tbuckley/cabot-search huggingface dataset:
Inexpensive biomarkers for determining individuals at increased risk for colorectal cancer and hence have the repeat screening colonoscopy after the first normal earlier than guidelines recommend.
Authors: Garry Mahon, Alain Menzel, Marc Pauly, Bernard Weber, Mario-A Dicato
Journal: Journal of Clinical Oncology (2015)

e14653 Background: Screening for colorectal cancer (CRC) is currently based on colonoscopy and other methods such as the fecal occult blood test. We are interested in the role of blood-based genetic markers in CRC screening because of their low cost and relative nonintrusiveness. However, the performance of test strategies involving different numbers of markers of various properties needs further study. Methods: We have shown an association between colorectal cancer (185 case vs. 93 controls) and SNP or deletion status for TGFBR1, GSTT, INSR, telRNA, LRRC1, GSTM1, CHR8 and FOXO1. The information from all these tests was combined using a discriminant function. All information for each subject was condenseded into a single index which gives the best discrimination between cases and controls. The index could be used to distinguish high-risk subjects from low-risk ones, so that the high-risk group would become the focus of further screening and early detection of cancer. Furthermore, various thresholds of the index could be defined to optimise the economic performance of the test for various relative costs of false positives or false negatives. Results: We have used data on the SNPs and deletions to enable us to evaluate the performance of the test based on different numbers of variants. The addition of variants led to increased sensitivity and specificity of the test. For example, with only three variants (TGFBR1, GSTT1 and INSR) the sensitivity was found to be 0.746 and the specificity 0.774. With all eight markers, sensitivity was 0.703 and sensitivity 0.677. Conclusions: Presently the yield of mass screening for colorectal cancer has by its nature a vast number of persons of which the majority will not have cancer. Based on this fact, repeat screening after normal first colonoscopy has a low yield and still misses a certain number of intermediary cancers. By being able to predict a higher risk group, the repeat colonoscopy might have to be done earlier than stated by guidelines for these individuals.
Performance of Screening Ultrasonography as an Adjunct to Screening Mammography in Women Across the Spectrum of Breast Cancer Risk
Authors: Janie M. Lee, Robert F. Arao, Brian L. Sprague, Karla Kerlikowske, Constance D. Lehman, Robert A. Smith, Louise M. Henderson, Garth H. Rauscher, Diana L. Miglioretti
Journal: JAMA Internal Medicine (2019)

Whole-breast ultrasonography has been advocated to supplement screening mammography to improve outcomes in women with dense breasts.To determine the performance of screening mammography plus screening ultrasonography compared with screening mammography alone in community practice.Observational cohort study. Two Breast Cancer Surveillance Consortium registries provided prospectively collected data on screening mammography with vs without same-day breast ultrasonography from January 1, 2000, to December 31, 2013. The dates of analysis were March 2014 to December 2018. A total of 6081 screening mammography plus same-day screening ultrasonography examinations in 3386 women were propensity score matched 1:5 to 30 062 screening mammograms without screening ultrasonography in 15 176 women from a sample of 113 293 mammograms. Exclusion criteria included a personal history of breast cancer and self-reported breast symptoms.Screening mammography with vs without screening ultrasonography.Cancer detection rate and rates of interval cancer, false-positive biopsy recommendation, short-interval follow-up, and positive predictive value of biopsy recommendation were estimated and compared using log binomial regression.Screening mammography with vs without ultrasonography examinations was performed more often in women with dense breasts (74.3% [n = 4317 of 5810] vs 35.9% [n = 39 928 of 111 306] in the overall sample), in women who were younger than 50 years (49.7% [n = 3022 of 6081] vs 31.7% [n = 16 897 of 112 462]), and in women with a family history of breast cancer (42.9% [n = 2595 of 6055] vs 15.0% [n = 16 897 of 112 462]). While 21.4% (n = 1154 of 5392) of screening ultrasonography examinations were performed in women with high or very high (≥2.50%) Breast Cancer Surveillance Consortium 5-year risk scores, 53.6% (n = 2889 of 5392) had low or average (<1.67%) risk. Comparing mammography plus ultrasonography with mammography alone, the cancer detection rate was similar at 5.4 vs 5.5 per 1000 screens (adjusted relative risk [RR], 1.14; 95% CI, 0.76-1.68), as were interval cancer rates at 1.5 vs 1.9 per 1000 screens (RR, 0.67; 95% CI, 0.33-1.37). The false-positive biopsy rates were significantly higher at 52.0 vs 22.2 per 1000 screens (RR, 2.23; 95% CI, 1.93-2.58), as was short-interval follow-up at 3.9% vs 1.1% (RR, 3.10; 95% CI, 2.60-3.70). The positive predictive value of biopsy recommendation was significantly lower at 9.5% vs 21.4% (RR, 0.50; 95% CI, 0.35-0.71).In a relatively young population of women at low, intermediate, and high breast cancer risk, these results suggest that the benefits of supplemental ultrasonography screening may not outweigh associated harms.
Long Noncoding RNA MPRL Promotes Mitochondrial Fission and Cisplatin Chemosensitivity via Disruption of Pre-miRNA Processing
Authors: Tian Tian, Xiaobin Lv, Guokai Pan, Yingjuan Lu, Weixiong Chen, Wang He, Xinyuan Lei, Hanqing Zhang, Mo Liu, Sheng Sun, Zhanpeng Ou, Xinyu Lin, Lei Cai, Lile He, Zhiming Tu, Xinhui Wang, Bakhos A. Tannous, Soldano Ferrone, Jinsong Li, Song Fan
Journal: Clinical Cancer Research (2019)

Abstract Purpose: The overall biological roles and clinical significance of most long noncoding RNAs (lncRNA) in chemosensitivity are not fully understood. We investigated the biological function, mechanism, and clinical significance of lncRNA NR_034085, which we termed miRNA processing–related lncRNA (MPRL), in tongue squamous cell carcinoma (TSCC). Experimental Design: LncRNA expression in TSCC cell lines with cisplatin treatment was measured by lncRNA microarray and confirmed in TSCC tissues. The functional roles of MPRL were demonstrated by a series of in vitro and in vivo experiments. The miRNA profiles, RNA pull-down, RNA immunoprecipitation, serial deletion analysis, and luciferase analyses were used to investigate the potential mechanisms of MPRL. Results: We found that MPRL expression was significantly upregulated in TSCC cell lines treated with cisplatin and transactivated by E2F1. MPRL controlled mitochondrial fission and cisplatin sensitivity through miR–483-5p. In exploring the underlying interaction between MPRL and miR–483-5p, we identified that cytoplasmic MPRL directly binds to pre–miR–483 within the loop region and blocks pre–miR–483 recognition and cleavage by TRBP–DICER-complex, thereby inhibiting miR–483-5p generation and upregulating miR–483-5p downstream target-FIS1 expression. Furthermore, overexpression or knockdown MPRL altered tumor apoptosis and growth in mouse xenografts. Importantly, we found that high expression of MPRL and pre–miR–483, and low expression of miR–483-5p were significantly associated with neoadjuvant chemosensitivity and better TSCC patients’ prognosis. Conclusions: We propose a model in which lncRNAs impair microprocessor recognition and are efficient of pre-miRNA cropping. In addition, our study reveals a novel regulatory network for mitochondrial fission and chemosensitivity and new biomarkers for prediction of neoadjuvant chemosensitivity in TSCC. These findings uncover a novel mechanism by which lncRNA determines mitochondrial fission and cisplatin chemosensitivity by inhibition of pre-miRNA processing and provide for the first time the rationale for lncRNA and miRNA biogenesis for predicting chemosensitivity and patient clinical prognosis.
Measurement of Phosphorylated ERK As a Prognostic and Predictive Marker for MEK Inhibition in Pediatric B-Lymphoblastic Leukemia: A Pilot Study
Authors: Pillai Pallavi Madhusoodhan, Nikki Ann Evensen, Jason Saliba, Ashfiyah Chowdhury, Daniel Newman, Cristina Delgado-Martin, Teena Bhatla, Mignon L. Loh, Michelle L. Hermiston, William L. Carroll
Journal: Blood (2016)
A risk score to predict in-hospital mortality in patients with pancreatic cancer.
Authors: Shuang Yin Zhang, Jimmy Jinghua Jiang, Bassel F. El-Rayes
Journal: Journal of Clinical Oncology (2015)

e15256 Background: The risk factors closely associated with mortality in hospitalized patients with pancreatic cancer (HPC) are not well defined. The aim of this study is to identify these risk factors in order to formulate a risk score for the prediction of mortality in HPC patients. This may be clinically utilized to determine the appropriate acuity of care upon hospital admission. Methods: The Nationwide Inpatient Sample (NIS) database was queried to collect inpatient data from 2009 to 2011 on non-surgical patients with pancreatic cancer. Demographics and comorbidities were analyzed to identify potential risk factors of in-hospital mortality. Variables that were significant in predicting in-hospital mortality were assessed by univariate and multivariate analysis. A predictive model to estimate the probability of mortality was developed by incorporating these risk factors and internally validated by bootstrapping technique. Results: A total of 12,297 patient discharges were identified to meet the inclusion criteria. The mortality rate was 6.2% (N = 765). Independent predictors for in-hospital mortality were age (RR = 1.014/year, p < 0.001), male gender (RR = 1.16, p = 0.05), location of primary tumor (RR = 1.68, p < 0.001 for neoplasm of tail vs head), hospital region (RR = 1.68, p < 0.001 for Northeast vs West), coagulopathy (RR = 2.13, p < 0.001), liver disease (RR = 1.56, p = 0.005), renal failure (RR = 2.04, p < 0.001), pulmonary circulatory disorder (RR = 1.46, p = 0.02), and electrolyte abnormalities (RR = 1.87, p < 0.001). The estimated mortality rates of the predictive model designed from these risk factors ranged from 2% to > 40%. The internal validation of this predictive model showed sufficient discrimination with a concordance index (area under the curve) of 0.66 (95% confidence interval = 0.64-0.67, p < 0.001). Conclusions: Nine risk factors were identified to have a statistically significant impact on the mortality of HPC patients. Coagulopathy, renal failure, and electrolyte abnormalities appear to be the strongest predictors. A risk score may be used to identify HPC with high-risk mortality to guide medical decision-making upon admission.
Impact of new systemic therapies on outcomes of patients with non-metastatic castration resistant prostate cancer (nmCRPC).
Authors: Cecile Vicier, Wanling Xie, Anis Hamid, Carolyn Evan, Christopher Sweeney
Journal: Journal of Clinical Oncology (2019)

244 Background: Treatments and outcomes of men with nmCRPC in routine care are poorly described. We assessed the cumulative impact of new therapies in men who transition through nmCRPC using a single-institution database. Methods: We conducted a retrospective study of consecutive nmCRPC pts enrolled into a hospital-based registry at Dana-Farber Cancer Institute. Pts were analyzed by era of diagnosis of nmCRPC: 2000-2009 (when docetaxel was the only life prolonging metastatic CRPC therapy) (cohort A) and 2010-2018 (when new systemic therapies were approved for mCRPC or in trials for nmCRPC) (cohort B). We collected pt, treatment, metastasis-free survival (MFS) and overall survival (OS) data. Results: 230 men were included: 148 in cohort A and 62 in cohort B. Despite only 39% of cohort B pts receiving new hormonal therapies for nmCRPC, there was no difference in median MFS between both eras: 2.7 yrs (2.1-3.2) in cohort A and 2.2 yrs (1.4-3.3) in cohort B. 30% of pts in cohort A and 53% of pts in cohort B had two or more life prolonging mCRPC therapies at any time (Table). No difference in 3-year OS was seen but 4-year OS was numerically higher in cohort B, with a trend towards improved OS in the new era. Conclusions: In an era with access to more than one life prolonging therapy for mCRPC, greater use of these agents in pts who transition through nmCRPC to mCRPC did not improve 3-year OS but may impact longer term OS. [Table: see text]
Effect of metformin on clinical outcome in advanced HCC patients receiving sorafenib.
Authors: Andrea Casadei Gardini, Giorgia Marisi, Emanuela Scarpi, Mario Scartozzi, Luca Faloppi, Stefano Tamberi, francesco Giuseppe Foschi, Paola Ulivi, Caterina Vivaldi, Gianluca Masi, Nicola Silvestris, Stefano Cascinu, Dino Amadori, Giovanni Luca Frassineti
Journal: Journal of Clinical Oncology (2015)

e15156 Background: Several studies reported an association between type 2 diabetes mellitus (DM2) and hepatocellular carcinoma (HCC). Data from several retrospective studies and meta-analysis have demonstrated a risk reduction of about 50% of developing HCC in cirrhotic patients treated with metformin for DM2. Several in vitro studies have shown anti-tumor activity of metformin (M) in HCC. The aim of this study is to evaluate the different outcomes of patients that have received or not metformin during treatment with sorafenib (S). Methods: 93 patients consecutively treated with sorafenib were analyzed. Of these, 42 patients (45.2%) were diabetic and 31 (33.3%) of these have received M for DM2. Progression-Free Survival (PFS), Overall Survival (OS) and their 95% Confidence Interval (95% CI) were estimated by Kaplan-Meier method and compared with log-rank test. Results: The concomitant use of S and M was associated with a median PFS of 2.6 months (95% CI 1.9-3.3) compared to 5.0 months (95% CI 2.5-8.2) for patients who have not received M (p = 0.029). The concomitant use of S and M was associated with a median OS of 10.4 months (95% CI 3.9-14.4) compared to 15.1 months (95% CI 11.7-17.8) for patients who have not received M (p = 0.014). Conclusions: These findings could be explained by an increased tumor aggressiveness and resistance to S in patients treated with M. M usually enhanced the activity of S , but probably molecular alterations in transporter genes or transcription factors involved in M molecular action and pharmacokinetics could contribute to a different response to these drugs combination. Further studies are needed to confirm the data and to identify possible mechanisms of resistance that may occur during treatment with S.
Validation study of combination chemotherapy in vitro for biliary tract carcinoma.
Authors: Yasunari Sakamoto, Hidenori Ojima, Seri Yamagishi, Chigusa Morizane, Hiroko Hosoi, Shunsuke Kondo, Hideki Ueno, Takuji Okusaka, Yae Kanai
Journal: Journal of Clinical Oncology (2015)

e15115 Background: Gemcitabine (GEM) + cisplatin (CDDP) combination chemotherapy is the first choice for advanced biliary tract carcinoma (BTC). In Japan, clinically, we can use S-1 which is oral fluoropyrimidine prodrug for advanced BTC. The GEM + S-1 therapy has shown promise for the treatment of BTC, and it is in clinical trial. Our aim was to investigate the synergic effects of GEM, CDDP and S-1 in vitro on BTC cell lines. Methods: We evaluated the efficacy of GEM, CDDP, and S-1 by means of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay of 17 BTC cell lines. Moreover, pairwise studies were conducted using the MTT assay, Bliss additivism model, and Combination Index for analysis. In addition, to approximate clinical situation, we demonstrate pairwise studies by the molar concentration of GEMFCDDP7F1. Results: In the single-agent MTT assays, among the 17 tumor cell lines, 11 were sensitive to GEM, 13 to CDDP, and 11 to S-1. In 5 cell lines. In pairwise MTT assays (combination therapy), we demonstrated the synergy of GEM with CDDP in 9 tumor cell lines (53%) and the synergy of GEM with S-1 in 4 tumor cell lines(24%). Also, among the 14 cell lines, 7 (50%) were demonstrated the synergy by GEMFCDDP = 7F1 concentration. Conclusions: Although, the effect of GEM + S-1 therapy is unknown in clinical practice. In our study, GEM + S-1 therapy have less synergic effect than Gemcitabine + cisplatin therapy, and pairwise study have the potential to become promising method.
Reply:
Authors: Virginia Hernández‐Gea, Juan Carlos Garcia‐Pagan
Journal: Hepatology (2019)

Potential conflict of interest: Nothing to report. We thank Dr. Lo for his interest in our recent publication and for his correspondence. We agree that selection bias is a major concern in observational studies, and therefore we carried out an extensive multianalysis approach to minimize it as much as possible. First, we performed our comparative analysis after adjusting the population included for propensity score and covariates that were shown to be predictors for receiving preemptive transjugular intrahepatic portosystemic shunt (p‐TIPS), therefore reducing the potential clinicians selection bias; moreover, the mortality observed in the group not receiving p‐TIPS was the expected, according with the recently described Model for End‐Stage Liver Disease–predictive model, and significantly higher than that observed in patients receiving p‐TIPS, confirming the benefit of p‐TIPS in the population evaluated. Regarding the possible confounding effect of liver transplantation and of lost to follow‐up, we want to emphasize that survival was estimated using the cumulative incidence function with orthotropic liver transplant as a competing risk, and lost to follow‐up was similar in patients receiving or not p‐TIPS. Besides, a recent Chinese multicenter observational study recently confirmed our data and demonstrated the survival benefit of Child‐Pugh C (<14 points) patients admitted with acute variceal bleeding.1 Of note, the metanalysis mentioned by Lo et al. showed a trend toward a better survival in Child‐Pugh C patients (odds ratio = 0.34; 95% confidence interval [CI] = 0.10‐1.11; P = 0.074), despite a high heterogeneity between studies (P = 0.06; I 2 = 60%), suggesting that these data should be interpreted with caution. Indeed, when examining carefully the data, the study disagreeing the most was retrospective, using historical controls (that may have a different risk) and with a more permissive high‐risk definition. In our opinion, all the data available so far1 strongly support p‐TIPS as the best strategy to improve survival in Child‐Pugh C patients, provided the criteria of the above‐mentioned studies are fulfilled.
Abstract P157: Association of Rurality With Death in Patients With Heart Failure: a Community Study
Authors: Sheila Manemann, Jennifer St. Sauver, Lila Finney Rutten, Matteo Fabbri, Alanna Chamberlain, Susan Weston, Ruoxiang Jiang, Veronique L Roger
Journal: Circulation (2019)

Background: Previous studies have indicated that living in a rural or non-urban area may be associated with poor health outcomes. However, data on rurality and death in heart failure (HF) are scarce. Methods: Residents from 11 southeast MN counties with a first-ever code for HF (including codes ICD-9 428 and ICD-10 I50) between 1/1/2013 and 12/31/2016 were identified. Resident address was geo-coded and classified according to the Rural-Urban Commuting Area (RUCA) codes, which classifies US census tracts to measure population density, urbanization and daily commuting. Rurality was defined as living in a non-metropolitan area. Cox proportional hazards regression was used to determine the association between living in a rural vs. urban area and death. Results: Among 6,996 patients (mean age 73 years, 52% male), 54% of patients lived in a rural area. These patients were older and had a lower level of educational attainment and comorbidity burden (p&lt;0.001). After a mean (SD) follow-up of 2.9 (1.3) years, 1,856 deaths occurred. Living in a rural area was univariately associated with a higher risk of death (HR 1.20, 95% CI: 1.09-1.31; Table). After adjustment for age, sex, education status and comorbidity burden, rurality remained associated with an increased risk of death (HR 1.15; 95% CI: 1.04-1.27). Conclusions: Among patients with HF, living in a rural area is associated with an increased risk of death. Further study to identify and address the mechanisms through which rural residence influences mortality in patients with HF is needed.
Penile squamous cell carcinoma is genomically similar to other HPV-driven tumors.
Authors: Jad Chahoud, Barrett Z. McCormick, Frederico Netto, Priya Rao, Curtis R. Pickering, Curtis Alvin Pettaway
Journal: Journal of Clinical Oncology (2019)

505 Background: PSCC is rare with limited treatment options for advanced disease. There have been no published genome-wide studies on the genetic alterations of PSCCs or on the differences between HPV (+) and HPV (−) PSCCs. We report the largest WES analysis of PSCC. Methods: We identified 34 pts diagnosed with PSCC, at MD Anderson, with primary tumors or metastatic lesions sufficient for WES. Patients, tumor and surgical characteristics were available through the MD Anderson prospective registry. Genomic DNAs from both Fresh frozen macrodissected tumors and paired-normal penile tissues were analyzed by WES. Results: Patients clinical characteristics are summarized in table 1. Eight of the most frequently mutated PSCC genes (NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%)) were significantly mutated in other SCC tumor types. Importantly, 8/8 and 5/8 genes were significant in head and neck SCC and cervical SCC, respectively, including 3 (CASP8, FXBW7, and EP300) genes that are only significant in these tumor types. TP53 mutations were associated with HPV (-) PSCC and were absent in HPV (+) SCC (P= 0.03). EP300 mutations were associated with advanced primary tumor stage. Of note we did not identify unique mutations associated with lymph node status. Conclusions: This is the largest systematic analyses of PSCC genomics uncovering the involvement of multiple cancer genes that are likely to be contributing to tumor development including; TP53, squamous differentiation, cell cycle, and chromatin regulation. PSCC are genomically similar to other HPV related SCC, and provide a therapeutic rationale for considering strategies successful in HPV related cancers. [Table: see text]