bluuebunny/crossref_metadata_2025_split huggingface dataset:
Connecting Cancer to Its Causes Requires Incorporation of Effects on Tissue Microenvironments
Authors: DeGregori James 
Published: July 2017

Abstract
In a recent article in Science, Tomasetti and colleagues present an expanded model for cancer risk, which they claim demonstrates the relative contribution of mutations caused by replication errors, environment, and heredity. The foundation of this model is the theory that the overwhelming driver of cancer risk is mutations. This perspective will present experimental evidence and evolutionary theory to challenge the basis of this underlying theory. An argument will be presented that the mutation-centric model of cancer suggests unrealistic solutions to cancer and distracts the research community from more promising approaches that consider tissue context. Cancer Res; 77(22); 6065–8. ©2017 AACR.
Protecting Privacy in Large Datasets—First We Assess the Risk; Then We Fuzzy the Data
Authors: Ursin Giske , Sen Sagar , Mottu Jean-Marie , Nygård Mari 
Published: July 2017

Abstract
Background: Privacy of information is an increasing concern with the availability of large amounts of data from many individuals. Even when access to data is heavily controlled, and the data shared with researchers contain no personal identifying information, there is a possibility of reidentifying individuals. To avoid reidentification, several anonymization protocols are available. These include categorizing variables into broader categories to ensure more than one individual in each category, such as k-anonymization, as well as protocols aimed at adding noise to the data. However, data custodians rarely assess reidentification risks.
Methods: We assessed the reidentification risk of a large realistic dataset based on screening data from over 5 million records on 0.9 million women in the Norwegian Cervical Cancer Screening Program, before and after we used old and new techniques of adding noise (fuzzification) of the data.
Results: Categorizing date variables (applying k-anonymization) substantially reduced the possibility of reidentification of individuals. Adding a random factor, such as a fuzzy factor used here, makes it even more difficult to reidentify specific individuals.
Conclusions: Our results show that simple techniques can substantially reduce the risk of reidentification.
Impact: Registry owners and large-scale data custodians should consider estimating and if necessary, reducing reidentification risks before sharing large datasets. Cancer Epidemiol Biomarkers Prev; 26(8); 1219–24. ©2017 AACR.
A Comparative Study on the WCRF International/University of Bristol Methodology for Systematic Reviews of Mechanisms Underpinning Exposure–Cancer Associations
Authors: Ertaylan Gökhan , Le Cornet Charlotte , van Roekel Eline H. , Jung Audrey Y. , Bours Martijn J.L. , Damms-Machado Antje , van den Brandt Piet A. , Schock Helena , de Kok Theo M. , Theys Jan , Arts Ilja C.W. , Kaaks Rudolf , Weijenberg Matty P. , Fortner Renée Turzanski 
Published: July 2017

AbstractThe World Cancer Research Fund (WCRF) International and the University of Bristol have developed a novel framework for providing an overview of mechanistic pathways and conducting a systematic literature review of the biologically plausible mechanisms underlying exposure–cancer associations. Two teams independently applied the two-stage framework on mechanisms underpinning the association between body fatness and breast cancer to test the framework feasibility and reproducibility as part of a WCRF-commissioned validation study. In stage I, a “hypothesis-free” approach was used to provide an overview of potential intermediate mechanisms between body fatness and breast cancer. Dissimilar rankings of potential mechanisms were observed between the two teams due to different applications of the framework. In stage II, a systematic review was conducted on the insulin-like growth factor 1 receptor (IGF1R) chosen as an intermediate mechanism. Although the studies included differed, both teams found inconclusive evidence for the body fatness–IGF1R association and modest evidence linking IGF1R to breast cancer, and therefore concluded that there is currently weak evidence for IGF1R as mechanism linking body fatness to breast cancer. The framework is a good starting point for conducting systematic reviews by integrating evidence from mechanistic studies on exposure–cancer associations. On the basis of our experience, we provide recommendations for future users. Cancer Epidemiol Biomarkers Prev; 26(11); 1583–94. ©2017 AACR.
Impact of Sixteen Established Pancreatic Cancer Susceptibility Loci in American Jews
Authors: Streicher Samantha A. , Klein Alison P. , Olson Sara H. , Amundadottir Laufey T. , DeWan Andrew T. , Zhao Hongyu , Risch Harvey A. 
Published: July 2017

Abstract
Background: The higher risk of pancreatic cancer in Ashkenazi Jews compared with non-Jews is only partially explained by the increased frequency of BRCA1 and BRCA2 mutations in Ashkenazi Jews.
Methods: We evaluated the impact of 16 established pancreatic cancer susceptibility loci in a case–control sample of American Jews, largely Ashkenazi, including 406 full-Jewish pancreatic cancer patients and 2,332 full-Jewish controls, genotyped as part of the Pancreatic Cancer Cohort and Case–Control Consortium I/II (PanScan I/II), Pancreatic Cancer Case-Control Consortium (PanC4), and Resource for Genetic Epidemiology Research on Adult Health and Aging (GERA) datasets. We compared risk in full-Jewish subjects with risk in part-Jewish; non-Jewish Southern European; and in the combined non-Jewish Eastern, Northern, Southern, and Western European (non-Jewish white European) subjects from the same datasets. Jewish ancestries were genetically identified using seeded Fast principal component analysis. Data were analyzed by unconditional logistic regression, and adjusted for age, sex, and principal components.
Results: One SNP on chromosome 13q22.1 (rs9543325; OR, 1.36; 95% confidence interval, 1.16–1.58; P = 10−4.1) was significant in full-Jews. Individual ORs and minor allele frequencies were similar between Jewish and non-Jewish white European subjects. The average ORs across the 16 pancreatic cancer susceptibility loci for full-Jewish, full- plus part-Jewish, non-Jewish Southern European, and non-Jewish white European subjects were 1.25, 1.30, 1.31, and 1.26, respectively.
Conclusions: The 16 pancreatic cancer susceptibility loci similarly impact Jewish and non-Jewish white European subjects, both individually and as summary odds.
Impact: These 16 pancreatic cancer susceptibility loci likely do not explain the higher risk seen in Ashkenazi Jews. Cancer Epidemiol Biomarkers Prev; 26(10); 1540–8. ©2017 AACR.
A Prospective Study of Chronic Inflammation in Benign Prostate Tissue and Risk of Prostate Cancer: Linked PCPT and SELECT Cohorts
Authors: Platz Elizabeth A. , Kulac Ibrahim , Barber John R. , Drake Charles G. , Joshu Corinne E. , Nelson William G. , Lucia M. Scott , Klein Eric A. , Lippman Scott M. , Parnes Howard L. , Thompson Ian M. , Goodman Phyllis J. , Tangen Catherine M. , De Marzo Angelo M. 
Published: July 2017

Abstract
Background: We leveraged two trials to test the hypothesis of an inflammation–prostate cancer link prospectively in men without indication for biopsy.
Methods: Prostate Cancer Prevention Trial (PCPT) participants who had an end-of-study biopsy performed per protocol that was negative for cancer and who subsequently enrolled in the Selenium and Vitamin E Cancer Prevention Trial (SELECT) were eligible. We selected all 100 cases and sampled 200 frequency-matched controls and used PCPT end-of-study biopsies as “baseline.” Five men with PSA &gt; 4 ng/mL at end-of-study biopsy were excluded. Tissue was located for 92 cases and 193 controls. We visually assessed inflammation in benign tissue. We estimated ORs and 95% confidence intervals (CI) using logistic regression adjusting for age and race.
Results: Mean time between biopsy and diagnosis was 5.9 years. In men previously in the PCPT placebo arm, 78.1% of cases (N = 41) and 68.2% of controls (N = 85) had at least one baseline biopsy core (∼5 evaluated per man) with inflammation. The odds of prostate cancer (N = 41 cases) appeared to increase with increasing mean percentage of tissue area with inflammation, a trend that was statistically significant for Gleason sum &lt;4+3 disease (N = 31 cases; vs. 0%, &gt;0–&lt;1.8% OR = 1.70, 1.8–&lt;5.0% OR = 2.39, ≥5% OR = 3.31, Ptrend = 0.047). In men previously in the finasteride arm, prevalence of inflammation did not differ between cases (76.5%; N = 51) and controls (75.0%; N = 108).
Conclusions: Benign tissue inflammation was positively associated with prostate cancer.
Impact: This first prospective study of men without biopsy indication supports the hypothesis that inflammation influences prostate cancer development. Cancer Epidemiol Biomarkers Prev; 26(10); 1549–57. ©2017 AACR.
Multifaceted Role of BTLA in the Control of CD8+ T-cell Fate after Antigen Encounter
Authors: Ritthipichai Krit , Haymaker Cara L. , Martinez Melisa , Aschenbrenner Andrew , Yi Xiaohui , Zhang Minying , Kale Charuta , Vence Luis M. , Roszik Jason , Hailemichael Yared , Overwijk Willem W. , Varadarajan Navin , Nurieva Roza , Radvanyi Laszlo G. , Hwu Patrick , Bernatchez Chantale 
Published: July 2017

Abstract
Purpose: Adoptive T-cell therapy using autologous tumor-infiltrating lymphocytes (TIL) has shown an overall clinical response rate 40%–50% in metastatic melanoma patients. BTLA (B-and-T lymphocyte associated) expression on transferred CD8+ TILs was associated with better clinical outcome. The suppressive function of the ITIM and ITSM motifs of BTLA is well described. Here, we sought to determine the functional characteristics of the CD8+BTLA+TIL subset and define the contribution of the Grb2 motif of BTLA in T-cell costimulation.
Experimental Design: We determined the functional role and downstream signal of BTLA in both human CD8+ TILs and mouse CD8+ T cells. Functional assays were used including single-cell analysis, reverse-phase protein array (RPPA), antigen-specific vaccination models with adoptively transferred TCR-transgenic T cells as well as patient-derived xenograft (PDX) model using immunodeficient NOD-scid IL2Rgammanull (NSG) tumor-bearing mice treated with autologous TILs.
Results: CD8+BTLA− TILs could not control tumor growth in vivo as well as their BTLA+ counterpart and antigen-specific CD8+BTLA− T cells had impaired recall response to a vaccine. However, CD8+BTLA+ TILs displayed improved survival following the killing of a tumor target and heightened “serial killing” capacity. Using mutants of BTLA signaling motifs, we uncovered a costimulatory function mediated by Grb2 through enhancing the secretion of IL-2 and the activation of Src after TCR stimulation.
Conclusions: Our data portrays BTLA as a molecule with the singular ability to provide both costimulatory and coinhibitory signals to activated CD8+ T cells, resulting in extended survival, improved tumor control, and the development of a functional recall response. Clin Cancer Res; 23(20); 6151–64. ©2017 AACR.
Tumor Purity as an Underlying Key Factor in Glioma
Authors: Zhang Chuanbao , Cheng Wen , Ren Xiufang , Wang Zheng , Liu Xing , Li Guanzhang , Han Sheng , Jiang Tao , Wu Anhua 
Published: July 2017

Abstract
Purpose: Glioma tissues consist of not only glioma cells but also glioma-associated nontumor cells, such as stromal cells and immune cells. These nontumor cells dilute the purity of glioma cells and play important roles in glioma biology. Currently, the implications of variation in glioma purity are not sufficiently clarified.
Experimental Design: Here, tumor purity was inferred for 2,249 gliomas and 29 normal brain tissues from 5 cohorts. Based on the transcriptomic profiling method, we classified CGGA and TCGA-RNAseq cohorts as the RNAseq set for discovery. Cases from TCGA-microarray, REMBRANDT, and GSE16011 cohorts were grouped as a microarray set for validation. Tissues from the CGGA cohort were reviewed for histopathologic validation.
Results: We found that glioma purity was highly associated with major clinical and molecular features. Low purity cases were more likely to be diagnosed as malignant entities and independently correlated with reduced survival time. Integrating glioma purity into prognostic nomogram significantly improved the predictive validity. Moreover, most recognized prognostic indicators were no longer significantly effective under different purity conditions. These results highlighted the clinical importance of glioma purity. Further analyses found distinct genomic patterns associated with glioma purity. Low purity cases were distinguished by enhanced immune phenotypes. Macrophages, microglia, and neutrophils were mutually associated and enriched in low purity gliomas, whereas only macrophages and neutrophils served as robust indicators for poor prognosis.
Conclusions: Glioma purity and relevant nontumor cells within microenvironment confer important clinical, genomic, and biological implications, which should be fully valued for precise classification and clinical prediction. Clin Cancer Res; 23(20); 6279–91. ©2017 AACR.
TP53 Mutation and Its Prognostic Significance in Waldenstrom's Macroglobulinemia
Authors: Poulain Stéphanie , Roumier Christophe , Bertrand Elisabeth , Renneville Aline , Caillault-Venet Aurélie , Doye Emmanuelle , Geffroy Sandrine , Sebda Sheherazade , Nibourel Olivier , Nudel Morgane , Herbaux Charles , Renaud Loic , Tomowiak Cécile , Guidez Stéphanie , Tricot Sabine , Roche-Lestienne Catherine , Quesnel Bruno , Preudhomme Claude , Leleu Xavier 
Published: July 2017

Abstract
Purpose: TP53 is a tumor-suppressor gene that functions as a regulator influencing cellular responses to DNA damage, and TP53 alterations are associated with pejorative outcome in most B-lymphoid disorders. Little is known regarding TP53 alteration in Waldenstrom's macroglobulinemia (WM).
Experimental Design: Here, we have explored the incidence of TP53 alteration using Sanger sequencing and ultradeep-targeted sequencing in 125 WM and 10 immunoglobulin M (IgM) monoclonal gammopathy of undetermined significance (MGUS), along with the clinical features and the associated genomic landscape using single-nucleotide polymorphism array and mutational landscape in an integrative study.
Results: Overall, we have identified alteration of TP53 locus including mutation, deletion, and copy-neutral LOH in 11.2% of WM. TP53 mutation was acquired in 7.3% of patients with WM at diagnosis, being absent in IgM MGUS, and was highly correlated to deletion 17p. No correlation with CXCR4 mutations was observed. Patients with TP53 alteration had a greater number of genomic abnormalities. Importantly, WM with TP53 alteration had a significantly shorter overall survival, particularly in symptomatic WM, and independently of the international prognostic scoring system for Waldenstrom macroglobulinemia (IPSSWM) score. Specific treatment for WM with TP53 may have to be studied. Nutlin-3a–targeted p53 signaling induced cytotoxicity preclinically, along with new compounds such as ibrutinib, PrimaMet, or CP31398 that bypass p53 pathway in WM, paving the path for future treatment-tailored options.
Conclusions: Our results highlight the clinical significance of detection of TP53 alteration in WM to determine the prognosis of WM and guide the treatment choice. Clin Cancer Res; 23(20); 6325–35. ©2017 AACR.
An Integrative Scoring System for Survival Prediction Following Umbilical Cord Blood Transplantation in Acute Leukemia
Authors: Shouval Roni , Ruggeri Annalisa , Labopin Myriam , Mohty Mohamad , Sanz Guillermo , Michel Gerard , Kuball Jürgen , Chevallier Patrice , Al-Seraihy Amal , Milpied Noel-Jean , de Heredia Cristina Diaz , Arcese William , Blaise Didier , Rocha Vanderson , Fein Joshua , Unger Ron , Baron Frederic , Bader Peter , Gluckman Eliane , Nagler Arnon 
Published: July 2017

Abstract
Purpose: Survival of acute leukemia (AL) patients following umbilical cord blood transplantation (UCBT) is dependent on an array of individual features. Integrative models for risk assessment are lacking. We sought to develop a scoring system for prediction of overall survival (OS) and leukemia-free survival (LFS) at 2 years following UCBT in AL patients.
Experimental Design: The study cohort included 3,140 pediatric and adult AL UCBT patients from the European Society of Blood and Marrow Transplantation and Eurocord registries. Patients received single or double cord blood units. The dataset was geographically split into a derivation (n = 2,362, 65%) and validation set (n = 778, 35%). Top predictors of OS were identified using the Random Survival Forest algorithm and introduced into a Cox regression model, which served for the construction of the UCBT risk score.
Results: The score includes nine variables: disease status, diagnosis, cell dose, age, center experience, cytomegalovirus serostatus, degree of HLA mismatch, previous autograft, and anti-thymocyte globulin administration. Over the validation set an increasing score was associated with decreasing probabilities for 2 years OS and LFS, ranging from 70.21% [68.89–70.71, 95% confidence interval (CI)] and 64.76% (64.33–65.86, 95% CI) to 14.78% (10.91–17.41) and 18.11% (14.40–22.30), respectively. It stratified patients into six distinct risk groups. The score's discrimination (AUC) over multiple imputations of the validation set was 68.76 (68.19–69.04, range) and 65.78 (65.20–66.28) for 2 years OS and LFS, respectively.
Conclusions: The UCBT score is a simple tool for risk stratification of AL patients undergoing UCBT. Widespread application of the score will require further independent validation. Clin Cancer Res; 23(21); 6478–86. ©2017 AACR.
Real-Time Genomic Profiling of Pancreatic Ductal Adenocarcinoma: Potential Actionability and Correlation with Clinical Phenotype
Authors: Lowery Maeve A. , Jordan Emmet J. , Basturk Olca , Ptashkin Ryan N. , Zehir Ahmet , Berger Michael F. , Leach Tanisha , Herbst Brian , Askan Gokce , Maynard Hannah , Glassman Danielle , Covington Christina , Schultz Nikolaus , Abou-Alfa Ghassan K. , Harding James J. , Klimstra David S. , Hechtman Jaclyn F. , Hyman David M. , Allen Peter J. , Jarnagin William R. , Balachandran Vinod P. , Varghese Anna M. , Schattner Mark A. , Yu Kenneth H. , Saltz Leonard B. , Solit David B. , Iacobuzio-Donahue Christine A. , Leach Steven D. , O'Reilly Eileen M. 
Published: July 2017

Abstract
Purpose: Molecular profiling in cancer has identified potential actionable drug targets that have prompted attempts to discover clinically validated biomarkers to guide therapeutic decision-making and enrollment to clinical trials. We evaluated whether comprehensive genetic analysis of patients with pancreatic adenocarcinoma is feasible within a clinically relevant timeframe and whether such analyses provide predictive and/or prognostic information along with identification of potential targets for therapy.
Experimental Design: Archival or prospectively acquired FFPE samples and matched normal DNA from N = 336 patients with pancreatic cancer were analyzed using a hybridization capture–based, next-generation sequencing assay designed to perform targeted deep sequencing of all exons and selected introns of 410 key cancer-associated genes. Demographic and treatment data were prospectively collected with the goal of correlating treatment outcomes and drug response with molecular profiles.
Results: The median time from protocol consent to reporting of the genomic results was 45 days with a median time from tissue delivery of 20 days. All genetic alterations identified were stratified based upon prior evidence that the mutation is a predictive biomarker of drug response using the MSKCC OncoKB classification. Three of 225 patients (1%) received a matched therapy based upon the sequencing results.
Conclusions: The practical application of molecular results to guide individual patient treatment is currently limited in patients with pancreatic adenocarcinoma. Future prospective molecular profiling efforts should seek to incorporate routine germline genetic analysis and the identification of DNA profiles that predict for clinical benefit from agents that target DNA damage repair and or immunotherapy. Clin Cancer Res; 23(20); 6094–100. ©2017 AACR.
Multiparametric Detection of Antibodies against Different EBV Antigens to Predict Risk for Nasopharyngeal Carcinoma in a High-Risk Population of China
Authors: Chen Hao , Chen Shulin , Lu Jie , Wang Xueping , Li Jianpei , Li Linfang , Fu Jihuan , Scheper Thomas , Meyer Wolfgang , Peng Yu-Hui , Liu Wanli 
Published: July 2017

Abstract
In this study, we aimed to use the combined detection of multiple antibodies against Epstein–Barr virus (EBV) antigens to develop a model for screening and diagnosis of nasopharyngeal carcinoma (NPC). Samples of 300 nasopharyngeal carcinoma patients and 494 controls, including 294 healthy subjects (HC), 99 non-nasopharyngeal carcinoma cancer patients (NNPC), and 101 patients with benign nasopharyngeal lesions (BNL), were incubated with the EUROLINE Anti-EBV Profile 2, and band intensities were used to establish a risk prediction model. The nasopharyngeal carcinoma risk probability analysis based on the panel of VCAgp125 IgA, EBNA-1 IgA, EA-D IgA, EBNA-1 IgG, EAD IgG, and VCAp19 IgG displayed the best performance. When using 26.1% as the cutoff point in ROC analysis, the AUC value and sensitivity/specificity were 0.951 and 90.7%/86.2%, respectively, in nasopharyngeal carcinoma and all controls. In nasopharyngeal carcinoma and controls without the non-nasopharyngeal carcinoma and BNL groups, the AUC value and sensitivity/specificity were 0.957 and 90.7%/88.1%, respectively. The diagnostic specificity and sensitivity of the EUROLINE Anti-EBV Profile 2 assay for both nasopharyngeal carcinoma and early-stage nasopharyngeal carcinoma were higher than that of mono-antibody detection by immune-enzymatic assay and real-time PCR (EBV DNA). In the VCA-IgA–negative group, 82.6% of nasopharyngeal carcinoma patients showed high probability for nasopharyngeal carcinoma, and the negative predictive value was 97.1%. In the VCA-IgA–positive group, 73.3% of healthy subjects showed low probability. The positive predictive value reached 98.2% in this group. The nasopharyngeal carcinoma risk probability value determined by the EUROLINE Anti-EBV Profile 2 might be a suitable tool for nasopharyngeal carcinoma screening. Cancer Prev Res; 10(9); 542–50. ©2017 AACR.