tbuckley/cabot-search huggingface dataset:
Long-term Efficacy of Interferon-Free Antiviral Treatment Regimens in Patients With Hepatitis C Virus–Associated Cryoglobulinemia Vasculitis
Authors: Patrice Cacoub, Si Nafa Si Ahmed, Yasmina Ferfar, Stanislas Pol, Dominique Thabut, Christophe Hezode, Laurent Alric, Cloe Comarmond, Gafaar Ragab, Luca Quartuccio, Mohamed Hegazy, Thierry Poynard, Matthieu Resche Rigon, David Saadoun
Journal: Clinical Gastroenterology and Hepatology (2018)
Inappropriate Use of Steroids for Acute Respiratory Infection
Authors: Deborah Grady
Journal: JAMA Internal Medicine (2018)

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EORTC QLQ-C30 (QLQ-C30) symptoms in patients (pts) with HER2-negative metastatic breast cancer (mBC) and a germline <i>BRCA</i> mutation (g<i>BRCA</i>m) receiving olaparib vs chemotherapy treatment of physician’s choice (TPC) in OlympiAD.
Authors: Mark E. Robson, Kathryn Jean Ruddy, Seock-Ah Im, Elzbieta Senkus-Konefka, Binghe Xu, Susan M. Domchek, Norikazu Masuda, Wei Li, Nadine M. Tung, Anne Caroline Armstrong, Wendy Bannister, Carsten Dietrich Goessl, Arnold Degboe, Robert Hettle, Pier Franco Conte
Journal: Journal of Clinical Oncology (2018)

1045 Background: In the Phase III OlympiAD study, pts with HER2-negative mBC and a gBRCAm who received olaparib vs TPC showed statistically significant and clinically meaningful benefit in progression-free survival (NCT02000622; Robson et al. NEJM 2017). Global health status/quality of life also favored olaparib. This analysis reports the impact of treatment on symptoms using the QLQ-C30 questionnaire. Methods: Pts were randomized (open label) to olaparib tablet monotherapy or single-agent TPC (capecitabine, vinorelbine or eribulin). QLQ-C30, completed by patients at baseline and every 6 weeks until disease progression, evaluated three multi-item symptom scales and five single items (common cancer symptoms). Symptoms were scored on a 0 to 100 scale (higher scores indicated worse symptoms). Statistical analysis included clinically meaningful improvement (reduction in score of ≥10 points) and adjusted mean change from baseline scores. Results: Overall questionnaire compliance rates were 93.2% for olaparib and 77.3% for TPC. Improvement (symptom response) was more frequent with olaparib vs TPC for all symptoms (Table). Adjusted mean changes in pain scores (estimated difference [ED] −7.4; 95% CI −12.68, −2.03) and dyspnea scores (ED −5.8; 95% CI −10.84, −0.66) favored olaparib over TPC. An increase was seen in nausea/vomiting scores (ED 3.7; 95% CI 0.63, 6.82), despite a numerically higher proportion of pts in the olaparib arm having improvement in nausea/vomiting. Conclusions: Overall, more pts demonstrated a clinically meaningful improvement in symptom scores with olaparib than with TPC. Clinical trial information: NCT02000622.Pts (%) with clinically meaningful improvement in QLQ-C30 symptoms. Olaparib N = 205 TPC N = 97 Odds ratio* (95% CI) Fatigue† 32.7 18.6 2.16 (1.21, 4.00) Pain† 34.6 16.5 2.70 (1.50, 5.10) Nausea/vomiting† 16.6 13.4 1.30 (0.66, 2.68) Dyspnea‡ 18.0 7.2 2.85 (1.29, 7.24) Insomnia‡ 23.9 12.4 2.24 (1.16, 4.63) Appetite loss‡ 19.5 8.2 2.73 (1.28, 6.53) Constipation‡ 16.6 5.2 3.69 (1.51, 11.05) Diarrhea‡ 11.2 7.2 1.63 (0.70, 4.24) *Odds ratio > 1 favors olaparib; †multi-item; ‡single item
CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation
Authors: Pradip Bajgain, Supannikar Tawinwung, Lindsey D’Elia, Sujita Sukumaran, Norihiro Watanabe, Valentina Hoyos, Premal Lulla, Malcolm K. Brenner, Ann M. Leen, Juan F. Vera
Journal: Journal for ImmunoTherapy of Cancer (2018)

The adoptive transfer of T cells redirected to tumor via chimeric antigen receptors (CARs) has produced clinical benefits for the treatment of hematologic diseases. To extend this approach to breast cancer, we generated CAR T cells directed against mucin1 (MUC1), an aberrantly glycosylated neoantigen that is overexpressed by malignant cells and whose expression has been correlated with poor prognosis. Furthermore, to protect our tumor-targeted cells from the elevated levels of immune-inhibitory cytokines present in the tumor milieu, we co-expressed an inverted cytokine receptor linking the IL4 receptor exodomain with the IL7 receptor endodomain (4/7ICR) in order to transform the suppressive IL4 signal into one that would enhance the anti-tumor effects of our CAR T cells at the tumor site.First (1G - CD3ζ) and second generation (2G - 41BB.CD3ζ) MUC1-specific CARs were constructed using the HMFG2 scFv. Following retroviral transduction transgenic expression of the CAR±ICR was assessed by flow cytometry. In vitro CAR/ICR T cell function was measured by assessing cell proliferation and short- and long-term cytotoxic activity using MUC1+ MDA MB 468 cells as targets. In vivo anti-tumor activity was assessed using IL4-producing MDA MB 468 tumor-bearing mice using calipers to assess tumor volume and bioluminescence imaging to track T cells.In the IL4-rich tumor milieu, 1G CAR.MUC1 T cells failed to expand or kill MUC1+ tumors and while co-expression of the 4/7ICR promoted T cell expansion, in the absence of co-stimulatory signals the outgrowing cells exhibited an exhausted phenotype characterized by PD-1 and TIM3 upregulation and failed to control tumor growth. However, by co-expressing 2G CAR.MUC1 (signal 1 - activation + signal 2 - co-stimulation) and 4/7ICR (signal 3 - cytokine), transgenic T cells selectively expanded at the tumor site and produced potent and durable tumor control in vitro and in vivo.Our findings demonstrate the feasibility of targeting breast cancer using transgenic T cells equipped to thrive in the suppressive tumor milieu and highlight the importance of providing transgenic T cells with signals that recapitulate physiologic TCR signaling - [activation (signal 1), co-stimulation (signal 2) and cytokine support (signal 3)] - to promote in vivo persistence and memory formation.
POSITIVE (IBCSG 48-14/BIG 8-13/A221405): Evaluating outcomes after interrupting endocrine therapy (ET) for women with endocrine responsive (ER+) early breast cancer (BC) who desire pregnancy.
Authors: Ann H. Partridge, Olivia Pagani, Hatem A. Azim, Fedro Peccatori, Monica Ruggeri, Meredith M. Regan, Richard D. Gelber, Zhuoxin Sun
Journal: Journal of Clinical Oncology (2018)

TPS596 Background: Retrospective evidence suggests that pregnancy after BC does not negatively impact disease outcomes in pts with ER+ BC and is safe for the offspring. Young BC pts are often diagnosed before completing family planning, and cannot wait 5-10 yrs to complete ET before attempting pregnancy. Thus, prospectively evaluating the safety of temporary interruption of ET to allow conception is an unmet, patient-oriented, medical need. Methods: Young pts with ER+ early BC who desire pregnancy interrupt ET for approximately 2 yrs to attempt pregnancy [treatment wash-out (3 mos), and, ideally, conception (~3-6 mos), delivery (~9 mos), breast feeding if feasible (~6 mos)]. Pts are advised to resume ET as soon as child-bearing is completed to finish 5-10 yrs ET. Major eligibility requirements: pt wishes to become pregnant; histologically-proven stage I-III ER+ BC; age ≥ 18 and ≤ 42 yrs; prior adjuvant ET for ≥18 mos but ≤30 mos; premenopausal status at BC diagnosis. With 500 pts enrolled and followed for a median of 3 yrs, the statistical design is based on the 95% CI for the 3 yr BC recurrence rate; interim monitoring assumes a 2% BC recurrence risk/yr with continuous ET and high chance to stop early if the BC risk exceeds 4%/yr with ET interruption. Translational research will evaluate aspects related to fertility, pregnancy and BC biology. The Psycho-oncological Companion Study (POCS) explores psychological distress, fertility concerns and decisional conflicts (mandatory in the US and open to interested centers elsewhere), with a target accrual of 200. More than 170 participating centers in 20 countries: USA/Alliance, Canada/CCTG, Switzerland/SAKK, Italy, Belgium, Spain/SOLTI/GEICAM, Slovenia, Japan/JBCRG, Norway/NBCG, Netherlands/BOOG, Ireland/CTI, Portugal/SOLTI, Australia, Israel, Greece/HORG, Hungary, South Korea, Serbia, Austria/ABCSG and France. Eligible sites can open POSITIVE through NCTN (Alliance) or IBCSG, and referral to participating centers of eligible pts on ET who are interested in having a pregnancy after BC is strongly encouraged. Current Accrual (13 Feb 2018): 205 main study; 114 POCS. Clinical trial information: NCT02308085.
Author Correction: Cytotoxic and regulatory roles of mucosal-associated invariant T cells in type 1 diabetes
Authors: Ophélie Rouxel, Jennifer DaSilva, Lucie Beaudoin, Isabelle Nel, Céline Tard, Lucie Cagninacci, Badr Kiaf, Masaya Oshima, Marc Diedisheim, Marion Salou, Alexandra Corbett, Jamie Rossjohn, James McCluskey, Raphael Scharfmann, Manuela Battaglia, Michel Polak, Olivier Lantz, Jacques Beltrand, Agnès Lehuen
Journal: Nature Immunology (2018)
Increased Risk of Herpes Zoster Infection in Patients With Inflammatory Bowel Diseases in Korea
Authors: Kiju Chang, Ho-Su Lee, Ye-Jee Kim, Seon-Ok Kim, Sung-Han Kim, Sun-Ho Lee, Eun Mi Song, Sung Wook Hwang, Sang Hyoung Park, Dong-Hoon Yang, Byong Duk Ye, Jeong-Sik Byeon, Seung-Jae Myung, Suk-Kyun Yang
Journal: Clinical Gastroenterology and Hepatology (2018)

Few data are available on risk of herpes zoster (HZ) infection in Asian patients with inflammatory bowel diseases (IBD). We investigated whether patients with IBD in Korea have an increased risk of HZ and sought to identify risk factors for infection.We performed a nationwide population-based study and a hospital-based, nested case-control study. Using the 2009-2013 data from the Korean national health insurance claims database, we calculated incidence rates and standardized incidence ratios (SIRs) of HZ infection in patients with IBD compared with the entire Korean population. In the nested case-control study, within a hospital-based cohort, 300 patients with IBD and HZ infection were matched with 895 patients with IBD without HZ.In the nationwide population-based study, the incidence rate and SIR of HZ infection in patients with IBD were 18.34/1000 person-years and 1.48 (95% CI, 1.42-1.54), respectively. The SIR for HZ infection was higher in patients with Crohn's disease than in patients with ulcerative colitis (1.90 vs 1.36; P < .001) and higher in male patients than female patients (1.63 vs 1.33; P < .001). The incidence rate of HZ increased with age (P trend < .001), whereas the SIR of HZ infection decreased with age (P trend < .001). In the nested case-control study, corticosteroid use was associated with HZ infection (for ulcerative colitis, adjusted odds ratio, 2.44; 95% CI, 1.18-5.05 and for Crohn's disease, adjusted odds ratio, 2.70; 95% CI 1.25-5.83).In a population-based study in Korea, we found patients with IBD to have an increased risk for HZ infection-especially among patients who are male, younger, or have Crohn's disease. Corticosteroid use increases risk of HZ infection in patients with IBD.
Dysregulation of the “inflammatory reflex” with abnormal neurohumoral activation may contribute to proinflammatory activity driving the progression of COPD
Authors: Fabrizio Ricci, Per Wollmer, Gunnar Engström, Artur Fedorowski, Viktor Hamrefors
Journal: European Respiratory Journal (2018)

We would like to thank S. Andreas for his interest in our study [1] and for the interesting comments. We agree with the insightful reasoning that subtle neurohormonal activation may be one of the explanations underlying the longitudinal association between subtle signs of cardiovascular autonomic dysfunction and higher risk of chronic obstructive pulmonary disease (COPD). In parallel to the findings in heart failure [2] and COPD [3], manifest clinical entities of cardiovascular autonomic dysfunction, such as orthostatic hypotension [4, 5] and postural orthostatic tachycardia syndrome [6], are all associated with clear signs of neurohormonal activation and inflammatory activation playing in the background. Dysregulation of the "inflammatory reflex" with abnormal neurohumoral activation may contribute to proinflammatory activity driving the progression of COPD <http://ow.ly/e9xx30k4kCk>
Sustained release of targeted cardiac therapy with a replenishable implanted epicardial reservoir
Authors: William Whyte, Ellen T. Roche, Claudia E. Varela, Keegan Mendez, Shahrin Islam, Hugh O’Neill, Fiona Weafer, Reyhaneh Neghabat Shirazi, James C. Weaver, Nikolay V. Vasilyev, Peter E. McHugh, Bruce Murphy, Garry P. Duffy, Conor J. Walsh, David J. Mooney
Journal: Nature Biomedical Engineering (2018)
Inhibitory effect of TGFβ receptor inhibitor, SB-431542, on the lymph node metastasis of gastric cancer
Authors: Osamu Shinto, Masakazu Yashiro, Takafumi Nishii, Hidemi Kawajiri, Nobuya Yamada, Bunzo Nakata, Tetsuji Sawada, Masaichi Ohira, Kosei Hirakawa
Journal: Cancer Research (2008)

4884  Background: Human gastric cancer is characterized by a rapid progressive invasion and a high frequency of metastasis to lymph nodes. Lymph node metastasis is an important prognostic indication for patient outcome. Transforming growth factor-s (TGFs) is closely associated with the cancer cell infiltration and metastases. TGFs acts through the TGFs receptor (TGFs-R) type I and type II to Smad families. The aim of the current study is to clarify the effect of TGFs-R phosphorylation inhibitor with the anti-cancer drugs on the lymph node metastasis of human gastric cancer.  Materials and Methods:TGFs-R inhibitor, SB-431542, inhibits phosphorylation of Smad2 of an ATP binding site of TGFs-R. Human gastric cancer cell line, OCUM-2MLN, was used in this study. The effect of TGFs or SB-431542 on the morphology was examined by a phase-contrast microscopy. In vivo gastric carcinoma models by orthotopic inoculation of OCUM-2MLN cells showed diffusely infiltrating adenocarcinoma in the stomach and developed lymph node metastasis. Four days after, SB-431542 and/or S-1 (Tegafur) was administered orally 5 times per week. We divided these mice into 4 groups, including control group, SB-431542 treated group, S-1 treated group, or SB-431542 and S-1 combination group. Mice were sacrificed 4 weeks after inoculation, and tumor size, lymphatic involvement and lymph nodes metastasis were examined.  Results: TGFs induced the epithelial to mesenchymaltransition (EMT) of OCUM-2MLN cells, EMT was inhibited by SB-431542. SB-431542 decreased Smad2/Smad3 phosphorylation. In vivo tumor size in the stomach was decreased in SB-431542 treated group, a S-1 treated group, compared to the control group. In addition, combined administration of SB-431542 and S-1 decreased lymphatic involvement and lymph node metastasis more effectively than either alone.  Conclusion: TGFs-R phosphorylation inhibitor, SB-431542, is useful for the treatment of lymph node metastasis of human gastric cancer in combination with anticancer agent.
Abstract 17780: Influence of Cardiac Catheterization and Automated Implantable Cardioverter Defibrillator Placement on Long-Term Cause of Death in Cardiac Arrest Patients Discharged From the Hospital
Authors: Patrick J Coppler, David J Wallace, Cameron Dezfulian, Jon C Rittenberger, Clifton W Callaway, Jonathan Elmer
Journal: Circulation (2016)

Introduction: We and others have associated cardiac catheterization (cath) and cardioverter-defibrillator (AICD) implantation with improved long-term survival after cardiac arrest. It is unclear if...
The clinical utility of <i>ERBB2</i> amplification detection in breast carcinoma using a 341 gene hybrid capture-based next generation sequencing (NGS) assay: Comparison with standard immunohistochemistry (IHC) and Fluorescence In Situ Hybridization (FISH) assays.
Authors: Dara S. Ross, Ahmet Zehir, Donavan T. Cheng, Khedoudja Nafa, George Jour, Pedram Razavi, David Michael Hyman, Jose Baselga, Michael F. Berger, Marc Ladanyi, Maria E. Arcila
Journal: Journal of Clinical Oncology (2015)

604 Background: Approximately 15-20% of invasive breast carcinomas (BCA) show HER2/ERBB2 gene amplification which determines eligibility for treatment by targeted therapy. Traditionally, HER2 status is determined by IHC and FISH. NGS methods can be used to assess HER2 status in clinical practice but concordance with IHC/FISH is not well established. We report our experience using NGS for the assessment of HER2 amplification in conjunction with the detection of potentially targetable mutations. Methods: BCA samples ( > 10% tumor) were analyzed in a CLIA-certified lab using a hybrid capture-based NGS assay (“MSK-IMPACT”) designed to detect somatic genetic alterations in 341 genes, including copy number alterations. Tumor percentage and concurrent IHC/FISH results were recorded (using ASCO/CAP 2013 guidelines). Criteria for amplification by NGS were defined as a fold change (FC) ≥ 2, p-value < 0.05. Results: A total of 133 BCA samples (63 primaries, 70 mets) were analyzed. Compared to the combined IHC/FISH methodology, ERBB2 amplification status by NGS had an overall concordance of 97% (129/133) (sensitivity = 82%, specificity = 100%, PPV = 100%). Discordant cases showed low tumor purity, heterogeneous IHC staining, and/or low level amplification by FISH. One sample status post trastuzumab was negative by IHC but ERBB2 amplified by FISH (ratio 4.0) and NGS (FC 2.3). The assay also uncovered somatic alterations in 133 cancer genes including TP53, PIK3CA, CDH1 and ESR1. ER and PR IHC results were available for 94 cases; 1/13 triple negative cases showed an actionable PIK3CA E542K mutation. Of the 22 ERBB2 amplified cases, 6 had actionable PIK3CA mutations (H1047R or E545K); 4/6 were metastatic lesions in patients previously treated with trastuzumab. Conclusions: HER2 status can be reliably determined by hybrid capture NGS methods and allows the concurrent testing for other potentially actionable genomic alterations, particularly in limited material. Samples with low tumor content, heterogeneity and low level amplification may result in false negatives.
<i>MACROD2</i> Haploinsufficiency Impairs Catalytic Activity of PARP1 and Promotes Chromosome Instability and Growth of Intestinal Tumors
Authors: Anuratha Sakthianandeswaren, Marie J. Parsons, Dmitri Mouradov, Ruth N. MacKinnon, Bruno Catimel, Sheng Liu, Michelle Palmieri, Christopher Love, Robert N. Jorissen, Shan Li, Lachlan Whitehead, Tracy L. Putoczki, Adele Preaudet, Cary Tsui, Cameron J. Nowell, Robyn L. Ward, Nicholas J. Hawkins, Jayesh Desai, Peter Gibbs, Matthias Ernst, Ian Street, Michael Buchert, Oliver M. Sieber
Journal: Cancer Discovery (2018)

ADP-ribosylation is an important posttranslational protein modification that regulates diverse biological processes, controlled by dedicated transferases and hydrolases. Here, we show that frequent deletions (∼30%) of the
Survivorship care delivery: From a consultative clinic to an integrative program based on patient outcome and resource analyses.
Authors: Kevin Schreffler, Carol DelCampo, Dawn Hayes, Donna L. Meyer, Bryan Miller, Amy Sickles, Mildred Jones, Hiba Tamim
Journal: Journal of Clinical Oncology (2018)

37 Background: Delivery of survivorship care plan (SCP) using a multidisciplinary approach is optimal (Hewitt et al., 2006). However, many institutions experience implementation barriers (Dulko et al., 2013). The pilot study aim compared the effectiveness of two SCP delivery methods (extended vs. brief) on self-reported confidence in disease management (breast cancer). Secondary aim evaluated timeliness and patient/provider burden. Methods: Quasi-experimental pre- and post-survey design with control group (brief explanation/ delivery of SCP) and treatment group (comprehensive consultative visit). Pretesting included distress screening and self-efficacy survey. Post-testing included self-efficacy survey, tracking of referral activity, and patient satisfaction. Time study data and process mapping were included. Descriptive data analyses and Mixed ANOVA; significance set p &lt; .05. Results: 73 eligible patients identified (age 61.93 ±11.6 years), 36 completing pre/post testing, and 62% declined consultative visit. At pre-testing, 45% rated distress &gt; 3 [emotional (58%), physical (50%), nutritional (30%)]. Post-testing showed 94% compliance with support service referral(s). 89% felt understanding improved, 66% found SCP helpful, 59% said SCP prepared them for transition, and 77% were satisfied. Time main effect was significant for self-efficacy, Wilks Lambda = .89, F (1,34) = 4.2, p = .048. Follow-up paired-samples t-test showed significant improvement in consultative group, t (21) = -2.56, p = .018. Group differences not significant, but both groups demonstrated positive change (7% consultative; 4% control). Time study data revealed overall time spent per patient was 3.7 hours for consultative group vs. 2.2 hours for control group. New process change to integrative model reduced time by 65%. Conclusions: Both SCP delivery methods demonstrated improved patient confidence in managing disease and positive satisfaction. However, the extended visit did not yield outcomes justifying the increased program cost and resource. The pilot fostered a multidisciplinary approach to SCP delivery and yielded a process for improved timeliness and optimal delivery model.