tbuckley/cabot-search huggingface dataset:
Representativeness of Randomized Clinical Trial Cohorts in End-stage Kidney Disease
Authors: Brendan Smyth, Anna Haber, Konlawij Trongtrakul, Carmel Hawley, Vlado Perkovic, Mark Woodward, Meg Jardine
Journal: JAMA Internal Medicine (2019)

Systematic differences between patients included in randomized clinical trials (RCTs) and the general patient population may influence the generalizability of RCT findings. Comprehensive national registries of patients with end-stage kidney disease who are undergoing dialysis provide a unique opportunity to compare trial and real-world patient cohorts.To determine if participants in large, multicenter dialysis trials were similar to the general population undergoing dialysis in terms of age, comorbidities, and mortality rate.MEDLINE, PubMed, and the Cochrane Central Register of Controlled Trials were systematically searched on January 6, 2017, for studies published from January 1, 2007, to December 31, 2016. Data sources were published manuscripts, supplementary material, and trial registration information. Data on the general population undergoing dialysis were derived from the US Renal Data System (USRDS). Data were analyzed from March 17 to July 22, 2018.Randomized clinical trials enrolling only participants undergoing dialysis for end-stage kidney disease with 100 or more adult participants from 2 or more sites.Abstract screening and data extraction were performed independently by 2 researchers. Data were pooled using a random-effects model.The primary outcome was difference in mean age between the RCT and USRDS populations. Secondary outcomes included differences in mortality rate and comorbidities.The search identified 186 RCTs, enrolling 79 104 participants. Compared with the 2011 USRDS population, RCT participants were younger (mean age, 58.9 years; 95% CI, 58.3-59.5 years vs 61.2 years; P < .001), more likely to be male (58.9%; 95% CI, 57.6%-60.1% vs 55.7%; P < .001), and have coronary artery disease (26.9%; 95% CI, 22.2%-31.7% vs 17.7%; P < .001) and less likely to have diabetes (40.2%; 95% CI, 36.7%-43.6% vs 44.2%; P = .03) or heart failure (19.6%; 95% CI, 15.1%-24.0% vs 29.8%; P < .001). The mortality rate per 100 patient-years during trial participation was less than half that of the USRDS population (8.9; 95% CI, 7.8-10.0 vs 18.6; P < .001). The differences in age, mortality, and coronary artery disease remained when studies recruiting only from the United States were considered. Diabetes was more common in RCT participants from the United States than in the registry population.Participants in large, multicenter RCTs of patients with end-stage kidney disease undergoing dialysis are younger, have a different pattern of comorbidities, and have a lower mortality rate than the general population of patients undergoing dialysis. This finding has implications for the generalization of trial results to the broader patient population and for future trial design.
Metabolic perturbations and cellular stress underpin susceptibility to symptomatic live-attenuated yellow fever infection
Authors: Kuan Rong Chan, Esther Shuyi Gan, Candice Yuen Yue Chan, Cui Liang, John Zhong Heng Low, Summer Li-Xin Zhang, Eugenia Ziying Ong, Ashwin Bhatta, Limin Wijaya, Yie Hou Lee, Jenny Guek-Hong Low, Eng Eong Ooi
Journal: Nature Medicine (2019)
PTU-019 Magnetically steered capsule endoscopy (msce) of the upper and mid gut in recurrent and refractory iron deficiency anaemia
Authors: H-L Ching, MF Hale, JA Campbell, A Healy, V Thurston, R Sidhu, ME McAlindon
Journal: Gut (2017)

Introduction  Guidelines suggest that repeat gastroscopy (OGD) and small bowel capsule endoscopy (CE) should be considered in recurrent and refractory iron deficiency anaemia (1). Upper and mid gut CE might satisfy both requirements with a single procedure. We compare the diagnostic ability of MSCE in the upper and mid gut to OGD.  Method  After ingestion of 1L water with simethicone, the Mirocam Navi (Intromedic Ltd., Korea) was steered around the stomach using a handheld magnet before allowing it to pass through the small bowel. Diagnoses were compared with subsequent OGD performed within 14 days. Visibility of MSCE and patient comfort was assessed.  Results  33 patients (mean age 64±14 years, 45.5% male) underwent MSCE gastric examination for a mean of 26±11 mins before the capsule left the stomach. 39.4% of patients received sedation for OGD. MSCE visibility scores (worst-best:1–5) for greater and lesser curves, anterior and posterior body, second part of duodenum (D2) were: 4.5 (±0.8), 4.7 (±0.6), 4.5 (±0.7), 4.5 (±0.7), 4.6 (±0.8) respectively. Views of the oesophagus (2.6±2), proximal stomach (cardia, 3.2±1.7; fundus, 2.8±1.3) and the first part of the duodenum (D1, 3.4±0.9) were more challenging. 33.7% of upper GI lesions were detected by both techniques: oesophagitis (n=1), hiatus hernia (n=3), gastritis (18), pancreatic rest (n=1), active duodenal bleeding (n=1) and gastric polyps (n=3). 14% of lesions were only detected by OGD: oesophagitis (n=1), Barrett’s oesophagus (n=1), hiatus hernia (n=2), gastritis (n=1), gastric polyps (n=2) gastric angioectasia (AE, n=1), duodenitis (n=2), duodenal AE (n=2). However, MSCE identified 52.3% of all lesions that OGD missed: oesophagitis (n=1), hiatus hernia (n=3), gastritis (n=15), gastric ulcers (n=3), benign gastric polyps (n=6), gastric AE (n=4), altered blood in the stomach (n=1), gastric lymphangiectasia (n=1), suspected intestinal metaplasia (n=1), duodenitis (n=4), duodenal ulcers (n=2), duodenal AE (n=2), duodenal diverticulum (n=1). CE additionally identified normal small bowel (n=11), small bowel angioectasia (n=11), erosions (n=8), ulcers (n=2), polyps (n=2), active bleeding (n=2) and suspected small bowel varices (n=1). Pain, discomfort and distress scores for MSCE were all significantly lower than those for OGD (p  Conclusion  Both CE and OGD miss upper GI pathologies. The Mirocam Navi identifies as many upper GI pathologies as OGD in addition to small bowel pathologies as likely to contribute to IDA, without pain, discomfort or distress. This non-invasive investigative modality might reasonably be considered in patients with recurrent or refractory IDA.  Reference  . Goddard AF, et al. Guidelines for the management of iron deficiency anaemia. Gut. 2011;60(10):1309–16.  Disclosure of Interest  None Declared
Proteasome inhibitor associated cardiovascular adverse events: A real-world claims based study.
Authors: Adam Justin Waxman, Suparna Clasen, Alfred L. Garfall, Joseph R. Carver, Dan T. Vogl, Rupal O'quinn, Adam D. Cohen, Edward Allen Stadtmauer, Sean Hennessy, Bonnie Ky
Journal: Journal of Clinical Oncology (2019)

e19534 Background: Cardiovascular adverse events (CVAE) are common in patients with multiple myeloma (MM). Recent evidence suggests higher rates of CVAE occur among patients receiving carfilzomib (CFZ) compared to other MM therapies. We sought to determine the real-world relative incidence of CVAE in patients receiving CFZ and bortezomib (BTZ). Methods: We conducted a retrospective cohort study using the Optum Clinformatics Datamart. Patients with MM were included if they received BTZ or CFZ from 2012 to 2016. Exposure periods were defined as 90 days following infusion of either drug. Cardiac hospitalizations were identified using validated ICD-9 or ICD-10 code algorithms for heart failure, arrhythmia, myocardial infarction, and hypertensive urgency. Incidence rate ratios (IRR) were calculated using Poisson regression. Results: We identified 922 patients receiving CFZ and 4092 patients receiving BTZ (median age 70 and 72; median treatment duration 99 and 107 days; concurrent immunomodulatory drugs received in 28% and 25%, respectively). Unadjusted CVAE rates are summarized below. A multivariable regression model showed age (IRR 1.43, 95% CI 1.33-1.55) and male gender (IRR 1.22, 95% CI 1.07-1.40) were independent risk factors for CVAE while concurrent IMiD prescription was associated with lower risk (IRR 0.70, 95% CI 0.58-0.85). Adjusted CVAE rates were similar for patients treated with CFZ and BTZ (IRR 1.06, 95% CI 0.89-1.27). Conclusions: We found higher rates of CVAE hospitalizations than described in clinical trials. This may reflect differences in real-world treatment, patient selection patterns, or later identification of CVAE. Further study is need to identify patients at high-risk of CVAE and to develop risk reduction strategies. [Table: see text]
Phase I/Ib study of pembrolizumab and vorinostat in patients with metastatic NSCLC (mNSCLC): Updated results.
Authors: Andreas Nicholas Saltos, Tawee Tanvetyanon, Eric B. Haura, Ben C. Creelan, Scott Joseph Antonia, Michael Rahman Shafique, Hong Zheng, Wenjie Dai, Zhihua Chen, James Joseph Saller, Nishan Tchekmedyian, Kristen Goas, Ram Thapa, Theresa A. Boyle, Dung-Tsa Chen, Amer A Beg, Jhanelle Elaine Gray
Journal: Journal of Clinical Oncology (2019)

9073 Background: Histone deacetylase inhibitors (HDACi) enhance tumor immunogenicity through several mechanisms and may augment response to immune checkpoint inhibitors (ICI). We report updated results from a phase I/Ib trial testing the combination of oral HDACi vorinostat (V) with PD-1 inhibitor pembrolizumab (P) in mNSCLC. Methods: In phase I, pts with ICI-naïve or ICI-pretreated mNSCLC were treated with P (200mg IV q3 wk) + V (200 or 400 mg PO daily). In phase Ib expansion, pts were required to have progressed on prior ICI treatment. Primary endpoints were safety/tolerability; secondary endpoints included RR, PFS, DOR, and OS. Tissue and blood specimens from pre- and on-treatment were collected for correlative analyses to determine tumor gene expression changes, T cell density and levels of myeloid-derived suppressor cells. Results: Between 3/2016 - 12/2018, Phase I: 13 pts were treated (4 at 200mg, and 9 at 400mg V dose); and Phase Ib: 20 pts were treated. Median age: 68 (range 38-82); Females: 11 (33%); ECOG 1: 31 (94%); and never/former/current smokers: 3/22/8 (9%/67%/24%). PD-L1 expression was &lt; 1% in 8/33 (18%), ≥1-49% in 7/33 (21%), ≥ 50% in 9/33 (27%) and unknown in 11/30 (33%). No DLTs or treatment related deaths were observed. The RP2D was P 200mg and V 400mg. Most common any grade AEs was fatigue (11%) and nausea/vomiting (8%). 2 (6%) patients had treatment discontinued due to toxicity. 30 pts are evaluable for response, 6 ICI-naïve and 24 ICI-pretreated. 4 (13%) had PR (2 confirmed), 16 (53%) had SD, and 10 (33%) had PD for a disease control rate of 67%. In the ICI-pretreated Ib cohort, 3 pts (1 confirmed; 2 unconfirmed) had a PR and 10 had SD (8 confirmed). For ICI-pretreated pts, mPFS was 3.2 and mOS was 7.3 months, and 1-year PFS was 17% (4 pts). For ICI-naïve, mPFS was 7.6 months and mOS was 16 months. CD8 T cell presence in tumor stromal regions was associated with benefit to P + V treatment. Conclusions: P + V were well tolerated. The combination demonstrates preliminary anti-tumor activity despite progression on prior ICI treatment and stromal CD8 T cells may be associated with benefit from P + V treatment. A randomized phase II portion of this study, examining P combined with V vs. placebo in immunotherapy naïve pts, is ongoing. Clinical trial information: NCT02638090.
The Cytokine TNF Promotes Transcription Factor SREBP Activity and Binding to Inflammatory Genes to Activate Macrophages and Limit Tissue Repair
Authors: Anthony Kusnadi, Sung Ho Park, Ruoxi Yuan, Tania Pannellini, Eugenia Giannopoulou, David Oliver, Theresa Lu, Kyung-Hyun Park-Min, Lionel B. Ivashkiv
Journal: Immunity (2019)
SAT0130 Toxic psychosis related with hydroxychloroquine
Authors: P Barbosa, M França, I Almeida, F Farinha, C Vasconcelos
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Hydroxychloroquine is one of the commonest antirrheumatic drugs, being well tolerated and traditionally safe. <h3>Objectives</h3> <h3>Methods</h3> The authors report a case of a 52-year-old woman with a 8 week symmetric polyarththritis, involving the hands, feet, knees and elbows and morning stiffness lasting for more than 60 min. The rheumatoid factor was positive and the X-rays findings were normal. At the time of the first appointment she already had been treated with different NSAID without clinical improvement. Initially we tried low dose steroids only achieving a slight improvement of the patient´s complaints. At the same time, we noticed an enlarged, tender thyroid gland, presenting high T3 and T4 values, low TSH value and positive anti-thyroid antibodies. She initiated specific therapy. <h3>Results</h3> Facing a progressive polyarthritis, hydroxychloroquine was started in a 400 mg/d dose. Four weeks later the patient was referred to our out-patient clinic with the following complaints: insomnia, nervousness, incapacity of accomplish her routine daily work, and a fixed idea of general dislike towards her simultaneously with the feeling that everyone´s around was looking at her in a strange way. Hydroxychloroquine was immediately stopped and 72 h later her behaviour was back to normal. <h3>Conclusion</h3> We strongly believe that the psychiatric symptoms above were related with the hydroxychloroquine therapy.
An IgG-induced neutrophil activation pathway contributes to human drug-induced anaphylaxis
Authors: Friederike Jönsson, Luc de Chaisemartin, Vanessa Granger, Aurélie Gouel-Chéron, Caitlin M. Gillis, Qianqian Zhu, Fadia Dib, Pascale Nicaise-Roland, Christelle Ganneau, Maria Hurtado-Nedelec, Catherine Paugam-Burtz, Skander Necib, Hawa Keita-Meyer, Matthieu Le Dorze, Bernard Cholley, Olivier Langeron, Laurent Jacob, Benoit Plaud, Marc Fischler, Caroline Sauvan, Marie-Thérèse Guinnepain, Philippe Montravers, Michel Aubier, Sylvie Bay, Catherine Neukirch, Florence Tubach, Dan Longrois, Sylvie Chollet-Martin, Pierre Bruhns
Journal: Science Translational Medicine (2019)

Co-existence of drug-specific IgE and IgG antibodies aggravates neuromuscular-blocking agent-induced anaphylaxis in humans.
Impact of community based screening for hypertension on blood pressure after two years: regression discontinuity analysis in a national cohort of older adults in China
Authors: Simiao Chen, Nikkil Sudharsanan, Feng Huang, Yuanli Liu, Pascal Geldsetzer, Till Bärnighausen
Journal: BMJ (2019)

Abstract Objective To estimate the causal impact of community based blood pressure screening on subsequent blood pressure levels among older adults in China. Design Regression discontinuity analysis using data from a national cohort study. Setting 2011-12 and 2014 waves of the Chinese Longitudinal Healthy Longevity Survey, a national cohort of older adults in China. Participants 3899 older adults who had previously undiagnosed hypertension. Intervention Community based hypertension screening among older adults in 2011-12. Main outcome measure Blood pressure two years after initial screening. Results The intervention reduced systolic blood pressure: −6.3 mm Hg in the model without covariates (95% confidence interval −11.2 to −1.3) and −8.3 mm Hg (−13.6 to −3.1) in the model that adjusts additionally for demographic, social, and behavioural covariates. The impact on diastolic blood pressure was smaller and non-significant in all models. The results were similar when alternative functional forms were used to estimate the impact and the bandwidths around the intervention threshold were changed. The results did not vary by demographic and social subgroups. Conclusions Community based hypertension screening and encouraging people with raised blood pressure to seek care and adopt blood pressure lowering behaviour changes could have important long term impact on systolic blood pressure at the population level. This approach could address the high burden of cardiovascular diseases in China and other countries with large unmet need for hypertension diagnosis and care.
Adjuvant radiotherapy after primary surgical resection in patients with adrenocortical carcinoma: Retrospective cohort analysis.
Authors: Mouhammed Amir Habra, Shamim Ejaz, Lei Feng, Prajnan Das, Ferhat Deniz, Elizabeth Gardner Grubbs, Alexandria T. Phan, Steven Waguespack, Montserrat Ayala-Ramirez, Camilo Jimenez, Rena Vassilopoulou-Sellin
Journal: Journal of Clinical Oncology (2012)

4641 Background: Adrenocortical carcinoma (ACC) is a rare malignancy with high recurrence and mortality rates. The role of adjuvant radiotherapy (RT) to improve outcome remains unclear. Considering the rarity of ACC, we conducted a historical cohort study to ascertain the effect of adjuvant RT on overall survival and recurrence rates. Methods: Patients were selected from the MD Anderson Cancer Center (MDACC) ACC registry (1998- 2011) who had primary tumor resection with no evidence of distant metastasis at the time of initial diagnosis and a minimum follow-up of 6-months. The adjuvant RT group included patients who received adjuvant RT within 3 months of diagnosis. Control group included patients who did not receive RT and matched based on resection margin status and stage at diagnosis. Results: There were no significant differences between the adjuvant RT group (n=15) and comparison group (n =45) in gender distribution, age, tumor size, functional status, and use of adjuvant mitotane therapy. On multivariate Cox proportional hazard model for overall survival, the adjuvant RT group had hazard ratio of 1.981(95% confidence interval [CI] 0.894-4.391, p=0.0922) compared to the control group. The differences in median time to local recurrence, distant recurrence and of recurrence free survival were not significant between the two groups. In subgroup analysis including only the patients whose initial treatments were from outside of MDACC, RT group (n=15) had hazard ratio of overall survival of 1.604 (95% CI 0.712- 3.613, p=0.2543) compared to group without adjuvant RT (n= 32). Median times to local recurrence, distant recurrence, or of recurrence free survival were also not significantly different between the two groups. Conclusions: To our knowledge, this is the largest single institution report about adjuvant RT use in ACC. In our study, RT did not appear to cause a significant difference in overall survival, recurrence rate, or time to recurrence. However, it is still possible that patients offered adjuvant RT and control groups may have been inherently different. Hence, a prospective study is needed to clarify the role of adjuvant RT in patients with resectable ACC.
Time to next treatment in patients with previously treated cutaneous T-cell lymphoma (CTCL) receiving mogamulizumab or vorinostat: A MAVORIC post-hoc analysis.
Authors: Barbara Pro, Youn H. Kim, Pablo L. Ortiz-Romero, Lubomir Sokol, Julia Scarisbrick, Amy Musiek, Maarten Vermeer, Reinhard Dummer, Ahmad Sami Halwani, Maria Teresa Fierro, Junji Moriya, Mollie Leoni, Martine Bagot
Journal: Journal of Clinical Oncology (2019)

7539 Background: CTCLs are chronic skin malignancies, characterized by relapsing/remitting behavior and progressive resistance to treatments, with a reported median time to next treatment (TTNT; ie, systemic treatment excluding topical steroids) in mycosis fungoides (MF) and Sezary syndrome (SS) of 5.4 months (mo) (Hughes et al. Blood, 2015). The phase 3 MAVORIC study demonstrated mogamulizumab (MOGA) was superior to vorinostat (VORI) in progression-free survival (median 7.7 vs 3.1 mo, P&lt;0.0001) and confirmed overall response rates (28% vs 4.8%, P&lt;0.0001) in previously treated patients with MF/SS (Kim et al. Lancet Oncol 2018). This post-hoc analysis examines TTNT to further explore the patient clinical experience. Methods: Patients with MF/SS who were treated with ≥1 prior systemic therapy were randomized 1:1 to receive MOGA (1.0 mg/kg, administered once weekly for the first 28-day cycle, then on Days 1 and 15 of subsequent cycles) or oral VORI (400 mg daily). Patients on VORI were permitted to crossover to MOGA upon approval. TTNT was defined as time to any therapy excluding topical steroids or focal radiation. The length of TTNT was assessed overall and by disease stage grouping (IB/II and III/IV) and disease type (MF and SS). Results: Median TTNT for the full ITT population was longer with MOGA at 11 mo (95% CI, 8.8-12.6) compared to VORI at 3.5 mo and consistently longer for MOGA vs VORI across disease stage grouping or by disease type (Table). Conclusions: TTNT in MF/SS represents an additional measure of clinical benefit and disease control in patients who may have progressed based on strict protocol definitions of progression. This post hoc analysis showing a prolonged TTNT across disease stages and types supports a clinical benefit for MF and SS patients who receive MOGA. Clinical trial information: NCT01728805. [Table: see text]
Phase I study of cemiplimab, a human monoclonal antibody to programmed death (PD)-1, in Japanese patients (pts) with advanced malignancies: Results from the dose exploration.
Authors: Shigehisa Kitano, Toshio Shimizu, Takafumi Koyama, Takahiro Ebata, Satoru Iwasa, Shunsuke Kondo, Akihiko Shimomura, Yutaka Fujiwara, Noboru Yamamoto, Anne Josee Paccaly, Clifford Baum, Siyu Li, Petra Rietschel, Tasha Nicholle Sims
Journal: Journal of Clinical Oncology (2019)

33 Background: Cemiplimab (REGN2810), a high-affinity, highly potent, human monoclonal antibody to PD-1, has demonstrated a safety profile comparable with that of other anti-PD-1 antibodies and antitumor activity in various solid tumors including cutaneous squamous cell carcinoma and non-small-cell lung cancer (NSCLC) in pts outside of Japan. We present analysis of Part 1 of a two-part, multicenter, open-label, Phase 1 study of cemiplimab in Japanese pts with advanced malignancies. Methods: Part 1 dose exploration pts received either cemiplimab 250 mg (n=6) or 350 mg (n=7) Q3W IV for up to 108 weeks. Tumor measurements were performed every 9 weeks according to RECIST 1.1. Data cut-off date was July 13, 2018. Results: Thirteen pts were enrolled: median age, 62 years (range: 33–75); 8 F. Twelve (92.3%) and 7 (53.8%) pts had received prior cancer-related systemic therapy and radiotherapy, respectively. Median duration of cemiplimab exposure was 13.1 weeks (range: 3.0–54.6). At the data cut-off date Part 1 was fully enrolled and 9 pts (69.2%) had discontinued treatment, primarily due to disease progression (n=7, 53.8%). The most common treatment-emergent adverse events (TEAEs) of any grade were contact dermatitis, rash, and viral upper respiratory tract infection, each occurring in 3 pts (23.1%). The following grade ≥3 TEAEs occurred in 1 pt (7.7%): hypophosphatemia, hyponatremia, autoimmune colitis, and dehydration; the last two events occurred in the same pt. No dose-limiting toxicities were reported. Cemiplimab serum concentrations were as expected from the reported PK characteristics of cemiplimab. Objective response rate (ORR; complete response + partial response [PR]) and disease control rate (ORR + stable disease [SD]) were 23.1% (3 PR) and 53.8% (7/13; 4 SD), respectively. Conclusions: Cemiplimab exhibited substantial antitumor activity in Japanese pts with advanced malignancies. Cemiplimab 350 mg Q3W dosing regimen was selected for the expansion studies. The safety profile was comparable with those previously reported for cemiplimab and other anti-PD-1 agents. Part 2 is open and enrolling pts with NSCLC in Japan. Clinical trial information: NCT02760498.