tbuckley/cabot-search huggingface dataset:
Abstract AP07: USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS
Authors: Melissa A. Merritt, Megan S. Rice, Shelley S. Tworoger, Elizabeth M. Poole
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND: Ovarian cancer is the 5th deadliest cancer among US women. Although clinical characteristics (e.g., disease stage and histology) and treatment (e.g., optimal debulking) predict outcomes, little is known about whether modifiable factors contribute to prognosis. Inflammation and chronic stress have both been implicated in ovarian cancer progression. Therefore, we evaluated whether use of analgesics (aspirin; other non–steroidal anti–inflammatory drugs [NSAIDs], or acetaminophen) or beta–blockers (a common medication for hypertension that targets stress signaling pathways) is associated with ovarian cancer prognosis. METHODS: The Nurses' Health Study is a prospective study of 121,700 US nurses who have completed biennial questionnaires on lifestyle, medications, and disease diagnosis since 1976. Regular aspirin use (&amp;gt; 2 times/week over the prior year) was queried on every questionnaire since 1980; regular use of other NSAIDs or acetaminophen was queried since 1990; and use of beta–blockers was queried since 1988. We used Cox proportional hazards regression to calculate relative risks (RRs) and 95% confidence intervals (CI), adjusting for tumor and personal characteristics. Women diagnosed with stage IV ovarian cancer were excluded from the analysis. RESULTS: Available case numbers ranged from 427–779, depending on the medication. Women who regularly used aspirin after diagnosis had a 45% lower risk of dying due to ovarian cancer (RR: 0.55; 95% CI: 0.35–0.86). Post–diagnosis use of other NSAIDs was associated with a suggestive decreased risk of ovarian cancer death (RR: 0.89; 95% CI: 0.60–1.32). There was no association of pre–diagnosis use of any of the analgesic medications with prognosis, nor was there an association of post–diagnosis acetaminophen use with survival. Similarly, there was no association with either pre–diagnosis (RR: 0.92; 95% CI: 0.69–1.23) or post–diagnosis (RR: 0.93; 95% CI: 0.62–1.40) use of beta blockers. CONCLUSIONS: In this study of analgesic and beta blocker use among ovarian cancer patients, regular use of aspirin after diagnosis appeared to improve survival. Power was limited for some analysis, particularly current use of non–aspirin NSAIDS as there were relatively few current users available for analysis (114 women were current users; 49 of whom died of ovarian cancer during follow–up). Overall, our results suggest that reducing inflammation after diagnosis may be beneficial for improving survival. Future analyses will consider other hypertension medications and well as other modifiable lifestyle factors. Citation Format: Melissa A. Merritt, Megan S. Rice, Shelley S. Tworoger, Elizabeth M. Poole. USE OF COMMON MEDICATIONS AND SURVIVAL AFTER OVARIAN CANCER DIAGNOSIS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP07.
Endometrial carcinoma in the Baby Boomer generation: Tumor characteristics and clinical outcome.
Authors: Mohamed A. Elshaikh, Mira Shah, Richard Cattaneo II, Meredith Mahan, Thomas E. Buekers
Journal: Journal of Clinical Oncology (2012)

e15512 Background: Baby Boomers (BB) enterring retirement are representing a significant burden on medical resources. The unique lifestyle characteristics engendered by the BB may lead to different endometrial cancer characteristics that bear understanding. We sought to characterize surgically staged BB patients with endometrioid carcinoma and compare the results to pre-Boomers (PB) patients. Methods: After reviewing our database of 1,450 patients with endometrial cancer, we identified 595 patients with 2009 FIGO stage I-II uterine endometrioid carcinoma who were born between 1926 and 1964. Their medical records were reviewed in this IRB-approved study. Patients with non-endometrioid carcinoma and those received preoperative therapy or chemotherapy were excluded. Patients were defined as BB (born 1946-1964) or PB (born in 1926-1945). The two groups were compared regarding patient’s demographics, tumor characteristics and survival. Results: All patients were surgically staged with a minimum of two years follow-up.BB group included 234 patients (39%) and PB with 361 patients (61%).Median follow-up for the study cohort was 72 months. Baby boomers had higher BMI (p=0.027), younger age at diagnosis (p=0.002), lower tumor grade (p=0.002), earlier FIGO stage (p=0.023), higher number of lymph dissected (p=0.008), less lymphovascular space involvement (LVSI) (p=&lt;0.034), and less frequent utilization of adjuvant therapy (p=&lt;0.001). However, there was no statistically significant difference found between the BB and PB in regards to local control, disease-specific survival and overall survival. For the study cohort, FIGO stage and tumor grade were independent predictors of local control and disease-specific survival. As to be expected, there was a trend towards shorter overall survival for the PB patients (p=0.063). Conclusions: Athough tumor characteristics were more favorable in the baby boomers generation, local control and survival endpoints were not statistically different compared to pre boomers. As more baby boomers are diagnosed with endometrial carcinoma, further research is warranted to further elucidate the characteristic differences of endometrial carcinoma, if any, in this generation.
A gene signature of chemo-immunization to predict outcome in patients with triple negative breast cancer treated with neoadjuvant chemotherapy.
Authors: Mohamed-Amine Bayar, Carmen Criscitiello, Giuseppe Curigliano, William Fraser Symmans, Christine Desmedt, Herve R. Bonnefoi, Bruno Valentin Sinn, Giancarlo Pruneri, Cecile Vicier, Jean-Yves Pierga, Carsten Denkert, Sibylle Loibl, Christos Sotiriou, Stefan Michiels, Fabrice Andre
Journal: Journal of Clinical Oncology (2017)

575 Background: In patients with triple-negative breast cancer (TNBC), the extent of tumor-infiltrating lymphocytes (TILs) in the residual disease after anthracycline-based neoadjuvant chemotherapy (NACT) is associated with a better prognosis. We aimed to develop a genomic signature from pre-treatment samples to predict the extent of TILs after NACT, and then to test its prognostic value on survival. Methods: Using 99 pre-treatment samples (training set), we generated a four-gene signature that predicts post-NACT TILs using the LASSO technique. Prognostic value of the signature on survival was assessed on the training set (n=99) and then evaluated on an independent validation set including 185 patients with TNBC treated with NACT. Results: A four-gene signature, assessed on pre-treatment samples and combining the expression levels of HLF, CXCL13, SULT1E1, and GBP1 predicted the extent of lymphocytic infiltration after NACT. In a multivariate analysis performed on the training set, a one-unit increase in the signature value was associated with distant-relapse free survival (DRFS) (HR: 0.28, 95%CI: 0.13-0.63, p=0.002). For the validation set, the four-gene signature was significantly associated with DRFS in the entire set (HR: 0.26, 95%CI: 0.11-0.59, p=0.001) and in the subset of patients with residual disease (HR: 0.23, 95%CI: 0.10-0.55, p&lt; 0·001). Conclusions: We developed a four-gene signature of chemotherapy-induced immune-activation, which predicts outcome in patients with TNBC treated with NACT. [Table: see text]
PWE-273 Enhanced liver fibrosis test accurately identifies liver fibrosis and predicts clinical outcomes in alcoholic liver disease: Abstract PWE-273 Table 1
Authors: P M Trembling, J Parkes, S Tanwar, A D Burt, W M Rosenberg
Journal: Gut (2012)

<h3>Introduction</h3> Alcohol is the major cause of chronic liver disease (CLD), the fifth commonest cause of death in the UK. Traditionally, liver fibrosis has been assessed using liver biopsy. The enhanced liver fibrosis (ELF) test is a validated panel of biomarkers of matrix biology. We report the performance of the ELF test in assessing liver fibrosis and predicting liver related clinical outcomes (LRO) (morbidity and mortality attributable to cirrhosis) 7 years after ascertainment in subjects with alcoholic liver disease (ALD). <h3>Methods</h3> Serum samples were obtained at the time of liver biopsy from 81 patients with a clinical diagnosis of ALD. The ELF test was performed at a central laboratory and liver biopsies were staged by one histopathologist using the Scheuer classification. Clinical outcomes were assessed 7 years (median) after biopsy in all patients by reviewing clinical notes, routine data sources and by contacting primary care physicians. Diagnostic performance of the ELF test for detection of histological stages of liver fibrosis, and in predicting LRO was assessed by calculating the area under the receiver operator characteristic curves (AUROC). <h3>Results</h3> Median age was 47 years. Biopsies stages were; F0: 14 subjects (17%); F1: 17 (21%); F2: 5 (6%); F3: 17 (21%); F4: 28 (35%). The ELF test demonstrated good performance in identifying fibrosis at all stages (Abstract PWE-273 table 1). ELF predicted LRO at 7 years, AUROC=0.81 (95% CI 0.71 to 0.90). An ELF score ≥9.5 was better at predicting LRO than cirrhosis on biopsy (p=0.002), correctly predicting outcomes in 84% of patients with LRO compared to 55% predicted by biopsy. <h3>Conclusion</h3> In ALD, the ELF test correlates closely with histological staging conducted by an expert liver pathologist at all stages of fibrosis and performs better than biopsy staging in predicting LRO at 7 years. <h3>Competing interests</h3> P Trembling: None declared, J Parkes: None declared, S Tanwar: None declared, A Burt: None declared, W Rosenberg Grant/Research Support from: Siemens Healthcare Diagnostics.
Efficacy, Safety, and Risk Factors for Failure of Standalone Ab Interno Gelatin Microstent Implantation versus Standalone Trabeculectomy
Authors: Matthew B. Schlenker, Husayn Gulamhusein, Ina Conrad-Hengerer, Alix Somers, Markus Lenzhofer, Ingeborg Stalmans, Herbert Reitsamer, Fritz H. Hengerer, Iqbal Ike K. Ahmed
Journal: Ophthalmology (2017)
Ublituximab and ibrutinib for previously treated genetically high-risk chronic lymphocytic leukemia: Results of the GENUINE phase 3 study.
Authors: Jeff Porter Sharman, Danielle M. Brander, Anthony R. Mato, Suman Kambhampati, John M. Burke, Frederick Lansigan, Marshall T. Schreeder, Scott D. Lunin, Nilanjan Ghosh, Alexander Zweibach, Mikhail Shtivelband, Patrick M. Travis, Jason Claud Chandler, Kathryn S. Kolibaba, Peter Sportelli, Hari P. Miskin, Michael S. Weiss, Ian Flinn
Journal: Journal of Clinical Oncology (2017)

7504 Background: Patients (pts) with high-risk chronic lymphocytic leukemia (CLL) defined by interruptions in TP53 (either by mutation or deletion) or loss of chromosome 11q experience inferior outcomes with ibrutinib (IB) monotherapy (O’Brien ASH 2016). Ublituximab (UTX) is a novel glycoengineered mAb with enhanced ADCC targeting a unique epitope on the CD20 antigen. GENUINE is the first randomized Ph 3 trial conducted assessing the addition of a novel agent to ibrutinib in high-risk rel/ref CLL, and evaluates IB monotherapy vs. UTX + IB. Methods: Eligible pts with rel/ref CLL and centrally confirmed del17p, del11q, and/or a TP53 mutation were randomized 1:1 to receive IB (420 mg QD) alone or with UTX (900 mg on D1, 8, 15 of Cycle 1, D1 of Cycle 2-6, and Q3 Cycles thereafter). There was no limit on number of prior therapies. Prior IB exposure was excluded. The primary endpoint was overall response rate (ORR) per iwCLL 2008 criteria, with secondary endpoints including CR rate, MRD negativity, PFS, time to response (TTR) and safety. Results: 126 pts were randomized at sites in the US and Israel, with 117 pts treated (59 on UTX + IB, 58 on IB alone). Median age 67, median 3 prior therapies (range 1-8), &gt; 70% of were male. High-risk cytogenetics were relatively balanced with ~ 50% of pts having del17p. UTX+IB was well tolerated, with infusion reactions the most prevalent AE (44%, GR3/4 5%). Neutropenia was comparable with the combination (17%, Gr3/4 7% vs. 10%, Gr3/4 9%), and other AE’s were similar or lower with UTX+IB vs. IB alone (all grades), including fatigue (17% vs. 31%), dizziness (12% vs. 21%), contusion (12% vs. 26%), anemia (10% vs. 16%), and myalgia (9% vs. 14%). At median follow-up of 12 mo, best ORR per independent central review was 80% for UTX + IB vs. 47% for IB alone (p &lt; 0.001). While not powered for secondary endpoints, observed advantages were seen in PFS and radiographic CR rate in the UTX + IB arm. CR and MRD confirmation is ongoing. Median TTR for the combo was 1.97 mo vs. 3.8 mo for IB alone. Both arms have responses pending confirmatory assessments. Conclusions: The addition of UTX to IB demonstrated a superior response rate compared to IB alone without additional clinically significant toxicity. Clinical trial information: NCT02301156.
Nonalcoholic fatty liver disease in chronic obstructive pulmonary disease
Authors: Damien Viglino, Ingrid Jullian-Desayes, Mélanie Minoves, Judith Aron-Wisnewsky, Vincent Leroy, Jean-Pierre Zarski, Renaud Tamisier, Marie Joyeux-Faure, Jean-Louis Pépin
Journal: European Respiratory Journal (2017)

Nonalcoholic fatty liver disease (NAFLD) is independently linked to cardiometabolic morbidity and mortality. Low-grade inflammation, oxidative stress and ectopic fat, common features of chronic obstructive pulmonary disease (COPD), might contribute to the development of NAFLD. We aimed to investigate the prevalence of NAFLD and to evaluate the relationship between various types of liver damage and COPD severity, comorbidities and circulating inflammatory cytokines. Validated noninvasive tests (FibroMax: SteatoTest, NashTest and FibroTest) were used to assess steatosis, nonalcoholic steatohepatitis (NASH) and liver fibrosis. Patients underwent an objective assessment of COPD comorbidities, including sleep studies. Biological parameters included a complete lipid profile and inflammatory markers. In COPD patients the prevalence of steatosis, NASH and fibrosis were 41.4%, 36.9% and 61.3%, respectively. In multivariate analysis, SteatoTest and FibroTest were significantly associated with sex, body mass index (BMI), untreated sleep apnoea and insulin resistance, and, in addition, COPD Global Initiative for Chronic Obstructive Lung Disease stage for SteatoTest. Patients with steatosis had higher tumour necrosis factor-α levels and those with NASH or a combination of liver damage types had raised leptin levels after adjustment for age, sex and BMI. We concluded that NAFLD is highly prevalent in COPD and might contribute to cardiometabolic comorbidities.
Abstract 282: Phospholamban Truncation Mutations Including Heart Failure Mutant L39stop Disrupt Membrane Localization.
Authors: Neha Abrol, Nikolai Smolin, Chris Stefonowicz, Seth L Robia
Journal: Circulation Research (2013)

Introduction: Phospholamban (PLB) is an integral sarcoplasmic reticulum (SR) membrane protein, which directly regulates cardiac Ca 2+ handling and contractility by reversibly inhibiting SR Ca 2+ ATPase (SERCA). Our previous studies have suggested that the naturally occurring human heart failure mutation of PLB, L39X disrupts membrane localization. Hypothesis: We hypothesize that the membrane localization of PLB is a prerequisite for PLB oligomerization and interaction with SERCA. The truncation mutations in C-terminus of PLB will disrupt membrane localization, PLB oligomerization, and SERCA regulation. Results and Methods: To identify the minimum length of PLB required for membrane localization and function, we generated a series of C-terminal transmembrane truncation mutants of PLB (tagged N-terminally with Cer or YFP) including L51X, M50X, V49X, I48X, I38X, I33X, and the heart-failure mutant L39X. Confocal microscopy revealed that progressive truncation of the C-terminal residues of PLB resulted in escalating increase in mislocalization of PLB to the cytoplasm and nucleus. In addition, we observed an increased solubilization of PLB as indicated by loss of YFP fluorescence after selective permeabilization of the plasma membrane by saponin. As expected, there was no change in localization of Cer-SERCA upon saponin permeabilization. Next, western blot analysis exhibited a decrease in molecular weight corresponding to the relative sizes of truncation mutants compared to full length PLB, indicating that protein degradation is not the cause of membrane mislocalization. Fluorescence resonance energy transfer analysis revealed that truncating the C-terminal residues of PLB results in a progressive decrease in apparent affinity of PLB oligomerization and interaction with SERCA. Finally, molecular dynamics simulations exhibited that the heart failure mutant L39X was unstable compared to full length PLB pentamer and started protruding out of the bilayer until complete solubilization. Conclusions: Truncating only two C-terminal residues of PLB resulted in significant mislocalization, while deleting five or more residues profoundly disrupted membrane localization, PLB oligomerization and SERCA regulation.
Monitoring of plasma pro-GRP level during EGFR-TKI treatment.
Authors: Yuko Kawano, Atsushi Horiike, Azusa Tanimoto, Toshio Sakatani, Ryota Saito, Kyohei Kaburaki, Noriko Yanagitani, Keita Kudo, Fumiyoshi Ohyanagi, Sachiko Hagiwara, Takeshi Horai, Makoto Nishio
Journal: Journal of Clinical Oncology (2012)

10604 Background: Lung cancers harboring mutations in the epidermal growth factor receptor gene (EGFR) respond to EGFR tyrosine kinase inhibitors (EGFR-TKI), but drug resistance invariably emerges. The major acquired mechanisms of resistance are the EGFR T790M mutation or MET gene amplification. Transformation from NSCLC into small-cell lung cancer (SCLC) has been recently identified in acquired resistance to EGFR-TKI. However, it is difficult to predict the transformation during EGFR-TKI treatment because obtaining serial and sufficient specimens for biopsy is difficult. Pro-gastrin-releasing peptide (Pro-GRP) is a specific and sensitive tumor marker for SCLC. We evaluated the plasma Pro-GRP levels in EGFR-mutant NSCLCs and determined whether plasma Pro-GRP levels could predict SCLC transformation in resistance to EGFR-TKI. Methods: From July 2008 to December 2011, 49 patients with EGFR-mutant NSCLC who received EGFR-TKI treatment were enrolled. Plasma was obtained from these patients before EGFR-TKI treatment and when EGFR-TKI treatment failed. Pro-GRP and CEA levels were measured and compared before and after treatment. Results: Patient characteristics for 49 patients (15 men, 34 women) were as follows: median age, 62 years (41–81 years); histology, 46 adenocarcinomas (AD) and 3 non-AD tumors; and EGFR mutation type, 25 exon 19 deletions and 24 exon 21 L858R. All 49 patients had received EGFR-TKI treatment (45 with gefitinib and 4 with erlotinib); the response to EGFR-TKI treatment was PR in 39 patients, SD in 7, PD in 2, and NE in 1. Positive rate of ProGRP and CEA at pre-EGFR-TKI treatment was 2.0% and 57.2% and that at post-EGFR-TKI treatment was 6.1% and 69.4%, respectively. In 3 of 49 patients, the Pro-GRP levels had increased after treatment, but the CEA level did not increase. Objective responses to cytotoxic chemotherapy were noted in all 3 patients after EGFR-TKI treatment. Conclusions: Monitoring of plasma Pro-GRP during EGFR-TKI treatment may be useful for early detection of SCLC transformation in resistance to EGFR-TKI.
Anti-tumor effect of primaquine compounds in human breast cancer cells
Authors: Gunjan Gakhar, Takahiro Ohira, Sreenivas Battina, Duy H. Hua, Thu Annelise Nguyen
Journal: Cancer Research (2007)

444  Purpose: Cancer in part is caused by the disruption in cell’s homeostasis, affecting its ability to respond to extracellular signals, triggering some intracellular events which affect the gap junctional intercellular communication (GJIC). Cancer cells have reduced or altered GJIC capacity. Therefore, one feasible approach to reduce growth of cancer cells is to enhance/alter GJIC. Substituted quinolines were used in this study to find their effect on human breast cancer cells.  Methods: Parachute assay using dye-labeled donor and acceptor cells was performed to measure GJIC. The results were obtained by the flow cytometric analysis based on the dye transfer between the donor and acceptor cells. Colony growth assay using soft agar was done to determine the effect of the primaquine (PQ) compounds on the colony formation in human breast cancer cells.  Results: Substituted quinolines synthesized based on the computational docking with the gap junction proteins (connexins), showed a tremendous anti-tumor effect in human breast cancer cell lines. PQ1 (500 nM) showed a 20-50 % increase in the GJIC in MDA-MB-453 cells and T47D cell lines. In addition to an increase in GJIC, 80-95 % growth attenuation was observed by PQ1 in colony growth assay. On the contrary, PQ3 decreased the GJIC and increased the colony formation in MDA-MB-453 cells. These results were also observed by Saez et al. that an increase in GJIC is directly related to the anti-tumor effect in human mammary cancer cell line. Further studies are being conducted to know the exact mechanism of action of the substituted quinolines.  Conclusions: So far these results show that PQ compounds have a promising role in exerting anti-tumor activity in human breast cancer cells.
Modulating microRNAs as Novel Therapeutic Targets in Cardiac Fibrosis
Authors: Zhongxiu Chen, Yajiao Li, Ke Dian, Li Rao
Journal: Theranostics (2017)

This commentary highlights the findings by Tao et al. (Theranostics 2016; 6: 2068-2083) that targeting miR-433 may be a potential therapeutic strategy for myocardial fibrosis and subsequently discusses the obstacles and prospects associated with the application of therapeutic microRNAs in anti-fibrosis treatment.