tbuckley/cabot-search huggingface dataset:
Effect of a soy isoflavone intervention on estrogen-related gene expression in the healthy high risk breast.
Authors: S. A. Khan, O. Lee, I. B. Helenowski, D. Ivancic, B. Jovanovic, R. C. Bergan
Journal: Journal of Clinical Oncology (2011)

635 Background: Soy isoflavone consumption may reduce breast cancer risk, and should cause measureable changes in gene expression in the breast. We conducted a Phase IIB trial of soy intervention (1:1 randomization to G- 2535or placebo) and studied effects on the expression of a 28- gene panel, and other biomarkers. Methods: Breast sampling was performed using random fine needle aspiration; cDNA was prepared from 100 ng of purified RNA and amplified. We selected 30 genes: 14 targets of genistein, 9 related to ERα, 5 associated with epithelial atypia, and 2 housekeeping (HSK) genes (GAPDH and HPRT1). Taqman low density arrays (TLDA) were used to perform quantitative PCR reactions. The mean Ct values of triplicates were normalized against HSK and month-6 minus baseline differences were t-tested. ANOVA was used for global comparisons between groups. Results: RNA analyses could be performed on 89 of 98 women (9 had insufficient RNA). The soy group showed increased expression of 18/28 genes post-intervention; Benjamini-Hochberg adjustment reduced this number to 14 genes. These included 7 related to genistein effect (BCL-2, CDKN1A, CDKN2A, DDIT3, FAS, PARP-1, and TP53), 5 related to estrogen response (ESR1, FOXA1, MYB, PGR, SCUBE2) and 2 related to breast atypia (AR and Wnt5B). The control group showed increased expression of 8 genes, but after adjustment, one (IGF-1) remained significant. On comparing the change in gene expression between the soy and control groups, there were significant increases in 4 genes: FAS, FGFR3, FOXA1, MYB, which were non-significant after adjustment. The mean change across all 28 genes in the soy group from baseline to 6-months was 1.56-fold, whereas for control subjects it was 1.25-fold (p=0.02). At 6-months, gene expression in the soy group was 1.66-fold that of HSK, compared to 1.31 for the control subjects (p=0.0001). Conclusions: We saw significant increases in soy-induced genes in the breast following a 6-month intervention suggest an estrogenic effect on the breast. However, spontaneous variation in gene expression resulted in statistically non-significant change between groups. The reproducibility of expression of specific genes needs to be considered in design of future studies.
Early adulthood body mass index, cumulative smoking, and esophageal adenocarcinoma survival.
Authors: Anna Spreafico, Linda E. Coate, Xiaowei Shen, Rihong Zhai, Wei Xu, Zhen-Fei Chen, Zhuo Chen, Devalben Patel, Catherine Brown, Qin Kuang, Kevin Boyd, Matthew Kulke, Li Su, Helen Mackay, Jennifer J. Knox, Rebecca Wong, Gail Darling, David C. Christiani, Geoffrey Liu
Journal: Journal of Clinical Oncology (2014)

10 Background: Little is known about the individual and combined effect of early-adulthood obesity and cumulative smoking on the survival of esophageal adenocarcinoma (EAC) patients. Methods: We analyzed two independent cohorts of EAC patients: 235 patients from Toronto, Canada (TO, 2006-2011) and 329 patients from Boston, USA (BO,1999-2004). Associations between early adulthood body mass index (EA-BMI) and smoking with overall survival (OS) were assessed using Cox proportional hazard models, adjusted for stage, treatment, and other relevant covariates. Results: Median age (range) for TO dataset was 64(29-88)yrs; for BO dataset, 64(21-91)yrs. Males comprised 86% of TO and 89% of BO datasets. 90% of TO and 98% of BO patients were Caucasians. The Median (range) for packyears was 34 (0.2-118; TO) and 34 (0.2-212; BO). The Median (range) for EA-BMI was 24(15-44; TO) and 24(15-47; BO). Median BMI 1 yr prior to diagnosis was 25(16-43; TO) and 25(20-49; BO). 92% of TO and 88% of BO patients had ECOG 0 or 1. Disease stage distribution (early/locally-advanced/metastatic) was 11%/64%/25% (TO) and 30%/52%/18% (BO). For TO, the aHR for smoking was 1.03 (95%CI: 1.02-1.04; p=8E-08) per packyear, while for BO, smoking also independently conferred worse OS, with aHR of 1.007 (95%CI: 1.002-1.01; p=0.003) for each packyear increase. The aHRs for being underweight (EA-BMI&lt;18.5), overweight (EA-BMI 25-30), and obese (EA-BMI&gt;30) in early adulthood were 2.19 (95%CI: 1.0-4.6), 1.89 (95%CI:1.2-3.0), and 2.49 (95%CI:1.5-4.2), respectively for the TO dataset (global p=0.003 for EA-BMI). In BO, the corresponding values were 1.30 (95%CI: 0.8-2.2), 1.45 (95%CI: 1.0-2.5), and 2.39 (95%CI:1.5-3.8), respectively (global p=0.002). In contrast, BMI at one year prior to diagnosis had no association with OS in either study. Conclusions: Elevated BMI in early adulthood and heavy cumulative smoking history are independently associated with increased mortality risk in two North American EAC populations. These survival differences may reflect comorbidity differences, biological differences or both, and offer insight into how key modifiable behaviors in prevention can also affect cancer prognoses. AS, LC, DCC and GL contributed equally.
Transcriptional silencing of dual specificity phosphatase type 2 (DUSP2) abrogates drug-induced apoptosis and predicts cisplatin resistance in head and neck squamous carcinomas
Authors: M. Gasco, N. Syed, J. Taylor, P. Smith, T. Crook, R. Vitiello, M. Merlano
Journal: Journal of Clinical Oncology (2008)

11030 Background: Deregulated mitogen activated protein kinase (MAPK) signalling occurs in many cancers. Mechanisms underlying deregulation of MAPK remain poorly understood. The Dual Specificity Phosphatases (DUSP) are negative regulators of MAPK, but there is little if any evidence of DUSP gene inactivation in human neoplasia. Methods: We used methylation reversal with 5’deazacytidine combined with genome-wide micro-array to identify epigenetically regulated genes in 146 cases of locally advanced, stage III-IV, head and neck squamous cell carcinomas (HNSCC) treated with cisplatin-based chemo-radiotherapy. Analysis of methylation was performed using bisulphite sequencing and methylation specific PCR (MSP). Results: We identified down-regulation of Dual Specificity Phosphatase 2 (DUSP2), a negative regulator of MAPK activity, in HNSCC. Down-regulation of DUSP2 is associated with aberrant methylation in the CpG island located at the 5’end of the gene and is reversible by treatment with demethylating agents. In vitro, down-regulation of DUSP2 confers resistance to cisplatin and ectopic expression restores sensitivity. In locally advanced HNSCC treated with cisplatin-based chemo-radiotherapy, complete response is less common in cases with methylation of DUSP2 (p=0.03). DUSP2 methylation predicts worse overall survival (p=0.02) and progression free survival (p=0.01). The appearance of methylated DUSP2 genomic DNA in serum after apparently successful chemo-radiotherapy is associated with clinical relapse (p=0.04). Conclusions: Our data reveal that DUSP2 is epigenetically regulated in HNSCC and is a determinant of the outcome of cisplatin-based chemo-radiotherapy. Furthermore, epigenetic analysis of DUSP2 in biopsies and in serum may have utility as a biomarker of clinical outcome in HNSCC. No significant financial relationships to disclose.
Refining epidermal growth factor receptor (EGFR) -inhibition-related rash (EIRR) phenotypes with a cetuximab (C) monotherapy stage of a phase II trial for non-small cell lung cancer (NSCLC)
Authors: M. L. Maitland, K. E. Kasza, M. E. Lacouture, W. Liu, K. Soltani, M. F. Kozloff, P. C. Hoffman, R. Salgia, T. Karrison, E. E. Vokes
Journal: Journal of Clinical Oncology (2008)

8089 Background: Papulopustular rash (R) severity by National Cancer Institute Common Terminology Criteria (CTC) across disease settings and EGFR inhibitors correlates with improved tumor response rates. Better characterizing EIRR will advance development of biomarkers for individualizing EGFR-inhibitor therapy. Methods: An EIRR-specific rating scale (ES) (based on a validated rosacea scale: 0 = no R, 1 = isolated lesion¼, 5 = pustules/erythema on face/head/neck + chest/back) and time-to-R were assessed prospectively. 50 patients (pts) with: metastatic/recurrent NSCLC following prior platinum, no prior EGFR inhibitors, and ≤ 2 prior regimens, received C [400mg/m2 then 250mg/m2/week (w)] for 2w and were randomized to combined C and pemetrexed (P) [500mg/m2 q 3 w] or to continue C followed at progression by P. Each pt’s R was rated by CTC and ES scales at baseline, 1, 2, and 3 w and every 3 w until progression. To optimize R phenotypes for future genotype/treatment response studies, we compared grading by CTC and ES and determined the distributions of time to initial and peak grade R. Results: As of 12/20/07, 40 pts treated for ≥ 6w were evaluable for R endpoints. Table 1: for each subject the maximum R grade on each scale was determined, the number of subjects with each pairing of CTC (vertical axis) and ES (horizontal) grade is plotted. The ES scale better distributes CTC 1 grades primarily into ES grades 1 and 2, while CTC 2 grades primarily cluster in ES 4 and 5 (Stuart-Maxwell p < 0.001). The distributions of time to initial R onset were similar for both scales (Wilcoxon signed-rank p=0.32), but time to worst R differed (p=0.01). Conclusions: The ES is a simple rating scale that distributes EIRR more broadly than CTC. Either scale can determine time to initial R onset, but time to maximum grade differs between them. The next step is to validate ES prospectively in earlier treatment settings for association with treatment outcomes. Maximum Grade Rash ES Scale Maximum 0 1 2 3 4 5 Grade 0 5 0 0 0 0 0 Rash 1 0 5 5 2 0 1 CTC Scale 2 0 0 1 2 11 8 Number of Subjects with Each Pair of Maximum Rash Grades on Each Scale Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Amgen, Bristol-Myers Squibb, Eli Lilly, ImClone Systems Incorporated Amgen, Bristol-Myers Squibb, Eli Lilly, ImClone Systems Incorporated Bristol-Myers Squibb
Presentation of early-stage non-small cell lung cancer (NSCLC) without radiographic screening: End of an era?
Authors: E. Taiwo, J. Yorio, J. Yan, D. E. Gerber
Journal: Journal of Clinical Oncology (2011)

e17506 Background: In contrast to other common malignancies, screening for lung cancer is currently not recommended. However, recent evidence suggests that computed tomography (CT)-based screening of select populations may decrease lung cancer mortality. We determined how screening would impact current presentation patterns of early stage disease. Methods: Retrospective analysis of patients diagnosed with stage 1-2 NSCLC from 2000-2009 at the University of Texas Southwestern Medical Center. Data were obtained from tumor registries and medical records. Associations between baseline characteristics and the reason for and type of imaging were assessed using univariate analysis and multivariate logistic regression. Results: A total of 412 patients were included in the analysis. Mean age was 67 years, 49% were men, 70% were white, and 79% had stage I disease. Only 52% were age 55-74 years and had 30+ pack-year smoking history and would therefore have met criteria for the National Lung Screening Trial (NLST). Reason for initial imaging was symptoms in 51%, follow-up of other medical conditions in 43%, and lung cancer screening in 6%. Dominant symptoms were cough/hemoptysis (36%), dyspnea (29%), and chest pain (15%). Chest x-ray was the initial imaging modality in 57%, with CT scans accounting for almost all other cases. Reason for imaging was significantly associated with race (P<0.001), socioeconomic status (P=0.005), and stage (P<0.001), with non-white patients, indigent patients, and those diagnosed with stage 2 disease more likely to present with symptoms. Type of imaging was associated with reason for imaging (P<0.001), year of diagnosis (CXR 67% 2000-2004 vs. 49% 2005-2009; P<0.001), and disease stage (P=0.005). Conclusions: Symptoms remain the dominant reason for initial detection of early stage NSCLC, particularly among underrepresented populations. The proportion of early stage NSCLC initially detected by CT scan, principally for follow-up of other medical conditions, has increased markedly in recent years. If widespread lung cancer screening is implemented, these patterns may persist, as only half of patients currently diagnosed with early stage NSCLC meet NLST eligibility criteria.
Lessons learned from a clinical-research partnership in outpatient palliative care.
Authors: Mary Cunningham, Karla T Washington, Diane L Huenke
Journal: Journal of Clinical Oncology (2016)

238 Background: Palliative care providers and investigators at the University of Missouri developed a clinical-research partnership to conduct a randomized clinical trial (R21CA191165; NCT02427490; PI: Washington) of a technologically-mediated intervention for family caregivers of cancer patients aimed at decreasing caregivers’ distress and improving their quality of life. As the first year of the project drew to a close, the clinician-research team sought to systematically examine the challenges they had encountered conducting research in the outpatient palliative care clinic, which serves a 91-county catchment area that is highly rural and underserved, and to document the strategies they had employed to address them. Methods: Researchers conducted a content analysis of all weekly meeting notes and communication (i.e., emails, memos) related to Year 1 of the project, identifying major categories of identified challenges and related solutions. Results were presented to other members of the team for verification and/or clarification of key points. Results: Researchers identified five categories of challenges and related strategies: adapting processes and materials for use earlier in the cancer trajectory, accommodating a broad range of literacy levels, reaching rural caregivers, responding to technological constraints, and integrating research into the clinic workflow. Selected strategies included consultation with a Patient Advisory Board to revise recruitment materials, broadening inclusion criteria to accommodate rural caregivers without broadband internet availability in their communities, and establishing processes to allow researchers to meet with potential participants between scheduled appointments during busy clinic days. Conclusions: There are many unique considerations clinicians and researchers should take into account when developing partnerships in outpatient palliative oncology settings, particularly within predominantly rural, publicly-funded health care systems. While challenging to develop, such partnerships are instrumental in establishing an evidence base for care for individuals who are otherwise often underrepresented in large research projects. Clinical trial information: NCT02427490.
ARID1A alterations in gastrointestinal cancers as therapeutic opportunities.
Authors: Gargi D. Basu, Tracey White, Janine R LoBello, Kevin R Lau, Michael Syring, Subha Krishnan, Laura Gonzalez, Thomas Royce, Ahmet Kurdoglu, Matthew J Halbert, Jeff Kiefer, Irene Cherni, Jessica Aldrich, Tyler Izatt, Megan Russell, Sara Nasser, John D. Carpten, David W. Craig, Michael J Demeure
Journal: Journal of Clinical Oncology (2016)

671 Background: The gene encoding the AT-rich interacting domain (ARID1A) is a tumor suppressor and a subunit of the Switch/Sucrose Non fermentable (SWI/SNF) chromatin remodeling complex that regulates gene expression. Additionally, ARID1A functions to maintain genomic integrity by interacting with ATR. Mutations in ARID1A have been observed in a number of cancers. Inactivation of ARID1A has been reported to lead to increased sensitivity to inhibitors of PARP and PI3K/AKT pathway. We evaluated ARID1A alterations in gastrointestinal (GI) cancers to identify new therapeutic options. Methods: Comprehensive genomic profiling was performed on 55 GI cancer samples with 28 metastatic and 27 primary samples. Targeted sequencing was performed on 562 cancer associated genes in paired tumor and blood DNA samples. Results: ARID1A alterations were noted in 20% (11/55) of GI cancers. Alterations included frameshift and nonsense mutations, INDELs and structural breakpoints which are predicted to cause loss of ARID1A function. Tumor tissues harboring ARID1A alterations included 2/8 gastro-esophageal cancers, 2/2 duodenal cancers, 3/29 colorectal (CRC) cancers, 2/2 small bowel cancers, and 2/7 bile duct cancers. Mutations in the C-terminal half of ARID1A, known to interact with ATR and mediate its recruitment to double strand breakpoints was present in 2/11 samples. No pathogenic changes in the DNA repair genes (BRCA1/2, CHEK1/2, ATM, ATR or PALB2) or MMR genes were present in the tumors harboring ARID1A alterations. Interestingly, ARID1A mutations frequently coexisted with alterations leading to activation of the PI3K pathway. We found 45% (5/11) samples with mutated ARID1A had pathogenic alterations in PIK3CA, AKT, NF1, STK11, TSC1 and TSC2 genes which may increase sensitivity to PI3K pathway inhibitors. Conclusions: Targeted sequencing demonstrated that ARID1A is a frequent event in GI cancer. Our results suggest there may be a correlation between samples with ARID1A alteration and PI3K/AKT pathway activation which may lead to therapeutic opportunities with PI3K pathway inhibitors. The presence of ARID1A mutations especially those in the C-terminal half may predict clinical utility of PARP inhibitors in GI cancer.
Nurse-like Cells Engage Sigm and Sigd on Chronic Lymphocytic Leukemia (CLL) Cells: Implications for BCR Signaling Activation and Functional Outcome
Authors: Elisa ten Hacken, Cristina Scielzo, Susan O'Brien, William G. Wierda, Michael Keating, Paolo Ghia, Federico Caligaris-Cappio, Jan A. Burger
Journal: Blood (2014)
Cellular and Molecular Identity of Tumor-Associated Macrophages in Glioblastoma
Authors: Zhihong Chen, Xi Feng, Cameron J. Herting, Virginia Alvarez Garcia, Kai Nie, Winnie W. Pong, Rikke Rasmussen, Bhakti Dwivedi, Sandra Seby, Susanne A. Wolf, David H. Gutmann, Dolores Hambardzumyan
Journal: Cancer Research (2017)

Abstract In glioblastoma (GBM), tumor-associated macrophages (TAM) represent up to one half of the cells of the tumor mass, including both infiltrating macrophages and resident brain microglia. In an effort to delineate the temporal and spatial dynamics of TAM composition during gliomagenesis, we used genetically engineered and GL261-induced mouse models in combination with CX3CR1GFP/WT;CCR2RFP/WT double knock-in mice. Using this approach, we demonstrated that CX3CR1LoCCR2Hi monocytes were recruited to the GBM, where they transitioned to CX3CR1HiCCR2Lo macrophages and CX3CR1HiCCR2− microglia-like cells. Infiltrating macrophages/monocytes constituted approximately 85% of the total TAM population, with resident microglia accounting for the approximately 15% remaining. Bone marrow–derived infiltrating macrophages/monocytes were recruited to the tumor early during GBM initiation, where they localized preferentially to perivascular areas. In contrast, resident microglia were localized mainly to peritumoral regions. RNA-sequencing analyses revealed differential gene expression patterns unique to infiltrating and resident cells, suggesting unique functions for each TAM population. Notably, limiting monocyte infiltration via genetic Ccl2 reduction prolonged the survival of tumor-bearing mice. Our findings illuminate the unique composition and functions of infiltrating and resident myeloid cells in GBM, establishing a rationale to target infiltrating cells in this neoplasm. Cancer Res; 77(9); 2266–78. ©2017 AACR.
Antiemetic choice based on economic advantage.
Authors: E. Z. Touloukian, A. Yakan, R. E. Bloom
Journal: Journal of Clinical Oncology (2011)

9018 Background: Some advances in oncology have shown real but small benefits despite vast additional cost. Considering rising costs, strategies have been suggested to encourage patients to select cost effective therapies. The disincentive to choose costly care by using co-pays is often thwarted by Pharma funded co-pay assistance programs. We considered using a “carrot” instead of a “stick”; a cash rebate earned by choosing less costly care. We selected antiemetic therapy as our investigative model, as they do not require a choice that affects survival. Methods: Participants completed a survey that portrayed two antiemetic programs. Program A would have a 60% chance of completely eliminating nausea at a cost of $200 per cycle. Program B would have 80% efficacy with a cost of $800. If A was ineffective the patient could switch to B at any time. Both were described as covered by insurance; however, if program A was selected, the patient would receive half of the savings, a $300 rebate per cycle. Results: 162 patients were evaluated, half received prior chemotherapy. Most were female (79.5%) and had cancer (74.5%). More patients chose program A than program B (58.3% versus 41.6%). Neither having had cancer nor previous receipt of chemotherapy significantly affected program selection (p=1.0 and p=0.52, respectively). Within the cohort who had previously received chemotherapy, 63% of patients who had mild or no nausea chose program A compared to 38% of patients who had moderate to severe nausea (p=0.033). We were greatly surprised that 38% of patients who had trouble with prior nausea still chose the less effective program. If all patients received 6 cycles of program B, it would cost $777,600. By giving the patients a choice and reassigning the 40% of patients whose nausea was ineffectively controlled by program A to program B after one cycle, the cost dropped to $556,820. A $220,780 (28.4%) cost savings without access limitation, half going to the patients and half saved by the payers. Conclusions: We demonstrate that a model of shared cost savings utilizing incentives such as cash rebates can potentially decrease the high cost of some pharmaceuticals while maintaining free patient access. We intend to look further into this by investigating patient choice of expensive, low activity therapy.