bluuebunny/crossref_metadata_2025_split huggingface dataset:
Two-year outcomes of RTOG 0529: A phase II evaluation of dose-painted IMRT in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in carcinoma of the anal canal.
Authors: Kachnic L. A. , Winter K. A. , Myerson R. J. , Goodyear M. D. , Willins J. , Esthappan J. , Haddock M. G. , Rotman M. , Parikh P. J. , Willett C. G. 
Published: February 2017

368 Background: 5-Fluorouracil (5FU) and mitomycin-C (MMC) chemoradiation for anal cancer is associated with high rates of acute morbidity. We have previously shown that dose-painted IMRT (DP-IMRT) significantly reduces grade 3+ GI and dermatologic acute toxicity, as compared to the RTOG 9811 5FU/MMC arm, which used non-conformal radiation techniques. We now report on the two-year outcomes of this DP-IMRT approach. Methods: T2-4N0-3M0 anal canal cancers received 5FU (1,000 mg/m2/day 96 hour infusion) and MMC (10 mg/m2 bolus) days 1 and 29 of DP-IMRT prescribed as follows - T2N0: 42 Gy elective nodal and 50.4 Gy anal tumor planning target volumes (PTVs), 28 fractions; T3-4N0-3: 45 Gy elective nodal, 50.4 Gy ≤ 3 cm and 54 Gy > 3 cm metastatic nodal and 54 Gy anal tumor PTVs, 30 fractions. The following two-year outcomes were assessed: local-regional (LRF) and colostomy failures (CF) using the cumulative incidence method, and disease-free (DFS), overall (OS) and colostomy-free survivals (CFS) using the Kaplan-Meier method. Results: Of 63 accrued patients, 52 were analyzable. Median age was 58 years; 81% female; 54% stage II; 25% IIIA; 21% IIIB. Median follow-up was 23.2 months (0.2-33). Two-year LRF, CF, DFS and 95% confidence intervals are 20% (9%, 31%), 8% (0.4%, 15%) and 77% (62%, 86%), respectively. The causes of death for the 7 patients that died are: anal cancer in 5, morbidity in one and second primary outside the radiation field in one. Two-year comparison data from the RTOG 9811 5FU/MMC arm are shown in the table below. Conclusions: DP-IMRT with 5FU/MMC for the treatment of anal canal cancer yields similar two-year outcomes as the RTOG 9811 conventional radiation, 5FU/MMC arm. Because of the associated acute toxicity sparing, DP-IMRT will be used as the platform, and may allow for radiation dose escalation, in future RTOG anal canal trials. Supported by RTOG U10 CA21661, CCOP U10 CA3742 and ATC U24 CA 81647 NCI grants. [Table: see text] No significant financial relationships to disclose.
A circulating microvesicle-based biosignature for the detection of colorectal cancer.
Authors: Spetzler D. , Tinder T. , Kankipati S. , Maheshwari M. , Kuslich C. D. 
Published: February 2017

373 Background: Microvesicles are principally derived either from the endosomal pathway (as exosomes) or shed directly from the plasma membrane. They are between 40-500 nm in diameter and are secreted by most cell types, including tumor cells. In circulation, microvesicles appear to participate in cellular communication by transporting mRNAs, miRs and proteins from their cell of origin to target cells where they can elicit biological responses. The quantity and protein topography of microvesicles shed from cancer cells varies considerably compared to those shed from normal cells. Thus, the concentration of circulating plasma microvesicles with molecular markers indicative of the disease state can be used as a robust and informative blood-based biosignature. In this study we report the results of the application of a novel multiplexed method for quantifying and profiling microvesicles in plasma for the detection of colorectal cancer. Methods: We have developed a versatile mulitplexed microvesicle-based discovery panel with 73 different antibodies that target surface proteins of various microvesicle subpopulations. This system was used to develop a microvesicle-derived biosignature composed of 2 different surface membrane protein biomarkers. Results: In this study, we demonstrate that a combination of TMEM211 and CD24 provide a robust signature for the detection of colorectal cancer (CRC). We isolated microvesicles from plasma of 257 patients with CRC, 57 stage I, 104 stage II, 80 stage 3, 6 stage IV, and 11 of unknown stage; 327 self-described, age-range matched normal plasma specimens were used for the control population. The level of TMEM211 and CD24 containing microvesicles for these samples was determined using a multiplexed immunoassay. Thresholds were empirically determined to maximize the sensitivity and specificity of CRC detection, resulting in a sensitivity of 90% with a specificity of 85% with an AUC of .91. Conclusions: This study demonstrates that it is possible to use circulating microvesicles for the development of a highly sensitive and specific blood-based assay to detect CRC. [Table: see text]
Evaluation of physician knowledge and referral practices for colorectal cancer (CRC) genetic risk assessment: The experience at the Hospital of University of Pennsylvania (HUP).
Authors: Jenab-Wolcott J. , Tan K. , Heitjan D. F. , Giantonio B. J. , Garin M. , Powers J. , Stopfer J. , Hoops T. , Rustgi A. 
Published: February 2017

379 Background: 3-5% of CRCs are due to inherited genetic mutations. We surveyed knowledge and practices of academic physicians for identification and care of individuals at risk for inherited CRC. Methods: 264 physicians (oncologists (ON), gastroenterologists (GA), surgeons, internists, gynecologists, and radiation oncologists) at HUP were invited to participate in a web-based 9-min survey. The ability to obtain appropriate medical history and to make referral to genetic services was evaluated. Knowledge of hereditary CRC syndromes was examined both pre and post viewing of an educational web-page on inherited CRCs. Mantel-Haenszel, Fisher exact, and McNemar statistical tests were applied. Results: Response rate was 33.3%; and of those, 97.4% accessed the educational webpage. In the cohort, 98.9 % obtained a medical history very frequently (VF), 88.6% obtained cancer history in 1st and 45.5% in the 2nd degree relatives VF, and 63.9% asked about the relatives' age at time of cancer diagnosis VF. Of those most likely to care for patients with CRC, the GA more frequently asked about relatives' age at cancer diagnosis (p=0.014) and family history of polyps (p< 0.001) than ON. GA were more likely than ON to refer patients for genetic counseling (73.9% vs. 36.8%, p=0.008). GA had superior knowledge of the availability of genetic testing for Lynch syndrome (LS) (95.6% GA vs. 63.2% ON, p=0.005) and for familial adenomatous polyposis (FAP) (100.0% GA vs. 65.8% ON, p<0.001). For the entire cohort, the educational intervention raised awareness of genetic testing for LS (64.5% pre vs. 94.7% post, p<0.001), FAP (69.7% pre vs. 97.4% post, p<0.001), and Peutz-Jeghers Syndrome (31.6% pre vs. 84.2% post, p<0.001); and it significantly improved recognition of LS family pedigrees and selection of appropriate surveillance. Conclusions: Of the respondents, GA are more likely to obtain a detailed family history, utilize genetic services, and have a greater awareness of the availability of genetic testing, than ON. A simple educational intervention improves physician knowledge on inherited CRC risk recognition and surveillance recommendations. No significant financial relationships to disclose.
Causes of suboptimal colorectal cancer screening (CRCS) in U.S. immigrants.
Authors: Shahidi N. C. , Homayoon B. , Cheung W. Y. 
Published: February 2017

380 Background: Research shows that CRCS in U.S. immigrants is low, but causes for this poor uptake are unclear. Our aims were to 1) compare CRCS among U.S. born citizens (USB), naturalized citizens (NAC) and non-citizens (NOC), 2) evaluate clinical factors associated with CRCS, and 3) explore health system barriers to CRCS for immigrants. Methods: Screening eligible patients were identified from the 2007 California Health Interview Survey. CRCS was defined as a fecal occult blood test within 1 year, a sigmoidoscopy within 5 years or a colonoscopy within 10 years. Using logistic regression, we determined the effect of immigrant status and other clinical factors on CRCS. We devised a 3-point composite scoring system based on survey responses to questions about health system barriers (where 0=worst and 3=best). Stratified analyses based on residence (urban vs rural), healthcare coverage (insured vs uninsured), English proficiency (good vs. poor), and composite score were conducted to assess their relationship with CRCS. Results: We identified 30,434 respondents: USB 83%, NAC 13%, NOC 4%; mean age 66, 65, 61 years; male 39%, 41%, 48%; white 85%, 38%, 29%, respectively. Only 67% of USB, 61% of NAC and 46% of NOC underwent CRCS (p<0.001). Old age, male, high income earners, non-smokers, being married and those who visited their physicians frequently were more likely to receive CRCS (all p<0.05). When compared to USB, NAC and NOC were associated with decreased odds of CRCS (OR 0.88, 95%CI 0.73-1.05 and OR 0.67, 95%CI 0.52-0.87, respectively; global p=0.009). Stratified analyses revealed that the association between immigrants and decreased CRCS was more evident for immigrants who lived in rural areas, lacked insurance, or those who were not proficient in English (Table). Immigrants with a composite score ≤2 also reported worse CRCS. Conclusions: CRCS remains suboptimal, especially in new U.S. immigrants. Inferior healthcare access and language barriers are potential drivers of this disparity. Addressing these system issues for immigrants may promote CRCS in this population. [Table: see text] No significant financial relationships to disclose.
Impact of colonoscopy screening on individuals at high risk of hereditary nonpolyposis colorectal cancer (HNPCC).
Authors: Guillen-Ponce C. , Martinez-Sevila C. , Jover R. , Perea R. , Molina-Garrido M. , Carrato A. ,   Hereditary Cancer Group of the Comunidad Valenciana, Spain
Published: February 2017

384 Background: Colonoscopy screening reduces the incidence of, and mortality from, colorectal cancer (CRC) in individuals with HNPCC. The aim of this study was to determine the impact of colonoscopic follow-up in individuals at high risk of HNPCC, in terms of detection of precursor lesions (adenomas) or cancer. Methods: Between 2005-2008, 163 individuals with HNPCC were advised to undergo regular follow-up colonoscopy. Compliance and results of the scans were evaluated annually and were verified with medical documentation. Results: Of the 125 individuals who underwent at least one colonoscopy during the follow-up period of colonoscopy screening, in 33 subjects (26%) at least one colonic adenoma was detected. The median number of adenomas detected per colonoscopy in individuals with polyps was 2. The number of colonoscopies with polyps did not differ between women and men. However, the number of polyps removed by colonoscopy and the total number of polyps removed during the follow-up period was significantly higher in men (p = 0.005, p = 0.05 bilateral, respectively). 5 individuals (4%) were diagnosed with CRC, one of whom had two synchronous tumors. Of these, four individuals had properly followed the screening recommendations with the recommended frequency. In the case where two synchronous tumors were detected, it was the first colonoscopy screening that had been performed on the individual. None had had cancer previously, they were healthy relatives of an index case. All except one belonged to families that fulfilled the Amsterdam criteria I / II. All the tumors were diagnosed at an early stage, except two, which exhibited positive nodes. Conclusions: Colonoscopy screening is effective in diagnosing colorectal adenomas and cancer in individuals with HNPCC. Men with HNPCC have a greater number of colorectal adenomas. Screening allows the detection of colorectal cancer at an early stages. Funded by a young researcher's grant from the Spanish Society of Medical Oncology 2006. No significant financial relationships to disclose.
A multiplex technology platform for the rapid detection of relevant mutations in the EGFR signaling pathway.
Authors: Labourier E. , Smith D. , Laosinchai-Wolf W. , Friar L. , Houghton J. , Hadd A. , Latham G. 
Published: February 2017

386 Background: Determination of the mutational status of key gene effectors along the EGFR signaling pathway plays a critical role in the management of metastatic colorectal cancer (mCRC) and other cancer types. We previously reported the rapid, multiplex, and sensitive detection of 7 common KRAS mutations in mCRC FFPE specimens using the Signature KRAS Mutations (RUO) kit. We show here that the same technology platform can be applied to the detection of additional clinically relevant mutations in the EGFR, BRAF, KRAS, NRAS and HRAS genes. Methods: Mutation panels were designed for multiplex PCR amplification of an internal control gene and discrete mutation regions in independent target genes. PCR products were hybridized on a liquid bead array carrying target-specific probes and sorted by flow cytometry using a Luminex 200 system. Genomic DNA was extracted from cell lines and representative flash frozen, FFPE or FNA clinical specimens using laboratory-validated extraction methods. Results: Using model plasmids and cell lines we developed specific assays for distinct mutations in KRAS codon 12/13, KRAS 3' UTR (rs61764370), BRAF codon 600/601, HRAS codon 12/61, NRAS codon 61, and EGFR exon 19/20/21. The various assays reached 0.1 to 5% analytical sensitivity and could be further combined in multiplex panels relevant to specific applications. The Signature KRAS/BRAF Mutations (RUO) kit, an assay for 12 KRAS mutations in codon 12/13 and BRAF V600E, was validated in over 250 mCRC FFPE specimens with >99% agreement with clinically validated methods. Specific detection of these 13 mutations and 6 HRAS/NRAS mutations was also demonstrated in thyroid nodule FNA specimens. Single-well detection of EGFR deletions in exon 19 together with the point mutations L858R and T790M was also successfully evaluated in lung specimens. Conclusions: The Signature technology platform is a specific, sensitive and flexible tool for the assessment of various mutations in different tissue types. The development and validation of broader mutation panels would likely facilitate the rapid molecular characterization of individual tumor specimens and the optimization of personalized treatments for mCRC and other cancer types. [Table: see text]
Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinomas.
Authors: Serna D. S. , Martin L. K. , Li X. , Weatherby L. M. , Rose J. S. , Bekaii-Saab T. 
Published: February 2017

388 Background: Mutations in the KRAS oncogene are present in approximately 30-40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutational status is recognized to be predictive of tumor response with epidermal growth factor receptor-directed therapies such as cetuximab and panitumumab. Studies evaluating the prognostic value of KRAS status in localized (stage II and III) disease have been contradictory. The prognostic value in metastatic disease, either synchronous or metachronous, is less studied. Methods: Consecutive patients with metastatic colorectal adenocarcinoma underwent tumor testing for KRAS exon 2 (codons 12 and 13) mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then retrospectively analyzed, stratified by synchronous or metastatic disease and KRAS mutational status (WT or mutated). Results: For synchronous metastatic disease, KRAS WT patients (n = 39) had median overall survival (OS) of 34.3 months (95% CI, 21.8-58.3). KRAS mutated patients (n = 24) had median OS of 40.3 months (95% CI, 25.7-51.0; log-rank p = 0.55). By Kaplan-Meier survival analysis, 3-year OS was 48.9% (95% CI, 31.1-64.5) for KRAS WT and 51.1% (95% CI, 27.6-70.6) for KRAS mutated patients. Five-year OS was 27.8% (95% CI, 11.6-46.8) for KRAS WT and 9.7% (95% CI, 0.7-33.8) for KRAS mutated patients. For metachronous metastatic disease, from time of development of metastasis, KRAS WT patients (n = 29) had median OS of 33.2 months (95% CI, 28.3-40.7). KRAS mutated patients (n = 16) had median OS of 53.0 months (95% CI, 27.8-not applicable; log-rank p = 0.29). By Kaplan-Meier survival analysis, 3-year OS was 40.1% (95% CI, 19.9-59.7) for KRAS WT and 57.3% (95% CI, 25.0-80.0) for KRAS mutated patients. Five-year OS was 22.9% (95% CI, 7.6-43.2) for KRAS WT and 28.6% (95% CI, 1.7-68.1) for KRAS mutated patients. Conclusions: KRAS mutation status does not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma. No significant financial relationships to disclose.
Correlation between clinical-pathological parameters and family history to detect mutations in MLH1, MSH2, and MSH6.
Authors: Guillen-Ponce C. , Castillejo A. , Barbera V. M. , Alenda C. , Molina-Garrido M. , Carrato A. , Soto J. ,   Hereditary Cancer Group of the Comunidad Valenciana, Spain
Published: February 2017

391 Background: The Amsterdam I/II and Bethesda criteria are used to select individuals for the study of mutations in hereditary nonpolyposis colon cancer (HNPCC). The aim of this study was to analyze whether specific clinical features and family history of individuals suspected of HNPCC were correlated with the detection of germline mutations in MLH1, MSH2 and MSH6. Methods: Between 2005-2008, the study of germline mutations in one or more of the genes MLH1, MSH2 or MSH6 was carried out on 124 individuals who fullfield the Amsterdam I/II criteria or Bethesda criteria with microsatellite instability (MSI) or loss of expression by immunohistochemistry (IHC) of any of the repair proteins of MMR genes. Subsequently, we applied univariate and multivariate analyses including clinicopathological characteristics and family history to see if they were related to the presence of germline mutations. The characteristics were: age, sex, age at diagnosis, whether they fulfilled the Amsterdam or Bethesda criteria, diagnosis of cancer, tumor type, presence of multiple tumors and age of first diagnosis of cancer in the family. Results: Out of 124 patients studied, 29 gene mutations were detected (detection rate 25%). Of all the parameters studied, only endometrial cancer increased the risk of mutation 7.3 times (confidence interval [CI] 95%, from 1.83 to 29.2) for colorectal cancer (p = 0.005). 20.7% of mutations in MMR genes were explained by the type of cancer (R square Nagelkerke = 0.207). In the multivariate analysis none of the variables predicted the presence of mutation. Conclusions: The most important clinical feature to predict the presence of a mutation in the genes MLH1, MSH2 and/or MSH6 in families with HNPCC is the diagnosis of endometrial cancer (univariate analysis). No significant financial relationships to disclose.
Evaluation of glycolytic activity and HIF-1α expression in chemoresistant colorectal cancer cells.
Authors: Tozzi F. , Zhou Y. , Chen J. , Bose D. , Fan F. , Wang J. , Brusher H. , Widger W. , Weihua Z. , Ellis L. M. 
Published: February 2017

415 Background: Overcoming drug resistance in colorectal cancer (CRC) involves understanding the mechanisms by which cancer cells adapt to the genotoxic stress. We established a model of oxaliplatin resistant cells derived from HCT116/HT29 (HCT116 OxR/HT29 OxR). How these resistant clones reprogram their energy metabolism to gain a survival advantage remains unknown. We hypothesized that chemoresistant CRC cells exhibit altered cellular metabolism to survive following chronic genotoxic stress. Methods: The expression levels of glycolytic enzymes were detected by Western Blotting. Glucose and lactate concentrations were measured in the culturing media (CM). Intracellular ATP/ADP levels, oxygen consumption rate (OCR) and mitochondria ATP production were measured. In vivo xenograft study was used to compare the growth rate and angiogenesis of parental and oxaliplatin-resistant cells. Results: Both HT29-OxR and HCT116-OxR cells compared to parental cells exhibit increased aerobic glycolysis. Consistently, Glut1, Hexokinase 2 and LDHA glycolytic enzymes are upregulated. The OxR cells are defective in mitochondria complex I/II substrate and ATP production despite increased OCR. Importantly, the OXR cells maintain higher intracellular ATP and ATP/ADP ratio, increased HIF1a and VEGF levels in the CM. In tumor xenograft model, HT29 OxR cells grow significant slower than parental HT29 cells. Interestingly, when OxR cells were mixed with parental HT29 cells (50:50 and 90:10), tumor growth and microvessel counts were significantly accelerated. Conclusions: OxR cells demonstrate: 1) high aerobic glycolytic activity; 2) defective mitochondria functions; 3) increased ATP production; 4) increased HIF1a and angiogenesis. Likely, this metabolic switch contributes to the resistant phenotype. Metabolism intervention such as targeting HIF1a may provide a novel strategy to overcome drug-resistance in CRC. No significant financial relationships to disclose.
CDH1 structural alterations as novel prognostic biomarker in gastric cancer patients.
Authors: Corso G. , Pascale V. , Marrelli D. , Pinheiro H. , Carvalho J. , Garosi L. , Seruca R. , Oliveira C. , Roviello F. 
Published: February 2017

42 Background: Loss of CDH1 function occurs in sporadic gastric cancer (GC) progression by different molecular mechanisms. Hypermethylation and somatic mutations are considered the most frequent events. About 50% of sporadic diffuse GC shows CDH1 promoter of hypermethylation and 30% harbor somatic mutations; loss of heterozygosity (LOH) is documented in only 5% of diffuse GC cases. The present study aims to asses CDH1 alterations in 246 GC and study associated clinicopathologic features and family history of GC. Methods: Bisulphite treated tumoral DNA was used for E-cad promoter methylation. A region of 221 bps was amplified using flanking primers and direct sequencing. To search for somatic mutations the hotspot region of E-cad was amplified and directly sequenced. For LOH analysis tumor and matched normal mucosae were amplified in three microsatellite markers (D16S3025, D16S496, D16S3067) flanking the CDH1 locus. Results: Promoter hypermethylation was the most frequent event occurring in 20.7% (51 of 246) of the cases. We found 26 (10.6%) cases affected by structural alterations (three with somatic mutations and 23 with LOH). Promoter CDH1 methylation is associated with the diffuse type of GC (p = 0.017) and the presence of distant lymph node metastasis (p = 0.043). We identified association between male gender and structural CDH1 alterations (p = <0.001), R1/2 radicality of resection (p = 0.015). We verified a correlation between advanced stages and CDH1 promoter methylation (p = 0.033). Kaplan-Meier survival analysis estimates that CDH1 structural alterations participate as poor prognostic factor in GC patients (p = 0.017). Conclusions: Considering the reversible nature of hypermethylation phenomena, demethylating drugs have emerged as possible chemopreventive strategies in solid tumors. Moreover, we verify that epigenetic changes of E-cadherin leading to its decrease protein expression induce an invasive behaviour to neoplastic cells; as structural alterations of CDH1 gene is assess as predictive of worse prognosis we found a new molecular biomarker of prognosis in GC that can be used to predict the clinical prognosis of the patients. No significant financial relationships to disclose.