tbuckley/cabot-search huggingface dataset:
Surgical outcomes of laparoscopic transhiatal lower mediastinal lymphadenectomy for seiwert type II adenocarcinoma of the esophagogastric junction.
Authors: Masanori Tokunaga, Eigo Akimoto, Reo Sato, Akio Kaito, Takahiro Kinoshita
Journal: Journal of Clinical Oncology (2019)

155 Background: Optimal surgical approach for Siewert type II adenocarcinoma of the esophagogastric junction (AEG-II) has not yet been determined, presumably due to complex anatomical structures and the limited number of reports regarding this aspect. The transhiatal approach is preferred in East Asia in cases with 30 mm or less esophageal invasion, and laparoscopic surgery is increasingly performed. However, the feasibility of the laparoscopic transhiatal approach for AEG-II is still unclear, and thus was investigated in this study. Methods: A total of 51 consecutive patients who underwent total/proximal gastrectomy with lower mediastinal lymphadenectomy by laparoscopic transhiatal approach between January 2008 and May 2018 were included. Patients with greater than 30 mm esophageal invasion, and those who received preoperative chemotherapy, were excluded. Results: The male/female ratio was 38:13, and the median age (range) was 69 (37-81) years. Total gastrectomy and proximal gastrectomy were performed in 10 and 41 patients, respectively. All surgeries were performed by experienced surgical teams. Median operation time and intra-operative blood loss were 300 (141-511) minutes and 21 (0-267) g, respectively. Pathological tumor depth was T2 or deeper in 28 patients (55%), and nodal status was negative in 20 patients (39%). Clavien-Dindo grade IIIa or higher complications were observed in eight patients (16%), which included two anastomotic leakages and one pancreas fistula, and the mortality rate was 0%. The 5-year overall survival rate of all patients was 97% with a median observational period of 30 months. Conclusions: Laparoscopic transhiatal approach with lower mediastinal lymphadenectomy seems to be a technically feasible procedure, provided an experienced surgical team performs the surgeries. However, oncological safety for advanced disease needs to be confirmed, considering that the proportion of advanced stage cancer included in this study was limited.
Abstract 10893: Cardiac Troponin T Release is Correlated with Diastolic Load in Patients with Nonischemic Heart Failure
Authors: Seiji Takashio, Megumi Yamamuro, Sunao Kojima, Hisao Ogawa
Journal: Circulation (2011)

Background: Cardiac troponin T (cTnT) is established as a specific biomarker of ongoing myocardial damage and predicts adverse outcome in patients with heart failure (HF). As is well known that epi...
Abstract 12125: The CHARGE-AF Risk Score Performs Better at Predicting Risk of Atrial Fibrillation than the CHA2DS2-VASc Risk Score in the Framingham Heart Study
Authors: Ingrid E Christophersen, Xiaoyan Yin, Martin G Larson, Steven A Lubitz, Jared W Magnani, David D McManus, Patrick T Ellinor, Emelia J Benjamin
Journal: Circulation (2015)

Introduction: Atrial fibrillation (AF) is a common arrhythmia that affects more than 30 million individuals worldwide and confers serious complications, such as stroke, heart failure, dementia and death. The CHARGE-AF risk score was developed in 2013 to predict risk of AF in the general population. It was derived from the Framingham Heart Study, the Cardiovascular Health Study and the Atherosclerosis Risk In Communities study and validated in the Age, Gene/Environment Susceptibility Study and the Rotterdam Study, with more than 26,000 individuals of European, European-American, and African-American ancestry in total. The CHA2DS2-VASc risk score was derived in 2010 to predict risk of stroke in individuals already diagnosed with AF. CHA2DS2-VASc has not been validated for prediction of AF, but it has been used for this purpose in recent studies. Hypothesis: We hypothesized that the CHARGE-AF risk score would perform better than the CHA2DS2-VASc risk score for predicting risk of AF in a community-based cohort. Methods: Individuals from the Framingham Heart Study aged 45-94 years, without missing covariates or prevalent AF were included. For both risk scores, we performed Cox proportional hazards regression to assess the predicted risk of AF. Model fit was assessed using the likelihood ratio X2 statistic. We evaluated discrimination and calibration of each model using the C-statistic and Hosmer-Lemeshow X2 statistic. Results: We included 9722 observations (mean age 63.9±10.6 years, 56% women) from 4548 unique individuals: 752 (16.5%) developed incident AF and 793 (17.4%) died. The mean CHARGE-AF score was 12±1.2 and mean CHA2DS2-VASc score 2.0±1.5. The CHARGE-AF risk score was associated with a 115% increased risk of AF (95% CI, 99-131%; p&lt;0.0001) per unit increase, corresponding numbers for CHA2DS2-VASc were 43% (95% CI, 37-51%; p&lt;0.0001). CHARGE-AF had better model fit than CHA2DS2-VASc (Wald X2 = 403 vs. 209, both with 1 df), improved discrimination (C-statistic=0.75, 95% CI, 0.73-0.76 vs. C-statistic=0.71, 95% CI, 0.69-0.73) and better calibration (X2=5.6, p=0.69 vs. X2=28.5, p&lt;0.0001). Conclusions: The CHARGE-AF risk score performed better than the CHA2DS2-VASc risk score at predicting AF in a European-American ancestry cohort.
The Impact of Hematopoietic Cell Transplantation on Survival: An Exploratory Analysis of a Phase 3 Study of CPX-351 Versus 7+3 in Older Patients with Newly Diagnosed, High-Risk/Secondary AML
Authors: Tara L Lin, Jorge E. Cortes, Laura F. Newell, Ellen K. Ritchie, Robert K. Stuart, Stephen A. Strickland, Donna Hogge, Scott R Solomon, Richard M. Stone, Dale L. Bixby, Jonathan E. Kolitz, Gary J. Schiller, Matthew J. Wieduwilt, Daniel H. Ryan, Robert Ryan, Michael Chiarella, Arthur C. Louie, Geoffrey L. Uy
Journal: Blood (2018)
BKV Disease during the First 100 Days after Allogeneic Hematopoietic Stem Cell Transplantation - Results of a Screening Program and Retrospective Analysis
Authors: Philip Posdzich, Marco Herling, Silke Leitzke, Laura Hamacher, Veronica Di Christanziano, Konstantin Hoeller, Rolf Kaiser, Jens Chemnitz, Christof Scheid, Udo Holtick
Journal: Blood (2016)
Re: Melgarejo et al.: Glaucomatous optic neuropathy associated with nocturnal dip in blood pressure: findings from Maracaibo Aging Study (Ophthalmology. 2018;125:807-814)
Authors: Susmita Paul, Prafulla Sarma, Chengchira A. Sangma, Shahinur Tayab
Journal: Ophthalmology (2019)
Abstract IA15: SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities
Authors: Charles W. M. Roberts
Journal: Cancer Research (2018)

Abstract Data emerging over the last several years implicate SWI/SNF (BAF) chromatin remodeling complexes as a major tumor suppressor as frequent inactivating mutations in at least nine different SWI/SNF subunits, collectively identified in 20% of all cancers. These include recurrent mutations of ARID1A (BAF250a) in ovarian, endometrioid, bladder, stomach, colorectal, and pancreatic cancers and neuroblastoma; of the BRG1 (SMARCA4) subunit in medulloblastomas and non-small cell lung cancers; of the PBRM1 (BAF180) subunit in renal carcinomas; of the ARID2 subunit in hepatocellular, lung, and pancreas carcinomas as well as melanomas; and of the BRD7 subunit in breast cancers. The SWI/SNF complex includes both core and lineage-specific subunits and utilizes the energy of ATP to modulate chromatin structure and regulate transcription. My laboratory began studying the SWI/SNF complex when SNF5 (SMARCB1/INI1/BAF47) became the first SWI/SNF subunit linked to tumor suppression over fifteen years ago when it was found to be biallelically inactivated in nearly all cases of a highly aggressive type of pediatric cancer called malignant rhabdoid tumor (MRT). Despite the extremely aggressive and lethal nature of MRT, we have shown that these cancers are diploid and have remarkably simple genomes. We now study the complex using mouse models, cell lines, and primary human tumor samples. Insights into the normal function of SWI/SNF complexes, the mechanisms by which mutation of the complexes drive cancer formation, and potential therapeutic vulnerabilities created by mutation of the complex will be presented, including our recent efforts that identify a central role for SWI/SNF complexes in enhancer regulation. Citation Format: Charles W. M. Roberts. SWI/SNF (BAF) chromatin remodeling complexes are frequently mutated in cancer: Mechanisms and vulnerabilities [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr IA15.
Phase Ib study of WNT inhibitor ipafricept (IPA) with nab-paclitaxel (Nab-P) and gemcitabine (G) in patients (pts) with previously untreated stage IV pancreatic cancer (mPC).
Authors: Efrat Dotan, Dana Backlund Cardin, Heinz-Josef Lenz, Wells A. Messersmith, Bert O'Neil, Steven J. Cohen, Crystal S. Denlinger, Safi Shahda, Ann M. Kapoun, Rainer Karl Brachmann, Shailaja Uttamsingh, Colin D. Weekes
Journal: Journal of Clinical Oncology (2019)

369 Background: The first-in-class recombinant fusion protein IPA blocks WNT signaling by binding WNT ligands, and in combination with Nab-P/G caused tumor regression in pt-derived PC xenografts. This open-label Phase 1b dose escalation study evaluated the combination of IPA with Nab-P/G in untreated mPC pts using a standard 3+3 design. Methods: Dose escalation in cohort 1 started with Nab-P 125 mg/m 2 and G 1000 mg/m 2 given on days 1, 8 ,15, with IV IPA (3.5 mg/kg) on days 1 and 15, in 28-day cycles. Due to fragility fractures seen in other studies with similar targeted agents, cohorts 2-4 were 6-pt cohorts treated with weekly Nab-P/G + IPA 3 mg/kg (cohort 2) or 5 mg/kg (cohorts 3 and 4) on day 1. These cohorts included strict bone marker monitoring and use of bisphosphonates as indicated. Based on pre-clinical data suggesting improved efficacy with sequential dosing, pts in Cohort 4 received IPA on day 1 followed by weekly chemotherapy starting on day 3 of 28-day cycles. Objectives included safety, maximum tolerated dose, recommended phase 2 dose, pharmacokinetics, immunogenicity, pharmacodynamics, and preliminary efficacy. Results: Twenty-six pts in four dose escalation cohorts were enrolled, five in the cohort one and seven each in cohorts 2-4. Median age was 61.7 years and a majority were male (73%). Reported IPA-related AEs of any grade occurring in ≥ 20% of pts included fatigue, nausea, vomiting, anorexia and pyrexia. IPA-related AEs grade ≥ 3 included 2 events of AST elevation, and 1 each of nausea, maculopapular rash, vomiting and WBC decrease. No dose limiting toxicities or fragility fractures were observed. Of 26 evaluable pts, 9 (34.6%) had a partial response and 12 (46.2%) stable disease, with clinical benefit rate of 80.8%. The study was closed due to termination of the program by the sponsor. At time of data cut off, median progression free survival was 5.9 months (95% CI 3.4-18.4), median overall survival was 9.7 months (95% CI: 7.0-14). One pt remains on therapy under compassionate use with ongoing response. Conclusions: IPA can be safely administered with Nab-P and G in pts with mPC. Additional studies targeting the WNT pathway in pancreatic cancer are warranted. Clinical trial information: NCT02050178.
Abstract 19409: Post-Injury Administration of Estrogen Enhances Myocardial Functional Recovery and Improves Mitochondrial Performance Following Ischemia/Reperfusion
Authors: Meijing Wang, Yang Yang, I W Wang, Mark Turrentine
Journal: Circulation (2017)

Introduction: Although estrogen-mediated cardiac protection has been appreciated for many years, most these studies utilize an approach of pre-ischemic treatment in animal experiments and the preventive usage in clinical studies. Given clinical therapeutic potential in the treatment of acute myocardial ischemia, a strategy of post-ischemic administration of estrogen will be more practical compared to pretreatment. Therefore, in this study, we aimed to evaluate the therapeutic efficacy of this new approach on myocardial protection following ischemia, and to determine its influence on distribution of cardiac mitochondrial (mito-) connexin-43 (Cx43), mito-caveolin-3 (Cav3), and mito-estrogen receptor (ER)α, considering that the interaction of ERα/Cx43/Cav3 has been shown to improve mitochondrial function in other disease models. Methods: Langendorff perfused mouse hearts (age-matched normal females, ovariectomized females [OVX F] and OVX F with acute post-ischemic treatment of 17β-estradiol [E2, 2nM], n=4-6/...
The combination of TAS-102 and bevacizumab as the third-line chemotherapy for metastatic colorectal cancer (TAS-CC3 Study).
Authors: Chihiro Kosugi, Hirohiko Kamiyama, Yoichiro Yoshida, Hiroshi Yoshida, Keiichiro Ishibashi, Keisuke Ihara, Makoto Takahashi, Hidekazu Kuramochi, Hiromichi Sonoda, Kazuhiko Yoshimatsu, Atsuko Fukazawa, Akihisa Matsuda, Satoru Yamaguchi, Hideyuki Ishida, Suguru Hasegawa, Takeshi Yamada, Kazuo Narushima, Kiyohiko Shuto, Kazuhiro Sakamoto, Keiji Koda
Journal: Journal of Clinical Oncology (2019)

614 Background: TAS-102 improved overall survival of metastatic colorectal cancer (mCRC) patients with median progression free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, the combination of TAS-102 and bevacizumab has been shown to extend median PFS with 3.7 months (C-TASK FORCE). However, this study included patients with 2nd line and 3rd line chemotherapy. Our study was planned exclusively for patients receiving this combination as a 3rd line chemotherapy to investigate clinical impact of this combination beyond cytotoxic doublet. Methods: This phase II study was conducted in investigator-initiated, open-label, single-arm, multicentered manner in Japan. Eligible patients were 20-80 years old, and had to have an ECOG performance status of 0 or 1; had confirmed unresectable mCRC with histologically diagnosed adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in the 1st and the 2nd line chemotherapy. TAS-102 (35 mg/ m²) was given orally twice daily on days 1–5 and 8–12 in a 4-weeks cycle, and bevacizumab (5 mg/ kg) was administered by intravenous infusion for 30 minutes in every 2 weeks. The primary endpoint was progression free survival (PFS), and the secondary endpoints were time to treatment failure (TTF), response rate (RR), overall survival (OS), and safety. Results: Between June 2016 and August 2017, 32 pts were enrolled. The median PFS was 4.5 months, and the median OS was 9.3 months. Partial response was observed in 2 patients. The most common adverse events above grade 3 were neutropenia (15 patients) followed by thrombocytopenia (4 patients). Treatment-related serious adverse events were reported in 1 patient. There were no non-hematologic adverse events above grade 3. No treatment-related deaths occurred. Conclusions: This is the first study which involves the combination TAS-102 and bevacizumab as the 3rd line chemotherapy in the setting beyond cytotoxic doublet for the patients with mCRC. This study met its primary endpoint PFS, which is comparable to the results of C-TASK FORCE study. This combination has a potential to be one of therapeutic options of the 3rd line chemotherapy for mCRC. Clinical trial information: 000022438.
Epigenetic Co-Deregulation of EZH2/TET1 is a Senescence-Countering, Actionable Vulnerability in Triple-Negative Breast Cancer
Authors: Yong Yu, Jingjing Qi, Jieyi Xiong, Liping Jiang, Di Cui, Junlin He, Ping Chen, Lianjie Li, Chenjie Wu, Tonghui Ma, Su Shao, Jianjun Wang, Dansong Yu, Bing Zhou, Dongsheng Huang, Clemens A. Schmitt, Ran Tao
Journal: Theranostics (2019)

Triple-negative breast cancer (TNBC) cells lack the expression of ER, PR and HER2. Thus, TNBC patients cannot benefit from hormone receptor-targeted therapy as non-TNBC patients, but can only receive chemotherapy as the systemic treatment and have a worse overall outcome. More effective therapeutic targets and combination therapy strategies are urgently needed to improve the treatment effectiveness. Methods: We analyzed the expression levels of EZH2 and TET1 in TCGA and our own breast cancer patient cohort, and tested their correlation with patient survival. We used TNBC and non-TNBC cell lines and mouse xenograft tumor model to unveil novel EZH2 targets and investigated the effect of EZH2 inhibition or TET1 overexpression in cell proliferation and viability of TNBC cells. Results: In TNBC cells, EZH2 decreases TET1 expression by H3K27me3 epigenetic regulation and subsequently suppresses anti-tumor p53 signaling pathway. Patients with high EZH2 and low TET1 presented the poorest survival outcome. Experimentally, targeting EZH2 in TNBC cells with specific inhibitor GSK343 or shRNA genetic approach could induce cell cycle arrest and senescence by elevating TET1 expression and p53 pathway activation. Using mouse xenograft model, we have tested a novel therapy strategy to combine GSK343 and chemotherapy drug Adriamycin and could show drastic and robust inhibition of TNBC tumor growth by synergistic induction of senescence and apoptosis. Conclusions: We postulate that the well-controlled dynamic pathway EZH2-H3K27me3-TET1 is a novel epigenetic co-regulator module and provide evidence regarding how to exploit it as a novel therapeutic target via its pivotal role in senescence and apoptosis control. Of clinical and therapeutic significance, the present study opens a new avenue for TNBC treatment by targeting the EZH2-H3K27me3-TET1 pathway that can modulate the epigenetic landscape.
Abstract 14161: Increased Cardiovascular Risk in Patients With Statin-Controlled LDL Cholesterol and Residual Hypertriglyceridemia
Authors: Gregory A Nichols, Sephy Philip, Craig B Granowitz, Kristi Reynolds, Sergio Fazio
Journal: Circulation (2017)

Introduction: The value of treating high triglycerides (TG) despite statin therapy for cardiovascular (CV) risk reduction is being studied. We evaluated patients at high risk for CV events who had statin-controlled LDL cholesterol (LDL-C) to determine whether the presence of high TG levels influence CV risk. Methods: We combined data from the Southern California and Northwest regions of Kaiser Permanente to identify adults on statin therapy with LDL-C 40-100 mg/dL, no other lipid therapies, and with a diagnosis of atherosclerotic CV disease (ASCVD: myocardial infarction [MI], ischemic stroke, and peripheral artery disease). Patients were grouped into high (200-499 mg/dL, n=2,361) or low (<150 mg/dL, n=14,454) TG levels in 2010. We used follow-up data through September 2015 to compare the adjusted incidence rates per 1,000 person-years (p-y) between the high and low TG groups of first non-fatal MI, coronary revascularization, all-cause mortality, and a composite outcome. After testing covariates including ...
Wait times for colorectal cancer patients in a universal healthcare system over a decade: Is it sustainable?
Authors: Megan E Delisle, Ramzi Helewa, Jason Park, David J Hochman, Andrew McKay
Journal: Journal of Clinical Oncology (2019)

697 Background: Delays in treatment for colorectal cancer (CRC) may worsen prognosis and increase patient anxiety. This study aims to understand population-based trends and variations in wait times (WTs) for CRC in a universal healthcare system over a decade. Methods: Patients diagnosed with stage I-IV CRC in Manitoba, Canada between 2004 and 2014 were included. Data were obtained through province-wide administrative claims and cancer registry. WTs were defined as time from index contact to pathological diagnosis (diagnosis WT), time from pathological diagnosis to first treatment (treatment WT) and total (diagnosis + treatment WT). Index contact was the consult preceding the first gastrointestinal investigation in the year preceding the date of diagnosis. First treatment was radiation, chemotherapy or surgery. The association between WTs and year of diagnosis was estimated using Negative Binomial regression and reported as incidence rate ratio (IRR). Variability in WTs by year were estimated using the Coefficient of Variation (CV) and average annual percent change (AAPC). A CV &gt; 100 indicates high-variability and &lt; 100 indicates low-variaability. Results: A total of 5359 patients were diagnosed with CRC (1802 rectal vs 3557 colon). WTs increased overall. Total WTs for rectal cancer increased by 6% (IRR 1.06, 95% CI 1.04-1.07, p &lt; 0.01) per year from a median of 90 days in 2004 to 147 days in 2014. This was due increases in time to diagnosis (IRR 1.07, 95% CI 1.06-1.09, p &lt; 0.01) and treatment (IRR 1.04, 95% CI 1.03-1.06, p &lt; 0.01). Total colon cancer WTs increased an estimated 5% (IRR 1.05, 95% CI 1.04-1.06, p &lt; 0.01) per year from a median of 89 days in 2004 to 110 days in 2014. This was due to both time to diagnosis (IRR 1.05, 95% CI 1.04-1.07, p &lt; 0.01) and treatment (IRR 1.03, 95% CI 1.02-1.04, p &lt; 0.01). There was increasing variability in total WTs. The CV increased from 87 in 2004 to 102 in 2014 in rectal cancer (AAPC +3.85%) and from 86 in 2004 to 128 in 2014 in colon cancer (AAPC + 5.04%). Conclusions: Total WTs for CRC in Manitoba have increased from 2004 and 2014. This may reflect the growing challenges in providing increasingly complex cancer care to geographically dispersed populations in a universal healthcare system.
Abstract MP075: Profiles of Obese Depressed Adults in a Randomized Controlled Trial of Integrated Behavior Therapy
Authors: Jun Ma, Lan Xiao, Nan LV, Lisa Goldman Rosas, Mark Snowden, Megan A Lewis, Jeremy D Goldhaber-Fiebert, Elizabeth M Venditti, Lenard Lesser, Elizabeth Ward
Journal: Circulation (2017)

Objective: To identify distinct profiles of obese depressed patients in an ongoing trial that tests the effectiveness and implementation potential of an integrated care model in primary care combining standard behavioral weight loss treatment and problem solving therapy plus as-needed antidepressant(s). Design and Methods: Analysis of variance for continuous and Chi-square tests for categorical variables compared 4 domains (sociodemographic, behavioral, clinical and psychosocial characteristics) among 4 severity categories of obese depressed participants (i.e., body mass index [BMI]&lt;35 kg/m 2 and Depression Symptom Checklist 20 [SCL20]&lt;1.5; BMI&lt;35 and SCL20≥1.5; BMI≥35 and SCL20&lt;1.5; and BMI≥35 and SCL20≥1.5). Discriminant analysis identified combinations of characteristics that best differentiated these categories. Results: Participants (n=322) had baseline mean (SD) age of 50.4 (12.2) years, BMI of 36.7 (6.4) kg/m 2 , and SCL20 of 1.5 (0.5). Pairwise comparisons showed participants in the 4 categories had similar sociodemographic characteristics, but they differed significantly in the other 3 domains (Table). Discriminant analysis showed the combination of higher abdominal obesity, problems with usual activities (eg, work and family or leisure activities), higher anxiety, poorer self-reported mental health, and more obesity-related problems differentiated the highest from lowest severity category. The combination of lower abdominal obesity, more obese-related problems, and higher anxiety differentiated the 2 intermediate (lower obesity/high depression vs. high obesity/lower depression) categories. Conclusions: Discernable behavioral, clinical and psychosocial profiles reveal important variability according to comorbidity severity within a largely sociodemographically similar group of obese depressed adults. This insight may inform future analysis of heterogeneity of treatment effects and targeting of strategies to baseline participant profiles in a multicomponent intervention.