tbuckley/cabot-search huggingface dataset:
Concurrent versus sequential neoadjuvant chemoradiation therapy for esophageal and gastroesophageal junction adenocarcinoma.
Authors: Robert J. Torphy, Felix Ho, Chloe Friedman, Stephen Leong, Sachin Wani, Christopher D. Scott, Michael J. Weyant, Robert A. Meguid, Ana Gleisner, Karyn A. Goodman, Martin D. McCarter
Journal: Journal of Clinical Oncology (2020)

395 Background: Neoadjuvant therapy is the standard of care for locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma, with most patients receiving neoadjuvant chemoradiation (CRT). CRT can be delivered concurrently or sequentially after induction chemotherapy. The purpose of this study was to evaluate pathologic complete response (pCR) and overall survival (OS) among patients who received concurrent versus sequential CRT in the National Cancer Database (NCDB). Methods: Patients who received neoadjuvant CRT and underwent curative intent esophagectomy for esophageal or GEJ adenocarcinoma from 2006-2015 were included. Patients with clinical T4 or metastatic disease were excluded. Concurrent CRT was defined as radiation treatment starting within 6 weeks of chemotherapy start. Sequential CRT was defined as radiation treatment starting greater than 6 weeks after chemotherapy start. Propensity weighting was conducted to balance patient, disease, and facility covariates between groups. Results: 12,460 patients met inclusion criteria. 11,880 (95%) patients received concurrent CRT and 580 (5%) patients received sequential CRT. Patients who received sequential CRT were significantly younger (mean age: 60.7 vs 62.2 years), had higher clinical nodal stage (N2-3: 14.7% vs 10.1%), and were more often treated at academic/research hospitals (67.1 vs 55.5) (all p≤0.001). pCR was achieved in 16.2% of patients who received sequential CRT and in 14.0% of patients who received concurrent CRT (p = 0.131). Following propensity weighting, OS was significantly improved among patients who received sequential versus concurrent CRT (HR 0.82; 95% CI 0.74-0.92; p &lt; 0.001) with a median OS for the sequential cohort of 41.4 months versus 29.4 months for those who received concurrent CRT. Conclusions: In this retrospective study from a large national database of patients who received neoadjuvant CRT for esophageal and GEJ adenocarcinoma, sequential CRT is associated with a significant OS benefit. These results merit consideration of a well powered prospective multi-institutional randomized clinical trial to further evaluate this observed difference.
Abstract 388: Long-Distance Running Races Supported by Running Doctors Provide Better Clinical Outcomes for Runners With Cardiac Arrest
Authors: Norihiro Kuroki, Daisuke Abe, Kou Suzuki, Takao Yuba, Yoshiaki Yui, Akira Takayama, Koichi Ohashi, Hitoshi Hirano, Takunori Aoyama, Takuto Mukaida, Yumi Kimura, Mikiko Okouchi, Taichi Kato, Riki Nagatomo, Yuichi Hamabe
Journal: Circulation (2019)

Background: Approximately 10million people enjoy running in Japan annually. It is reported that the risk of an out-of-hospital cardiac arrest (OHCA) is temporarily increased during running. Several races in Japan supported by Running Doctors (RD) respond to runners with OHCA. The RDs are doctors who belong to the Japan Medical Joggers Association. The RDs participate in running races as general runners, perform medical monitoring from the inside of the running course, and if they encounter a serious health problem, especially OHCA, with a runner, they cancel their race and make an initial response. For example, 49 RDs cooperated in Tokyo Marathon 2019. However, the effectiveness of their activities is unclear. We investigated whether their activities were effective. Methods: A cohort of 8,884 patients with OHCA were admitted with return of spontaneous circulation (ROSC) or on-going resuscitation at our hospital arrival from 2006 to 2018. The 13 runners with OHCA which occurred during long distance running races were analyzed from the medical records and interviews of survivors and relatives. We divided runners into two groups depending on whether RD responded: RD group (n=7) and non-RD group (n=6). The clinical outcome was 30-day survival with minimal neurologic impairment. Results; Overall, the 12 (92%) runners were male. The RD group was older than Non-RD group (RD vs. Non-RD, 52±9 vs. 35±17 years old; P=0.04). The time interval between collapse and starting cardiopulmonary resuscitation (0.4±0.5 vs. 4.2±3.6 min; P=0.02) and between collapse and ROSC (6.6±2.9 vs. 23.3±19.3 min ; P=0.04) were significantly shorter in RD group. On Kaplan-Meier analysis, runners with OHCA in RD group were better clinical outcome than Non-RD group (100% vs. 67%; P=0.11; log-rank test). (Figure) Conclusion; The long-distance running races supported by running doctors provided early response to runners with OHCA. This might lead to better clinical outcomes for runners with OHCA.
A phase Ib study of alofanib, an allosteric FGFR2 inhibitor, in patients with advanced or metastatic gastric cancer.
Authors: Galina Statsenko, Mikhail Fedyanin, Vladimir Moiseyenko, Liubov Yu Vladimirova, Ilya Tsimafeyeu, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2020)

TPS466 Background: Fibroblast growth factor receptor 2 (FGFR2) is amplified or overexpressed in 3% to 61% of patients with gastric cancer and associated with a poor prognosis. Acquired mutations in FGFR2 develop resistance to multikinase inhibitors. Besides, resistance to monoclonal antibodies depends on the type of FGFR2 isoforms IIIc or IIIb expressed by cancer cells. Alofanib (RPT835) is a novel selective allosteric inhibitor of FGFR2. Alofanib could bind to the non-active site of FGFR2 extracellular domain and had an inhibitory effect on FGF2-induced phosphorylation of FRS2α. On preclinical models no severe organ and function test changes were observed. Based on these results, alofanib has advanced into clinical evaluation. Methods: RPT835GC1B is a Phase 1b study, being conducted in at least four sites in Russia, evaluating the safety and preliminary efficacy of alofanib in patients with advanced and metastatic gastric adenocarcinoma pretreated with ≥ 1 previous lines of therapy. This trial consists of two parts. The standard dose-escalation part (design 3+3) aims to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (R2PD) as a primary endpoint. The first part of the study includes a 28-day period when alofanib is administered daily intravenously for 5-days followed by a 2-day interval (rest). There are five dose levels: 50, 100, 165, 250, and 350 mg/m2. The dose-expansion phase accrues additional 20 patients, where comprehensive information to be collected. Secondary endpoints include pharmacokinetic parameters, rate of adverse events, progression-free survival, overall survival, and objective response rate. All patients will receive alofanib until disease progression or unacceptable toxicity. FGFR2 amplification, fusion, and overexpression will be assessed as well. Clinical trial information: NCT04071184.
A phase II trial of cytoreduction, gastrectomy, and hyperthermic intraperitoneal perfusion with chemotherapy for patients with gastric cancer and stage IV peritoneal disease.
Authors: Brian D. Badgwell, Naruhiko Ikoma, Mariela A. Blum Murphy, Xuemei Wang, Jeannelyn Estrella, Sinchita Roy-Chowdhuri, Prajnan Das, Bruce D. Minsky, Paul F. Mansfield, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2020)

361 Background: Current national guidelines do not include hyperthermic intraperitoneal chemoperfusion (HIPEC) as treatment for gastric cancer, and there are no completed clinical trials of cytoreduction, gastrectomy, and HIPEC from the U.S. However, recent international studies report long-term survival rates of approximately 20% with cytoreduction/gastrectomy/HIPEC. Methods: Patients with gastric adenocarcinoma and positive peritoneal cytology or carcinomatosis who had completed systemic chemotherapy and laparoscopic HIPEC underwent cytoreduction, gastrectomy, and HIPEC with 30 mg mitomycin C and 200 mg cisplatin. The primary end point was overall survival (OS), with secondary end points of safety and postoperative complications. Results: We enrolled 20 patients from 9/2016 to 3/2019, with a median age of 58 years (range, 20-75 years). Six patients had positive cytology only at diagnosis of stage IV disease, whereas 14 had carcinomatosis. All patients were treated with systemic chemotherapy with a median of 8 cycles (range, 5-11 cycles) and at least one laparoscopic HIPEC. The median peritoneal carcinomatosis index at cytoreduction/gastrectomy/HIPEC was 2 (range, 0-13). After surgery, the 90-day morbidity and mortality rates were 70% and 0%, respectively. Median length of hospital stay was 13 days (range, 7-23 days). Median follow-up was 1.8 years. Median OS from the date of diagnosis of metastatic disease was 2.1 years. Median OS from the date of cytoreduction, gastrectomy, and HIPEC was 1.4 years. One, 2, and 3-year OS rates from the diagnosis of metastatic disease are 90%, 54%, and 29%. Conclusions: Survival rates for patients with gastric adenocarcinoma and peritoneal disease treated with cytoreduction, gastrectomy, and HIPEC are encouraging; our early results are similar to those of recent prospective registry studies. Cooperative group trials should be supported and will be required to confirm survival and safety outcomes. Clinical trial information: NCT02891447.
Efficacy of dupilumab reveals therapeutic target for IgG4-related disease: simultaneous control of inflammation and fibrosis
Authors: Motohisa Yamamoto, Noritada Yoshikawa, Hirotoshi Tanaka
Journal: Annals of the Rheumatic Diseases (2020)

We read with great interest the article from Simpson et al on the clinical efficacy of dupilumab in a patient with IgG4-related disease (IgG4-RD).1 Glucocorticoid is currently the first-line induction therapy for IgG4-RD.2 Since it generally suppresses acquired immune cells, we could not know the therapeutic targets in IgG4-RD. So far, the efficacy of rituximab, targeting B cells, has been discussed,3 but we reconfirm that type 2 helper T (Th2) cells can be one of the therapeutic targets in IgG4-RD by this article. Tanaka et al previously disclosed that the expression of Th2 cytokine mRNA was elevated in the labial glands from patients with IgG4-RD, compared with the patients with Sjogren’s syndrome and healthy controls.4 We have shown that the levels of serum interleukin (IL)-5 were elevated according to the disease …
Carbon-coated FeCo nanoparticles as sensitive magnetic-particle-imaging tracers with photothermal and magnetothermal properties
Authors: Guosheng Song, Michael Kenney, Yun-Sheng Chen, Xianchuang Zheng, Yong Deng, Zhuo Chen, Shan X. Wang, Sanjiv Sam Gambhir, Hongjie Dai, Jianghong Rao
Journal: Nature Biomedical Engineering (2020)
Compartmentalized β1-adrenergic signalling synchronizes excitation–contraction coupling without modulating individual Ca2+ sparks in healthy and hypertrophied cardiomyocytes
Authors: Hua-Qian Yang, Peng Zhou, Li-Peng Wang, Yan-Ting Zhao, Yu-Jie Ren, Yun-Bo Guo, Ming Xu, Shi-Qiang Wang
Journal: Cardiovascular Research (2020)

Abstract Aims β-adrenergic receptors (βARs) play pivotal roles in regulating cardiac excitation–contraction (E-C) coupling. Global signalling of β1ARs up-regulates both the influx of Ca2+ through sarcolemmal L-type Ca2+ channels (LCCs) and the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptors (RyRs). However, we recently found that β2AR stimulation meditates ‘offside compartmentalization’, confining β1AR signalling into subsarcolemmal nanodomains without reaching SR proteins. In the present study, we aim to investigate the new question, whether and how compartmentalized β1AR signalling regulates cardiac E-C coupling. Methods and results By combining confocal Ca2+ imaging and patch-clamp techniques, we investigated the effects of compartmentalized βAR signalling on E-C coupling at both cellular and molecular levels. We found that simultaneous activation of β2 and β1ARs, in contrast to global signalling of β1ARs, modulated neither the amplitude and spatiotemporal properties of Ca2+ sparks nor the kinetics of the RyR response to LCC Ca2+ sparklets. Nevertheless, by up-regulating LCC current, compartmentalized β1AR signalling synchronized RyR Ca2+ release and increased the functional reserve (stability margin) of E-C coupling. In circumstances of briefer excitation durations or lower RyR responsivity, compartmentalized βAR signalling, by increasing the intensity of Ca2+ triggers, helped stabilize the performance of E-C coupling and enhanced the Ca2+ transient amplitude in failing heart cells. Conclusion Given that compartmentalized βAR signalling can be induced by stress-associated levels of catecholamines, our results revealed an important, yet unappreciated, heart regulation mechanism that is autoadaptive to varied stress conditions.
HALO 109-301: A randomized, double-blind, placebo-controlled, phase 3 study of pegvorhyaluronidase alfa (PEGPH20) + nab-paclitaxel/gemcitabine (AG) in patients (pts) with previously untreated hyaluronan (HA)-high metastatic pancreatic ductal adenocarcinoma (mPDA).
Authors: Margaret A. Tempero, Eric Van Cutsem, Darren Sigal, Do-Youn Oh, Nicola Fazio, Teresa Macarulla, Erika Hitre, Pascal Hammel, Andrew Eugene Hendifar, Susan Elaine Bates, Chung-Pin Li, Christelle De La Fouchardiere, Volker Heinemann, Anthony Maraveyas, Nathan Bahary, Laura Layos, Vaibhav Sahai, Lei Zheng, Jill Lacy, Andrea J. Bullock
Journal: Journal of Clinical Oncology (2020)

638 Background: HA is a major component of the tumor microenvironment (TME) in PDA. PEGPH20 degrades tumor HA, remodeling the TME. In PDA models, PEGPH20 has shown antitumor activity and increased TME delivery of anticancer agents to improve efficacy. A randomized phase 2 study showed promising results for PEGPH20+AG (PAG) in mPDA and identified HA accumulation as a biomarker. We present results from a phase 3 study (NCT02715804) of PAG for pts with HA-high mPDA. Methods: Pts ≥18 years with untreated HA-high mPDA were randomized (stratified by geographic region) 2:1 to PAG or placebo+AG (AG). HA status was prospectively determined with VENTANA HA RxDx Assay, with HA-high defined as ≥50% staining of a tumor sample. Treatment was administered IV in 4-wk cycles (3 wks on, 1 wk off) until progression or intolerable adverse events (AEs): PEGPH20 3.0 µg/kg twice wkly for Cycle 1 and once wkly (QW) thereafter, A 125 mg/m 2 QW and G 1000 mg/m 2 QW. Prophylactic enoxaparin 1 mg/kg was given daily for thromboembolism (TE) risk. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. Response was independently assessed per RECIST v1.1. The estimated sample size was ~500 pts to detect a hazard ratio (HR) for OS of 0.67 (93% power, 2-sided α = 0.05) after 330 deaths. Results: As of 20 May 2019, 494 pts were randomized with 492 (327 for PAG and 165 for AG) included in ITT analyses (2 pts excluded due to site violations). Baseline characteristics were balanced for PAG vs AG. After 330 deaths, median OS for PAG vs AG was 11.2 vs 11.5 mo (HR 1.00, 95% CI 0.80–1.27; P = 0.97); median PFS was 7.1 vs 7.1 mo (HR 0.97, 95% CI 0.75–1.26); confirmed ORR was 34% vs 27%. Grade (G) 3+ AEs (PAG vs AG) included neutropenia (44% vs 47%), thrombocytopenia (21% vs 16%) and fatigue (16% vs 10%); G3+ rates were 6% vs 7% for TE events, 5% vs 2% for bleeding events and 13% vs 5% for musculoskeletal events. Conclusions: PAG did not improve clinical outcomes vs AG. The PAG safety profile was consistent with that of previous studies. Clinical trial information: NCT02715804.
The applied implications of epigenetics in anxiety, affective and stress-related disorders - A review and synthesis on psychosocial stress, psychotherapy and prevention
Authors: Miriam A. Schiele, Michael G. Gottschalk, Katharina Domschke
Journal: Clinical Psychology Review (2020)

Mental disorders are highly complex and multifactorial in origin, comprising an elaborate interplay of genetic and environmental factors. Epigenetic mechanisms such as DNA modifications (e.g. CpG methylation), histone modifications (e.g. acetylation) and microRNAs function as a translator between genes and the environment. Indeed, environmental influences such as exposure to stress shape epigenetic patterns, and lifetime experiences continue to alter the function of the genome throughout the lifespan. Here, we summarize the recently burgeoning body of research regarding the involvement of aberrant epigenetic signatures in mediating an increased vulnerability to a wide range of mental disorders. We review the current knowledge of epigenetic changes to constitute useful markers predicting the clinical response to psychotherapeutic interventions, and of psychotherapy to alter - and potentially reverse - epigenetic risk patterns. Given first evidence pointing to a transgenerational transmission of epigenetic information, epigenetic alterations arising from successful psychotherapy might be transferred to future generations and thus contribute to the prevention of mental disorders. Findings are integrated into a multi-level framework highlighting challenges pertaining to the mechanisms of action and clinical implications of epigenetic research. Promising future directions regarding the prediction, prevention, and personalized treatment of mental disorders in line with a 'precision medicine' approach are discussed.
Lineage- and Sex-Dependent Behavioral and Biochemical Transgenerational Consequences of Developmental Exposure to Lead, Prenatal Stress, and Combined Lead and Prenatal Stress in Mice
Authors: Marissa Sobolewski, Kadijah Abston, Katherine Conrad, Elena Marvin, Katherine Harvey, Martha Susiarjo, Deborah A. Cory-Slechta
Journal: Environmental Health Perspectives (2020)

Background: Lead (Pb) exposure and prenatal stress (PS) during development are co-occurring risk factors with shared biological substrates. PS has been associated with transgenerational passage of altered behavioral phenotypes, whereas the transgenerational behavioral or biochemical consequences of Pb exposure, and modification of any such effects by PS, is unknown. Objectives: The present study sought to determine whether Pb, PS, or combined Pb and PS exposures produced adverse transgenerational consequences on brain and behavior. Methods: Maternal Pb and PS exposures were carried out in F0 mice. Outside breeders were used at each subsequent breeding, producing four F1-F2 lineages: [F1 female-F2 female (FF), FM (male), MF, and MM]. F3 offspring were generated from each of these lineages and examined for outcomes previously found to be altered by Pb, PS, or combined Pb and PS in F1 offspring: behavioral performance [fixed-interval (FI) schedule of food reward, locomotor activity, and anxiety-like behavior], dopamine function [striatal expression of tyrosine hydroxylase (Th)], glucocorticoid receptor (GR) and plasma corticosterone, as well as brain-derived neurotrophic factor (BDNF) and total percent DNA methylation of Th and Bdnf genes in the frontal cortex and hippocampus. Results: Maternal F0 Pb exposure produced runting in F3 offspring. Considered across lineages, F3 females exhibited Pb-related alterations in behavior, striatal BDNF levels, frontal cortical Th total percentage DNA methylation levels and serum corticosterone levels, whereas F3 males showed Pb- and PS-related alterations in behavior and total percent DNA methylation of hippocampal Bdnf. However, numerous lineage-specific effects were observed, most of greater magnitude than those observed across lineages, with outcomes differing by F3 sex. Discussion: These findings support the possibility that exposures of previous generations to Pb or PS may influence the brain and behavior of future generations. Observed changes were sex-dependent, with F3 females showing multiple changes through Pb-exposed lineages. Lineage effects may occur through maternal responses to pregnancy, altered maternal behavior, epigenetic modifications, or a combination of mechanisms, but they have significant public health ramifications regardless of mechanism. https://doi.org/10.1289/EHP4977
Perioperative FLOT in resectable gastric cancer: Italian real-world data from the RealFLOT study.
Authors: Elisa Giommoni, Ferdinando De Vita, Irene Pecora, Francesco Iachetta, Antonia Strippoli, Maria Antonietta Satolli, Andrea Spallanzani, Marco Puzzoni, Silvia Stragliotto, Michele Sisani, Vincenzo Formica, Filippo Giovanardi, Carmelo Pozzo, Michele Prisciandaro, Samantha Di Donato, Angelica Petrillo, Silvia Catanese, Giuseppe Tirino, Daniele Lavacchi, Lorenzo Antonuzzo
Journal: Journal of Clinical Oncology (2020)

300 Background: Perioperative treatments have significantly improved survival in patients with resectable gastric cancer, increasing 5-year overall survival from 23% with surgery alone to 45% with FLOT (fluorouracil, oxaliplatin, docetaxel). Pathological regression is a prognostic marker of better survival. Methods: In this observational, retro- and prospective study we collected data from patients with resectable gastric or gastro-oesophageal junction (GEJ) adenocarcinoma treated, as clinical practice, with perioperative FLOT. All patients had clinical T2 or higher and/or nodal involvement, according to FLOT4-AIO trial. Results: A total of 206 patients received perioperative chemotherapy with FLOT at 15 Italian centres, between September 2016 and September 2019. Overall, 186 (90.3%) patients completed the preoperative phase, 190 (92%) underwent surgery, and 142 (68.9%) started the postoperative phase. Among patients who started the postoperative phase, 105 (51.0%) received FLOT, while 37 (18%) received less intensive regimens (e.g. FOLFOX or De Gramont), depending on performance status after surgery or toxicity in the preoperative phase. Pathological complete response (pCR) was obtained in 7.3% of cases. In the preoperative phase, grade (G) 3-4 hematological and gastrointestinal adverse events (AEs) were reported in 42 (20.4%) and 13 (6.3%) patients, respectively. Conclusions: These real data confirmed the feasibility of perioperative FLOT in a less-selected population, representative of the clinical practice. The pCR rate was lower than in the FLOT4-AIO trial. The survival outcomes, potential predictive or prognostic factors and comprehensive safety data will be included in the final analysis. [Table: see text]