechanisms. Therefore, a lack of albumin may exacerbate the antioxidant imbalance.\n\nWe present a case report of a proprietary dietary supplement (consisting of a patent pending proprietary formula composed of 11 food grade supplements/ingredients in the proprietary formula that optimize the vascular system) regimen associated with recovery from ESKD and MCD. Our hypothesis builds upon current evidence that the albuminuric state itself might lead to systemic alterations in endothelial cell function, likely involving a combination of mechanisms. We are now developing animal modeling, to better understand the pathways underlying the effects of albuminuric plasma on the endothelial glycocalyx, assessing whether the endothelial glycocalyx is damaged in blood vessels in situ in patients with kidney disease, and examining whether the endothelial glycocalyx can be restored (and endothelial cell function improved) by manipulating these pathways. Our long-term goal is to manipulate endothelial glycocalyx regulation to develop an entirely new class of treatments for vascular protection in difficult to treat nephrotic syndrome and other chronic kidney diseases.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nAll authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.\n\nConflict of Interest\n\nPB consults for Zeta Biolongevity, Inc. and receives royalties from UpToDate.\n\nThe remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nMr. Chris Ruiz for providing the proprietary dietary compound.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fped.2021.614948/full#supplementary-material\n\nClick here for additional data file.\n\n1https://www.clinicaltrials.gov/ct2/results?term=SFN+broccoli+extract\n==== Refs\nReferences\n\n1. Vivarelli M Massella L Ruggiero B Emma F . Minimal change disease. Clin J Am Soc Nephrol. (2017) 12 :332–45. 10.2215/CJN.05000516 27940460\n2. Straatmann C Ayoob R Gbadegesin R Gibson K Rheault MN Srivastava T . Treatment outcome of late steroid-resistant nephrotic syndrome: a study by the Midwest Pediatric Nephrology Consortium. Pediatr Nephrol. (2013) 28 :1235–41. 10.1007/s00467-013-2483-y 23633037\n3. Ding WY Koziell A McCarthy HJ Bierzynska A Bhagavatula MK Dudley JA . Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence. J Am Soc Nephrol. (2014) 25 :1342–8. 10.1681/ASN.2013080852 24511128\n4. Pelletier JH Kumar KR Engen R Bensimhon A Varner JD Rheaul MN . Recurrence of nephrotic syndrome following kidney transplantation is associated with initial native kidney biopsy findings. Pediatr Nephrol. (2018) 33 :1773–80. 10.1007/s00467-018-3994-3 29982878\n5. Glassock RJ . Therapy of relapsing minimal-change disease in adults: a new approach? Kidney Int. (2013) 83 :343–5. 10.1038/ki.2012.412 23446250\n6. Radhakrishnan J Hogan J . The treatment of minimal change disease in adults. J Am Soc Nephrol. (2013) 24 :702–11. 10.1681/ASN.2012070734 23431071\n7. Gbadegesin RA Adeyemo A Webb NJ Greenbaum LA Abeyagunawardena A Thalgahagoda S . HLA-DQA1 and PLCG2 are candidate risk loci for childhood-onset steroid-sensitive nephrotic syndrome. J Am Soc Nephrol. (2015) 26 :1701–10. 10.1681/ASN.2014030247 25349203\n8. Hjorten R Skorecki K . Leveraging ancestral heterogeneity to map shared genetic risk loci in pediatric steroid-sensitive nephrotic syndrome. J Am Soc Nephrol. (2018) 30 :1793–4. 10.1681/ASN.2018050465 29903749\n9. Dufek S Cheshire C Levine AP Trompeter RS Issler N Stubbs M . Genetic identification of two novel loci associated with steroid-sensitive nephrotic syndrome. J Am Soc Nephrol. (2019) 31 :1375–84. 10.1681/ASN.2018101054 31263063\n10. Jia X Yamamura T Gbadegesin R McNulty MT Song K Nagano C . Common risk variants in NPHS1 and TNFSF15 are associated with childhood steroid-sensitive nephrotic syndrome. Kidney Int. (2020) 98 :1308–22. 10.1016/j.kint.2020.05.029 32554042\n11. Clement LC Avila-Casado C Macé C Soria E Bakker WW Kersten S . Podocyte secreted angiopoietin-like-4 mediates proteinuria in glucocorticoid-sensitive nephrotic syndrome. Nat Med. (2011) 17 :117–22. 10.1038/nm.2261 21151138\n12. Santos Salmito FT de Oliveira Neves FM Cavalcante Meneses G de Almeida Leitão R Costa Martins AM Braga Libório A . Glycocalyx injury in adults with nephrotic syndrome: association with endothelial function. Clin Chim Acta. (2015) 447 :55–8. 10.1016/j.cca.2015.05.013 26027550\n13. Chaves MMS Mendes MS Schwermann MP Queiroz R Coelho RF Salmito FTS . Angiopoietin-2: a potential mediator of the glycocalyx injury in adult nephrotic patients. J Clin Med. (2018) 7 :401. 10.3390/jcm7110401 30384404\n14. Salmon AHJ Ferguson JK Burford JL Gevorgyan H Nakano D Harper SJ . Loss of the endothelial glycocalyx links albuminuria and vascular dysfunction. J A Soc Nephrol. (2012) 23 :1339–50. 10.1681/ASN.2012010017 22797190\n15. Araya C Diaz L Wasserfall C Atkinson M Mu W Johnson R . T regulatory cell function in idiopathic minimal lesion nephrotic syndrome. Pediatr Nephrol. (2009) 24 :1691–8. 10.1007/s00467-009-1214-x 19495805\n16. Eckardt K-U Kasiske BL . Chapter 5: minimal-change disease in adults. Kidney Int Suppl. (2012) 2 :177–80. 10.1038/kisup.2012.18 25018930\n17. Shinzawa M Yamamoto R Nagasawa Y Oseto S Mori D Tomida K . Comparison of methylprednisolone plus prednisolone with prednisolone alone as initial treatment in adult-onset minimal change disease: a retrospective cohort study. Clin J Am Soc Nephrol. (2014) 9 :1040–8. 10.2215/CJN.12331213 24721890\n18. Eguchi A Takei T Yoshida T Tsuchiya K Nitta K . Combined cyclosporine and prednisolone therapy in adult patients with the first relapse of minimal-change nephrotic syndrome. Nephrol Dial Transplant. (2010) 25 :124–9. 10.1093/ndt/gfp422 19740915\n19. Ponticelli C Glassock RJ . Prevention of complications from use of conventional immunosuppressants: a critical review. J Nephrol. (2019) 32 :851–70. 10.1007/s40620-019-00602-5 30927190\n20. Wilcox C Berl T Himmelfarb J Mitch WE Murphy B Salant D . Therapy in nephrology & hypertension: a companion to brenner & rector's the kidney. J Kidney Care. (2008).\n21. Huang JJ Hsu SC Chen FF Sung JM Tseng CC Wang MC . Adult-onset minimal change disease among Taiwanese. Am J Nephrol. (2001) 21 :28–34. 10.1159/000046215 11275629\n22. Seliger SL Salimi S Pierre V Giffuni J Katzel L Parsa A . Microvascular endothelial dysfunction is associated with albuminuria and CKD in older adults. BMC Nephrol. (2016) 17 :82. 10.1186/s12882-016-0303-x 27412615\n23. Annuk M Zilmer M Fellström B . Endothelium-dependent vasodilation and oxidative stress in chronic renal failure: impact on cardiovascular disease. Kidney Int. (2003) 63 :S50–3. 10.1046/j.1523-1755.63.s84.2.x 12694308\n24. Jun M Venkataraman V Razavian M Cooper B Zoungas S Ninomiya T . Antioxidants for chronic kidney disease. Cochrane Database Syst Rev. (2012) 10 :CD008176. 10.1002/14651858.CD008176.pub2 23076940\n25. Tin A Scharpf R Estrella MM Yu B Grove ML Chang PP . The loss of GSTM1 associates with kidney failure and heart failure. J Am Soc Nephrol. (2017) 28 :3345–52. 10.1681/ASN.2017030228 28720685\n26. Bodonyi-Kovacs G Ma JZ Chang J Lipkowitz MS Kopp JB Winkler CA . Le combined effects of GSTM1 null allele and APOL1 renal risk alleles in CKD Progression in THE African American Study of Kidney Disease and Hypertension Trial. J Am Soc Nephrol. (2016) 27 :3140–52. 10.1681/ASN.2015050487 26940095\n27. Chang J Ma JZ Zeng Q Cechova S Gantz A Nievergelt C . Loss of GSTM1, a NRF2 target, is associated with accelerated progression of hypertensive kidney disease in the African American Study of Kidney Disease (AASK). Am J Physiol Renal Physiol. (2013) 314 :F348–55. 10.1152/ajprenal.00568.2012 23220723\n28. Gigliotti JC Tin A Pourafshar S Cechova S Wang YT Sung SJ . GSTM1 deletion exaggerates kidney injury in experimental mouse models and confers the protective effect of cruciferous vegetables in mice and humans. JASN. (2020) 31 :102–16. 10.1681/ASN.2019050449 31727850\n29. Guerrero-Beltrána CE Calderón-Olivera M Pedraza-Chaverria J Chirino YI . Protective effect of sulforaphane against oxidative stress: recent advances. Exp Toxicologic Pathol. (2012) 64 :503–8. 10.1016/j.etp.2010.11.005 21129940\n30. Musante L Candiano G Petretto A Bruschi M Dimasi N Caridi G . Active focal segmental glomerulosclerosis is associated with massive oxidation of plasma albumin. J Am Soc Nephrol. (2007) 18 :799–810. 10.1681/ASN.2006090965 17287427\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-2360",
"issue": "9()",
"journal": "Frontiers in pediatrics",
"keywords": "antioxidants; glycocalyx; kidney disease; minimal change disease; nephrotic syndrome",
"medline_ta": "Front Pediatr",
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"pages": "614948",
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"title": "Case Report: Novel Dietary Supplementation Associated With Kidney Recovery and Reduction in Proteinuria in a Dialysis Dependent Patient Secondary to Steroid Resistant Minimal Change Disease.",
"title_normalized": "case report novel dietary supplementation associated with kidney recovery and reduction in proteinuria in a dialysis dependent patient secondary to steroid resistant minimal change disease"
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"abstract": "Cat scratch disease is an infectious disorder transmitted by cats that typically affects children and young adults. Immunosuppression is a well-known risk factor for the development of severe and atypical forms of the disease; hence it is under-diagnosed in patients with compromised immunity. We are reporting the first case of cat scratch disease, which presented as fever and fatigue, in a patient with systemic lupus erythematosus while receiving immunosuppressant therapy after a kidney transplant.",
"affiliations": "Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain joseantoniovh@hotmail.com.;Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain.;Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain.;Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain.;Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain.;Systemic Autoimmune Diseases Unit. Internal Medicine Department, Virgen de las Nieves University Hospital, Granada, Spain.",
"authors": "Vargas-Hitos|J A|JA|;Sabio|J M|JM|;Navarrete-Navarrete|N|N|;Arenas-Miras|M del M|Mdel M|;Zamora-Pasadas|M|M|;Jiménez-Alonso|J|J|",
"chemical_list": "D000900:Anti-Bacterial Agents; D007166:Immunosuppressive Agents",
"country": "England",
"delete": false,
"doi": "10.1177/0961203315610207",
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"issn_linking": "0961-2033",
"issue": "25(3)",
"journal": "Lupus",
"keywords": "Bartonella; Cat scratch disease; immunosuppression; systemic lupus erythematosus; transplantation",
"medline_ta": "Lupus",
"mesh_terms": "D000368:Aged; D000818:Animals; D000900:Anti-Bacterial Agents; D002372:Cat-Scratch Disease; D002415:Cats; D005221:Fatigue; D005260:Female; D005334:Fever; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008180:Lupus Erythematosus, Systemic; D008181:Lupus Nephritis; D016896:Treatment Outcome",
"nlm_unique_id": "9204265",
"other_id": null,
"pages": "310-1",
"pmc": null,
"pmid": "26453661",
"pubdate": "2016-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus.",
"title_normalized": "cat scratch disease in an immunosuppressed patient with systemic lupus erythematosus"
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"companynumb": "ES-ACCORD-044638",
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"abstract": "We report two cases of mortality associated with the recent winter influenza outbreak. Both cases were associated with self-medication. In one case an elderly lady died from haemorrhagic duodenitis induced by over the counter ibuprofen. In the second case the lady died from the consequences of exceeding the recommended doses of paracetamol by combining doses of the generic product with proprietary flu-remedies and Tylex (paracetamol and codeine).",
"affiliations": "Department of Medicine, Ninewells Hospital & Medical School, Dundee DD1 9SY.",
"authors": "Stevenson|R|R|;MacWalter|R S|RS|;Harmse|J D|JD|;Wilson|E|E|",
"chemical_list": "D000082:Acetaminophen; D007052:Ibuprofen",
"country": "Scotland",
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"issue": "46(3)",
"journal": "Scottish medical journal",
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"mesh_terms": "D000082:Acetaminophen; D000368:Aged; D000369:Aged, 80 and over; D004196:Disease Outbreaks; D004382:Duodenitis; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007052:Ibuprofen; D007251:Influenza, Human; D008875:Middle Aged; D012621:Seasons; D012651:Self Medication",
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"pubdate": "2001-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Mortality during the winter flu epidemic--two cases of death associated with self-medication.",
"title_normalized": "mortality during the winter flu epidemic two cases of death associated with self medication"
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"companynumb": "GB-RANBAXY-2014R1-91319",
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{
"abstract": "Ruptured coronary artery aneurysm is rare, but the most serious complications of an acute phase of Kawasaki disease (KD) with giant coronary artery aneurysm (GCAA). Progressive or super GCAA, which rapidly dilates and continue to increase over a diameter of 10 mm, are more susceptible to rupture.\nWe report the case of a 6-year-old boy with KD who had multiple super GCAAs with a high risk of GCAA rupture. On admission to our hospital, he presented with fever, chest pain, and Stage II hypertension. Echocardiographic Z-scores adjusted for body surface area were used for measurements. The coronary artery diameter of segment 1 was 24.3 mm with a Z-score of 20.8; the diameter of segment 3 was 24.4 mm; the diameter of the left anterior descending branch was 32.6 mm with a Z-score of 20.1. The super GCAAs showed a tendency to expand compared to the latest echocardiography, and thrombus formation was observed in the super GCAA of segment 3. The patient was treated with anti-inflammatory therapy, antithrombotic therapy, and antihypertensive therapy with continuous arterial pressure monitoring with the goal of not exceeding the 5th percentile of the normal standard during the period when there was a risk of progressive coronary aneurysm expansion. He was discharged without any neurological complications.\nWe speculated that the patient's hypertension was the cause of an expanding coronary artery aneurysm. In conclusion, KD patients with super GCAA may benefit from aggressive blood pressure control with continuous arterial pressure monitoring.",
"affiliations": "Department of Pediatric Cardiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan.;Department of Pediatric Cardiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan.;Department of Anesthesiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan.;Department of Anesthesiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan.",
"authors": "Moritoh|Yuji|Y|https://orcid.org/0000-0002-7032-4807;Kamada|Masahiro|M|https://orcid.org/0000-0002-4008-8567;Matsumoto|Shinsaku|S|;Kido|Koji|K|https://orcid.org/0000-0001-8143-414X",
"chemical_list": null,
"country": "England",
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"doi": "10.1093/ehjcr/ytab161",
"fulltext": "\n==== Front\nEur Heart J Case Rep\nEur Heart J Case Rep\nehjcr\nEuropean Heart Journal: Case Reports\n2514-2119\nOxford University Press\n\n34222780\n10.1093/ehjcr/ytab161\nytab161\nCase Report\nAcademicSubjects/MED00200\nImportance of blood pressure control in Kawasaki disease with expanded multiple giant coronary aneurysms with a 32 mm maximum diameter: a case report\nhttps://orcid.org/0000-0002-7032-4807\nMoritoh Yuji 1\nhttps://orcid.org/0000-0002-4008-8567\nKamada Masahiro 1\nMatsumoto Shinsaku 2\nhttps://orcid.org/0000-0001-8143-414X\nKido Koji 2\n1 Department of Pediatric Cardiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan\n2 Department of Anesthesiology, Hiroshima Citizens Hospital, 7-33 Moto-machi, Hiroshima 730-8518, Japan\nArzanauskaite Monika Handling Editor\nJanosi Andras Editor\nXaplanteris Panagiotis Editor\nMoreno-Ruiz Luis Antonio Editor\nMcNaughton Edwina Editor\nJakstaite Aiste Monika Editor\nCorresponding author. Tel: +81 822 21 2291, Email: yuji6103031945@gmail.com\n6 2021\n07 6 2021\n07 6 2021\n5 6 ytab16101 9 2020\n26 10 2020\n01 3 2021\n© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com\n\nAbstract\n\nBackground\n\nRuptured coronary artery aneurysm is rare, but the most serious complications of an acute phase of Kawasaki disease (KD) with giant coronary artery aneurysm (GCAA). Progressive or super GCAA, which rapidly dilates and continue to increase over a diameter of 10 mm, are more susceptible to rupture.\n\nCase summary\n\nWe report the case of a 6-year-old boy with KD who had multiple super GCAAs with a high risk of GCAA rupture. On admission to our hospital, he presented with fever, chest pain, and Stage II hypertension. Echocardiographic Z-scores adjusted for body surface area were used for measurements. The coronary artery diameter of segment 1 was 24.3 mm with a Z-score of 20.8; the diameter of segment 3 was 24.4 mm; the diameter of the left anterior descending branch was 32.6 mm with a Z-score of 20.1. The super GCAAs showed a tendency to expand compared to the latest echocardiography, and thrombus formation was observed in the super GCAA of segment 3. The patient was treated with anti-inflammatory therapy, antithrombotic therapy, and antihypertensive therapy with continuous arterial pressure monitoring with the goal of not exceeding the 5th percentile of the normal standard during the period when there was a risk of progressive coronary aneurysm expansion. He was discharged without any neurological complications.\n\nDiscussion\n\nWe speculated that the patient's hypertension was the cause of an expanding coronary artery aneurysm. In conclusion, KD patients with super GCAA may benefit from aggressive blood pressure control with continuous arterial pressure monitoring.\n\nKawasaki disease\nCoronary artery aneurysm\nBlood pressure\nPlasma exchange\nCase report\n==== Body\npmcFor the podcast associated with this article, please visit https://academic.oup.com/ehjcr/pages/podcast\n\nLearning points\n\nIn Kawasaki disease (KD), super giant coronary artery aneurysms (GCAAs), which rapidly dilate and can exceed 10 mm in diameter, carry a high risk of rupture.\n\nStrict control of blood pressure with continuous monitoring of arterial pressure under general anaesthesia can be useful in KD patients with super GCAA.\n\nIntroduction\n\nKawasaki disease (KD) is an acute systemic vasculitis of childhood that leads to coronary artery aneurysms (CAAs). In KD, the complication rate of giant CAAs (GCAAs)—those with a diameter >8 mm or Z-score of 10—is only 0.13%.1–3 However, the rupture risk is reportedly high in KD patients with a progressively expanding GCAA of at least 10 mm in diameter, which can be termed a ‘super GCAA’.4,5\n\nHere we report on the case of a boy with refractory KD and present the importance of managed treatment, especially with regard to blood pressure (BP) control. This is the first case of a paediatric patient in acute phase of KD with multiple GCCAs over 20 mm and left anterior descending branch (LAD) with a 32 mm maximum diameter who survived without neurological sequelae.\n\nTimeline\n\nDay 4 from fever onset\tA typical Kawasaki disease (KD) case was diagnosed, and high-dose intravenous immunoglobulin was administered\t\nDay 8–10\tIntravenous methylprednisolone was administered\t\nDay 11\tPrednisolone was started and continued until the Day 41\t\nDay 13\tEchocardiography showed dilatation of up to 8.5 and 7.3 mm in the right coronary artery (RCA) and left anterior descending branch (LAD), respectively; therefore, oral administration of warfarin was started\t\nDay 38\tSerum C-reactive protein positivity persisted and echocardiography showed severe dilation of the maximum diameters of the RCA and LAD giant coronary artery aneurysms (GCAA) of 21.6 and 30.4 mm, respectively\t\nDay 41\tThe patient was admitted to our tertiary hospital due to chest pain\n\nEchocardiography showed multiple super GCAAs and thrombus formation was observed in the super GCAA\n\nThe patient was treated with anti-inflammatory therapy, antithrombotic therapy, and aggressive antihypertensive therapy\n\n\t\nDay 49\tEchocardiography showed that the progressive expansion of the GCAAs had ceased, and the thrombus had almost disappeared\t\nDay 67\tEchocardiography showed a thrombus formation again in the GCAA\t\nDay 91\tEchocardiography confirmed that the thrombus had disappeared\n\nThe patient was discharged without neurological sequelae\n\n\t\nOne year after the onset of KD\tThe patient is doing well as an outpatient\t\n\nCase presentation\n\nA 6-year-old Japanese boy with history of autism spectrum disorder was admitted to a referral hospital on Day 4 of fever with conjunctival hyperaemia, redness of the lips, enlarged cervical lymph nodes, swollen hands and feet, and a polymorphous rash. Kawasaki disease was diagnosed, and high-dose intravenous immunoglobulin (IVIG; 4 g/kg total) administered. After 4 days, the serum C-reactive protein (CRP) level had increased to 22.0 mg/dL. Intravenous methylprednisolone (30 mg/kg) was therefore administered for 3 days, followed by oral prednisolone treatment. On Day 13 of the illness, echocardiography revealed dilatation of the right coronary artery (RCA) and LAD, respectively. Oral administration of warfarin was therefore initiated. On Day 38, echocardiography showed severe dilation of the maximum diameters of the RCA and LAD CAAs of 21.6 and 30.4 mm, respectively. On Day 41, he was admitted to our tertiary hospital with chest pain.\n\nOn admission, his temperature was 38.4°C, pulse 120 beats/min, and BP 128/75 mmHg. His heart rhythm was regular, with a systolic murmur of Levine II/VI due to mitral regurgitation. Serum CRP (2.1 mg/dL) and troponin T (0.18 ng/mL) values were elevated, with transient mild ST depression in the lateral leads (Supplementary material online, Figure S1). Echocardiography showed multiple GCAAs, particularly with marked RCA dilation, and the LAD appeared to be expanding. Furthermore, thrombus formation was observed in the super GCAA in segment 3 of the peripheral RCA, with the super GCAA in segment 6 of the LAD exerting slight pressure on the left ventricle (LV) (Figure 1, Video 1–2).6\n\nFigure 1 (A) Parasternal short-axis view (left) and modified apical four-chamber view (right) echocardiography upon admission to our hospital shows that the right coronary artery segments 1 and 3 maximum diameter (Z-score for body surface area) of the coronary arteries is 24.3 mm (+20.8) and 24.4 mm, respectively, and a thrombus (*) is found in the giant coronary artery aneurysm of the right coronary artery segment 3. (B) Parasternal short-axis view echocardiography at admission shows that the left anterior descending branch segment 6 maximum diameter (Z-score for body surface area) of the coronary arteries is 32.6 mm (+20.1) and the prominently dilated left anterior descending branch aneurysm mildly compresses the left ventricle from the left upper side during diastole. Ao, aorta; LAD, left anterior descending branch; LV, left ventricle; RCA, right coronary artery; RV, right ventricle.\n\nOwing to the high risk of CAA rupture, the patient was immediately transferred to the intensive care unit (ICU) for endotracheal intubation and general anaesthesia. Various antihypertensive agents, including nicardipine hydrochloride, carperitide, and sodium nitroprusside hydrate, were administered to ensure strict BP control, that is, a systolic BP ≤80 mmHg under continuous arterial BP monitoring. Continuous heparin infusion was administered as antithrombotic therapy, and plasma exchange performed for 6 days as an anti-inflammatory therapy. After plasma exchange, infliximab (5 mg/kg) and additional IVIG (6 g/kg total) were administered. Echocardiography on Day 49 confirmed that the thrombus in the GCAA of the RCA had almost completely disappeared. The CAA failed to expand under strict BP control and plasma exchange; thus, the sedative was gradually discontinued, and the antihypertensive drug switched to an oral formulation. The patient was discharged from the ICU on hospital day 23 (Figure 2). Thereafter, he continued receiving continuous heparin infusion and a combination of oral aspirin (from Day 4, 5 mg/kg/day), warfarin (from Day 59, 0.15–0.25 mg/kg/day), and clopidogrel (from Day 64, 1 mg/kg/day) to prevent GCAA thrombus formation, as his prothrombin time and international normalized ratio (PT/INR) had not reached the target of 2.5–3.0 s. However, echocardiography on Day 67 showed GCAA thrombus formation in segment 3 of the RCA. When intravenous alteplase (0.75 mg/kg) was administered and the warfarin dose increased to achieve a PT/INR of 3.0–3.5 s, the thrombus gradually shrank and disappeared (Figure 3). The patient was discharged on Day 91. Cardiac computed tomography (CT) and cardiac magnetic resonance imaging (CMR) performed 4 months after illness onset showed no change in CAA size (Figure 4), no thrombus formation in segment 3 of the RCA, and well-preserved cardiac function (Video 3), respectively. However, myocardial perfusion imaging by first-pass contrast-enhanced CMR showed hypoperfusion in the RCA perfusion region of the LV upon adenosine loading. Furthermore, late gadolinium enhancement (LGE) was observed in the same region at rest (Figure 5). One year has passed since the onset of KD, and he is doing well as an outpatient on triple antithrombotic therapy.\n\nFigure 2 Clinical course. BP, blood pressure; CRP, C-reactive protein; ICU, intensive care unit; IVIG, intravenous immunoglobulin.\n\nFigure 3 (A) On the 67th day of the illness, subcostal view echocardiography shows a thrombus (*) in the giant coronary artery aneurysm of the right coronary artery segment 3. (B) Echocardiography at discharge shows the disappearance of the thrombus in the giant coronary artery aneurysm of the right coronary artery segment 3. RCA, right coronary artery.\n\nFigure 4 Three-dimensional cardiac computed tomography image 4 months after onset. Image showing marked enlargement of the right coronary artery and left anterior descending branch and no visualization of the segment 3 and segment 7 by contrast media (arrows). Ao, aorta; LAD, left anterior descending branch; LCX, left circumflex; RCA, right coronary artery.\n\nFigure 5 (A) Myocardial perfusion imaging by first-pass contrast-enhanced cardiac magnetic resonance imaging at 4 months after onset. It shows subendocardial hypoperfusion from the ventricular septum to the inferior wall region of the left ventricle when a coronary artery vasodilator, adenosine, was loaded. (B) Late gadolinium enhancement cardiac magnetic resonance imaging at 4 months after onset is observed from the ventricular septum to the inferior wall region of the left ventricle (*) at rest.\n\nDiscussion\n\nKawasaki disease-associated GCAA rupture occurs within the first few months of onset.4 Rupture is a life-threatening complication. We examined 14 cases of CAA rupture since 1990, when IVIG treatment was introduced worldwide.7 In nine of them for which echocardiographic findings were described, the maximum CAA diameter was 10–19 mm in six, maximum RCA diameter was 20 mm in one, and maximum RCA diameter was 30 mm in one (Supplementary material online, Table S1). Twelve patients died (86%). The neurological prognosis of the survivors was not specified.4,8 Including unruptured cases, there are no reports of paediatric patients in the acute phase of KD with multiple GCCAs over 20 mm or a LAD with a 32 mm maximum diameter.\n\nHypertension reportedly increases the risk of various cardiovascular lesions in adults.9 However, few reports have examined the relationship between BP and the acute phase of KD when the coronary artery may expand. In KD patients with CAA, the internal elastic lamina of the coronary artery wall, an important component of arterial architecture, becomes dissociated and is destroyed.10 We speculate that these patients are more vulnerable to elevated BP. Our patient had multiple super GCAAs and Stage II hypertension (>99th percentile of normal), probably due to the steroids.11 He was subjected to actively administered antihypertensive therapy to prevent CAA expansion and rupture.\n\nThere are no specific guidelines for BP control in patients with KD. The 2017 American College of Cardiology/American Heart Association/etc. hypertension management guidelines do not consider diastolic BP in determining cardiovascular risk.9 We therefore placed emphasis on the systolic BP—which exerts the highest pressure on the coronary wall—in achieving BP control. Blood pressure was controlled not to exceed the normal systolic BP—the 5th percentile of normal—when there was a risk of progressive CAA expansion.12 Although the urine volume decreased with decreased BP, it was managed by temporary haemodialysis.\n\nAntithrombotic therapy is also essential for patients with super GCAAs (Supplementary material online, Table S2).1,13 Cardiac CT in our case showed a highly dilated RCA and LAD with severely diminished peripheral coronary blood flow. Thrombus formation was observed again in the peripheral RCA, necessitating further warfarin dose adjustment. In addition, the CMR findings suggested ischaemia and fibrosis in the RCA perfusion region of the LV. Although LGE is rare in patients with KD, it is reportedly associated with long-term LV dysfunction.14 Fortunately, in our case, the acute phase of KD was concluded without neurological sequelae. Nevertheless, since the risk level is classified as 5.1 in the American Heart Association 2017 statement, a high risk of cardiovascular events exists and careful follow-up, with focus on oral medications and exercise restriction is required.1\n\nConclusion\n\nStrict BP control with continuous arterial pressure monitoring under general anaesthesia could be useful in patients with KD and GCAA at a high risk of CAA rupture.\n\nLead author biography\n\nDr Yuji Moritoh is a deputy manager at the Department of Paediatric Cardiology, Hiroshima Citizens Hospital. In 2018, he was a winner of the Excellent Paper Award of Japan Foundation for Pediatric Research.\n\nSupplementary material\n\nSupplementary material is available at European Heart Journal - Case Reports online.\n\nSlide sets: A fully edited slide set detailing this case and suitable for local presentation is available online as Supplementary data.\n\nConsent: The authors confirm that written consent for submission and publication of this case report including images and associated text has been obtained from the patient in line with COPE guidance.\n\nConflict of interest: None declared.\n\nFunding: None declared.\n\nSupplementary Material\n\nytab161_Supplementary_Data Click here for additional data file.\n==== Refs\nReferences\n\n1 McCrindleBW, RowleyAH, NewburgerJW, BurnsJC, BolgerAF, GewitzM. Diagnosis, treatment, and long-term management of Kawasaki disease: a scientific statement for health professionals from the American Heart Association. Circulation 2017;135 :e927–e999.28356445\n2 MakinoN, NakamuraY, YashiroM, KosamiK, MatsubaraY, AeR. Nationwide epidemiologic survey of Kawasaki disease in Japan, 2015-2016. Pediatr Int 2019;61 :397–403.30786118\n3 KobayashiT, FuseS, SakamotoN, MikamiM, OgawaS, HamaokaK. A new Z score curve of the coronary arterial internal diameter using the lambda-mu-sigma method in a pediatric population. J Am Soc Echocardiogr 2016;29 :794–801.27288089\n4 MiyamotoT, IkedaK, IshiiY, KobayashiT. Rupture of a coronary artery aneurysm in Kawasaki disease: a rare case and review of the literature for the past 15 years. J Thorac Cardiovasc Surg 2014;147 :e67–e69.24837735\n5 ImaiY, SunagawaK, AyusawaM, MiyashitaM, AbeO, SuzukiJ. A fatal case of ruptured giant coronary artery aneurysm. Eur J Pediatr 2006;165 :130–133.16215725\n6 AustenWG, EdwardsJE, FryeRL, GensiniGG, GottVL, GriffithLS et al A reporting system on patients evaluated for coronary artery disease. Report of the Ad Hoc Committee for Grading of Coronary Artery Disease, Council on Cardiovascular Surgery, American Heart Association. Circulation 1975;51 (4 Suppl):5–40.1116248\n7 AgarwalS, AgrawalDK. Kawasaki disease: etiopathogenesis and novel treatment strategies. Expert Rev Clin Immunol 2017;13 :247–258.27590181\n8 FukazawaR, KobayashiT, MikamiM, SajiT, HamaokaK, KatoH. Nationwide survey of patients with giant coronary aneurysm secondary to Kawasaki disease 1999-2010 in Japan. Circ J 2017;82 :239–246.28855435\n9 WheltonPK, CareyRM, AronowWS, CaseyDEJr, CollinsKJ, HimmelfarbCD. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. Circulation 2018;138 :e484–e594.30354654\n10 TakahashiK, OharasekiT, NaoeS, WakayamaM, YokouchiY. Neutrophilic involvement in the damage to coronary arteries in acute stage of Kawasaki disease. Pediatr Int 2005;47 :305–310.15910456\n11 DionneJM, HarrisKC, BenoitG, FeberJ, PoirierL, CloutierL. Hypertension Canada’s 2017 guidelines for the diagnosis, assessment, prevention, and treatment of pediatric hypertension. Can J Cardiol 2017;33 :577–585.28449829\n12 BankerA, BellC, Gupta-MalhotraM, SamuelsJ. Blood pressure percentile charts to identify high or low blood pressure in children. BMC Pediatr 2016;16 :98.27430884\n13 FukazawaR, KobayashiJ, AyusawaM, HamadaH, MiuraM, MitaniY; Japanese Circulation Society Joint Working Group. JCS/JSCS 2020 guideline on diagnosis and management of cardiovascular sequelae in Kawasaki disease. Circ J 2020;84 :1348–1407.32641591\n14 TackeCE, RomeihS, KuipersIM, SpijkerboerAM, GroeninkM, KuijpersTW. Evaluation of cardiac function by magnetic resonance imaging during the follow-up of patients with Kawasaki disease. Circ Cardiovasc Imaging 2013;6 :67–73.23197079\n\n",
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"journal": "European heart journal. Case reports",
"keywords": "Blood pressure; Case report; Coronary artery aneurysm; Kawasaki disease; Plasma exchange",
"medline_ta": "Eur Heart J Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101730741",
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"pages": "ytab161",
"pmc": null,
"pmid": "34222780",
"pubdate": "2021-06",
"publication_types": "D002363:Case Reports",
"references": "30354654;16215725;15910456;28449829;32641591;27430884;28855435;30786118;27288089;24837735;28356445;23197079;27590181;1116248",
"title": "Importance of blood pressure control in Kawasaki disease with expanded multiple giant coronary aneurysms with a 32 mm maximum diameter: a case report.",
"title_normalized": "importance of blood pressure control in kawasaki disease with expanded multiple giant coronary aneurysms with a 32 mm maximum diameter a case report"
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"abstract": "BACKGROUND\nProcedures to prevent severe graft-versus-host disease (GVHD) delay immune reconstitution secondary to transplants of haploidentical haemopoietic stem cells for the treatment of leukaemia, leading to high rates of late infectious mortality. We aimed to systematically add back genetically engineered donor lymphocytes to facilitate immune reconstitution and prevent late mortality.\n\n\nMETHODS\nIn a phase I-II, multicentre, non-randomised trial of haploidentical stem-cell transplantation, we infused donor lymphocytes expressing herpes-simplex thymidine kinase suicide gene (TK-cells) after transplantation. The primary study endpoint was immune reconstitution defined as circulating CD3+ count of 100 cells per muL or more for two consecutive observations. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00423124.\n\n\nRESULTS\nFrom Aug 13, 2002, to March 26, 2008, 50 patients (median age 51 years, range 17-66) received haploidentical stem-cell transplants for high-risk leukaemia. Immune reconstitution was not recorded before infusion of TK-cells. 28 patients received TK-cells starting 28 days after transplantation; 22 patients obtained immune reconstitution at median 75 days (range 34-127) from transplantation and 23 days (13-42) from infusion. Ten patients developed acute GVHD (grade I-IV) and one developed chronic GVHD, which were controlled by induction of the suicide gene. Overall survival at 3 years was 49% (95% CI 25-73) for 19 patients who were in remission from primary leukaemia at the time of stem-cell transplantation. After TK-cell infusion, the last death due to infection was at 166 days, this was the only infectious death at more than 100 days. No acute or chronic adverse events were related to the gene-transfer procedure.\n\n\nCONCLUSIONS\nInfusion of TK-cells might be effective in accelerating immune reconstitution, while controlling GVHD and protecting patients from late mortality in those who are candidates for haploidentical stem-cell transplantation.\n\n\nBACKGROUND\nMolMed SpA, Italian Association for Cancer Research.",
"affiliations": "Haematology and BMT Unit, San Raffaele Scientific Institute, Milan, Italy.",
"authors": "Ciceri|Fabio|F|;Bonini|Chiara|C|;Stanghellini|Maria Teresa Lupo|MT|;Bondanza|Attilio|A|;Traversari|Catia|C|;Salomoni|Monica|M|;Turchetto|Lucia|L|;Colombi|Scialini|S|;Bernardi|Massimo|M|;Peccatori|Jacopo|J|;Pescarollo|Alessandra|A|;Servida|Paolo|P|;Magnani|Zulma|Z|;Perna|Serena K|SK|;Valtolina|Veronica|V|;Crippa|Fulvio|F|;Callegaro|Luciano|L|;Spoldi|Elena|E|;Crocchiolo|Roberto|R|;Fleischhauer|Katharina|K|;Ponzoni|Maurilio|M|;Vago|Luca|L|;Rossini|Silvano|S|;Santoro|Armando|A|;Todisco|Elisabetta|E|;Apperley|Jane|J|;Olavarria|Eduardo|E|;Slavin|Shimon|S|;Weissinger|Eva M|EM|;Ganser|Arnold|A|;Stadler|Michael|M|;Yannaki|Evangelia|E|;Fassas|Athanasios|A|;Anagnostopoulos|Achilles|A|;Bregni|Marco|M|;Stampino|Corrado Gallo|CG|;Bruzzi|Paolo|P|;Bordignon|Claudio|C|",
"chemical_list": "D006680:HLA Antigens; D013937:Thymidine Kinase",
"country": "England",
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"doi": "10.1016/S1470-2045(09)70074-9",
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"issue": "10(5)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D005260:Female; D018014:Gene Transfer Techniques; D041722:Genes, Transgenic, Suicide; D006086:Graft vs Host Disease; D006680:HLA Antigens; D006239:Haplotypes; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D017710:Lymphocyte Transfusion; D008297:Male; D008875:Middle Aged; D018139:Simplexvirus; D013937:Thymidine Kinase; D019172:Transplantation Conditioning; D055815:Young Adult",
"nlm_unique_id": "100957246",
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"pubdate": "2009-05",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Infusion of suicide-gene-engineered donor lymphocytes after family haploidentical haemopoietic stem-cell transplantation for leukaemia (the TK007 trial): a non-randomised phase I-II study.",
"title_normalized": "infusion of suicide gene engineered donor lymphocytes after family haploidentical haemopoietic stem cell transplantation for leukaemia the tk007 trial a non randomised phase i ii study"
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"abstract": "Acute myeloid leukemia (AML) with inv(16)(p13.1q22) resulting in CBFB-MYH11 fusion is associated with a favorable prognosis. The presence of a KIT mutation modifies it to an intermediate prognosis. Additionally, inv(16) can cooperate with other genetic aberrations to further increase cell proliferation. Coexistence of inv(16) and t(9;22) is extremely rare (20 cases). We present a case of a 55-year-old male with elevated white blood cell count. Bone marrow evaluation and flow cytometry analysis were compatible with AML with monocytic features. Cytogenetic studies revealed two-related clones, a minor clone with inv(16) and a major clone with concurrent inv(16) and t(9;22) rearrangements. Fluorescent in situ hybridization studies confirmed these rearrangements. Molecular analysis detected a p190 BCR-ABL1 transcript protein. KIT mutations were negative. The patient was initially treated with standard induction regimen; 7 daily doses of cytarabine from day 1-day 7, 3 daily doses of daunorubicin from day 1-day 3, and 1 dose of Mylotarg (gemtuzumab ozogamicin) on day 1. The detection of t(9;22) led to the addition of daily doses of dasatinib (tyrosine kinase inhibitor) from day 7 onwards. The patient achieved complete remission on day 45. During his treatment course, he acquired disseminated Fusarium infection. Day 180 bone marrow evaluation revealed florid relapse with 64% blasts. Cytogenetic study showed clonal evolution of the inv(16) clone with no evidence of the t(9;22) subclone. Eventually, bone marrow transplantation was contraindicated, and the patient was transferred to palliative care. Literature review revealed that AML with co-occurrence of CBFB-MYH11 and BCR-ABL1 gene rearrangements was involved by only a small number of cases with de novo and therapy-related AML. Most cases were in myeloid blast crisis of chronic myeloid leukemia (CML). Treatment and prognosis among the de novo AML cases varied and majority of them achieved clinical remission. In contrast, these cytogenetic abnormalities in the blast phase of CML had a poor prognosis. As the prognosis and management of AML is dependent upon the underlying genetic characteristics of the neoplasm, it is imperative to include clinical outcome with such rare combinations of genetic alterations.",
"affiliations": "University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.;University of Kansas Medical Center, Kansas City, KS, USA.",
"authors": "Sethapati|Venkata Rakesh|VR|;Jabr|Ra'ed|R|https://orcid.org/0000-0001-6514-4206;Shune|Leyla|L|;El Atrouni|Wissam|W|;Gonzales|Patrick R|PR|https://orcid.org/0000-0003-1594-0233;Cui|Wei|W|;Golem|Shivani|S|https://orcid.org/0000-0002-4379-8660",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2020/8822670",
"fulltext": "\n==== Front\nCase Rep Hematol\nCase Rep Hematol\nCRIHEM\nCase Reports in Hematology\n2090-6560 2090-6579 Hindawi \n\n10.1155/2020/8822670\nCase Report\nDe Novo Acute Myeloid Leukemia with Combined CBFB-MYH11 and BCR-ABL1 Gene Rearrangements: A Case Report and Review of Literature\nSethapati Venkata Rakesh https://orcid.org/0000-0001-6514-4206Jabr Ra'ed Shune Leyla El Atrouni Wissam https://orcid.org/0000-0003-1594-0233Gonzales Patrick R. Cui Wei https://orcid.org/0000-0002-4379-8660Golem Shivani sgolem@kumc.edu University of Kansas Medical Center, Kansas City, KS, USA\nAcademic Editor: Sudhir Tauro\n\n\n2020 \n16 12 2020 \n2020 88226704 9 2020 17 11 2020 1 12 2020 Copyright © 2020 Venkata Rakesh Sethapati 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.Acute myeloid leukemia (AML) with inv(16)(p13.1q22) resulting in CBFB-MYH11 fusion is associated with a favorable prognosis. The presence of a KIT mutation modifies it to an intermediate prognosis. Additionally, inv(16) can cooperate with other genetic aberrations to further increase cell proliferation. Coexistence of inv(16) and t(9;22) is extremely rare (20 cases). We present a case of a 55-year-old male with elevated white blood cell count. Bone marrow evaluation and flow cytometry analysis were compatible with AML with monocytic features. Cytogenetic studies revealed two-related clones, a minor clone with inv(16) and a major clone with concurrent inv(16) and t(9;22) rearrangements. Fluorescent in situ hybridization studies confirmed these rearrangements. Molecular analysis detected a p190 BCR-ABL1 transcript protein. KIT mutations were negative. The patient was initially treated with standard induction regimen; 7 daily doses of cytarabine from day 1–day 7, 3 daily doses of daunorubicin from day 1–day 3, and 1 dose of Mylotarg (gemtuzumab ozogamicin) on day 1. The detection of t(9;22) led to the addition of daily doses of dasatinib (tyrosine kinase inhibitor) from day 7 onwards. The patient achieved complete remission on day 45. During his treatment course, he acquired disseminated Fusarium infection. Day 180 bone marrow evaluation revealed florid relapse with 64% blasts. Cytogenetic study showed clonal evolution of the inv(16) clone with no evidence of the t(9;22) subclone. Eventually, bone marrow transplantation was contraindicated, and the patient was transferred to palliative care. Literature review revealed that AML with co-occurrence of CBFB-MYH11 and BCR-ABL1 gene rearrangements was involved by only a small number of cases with de novo and therapy-related AML. Most cases were in myeloid blast crisis of chronic myeloid leukemia (CML). Treatment and prognosis among the de novo AML cases varied and majority of them achieved clinical remission. In contrast, these cytogenetic abnormalities in the blast phase of CML had a poor prognosis. As the prognosis and management of AML is dependent upon the underlying genetic characteristics of the neoplasm, it is imperative to include clinical outcome with such rare combinations of genetic alterations.\n==== Body\n1. Introduction\nAcute myeloid leukemia (AML) is one of the most commonly encountered types of leukemias in adults. AML is characterized by clonal expansion of undifferentiated myeloid blasts and consequentially results in impaired hematopoiesis and bone marrow failure. It is a heterogenous disease clinically, morphologically, and genetically. Cytogenetic aberrations and gene mutations play critical roles in the pathogenesis of AML. There are many driver mutations, and the disease can evolve to accumulate more competing clones.\n\nCore binding factor (CBF) leukemias include t(8;21)/RUNX1-RUNX1T1 and inv(16)/t(16;16)/CBFB-MYH11 and are classified as AML with recurrent genetic abnormalities under the World Health Organization (WHO) classification [1, 2]. Inv(16) is found in 5–8% of younger patients with AML and accounts for around 7–10% of all patients with de novo AML [1, 3]. This abnormality results in the fusion of myosin heavy chain 11 gene (MYH11) at 16p13 and the core binding factor beta subunit gene (CBFB) at 16q12. This gene fusion results in chimeric proteins that suppress transactivation mediated by CBF and lead to impaired hematopoietic differentiation [3]. A bone marrow biopsy typically shows an acute myelomonocytic leukemia, accompanied with atypical eosinophils classified as the FAB subtype M4Eo [3]. Chromosome abnormalities involving CBF rearrangements are associated with a favorable prognosis, except when a KIT mutation is present [1].\n\nIn addition, genetic alterations can also activate signal transduction pathways and confer a proliferation advantage on hematopoietic cells. BCR-ABL1 is one such example. BCR-ABL1 translocation, also known as the Philadelphia (Ph) chromosome, results from a reciprocal translocation between chromosomes 9 and 22: t(9;22)(q34; q11.2). This translocation is necessary in defining chronic myeloid leukemia (CML) and is also responsible for a subset of B cell acute lymphoblastic leukemia (B-ALL) and less commonly in de novo AML [4]. The most common form of BCR-ABL1 fusion (b2a2 or b3a2) in CML and blast phase of CML results in a 210 kDa product (Major breakpoint), whereas in B-ALL, the main fusion form (e1a2) results in a 190 kDa product (minor breakpoint) [5].\n\nWe report a case with combined occurrence of inv(16) and BCR-ABL1 rearrangements, presenting as de novo AML. Our case also utilized the 190 kDa BCR-ABL1 fusion protein. With only 20 cases of AML described in literature with similar coexisting inv(16) and BCR-ABL1 rearrangements, there is a greater need to report such cases.\n\n2. Case Presentation\nA 55-year-old male presented with worsening fatigue. Upon evaluation, he had leukocytosis (white blood cell count—103 × 109/L), thrombocytopenia (platelets—25 × 109/L), and anemia (hemoglobin—7.6 g/dL). Review of the peripheral blood smear revealed 57% circulating blasts, and flow cytometry was compatible with AML with monocytic features. Myeloblasts comprised 15% of cells and showed expression of CD13, CD33, CD117, CD34, HLA-DR, partial CD123, minimal CD64, CD38, and partial cMPO; the blasts were negative for CD56, CD15, CD11b/C, CD14, TdT, and B and T cell markers. There were around 8% immature monocytic cells present which expressed dim CD45, CD13, CD117, CD33, CD15, partial CD11b, and partial CD64 and were negative for CD34. There were also 14% mature monocytic cells.\n\nA comprehensive bone marrow evaluation was diagnostic for acute myeloid leukemia involving a hypercellular bone marrow (100%) with decreased erythropoiesis, decreased megakaryopoiesis, increased eosinophils, 19% monocytes, and 24% blasts and promonocytes. Morphologically, the blasts appeared large, with irregular and convoluted nuclear contours, dispersed chromatin, and small amounts of basophilic cytoplasm. They were admixed with an increased number of promonocytes that had delicately folded nuclei, dispersed chromatin, inconspicuous nucleoli, and finely granulated cytoplasm. Importantly, there were increased eosinophils that had increased and coarse basophilic granules (Figure 1). Flow cytometry evaluation of the bone marrow biopsy yielded a hemodiluted specimen with myeloblasts expressing CD34, CD13, CD33, CD117, and HLA-DR comprising 1.1% of total cells.\n\nConventional cytogenetics at diagnosis demonstrated two-related clones. Two metaphases had pericentric inversions of chromosome 16 (Figure 2(a)). The second related clone was observed in majority of the metaphases, and each had a Philadelphia chromosome with the classic (9;22) translocation along with an inversion 16 abnormality (Figure 2(b)). Fluorescence in situ hybridization (FISH) assays were positive for CBFB rearrangement and BCR/ABL1 translocation in 94.0∼95.0% of the interphase nuclei (Figures 3(a) and 3(b)). A FISH assay for rearrangement of RUNX1T1/RUNX1 was normal (Figure 3(c)).\n\nA qualitative reverse transcriptase polymerase chain reaction (RT-PCR) was positive for an e1a2 BCR-ABL1 fusion transcript coding for the 190 kDa BCR-ABL1 fusion protein. A hematologic neoplasm next generation sequencing (NGS) 141 gene panel that was obtained based on the first bone marrow reported only two mutations of unknown significance in TET2 (p.L1322R) and P2RY2 (p.V77A). There were no pathogenic variants detected for FLT3 exon 14 (internal tandem duplication), FLT3 exon 20 (tyrosine kinase domain), NPM1 exon 11, CEBPA, and KIT exon 17 p.D816V at a minimum allelic fraction of 1.0%.\n\nThe patient was initially treated with a 7 + 3 cytarabine-based induction regimen: seven daily doses of cytarabine (100 mg/m2) from day 1 to day 7, three daily doses of daunorubicin (90 mg/m2) from day 1 to day 3, and a single dose of Mylotarg (gemtuzumab ozogamicin, 4.5 mg/m2) on day 1. The detection of p190 BCR-ABL1 transcript at day 5 led to the addition of daily doses of 100 mg of dasatinib (tyrosine kinase inhibitor, TKI) from day 7 onwards. Intrathecal cytarabine therapy was omitted due to a low number of platelets. The patient was pancytopenic and needed multiple red blood cells and platelets transfusions. On day 14, peripheral blood showed severe pancytopenia and bone marrow showed a hypocellular (<5%) bone marrow with decreased trilineage hematopoiesis and 1% blasts. Although flow cytometry evaluation revealed a negative immunophenotypic study, FISH studies were positive for t(9;22) and inv(16) in 25.1–27.1% of the interphase cells. Conventional cytogenetics did not yield enough metaphases for a complete study. Dasatinib was stopped on day 21 due to persistent leukopenia. G-colony stimulating factor was given once on day 21 and on day 23. Notably on day 20, the patient's clinical course was complicated by a skin ulceration in his toes that later resulted in disseminated Fusarium infection (Figure 4). Unable to obtain a bone marrow biopsy to evaluate for hematopoietic recovery, dasatinib was restarted on day 34. On day 45, peripheral blood was significant for absolute lymphopenia and monocytosis. Day 45 bone marrow biopsy showed a hypercellular marrow (80%), increased trilineage hematopoiesis, and less than 1% blasts. Flow cytometry on the same specimen was reported as a negative immunophenotypic study. The conventional cytogenetic study showed normal karyotype, and RT-PCR analysis for p190 BCR/ABL1 transcript was undetectable. His clinical status was in complete remission (CR), and the patient was eventually discharged on day 60.\n\nPatient was kept on a continued daily dose of 100 mg of dasatinib. However, the patient had gradually increasing Fungitell values and eventually developed fulminant Fusarium infection. He was admitted for bilateral pneumonia on day 120 and was treated with amphotericin (5 mg/kg). He was later enrolled on a clinical trial for an alternative oral-based antifungal medication therapy. His fungal infection was reported to have improved with decreased pulmonary infiltrates and a healed foot wound. The patient returned on day 180 for bone marrow transplant evaluation. His peripheral blood smear was remarkable for pancytopenia and 9% circulating blasts. His bone marrow showed persistent AML with 64% blasts and blast equivalents involving a mildly hypercellular bone marrow (50–60%) with decreased trilineage hematopoiesis. The corresponding flow cytometry on the bone marrow specimen revealed 30% of aberrant myeloid blasts that were positive for CD45 (dim), CD34, CD117, HLA-DR, CD13, CD33, and CD38. Chromosome study showed complete resolution of the t(9;22) subclone (negative by FISH and RT-PCR); however, the inv(16) clone resurfaced with other additional abnormalities significant for clonal evolution (Figure 5). Fungitell values were again high, and CT scan showed findings consistent with pneumonia and pansinusitis. Bronchial lavage cultures and blood cultures were negative for microorganism growth. Bone marrow hematopoietic stem cell transplantation (HSCT) was eventually contraindicated. The patient preferred hospice care and died two months after.\n\n3. Discussion\nAn inv(16) abnormality is found in 5–8% of younger patients with AML, while the Ph chromosome is a rare event in AML with a reported incidence ranging from 0.5% to 3% [1, 6]. BCR-ABL1 AML is now included as a new provisional entity in the 2017 revised WHO classification of hematopoietic malignancies [1, 7]. This entity excludes cases with evidence of the history of CML. Literature review describes a limited number of cases with AML with BCR-ABL1 translocation that tend to incorporate additional distinct genetic aberrations including inv(16), t(8;21)/RUNX1-RUNX1T1, t(15;17)/PML-RARA, inv(3), 5q deletion, and NPM1 mutation [8, 9]. Our case report similarly illustrates a patient with de novo AML with combined BCR-ABL1 (p190 form) and inv(16) abnormalities.\n\nThe Ph chromosome was observed as a subclone in our patient suggestive for “real AML” as Bacher et al. described in his case series [8]. In case #2, their patient had Ph chromosome-positive subclones as a secondary genetic alternation along with inv(16) at initial diagnosis. The patient was treated with hydroxycarbamide and daunorubicin/cytarabine followed by a TKI, imatinib. The patient went into remission but relapsed three months later. At relapse, cytogenetics showed 22 metaphases carrying an inv(16), two of which had an additional t(9;22). The first relapse was treated by intensified chemotherapy using fludarabine, cytarabine, G-CSF, and idarubicin, and again complete remission was achieved. A second relapse occurred ten months from initial diagnosis where 10 of 18 metaphases showed inv(16), while the other eight had evidence of both inv(16) and t(9;22). Their patient's clinical status after the second relapse is unknown. In contrast, our case at relapse showed complete resolution of the t(9;22) subclone (negative FISH and RT-PCR for BCR-ABL1), but the inv(16) clone resurfaced with other additional abnormalities significant for clonal evolution. This finding substantiates the efficacy of a TKI inhibitor in cases of Ph-positive AML.\n\nSimilar de novo and therapy-related AML cases with concurrent inv(16) and BCR-ABL1 rearrangements are compared in Table 1 [10–14]. Bustamante and team described a rapid response to single agent treatment with imatinib and demonstrated a negative finding of BCR-ABL1 fusion by FISH or RT-PCR after 3 weeks of therapy. Salem et al. included one patient with de novo AML and one with initial AML with CBFB rearrangement but subsequently acquired a BCR-ABL1 translocation [4]. The former received induction therapy with FLAG-IDA (fludarabine, cytarabine, idarubicin, and G-CSF) regimen and dasatinib with clinical remission in 21 months, and the latter received an induction with 7 + 3 regimen and dasatinib but relapsed after 8 months and died 2 years after initial diagnosis [4]. Miura et al. and Secker-Walker et al. reported stable remissions up to 70 months were achieved after allogenic stem cell transplantation.\n\nWe also know that the Ph chromosome can pair up with other abnormalities in AML. Han JY and team presented an AML case with a known prognostically adverse aberration inv(3) and monosomy 7 with Ph chromosome as a secondary abnormality at diagnosis [15]. The patient was treated with induction chemotherapy, but the patient's course was complicated by neutropenic fever and acute renal failure. Repeated bone marrow examinations showed the presence of persistent leukemia, and the patient subsequently went into hospice care. Mozziconacci et al. described two cases, one in which BCR-ABL1 translocation was in combination with inv(3) where the patient did not respond to initial treatment and died [9]. The other case was a more favorable rearrangement involving acute promyelocytic leukemia where a total of 100 mitoses were analyzed and two metaphases with t(15;17) and t(9;22) were found. The patient was treated with all‐trans retinoic acid and chemotherapy and achieved complete remission on day 30. At 3 months, a very low level of MBCR (b2a2) transcript was detected. RT-PCR was still positive at 4 months but negative at 9, 14, 17, and 30 months. 4 years after diagnosis, the patient was still in remission. These findings suggest prognosis of AML with Ph-positive subclones can be associated with the corresponding cytogenetic abnormality.\n\nInterestingly, cases with CML in the blast phase that acquire an inv(16) aberration have a poor prognosis. Salem et al. studied ten patients with combined inv(16) and BCR-ABL1 cytogenetic abnormalities and seven of which were CML cases [4]. In the seven patients, six died with a median overall survival time of 14 months despite intensive chemotherapy and targeted therapy with TKI [4]. Analyzing these cases and cases from Table 1, we can conclude that the p210 form was found in CML cases that transformed into the blast phase, and the p190 form was found in ‘true AML' with the exception of the case by Ninomiya et al. [16]. The p190 isoform is also more commonly associated with leukemogenesis leading to BCR-ABL1-positive acute lymphoblastic leukemia than AML [17, 18]. However, the immunophenotypic study from our case is against a lymphoblastic or mixed phenotypic leukemia.\n\nDue to the rarity of this disease, the prognosis is difficult to determine. CBFB rearrangement in AML with no additional mutation is known to have a favorable prognosis. A study with 201 de novo AML patients indicated that the 5-year survival probability was 43% for CBFB-MYH11 rearrangements [19]. Ph-positive AML appears to be an aggressive disease with poor response to traditional AML therapy or TKI alone [1, 4]. Additionally, only limited cases in literature included multigene mutation analysis in these rare co-occurring inv(16) and BCR-ABL1 abnormalities. Our case and the study by Salem et al. did not detect any pathogenic variants. This indicates that these co-occurring abnormalities act independently of other commonly seen mutations in myeloid neoplasms. Our patient had initially shown a favorable response to treatment and achieved CR by day 45 postdiagnosis. He later developed disseminated Fusarium infection, which compromised his leukemic treatment. Incidence of Fusarium spp. infection in patients with acute leukemia is 0.06% and the survival rate is 4% [20]. Despite enrolling in an investigational antifungal clinical trial, his fungal infection persisted and was not a suitable candidate for HSCT. Overall, we feel that the combination of inv(16) and BCR-ABL1 genetic abnormalities confers an intermediate prognosis.\n\nDe novo AML patients with combined inv(16) and t(9;22) cytogenetic abnormalities seem to benefit from intensive chemotherapy and targeted TKIs. Decisions about HSCT in intermediate-risk AML were less clear-cut in the past, and nowadays, most patients are considered for HSCT in their first CR [21]. Patient fitness, availability of a sibling donor or an alternative donor, a clinical trial option, and the transplant center experience must be considered when making a decision about HSCT. It is important to note that a longer duration of BCR-ABL1 fusion transcript surveillance can be used to establish a standard of care for such Ph-positive AML patients with additional rearrangements [7].\n\n4. Conclusion\nMolecularly defined genetic abnormalities in AML have a significant impact on a patient's management and prognosis. AML presenting with both inv(16) and t(9;22) abnormalities confers an intermediate prognosis. The pathognomic effect of the occurrence of these abnormalities acts independent of other common molecular mutations seen in myeloid neoplasms. These cases are rare and need to be documented and studied further to formulate better management strategies. Such cases may benefit from intensive chemotherapy and TKIs as a bridge to stem cell transplantation. Comorbidities and infectious diseases arising from an immunocompromised state must be taken into consideration when planning treatment regimens to prevent doing more harm than benefit to the patient.\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConflicts of Interest\nThe authors declare that they have no conflicts of interest.\n\nFigure 1 Bone marrow morphology: increased blasts, promonocytes, and atypical eosinophils with large basophilic granules.\n\nFigure 2 Representative G-banded karyogram showing (a) the inv(16)(p13.1q22) as a sole abnormality and (b) co-occurrence of inv(16)(p13.1q22) and t(9;22)(q34; q11.2). The arrows indicate the rearranged chromosomes.\n\nFigure 3 Fluorescence in situ hybridization (FISH) studies on interphase cells showing (a) CBFB and MYH11 rearrangement, dual fusion probe (Cytocell); (b) BCR/ABL1 translocation, dual fusion probe (Cytocell); and (c) normal FISH signal pattern for RUNX1T1/RUNX1 rearrangement, dual fusion probe (Abbott molecular).\n\nFigure 4 Fusarium infection presenting as a skin ulceration in his toes.\n\nFigure 5 (a) Fluorescence in situ hybridization (FISH) studies on interphase cells showing BCR and ABL1 FISH probe signals, dual fusion probe (Cytocell) and (b) representative G-banded karyogram showing relapsed clone of the inv(16)(p13.1q22) primary clone.\n\nTable 1 AML cases with concurrent inv(16) and BCR-ABL genetic abnormalities in this study and selected cases from literature review.\n\nSex/age\tAML subtype\tFAB classification\tKaryotype\tOther mutation assay(s)\tClinical course\tPMID\t\nM/40\tDe novo\tM4eo\t46,XY,inv(16)(p13q22)[17]/46,XY,idem,t(9;22)(q34:q11)[3]\tNot performed\tChemotherapy and HSCT; stable remission\t8250017\t\nF/9\tDe novo\tM4eo\t46,XX,inv(16)(p13q22)[21]/46,XX,t(9;22)(q34;q11),inv(16)(p13q22)[8]/46,XX [10]\tNot performed\tChemotherapy and HSCT; died soon after HSCT\t1728947\t\nM/13\tDe novo\tM4\t46,XY,inv(16)(p13.1q22)[2]/46,idem,del(7)(q22q32)[16]/46,idem,t(9;22;19)(q34;q11.2;p13.1)[2]\tNot performed\tCytarabine, daunomycin, etoposide + gemtuzumab\t20513535\t\nF/40\tDe novo\tM1\t46,XX,inv(16)(p13q22)[4]/46,XX,t(9;22)(q34;q11),inv(16)(p13q22)[18]\tNot performed\tOne cycle of conventional induction therapy\t11368385\t\nM/63\tDe novo\tM4eo\tAt diagnosis: 46,XY,inv(16)(p13q22)[20]/46,XY,t(9;22)(q34;q11),inv(16)(p13q22)[2]\nAt last relapse: 46,XY,inv(16)(p13q22)[10]/46,XY,+8,t(9;22)(q34;q11),inv(16)(p13q22)[8]\tNot performed\tHydroxycarbamide, daunorubicin/ cytarabine and imatinib with relapse in 3 months. Fludarabine, cytarabine, G-CSF and Idarubicine with complete remission but relapsed 10 months later\t21275954\t\nF/49\tTherapy- related\tM4eo\t46,XX,inv(16)(p13.1q22)[5]/46,XX,t(9;22)(q34;q11.2)[7]/46,XX[8]\tNot performed\tImatinib; remission in 3 weeks\t22370710\t\nM\tDe novo\tM4eo\t46,XY,inv(16)(p13.1q22)[3]/46,idem,t(9;22)(q34;q11.2)[17]\tNone (NGS, multiple genes)\tFludarabine, cytarabine, G-CSF and Idarubicine + dasatinib; stable remission\t28253536\t\nM/55\tDe novo\tM4eo\tAt Diagnosis: 46,XY,inv(16)(p13.1q22)[2]/46,sl,t(9;22)(q34;q11.2)[20]/46,XX[1].nuc ish(MYH11,CBFB)x3(MYH11 con CBFBx2)[190/200]/(ABL1,BCR)x3(ABL1 con BCRx2)[188/200]\n13-day follow-up: 46,XY[2].nuc ish(ABL1,BCR)x3(ABL1 con BCRx2)[88/350]/(MYH11,CBFB)x3(MYH11 con CBFBx2)[95/350]\n45-day follow-up: 46,XY[20]\n188-day follow-up: 51,XY,+8,+9,+13,inv(16)(p13.1q22),+18,+22[19]/46,XY[1].nuc ish(MYH11,CBFB)x3(MYH11 con CBFBx2)[155/200]/(ABL1x2∼3,BCRx2∼3)[372/500]\tNone (NGS, multiple genes)\tGemtuzumab ozogamicin induction + Dasatinib; a first relapse diagnosed 6 months from initial diagnosis. Hospice.\tCurrent case\n==== Refs\n1 Swerdlow S. H. Campo E. Harris N. L. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues 2017 4th Lyon, France International Agency for Research on Cancer \n2 Wang M. L. Bailey N. G. Bailey N. Acute myeloid leukemia genetics: risk stratification and implications for therapy Archives of Pathology & Laboratory Medicine 2015 139 10 1215 1223 PMID 26414465 10.5858/arpa.2015-0203-RA 2-s2.0-84942914171 26414465 \n3 Schnittger S. Bacher U. Haferlach C. Kern W. Haferlach T. Rare CBFB-MYH11 fusion transcripts in AML with inv(16)/t(16;16) are associated with therapy-related AML M4eo, atypical cytomorphology, atypical immunophenotype, atypical additional chromosomal rearrangements and low white blood cell count: a study on 162 patients Leukemia 2007 21 4 725 731 PMID—17287858 10.1038/sj.leu.2404531 2-s2.0-33947364435 17287858 \n4 Salem A. Loghavi S. Tang G. Myeloid neoplasms with concurrent BCR-ABL1 and CBFB rearrangements: a series of 10 cases of a clinically aggressive neoplasm American Journal of Hematology 2017 92 6 520 528 10.1002/ajh.24710.PMID.28253536 28253536 \n5 Jabbour E. Kantarjian H. Chronic myeloid leukemia: 2016 update on diagnosis, therapy, and monitoring American Journal of Hematology 2016 91 2 252 265 PMID—26799612 10.1002/ajh.24275 2-s2.0-84961381646 26799612 \n6 Konoplev S. Yin C. C. Kornblau S. M. Molecular characterization OFDE novo Philadelphia chromosome-positive acute myeloid leukemia Leukemia & Lymphoma 2013 54 1 138 144 10.3109/10428194.2012.701739.PMID-22691121 22691121 \n7 Neuendorff N. R. Burmeister T. Dörken B. Westermann J. BCR-ABL-positive acute myeloid leukemia: a new entity? Analysis of clinical and molecular features Annals of Hematology 2016 95 8 1211 1221 10.1007/s00277-016-2721-z 2-s2.0-84974808882 27297971 \n8 Bacher U. Haferlach T. Alpermann T. Subclones with the t(9;22)/BCR-ABL1 rearrangement occur in AML and seem to cooperate with distinct genetic alterations British Journal of Haematology 2011 152 6 713 720 PMID— 21275954 10.1111/j.1365-2141.2010.08472.x 2-s2.0-79951966910 21275954 \n9 Mozziconacci M.-J. Sainty D. Gabert J. The Philadelphia chromosome as a secondary abnormality in two cases of acute myeloid leukemia British Journal of Haematology 1998 102 3 873 875 PMID—9722319 10.1046/j.1365-2141.1998.0887b.x 2-s2.0-0031839826 9722319 \n10 Bustamante D. Chan K. R. Czuchlewski D. R. Al Saadi A. A. Patterns of BCR breakpoints in patients with coexisting inv(16)(p13.1q22) and t(9;22)(q34;q11.2) International Journal of Hematology 2012 95 3 324 326 PMID—22370710 10.1007/s12185-011-0990-9 2-s2.0-84863004910 22370710 \n11 Miura I. Takatsu H. Yamaguchi A. Standard Ph chromosome, t(9;22)(q34;q11), as an additional change in a patient with acute myelomonocytic leukemia (M4Eo) associated with inv(16)(p13q22) American Journal of Hematology 1994 45 1 94 96 PMID—8250017 10.1002/ajh.2830450118 2-s2.0-0028366380 \n12 Secker‐Walker L. M. Morgan G. J. Min T. Inversion of chromosome 16 with the Philadelphia chromosome in acute myelomonocytic leukemia with eosinophilia. Report of two cases Cancer Genetics and Cytogenetics 1992 58 29 34 PMID—1728947 \n13 Svaldi M. Lanthaler A. Venturi R. Coser P. Mitterer M. Simultaneous occurrence of BCR-ABL and inv16 in a case of M1 acute myeloid leukemia Leukemia 2001 15 4 p. 695 PMID—11368385 10.1038/sj.leu.2402082 2-s2.0-0035071991 \n14 Tirado C. A. Valdez F. Klesse L. Acute myeloid leukemia with inv(16) with CBFB-MYH11, 3′CBFB deletion, variant t(9;22) with BCR-ABL1, and del(7)(q22q32) in a pediatric patient: case report and literature review Cancer Genetics and Cytogenetics 2010 200 1 54 59 PMID: 20513535 10.1016/j.cancergencyto.2010.03.001 2-s2.0-77953350446 20513535 \n15 Han J.-Y. Theil K. S. The Philadelphia chromosome as a secondary abnormality in inv(3)(q21q26) acute myeloid leukemia at diagnosis: confirmation of p190 BCR-ABL mRNA by real-time quantitative polymerase chain reaction Cancer Genetics and Cytogenetics 2006 165 1 70 74 PMID: 16490599 10.1016/j.cancergencyto.2005.07.015 2-s2.0-33747367939 16490599 \n16 Ninomiya S. Kanemura N. Tsurumi H. Coexistence of inversion 16 and the Philadelphia chromosome comprising P190 BCR/ABL in chronic myeloid leukemia blast crisis International Journal of Hematology 2011 93 6 806 810 PMID—21523337 10.1007/s12185-011-0854-3 2-s2.0-79960104116 21523337 \n17 Thomas X. Heiblig M. The development of agents targeting the BCR-ABL tyrosine kinase as Philadelphia chromosome-positive acute lymphoblastic leukemia treatment Expert Opinion on Drug Discovery 2016 11 11 1061 1070 PMID: 27548716 10.1080/17460441.2016.122731831 27548716 \n18 Vinhas R. Lourenço A. Santos S. A novel BCR-ABL1 mutation in a patient with Philadelphia chromosome-positive B-cell acute lymphoblastic leukemia OncoTargets and Therapy 2018 11 8589 8598 PMID: 30584318; PMCID: PMC 6280987 10.2147/OTT.S177019 2-s2.0-85057960536 30584318 \n19 Sinha C. Cunningham L. C. Liu P. P. Core binding factor acute myeloid leukemia: new prognostic categories and therapeutic opportunities Seminars in Hematology 2015 52 3 215 222 Epub 2015 Apr 7. PMID: 26111469; PMCID: PMC 4484884 10.1053/j.seminhematol.2015.04.002 2-s2.0-84937401084 26111469 \n20 Liu Y.-S. Wang N.-C. Ye R.-H. Kao W.-Y. Disseminated Fusarium infection in a patient with acute lymphoblastic leukemia: a case report and review of the literature Oncology Letters 2014 7 2 334 336 10.3892/ol.2013.1738PMID-24396442 24396442 \n21 Kassim A. A. Savani B. N. Hematopoietic stem cell transplantation for acute myeloid leukemia: a review Hematology/Oncology and Stem Cell Therapy 2017 Dec 10 4 245 251 Epub 2017 Jun 20. PMID: 28666104 10.1016/j.hemonc.2017.05.021 2-s2.0-85022009682 28666104\n\n",
"fulltext_license": "CC BY",
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"title": "De Novo Acute Myeloid Leukemia with Combined CBFB-MYH11 and BCR-ABL1 Gene Rearrangements: A Case Report and Review of Literature.",
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"abstract": "A 44-year-old man presented to the emergency department with fever and right anterior chest pain. He reported a persistent cough and the development of sudden-onset right anterior chest pain after coughing. The inspiratory pain in the right lung was severe, and therefore deep breathing was impossible. Chest CT revealed a fracture in the right seventh rib with consolidation and pleural effusion. A pleural fluid culture test result was positive for methicillin-susceptible Staphylococcus aureus He was diagnosed with empyema associated with a cough-induced rib fracture. Thoracic drainage tube placement and intravenous antibiotic therapy successfully ameliorated his condition. He was discharged on day 13 and switched to an 8-week course of oral antibiotic therapy. There was no clinical relapse at the 6-month follow-up.",
"affiliations": "Department of Internal Medicine, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan 059m2076@gmail.com.;Department of Internal Medicine, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan.",
"authors": "Hayano|Satoshi|S|http://orcid.org/0000-0003-3554-1600;Kashima|Masayuki|M|",
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"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n34035027\nbcr-2021-242656\n10.1136/bcr-2021-242656\nCase Report\n1506\n1330\n192\nEmpyema associated with a cough-induced rib fracture\nhttp://orcid.org/0000-0003-3554-1600\nHayano Satoshi\nKashima Masayuki\nDepartment of Internal Medicine, Japanese Red Cross Kumamoto Hospital, Kumamoto, Japan\nCorrespondence to Dr Satoshi Hayano; 059m2076@gmail.com\n2021\n25 5 2021\n25 5 2021\n14 5 e24265622 4 2021\n© BMJ Publishing Group Limited 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nA 44-year-old man presented to the emergency department with fever and right anterior chest pain. He reported a persistent cough and the development of sudden-onset right anterior chest pain after coughing. The inspiratory pain in the right lung was severe, and therefore deep breathing was impossible. Chest CT revealed a fracture in the right seventh rib with consolidation and pleural effusion. A pleural fluid culture test result was positive for methicillin-susceptible Staphylococcus aureus. He was diagnosed with empyema associated with a cough-induced rib fracture. Thoracic drainage tube placement and intravenous antibiotic therapy successfully ameliorated his condition. He was discharged on day 13 and switched to an 8-week course of oral antibiotic therapy. There was no clinical relapse at the 6-month follow-up.\n\npneumonia (infectious disease)\nempyema\nspecial-featureunlocked\n==== Body\nBackground\n\nCough-induced rib fracture is a type of stress fracture.1–4 Typically, postinfectious cough, chronic bronchitis, asthma attack and postnasal drip are associated with cough-induced rib fractures; furthermore, the fracture is followed by a sudden onset of chest pain after the cough.1 3 Rib fractures are more likely to occur in the lateral aspect of the 5th–10th ribs because of their known susceptibility to shear forces.1 5 Approximately 30% of patients with a cough-induced rib fracture have no underlying disease or osteoporosis, meaning it can occur in patients with no specific risk factors and in healthy adults.1–4\n\nRib fractures are considered a risk factor for both pneumonia and empyema.6–9 In particular, multiple rib fractures due to trauma can worsen the drainage of sputum from cough owing to pain and flail chest syndrome and increase the risk of subsequent pneumonia. The prevalence of pneumonia after rib fractures is estimated to be 6%–9.1%, and this also increases mortality, especially in those aged >65 years.7 10 The rate of complications depends on the number and severity of rib fractures, with more fractures resulting in more severe complications and pneumonia.8 11 In 50% of cough-induced rib fractures, a single rib fracture is involved.1 4 Although the prognosis for cough-induced rib fracture is good generally, complications, such as pneumonia, haemothorax, pneumothorax, pneumomediastinum, subcutaneous emphysema, chest wall haematoma and intercostal pulmonary herniation, have also been reported.1 12 13 Most post-traumatic empyema cases are related to contusion trauma and to chest tube insertion, with a reported incidence of approximately 3.1%.9 Empyema has not previously been reported to be associated with cough-induced rib fractures, and its epidemiology is unknown. Here, we present a novel case of empyema associated with a cough-induced rib fracture.\n\nCase presentation\n\nA 44-year-old man with a history of asthma presented to the emergency department (ED) with fever and right anterior chest pain. Two weeks before presentation, he had had a persistent cough with an asthma attack after an upper respiratory tract infection. One week later, he developed sudden-onset right anterior chest pain after coughing. He reported no history of trauma, and an orthopaedic surgeon diagnosed him with a fracture of the right seventh rib. He had not been taking any oral medications. He was previously diagnosed with contact dermatitis and had been receiving monthly injections of intramuscular triamcinolone acetonide for the previous 10 years. He drank one beer daily and had smoked half a pack of cigarettes per day for >20 years. On presentation, his body temperature was 37.5°C, blood pressure was 131/95 mm Hg, heart rate was 80 beats per minute, respiratory rate was 18 breaths per minute and SpO2 (arterial oxygen saturation of pulse oxymetry) level was 98% (ambient air). Physical examination revealed right anterior chest pain at the level of the seventh rib. The respiratory sounds on auscultation were unremarkable.\n\nInvestigations\n\nA chest X-ray (figure 1) revealed a fracture of the seventh rib, and chest CT showed consolidation and a small amount of pleural effusion (figure 2). A rib fracture with haemothorax and pneumonia was initially suspected. The patient was initiated on oral amoxicillin/clavulanate. Two days after his initial visit, he was rushed to the ED with worsening right chest pain and shortness of breath. The inspiratory pain in the right lung had markedly worsened, and deep breathing had become impossible. On arrival at the ED, his body temperature was 38.5°C, blood pressure was 131/95 mm Hg, heart rate was 107 beats per minute, respiratory rate was 30 breaths per minute and SpO2 level was 98% (O2, 6 L/min). The laboratory test results were as follows: leucocyte count, 10.18 ×109/L; haemoglobin level, 137g/L; platelet count, 211 ×109/L; serum creatinine level, 0.96 mg/dL; lactate dehydrogenase level, 227 U/L; total protein level, 6.5 g/dL; serum albumin level, 3.2 mg/dL; blood glucose level, 197 mg/dL; and C reactive protein level, 17.83 mg/dL. The chest X-ray showed an increased level of pleural effusion. Thus, thoracentesis was performed, revealing an exudative neutrophilic pleural effusion with the following: total protein level of 5.8 g/dL, glucose level of 138 mg/dL and lactate dehydrogenase level of 779 U/L. Gram staining of the pleural fluid showed gram-positive cocci. Pleural fluid culture results revealed methicillin-susceptible Staphylococcus aureus (MSSA). Two sets of blood cultures were negative.\n\nFigure 1 Anterioposterior chest radiograph of our patient. (A) Blunt, right costophrenic angle with a seventh rib fracture at presentation. Increased pleural effusion was observed 12 hours after admission (B) and on day 2 (C).\n\nFigure 2 Chest CT of our patient at presentation. A fracture of the right seventh rib was observed (A) with right lower lung consolidation and pleural effusion on day 2 (B).\n\nTreatment\n\nEmpirical treatment was initiated with ampicillin/sulbactam and vancomycin after admission. However, once the results of antibiotic sensitivity tests were available, the antibiotics were switched to cefazolin. A right thoracic drainage tube was inserted on admission, draining 520 mL of pleural fluid over 1 hour. The patient’s respiratory distress and right inspiratory chest pain were intense, but the symptoms gradually improved after drainage. On day 3, the fever abated, and he could take deep breaths; thereafter, the thoracic drainage tube was removed. After 13 days of intravenous antimicrobial treatment, the patient was discharged and switched to an oral antibiotic to continue outpatient treatment with an 8-week course of cephalexin.\n\nOutcome and follow-up\n\nTwo months after discharge from our hospital, chest CT revealed that the pleural effusion had markedly improved. The patient completed the 8-week course of cephalexin therapy, and no relapse was noted at the 6-month follow-up. The rib fracture was treated conservatively, and posterior follow-up CT showed bone fusion had occurred. Bone densitometry revealed osteopenia: the T-score of the lumbar spine was −1.6 and that of the total hip was −2.0.\n\nDiscussion\n\nCough-induced rib fracture can occur in healthy young people and it is also occurs in patients with osteopenia and osteoporosis.1 2 It has been reported by Hanak et al that 17 of their 26 patients with a cough-induced rib fracture met the criteria for either osteopenia or osteoporosis.1 Prins et al reported that patients with osteopenia or osteoporosis had a higher risk of rib fracture than patients with normal bone density on blunt thoracic trauma.14 In our case, no oral steroids or immunosuppressive drugs were used, but a detailed medical history revealed that the patient had received regular intramuscular injections of triamcinolone acetonide for over 10 years. Any association between cough-induced rib fractures and steroid-induced bone loss is unclear.1 4 Our patient was at a high risk of fracture and pneumonia due to both his steroid use and his prolonged smoking habit.\n\nChauny et al reported that generally the time between a rib fracture and the onset of pneumonia is between 2 and 14 days; furthermore, the onset of pneumonia can also occur soon after rib fracture, during the acute phase of the disease.15 In our case, the patient developed pneumonia on the third day after the fracture occurred, which, considering the above, was a relatively early onset. Among the complications arising from rib fractures, pneumonia is the leading cause of death in trauma patients and is particularly problematic in those aged >65 years.7 Brasel et al reported that the development of pneumonia after a rib fracture was a risk factor for death (OR, 3.5; 95% CI, 2.2 to 5.7). Risk factors for pneumonia after rib fracture include the following: male sex; age >65 years; >6 rib fractures; brain injury; spinal cord injury; underlying disease, such as congestive heart failure; paralysis; chronic pulmonary disease; obesity; weight loss; alcohol consumption; and high initial fluid volume.8 10 11 Although increasing age and number of fractures have been reported to increase complications, those aged <45 years at risk of multiple rib fractures have been reported to have adverse outcomes.11 16 Thus, complications after rib fractures should be monitored in at-risk patients of all ages.\n\nThe incidence of pneumonia in minor rib fractures is as low as 0.6%–1.6%.7 17 However, Ho et al reported that even one or two rib fractures were associated with an increased risk of pneumonia (adjusted HR, 8.94; 95% CI, 3.79 to 21.09; p<0.001).17 Risk factors for pneumonia complications in minor fractures include age >65 years and chronic obstructive pulmonary disease, but the likelihood of pneumonia secondary to a minor rib fracture in healthy adults is low.17\n\nTo the best of our knowledge, this is the first report of empyema due to MSSA associated with a cough-induced rib fracture. Post-traumatic empyema has been previously reported as a complication, secondary to thoracic trauma, and mainly occurs after penetrating trauma with an inserted chest tube, but it has also been reported in combination with blunt trauma complicated by rib fracture.9 18 19 Previous studies have reported that haemothorax, prolonged tube placement, ≥2 rib fractures and contusion are risk factors for empyema.9 Regarding the microbiological aetiology of post-traumatic empyema, pleural fluid culture was reported to be positive in 73% of cases.20 S. aureus is the most common bacterial pathogen, and MSSA accounts for 35.1% of cases.20 Causative bacteria include methicillin-resistant S. aureus, Streptococcus pneumoniae, Pseudomonas aeruginosa, Klebsiella pneumoniae and anaerobic organisms.18–20 It has been reported that bacteria detectable in sputum and pleural fluid cultures in post-traumatic empyema do not always correlate. Contamination at the time of injury, or tube insertion, has been shown as the cause of empyema due to penetrating trauma.20\n\nAlthough there was no perforating trauma in our case, we conjecture the mechanism to be that the patient’s severe chest pain made it difficult to expel sputum and that steroid use and smoking were involved in the progression to empyema. As the patient was unable to expel sputum due to pain, sputum examination could not be performed. Contamination from an external surface was unlikely, and the patient may have progressed from pneumonia to empyema. The treatment of parapneumonic empyema requires drainage, and in our case, the initial medical treatment alone did not improve the patient’s condition, necessitating the insertion of a drain, which resulted in a marked improvement. Possible complications of pneumonia and empyema after a cough-induced rib fracture should be considered, even if the patient has a small number of fractures.\n\nLearning points\n\nCough-induced rib fracture is a stress fracture that occurs after persistent cough, followed by a sudden onset of chest pain.\n\nPneumonia is an important complication of the acute phase of rib fracture and can even occur after a minor rib fracture, particularly in older adults and smokers.\n\nIn cases of empyema complicated with a rib fracture, it is crucial to differentiate empyema from simple haemothorax.\n\nStaphylococcus aureus is the most common bacterial pathogen of rib fracture-associated empyema.\n\nContributors: SH was involved in conceptualisation, writing and original draft preparation; MK was involved in writing, reviewing and editing, and supervising.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n\n1 Hanak V, Hartman TE, Ryu JH. Cough-Induced rib fractures. Mayo Clin Proc 2005;80 :879–82. 10.4065/80.7.879 16007893\n2 Yeh C-F, Su S-C. Cough-Induced rib fracture in a young healthy man. J Formos Med Assoc 2012;111 :179–80. 10.1016/j.jfma.2011.07.020 22423673\n3 De Maeseneer M, De Mey J, Debaere C, et al . Rib fractures induced by coughing: an unusual cause of acute chest pain. Am J Emerg Med 2000;18 :194–7. 10.1016/S0735-6757(00)90019-6 10750931\n4 Sano A, Tashiro K, Fukuda T. Cough-Induced rib fractures. Asian Cardiovasc Thorac Ann 2015;23 :958–60. 10.1177/0218492315596893 26207003\n5 Karlson KA. Rib stress fractures in elite Rowers. Am J Sports Med 1998;26 :516–9. 10.1177/03635465980260040701 9689370\n6 Martin TJ, Eltorai AS, Dunn R, et al . Clinical management of rib fractures and methods for prevention of pulmonary complications: a review. Injury 2019;50 :1159–65. 10.1016/j.injury.2019.04.020 31047683\n7 Brasel KJ, Guse CE, Layde P, et al . Rib fractures: relationship with pneumonia and mortality. Crit Care Med 2006;34 :1642–6. 10.1097/01.CCM.0000217926.40975.4B 16625122\n8 Marco CA, Sorensen D, Hardman C, et al . Risk factors for pneumonia following rib fractures. Am J Emerg Med 2020;38 :610–2. 10.1016/j.ajem.2019.10.021 31831351\n9 Eren S, Esme H, Sehitogullari A, et al . The risk factors and management of posttraumatic empyema in trauma patients. Injury 2008;39 :44–9. 10.1016/j.injury.2007.06.001 17884054\n10 Mangram AJ, Sohn J, Zhou N, et al . Trauma-associated pneumonia: time to redefine ventilator-associated pneumonia in trauma patients. Am J Surg 2015;210 :1056–62. Discussion 61-2. 10.1016/j.amjsurg.2015.06.029 26477792\n11 Bulger EM, Arneson MA, Mock CN, et al . Rib fractures in the elderly. J Trauma 2000;48 :1040–7. 10.1097/00005373-200006000-00007 10866248\n12 Camarillo-Reyes LA, Marquez-Córdova RI, Surani S, et al . Hemothorax induced by severe cough: an unusual presentation. SAGE Open Med Case Rep 2019;7 :2050313X1984604. 10.1177/2050313X19846043\n13 Shukri WNA, Ng VH, Ismail AK. A case of cough induced rib fracture with subcutaneous emphysema and pneumothorax. Med J Malaysia 2019;74 :551–2.31929488\n14 Prins JTH, Van Lieshout EMM, Reijnders MRL, et al . Rib fractures after blunt thoracic trauma in patients with normal versus diminished bone mineral density: a retrospective cohort study. Osteoporos Int 2020;31 :225–31. 10.1007/s00198-019-05219-9 31828365\n15 Chauny J-M, Émond M, Plourde M, et al . Patients with rib fractures do not develop delayed pneumonia: a prospective, multicenter cohort study of minor thoracic injury. Ann Emerg Med 2012;60 :726–31. 10.1016/j.annemergmed.2012.03.020 22542306\n16 Testerman GM. Adverse outcomes in younger rib fracture patients. South Med J 2006;99 :335–9. 10.1097/01.smj.0000203815.29757.d3 16634240\n17 Ho S-W, Teng Y-H, Yang S-F, et al . Risk of pneumonia in patients with isolated minor rib fractures: a nationwide cohort study. BMJ Open 2017;7 :e013029. 10.1136/bmjopen-2016-013029\n18 Villalba M, Lucas CE, Ledgerwood AM, et al . The etiology of post-traumatic empyema and the role of decortication. J Trauma 1979;19 :414–21. 10.1097/00005373-197906000-00005 448781\n19 Hoth JJ, Burch PT, Richardson JD. Posttraumatic empyema. European Journal of Trauma 2002;28 :323–32. 10.1007/s00068-002-1264-2\n20 Hoth JJ, Burch PT, Bullock TK, et al . Pathogenesis of posttraumatic empyema: the impact of pneumonia on pleural space infections. Surg Infect 2003;4 :29–35. 10.1089/109629603764655254\n\n",
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"title": "Empyema associated with a cough-induced rib fracture.",
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"abstract": "Statins can cause a wide spectrum of muscular adverse effects ranging from asymptomatic elevation of Creatine Kinase (CK), myalgia and exercise intolerance to rhabdomyolysis. Most of these effects generally resolve on stopping the medication. However, statins can be associated with a unique autoimmune myopathy wherein symptoms persist or even progress after statin discontinuation and require immunosuppressive therapy. The case presented is a 60-year-old woman who was on statin treatment for a period of 2 years. She developed muscle weakness with a limb girdle distribution. She had persistent elevation of CK even after discontinuation of statin therapy. EMG done revealed irritable myopathy and muscle biopsy showed necrosis without inflammation. She subsequently tested positive for anti-3-hydroxy-3-methylglutaryl-coenzyme A (anti-HMG CoA) antibody which is found to be present in patients with statin-associated necrotizing autoimmune myopathy. Patient was started on steroid without much improvement in her symptoms. After a month of follow up, her upper extremity strength was back but lower extremity continued to be weak which prompted us to start her on Methotrexate and Azathioprine. Like our patient, there are rare subgroup of patients with an immune-mediated necrotizing myopathy that does not improve after discontinuation of the drug and requires aggressive treatment with immunosuppressive agents. Awareness and early recognition of this disease is very important in patients who continue to have CK elevation and weakness after discontinuation of statin therapy.",
"affiliations": "Department of Internal Medicine, Creighton University School of Medicine.;Department of Internal Medicine, Creighton University School of Medicine.;Department of Internal Medicine, Creighton University School of Medicine.;Department of Internal Medicine, Creighton University School of Medicine.",
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"mesh_terms": "D001323:Autoantibodies; D001327:Autoimmune Diseases; D001379:Azathioprine; D003402:Creatine Kinase; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007166:Immunosuppressive Agents; D008727:Methotrexate; D008875:Middle Aged; D009220:Myositis; D012206:Rhabdomyolysis; D016896:Treatment Outcome",
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"abstract": "A 76-year-old previously healthy Japanese man experienced severe diarrhea (8,000 mL per day) after undergoing laparotomy for small bowel obstruction and was diagnosed with Clostridium difficile infection. Although he developed a maculopapular rash secondary to the systemic absorption of enteral vancomycin (VCM), the patient was successfully treated with the continuous administration of VCM through a long intestinal tube placed in the terminal ileum. This method ensured the reliable delivery of VCM to the colon, while the continuous administration maintained high fecal levels of the drug. This treatment approach is an effective minimally invasive option for patients with severe diarrhea.",
"affiliations": "Department of Surgery, Bellland General Hospital, Japan.",
"authors": "Mizumura|Naoto|N|;Demura|Koichi|K|;Kawasaki|Masayasu|M|;Okumura|Satoshi|S|;Toyoda|Sho|S|;Imagawa|Atsuo|A|;Ogawa|Masao|M|;Ohba|Kazuki|K|;Kameyama|Masao|M|",
"chemical_list": "D000900:Anti-Bacterial Agents; D014640:Vancomycin",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.54.4026",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "54(12)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D000285:Administration, Rectal; D000368:Aged; D000900:Anti-Bacterial Agents; D044466:Asians; D016360:Clostridioides difficile; D003967:Diarrhea; D004761:Enterocolitis, Pseudomembranous; D005243:Feces; D006801:Humans; D008297:Male; D016896:Treatment Outcome; D014640:Vancomycin",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1559-62",
"pmc": null,
"pmid": "26073250",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Continuous Administration of Vancomycin through a Long Intestinal Tube for Clostridium difficile Infection.",
"title_normalized": "continuous administration of vancomycin through a long intestinal tube for clostridium difficile infection"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2015-02096",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "VANCOMYCIN"
},
"drugadditional... |
{
"abstract": "Data on prescribing patterns of antiepileptic drugs (AEDs) to older adult inpatients are limited.\n\n\n\nTo assess changes in prescribing patterns of AEDs to older adult inpatients with late-onset epilepsy between 2009-2010 and 2015-2019, and to interpret any unexpected patterns over the 2015-2019 period.\n\n\n\nPatients aged ≥60 years with late-onset epilepsy from a tertiary center were selected. Demographic data, seizure characteristics and etiology, comorbidities, and comedications were analyzed, in addition to prescription regimens of inpatients taking AEDs to treat epilepsy. AED regimens were categorized into two groups: group 1 included appropriate AEDs (carbamazepine, oxcarbazepine, valproic acid, gabapentin, clobazam, lamotrigine, levetiracetam, topiramate, and lacosamide); and group 2 comprised suboptimal AEDs (phenytoin and phenobarbital). Multivariate logistic regression analysis was performed to identify risk factors for prescription of suboptimal AEDs.\n\n\n\n134 patients were included in the study (mean age: 77.2±9.6 years). A significant reduction in the prescription of suboptimal AEDs (from 73.3 to 51.5%; p<0.001) was found; however, phenytoin remained the most commonly prescribed AED to older adult inpatients. We also found an increase in the prescription of lamotrigine (from 5.5 to 33.6%) and levetiracetam (from 0 to 29.1%) over time. Convulsive status epilepticus (SE) and acute symptomatic seizures associated with remote and progressive etiologies were risk factors for the prescription of suboptimal AEDs.\n\n\n\nPhenytoin was the main suboptimal AED prescribed in our population, and convulsive SE and acute symptomatic seizures associated with some etiologies were independent risk factors for phenytoin prescription. These results suggest ongoing commitment to reducing the prescription of suboptimal AEDs, particularly phenytoin in Brazilian emergence rooms.",
"affiliations": "Hospital São Rafael, Department of Neurology, D'Or Institute for Research and Education (IDOR), Salvador BA, Brazil.;Hospital São Rafael, Department of Neurology, D'Or Institute for Research and Education (IDOR), Salvador BA, Brazil.;Resident of the Department of Neurology, Hospital São Rafael, Monte Tabor Foundation, Italian-Brazilian Center for Health Promotion, Salvador BA, Brazil.;Resident of the Department of Neurology, Hospital São Rafael, Monte Tabor Foundation, Italian-Brazilian Center for Health Promotion, Salvador BA, Brazil.;Hospital São Rafael, Department of Neurology, D'Or Institute for Research and Education (IDOR), Salvador BA, Brazil.;Universidade Federal Fluminense, Department of Neurology, Niterói RJ, Brazil.",
"authors": "Assis|Telma|T|0000-0002-9943-3396;Bacellar|Aroldo|A|0000-0001-8452-0932;CÔrtes|Luan|L|0000-0001-8465-1289;Santana|Silas|S|0000-0001-8291-8445;Costa|Gersonita|G|0000-0002-6715-8035;Nascimento|Osvaldo|O|0000-0003-3516-485X",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D010672:Phenytoin",
"country": "Brazil",
"delete": false,
"doi": "10.1590/0004-282X-anp-2020-0012",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-282X",
"issue": "79(1)",
"journal": "Arquivos de neuro-psiquiatria",
"keywords": null,
"medline_ta": "Arq Neuropsiquiatr",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000927:Anticonvulsants; D001938:Brazil; D006801:Humans; D007297:Inpatients; D000077287:Levetiracetam; D010672:Phenytoin",
"nlm_unique_id": "0125444",
"other_id": null,
"pages": "22-29",
"pmc": null,
"pmid": "33656108",
"pubdate": "2021-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Trends in prescribing patterns of antiepileptic drugs among older adult inpatients in a Brazilian tertiary center.",
"title_normalized": "trends in prescribing patterns of antiepileptic drugs among older adult inpatients in a brazilian tertiary center"
} | [
{
"companynumb": "BR-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-303001",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
},
"druga... |
{
"abstract": "Congenital tuberculosis is a rare disease, especially in non-endemic countries. We present a preterm infant who developed congenital tuberculosis in a neonatal intensive care unit (NICU). The male patient, weighing 1140 g was born by cesarean section at 26 weeks gestation. The baby's respiratory condition suddenly deteriorated at 18 days old, and he was diagnosed with congenital tuberculosis after Gram stain revealed \"ghost bacilli\" in his tracheal aspirate. The mother, who was born in an endemic country, had fever with unknown cause during labor and was diagnosed with miliary tuberculosis after the infant was diagnosed. Both were successfully treated for tuberculosis with a four-drug regimen. The genotyping profiles of Mycobacterium tuberculosis were identical in both mother and baby based on variable number of tandem repeat (VNTR) analysis. The lineage was considered to be East-African Indian. To prevent nosocomial infection in the NICU, 23 potentially exposed infants received isoniazid for 2 months. Two infants showed a transient liver enzyme elevation that seemed to be due to isoniazid. For 10 months after the incident, there were no infants and medical staff who developed tuberculosis. Although the incidence of tuberculosis has steadily decreased in Japan, the percentage of foreign-born individuals has increased yearly, especially those of reproductive age. The evaluation of active tuberculosis should be considered in pregnant women with unexplained fever, history of tuberculosis, or emigration from high-burden areas.",
"affiliations": "Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan. Electronic address: tamura-tym@umin.ac.jp.;Department of Clinical Infectious Diseases, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan; Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Clinical Infectious Diseases, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Clinical Infectious Diseases, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Bacteriology, Toyama Institute of Health, 17-1 Nakataikoyama, Imizu, Toyama, 939-0363, Japan.;Department of Bacteriology, Toyama Institute of Health, 17-1 Nakataikoyama, Imizu, Toyama, 939-0363, Japan.;Department of Mycobacterium Reference and Research, The Research Institute of Tuberculosis, 3-1-24 Matsuyama, Kiyose, Tokyo, 204-0022, Japan.;Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Department of Obstetrics and Gynecology, University of Toyama, 2630 Sugitani, Toyama, 930-0194, Japan.;Division of Neonatology, Maternal and Perinatal Center, Toyama University Hospital, 2630 Sugitani, Toyama, 930-0194, Japan.",
"authors": "Tamura|Kentaro|K|;Kawasuji|Hitoshi|H|;Tachi|Sayaka|S|;Kawasaki|Yukako|Y|;Nagaoka|Mitsuhide|M|;Makimoto|Masami|M|;Sakamaki|Ippei|I|;Yamamoto|Yoshihiro|Y|;Kanatani|Junichi|J|;Isobe|Junko|J|;Mitarai|Satoshi|S|;Yoneda|Noriko|N|;Yoneda|Satoshi|S|;Saito|Shigeru|S|;Yoshida|Taketoshi|T|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.03.003",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(9)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Congenital tuberculosis; Neonatal intensive care unit; Nosocomial infection; Preterm infant",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D003428:Cross Infection; D005260:Female; D006801:Humans; D062071:Infant, Extremely Premature; D007231:Infant, Newborn; D007232:Infant, Newborn, Diseases; D007363:Intensive Care Units, Neonatal; D007538:Isoniazid; D007564:Japan; D008297:Male; D009169:Mycobacterium tuberculosis; D014391:Tuberculosis, Miliary; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "727-730",
"pmc": null,
"pmid": "30910506",
"pubdate": "2019-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Congenital tuberculosis in an extremely preterm infant and prevention of nosocomial infection.",
"title_normalized": "congenital tuberculosis in an extremely preterm infant and prevention of nosocomial infection"
} | [
{
"companynumb": "PHHY2019JP201525",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ETHAMBUTOL HYDROCHLORIDE"
},
"drugadditional": "1",
... |
{
"abstract": "The ability to assess tumor biology is a benefit of molecular imaging with (18)F-FDG PET/CT, which performs better than anatomic imaging in evaluating malignancies. We present an unusual case of fatal dermatofibrosarcoma protuberans, a usually indolent entity for which high-grade (18)F-FDG uptake was predictive of an aggressive clinical course unabated by tyrosine kinase inhibitor imatinib mesylate, to which the patient showed a poor response.",
"affiliations": "Radiation Medicine Centre, Bhabha Atomic Research Centre, Tata Memorial Hospital Annexe, Mumbai, India; and drsanb@yahoo.com.;Solapur Cancer Center, Solapur, India.",
"authors": "Basu|Sandip|S|;Goliwale|Fahim|F|",
"chemical_list": "D019788:Fluorodeoxyglucose F18",
"country": "United States",
"delete": false,
"doi": "10.2967/jnmt.115.163212",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0091-4916",
"issue": "44(2)",
"journal": "Journal of nuclear medicine technology",
"keywords": "FDG PET-CT; dermatofibrosarcoma protuberans; tumor biology",
"medline_ta": "J Nucl Med Technol",
"mesh_terms": "D018223:Dermatofibrosarcoma; D019788:Fluorodeoxyglucose F18; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D000072078:Positron Emission Tomography Computed Tomography; D016896:Treatment Outcome",
"nlm_unique_id": "0430303",
"other_id": null,
"pages": "88-9",
"pmc": null,
"pmid": "26338485",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "18F-FDG PET/CT Prediction of an Aggressive Clinical Course for Dermatofibrosarcoma Protuberans.",
"title_normalized": "18f fdg pet ct prediction of an aggressive clinical course for dermatofibrosarcoma protuberans"
} | [
{
"companynumb": "PHHY2016IN101962",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "IMATINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "The most common cause of persistent hypoglycemia in the neonatal period is hyperinsulinism. Severe, refractory hypoglycemia resulting from hyperinsulinism can lead to significant brain injury and permanent cognitive disability. Diazoxide is the first-line and only US Food and Drug Administration-approved, pharmacologic treatment for refractory hyperinsulinism. In recent years, the use of diazoxide in neonates with persistent hyperinsulinemic hypoglycemia has increased in the United States. Known adverse effects of diazoxide include fluid retention, hypertrichosis, neutropenia, thrombocytopenia, and more recently, pulmonary hypertension. It is currently unknown if diazoxide exposure is associated with an increased risk of necrotizing enterocolitis (NEC) in neonates. We reviewed the cases of 24 patients in a level IV NICU at Massachusetts General Hospital who received diazoxide over 12 years (April 2006-April 2018). All 24 patients received enteral diazoxide for refractory hyperinsulinemic hypoglycemia. A total of 5 patients developed NEC after initiation of diazoxide based on clinical and radiographic findings, corresponding to 20% of infants exposed to diazoxide. This is above our baseline incidence of NEC (1% for all inborn infants and 6% for all inborn very low birth weight infants). More research and monitoring are necessary to characterize the potential risk of NEC associated with the use of diazoxide in the neonatal period.",
"affiliations": "Division of Neonatology and Newborn Medicine, Department of Pediatrics, and.;Division of Neonatology and Newborn Medicine, Department of Pediatrics, and.;Division of Neonatology and Newborn Medicine, Department of Pediatrics, and.;Department of Pharmacy, Massachusetts General Hospital, Boston, Massachusetts; and.;Division of Neonatology and Newborn Medicine, Department of Pediatrics, and.;Division of Neonatology and Newborn Medicine, Department of Pediatrics, and.;Division of Neonatology and Newborn Medicine, Department of Pediatrics, and jmatute@mgh.harvard.edu.",
"authors": "Keyes|Madeline L|ML|;Healy|Helen|H|;Sparger|Katherine A|KA|;Orth|Lucas E|LE|;Geha|Mayya|M|;Roumiantsev|Sergei|S|;Matute|Juan D|JD|",
"chemical_list": "D003981:Diazoxide",
"country": "United States",
"delete": false,
"doi": "10.1542/peds.2019-3202",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0031-4005",
"issue": "147(2)",
"journal": "Pediatrics",
"keywords": null,
"medline_ta": "Pediatrics",
"mesh_terms": "D044903:Congenital Hyperinsulinism; D003981:Diazoxide; D020345:Enterocolitis, Necrotizing; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D007234:Infant, Premature; D007235:Infant, Premature, Diseases; D008297:Male; D012189:Retrospective Studies; D012307:Risk Factors",
"nlm_unique_id": "0376422",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33483452",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "23594884;29385640;17179930;30246418;31413952;32008132;18534621;27910218;30115546;29406007;31235383;26316429;14715916;18059080;30889588;28984754;30247666;26608306;32161713;24720579;21877999;30206345;27866661;19558634;25957977;23730298;20563830",
"title": "Necrotizing Enterocolitis in Neonates With Hyperinsulinemic Hypoglycemia Treated With Diazoxide.",
"title_normalized": "necrotizing enterocolitis in neonates with hyperinsulinemic hypoglycemia treated with diazoxide"
} | [
{
"companynumb": "US-TEVA-2021-US-1938779",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DIAZOXIDE"
},
"drugadditional": null,
... |
{
"abstract": "Recent trials in adult PAH revealed the efficacy of ambrisentan. However, in children with PAH, the clinical safety and pharmacokinetics of ambrisentan has not been well studied. Our aim was to investigate the clinical safety, pharmacokinetics, tolerability, and efficacy of endothelin receptor antagonist therapy with ambrisentan in children with pulmonary arterial hypertension (PAH). This retrospective cohort study provides clinical data from pediatric patients with PAH receiving ambrisentan as add-on therapy or transition from bosentan. Safety included evaluation of adverse events including aminotransferase abnormalities. The clinical impact was evaluated by improvement from baseline in clinical variables. A total of 38 pediatric patients with PAH received ambrisentan. Fifteen of 38 patients were switched from bosentan to ambrisentan. The remaining 23 children were treated with ambrisentan as an add-on therapy due to disease progression. In both transition and add-on cases, mean pulmonary artery pressure significantly improved (transition; 55 ± 18 vs. 45 ± 20 mmHg, n = 13, P = 0.04, add-on; 52 ± 17 vs. 45 ± 19 mmHg, n = 13, P = 0.03) during the follow-up. World Health Organization functional class improved in 31% of patients, but one patient required an atrial septostomy due to disease progression during the follow-up period (median, range; 20, 4-44 months). Five patients (13%) discontinued ambrisentan due to severe headache, lack of clinical efficacy, or near syncope. Ten patients (26%) had side effects associated with ambrisentan treatment, including nasal congestion, headache, and flushing. However, no patients had aminotransferase abnormalities and there were no deaths after initiation of ambrisentan during follow-up. Pharmacokinetics were evaluated in sixteen children treated with ambrisentan from 2.5 mg to 10.0 mg; the mean peak plasma concentration was 738 ± 452 ng/ml, mean time to peak plasma concentration was 3.2 ± 2.1 hours, and mean area under the curve plasma concentration was 6657 ± 4246 ng·hour/ml. In conclusion, initial experience with ambrisentan in children suggests that treatment is safe with similar pharmacokinetics to those in adults and may improve PAH in some children.",
"affiliations": "Pediatric Cardiology, University of Colorado School of Medicine, Children's Hospital, Aurora, CO 80045, USA. tekeshin0621@msn.com",
"authors": "Takatsuki|Shinichi|S|;Rosenzweig|Erika B|EB|;Zuckerman|Warren|W|;Brady|Daniela|D|;Calderbank|Michelle|M|;Ivy|D Dunbar|DD|",
"chemical_list": "D000959:Antihypertensive Agents; D010666:Phenylpropionates; D011724:Pyridazines; D013449:Sulfonamides; C467894:ambrisentan; D000077300:Bosentan",
"country": "United States",
"delete": false,
"doi": "10.1002/ppul.22555",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1099-0496",
"issue": "48(1)",
"journal": "Pediatric pulmonology",
"keywords": null,
"medline_ta": "Pediatr Pulmonol",
"mesh_terms": "D000293:Adolescent; D000959:Antihypertensive Agents; D000077300:Bosentan; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D065627:Familial Primary Pulmonary Hypertension; D005260:Female; D006801:Humans; D006976:Hypertension, Pulmonary; D008297:Male; D010666:Phenylpropionates; D011724:Pyridazines; D012189:Retrospective Studies; D013449:Sulfonamides",
"nlm_unique_id": "8510590",
"other_id": null,
"pages": "27-34",
"pmc": null,
"pmid": "22511577",
"pubdate": "2013-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "14736539;8497283;18506008;11907289;20142023;19552747;8176102;20705798;19804142;18832294;15568889;20002090;18562303;2451132;15194180;7788905;19601701;16053970;18305126;21371683;18040672",
"title": "Clinical safety, pharmacokinetics, and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension.",
"title_normalized": "clinical safety pharmacokinetics and efficacy of ambrisentan therapy in children with pulmonary arterial hypertension"
} | [
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-321072",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AMBRISENTAN"
},
"dru... |
{
"abstract": "A 39-year-old woman underwent partial mastectomy with sentinel lymph node biopsy for right triple negative breast cancer(T2N0M0, Stage ⅡA). Six months later, ipsilateral breast tumor recurrence(IBTR)was observed and paclitaxel plus bevacizumab therapy was started, but anaphylactoid symptoms appeared and the patient was discontinued. Subsequently, eribulin was started, but the IBTR was increased ineffectively. At that point, IBTR had progressed, apparently unresectable, with no distant metastases. We predicted from the patient's background that the patient may be associated with BRCA1 gene mutation and was sensitive to the platinum salts. Carboplatin plus gemcitabine was selected and 6 courses were performed. After the 6 courses, the IBTR were remarkably reduced and resectable, and mastectomy with axillary lymph node dissection were performed. One year after the operation, contralateral breast cancer develop and found to be hereditary breast and ovarian cancer syndrome (HBOC) by Genetic test. About 6 years have passed since local recurrence, but no distant metastases have been observed.",
"affiliations": "Dept. of Breast Surgery, Tokyo Saiseikai Central Hospital.",
"authors": "Sato|Takanobu|T|;Kouno|Tsutomu|T|;Hirose|Shigemichi|S|;Oikawa|Haruna|H|;Machino|Chiaki|C|;Funakoshi|Shinsuke|S|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "47(13)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D016190:Carboplatin; D003841:Deoxycytidine; D005260:Female; D006801:Humans; D008408:Mastectomy; D015412:Mastectomy, Segmental; D009364:Neoplasm Recurrence, Local",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "1747-1749",
"pmc": null,
"pmid": "33468816",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Ipsilateral Breast Tumor Recurrence(IBTR)after Breast-Conserving Surgery Which Successfully Resected after Chemotherapy Using Carboplatin plus Gemcitabine.",
"title_normalized": "a case of ipsilateral breast tumor recurrence ibtr after breast conserving surgery which successfully resected after chemotherapy using carboplatin plus gemcitabine"
} | [
{
"companynumb": "JP-TEVA-2021-JP-1885407",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "Scleromyxedema is a rare and progressive disease that currently has no standard treatment. Triplet therapy with lenalidomide, bortezomib, and dexamethasone can be an effective therapy for scleromyxedema, especially in patients with refractory or relapsed disease.",
"affiliations": "Department of Medicine University of Arizona Tucson Arizona.;Department of Hematology and Oncology University of Arizona Tucson Arizona.",
"authors": "Win|Hninyee|H|https://orcid.org/0000-0003-3340-3618;Gowin|Krisstina|K|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1002/ccr3.3302",
"fulltext": "\n==== Front\nClin Case Rep\nClin Case Rep\n10.1002/(ISSN)2050-0904\nCCR3\nClinical Case Reports\n2050-0904 John Wiley and Sons Inc. Hoboken \n\n10.1002/ccr3.3302\nCCR33302\nCase Report\nCase Reports\nTreatment of scleromyxedema with lenalidomide, bortezomib and dexamethasone: A case report and review of the literature\nWIN and GOWINWin Hninyee https://orcid.org/0000-0003-3340-3618\n1\n Gowin Krisstina \n2\ngowink@email.arizona.edu \n1 \nDepartment of Medicine\nUniversity of Arizona\nTucson\nArizona\n\n\n2 \nDepartment of Hematology and Oncology\nUniversity of Arizona\nTucson\nArizona\n\n* Correspondence\n\nKrisstina Gowin, 1501 N Campbell Ave, Tucson, AZ 85724.\n\nEmail: gowink@email.arizona.edu\n\n17 9 2020 \n12 2020 \n8 12 10.1002/ccr3.v8.123043 3049\n02 7 2020 28 7 2020 12 8 2020 © 2020 The Authors. Clinical Case Reports published by John Wiley & Sons LtdThis 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.Abstract\nScleromyxedema is a rare and progressive disease that currently has no standard treatment. Triplet therapy with lenalidomide, bortezomib, and dexamethasone can be an effective therapy for scleromyxedema, especially in patients with refractory or relapsed disease.\n\nScleromyxedema is a rare and progressive disease that currently has no standard treatment. Triplet therapy with lenalidomide, bortezomib, and dexamethasone can be an effective therapy for scleromyxedema, especially in patients with refractory or relapsed disease.\n\n\n\nbortezomiblenalidomideparaproteinemiaplasma cellsscleromyxedematreatment source-schema-version-number2.0cover-dateDecember 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.6 mode:remove_FC converted:21.12.2020\n\n\nWin \nH \n, \nGowin \nK \n. Treatment of scleromyxedema with lenalidomide, bortezomib and dexamethasone: A case report and review of the literature\n. Clin Case Rep . 2020 ;8 :3043 –3049\n. 10.1002/ccr3.3302\n==== Body\n1 INTRODUCTION\nScleromyxedema currently has no standard treatment. Triplet combination chemotherapy, lenalidomide, bortezomib, and dexamethasone (RVD), is standard in plasma cell disorders, such as multiple myeloma. However, literature supporting its use in scleromyxedema is limited. We report a scleromyxedema patient who had complete clinical and very good hematologic response with RVD therapy.\n\nScleromyxedema is a rare disease that affects middle‐aged adults (30‐80 years) with similar incidence rates in males and females. The diagnostic criteria require a generalized papular and sclerodermoid eruption, histologic triad of mucin deposition and fibroblast proliferation, monoclonal gammopathy, and the absence of thyroid disease.\n1\n The most common monoclonal gammopathy is IgG with lambda light chains, observed in more than 80% of the patients.\n2\n Exact prevalence and incidence of scleromyxedema are unknown but as of 2009, 150 cases of patients have been reported.\n3\n\n\n\nScleromyxedema patients initially present with a gradual progression of a diffuse papular eruption over months, usually involving the hands and face.\n4\n Advanced disease can be widespread, progressive, and unpredictable. Systemic symptoms associated with scleromyxedema are peripheral neuropathy, involvement of joints, lung involvement with dyspnea in the form of restrictive or obstructive lung involvement, dysphagia, \n1\n and dermato‐neuro syndrome. Dermato‐neuro syndrome is a rare and sometimes fatal neurologic manifestation that can lead to fever, convulsions, and coma.\n5\n\n\n\nSkin biopsy is the mainstay for diagnosis of scleromyxedema. Histologically, scleromyxedema is characterized by a triad of microscopic features—a diffuse deposit of mucin in the upper and mid‐reticular dermis, an increase in collagen deposition and a marked proliferation of irregularly arranged fibroblasts.\n6\n Evaluation for monoclonal gammopathy workup includes serum protein immunoelectrophoresis and immunofixation, urine protein immunoelectrophoresis and immunofixation, serum free light chain assay, and quantitation of immunoglobulins. Additional laboratories such as thyroid studies, rheumatologic studies, complete blood count, comprehensive metabolic panel, muscle enzymes, and urinalysis are routinely completed to evaluate for systemic disease, and to rule out thyroid dysfunction. Additional imaging and tests may be indicated for patients with extracutaneous symptoms depending on the specific organ involvement.\n\nThe course of scleromyxedema is unpredictable, especially due to the variable response to treatment and the high relapse rate after cessation of treatment. The overall survival rate at 3 years was reported to be 97% in a recent retrospective study,\n7\n which is an improvement compared to 76.2% in a previous study.\n8\n\n\n\nTreatment of scleromyxedema has been challenging due to the rarity and unclear pathogenesis of the disease. Currently, there are no randomized trials to compare different therapies. Treatments that have been frequently used to treat scleromyxedema include intravenous immunoglobulin (IVIG), steroids, thalidomide, autologous stem cell transplantation, and plasma cell‐directed therapies. Treatment data have been largely limited to case reports and case series with variable success for initial and refractory disease. We report a case of scleromyxedema that responded to treatment with lenalidomide (R), bortezomib (V), and dexamethasone (D).\n\n2 CLINICAL CASE\nA 73‐year‐old Caucasian man first developed redness on his bilateral volar forearms. He was prescribed topical steroid preparations for his skin lesions by a dermatologist which did not help. He subsequently developed concurrent bilateral upper extremity neuropathy and finger pad tenderness. He was evaluated by a neurologist for peripheral neuropathy; serum and urine protein electrophoresis were ordered. Laboratory evaluation revealed a small monoclonal protein spike measuring 0.3 g/dL with IgG lambda immunofixation. His skin findings progressed to woody firmness of the nose and extremities in conjunction with dome‐shaped papules on the hands, digits, and upper back. Bone marrow biopsy was performed which revealed normal lineage hematopoiesis with no evidence of plasma cell dyscrasia. Flow cytometry revealed no clonal abnormality. His other workup included high normal hemoglobin likely secondary to testosterone supplementation, normal renal function, normal calcium, no evidence of bony lesions on skeletal survey, and free light chain ratio of 1.1. His thyroid function was normal and he was on exogenous levothyroxine. He had multiple dermatologic biopsies exhibiting classical features consistent with scleromyxedema including mucin production. He had trials of both methotrexate and systemic prednisone with little effect. His monoprotein cleared temporarily on laboratories drawn about one month prior to his initial hematology clinic visit, most likely due to methotrexate and/or prednisone exposure. At the time of presentation to the University of Arizona Cancer Center hematology clinic, he was only on single‐agent prednisone. On the laboratories drawn on the day of his initial visit, his M protein was 0.3 g/dL. He also complained of mild dysphagia and abnormal bowel movements with bloating.\n\nInitially, he was continued on Prednisone 40 mg daily, with a plan to start on IVIG 2 g/kg monthly. However, patient's health insurance did not provide coverage for the IVIG at the time. Due to this, the patient was instead started on bortezomib 1.3 mg/m2 once a week for one cycle (3 weeks). After the patient complained of worsening peripheral neuropathy of his hands after one cycle, bortezomib was held. Once insurance approval was obtained, the patient received a trial of IVIG but he reported worsening erythema in his extremities. He was then started on triple therapy with RVD Lite (lenalidomide 15 mg daily days 1‐21, bortezomib 1.3 mg/m2 weekly days 1, 8, 15, and 22 and dexamethasone 40 mg weekly on 35‐day treatment cycle) with intent on treating the underlying clonal disease causing his cutaneous manifestations. Prednisone was tapered and switched to dexamethasone. After one cycle of RVD Lite, patient's cutaneous symptoms and dysphagia improved. His M protein remained detectable at 0.3 g/dL. For the second cycle of RVD Lite, lenalidomide was decreased to 10 mg due to complaint of fatigue. After 4 cycles of modified RVD Lite, bortezomib was stopped and only lenalidomide and dexamethasone were continued. Dexamethasone was decreased to 32 mg weekly due to concerns of chronic steroid use and feeling irritable on his off days and was eventually tapered off over 7 weeks. M protein of 0.1 g/dL reappeared at the subsequent laboratory after stopping dexamethasone. Patient was restarted back on Prednisone 5 mg daily after he complained of increased fatigue after stopping dexamethasone. His laboratory draws have fluctuated between M protein of 0.1 g/dL and no M protein despite being on the same regimen: Prednisone 5 mg daily and lenalidomide 10 mg daily days 1‐21. Although his fatigue and neuropathic pain remains, his skin findings and dysphagia which resolved after starting RVD Lite has not returned.\n\n3 DISCUSSION\nEffective treatment for scleromyxedema has been difficult to establish due to unclear pathogenesis of the disease. The role of paraproteins in the stimulation of fibroblasts and overproduction of mucin is not definitive. While serums from scleromyxedema patients have been shown to induce proliferation of fibroblasts in vitro,\n9\n hyaluronic acid and prostaglandin E,\n10\n the isolated paraproteins did not.\n9\n These studies support case reports which have noted paraprotein levels do not correlate with disease outcomes, including our case. Our patient's M protein level fluctuated after tapering off dexamethasone even though he remained in clinical remission. A leading hypothesis is that circulating cytokines such as interleukin 1, tumor necrosis factor, and transforming growth factor‐B play a central role in the pathogenesis of scleromyxedema. One recent study found scleromyxedema patients have abnormally high interleukin‐4 secretion, a profibrotic cytokine.\n11\n Furthermore, the patients also had decreased levels of interferon‐gamma cytokine, which are known to inhibit proliferation and extracellular matrix production in fibroblasts.\n12\n The authors believe a chronic immune system activation against an unknown target antigen may be responsible for these changes.\n11\n However, a big limitation of this study is most of the patients were on therapy at the time of blood collection which may have altered relevant biological signals. There have also been two cases of scleromyxedema that developed after breast silicone implantation and injections of dermal fillers including hyaluronic acid, suggesting the disease can be triggered by adjuvants.\n13\n, \n14\n Our patient may have improved with bortezomib and lenalidomide therapy as both are speculated to have immunomodulatory properties in addition to addressing plasma cell clones.\n15\n, \n16\n There is a definite need for further studies with treatment‐naïve patients to get a more accurate and clear pathophysiology behind scleromyxedema.\n\nWe reviewed published literature on treatment of scleromyxedema with an emphasis on plasma cell‐directed therapies. In the past, melphalan was often considered first‐line treatment for scleromyxedema but has since been discouraged due to high risk of death (over 30%) related to hematologic malignancies and septic complications.\n17\n Recently, IVIG is recommended as a first‐line treatment in scleromyxedema in multiple case reports due to its immunomodulatory potential and low incidence of severe side effects.\n7\n, \n18\n, \n19\n It has been found to be effective for both cutaneous and extracutaneous symptoms. IVIG is hypothesized to have antifibrotic properties through modulation of cytokine production and it may have a role in blocking an unknown circulating factor.\n18\n, \n20\n Frequent relapses after stopping treatment are common and long‐term IVIG treatment with maintenance infusions is necessary to control the disease. However, as evident in our case, there may be delay in initiation of treatment with IVIG due to lengthy insurance approval process, high cost and, time‐consuming administration. These treatment barriers are significant especially in the setting of requiring long‐term maintenance to remain in remission.\n7\n\n\n\nOther treatments which have reported success with scleromyxedema include thalidomide \n21\n, \n22\n, \n23\n, \n24\n and autologous stem cell transplantation (ASCT).\n25\n Thalidomide's mechanism of action in treatment of the disease is not clear but is thought to have antiangiogenic properties that block fibroblast growth.\n20\n Thalidomide is teratogenic and can cause peripheral neuropathy. It is also known to cause prothrombic activity.\n26\n Due to our patient's complaint of peripheral neuropathy on initial presentation to our clinic, we opted for lenalidomide which is a derivative of thalidomide with a more favorable toxicity profile. The first case of treating refractory scleromyxedema with ASCT was reported in 2001.\n25\n Since 2001, 17 patients have been treated with ASCT; 50% of the patients had complete remissions of all clinical symptoms, including serum paraprotein and 29% had partial remission.\n27\n Only 12% of patients had persistent complete remission at a median follow‐up of over 40 months. It is suggested that pre‐induction of thalidomide and dexamethasone prior to ASCT may improve the long‐term outcome.\n27\n We did not pursue ASCT for our patient due to his advanced age.\n\nPrior to presentation to our hematology clinic, our patient was taking oral prednisone 40 mg. There are case reports (Table 1) of successful treatment of scleromyxedema with prednisone or dexamethasone alone.\n28,29\n It is hypothesized dexamethasone pulse dose can rapidly suppress inflammatory conditions and it can target both the paraprotein production and hyperactive fibroblasts through its immunosuppressive and anti‐fibroblast effects.\n30\n, \n31\n Due to its relatively safe side effects profile compared to alkylating agents, corticosteroid therapy can be considered as a first‐line option. However, the rate of treatment success with steroids alone is low. On review of 25 patients with scleromyxedema, two patients received steroids alone and had treatment failure.\n8\n Similarly, a retrospective study of 33 scleromyxedema patients showed corticosteroids alone (0.75 mg/kg/day of equivalent prednisone) was successful in only 1 patient out of 3 total.\n7\n This was similar to our patient as he had treatment failure with oral prednisone alone. Due to its ineffectiveness alone, glucocorticoids are more often used in conjunction with other treatment regimens such as melphalan, methotrexate, thalidomide, hydroxychloroquine, cyclophosphamide, and bortezomib.\n8\n\n\n\nTable 1 Bortezomib, lenalidomide, and dexamethasone use in scleromyxedema: A Literature Review\n\nAuthor\tTitle\tOutcome\tLimitations\t\n\nHorn, K, B. 2004\n29\n\n\n\n\n\tA complete and durable clinical response to high‐dose dexamethasone in a patient with scleromyxedema\t\n▪ A 63‐year‐old man with scleromyxedema limited to the skin and IgG lambda monoclonal protein received 3 consecutive weekly cycles each month of oral high‐dose dexamethasone 40 mg once daily for four days (total: 160 mg/week) for four months. He remained on oral dexamethasone 40 mg once daily for maintenance for four days every month.\n\n▪ His cutaneous symptoms resolved and his IgG paraproteinemia disappeared for over one year, suggesting that dexamethasone therapy can target both paraproteinemia and SM.\n\n▪ Case report argues that corticosteroid can be a good, potential first‐line therapy as it is well tolerated while alkylating agents with significant toxicities should be reserved for refractory scleromyxedema.\n\n\n\t\n▪ Small sample size\n\n▪ Due to the short follow‐up time, it is uncertain how durable the therapy is\n\n▪ Article did not mention the side effects of long‐term steroids\n\n▪ Did not address appropriate duration for maintenance dexamethasone\n\n\n\t\nKreuter, A. 2005\n28\n\n\tHigh‐dose dexamethasone in scleromyxedema: report of 2 additional cases\t\n▪ Case report of two women (48 and 55 years old) with scleromyxedema who have failed treatment with methotrexate and extracorporeal photopheresis. The same oral dexamethasone regimen reported by Horn was used.\n\n▪ While high‐dose dexamethasone did improve their skin findings, IgG paraprotein did not disappear during therapy\n\n▪ Case report emphasizes that long‐term follow‐up is mandatory for recurrence of disease especially as underlying monoclonal gammopathy cannot be eliminated\n\n\n\t\n▪ Similar limitations as above\n\n\n\t\nAtaergin, S. 2008\n32\n\n\tTransient efficacy of double high‐dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema\t\n▪ A 38‐year‐old man with IgG lambda monoclonal gammopathy and scleromyxedema whose papular mucinosis did not resolve despite treatment with oral cyclophosphamide, methylprednisolone, interferon‐alpha, autologous stem cell transplantation (ASCT), immunoglobulin and thalidomide. A second ASCT was performed to consolidate the efficiency of the first transplant and only after the second transplant, patient's IgG level had returned to normal and papular lesions regressed.\n\n▪ Thalidomide (100 mg/day) and low‐dose bortezomib 1.5 mg/day on days 1,4,8 and 11 every 3 weeks for 6 cycles was used as maintenance therapy\n\n▪ Patient had transient remission of paraproteinemia and skin lesions that lasted 30 months\n\n▪ Highlights need for durable and curative therapies\n\n\n\t\n▪ Uncertain of bortezomib's efficacy as a maintenance therapy as it was stopped at 6 cycles (3 weeks each)\n\n▪ Did not address tolerability or side effects of each treatment modality\n\n\n\t\nMigkou, M. 2011\n15\n\n\tResponse to Bortezomib of a patient with scleromyxedema refractory to other therapies\t\n▪ 70‐year‐old man with scleromyxedema and monoclonal IgG lambda gammopathy was initially treated with intravenous methotrexate, oral melphalan and low‐dose methylprednisolone with no improvement of his skin lesions or reduction of his M protein. Lenalidomide/dexamethasone was trialed but symptoms worsened.\n\n▪ Skin lesions only resolved with 8 cycles of bortezomib and dexamethasone. There was also reduction of M protein levels but the hematologic response to bortezomib was modest.\n\n\n\t\n▪ Uncertain whether symptoms returned due to short follow‐up time\n\n▪ Did not mention possible side effects of Bortezomib\n\n\n\t\nCanueto, J. 2012\n33\n\n\tThe combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights\t\n▪ 29‐year‐old woman with scleromyxedema who relapsed after melphalan and autologous peripheral blood stem cell transplantation achieve complete response with 7 courses of 21 day regimen of bortezomib (1.3 mg/m2, days 1,4,8, and 11) and dexamethasone (20 mg/d, days 1,2,4,5,8,9,11 and 12).\n\n▪ Skin lesions responded before M component modifications, suggesting paraprotein is not the pathogenic substance\n\n\n\t\n▪ Small sample size\n\n▪ Short follow‐up time (9 months)\n\n\n\t\nBrunet‐Possenti, F. 2013\n16\n\n\tCombination of intravenous immunoglobulins and lenalidomide in the treatment of scleromyxedema\t\n▪ 44‐year‐old man with scleromyxedema and Iambda light chain monoclonal gammopathy failed multiple treatments including hydroxychloroquine, corticosteroid therapy and thalidomide.\n\n▪ Improvement of skin changes after starting on lenalidomide (25 mg per day, 3 weeks a month). Monthly infusions of IVIG (2g/kg) was added and combined treatment led to complete regression of scleromyxedema. Paraproteinemia persisted.\n\n▪ Case report shows that lenalidomide can be used as a maintenance therapy and is better tolerated than thalidomide with less somnolence, constipation and neuropathy\n\n▪ Also shows that IVIG and lenalidomide may have a synergistic effect\n\n\n\t\n▪ Short follow‐up time ‐ around 24 hours after last IVIG administration\n\n\n\t\nMahévas, T. 2020\n7\n\n\tPlasma cell‐directed therapies in monoclonal gammopathy‐associated scleromyxedema\t\n▪ Multicenter French retrospective study of 33 scleromyxedema patients. Patients were defined to have severe scleromyxedema if there was neurological and cardiac involvement\n\n▪ Provided a treatment algorithm for scleromyxedema with IVIG (2 g/kg) every month as a first‐line therapy due to high efficacy and good safety profile with maintenance for at least six months\n\n▪ Recommended plasma cell‐directed therapies such as lenalidomide or bortezomib plus dexamethasone combined with IVIG for IVIG refractory or severe scleromyxedema\n\n▪ Reported first known case of successful treatment with RVD therapy\n\n▪ Found increased levels of TGFß and collagen 1‐a in skin samples ‐ highlights need for prospective studies targeting fibrotic pathways or plasma cell clones to gain insights into pathophysiology of scleromyxedema and to guide therapeutic strategies\n\n▪ Argued that mortality rate of scleromyxedema patients have decreased and this may be due to increase use in IVIG therapies\n\n\n\t\n▪ Does not address difficulties with IVIG treatment although it is recommended as first‐line treatment\n\n▪ Limited sample of patients for skin biopsy (n = 6)\n\n\n\t\nJohn Wiley & Sons, LtdPrior literature has reported bortezomib and lenalidomide used in combination with dexamethasone or IVIG (Table 1) for treatment of scleromyxedema. Bortezomib was first used for refractory scleromyxedema as a maintenance therapy in 2008\n32\n and has found success with dexamethasone in two cases.\n15\n, \n33\n Possible mechanism of bortezomib is thought to be due to the direct apoptotic effects on the plasma cell clone but is speculated to also have an “immunosuppressive” effect.\n15\n Lenalidomide was first used to treat refractory scleromyxedema in 2013. The pathophysiology of lenalidomide is thought to stimulate natural killer cell activity and increase IL‐2 production which enhances T‐cell activity. It is speculated IVIG and lenalidomide may have a synergistic effect as both have antifibrotic properties, present in mouse model.\n34\n Lenalidomide may sustain remission due to its immunomodulatory properties and its tolerability profile compared to thalidomide, especially for patients with neuropathy \n16\n such as ours. A recent retrospective study recommended adding bortezomib and dexamethasone or lenalidomide and dexamethasone to IVIG for patients who have IVIG refractory disease.\n7\n The same study reported the first known case of scleromyxedema patient treated with RVD therapy. The patient had IVIG refractory disease and had treatment failure with IVIG as well as a treatment regimen of bortezomib, cyclophosphamide, and dexamethasone. With RVD therapy, the patient had near complete clinical response and complete hematologic response. The successful responses to RVD therapy of this patient and our patient are encouraging, especially in the treatment of severe, refractory disease.\n\n4 CONCLUSION\nWe have presented a case of successful treatment of scleromyxedema with RVD therapy. After 4 cycles of RVD Lite, our patient had complete clinical and very good hematologic response. Having a new treatment option for severe or refractory scleromyxedema is imperative as the course of the disease is unpredictable and progressive with high relapse rates. Review of literature and the case study show RVD may be an effective triplet therapy for the treatment of scleromyxedema. In contrast to glucocorticoids and IVIG, RVD therapy may represent a more potent therapeutic approach to address underlying plasma cell clone especially in patients with refractory or relapsed disease. Pathophysiology of scleromyxedema remains poorly studied. Priority should be placed on recruiting treatment‐naïve scleromyxedema patients for prospective studies. Patient's blood samples should be collected prior to treatment and be compared to blood samples collected after treatment with agents known to target fibrotic pathways or plasma cell clones. Additional research is needed to better understand the underlying pathophysiology and treatment of this rare disease.\n\nCONFLICT OF INTEREST\nNone declared.\n\nAUTHOR CONTRIBUTIONS\nHW: analyzed the data, performed literature review, and drafted the manuscript. KG: conceived of the study, provided data, supervised, reviewed, and edited the manuscript. All authors read and approved the final manuscript.\n\nETHICAL APPROVAL STATEMENT\nThis case report was conducted in accordance with the Declaration of Helsinki. The collection and evaluation of all protected patient health information was performed in a Health Insurance Portability and Accountability Act (HIPAA)—compliant manner. Informed consent was obtained for publication.\n\nACKNOWLEDGMENTS\nWe would like to thank Ashley Larsen for her assistance in the editing and submission process. Published with written consent of the patient.\n==== Refs\nREFERENCES\n1 \n\nRongioletti \nF \n, \nRebora \nA \n. Updated classification of papular mucinosis, lichen myxedematosus, and scleromyxedema\n. J Am Acad Dermatol . 2001 ;44 (2 ):273 ‐281\n.11174386 \n2 \n\nCokonis Georgakis \nCD \n, \nFalasca \nG \n, \nGeorgakis \nA \n, \nHeymann \nWR \n. Scleromyxedema\n. Clin Dermatol . 2006 ;24 (6 ):493 ‐497\n.17113967 \n3 \n\nMehta \nV \n, \nBalachandran \nC \n, \nRao \nR \n. Arndt Gottron scleromyxedema: successful response to treatment with steroid minipulse and methotrexate\n. Indian J Dermatol . 2009 ;54 (2 ):193 ‐195\n.20101325 \n4 \n\nHummers \nLK \n. Scleromyxedema\n. Curr Opin Rheumatol . 2014 ;26 (6 ):658 ‐662\n.25215418 \n5 \n\nFleming \nKE \n, \nVirmani \nD \n, \nSutton \nE \n, et al. Scleromyxedema and the dermato‐neuro syndrome: case report and review of the literature\n. J Cutan Pathol . 2012 ;39 (5 ):508 ‐517\n.22515222 \n6 \n\nRongioletti \nF \n, \nSmoller \nBR \n. Clinical and pathological aspects of skin diseases in endocrine, metabolic, nutritional and deposition disease\n. In: New York, NY : Springer ; 2010 : 10.1007/978-1-60761-181-3 \n\n7 \n\nMahevas \nT \n, \nArnulf \nB \n, \nBouaziz \nJD \n, et al. Plasma cell‐directed therapies in monoclonal gammopathy‐associated scleromyxedema\n. Blood . 2020 ;135 (14 ):1101 ‐1110\n.32027747 \n8 \n\nRongioletti \nF \n, \nMerlo \nG \n, \nCinotti \nE \n, et al. Scleromyxedema: a multicenter study of characteristics, comorbidities, course, and therapy in 30 patients\n. J Am Acad Dermatol . 2013 ;69 (1 ):66 ‐72\n.23453242 \n9 \n\nHarper \nRA \n, \nRispler \nJ \n. Lichen myxedematosus serum stimulates human skin fibroblast proliferation\n. Science . 1978 ;199 (4328 ):545 ‐547\n.622555 \n10 \n\nYaron \nM \n, \nYaron \nI \n, \nYust \nI \n, \nBrenner \nS \n. Lichen myxedematosus (scleromyxedema) serum stimulates hyaluronic acid and prostaglandin E production by human fibroblasts\n. J Rheumatol . 1985 ;12 (1 ):171 ‐175\n.3981505 \n11 \n\nKalli \nF \n, \nCioni \nM \n, \nParodi \nA \n, et al. Increased frequency of interleukin‐4 and reduced frequency of interferon‐gamma and IL‐17‐producing CD4+ and CD8+ cells in scleromyxedema\n. J Eur Acad Dermatol Venereol . 2020 ;34 (5 ):1092 ‐1097\n.31912592 \n12 \n\nYuan \nW \n, \nYufit \nT \n, \nLi \nL \n, \nMori \nY \n, \nChen \nSJ \n, \nVarga \nJ \n. Negative modulation of alpha1(I) procollagen gene expression in human skin fibroblasts: transcriptional inhibition by interferon‐gamma\n. J Cell Physiol . 1999 ;179 (1 ):97 ‐108\n.10082137 \n13 \n\nAlijotas‐Reig \nJ \n, \nGarcia‐Gimenez \nV \n, \nLlurba \nE \n, \nVilardell‐Tarres \nM \n. Autoimmune/inflammatory syndrome (ASIA) induced by biomaterials injection other than silicone medical grade\n. Lupus . 2012 ;21 (12 ):1326 ‐1334\n.22952322 \n14 \n\nRongioletti \nF \n, \nCattarini \nG \n, \nSottofattori \nE \n, \nRebora \nA \n. Granulomatous reaction after intradermal injections of hyaluronic acid gel\n. Arch Dermatol . 2003 ;139 (6 ):815 ‐816\n.12810524 \n15 \n\nMigkou \nM \n, \nGkotzamanidou \nM \n, \nTerpos \nE \n, \nDimopoulos \nMA \n, \nKastritis \nE \n. Response to bortezomib of a patient with scleromyxedema refractory to other therapies\n. Leuk Res . 2011 ;35 (11 ):e209 ‐e211\n.21831425 \n16 \n\nBrunet‐Possenti \nF \n, \nHermine \nO \n, \nMarinho \nE \n, \nCrickx \nB \n, \nDescamps \nV \n. Combination of intravenous immunoglobulins and lenalidomide in the treatment of scleromyxedema\n. J Am Acad Dermatol . 2013 ;69 (2 ):319 ‐320\n.23866873 \n17 \n\nDinneen \nAM \n, \nDicken \nCH \n. Scleromyxedema\n. J Am Acad Dermatol . 1995 ;33 (1 ):37 ‐43\n.7601944 \n18 \n\nHoffmann \nJHO \n, \nEnk \nAH \n. High‐dose intravenous immunoglobulin in skin autoimmune disease\n. Front Immunol . 2019 ;10 :1090 .31244821 \n19 \n\nGuarneri \nA \n, \nCioni \nM \n, \nRongioletti \nF \n. High‐dose intravenous immunoglobulin therapy for scleromyxoedema: a prospective open‐label clinical trial using an objective score of clinical evaluation system\n. J Eur Acad Dermatol Venereol . 2017 ;31 (7 ):1157 ‐1160\n.28370513 \n20 \n\nEfthimiou \nP \n, \nBlanco \nM \n. Intravenous gammaglobulin and thalidomide may be an effective therapeutic combination in refractory scleromyxedema: case report and discussion of the literature\n. Semin Arthritis Rheum . 2008 ;38 (3 ):188 ‐194\n.18221985 \n21 \n\nSansbury \nJC \n, \nCocuroccia \nB \n, \nJorizzo \nJL \n, \nGubinelli \nE \n, \nGisondi \nP \n, \nGirolomoni \nG \n. Treatment of recalcitrant scleromyxedema with thalidomide in 3 patients\n. J Am Acad Dermatol . 2004 ;51 (1 ):126 ‐131\n.15243538 \n22 \n\nGuarenti \nI \n, \nSebastiani \nV \n, \nPinto \nG \n, \nde Souza \nPR \n, \nde Almeida \nH \n. Successful treatment of scleromyxedema with oral thalidomide\n. Int J Dermatol . 2013 ;52 (5 ):631 ‐632\n.23231733 \n23 \n\nAmini‐Adle \nM \n, \nThieulent \nN \n, \nDalle \nS \n, \nBalme \nB \n, \nThomas \nL \n. Scleromyxedema: successful treatment with thalidomide in two patients\n. Dermatology . 2007 ;214 (1 ):58 ‐60\n.17191049 \n24 \n\nJacob \nSE \n, \nFien \nS \n, \nKerdel \nFA \n. Scleromyxedema, a positive effect with thalidomide\n. Dermatology . 2006 ;213 (2 ):150 ‐152\n.16902294 \n25 \n\nFeasel \nAM \n, \nDonato \nML \n, \nDuvic \nM \n. Complete remission of scleromyxedema following autologous stem cell transplantation\n. Arch Dermatol . 2001 ;137 (8 ):1071 ‐1072\n.11493100 \n26 \n\nEl Accaoui \nRN \n, \nShamseddeen \nWA \n, \nTaher \nAT \n. Thalidomide and thrombosis. A meta‐analysis\n. Thromb Haemost . 2007 ;97 (6 ):1031 ‐1036\n.17549307 \n27 \n\nBos \nR \n, \nde Waal \nEG \n, \nKuiper \nH \n, \nHazenberg \nBP \n, \nVellenga \nE \n. Thalidomide and dexamethasone followed by autologous stem cell transplantation for scleromyxoedema\n. Rheumatology (Oxford) . 2011 ;50 (10 ):1925 ‐1926\n.21719421 \n28 \n\nKreuter \nA \n, \nAltmeyer \nP \n. High‐dose dexamethasone in scleromyxedema: report of 2 additional cases\n. J Am Acad Dermatol . 2005 ;53 (4 ):739 ‐740\n.16198811 \n29 \n\nHorn \nKB \n, \nHorn \nMA \n, \nSwan \nJ \n, \nSinghal \nS \n, \nGuitart \nJ \n. A complete and durable clinical response to high‐dose dexamethasone in a patient with scleromyxedema\n. J Am Acad Dermatol . 2004 ;51 (2 suppl ):S120 ‐123\n.15280830 \n30 \n\nBarnes \nPJ \n. Anti‐inflammatory actions of glucocorticoids: molecular mechanisms\n. Clin Sci (Lond) . 1998 ;94 (6 ):557 ‐572\n.9854452 \n31 \n\nSilvestri \nM \n, \nSabatini \nF \n, \nScarso \nL \n, \nCordone \nA \n, \nDasic \nG \n, \nRossi \nGA \n. Fluticasone propionate downregulates nasal fibroblast functions involved in airway inflammation and remodeling\n. Int Arch Allergy Immunol . 2002 ;128 (1 ):51 ‐58\n.12037401 \n32 \n\nAtaergin \nS \n, \nArpaci \nF \n, \nDemiriz \nM \n, \nOzet \nA \n. Transient efficacy of double high‐dose chemotherapy and autologous peripheral stem cell transplantation, immunoglobulin, thalidomide, and bortezomib in the treatment of scleromyxedema\n. Am J Clin Dermatol . 2008 ;9 (4 ):271 ‐273\n.18572979 \n33 \n\nCanueto \nJ \n, \nLabrador \nJ \n, \nRoman \nC \n, et al. The combination of bortezomib and dexamethasone is an efficient therapy for relapsed/refractory scleromyxedema: a rare disease with new clinical insights\n. Eur J Haematol . 2012 ;88 (5 ):450 ‐454\n.22404151 \n34 \n\nBlank \nM \n, \nLevy \nY \n, \nAmital \nH \n, \nShoenfeld \nY \n, \nPines \nM \n, \nGenina \nO \n. The role of intravenous immunoglobulin therapy in mediating skin fibrosis in tight skin mice\n. Arthritis Rheum . 2002 ;46 (6 ):1689 ‐1690\n.12115202\n\n",
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"keywords": "bortezomib; lenalidomide; paraproteinemia; plasma cells; scleromyxedema; treatment",
"medline_ta": "Clin Case Rep",
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"title": "Treatment of scleromyxedema with lenalidomide, bortezomib and dexamethasone: A case report and review of the literature.",
"title_normalized": "treatment of scleromyxedema with lenalidomide bortezomib and dexamethasone a case report and review of the literature"
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"abstract": "We are describing a case of an 18-year-old male patient with cytomegalovirus (CMV) associated guillain-barre syndrome (GBS) who presented with an acute onset of generalized weakness and numbness in the extremities, dysphagia, and facial diplegia, followed by respiratory failure, which led to mechanical ventilation. He had positive immunoglobulin G and immunoglobulin M antibodies against CMV, and CMV polymerase chain reaction was positive with <2000 copies of deoxyribonucleic acid. Human immunodeficiency virus test was negative. He received a course of ganciclovir, intravenous immunoglobulin, and plasmapheresis. After improving from acute episode, patient was transferred to a rehabilitation facility for physical and occupational therapy. At the rehabilitation facility, he exhibited signs of acute abdomen with pain in the left upper quadrant secondary to peritonitis from dislodged gastrostomy tube and underwent exploratory laparotomy. During the hospital course he was found to have splenic infarct and colitis on the computed tomography of abdomen. This case showed an immunocompetent young patient with multisystem complications including guillain-barre syndrome (GBS), splenic infarct, hepatitis, and colitis due to CMV.",
"affiliations": "Department of Research, Health East Care System, Saint Paul, Minnesota, USA.;Department of Internal Medicine, Health East Care System, Saint Paul, Minnesota, USA.",
"authors": "Pulivarthi|Swaroopa|S|;Gurram|Murali Krishna|MK|",
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"doi": "10.4103/0976-3147.127876",
"fulltext": "\n==== Front\nJ Neurosci Rural PractJ Neurosci Rural PractJNRPJournal of Neurosciences in Rural Practice0976-31470976-3155Medknow Publications & Media Pvt Ltd India JNRP-5-5910.4103/0976-3147.127876Case ReportA young patient with multisystem complications after cytomegalovirus infection Pulivarthi Swaroopa Gurram Murali Krishna 1Department of Research, Health East Care System, Saint Paul, Minnesota, USA1 Department of Internal Medicine, Health East Care System, Saint Paul, Minnesota, USAAddress for correspondence: Dr. Murali Krishna Gurram, 45, 10th Street West, Saint Paul, Minnesota 55102, USA. E-mail: gmk_doctor@yahoo.co.ukJan-Mar 2014 5 1 59 62 Copyright: © Journal of Neurosciences in Rural Practice2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We are describing a case of an 18-year-old male patient with cytomegalovirus (CMV) associated guillain-barre syndrome (GBS) who presented with an acute onset of generalized weakness and numbness in the extremities, dysphagia, and facial diplegia, followed by respiratory failure, which led to mechanical ventilation. He had positive immunoglobulin G and immunoglobulin M antibodies against CMV, and CMV polymerase chain reaction was positive with <2000 copies of deoxyribonucleic acid. Human immunodeficiency virus test was negative. He received a course of ganciclovir, intravenous immunoglobulin, and plasmapheresis. After improving from acute episode, patient was transferred to a rehabilitation facility for physical and occupational therapy. At the rehabilitation facility, he exhibited signs of acute abdomen with pain in the left upper quadrant secondary to peritonitis from dislodged gastrostomy tube and underwent exploratory laparotomy. During the hospital course he was found to have splenic infarct and colitis on the computed tomography of abdomen. This case showed an immunocompetent young patient with multisystem complications including guillain-barre syndrome (GBS), splenic infarct, hepatitis, and colitis due to CMV.\n\nCytomegalovirusguillain-barre syndromehepatitissplenic infarct\n==== Body\nIntroduction\nCytomegalovirus (CMV) associated guillain-barre syndrome (GBS) accounts up to 15% of all GBS cases.[1] The clinical manifestations of GBS associated with CMV occur often after respiratory tract symptoms, preferentially affects young women (<35 years), and are frequently associated with sensory loss.[2] The clinical presentation of acute CMV infection include infectious mononucleosis syndrome (i.e., fever, rash, sore throat, atypical lymphocytes in the peripheral blood, monocytosis, thrombocytopenia, and elevated liver enzymes), pneumonitis, retinitis, colitis, and any other organ involvement.[345] CMV infection may rarely present with severe organ specific complications in immunocompetent hosts. The frequent presentation is severe hepatitis.[67] The second frequent complications in immunocompetent patients are central nervous system disorders such as meningitis, encephalitis, myelitis, nerve palsies, and GBS.[8] The cases involving multiple systems due to CMV are very rare. We are describing a case of CMV-induced hepatitis, colitis, splenic infarct, and GBS in an 18-year-old male with intact immune status.\n\nCase Report\nAn 18-year-old previously healthy male presented to the clinic with the complaints of sore throat and generalized malaise. The patient denied any history of alcohol or drug use. He denied any history of recurrent infections. The patient had no history of bleeding diathesis. His platelet count was normal. He had a negative rapid monospot and rapid strep antigen test. He recovered from acute illness in 3 days.\n\nHe noticed dysphagia and paresthesias of both lower extremities and weakness in all extremities (lower > upper, proximal > distal) one day after recovering from sore throat. On neurological examination, patient had bilateral facial nerve palsy and bulbar palsy. Motor strength was grade 1 in lower extremities and grade 2 in upper extremities. Muscle tone of the limbs was decreased. Deep tendon reflexes on the upper limbs were diminished and absent on the lower limbs.\n\nBlood chemistry was normal, except for total bilirubin of 2.3 mg/dL, alanine transferase and aspartate transferase levels of 87 IU/L and 67 IU/L respectively, indicating hepatitis, which may be due to acute CMV infection. Test for human immunodeficiency virus was negative. His serology was positive for CMV immunoglobulin M (IgM) and Immunoglobulin G (IgG) antibodies. CMV polymerase chain reaction (PCR) was positive with <2000 copies of deoxyribonucleic acid (DNA). Cerebrospinal fluid analysis was done, and it was positive for CMV IgG antibody and increased amount of proteins. He was treated with ganciclovir for acute CMV viremia and received three doses of intravenous immunoglobulin without much response. Patient had diffuse decrease in sensory and motor amplitudes, low normal conduction velocities, prolonged distal motor latencies in the left upper limb, and absent or prolonged F-wave responses on nerve conduction studies with severely decreased recruitment throughout, and a few positive sharp waves and fibrillation potentials on needle electromyography. These findings were most consistent with an acute diffuse neuropathy, most likely acute inflammatory demyelinating polyradiculopathy in early stage.\n\nDay 4: Patient developed acute respiratory failure and was placed on mechanical ventilator.\n\nDay 12: He demonstrated a slow and gradual improvement in his strength mostly in upper extremities after starting plasma exchange daily for 5 days.\n\nDay 15: He was discharged to a rehabilitation facility. He had bifacial weakness; motor strength was 2/5 in lower and 3/5 in upper extremities. Sensations were intact.\n\nDay 16: He developed acute onset of abdominal pain in left upper quadrant with high grade fever (103.4 F) and was admitted to the hospital. He was found to have dislodged gastrostomy tube, which was replaced by the interventional radiology. After that, the patient had an exploratory laparotomy. He was started on broad-spectrum antibiotics and culture was sent which grew coagulase negative staphylococcus. The patient continued to have high-grade fevers (102.9 F) despite exploratory laparotomy and aggressive wash out. Repeat CMV PCR was negative. Serum IgG ganglioside GQ1b antibody was <1:100 titers.\n\nDay 21: Repeat computed tomography (CT) abdomen showed modest sized splenic infarct [Figures 1 and 2] and prominent colitis. Patient had a small hypodense focus in the periphery of the spleen on the follow-up CT abdomen on day 25 and day 32, which was consistent with evolution of splenic infarct.\n\nFigure 1 Horizontal section of CT abdomen showing splenic infarct\n\nFigure 2 Coronal section of CT abdomen showing splenic infarct\n\nDay 42: CT abdomen on the day of discharge showed decrease in the size of splenic infarct. Patient's condition was improved gradually and ultimately he was discharged to a rehabilitation facility.\n\nDiscussion\nThe clinical features of CMV infection in immunocompromised hosts have been extensively reported, but comparatively less attention has received for those observed in immunocompetent patients. Table 1 describes the clinical manifestations of CMV infection in immunocompetent patients. The diagnosis of acute CMV infection is based on positive CMV-specific IgG and IgM antibodies, peripheral blood positive for CMV pp65 antigens, and ≥600 copies of CMV DNA/mL.[9]\n\nTable 1 Clinical manifestations of cytomegalovirus infection in immunocompetent patients\n\nArterial or venous thrombosis in patients with acute CMV infection is not rare and is independent of the typical risk factors for thrombosis. In a retrospective study by Atzmony et al.,[9] the incidence of thrombosis was 6.4% (n = 9) in 140 patients with acute CMV infection. Splenic infarcts (n = 4) and renal infarct (n = 1) were the manifestations of arterial thrombosis. Venous thrombosis was presented as pulmonary embolism (n = 1), lower limb deep vein thrombosis (n = 1), upper limb deep vein thrombosis (n = 1), and jugular vein thrombosis (n = 1).\n\nGBS is an acute demyelinating polyneuropathy that can occur after an infectious disease accounting for 60-70% of cases with CMV infection.[10] Neurological involvement by CMV is usually attributed to aberrant immunological responses triggered by CMV.[11] The outcomes have significantly improved in GBS patients with management in intensive care unit on ventilator support, the use of intravenous immunoglobulin, and plasmapheresis.[12] The diagnosis of CMV associated GBS was based on the presence of clinical features of acute onset of generalized weakness and numbness, which progress rapidly, together with facial diplegia and bulbar palsy; the cytoalbumino dissociation on cerebrospinal fluid analysis; the demyelinating motor and sensory neuropathy on electromyography; and serological evidence of increased IgM and IgG antibodies against CMV. Our patient was unique in that he developed splenic infarct and colitis after the initial episode of GBS and hepatitis.\n\nIn the prospective cohort study by Orlikowski et al.,[2] sensory deficits were observed in 72% of cases and facial palsy in 49% of cases, and test results positive for CMV DNA in 62% of cases tend to be associated with objective sensory defect (P = 0.052). The main factors associated with long-term neurological deficits (21%) were older age (P = 0.001) and assisted ventilation during hospitalization (P = 0.005). Our patient had sensory deficits, positive for CMV DNA, and required the mechanical ventilation.\n\nTwo case reports highlighted the acute CMV patients presenting with bilateral abducens palsy.[1314] In another case report patient had GBS along with periodontitis which may serve as a reservoir for CMV and its replication.[15] Sinardi et al.,[16] reported an uncommon case of isolated vasculitis, restricted to the left sylvian artery in a patient with an autoimmune CMV associated GBS.\n\nConclusion\nMultisystem complications can occur after CMV infection even in immunocompetent patients. Early recognition of complications is important and prompt treatment is critical to improve overall outcome. We cannot rule out a rare hereditary immunodeficiency in our patient. However, it is unlikely as the patient was healthy in the past.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Visser LH van der Meche FG Meulstee J Rothbarth PP Jacobs BC Schmitz PI Cytomegalovirus infection and Guillain-Barre syndrome: The clinical, electrophysiologic, and prognostic features. Dutch Guillain-Barre Study Group Neurology 1996 47 668 73 8797462 \n2 Orlikowski D Porcher R Sivadon-Tardy V Quincampoix JC Raphael JC Durand MC Guillain-Barre syndrome following primary cytomegalovirus infection: A prospective cohort study Clin Infect Dis 2011 52 837 44 21427390 \n3 Vancikova Z Dvorak P Cytomegalovirus infection in immunocompetent and immunocompromised individuals: A review Curr Drug Targets Immune Endocr Metabol Disord 2001 1 179 87 12476798 \n4 Rafailidis PI Mourtzoukou EG Varbobitis IC Falagas ME Severe cytomegalovirus infection in apparently immunocompetent patients: A systematic review Virol J 2008 5 47 18371229 \n5 Taylor GH Cytomegalovirus Am Fam Physician 2003 67 519 24 12588074 \n6 Azad AK Ahmed T Chowdhury AJ Rahim MA Mahmud AK Rahman MA Cytomegalovirus induced hepatitis in an immunocompetent host Mymensingh Med J 2008 17 S104 6 18946441 \n7 Mamun-Al-Mahtab Rahman S Khan M Acute cytomegalovirus hepatitis in immunocompetent host Kathmandu Univ Med J (KUMJ) 2009 7 79 81 19483460 \n8 Eddleston M Peacock S Juniper M Warrell DA Severe cytomegalovirus infection in immunocompetent patients Clin Infect Dis 1997 24 52 6 8994755 \n9 Atzmony L Halutz O Avidor B Finn T Zimmerman O Steinvil A Incidence of Cytomegalovirus-associated thrombosis and its risk factors: A case-control study Thromb Res 2010 126 e439 43 20926120 \n10 Kuwabara S Guillain-Barre syndrome: Epidemiology, pathophysiology and management Drugs 2004 64 597 610 15018590 \n11 Hughes RA Cornblath DR Guillain-Barre syndrome Lancet 2005 366 1653 66 16271648 \n12 van der Meche FG Schmitz PI A randomized trial comparing intravenous immune globulin and plasma exchange in Guillain-Barre syndrome. Dutch Guillain-Barre Study Group N Engl J Med 1992 326 1123 9 1552913 \n13 Harada T Kohriyama T Ishizaki F Nakamori K Nakagawa Y Ohtani M Guillain–Barre syndrome and disturbance in multiple organs associated with cytomegalovirus infection No To Shinkei 1990 42 245 51 2164409 \n14 Kishi M Sakakibara R Ogawa E Tateno F Takahashi O Koga M Bilateral abducens palsy in a case of cytomegalovirus-associated Guillain-Barre syndrome Neurol Sci 2011 32 1219 22 21833717 \n15 Tabanella G Nowzari H Cytomegalovirus-associated periodontitis and guillain-barre syndrome J Periodontol 2005 76 2306 11 16332244 \n16 Sinardi D Spada A Marino A Mondello E A case of central nervous system vasculitis related to an episode of Guillain-Barrè syndrome Crit Care 2000 4 245 7 11056753\n\n",
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"issn_linking": "0976-3155",
"issue": "5(1)",
"journal": "Journal of neurosciences in rural practice",
"keywords": "Cytomegalovirus; guillain-barre syndrome; hepatitis; splenic infarct",
"medline_ta": "J Neurosci Rural Pract",
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"nlm_unique_id": "101533710",
"other_id": null,
"pages": "59-62",
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"pubdate": "2014-01",
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"title": "A young patient with multisystem complications after cytomegalovirus infection.",
"title_normalized": "a young patient with multisystem complications after cytomegalovirus infection"
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"abstract": "Bortezomib is a pivotal drug for the management of multiple myeloma. However, bortezomib is a neurotoxic anticancer drug responsible for chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with psychological distress and a decrease of health-related quality of life (HRQoL), but little is known regarding bortezomib-related CIPN. This single center, cross-sectional study assessed the prevalence and severity of sensory/motor CIPN, neuropathic pain and ongoing pain medications, anxiety, depression, and HRQoL, in multiple myeloma patients after the end of bortezomib treatment. Paper questionnaires were sent to patients to record the scores of sensory and motor CIPNs (QLQ-CIPN20), neuropathic pain (visual analogue scale and DN4 interview), anxiety and depression (HADS), the scores of HRQoL (QLQ-C30 and QLQ-MY20) and ongoing pain medications. Oncological data were recorded using chemotherapy prescription software and patient medical records. The prevalence of sensory CIPN was 26.9% (95% CI 16.7; 39.1) among the 67 patients analyzed and for a mean time of 2.9 ± 2.8 years since the last bortezomib administration. The proportion of sensory CIPN was higher among patients treated by intravenous and subcutaneous routes than intravenous or subcutaneous routes (p = 0.003). QLQ-CIPN20 motor scores were higher for patients with a sensory CIPN than those without (p < 0.001) and were correlated with the duration of treatment and the cumulative dose of bortezomib (coefficient: 0.31 and 0.24, p = 0.01 and 0.0475, respectively), but not sensory scores. Neuropathic pain was screened in 44.4% of patients with sensory CIPN and 66.7% of them had ongoing pain medications, but none were treated with duloxetine (recommended drug). Multivariable analysis revealed that thalidomide treatment (odds-ratio: 6.7, 95% CI 1.3; 35.5, p = 0.03) and both routes of bortezomib administration (odds-ratio: 13.4, 95% CI 1.3; 139.1, p = 0.03) were associated with sensory CIPN. Sensory and motor CIPNs were associated with anxiety, depression, and deterioration of HRQoL. Sensory CIPN was identified in a quarter of patients after bortezomib treatment and associated with psychological distress that was far from being treated optimally. There is a need to improve the management of patients with CIPN, which may include better training of oncologists regarding its diagnosis and pharmacological treatment.",
"affiliations": "INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.;INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.;CHU Clermont-Ferrand, Direction de La Recherche Clinique et de l'Innovation, Clermont-Ferrand, France.;Service d'Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France.;College of Pharmacy, University of Oklahoma, Oklahoma City, OK, United States.;INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.;INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.;Service d'Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France.;Service d'Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France.;Service de Rhumatologie, CHU Clermont-Ferrand, Clermont-Ferrand, France.;Service d'Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France.;Service d'Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France.;INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France.",
"authors": "Selvy|Marie|M|;Kerckhove|Nicolas|N|;Pereira|Bruno|B|;Barreau|Fantine|F|;Nguyen|Daniel|D|;Busserolles|Jérôme|J|;Giraudet|Fabrice|F|;Cabrespine|Aurélie|A|;Chaleteix|Carine|C|;Soubrier|Martin|M|;Bay|Jacques-Olivier|JO|;Lemal|Richard|R|;Balayssac|David|D|",
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"doi": "10.3389/fphar.2021.637593",
"fulltext": "\n==== Front\nFront Pharmacol\nFront Pharmacol\nFront. Pharmacol.\nFrontiers in Pharmacology\n1663-9812\nFrontiers Media S.A.\n\n637593\n10.3389/fphar.2021.637593\nPharmacology\nOriginal Research\nPrevalence of Chemotherapy-Induced Peripheral Neuropathy in Multiple Myeloma Patients and its Impact on Quality of Life: A Single Center Cross-Sectional Study\nSelvy et al.\nBortezomib-Induced Peripheral Neuropathy\nSelvy Marie 1 2\nKerckhove Nicolas 1 3 4\n\nPereira Bruno 5\n\nBarreau Fantine 6\nNguyen Daniel 7\nBusserolles Jérôme 1\n\nGiraudet Fabrice 1\n\nCabrespine Aurélie 6\nChaleteix Carine 6\nSoubrier Martin 8 9\nBay Jacques-Olivier 6 10\nLemal Richard 6 10\nBalayssac David 1 5 *\n\n1 INSERM U1107 NEURO-DOL, Université Clermont Auvergne, Clermont-Ferrand, France\n2 Service de Chirurgie digestive, CHU Clermont-Ferrand, Clermont-Ferrand, France\n3 Service de Pharmacologie, CHU Clermont-Ferrand, Clermont-Ferrand, France\n4 Institut Analgesia, Université Clermont Auvergne, Clermont-Ferrand, France\n5 CHU Clermont-Ferrand, Direction de La Recherche Clinique et de l’Innovation, Clermont-Ferrand, France\n6 Service d’Hématologie clinique adulte, CHU Clermont-Ferrand, Clermont-Ferrand, France\n7 College of Pharmacy, University of Oklahoma, Oklahoma City, OK, United States\n8 Service de Rhumatologie, CHU Clermont-Ferrand, Clermont-Ferrand, France\n9 UNH-UMR 1019, INRA, Université Clermont Auvergne, Clermont-Ferrand, France\n10 EA 7453 CHELTER, Université Clermont Auvergne, Clermont-Ferrand, France\nEdited by: Raquel Abalo, Rey Juan Carlos University, Spain\n\nReviewed by: Stefanie Geisler, Washington University School of Medicine in St. Louis, United States\n\nRobert Knoerl, Dana–Farber Cancer Institute, United States\n\n*Correspondence: David Balayssac, dbalayssac@chu-clermontferrand.fr\nThis article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology\n\n22 4 2021\n2021\n12 63759303 12 2020\n08 3 2021\nCopyright © 2021 Selvy, Kerckhove, Pereira, Barreau, Nguyen, Busserolles, Giraudet, Cabrespine, Chaleteix, Soubrier, Bay, Lemal and Balayssac.\n2021\nSelvy, Kerckhove, Pereira, Barreau, Nguyen, Busserolles, Giraudet, Cabrespine, Chaleteix, Soubrier, Bay, Lemal and Balayssac\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBortezomib is a pivotal drug for the management of multiple myeloma. However, bortezomib is a neurotoxic anticancer drug responsible for chemotherapy-induced peripheral neuropathy (CIPN). CIPN is associated with psychological distress and a decrease of health-related quality of life (HRQoL), but little is known regarding bortezomib-related CIPN. This single center, cross-sectional study assessed the prevalence and severity of sensory/motor CIPN, neuropathic pain and ongoing pain medications, anxiety, depression, and HRQoL, in multiple myeloma patients after the end of bortezomib treatment. Paper questionnaires were sent to patients to record the scores of sensory and motor CIPNs (QLQ-CIPN20), neuropathic pain (visual analogue scale and DN4 interview), anxiety and depression (HADS), the scores of HRQoL (QLQ-C30 and QLQ-MY20) and ongoing pain medications. Oncological data were recorded using chemotherapy prescription software and patient medical records. The prevalence of sensory CIPN was 26.9% (95% CI 16.7; 39.1) among the 67 patients analyzed and for a mean time of 2.9 ± 2.8 years since the last bortezomib administration. The proportion of sensory CIPN was higher among patients treated by intravenous and subcutaneous routes than intravenous or subcutaneous routes (p = 0.003). QLQ-CIPN20 motor scores were higher for patients with a sensory CIPN than those without (p < 0.001) and were correlated with the duration of treatment and the cumulative dose of bortezomib (coefficient: 0.31 and 0.24, p = 0.01 and 0.0475, respectively), but not sensory scores. Neuropathic pain was screened in 44.4% of patients with sensory CIPN and 66.7% of them had ongoing pain medications, but none were treated with duloxetine (recommended drug). Multivariable analysis revealed that thalidomide treatment (odds-ratio: 6.7, 95% CI 1.3; 35.5, p = 0.03) and both routes of bortezomib administration (odds-ratio: 13.4, 95% CI 1.3; 139.1, p = 0.03) were associated with sensory CIPN. Sensory and motor CIPNs were associated with anxiety, depression, and deterioration of HRQoL. Sensory CIPN was identified in a quarter of patients after bortezomib treatment and associated with psychological distress that was far from being treated optimally. There is a need to improve the management of patients with CIPN, which may include better training of oncologists regarding its diagnosis and pharmacological treatment.\n\nbortezomib\nmultiple myeloma\nchemotherapy-induced peripheral neuropathy\nneuropathic pain\nhealth-related quality of life\nanxiety\ndepression\n==== Body\nIntroduction\n\nChemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic anticancer drugs, such as platinum derivative drugs (cisplatin, oxaliplatin), spindle poisons (taxanes: paclitaxel, docetaxel; vinca alkaloids: vincristine; epothilones; eribulin), bortezomib and thalidomide (Kerckhove et al., 2017). CIPN is commonly described as a distal and symmetric polyneuropathy (stocking and glove distribution). Overall symptomatology includes paresthesia (tingling, numbness), dysesthesia (thermal, tactile allodynia and neuropathic pain). The incidence of CIPN is close to 38%, but it can vary considerably according to the anticancer drugs and regimen prescribed (Kerckhove et al., 2017). CIPN remains a problematic adverse effect associated with a decline of health-related quality of life (HRQoL), and no preventive and unequivocally effective curative treatment (except duloxetine) is available today (Hershman et al., 2014; Loprinzi et al., 2020). Consequently, oncologists must decrease or stop the neurotoxic anticancer regimen to limit the severity of CIPN (Dault et al., 2016), possibly having a negative impact on disease control and progression free survival (Chibaudel et al., 2009).\n\nAmong all these neurotoxic anticancer drugs, bortezomib is probably one of the least studied whereas it is used in the treatment of multiple myeloma, the second most common hematologic malignancy after lymphoma (Kazandjian, 2016). Multiple myeloma arises from an asymptomatic premalignant proliferation of monoclonal plasma cells derived from post–germinal-center B cells. In the Western world, the age-standardized incidence of multiple myeloma has been reported to be approximately 5 cases per 100,000. The median age of patients at diagnosis is approximately 70 years (Palumbo and Anderson, 2011), and the five-year relative survival ratio, between 2003–2013, was 0.41 (95% CI 0.40; 0.43) (Thorsteinsdottir et al., 2018). According to the Cochrane database of Systematic Reviews, the increased risk (odds-ratio) of peripheral neuropathy in patients treated with bortezomib was 3.71 (95% CI 2.92; 4.70, p < 0.00001) (Scott et al., 2016). Li et al. described a median incidence of 37.8% for all grades of sensory CIPN for bortezomib treated patients in phase III clinical trials (Li et al., 2019). CIPN symptoms commonly include paresthesia and numbness occurring in the extremities, and progressing proximally in a glove and stocking distribution. Small nerve fiber involvement is common, characterized by pain in the toes and soles of the feet. CIPN is often under recognized in multiple myeloma patients. This can be explained in part by the fact that up to 54% of treatment-naïve patients demonstrated either clinical signs of peripheral neuropathy or presented abnormal neurophysiological results at baseline (Richardson et al., 2009). Moreover, bortezomib is often administered in combination with other drugs, such as thalidomide, which are also neurotoxic and have demonstrated a different mechanism of neurotoxicity. Consequently, the interaction of bortezomib with other treatments may lead to CIPN resulting from multiple pathophysiological pathways (Li et al., 2019).\n\nBortezomib-related CIPN is associated with a significant economic burden. A cost analysis based on US administrative claim databases showed a significantly higher healthcare utilization and expenditure per patient per month by $1509 for multiple myeloma patients with peripheral neuropathy than controls, driven by higher hospitalization (peripheral neuropathy 77.4%, controls 67.2%; p < 0.001) and emergency department rates (peripheral neuropathy 67.8%, controls 58.4%; p < 0.001) and more outpatient hospital-based visits (peripheral neuropathy 13.5 ± 14.7, controls 11.5 ± 18.0; p < 0.001) (Song et al., 2019).\n\nThe most commonly used evaluation tool for CIPN in clinical trials is the National Cancer Institute's common terminology criteria Adverse Reactions (NCI-CTCAE) (Li et al., 2019), which is a clinician-reported outcome (CROs) that includes criteria and definitions for quantifying the severity of CIPN in both sensory and motor components, utilizing a 5-point scale [grade 1 (asymptomatic) to grade 5 (death)] (Molassiotis et al., 2019a). However, this scale only demonstrates moderate inter-observer agreement (Postma et al., 1998) and is limited by floor and ceiling effects with limited responsiveness to change (Griffith et al., 2010). It is also well established that CROs underreport symptoms experienced by patients and that patient-reported outcomes (PROs) showed a higher incidence and severity of treatment-related toxicities, including CIPN (Beutler et al., 2017). Among the PROs, the QLQ-CIPN20 from the European Organization for Research and Treatment of Cancer (EORTC) is a valuable tool for the assessment of CIPN (Postma et al., 2005; Le-Rademacher et al., 2017).\n\nTo our knowledge, only 4 studies have assessed bortezomib associated CIPN with the QLQ-CIPN20 questionnaire for a total of 102 multiple myeloma patients treated by bortezomib: two studies including 80 patients (Beijers et al., 2016, 2017), another with 20 patients, (Mendoza et al., 2020), and the last one with 2 patients (Lavoie Smith et al., 2017). Moreover, very little information is available regarding the time since the last bortezomib administration. Only the study of Beijers et al. provides the time since the last chemotherapy administration (median: 10 months and range: 0–158) (Beijers et al., 2017). Thus, the prevalence and severity of bortezomib associated CIPN after the end of treatment has been studied only partially, likewise for psychological distress and HRQoL.\n\nThe aim of this study was to assess the prevalence and severity of CIPN associated with bortezomib based chemotherapy in patients with multiple myeloma, after the end of bortezomib administration. In addition, neuropathic pain, the use of pain medications, anxiety, depression, and HRQoL were assessed.\n\nMaterials and Methods\n\nStudy Design\n\nThis single center, observational and cross-sectional study was designed to assess CIPN in patients who were treated by bortezomib-based chemotherapy for multiple myeloma. The primary objective was the assessment of prevalence and severity of sensory CIPN. The secondary objectives were the severity of motor CIPN, the prevalence of neuropathic pain, the use of pain medications, the prevalence of anxiety and depression, and the HRQoL. Patients were assessed once and no longitudinal assessment was performed.\n\nThe study was designed according to the STROBE (Strengthening the Reporting of Observational Studies in Epidemiology) guidelines (von Elm et al., 2007). The study protocol was registered on the ClinicalTrials.gov website NCT03344328. The study was anonymous and approved by a local ethics committee (Comité de Protection des Personnes sud-est 5, IRB: 6705, No. 2017-A00651–52, april 25, 2017). The participants’ consent was obtained orally by contacting each eligible patient by phone.\n\nThe study design, the recruitment of patients and the data analysis were performed by the authors M.S., N.K. and D.B., none of whom were involved in the management of the patients included.\n\nSetting\n\nThis single center study was conducted in the rheumatology and clinical hematology departments of the University Hospital of Clermont-Ferrand (CHU Clermont-Ferrand). The inclusion of patients and data collection were carried out from March 13, 2019 until April 02, 2019.\n\nParticipants\n\nInclusion criteria were patients having been treated by bortezomib-based chemotherapy for multiple myeloma. Exclusion criteria were patients <18 years, and neurological disease (stroke, Parkinson disease, Alzheimer disease, fibromyalgia).\n\nEligible patients were identified from the database of the chemotherapy prescription software (CHIMIO®, Computer Engineering, France) of the University Hospital of Clermont-Ferrand. A specific algorithm was prepared for the systematic extraction of patient data. Thereafter, this first selection of patients was checked by the oncologists in charge of patients, to select patients according to inclusion and exclusion criteria. Patients were phoned to inquire whether they would participate in the study. After patient acceptance, a paper questionnaire and a stamped envelope for the response were sent to the patient. Patients returned their questionnaires to the University Hospital of Clermont-Ferrand, where their responses were recorded and analyzed.\n\nVariables\n\nThe primary endpoints were the sensory score of the QLQ-CIPN20 rated from 0 (least) to 100 (worst) (Postma et al., 2005) (for scoring see: https://www.eortc.org/app/uploads/sites/2/2018/02/SCmanual.pdf), used as a quantitative variable, and the sensory CIPN defined as a sensory QLQ-CIPN20 score of ≥30/100 (Alberti et al., 2014; Selvy et al., 2020b), used as a qualitative variable. The secondary endpoints were the motor and vegetative scores of the QLQ-CIPN20 rated from 0 (least) to 100 (worst) (Postma et al., 2005). Present pain was reported by the patient (yes/no). Screening for pain was assessed with a visual analogue scale (VAS, 0 = no pain and 10 = maximum imaginable pain), and defined for a threshold ≥4/10. Among patients with a positive screening for pain (VAS score ≥4/10), neuropathic pain was assessed with DN4 interview (French abbreviation: Douleur Neuropathique 4, for neuropathic pain 4) questionnaire and detected for a DN4 interview score ≥3/7 (Bouhassira et al., 2005). The history of neuropathy and neuropathic pain before the diagnosis of multiple myeloma was also recorded. Ongoing pain medications in the past month were recorded, based on an established list of pain medications. Anxiety and depression were assessed with the Hospital Anxiety and Depression Scale (HADS) at the time of the answer, considering the following thresholds, normal (total score ≤7), borderline or suggestive of possible anxiety/depression (total score of 8–10) and indicative of anxiety/depression (total score ≥11) (Zigmond and Snaith, 1983). The HRQoL was assessed with the QLQ-C30 and QLQ-MY20 questionnaire (EORTC) (Aaronson et al., 1993; Cocks et al., 2007). The scoring of QLQ-C30 and QLQ-MY20 was done according to EORTC recommendations. The QLQ-C30 was divided into 3 subscales with a Global health status (0 worst to 100 best), the functional scales (0 worst to 100 best for physical functioning, role functioning, emotional functioning, cognitive functioning and social functioning) and the symptom scales (0 least to 100 worst for fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea and financial difficulties). The QLQ-MY20 was divided into 2 subscales with symptom scales (0 least to 100 worst for disease symptoms and side effects of treatment) and functional scales (0 worst to 100 best for body image and future perspective).\n\nThe oncological characteristics were recorded such as cumulative dose (mg/m2), route of administration (intravenous, subcutaneous), the date of the last bortezomib administration, the duration of bortezomib treatment, the administration of thalidomide, the date of the last thalidomide treatment, and the hematopoietic stem cell transplantation.\n\nThe socio-demographic characteristics of patients were also recorded such as gender, age, daily use of cigarettes, occasional alcohol use and hazardous alcohol use (>10 alcohol units per week) (France, 2017). Tobacco use has been associated to the severity of oxaliplatin-related CIPN in a previous study of our group (Selvy et al., 2020b). Alcohol use is a debated risk factor of CIPN (Molassiotis et al., 2019a).\n\nData Sources/Measurement\n\nData assessing CIPN, neuropathic pain, ongoing pain medications, anxiety, depression, and HRQoL were obtained from the completed questionnaire. Oncological data and patient characteristics were obtained from the software of chemotherapy prescription and patient medical records. All the data were recorded and managed using REDCap™ electronic data capture tools hosted at the University Hospital of Clermont-Ferrand (Harris et al., 2009).\n\nStatistical Methods\n\nThe sample size was determined to ensure that the confidence interval (CI) of the sensory score of the QLQ-CIPN20 had an accuracy of around 5 points for a standard-deviation at 20. The calculation showed that at least 65 patients were necessary to ensure a two-sided type I error of 5%.\n\nThe internal consistency of the QLQ-CIPN20 sensory scale was assessed and determined using Cronbach’s α coefficient, with a minimum accepted value of 0.70. Then, the categorical data were presented using number of patients, percentage, and appropriate 95% CI. Continuous data were expressed as mean and standard-deviation. The normality of the data was assessed using the Shapiro–Wilk test. Continuous data were compared between independent groups (such as no sensory CIPN vs. sensory CIPN) using the Student’s t-test or the Mann–Whitney U test when the assumptions of the t-test were not met. The homoscedasticity of the data was assessed using the Fisher–Snedecor test. The results were expressed using Hedge’s effect-size (ES) and 95% CI, and were interpreted according to the rules of thumb reported by Cohen (Cohen, 1988), who defined the ES bounds as small (ES = 0.2), medium (ES = 0.5), and large (ES = 0.8). Categorical data were compared between groups (independent proportions) using the chi-squared test or Fisher’s exact test, and McNemar test for paired proportions. To analyze the relationships between continuous parameters, Pearson and Spearman correlation coefficients were estimated according to the statistical distribution of variables and by applying Sidak’s type I error correction, and interpreted as: <0.2 negligible, 0.2–0.4 weak, 0.4–0.7 moderate, >0.7 strong (Altman, 1999). To determine factors associated with the sensory CIPN (dependent variable), multivariable analysis (i.e. generalized linear logistic regression) was performed, including patients’ characteristics (gender, age, tobacco and alcohol consumptions) and characteristics of chemotherapy (time since last bortezomib administration, cumulative dose of bortezomib, and thalidomide treatment). Particular attention was paid to the study of multicollinearity and to the interactions between covariates: 1) studying the relationships between the covariables, and 2) evaluating the impact of adding or deleting variables on a multivariable model. The results are expressed as odds-ratios and 95% CI, and forest plots were used to present the results. Statistical analyses were performed using Stata 15 (StataCorp, College Station, US). All the tests were two-sided, with a type I error set at 5%. In accordance with the literature (Rothman, 1990; Bender and Lange, 2001; Feise, 2002), we reported all individual p-values without systematically applying any mathematical correction to the aforementioned tests comparing groups. Specific attention was given to the magnitude of differences (i.e., ES) and clinical relevance.\n\nResults\n\nCharacteristics of Patients\n\nOne hundred and fifteen patients were screened by oncologists for inclusion in the study. Among them, 74 patients accepted to participate to the study and 67 sent back a filled questionnaire (response rate: 90.5%) (Figure 1). The characteristics of these 67 included patients are presented in Table 1.\n\nFIGURE 1 Flowchart.\n\nTABLE 1 Characteristics of the analyzed patients (N = 67).\n\nItems\tTotal N = 67\tNo sensory CIPN N = 49 (73.1)\tSensory CIPN N = 18 (26.9)\tp Value\tEffect size (95% CI) #\t\nFemale n (%)\t35 (52.2)\t27 (55.1)\t8 (44.4)\t0.44\t−0.11 [−0.38; 0.16]\t\nAge (years)\t66.7 ± 10.4\t66.2 ± 10.7\t68.3 ± 9.7\t0.44\t0.20 [−0.33; 0.74]\t\nTobacco n (%)\t3 (4.6)\t2 (4.2)\t1 (5.6)\t0.81\t0.01 [−0.11; 0.13]\t\nAlcohol n (%)\t32 (47.8)\t25 (51.0)\t7 (38.9)\t0.38\t−0.12 [−0.39; 0.14]\t\nHazardous alcohol use\t4 (9.1)\t3 (9.1)\t1 (9.1)\t1\t0 [−0.20; 0.20]\t\nHistory of neuropathic pain\t40 (59.7)\t29 (59.2)\t11 (61.1)\t0.89\t−0.02 [−0.28; 0.24]\t\nBortezomib treatment\t67 (100)\t\t\t\t\t\n Cumulative dose (mg/m²)\t68.8 ± 41.9\t61.8 ± 35.3\t88.0 ± 52.8\t0.12\t0.64 [0.09; 1.18]\t\n Duration of treatment (months)\t15.5 ± 21.8\t11.8 ± 18.0\t25.5 ± 28.0\t0.13\t0.64 [0.10; 1.19]\t\n Time since last administration (years)\t2.9 ± 2.8\t2.6 ± 2.7\t3.7 ± 2.9\t0.08\t0.41 [−0.13; 0.94]\t\n Subcutaneous route\t50 (74.6)\t41 (83.7)\t9 (50.0)\t\t\t\n Intravenous route\t9 (13.4)\t6 (12.2)\t3 (16.7)\t0.003\t0.04 [−0.15; 0.24] ##\t\n Both routes\t8 (11.9)\t2 (4.1)\t6 (33.3)\t\t0.29 [0.07; 0.52] ##\t\n Thalidomide treatment\t35 (53.8)\t23 (48.9)\t12 (66.7)\t0.20\t0.18 [−0.8; 0.44]\t\n Duration of treatment (months)\t6.1 ± 3.2\t6.5 ± 3.1\t5.5 ± 3.4\t0.39\t−0.32 [−1.04; 0.40]\t\n Time since last administration (years)\t3.9 ± 2.6\t3.2 ± 2.0\t5.4 ± 3.1\t0.0495\t0.87 [0.12; 1.61]\t\nHematopoietic stem cell transplantation\t\n One transplantation\t41 (62.1)\t29 (60.4)\t12 (66.7)\t0.78\t0.06 [−0.20; 0.32]\t\n Two transplantations\t13 (31.7)\t9 (31.0)\t4 (33.3)\t1\t0.02 [−0.29; 0.34]\t\nQLQ-CIPN20 scores\t\n Sensory\t18.9 ± 20.3\t9.0 ± 10.5\t45.7 ± 15.5\t<0.001\t3.02 [2.27; 3.76]\t\n Motor\t17.8 ± 20.7\t10.9 ± 14.2\t36.7 ± 23.9\t<0.001\t1.47 [0.88; 2.06]]\t\nHADS scores\t\n Anxiety\t5.6 ± 3.7\t4.7 ± 3.7\t7.9 ± 2.7\t<0.001\t0.90 [0.35; 1.46]\t\n Depression\t5.6 ± 4.4\t4.5 ± 4.0\t8.7 ± 3.7\t<0.001\t1.06 [0.49; 1.62]\t\nCategorical variables are expressed as percentages (number). Continuous variables are expressed as mean ± standard deviation.\n\nStandardized mean difference for continuous variables and absolute difference for categorical variables, and 95% confidence interval [95%CI].\n\nComparison vs. reference (subcutaneous route). Statistical analyzes were performed using student or Mann–Whitney tests for continuous variables and Chi-squared or Fisher’s exact tests for categorical variables.\n\nSensory CIPN\n\nThe 20 items of the QLQ-CIPN20 indicated an excellent level of internal consistency (Cronbach α = 0.92), the 9 items of the sensory scale a good level (Cronbach α = 0.82), the 8 items of the motor scale indicated a good level (Cronbach α = 0.86) and the 3 items of the vegetative scale indicated a poor level (Cronbach α = 0.65). Thereafter, the vegetative scale of the QLQ-CIPN20 was not used for the analysis.\n\nAmong the patients analyzed, 26.9% 18) (95% CI 16.7; 39.1) had a sensory CIPN (sensory QLQ-CIPN20 score ≥30/100). The distribution of the sensory scores of the QLQ-CIPN20 over the years after the end of chemotherapy is presented in Figure 2. Sensory scores were not different between males and females (20.1 ± 19.9 vs. 17.8 ± 20.8, p = 0.51) and not correlated with the age of patients (Table 2).\n\nFIGURE 2 Distribution of the sensory scores of the QLQ-CIPN20 for each patient and over years after the end of bortezomib administration.\n\nTABLE 2 Correlations between quantitative variables and the sensory scores of the QLQ-CIPN20 and the motor scores of the QLQ-CIPN20.\n\nQLQ-CIPN20 sensory scores\tSpearman coefficient\tp values\t\nAge (years)\t0.11\t>0.05\t\nBortezomib treatment\t\n Cumulative dose (mg/m²)\t0.19\t0.12\t\n Duration of treatment (months)\t0.19\t0.12\t\n Time since last administration (years)\t0.04\t0.72\t\nThalidomide treatment\t\n Duration of treatment (months)\t0.13\t0.47\t\n Time since last administration (years)\t0.26\t0.16\t\nQLQ-CIPN20 motor scores\t\nAge (years)\t0.21\t>0.05\t\nBortezomib treatment\t\n Cumulative dose (mg/m²)\t0.24\t0.0475\t\n Duration of treatment (months)\t0.31\t0.0099\t\n Time since last administration (years)\t−0.16\t0.18\t\nThalidomide treatment\t\n Duration of treatment (months)\t−0.06\t0.77\t\n Time since last administration (years)\t0.23\t0.21\t\n\nCharacteristics of bortezomib treatments (cumulative dose, duration, and time since last administration) were not different between patients with or without a sensory CIPN (Table 1). Likewise, sensory scores were not correlated with the cumulative bortezomib dose, with the duration of bortezomib treatment, or with the time since last bortezomib administration (Table 2 and Figure 2). The proportions of sensory CIPN were significantly different according to the route of bortezomib administration (p = 0.003) (Table 1). Post hoc analysis revealed a higher proportion of sensory CIPN in patients with both routes of bortezomib administration (intravenous + subcutaneous) compared to the subcutaneous route only (p < 0.05). Interestingly, the proportions of sensory CIPN were not different between intravenous and subcutaneous routes. Similarly, the sensory scores of the QLQ-CIN20 were different according to the route of bortezomib administration (intravenous vs. subcutaneous vs. both routes: 21.7 ± 28.9 vs. 15.8 ± 17.7 vs. 35.2 ± 18.8, p = 0.02).\n\nProportions of patients with a sensory CIPN and sensory scores (20.0 ± 22.4 vs. 17.5 ± 18.3, p = 0.95) were not different between patients treated or not with thalidomide (Table 1). The durations of thalidomide treatment were not different between patients with or without a sensory CIPN (Table 1), and were not correlated with the sensory scores (Table 2). Times since last thalidomide administration were longer for patients with a sensory CIPN than patients without a sensory CIPN (Table 1), but were not correlated with the sensory scores (Table 2). Moreover, proportions of patients with a sensory CIPN and the sensory scores were not different between patients having received a hematopoietic stem cell transplantation or not (for proportion see Table 1, and 17.8 ± 21.6 vs. 20.2 ± 18.5, p = 0.42, respectively). Finally, among patients with a sensory CIPN, tingling and numbness were proportionally higher in feet than in hands (p < 0.05) (Figure 3).\n\nFIGURE 3 Severity proportions of the QLQ-CIPN20 items assessing tingling, numbness, pain and cramp in hands and feet, among patients with a sensory CIPN. The response categories were recoded to yield a dichotomous outcome per item (white: “not at all” and “a little” vs. black: “quite a bit” and “very much”). *p < 0.05, **p < 0.01. Statistical analysis was performed using McNemar test for paired proportions.\n\nIn parallel, a multivariable analysis of the sensory CIPN was performed on associated factors (male, age, tobacco, alcohol, time since last bortezomib administration, bortezomib routes, and thalidomide treatment). Bortezomib administration via intravenous + subcutaneous routes was associated with a higher proportion of patients with a sensory CIPN, compared to other routes (intravenous route only or subcutaneous route only). Thalidomide treatment was associated with a higher proportion of patients with a sensory CIPN compared to no thalidomide treatment (Figure 4).\n\nFIGURE 4 Forrest plot of the regression coefficients comparing sensory CIPN with patient characteristics and treatments. Multivariable analyses were performed, including patient characteristics: gender (male vs. female), age, tobacco, and alcohol; and chemotherapy characteristics: time since last bortezomib (BTZ) administration (logarithmic transformation), BTZ cumulative dose (logarithmic transformation), route of BTZ administration (intravenous (i.v.) vs. subcutaneous (s.c.) and i. v. + s. c. vs. s. c.), and thalidomide administration. Statistical analysis was performed using multivariable logistic regression.\n\nMotor CIPN\n\nMotor scores of the QLQ-CIPN20 were strongly correlated with sensory scores (Spearman coefficients: 0.74, p < 0.05), were higher for patients with a sensory CIPN than patients without a CIPN (36.7 ± 23.9 vs. 10.9 ± 14.2, p < 0.001), were not different between males and females (15.1 ± 19.7 vs. 20.4 ± 21.5, p = 0.3), and were not correlated with age of patients (Table 2). Motor scores were weakly correlated with the duration and the cumulative dose of bortezomib treatment, but not with the time since last bortezomib administration (Table 2). Motor scores were not different between patients having been treated by thalidomide or not (18.7 ± 20.4 vs. 17.0 ± 21.9, p = 0.65), and were not correlated with the time since last thalidomide administration, or the duration of thalidomide treatment (Table 2). Lastly, motor scores were not different between patient having received a hematopoietic stem cell transplantation or not (15.2 ± 20.0 vs. 21.9 ± 21.8, p = 0.11).\n\nNeuropathic Pain and Pain Medications\n\nHistory of neuropathy and neuropathic pain was similar between patients with or without sensory CIPN. However, this data must be interpreted cautiously because patients tended to mix past neuropathy history, actual CIPN and multiple myeloma symptoms.\n\nAmong the patients analyzed, 59.7% (40) declared having present pain (yes/no), 25.4% 17) were screened positively for pain (pain VAS ≥4/10), and 14.9% (10) for neuropathic pain (pain VAS ≥4/10 and DN4 interview ≥3/7). Among patients with a sensory CIPN, 50.0% 9) were screened positively for pain, and 44.4% 8) for neuropathic pain; the latter proportion was higher than for patients without a sensory CIPN (4.1%, p < 0.001). Sensory and motor scores were higher for patients with a neuropathic pain than patients without (Sensory: 46.5 ± 21.7 vs. 14.1 ± 15.7, p < 0.001; Motor: 38.8 ± 19.8 vs. 14.2 ± 18.7, p < 0.001).\n\nFinally, 52.0% of all the patients analyzed and 66.7% of patients with a sensory CIPN declared they took pain medications (Table 3). Most of the patients both in the sensory CIPN and neuropathic pain groups, declared to take paracetamol (75.0 and 62.5%, respectively), which was also similar to patients without sensory CIPN or neuropathic pain. No patient received duloxetine, one patient with a sensory CIPN received gabapentin and another one pregabalin. It is noteworthy that two patients without sensory CIPN took pregabalin (Table 3).\n\nTABLE 3 Ongoing analgesic treatments among all the patients included, patients without or with a sensory CIPN and patients without or with neuropathic pain. Categorical variables are expressed as numbers (%).\n\n\tTotal (N = 67)\tNo sensory CIPN (N = 49)\tSensory CIPN (N = 18)\tNo neuropathic pain (N = 57)\tNeuropathic pain (N = 10)\t\nAnalgesic treatment\t35 (52.2)\t23 (46.9)\t12 (66.7)\t27 (47.4)\t8 (80.0)\t\nParacetamol\t26 (74.3)\t17 (73.9)\t9 (75.0)\t21 (77.8)\t5 (62.5)\t\nAspirin\t5 (14.3)\t4 (17.4)\t1 (8.3)\t4 (14.8)\t1 (12.5)\t\nMorphine\t4 (11.4)\t3 (13.0)\t1 (8.3)\t3 (11.1)\t1 (12.5)\t\nTramadol + paracetamol\t3 (8.6)\t2 (8.7)\t1 (8.3)\t3 (11.1)\t0 (0)\t\nPregabalin\t3 (8.6)\t2 (8.7)\t1 (8.3)\t3 (11.1)\t0 (0)\t\nIbuprofen\t2 (5.7)\t2 (8.7)\t0 (0)\t2 (7.4)\t0 (0)\t\nCodeine + paracetamol\t2 (5.7)\t0 (0)\t2 (16.7)\t0 (0)\t2 (25.0)\t\nTramadol\t2 (5.7)\t2 (8.7)\t0 (0)\t2 (7.4)\t0 (0)\t\nOpium + paracetamol\t2 (5.7)\t1 (4.4)\t1 (8.3)\t1 (3.7)\t1 (12.5)\t\nParacetamol + opium + caffeine\t1 (2.9)\t1 (4.4)\t0 (0)\t0 (0)\t1 (12.5)\t\nGabapentin\t1 (2.9)\t0 (0)\t1 (8.3)\t0 (0)\t1 (12.5)\t\nAmitriptyline\t1 (2.9)\t0 (0)\t1 (8.3)\t1 (3.7)\t0 (0)\t\nCodeine\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\nDuloxetine\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\nDihydrocodeine\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\nImipramine\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t0 (0)\t\n\nImpact of CIPN on Anxiety, Depression and Quality of Life\n\nProportions of anxiety and depression were higher in patients with sensory CIPN than those without (Figure 5). Sensory scores were higher among patients with anxiety or depression disorders (normal vs. suggestive vs. indicative scores of anxiety: 13.2 ± 15.4 vs. 34.2 ± 22.2 vs. 37.1 ± 27.3, p < 0.001; normal vs. suggestive vs. indicative scores of depression: 11.4 ± 15.9 vs. 34.5 ± 22.0 vs. 27.1 ± 18.8, p < 0.001). The same results were observed for motor scores (normal vs. suggestive vs. indicative scores of anxiety: 12.0 ± 16.2 vs. 34.1 ± 23.3 vs. 35.9 ± 24.8, p < 0.001; normal vs. suggestive vs. indicative scores of depression: 9.9 ± 15.4 vs. 26.5 ± 20.2 vs. 38.2 ± 23.3, p < 0.001).\n\nFIGURE 5 Proportion of anxiety and depression according to sensory CIPN. The results are expressed as percentages. Normal scores of HADS were ≤7, suggestive 8–10 and indicative ≥11 for anxiety or depression. Statistical analysis was performed using Fisher’s exact test.\n\nThe scores of sensory CIPN were moderately correlated with the scores of quality of life of the QLQ-C30 questionnaire for several dimensions (global health status, physical functioning, role functioning, emotional functioning, cognitive functioning, social functioning, pain and insomnia) (Table 4). Moreover, the scores of these dimensions were significantly different between patients with a sensory CIPN and those without (Table 4). The scores of sensory CIPN were moderately to strongly correlated with the scores of all the dimensions of the QLQ-MY20 (disease symptoms, side effects of treatment, body image and future perspective) and the scores of these dimensions were different between patients with a sensory CIPN and those without (Table 4).\n\nTABLE 4 Scores of quality of life (QLQ-C30 and QLQ-MY20) according to sensory CIPN, and correlation with sensory and motor scores of the QLQ-CIPN20.\n\n\tAll the patients\tNo sensory CIPN\tSensory CIPN\tEffect size [CI 95%]\tCorrelations sensory scores\tCorrelations motor scores\t\nQLQ-C30\t\n Global health status\t63.5 ± 24.1\t68.1 ± 22.7\t51.9 ± 24.3*\t−0.69 [−1.24; −0.14]\t−0.52*\t−0.60*\t\n Physical functioning\t74.5 ± 23.0\t79.5 ± 22.5\t60.0 ± 18.3***\t−0.90 [−1.46; −0.33]\t−0.66*\t−0.65*\t\n Role functioning\t75.8 ± 29.7\t83.0 ± 25.8\t54.9 ± 31.0**\t−1.02 [−1.59; −0.44]\t−0.56*\t−0.59*\t\n Emotional functioning\t74.8 ± 26.2\t77.8 ± 26.1\t67.0 ± 25.5*\t−0.42 [−0.95; 0.13]\t−0.47*\t−0.58*\t\n Cognitive functioning\t83.3 ± 22.5\t87.5 ± 19.3\t72.2 ± 26.8*\t−0.70 [−1.25; −0.15]\t−0.48*\t−0.59*\t\n Social functioning\t71.3 ± 27.7\t77.3 ± 25.6\t55.6 ± 27.4**\t−0.82 [−1.37; −0.26]\t−0.59*\t−0.70*\t\n Fatigue\t36.5 ± 31.4\t30.2 ± 30.1\t53.7 ± 28.8**\t0.78 [0.23; 1.33]\t0.51\t0.65*\t\n Nausea and vomiting\t7.1 ± 17.8\t6.5 ± 14.8\t8.8 ± 25.1\t0.13 [−0.42; 0.67]\t0.11\t0.30*\t\n Pain\t25.0 ± 27.6\t18.1 ± 24.0\t43.5 ± 28.7c\t0.99 [0.43; 1.55]\t0.54*\t0.58*\t\n Dyspnea\t28.3 ± 29.4\t27.2 ± 26.9\t31.4 ± 36.3\t0.14 [−0.41; 0.68]\t0.19\t0.29*\t\n Insomnia\t35.4 ± 35.0\t27.9 ± 32.9\t56.9 ± 32.8**\t0.87 [0.30; 1.43]\t0.49*\t0.61*\t\n Appetite loss\t18.7 ± 31.6\t16.3 ± 29.7\t25.5 ± 36.4\t0.29 [−0.26; 0.83]\t0.19\t0.40*\t\n Constipation\t27.8 ± 33.9\t24.5 ± 31.7\t37.2 ± 38.9\t0.37 [−0.18; 0.92]\t0.27*\t0.37*\t\n Diarrhea\t16.4 ± 29.2\t15.0 ± 28.1\t20.4 ± 32.6\t0.18 [−0.35; 0.72]\t0.13\t0.36*\t\n Financial difficulties\t8.6 ± 21.3\t5.6 ± 17.3\t16.7 ± 28.6\t0.52 [−0.02; 1.07]\t0.29*\t0.35*\t\nQLQ-MY20\t\n Disease symptoms\t20.8 ± 20.5\t15.8 ± 16.2\t34.6 ± 25.0**\t0.98 [0.42; 1.54]\t0.55*\t0.58*\t\n Side effects of treatment\t22.4 ± 21.1\t16.3 ± 17.4\t38.9 ± 21.8***\t1.19 [0.62; 1.76]\t0.74*\t0.76*\t\n Body image\t75.4 ± 34.0\t83.0 ± 30.2\t55.6 ± 36.1**\t−0.85 [−1.40; −0.29]\t−0.44*\t−0.62*\t\n Future perspective\t61.2 ± 31.7\t67.8 ± 29.2\t43.8 ± 32.0**\t−0.79 [−1.34; −0.23]\t−0.47*\t−0.49*\t\nThe results present the Spearman coefficient (correlation) between the sensory and motor scores of the QLQ-CIPN20 and the scores of the QLQ-C30 and the scores of the QLQ-MY20. The mean (±standard deviation) scores of the QLQ-C30 dimensions and the QLQ-MY20 dimensions are presented for all the patients, the patients with no sensory CIPN and the patients with a sensory CIPN. Effect size (Hedge coefficient) and 95% interval confidence of this comparison are presented.\n\n* p < 0.05.\n\n** p < 0.01.\n\n*** p < 0.001.\n\nNo sensory CIPN vs. sensory CIPN. Statistical analyzes were performed using student or Mann–Whitney tests for the comparisons between sensory CIPN (yes vs no), and Spearman correlation coefficient to the study of relationship between QLQ-C30, QLQ-MY20 and sensory/motor scores of the QLQ-CIPN20.\n\nThe scores of motor CIPN were moderately correlated with the scores of each dimension of the QLQ-C30 questionnaire (except: nausea and vomiting, dyspnea, constipation, diarrhea, and financial difficulties, which had weak correlations) (Table 4). The scores of motor CIPN were moderately to strongly correlated with the scores of all the dimensions of the QLQ-MY20 (Table 4).\n\nDiscussion\n\nA preliminary finding was that the analysis of the QLQ-CIPN20 questionnaire revealed good internal validity of the sensory and motor scales. In contrast, the results for the vegetative scale were questionable with a poor level of internal consistency, which has already been reported by other authors (Smith et al., 2019).\n\nAmong the 67 patients analyzed having completed bortezomib treatment for multiple myeloma, 26.9% had a sensory CIPN after a median of 1.8 years of bortezomib treatment (min: 0 and max: 10.8 years). In a recent meta-analysis of phase III randomized controlled trials involving bortezomib in any treatment arm for the treatment of multiple myeloma, the overall incidence of sensory peripheral neuropathy ranged from 8.4 to 80.5% (median = 37.8%) for all grades, and from 1 to 33.2% (median = 8%) for grade 3–4 (Li et al., 2019). In another study assessing the long-term outcomes (median follow-up time 24 months) of 128 bortezomib treated Chinese patients, the overall incidence of peripheral neuropathy was 48.4% for all grades, and 17.1% for grade 3–4 (Xia et al., 2016). Another study, focusing on CIPN in multiple myeloma patients, reported 65% of grade 2–3 CIPN assessed with the Indication for Common Toxicity Criteria Grading of Peripheral Neuropathy Questionnaire, which is a PRO (Beijers et al., 2016).\n\nThe sensory scores of the QLQ-CIPN20 and proportion of patients with a sensory CIPN were not related to the time since last bortezomib administration. These results suggested that this CIPN does not completely regress over time, unlike in other studies (Richardson et al., 2006). Our small number of patients may limit this interpretation. Nevertheless, this difference could be explained by the fact that screening and diagnosing CIPN are highly dependent on the tools and methods used. PROs identified a higher incidence and severity of treatment-related toxicities including CIPN than CROs (Beutler et al., 2017). Moreover, another study of our group with the same design and assessing oxaliplatin-related CIPN in a cohort of 406 patients showed a decrease of the QLQ-CIPN20 sensory scores (p = 0.048) but not of the prevalence of the sensory CIPN, over 5 years after the end of chemotherapy (Selvy et al., 2020b).\n\nThe characteristics of bortezomib treatments (cumulative dose and duration of treatment) did not influence neuropathy, as described previously (Beijers et al., 2017; Li et al., 2019). Our study revealed a higher proportion of sensory CIPN in patients with both routes of bortezomib administration (intravenous + subcutaneous) compared to the subcutaneous route, but not between intravenous and subcutaneous routes. Noteworthy, ES were weak to negligible between patients with or withour sensory CIPN. In the same way, Minarik et al. did not find any improvement in the incidence of peripheral neuropathy according to the subcutaneous route (Minarik et al., 2015). However, the subcutaneous route has also been described as more neuroprotective than the intravenous route (Peng et al., 2015). It should be noted that in the present study, the number of patients having been treated only by intravenous route was probably too small to show a statistical significance in comparison to other routes of administration.\n\nIn the multivariable analysis, thalidomide treatment was related to the severity of the sensory CIPN. This result has already been described in the literature (Li et al., 2019) since thalidomide is also a neurotoxic anticancer drug (Velasco et al., 2019).\n\nSensory CIPN was associated with a higher severity of motor CIPN, with a large ES. Besides being toxic to motor nerves, bortezomib can induce a myopathy with symmetrical and proximal lower limb muscle weakness, and without alteration of serum creatine kinase. Bortezomib-induced myopathy completely resolves after treatment discontinuation (Guglielmi et al., 2017). Bortezomib-induced myopathy may result from mitochondrial toxicity inducing or associating lipid accumulation within muscle fibers (Guglielmi et al., 2017).\n\nThe severity of the sensory CIPN was associated with neuropathic pain. Nearly half (44.4%) of the patients with a sensory CIPN had neuropathic pain. These results are very close to those of Lakshman et al. and Corso et al., who found a prevalence between 40 and 50% according to the NCI CTCAE (Corso et al., 2010; Lakshman et al., 2017). Comparatively, neuropathic pain seems to be lower in other types of CIPN, oxaliplatin-induced peripheral neuropathy (36.5% (Selvy et al., 2020b) and 20% (de Carvalho Barbosa et al., 2014)) and paclitaxel-induced peripheral neuropathy (22.5–50% (Golan-Vered and Pud, 2013)). Multiple myeloma is by itself a painful condition, because of osteolytic bone lesions, with back localization in over three quarters of patients. Such lesions are one of the most common complications of multiple myeloma. Myeloma bone disease affects up to 90% of patients complaining of bone pain (Coluzzi et al., 2019). This may be a confounding factor in the assessment of neuropathic pain.\n\nDue to the pain component of the CIPN and to multiple myeloma, the patients included received mainly conventional analgesic treatments. Interestingly, two patients without sensory CIPN declared to take pregabalin, which could be interpreted that pregabalin was effective to treat neuropathic symptoms in these two patients. Duloxetine, which remains the only treatment recommended by the American Society of Clinical Oncology (ASCO) for CIPN (Hershman et al., 2014; Loprinzi et al., 2020), was not used by oncologists to treat CIPN. There appears to be no clear or robust explanation capable of justifying this lack of management. The ASCO guidelines for the management of CIPN (Hershman et al., 2014; Loprinzi et al., 2020) may not have been correctly disseminated to French oncologists, a consideration also mentioned in another study of our group (Selvy et al., 2020b). A Japanese study demonstrated that the dissemination of the Japanese Clinical Guidelines for the Management of CIPN in 2017 (CIPN-GL2017), incorporating ASCO recommendations, increased the prescription rate of duloxetine by Japanese oncologists, for the management of CIPN (Hirayama et al., 2020). Moreover medications used for the management of peripheral neuropathic pain (antiepileptics and antidepressants) are associated with many adverse effects which are underestimated (Selvy et al., 2020a), and which may decrease patient adherence to treatment (Oladapo et al., 2012; Timmerman et al., 2016). Finally, the diagnosis of CIPN is still a concern, as there is no clear consensus on a robust and easy-to-use tool (Colvin, 2019), so perhaps difficulties in the diagnosis and treatment have led to under-diagnosing and under-treating these patients.\n\nIn this population of patients with multiple myeloma and treated with bortezomib, sensory and motor CIPNs were strongly associated with depression, anxiety, and a reduced HRQoL, with large ESs for most of the QLQ-C30 and QLQ-MY20 items. To our knowledge, no publication has explored the association of CIPN and anxiety. Only two publications presented results between CIPN and depression (Beijers et al., 2016; Azoulay et al., 2019). In a cohort of 289 multiple myeloma patients, bone pain and peripheral neuropathy were the two leading symptoms interfering with daily life (Zaleta et al., 2020). Our findings are also shared by other types of CIPNs (Simon et al., 2017; Bonhof et al., 2019; Soveri et al., 2019; Selvy et al., 2020b) and they confirmed Beijers' findings (Beijers et al., 2016) that CIPN significantly alters patients' quality of life over the long term. However, number of treatment lines, disease and treatment status were not recorded in the study, whereas these parameters could also influence HRQoL and psychological distress (Despiégel et al., 2019). Importantly, scores of the QLQ-C30 and HADS questionnaire in our study were very close to those of the study of Servadio et al. assessing HRQoL in 99 multiple myeloma survivors up to 11 years after diagnosis (Servadio et al., 2019).\n\nLimitations of the Study\n\nThe use of the QLQ-CIPN20 questionnaire to assess the prevalence of CIPN may be controversial. In the present study, based on a work by Alberti et al., we used QLQ-CIPN20 scoring to approximate the prevalence of sensory CIPN, considering a QLQ-CIPN20 threshold of ≥30/100 to approximate a grade ≥2 sensory CIPN (Alberti et al., 2014). Alberti et al. showed a close relation between QLQ-CIPN20 scores and NCI-CTCAE sensory grade (p < 0.001). QLQ-CIPN20 scores between 30 and 40 (median ≈ 35, interquartile range ≈ 26–50, and mean ≈ 39) were associated with an NCI-CTCAE sensory neuropathy grade 2 and QLQ-CIPN20 scores >40 (median ≈ 59, interquartile range ≈ 39–62, and mean ≈ 57) were associated with an NCI-CTCAE sensory neuropathy grade 3/4 (Alberti et al., 2014). The QLQ-CPIN20 scoring was able to discriminate NCI-CTCAE neuropathy grade 1 vs. grade 2 (p < 0.001), and grade 2 vs. grade 3/4 (p < 0.001). However, the QLQ-CIPN20 scoring was not able to discriminate neuropathy grade 0 vs. grade 1 (p = 0.53). Le-Rademacher et al. concluded that there are no QLQ-CIPN20 score ranges that correspond directly with NCI-CTCAE grading levels (Le-Rademacher et al., 2017). However, they also emphasized that the QLQ-CIPN20 provided detailed information, distinguished more subtle degrees of neuropathy, and that it was more responsive to change over time than the NCI-CTCAE (Le-Rademacher et al., 2017). Importantly, the sensory score of the QLQ-CIPN20 of the present study (18.9 ± 20.3) were very close to those of the studies of Mendoza et al. (17.2 ± 4.7) (Mendoza et al., 2020) and Beijers et al. (15.3 ± 16.7) (Beijers et al., 2017). In our study, the self-administered questionnaire was particularly useful to assess CIPN severity using a paper questionnaire sent to patients. Neuropathy history was initially recorded but data were excluded from the analysis because the patients tended to mix past neuropathy history and ongoing CIPN. However, neuropathy history would have been of interest, because it has already been described as a risk factor of CIPN (Molassiotis et al., 2019b). Selection bias may be present in the study, since the patients came from a single center. However, the patients were managed in two different medical departments of the university hospital of Clermont-Ferrand. It is also possible that neuropathic patients are over-represented because these patients have felt compelled to respond to the questionnaires. Information bias was probably present, since the patients’ answers were subjective and unsupported by clinical assessment (such as neurological examination, nerve conduction studies, quantitative sudomotor axon reflex test or skin biopsies). Moreover, PRO measures may overestimate CIPN prevalence as they include symptoms that may have pre-existed the chemotherapy (Molassiotis et al., 2019b). Although the oncological data came from the medical prescription software of the university hospital.\n\nConclusion\n\nSensory CIPN was identified in a quarter of the patients after ending bortezomib treatment, underlining the high prevalence and persistence of this adverse effect. Interestingly, neuropathic pain was highly prevalent in patients with a sensory CIPN, unlike CIPN associated with other neurotoxic anticancer drugs. The bortezomib-related CIPN was associated with considerable psychological distress. Management of patients with a sensory CIPN was not adequate, a finding in agreement with other studies, and which highlights the global lack of management of CIPN in France. There is a need to improve CIPN management which could include better screening, treatment and follow-up of patients. Such strategy should also include a better training for oncologists, since French oncologists’ professional practices are not optimal (Selvy et al., 2021).\n\nCIPN considerably decreases the HRQoL of cancer patients and there is a current lack of innovative strategies for both assessing and managing it.\n\nThe authors thank the patients who participated in the study.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, upon request.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by Comité de Protection des Personnes sud-est 5, IRB: 6705. The ethics committee waived the requirement of written informed consent for participation.\n\nAuthor Contributions\n\nConceptualization, DB methodology, DB, and FG; software, DB validation, BP and DB formal analysis, MSy. BP, and DB investigation, MSy, NK, AC, CC, MSr, JB, RL, and DB resources, DB data curation, FB, DN, and DB writing—original draft preparation, MSy, BP, NK, JB, RL, and DB writing—review and editing, MSy, BP, NK, JB, RL, and DB visualization, BP, JB, and DB supervision, RL, and DB project administration, DB. All the authors have read and agreed to the published version of the manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n==== Refs\nReferences\n\nAaronson N. K. Ahmedzai S. Bergman B. Bullinger M. Cull A. Duez N. J. (1993). The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. JNCI J. Natl. Cancer Inst. 85 , 365–376. 10.1093/jnci/85.5.365 8433390\nAlberti P. Rossi E. Cornblath D. R. Merkies I. S. J. Postma T. J. Frigeni B. (2014). Physician-assessed and patient-reported outcome measures in chemotherapy-induced sensory peripheral neurotoxicity: two sides of the same coin. Ann. Oncol. 25 , 257–264. 10.1093/annonc/mdt409 24256846\nAltman D. G. (1999). Practical statistics for medical research. Boca Raton: Chapman & Hall/CRC.\nAzoulay D. Giryes S. Nasser R. Sharon R. Horowitz N. A. (2019). Prediction of chemotherapy-induced peripheral neuropathy in patients with lymphoma and myeloma: the roles of brain-derived neurotropic factor protein levels and A gene polymorphism. J. Clin. Neurol. 15 , 511. 10.3988/jcn.2019.15.4.511 31591840\nBeijers A. J. M. Oerlemans S. Mols F. Eurelings M. Minnema M. C. Vreugdenhil A. (2017). The magnitude of neurotoxicity in patients with multiple myeloma and the impact of dose modifications: results from the population-based PROFILES registry. Ann. Hematol. 96 , 653–663. 10.1007/s00277-017-2927-8 28116479\nBeijers A. J. M. Vreugdenhil G. Oerlemans S. Eurelings M. Minnema M. C. Eeltink C. M. (2016). Chemotherapy-induced neuropathy in multiple myeloma: influence on quality of life and development of a questionnaire to compose common toxicity criteria grading for use in daily clinical practice. Support Care Cancer 24 , 2411–2420. 10.1007/s00520-015-3032-y 26634561\nBender R. Lange S. (2001). Adjusting for multiple testing-when and how? J. Clin. Epidemiol. 54 , 343–349. 10.1016/s0895-4356(00)00314-0 11297884\nBeutler A. S. Majithia N. Loprinzi C. L. (2017). The past and future of 'reported outcomes' in studies on chemotherapy neuropathy. Ann. Oncol. 28 , 2631–2632. 10.1093/annonc/mdx520 28950347\nBonhof C. S. Poll‐Franse L. V. Vissers P. A. J. Wasowicz D. K. Wegdam J. A. Révész D. (2019). Anxiety and depression mediate the association between chemotherapy‐induced peripheral neuropathy and fatigue: results from the population‐based PROFILES registry. Psycho‐Oncology 28 , 1926–1933. 10.1002/pon.5176 31293046\nBouhassira D. Attal N. Alchaar H. Boureau F. Brochet B. Bruxelle J. (2005). Comparison of pain syndromes associated with nervous or somatic lesions and development of a new neuropathic pain diagnostic questionnaire (DN4). Pain 114 , 29–36. 10.1016/j.pain.2004.12.010 15733628\nChibaudel B. Maindrault-Goebel F. Lledo G. Mineur L. André T. Bennamoun M. (2009). Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. Jco 27 , 5727–5733. 10.1200/JCO.2009.23.4344\nCocks K. Cohen D. Wisløff F. Sezer O. Lee S. Hippe E. (2007). An international field study of the reliability and validity of a disease-specific questionnaire module (the QLQ-MY20) in assessing the quality of life of patients with multiple myeloma. Eur. J. Cancer 43 , 1670–1678. 10.1016/j.ejca.2007.04.022 17574838\nCohen J. (1988). Statistical power analysis for the behavioral sciences. 2nd ed. Hillsdale, N.J: L. Erlbaum Associates.\nColuzzi F. Rolke R. Mercadante S. (2019). Pain management in patients with multiple myeloma: an update. Cancers 11 , 2037. 10.3390/cancers11122037\nColvin L. A. (2019). Chemotherapy-induced peripheral neuropathy: where are we now? Pain 160 (Suppl. 1 ), S1–S10. 10.1097/j.pain.0000000000001540 31008843\nCorso A. Mangiacavalli S. Varettoni M. Pascutto C. Zappasodi P. Lazzarino M. (2010). Bortezomib-induced peripheral neuropathy in multiple myeloma: a comparison between previously treated and untreated patients. Leuk. Res. 34 , 471–474. 10.1016/j.leukres.2009.07.022 19674790\nDault R. Rousseau M. P. Beaudoin A. Frenette M. A. Lemay F. Beauchesne M. F. (2016). Impact of oxaliplatin-induced neuropathy in patients with colorectal cancer: a prospective evaluation at a single institution. Curr. Oncol. 23 , 65–69. 10.3747/co.23.2780\nde Carvalho Barbosa M. Kosturakis A. K. Eng C. Wendelschafer-Crabb G. Kennedy W. R. Simone D. A. (2014). A quantitative sensory analysis of peripheral neuropathy in colorectal cancer and its exacerbation by oxaliplatin chemotherapy. Cancer Res. 74 , 5955–5962. 10.1158/0008-5472.CAN-14-2060 25183707\nDespiégel N. Touboul C. Flinois A. Saba G. Suzan F. Gonzalez-McQuire S. (2019). Health-related quality of life of patients with multiple myeloma treated in routine clinical practice in France. Clin. Lymphoma Myeloma Leuk. 19 , e13–e28. 10.1016/j.clml.2018.08.019 30292736\nElm E. v. Altman D. G. Egger M. Pocock S. J. Gøtzsche P. C. Vandenbroucke J. P. (2007). Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. J. Clin. Epidemiol., 61 (4 ):344–349. 10.1016/j.jclinepi.2007.11.008\nFeise R. J. (2002). Do multiple outcome measures require p-value adjustment? BMC Med. Res. Methodol. 2 , 8. 10.1186/1471-2288-2-8 12069695\nFrance Santé. Publique. (2017). Avis d’experts relatif à l’évolution du discours public en matière de consommation d’alcool en France. Available at: https://www.santepubliquefrance.fr/content/download/2143/18554/version/3/file/avis_alcool_040517.pdf (Accessed March 5, 2019).\nGolan-Vered Y. Pud D. (2013). Chemotherapy-induced neuropathic pain and its relation to cluster symptoms in breast cancer patients treated with paclitaxel. Off. J. World Inst. Pain 13 , 46–52. 10.1111/j.1533-2500.2012.00554.x\nGriffith K. A. Merkies I. S. J. Hill E. E. Cornblath D. R. (2010). Measures of chemotherapy-induced peripheral neuropathy: a systematic review of psychometric properties. J. Peripher. Nerv. Syst. JPNS 15 , 314–325. 10.1111/j.1529-8027.2010.00292.x 21199103\nGuglielmi V. Nowis D. Tinelli M. Malatesta M. Paoli L. Marini M. (2017). Bortezomib-induced muscle toxicity in multiple myeloma. J. Neuropathol. Exp. Neurol. 76 , 620–630. 10.1093/jnen/nlx043 28863457\nHarris P. A. Taylor R. Thielke R. Payne J. Gonzalez N. Conde J. G. (2009). Research electronic data capture (REDCap)-A metadata-driven methodology and workflow process for providing translational research informatics support. J. Biomed. Inform. 42 , 377–381. 10.1016/j.jbi.2008.08.010 18929686\nHershman D. L. Lacchetti C. Dworkin R. H. Lavoie Smith E. M. Bleeker J. Cavaletti G. (2014). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: American society of clinical oncology clinical practice guideline. Jco 32 , 1941. 10.1200/JCO.2013.54.0914\nHirayama Y. Yoshida Y. Mori M. Tamura K. (2020). Effects of the publication of clinical guidelines for the management of chemotherapy-induced peripheral neuropathy on the administration preferences of oncology specialists: Japanese association of supportive care in cancer. Jpn. J. Clin. Oncol. Hyaa056 50 , 897. 10.1093/jjco/hyaa056\nKazandjian D. (2016). Multiple myeloma epidemiology and survival: a unique malignancy. Semin. Oncol. 43 , 676–681. 10.1053/j.seminoncol.2016.11.004 28061985\nKerckhove N. Collin A. Condé S. Chaleteix C. Pezet D. Balayssac D. (2017). Long-term effects, pathophysiological mechanisms, and risk factors of chemotherapy-induced peripheral neuropathies: a comprehensive literature review. Front. Pharmacol. 8 , 86. 10.3389/fphar.2017.00086 28286483\nLakshman A. Modi M. Prakash G. Malhotra P. Khadwal A. Jain S. (2017). Evaluation of bortezomib-induced neuropathy using total neuropathy score (reduced and clinical versions) and NCI CTCAE v4.0 in newly diagnosed patients with multiple myeloma receiving bortezomib-based induction. Clin. Lymphoma Myeloma Leuk. 17 , 513–519.e1. 10.1016/j.clml.2017.06.035 28842138\nLavoie Smith E. Haupt R. Kelly J. Lee D. Kanzawa-Lee G. Knoerl R. (2017). The content validity of a chemotherapy-induced peripheral neuropathy patient-reported outcome measure. Onf 44 , 580–588. 10.1188/17.ONF.580-588\nLe-Rademacher J. Kanwar R. Seisler D. Pachman D. R. Qin R. Abyzov A. (2017). Patient-reported (EORTC QLQ-CIPN20) versus physician-reported (CTCAE) quantification of oxaliplatin- and paclitaxel/carboplatin-induced peripheral neuropathy in NCCTG/Alliance clinical trials. Support Care Cancer 25 , 3537–3544. 10.1007/s00520-017-3780-y 28634656\nLi T. Timmins H. C. King T. Kiernan M. C. Goldstein D. Park S. B. (2020). Characteristics and risk factors of bortezomib induced peripheral neuropathy: a systematic review of phase III trials. Hematological Oncol. 38 , 229. 10.1002/hon.2706\nLoprinzi C. L. Lacchetti C. Bleeker J. Cavaletti G. Chauhan C. Hertz D. L. (2020). Prevention and management of chemotherapy-induced peripheral neuropathy in survivors of adult cancers: ASCO guideline update. Jco 38 , 3325–3348. 10.1200/JCO.20.01399\nMendoza T. R. Williams L. A. Shi Q. Wang X. S. Bamidele O. Woodruff J. F. (2020). The Treatment-induced Neuropathy Assessment Scale (TNAS): a psychometric update following qualitative enrichment. J. Patient Rep. Outcomes 4 , 15. 10.1186/s41687-020-0180-8 32076879\nMinarik J. Pavlicek P. Pour L. Pika T. Maisnar V. Spicka I. (2015). Subcutaneous bortezomib in multiple myeloma patients induces similar therapeutic response rates as intravenous application but it does not reduce the incidence of peripheral neuropathy. PLoS One 10 , e0123866. 10.1371/journal.pone.0123866 25875484\nMolassiotis A. Cheng H. L. Leung K. T. Li Y. C. Wong K. H. Au J. S. K. (2019a). Risk factors for chemotherapy‐induced peripheral neuropathy in patients receiving taxane‐ and platinum‐based chemotherapy. Brain Behav. 9 –e01312. 10.1002/brb3.1312\nMolassiotis A. Cheng H. L. Lopez V. Au J. S. K. Chan A. Bandla A. (2019b). Are we mis-estimating chemotherapy-induced peripheral neuropathy? Analysis of assessment methodologies from a prospective, multinational, longitudinal cohort study of patients receiving neurotoxic chemotherapy. BMC Cancer 19 , 132. 10.1186/s12885-019-5302-4 30736741\nOladapo A. O. Barner J. C. Rascati K. L. Strassels S. A. (2012). A retrospective database analysis of neuropathic pain and oral antidiabetic medication use and adherence among Texas adults with type 2 diabetes enrolled in medicaid. Clin. Ther. 34 , 605–613. 10.1016/j.clinthera.2012.02.007 22386828\nPalumbo A. Anderson K. (2011). Multiple myeloma. N. Engl. J. Med. 364 , 1046–1060. 10.1056/NEJMra1011442 21410373\nPeng L. Ye X. Zhou Y. Zhang J. Zhao Q. (2015). Meta-analysis of incidence and risk of peripheral neuropathy associated with intravenous bortezomib. Support Care Cancer 23 , 2813–2824. 10.1007/s00520-015-2648-2 25676487\nPostma T. J. Aaronson N. K. Heimans J. J. Muller M. J. Hildebrand J. G. Delattre J. Y. (2005). The development of an EORTC quality of life questionnaire to assess chemotherapy-induced peripheral neuropathy: the QLQ-CIPN20. Eur. J. Cancer 41 , 1135–1139. 10.1016/j.ejca.2005.02.012 15911236\nPostma T. J. Heimans J. J. Muller M. J. Ossenkoppele G. J. Vermorken J. B. Aaronson N. K. (1998). Pitfalls in grading severity of chemotherapy-induced peripheral neuropathy. Ann. Oncol. 9 , 739–744. 10.1023/a:1008344507482 9739440\nRichardson P. G. Briemberg H. Jagannath S. Wen P. Y. Barlogie B. Berenson J. (2006). Frequency, characteristics, and reversibility of peripheral neuropathy during treatment of advanced multiple myeloma with bortezomib. Jco 24 , 3113–3120. 10.1200/JCO.2005.04.7779\nRichardson P. G. Xie W. Mitsiades C. Chanan-Khan A. A. Lonial S. Hassoun H. (2009). Single-agent bortezomib in previously untreated multiple myeloma: efficacy, characterization of peripheral neuropathy, and molecular correlations with response and neuropathy. Jco 27 , 3518–3525. 10.1200/JCO.2008.18.3087\nRothman K. J. (1990). No adjustments are needed for multiple comparisons. Epidemiology 1 , 43–46. 10.1097/00001648-199001000-00010 2081237\nScott K. Hayden P. J. Will A. Wheatley K. Coyne I. (2016). Bortezomib for the treatment of multiple myeloma. Cochrane Database Syst. Rev. 4 , CD010816. 10.1002/14651858.CD010816.pub2 27096326\nSelvy M. Cuménal M. Kerckhove N. Courteix C. Busserolles J. Balayssac D. (2020a). The safety of medications used to treat peripheral neuropathic pain, part 1 (antidepressants and antiepileptics): review of double-blind, placebo-controlled, randomized clinical trials. Expert Opin. Drug Saf. 19 , 707–733. 10.1080/14740338.2020.1764934 32363948\nSelvy M. Pereira B. Kerckhove N. Gonneau C. Feydel G. Pétorin C. (2020b). Long-term prevalence of sensory chemotherapy-induced peripheral neuropathy for 5 Years after adjuvant folfox chemotherapy to treat colorectal cancer: a multicenter cross-sectional study. Jcm 9 , 2400. 10.3390/jcm9082400\nSelvy M. Pereira B. Kerckhove N. Busserolles J. Farsi F. Guastella V. (2021). Prevention, diagnosis and management of chemotherapy-induced peripheral neuropathy: a cross-sectional study of French oncologists’ professional practices. Support Care Cancer 12 , 33. 10.1007/s00520-020-05928-6\nServadio M. Cottone F. Sommer K. Oerlemans S. van de Poll-Franse L. Efficace F. (2019). Physical activity and health-related quality of life in multiple myeloma survivors: the PROFILES registry. BMJ Support. Palliat. Carepalliat. Care 10 , e35. 10.1136/bmjspcare-2018-001755\nSimon N. B. Danso M. A. Alberico T. A. Basch E. Bennett A. V. (2017). The prevalence and pattern of chemotherapy-induced peripheral neuropathy among women with breast cancer receiving care in a large community oncology practice. Qual. Life Res. 26 , 2763–2772. 10.1007/s11136-017-1635-0 28664460\nSmith E. M. L. Banerjee T. Yang J. J. Bridges C. M. Alberti P. Sloan J. A. (2019). Psychometric testing of the European organisation for research and treatment of cancer quality of life questionnaire-chemotherapy-induced peripheral neuropathy 20-item scale using pooled chemotherapy-induced peripheral neuropathy outcome measures standardization and alliance for clinical trials in oncology A151408 study data. Cancer Nurs. 42 , 179–189. 10.1097/NCC.0000000000000596 29649081\nSong X. Wilson K. L. Kagan J. Panjabi S. (2019). Cost of peripheral neuropathy in patients receiving treatment for multiple myeloma: a US administrative claims analysis. Ther. Adv. Hematol. 10 , 204062071983902. 10.1177/2040620719839025\nSoveri L. M. Lamminmäki A. Hänninen U. A. Karhunen M. Bono P. Osterlund P. (2019). Long-term neuropathy and quality of life in colorectal cancer patients treated with oxaliplatin containing adjuvant chemotherapy. Acta Oncologica 58 , 398–406. 10.1080/0284186X.2018.1556804 30638100\nThorsteinsdottir S. Dickman P. W. Landgren O. Blimark C. Hultcrantz M. Turesson I. (2018). Dramatically improved survival in multiple myeloma patients in the recent decade: results from a Swedish population-based study. Haematologica 103 , e412–e415. 10.3324/haematol.2017.183475 29567776\nTimmerman L. Stronks D. L. Groeneweg J. G. Huygen F. J. (2016). Prevalence and determinants of medication non-adherence in chronic pain patients: a systematic review. Acta Anaesthesiol. Scand. 60 , 416–431. 10.1111/aas.12697 26860919\nVelasco R. Alberti P. Bruna J. Psimaras D. Argyriou A. A. (2019). Bortezomib and other proteosome inhibitors-induced peripheral neurotoxicity: from pathogenesis to treatment. J. Peripher. Nerv. Syst. 24 . 10.1111/jns.12338\nXia Z.-j. Wang H. Wang L. Lu Y. Chen X. Geng Q. (2016). Long-term outcomes of different bortezomib-based regimens in Chinese myeloma patients. Ott 587 , 587. 10.2147/OTT.S97457\nZaleta A. K. Miller M. F. Olson J. S. Yuen E. Y. N. LeBlanc T. W. Cole C. E. (2020). Symptom burden, perceived control, and quality of life among patients living with multiple myeloma. J. Natl. Compr. Canc. Netw. 18 , 1087–1095. 10.6004/jnccn.2020.7561 32755984\nZigmond A. S. Snaith R. P. (1983). The hospital anxiety and depression scale. Acta Psychiatr. Scand. 67 , 361–370. 10.1111/j.1600-0447.1983.tb09716.x 6880820\n\n",
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"keywords": "anxiety; bortezomib; chemotherapy-induced peripheral neuropathy; depression; health-related quality of life; multiple myeloma; neuropathic pain",
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"title": "Prevalence of Chemotherapy-Induced Peripheral Neuropathy in Multiple Myeloma Patients and its Impact on Quality of Life: A Single Center Cross-Sectional Study.",
"title_normalized": "prevalence of chemotherapy induced peripheral neuropathy in multiple myeloma patients and its impact on quality of life a single center cross sectional study"
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"abstract": "Clinical presentations associated with vitamin A deficiency persist in poor regions globally with the same clinical features as those described centuries ago. However, new forms of vitamin A deficiency affecting the eyes, which have become widespread, as a result of modern societal habits are of increasing concern. Ophthalmic conditions related to vitamin A deficiency require the combined attention of ophthalmologists, pediatricians, internists, dermatologists, and nutritionists due to their potential severity and the diversity of causes. As the eyes and their adnexa are particularly sensitive to vitamin A deficiency and excess, ocular disturbances are often early indicators of vitamin A imbalance. The present review describes the clinical manifestations of hypovitaminosis A with an emphasis on so-called modern dietary disorders and multidisciplinary treatment approaches. The present review also discusses the relationship between retinoic acid therapy and dry eye disease.",
"affiliations": "Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Patologia e Medicina Legal, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Medicina Social, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.;Departamento de Oftalmologia e Otorrinolaringologia, Faculdade de Ciências Médicas, Universidade Estadual de Campinas, Ribeirão Preto, SP, Brazil.;Departamento de Oftalmologia, Otorrinolaringologia e Cirurgia de Cabeça e Pescoço, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Ribeirão Preto, SP, Brazil.",
"authors": "Faustino|Jacqueline Ferreira|JF|;Ribeiro-Silva|Alfredo|A|;Dalto|Rodrigo Faeda|RF|;Souza|Marcelo Martins de|MM|;Furtado|João Marcello Fortes|JM|;Rocha|Gutemberg de Melo|Gde M|;Alves|Monica|M|;Rocha|Eduardo Melani|EM|",
"chemical_list": "D014801:Vitamin A",
"country": "Brazil",
"delete": false,
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"issue": "79(1)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D000152:Acne Vulgaris; D000368:Aged; D002675:Child, Preschool; D002908:Chronic Disease; D005128:Eye Diseases; D006801:Humans; D008297:Male; D014801:Vitamin A; D014802:Vitamin A Deficiency; D055815:Young Adult",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "56-61",
"pmc": null,
"pmid": "26840172",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Vitamin A and the eye: an old tale for modern times.",
"title_normalized": "vitamin a and the eye an old tale for modern times"
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"companynumb": "BR-MYLANLABS-2016M1056020",
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"abstract": "We present the case of a patient with human immunodeficiency virus (HIV) with a LTCD4 + 49 cells/mm3, who was admitted due to a seven-month period of weight loss, abdominal pain, chronic diarrhea and rubbery skin lesions. Myeloculture and blood cultures were positive for Rhodococcus equi. In addition, histological lesions in the skin and intestine compatible with this agent were observed, such as malacoplachy, granulomatous reaction and Michaelis-Gutmann bodies. Pulmonary involvement was ruled out by chest tomography. The patient received antibacterial therapy combined with clarithromycin, imipenem, and vancomycin. Despite the treatment, the patient evolved unfavorably and died.",
"affiliations": "Facultad de Medicina Humana \"Manuel Huamán Guerrero\", Universidad Ricardo Palma, Lima, Perú.;Facultad de Medicina \"San Fernando\", Universidad Nacional Mayor de San Marcos, Lima, Perú.",
"authors": "Patrón-Ordóñez|Gino|G|;Risco-Rebaza|Jean Carlos|JC|",
"chemical_list": null,
"country": "Chile",
"delete": false,
"doi": "10.4067/S0716-10182020000500610",
"fulltext": null,
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"issn_linking": "0716-1018",
"issue": "37(5)",
"journal": "Revista chilena de infectologia : organo oficial de la Sociedad Chilena de Infectologia",
"keywords": null,
"medline_ta": "Rev Chilena Infectol",
"mesh_terms": "D000193:Actinomycetales Infections; D015658:HIV Infections; D006801:Humans; D010568:Peru; D016929:Rhodococcus equi",
"nlm_unique_id": "9305754",
"other_id": null,
"pages": "610-614",
"pmc": null,
"pmid": "33399812",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Rhodococcus equi, first case report of disseminated disease in Peru.",
"title_normalized": "rhodococcus equi first case report of disseminated disease in peru"
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"companynumb": "PE-SUN PHARMACEUTICAL INDUSTRIES LTD-2021RR-293604",
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"abstract": "Approximately 10% to 20% of prolactinomas are resistant to dopamine agonist therapy. The ErbB signaling pathway may drive aggressive prolactinoma behavior.\n\n\n\nWe evaluated lapatinib, an ErbB1-epidermal growth factor receptor (EGFR)/ErbB2 or human EGFR2 (HER2) tyrosine kinase inhibitor (TKI), in aggressive prolactinomas.\n\n\n\nA prospective, phase 2a multicenter trial was conducted.\n\n\n\nThis study took place at a tertiary referral pituitary center.\n\n\n\nStudy participants included adults with aggressive prolactinomas showing continued tumor growth despite maximally tolerated dopamine agonist therapy.\n\n\n\nIntervention included oral lapatinib 1250 mg/day for 6 months.\n\n\n\nThe primary end point was 40% reduction in any tumor dimension assessed by magnetic resonance imaging at study end; tumor response was assessed by Response Evaluation Criteria in Solid Tumors criteria. Secondary end points included prolactin (PRL) reduction, correlation of response with EGFR/HER2 expression, and safety.\n\n\n\nOwing to rigorous inclusion criteria, of 24 planned participants, only 7 consented and 4 were treated. None achieved the primary end point but 3 showed stable disease, including 2 with a 6% increase and 1 with a 16.8% decrease in tumor diameter. PRL response was not always concordant with tumor response, as 2 showed 28% and 59% increases in PRL. The fourth participant had a PRL-secreting carcinoma and withdrew after 3 months of lapatinib because of imaging and PRL progression. EGFR/HER2 expression did not correlate with treatment response. Lapatinib was well tolerated overall, with reversible grade 1 transaminitis in 2 patients, grade 2 rash in 2 patients, and grade 1 asymptomatic bradycardia in 2 patients.\n\n\n\nAn oral TKI such as lapatinib may be an effective option for a difficult-to-treat patient with an aggressive prolactinoma.",
"affiliations": "Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.;Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.;Departments of Medicine, Neurology, and Neurosurgery, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.;Department of Imaging, Cedars-Sinai Medical Center, Los Angeles, California.;Neuroendocrine Unit, Massachusetts General Hospital, Boston, Massachusetts.;Division of Endocrinology, Diabetes, and Metabolism and Pituitary Center, Johns Hopkins Hospital, Baltimore, Maryland.;Department of Neuroendocrinology and Neurosurgery, Barrow Pituitary Center, Barrow Neurological Institute, University of Arizona College of Medicine and Creighton School of Medicine, Phoenix, Arizona.;Pituitary Center, Departments of Medicine (Endocrinology) and Neurological Surgery, Oregon Health & Science University, Portland, Oregon.;Pituitary Center, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California.",
"authors": "Cooper|Odelia|O|;Bonert|Vivien S|VS|;Rudnick|Jeremy|J|;Pressman|Barry D|BD|;Lo|Janet|J|;Salvatori|Roberto|R|;Yuen|Kevin C J|KCJ|;Fleseriu|Maria|M|;Melmed|Shlomo|S|",
"chemical_list": "D000970:Antineoplastic Agents; D000077341:Lapatinib; C512478:EGFR protein, human; C508053:ERBB2 protein, human; D066246:ErbB Receptors; D018719:Receptor, ErbB-2",
"country": "United States",
"delete": false,
"doi": "10.1210/clinem/dgaa805",
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"issn_linking": "0021-972X",
"issue": "106(2)",
"journal": "The Journal of clinical endocrinology and metabolism",
"keywords": "ErbB; HER2; epidermal growth factor receptor; lapatinib; prolactinoma; tyrosine kinase inhibitor",
"medline_ta": "J Clin Endocrinol Metab",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D066246:ErbB Receptors; D005260:Female; D005500:Follow-Up Studies; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077341:Lapatinib; D008297:Male; D008875:Middle Aged; D010911:Pituitary Neoplasms; D011379:Prognosis; D015175:Prolactinoma; D011446:Prospective Studies; D018719:Receptor, ErbB-2; D055815:Young Adult",
"nlm_unique_id": "0375362",
"other_id": null,
"pages": "e917-e925",
"pmc": null,
"pmid": "33150390",
"pubdate": "2021-01-23",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D052061:Research Support, N.I.H., Extramural",
"references": "18832099;11701688;19470835;32130815;29936681;26392518;31746334;19223454;21106881;28520590;19097774;21917845;1670924;28432119;24287797;31617128;6195656;21296991;19401448;18676863;29046323;29330228;27468100;30699424;25375038;30400048",
"title": "EGFR/ErbB2-Targeting Lapatinib Therapy for Aggressive Prolactinomas.",
"title_normalized": "egfr erbb2 targeting lapatinib therapy for aggressive prolactinomas"
} | [
{
"companynumb": "NVSC2020US306628",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LAPATINIB"
},
"drugadditional": null,
"druga... |
{
"abstract": "Frostbite injury causes direct damage to tissues following exposure to temperatures below their freezing point causing tissue death potentially leading to serious amputations. After rewarming, a variety of treatment options have been employed to avoid amputation. This case report details the use of indocyanine green fluorescence microangiography to monitor the clinical progression of perfusion following hyperbaric oxygen therapy (HBOT) for severe frostbite injury. We present a case report of a man with deep frostbite of the bilateral hands treated with thrombolytics and HBOT. After rewarming, the patient received thrombolytics shortly after arrival and then went on to be treated with HBOT on hospital day 5. Patient's healing progress was monitored using serial microangiography. Microangiography evaluation was performed on day 6 and then weekly to track treatment progress. A more uniform brightness appears in his left hand by completion of his therapies, consistent with normal perfusion. The dark ischemic areas in the right hand receded in digits 1 to 3 and appeared normalized in the fourth digit. The patient received a total of 20 HBO treatments. After completion of therapy, the patient went on to have a partial amputation of his first, second, and third fingers on his right hand. Our case report demonstrates serial microangiography to monitor a frostbite patient's progress during HBOT and provided additional information allowing us to plan duration of treatments. Our case report describes the role that microangiography may serve in monitoring patient progress following severe frostbite injury.",
"affiliations": "Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.;Hennepin County Medical Center, Minneapolis, Minnesota.",
"authors": "Masters|Thomas|T|;Omodt|Steven|S|;Gayken|Jon|J|;Logue|Christopher|C|;Westgard|Bjorn|B|;Hendriksen|Stephen|S|;Walter|Joseph|J|;Nygaard|Rachel|R|",
"chemical_list": "D004396:Coloring Agents; D007208:Indocyanine Green",
"country": "England",
"delete": false,
"doi": "10.1097/BCR.0000000000000526",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1559-047X",
"issue": "39(1)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": "D000792:Angiography; D004396:Coloring Agents; D005627:Frostbite; D006230:Hand Injuries; D006801:Humans; D006931:Hyperbaric Oxygenation; D007208:Indocyanine Green; D008297:Male; D008856:Microscopy, Fluorescence; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "162-167",
"pmc": null,
"pmid": "28328661",
"pubdate": "2018-01-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Microangiography to Monitor Treatment Outcomes Following Severe Frostbite Injury to the Hands.",
"title_normalized": "microangiography to monitor treatment outcomes following severe frostbite injury to the hands"
} | [
{
"companynumb": "US-ALSI-201700105",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "OXYGEN"
},
"drugadditional": null,
"drugad... |
{
"abstract": "OBJECTIVE\nFew studies support oral diabetic treatment in pregnant women with type 2 diabetes mellitus (T2DM). The objective of this study was to compare the effects of metformin versus insulin on achieving glycemic control and improving maternal and neonatal outcomes in pregnant women with T2DM.\n\n\nMETHODS\nA pilot randomized, controlled trial was conducted of metformin versus insulin for the treatment of T2DM during pregnancy. The primary outcome was glycemic control measured with hemoglobin A1c < 7% at delivery. Maternal and neonatal outcomes were compared between groups.\n\n\nRESULTS\nIn this study, 8 women received metformin and 11 received insulin. All women in both groups achieved glycemic control by delivery (HgbA1c: metformin 5.96 ± 5.88 vs. insulin 6.34 ± 0.92%). There were similar rates of cesarean delivery, birth weights, neonatal intensive care unit admissions, respiratory distress syndrome, and neonatal dextrose treatment between groups. There was one case of fetal macrosomia in the insulin group, one case of shoulder dystocia in the metformin group and no cases of failed metformin therapy.\n\n\nCONCLUSIONS\nIn this pilot study, glycemic control was achieved in women who received metformin and insulin. Larger studies are needed to determine whether metformin can be considered a reasonable alternative to insulin in pregnant women with T2DM.",
"affiliations": "Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas.;Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Brownsville, Brownsville, Texas.;Center for Clinical Research and Evidence-Based Medicine, University of Texas Health Science Center at Houston, Houston, Texas.;Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas.;Division of Maternal Fetal Medicine, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Texas Health Science Center at Houston, Houston, Texas.;Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas.",
"authors": "Refuerzo|Jerrie S|JS|;Gowen|Rose|R|;Pedroza|Claudia|C|;Hutchinson|Maria|M|;Blackwell|Sean C|SC|;Ramin|Susan|S|",
"chemical_list": "D001786:Blood Glucose; D006442:Glycated Hemoglobin A; D007004:Hypoglycemic Agents; D007328:Insulin; C517652:hemoglobin A1c protein, human; D008687:Metformin",
"country": "United States",
"delete": false,
"doi": "10.1055/s-0034-1378144",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0735-1631",
"issue": "30(2)",
"journal": "American journal of perinatology",
"keywords": null,
"medline_ta": "Am J Perinatol",
"mesh_terms": "D000328:Adult; D001724:Birth Weight; D001786:Blood Glucose; D003924:Diabetes Mellitus, Type 2; D004420:Dystocia; D005260:Female; D005320:Fetal Macrosomia; D006442:Glycated Hemoglobin A; D006801:Humans; D007004:Hypoglycemic Agents; D007231:Infant, Newborn; D007328:Insulin; D008687:Metformin; D010865:Pilot Projects; D011247:Pregnancy; D011254:Pregnancy in Diabetics; D016896:Treatment Outcome",
"nlm_unique_id": "8405212",
"other_id": null,
"pages": "163-70",
"pmc": null,
"pmid": "24896141",
"pubdate": "2015-02",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "A pilot randomized, controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy.",
"title_normalized": "a pilot randomized controlled trial of metformin versus insulin in women with type 2 diabetes mellitus during pregnancy"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2021-06007",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METFORMIN HYDROCHLORIDE"
},
... |
{
"abstract": "Malignant pleural mesothelioma (MPM) is the aggressive disease typically spreading along the pleural surface and encasing the lung, leading to respiratory failure or cachexia. Rare cases with atypical clinical manifestation or presentation have been reported in MPM. We experienced a unique case of MPM concurrently associated with miliary pulmonary metastases and nephrotic syndrome. A 73-year-old Japanese man with past history of asbestos exposure was referred to our hospital for the investigation of the left pleural effusion. Chest computed tomography showed thickening of the left parietal pleura. Biopsy specimen of the pleura showed proliferating epithelioid tumor cells, leading to the pathological diagnosis of epithelioid MPM with the aid of immunohistochemistry. After the diagnosis of MPM, chemotherapy was performed without effect. Soon after the clinical diagnosis of progressive disease with skull metastasis, edema and weight gain appeared. Laboratory data met the criteria of nephrotic syndrome, and renal biopsy with electron microscopic examination revealed the minimal change disease. Steroid therapy was started but showed no effect. Around the same time of onset of nephrotic syndrome, multiple miliary lung nodules appeared on chest CT. Transbronchial biopsy specimen of the nodules showed the metastatic MPM in the lung. The patient died because of the worsening of the general condition. To our knowledge, this is the first case of MPM concurrently associated with multiple miliary pulmonary metastases and nephrotic syndrome.",
"affiliations": "Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan. Electronic address: tsuka-y@hyo-med.ac.jp.;Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Respiratory Medicine, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Division of Kidney and Dialysis, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.;Department of Surgical Pathology, Hyogo College of Medicine, 1-1 Mukogawa-cho, Nishinomiya, Hyogo 663-8501, Japan.",
"authors": "Tsukamoto|Yoshitane|Y|;Otsuki|Taiichiro|T|;Hao|Hiroyuki|H|;Kuribayashi|Kozo|K|;Nakano|Takashi|T|;Kida|Aritoshi|A|;Nakanishi|Takeshi|T|;Funatsu|Eriko|E|;Noguchi|Chihiro|C|;Yoshihara|Shunya|S|;Kaku|Koji|K|;Hirota|Seiichi|S|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-0338",
"issue": "211(12)",
"journal": "Pathology, research and practice",
"keywords": "Mesothelioma; Miliary pulmonary metastases; Nephrotic syndrome",
"medline_ta": "Pathol Res Pract",
"mesh_terms": "D000368:Aged; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008654:Mesothelioma; D000086002:Mesothelioma, Malignant; D009402:Nephrosis, Lipoid; D010997:Pleural Neoplasms",
"nlm_unique_id": "7806109",
"other_id": null,
"pages": "1014-9",
"pmc": null,
"pmid": "26376466",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Epithelioid pleural mesothelioma concurrently associated with miliary pulmonary metastases and minimal change nephrotic syndrome - A hitherto undescribed case.",
"title_normalized": "epithelioid pleural mesothelioma concurrently associated with miliary pulmonary metastases and minimal change nephrotic syndrome a hitherto undescribed case"
} | [
{
"companynumb": "JP-ACTAVIS-2016-11739",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"druga... |
{
"abstract": "BACKGROUND Up to 47% of pregnant women with COVID-19 have preterm deliveries. A severe, symptomatic COVID-19 infection in close-to-term pregnancies can have a poor prognosis. Early identification of COVID-19 in pregnant women can prevent the progression of the disease. Currently, there is very little guidance on treating pregnant close-to-term women with COVID-19; this case report suggests changes to current management to maximize positive maternal and fetal outcomes. CASE REPORT A pregnant woman (37 weeks of gestation) presented to the Emergency Department with a chief complaint of fever with an associated cough for 2 days. She was diagnosed with COVID-19 in the Emergency Department, and discharged in a stable condition. She returned 5 days later in preterm labor with severe respiratory distress. After an emergency cesarean section, she remained intubated in the Surgical Intensive Care Unit; she was persistently hypotensive and hypoxic despite maximal ventilator and medical treatment. She died after a cardiac arrest and unsuccessful resuscitation, 15 days after the delivery. We discuss the possible benefit of a planned C-section for close-to-term pregnancies prior to the onset of COVID-19 symptoms. The patient's next of kin gave informed consent for this case report. Approval from the Institutional Review Board or Ethics Review Board was not required as this is a case report. CONCLUSIONS Currently, asymptomatic pregnant women are not tested for COVID-19 infection until hospitalization for delivery. It could be beneficial to have a protocol in place to screen asymptomatic pregnant women so they can be identified early and monitored, as COVID-19 symptoms can escalate quickly.",
"affiliations": "St. George's University School of Medicine, True Blue, Grenada.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.;Department of Surgery, St. Joseph's University Medical Center, Paterson, NJ, USA.",
"authors": "Patel|Priya|P|;Kulkarni|Sayali|S|;Guerrero|Manrique|M|;Persaud|Clive|C|;Zuberi|Jamshed|J|;Rebein|Benjamin|B|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.926591",
"fulltext": "\n==== Front\nAm J Case Rep\nAm J Case Rep\namjcaserep\nThe American Journal of Case Reports\n1941-5923 International Scientific Literature, Inc. \n\n33339814\n10.12659/AJCR.926591\n926591\nArticles\nEmergency Cesarean Section at 38 Weeks of Gestation with COVID-19 Pneumonia: A Case Report\nPatel Priya EF1 Kulkarni Sayali EF2 Guerrero Manrique EF2 Persaud Clive EF2 Zuberi Jamshed EF2 Rebein Benjamin DE2 \n1 St. George’s University School of Medicine, True Blue, Grenada, West Indies\n\n2 Department of Surgery, St. Joseph’s University Medical Center, Paterson, NJ, U.S.A.\nCorresponding Authors: Sayali Kulkarni, e-mail: sayalikulkarni01@gmail.com, Priya Patel, e-mail: ppatel31091@gmail.comAuthors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\n\n2020 \n19 12 2020 \n21 e926591-1 e926591-4\n05 6 2020 20 8 2020 02 12 2020 © Am J Case Rep, 20202020This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 30-year-old\n\nFinal Diagnosis: COVID-19\n\nSymptoms: Chills • cough • diarrhea • fatigue • fever • headache • myalgia • nausea • rhinorrea • shortness of breath • vomiting\n\nMedication: —\n\nClinical Procedure: Cesarean section\n\nSpecialty: Critical Care Medicine • Obstetrics and Gynecology • Surgery\n\nObjective:\nRare disease\n\nBackground:\nUp to 47% of pregnant women with COVID-19 have preterm deliveries. A severe, symptomatic COVID-19 infection in close-to-term pregnancies can have a poor prognosis. Early identification of COVID-19 in pregnant women can prevent the progression of the disease. Currently, there is very little guidance on treating pregnant close-to-term women with COVID-19; this case report suggests changes to current management to maximize positive maternal and fetal outcomes.\n\nCase Report:\nA pregnant woman (37 weeks of gestation) presented to the Emergency Department with a chief complaint of fever with an associated cough for 2 days. She was diagnosed with COVID-19 in the Emergency Department, and discharged in a stable condition. She returned 5 days later in preterm labor with severe respiratory distress. After an emergency cesarean section, she remained intubated in the Surgical Intensive Care Unit; she was persistently hypotensive and hypoxic despite maximal ventilator and medical treatment. She died after a cardiac arrest and unsuccessful resuscitation, 15 days after the delivery. We discuss the possible benefit of a planned C-section for close-to-term pregnancies prior to the onset of COVID-19 symptoms. The patient’s next of kin gave informed consent for this case report. Approval from the Institutional Review Board or Ethics Review Board was not required as this is a case report.\n\nConclusions:\nCurrently, asymptomatic pregnant women are not tested for COVID-19 infection until hospitalization for delivery. It could be beneficial to have a protocol in place to screen asymptomatic pregnant women so they can be identified early and monitored, as COVID-19 symptoms can escalate quickly.\n\nMeSH Keywords:\nCesarean SectionCOVID-19Pregnancy Complications, InfectiousPregnancy, High-Risk\n==== Body\nBackground\nThe symptoms of the coronavirus disease 2019 (COVID-19) infection can range from mild symptoms including fever, cough, sore throat, myalgia, and malaise to severe illness requiring immediate advanced critical-care support, including pneumonia with or without acute respiratory distress syndrome, renal failure, and multiorgan dysfunction. In pregnant women, the clinical presentations can be atypical with normal body temperatures and normal white blood cell counts [1]. A positive COVID-19 result does not assure maternal or fetal compromise, or an indication for expedited birth.\n\nThe adverse effects of severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS) on pregnant women include preterm deliveries, stillbirths, and respiratory complications. Respiratory complications can occur because a gravid uterus can cause basal atelectasis, reduced functional residual capacity, and increased oxygen consumption. In pregnant women, this can result in poorer outcomes during respiratory illnesses. Studies have shown that pregnant women can be more susceptible to viral illnesses, and these illnesses can lead to consequences including abortion, spontaneous early delivery, and an increased incidence of stillbirth [1]. The current COVID-19 virus is about 85% similar to the SARS and MERS coronaviruses [2]. However, the COVID-19 virus appears to be less lethal in comparison with SARS and MERS [3].\n\nA real-time polymerase chain reaction (RT-PCR) test from nasal and throat swabs, sputum, and feces is used to diagnose COVID-19. The virus has not been detected in samples from vaginal swabs, amniotic fluid, placenta, cord blood, neonatal blood, and breast milk. This suggests that the risk of vertical transmission from the mother to the baby is unlikely. There have been no previous cases of vertical transmission during the SARS or MERS pandemics [4].\n\nThe management of COVID-19 in pregnancy includes early isolation, aggressive infection-control procedures, laboratory testing for the virus and co-infections, along with the prevention of fluid overload, fetal monitoring, monitoring uterine contractions, oxygen therapy when necessary, and early mechanical ventilation for progressive respiratory failure. Individualized delivery planning and having a multispecialty management approach can be beneficial [5]. The National Health Commission of China has proposed strengthening health counseling, screening, and follow-ups for pregnant women. They have recommended a designated isolation unit for at least 14 days after the birth and avoiding close contact between the neonate and the mother while she has a suspected or confirmed COVID-19 infection [6]. Conversely, the United Kingdom suggests keeping the mother and neonate together in the immediate postpartum period unless critical care is necessary for the mother or neonatal care is necessary for the infant. The UK also promotes breast-feeding, even if the mother is diagnosed with COVID-19 [7]. Guidelines from other countries have not yet been published.\n\nDespite the fact that COVID-19 is less lethal than SARS and MERS, the COVID-19 infection can result in severe symptoms in pregnant women. Therefore, they should be identified early and efforts should be made to prevent the progression of the disease, especially since women with severe COVID-19 infection at the time of giving birth have required ventilation and extracorporeal membrane oxygenation (ECMO). Currently, there is very little guidance on the management of close-to-term pregnant women with COVID-19, to maximize positive maternal and fetal outcomes. In the light of previous cases of preterm labor induced by COVID-19, it is unclear whether scheduling a cesarean section prior to the onset of COVID-19 symptoms can decrease maternal and fetal mortality.\n\nCase Report\nA 30-year-old woman, who was gravida 4, para 2 (1 term birth, 1 premature birth, 1 abortion) with an intrauterine pregnancy of 37 weeks and 5 days presented to the Emergency Department with a chief complaint of fever and an associated cough for 2 days. Her medical history was a previous cesarean section (C-section), endometriosis status after excision of the anterior abdominal wall endometrioma, and atypical squamous cells of undetermined significance. She denied smoking, alcohol use, and recreational drug use. She reported decreased fetal movements for the past day. She denied contractions, loss of fluid, and vaginal bleeding. She reported remission of the fever with 650 mg of acetaminophen. As these findings were consistent with a COVID-19 infection, an obstetrician-gynecologist (OB/GYN) assessed her and determined that the patient and pregnancy were stable for discharge. She was swabbed for RT-PCR testing with a nasopharyngeal swab using the Becton Dickinson (BD) BioGX SARS-CoV-2 reagents for the BD Max™ System (Becton, Dickinson and Company, Franklin Lakes, New Jersey, USA) [8]. She was then started on azithromycin (Zithromax, Pfizer, New York City, USA) with an initial 500 mg PO (per os) on day 1, and subsequent 250 mg PO daily for the next 4 days for possible community-acquired pneumonia. She was discharged with instructions to follow-up with her primary-care physician and OB/GYN.\n\nShe returned 5 days later in preterm labor and respiratory distress. Her X-ray on admission showed bilateral infiltrates (Figure 1). Initially, she had an oxygen saturation of 75% on room air; however, her oxygen saturation further deteriorated to 60% on room air. A nonrebreather mask was used while she was rushed to the operating room for an emergency C-section. In the operating room, she was intubated and a viable female infant was delivered from a vertex presentation.\n\nPostoperatively, she remained intubated and was transferred to the Surgical Intensive Care Unit (SICU). On postoperative day 2, she developed a fever from an unknown source. She was not febrile when she presented to the hospital in preterm labor or on postoperative day 1. Blood and sputum cultures were drawn and she was started on intravenous (IV) piper-acillin-tazobactam (Zosyn, Pfizer, New York City, USA) 3.387 mg/8 h and vancomycin 500 mg IV/6 h. The bedside cardiac and inferior vena cava (IVC) ultrasound showed good contractility, a normal appearance of the right atrium and ventricle, and a dilated, non-collapsing IVC, indicating an euvolemic state. Throughout the course of her SICU stay, she displayed no significant neurologic improvement and developed worsening tachycardia, hypertension, and ventilator dyssynchrony. She required maximum ventilatory support with 100% fractional inspiration of oxygen (FiO2) and a positive end-expiratory pressure (PEEP) of 20 cmH20 to maintain hemoglobin-oxygen saturations above 90%. A chest tube was placed on the right side due to barotrauma as she required a high PEEP to maintain oxygenation. Her D-dimer levels rose to 9.56 mcg/ ml fibrinogen equivalent units; therefore, a heparin drip was added for therapeutic anticoagulation. She was registered for a Mayo Clinic convalescent plasma trial and received 1 dose of 200 ml convalescent plasma. The repeated intervals of pro-nation initially improved her respiratory status; however, her condition worsened on day 15 after intubation, with the chest X-ray showing worsening confluent opacities (Figure 2). She desaturated to 80% to 86% during a pronation attempt. In addition, she was persistently hypotensive and hypoxic without improvement, despite maximal ventilation and medical treatment. A cardiac arrest ensued 15 days after the delivery and admission to the SICU, and resuscitation was unsuccessful.\n\nInformed consent was obtained from her next of kin. As this is a case report, approval from the Institutional Review Board or Ethics Review Board was not necessary.\n\nDiscussion\nCurrent data suggest that pregnant women are no more likely to contract COVID-19 than the general population. While pregnant women are not necessarily more susceptible to a viral illness, pregnancy can result in immune system changes resulting in an increased severity of the symptoms. Since COVID-19 infection can result in severe symptoms in pregnant women, they should be identified early and all efforts should be made to prevent the progression of the disease, especially since there have been case reports similar to the present case, where the women with severe COVID-19 infection at the time of giving birth have required ventilation and ECMO [6].\n\nA recent study of pregnant women affected by COVID-19 to date suggests that women who gave birth did so within 13 days of the onset of the illness [3]. Thirteen pregnant women aged between 22 years and 36 years were diagnosed with COVID-19 and admitted to the hospital. Eleven women were in their 3rd trimester with no underlying medical conditions. Ten out of 13 patients (77%) presented with fever, and 3/13 (23%) patients complained of dyspnea. Only 3/13 patients (23%) improved after hospitalization and were discharged with an uncomplicated ongoing pregnancy. Ten women (77%) underwent C-sections; 5/10 (50%) delivered emergently because of pregnancy complications, including fetal distress and premature rupture of the membranes. One patient had a stillbirth. Six patients (46%) had preterm labor between 32 weeks and 36 weeks of gestation [9]. Two patients were admitted to the Intensive Care Unit (ICU), 1 developed multiorgan dysfunction and had to be placed on the ECMO [9]. The woman in the present study (38 weeks of gestation) presented with dyspnea and required intubation and an emergent C-section. She did not have any significant comorbidities. Recent evidence suggests that while the current COVID-19 virus is less lethal than the SARS or MERS virus, 47% of women affected by COVID-19 delivered preterm. This is significantly greater than the reported 4/16 (25%) pregnant women with SARS who had preterm deliveries, and the 3/11 (27%) pregnant women with MERS who delivered preterm by C-section [3].\n\nPregnant women affected by SARS and MERS had a higher case-fatality rate compared to non-pregnant women. The case-fatality rate was 15% for all reported pregnancy cases of SARS, with an ICU admission rate of 60%. In pregnant women affected by MERS, the case-fatality rate was 27% while the ICU admission rate was 64% [3]. The case-fatality rate and ICU admission rate of pregnant women affected by COVID-19 is yet to be determined.\n\nThe risk to pregnant women with coronavirus infections (SARS, MERS) appears to increase particularly during the last trimester of pregnancy. Pregnancy is known to be a hypercoagulable state. Emerging evidence suggests that patients hospitalized with COVID-19 are also hypercoagulable, suggesting that a COVID-19 infection during pregnancy can result in an increased risk of maternal venous thromboembolism [7]. In addition, although viral infections during pregnancy can be asymptomatic, approximately half of all preterm deliveries are associated with histologic evidence of chorioamnionitis, which could be due to a viral infection [10].\n\nStudies comparing the frequency of adverse maternal outcomes between preterm emergency cesarean deliveries and term emergency cesarean deliveries in patients unaffected by COVID-19 show that the preterm cesarean deliveries have significantly higher rates of abnormal bleeding, which can require transfusion, and the use of antibiotics, compared to term cesarean deliveries. In addition, a classic abdominal incision for C-sections was related to an increased rate of blood transfusion and the need for antibiotic treatment [11]. Elective C-section prior to the progression of normal labor has risks, including infection, thromboembolism, postpartum hemorrhage, surgical injury to the mother or neonate, and neonatal transient tachypnea.\n\nConclusions\nCurrently, we do not test asymptomatic pregnant women (for isolation purposes) for COVID-19 until they are admitted to the hospital in labor. It would be beneficial to have a protocol in place to screen asymptomatic pregnant women so they can be identified early and monitored, as COVID-19 symptoms can escalate quickly. It could be beneficial to induce labor or perform a C-section early if pregnancies are close to term (at the discretion of the OB/GYN and the patient) to prevent the onset of severe symptoms and labor simultaneously, as this can affect maternal and fetal outcomes.\n\nWe would like to acknowledge the patient and her family for allowing us to share her story.\n\nDepartment and Institution where work was done\n\nDepartment of Surgery, St. Joseph’s University Medical Center, Paterson, NJ, U.S.A.\n\nConflicts of interest\n\nNone.\n\nFigure 1. Chest X-ray on admission shows diffuse bilateral infiltrates (arrows).\n\nFigure 2. Chest X-ray on postoperative day 15 shows a worsening course with increased confluent opacities (arrows).\n==== Refs\nReferences:\n1. Wang X Zhou Z Zhang J A Case of 2019 novel coronavirus in a pregnant woman with preterm delivery Clin Infect Dis 2020 71 844 46 32119083 \n2. Ashokka B Loh MH Tan CH Care of the pregnant woman with coronavirus disease 2019 in labor and delivery: Anesthesia, emergency cesarean delivery, differential diagnosis in the acutely ill parturient, care of the newborn, and protection of the healthcare personnel Am J Obstet Gynecol 2020 223 1 66 74 e3 32283073 \n3. Mullins E Evans D Viner RM Coronavirus in pregnancy and delivery: Rapid review Ultrasound Obstet Gynecol 2020 55 5 586 92 32180292 \n4. Lamouroux A Attie-Bitach T Martinovic J Evidence for and against vertical transmission for severe acute respiratory syndrome coronavirus 2 Am J Obstet Gynecol 2020 223 91 e1 4 \n5. Rasmussen SA Smulian JC Lednicky JA Coronavirus disease 2019 (COVID-19) and pregnancy: What obstetricians need to know Am J Obstet Gynecol 2020 222 5 415 26 32105680 \n6. Qiao J What are the risks of COVID-19 infection in pregnant women? Lancet 2020 395 760 62 32151334 \n7. Royal College of Obstetricians and Gynaecologists Coronavirus (COVID-19) Infection in Pregnancy [Internet] 2020 https://www.rcog.org.uk/globalas-sets/documents/guidelines/2020-04-17-coronavirus-covid-19-infection-in-pregnancy.pdf \n8. BioGX SARS-CoV-2 Reagents for BD MAX™ System 2020 https://www.bd.com/en-us/offerings/capabilities/molecular-diagnostics/molecular-tests/biogx-sars-cov-2-reagents \n9. Liu Y Chen H Tang K Guo Y Clinical manifestations and outcome of SARSCoV-2 infection during pregnancy J Infect 2020 [Online ahead of print] \n10. Mor G Cardenas I The immune system in pregnancy: A unique complexity Am J Reprod Immunol 2010 63 6 425 33 20367629 \n11. Kino T Yamamoto Y Saigusa Y Adverse pregnancy outcomes related to preterm cesarean delivery Eur J Obstet Gynecol Reprod Biol 2019 234 89 91 30669118\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "1941-5923",
"issue": "21()",
"journal": "The American journal of case reports",
"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000328:Adult; D000086382:COVID-19; D002585:Cesarean Section; D004638:Emergency Treatment; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "e926591",
"pmc": null,
"pmid": "33339814",
"pubdate": "2020-12-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "32145216;32151334;32180292;20367629;32119083;32283073;32105680;30669118;32376317",
"title": "Emergency Cesarean Section at 38 Weeks of Gestation with COVID-19 Pneumonia: A Case Report.",
"title_normalized": "emergency cesarean section at 38 weeks of gestation with covid 19 pneumonia a case report"
} | [
{
"companynumb": "US-MYLANLABS-2021M1094978",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": "3",
... |
{
"abstract": "Limited information is available regarding SARS-CoV-2 infections in children with underlying diseases. A retrospective study of children less than 15 years old with primary or secondary immunosuppression infected with SARS-CoV-2 during March 2020 was performed. In this series, 8 immunocompromised patients with COVID-19 disease are reported, accounting for 15% of the positive cases detected in children in a reference hospital. The severity of the symptoms was mild-moderate in the majority with a predominance of febrile syndrome, with mild radiological involvement and in some cases with mild respiratory distress that required oxygen therapy. The rational and prudent management of these patients is discussed, evaluating possible treatments and options for hospitalization or outpatient follow-up.Conclusion: In our experience, monitoring of children with immunosuppression and COVID-19 disease can be performed as outpatients if close monitoring is possible. Hospitalization should be assessed when high fever, radiological involvement, and/or respiratory distress are present. What is Known: • SARS-CoV-2 infection is usually mild in children. What is New: • Outcome of immunosuppressed children with COVID-19 is generally good, with a mild-moderate course.",
"affiliations": "Pediatric Hemato-Oncology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric Hemato-Oncology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric Nephrology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric Hepatology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric Nephrology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric Rheumatology Department, Hospital Universitario La Paz, Madrid, Spain.;Pediatric and Infectious Diseases Department, Hospital Universitario La Paz, Paseo de la Castellana, 261 28046, Madrid, Spain. ccalvorey@gmail.com.",
"authors": "Pérez-Martinez|Antonio|A|;Guerra-García|Pilar|P|;Melgosa|Marta|M|;Frauca|Esteban|E|;Fernandez-Camblor|Carlota|C|;Remesal|Agustin|A|;Calvo|Cristina|C|http://orcid.org/0000-0002-6503-3423",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00431-020-03793-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0340-6199",
"issue": "180(3)",
"journal": "European journal of pediatrics",
"keywords": "COVID-19; Cancer; Immunosuppression; Transplant",
"medline_ta": "Eur J Pediatr",
"mesh_terms": "D000293:Adolescent; D000086382:COVID-19; D000086742:COVID-19 Testing; D002648:Child; D005260:Female; D006760:Hospitalization; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D008297:Male; D011379:Prognosis; D012189:Retrospective Studies; D012720:Severity of Illness Index; D013030:Spain",
"nlm_unique_id": "7603873",
"other_id": null,
"pages": "967-971",
"pmc": null,
"pmid": "32860101",
"pubdate": "2021-03",
"publication_types": "D016428:Journal Article",
"references": "32179660",
"title": "Clinical outcome of SARS-CoV-2 infection in immunosuppressed children in Spain.",
"title_normalized": "clinical outcome of sars cov 2 infection in immunosuppressed children in spain"
} | [
{
"companynumb": "ES-MYLANLABS-2021M1055825",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MERCAPTOPURINE"
},
"drugadditional": "3",
... |
{
"abstract": "Amidst the opioid overdose crisis, there are increased efforts to expand access to medications for opioid use disorder (MOUD). Hospitalization for the complications of substance use in the United States (US) provides an opportunity to initiate methadone, buprenorphine, and extended release naltrexone and link high-risk, not otherwise engaged, patients into outpatient care. However, treatment options for patients are quickly exhausted when these medications are not desired, tolerated, or beneficial. As an example, we discuss the case of a man who was hospitalized 27 times over 2 years for complications related to his opioid use disorder (OUD), including recurring methicillin-resistant Staphylococcus aureus vertebral osteomyelitis, increasing antimicrobial resistance, new infections, and multiple overdoses in and out of the hospital. The patient suffered these complications despite efforts to treat his OUD with methadone and buprenorphine while hospitalized, and repeated attempts to link him to outpatient care. We use this case to review evidence-based treatments for refractory OUD, which are not approved in the US, but are available in Canada. If hospitalized in Vancouver, Canada, this patient could have been offered slow-release oral morphine and injectable opioid agonist therapy, as well as access to sterile syringes and injection equipment at an in-hospital supervised injection facility. Each of these approaches is supported by evidence and has been implemented successfully in Canada, yet none are available in the US. In order to combat the multiple harms from opioids, it is critical that we consider every evidence-based tool.",
"affiliations": "Grayken Center for Addiction, Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Department of Medicine, Boston Medical Center, Boston, MA, USA. Simeon.kimmel@bmc.org.;British Columbia Centre on Substance Use, Vancouver, Canada.;Grayken Center for Addiction, Clinical Addiction Research and Education Unit, Section of General Internal Medicine, Department of Medicine, Boston Medical Center, Boston, MA, USA.",
"authors": "Kimmel|Simeon|S|0000-0002-5029-9384;Bach|Paxton|P|;Walley|Alexander Y|AY|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1007/s11606-020-05920-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0884-8734",
"issue": "35(8)",
"journal": "Journal of general internal medicine",
"keywords": "harm reduction; injection drug use; opioid agonist therapy; opioid use disorder",
"medline_ta": "J Gen Intern Med",
"mesh_terms": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D002170:Canada; D006801:Humans; D008297:Male; D008691:Methadone; D055624:Methicillin-Resistant Staphylococcus aureus; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D014481:United States",
"nlm_unique_id": "8605834",
"other_id": null,
"pages": "2418-2426",
"pmc": null,
"pmid": "32462569",
"pubdate": "2020-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": "25427944;26467975;14563546;25064422;30055424;24029536;25090173;19032534;15933353;20237960;30765118;25456324;22161378;22410375;26597670;18201934;16393744;20728288;26469651;30357363;30007032;31021491;25679130;30605448;28583121;24508718;27140989;21791093;31474225;15265090;30944135;27978771;28446428;29913516;29589873;27049826;28687187;28526932;19638238;16042640;25754871;29507156;28673521",
"title": "Comparison of Treatment Options for Refractory Opioid Use Disorder in the United States and Canada: a Narrative Review.",
"title_normalized": "comparison of treatment options for refractory opioid use disorder in the united states and canada a narrative review"
} | [
{
"companynumb": "CH-ALKEM LABORATORIES LIMITED-CH-ALKEM-2020-03104",
"fulfillexpeditecriteria": "1",
"occurcountry": "CH",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREGABALIN"
},
"druga... |
{
"abstract": "OBJECTIVE\nTo assess the incidence and management of infusion reactions to infliximab, a chimeric monoclonal antibody that targets human tumor necrosis factor-alpha, in patients with Crohn's disease treated at a large infusion center.\n\n\nMETHODS\nA total of 165 consecutive patients who received 479 infliximab infusions in the Division of Clinical Immunology Infusion Center at Mount Sinai Medical Center from July, 1998 to January, 2001 were evaluated. Specific treatment protocols for initial and subsequent acute infusion reactions were followed and the outcomes documented.\n\n\nRESULTS\nThe overall incidence of infusion reactions to infliximab was 6.1% (29 of 479) of infusions, affecting 9.7% (16 of 165) of patients. Mild, moderate, or severe acute reactions occurred in 3.1% (15 of 479), 1.2% (six of 479), and 1.0% (five of 479) of infliximab infusions, respectively. Use of treatment protocols resulted in rapid resolution of all acute reactions to infliximab. With the prophylaxis protocol, all patients who experienced an initial mild or moderate acute reaction were able to receive additional infusions. Four patients experienced a total of five severe acute reactions. Three patients were retreated: two patients had no further problems, whereas one patient had a second severe acute reaction that rapidly resolved with treatment. Suggesting that acute infusion reactions are not type I hypersensitivity reactions, in 11 patients who experienced 14 acute infusion reactions, serum tryptase levels were normal. Delayed infusion reactions occurred in 0.6% (three of 479) of infusions.\n\n\nCONCLUSIONS\nInfliximab infusions were accompanied by acute reactions in approximately 5% of infusions. These reactions did not seem to be true IgE-mediated type I hypersensitivity events. Using appropriate treatment protocols, these reactions were effectively treated and prevented upon retreatment in nearly all patients. Delayed reactions were rare, occurring in <1% of infusions.",
"affiliations": "Division of Clinical Immunology, Department of Medicine, The Mount Sinai School of Medicine, New York, New York, USA.",
"authors": "Cheifetz|Adam|A|;Smedley|Michelle|M|;Martin|Sara|S|;Reiter|Monica|M|;Leone|Grace|G|;Mayer|Lloyd|L|;Plevy|Scott|S|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "United States",
"delete": false,
"doi": "10.1111/j.1572-0241.2003.07457.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9270",
"issue": "98(6)",
"journal": "The American journal of gastroenterology",
"keywords": null,
"medline_ta": "Am J Gastroenterol",
"mesh_terms": "D000911:Antibodies, Monoclonal; D018890:Chemoprevention; D002985:Clinical Protocols; D003424:Crohn Disease; D004342:Drug Hypersensitivity; D064420:Drug-Related Side Effects and Adverse Reactions; D005765:Gastrointestinal Agents; D006801:Humans; D015994:Incidence; D000069285:Infliximab; D007262:Infusions, Intravenous; D012189:Retrospective Studies; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "0421030",
"other_id": null,
"pages": "1315-24",
"pmc": null,
"pmid": "12818276",
"pubdate": "2003-06",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The incidence and management of infusion reactions to infliximab: a large center experience.",
"title_normalized": "the incidence and management of infusion reactions to infliximab a large center experience"
} | [
{
"companynumb": "US-JNJFOC-20140908947",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Despite being reported since 1943 as well as being the subject of a large body of literature since that time, no consensus has been reached regarding the etiology of opioid induced hyperalgesia (OIH). It is often described as a paradoxical increased pain response to noxious stimuli due to increased sensitization or an acute tolerance to opioids.\n\n\n\nWe report the case of a 60 year old patient on chronic Intrathecal combined fentanyl and Bupivacaine who had worsening pain with increasing doses and improved after weaning off intrathecal opioids.\n\n\n\nOIH has been described in various settings including patients on methadone maintenance therapy, perioperative opioid administration, cancer patients on opioids, and healthy volunteers who are acutely exposed to opioids, including high dose intrathecal opioids such as Morphine and Sufentanil. To our knowledge, no cases of opioid induced hyperalgesia was previously reported in the case of intrathecal Fentanyl.",
"affiliations": "Department of Anesthesiology, Critical Care & Pain Medicine, St Elizabeth Medical Center, Boston, Massachusetts, U.S.A.;Department of Anesthesiology, Critical Care & Pain Medicine, St Elizabeth Medical Center, Boston, Massachusetts, U.S.A.;Department of Anesthesiology, Critical Care & Pain Medicine, St Elizabeth Medical Center, Boston, Massachusetts, U.S.A.;Anesthesiology, Tufts University School of Medicine, Boston, Massachusetts, U.S.A.;Tufts University School of Medicine, Boston, Massachusetts, U.S.A.",
"authors": "Kalaydjian|Antranig|A|;Farah|Fadi|F|;Cheng|Yuen|Y|;Acquadro|Martin A|MA|;Gerges|Frederic J|FJ|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl; D002045:Bupivacaine",
"country": "United States",
"delete": false,
"doi": "10.1111/papr.12726",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1530-7085",
"issue": "19(2)",
"journal": "Pain practice : the official journal of World Institute of Pain",
"keywords": "hyperalgesia; implantable; infusion pumps; intrathecal; low back pain; opioid receptors; recurrent",
"medline_ta": "Pain Pract",
"mesh_terms": "D000701:Analgesics, Opioid; D002045:Bupivacaine; D005260:Female; D005283:Fentanyl; D006801:Humans; D006930:Hyperalgesia; D015918:Infusion Pumps, Implantable; D007278:Injections, Spinal; D008875:Middle Aged; D010146:Pain; D010147:Pain Measurement",
"nlm_unique_id": "101130835",
"other_id": null,
"pages": "222-223",
"pmc": null,
"pmid": "30267637",
"pubdate": "2019-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Opioid Induced Hyperalgesia with Intrathecal Infusion of High-Dose Fentanyl.",
"title_normalized": "opioid induced hyperalgesia with intrathecal infusion of high dose fentanyl"
} | [
{
"companynumb": "US-HIKMA PHARMACEUTICALS USA INC.-US-H14001-18-08317",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drug... |
{
"abstract": "BACKGROUND\nSafety profiles of biologics for treatment of psoriasis are limited to data from randomized controlled trials. There is a need for comparative safety reports of biologics based on data from clinical practice.\n\n\nOBJECTIVE\nWe sought to estimate and compare the incidence of adverse events (AEs) leading to withdrawal of biologics (etanercept, infliximab, adalimumab, and ustekinumab) in the treatment of psoriasis.\n\n\nMETHODS\nWe conducted a multicenter retrospective chart review from September 2005 to September 2014. Incidence proportion and rate of AEs leading to withdrawal by biologic agent and AE were calculated.\n\n\nRESULTS\nFor 545 treatments administered in 398 patients, 22 (4.04%) AEs were associated with withdrawal, for a rate of 1.97/100 patient-years (95% confidence interval [CI] 1.32-2.94). Common AEs were injection-/infusion-site reactions (0.55%, 0.92%, 0%, and 0% for etanercept, infliximab, adalimumab, and ustekinumab, respectively); infections (0%, 0.18%, 0.55%, 0.18%); and malignancies (0.18%, 0.18%, 0%, 0.37%).\n\n\nCONCLUSIONS\nPossible incompleteness of chart details and small study population limit the conclusiveness of findings.\n\n\nCONCLUSIONS\nBiologic agents for treatment of psoriasis are safe; AEs associated with withdrawal occurred in 4% of all administered biologic therapies. It does not appear that real-world patients encounter more AEs with biologics than patients in clinical trials.",
"affiliations": "Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.;Michael G. DeGroote School of Medicine, McMaster University, Hamilton, Ontario, Canada.;School of Medicine, University of Toronto, Toronto, Ontario, Canada.;School of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.;Division of Dermatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Health Sciences Center, Toronto, Ontario, Canada; Women's College Hospital, Toronto, Ontario, Canada. Electronic address: jensen.yeung@utoronto.ca.",
"authors": "Kim|Whan B|WB|;Marinas|Joseph E C|JE|;Qiang|Judy|J|;Shahbaz|Ali|A|;Greaves|Simon|S|;Yeung|Jensen|J|",
"chemical_list": "D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000069285:Infliximab; D000069549:Ustekinumab; D000068879:Adalimumab; D000068800:Etanercept",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0190-9622",
"issue": "73(2)",
"journal": "Journal of the American Academy of Dermatology",
"keywords": "adverse event; biologic; clinical practice; psoriasis; real world; safety; tumor necrosis factor inhibitor",
"medline_ta": "J Am Acad Dermatol",
"mesh_terms": "D000068879:Adalimumab; D000328:Adult; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001691:Biological Therapy; D002170:Canada; D015331:Cohort Studies; D064420:Drug-Related Side Effects and Adverse Reactions; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G; D015994:Incidence; D007239:Infections; D000069285:Infliximab; D007279:Injections, Subcutaneous; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D011565:Psoriasis; D018124:Receptors, Tumor Necrosis Factor; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D000069549:Ustekinumab; D028761:Withholding Treatment",
"nlm_unique_id": "7907132",
"other_id": null,
"pages": "237-41",
"pmc": null,
"pmid": "26026334",
"pubdate": "2015-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Adverse events resulting in withdrawal of biologic therapy for psoriasis in real-world clinical practice: A Canadian multicenter retrospective study.",
"title_normalized": "adverse events resulting in withdrawal of biologic therapy for psoriasis in real world clinical practice a canadian multicenter retrospective study"
} | [
{
"companynumb": "CA-JNJFOC-20150717829",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
... |
{
"abstract": "Tumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR-mutant non-small-cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole-genome sequencing on samples from three patients who underwent histological transformation to small-cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small-cell lung cancer-associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non-druggable genetic information that may guide clinical management.",
"affiliations": "Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.;Parkway Cancer Center, Singapore, Singapore.;Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.;Department of Oncology, University of Cambridge, Cambridge, UK.;Department of Haematology-Oncology, National University Cancer Institute, National University Health System, Singapore, Singapore csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.;Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK csictm@nus.edu.sg nitzan.rosenfeld@cruk.cam.ac.uk.",
"authors": "Tsui|Dana Wai Yi|DWY|0000-0002-0595-6664;Murtaza|Muhammed|M|;Wong|Alvin Seng Cheong|ASC|;Rueda|Oscar M|OM|;Smith|Christopher G|CG|;Chandrananda|Dineika|D|;Soo|Ross A|RA|;Lim|Hong Liang|HL|;Goh|Boon Cher|BC|;Caldas|Carlos|C|;Forshew|Tim|T|;Gale|Davina|D|;Liu|Wei|W|;Morris|James|J|;Marass|Francesco|F|;Eisen|Tim|T|;Chin|Tan Min|TM|0000-0002-3289-8498;Rosenfeld|Nitzan|N|0000-0002-2825-4788",
"chemical_list": "D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D006886:Hydroxychloroquine; C512478:EGFR protein, human; D066246:ErbB Receptors; D000077156:Gefitinib",
"country": "England",
"delete": false,
"doi": "10.15252/emmm.201707945",
"fulltext": "\n==== Front\nEMBO Mol MedEMBO Mol Med10.1002/(ISSN)1757-4684EMMMembommEMBO Molecular Medicine1757-46761757-4684John Wiley and Sons Inc. Hoboken 10.15252/emmm.201707945EMMM201707945Research ArticleResearch ArticlesDynamics of multiple resistance mechanisms in plasma DNA during EGFR‐targeted therapies in non‐small cell lung cancer Dana Wai Yi Tsui et alTsui Dana Wai Yi http://orcid.org/0000-0002-0595-6664\n1\n\n2\n\n10\n\n†\nMurtaza Muhammed \n1\n\n2\n\n3\n\n11\n\n12\n\n†\nWong Alvin Seng Cheong \n4\nRueda Oscar M \n1\n\n2\nSmith Christopher G \n1\n\n2\nChandrananda Dineika \n1\n\n2\nSoo Ross A \n4\n\n5\nLim Hong Liang \n6\nGoh Boon Cher \n4\n\n5\nCaldas Carlos \n1\n\n2\n\n3\n\n7\nForshew Tim \n1\n\n2\n\n13\nGale Davina \n1\n\n2\nLiu Wei \n1\n\n2\n\n14\nMorris James \n1\n\n2\nMarass Francesco \n1\n\n2\n\n15\n\n16\nEisen Tim \n3\n\n7\n\n8\nChin Tan Min http://orcid.org/0000-0002-3289-8498csictm@nus.edu.sg \n4\n\n5\n\n9\n\n‡\nRosenfeld Nitzan http://orcid.org/0000-0002-2825-4788nitzan.rosenfeld@cruk.cam.ac.uk \n1\n\n2\n\n‡\n\n1 \nCancer Research UK Cambridge Institute\nLi Ka Shing Centre\nUniversity of Cambridge\nCambridge\nUK\n\n2 \nCancer Research UK Major Center ‐ Cambridge\nCambridge\nUK\n\n3 \nDepartment of Oncology\nUniversity of Cambridge\nCambridge\nUK\n\n4 \nDepartment of Haematology‐Oncology\nNational University Cancer Institute\nNational University Health System\nSingapore\nSingapore\n\n5 \nCancer Science Institute\nCentre for Translational Medicine\nNational University of Singapore\nSingapore\nSingapore\n\n6 \nParkway Cancer Center\nSingapore\nSingapore\n\n7 \nDepartment of Oncology\nAddenbrooke's Hospital\nCambridge University Health Partners\nCambridge\nUK\n\n8 \nOncology Early Clinical Development\nAstraZeneca\nCambridge\nUK\n\n9 \nRaffles Cancer Centre\nRaffles Hospital\nSingapore\nSingapore\n10 Present address:\nDepartment of Pathology\nCenter for Molecular Oncology\nMemorial Sloan Kettering Cancer Center\nNew York\nNY\nUSA\n11 Present address:\nCenter for Noninvasive Diagnostics\nTranslational Genomics Research Institute\nPhoenix\nAZ\nUSA\n12 Present address:\nMayo Clinic\nCenter for Individualized Medicine\nScottsdale\nAZ\nUSA\n13 Present address:\nInivata Ltd.\nGranta Park\nCambridge\nUK\n14 Present address:\nUniversity of Glasgow\nGlasgow\nUK\n15 Present address:\nDepartment of Biosystems Science and Engineering\nETH Zurich\nBasel\nSwitzerland\n16 Present address:\nSIB Swiss Institute of Bioinformatics\nLausanne\nSwitzerland\n* \nCorresponding author. Tel: +65 63112306; E‐mail: csictm@nus.edu.sg\n\nCorresponding author. Tel: +44 1223 769769; E‐mail: nitzan.rosenfeld@cruk.cam.ac.uk\n† These authors contributed equally to this work\n\n‡ These authors should be considered as (co‐)senior authors and project co‐leaders\n\n30 5 2018 6 2018 10 6 10.1002/emmm.v10.6e794525 4 2017 04 4 2018 09 4 2018 © 2018 The Authors. Published under the terms of the CC BY 4.0 licenseThis is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nTumour heterogeneity leads to the development of multiple resistance mechanisms during targeted therapies. Identifying the dominant driver(s) is critical for treatment decision. We studied the relative dynamics of multiple oncogenic drivers in longitudinal plasma of 50 EGFR‐mutant non‐small‐cell lung cancer patients receiving gefitinib and hydroxychloroquine. We performed digital PCR and targeted sequencing on samples from all patients and shallow whole‐genome sequencing on samples from three patients who underwent histological transformation to small‐cell lung cancer. In 43 patients with known EGFR mutations from tumour, we identified them accurately in plasma of 41 patients (95%, 41/43). We also found additional mutations, including EGFR T790M (31/50, 62%), TP53 (23/50, 46%), PIK3CA (7/50, 14%) and PTEN (4/50, 8%). Patients with both TP53 and EGFR mutations before treatment had worse overall survival than those with only EGFR. Patients who progressed without T790M had worse PFS during TKI continuation and developed alternative alterations, including small‐cell lung cancer‐associated copy number changes and TP53 mutations, that tracked subsequent treatment responses. Longitudinal plasma analysis can help identify dominant resistance mechanisms, including non‐druggable genetic information that may guide clinical management.\n\ncirculating tumour DNAliquid biopsylung cancerresistance mechanismstargeted therapySubject Categories\nCancerPharmacology & Drug DiscoveryRespiratory SystemUniversity of CambridgeCancer Research UKA20240A11906Hutchison Whampoa LimitedEC | H2020 | H2020 Priority Excellent Science | H2020 European Research Council (ERC)FP/2007‐2013337905MOH | National Medical Research Council (NMRC) source-schema-version-number2.0component-idemmm201707945cover-dateJune 2018details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.1 mode:remove_FC converted:07.06.2018\n\nEMBO Mol Med (2018 ) 10 : e7945\n==== Body\nIntroduction\nMolecularly targeted therapies offer substantial clinical benefit in a subset of patients whose tumours harbour specific oncogenic drivers. Unfortunately, treatment resistance inevitably develops, partly driven by the evolving genetic landscape of cancer cells. For example, though non‐small‐cell lung cancer (NSCLC) patients carrying activating mutations in EGFR (epidermal growth factor receptor) initially respond to EGFR‐targeted tyrosine kinase inhibitors (EGFR‐TKIs; Lynch et al, 2004; Paez et al, 2004), the emergence of mutations that confer resistance to these TKIs or activate alternative drivers (such as EGFR T790M, MET/HER2 amplifications, PIK3CA mutation) leads to eventual drug resistance (Yu et al, 2013; Camidge et al, 2014). Some of these resistance mechanisms are targetable, such as T790M (Janne et al, 2015; Sequist et al, 2015) and MET amplification (Sierra & Tsao, 2011). Apart from such individual genetic changes, a small subset of EGFR‐mutant NSCLC patients develop resistance to EGFR‐TKI therapy by undergoing histological transformation to small‐cell lung cancer (SCLC) and become sensitive to standard SCLC treatment (Sequist et al, 2011; Niederst et al, 2015). Therefore, longitudinal monitoring of the dynamic genetic changes during the course of a patient’s treatment has become increasingly important to guide treatment at progression or when resistance occurs. Plasma circulating tumour DNA (ctDNA) is a non‐invasive method that has been used to identify EGFR mutations and other genetic drivers in NSCLC and in response to treatment of NSCLC patients with EGFR‐TKIs (Yung et al, 2009; Couraud et al, 2014; Douillard et al, 2014; Newman et al, 2014, 2016; Weber et al, 2014; Paweletz et al, 2015; Wan et al, 2017). During treatment of NSCLC patients with first‐generation EGFR‐TKIs, serial assessment of EGFR mutations in plasma ctDNA has proved successful in allowing early detection of T790M‐driven resistance prior to radiographic progression (Oxnard et al, 2014; Mok et al, 2015). However, a subset of the patients develop resistance that is independent of the EGFR pathway, and multiple resistance mechanisms may co‐exist because of tumour heterogeneity (Sequist et al, 2015; Abbosh et al, 2017). Here, we performed longitudinal analysis of plasma ctDNA to study the dynamics of co‐existing multiple resistance mechanisms during sequential therapy in NSCLC patients.\n\nIn this study, we analysed a cohort of 392 plasma samples collected longitudinally from 50 Stage IV NSCLC patients. All were treated with the first‐generation TKI gefitinib in combination with hydroxychloroquine as part of the “Hydroxychloroquine and Gefitinib to Treat Lung Cancer” trial (NCT00809237). Thirty‐four patients were TKI‐naïve (i.e. not previously treated with EGFR‐TKI), and 16 were TKI‐treated (i.e. previously treated with TKI with a 2‐week washout period). Eligibility for the trial and patient characteristics are summarized in the Appendix Supplementary Methods. This is a phase II study with a phase I lead in that studies the tolerability, safety profile and efficacy of hydroxychloroquine and gefitinib in advanced non‐small‐cell lung cancer. Appendix Fig S1 summarizes the number of patients in each arm (Appendix Fig S1). We performed tagged‐amplicon deep sequencing (TAm‐Seq; Forshew et al, 2012) for de novo identification and quantification of mutations in EGFR exons 18–21, coding regions of TP53 and PTEN, and selected hotspot regions of PIK3CA, KRAS and BRAF; and digital PCR for detection and quantification of hotspot mutations in EGFR. For a subset of patients, we also performed shallow whole‐genome sequencing to analyse global copy number changes during treatment (Heitzer et al, 2013).\n\nResults\nMutational profiling by plasma DNA\nTo determine whether plasma was a good surrogate of EGFR mutation status in the tumour, we compared the EGFR mutation status in plasma samples (as determined by our assays) with the tumour status reported in hospital records. The EGFR status was known in the tumour of 43 of the 50 patients, and we detected the same EGFR mutation in any follow‐up plasma samples of 41 of 43 (95%) patients (Fig 1A and Appendix Table S1). In the remaining seven patients, two were found to be EGFR wild‐type in both tumour and plasma, and the remaining five have EGFR mutations detected in plasma. In 24 patients who responded to the treatment within the initial 70 days, 19 of them showed a drop in EGFR cfDNA levels within that period (Appendix Fig S2 and Appendix Table S2). In addition to EGFR, somatic mutations in other cancer genes, such as in TP53 or the PI3K/AKT/mTOR pathway (PIK3CA and PTEN), were also identified in the plasma of 29 patients (Fig 1B). Of the identified mutations, 25–43% are likely oncogenic (TP53, 10/23, 43%; PIK3CA, 3/7, 43%; PTEN, 1/4, 25%) according to OncoKB annotation (Chakravarty et al, 2017). To further compare molecular profiles between tumour and plasma, we studied paired tumour and plasma samples in four patients, where tumour samples were available before and after disease progression. The types of EGFR mutations identified in plasma and tumour (EGFR activating, resistance‐conferring mutations in EGFR and other mutations) were identical for 11 of 12 (92%) mutations before treatment, and for 9 of 12 (75%) mutations after treatment (Appendix Fig S3 and Appendix Table S3). Plasma captured the same or more mutations than tumour in 23 of 24 cases (96%). These results confirmed that plasma analysis is informative for mutation profiling in NSCLC patients using our assays. Initial changes in EGFR ctDNA levels after start of treatment mirrored in most cases the radiographic assessment of clinical response.\n\nFigure 1 Summary of somatic mutations identified in the 50 NSCLC patients\n\nDetection of tumour EGFR mutations in plasma. EGFR mutation status in tumour samples was documented in the clinical record for 43 patients (Appendix Table S1), of which 38 had verified hotspot activating mutations (deletion in exon 19 for 23 patients and the L858R mutation for 15 patients), three patients had other mutations in EGFR (one of these patients had two different mutations detected in the tumour sample), and two patients were wild‐type for EGFR according to tumour analysis and confirmed by plasma analysis.\n\nSummary of the mutations identified in any of the plasma samples during longitudinal follow‐up in the 50 patients. TKI‐naïve (n = 34) and TKI‐treated (n = 16) patients are presented separately.\n\n\n\n\nPrognostic value of baseline plasma DNA\nWe studied the relationship between pre‐treatment EGFR ctDNA levels and prognosis in 19 TKI‐naïve patients (Appendix Table S4), for which at least one plasma sample was collected before initiation of treatment. Patients with low levels of EGFR‐activating mutations pre‐treatment tended to have better progression‐free survival (PFS) and overall survival (OS; Fig 2A and B), though this did not reach statistical significance level of 0.05 (their corresponding Cox P‐values were 0.06 for both PFS and OS). Of note, patients with low levels of EGFR‐activating mutation allele fractions had reduced tumour burden (median 17 mm) by RECIST measurements, as compared to those with intermediate (median 42 mm) and high (median 80 mm) levels of EGFR‐activating mutation (Appendix Table S4). These findings suggest that baseline mutation concentrations in the plasma correlate with tumour burden. In addition, patients with both EGFR and TP53 detected in pre‐treatment plasma tended to have worse prognosis (Fig 2C and D, Cox P‐value 0.109 for PFS and 0.035 for OS). We repeated the analysis with copies/ml instead of mutant allele fractions, and the conclusions were the same. These data suggest that both the molecular profile of genomic alterations, and the quantification of ctDNA levels in baseline plasma, can have prognostic implications.\n\nFigure 2 Prognostic value of qualitative and quantitative assessments of pre‐treatment ctDNA\n\nA, B The relationship of pre‐treatment EGFR‐activating mutation levels (allele fractions) with progression‐free survival (PFS) and overall survival (OS) of 19 first‐line TKI‐treated patients where baseline plasma samples (collected before the start of treatment) were available. Patients were grouped into three groups according to their pre‐treatment ctDNA levels, as measured by EGFR‐activating mutation allele fractions: low (< 25% quartile), intermediate (25–75% quartile) and high (> 75% quartile) ctDNA levels. Kaplan–Meier survival curves indicated that patients with high baseline pre‐treatment EGFR‐activating mutant allele fractions were non‐significantly associated with unfavourable (A) PFS (log‐rank P‐value = 0.11) and (B) OS (log‐rank P‐value = 0.16), Cox P‐value of 0.06 for either PFS or OS.\n\nC, D The prognostic value of concurrent TP53 and EGFR mutations in pre‐treatment plasma samples before EGFR‐TKI therapy. This analysis was performed in 30 first‐line EGFR‐TKI patients where plasma samples were available within 2 months of start of treatment. The presence of both TP53 and EGFR mutations in plasma was associated with a trend of worse PFS (log‐rank P‐value = 0.109, hazard ratio and 95% confidence interval: 0.53 [0.24–1.17]) and significantly worse OS (log‐rank P‐value = 0.035, hazard ratio and 95% confidence interval: 0.43 [0.20–0.97]).\n\n\n\n\nMutation dynamics in plasma DNA reveals heterogeneous resistance mechanisms\nFor 45 of 50 patients, EGFR mutations were detected before treatment in tumour and/or plasma and more than one plasma sample was available from clinical follow‐up. Longitudinal analysis of ctDNA in plasma revealed heterogeneity of resistance mechanisms (Fig 3A). During longitudinal follow‐up, a large subset of patients retained the sensitizing mutation and developed resistance‐conferring EGFR T790M mutation (n = 28/45, 62%, Fig 3B). To estimate the detection lead time (i.e. the interval between detection of the resistance‐conferring mutation in plasma and radiographic evidence of disease progression), we focus on 28 patients where T790M was detected in plasma at any time during EGFR‐TKI, including detection before disease progression became evident. In patients treated with first‐line EGFR‐TKI, we found that the median time‐to‐appearance of T790M in plasma was 4 months from the start of TKI treatment, with a lead time between T790M detection and clinical progression of 6.8 months. Patients with EGFR T790M can now be treated with third‐generation, irreversible EGFR‐TKIs (Janne et al, 2015; Piotrowska et al, 2015). One patient (220) had a biopsy of the lung tumour after progression, in which both activating EGFR exon 19 and T790M mutations were detected. The same mutations were detected in plasma at the time of progression. This patient was then treated with a third‐generation EGFR‐TKI (EGF‐816, Novartis (NCT02108964)) and demonstrated partial radiological response. Subsequent plasma samples showed no further EGFR mutations (data shown in Dataset EV1).\n\nFigure 3 Longitudinal analysis of ctDNA dynamics reveals distinct patterns of resistance mechanisms\n\nLongitudinal analysis of ctDNA dynamics in 45 NSCLC patients revealed three main groups of concurrent heterogeneous resistance mechanisms.\n\nIn the first group (n = 28/45, 62%), patients retained EGFR‐sensitizing mutations before and after disease progression, with the development of T790M in their plasma samples, indicating that at least some of the progressing clones developed resistance to TKI by acquiring T790M.\n\nIn the second group (n = 10/45, 22%), patients retained EGFR‐sensitizing mutations but progressed without developing T790M in their plasma samples, suggesting that resistance arose due to other mechanisms which were not analysed in this dataset.\n\nIn the third group (n = 7/45, 15%), patients progressed without EGFR‐sensitizing nor resistance‐conferring T790M mutations detected in their plasma samples. Resistance possibly develops through dependence on alternative cancer driver pathways.\n\nData information: For patients where multiple EGFR‐activating mutations were identified in plasma, only the most abundant one is shown here (complete data for all patients are shown in Dataset EV1). Clinical progression and CT imaging times are indicated with a dotted line, with RECIST classification: SD, stable disease; PR, partial response; PD, progressive disease. Progressive disease defined by presentation of symptoms on brain or bone scan is indicated by PD**.\n\nIn a second group of patients (n = 10/45, 22%), the activating EGFR mutation was detected in plasma before and after progression, with an average mutant allele fraction (AF, i.e. the fractional concentration of mutant allele over total DNA) of 7.9%, but not T790M (Fig 3C). The continued presence of activating mutations in plasma suggests possible positive selection of the mutations in the EGFR pathway in the corresponding cancers. In these patients, mutations in other pathways also emerged in plasma, such as TP53 and PIK3CA (Dataset EV1). One possible hypothesis is that tumours of patients in this group may retain partial sensitivity to EGFR‐TKI treatment, and may respond clinically if EGFR‐TKI is used in combination with treatments targeting additional resistance pathway.\n\nThe third group of patients (n = 7/45, 15%) did not have EGFR‐activating nor known resistance‐conferring mutations in EGFR detected in plasma when they progressed. These patients initially had exon 19 deletion detected in the tumour (7/7) and their first plasma sample (6/7). Interestingly, comparing to the other two groups, this group of patients had EGFR‐activating mutations present at relatively lower allele fractions in their first plasma samples [groups 1 and 2: median EGFR mutations mutant allele fractions was 3% (range: 0.07–65.7%) versus group 3: median 0.23% (range: 0.06–2.11%)]. We do not rule out the possibility that the tumours of these patients might release less tumour‐derived DNA into the circulation. In some of these patients, we detected alternative cancer mutations such as TP53 and PIK3CA in plasma before treatment was initiated, and the levels of these mutations then increased to present the highest allele fractions in ctDNA when disease progressed (Fig 3D). We speculate that one possible explanation for the absence of EGFR mutations in cfDNA at disease progression could be that, EGFR mutations were subclonal in those patients initially, and under the selective pressure of the EGFR‐targeting therapy, the EGFR‐driven clones shrank below detection limit of the assay, while clones that were driven by alterative drivers (such as TP53 and PIK3CA) and did not carry the EGFR‐sensitizing mutations, expanded. Based on our data from cfDNA, these alternative drivers pre‐existed even before treatment initiation, but were present in parts of the tumour that were not analysed, or alternatively were present at very low cellularity such that their allele fractions in those samples were below the detection limit by standard clinical tumour sequencing assay. Recent data from tumour sequencing suggested EGFR may be subclonal in a small subset of EGFR‐mutant NSCLC tumour (McGranahan et al, 2015), which agrees with our hypothesis. A recent plasma‐based study also reported 4 out of 24 NSCLC patients had EGFR‐sensitizing mutations detected in plasma at T0 but absent when the patients progressed, which agreed with our findings (Pecuchet et al, 2016). The fact that EGFR T790M was not detected in the third group suggested that the cancers have developed resistance mechanisms that are alterative to the EGFR pathway, which agreed with the observations of alternative drivers in plasma in some patients. For the patients whom we did not detect T790M nor other drivers were detected, they may have progressed due to other resistance mechanisms that were not covered by our targeted sequencing assay.\n\nOf note, overall, TKI‐naïve patients who progressed without T790M detection (13 patients selected from the second and the third groups) had a significantly worse PFS (Appendix Fig S4A and Appendix Table S5, P‐value = 0.008), and a trend towards worse OS (Appendix Fig S4B, P‐value = 0.22), as compared to T790M‐positive patients. These observations confirm results from a re‐biopsy study (Oxnard et al, 2011), suggesting that patients that progress without T790M are less likely to benefit from TKI continuation, possibly due to the more aggressive nature of their disease or reduced dependency on the EGFR pathway.\n\nDynamics of EGFR mutations in plasma across multiple lines of treatment\nTo explore the utility of monitoring both activating and resistance‐conferring mutations, we investigated their relative representation in plasma in relation to radiographic assessment in one patient for whom samples were available spanning sequential lines of first‐generation EGFR‐TKI and chemotherapy (Fig 4). Three lesions were tracked by imaging (Fig 4B): in the lung (L1), left liver lobe (L2) and right liver lobe (L3). During treatment with TKI, all three lesions initially shrank, before a small incremental increase in the size of L3 from day 49, although this did not amount to RECIST progression. The mutant AF of EGFR‐activating mutation (exon 19 deletion) decreased initially but increased from day 134 (Fig 4A). The T790M mutation was detected from day 189.\n\nFigure 4 Analysis of relative representation of activating and resistance‐conferring mutations in EGFR during sequential therapy\n\n(i) Sizes of three different lesions in patient 103 over time, measured from the start of first‐line TKI treatment. Shading indicates duration of treatment with TKI (days 0–297), chemotherapy (days 297–679), and TKI re‐challenge (days 679–783). From day 783, the patient was treated with supportive care. Dotted lines indicate the CT imaging assessment at select timepoints. (ii) Levels of activating EGFR mutations (exon 19 deletion) and resistance‐conferring EGFR T790M mutations for patient 103 (Dataset EV1). (iii) Ratio of resistance‐conferring/activating mutations, calculated from data shown in Appendix Table S1 (excluding the data at T = 300 days).\n\nCT imaging scans performed at the start of TKI treatment (day 0), at the change of treatment to chemotherapy (day 297), at the end of chemotherapy and start of TKI re‐challenge (day 679), and after initiating TKI re‐challenge (day 741). Sizes are assessed from CT imaging scans, and indicated by blue (i, lung), green (ii, left lobe liver) and orange (iii, right lobe liver) lines. Lesions identified in the lung (blue arrow), left lobe liver (green arrow) and right lobe liver (orange arrow) are indicated. PR, partial responses; PD, progressive disease.\n\n\n\n\nOn day 297, L3 showed a substantial growth. The T790M mutation at that timepoint reached AF of 3.6%. Treatment was changed to platinum‐based doublet chemotherapy at which point L3 showed a reduction on serial CT imaging, which coincided with a drop of the T790M mutation AF to 0.7% (Fig 4A). At day 679, despite the shrinkage of L3, L1 and L2 grew, coinciding with an increase in the AF of the activating mutation from 8.6% (when responding to initial TKI) to 43%. The patient was given a first‐generation EGFR‐TKI re‐challenge (newer TKIs were not yet approved at the time this patient was treated), and activating mutation sharply dropped back to 6.4%, corresponding to a reduction in L1 and L2.\n\nFrom day 217 to 244, both EGFR mutations exhibited a sharp drop in AF in plasma, for reasons we do not understand, and may be related to metabolic effects or technical artefacts. The increased AFs from days 244 to 272 may be a related transient effect. Similarly, the sample collected on day 300 from patient 103 presented an unexpectedly low total cfDNA level (> 10‐fold different from the timepoint immediately before and after), which could potentially influence the interpretation of mutant allele fractions at that timepoint. Such variations could be contributed by effects of processing, collection or other technical reasons. We have therefore excluded that timepoint from the analysis. To normalize for these kinds of pre‐analytic effects, and to explore the relative representation of the alleles, we calculated the ratio of AFs of the resistance‐conferring/activating EGFR mutations (Fig 4A). The ratio was zero before the start of TKI. It reached a maximal value of 0.43 during first‐line TKI (when L3 grew substantially), dropped to 0.02 after chemotherapy (corresponding to a reduction in L3), then rapidly increased upon TKI re‐challenge to 0.67.\n\nAlthough a liver biopsy was not performed, which may have been able to confirm the presence of T790M in L3, the clinical and radiological evidence in conjunction with the dynamics of EGFR mutations in plasma strongly suggests that the T790M was present in L3 but not in L1/L2. This suggests that the ratio of resistance‐conferring/activating mutations in plasma can help identify dominant drivers of disease and progression in real time (Oxnard et al, 2016).\n\nCopy number changes and mutations detected in plasma after SCLC transformation\nRecent findings have shown that around 2–3% of NSCLC patients develop resistance to EGFR‐targeted therapies by undergoing histological transformation to small‐cell lung cancer (SCLC; Sequist et al, 2011). In our cohort, three patients (patients 122, 223, 218) were confirmed to present SCLC histology based on re‐biopsy examination at progression. We used targeted deep sequencing and shallow whole‐genome sequencing of plasma DNA to track and study the dynamics of somatic point mutations and global copy number alterations (CNAs) in samples collected before and after SCLC transformation in those patients.\n\nT790M mutations were not detected in plasma at disease progression for any of the three SCLC‐transformed patients, and two of them (patients 122 and 218) retained the EGFR‐activating mutations in plasma after SCLC transformation. TP53 mutations were detected before EGFR‐TKI initiation in all three patients’ baseline plasma samples, at low levels (< 1%) compared to the EGFR‐activating mutations, and their levels in plasma increased with disease progression (patient 122, 223) or decreased when patient demonstrated clinical response (patient 218) during small‐cell lung cancer‐directed chemotherapy (Figs 5 and 6, and Appendix Fig S5). Analysis of the plasma samples collected after transformation in all three patients revealed the emergence of CNAs that have been previously reported to be associated with SCLC, including MYCL1, SOX2 and SOX4 (George et al, 2015; Figs 5 and 6, and Appendix Fig S5). In each patient, we also identified gain or loss of cancer genes as part of larger chromosomal events (> 5 Mb; Figs 5 and 6, and Appendix Fig S5). These may have contributed to the biological change or may represent passenger events as a result of greater genomic instability of the TP53‐mutant clones. We observed focal copy number changes at key oncogenic drivers that may play a role in driving disease progression, for example, amplification of KRAS in patient 223 (Fig 5) and amplification of EGFR in patients 122 and 218 (Appendix Fig S5 and Fig 6).\n\nFigure 5 Plasma analysis reveals global copy number changes and ctDNA dynamics in patients who have undergone histological transformation to SCLC (patient 223)\n\nCT liver scans are shown: At day 63, the patient had progressed on platinum‐based chemotherapy, and CT of the liver showed appearance of new liver lesions. Liver biopsy at that point confirmed small‐cell lung cancer in new lesions in the liver. CT of the liver at day 354 shows marked growth in the liver lesions, after a period of transient response to cisplatin and irinotecan.\n\nThe timeline of the patient's treatment is charted, alongside the timepoints where plasma and tumour samples are available for molecular analyses. Per diagram timeline, tumour samples were available from diagnosis (3 years prior to recruitment for study) (i) and at day 63 (iii). Plasma samples were available at day 0 (ii) and day 354 (iv). The mutations allele fractions for TP53 and PIK3CA are shown.\n\nGlobal copy number profiles in plasma samples collected prior to small‐cell transformation (ii) and after SCLC transformation and progression on cisplatin and irinotecan (iv). Global copy number profiles in tumour samples collected at diagnosis of NSCLC (i) and at small‐cell transformation (iii). CNA events that were significantly identified and coincide with literature‐reported SCLC events are denoted in colours: blue for gain and orange for loss.\n\n\n\n\nFigure 6 Plasma analysis reveals global copy number changes and ctDNA dynamics in patients who have undergone histological transformation to SCLC (patient 218)\n\nCT images of the left lung tumour at baseline (day −730), and upon progression on EGFR‐TKI (day 78). The patient was treated for non‐small‐cell lung cancer from days 78 to 329 with two lines of chemotherapy: initially carboplatin and pemetrexed, followed by docetaxel. The CT image corresponding to plasma 2 and re‐biopsy of the tumour at day 329 was upon progression on the above two lines of chemotherapy. CT image corresponding to plasma 3 at day 379 was upon response to small‐cell lung cancer chemotherapy. CT corresponding to days 500 and 524 are upon progression on cisplatin and etoposide. Marked growth of the lung and liver lesions are demonstrated, and this corresponds to marked CNA changes on plasma drawn on those respective days.\n\nThe timeline of the patient's treatment is shown, alongside timepoints where tumour and plasma samples were available for analyses. The bottom chart shows the respective mutations that were found, and the changes to the mutation allele fractions in a longitudinal timeline.\n\nGlobal copy number profiles in tumour and plasma samples are shown: Tumour samples at baseline diagnosis of non‐small‐cell lung cancer (day −730) and at transformation to small‐cell lung cancer (day 329). For plasma samples, the following were available: days 78 (upon progression on EGFR‐TKI); 329 (at transformation to small‐cell lung cancer); 379 (at response to small‐cell lung cancer); 500 and 534 (progression on small‐cell lung cancer treatment).\n\n\n\n\nPatient 223 (Fig 5A) initially harboured an exon 19 activating EGFR mutation, had indolent disease and remained clinically and radiologically responsive to first‐line EGFR‐TKI for 2 years. Subsequently, there was development of PET FDG‐avid, but subcentimetre, liver lesions that were not clearly appreciated on CT imaging. At this point, even though progression was only obvious in two new small spots on PET imaging (stable disease by CT and RECIST criteria), ctDNA showed multiple copy number changes (Fig 5B and C, plasma 1). There was subsequent rapid growth of the liver lesions, despite two lines of chemotherapy. A liver biopsy was performed at that point, and showed only small‐cell carcinoma, with no further activating nor T790M EGFR mutations found in the small‐cell cancer. Figure 5C demonstrates that a few months prior to the confirmation of small‐cell transformation, plasma analysis already showed marked copy number changes, this time of focal amplification of MYCL1 and KRAS, known oncogenic drivers in the KRAS pathway. These focal genomic changes were also observed in the subsequent liver biopsy, showing parallel changes in both tumour and plasma, suggesting that plasma is a good surrogate for study of genomic copy number alterations and evolution. In this particular case, the copy number changes were more markedly observed in the plasma, compared to the tumour, likely due to scarcity of tumour cells in the repeat biopsy.\n\nAnother patient with SCLC transformation (patient 218, Fig 6A) harboured an EGFR L858R‐activating mutation at diagnosis, and again demonstrated a good clinical and radiological response, with progression‐free survival of 14 months on first‐line EGFR‐TKI (Fig 6B). Upon clinical progression while on treatment with EGFR‐TKI (day 78), the plasma analysis (Fig 6B plasma 1) showed increased levels of EGFR L858R as well as a TP53 R175H mutation, one of the most frequently observed mutations in TP53. On treatment with platinum‐based doublet chemotherapy with pemetrexed, the patient achieved stability of disease. There was however early progression on maintenance pemetrexed and despite a switch to carboplatin and docetaxel, the patient's lung mass progressed, and a biopsy confirmed SCLC, harbouring the original activating EGFR L858R mutation. At this point, the patient was switched to treatment for SCLC with carboplatin and etoposide, with a radiological response and corresponding reduction in TP53 R175H mutation (Fig 6B, plasma 3). Unfortunately, the treatment response was transient, and there was development of widespread symptomatic metastases in both the brain and spine, necessitating radiotherapy to those areas. At the completion of radiotherapy, the patient had developed liver metastases with rapid progression. At this point, we observed marked copy number change in plasma 4 and 5 analyses (Fig 6C and Appendix Fig S6). This example illustrates that dynamics of genomic copy number changes in plasma reflect the mutational burden and radiologic responses.\n\nThe losses of TP53 and RB1 are common in SCLC (George et al, 2015), and we therefore attempted to look for RB1 somatic copy number alterations but did not find any significant signal by sWGS. In patient 218, RB1 did appear to have a reduced copy number, but this event could be part of a much larger chromosomal aberration, and thus, we cannot rule this out as being a passenger event. RB1 alterations are important driver in SCLC, but it is not necessarily the only driver (Karachaliou et al, 2016). All three SCLC‐transformed patients have evidence of TP53 mutations in their SCLC re‐biopsies, and pre‐ and post‐transformation plasma suggest that TP53 is an important driver in these particular patients.\n\nIn all three patients, CNAs were more evident in plasma as compared to tumour DNA analysis, likely due to scarcity of tumour cells at repeat biopsy. The data also illustrate that the global CNA profile in plasma can act as an indicator of disease burden and can be used to track clinical progression, as previously suggested in other cancer types (Heitzer et al, 2013). Subtype‐specific mutational and CNA signatures can be identified in plasma in association with histological transformation that warrants different treatment strategy, and their increasing levels in plasma can pre‐date radiological progression (by CT imaging). These observations suggest that plasma genomic changes could be indicative of early progression, and may complement current imaging modalities in monitoring response.\n\nDiscussion\nWe studied the dynamics of concurrent somatic point mutations and copy number alterations in plasma DNA during treatment of NSCLC patients with EGFR inhibitor. Several observations may provide information for the design of future plasma DNA studies of patients treated with targeted therapies:\n\nFirst, we found a strong concordance between EGFR status in tumour and plasma samples, and showed that mutations in multiple cancer‐related genes can be identified directly in plasma by targeted sequencing. These results confirm findings from a previous validation study (Douillard et al, 2014; Weber et al, 2014; Huang et al, 2017), and lend further credibility to the application of circulating DNA in plasma for non‐invasive molecular profiling and treatment stratification (Jamal‐Hanjani et al, 2017; Remon et al, 2017). Second, high pre‐treatment levels of ctDNA, and specifically of EGFR mutations in plasma prior to treatment with EGFR‐TKI, correlated with increased tumour burden and were associated with poor prognosis, echoing previous findings (Mok et al, 2015). We also showed that early changes in levels of ctDNA (in our case, of EGFR mutations) may predict initial response (Parkinson et al, 2016). Both of these findings lend support to the analysis of baseline and subsequent plasma samples for EGFR mutations to track treatment responses. Third, we detected the emergence of the T790M mutation in approximately 50% of patients who progressed on TKI, at a median of 6.8 months before clinical progression. Early identification of emerging resistance highlights the potential to use ctDNA to guide clinical interventions such as therapies that target T790M‐mutant cells (Janne et al, 2015; Sequist et al, 2015; Chabon et al, 2016; Remon et al, 2017).\n\nIn addition, we showed that profiling TP53 in plasma before EGFR‐targeted therapy can provide prognostic value. Cancers harbouring both TP53 and EGFR mutations in baseline plasma were associated with inferior overall survival in patients treated with EGFR‐targeted TKI. This confirmed observations from a tumour sequencing study (Labbe et al, 2017), and because plasma DNA captures the mutations coming from different parts of the tumour, we found that in some patients, these TP53 mutations pre‐existed at AF < 1% in plasma prior to treatment and later became the dominant mutations in plasma when patients progressed or exhibited histological transformation to SCLC. This echoes one of the recent findings that EGFR‐TKI‐resistant SCLCs can branch out from early events that pre‐existed in NSCLC prior to transformation based on tumour biopsy analysis (Lee et al, 2017).\n\nThese data highlight the potential value for clinical management of analysing mutations which may not be perceived as “actionable”, such as mutations in the tumour suppressor TP53, and suggests that the genetic context of an EGFR‐mutant tumour may determine its dependence on the EGFR and/or other pathways and predict sensitivity or resistance to EGFR‐directed treatment. Tracking the dynamics of multiple mutations showed that different resistance mechanisms co‐existed, and are likely to be the result of tumour heterogeneity (Piotrowska et al, 2015). As illustrated by the above clinical cases, the response and progression of different lesions coincided with the changing levels of distinct mutations in plasma. As treatment selection pressure is dynamic, analysing the relative proportions of different oncogenic drivers in plasma at any one point may provide insight on a particular dominant oncogenic pathway dependence and guide decisions on subsequent treatment by targeting the current dominant clone.\n\nFinally, we showed that tracking the dynamics of plasma EGFR mutations alone may not provide the most accurate estimate of tumour responses, as seen in the 14% of patients who progressed with decreasing levels of EGFR mutations in plasma. We speculate that this observation may be explained by the recent finding of subclonal EGFR driver mutations in 3 of 21 (14%) NSCLC cases (McGranahan et al, 2015), and suggest that monitoring EGFR‐targeted therapies by ctDNA would require tracking mutations beyond EGFR. These findings will need to be confirmed by further studies in larger cohorts. Nonetheless, using a multi‐gene assay, our data revealed the presence of concurrent oncogenic drivers before treatment. Parallel analysis of somatic point mutations and global CNA events (by shallow WGS) could more accurately track disease burden and detect subtype‐specific events (e.g. marked copy number changes associated with histological transformation). In particular, we identified multiple genomic changes in the plasma of three patients who underwent transformation to SCLC (patients 122, 223 and 218), which correlated closely with burden of disease. All three patients presented increasing fractions of TP53 mutations that pre‐existed at < 1% levels in plasma before treatment, together with recurrent SCLC CNA events in ctDNA at the time of transformation. These changes correlated closely with burden of disease, and CNA signals in plasma reduced accordingly when computerized tomography imaging showed radiological response to chemotherapy. In these cases, it was interesting to note that all cases exhibited different drivers, TP53 in the first case, MYCL‐1 and KRAS in the second, and two TP53 mutations in the third. It may be that each patient has a unique signature of genomic copy number change that may reflect disease burden, and this can be used to determine responding or progressive disease at various timepoints, with relation to each line of treatment received. However, the complex and varied genomic landscape in these transformed small‐cell lung cancers underscores the difficulty in targeting any one of these genomic signatures (even if actionable), and providing support for the use of chemotherapy, which is currently the most appropriate treatment for targeting these multiple genomic instabilities. Our findings suggest that an observation of multiple genomic copy number changes in the plasma of a patient with rapid progression of disease on EGFR‐TKI should prompt the need to re‐biopsy to exclude the possibility of small‐cell transformation. To date, EGFR T790M remains the main actionable resistance mechanisms in the context of EGFR‐TKI. However, the ability to reveal TP53 mutations or other possible SCLC‐associated genomic signatures in plasma would provide additional insight into possible resistance mechanisms that are particularly important in individuals that show no evidence of T790M or other known resistance mechanisms, and may justify the need for a re‐biopsy to confirm the histological transformation.\n\nOur study, spanning 392 clinical samples analysed by a combination of genomic techniques, describes multiple genomic changes in EGFR‐mutant patients with acquired resistance to first‐generation EGFR‐TKIs, and may explain the heterogeneity of treatment response to EGFR‐TKIs in EGFR‐mutant patients with similar activating mutations. We studied key genomic driver events of lung cancer, and evaluated their significance in a temporal and dynamic way with respect to disease response and progression in patients with analyses of longitudinal plasma studies. As the majority of patients were treated when second‐ and third‐generation EGFR‐TKIs were not readily available, most patients with acquired EGFR T790M mutation were not routinely re‐biopsied and were treated with chemotherapy. Analyses of changes in ctDNA in response to treatment with second‐ and third‐generation EGFR‐TKIs are not within the scope of this study. Nonetheless, some of the acquired resistance mechanisms described here may also apply to acquired resistance to a wide range of EGFR‐TKIs. Importantly, our study represents the first report on ctDNA changes in EGFR‐mutant cancers before and after histological transformation to SCLC and provides important insight into the management of this alterative form of resistance mechanism to EGFR‐TKI.\n\nIn summary, our data show that in the NSCLC EGFR‐targeted therapy setting, analysing the presence and dynamics of both actionable oncogenic drivers (such as EGFR mutations) and other, potentially “non‐actionable” alterations (such as TP53 mutations and global copy number changes), before and during treatment, can offer clinically relevant information to potentially guide subsequent clinical management.\n\nMaterials and Methods\nSample collection and processing\nPatients with metastatic NSCLC treated by gefitinib in combination with hydroxychloroquine therapy attending the University Hospital of Singapore, Singapore, during January 2009 to May 2014 were recruited as part of the “Hydroxychloroquine and Gefitinib to Treat Lung Cancer” study (NCT00809237). This was a single‐arm phase II study that recruited two groups of patients. In the first group, EGFR‐TKI‐naive patients who were known to have activating EGFR mutations were recruited to determine whether hydroxychloroquine improved the efficacy of gefitinib. The second group included patients who had previously responded to EGFR‐TKIs for at least 12 weeks (per Jackman criteria for acquired resistance to EGFR‐TKI) and aimed to determine whether the addition of hydroxychloroquine to gefitinib would reverse acquired resistance in these patients. Please see consort diagram (Appendix Fig S1) for further details including number of patients in each arm included for the purpose of this cDNA study (note that this represents a subset of the original clinical study—as this was subject to availability of plasma samples). Blood was collected from patients in a CPT sodium citrate tube (BD) every 4 weeks and stored at −80°C. CT imaging of relevant measurable sites of disease was performed every 8 weeks. This study was approved by the Singapore National Healthcare Group (Singapore National Healthcare Group Domain Specific Review Board NHG DSRB Reference: 2008/00196). Blood and tumor collection were also collected and approved by NHG DSRB 2014/00131. Informed consent has been obtained from all patients involved in this study. DNA was extracted from 0.8 to 2 ml of plasma using the Qiagen QIAamp Circulating Nucleic Acid Kit (Qiagen) and eluted into 50 μl buffer AVE. More details of sample processing are given in Appendix Supplementary Methods. A spike‐in control, non‐human DNA PCR product was added to the lysis buffer during DNA extraction to control for extraction efficiency.\n\nMutation identification and quantification by TAm‐Seq and digital PCR\nAnalysis by tagged‐amplicon deep sequencing (TAm‐Seq) was performed using the panel described previously (Forshew et al, 2012), with the addition of an amplicon that covers exon 18 of EGFR (additional details in Appendix Supplementary Methods). All samples were analysed by at least two replicates to control for errors arising during PCR. The purified libraries were sequenced using paired‐end 100 bp read length of a HiSeq 2000 or HiSeq 2500 System (Illumina, USA). Somatic mutations were identified based on filtering against the matched normal control (white blood cells) of the same patient. For quantification of known hotspot mutations in EGFR, namely exon 19 deletion, T790M and L858R, digital PCR analysis was developed and optimized: sensitivity and specificity and limit of detection was determined using samples with known mutations and samples from healthy volunteer controls (Appendix Fig S7 and Appendix Table S6). Assays were performed using the BioMark system using 12.765 Digital Arrays (Fluidigm, USA) following manufacturer's instructions and protocol. Total DNA levels (amplifiable copies per ml) were also quantified in every plasma sample by digital PCR using a 65‐bp assay targeting a region on the RPP30 gene (Appendix Table S7), a region in the genome that is not amplified in lung cancer (Wang et al, 2010). Two samples were excluded from analysis due to an unexplained sharp drop in total circulating DNA levels extracted from plasma, with >10‐fold drop in those levels compared to samples collected few weeks prior and no evident association with any clinical or treatment parameters. This is suspected to be related to technical fault either at collection or processing of samples. Evaluation of the specificity and sensitivity of the assays was described in Appendix Supplementary Methods. The primer and probe sequences of all the digital PCR assays are summarized in Appendix Table S7. The mutant allele fractions measured by TAM‐Seq and ddPCR strongly correlate with each other (Appendix Fig S8).\n\nShallow whole‐genome sequencing (sWGS)\nLibraries were prepared from either plasma DNA (5–10 ng), sheared tumour DNA, or sheared buffy coat DNA using the Plasma‐Seq protocol (Rubicon, USA). Briefly, end repair and “A‐tailing” of fragment ends preceded the ligation of truncated Illumina sequencer‐compatible adapters to fragment ends. Thermocycling of libraries completed the adapters through the addition of sample‐specific index sequences, and was performed as described in the Plasma‐Seq protocol (Heitzer et al, 2013), using 10 (plasma) or 8 (tumour and buffy coat) amplification cycles. Upon amplification libraries were cleaned using Agencourt AMPure XP beads (Beckman Coulter, USA) at a 1:1 (v/v) ratio and eluted in 30 μl nuclease‐free water. Successful library preparation was confirmed by running 1 μl of library on a High‐Sensitivity Bioanalyser gel, and libraries were quantified using SYBRgreen‐based qPCR (Kapa Biosystems, USA). Libraries were pooled in an equimolar fashion, and 125‐bp paired‐end sequencing was performed on Illumina sequencers (Illumina, USA).\n\nPaired‐end sequence reads were aligned to the human reference genome (GRCh37) using BWA, SAMtools was used to convert files to BAM format, to which mate pair information was added. PCR duplicates were marked using Picard‐Tools’ “MarkDuplicates” feature and were excluded from downstream analysis. Fragment lengths were analysed using Picard‐Tools’ “CollectInsertSizeMetrics”. CNA calling was performed in R using the program QDNAseq (Scheinin et al, 2014). Briefly, sequence reads were allocated into equally sized (here 1 Mb and 50‐kb bins) non‐overlapping bins throughout the length of the genome. Read counts in each bin were corrected to account for sequence GC content and mappability, and regions corresponding to previously “blacklisted” regions (ENCODE) were excluded from downstream analysis. Within the QDNAseq package, bins were segmented using the “Circular Binary Segmentation” algorithm (Venkatraman & Olshen, 2007) and significantly “amplified” or “lost” regions were called using CGHcall (van de Wiel et al, 2007).\n\nData deposition\nSequence data have been deposited at the European Genome‐phenome Archive (EGA), which is hosted by the EBI and the CRG, under Accession no. EGAS00001002908.\n\nSurvival analysis\nKaplan–Meier curves were computed for prognostic groups defined by their mutation fractions, and log‐rank tests were computed for testing differences in survival. We measured pre‐treatment ctDNA levels using allele fractions of the EGFR‐activating mutations and computed Kaplan–Meier survival curves to evaluate the effects of different levels of pre‐treatment ctDNA: We divided patients into three groups: low pre‐treatment ctDNA levels (less than the lower quartile), intermediate (second and third quartiles) or high (upper quartile). All survival analyses were performed using the R package survival (Therneau, 2012). It should be noted that only the EGFR‐TKI‐naïve group of patients with available pre‐treatment plasma samples (n = 19) were used for progression‐free and overall survival analyses, and correlative prognostic study. This is to ensure analyses of a homogeneous population. The survival analyses of both groups of patients will be reported in a separate clinical paper that would include response rates and other clinical parameters.\n\nThe experiments conformed to the principles set out in the WMA Declaration of Helsinki and the Department of Health and Human Services Belmont Report.\n\nAuthor contributions\nDWYT, TE, TMC and NR initiated and designed the study. DWYT, CGS, DC, TF, MM, FM, DG and NR developed methods. DWYT, MM, TMC and NR analysed the data, with assistance from OMR, CC, CGS, DC, FM, JM and WL. ASCW, RAS, HLL, BCG and TMC are the treating physicians of the patients included in this study, and collected samples and clinical data. DWYT, MM, TMC and NR interpreted the data and wrote the manuscript with assistance from other authors. All authors approved the final manuscript.\n\nConflict of interest\nT.F., D.G. and N.R. are co‐founders, shareholders and employees/consultants of Inivata Ltd., a company that seeks to commercialize ctDNA technologies and has licensed patents and technologies from Cancer Research Technology and the University of Cambridge. D.T. and F.M are former consultants of Inivata Ltd. D.T., M.M., T.F., F.M., J.M., D.G. and N.R. may receive royalties related to the licences of IP to Inivata Ltd, and the terms of these royalties are managed by Cancer Research Technology and Cambridge Enterprise. T.E. and N.R. have received research support from AstraZeneca. T.E. is an employee of AstraZeneca on leave of absence from the University of Cambridge.\n\nThe paper explained\nProblem\nThe cancer genome evolves under the selective pressure of targeted therapies. One of the key challenges is to identify resistance mechanisms and the most dominant drivers as early as possible. Analysis of plasma cell‐free DNA allows one to track molecular dynamics non‐invasively.\n\nResults\nThis study found that cell‐free DNA analysis reveals clinically important information during EGFR‐targeted therapy in non‐small‐cell lung cancer (NSCLC): At baseline, quantitative tumour‐derived cell‐free DNA levels in plasma provided prognostic information and correlated with tumour burden. During treatment, multiple potential indications of resistance such as EGFR T790M or TP53 can be detected in plasma months before disease progression became clinically evident. Longitudinal analysis of tumour‐derived cell‐free DNA levels tracks tumour responses and reveals heterogeneous resistance mechanisms: The majority depend on the EGFR pathway while a small subset developed alterative drivers that could be identified by tracking multiple mutations in plasma DNA. In patients who developed resistance by transforming to small‐cell lung cancer (SCLC), we identified TP53 mutations, one of the key drivers of SCLC, and SCLC‐specific copy number events in plasma before the transformation.\n\nImpact\nParallel analysis of multiple mutations and copy number alterations in plasma allows identification of dominant drivers at any given time during treatment. Tracking EGFR mutations alone in plasma during EGFR‐targeted therapy may not accurately reflect tumour burden due to underlying tumour heterogeneity. The results of this study provide important insight about the implication of cell‐free DNA analysis for management of targeted therapies.\n\nSupporting information\n Appendix\n\nClick here for additional data file.\n\n Dataset EV1\n\nClick here for additional data file.\n\n Review Process File\n\nClick here for additional data file.\n\n Acknowledgements\nWe are grateful to the following physicians who recruited patients on the study—Dr. Pei Jye VOON, Dr. Winnie LING, Dr. Thomas SOH, Dr. Chee Seng TAN, Dr. Angela PANG and Dr. Yew Oo TAN. We also thank the following for technical support—Maricel Tiemsin CODERO, Hui Hui SHEE, Shiau Hui Diong, and Dr. Azhar ALI from The Centre for Translational Research and Diagnostics, National University of Singapore and Cancer Science Institute, Singapore. We thank the sequencing support by the Genomics Core of the Cancer Research UK Cambridge Institute, and by David Bentley and Sean Humphray from Illumina. We would like to acknowledge the support of The University of Cambridge, Cancer Research UK (grant numbers A11906, A20240; to N.R.), the European Research Council under the European Union’s Seventh Framework Programme (FP/2007‐2013)/ERC Grant Agreement no. 337905 (to N.R.), and Hutchison Whampoa Limited (to N.R.), and National Medical Research Council, Singapore (to T.M.C.).\n==== Refs\nReferences\n\n\nAbbosh \nC \n, \nBirkbak \nNJ \n, \nWilson \nGA \n, \nJamal‐Hanjani \nM \n, \nConstantin \nT \n, \nSalari \nR \n, \nLe Quesne \nJ \n, \nMoore \nDA \n, \nVeeriah \nS \n, \nRosenthal \nR \n\net al (2017 ) Phylogenetic ctDNA analysis depicts early‐stage lung cancer evolution . Nature \n545 : 446 –451 \n28445469 \n\n\nCamidge \nDR \n, \nPao \nW \n, \nSequist \nLV \n (2014 ) Acquired resistance to TKIs in solid tumours: learning from lung cancer . Nat Rev Clin Oncol \n11 : 473 –481 \n24981256 \n\n\nChabon \nJJ \n, \nSimmons \nAD \n, \nLovejoy \nAF \n, \nEsfahani \nMS \n, \nNewman \nAM \n, \nHaringsma \nHJ \n, \nKurtz \nDM \n, \nStehr \nH \n, \nScherer \nF \n, \nKarlovich \nCA \n\net al (2016 ) Circulating tumour DNA profiling reveals heterogeneity of EGFR inhibitor resistance mechanisms in lung cancer patients . Nat Commun \n7 : 11815 \n27283993 \n\n\nChakravarty \nD \n, \nGao \nJ \n, \nPhillips \nSM \n, \nKundra \nR \n, \nZhang \nH \n, \nWang \nJ \n, \nRudolph \nJE \n, \nYaeger \nR \n, \nSoumerai \nT \n, \nNissan \nMH \n\net al (2017 ) OncoKB: A precision oncology knowledge base . JCO Precis Oncol doi: 10.1200/PO.17.00011\n\n\n\nCouraud \nS \n, \nVaca‐Paniagua \nF \n, \nVillar \nS \n, \nOliver \nJ \n, \nSchuster \nT \n, \nBlanche \nH \n, \nGirard \nN \n, \nTredaniel \nJ \n, \nGuilleminault \nL \n, \nGervais \nR \n\net al (2014 ) Noninvasive diagnosis of actionable mutations by deep sequencing of circulating free DNA in lung cancer from never‐smokers: a proof‐of‐concept study from BioCAST/IFCT‐1002 . Clin Cancer Res \n20 : 4613 –4624 \n25013125 \n\n\nDouillard \nJY \n, \nOstoros \nG \n, \nCobo \nM \n, \nCiuleanu \nT \n, \nCole \nR \n, \nMcWalter \nG \n, \nWalker \nJ \n, \nDearden \nS \n, \nWebster \nA \n, \nMilenkova \nT \n\net al (2014 ) Gefitinib treatment in EGFR mutated caucasian NSCLC: circulating‐free tumor DNA as a surrogate for determination of EGFR status . J Thorac Oncol \n9 : 1345 –1353 \n25122430 \n\n\nForshew \nT \n, \nMurtaza \nM \n, \nParkinson \nC \n, \nGale \nD \n, \nTsui \nDW \n, \nKaper \nF \n, \nDawson \nSJ \n, \nPiskorz \nAM \n, \nJimenez‐Linan \nM \n, \nBentley \nD \n\net al (2012 ) Noninvasive identification and monitoring of cancer mutations by targeted deep sequencing of plasma DNA . Sci Transl Med \n4 : 136ra168 \n\n\n\nGeorge \nJ \n, \nLim \nJS \n, \nJang \nSJ \n, \nCun \nY \n, \nOzretic \nL \n, \nKong \nG \n, \nLeenders \nF \n, \nLu \nX \n, \nFernandez‐Cuesta \nL \n, \nBosco \nG \n\net al (2015 ) Comprehensive genomic profiles of small cell lung cancer . Nature \n524 : 47 –53 \n26168399 \n\n\nHeitzer \nE \n, \nUlz \nP \n, \nBelic \nJ \n, \nGutschi \nS \n, \nQuehenberger \nF \n, \nFischereder \nK \n, \nBenezeder \nT \n, \nAuer \nM \n, \nPischler \nC \n, \nMannweiler \nS \n\net al (2013 ) Tumor‐associated copy number changes in the circulation of patients with prostate cancer identified through whole‐genome sequencing . Genome Med \n5 : 30 \n23561577 \n\n\nHuang \nWL \n, \nChen \nYL \n, \nYang \nSC \n, \nHo \nCL \n, \nWei \nF \n, \nWong \nDT \n, \nSu \nWC \n, \nLin \nCC \n (2017 ) Liquid biopsy genotyping in lung cancer: ready for clinical utility? \nOncotarget \n8 : 18590 –18608 \n28099915 \n\n\nJamal‐Hanjani \nM \n, \nWilson \nGA \n, \nMcGranahan \nN \n, \nBirkbak \nNJ \n, \nWatkins \nTBK \n, \nVeeriah \nS \n, \nShafi \nS \n, \nJohnson \nDH \n, \nMitter \nR \n, \nRosenthal \nR \n\net al (2017 ) Tracking the evolution of non‐small‐cell lung cancer . N Engl J Med \n376 : 2109 –2121 \n28445112 \n\n\nJanne \nPA \n, \nYang \nJC \n, \nKim \nDW \n, \nPlanchard \nD \n, \nOhe \nY \n, \nRamalingam \nSS \n, \nAhn \nMJ \n, \nKim \nSW \n, \nSu \nWC \n, \nHorn \nL \n\net al (2015 ) AZD9291 in EGFR inhibitor‐resistant non‐small‐cell lung cancer . N Engl J Med \n372 : 1689 –1699 \n25923549 \n\n\nKarachaliou \nN \n, \nPilotto \nS \n, \nLazzari \nC \n, \nBria \nE \n, \nde Marinis \nF \n, \nRosell \nR \n (2016 ) Cellular and molecular biology of small cell lung cancer: an overview . Transl Lung Cancer Res \n5 : 2 –15 \n26958489 \n\n\nLabbe \nC \n, \nCabanero \nM \n, \nKorpanty \nGJ \n, \nTomasini \nP \n, \nDoherty \nM \n, \nMascaux \nC \n, \nJao \nK \n, \nPitcher \nB \n, \nWang \nR \n, \nPintilie \nM \n\net al (2017 ) Prognostic and predictive effects of TP53 mutation in patients with EGFR‐mutated non‐small cell lung cancer . Lung Cancer \n111 : 23 –29 \n28838393 \n\n\nLee \nJK \n, \nLee \nJ \n, \nKim \nS \n, \nKim \nS \n, \nYouk \nJ \n, \nPark \nS \n, \nAn \nY \n, \nKeam \nB \n, \nKim \nDW \n, \nHeo \nDS \n\net al (2017 ) Clonal history and genetic predictors of transformation into small‐cell carcinomas from lung adenocarcinomas . J Clin Oncol \n35 : 3065 –3074 \n28498782 \n\n\nLynch \nTJ \n, \nBell \nDW \n, \nSordella \nR \n, \nGurubhagavatula \nS \n, \nOkimoto \nRA \n, \nBrannigan \nBW \n, \nHarris \nPL \n, \nHaserlat \nSM \n, \nSupko \nJG \n, \nHaluska \nFG \n\net al (2004 ) Activating mutations in the epidermal growth factor receptor underlying responsiveness of non‐small‐cell lung cancer to gefitinib . N Engl J Med \n350 : 2129 –2139 \n15118073 \n\n\nMcGranahan \nN \n, \nFavero \nF \n, \nde Bruin \nEC \n, \nBirkbak \nNJ \n, \nSzallasi \nZ \n, \nSwanton \nC \n (2015 ) Clonal status of actionable driver events and the timing of mutational processes in cancer evolution . Sci Transl Med \n7 : 283ra254 \n\n\n\nMok \nT \n, \nWu \nYL \n, \nLee \nJS \n, \nYu \nCJ \n, \nSriuranpong \nV \n, \nSandoval‐Tan \nJ \n, \nLadrera \nG \n, \nThongprasert \nS \n, \nSrimuninnimit \nV \n, \nLiao \nM \n\net al (2015 ) Detection and dynamic changes of EGFR mutations from circulating tumor DNA as a predictor of survival outcomes in NSCLC patients treated with first‐line intercalated erlotinib and chemotherapy . Clin Cancer Res \n21 : 3196 –3203 \n25829397 \n\n\nNewman \nAM \n, \nBratman \nSV \n, \nTo \nJ \n, \nWynne \nJF \n, \nEclov \nNC \n, \nModlin \nLA \n, \nLiu \nCL \n, \nNeal \nJW \n, \nWakelee \nHA \n, \nMerritt \nRE \n\net al (2014 ) An ultrasensitive method for quantitating circulating tumor DNA with broad patient coverage . Nat Med \n20 : 548 –554 \n24705333 \n\n\nNewman \nAM \n, \nLovejoy \nAF \n, \nKlass \nDM \n, \nKurtz \nDM \n, \nChabon \nJJ \n, \nScherer \nF \n, \nStehr \nH \n, \nLiu \nCL \n, \nBratman \nSV \n, \nSay \nC \n\net al (2016 ) Integrated digital error suppression for improved detection of circulating tumor DNA . Nat Biotechnol \n34 : 547 –555 \n27018799 \n\n\nNiederst \nMJ \n, \nSequist \nLV \n, \nPoirier \nJT \n, \nMermel \nCH \n, \nLockerman \nEL \n, \nGarcia \nAR \n, \nKatayama \nR \n, \nCosta \nC \n, \nRoss \nKN \n, \nMoran \nT \n\net al (2015 ) RB loss in resistant EGFR mutant lung adenocarcinomas that transform to small‐cell lung cancer . Nat Commun \n6 : 6377 \n25758528 \n\n\nOxnard \nGR \n, \nArcila \nME \n, \nSima \nCS \n, \nRiely \nGJ \n, \nChmielecki \nJ \n, \nKris \nMG \n, \nPao \nW \n, \nLadanyi \nM \n, \nMiller \nVA \n (2011 ) Acquired resistance to EGFR tyrosine kinase inhibitors in EGFR‐mutant lung cancer: distinct natural history of patients with tumors harboring the T790M mutation . Clin Cancer Res \n17 : 1616 –1622 \n21135146 \n\n\nOxnard \nGR \n, \nPaweletz \nCP \n, \nKuang \nY \n, \nMach \nSL \n, \nO'Connell \nA \n, \nMessineo \nMM \n, \nLuke \nJJ \n, \nButaney \nM \n, \nKirschmeier \nP \n, \nJackman \nDM \n\net al (2014 ) Noninvasive detection of response and resistance in EGFR‐mutant lung cancer using quantitative next‐generation genotyping of cell‐free plasma DNA . Clin Cancer Res \n20 : 1698 –1705 \n24429876 \n\n\nOxnard \nGR \n, \nThress \nKS \n, \nAlden \nRS \n, \nLawrance \nR \n, \nPaweletz \nCP \n, \nCantarini \nM \n, \nYang \nJC \n, \nBarrett \nJC \n, \nJanne \nPA \n (2016 ) Association between plasma genotyping and outcomes of treatment with osimertinib (AZD9291) in advanced non‐small‐cell lung cancer . J Clin Oncol \n34 : 3375 –3382 \n27354477 \n\n\nPaez \nJG \n, \nJanne \nPA \n, \nLee \nJC \n, \nTracy \nS \n, \nGreulich \nH \n, \nGabriel \nS \n, \nHerman \nP \n, \nKaye \nFJ \n, \nLindeman \nN \n, \nBoggon \nTJ \n\net al (2004 ) EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy . Science \n304 : 1497 –1500 \n15118125 \n\n\nParkinson \nCA \n, \nGale \nD \n, \nPiskorz \nAM \n, \nBiggs \nH \n, \nHodgkin \nC \n, \nAddley \nH \n, \nFreeman \nS \n, \nMoyle \nP \n, \nSala \nE \n, \nSayal \nK \n\net al (2016 ) Exploratory analysis of TP53 mutations in circulating tumour DNA as biomarkers of treatment response for patients with relapsed high‐grade serous ovarian carcinoma: a retrospective study . PLoS Med \n13 : e1002198 \n27997533 \n\n\nPaweletz \nCP \n, \nSacher \nA \n, \nRaymond \nCK \n, \nAlden \nRS \n, \nO'Connell \nA \n, \nMach \nSL \n, \nKuang \nY \n, \nGandhi \nL \n, \nKirschmeier \nP \n, \nEnglish \nJM \n\net al (2015 ) Bias‐corrected targeted next‐generation sequencing for rapid, multiplexed detection of actionable alterations in cell‐free DNA from advanced lung cancer patients . Clin Cancer Res \n22 : 915 –922 \n26459174 \n\n\nPecuchet \nN \n, \nZonta \nE \n, \nDidelot \nA \n, \nCombe \nP \n, \nThibault \nC \n, \nGibault \nL \n, \nLours \nC \n, \nRozenholc \nY \n, \nTaly \nV \n, \nLaurent‐Puig \nP \n\net al (2016 ) Base‐position error rate analysis of next‐generation sequencing applied to circulating tumor DNA in non‐small cell lung cancer: a prospective study . PLoS Med \n13 : e1002199 \n28027313 \n\n\nPiotrowska \nZ \n, \nNiederst \nMJ \n, \nKarlovich \nCA \n, \nWakelee \nHA \n, \nNeal \nJW \n, \nMino‐Kenudson \nM \n, \nFulton \nL \n, \nHata \nAN \n, \nLockerman \nEL \n, \nKalsy \nA \n\net al (2015 ) Heterogeneity underlies the emergence of EGFRT790 wild‐type clones following treatment of T790M‐positive cancers with a third‐generation EGFR inhibitor . Cancer Discov \n5 : 713 –722 \n25934077 \n\n\nRemon \nJ \n, \nCaramella \nC \n, \nJovelet \nC \n, \nLacroix \nL \n, \nLawson \nA \n, \nSmalley \nS \n, \nHowarth \nK \n, \nGale \nD \n, \nGreen \nE \n, \nPlagnol \nV \n\net al (2017 ) Osimertinib benefit in EGFR‐mutant NSCLC patients with T790M‐mutation detected by circulating tumour DNA . Ann Oncol \n28 : 784 –790 \n28104619 \n\n\nScheinin \nI \n, \nSie \nD \n, \nBengtsson \nH \n, \nvan de Wiel \nMA \n, \nOlshen \nAB \n, \nvan Thuijl \nHF \n, \nvan Essen \nHF \n, \nEijk \nPP \n, \nRustenburg \nF \n, \nMeijer \nGA \n\net al (2014 ) DNA copy number analysis of fresh and formalin‐fixed specimens by shallow whole‐genome sequencing with identification and exclusion of problematic regions in the genome assembly . Genome Res \n24 : 2022 –2032 \n25236618 \n\n\nSequist \nLV \n, \nWaltman \nBA \n, \nDias‐Santagata \nD \n, \nDigumarthy \nS \n, \nTurke \nAB \n, \nFidias \nP \n, \nBergethon \nK \n, \nShaw \nAT \n, \nGettinger \nS \n, \nCosper \nAK \n\net al (2011 ) Genotypic and histological evolution of lung cancers acquiring resistance to EGFR inhibitors . Sci Transl Med \n3 : 75ra26 \n\n\n\nSequist \nLV \n, \nSoria \nJC \n, \nGoldman \nJW \n, \nWakelee \nHA \n, \nGadgeel \nSM \n, \nVarga \nA \n, \nPapadimitrakopoulou \nV \n, \nSolomon \nBJ \n, \nOxnard \nGR \n, \nDziadziuszko \nR \n\net al (2015 ) Rociletinib in EGFR‐mutated non‐small‐cell lung cancer . N Engl J Med \n372 : 1700 –1709 \n25923550 \n\n\nSierra \nJR \n, \nTsao \nMS \n (2011 ) c‐MET as a potential therapeutic target and biomarker in cancer . Ther Adv Med Oncol \n3 : S21 –S35 \n22128285 \n\n\nTherneau \nT \n (2012 ) A package for survival analysis in S In R package version 2.36‐14 .\n\n\nVenkatraman \nES \n, \nOlshen \nAB \n (2007 ) A faster circular binary segmentation algorithm for the analysis of array CGH data . Bioinformatics \n23 : 657 –663 \n17234643 \n\n\nWan \nJC \n, \nMassie \nC \n, \nGarcia‐Corbacho \nJ \n, \nMouliere \nF \n, \nBrenton \nJD \n, \nCaldas \nC \n, \nPacey \nS \n, \nBaird \nR \n, \nRosenfeld \nN \n (2017 ) Liquid biopsies come of age: towards implementation of circulating tumour DNA . Nat Rev Cancer \n17 : 223 –238 \n28233803 \n\n\nWang \nJ \n, \nRamakrishnan \nR \n, \nTang \nZ \n, \nFan \nW \n, \nKluge \nA \n, \nDowlati \nA \n, \nJones \nRC \n, \nMa \nPC \n (2010 ) Quantifying EGFR alterations in the lung cancer genome with nanofluidic digital PCR arrays . Clin Chem \n56 : 623 –632 \n20207772 \n\n\nWeber \nB \n, \nMeldgaard \nP \n, \nHager \nH \n, \nWu \nL \n, \nWei \nW \n, \nTsai \nJ \n, \nKhalil \nA \n, \nNexo \nE \n, \nSorensen \nBS \n (2014 ) Detection of EGFR mutations in plasma and biopsies from non‐small cell lung cancer patients by allele‐specific PCR assays . BMC Cancer \n14 : 294 \n24773774 \n\n\nvan de Wiel \nMA \n, \nKim \nKI \n, \nVosse \nSJ \n, \nvan Wieringen \nWN \n, \nWilting \nSM \n, \nYlstra \nB \n (2007 ) CGHcall: calling aberrations for array CGH tumor profiles . Bioinformatics \n23 : 892 –894 \n17267432 \n\n\nYu \nHA \n, \nArcila \nME \n, \nRekhtman \nN \n, \nSima \nCS \n, \nZakowski \nMF \n, \nPao \nW \n, \nKris \nMG \n, \nMiller \nVA \n, \nLadanyi \nM \n, \nRiely \nGJ \n (2013 ) Analysis of tumor specimens at the time of acquired resistance to EGFR‐TKI therapy in 155 patients with EGFR‐mutant lung cancers . Clin Cancer Res \n19 : 2240 –2247 \n23470965 \n\n\nYung \nTK \n, \nChan \nKC \n, \nMok \nTS \n, \nTong \nJ \n, \nTo \nKF \n, \nLo \nYM \n (2009 ) Single‐molecule detection of epidermal growth factor receptor mutations in plasma by microfluidics digital PCR in non‐small cell lung cancer patients . Clin Cancer Res \n15 : 2076 –2084 \n19276259\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1757-4676",
"issue": "10(6)",
"journal": "EMBO molecular medicine",
"keywords": "circulating tumour DNA; liquid biopsy; lung cancer; resistance mechanisms; targeted therapy",
"medline_ta": "EMBO Mol Med",
"mesh_terms": "D000970:Antineoplastic Agents; D002289:Carcinoma, Non-Small-Cell Lung; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors; D000077156:Gefitinib; D006801:Humans; D006886:Hydroxychloroquine; D008137:Longitudinal Studies; D008175:Lung Neoplasms; D009154:Mutation; D011379:Prognosis; D016019:Survival Analysis; D016896:Treatment Outcome; D016159:Tumor Suppressor Protein p53",
"nlm_unique_id": "101487380",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29848757",
"pubdate": "2018-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "25923550;23561577;25236618;28445469;20207772;24773774;27018799;25877892;22128285;22649089;27283993;25829397;28838393;25013125;27354477;24981256;17234643;23470965;28445112;24429876;19276259;21135146;17267432;15118125;25923549;15118073;26168399;25934077;25122430;27997533;28498782;21430269;28099915;26459174;26958489;28027313;25758528;28233803;28890946;28104619;24705333",
"title": "Dynamics of multiple resistance mechanisms in plasma DNA during EGFR-targeted therapies in non-small cell lung cancer.",
"title_normalized": "dynamics of multiple resistance mechanisms in plasma dna during egfr targeted therapies in non small cell lung cancer"
} | [
{
"companynumb": "GB-MYLANLABS-2019M1001397",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
... |
{
"abstract": "HER2-targeted treatments have improved outcomes in patients with HER2-positive breast cancer in the neoadjuvant, adjuvant, and metastatic settings; however, some patients remain at risk of relapse or death for many years after treatment of early-stage disease. Therefore, new strategies are needed. We did a phase 3 trial to assess a neoadjuvant regimen for HER2-positive breast cancer that replaces traditional systemic chemotherapy with targeted treatment.\n\n\n\nWe did a randomised, open-label phase 3 KRISTINE trial in 68 Translational Research In Oncology centres (hospitals and specialty cancer centres in Asia, Europe, USA, and Canada). Eligible participants were aged 18 years or older with centrally confirmed HER2-positive stage II-III operable breast cancer (>2 cm tumour size), an Eastern Cooperative Oncology Group performance status of 0-1, and a baseline left ventricular ejection fraction of at least 55% (by echocardiogram or multiple-gated acquisition scan). We randomly assigned participants (1:1) to receive either trastuzumab emtansine plus pertuzumab or docetaxel, carboplatin, and trastuzumab plus pertuzumab. We did the randomisation via an interactive response system under a permuted block randomisation scheme (block size of four), stratified by hormone receptor status, stage at diagnosis, and geographical location. Patients received six cycles (every 3 weeks) of neoadjuvant trastuzumab emtansine plus pertuzumab (trastuzumab emtansine 3·6 mg/kg; pertuzumab 840 mg loading dose, 420 mg maintenance doses) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (docetaxel 75 mg/m2; carboplatin area under the concentration-time curve 6 mg/mL × min; trastuzumab 8 mg/kg loading dose, 6 mg/kg maintenance doses) plus pertuzumab [same dosing as in the other group]). All treatments were administered intravenously. The primary objective was to compare the number of patients who achieved a pathological complete response (ypT0/is, ypN0), between groups in the intention-to-treat population (two-sided assessment), based on local evaluation of tumour samples taken at breast cancer surgery done between 14 days and 6 weeks after completion of neoadjuvant therapy. Safety was analysed in patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02131064, and follow-up of the adjuvant phase is ongoing.\n\n\n\nBetween June 25, 2014, and June 15, 2015, we randomly assigned 444 patients to neoadjuvant treatment with trastuzumab emtansine plus pertuzumab (n=223) or docetaxel, carboplatin, and trastuzumab plus pertuzumab (n=221). A pathological complete response was achieved by 99 (44·4%) of 223 patients in the trastuzumab emtansine plus pertuzumab group and 123 (55·7%) of 221 patients in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group (absolute difference -11·3 percentage points, 95% CI -20·5 to -2·0; p=0·016). During neoadjuvant treatment, compared with patients receiving docetaxel, carboplatin, and trastuzumab plus pertuzumab, fewer patients receiving trastuzumab emtansine plus pertuzumab had a grade 3-4 adverse event (29 [13%] of 223 vs 141 [64%] of 219) or a serious adverse event (11 [5%] of 223 vs 63 [29%] of 219). The most common grade 3-4 adverse events in the trastuzumab emtansine plus pertuzumab group were decreased platelet count (three [1%] of 223 patients vs 11 [5%] of 219 with docetaxel, carboplatin, and trastuzumab plus pertuzumab), fatigue (three [1%] vs seven [3%]), alanine aminotransferase increase (three [1%] vs four [2%]), and hypokalaemia (three [1%] vs five [2%]). The most common grade 3-4 adverse events in the docetaxel, carboplatin, and trastuzumab plus pertuzumab group were neutropenia (55 [25%] of 219 vs one [<1%] of 223 with trastuzumab emtansine plus pertuzumab), diarrhoea (33 [15%] vs 2 [<1%]), and febrile neutropenia (33 [15%] vs 0). No deaths were reported during neoadjuvant treatment.\n\n\n\nTraditional neoadjuvant systemic chemotherapy plus dual HER2-targeted blockade (docetaxel, carboplatin, and trastuzumab plus pertuzumab) resulted in significantly more patients achieving a pathological complete response than HER2-targeted chemotherapy plus HER2-targeted blockade (trastuzumab emtansine plus pertuzumab); however, numerically more grade 3-4 and serious adverse events occurred in the chemotherapy plus trastuzumab and pertuzumab group. Further efforts to improve the efficacy of chemotherapy without imparting more toxicity are warranted.\n\n\n\nF Hoffmann-La Roche and Genentech.",
"affiliations": "David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA. Electronic address: SHurvitz@mednet.ucla.edu.;Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, CiberOnc, GEICAM, Madrid, Spain.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Asan Medical Center, University of Ulsan College of Medicine, Songpa-gu, Seoul, Korea.;National Taiwan University Hospital, National Taiwan University College of Medicine, Taipei, Taiwan.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Breast Center, University of Munich (LMU), Munich, Germany.;The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Moscow City Oncology Hospital 62, Moscow, Russia.;Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium.;Centre René Gauducheau, St Herblain cedex, France.;McGill University, Sir Mortimer B Davis Jewish General Hospital, Montreal, QC, Canada.;University Hospital Erlangen, Department of Obstetrics and Gynecology, Friedrich-Alexander-Universität Erlangen, Comprehensive Cancer Center Erlangen-Europäische Metropolregion Nuremberg, Erlangen, Germany.;Translational Research in Oncology, Biopark, Paris, France.;Translational Research in Oncology, Luis Alberto de Herrera, Montevideo, Uruguay.;F Hoffmann-La Roche, Basel, Switzerland.;Genentech, San Francisco, CA, USA.;Genentech, San Francisco, CA, USA.;Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, NY, USA.;David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.",
"authors": "Hurvitz|Sara A|SA|;Martin|Miguel|M|;Symmans|W Fraser|WF|;Jung|Kyung Hae|KH|;Huang|Chiun-Sheng|CS|;Thompson|Alastair M|AM|;Harbeck|Nadia|N|;Valero|Vicente|V|;Stroyakovskiy|Daniil|D|;Wildiers|Hans|H|;Campone|Mario|M|;Boileau|Jean-François|JF|;Beckmann|Matthias W|MW|;Afenjar|Karen|K|;Fresco|Rodrigo|R|;Helms|Hans-Joachim|HJ|;Xu|Jin|J|;Lin|Yvonne G|YG|;Sparano|Joseph|J|;Slamon|Dennis|D|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D043823:Taxoids; D008453:Maytansine; D000077143:Docetaxel; D016190:Carboplatin; C508053:ERBB2 protein, human; D018719:Receptor, ErbB-2; C485206:pertuzumab; D000068878:Trastuzumab; D000080044:Ado-Trastuzumab Emtansine",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(17)30716-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "19(1)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000080044:Ado-Trastuzumab Emtansine; D000328:Adult; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001208:Asia; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms; D002170:Canada; D016190:Carboplatin; D017024:Chemotherapy, Adjuvant; D000077143:Docetaxel; D005060:Europe; D005260:Female; D006801:Humans; D008453:Maytansine; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D009367:Neoplasm Staging; D018719:Receptor, ErbB-2; D043823:Taxoids; D013997:Time Factors; D000068878:Trastuzumab; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "115-126",
"pmc": null,
"pmid": "29175149",
"pubdate": "2018-01",
"publication_types": "D017428:Clinical Trial, Phase III; D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neoadjuvant trastuzumab, pertuzumab, and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with HER2-positive breast cancer (KRISTINE): a randomised, open-label, multicentre, phase 3 trial.",
"title_normalized": "neoadjuvant trastuzumab pertuzumab and chemotherapy versus trastuzumab emtansine plus pertuzumab in patients with her2 positive breast cancer kristine a randomised open label multicentre phase 3 trial"
} | [
{
"companynumb": "US-CIPLA LTD.-2018US02360",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": "3",
... |
{
"abstract": "Drug-induced hypersensitivity syndrome (DIHS) is a multi-system syndrome resulting from an idiosyncratic reaction to medication. While it commonly results in multi-organ involvement, particularly the liver, there are few reports of DIHS causing cerebral vasculitis and neurological deficits. We report the case of a 63-year old woman with DIHS secondary to allopurinol leading to multiple neurological deficits with magnetic resonance imaging findings consistent with a cerebral vasculitis.",
"affiliations": "Department of Dermatology, Waikato Hospital, Hamilton, Waikato, New Zealand.",
"authors": "Lim|David|D|;Rademaker|Marius|M|;Asztely|Fredrik|F|;Ratnaweera|Manjula|M|;Coltman|Glenn|G|",
"chemical_list": "D006074:Gout Suppressants; D000493:Allopurinol",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajd.12016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0004-8380",
"issue": "55(1)",
"journal": "The Australasian journal of dermatology",
"keywords": "adverse drug reaction; drug reaction with eosinophilia and systemic symptom; drug-induced hypersensitivity syndrome",
"medline_ta": "Australas J Dermatol",
"mesh_terms": "D000493:Allopurinol; D063926:Drug Hypersensitivity Syndrome; D005260:Female; D006074:Gout Suppressants; D006801:Humans; D008875:Middle Aged; D009460:Neurologic Examination; D020293:Vasculitis, Central Nervous System",
"nlm_unique_id": "0135232",
"other_id": null,
"pages": "84-7",
"pmc": null,
"pmid": "23330880",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Cerebral vasculitis and multi-focal neurological deficits due to allopurinol-induced hypersensitivity syndrome.",
"title_normalized": "cerebral vasculitis and multi focal neurological deficits due to allopurinol induced hypersensitivity syndrome"
} | [
{
"companynumb": "NZ-WATSON-2015-09626",
"fulfillexpeditecriteria": "1",
"occurcountry": "NZ",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": null,
"dr... |
{
"abstract": "A syndrome of hepatosplenomegaly, thrombocytopenia, and anemia and the presence of sea-blue histiocytes in bone marrow has been associated with parenteral soybean oil administration in patients receiving long-term total parenteral nutrition (TPN). A case is described here where this syndrome was observed in a pediatric patient who received long-term parenteral fish oil nutrition.",
"affiliations": "Pharmacy Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.;Pharmacy Department, Children's Hospitals and Clinics of Minnesota, Minneapolis, Minnesota.",
"authors": "Wu|Ting Ting|TT|;Hoff|David S|DS|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.5863/1551-6776-20.3.217",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1551-6776",
"issue": "20(3)",
"journal": "The journal of pediatric pharmacology and therapeutics : JPPT : the official journal of PPAG",
"keywords": "fatty acids; fish oils; omega-3; parenteral nutrition; sea-blue histiocyte syndrome; soybean oil",
"medline_ta": "J Pediatr Pharmacol Ther",
"mesh_terms": null,
"nlm_unique_id": "101089851",
"other_id": null,
"pages": "217-21",
"pmc": null,
"pmid": "26170774",
"pubdate": "2015",
"publication_types": "D002363:Case Reports",
"references": "10484010;4242937;19592052;8797061;17436017;11732877;23480915;8904878;23845629;9613982;11071594;19661785;23164314;9352150;21982303;11095479",
"title": "Fish Oil Lipid Emulsion-Associated Sea-Blue Histiocyte Syndrome in a Pediatric Patient.",
"title_normalized": "fish oil lipid emulsion associated sea blue histiocyte syndrome in a pediatric patient"
} | [
{
"companynumb": "US-B. BRAUN MEDICAL INC.-2063992",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "SOYBEAN OIL"
},
"drugadditional": nul... |
{
"abstract": "BACKGROUND\nThis prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year.\n\n\nMETHODS\nEligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1-6, 8-13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals.\n\n\nRESULTS\nBetween 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48-66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59-100], 53% [34-83], 41% [23-73], and 29% [14-61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40-88], 35% [19-67], and 29% [14-61], corresponding cumulative incidences of loco-regional progressions were 18% [4-39%], 35% [14-58%], and 41% [17-64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%).\n\n\nCONCLUSIONS\nDose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound. Trial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE ) and authorized to proceed on 2006-09-25.",
"affiliations": "Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.;Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.;Department of Medical Oncology and Hematology, Evang. Kliniken Essen-Mitte, Essen, Germany.;Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.;Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany.;Department of Medical Oncology, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany.;Department of Medical Oncology, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany.;Department of Nuclear Medicine, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany.;Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.;Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.;Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany.;Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147, Essen, Germany. martin.stuschke@uk-essen.de.",
"authors": "Pöttgen|C|C|http://orcid.org/0000-0002-9224-9318;Gkika|E|E|;Stahl|M|M|;Abu Jawad|J|J|;Gauler|T|T|;Kasper|S|S|;Trarbach|T|T|;Herrmann|K|K|;Lehmann|N|N|;Jöckel|K-H|KH|;Lax|H|H|;Stuschke|M|M|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s13014-021-01788-4",
"fulltext": "\n==== Front\nRadiat Oncol\nRadiat Oncol\nRadiation Oncology (London, England)\n1748-717X\nBioMed Central London\n\n1788\n10.1186/s13014-021-01788-4\nResearch\nDose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial\nhttp://orcid.org/0000-0002-9224-9318\nPöttgen C. 1\nGkika E. 12\nStahl M. 3\nAbu Jawad J. 1\nGauler T. 1\nKasper S. 4\nTrarbach T. 45\nHerrmann K. 6\nLehmann N. 7\nJöckel K.-H. 7\nLax H. 7\nStuschke M. martin.stuschke@uk-essen.de\n\n1\n1 grid.5718.b 0000 0001 2187 5445 Department of Radiation Oncology, West German Cancer Centre, University of Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany\n2 Department of Radiation Oncology, University Hospitals Freiburg, Freiburg, Germany\n3 grid.461714.1 0000 0001 0006 4176 Department of Medical Oncology and Hematology, Evang. Kliniken Essen-Mitte, Essen, Germany\n4 grid.5718.b 0000 0001 2187 5445 Department of Medical Oncology, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany\n5 grid.478098.a Center for Tumor Biology and Integrative Medicine, Klinikum Wilhelmshaven, Wilhelmshaven, Germany\n6 grid.5718.b 0000 0001 2187 5445 Department of Nuclear Medicine, West German Cancer Centre, University of Duisburg-Essen, Essen, Germany\n7 grid.5718.b 0000 0001 2187 5445 Institute of Medical Informatics, Biometry and Epidemiology, University of Duisburg-Essen, Essen, Germany\n23 3 2021\n23 3 2021\n2021\n16 5916 12 2020\n15 3 2021\n© The Author(s) 2021\nOpen 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\nThis prospective phase I/II trial assessed feasibility and efficacy of dose-escalated definitive chemoradiation after induction chemotherapy in locally advanced esophageal cancer. Primary study endpoint was loco-regional progression-free survival at 1 year.\n\nMethods\n\nEligible patients received 2 cycles of induction chemotherapy with irinotecan, folinic acid and 5-fluorouracil weekly and cisplatin every 2 weeks (weeks 1–6, 8–13) followed by concurrent chemoradiation with cisplatin and irinotecan (weeks 14, 15, 17, 18, 20). Radiotherapy dose escalation was performed in three steps (60 Gy, 66 Gy, 72 Gy) using conventional fractionation, planning target volumes were delineated with the aid of 18F-FDG-PET/CT scans. During follow-up, endoscopic examinations were performed at regular intervals.\n\nResults\n\nBetween 09/2006 and 02/2010, 17 patients were enrolled (male/female:13/4, median age: 59 [range 48–66] years, stage uT3N0/T3N1/T4N1: 4/12/1). One patient progressed during induction chemotherapy and underwent surgery. Of 16 patients treated with definitive chemoradiotherapy, 9 (56%) achieved complete response after completion of chemoradiation. One-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59–100], 53% [34–83], 41% [23–73], and 29% [14–61], respectively. Loco-regional progression-free survival at 1, 3, and 5 years was 59% [40–88], 35% [19–67], and 29% [14–61], corresponding cumulative incidences of loco-regional progressions were 18% [4–39%], 35% [14–58%], and 41% [17–64%]. No treatment related deaths occurred. Grade 3 toxicities during induction therapy were: neutropenia (41%), diarrhoea (41%), during combined treatment: neutropenia (62%) and thrombocytopenia (25%).\n\nConclusions\n\nDose-escalated radiotherapy and concurrent cisplatin/irinotecan after cisplatin/irinotecan/5FU induction chemotherapy was tolerable. The hypothesized phase II one-year loco-regional progression free survival rate of 74% was not achieved. Long-term survival compares well with other studies on definitive radiotherapy using irinotecan and cisplatin but is not better than recent trials using conventionally fractionated radiotherapy ad 50 Gy with concurrent paclitaxel or 5FU and platinum compound.\n\nTrial registration The present trial was registered as a phase I/II trial at the EudraCT database: Nr. 2005-006097-10 (https://www.clinicaltrialsregister.eu/ctr-search/trial/2005-006097-10/DE) and authorized to proceed on 2006-09-25.\n\nKeywords\n\nEsophageal cancer\nSquamous cell carcinoma\nDose-escalation\nDefinitive chemoradiation\nUniversitätsklinikum Essen (8912)Open Access funding enabled and organized by Projekt DEAL.\n\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nEsophageal cancer has become the seventh most common cancer worldwide but prognosis remains poor (WHO 2018) [1]. Patients with locally advanced tumors (T3–T4 N0-1 M0) are a domain of combined preoperative or definitive chemoradiotherapy but experienced long-term survival rates of about only 14–26% [2, 3].\n\nLong-term survival rates at 3 years after definitive radiochemotherapy at a total dose of 50.4 Gy approach about 20–50% in recent prospective trials [4–6]. In the past, randomized studies have demonstrated promising results of combined definitive radiochemotherapy not inferior to multimodality protocols including surgery especially in responders after induction chemotherapy [7, 8]. Loco-regional recurrences remain the dominant risk for the patient after definitive radiochemotherapy [4–6, 9].\n\nPatients who show clinical response to induction treatment (chemo- or chemo-radiotherapy) have the best prognosis and according to the data of the German Esophageal Cancer Study Group long-term survival of about 50% can be achieved in this group of patients with definitive radiochemotherapy [7]. Overall, local (in-field) disease recurrences remain a major therapeutic problem after radiochemotherapy and account for 65% of all disease relapses.\n\nConsequently, improving induction chemotherapy to increase the proportion of “responders”, as well as intensification of the radiotherapy by dose-escalation could be a strategy to improve local disease control.\n\nRecent benchmark randomized trials showed that combined radiochemotherapy was more effective than radiotherapy alone, but radiation dose escalation during concurrent chemotherapy did not result in a better survival [9–11]. The comparison of randomized trials using surgery after neoadjuvant chemoradiotherapy and those with definitive chemoradiotherapy did not show significant differences regarding survival despite using maximum local treatment, e.g. radical resection [12]. The benefit of radiation dose-escalation may depend on the type of concurrent chemotherapy. Here, we have conducted a prospective trial on the basis of induction chemotherapy with irinotecan added to cisplatin/5-FU/FA and a stepwise dose-escalation of three-dimensional conformal radiotherapy with PET/CT based treatment planning. The experience of a good tolerance to combined chemoradiotherapy schedules with cisplatin/irinotecan and promising rates of pathologic remissions form the basis for this investigation [13–15]. A more recent randomized trial comparing neoadjuvant radiochemotherapy with cisplatin/irinotecan with carbo/paclitaxel found similar overall survival, pCR rate and tolerability [16].\n\nPatients and methods\n\nThis is an oligocentric prospective phase I/II trial (EudraCT-Nr. 2005-006097-10). Patients were accrued from November 2006 to February 2010. The trial was approved by the Ethics Committee of the University of Duisburg-Essen as well as by the national legal authorities. All patients provided written informed consent. Primary study endpoint was loco-regional progression-free survival at one year. Secondary endpoints were: rate of objective remissions, treatment lethality, overall survival at 2 years, distant metastasis rates, and rates of acute and chronic toxicities.\n\nEligibility\n\nPatients of 18–70 years with biopsy-proven squamous cell carcinoma of the esophagus, up to 3 cm above the anatomic cardia, with locally advanced disease (uT3–4 anyN M0), according to the American Joint Committee of Cancer (6th Edition, 2003) were eligible.\n\nIn addition, good clinical condition (WHO performance status 0 to 1) with normal liver (bilirubin < 1.5 mg/dl, cholinesterase > 3000 U/l, total protein > 60 g/l), renal (creatinine clearance > 60 ml/min, creatinin < 1,3 mg/dl) and bone marrow function (leukocytes > 4000/μl, thrombocytes > 150,000/μl, Hb > 10 g/dl) were prerequisites for study enrolment. Patients should be fit for surgery (‘medical operability’: no cardio-pulmonary insufficiency, ejection fraction > 2.5 l/min, arterial pO2 > 65 mmHg, FEV1 > 70%).\n\nThis study was planned as a phase I/II study for optimization of definitive radiochemotherapy based on the results of arm B of our previous phase III study. Consequently, surgery was not planned within the study, and offered only after study dropout (e.g. in case of minor response and/or inadequate symptom relief). An upfront interdisciplinary decision that definitive radiochemotherapy represents the preferable treatment option and surgery is not offered in the primary treatment after neoadjuvant radiochemotherapy was presumed.\n\nPretreatment evaluation\n\nAll patients underwent pretreatment staging including physical examination, cardiopulmonary function tests, routine hematologic and biochemical tests, esophageal barium swallows, upper gastrointestinal endoscopy with histological biopsy, EUS and PET/CT. After completion of the induction chemotherapy patients again underwent barium swallow and endoscopy. A second PET/CT scan was planned at this time point for radiotherapy treatment planning.\n\nTreatment\n\nChemotherapy\n\nPatients received 2 cycles of induction chemotherapy with cisplatin 50 mg/m2 (1 h infusion) on weeks 1,3,5 and 8,10,12 combined with 5-FU 2 g/m2 (24 h-infusion), folinic acid (FA) 500 mg/m2 (2 h infusion) and irinotecan 80 mg/m2 (1 h infusion, weekly during weeks 1–6 and 8–13). This regimen was followed by concurrent chemoradiation with cisplatin 30 mg/m2 and irinotecan (Iri) 60 mg/m2 on day 1, 8, 22, 29, 43 (Fig. 1). Adequate hydration, antiemetics, and supportive medications were administered. Non-hematologic toxicities > grade 1, according to the common terminology criteria of adverse events v3.0 (CTCAE), lead to treatment delay of one week and > grade 2 to an additional reduction of 5-FU to 1.6 g/m2. Neutro- and thrombocytopenias > grade 1 on treatment day resulted in discontinuation of irinotecan, and neutropenia > grade 3 as well as thrombocytopenia of > grade 2 resulted in a delay of chemotherapy and a dose reduction of cisplatin and irinotecan for upcoming therapies. Toxic nephro- and neuropathy > grade 1 resulted in discontinuation of cisplatin. If there was a disease progression after induction chemotherapy patients were excluded from the study and were offered individual treatment.Fig. 1 a Study scheme. b CONSORT diagram\n\nRadiotherapy\n\nThe macroscopic tumor volume (GTV) was defined using all information from the findings of initial EUS and PET/CT before and after induction therapy. The initial clinical target volume (CTV1) was constructed from the pretreatment GTV with an axial margin of 0.5 to 1 cm and craniocaudal (cc) margins of 4 cm with respect to anatomic boundaries. For the planning target volume (PTV1) the CTV1 was extended circumferentially with margins of 0.5 to 1 cm. PTV1 was planned to receive 50 Gy in 25 fractions.\n\nFor the boost volume the GTV was delineated according to the pre- and post-induction chemotherapy PET/CTs and CTs (GTV1: gross tumor volume based on pre-induction scans, GTV2: gross tumor volume based on post-induction scans). The CTV2 included the GTV2 with an axial margin of 0.5 to 1 cm and a cranio-caudal margin of 1 cm; the PTV2 included the CTV2 with a 0.5–0.7 cm axial and a 1 cm cranio-caudal margin. For PTV2, a risk adapted dose escalation was intended. In the first escalation level (level 1) the PTV1 received a dose of 60 Gy, in the second escalation level (level 2) a total dose of 66 Gy, and in the third escalation level (level 3) the PTV2 received 72 Gy. Predefined dose limiting toxities were: non-malignant ulcerations, treatment-related death, tumor associated bleedings.\n\nThe escalation schedule depended on the incidence of dose limiting toxicities. If there were no ulcerations described in the first 5 patients within 2 months after therapy completion, the next 5 patients proceeded to the next escalation level. At the presence of up to 2 treatment related ulcerations, the next 5 patients did not proceed to the next escalation level.\n\nThe maximum spinal cord dose permitted was 42 Gy, the mean lung dose was restricted to 17 Gy and the total lung volume receiving > 20 Gy (V20) was to be kept below 30%, the total myocardium volume receiving > 45 Gy was < 65%. The volume of the esophagus receiving more than 50 Gy should not exceed 12 cm length.\n\nFollow-up evaluation and toxicity criteria\n\nAfter treatment completion, patients were evaluated every three months for the first two years, then every 6 months for the next three years, then annually including physical examination, cardiopulmonary function tests; routine hematologic and biochemical tests; EUS with biopsy of suspect lesions and CTs of thorax and abdomen. Toxicity was documented according to the common terminology criteria of adverse events v3.0 (CTCAE).\n\nStatistical analysis\n\nThe Kaplan Meier method was used to estimate overall survival (OS), progression-free survival (PFS) and loco-regional control (LRC) probability. For the latter, death and loss of follow-up were considered as censoring events. The log-rank test was used for univariate analysis of prognostic factors and Cox proportional hazard model was used for multivariate analysis. A significance level of p = 0.05 was used, all tests were two-sided. For phase I radiotherapy dose escalation, the following phase I rule was applied:\n\nStarting at a total dose of 60 Gy, 5 patients are treated at the respective dose level, if nill therapy related and not tumor-associated esophageal ulcers of Grade III-V occur in the treated volume then proceed to the next dose level. If 1–2 ulcers occur, then treat another 5 patients. If there are ≤ 2 ulcers among the 10 treated patients in this dose group than proceed to the next dose level. Otherwise, continue the trial at the previous dose level, if one is at an escalated dose level or stop the trial, if one is at the base total dose level. The study would have been stopped if more than 3 therapy-related deaths would have occurred among the first 20 patients. Primary end-point for the phase II part of this trial: Under H0, loco-regional progression free survival (loco-regional PFS) was assumed to be 54% at 1 year follow-up as in our previous trial on resectable locally advanced squamous cell carcinomas of the esophagus [7], under H1, loco-regional PFS was expected to be ≥ 74%. In addition, the prognostic value of the gross tumor volume (GTV), total radiation dose, and PET-response to induction chemotherapy was analysed.\n\nPer protocol, no cut-off values had been pre-specified for classification of patients as metabolic responders using pre- and post-induction PET scans. Thus, during the present analysis, %SUV remaining was taken as a continuous parameter in multivariable analysis and having a positive finding, a median split was chosen as threshold value for visualisation of the influence. Patients who had lower SUV values than the corresponding median (response to induction chemotherapy: responder vs. non-responder measured as deltaSUVmax = SUVmax(after Induction)/SUVmax(before Induction): ≤ median vs. > median) were classified as responders, the remaining patients as non-responders, respectively.\n\nIn addition, for the following factors cut-off levels were used: initial GTV volume ≤ median versus > median; radiation dose: ≤ 60 Gy versus > 60 Gy. Statistical analysis was performed using SAS (Version 9.4, SAS Institute, Cary, NC) and R (version 3.6.1, R Core Team (2019)) [17, 18].\n\nCumulative incidences based on competing risk analysis were calculated with R package ‘cmprsk’ [19].\n\nResults\n\nPatients\n\nSeventeen patients were enrolled from September 2006 until February 2010. The patient and treatment characteristics are listed in Table 1.Table 1 Patient and treatment characteristics (of the patients undergoing combined chemoradiotherapy)\n\nCharacteristics\tNo. (%)\t\nAge (median: 59, range: 46–65 years)\t\n < 60 years\t9 (53)\t\n ≥ 60 years\t8 (47)\t\nSex\t\n Male\t13 (77)\t\n Female\t4 (23)\t\nClinical T stage\t\n T3 N0\t4 (24)\t\n T3 N1\t12 (70)\t\n T4 N1\t1 (6)\t\nPretreatment metabolic tumor volume\t\n Median 33.2 ml (range: 4.5–195.3 ml)\t\nPretreatment SUVmax\t\n Median 13.7 (range: 2.8–20.9)\t\nPostinduction SUVmax\t\n Median 2.95 (range: 2.2–12.4)\t\nMetabolic response (SUVmax[post-induction]/SUVmax[pretreatment])\t\n Median 0.39 (range: 0.1–1.3)\t\nResponse to ICT\t\n Responders\t12 (71)\t\n Non-responders\t5 (29)\t\nConcurrent chemoradiation\t\n Complete response\t9 (56)\t\n Evidence of disease\t7 (44)\t\nPhysical dose\t\n < 66 Gy\t9 (56)\t\n ≥ 66 Gy\t7 (44)\t\n\nAll patients had T3-/T4-tumors proven by endosonography and were discussed interdisciplinary. Most had upper third carcinomas. Surgery was not offered due to high tumor localization, extensive nodal involvement, and/or patient’s denial.\n\nOne patient showed local progression during induction chemotherapy, underwent surgery and was resected. The remaining patients proceeded to concurrent radiochemotherapy (Fig. 1b). The trial was closed after more than 3 years of recruitment due to slow accrual.\n\nInduction chemotherapy\n\nAll patients received two cycles of induction chemotherapy according to the protocol except one who changed to another drug combination (cisplatin/5FU/FA) due to subject-related complaints. During induction chemotherapy 7 patients (41%) developed grade 3 neutropenia, one patient grade 3 and one patient grade 4 thrombocytopenia. A grade 3 diarrhoea occurred in 7 (41%) patients. One patient experienced bradycardia after the first course of chemotherapy which needed subsequent pacemaker implantation, one patient suffered stenocardia, and one patient developed an acute femoral occlusion requiring acute intervention.\n\nObjective responses after induction chemotherapy were observed in 12 of 17 patients (71%, 2 complete remissions, 10 partial remissions). One patient was evaluated as progressive, was taken from study, underwent surgery and was resected, further 4 patients showed stable disease. Apart from the patient who progressed during induction chemotherapy, no further patients underwent subsequent surgery. The remaining patients proceeded to concurrent radiochemotherapy (Fig. 1b).\n\nMetabolic responses with SUVmax decreases below 35% of the initial SUVmax were observed in 6 patients (see Table 1), the median deltaSUV was 39%.\n\nChemoradiation\n\nOverall, 7 patients were assigned to 60 Gy total dose and received 60 Gy, 7 patients were assigned to 66 Gy and 6 patients received 64–66 Gy (1 patient rejected the last fraction). One patient planned for dose escalation level 2 (66 Gy) actually received 24 Gy until development of septic candida pneumonia with pulmonary insufficiency which resulted in a treatment break and disease progression with pulmonary metastases in the subsequent CT scans. Two patients were irradiated up to a total dose of 72 Gy. The study was closed early due to slow accrual.\n\nDuring chemoradiation 10 patients developed grade 3 neutropenia (63%), grade 3 thrombocytopenia was observed in 3 patients (19%), grade 4 thrombocytopenia in 2 patients (13%). Five patients received concurrent chemotherapy applications as planned while in all other patients treatment reductions or modifications were necessary. One patient received concurrent chemotherapy according to the RTOG 85-01 protocol (cisplatin/5-FU) due to the side-effects of induction chemotherapy.\n\nNon-hematological grade 3 toxicities were found during radiochemotherapy in one third of the patients, esophagitis greater than grade 2 was found in 2 patients. Grade 4 toxicities or treatment related deaths were not observed.\n\nEfficacy\n\nTwo months after chemoradiation 7 patients had biopsy proven residual disease and 9 (53%) had a complete remission.\n\nTwo patients showed early local progression after definitive chemoradiotherapy. Salvage surgery was discussed but was not performed due to tracheo-bronchial infiltration in one patient, and patient denial of resection in the other.\n\nLoco-regional progression inside the high dose volume was observed in 9 patients overall: 6 patients in the group receiving 60 Gy, and 3 patients in the group receiving > 60 Gy. All progression sites were concordant with FDG-avid areas after induction.\n\nOut-field recurrences, mainly in adjacent lymph node areas, were detected in 3 patients.\n\nFour of the patients in complete remission developed a local recurrence. Metastases occurred in 6 patients (4 pulmonary, 2 hepatic).\n\nTwo patients developed head and neck tumors as second malignancy (location: nasopharyngeal, base of tongue).\n\nDuring follow-up (median 147 months) 15 patients died, 14 due to disease progression, or metastasizing second malignancy (one patient), respectively.\n\nOne-, 2-, 3- and 5-year overall survival rates (OS) were 77% [95%CI: 59–100], 53% [34–83], 41% [23–73], and 29% [14–61], respectively (Fig. 2a). Pretreatment gross tumor volume (GTV) was significantly related to overall survival (Fig. 2b). Patients with tumors larger than the median volume of 33.2 ml had 1-, 2-, 3- and 5-year survival rates of 63% [95%CI: 37–100%], 25% [95%CI: 8–83%], 13% [95%CI: 2–78%], and 13% [95%CI: 2–78%], while patients with smaller tumors had corresponding survival rates of 88% [95%CI: 67–100%], 75% [95%CI: 50–100%], 75% [95%CI: 50–100%], and 50% [95%CI: 25–100%], respectively (p = 0.02, logrank).Fig. 2 a Overall survival of all patients (n = 17). b Overall survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median pretreatment gross tumor volume (≤ 33.2 ml vs > 33.2 ml). c Overall survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median metabolic response to induction chemotherapy (deltaSUV = SUVmax[postinduction]/SUVmax[pretreatment] ≤ 0.39 vs deltaSUV > 0.39)\n\nPatients with metabolic response to induction chemotherapy (deltaSUV ≤ 0.39) had significantly better overall survival than patients with less SUV reduction after induction (Fig. 2c): 1-, 2-, 3-, and 5-year survival rates were 100%, 100%, 100%, and 67% [95%CI: 38–100%) in contrast to 67% [95%CI: 38–100%], 17% [95%CI: 3–99%], 17% [95%CI: 3–99%], and 17% [95%CI: 3–99%] (p = 0.005, logrank).\n\nMultivariable Cox proportional hazard analysis using several prognostic factors (including age, T-, N-status, pretreatment tumor volume, metabolic response, dose) confirmed metabolic response as single significant effect for overall survival (p = 0.03, HR 5.87, 95%CI: 1.08–31.9).\n\nThe primary end-point of this study, loco-regional progression-free survival at 1 year was 59% [95%CI: 40–88%] not clinical meaningfully better than the 54% expected under H0 and not approaching the predefined benchmark under H1 of 74%. In addition, loco-regional progression free survival at 3, and 5 years for patients after concurrent radiochemotherapy was 35% [19–67%], and 29% [14–61%] (Fig. 3a). Corresponding cumulative incidences of loco-regional progressions were 18% [4–39%], 35% [14–58%], and 41% [17–64%] (Fig. 4a).Fig. 3 a Loco-regional progression-free survival of all patients (n = 17). b Loco-regional progression-free survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median pretreatment gross tumor volume (≤ 33.2 ml vs > 33.2 ml). c Loco-regional progression-free survival of all patients treated with concurrent radiochemotherapy (n = 16), stratified by median metabolic response to induction chemotherapy (deltaSUV ≤ 0.39 vs deltaSUV > 0.39)\n\nFig. 4 Competing risk analysis. a Cumulative incidences of the events: death without relapse (black), distant metastases (red), or loco-regional recurrence (green), all patients (n = 17). b cumulative incidences of death without relapse (black), distant metastases (red), or loco-regional recurrence (green), grouped by radiotherapy dose (≤ 60 Gy [solid lines] versus > 60 Gy [dashed lines])\n\nPretreatment gross tumor volume (GTV) was significantly correlated with better loco-regional progression-free survival rates. Patients with tumor volumes at baseline smaller than 33.2 ml had loco-regional progression-free survival rates at 1, 3, and 5 years of 88% [95%CI: 67–100%], 63% [95%CI: 37–100%], and 50% [95%CI: 25–100%] versus 25% [95%CI: 8–83%], 13% [95%CI: 2–78%], and 13% [95%CI: 2–78%] (p = 0.009, logrank, Fig. 3b). Metabolic responder had loco-regional progression-free survival rates at 1, 3, and 5 years of 100%, 83% [95%CI: 58–100%], and 83% [95%CI: 58–100%] versus 33% [95%CI: 11–100%], 17% [95%CI: 3–99%], 17% [95%CI: 3–99%], and 0% (p = 0.002, logrank, Fig. 3c).\n\nMetabolic response was confirmed as single significant effect for loco-regional progression-free survival in Cox proportional hazard analysis (HR 11.7, 95%CI: 1.3–106, p = 0.028).\n\nTwo patients developed esophago-tracheal fistulae related to tumor recurrence and one of them needed tracheotomy two months after chemoradiation due to obstructive larynx edema.\n\nRadiotherapy dose (≤ 60 Gy vs > 60 Gy) was not found to influence loco-regional control. Loco-regional progression-free survival in patients receiving concurrent chemoradiotherapy with doses ≤ 60 Gy was 50% [95%CI: 25–100%], 25% [8–83%], and 13% [2–78%] at 1, 3, and 5 years. Patients in the higher dose group (> 60 Gy) experienced loco-regional progression-free survival rates of 63% [95%CI: 37–100%], 50% [25–100%], and 50% [25–100%] (p = 0.2, logrank).\n\nCumulative incidences of loco-regional relapse in competing risk analysis (death without relapse versus distant metastasis versus loco-regional progression as first event of relapse) were not different between low- and high-dose radiotherapy group (Fig. 4b). Loco-regional progression-rates were 13% [95%CI: 0–46%], 38% [6–71%], and 50% [10–81%] at 1, 3, and 5 years in the group of patients (n = 8) receiving ≤ 60 Gy. The corresponding loco-regional recurrence rates in the group of patients receiving > 60 Gy (n = 8) were 25% [95%CI: 3–58%] at all time points (p = 0.4, Fine and Gray’s test, Fig. 4b).\n\nDiscussion\n\nAt the time when this study was designed, a series of prospective trials tested induction chemotherapy with cisplatin and irinotecan followed by concurrent chemoradiation with radiotherapy doses at about 50 Gy with or without surgery.\n\nMedian survival ranged from 25 to 31 months for the patients treated with trimodality therapy [13, 20–22]. Patients treated with definitive radiochemotherapy had overall survival rates at 2 years ranging from 28 to 42% [14, 23]. In two studies patients received additional cetuximab [22, 23].\n\nThree-year overall survival in the present study was 41%, well in the range of other studies on definitive radiochemotherapy (50 Gy with second- or third-generation chemotherapy) which observed 27–47% [4–6, 11].\n\nLoco-regional progression rates were 35% in this study, well in comparison with 49% in the standard arm of the RTOG 0436 trial [6], and 52% in the standard arm of ARTDECO, respectively [11]. Similarly to the latter study, no significant difference in the local efficacy between radiotherapy dose groups of ≤ 60 Gy versus > 60 Gy could be determined.\n\nRetro- and prospective trials on definitive radiochemotherapy with concurrent cisplatin/irinotecan are rather limited. In relation to the single institution retrospective comparison of Ruppert et al. [24] who found a three-year overall survival rate of 20% (10–41%), and freedom from loco-regional progression of 28% at three years, the present data are more favorable. This applies as well for the comparison with 2-year-overall survival of 28% and 33%, and 24% 2-year-progression-free survival of prospective trials [14, 23].\n\nThe incidence of hematologic and non-hematologic toxicities was moderate in the present study similar to other trials [13, 14, 21–23].\n\nA subsequent retrospective trial has claimed a benefit of paclitaxel over irinotecan [24] but a prospective randomized trial on neoadjuvant radiochemotherapy using cisplatin/irinotecan or carboplatin/paclitaxel showed similar results [16].\n\nFor squamous cell carcinomas the effect of adding surgery to chemoradiation has been evaluated in randomised trials showing no difference in overall survival for responders to induction chemotherapy although there was a substantial improvement in local control for the surgical arms [7, 8]. A meta-analysis of definitive radiotherapy versus surgery within multimodality protocols confirmed that overall survival was equivalent in both arms (HR 0.98, 95%CI 0.8–1.2, p = 0.84), with freedom from locoregional progression favouring also the surgical treatment arms. Furthermore, a high concurrent risk of distant metastases worsens the cancer specific survival of patients with loco-regionally controlled, resected squamous cell carcinoma [12]. In the present study, the competing risk of distant metastasis was as high as loco-regional progression.\n\nAlthough loco-regional failure remains a major risk for patients treated with definitive chemoradiation, radiotherapy dose escalation remains controversial.\n\nUp to now no randomized dose-escalation trials on definitive radiochemotherapy could demonstrate a survival benefit for higher total doses than 50.4 Gy using conventional fractionation [9, 11]. On the other hand, older trials using total radiation doses > 60 Gy showed equivalent survival of high dose radiotherapy and concurrent chemotherapy in comparison to tri-modality treatment for responders to induction chemotherapy. The exploratory analysis of the FFCD 9102 trial supported a dose response relation comparing continuous course radiotherapy to 66 Gy at 2 Gy per fraction or split course hypofractionated radiotherapy to 45 Gy at 3 Gy per fraction [25].\n\nIn order to limit the potential toxicity of the increased total dose, we have decided to adapt the high-dose PTV to the extension of the residual gross tumor volume after induction-chemotherapy using 18F-FDG-PET/CT plus a margin of 1.0–1.5 cm in axial and 2.0 cm in cranio-caudal direction. Although the value of PET/CT has not been consistently shown in esophageal cancer, several efforts have been made to improve target volume definition using PET/CT [26–29].\n\nProspective trials investigating high dose radiotherapy have shown that a small target volume is adequate since even after escalated doses local recurrences are the remaining problem and not regional recurrences outside the fields [30].\n\nOther dose escalation trials with lesser follow-up pointed into the same direction that local recurrences remain a major problem even after high-dose radiotherapy [31, 32].\n\nIrradiation techniques have made significant progress during recent years. While the patients in the present study were treated with 3D-conformal radiotherapy, IMRT and VMAT represent current standards of care. Intensity-modulated radiotherapy techniques have fostered the use of integrated-boost irradiation and are under active investigation in prospective dose-escalation trials [33]. The simultaneous integrated boost (SIB) technique has been developed with the aim to increase the dose to macroscopic tumor (GTV) while simultaneously limiting the dose to normal tissues, particularly heart and lungs. Radiobiological modeling suggested a potential gain of tumor control by dose escalation in the GTV [34] and shall be validated in ongoing clinical trials [35].\n\nPET/CT, especially during an induction phase of combined treatment, has been shown to carry prognostic information for definitive and neoadjuvant radiochemotherapy of esophageal squamous cell carcinomas [20, 36, 37]. Our study, although of limited size, confirms that FDG-response to induction treatment is able to separate patient groups with significantly improved prognosis after definitive chemoradiation in relation to patients with non-responding tumors. Prospectively, this might become a valid selection criterion for more or less aggressive local therapy.\n\nConclusions\n\nFrom the present trial, induction chemotherapy using irinotecan (80 mg/m2), folinic acid (500 mg/m2) and 5-fluorouracil (5-FU, 2 g/m2) weekly and cisplatin followed by dose escalated radiotherapy and concomitant cisplatin and irinotecan was tolerable but there was no signal for an improved loco-regional progression-free survival. The benchmark progression-free survival at one year of 74% was not reached. Metabolic response of the tumor after induction chemotherapy was validated as a prognostic factor.\n\nAuthors' contributions\n\nConceptualization and methodology, CP, MSta, and MStu; software, NL, KHJ, CP, MStu; validation, KHJ, HL, NL, MStu; formal analysis, CP, EG, MStu; investigation, CP, EG, JAJ, TG, SK, TT, MSta, MStu; writing—original draft preparation, CP, EG. All authors have read and approved the final manuscript.\n\nFunding\n\nOpen Access funding enabled and organized by Projekt DEAL. This research was funded by an institutional grant of PFIZER, Germany. The funder had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.\n\nAvailability of data and materials\n\nThe datasets generated and/or analysed during the current study are not publicly available because individual privacy could be compromised but are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study was approved by the Ethics committee of the Medical Faculty of University of Duisburg-Essen (Reference Number 05-2682).\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nC. Pöttgen: honoraria from Roche, Boehringer Ingelheim, AstraZeneca. M. Stahl: honoraria from Roche, Pfizer, Ortho Biotech. T. Gauler: honoraria from Roche, AstraZeneca, Lilly Germany. S. Kasper: honoraria from Amgen, Bayer, BMS, Celgene, Lilly, Merck, MSD, Roche and Sanofi. T Trarbach: honoraria from Schering-Plough, Novartis; Research funding: Amgen, Eli Lilly, Saladex. E. Gkika, J. Abu Jawad, K. Herrmann, N. Lehmann, K.-H. Jöckel, H. Lax, and M. Stuschke declare no conflicts of interest.\n\nPublisher's Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. World Health Organization. International Agency for Research on Cancer. GLOBOCAN 2018: oesophagus cancer fact sheet.2018. http://gco.iarc.fr/today/data/factsheets/cancers/6-Oesophagus-fact-sheet.pdf. Accessed 23 Nov 2020.\n2. Cooper JS Guo MD Herskovic A Macdonald JS Martenson JA Jr Al-Sarraf M Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85–01). Radiation Therapy Oncology Group JAMA 1999 281 1623 1627 10.1001/jama.281.17.1623 10235156\n3. al-Sarraf M Martz K Herskovic A Leichman L Brindle JS Vaitkevicius VK Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer: an intergroup study J Clin Oncol. 1997 15 277 284 10.1200/JCO.1997.15.1.277 8996153\n4. Conroy T Galais MP Raoul JL Bouché O Gourgou-Bourgade S Douillard JY Fédération Francophone de Cancérologie Digestive and UNICANCER-GI Group. Definitive chemoradiotherapy with FOLFOX versus fluorouracil and cisplatin in patients with oesophageal cancer (PRODIGE5/ACCORD17): final results of a randomised, phase 2/3 trial Lancet Oncol. 2014 15 305 314 10.1016/S1470-2045(14)70028-2 24556041\n5. Crosby T Hurt CN Falk S Gollins S Staffurth J Ray R Long-term results and recurrence patterns from SCOPE-1: a phase II/III randomised trial of definitive chemoradiotherapy +/- cetuximab in oesophageal cancer Br J Cancer 2017 116 709 716 10.1038/bjc.2017.21 28196063\n6. Suntharalingam M Winter K Ilson D Dicker AP Kachnic L Konski A Effect of the addition of cetuximab to paclitaxel, cisplatin, and radiation therapy for patients with esophageal cancer: the NRG oncology RTOG 0436 phase 3 randomized clinical trial JAMA Oncol 2017 3 1520 1528 10.1001/jamaoncol.2017.1598 28687830\n7. Stahl M Stuschke M Lehmann N Meyer HJ Walz MK Seeber S Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus J Clin Oncol 2005 23 2310 2317 10.1200/JCO.2005.00.034 15800321\n8. Bedenne L Michel P Bouché O Milan C Mariette C Conroy T Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102 J Clin Oncol 2007 25 1160 1168 10.1200/JCO.2005.04.7118 17401004\n9. Minsky BD Pajak TF Ginsberg RJ Pisansky TM Martenson J Komaki R INT 0123 (Radiation Therapy Oncology Group 94-05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy J Clin Oncol 2002 20 1167 1174 10.1200/JCO.2002.20.5.1167 11870157\n10. Herskovic A Martz K al-Sarraf M Leichman L Brindle J Vaitkevicius V Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus N Engl J Med. 1992 326 1593 1598 10.1056/NEJM199206113262403 1584260\n11. Hulshof MCCM Geijsen D Rozema T Oppedijk V Buijsen J Neelis KJ A randomized controlled phase III multicenter study on dose escalation in definitive chemoradiation for patients with locally advanced esophageal cancer: ARTDECO study J Clin Oncol. 2020 38 Suppl 4 281 10.1200/JCO.2020.38.4_suppl.281 31557087\n12. Pöttgen C Stuschke M Radiotherapy versus surgery within multimodality protocols for esophageal cancer—a meta-analysis of the randomized trials Cancer Treat Rev 2012 38 599 604 10.1016/j.ctrv.2011.10.005 22116018\n13. Ilson DH Bains M Kelsen DP Ilson DH Bains M Kelsen DP Phase I trial of escalating-dose irinotecan given weekly with cisplatin and concurrent radiotherapy in locally advanced esophageal cancer J Clin Oncol 2003 21 2926 2932 10.1200/JCO.2003.02.147 12885811\n14. Michel P Adenis A Di Fiore F Boucher E Galais MP Dahan L Induction cisplatin-irinotecan followed by concurrent cisplatin-irinotecan and radiotherapy without surgery in oesophageal cancer: multicenter phase II FFCD trial Br J Cancer 2006 95 6 705 709 10.1038/sj.bjc.6603328 16967056\n15. Rivera F Galán M Tabernero J Cervantes A Vega-Villegas ME Gallego J Spanish Cooperative Group for Digestive Tumor Therapy. Phase II trial of preoperative irinotecan-cisplatin followed by concurrent irinotecan-cisplatin and radiotherapy for resectable locally advanced gastric and esophagogastric junction adenocarcinoma Int J Radiat Oncol Biol Phys. 2009 75 1430 1436 10.1016/j.ijrobp.2008.12.087 19540072\n16. Kleinberg LR Catalano PJ Forastiere AA Keller SM Mitchel EP Anne PR Benson AB 3rd Eastern Cooperative Oncology Group and American College of Radiology Imaging Network randomized phase 2 trial of neoadjuvant preoperative paclitaxel/cisplatin/radiation therapy (RT) or irinotecan/cisplatin/RT in esophageal adenocarcinoma: long-term outcome and implications for trial design Int J Radiat Oncol Biol Phys 2016 94 738 746 10.1016/j.ijrobp.2015.12.009 26972646\n17. SAS Institute Inc Base SAS® 9.4 procedures guide: statistical procedures 2016 6 SAS Institute Inc.\n18. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/.\n19. Scrucca L Santucci A Aversa F Regression modeling of competing risk using R: an in depth guide for clinicians Bone Marrow Transplant 2010 45 1388 1395 10.1038/bmt.2009.359 20062101\n20. Ilson DH Minsky BD Ku GY Rusch V Rizk N Shah M Phase 2 trial of induction and concurrent chemoradiotherapy with weekly irinotecan and cisplatin followed by surgery for esophageal cancer Cancer 2012 118 2820 2827 10.1002/cncr.26591 21990000\n21. Knox JJ Wong R Visbal AL Horgan AM Guindi M Hornby J Phase 2 trial of preoperative irinotecan plus cisplatin and conformal radiotherapy, followed by surgery for esophageal cancer Cancer 2010 116 4023 4032 10.1002/cncr.25349 20533506\n22. Lee MS Mamon HJ Hong TS Choi NC Fidias PM Kwak EL Preoperative cetuximab, irinotecan, cisplatin, and radiation therapy for patients with locally advanced esophageal cancer Oncologist 2013 18 281 287 10.1634/theoncologist.2012-0208 23429739\n23. Tomblyn MB Goldman BH Thomas CR Jr Benedetti JK Lenz HJ Mehta V SWOG GI Committee. Cetuximab plus cisplatin, irinotecan, and thoracic radiotherapy as definitive treatment for locally advanced, unresectable esophageal cancer: a phase-II study of the SWOG (S0414) J Thorac Oncol. 2012 7 906 912 10.1097/JTO.0b013e31824c7bed 22481235\n24. Ruppert BN Watkins JM Shirai K Wahlquist AE Garrett-Mayer E Aguero EG Cisplatin/Irinotecan versus carboplatin/paclitaxel as definitive chemoradiotherapy for locoregionally advanced esophageal cancer Am J Clin Oncol 2010 33 346 352 10.1097/COC.0b013e3181aaca26 19841574\n25. Crehange G Maingon P Peignaux K N’guyen TD Mirabel X Marchal C Phase III trial of protracted compared with split-course chemoradiation for esophageal carcinoma: Federation Francophone de Cancerologie Digestive 9102 J Clin Oncol. 2007 25 4895 4901 10.1200/JCO.2007.12.3471 17971585\n26. Leong T Everitt C Yuen K Condron S Hui A Ngan SY A prospective study to evaluate the impact of FDG-PET on CT-based radiotherapy treatment planning for oesophageal cancer Radiother Oncol 2006 78 254 261 10.1016/j.radonc.2006.02.014 16545881\n27. Muijs CT Beukema JC Pruim J Mul VE Groen H Plukker JT Langendijk JA A systematic review on the role of FDG-PET/CT in tumour delineation and radiotherapy planning in patients with esophageal cancer Radiother Oncol 2010 97 165 171 10.1016/j.radonc.2010.04.024 20541273\n28. Lu J Sun XD Yang X Tang XY Qin Q Zhu HC Impact of PET/CT on radiation treatment in patients with esophageal cancer: a systematic review Crit Rev Oncol Hematol 2016 107 128 137 10.1016/j.critrevonc.2016.08.015 27823640\n29. Jimenez-Jimenez E Mateos P Aymar N Roncero R Ortiz I Gimenez M Pardo J Salinas J Sabater S Radiotherapy volume delineation using 18F-FDG-PET/CT modifies gross node volume in patients with oesophageal cancer Clin Transl Oncol 2018 20 11 1460 1466 10.1007/s12094-018-1879-3 29721766\n30. Chen J Guo H Zhai T Chang D Chen Z Huang R Radiation dose escalation by simultaneous modulated accelerated radiotherapy combined with chemotherapy for esophageal cancer: a phase II study Oncotarget 2016 7 22711 22719 10.18632/oncotarget.8050 26992206\n31. Welsh JW Seyedin SN Allen PK Hofstetter WL Ajani JA Chang JY Local control and toxicity of a simultaneous integrated boost for dose escalation in locally advanced esophageal cancer: interim results from a prospective phase I/II trial J Thorac Oncol 2017 12 375 382 10.1016/j.jtho.2016.10.013 27794500\n32. Chen D Menon H Verma V Seyedin SN Ajani JA Hofstetter WL Results of a phase 1/2 trial of chemoradiotherapy with simultaneous integrated boost of radiotherapy dose in unresectable locally advanced esophageal cancer JAMA Oncol 2019 5 1597 1604 10.1001/jamaoncol.2019.2809 31529018\n33. Gwynne S Higgins E Poon King A Radhakrishna G Wills L Mukherjee S Driving developments in UK oesophageal radiotherapy through the SCOPE trials Radiat Oncol 2019 14 26 10.1186/s13014-019-1225-0 30717810\n34. Warren S Partridge M Carrington R Hurt C Crosby T Hawkins MA Radiobiological determination of dose escalation and normal tissue toxicity in definitive chemoradiation therapy for esophageal cancer Int J Radiat Oncol Biol Phys 2014 90 423 429 10.1016/j.ijrobp.2014.06.028 25304796\n35. The SCOPE 2 Trial: Study of chemoradiotherapy in oesophageal cancer including PET response and dose escalation. ISRCTN97125464. 10.1186/ISRCTN97125464. Accessed 07/02/2021.\n36. Chhabra A Ong LT Kuk D Ku G Ilson D Janjigian YY Prognostic significance of PET assessment of metabolic response to therapy in oesophageal squamous cell carcinoma Br J Cancer 2015 113 1658 1665 10.1038/bjc.2015.416 26657654\n37. Zschaeck S Li Y Bütof R Lili C Hua W Troost ECG Combined tumor plus nontumor interim FDG-PET parameters are prognostic for response to chemoradiation in squamous cell esophageal cancer Int J Cancer 2020 147 1427 1436 10.1002/ijc.32897 32010957\n\n",
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"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D004938:Esophageal Neoplasms; D000077277:Esophageal Squamous Cell Carcinoma; D005260:Female; D006801:Humans; D060828:Induction Chemotherapy; D008297:Male; D008875:Middle Aged; D000072078:Positron Emission Tomography Computed Tomography; D011446:Prospective Studies; D011879:Radiotherapy Dosage; D011880:Radiotherapy Planning, Computer-Assisted",
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"title": "Dose-escalated radiotherapy with PET/CT based treatment planning in combination with induction and concurrent chemotherapy in locally advanced (uT3/T4) squamous cell cancer of the esophagus: mature results of a phase I/II trial.",
"title_normalized": "dose escalated radiotherapy with pet ct based treatment planning in combination with induction and concurrent chemotherapy in locally advanced ut3 t4 squamous cell cancer of the esophagus mature results of a phase i ii trial"
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"abstract": "Secondary acute myeloid leukemia is a very rare complication in patients with solid organ transplantation. We report a 62 years old female who received a right single lung allograft for idiopathic pulmonary fibrosis. Her immunosuppression scheme consisted in prednisone, azathioprine, and tacrolimus. Two years after the transplantation, she presented with progressive pancytopenia. Bone marrow aspiration was informed as a M4 acute myeloid leukemia, confirmed by flow cytometry. Cytogenetic study was complex, including alterations in chromosome 5. A secondary acute myeloid leukemia was diagnosed. The patient developed nosocomial pneumonia and died a few days after the diagnosis, without specific treatment. The pathogenesis of acute myeloid leukemia is probably related to the intensive exposure to immunosuppressant, especially azathioprine, in these patients.",
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"authors": "Peña|Camila|C|;Sepúlveda|Claudia|C|;Melo|Joel|J|;Guerra|Carolina|C|",
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"title": "Secondary acute myeloid leukemia in a lung allograft recipient. Report of one case.",
"title_normalized": "secondary acute myeloid leukemia in a lung allograft recipient report of one case"
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"abstract": "The aim of this retrospective study was to evaluate the toxicity profiles of dasatinib in patients with Philadelphia chromosome positive chronic myeloid leukemia (CML) or acute lymphatic leukemia (ALL) who were intolerant to imatinib, and who had been enrolled in our previous clinical trials to evaluate efficacy of dasatinib in patients resistant or tolerant to imatinib therapy. Twenty-four patients with CML and four with ALL were enrolled in the clinical studies to evaluate the efficacy according to the eligibility criteria related to intolerance to imatinib therapy. The toxicities reported during imatinib therapy were non-hematological toxicities in 23 patients and hematological toxicities in six patients. Patients were administered dasatinib 50-70 mg BID or 100 mg QD. Cross intolerance was observed in four patients who showed hematological toxicity after dasatinib treatment. However, it was possible to successfully continue therapy with only temporary interruption. No cross intolerance in non-hematological toxicity was found with the exception of one patient who showed cross intolerance, which did not result in treatment interruption. Dasatinib can be safely administered to imatinib-intolerant CML or Ph-positive ALL patients.",
"affiliations": "Hematology Division, National Cancer Center Hospital, Tokyo, Japan. ykkobaya@ncc.go.jp.;Hematology Division, Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital, Tokyo, Japan.;Department of Hematology, Yokohama City University Medical Center, Yokohama, Japan.;Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.;Hematology and Cell Therapy Division, Aichi Cancer Center Hospital, Nagoya, Japan.;Division of Hematology, Department of Internal Medicine, Hyogo College of Medicine, Nishinomiya, Japan.;Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan.;Division of Hematology, Jichi Medical University, Shimotsuke, Japan.;Leukemia Research Center, Saiseikai Maebashi Hospital, Maebashi, Japan.;Department of Hematology, Tokyo Women's Medical University, Tokyo, Japan.;Division of Clinical Oncology and Hematology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan.;Department of Medical Oncology and Immunology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.;Division of Hematology and Oncology, Department of Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Internal Medicine, Matsushita Memorial Hospital, Osaka, Japan.;Bristol-Myers K.K, Tokyo, Japan.;Aichi Cancer Center Hospital, Nagoya, Japan.",
"authors": "Kobayashi|Yukio|Y|;Sakamaki|Hisashi|H|;Fujisawa|Shin|S|;Ando|Kiyoshi|K|;Yamamoto|Kazuhito|K|;Okada|Masaya|M|;Ishizawa|Kenichi|K|;Nagai|Tadashi|T|;Miyawaki|Syuichi|S|;Motoji|Toshiko|T|;Usui|Noriko|N|;Iida|Shinsuke|S|;Taniwaki|Masafumi|M|;Uoshima|Nobuhiko|N|;Seriu|Taku|T|;Ohno|Ryuzo|R|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000068877:Imatinib Mesylate; D000069439:Dasatinib",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-011-0864-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "93(6)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001549:Benzamides; D000069439:Dasatinib; D006402:Hematologic Diseases; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008875:Middle Aged; D010879:Piperazines; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D012189:Retrospective Studies; D013844:Thiazoles",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "745-749",
"pmc": null,
"pmid": "21594763",
"pubdate": "2011-06",
"publication_types": "D016428:Journal Article",
"references": "17151364;17185463;19263190;16757427;20525995;15930265;16775235;17138817;17264298;12114417;18541900;17317857;11287973;19349618;19455391;11287972;17496201",
"title": "Lack of non-hematological cross intolerance of dasatinib to imatinib in imatinib-intolerant patients with Philadelphia chromosome positive chronic myeloid leukemia or acute lymphatic leukemia: a retrospective safety analysis.",
"title_normalized": "lack of non hematological cross intolerance of dasatinib to imatinib in imatinib intolerant patients with philadelphia chromosome positive chronic myeloid leukemia or acute lymphatic leukemia a retrospective safety analysis"
} | [
{
"companynumb": "NVSC2019JP073650",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": "3",
... |
{
"abstract": "BACKGROUND\nErlotinib is an agent in the class of oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. Although this class of agents is considered to be relatively safe, the most serious, but rare, adverse reaction is drug-associated interstitial lung disease (ILD). This potentially fatal adverse reaction has been often described with gefitinib, but has been less well described for erlotinib. We here describe a case report of fatal interstitial lung disease in a Caucasian man associated with erlotinib and high erlotinib and metabolite plasma levels and discuss it in the context of all documented cases of erlotinib associated ILD.\n\n\nMETHODS\nOur case was described and for the literature review a Pubmed and Google Scholar search was conducted for cases of erlotinib associated ILD. The retrieved publications were screened for relevant literature.\n\n\nRESULTS\nBesides our case, a total of 19 cases of erlotinib-associated ILD were found. Eleven out 19 cases had a fatal outcome and in only one case erlotinib plasma concentrations were measured and found to be high.\n\n\nCONCLUSIONS\nErlotinib-associated ILD is a rare, serious and often fatal adverse reaction. Most likely, the cause for erlotinib-associated ILD is multifactorial and high drug levels may be present in patients without serious adverse reactions. However, considering the pharmacology of EGFR inhibitors, high drug and metabolite levels may play a role and future studies are warranted to identify risk factors and to investigate the role of elevated levels of erlotinib and its metabolites in the development of pulmonary toxicity.",
"affiliations": "Department of Pharmacy, Meander Medical Center, Utrechtseweg 160, 3818ES Amersfoort, The Netherlands. rob@terheine.nl",
"authors": "ter Heine|R|R|;van den Bosch|R T A|RT|;Schaefer-Prokop|C M|CM|;Lankheet|N A G|NA|;Beijnen|J H|JH|;Staaks|G H A|GH|;van der Westerlaken|M M|MM|;Malingré|M M|MM|;van den Brand|J J G|JJ|",
"chemical_list": "D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D000069347:Erlotinib Hydrochloride; D000077156:Gefitinib",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.lungcan.2011.10.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0169-5002",
"issue": "75(3)",
"journal": "Lung cancer (Amsterdam, Netherlands)",
"keywords": null,
"medline_ta": "Lung Cancer",
"mesh_terms": "D000368:Aged; D002289:Carcinoma, Non-Small-Cell Lung; D000069347:Erlotinib Hydrochloride; D017809:Fatal Outcome; D000077156:Gefitinib; D006801:Humans; D017563:Lung Diseases, Interstitial; D008175:Lung Neoplasms; D008297:Male; D009203:Myocardial Infarction; D010997:Pleural Neoplasms; D047428:Protein Kinase Inhibitors; D011799:Quinazolines",
"nlm_unique_id": "8800805",
"other_id": null,
"pages": "391-7",
"pmc": null,
"pmid": "22101147",
"pubdate": "2012-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Fatal interstitial lung disease associated with high erlotinib and metabolite levels. A case report and a review of the literature.",
"title_normalized": "fatal interstitial lung disease associated with high erlotinib and metabolite levels a case report and a review of the literature"
} | [
{
"companynumb": "NL-RANBAXY-2012R1-55515",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METOPROLOL"
},
"drugadditional": null,
... |
{
"abstract": "An 80-year-old male patient was diagnosed to have squamous cell carcinoma of the lung which had a high level of programmed death-ligand 1 (PD-L1) expression. He was prescribed with intravenously administered nivolumab combined with carboplatin and paclitaxel as the first-line therapy. A rapid remission was achieved with nearly total necrosis and cavitation of the original tumor. However, the successful treatment result was accompanied with pneumonitis most likely as an adverse effect of nivolumab. After discontinuation of nivolumab and starting prednisolone treatment, the pneumonitis was soon brought under control. During the treatment course, temporary exacerbation of the disease status led to an interesting differential diagnosis between hyperprogression and pseudoprogression. Tremendous efficacy of combination immunochemotherapy as the first-line treatment for squamous non-small cell lung cancer (NSCLC) with highly expressed PD-L1 has been well demonstrated in this case.",
"affiliations": "Haematology and Oncology, Changhua Hospital, Ministry of Health and Welfare, Chang-Hua County, TWN.;Pathology, Changhua Hospital, Ministry of Health and Welfare, Chang-Hua County, TWN.;Haematology and Oncology, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung City, TWN.",
"authors": "Fan|Frank S|FS|;Yang|Chung-Fan|CF|;Chang|Chia-Lin|CL|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.5881",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5881PathologyOncologyPulmonologyNivolumab plus Carboplatin and Paclitaxel as the First-line Therapy for Advanced Squamous Cell Carcinoma of the Lung with Strong Programmed Death-ligand 1 Expression: A Case Report Muacevic Alexander Adler John R Fan Frank S 1Yang Chung-Fan 2Chang Chia-Lin 3\n1 \nHaematology and Oncology, Changhua Hospital, Ministry of Health and Welfare, Chang-Hua County, TWN \n2 \nPathology, Changhua Hospital, Ministry of Health and Welfare, Chang-Hua County, TWN \n3 \nHaematology and Oncology, Feng-Yuan Hospital, Ministry of Health and Welfare, Taichung City, TWN \nFrank S. Fan fantast.fan@msa.hinet.net10 10 2019 10 2019 11 10 e588123 9 2019 10 10 2019 Copyright © 2019, Fan et al.2019Fan et al.This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.This article is available from https://www.cureus.com/articles/23629-nivolumab-plus-carboplatin-and-paclitaxel-as-the-first-line-therapy-for-advanced-squamous-cell-carcinoma-of-the-lung-with-strong-programmed-death-ligand-1-expression-a-case-reportAn 80-year-old male patient was diagnosed to have squamous cell carcinoma of the lung which had a high level of programmed death-ligand 1 (PD-L1) expression. He was prescribed with intravenously administered nivolumab combined with carboplatin and paclitaxel as the first-line therapy. A rapid remission was achieved with nearly total necrosis and cavitation of the original tumor. However, the successful treatment result was accompanied with pneumonitis most likely as an adverse effect of nivolumab. After discontinuation of nivolumab and starting prednisolone treatment, the pneumonitis was soon brought under control. During the treatment course, temporary exacerbation of the disease status led to an interesting differential diagnosis between hyperprogression and pseudoprogression. Tremendous efficacy of combination immunochemotherapy as the first-line treatment for squamous non-small cell lung cancer (NSCLC) with highly expressed PD-L1 has been well demonstrated in this case.\n\nnivolumabchemotherapysquamous non-small cell lung cancerimmune checkpoint inhibitorpneumonitisThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nImmune checkpoint inhibitors (ICI), including anti-programmed death 1 (PD-1) and anti-programmed death-ligand 1 (PD-L1) antibodies, have evolved to be the most hopeful and attractive therapeutic modalities for non-small cell lung cancer (NSCLC) without targetable genetic mutations [1]. Theoretically, ICI treatment effects could be potentiated by tumor antigen release during traditional systemic chemotherapy and this assumption has led to the development of combining ICI and chemotherapy together as a new anti-cancer strategy [2]. Accordingly, several clinical trials testing this hypothesis have been designed to see whether combination therapy as first-line treatment could achieve better survival than chemotherapy alone in advanced NSCLC [3].\n\nNivolumab, an anti-PD-1 antibody, combined with platinum doublet chemotherapy, has shown satisfactory tumor size reduction and response duration for chemotherapy-naïve advanced NSCLC in two phase I clinical trials [4-5]. In the phase III trial CheckMate 227 Part 2, although nivolumab plus chemotherapy versus chemotherapy alone did not meet its primary endpoint of overall survival in first-line treatment for non-squamous NSCLC, an exploratory analysis of patients with first-line treatment for squamous NSCLC disclosed that the median overall survival was 18.27 months for nivolumab plus chemotherapy versus 11.96 months for chemotherapy with a hazard ratio of 0.69 and 95% confidence interval 0.50-0.97 [6]. \n\nHerein, we present the clinical course, astonish efficacy, and ICI-related pneumonitis in an inoperable squamous NSCLC patient receiving nivolumab and carboplatin plus paclitaxel as the first-line treatment.\n\nCase presentation\nAn 80-year-old male patient appeared in our clinic with the primary complaint of low back pain for one month and progressive weakness for one week in February 2019. Frequent dry cough lasting for about six weeks was also noted. He took daily low-dose aspirin and underwent occasional therapeutic phlebotomy for polycythemia vera, an inherited condition in his family without identifiable JAK2 gene variants in the past five years. Besides, he had been on regular medical control for hyperlipidemia and benign prostate hyperplasia. His surgical history included a right nephrectomy for lesions of unknown nature and fixation for left clavicle fracture more than 10 years ago. He is a cigarette smoker, consuming half a pack per day for about 60 years.\n\nOn physical examination, there was no superficial lymphadenopathy and other remarkable findings except for coarse breathing sound over the left upper lung area and a certain tenderness over the lumbar spine. Mild elevation of fasting blood sugar (122 mg/dl) was noted upon laboratory examination. Serum carcinoembryonic antigen, cancer antigen 19-9, prostate-specific antigen, and renal and liver function were within normal limits. There was no evidence of viral hepatitis B and C infection. His blood routine showed slight leukocytosis (white blood cell 12,500/ml, neutrophil 81.5%), rather than normal thrombocyte count (314,000/ml), hemoglobin level (14.9 gm/dl), and hematocrit (45.1%).\n\nMagnetic resonance imaging revealed a degenerative thoracic spine and a compression fracture of the lumbar 1 vertebral body without evidence of metastasis. Chest X-ray, however, disclosed a massive space-occupying opacity over the left upper lung field (Figure 1A). Computed tomography (CT) scan showed an approximately 10-cm mass with central low attenuation and gas in the left upper lobe, abutting the left pulmonary artery and pleura with contrast enhancement of the solid portions (Figures 1B, 1C). \n\nFigure 1 Radiological findings of a massive space-occupying lesion in the upper lobe of the lung at presentation: A. chest X-ray film, B and C. CT scan\nArrows: Targets of interest\n\nSubsequent bronchoscopy brushing cytology and biopsy from an occlusive lesion in the left upper lobe bronchus led to a diagnosis of poorly differentiated carcinoma positive to p40 (+++) and CK5/6(+++), negative to CK7, TTF-1, and Napsin-A immunostains, in favor of squamous cell carcinoma (Figure 2A). Strongly positive PD-L1 expression was found in immunohistochemical staining with DAKO monoclonal rabbit anti-PD-L1 antibody clone 28-8 (Figure 2B). The tumor proportion score category for PD-L1 was ≥50%. \n\nFigure 2 Poorly differentiated squamous non-small cell carcinoma of the lung, left upper lobe, bronchoscopy biopsy: A. Hematoxylin and eosin stain x400, B. PD-L1 strongly positive on immunohistochemical stain with tumor proportion score over 50%\nThe patient’s daughter and son brought the patient to another hospital for second opinion consultation. Chest medicine specialists in that hospital gave a suggestion of hospice care only which was unacceptable to them. We decided to treat him with carboplatin (target area under the curve 5) and paclitaxel (175 mg/m2) every four weeks as the first-line therapy in March 2019. On the request of the patient’s family, nivolumab (3 mg/kg every two weeks) was added ever since the second course of chemotherapy. After two doses of both nivolumab and carboplatin plus paclitaxel, dramatic response was detected on chest radiographs (Figures 3A, 3B). Nonetheless, the pulmonary opacity rebounded two weeks later after one more dose of nivolumab (Figure 3C). This warning change was considered to be either pseuoprogression or hyperprogression phenomenon.\n\nFigure 3 Chest X-ray films along the clinical course: A. March 19, 2019, B. April 30, 2019, C. May 13, 2019\nArrows: Targets of interest\n\nFortunately, hyperprogression was thought to be ruled out based on improvement of chest image after the fourth course of nivolumab and carboplatin plus paclitaxel (Figure 4A). Nevertheless, he complained of mild chest discomfort and multiple strange dense shadows appeared in the chest X-ray film shortly after the fifth dose of nivolumab, suggesting nivolumab-induced pneumonitis (Figure 4B). These new lesions resolved to a great extent following a further course of nivolumab plus carboplatin and paclitaxel therapy along with oral prednisolone (1 mg/kg) in eight days (Figure 4C). There was neither respiratory distress nor the need for oxygen inhalation support up to this point. \n\nFigure 4 Chest X-ray films along the clinical course: A. May 29, 2019. B. June 10, 2019. C. June 20, 2019\nArrows: Targets of interest\n\nCT scan performed at the appearance of suspect pneumonitis confirmed the diagnosis. Although astonish tumor necrosis and cavitation were achieved as compared with scans taken prior to combined immunochemotherapy (Figures 5A-5D), newly developed cryptogenic organizing pneumonia, a form of idiopathic interstitial pneumonia, over both the lung fields could be clearly observed (Figures 6A-6D, 7A-7D). \n\nFigure 5 CT scan showing nearly complete necrosis and cavitation of the tumor after therapy: A and C. February 21, 2019. B and D. June 12, 2019\nArrows: Targets of interest\n\nCT, computed tomography\n\nFigure 6 CT scan (lung window) disclosing development of pneumonitis (red arrows) along with tumor necrosis (yellow arrows) after therapy: A and C. February 21, 2019. B and D. June 12, 2019\nFigure 7 Tumor cavitation (yellow arrows) and multiple foci of pneumonitis (red arrows) on sequential axial CT scan (lung window): A to D. June 12, 2019\nNivolumab was discontinued after the sixth dose to avoid pneumonitis progression. Carboplatin and paclitaxel were given up to a total of five courses. Prednisolone therapy continued with the same dose for six weeks and then was shifted to a tapering schedule. Despite satisfactory tumor control has been maintained so far (Figures 8A-8C), severity of pneumonitis exacerbated and oxygen support became necessary upon a very low dose of prednisolone. His symptoms resolved when a prednisolone dose was included again. While preparing this case report, more than two months after stopping all immunochemotherapy, the patient has to continue the intake of prednisolone 10 mg twice daily for maintaining proper pulmonary function. At follow-up, CT scan showed progressive shrunken size of the tumor cavity and much improvement of the pneumonitis with some residual bronchiectasis-like pattern (Figures 9A-9D). \n\nFigure 8 Radiological findings of nearly complete remission of the original malignant lesion, as compared with Figure 1: A. Chest X-ray film, September 6, 2019; B and C. CT scan, September 9, 2019\nArrows: Targets of interest\n\nFigure 9 Progressively shrunken tumor cavity (yellow arrows) and much improvement of the pneumonitis with residual fibrotic changes (red arrows) on sequential axial CT scan (lung window) as compared with Figure 7: A to D, September 9, 2019\nDuring the whole course, there were no skin rash, diarrhea, abdomen pain, cardiac attack, neurologic deficit, renal insufficiency, liver function impairment, and thyroid and adrenal function abnormalities. Febrile neutropenia was noted once after the first course of chemotherapy. Adequate granulocyte-stimulating-factor prophylaxis was given since the second course of chemotherapy and the post-chemotherapy pancytopenia was generally tolerable thereafter.\n\nDiscussion\nA recent systemic review and meta-analysis of published clinical trials identified PD-L1 immunohistochemistry, tumor mutation burden, and gene expression profile to be the most valuable biomarkers for predicting tumor response to anti-PD-1/PD-L1 therapy [7]. A real-world study also showed that tumor PD-L1 expression correlated very well with clinical outcomes in NSCLC treated with anti-PD-1 antibody nivolumab and pembrolizumab [8]. Our patient’s high PD-L1 score and distinguished efficacy of nivolumab treatment are thus very compatible with these reports, supporting PD-L1 expression as a reliable biomarker for anti-PD-1 therapy in NSCLC.\n\nIn spite of the good therapeutic result, a short period of rebound opacity in chest film during the patient’s immunochemotherapy led to a difficult differential diagnosis between hyperprogression and pseudoprogression [9-10]. The fact that the opacity soon resolved on continuous nivolumab therapy made pseudoprogression a more likely diagnosis. However, the reverse of hyperprogression due to suppression of regulatory T cell (Treg) activity by simultaneous chemotherapy remained an interesting possibility [11]. If the latter presumption is true, a combination of ICI and chemotherapy might turn out to be a more reasonable choice against squamous cell lung cancer in the future.\n\nAs known, autoimmune adverse effects of ICI could almost take place in all organs over the body. The incidence of pneumonitis is about 3% to 8% [12]. The patterns of nivolumab-related interstitial lung disease in NSCLC mainly included acute interstitial pneumonia with diffuse alveolar damage, cryptogenic organizing pneumonia, hypersensitivity pneumonitis, and nonspecific interstitial pneumonia [13]. The initial management of ICI-related pneumonitis includes holding ICI agents immediately and starting prednisolone 1-2 mg/kg for at least four weeks before tapering slowly. Other immunosuppressive therapy such as infliximab, mycophenolate mofetil, intravenous immunoglobulin, and cyclophosphamide should be added if the pneumonitis status worsens out of control [14]. \n\nOur patient’s pneumonitis improved rapidly on recommended full dose prednisolone, but apparently, complete withdrawal of steroid is difficult if the underlying autoimmune process is still active. We do consider adopting additional immunosuppressive agents when necessary. On the other hand, in nivolumab-treated NSCLC, the occurrence of immune-related adverse events was found to be associated with better clinical outcomes, and severe nivolumab-induced pneumonitis leading to durable remission in a squamous NSCLC patient had been reported [15-16]. Hence, our patient would enjoy a rather good prognosis with regard to his lung cancer.\n\nThe question of whether durable remission could be maintained after stopping ICI similar to our case necessitates further studies; however, two recent case series have yielded positive results. One of them even concluded that durable response could be achieved after discontinuation of ICI in the absence of toxicity [17-18]. This point of view shall be appreciated by patients who develop intolerable adverse effects or lack enough financial support for ceaseless ICI treatment.\n\nThe U.S. Food and Drug Administration has published a meta-analysis of randomized NSCLC clinical trials, revealing that advanced NSCLC patients over 75 years of age seem to gain survival benefits from anti-PD-1/PD-L1 antibodies similar to patients younger than 65 years of age [19]. This finding should be very encouraging to our 80-year-old patient. Finally, the patient might also find some comfort that he had been a long-term smoker because, in comparison with chemotherapy, ICI treatment in NSCLC trials improved survival significantly in ever-smokers but not in never-smokers according to a recent analysis [20]. Of course, more investigations are required to confirm this result.\n\nConclusions\nCombination of nivolumab and carboplatin plus paclitaxel as the first-line therapy successfully brought a PD-L1-strongly-positive advanced squamous NSCLC in an elder patient into remission with the price of controllable ICI-related pneumonitis. Adverse effects of ICI may be awful but correlate with better response and longer survival. Concurrent chemotherapy not only destroys tumor cells and promotes tumor antigen release and presentation to immune cells, but could also contribute immensely to the suppression of Treg activity that plays a major role in hyperprogression under ICI therapy. We look forward to considering ICI combined with chemotherapy as the mainstay treatment for squamous NSCLC with high PD-L1 expression in the future. \n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 How to make the best use of immunotherapy as first-line treatment for advanced/metastatic non-small-cell lung cancer Ann Oncol Peters S Reck M Smit EF Mok T Hellmann MD 884 896 30 2019 \n2 New combination strategies using programmed cell death 1/programmed cell death ligand 1 checkpoint inhibitors as a backbone Cancer J Hu-Lieskovan S Ribas A 10 22 23 2017 28114250 \n3 A changing of the guard: immune checkpoint inhibitors with and without chemotherapy as first line treatment for metastatic non-small cell lung cancer Front Oncol Pacheco JM Camidge DR Doebele RC Schenk E 195 9 2019 30984621 \n4 Nivolumab in combination with platinum-based doublet chemotherapy for first-line treatment of advanced non-small-cell lung cancer J Clin Oncol Rizvi NA Hellmann MD Brahmer JR 2969 2979 34 2016 27354481 \n5 Safety and efficacy of nivolumab and standard chemotherapy drug combination in patients with advanced non-small-cell lung cancer: a four arms phase Ib study Ann Oncol Kanda S Goto K Shiraishi H 2242 2250 27 2016 27765756 \n6 Press Release: Bristol-Myers Squibb Provides Update on Part 2 of CheckMate-227 10 2019 2019 https://news.bms.com/press-release/rd-news/bristol-myers-squibb-provides-update-part-2-checkmate-227 \n7 Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: a systematic review and meta-analysis JAMA Oncol Lu S Stein JE Rimm DL 2019 \n8 Tumor PD-L1 expression and clinical outcomes in advanced-stage non-small cell lung cancer patients treated with nivolumab or pembrolizumab: real-world data in Taiwan J Cancer Lin SY Yang CY Liao BC 1813 1820 9 2018 29805708 \n9 Hyperprogressive disease in patients with non-small cell lung cancer treated with nivolumab: A case series Thorac Cancer Kanazu M Edahiro R Krebe H 1782 1787 9 2018 30328672 \n10 Sequential CT findings in patients with non-small-cell lung cancer receiving nivolumab Clin Lung Cancer Johnson DY Short RG Patz EF Jr 175 180 19 2018 29153896 \n11 The interplay of immunotherapy and chemotherapy: harnessing potential synergies Cancer Immunol Res Emens LA Middleton G 436 443 3 2015 25941355 \n12 Checkpoint inhibitors Dtsch Arztebl Int Heinzerling L de Toni EN Schett G Hundorfean G Zimmer L 119 126 116 2019 30940340 \n13 Radiologic features of pneumonitis associated with nivolumab in non-small-cell lung cancer and malignant melanoma Future Oncol Baba T Sakai F Kato T 1911 1920 15 2019 31020849 \n14 Clinical management of pneumonitis in patients receiving anti-PD-1/PD-L1 therapy J Adv Pract Oncol Bala-Hampton JE Bazzell AF Dains JE 422 428 9 2018 https://doi.org/10.6004/jadpro.2018.9.4.5 30719394 \n15 Correlation between immune-related adverse events and efficacy in non-small cell lung cancer treated with nivolumab Lung Cancer Sato K Akamatsu H Murakami E 71 74 115 2018 29290265 \n16 Severe nivolumab-induced pneumonitis preceding durable clinical remission in a patient with refractory, metastatic lung squamous cell cancer: a case report J Hematol Oncol Li H Ma W Yoneda KY 64 10 2017 28245875 \n17 Efficacy of anti-PD-1/PD-L1 antibodies after discontinuation due to adverse events in non-small cell lung cancer patients (HANSHIN 0316) BMC Cancer Tachihara M Negoro S Inoue T 946 18 2018 30285770 \n18 Durable response after discontinuation of nivolumab therapy in the absence of disease progression or toxicity with two advanced NSCLC patients J Oncol Pharm Pract Yilmaz M Guven Mese S 1078155219867131 18 2019 \n19 FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies Semin Oncol Marur S Singh H Mishra-Kalyani P 220 225 45 2018 30391014 \n20 Prognostic value of smoking status in non-small-cell lung cancer patients treated with immune checkpoint inhibitors: a meta-analysis Oncotarget Kim JH Kim HS Kim BJ 93149 93155 8 2017 29190984\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(10)",
"journal": "Cureus",
"keywords": "chemotherapy; immune checkpoint inhibitor; nivolumab; pneumonitis; squamous non-small cell lung cancer",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e5881",
"pmc": null,
"pmid": "31772851",
"pubdate": "2019-10-10",
"publication_types": "D002363:Case Reports",
"references": "30328672;29190984;30940340;31020849;25941355;27354481;29290265;28245875;29805708;31423946;31318407;27765756;30285770;30391014;29153896;30912805;30719394;30984621;28114250",
"title": "Nivolumab plus Carboplatin and Paclitaxel as the First-line Therapy for Advanced Squamous Cell Carcinoma of the Lung with Strong Programmed Death-ligand 1 Expression: A Case Report.",
"title_normalized": "nivolumab plus carboplatin and paclitaxel as the first line therapy for advanced squamous cell carcinoma of the lung with strong programmed death ligand 1 expression a case report"
} | [
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"abstract": "EGFR tyrosine kinase inhibitors are one of the key drugs for treatment of NSCLC with EGFR mutations. In recent times, immune check-point inhibitors (ICIs) have also been widely used for patients with NSCLC. Although a subset of patients obtain benefit from ICIs, adverse events (AEs) that are different from those of cytotoxic chemotherapies may occur. Moreover, some patients develop AEs, which seem to be caused by the previously discontinued nivolumab.\nWe identified patients with NSCLC who developed AEs, which started shortly after discontinuation of nivolumab and during treatment with osimertinib. We conducted liquid chromatography-mass spectrometry analyses to estimate the concentration of serum nivolumab.\nThree patients with AEs were identified. Two patients developed interstitial lung disease (cases 1 and 2) and one developed hepatotoxicity (case 3) during osimertinib therapy initiated after nivolumab administration. They received several treatments, including cytotoxic chemotherapies or EGFR tyrosine kinase inhibitors other than osimertinib, followed by nivolumab for three to five cycles; nevertheless, the disease progressed. After discontinuation of nivolumab, osimertinib was administered from day 22 to 46; but treatment-related toxicities developed 56 to 96 days later. Liquid chromatography-mass spectrometry analyses revealed that the remaining levels of nivolumab in the blood (2.1 μg/mL, 12.8 μg/mL, and 31.1 μg/mL, respectively, for cases 1, 2, and 3) were enough to induce an immune response.\nThe presence of the ICI antibody that persists even after drug discontinuation may account not only for the prolonged efficacy of these agents but also for the late onset of AEs, especially when the antibodies may have interacted during subsequent treatments.",
"affiliations": "Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.;Division of Molecular Pharmacology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan.;Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan.;Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Kuramoto-cho, Tokushima, Tokushima, Japan.;Department of Breast and Medical Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.;Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan.",
"authors": "Shinno|Yuki|Y|;Goto|Yasushi|Y|;Ohuchi|Mayu|M|;Hamada|Akinobu|A|;Nokihara|Hiroshi|H|;Fujiwara|Yasuhiro|Y|;Ohe|Yuichiro|Y|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1016/j.jtocrr.2020.100008",
"fulltext": "\n==== Front\nJTO Clin Res Rep\nJTO Clin Res Rep\nJTO Clinical and Research Reports\n2666-3643\nElsevier\n\nS2666-3643(20)30008-4\n10.1016/j.jtocrr.2020.100008\n100008\nOriginal Article\nThe Long Half-Life of Programmed Cell Death Protein 1 Inhibitors May Increase the Frequency of Immune-Related Adverse Events After Subsequent EGFR Tyrosine Kinase Inhibitor Therapy\nShinno Yuki MD a\nGoto Yasushi MD, PhD ygoto@ncc.go.jp\na∗\nOhuchi Mayu b\nHamada Akinobu c\nNokihara Hiroshi d\nFujiwara Yasuhiro e\nOhe Yuichiro a\na Department of Thoracic Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan\nb Division of Molecular Pharmacology, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan\nc Division of Clinical Pharmacology and Translational Research, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Tsukiji, Chuo-ku, Tokyo, Japan\nd Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Kuramoto-cho, Tokushima, Tokushima, Japan\ne Department of Breast and Medical Oncology, National Cancer Center Hospital, Tsukiji, Chuo-ku, Tokyo, Japan\n∗ Corresponding author. Address for correspondence: Yasushi Goto, MD, PhD, Department of Thoracic Oncology, The National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. ygoto@ncc.go.jp\n11 2 2020\n3 2020\n11 2 2020\n1 1 10000814 1 2020\n15 1 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nIntroduction\n\nEGFR tyrosine kinase inhibitors are one of the key drugs for treatment of NSCLC with EGFR mutations. In recent times, immune check-point inhibitors (ICIs) have also been widely used for patients with NSCLC. Although a subset of patients obtain benefit from ICIs, adverse events (AEs) that are different from those of cytotoxic chemotherapies may occur. Moreover, some patients develop AEs, which seem to be caused by the previously discontinued nivolumab.\n\nMethods\n\nWe identified patients with NSCLC who developed AEs, which started shortly after discontinuation of nivolumab and during treatment with osimertinib. We conducted liquid chromatography-mass spectrometry analyses to estimate the concentration of serum nivolumab.\n\nResults\n\nThree patients with AEs were identified. Two patients developed interstitial lung disease (cases 1 and 2) and one developed hepatotoxicity (case 3) during osimertinib therapy initiated after nivolumab administration. They received several treatments, including cytotoxic chemotherapies or EGFR tyrosine kinase inhibitors other than osimertinib, followed by nivolumab for three to five cycles; nevertheless, the disease progressed. After discontinuation of nivolumab, osimertinib was administered from day 22 to 46; but treatment-related toxicities developed 56 to 96 days later. Liquid chromatography-mass spectrometry analyses revealed that the remaining levels of nivolumab in the blood (2.1 μg/mL, 12.8 μg/mL, and 31.1 μg/mL, respectively, for cases 1, 2, and 3) were enough to induce an immune response.\n\nConclusion\n\nThe presence of the ICI antibody that persists even after drug discontinuation may account not only for the prolonged efficacy of these agents but also for the late onset of AEs, especially when the antibodies may have interacted during subsequent treatments.\n\nKeywords\n\nNon−small cell lung cancer\nEGFR\nprogrammed cell death protein 1\nOsimertinib\nImmune-related adverse events\n==== Body\npmcIntroduction\n\nEGFR tyrosine kinase inhibitors (TKIs) are key drugs for patients with sensitizing EGFR mutations involved in NSCLC. Osimertinib is a third-generation EGFR TKI that is effective against tumors with sensitizing mutations and the T790M-resistant mutation. Osimertinib was approved in March 2016 for use in Japan, and many patients are now receiving this new EGFR TKI after having been previously treated with other anticancer therapies. Interstitial lung disease (ILD) is a major adverse effect of EGFR TKIs. Its incidence is higher in Japan; however, the reasons for this are not yet known. In a global phase 3 trial comparing osimertinib and platinum plus pemetrexed in EGFR T790M–positive patients with NSCLC, the incidence of ILD was 4% among all patients and 7% among Japanese patients.1,2 Nivolumab is a human immunoglobulin G4 programmed cell death protein 1 (PD-1) antibody that is effective in the treatment of NSCLC. Among previously treated patients with NSCLC, overall survival was better with nivolumab than with docetaxel.3 Moreover, several studies revealed a durable response of nivolumab even after therapy was discontinued.4,5 Owing to the biological nature of antibodies, nivolumab may remain in the blood for extended periods of time.\n\nHowever, the long-lasting effects of nivolumab may be partly responsible for the late onset of adverse events (AEs). A previous study revealed that sequential PD-1 blockade and osimertinib frequently induce immune-related AEs (irAEs).6 However, little is known about the extent of nivolumab that may contribute to this phenomenon.\n\nMaterials and Methods\n\nWe identified patients who developed AEs during treatment with osimertinib shortly after discontinuation of nivolumab (PD-1 antibody) after March 2016 when osimertinib was approved in Japan. We conducted liquid chromatography-mass spectrometry (LC-MS) analyses to estimate the concentration of serum nivolumab in these patients.7 We repeated the analyses with the remaining serum samples. AEs were graded according to the Common Terminology Criteria for Adverse Events (CTCAE) guidelines version 4.0. We obtained ethical approval from the National Cancer Center Hospital, and confidentiality of the patient data was maintained. Written informed consent was obtained from the patients for the analysis of blood samples and for publication.\n\nResults\n\nThree patients with related AEs were identified. Two patients suffered from ILDs (cases 1 and 2) and one developed hepatotoxicity (case 3) during osimertinib therapy initiated after nivolumab administration. Here, we describe the detailed clinical courses of these patients.\n\nCase 1 (Fig. 1) was a man in his late 50s who had recurrent lung adenocarcinoma with an EGFR exon 19 deletion. He was an ex-smoker and had no comorbidities. He received gefitinib, erlotinib, carboplatin, pemetrexed, and bevacizumab for 3 years. He was then treated with nivolumab at a dosage of 3 mg/kg every 2 weeks. He received three cycles of nivolumab with no obvious AEs. However, the treatment was discontinued because his disease progressed rapidly. He underwent another biopsy of the lung tumor through bronchoscopy, and a new EGFR T790M mutation was detected. Osimertinib (80 mg/d) was started 46 days after the final nivolumab administration. The efficacy of osimertinib was confirmed by computed tomography (CT) 50 days after administration, which was 96 days after the final dose of nivolumab. However, because nonsegmental, diffuse, ground-glass opacities were found in the CT scan, drug-induced ILD was suspected. Seven days later, his symptoms of dyspnea worsened and he underwent bronchoscopy for a differential diagnosis of abnormal findings in the lung. An analysis of his bronchoalveolar lavage fluid revealed that the fraction of lymphocytes had increased to 61% and the cluster of differentiation 4/cluster of differentiation 8 ratio was 1.93. There was no evidence of infection. At that time, his blood nivolumab concentration, as determined by LC-MS, was 2.1 μg/mL. Thus, he was diagnosed with grade 3 drug-induced ILD according to CTCAE guidelines. He was treated with prednisolone (0.5 mg/kg), and his symptoms improved dramatically within 1 week.Figure 1 Clinical course of case 1. A computed tomography scan taken 15 days after three cycles of nivolumab revealed disease progression (A). After 50 days of administration, the efficacy of osimertinib was confirmed, although abnormal findings indicating interstitial lung disease were found (B). Seven days later, the symptoms and computed tomography findings of drug–induced interstitial lung disease worsened and prednisolone was started (C). The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood (D).\n\nCase 2 (Fig. 2) was a woman in her early 70s who was diagnosed with stage IV lung adenocarcinoma characterized by an EGFR exon 19 deletion. She received erlotinib, carboplatin, and pemetrexed for 2 years. When the disease progressed, she underwent another biopsy of the primary lung tumor, and a T790M resistance mutation was identified. She received an investigational drug for 9 months followed by nivolumab (3 mg/kg) every 2 weeks for three cycles. She had no AEs during nivolumab therapy, but it was stopped because of disease progression. She was started on osimertinib 22 days after the final administration of nivolumab. Thirty-four days later, at 56 days after the final administration of nivolumab, CT scan results confirmed the efficacy of osimertinib but also revealed patchy, diffuse, ground-glass opacities. There were no other findings that implied an infection, and so drug-induced ILD was suspected. The nivolumab concentration in her blood, taken on the same day on which the CT scan revealed the abnormal findings, was calculated at 12.8 μg/mL. Because the patient had no symptoms related to abnormal findings, the AE was evaluated as grade 1 according to CTCAE guidelines. The patient continued to receive osimertinib with close follow-up. Sixty-three days after the CT scan, or 128 days after the final administration of nivolumab, she underwent another CT scan, which revealed disappearance of the abnormal shadow.Figure 2 Clinical course of case 2. A computed tomography scan taken 15 days after three cycles of nivolumab revealed disease progression (A). After 34 days of administration, the efficacy of osimertinib was confirmed, although ground-glass opacities indicating interstitial lung disease were found (B). Although the patient continued osimertinib treatment, the abnormal shadow in computed tomography disappeared spontaneously (C). The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood (D).\n\nCase 3 (Fig. 3) was a woman in her early 50s who was diagnosed with stage IV lung adenocarcinoma characterized by an EGFR L858R mutation. She received gefitinib, erlotinib, afatinib, pemetrexed, and radiation therapy for the brain, followed by nivolumab at 3 mg/kg for five cycles. However, the disease progressed. Her trough serum concentration of nivolumab before the final administration was 69.7 μg/mL. Biopsy from a liver metastasis revealed a T790M mutation, and she was started on osimertinib at 80 mg/d 35 days after the final administration of nivolumab. On day 15, grade 2 elevation of transaminase levels was found, and the osimertinib dosage was reduced to 40 mg. Nonetheless, her symptoms exacerbated, accompanied by grade 1 fever and grade 2 malaise, 5 days later, and a grade 3 increase of alanine aminotransferase levels was also observed. The treatment with osimertinib was stopped 63 days after the final nivolumab administration. Her blood concentration of nivolumab was 31.1 μg/mL. After osimertinib cessation, her liver function recovered within 2 weeks without any additional treatment. She was therefore restarted on osimertinib at a dosage of 40 mg on alternate days. The dosage was subsequently increased to 80 mg/d, but there were no signs of hepatotoxicity. Her blood nivolumab concentration decreased steadily (12.7 μg/mL on day 98 and 3.4 μg/mL on day 126 after the final nivolumab administration).Figure 3 Clinical course of case 3. The graph exhibits the treatment timeline and longitudinal changes in the nivolumab concentrations in the blood and serum ALT activities. ALT, alanine transaminase.\n\nDiscussion\n\nBecause ICIs targeting PD-1 or its ligand, programmed death ligand 1 (PD-L1), have revealed favorable results in patients with NSCLC, anti–PD-1 or anti–PD-L1 antibodies are considered standard treatment. These antibodies disrupt suppressive signaling between cytotoxic T cells and tumors and thereby exhibit clinical benefits.8 In some cases, a durable response to these antibodies may occur even after discontinuation.4 This phenomenon can be explained by ICIs, which may affect the immune response and occur even at low concentrations. In a phase I study of nivolumab, PD-1 occupancy was 60% to 80% even after nivolumab was no longer detected in the blood (< 1.2 μg/mL).9 Furthermore, according to an in vivo study, a concentration of 1 μg/mL of nivolumab is enough to activate a T-cell response.10 Durable efficacy may provoke delayed irAEs. On August 5, 2016, postmarketing surveillance revealed 68 severe AEs in 50 patients, which occurred more than 31 days after discontinuation of nivolumab (median, 49 days; range, 31–247 days). In the present study, the patients developed ILD or hepatotoxicity after discontinuation of nivolumab. The previous study revealed that PD-(L)1 blockade followed by osimertinib induces severe irAEs more frequently than does osimertinib followed by PD-(L)1 blockade.6 There are also several case reports of ILD caused by EGFR TKI administration after ICIs11,12 and possible interaction between the AEs and previously administered ICIs. However, this is the first case series that revealed the possible relation between late-onset AEs and the concentrations of nivolumab in the blood analyzed using LC-MS. The analyses revealed that nivolumab remained in the blood for months at a level sufficient to induce an immune response. Despite the lack of evidence, nivolumab could have affected the clinical course of our patients even after discontinuation. There has also been a report of a patient with melanoma who developed AEs related to vemurafenib, which occurred even after discontinuation of anti–PD-1 antibodies.13 Although it is known that a single dose of 3 mg/kg nivolumab has a half-life of 13 days (± 7 days),14 it remains unclear as to how long it takes to sufficiently diminish the effect of nivolumab on the immune system so as not to affect subsequent treatment.\n\nILD is one of the most severe AEs related to both ICIs and EGFR TKIs. Previous meta-analyses found that pneumonitis occurred in about 3% and 1.12% of patients with NSCLC who received anti–PD-(L)1 antibodies or EGFR TKI, respectively.15,16 In a clinical trial that evaluated the combination of osimertinib and durvalumab, an antibody targeting PD-L1, an extremely high incidence (38%) of interstitial pneumonia was seen.17 Since the approval of nivolumab in Japan, eight cases of ILD potentially attributed to EGFR TKI use after nivolumab therapy have been reported as of July 13, 2016. An ongoing postmarketing surveillance of osimertinib has, thus far, identified 39 cases of ILD, including at least six cases in which the patients previously received nivolumab. Although these epidemiologic reports are more sporadic rather than comprehensive, and the incidence rate is yet to be determined more rigorously, many physicians have observed related abnormalities. The drug distributors and the Ministry of Health and Welfare of Japan have even released a statement to warn physicians. Details regarding the incidence of ILD after nivolumab treatment are expected to be updated.\n\nFinally, we treated a patient who developed severe hepatotoxicity during osimertinib treatment after the failure of nivolumab. When osimertinib is administered as a single agent, hepatotoxicity is a relatively rare AE.1 However, hepatotoxicity is one of the major AEs associated with gefitinib, and the patients who were administered a combination of gefitinib and durvalumab had alanine aminotransferase levels that increased to 40%.18 ICIs may augment susceptibility to EGFR TKI–related AEs because of their contribution to immune response.\n\nIn summary, we have reported three cases of osimertinib-induced interstitial pneumonia or hepatotoxicity after the discontinuation of nivolumab. LC-MS revealed that their nivolumab concentrations were much lower than trough concentrations during treatment yet high enough to induce immune responses. Long-lasting antibodies may account for the prolonged effect of ICIs even after drug discontinuation, and they can also participate in unanticipated cross-interactions with subsequent treatments. Therefore, to avoid provoking an immune reaction that negatively alters the clinical course of the disease, careful consideration and closer follow-up are imperative during treatment after ICI therapy.\n\nAcknowledgments\n\nThis study was supported by grants from the Practical Research for Innovative Cancer Control from the 10.13039/100009619 Japan Agency for Medical Research and Development under grant number JP16ck0106191.\n\nDisclosure: Dr. Goto has a consulting or advisory role with Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Pfizer, Novartis, AstraZeneca, and GlaxoSmithKline; has served on the speaker’s bureau for AstraZeneca, Eli Lilly, Chugai, Taiho, Boehringer Ingelheim, Ono Pharmaceutical, Bristol Myers Squibb, Pfizer, MSD, Shionogi Pharma, and Novartis; and has received research funding from 10.13039/100006483 Abbvie , Eli 10.13039/100004312 Lilly , Taiho, 10.13039/100002491 Bristol Myers Squibb , 10.13039/501100013170 Ono Pharmaceutical , 10.13039/501100002973 Daiichi Sankyo , 10.13039/100004319 Pfizer , 10.13039/100004336 Novartis , and Kyorin. Dr. Nokihara has received research funding from 10.13039/501100013170 Ono Pharmaceutical , 10.13039/100004319 Pfizer , 10.13039/100004325 AstraZeneca , 10.13039/100010795 Chugai , and 10.13039/100009857 Regeneron ; he has also served on the speakers’ bureau for AstraZeneca, Chugai, Eisai, Eli Lilly, MSD, and Boehringer Ingelheim. Dr. Fujiwara has received grants from 10.13039/100009619 Japan Agency for Medical Research and Development and the 10.13039/501100003478 Ministry of Health Labor and Welfare , Japan, during the conduct of the study; he has also served on the speakers’ bureau for AstraZeneca, Daiichi Sankyo, Taiho, Chugai, Novartis, SRL Pharma, and Bristol Myers Squibb. Dr. Ohe has had consulting or advisory roles for AstraZeneca, Chugai, Ono Pharmaceutical, Bristol Myers Squibb, Kyorin, Celltrion, and Amgen; has received research funding from 10.13039/100004325 AstraZeneca , 10.13039/100010795 Chugai , Eli 10.13039/100004312 Lilly , 10.13039/501100013170 Ono Pharmaceutical , BMS, Kyorin, Dainippon-Sumitomo, 10.13039/100004319 Pfizer , Taiho, 10.13039/100004336 Novartis , Kissei, 10.13039/100014584 Ignyta , 10.13039/100008373 Takeda , Kissei, 10.13039/501100002973 Daiichi Sankyo , and Janssen; and has served on the speakers’ bureau for AstraZeneca, Chugai, Eli Lilly, Ono Pharmaceutical, Bristol Myers Squibb, Boehringer Ingelheim, Bayer, Pfizer, MSD, and Taiho. The remaining authors declare no conflict of interest.\n==== Refs\nReferences\n\n1 Mok T.S. Wu Y.L. Ahn M.J. Osimertinib or platinum-pemetrexed in EGFR T790M-positive lung cancer N Engl J Med 376 2017 629 640 27959700\n2 Akamatsu H. Katakami N. Okamoto I. Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non-small-cell lung cancer: AURA3 trial Cancer Sci 109 2018 1930 1938 29697876\n3 Brahmer J. Reckamp K.L. Baas P. Nivolumab versus docetaxel in advanced squamous-cell non-small-Cell lung cancer N Engl J Med 373 2015 123 135 26028407\n4 Takagi T. Yoshida K. Kobayashi H. Durable response after discontinuation of nivolumab therapy in patients with metastatic renal cell carcinoma Jpn J Clin Oncol 48 2018 860 863 30113653\n5 Gettinger S.N. Horn L. Gandhi L. Overall survival and long-term safety of nivolumab (anti-programmed death 1 antibody, BMS-936558, ONO-4538) in patients with previously treated advanced non-small-cell lung cancer J Clin Oncol 33 2015 2004 2012 25897158\n6 Schoenfeld A.J. Arbour K.C. Rizvi H. Severe immune related adverse events are common with sequential PD- (L) 1 blockade and osimertinib Ann Oncol 30 2019 839 844 30847464\n7 Iwamoto N. Shimada T. Terakado H. Hamada A. Validated LC-MS/MS analysis of immune checkpoint inhibitor nivolumab in human plasma using a fab peptide-selective quantitation method: nano-surface and molecular-orientation limited (nSMOL) proteolysis J Chromatogr B Analyt Technol Biomed Life Sci 1023 2016 9 16\n8 Dine J. Gordon R. Shames Y. Kasler M.K. Barton-Burke M. Immune checkpoint inhibitors: an innovation in immunotherapy for the treatment and management of patients with cancer Asia Pac J Oncol Nurs 4 2017 127 135 28503645\n9 Brahmer J.R. Drake C.G. Wollner I. Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates J Clin Oncol 28 2010 3167 3175 20516446\n10 Wang C. Thudium K.B. Han M. In vitro characterization of the anti-PD-1 antibody nivolumab, BMS-936558, and in vivo toxicology in non-human Primates Cancer Immunology Research 2 2014 846 856 24872026\n11 Mamesaya N. Kenmotsu H. Katsumata M. Nakajima T. Endo M. Takahashi T. Osimertinib-induced interstitial lung disease after treatment with anti-PD1 antibody Investig New Drugs 35 2016 105 107 27599705\n12 Takakuwa O. Oguri T. Uemura T. Osimertinib-induced interstitial lung disease in a patient with non-small cell lung cancer pretreated with nivolumab: A case report Mol Clin Oncol 7 2017 383 385 28808573\n13 Johnson D.B. Wallender E.K. Cohen D.N. Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy Cancer Immunol Res 1 2013 373 377 24490176\n14 Yamamoto N. Nokihara H. Yamada Y. Phase I study of nivolumab, an anti-PD-1 antibody, in patients with malignant solid tumors Investig New Drugs 35 2017 207 216 27928714\n15 Khunger M. Rakshit S. Pasupuleti V. Incidence of pneumonitis with use of programmed death 1 and programmed death-ligand 1 inhibitors in non-small cell lung cancer: a systematic review and meta-analysis of trials Chest 152 2017 271 281 28499515\n16 Suh C.H. Park H.S. Kim K.W. Pyo J. Hatabu H. Nishino M. Pneumonitis in advanced non-small-cell lung cancer patients treated with EGFR tyrosine kinase inhibitor: meta-analysis of 153 cohorts with 15,713 patients Lung Cancer 123 2018 60 69 30089596\n17 Ahn M.J. Yang J. Yu H. 136O: osimertinib combined with durvalumab in EGFR-mutant non-small cell lung cancer: results from the TATTON phase Ib trial J Thorac Oncol 11 2016 933 939 27211580\n18 Gibbons D.L. Chow L.Q. Kim D.W. 57O Efficacy, safety and tolerability of MEDI4736 (durvalumab [D]), a human IgG1 anti-programmed cell death-ligand-1 (PD-L1) antibody, combined with gefitinib (G): a phase I expansion in TKI-naïve patients (pts) with EGFR mutant NSCLC J Thorac Oncol 11 2016 S79\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2666-3643",
"issue": "1(1)",
"journal": "JTO clinical and research reports",
"keywords": "EGFR; Immune-related adverse events; Non−small cell lung cancer; Osimertinib; programmed cell death protein 1",
"medline_ta": "JTO Clin Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101769967",
"other_id": null,
"pages": "100008",
"pmc": null,
"pmid": "34589912",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": "28499515;27928714;25897158;28808573;27599705;24872026;30113653;26028407;27155936;30089596;30847464;29697876;28503645;27959700;20516446;24490176",
"title": "The Long Half-Life of Programmed Cell Death Protein 1 Inhibitors May Increase the Frequency of Immune-Related Adverse Events After Subsequent EGFR Tyrosine Kinase Inhibitor Therapy.",
"title_normalized": "the long half life of programmed cell death protein 1 inhibitors may increase the frequency of immune related adverse events after subsequent egfr tyrosine kinase inhibitor therapy"
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