tbuckley/cabot-search huggingface dataset:
A randomized phase II pilot study prospectively evaluating treatment for patients based on ERCC1 for advanced/ metastatic esophageal, gastric, or gastroesophageal junction cancer: SWOG S1201.
Authors: Syma Iqbal, Shannon McDonough, Heinz-Josef Lenz, David H. Ilson, Barbara Burtness, Chaitali Singh Nangia, Afsaneh Barzi, Charles Schneider, Jijun Liu, Efrat Dotan, Katherine A Guthrie, Howard S. Hochster
Journal: Journal of Clinical Oncology (2017)

4009 Background: Platinum based treatment (tx) is standard in HER2 negative patients (pts) with advanced esophagogastric cancer (AEGC). Retrospective data suggest intratumoral ERCC1 levels may determine platinum sensitivity. A randomized phase II study was performed in pts with AEGC to explore whether the efficacy of a platinum 5-FU/LV/Oxaliplatin (FOLFOX) vs. non-platinum containing regimen irinotecan/taxotere (IT) differed according to ERCC1 levels. Methods: 203 untreated pts with AEGC, Her2 -, Zubrod PS 0-1, were randomized to FOLFOX vs. IT, stratified by intratumoral ERCC1 low (&lt;1.7) vs. high (≥1.7). Objectives were to assess PFS and OS in all pts treated with FOLFOX compared with IT, and in those pts with low and high ERCC1 levels and to assess for interactive effects between ERCC1 expression and tx arm. Results: 86% of pts had ERCC1 values &lt;1.7. Thus, evaluation of ERCC1 pts in the high subgroup was not feasible. Tx groups were well matched by age, sex, race, ERCC1 level, and site. A series of K-M plots were used to explore whether tx arm differences in PFS varied based on ERCC1 levels; little evidence of such was noted. Grade ≥ 3 anemia, dehydration, diarrhea and fatigue were greater in pts with IT. Grade ≥ 3 neuropathy and decreased neutrophils were greater in pts with FOLFOX. Conclusions: In all pts, FOLFOX had a statistically superior PFS and RR, when compared with IT. In pts with ERCC1 &lt;1.7 receiving FOLFOX, PFS and RR was statistically superior, with no difference in OS. There was no significant evidence of differential treatment effect on PFS across ERCC1 levels. Clinical trial information: NCT01498289. [Table: see text]
Abstract 15835: Cold Air Inhalation Induces Differential Effects on Coronary Microvascular Resistance and Flow Depending on Presence of Significant Coronary Artery Disease
Authors: Rupert Williams, Kaleab Asrress, Matthew Lumley, Satpal Arri, Tiffany Patterson, Vasiliki Manou-Stathopoulou, Catherine Macfarlane, Howard Ellis, Zeeshan Khawaja, Natalia Briceno, Brian Clapp, Divaka Perera, Amedeo Chiribiri, Sven Plein, Michael Marber, Simon Redwood
Journal: Circulation (2015)

Introduction: Cold temperatures increase the incidence of myocardial infarction. Precise mechanisms remain unclear. Sudden severe myocardial oxygen supply/demand mismatch may be responsible. We measured coronary flow and myocardial work during cold air inhalation (CAI), invasively and with cardiac magnetic resonance imaging (CMR), aiming to elucidate the dominant mechanisms. Methods: All data were acquired at rest and peak stress during CAI: 5minutes -15oC via a face-mask. Simultaneous intracoronary pressure and flow velocity data were acquired in a target artery from 20 patients (10 with normal coronary arteries, 10 with a significant stenosis (CAD). Coronary flow average peak velocity (APV), microvascular resistance (MVR) and buckberg index (BI: a surrogate for subendocardial ischemia) were calculated. Wave intensity analysis also differentiated waves that accelerate and decelerate coronary flow. Separately CMR perfusion was performed in 7 patients with a significant stenosis to quantify myocardial perfusion reserve (MPR) and transmural perfusion gradients (TPG). Results: At rest MVR is lower in CAD patients, maintaining APV (1a,b). During CAI, although myocardial work increased similarly in normal and CAD patients (rate pressure product mean difference 2312 and 2651mmHg.min-1 respectively), there was a differential response in coronary flow, with a significant increase and a downward trend in APV respectively (1a). Relative hypoperfusion of stenosed segments was also noted on MPR (2a). This inability of CAD patients to augment APV is explained by a significant increase in MVR (1b) collaborating with a reduction in accelerating flow waves (1c). These cause a relative subendocardial perfusion deficit, demonstrated by a significant decrease in BI (1d) and increase in TPG (2b). Conclusions: CAI increases myocardial work but CAD patients are unable to augment flow due to microvascular vasoconstriction and adverse ventricular-vascular coupling.
TCT-614 The Obesity Paradox Revisited: Body Mass Index and Long-Term Outcomes After PCI From a Large Pooled Patient-Level Database
Authors: Rafal Wolny, Akiko Maehara, Yangbo Liu, Gary Mintz, Pieter Smits, Clemens von Birgelen, Roxana Mehran, Martin Leon, Gregg Stone
Journal: Journal of the American College of Cardiology (2018)
TCT-379 Effect of Family Characteristics on Therapeutic Delay in Patients with ST-Elevation Myocardial Infarction
Authors: Yukio Mizuguchi, Ayumi Ohama, Takeshi Yamada, Norimasa Taniguchi, Shunsuke Nakajima, Tetsuya Hata, Akihiko Takahashi
Journal: Journal of the American College of Cardiology (2018)
Impact of surveillance on long-term outcomes after curative liver resection for hepatocellular carcinoma: Analysis of 1,075 patients with chronic hepatitis B infection from a prospective database over 12 years.
Authors: Jiong-Jie Yu, Zhen-Li Li, Wen-Tao Yan, Li-Yang Sun, Jia-He Wang, Bing Quan, Zheng Wang, Jun Han, Hao Xing, Han Wu, Han Zhang, Chao Li, Ming-Da Wang, Meng-Chao Wu, Feng Shen, Tian Yang
Journal: Journal of Clinical Oncology (2018)

e16109 Background: Surveillance for early detection of hepatocellular carcinoma (HCC) in high-risk populations such as chronic hepatitis B virus (HBV) carriers thus following by curative treatments is becoming increasingly common in China. However, it is still largely unknown whether surveillance brings significant survival benefits for patients who received curative treatments for HCC. Methods: A prospective database of patients with known chronic HBV infection diagnosed with initial HCC detected by surveillance or symptomatic presentation from 2003 to 2014 was reviewed. Long-term overall survival (OS) and recurrence-free survival (RFS) was compared between the surveillance and symptomatic groups. The proportion of pre-diagnosis surveillance and long-term outcomes between patients operated in the first (2003-2008) and second (2009-2014) 6-year period were also compared. Results: Of 1,075 patients, 452 (42.0%) patients were diagnosed with HCC detected by surveillance. Compared with the symptomatic group, long-term OS and RFS after HCC resection were signifi cantly better in the surveillance group (5-year OS rates: 71.6% vs. 43.9%, P < 0.001, and 5-year RFS rates: 52.8% vs. 26.8%, P < 0.001, respectively). Pre-diagnosis surveillance was association with 55% and 48% reduction in overall death and recurrence risk after HCC resection, respectively. The proportion of HCC surveillance increased from 37.3% during 2003-2008 to 44.8% during 2009-2014. Compared with the first 6-year period, increased OS and RFS (5-year OS rates: 60.1% vs. 46.8%, P = 0.042, and 5-year RFS rates: 41.5% vs. 30.9%, P = 0.003, respectively), along with 12% and 19% reduction in overall death and recurrence risk were also observed in the second 6-year period. Conclusions: Pre-diagnosis surveillance was associated with 55% and 48% reduction in overall death and recurrence in patients treated with curative liver resection for HBV-related HCC. With the increasing of surveillance for HCC, the overall prognosis of patients undergoing curative resection for HCC has been improved.
A real-world experience of nivolumab in advanced malignant mesothelioma (MM).
Authors: Hussein Hamad, Sumaira Shafi, Veronica Lenge De Rosen, Jun Zhang
Journal: Journal of Clinical Oncology (2018)

8569 Background: Nivolumab showed promising results in phase II clinical trials for advanced MM patients with good performance status (PS). Limited data exists for poor PS patients treated outside of clinical trial. We report the efficacy and safety in patients enrolled in a Nivolumab expanded-access program (EAP). Methods: 27 advanced MM patients were enrolled in EAP and treated from 12/2015 - 12/2017 at Mesothelioma Treatment Center at Baylor College of Medicine. Nivolumab 3 mg/kg was administered every 2 weeks until disease progression. Blinded radiologist assessed responses using RECIST 1.1 criteria. Baseline tumor volumes (BTV) were measured. PD-L-1 expression on tumor samples was quantified by PD-L1 IHC 28-8 pharmDx assay. Results: 25 patients were evaluable (2 patients expired before evaluation for response). Median age was 67 years (range 38-89). 72% were male, 56% had PS ≥ 2; epithelioid/ biphasic histologies: 76%/24%. Median follow up time was 6 months (range 2-23). 72% received Nivolumab as second line or later therapy. Median progression free survival was 5 months. Response rate was 24% (3 CR, 3 PR); 9 stable disease (SD), disease control rate (DCR) was 60% (CR+PR+SD). Median duration of response 6 months (range 2-24). For patients with PS ≥ 2, DCR was 50%. For patients treated as first line, DCR was 42%. 20 patients had PDL-1 expression evaluated; DCR was 55% in patients (45%) with PDL1 < 1%, and 63% in those with PD L 1 > 1%. Median BTV was 251 cm3, DCR was 50% for patients with BTV > median and 75% for patients with BTV < median. At 6 months, 52% of patients were alive. Grade 1/2 adverse events (AE) include skin rash (1), body aches/arthritis (2) and enteritis/diarrhea (2). No grade 3/4 AE or treatment related death occurred. Conclusions: Nivolumab is effective and safe for MM patients with poor PS. Durable responses were achieved in a subset of patients. Our limited data showed responses regardless of tumor PD-L1 expression. Smaller BTV may predict response but validation of this observation is warranted.
Prognostic impact of PIK3CA mutation in esophageal cancer: Molecular profiling by next-generation sequencing using formalin-fixed, paraffin-embedded tissues.
Authors: Tomoya Yokota, Masakuni Serizawa, Ayumu Hosokawa, Kimihide Kusafuka, Keita Mori, Toshiro Sugiyama, Yasuhiro Tsubosa, Yasuhiro Koh
Journal: Journal of Clinical Oncology (2018)

e16003 Background: The tumor related gene profiling in esophageal cancer is further required to accelerate the development of novel molecular-targeting drugs. The aim of this study was to evaluate gene alteration profiles of in cancer-related genes in esophageal cancer patients and to correlate them with clinicopathological features, such as smoking status and survival outcomes. Methods: Surgically resected formalin-fixed, paraffin-embedded (FFPE) tissue was collected from 135 consecutive patients with esophageal cancer who underwent esophagectomy at the Shizuoka Cancer Center and University of Toyama between October 2002 and November 2011. Based on the assessment of DNA quality with a quantitative PCR (qPCR)-based assay, uracil DNA glycosylase pretreatment was performed to ensure quality and accuracy of amplicon-based massively parallel sequencing (MPS). Amplicon-based MPS was performed using the Illumina TruSeq Amplicon Cancer Panel. Gene amplification was detected by qPCR-based assay. Protein expression of HER2, MET, EGFR, ALK and HGF was determined by automated quantitative fluorescent immunohistochemistry. Prognostic factors associated with survival were identified by multivariate analyses using the Cox proportional hazards model. Results: Data on genetic alterations was available in 126 patients. Amplicon-based MPS identified frequent gene alterations in TP53 (66.7%), PIK3CA (13.5%), APC (10.3%), ERBB4 (7.9%), FBXW7 (7.9%). There was no association between clinicopathological features or prognosis with smoking status. Multivariate analyses revealed that the PIK3CA mutation and clinical T stage were independent favorable prognostic factors (hazard ratio 0.34, 95% confidence interval: 0.12-0.96, p = 0.042). PIK3CA mutations were significantly associated with APC alterations (p = 0.0007) and BRAF mutations (p = 0.0090). Conclusions: Our study provided profiles of cancer-related genes in Japanese patients with esophageal cancer by next-generation sequencing using surgically resected FFPE tissue, and identified the PIK3CA mutation as a favorable prognosis biomarker.
Abstract 17134: Cardiorenal Syndrome Arising From Chronic Diabetes Causes Maladaptive Carbohydrate Utilisation in the Heart and Kidneys
Authors: Marie A Schroeder, Antoinette Bugyei-Twum, Albert Chen, Albert Tsui, Michelle Mitchell, JF Desjardins, G Kabir, Charles H Cunningham, Kim A Connelly
Journal: Circulation (2015)

Clinical and epidemiological data have identified a cardiorenal syndrome (CRS), in which heart and/or kidney failure accelerates dysfunction in the other organ. There is a need for new therapeutics targeting the mechanisms that cause CRS, in order to treat the whole patient. Here, we tested the hypotheses that 1) chronic diabetes (aged Goto-Kakizaki [GK] rats) would yield a model of CRS, and 2) assessing in vivo cardiorenal metabolism using hyperpolarized 13 C MR spectroscopy (MRS) would identify targets for CRS therapy. Statistical significance between GK rats and Wistar controls was considered at P&lt;0.05. Glycated hemoglobin confirmed that GK rats were diabetic at 20 weeks. Forty-week-old GK rats (n=6) developed proteinuria, LV hypertrophy, and pulmonary congestion. Invasive pressure-volume loops (n=5) demonstrated preserved systolic, yet impaired diastolic, function. Histology demonstrated myocyte and glomerular hypertrophy, interstitial fibrosis and glomerulosclerosis. Intravenous infusion of hyperpolarized [1- 13 C]pyruvate (n=4), followed by MRS data acquisition that alternated between heart and kidney, indicated that carbohydrate metabolism was reprogrammed to promote lactate production over oxidation. In the heart, this was evidenced by reduced pyruvate dehydrogenase flux to form 13 C-bicarbonate, increased 13 C-lactate production, and reduced 13 C-alanine production. In the kidney, 13 C-lactate was increased at the expense of 13 C-alanine. Metabolic reprogramming to produce cardiorenal lactate was likely mediated by inflammation: in both organs, macrophage infiltration and expression of toll like receptor 4 protein were increased. Increased expression of renal Pck1 and G6pc mRNA indicated involvement of maladaptive systemic gluconeogenesis in CRS pathogenesis. Normalizing whole-body carbohydrate utilization represents a novel target for therapy of diabetes-induced CRS.
Paclitaxel and carboplatin chemotherapy in patients with metaststic melanoma refractory to BRAF/MEK inhibitors.
Authors: Igor Samoylenko, Galina Kharkevich, Natalia N. Petenko, Kristina V. Orlova, Igor Sinelnikov, Igor A Utyashev, Anastasia Vikhrova, Irina Markina, Lev V. Demidov
Journal: Journal of Clinical Oncology (2016)

9552 Background: Metastatic melanoma remains a disease with poor prognosis even in patients with BRAF mutation, treated by BRAF/MEK inhibitors. In many countries immune checkpoints inhibitors which could be used for 2nd line treatment are not registered, or not reimbursed. At the same time, experimantal evidence supports enhancing the effectiveness of chemotherapy after blocking the MAP-kinase pathway. We evaluated the immediate effectiveness of chemotherapy in patients after progression or intolerance on BRAF/MEK inhibitors. Methods: We conducted a retrospective analysis of all patients (pts) who received paclitaxel 175 mg / m2 day1 + carboplatin AUC = 5 day 1 (PC) from January 1 2012 to December 30 2015 (n = 51). Group 1 (n = 22) was treated with BRAF / MEK inhibitors (vemurafenib, dabrafenib, trametinib, encorafenib or binimetinib) before PC, group 2 (n = 29) received no inhibitors of BRAF / MEK prior to PC. Results: Both groups did not differ in demographic characteristics (mean age 51.5 ± 12,7 years in group 1 and 53.9 ± 11,5 years respectively, p = 0.5, males 54.5% and 58.6% respectively, p = 0.78), the primary tumor origin (Unknown 18.2% and 17.2% respectively, skin 79.3% and 81.8% respectively p> 0.5), or the tumor stage at the start of chemo (III unresectable 6.9% and 0%, IV M1a 10.3% and 13.6%, IV M1b 17.2% and 18.2%, IV M1c 65.5% and 68.2%, respectively, p>0.5). BRAF mutations rate was higher in Group 1 (95,5% vs 24,1%, p<0.05). NRAS mutations rate did not differ between groups (4,5% and 13,8% respectively, p>0.05). Best overall response rate was calculated (Table 1). The median time to progression in Group 1 was 15 weeks (95% CI 6.12 to 23.87 months) and 7.0 weeks (95% CI 5.17 to 8,28) in Group 2; p = 0.019, HR = 2,14 (95% CI 1.08 to 4.21). The median overall survival can not be calculated correctly due to short follow-up (median 25 weeks). Conclusions: MAP-kinase pathway inhibition could enhance effetivenes of subsequent chemotherapy with PC. To evaluate the clinical significance of this observation further studies are needed. Best overall response rate. Group 1, n(%) Group 2, n(%) P CR 1 (4.5%) 0 >0.05 PR 8 (36.4%) 1 (3.4%) <0.05 OR 9 (40,9%) 1 (3.4%) <0.05 SD 3 (13.6%) 3 (10.3%) >0.05 PD 10 (45.5%) 25 (86.5%) p = 0.007
Abstract 18690: Risk Factors of Cardiovascular Fatal Events: 10 Year Follow up Cohort of 8,224 Subjects in Chile
Authors: Maria Teresa Lira, Sonia Kunstmann, Gloria Icaza, Loreto Nunez
Journal: Circulation (2015)

Introduction: Understanding the contribution of cardiovascular risk factors (CVRF) of cardiovascular fatal events incidence in different populations is crucial to identify susceptible individuals more accurately. Objective: To analyze the 10 year follow up survival of this population with and without CVRF, and to estimate their attributable risk of CV fatal events. Method: A single cohort of 8,224 subjects (35-74y) free from CV disease was screened for CVRF in 2002-2003 using standard methods. From them, 114 suffered a CV fatal event. Comparison of survival and incidence, between exposed/non exposed to CVRF, Preventable Fraction (PF), Population Attributable Fraction (PPF) were estimated (Kaplan Meier, Log Rank, Z statistic). Results: A total of 3,975 men (48.3%) and 4,249 women (51.7%) mean age 50.3 ± 10.1 were follow-up. (mean 10.9y. 89,825 y/person observation). CVRF prevalence was Sedentarism (68,7%), Hypercholesterolemia (55,1%), Abnormal Waist Circumference IDF cutpoint (53,0%) Smoking (40,6%), Hypertension (35,3%), Diabetes M II (5,5%). Survival analysis showed that Hypertension (p&lt;0.0001), Diabetes (p&lt;0.0001), Men (p=0.004) and IDF abnormal Waist Circumference (p=0.02) were associated with higher risk of suffering a fatal CV event in the studied period. Sedentarism, Hypercholesterolemia and Smoking, evidenced no event risk difference (p values 0.4, 0.69 and 0.67, respectively). PF of Diabetes was 73% IC (56.2-82.7) p&lt;0.0001 and the PPF for Hypertension was 60.9% (51.8-68.2) p&lt;0.0001 Conclusions: In this population Hypertension and Diabetes add significant risk of suffering a fatal CV event in a 10y follow-up. 73% of events could be prevented in Diabetics II and up to 61% of CV fatal events incidence may be reduced with Hypertension control. Sedentarism, Hypercholesterolemia and Smoking are highly prevalent but evidenced no difference in survival rates. Identifying local attributable risk of CVRF aids to tailor preventive policies in different countries.
Frequency, cell lineage, and clinical correlates of lymphopenia in untreated T-cell lymphomas (TCL).
Authors: Nathan Denlinger, Sook (Susan) Hwang, David Kline, Eric McLaughlin, Stephanie Fabbro, Jonathan Edward Brammer, Anjali Mishra, Basem M. William, Pierluigi Porcu
Journal: Journal of Clinical Oncology (2017)

e19023 Background: Pre-treatment lymphopenia (Lp) independently predicts survival in TCL. However, lack of knowledge about the lineage of the decreased lymphocyte subset(s) prevents hypothesis formulation on pathophysiology of Lp and its effect on survival. Methods: We retrospectively identified 331 adult patients (pts) with biopsy-proven, newly diagnosed TCL between 2001-2016 at OSU. Pts had no prior chemotherapy or immunosuppressive treatment (tx). Clinical data including flow cytometry (FC) at diagnosis were abstracted from the EMR. Lp was defined as absolute lymphocyte count (ALC) &lt;1,000/µL. Cutaneous TCL (CTCL) stage was defined according to modified EORTC/ISLC criteria. Lymphocyte subsets were defined by FC and reported as proportions of ALC. We examined group differences with Fisher’s Exact or the Wilcoxon Rank Sum tests. Survival was analyzed using Cox regression models. Results: Of 331 pts with TCL, 102 were excluded due to prior tx or incomplete data. Of the 229 pts included, 67 had peripheral TCL (PTCL) and 162 had CTCL; 112 mycosis fungoides/sezary syndrome; 99 (61%) early stage (Stage IA-B), 22 (13%) advanced stage (Stage IIB-IVB), and 41 (26%) cutaneous CD30+ lymphoproliferative disorder (CD30+ LPD). Lp was present in 10% of CTCL, 8% in early stage, 22% in late stage, 12% of CD30+LPD, and 34% of PTCL, with overall frequency of 17%. After median follow up of 1,105 days, Lp was associated with worse progression-free survival (PFS) in CTCL pts with an unadjusted hazard ratio of 3.19 (p=0.19). Adjusting for stage and albumin level on multivariate analysis, Lp retained statistical significance for PFS (HR 3.46, p=.04). For the entire cohort, lymphopenia was associated with inferior OS (p=.0027). Analysis of lymphocyte subsets in late stage CTCL compared to early stage showed a significant decrease in B (CD19+) p=.014, NK (CD56+) p=.012, and CD8+ (p=.0045) cell populations. Conclusions: Lp was prevalent (10-34%) in our cohort of newly diagnosed TCL pts and was associated with worse OS. Lp was more prevalent and lymphocyte subsets were significant altered in pts with advanced stage CTCL. These findings will inform further investigations into mechanisms of Lp in TCL, and its potential as predictive biomarker.
RACK1 to modulate expression of MMP10 via Src/NF-κB pathway in gastric cancer.
Authors: Ling Chen, Hao Chen, Fenglin Liu
Journal: Journal of Clinical Oncology (2017)

e15529 Background: Receptor of activated C kinase 1 (RACK1) is regarded as a scaffolding protein in multiple intracellular signal transduction pathways. Our previous works had demonstrated that RACK1 might involve in progression of gastric cancer, and could be a criterion to predict the good prognosis for the patients after surgical resection. The aim of this study is to explore the regulatory role of RACK1 in matrix metalloproteinase 10 (MMP10) autocrine, and which may be involved in invasion of gastric cancer. Methods: RACK1 knockdown gastric cell lines were established by shRNA. Secretion of cytokines secretion, as well as MMP10 was measured by antibody arrays and enzyme-linked immunosorbent assay. Cell migration and invasion was compared between normal and RACK1 knockdown cells. Pharmacological inhibitors were employed in searching specific signaling pathway. The correlation of RACK1 and MMP10 expression in gastric cancer samples was analyzed by Spearman’s ρ test. Results: Expression of MMP10 was substantially enhanced after knockdown of RACK1 in vitro, which contributed to enhanced migration and invasiveness of gastric cancer cells in autocrine manner. Specific inhibitors of NF-κB and c-Src, as well as overexpression of dominant-negative c-Src mutant, could suppress the expression of MMP10. Finally, an inverse correlation of RACK1 and IL-8 expression was confirmed in gastric cancer samples. Conclusions: Down-regulation of RACK1 resulted in the up-regulation of MMP10 in gastric cancer, which might enhance invasiveness via Src/NF-κB pathway partially.