bluuebunny/crossref_metadata_2025_split huggingface dataset:
Improving risk stratification in superficial (T1) gastroesophageal adenocarcinoma: Association of the intestinal phenotype (MUC2 positive) with prognosis.
Authors: Davison Jon M. , Ellis Shane , Foxwell Tyler , Zaidi Ali H , Jobe Blair A , Gibson Michael K. , Kuan Shih-Fan , Nason Katie Sue 
Published: February 2017

33 Background: An increasing proportion of esophageal and gastroesophageal junction adenocarcinomas (EAC) are limited to the superficial mucosal layer (stage classification T1) at the time of diagnosis. Intramucosal lesions (stage classification T1a) are increasingly managed with endoscopic resection due to their relatively low risk of nodal metastasis and favorable prognosis compared to those with submucosal invasion (stage classification T1b). At esophagectomy, however, the majority of T1b EAC are node-negative; conversely, a small proportion of T1a EAC will have nodal metastasis at esophagectomy and/or develop recurrent disease. Additional prognostication tools, such as tumor biomarker panels, are needed to optimize treatment algorithms. Known to carry prognostic significance in other tumors, we evaluated mucin protein expression to determine whether the mucin phenotype in early EAC was associated with survival outcomes. Methods: We classified 141 induction naive, resected, T1 EAC as intestinal-, gastric- or ductal-type depending on the expression pattern of gastrointestinal mucins (MUC2, MUC5AC, MUC6 and MUC1) determined by immunohistochemistry (IHC) on tissue microarrays. CDX2 expression was assessed by IHC and EGFR amplification was assessed by in situ hybridization. The association between survival and mucin subtypes was determined in univariate and multivariate analyses. Results: The intestinal phenotype (MUC2+) is associated with poor prognosis in T1b (HR 2.1, 95%CI 1.1-4.0) and node negative T1 EAC (HR 2.5, 95%CI 1.1-5.7) after adjusting for other significant prognostic factors. Intestinal type EAC also showed accelerated time to first recurrence in these subgroups. The colloid histologic subtype and CDX2 expression were positively associated with MUC2 expression, but EGFR amplification was not. Conclusions: The mucin phenotype may serve as a useful adjunct to conventional risk assessment for optimizing therapy for potentially resectable, superficial EAC.
A phase II trial design with direct assignment option for initial marker validation.
Authors: Mandrekar Sumithra J. , An Ming-Wen , Sargent Daniel J. 
Published: February 2017

34 Background: Phase II clinical trials aim to identify promising experimental regimens for further testing in phase III trials. Testing targeted therapies with predictive biomarkers mandates efficient trial designs. Current biomarker-based trial designs, including the enrichment, all-comers, and adaptive designs, randomize patients to receive treatment or not throughout the entire duration of the trial. Recognizing the need for randomization yet acknowledging the possibility of promising but nonconclusive results after a preplanned interim analysis (IA), we propose a two-stage phase II design that allows for the possibility of direct assignment (i.e., stop randomization and assign all patients to the experimental arm in stage II) based on IA results. Methods: Using simulations, we compared properties of the direct assignment option design to a 1:1 randomized phase II design and assessed the impact of the timing of IA (after 33%, 50%, or 67% of accrual) and number of IA (one versus two with option for direct assignment at the first and second) over a range of response rate ratios (between 1.0 and 3.0). Results: Between 12% and 30% of the trials (out of 6,000 simulated trials) adopt direct assignment in stage II, with direct adoption depending on the treatment effect size and specified type I error rate (TIER). The direct assignment option design has minimal loss in power (<1.8%) and minimal increase in T1ER (<2.1%) compared to a 1:1 randomized design. The maximum loss in power across possible timings of IA was <1.2%. For the direct assignment option design, there was a 20%-50% increase in the number of patients treated on the experimental (vs. control) arm for the 1 IA case, and 40%-100% increase for the 2 IA case. Conclusions: Testing predictive biomarkers in clinical trials requires new design strategies. In the spectrum of phase II designs from adaptive to balanced randomized all-comers or enrichment designs, the direct assignment design provides a middle ground with desirable statistical properties that may appeal to both clinicians and patients.
The prognostic value of seven soluble proteins measured in plasma or serum from patients with colorectal cancer in TNM stages I-III.
Authors: Christensen Ib Jarle , Høyer-Hansen Gunilla , Thurison Tine , Dowell Barry , Johansen Julia S. , Henriksen Rikke , Rohrberg Kristoffer Staal , Brunner Nils , Nielsen Hans J. 
Published: February 2017

35 Background: In colorectal cancer (CRC) several independent blood-borne biomarkers have been proposed as prognostic and/or predictive markers. However only CEA is at present recommended as a serological CRC biomarker. We have identified 6 other biomarkers and the aim of this study is to see if a combination of markers improves the prognostic and/or predictive value. Methods: Two-hundred and twenty-eight patients with CRC have been included in this study, all with TNM stages I-III. Overall survival (OS) was chosen as the primary endpoint with 93 events and the minimum follow-up was 47 months. Seven biomarkers measured in plasma or serum were analysed: CEA, TIMP-1, the 3 soluble uPAR forms suPAR(I-III), suPAR(I-III)+(II-III) and uPAR(I), PAI-1 and YKL-40. Multivariable analyses of OS were done using regression analysis and results presented by 3 and 5 year OS rates with area under the receiver operating characteristic curve (AUC). All biomarker levels were analysed on the log scale (base 2). Results: High levels of each of the included biomarker were significantly associated in a multivariable analysis (adjusted for age, gender, TNM stage, tumor localization, adjuvant chemotherapy,interaction between adjuvant therapy and biomarker) to poor prognosis in patients not receiving adjuvant chemotherapy. The results are shown for those patients (see Table). The uPAR forms were the only biomarkers significantly associated to OS in patients receiving adjuvant chemotherapy. Combining the markers resulted in an enhanced prediction of 3 and 5 year OS. For TNM stage II patients not receiving adjuvant therapy, the AUC was 0.765 for 3 year OS and 0.745 for 5 year OS. The corresponding AUC’s for TNM stage III were 0.859 and 0.861. Conclusions: The presented combination of blood biomarkers are shown to predict OS with higher precision than any single marker for patients not receiving adjuvant chemotherapy and may provide useful information for use in the management of patients with CRC. [Table: see text]
Targeted deep sequencing as a diagnostic and research method for detecting EGFR and ALK pathway driver genes in FFPE tissue of lung and colorectal carcinomas.
Authors: Knuutila Sakari , Merkkiniemi Katja , Rönty Mikko , Wirtanen Aino , Remes Satu Maria , Bloor Stuart , Salmenkivi Kaisa , Knuuttila Aija , Sarhadi Virinder Kaur 
Published: February 2017

39 Background: Molecular targeted tyrosine kinase inhibitor (TKI) treatments have made it crucial to perform diagnostic tests of multiple molecular targets. In lung carcinoma there are close to ten clinically relevant gene mutations, copy number alterations and/or gene fusions, such as ALK, EGFR, ERBB2, KRAS, BRAF, MET, PTEN, PI3KCA, ROS1 and RET. Presently, several different tests are utilized, requiring a high amount of tumor material and long turnaround time. Next generation sequencing or targeted deep sequencing (TDS) has opened a new era for rapid genome-wide analyses of mutations, copy number alterations and gene fusions. Our aimwas to 1) prove feasibility for applying TDS to FFPE samples, 2) compare mutations detected by prevalent methods & TDS, and 3) mine novel clinically and biologically relevant genes in lung and colorectal carcinoma. Methods: For TDS, we selected 192 lung carcinoma and colorectal carcinoma related genes and microRNA genes, focusing on the EGFR and ALK pathways. In total, 98 FFPE specimens were studied. Agilent SureSelect system and Illumina sequencing was adopted for the analysis. For diagnostic validation the following genes were selected: EGFR, KRAS, BRAF, PTEN, PI3K, RET and ALK. TDS results were confirmed by PCR, FISH and IHC. Results: We focused on the genes selected for diagnostic validation. Successful results were obtained from all specimens. The results from TDS correlated significantly with those obtained from PCR, FISH, and IHC. Importantly, TDS revealed novel mutations not detected by targeted PCR. Conclusions: An enormous advantage of TDS is that multiple mutation screening can be achieved in one analysis (saving time and material), and most importantly, provides enormous amounts of novel information, for example understanding mechanisms for drug resistance. This study was supported by Finnish Academy, Sigrid Jusélius Foundation, Finnish Cancer Organizations, the special governmental subsidy research funds appropriated to the Helsinki and Uusimaa Hospital District (HUS EVO), Pfizer Oy, AstraZeneca AS, Lab21 Ltd, Abbott Molecular Inc.
Development and validation of a digital Gleason score biomarker signature for risk stratification of patients with prostate cancer.
Authors: Erho Nicholas , Vergara Ismael A. , Buerki Christine , Ghadessi Mercedeh , Crisan Anamaria , Sierocinski Thomas , Haddad Zaid , Zimmermann Benedikt , Harko Sebastian , Sosu-Sedzorme Worlanyo , Triche Timothy J. , Jenkins Robert B. , Davicioni Elai 
Published: February 2017

40 Background: Gleason score (GS) is the most widely used grading system of cell differentiation in prostate cancer and one of the best pathological predictors of disease progression. Patients with high GS (> 7) are the most likely to experience metastasis, whereas patients with low GS (< 7) are expected to have favorable long-term outcomes. In addition to the subjective nature of GS assessment, patients with GS 7 represent a heterogeneous group in terms of patient outcomes. In this study a biomarker signature is developed and validated which could improve the prediction of high risk disease among GS 7 radical prostatectomy (RP) patients. Methods: Patient specimens from the Mayo Clinic RP Registry (n = 764) were used for feature selection and training of a 392-feature K-nearest neighbor (KNN, k = 11) classifier. These 392 genomic features were identified by assessing differential expression between patients with GS < 7 and those with GS > 7, using a Bonferroni adjusted T-Test with a p-value threshold of 0.05. The classifier was subsequently validated in two independent patient cohorts (Memorial Sloan Kettering [MSKCC] and German Cancer Research Center [DKFZ]) and compared to a state of the art biomarker signature (Penney et al. 2011). Results: In the MSKCC dataset (GSE21034) our model segregated GS < 7 from GS > 7 patients (n = 56) with an area under the receiver operating characteristic curve (AUC) of 0.97, comparable to the AUC of 0.94 obtained by Penney et al. in their independent validation set (n = 45). Strong performance was observed by our model when discriminating between primary Gleason grade (pGG) 3 and pGG 4 & 5 patients in the MSKCC (n = 130) and DKFZ prostate cancer (GSE29079, n = 47) datasets, achieving AUCs of 0.75 and 0.87, respectively. In the challenging GS 7 subset, our model segregated GS 3 + 4 and 4 + 3 patients in the DKFZ dataset (n = 64) with an AUC of 0.81 outperforming the Penney et al. signature (AUC = 0.60). Conclusions: A biomarker signature was developed which discriminates between low and high GS patients, outperforming a previously reported signature. Further validation of this biomarker signature in additional post RP patients, as well as, pretreatment biopsy specimens is warranted.
Association of CD44s and CD44v6 expression with survival outcomes in malignant fibrious histiocytoma.
Authors: Peiper Matthias , Boelke Edwin , Matuschek Christiane , Stoecklein Nikolas H. , Poremba Christopher , Schauer Matthias , Knoefel Wolfram Trudo 
Published: February 2017

44 Background: New prognostic markers are being searched to determine the value of adjuvant and/or palliative treatment in soft tissue sarcomas (STS). Several studies showed that CD44 expression was associated with a better outcome in certain cancers, such as bladder tumors. The aim of this study was to evaluate the expression of CD44 in STS of the adult and to determine whether this correlates with the clinical outcome. Methods: We examined the clinical outcome of 34 adult MFH patients (19 males and 15 females, average age 62 years, median 63 years, ranged from 38 to 88 years) who underwent curative treatment The majority of patients received adjuvant radiotherapy (n = 25). No patients received initial adjuvant chemotherapy. The prognostic value of CD44s and isoform expression were evaluated by immunohistochemistry of tissue microarrays. Results: At first, we split the data for each variant of CD44 into two equally sized groups at the medians to the expression values (low and high). We apply a log rank test on the two groups and use the p value as an evaluation criterion for the usefulness of the grouping. CD44s and CD44v6 expression significantly correlated with an improved outcome whereas CD44v8 and h CD44 were not significant. Conclusions: CD44s and CD44v6 expression seem to be associated with improved survival in malignant fibrous histiocytoma.
Development and initial validation of a metabolite profile for the early detection of breast cancer recurrence.
Authors: Raftery Daniel , Gu Haiwei , Asiago Vincent , Alvarado Leiddy , Djukovic Danijel , Ballas Robert 
Published: February 2017

5 Background: The detection of recurrent breast cancer is limited by poorly performing CA markers that are both insensitive and late markers. Because of their sensitivity to biological status, metabolite markers may provide better diagnostic performance and earlier detection. Detectable perturbations in the metabolic profiles of patients often result from altered metabolism in cancer. We report on the discovery and initial validation of a metabolite profile for the early detection of recurrent breast cancer. Methods: We applied a combination of nuclear magnetic resonance (NMR) and gas chromatography-mass spectrometry (GC-MS) to analyze the metabolite profiles of 116 serial serum samples from 20 recurring patients and 141 serial samples from 36 breast cancer survivors with no evidence of disease (NED). Multivariate analysis was used to identify 11 metabolite markers that were used to build a model with high accuracy (AUROC >0.88 using 10 fold cross validation) with a sensitivity of 68% and specificity of 94%. Strikingly, over 55% of the patients could be correctly predicted to have recurrence on average 13 months before clinical diagnosis, representing a large improvement over the current diagnostic assays CA 27.29 and CA 15-3 (Cancer Res. 2010; 70, 8309-18). The metabolites were then ported to an LC-MS/MS platform and a method was developed to quantify these metabolites using stable isotope labeled compounds. Due to difficulty in obtaining some labeled compounds the profile was reduced to 9 metabolites. The multivariate algorithm was recalculating using five-fold cross validation and using 211 patient samples. During this work we found that the performance of the assay could be improved by adding CA27-29 values to the assay, which mainly ensured excellent specificity. Results: The profile was tested using a separate validation set of 96 patient samples run identically. The performance was similar to the training set with a sensitivity of 65% and specificity of 93%. Recurrence detection was approximately 11 months ahead of clinical diagnosis (based on imaging for symptomatic patients) and about 2 years ahead of CA 27-29 alone. Conclusions: This metabolite profile has promise for early recurrence detection.
Shed alcam as a biomarker for urogenital cancers.
Authors: Arnold Shanna , Jones-Paris Celestial , Hansen Amanda Georgia , Fadare Oluwole , Clark Peter , Zijlstra Andries 
Published: February 2017

50 Background: ALCAM (Activated Leukocyte Cell Adhesion Molecule) is thought to be involved in tumor cell adhesion, migration and metastasis. The ectodomain responsible for adhesion is proteolytically shed. Elevated shedding of ALCAM ectodomain is associated with malignant progression. Considering the proximity of urogentical cancer to both urinary secretions and hematogenous circulation we investigated if ALCAM shed into urine and/or blood could act as a prognostic or diagnostic marker of disease and patient outcome. Methods: Shed ALCAM in serum and urine was measured by ELISA while ALCAM shedding in tissues was detected with a unique immunohistochemical approach. ALCAM shedding was correlated with patient parameters including tumor stage, metastasis, recurrence, overall and disease-specific survival. Results: ALCAM shedding was compared across tissue and fluids from normal age-matched healthy adults, non-urological neoplasia, and non-cancer patients. Elevated ALCAM shedding was readily detected in fluids and tissue from patients with urogenital cancers. However, only the detection of shedding in tissue and urine correlated significantly with disease progression and patient outcome. Specifically, shed ALCAM detected in urine collected from bladder cancer patients undergoing cystectomy (Vanderbilt 2000-2010) correlated strongly with patient outcome. Urine ALCAM correlates positively with invasiveness (80%), and is predictive of recurrence as well as survival (HR=10.2 and 2.9). Urinary ALCAM ROC curves show the optimal sensitivity and specificity of predicting recurrence (90 and 68%) and survival (62 and 83%). Conclusions: We show for the first time that cleaved ALCAM is detectable in the urine and that urinary ALCAM is a novel biomarker in urogenital cancers. ALCAM shedding is marker of cancer progression and patient outcome with high specificity and accuracy. Evaluating levels of shed ALCAM in urine offers a unique and effective method to diagnose, assess, and stratify patients with urogenital cancers. We find this correlation particularly exciting because ALCAM is functionally involved in cancer progression and therefore reports on cellular behavior rather than mere presence of neoplastic disease.
DNA mismatch repair deficiency and benefit from adjuvant bevacizumab in NSABP C-08: Molecular profiling results.
Authors: Pogue-Geile Katherine L. , Tanaka Noriko , Gavin Patrick , Yothers Greg , Colangelo Linda H. , Kim Chungyeul , Kim Seong-Rim , Fumagalli Debora , Taniyama Yusuke , Sharif Saima , O'Connell Michael J. , Paik Soonmyung 
Published: February 2017

55 Background: The purpose of this study was to identify biomarkers that define a subset of patients who received benefit from bevacizumab (bev) in NSABP trial C-08, even though bev did not improve outcomes over standard adjuvant chemotherapy (CT) in the treatment of stage II and III colon cancer. Methods: A randomly selected cohort of C-08 cases (N=500) were profiled for whole genome expression (N=445) and for mutations (N=463) in KRAS, NRAS, PIK3CA, and MET. BRAF mutations and mismatch repair (MMR) status were profiled on the available cases (N=1,764 and 1,993, respectively). Cox proportional hazard models were used to assess prognosis and prediction for the value of bev using overall survival (0S) and time to recurrence (TTR) as end points. Results: The effect of bev was different for MMR deficient (MMR-d) and proficient tumors for OS (interaction p=.035) but not TTR (interaction p=.08). Patients with MMR-d (N=252) tumors showed a significant benefit from the addition of bev to CT for OS (hazard ratio =0.52 (95% CI: 0.29-0.94, p=0.028). KRAS, NRAS, PIK3CA, and MET were not significant for interaction with bev in the discovery cohort. BRAF mutations were associated with MMR status (p<.0001) and the prognostic value of MMR depended on BRAF for TTR (interaction p=.027) but not OS (interaction p=.31). The effect of bev was independent of BRAF (interaction p=.28 TTR and .37 OS). Three-factor interaction tests for bev, MMR, and BRAF were not significant for either endpoint. Gene expression analysis with BRB array tools identified 5 BioCarta pathways (p<0.05) which differentially expressed in 4 statistical tests; 4 of these pathways were directly or indirectly involved in T cell activation and one was involved in the activation of VEGF. Conclusions: Patients in C-08 with MMR-d tumors received benefit from bev treatment but these results need to be validated in a separate study. Gene expression data suggest that T-cells may be differentially expressed based on MMR status. Activation of VEGF has been shown to suppress T-cell development (Ohm et al. Blood. 2003:10;4878). A speculative possibility for the benefit of bev in MMR-d tumors may be due to blocking of VEGF, releasing T cells from VEGF suppression.
Correlation of oncogenic mutations in circulating cell-free DNA (cfDNA) and tumor tissue through a multiplex sequencing platform in patients under consideration for phase I trials.
Authors: Mateo Joaquin , Ong Michael , Pope Lorna , Mulick Cassidy Amy , Yap Timothy Anthony , Perkins Geraldine , Riisnaes Ruth , Flohr Penelope , Thway Khin , Gonzalez Michael , Saeed Sadiya , Young Anne Mary , Toloui Helen Nicole , Khan Khurum Hayat , Moran Kirsty , Ng Matthew , Molife L Rhoda , Banerji Udai , Kaye Stanley B. , De Bono Johann Sebastian 
Published: February 2017

6 Background: Previous studies suggest that tumoral cfDNA is a potential biomarker in cancer. Methods: Prospective collection of samples from patients (pts) referred to a phase I trials unit, in 2 cohorts: “A”(manual isolation of cfDNA, Sep09-Dec10) and “B”(robotic isolation, Jan11-Sep11) and from 41 healthy volunteers (HV). CfDNA and tumor DNA from matched formalin-fixed paraffin-embedded (FFPE) tissue were isolated, quantified and analyzed for 238 oncogenic mutations (OM) in 19 oncogenes using Sequenom OncoCarta Panel 1.0. Mutation data were used for trial allocation when available. Statistical analyses used Pearson’s Chi-squared test and Mann-Whitney test. Results: 280 pts were included: breast (60; 21%), ovarian (44; 16%), and colorectal (42; 15%). 265 (95%) plasma and 194 (69%) FFPE samples were suitable for analysis. In 181 pts (65%) both samples were available for comparison. Median turnover time for cfDNA 7 days (range 5-14). Median [cfDNA] (concentration; ng/ml) in pts was higher than in HV (“A” 21 v 6.4;p<0.01, “B” 34 v 24;p<0.01). Detection of OM in cfDNA was more frequent when [cfDNA] was above the HV range (67% v 33% p=0.002). Among 181 pts with both samples analyzed, 53 OM were detected in cfDNA, with high concordance with tumor analysis (Table), especially for RAS in colorectal tumors (10/11 91%) and PIK3CAin breast (4/4 100%). In contrast, 29 pts (16%) had OM detected in tumor but not in plasma. The rate of concordance between OM detected in plasma v FFPE was independent of [cfDNA]. 154 pts were enrolled in phase I trials and 26 were given a matched drug according to the mutational analysis. Conclusions: cfDNA may be a useful tool to detect OM in a time frame suitable for clinical decision-making. Concordance of OM found in cfDNA with FFPE samples is high; discordance in this study may be explained by limitations of multiplexed-sequencing techniques, tumor heterogeneity or biologic evolution of the disease. [Table: see text]