tbuckley/cabot-search huggingface dataset:
Abstract MIP-050: NON–CODING GENETIC ABERRATIONS IN HIGH GRADE SEROUS OVARIAN CANCER
Authors: Pradeep Chaluvally–Raghavan
Journal: Clinical Cancer Research (2017)

Abstract BACKGROUND The 3q26.2 loci amplification is present in a large proportion of high grade serous ovarian cancer (HGSOC) is less frequently curable disease in the clinic. The 3q26.2 loci, which is present in at least 35% of HGSOC, is large and structurally complex suggesting that multiple coding genes of the amplicon contribute to tumor initiation and progression either alone or through cooperative activity. Our high resolution SNP array mapping of 3q26.2 amplicon identified microRNAs miR569 and miR551b are highly amplified in addition to the coding genes in a large set of ovarian cancer samples. Potential role of miR569 and miR551b are not characterized previously in the context of ovarian cancer. Herein our studies provide new mechanisms underlying the oncogenic role of microRNAs amplified in 3q26 in ovarian cancer. RESULTS We demonstrated a strong correlation between 3q26.2 amplification and overexpression of miR569 in patient's samples of ovarian cancer. Using target based analysis, AGOCLIP methods, cellular and molecular approaches, we have demonstrated that 3q26 microRNAs altered the expression of TP53INP1, P53AIP1, and STAT3, which are critical regulators of survival and proliferation of ovarian cancer cells. Employing in silico and in vitro experiments, we have showed that miR569 directly targets and inhibited the expression of p53 induced tumor suppressor gene TP53INP1. miRNAs are thought to primarily downregulate the gene expression by binding 3'UTR of target genes. Our recent results identified a novel action of microRNAs, that miR551b can bind to the promoter of STAT3 and activate STAT3 transcription by recruiting transcription factors and RNA–Polymerase–II to the promoter. In sum, the discovery of miRNAs and lncRNAs as potent regulators of RNA stability and translation, dramatically changed our understanding of the mechanisms controlling the gene expression and protein levels. We are expecting that our studies will identify new biomarkers and novel targets for therapy. Citation Format: Pradeep Chaluvally–Raghavan, PhD. NON–CODING GENETIC ABERRATIONS IN HIGH GRADE SEROUS OVARIAN CANCER [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 MIP-050.
Overuse of Chest CT in Patients With Stage I and II Breast Cancer: An Opportunity to Increase Guidelines Compliance at an NCCN Member Institution
Authors: Barbara Dull, Andrew Linkugel, Julie A. Margenthaler, Amy E. Cyr
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) recommend that patients with clinical stage I/II breast cancer undergo advanced imaging for staging only when symptomatic. Regardless, many asymptomatic patients undergo chest CT. The goal of this study was to assess the use and results of chest CT in these patients at an NCCN Member Institution. Methods: Patients with breast cancer diagnosed between 1998 and 2012 were identified in a prospectively maintained database. All patients with clinical stage I/II disease who did not receive neoadjuvant chemotherapy were included. Data collected included demographics, tumor size, node status, chest CT within 6 months of diagnosis, imaging findings, need for additional workup, and identification of metastatic disease. Appropriate statistical tests were used for analysis. Results: From 1998 to 2012, 3,321 patients were diagnosed with early-stage breast cancer. Of these, 2,062 (62.1%) had clinical stage I breast cancer at diagnosis and 1,259 (37.9%) had stage II; 227 patients (11%) with stage I and 456 (36.2%) with stage II breast cancer received staging chest CT. Of patients undergoing CT, 184 (26.9%) were found to have pulmonary nodules, which measured ≤5 mm for 128 patients (69.6%), 5 to 10 mm for 46 patients (25.0%), 11 to 20 mm for 6 patients (3.2%), and ≥20 mm for 4 patients (2.2%). Patients undergoing chest CT for staging subsequently underwent a mean of 2.34 (range, 0–16) additional CTs in follow-up. Of all patients undergoing chest CT for staging, only 9 (1.3%) were ultimately diagnosed with pulmonary metastases at an average of 25 months (range, 0–97) after initial staging chest CT. Conclusions: A significant percentage of patients with stage I/II breast cancer underwent unnecessary chest CT as part of their initial workup. Nearly one-third of these patients were found to have pulmonary nodules, but only 1.3% were ever diagnosed with pulmonary metastases. Adherence to NCCN Guidelines will reduce the excessive use of CT chest imaging.
Vaccine priming is restricted to draining lymph nodes and controlled by adjuvant-mediated antigen uptake
Authors: Frank Liang, Gustaf Lindgren, Kerrie J. Sandgren, Elizabeth A. Thompson, Joseph R. Francica, Anja Seubert, Ennio De Gregorio, Susan Barnett, Derek T. O’Hagan, Nancy J. Sullivan, Richard A. Koup, Robert A. Seder, Karin Loré
Journal: Science Translational Medicine (2017)

Vaccine responses are initiated in vaccine-draining lymph nodes and depend on the efficiency by which adjuvants influence antigen uptake.
Real-time magnetic resonance imaging (MRI) of the time course of myocardial injury and cell death in a canine model of regional ischemia and reperfusion
Authors: PM Burns, P Kearns, P Vargas-Pinto, Y Nishijima, Y Ding, M Jekic, H Lin, J Lian, K Huang, OP Simonetti, JL Zweier
Journal: Journal of the American College of Cardiology (2008)
Dopamine signaling and myopia development: What are the key challenges
Authors: Xiangtian Zhou, Machelle T. Pardue, P. Michael Iuvone, Jia Qu
Journal: Progress in Retinal and Eye Research (2017)

In the face of an "epidemic" increase in myopia over the last decades and myopia prevalence predicted to reach 2.5 billion people by the end of this decade, there is an urgent need to develop effective and safe therapeutic interventions to slow down this "myopia booming" and prevent myopia-related complications and vision loss. Dopamine (DA) is an important neurotransmitter in the retina and mediates diverse functions including retina development, visual signaling, and refractive development. Inspired by the convergence of epidemiological and animal studies in support of the inverse relationship between outdoor activity and risk of developing myopia and by the close biological relationship between light exposure and dopamine release/signaling, we felt it is timely and important to critically review the role of DA in myopia development. This review will revisit several key points of evidence for and against DA mediating light control of myopia: 1) the causal role of extracellular retinal DA levels, 2) the mechanism and action of dopamine D1 and D2 receptors and 3) the roles of cellular/circuit retinal pathways. We examine the experiments that show causation by altering DA, DA receptors and visual pathways using pharmacological, transgenic, or visual environment approaches. Furthermore, we critically evaluate the safety issues of a DA-based treatment strategy and some approaches to address these issues. The review identifies the key questions and challenges in translating basic knowledge on DA signaling and myopia from animal studies into effective pharmacological treatments for myopia in children.
Locoregional surgery of the primary tumor in stage IV breast cancer patients.
Authors: Ying Wang, Yunfang Yu, Kai Chen, Tuping Fu, Herui Yao
Journal: Journal of Clinical Oncology (2017)

566 Background: Existing guidelines lack clear recommendations for the role of locoregional treatment for the primary tumor in women with stage IV breast cancer. We aimed to compare the effectiveness of locoregional surgery with no surgery of the primary tumour in stage IV breast cancer patients. Methods: Eligible studies were randomized clinical trials (RCTs) that investigated the effect of locoregional surgery versus no surgery of the primary tumour in stage IV breast cancer patients. The primary outcome was overall survival (OS), measured as hazard ratios (HRs). Secondly outcomes included 2-year and 3-year OS, expressed as odds ratios (ORs). Meta-analyses and trial sequential analysis (TSA) were conducted. Quality was evaluated using the GRADE. Results: Data were included from four RCTs involving 767 participants, including 377 who underwent locoregional surgery and 390 who with no surgery. The median follow-up was 28.6 months (95% confidence interval (CI) 24.1 to 33.9). In a meta-analysis of these trials, the low-quality evidence indicated that locoregional surgery versus no surgery did not significantly affect OS (HR = 0.87, 95% CI 0.59 to 1.29, P = 0.490), 2-year OS (OR = 1.23, 0.66 to 2.30, P = 0.510), or 3-year OS (OR = 1.08, 0.94 to 1.25, P = 0.263). TSA showed that more trials were needed before reliable conclusions could be drawn regarding in both 2-year and 3-year OS. Across the subgroup analysis of OS, we found the moderate-quality evidence that locoregional surgery followed by chemotherapy versus chemotherapy alone resulted into a significantly improved survival (HR = 0.65, 95% CI 0.49–0.87, P = 0.004); but no statistically significant difference was identified in term of response to chemotherapy with or without locoregional surgery (HR = 1.06, 95% CI 0.83–1.36, P = 0.632). Conclusions: The current evidence suggests that locoregional surgery followed by chemotherapy, compared with chemotherapy alone, was beneficial for prolonging OS in patients with stage IV breast cancer, but surgery did not impact OS among patients who have responded to chemotherapy.
Abemaciclib for the treatment of brain metastases (BM) secondary to hormone receptor positive (HR+), HER2 negative breast cancer.
Authors: Sara M. Tolaney, Nancy U. Lin, Donald Thornton, Suzanne Klise, Timothy Michael Costigan, P. Kellie Turner, Carey K. Anders
Journal: Journal of Clinical Oncology (2017)

1019 Background: Abemaciclib is an oral selective CDK4 and CDK6 inhibitor administered on a continuous dosing schedule, which has demonstrated clinical activity and an acceptable safety profile in patients (pts) with heavily pre-treated HR+ metastatic breast cancer (MBC). Abemaciclib has been shown preclinically to cross the blood-brain barrier, providing rationale for testing this agent in pts with BM. Furthermore, as previously presented, levels of abemaciclib similar to plasma were detected in resected BM in a subset of pts with HR+, HER2- MBC in this study. Methods: Study I3Y-MC-JPBO is an open-label, Phase 2, Simon 2-Stage trial evaluating the safety and efficacy of abemaciclib 200 mg BID in pts with new or progressive BM secondary to HR+ MBC, NSCLC, or melanoma. Eligible pts in Part B (the focus of this presentation) include pts with HR+, HER2- MBC who have ≥1 measurable brain lesion. The primary objective was objective intracranial (IC) response rate as defined by Response Assessment in Neuro-Oncology BM response criteria. Secondary objectives (IC related) include best overall response, duration of response, disease control rate, and clinical benefit rate. Exploratory objectives include assessment of drug concentrations in resected tumors. Safety, tolerability, and PK of abemaciclib were also assessed. Stage 1 includes 23 pts; if &lt; 2 of the 23 pts respond to abemaciclib, futility is met. However, if ≥2 respond, 33 additional pts are to be enrolled to Stage 2. Results: This Stage 1 efficacy analysis included 23 pts; 32 pts were included in the safety analysis. Although 5 pts were considered nonevaluable, 2 pts (8.7%) had confirmed partial response (PR) (meeting the predefined threshold for advancement to Stage 2); enrollment is ongoing. At the time of the analysis, the 2 pts with PR had completed 14 and 15 cycles each (21d cycles) of therapy. The majority of adverse events were gastrointestinal in nature, consistent with previous studies of abemaciclib. Conclusions: This study has provided preliminary evidence that abemaciclib penetrated BM in pts with HR+, HER2- MBC and had antitumor activity in this population. Final results will be presented following Stage 2 analyses. Clinical trial information: NCT02308020.
Third line chemotherapy in metastatic colorectal cancer: A single institution experience.
Authors: Wilver Federico Carbonel Luyo, Zoila Elizabeth Carranza Montenegro, Antia Cousillas Castineiras, Manuel Constenla Figueiras, Francisco Ramon Garcia Arroyo, Francisca Fernandez Ribeiro, Elena Gallardo Martin, Isabel Lorenzo Lorenzo, Lidia Maria Vazquez Tunas
Journal: Journal of Clinical Oncology (2013)

e14706 Background: The median overall survival for metastatic colorectal cancer (mCRC) has been increasing over the past two decades and is very common to see longer survivals with a good performance status. They may benefit from treatment after progression to second line chemotherapy. In this context, raltitrexed is an active and simple-administration drug that appears to be a convenient treatment. Our objetive was to determine if there is benefit in patient retreated with oxaliplatin based chemotherapy (OBCT), CPT 11 based-chemotherapy (CBCT) or raltitrexed every 21 days in a third line chemotherapy (3L CT) setting. Methods: We conducted an analytical epidemiological study, using descriptive analysis and Long Rank test. Between 2009 and 2012, were treated 28 mCRC with a 3L CT and 11 of which recieved adyuvant chemotherapy. All were treated previously with OBCT and CBCT. Treatment consisted in OBCT, CBCT or raltitrexed in monotherapy. Results: Male predominance in proportion of cases (67.9%) with a median of 62 years old (range 27-79 and 90% between 45-75) and 78.6% had aceptable clinical condition (ECOG 0-1). Median CEA level before 3L CT was 61.1 ng/dL. Sixteen patient had rectal cáncer, mostly male (75%). In our sample, the mCRC overall survival was 30.4 months (95% confidence interval(CI), 14.3 to 46.4) . Patients retreated with OBCT or CBCT had the same survival than treated with a particular sequence that includes OBCT, CBCT and raltitrexed in monotherapy (7.5 months (CI, 5.81 to 9.2) vs 7.4 months (CI, 2.5 to 12.3); p&lt;,598). Raltitrexed in monotherapy tends to have better survival in comparison with OBCT or CBCT, no reaching statistical significance (14.3 months (CI, 3.6 to 24.9) vs 7.5 months (CI, 5.9 to 9.1) vs 7.4 months (CI, 0.0 to 18.1); p&lt;,755). The most common toxicity with raltitrexed was asthenia grade 1 (32,1%), with OBCT was neurotoxicity grade 1 (75%) and with CBCT was abdominal pain grade 1 (55.5%). Conclusions: In our serie, there was a male predominance and median mCRC survival is better than reported in the literature. There is a trend for a better survival with raltitrexed in monotherapy with a good toxicity profile in a 3L CT setting. Future studies are needed to verify these findings.
miR-193a-3p is a Key Tumor Suppressor in Ulcerative Colitis–Associated Colon Cancer and Promotes Carcinogenesis through Upregulation of IL17RD
Authors: Joel Pekow, Katherine Meckel, Urszula Dougherty, Yong Huang, Xindi Chen, Anas Almoghrabi, Reba Mustafi, Fatma Ayaloglu-Butun, Zifeng Deng, Haider I. Haider, John Hart, David T. Rubin, John H. Kwon, Marc Bissonnette
Journal: Clinical Cancer Research (2017)

Purpose: Patients with ulcerative colitis are at increased risk for colorectal cancer, although mechanisms underlying neoplastic transformation are poorly understood. We sought to evaluate the role of microRNAs in neoplasia development in this high-risk population.Experimental Design: Tissue from 12 controls, 9 ulcerative colitis patients without neoplasia, and 11 ulcerative colitis patients with neoplasia was analyzed. miRNA array analysis was performed and select miRNAs assayed by real-time PCR on the discovery cohort and a validation cohort. DNA methylation of miR-193a was assessed. Following transfection of miR-193a-3p, proliferation, IL17RD expression, and luciferase activity of the 3'UTR of IL17RD were measured. Tumor growth in xenografts as well as EGFR signaling were assessed in HCT116 cells expressing IL17RD with either a mutant 3' untranslated region (UTR) or wild-type (WT) 3'UTR.Results: miR-31, miR-34a, miR-106b, and miR-193a-3p were significantly dysregulated in ulcerative colitis-neoplasia and adjacent tissue. Significant down-regulation of miR-193a-3p was also seen in an independent cohort of ulcerative colitis cancers. Changes in methylation of miR-193a or expression of pri-miR-193a were not observed in ulcerative colitis cancer. Transfection of miR-193a-3p resulted in decreased proliferation, and identified IL17RD as a direct target of miR-193a-3p. IL17RD expression was increased in ulcerative colitis cancers, and miR-193a-3p treatment decreased growth and EGFR signaling of HCT116 cells in xenografts expressing both IL17RD with WT 3'UTR compared with cells expressing IL17RD with mutant 3'UTR.Conclusions: miR-193a-3p is downregulated in ulcerative colitis neoplasia, and its loss promotes carcinogenesis through upregulation of IL17RD. These findings provide novel insight into inflammation-driven colorectal cancer and could suggest new therapeutic targets in this high-risk population. Clin Cancer Res; 23(17); 5281-91. ©2017 AACR.
Prospective study of UDP-glucuronosyltransferase (UGT) 2B17 genotype and exemestane (Exe) pharmacokinetics (PK) and pharmacodynamics (PD) in Asian, hormone receptor (HR) positive, metastatic breast cancer (MBC) patients.
Authors: Robert John Walsh, Soo Chin Lee, Kok Yong Seng, Ling-Zhi Wang, Gwo Fuang Ho, Samuel Guan Wei Ow, Nesaretnam Barr Kumarakulasinghe, Raghav Sundar, Xiao Wen Lee, Hui-Ling Yap, Anand Devaprasath Jeyasekharan, Angela Pang, Jingshan Ho, Chee Seng Tan, Yi Wan Lim, Rozita Abdul Malik, Wan Zamaniah Wan Ishak, Boon Cher Goh, Bee Choo Tai, Andrea Li Ann Wong
Journal: Journal of Clinical Oncology (2017)

1056 Background: The active metabolite of Exe, 17-dihydroexemestane (17DhExe), is glucuronidated by UGT2B17 to inactive exemestane-17-O-glucuronide (Exe17- O-glu). UGT2B17*2/*2null genotype is 7 times more common in Asians than Caucasians and leads to reduced Exe glucuronidation in vitro. We studied Exe PK and PD in MBC patients genotyped for UGT2B17. Methods: Eligible patients (HR+ MBC; ≥1 line of endocrine therapy) received Exe 25mg OD till progression. UGBT2B17 genotype was correlated with day 29 (D29) steady-state PK (Exe and metabolites), change in PD biomarkers (estrone and androstenedione) at D29 vs baseline (BL), objective response rate (ORR) [sum of complete and partial responses], and clinical benefit rate (CBR) [response or stable disease ≥ 24 weeks]. Results: In 64 patients enrolled, CBR was 25%; ORR was 3%. Frequencies of UGT2B17*2/*2, UGT2B17*1/*2 and UGT2B17*1/*1 were 72%, 26% and 2%, respectively. PD and PK data were available for 54 and 53 patients respectively. Mean Exe17- O-glu AUC and C max were significantly lower, and mean 17DhExe C max numerically higher in patients with UGT2B17*2/*2 vs other genotypes (Table 1). 17DhExe C max was higher in patients with clinical benefit vs none (5.6 vs 3.8 ng/ml, p=0.02). Frequency of desired PD effect (rise in androstenedione and fall in estrone at D29 vs BL) was 22%. Exe plasma active index (PAI) [Table 1] was higher in patients with a fall in D29 estrone vs those without (14.7 vs 9.5, p=0.05). Conclusions: UGT2B17 genotype affects Exe PK and may have significant PD correlates. Larger studies to examine effects on clinical treatment efficacy are needed. Clinical trial information: NCT01655004. [Table: see text]
Abstract AP03: OVARIAN CANCER AND PULP AND PAPER MANUFACTURING IN THE US: A GEOSPATIAL ANALYSIS
Authors: Carol L. Hanchette
Journal: Clinical Cancer Research (2017)

Abstract The goals of this research were to: 1) utilize geographic and geostatistical methods available in geographic information systems (GIS) software to gain an in-depth understanding of the spatial distribution of ovarian cancer incidence rates, at national, state and county levels; and2) based on patterns identified from the first goal, conduct a preliminary assessment of the hypothesized association between ovarian cancer occurrence and pulp and paper manufacturing. We used the following approaches: 1) exploratory spatial data analysis of 2008-2012 ovarian cancer incidence at the county level – choropleth mapping, trend surface analysis, spatial autocorrelation and hot spot analysis;2) exploratory spatial data analysis of pulp and paper production sites, using EPA's Toxic Release Inventory data from 1988-2012;3) geographically weighted regression analysis to examine the relationship between ovarian cancer incidence and toxic emissions to air and surface water; and4) preliminary fate and transport modeling of a case study area (Wisconsin) to examine river effluent and atmospheric dispersion of chemical by-products. Results indicate that there is a strong north-to-south trend (i.e. higher rates in the north) in ovarian cancer incidence at both state and county levels. This coincides with historically higher numbers of pulp and paper mills in northern states. Exceptions to this overall trend are statistically significant multi-county clusters of high rates in Georgia and Alabama, both of which have high levels of pulp and paper production. The hypothesis is weakly supported by geographically weighted regression, when migration patterns are taken into account. In conclusion, this research indicates that there is some support, at an ecological level, for the hypothesized association between ovarian cancer incidence rates and pulp and paper production. Citation Format: Carol L. Hanchette, PhD. OVARIAN CANCER AND PULP AND PAPER MANUFACTURING IN THE US: A GEOSPATIAL ANALYSIS [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 AP03.