tbuckley/cabot-search huggingface dataset:
Sipuleucel-T (sip-T) induced lytic CD8+ T cell responses to target antigens in men with hormone-sensitive and castration-resistant prostate cancer (CRPC).
Authors: Emmanuel S. Antonarakis, David I. Quinn, Adam S. Kibel, Daniel Peter Petrylak, Tuyen Vu, Dwayne Campogan, Nancy N. Chang, James B. Trager, Nadeem Anwar Sheikh, Charles G. Drake
Journal: Journal of Clinical Oncology (2017)

162 Background: Sip-T is an FDA-approved immunotherapy for patients (pts) with asymptomatic or minimally symptomatic metastatic CRPC. Sip-T is manufactured from autologous peripheral blood mononuclear cells cultured with the immunogen PA2024, a fusion antigen of prostatic acid phosphatase (PAP) conjugated to granulocyte macrophage colony-stimulating factor. After sip-T, antibody and T cell responses to PA2024 and/or PAP correlate with improved survival. To further elucidate the mechanism of sip-T–induced immune responses, we evaluated the proliferative and lytic ability of PA2024- and PAP-specific CD8+ T cells. Methods: Mononuclear blood cells were labeled with the membrane dye carboxyfluorescein succinimidyl ester (CFSE) and cultured with PA2024 or PAP. In vitro proliferative and lytic CD8+ (cytotoxic T lymphocyte [CTL]) T cell responses to these antigens were evaluated by flow cytometry. For proliferation, progressive dilution of CFSE was measured. For CTL activity, the loss of intracellular granzyme B (GzB), indicating exocytosis of this apoptosis-mediating enzyme, was assessed. Samples were from 2 sip-T clinical trials STAND (NCT01431391) and STRIDE (NCT01981122), hormone-sensitive and CRPC pts, respectively. Results: Six wk after sip-T administration, CD8+ PAP- and PA2024-specific responses were observed (n=14 pts assessed). The magnitude of PA2024-specific CD8+ proliferative responses was greater than that for PAP-specific responses. CD8+ T cells from a subset of pts who exhibited PA2024- and/or PAP-specific proliferative responses were assessed for lytic ability. After in vitro antigen stimulation, CTL activity in all evaluated samples (n=14, PA2024; n=13, PAP) was demonstrated by a significant decrease (p&lt;0.05) in intracellular GzB relative to a no-antigen control. Conclusions: Sip-T induced CD8+ CTL proliferation against the target antigens PAP and PA2024. Moreover, antigen-specific CTL activity provides the first direct evidence that sip-T can induce tumor cell lysis. These antigen-specific CD8+ lytic abilities were observed within 6 wk following sip-T, suggesting rapidly generated immune responses. Clinical trial information: NCT01431391; NCT01981122.
Assessing the Malignant Ventricular Arrhythmic Substrate in Patients With Brugada Syndrome
Authors: Carlo Pappone, Giuseppe Ciconte, Francesco Manguso, Gabriele Vicedomini, Valerio Mecarocci, Manuel Conti, Luigi Giannelli, Paolo Pozzi, Valeria Borrelli, Lorenzo Menicanti, Zarko Calovic, Giuseppe Della Ratta, Josep Brugada, Vincenzo Santinelli
Journal: Journal of the American College of Cardiology (2018)

Guidelines recommend the use of implanted cardioverter-defibrillators in patients with Brugada syndrome and induced ventricular tachyarrhythmias, but there is no evidence supporting it. This prospective registry study was designed to explore clinical and electrophysiological predictors of malignant ventricular tachyarrhythmia inducibility in Brugada syndrome. A total of 191 consecutive selected patients with (group 1; n = 88) and without (group 2; n = 103) Brugada syndrome–related symptoms were prospectively enrolled in the registry. Patients underwent electrophysiological study and substrate mapping or ablation before and after ajmaline testing (1 mg/kg/5 min). Overall, before ajmaline testing, 53.4% of patients had ventricular tachyarrhythmia inducibility, which was more frequent in group 1 (65.9%) than in group 2 (42.7%; p < 0.001). Regardless of clinical presentation, larger substrates with more fragmented long-duration ventricular potentials were found in patients with inducible arrhythmias than in patients without inducible arrhythmias (p < 0.001). One extrastimulus was used in more extensive substrates (median 13 cm2; p < 0.001), and ventricular fibrillation was the more frequently induced rhythm (p < 0.001). After ajmaline, patients without arrhythmia inducibility had arrhythmia inducibility without a difference in substrate characteristics between the 2 groups. The substrate size was the only independent predictor of inducibility (odds ratio: 4.51; 95% confidence interval: 2.51 to 8.09; p < 0.001). A substrate size of 4 cm2 best identified patients with inducible arrhythmias (area under the curve: 0.98; p < 0.001). Substrate ablation prevented ventricular tachyarrhythmia reinducibility. In Brugada syndrome dynamic substrate variability represents the pathophysiological basis of lethal ventricular tachyarrhythmias. Substrate size is independently associated with arrhythmia inducibility, and its determination after ajmaline identifies high-risk patients missed by clinical criteria. Substrate ablation is associated with electrocardiogram normalization and not arrhythmia reinducibility. (Epicardial Ablation in Brugada Syndrome [BRUGADA_I]; NCT02641431; Epicardial Ablation in Brugada Syndrome: An Extension Study of 200 BrS Patients; NCT03106701)
Resistance Mechanisms to Targeted Therapies in <i>ROS1</i>+ and <i>ALK</i>+ Non–small Cell Lung Cancer
Authors: Caroline E. McCoach, Anh T. Le, Katherine Gowan, Kenneth Jones, Laura Schubert, Andrea Doak, Adriana Estrada-Bernal, Kurtis D. Davies, Daniel T. Merrick, Paul A. Bunn, W. Tom Purcell, Rafal Dziadziuszko, Marileila Varella-Garcia, Dara L. Aisner, D. Ross Camidge, Robert C. Doebele
Journal: Clinical Cancer Research (2018)

Abstract Purpose: Despite initial benefit from tyrosine kinase inhibitors (TKIs), patients with advanced non–small cell lung cancer (NSCLC) harboring ALK (ALK+) and ROS1 (ROS1+) gene fusions ultimately progress. Here, we report on the potential resistance mechanisms in a series of patients with ALK+ and ROS1+ NSCLC progressing on different types and/or lines of ROS1/ALK–targeted therapy. Experimental Design: We used a combination of next-generation sequencing (NGS), multiplex mutation assay, direct DNA sequencing, RT-PCR, and FISH to identify fusion variants/partners and copy-number gain (CNG), kinase domain mutations (KDM), and copy-number variations (CNVs) in other cancer-related genes. We performed testing on 12 ROS1+ and 43 ALK+ patients. Results: One of 12 ROS1+ (8%) and 15 of 43 (35%) ALK+ patients harbored KDM. In the ROS1+ cohort, we identified KIT and β-catenin mutations and HER2-mediated bypass signaling as non-ROS1–dominant resistance mechanisms. In the ALK+ cohort, we identified a novel NRG1 gene fusion, a RET fusion, 2 EGFR, and 3 KRAS mutations, as well as mutations in IDH1, RIT1, NOTCH, and NF1. In addition, we identified CNV in multiple proto-oncogenes genes including PDGFRA, KIT, KDR, GNAS, K/HRAS, RET, NTRK1, MAP2K1, and others. Conclusions: We identified a putative TKI resistance mechanism in six of 12 (50%) ROS1+ patients and 37 of 43 (86%) ALK+ patients. Our data suggest that a focus on KDMs will miss most resistance mechanisms; broader gene testing strategies and functional validation is warranted to devise new therapeutic strategies for drug resistance. Clin Cancer Res; 24(14); 3334–47. ©2018 AACR.
Patients’ preferences for 3 months versus 6 months of adjuvant chemotherapy (ACT) for colon cancer in the SCOT trial: what survival benefits make longer chemotherapy worthwhile?
Authors: Prunella Louise Blinman, Andrew James Martin, Michael Jefford, David Goldstein, David Boadle, Michelle Frances Morris, Niall C. Tebbutt, Christine Aiken, James Paul, Eva Segelov, Andrew Mark Haydon, Tim Iveson, Martin R. Stockler
Journal: Journal of Clinical Oncology (2018)

3602 Background: The optimal duration of ACT following surgery for colon cancer remains controversial. SCOT is an international, randomised trial that compared 3 months versus 6 months of ACT in this setting. We sought the survival benefits that patients participating in SCOT judged necessary to make extra 3 months of ACT worthwhile. Methods: SCOT participants from Australia & New Zealand completed a validated questionnaire 3 and 18 months after randomisation to elicit the minimum survival benefit each participant judged necessary to make it worthwhile having ACT for 6 months rather than 3 months. Standardised hypothetical scenarios used the following baseline survivals with 3 months of ACT: life expectancies (LE) of 5 years (5Y) and 15 years (15Y), and 5-year survival rates (5YS) of 65% and 85%. Comparisons were non-parametric, 2-sided, and considered statistically significant if p < 0.05. Results: Questionnaires were completed by 160 participants, 82 allocated 3 months ACT, and 78 allocated 6 months ACT. ACT was FOLFOX in 121 (75%), XELOX in 39 (25%), and the mean age was 64. Preferences varied substantially among participants, and did not differ according to the randomly allocated treatment group. The median survival benefits judged necessary to make the extra 3 months of ACT worthwhile were an extra: 3 years beyond a LE of 5Y; 3 years beyond a LE of 15Y; 15% beyond a 65% 5YS; and 5% beyond an 85% 5YS. Preferences were similar at 3 months and 18 months. Participants with symptomatic peripheral neuropathy (132, 82%) judged a median benefit of an extra 5% beyond a 65% 5YS necessary to warrant their symptoms. Conclusions: Participants’ preferences varied substantially, and many judged much larger benefits needed to warrant having ACT for 6 months rather than 3 months than the estimates of the benefits based on the IDEA meta-analysis.
Efficacy of PD-1 &amp; PD-L1 inhibitors in older adults: a meta-analysis
Authors: Rawad Elias, Anita Giobbie-Hurder, Nadine Jackson McCleary, Patrick Ott, F. Stephen Hodi, Osama Rahma
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged ≥65&nbsp;years. <h3>Methods</h3> We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65&nbsp;years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/mixed effects (RE) models to allow for heterogeneity between the studies. <h3>Results</h3> Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta-analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random-effects HR for death was 0.64 with 95% CI of 0.54–0.76 in patients ≥65&nbsp;years vs. 0.68 with 95% CI of 0.61–0.75 in patients &lt; 65&nbsp;years. The overall estimated random-effects for HR for progression was 0.74 with 95% CI of 0.60–0.92 in patients ≥65&nbsp;years vs. 0.73 with 95% CI of 0.61–0.88 in patients &lt; 65&nbsp;years. <h3>Conclusions</h3> PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs ≥ 65&nbsp;years.
Abstract 222: Public Access Defibrillation Programs with Automated External Defibrillators Need Targeted Cardiopulmonary Resuscitation Training: Lessons from a Local Japanese City Database
Authors: Kenji Hayashi, Sho Nachi, Hiroaki Ushikoshi, Noriaki Yamada, Soichiro Nagaya, Hidemi Kanada, Takahiro Yoshida, Izumi Toyoda, Shinji Ogura
Journal: Circulation (2011)

Background: Public access defibrillation (PAD) with automated external defibrillator (AED) is well known as a common and good implication in the public location for out of hospital cardiac arrests (OHCAs). In Japan, AED is being implemented in public and residential space, and could be used by bystander since July 2004. PAD may improve survival from sudden OHCA, however, the effect for OHCA in a local Japanese city outcome and characteristics remains unclear. Here we examined to identify the clinical outcome, prevalence and problem of PAD five years later since 2004. Methods and Results: We studied 836 OHCAs in Gifu city between 2009 and 2010 using Gifu city emergency medical service database. Of these, only 42 (5.02%) were attached with AED (male 25 (mean 67.5 year-old), female 17 (mean 88.7 year-old)). After written informed consent was obtained, we interviewed and characterized bystanders. Location of OHCA were nursing home (n=27 (64.3%)), prison (n=6 (14.3%)), sports institution (n=3 (7.2%)), public space (n=3 (7.2%)), and others (shopping mall, hotel, and office). The incidence in nursing home was significantly older than other group (86.7 vs. 56.9 year-old) (p &lt; 0.01). Bystander cardiopulmonary resuscitation (CPR) was performed 36 (86%) with 50% witnessed. AED records showed the incidence of ventricular fibrillation was 26% (n=11), and asystole was 52%. Eight patients were shock delivered and eleven patients got return of spontaneous circulation by CPR and AED. The one month survival rate after OHCA was 14% (n=6). Lay rescuers were almost staff of the institution (n=38 (90%)) and the rate of health care provider (HCP) was 33% (n=14). We obtained and analyzed the data of 22 bystanders (including HCP (n=3)). Twenty one bystanders participated in any CPR training (non AHA program) within five years and the half of them within one year. However 18 (81.8%) bystanders had some difficulty and environmental stress in practical AED use as a PAD program. Conclusions: PAD with AED need to be more appropriately education and implementation with constant PAD program including targeted CPR training, such as AHA program.
Fluoroscopy-guided peroral endoscopic myotomy for sigmoid-type achalasia
Authors: In Yoo, Joo Cho, Sang Choi, Won Kim, Ki Hahm, Sung Hong
Journal: Endoscopy (2018)

A 28-year-old man was referred to hospital with dysphagia, a symptom that had persisted for 10 years. He had recently been admitted to another clinic for aspiration pneumonia before being referred to our hospital. Gastroscopy showed a tightened esophagogastric junction (EGJ).
What readers thought about <i>The BMJ</i> ’s articles on assisted dying
Authors: Birte Twisselmann
Journal: BMJ (2018)

The strongest argument against assisted dying, among more than 90 responses from readers to our recent cluster of articles (bmj.com/content/assisted-dying), was that under no circumstances should doctors intentionally kill patients. Eunice Minford, consultant surgeon in Northern Ireland, quoted Elizabeth Butler-Sloss: “The law . . . rests on the principle that we do not involve ourselves in deliberately bringing about the deaths of others. Once we start making exceptions based on arbitrary criteria such as terminal illness, the frontier becomes just a line in the sand, easily crossed and hard to defend.”1

Assisted suicide might also be open to abuse, some readers thought. Barry Cullen, retired GP from Fareham, Hampshire, asked, “Would there be the same level of support for physician assisted suicide if it were introduced as a cheaper alternative to palliative care in an NHS already starved of resources?”2 …
An analysis of the National Cancer Database (NCDB): Immunotherapy and survival in stage III melanoma.
Authors: Mridula Krishnan, Aabra Ahmed, Nabin Khanal, Peter T. Silberstein
Journal: Journal of Clinical Oncology (2017)

159 Background: High dose Interferon (IFN) was the standard adjuvant treatment used for stage III melanoma between 2004-2010. To our knowledge, this is the largest study using the NCDB to determine the impact of immunotherapy used prior to 2011 in stage III melanoma. Methods: We identified 19,864 patients with stage III melanoma between 2004-2010. Among these, 5,406 of them received immunotherapy. Chi-square analysis was used to determine demographic differences between those with versus without immunotherapy. Between-therapy survival differences were estimated by the Kaplan-Meier method and associated log-rank tests; Tukey-Kramer adjusted p &lt; 0.05 indicated statistical significance. Results: Patients who received immunotherapy had a mean survival of 89.8 months while those who did not had a mean survival of 71 months. The percentage of patients alive at 5 and 10 years was 62% and 52% (among those who received immunotherapy) compared to 46% and 32% (among those who did not receive immunotherapy) respectively. A much higher percentage of these patients were privately insured (73% vs. 47.1%, p&lt;0.001). Those who received immunotherapy were more likely to be younger, have a higher income (36.2% vs. 34.8%, p&lt;0.001), and a greater percentage of females received immunotherapy compared to males. (See Table 1.) Conclusions: Previously, Kirkwood et al. demonstrated a modest improvement in overall survival with IFN by 12 months (2.8 to 3.8 years). In our study, patients who received immunotherapy had a significant improvement in mean survival by 19 months. It was observed that patients who received immunotherapy were substantially younger, had private insurance and fewer comorbidities. [Table: see text]
Correlation between strength of T-cell response against HPV16 and survival after vaccination with HPV16 long peptides in combination with chemotherapy for late-stage cervical cancer.
Authors: Cornelis Joseph Melief, Winald R. Gerritsen, Marij Welters, Ignace Vergote, Judith R. Kroep, Gemma Kenter, P. B. Ottevanger, Wiebren Age Tjalma, Hannelore Denys, Hans Nijman, Mariette IE van Poelgeest, An K.L Reyners, Thierry J. Velu, Brent A. Blumenstein, Frederic Goffin, Roy Iqbal Lalisang, Richard B. Stead, Sjoerd van der Burg
Journal: Journal of Clinical Oncology (2017)

140 Background: Therapeutic vaccination with HPV type 16 synthetic long peptides (HPV16-SLP) results in T cell–mediated regression of HPV16-induced premalignant lesions but fails to install effective immunity in patients with advanced HPV16-positive cervical cancer. We showed that HPV16-SLP vaccination in mice and in patients with advanced cervical cancer patients fosters robust HPV16-specific T cell responses, when combined with chemotherapy. In this study we noted that a single dose of vaccine 2 weeks into the 2nd cycle of chemotherapy was optimal, because at this time the immunosuppressive myeloid cells were down. Methods: We now completed a chemo-immunotherapy study in a larger number of patients with late stage HPV16+ cervical cancer. Three HPV16-SLP vaccine doses were given 2 weeks after the second, third, and fourth cycles of standard chemotherapy. Cohorts of 12 patients each were vaccinated with each of 4 dose levels (20, 40, 100, and 300 µg/ per peptide) of 13 overlapping HPV16 synthetic long peptides (HPV16-SLP) together covering the length of the 2 E6 and E7 proteins. Results: Robust vaccine-induced HPV16-specific T cell responses as assessed by interferon-g Elispot were observed and were sustained throughout the cycles of chemotherapy. These T cell responses were substantially increased in all patients who received HPV16-SLP . In addition, the chemotherapy augmented recall responses to microbial antigens. Such robust T cell responses were not noted in previous trials when similar patients were vaccinated without timing of vaccination during chemotherapy. A marked correlation was observed between the strength of the vaccine-induced immune response and longer-term clinical outcomes such as overall survival. No such correlation exists between the strength of the T cell response against common recall antigens and survival. In addition, a remarkably high proportion of patients survived beyond 20 months after the start of therapy. Conclusions: These results indicate that the survival advantage is specifically related to the strength of the vaccine-induced T cell response and is not due to generally better immuno-competence. Clinical trial information: NCT02128126.
Ezetimibe
Authors: William G. Herrington, David Preiss, Jane Armitage
Journal: Circulation (2018)

MPROVE-IT (Improved Reduction of Outcomes: Vytorin Efficacy InternationalTrial), conducted in 18 144 participants who had recently experienced an acute coronary syndrome, demonstrated that the addition of ezetimibe 10 mg to simvastatin 40 mg, both taken daily, reduced low-density lipoprotein (LDL) cholesterol by an additional 16 mg/dL in comparison with placebo added to simvastatin 40 mg daily.This led to a 6% proportional reduction in the risk of the primary cardiovascular outcome (a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization, or nonfatal stroke) over 6 years (hazard ratio, 0.94; 95% confidence interval, 0.89-0.99;P=0.016). 1 It is well established from statin trials that the relative cardiovascular benefit of LDL cholesterol lowering is proportional to the absolute LDL cholesterol reduction, 2 and the additional vascular benefit afforded by adding ezetimibe to a statin-based regime in IMPROVE-IT was entirely consistent with this observation. 1,2n this issue of Circulation, the IMPROVE-IT investigators present exploratory analyses that raise hypotheses about groups of patients that may derive differential benefit from ezetimibe treatment.There is a particular focus on diabetes mellitus, which was present in 27% of participants at baseline.It is suggested that the relative benefits of ezetimibe may be enhanced both in the presence of diabetes mellitus (in comparison with its absence) and, when limited to nondiabetic patients, in those at higher cardiovascular risk (in comparison with nondiabetic patients at lower cardiovascular risk). 3The first conclusion rests on an interaction test (P=0.023)for the subgroup analysis comparing those with and without diabetes mellitus who achieved 15% and 2% reductions in the primary outcome, respectively, on ezetimibe/simvastatin versus placebo/simvastatin. 3 The second conclusion, based on an interaction test (P=0.034),rests on a further subgroup analysis, conducted in the subpopulation of IMPROVE-IT without diabetes mellitus; in this analysis, selected components of the primary outcome were used. 3t face value, these new IMPROVE-IT results appear to have important clinical implications.However, it should be remembered that subgroup analyses from clinical trials can be unreliable, and this may be especially true when the treatment effects are small, results from the primary analyses are of marginal statistical significance, or emphasis is placed on nominally significant findings in the context of multiple such analyses. 4Indeed 1 statistician has cautioned that "…the play of chance often produces qualitatively wrong answers in particular subgroups in trials (or in meta-analyses of trials) that could, if interpreted incautiously, lead to millions of people being treated inappropriately or untreated inappropriately." 4 To avoid such a situation occurring with ezetimibe, we should pause to reflect on these new findings and consider the likelihood that they simply represent chance.
233O Time to deterioration of symptoms with durvalumab in stage III, locally advanced, unresectable NSCLC: Post-hoc analysis of PACIFIC patient-reported outcomes
Authors: R. Hui, M. Özgüroğlu, A. Villegas, D. Daniel, D. Vicente, S. Murakami, A. Rydén, Y. Zhang, P. Dennis, S. Antonia
Journal: Journal of Thoracic Oncology (2018)