bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterization of rectal cancer in patients with Lynch syndrome.
Authors: Stadler Zsofia Kinga , Shia Jinru , Goodman Karyn A. , Cercek Andrea , Segal Neil Howard , Reidy Diane Lauren , Yaeger Rona D. , Nash Garrett Michael , Temple Larissa K. F. , Kemeny Nancy E. , Weiser Martin R. , Kelsen David Paul , Markowitz Arnold , Robson Mark E. , Offit Kenneth , Paty Philip , Guillem Jose G. , Saltz Leonard 
Published: February 2017

350 Background: Lynch syndrome (LS), resulting from a germline mutation in a DNA mismatch repair (MMR) gene, is associated with ~70% lifetime colorectal cancer (CRC) risk. Although LS-associated colon cancer is associated with both favorable prognosis and lack of efficacy to 5-fluorouracil, clinical features of LS-associated rectal cancer (RC) have not been characterized. Methods: Clinical genetics database review (1998–2012) identified all probands with CRC and a deleterious germline mutation in a MMR gene (MLH1, MSH2, MSH6, PMS2) diagnostic of LS. Probands without identifiable mutations or variants of unknown significance were excluded. Clinical history and pedigree was extracted from medical records and Progeny. Results: Of 119 LS patients with CRC, 16 (13.4%) had RC. Mean age at RC diagnosis was 40.6 (range, 23-56) with 31% having synchronous (n=3) or metachronous (n=2) colon cancer. All RC patients met Revised Bethesda and 63% met Amsterdam II criteria. As opposed to LS-associated colon cancer, the majority of RC patients harbored MSH2 mutations (36% colon vs 69% RC, p value 0.01). 11 tumors were analyzed for MSI or defective MMR protein expression by IHC; results were abnormal and thereby concordant with germline test results in all cases. Of 14 RC patients with clinical data, 5 proceeded directly to surgery (4 stage 0/I; 1 stage II). Nine patients received pre-op treatment for clinical stage II/III (n=7) or IV (n=2) disease, with all receiving chemoradiation and five also receiving pre-op FOLFOX. Downstaging of primary tumor occurred in 66.6% (6/9) and of lymph nodes in 77.7% (7/9) of cases. All nine patients underwent R0 resections; however, pCR was not observed in any of the cases. Notably, one patient with clinical T3N+ disease (by MRI and EUS) had upfront surgery identifying pT2N0 disease with prominent tumor infiltrating lymphocytes. Of 14 patients, mean follow-up of 4.3 years (range, 0.3-13.5), none had disease recurrence; however, one was diagnosed with a new primary colon cancer. Conclusions: Although less common than colon cancer,RC is an important component of LS and may be overrepresented in MSH2 mutation carriers. Given high risk of synchronous or metachronous cancers, appropriate surveillance for second malignancies is necessary.
Knowledge of the French population on colorectal cancer screening: Data from the EDIFICE 3 survey.
Authors: Viguier Jérôme , Coscas Yvan , Touboul Chantal , Morere Jean F. , Blay Jean-Yves , Pivot Xavier B. , Lhomel Christine , Eisinger François 
Published: February 2017

352 Background: In France, following a pilot population-based screening program in 2002-2003, a national organized program targeting 17 million people was progressively implemented from 2005 to 2009. EDIFICE surveys are iterative polls focusing on cancer screening behavior. The EDIFICE 3 survey was conducted in 2011 and partly dedicated to knowledge of the colorectal cancer screening process. Methods: This third nationwide observational study, EDIFICE 3, was conducted via phone interviews among a representative sample of 946 subjects aged between 50 and 74 years, who had never been treated for cancer. 59% of the population declared having undergone colorectal cancer screening (fecal test or colonoscopy). Results: Interviewed about the screening process, 510/946 (54%) of the French population were unaware of the procedure after a positive fecal test and 782/946 (83%) were unaware of how soon a new test should be performed after a negative result. Only 79/946 (8%) were aware of what to do after either a positive or a negative test and 47% in one out of the two cases. 84% of subjects over assessed (by a factor 2 to 10) the probability of having cancer after a positive test. In contrast, 65% were aware of the possibility of a false negative test. Only 3% of our sample know both the right screening agenda (every other year) and the need for a colonoscopy after a positive test. Neither gender, educational level and socio economic level significantly impacted the rate of right answers. Conclusions: This study demonstrates a lack of detailed knowledge on the colorectal cancer screening process in the French national program. This raises the issue of the fairness of the process (an ethical issue) and may be a reason for the current poor uptake (an effectiveness issue). This should be tackled by improving the transmission of information, preferentially via general practitioners, institutional letters sent directly to subjects (in our survey these two media were found to be readily accepted) and lay press.
The impact of number of cycles of targeted therapy on cost evaluation in metastatic colorectal cancers.
Authors: Guirgis Helmy M. 
Published: February 2017

359 Background: Increasing the number of cycles of cetuximab and bevacizumab in metastatic colorectal cancer might limit affordability and impact cost-effevctiveness. Methods: Average wholesale prices (AWPs) in U.S. dollars (US $) of cetuximab and bevacizumab were divided by reported median survival gain in days. Cost/survival of 90% of drugs was <$750. A reference scale between 0% and 100% was constructed with 0% assigned to cost/overall survival (OS) > $750, life threatening/fatal adverse events (AEs) and worsened quality of life (QoL). A plan was designed to correct for AEs and QoL. Results: Expressed as cost/overall survival (OS), crude and corrected scores (Table). Conclusions: Increasing number of cycles of cetuximab and bevacizumab increased the cost/survival and decreased scores. A limit on the purchase price of the entire treatment course of targeted therapy is recommended. [Table: see text]
KRAS testing of mCRC patients in a community-based oncology setting.
Authors: Cuyun Carter Gebra , Landsman-Blumberg Pamela , Johnson Barbara H , Sedgley Robert , Shankaran Veena 
Published: February 2017

364 Background: In late 2008, treatment guidelines were updated to recommend KRAS testing for patients at diagnosis (Dx) of metastatic colorectal cancer (mCRC). This study explored KRAS testing rates over time and compared characteristics of those mCRC patients who were tested and those not tested in a community-based setting. Methods: Patients ≥18 years old, with a mCRC Dx between 1/1/2008 - 12/31/2011, no other primary cancer, and 2+ outpatient visits were selected from the ACORN Data Warehouse (Memphis, TN). Text mining of progress notes and random forests modeling predicted if KRAS testing was done. If tested, test date and result were abstracted from charts. The proportions of those tested overall and at Dx (pre and ≤ 60 days post-mCRC Dx) were calculated by year. Chi-square and t-tests were used to compare demographic and cancer characteristics at Dx and clinical history of those tested and not. Results: Among 1,363 patients identified, 47.5% (n=648) were KRAS tested. Overall 48.1% were KRAS WT, 42.3% KRAS mutant, and 9.6% unknown. Proportion of eligible patients who underwent KRAS testing in pre-2008, 2008, 2009, 2010, and 2011 was 5.8%, 15.9%, 29.1%, 26.9%, and 28.0% respectively. Of those tested, 6.2% were tested at Dx pre-2008 and 27.4%, 65.4%, 73.2%, and 78.4% were at Dx in 2008, 2009, 2010, and 2011 respectively. KRAS tested patients were younger (59.5% vs. 51.5% <65 years, p=0.004), had more baseline comorbid conditions (3.7±4.0 vs. 2.7±3.4, p<0.001), were more likely to have bone (12.1% vs. 8.5%), lung (36.6% vs. 26.2%) and liver (73.5% vs. 66.2%) metastases, were less likely to have peritoneal (3.7% vs. 10.1%) metastases (all p<0.05), and had poorer performance status (PS) (ECOG >1: 41.9% vs. 34.0%, p=0.042). No significant differences were found by cancer location (colon, rectum, both), if the cancer was newly diagnosed or a recurrence, or in tumor histologic grade. Conclusions: While KRAS testing increased in 2008-2009 corresponding to changes in treatment guidelines and anti-EGFR product labels, the majority of patients were not tested. The proportion tested at diagnosis continued to increase annually from 2008-2011. Patients with greater comorbidities and poorer PS are more likely to undergo KRAS testing than healthier patients.
A nomogram based on clinical factors to predict locally advanced stage of rectal cancer.
Authors: Cai Guoxiang , Song Baorong , Huang Liyong , Xu Ye , Guan Zuqing , Sheng Weiqi , Cai Sanjun 
Published: February 2017

376 Background: Preoperative staging of rectal cancer is important for designing treatment strategy. The standard treatment for locally advanced rectal cancer is neoadjuvant radiochemotherapy followed by surgery. Magnetic resonance imaging (MRI) and transrectal ultrasonography are major staging approaches with a prediction accuracy of about 70-80% but not widely available in hospitals in China. We sought to define possible clinicopathological predictors and establish a simple nomogram as a reference tool for patients and clinicians to predict stage of rectal cancer and make decisions about neoadjuvant therapy. Methods: Preoperative staging of rectal cancer is important for designing treatment strategy. The standard treatment for locally advanced rectal cancer is neoadjuvant radiochemotherapy followed by surgery. Magnetic resonance imaging (MRI) and transrectal ultrasonography are major staging approaches with a prediction accuracy of about 70-80% but not widely available in hospitals in China. We sought to define possible clinicopathological predictors and establish a simple nomogram as a reference tool for patients and clinicians to predict stage of rectal cancer and make decisions about neoadjuvant therapy. Results: In the training set, 77.1% of patients had locally advanced stage by pathology. The multivariate analysis indicated that tumor size (Odds ratio (OR)=1.55, p< 0.001), differentiation (OR =0.38, p< 0.001), location (OR =1.06, p=0.038), serum CEA (OR =0.24, p< 0.001) and CA19-9 level (OR =0.13, p< 0.001) were associated with tumor stage. A nomogram consisting of these 5 factors was developed and predicted locally advanced stage with a concordance index of 0.756. The concordance index of this nomogram was 0.800 in the validation set. Conclusions: Large tumor size, far from anal verge, poor differentiation, elevated serum CEA and CA19-9 level were high-risk factors of locally advanced stage of rectal cancer. The nomogram based on these clinical factors can predicte locally advanced rectal cancer with a considerable accuracy and thus helpful for making neoadjuvant therapy recommendations.
Correlation of messenger RNA expression patterns of ERCC1, TS, EGFR, and VEGFR2 with KRAS and BRAF mutational status in advanced colorectal cancer: Implications for targeted therapies.
Authors: Maus Martin K. H. , Stephens Craig , Astrow Stephanie H. , Grimminger Peter Philipp , Yang Dongyun , Loupakis Fotios , Hsiang Jack , Zeger Gary , Huang Xu , Lenz Heinz-Josef 
Published: February 2017

383 Background: Gene expression levels of ERCC1, TS, EGFR and VEGFR2 may have predictive value for the personalized use of standard chemotherapeutics as well as agents targeting the EGFR and VEGF pathways and the efficacy of EGFR directed monoclonal antibodies like panitumumab and cetuximab has been confirmed to be dependent on wt KRAS and wt BRAF in patients with advanced colorectal cancer. We investigated the correlations between KRAS/BRAF mutational status and the mRNA expression levels of these genes. Methods: Formalin-fixed paraffin-embedded tumor specimens from 600 patients with advanced colorectal adenocarcinoma were microdissected and DNA and RNA was extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codon 12 and 13 of KRAS, V600E mutations in BRAF and the expression levels of ERCC1, TS, EGFR and VEGFR2 by RT-PCR. Results: Mt KRAS tumors had significantly lower TS and EGFR gene expression levels compared with wt KRAS (p<0,001), whereas mt BRAF tumors showed significantly increased TS and EGFR mRNA levels compared to wt BRAF (p<0,001). Mt BRAF tumors showed significantly higher mRNA levels than mt KRAS tumors (p<0,001). ERCC1 and VEGFR2 mRNA levels were significantly down-regulated in mt KRAS specimen (p<0,001), but showed no significant correlation with BRAF mutational status. Conclusions: KRAS and BRAF mutations are associated with opposite mRNA expression levels for TS and EGFR. Recently, resistance to BRAF inhibition in mt BRAF colorectal tumors has been shown in preclinical models to be associated with up-regulation of EGFR. Our data suggests that BRAF mutants are associated with high EGFR levels at the time of diagnosis, and not necessarily part of an acquired mechanism of resistance. Significantly lower mRNA expression levels of VEGFR2 in mt KRAS tumors may explain lower response to angiogenesis inhibition seen in the TML study.
Results from Ion AmpiSeq Cancer Panel in 200 cases of gastric and gastroesophageal junction cancer.
Authors: Lim Howard John , Kollmannsberger Christian K. , Gill Sharlene , Kong Esther , Ng Ying , Lum Amy , Woo Michelle , Huntsman David , Yip Stephen 
Published: February 2017

39 Background: We used the Ion AmpiSeq Cancer panel which contains multiplex PCR primers covering 739 potential cancer- related mutations in 46 genes to profile 200 gastric and gastroesophageal cancers. Methods: The assay requires only 10ng of genomic DNA isolated from formalin-fixed paraffin-embedded (FFPE) archival tissue blocks. Samples were retrieved from biopsies from either the primary or metastatic lesion. All samples generated usable DNA and the resultant amplicons were sequenced on the Ion Torrent PGM platform to achieve in depth coverage of potential mutations. Results: Mutations in the tumour suppressor gene TP53 (39.5%) are most commonly identified in our cohort which is consistent with known mutation profiling of gastric carcinoma. We have also identified mutations in MET (8%), PIK3CA (7.5%), KRAS (4%), BRAF (4%) in addition to other known oncogenes. Lastly, We identified two cases with hotspot mutations in IDH1 (R132H and R132C), hotspot mutation traditionally associated with glioma and acute leukemia, which suggest novel role(s) of this mutant protein in the pathogenic progression of this cancer. Conclusions: These findings might predict response to targeted therapeutic agents or have prognostic implications. This study highlights the potential of focused profiling of cancer related genes using the Ion Torrent platform and its advantage of utilizing small amount of DNA from archival pathology specimens.
Association of tissue factor pathway inhibitor gene polymorphism -33T→C with disease-free survival in colorectal cancer.
Authors: Bazzarelli Amy K , Scheer Adena S , Tai Lee-Hwa , Seth Rashmi , Tanese de Souza Christiano , Jonker Derek J. , Maroun Jean Alfred , Carrier Marc , Auer Rebecca Ann C 
Published: February 2017

395 Background: Tissue Factor Pathway Inhibitor (TFPI) is an anticoagulant protein exhibiting antimetastatic properties in preclinical models. The homozygous CC polymorphism on intron 7 of TFPI (-33T-->C) is associated with higher TFPI protein levels and a lower risk of venous thromboembolism (VTE). The present study is the first to evaluate the impact of the inherited TFPI polymorphism on disease-free survival (DFS) in cancer patients following curative resection. Methods: A prospectively maintained colorectal tumour bank with associated clinical data was used to identify patients who underwent curative surgery for colorectal cancer between 1994 and 2006. Germline DNA was extracted from formalin fixed, paraffin embedded normal colonic mucosa. Single nucleotide polymorphisms (SNPs) for Tissue Factor Pathway Inhibitor (TFPI, -33T-->C), Factor V Leiden (FVL, G1691A), and Prothrombin (PT, G20210A) were determined by polymerase chain reaction. DFS was described using the Kaplan-Meier method. Multivariable regression analysis, with known prognostic factors, was performed using the Cox Proportional Hazard model. Results: Of the 139 patients identified, the prevalence of the wildtype (TT) TFPI genotype was found in 57.3% of samples, the heterozygous genotype (TC) in 29.4%, and the homozygous genotype (CC) in 10.5%. The incidence of VTE was 21.6% in the TT/TC genotypes and 6.7% in the CC genotype (p=0.4). The CC genotype was associated with superior DFS (HR 0.38, [95%CI 0.17-0.88]; p=.02) with 5 year DFS 56.3% vs. 24.6% for CC vs. TT/TC respectively. In multivariate analysis female sex (HR=0.61, p=.02), chemotherapy (HR=0.66, p=.05), node negative (HR=0.47, p=.005) and TFPI CC polymorphism (HR=0.35, p=.01) were independently associated with improved DFS. The prevalence of FVL (0.7%) and PT (2.2%) polymorphisms was too low to detect any interaction with TFPI polymorphism and DFS. Conclusions: These findings indicate that the inherited anticoagulant homozygous -33T-->C TFPI polymorphism may protect against colon cancer recurrence, and suggest a causal role for the coagulation system in cancer outcomes.
Molecular profiles of appendiceal adenocarcinoma: The UCSD experience.
Authors: Shen John P. , McGee Devon Marcus , Lowy Andrew M. , Fanta Paul Timothy 
Published: February 2017

397 Background: Appendix cancer is rare, which precludes its study in randomized trials. As such, no evidence-based guidelines currently exist regarding the optimum systemic therapy for this disease entity. Typically, these patients are treated with regimens for colorectal carcinoma. Previous studies have shown high intra-tumoral mRNA levels of EGFR were significantly associated with response to irinotecan based chemotherapy, and that mucinous colorectal cancer overexpresses markers of resistance to 5-FU and oxaliplatin. We examined pharmacogenomics markers for appendiceal cancer and colon cancer to understand underlying similarities and differences between these tumor types. Methods: Intratumoral gene expression levels were assessed from paraffin-embedded tissue samples, using laser capture microdissection and quantitative real-time PCR from 69 colorectal and 34 appendiceal adenocarcinomas. A retrospective chart review was performed to correlate gene expression with overall survival. KRAS and BRAF mutational analyses and gene expression levels of ERCC1, TS, and EGFR were correlated with overall survival. Results: Appendiceal tumors had significantly higher expression of EGFR, (2.66 vs 1.4, p<.0001). No BRAF V600E mutations were found in the appendiceal tumors, incidence was 8.97% of the colon patients. UPDATE: In appendix cancer, KRAS mutations were noted in 65.5% of patients, there were no BRAF mutations. Median ERCC1, TS, EGFR, and VEGFR2A expression was 1.4, 1.21, 1.57, 2.19 respectively. Patients with metastatic appendiceal cancer had a significantly longer median OS than metastatic colon patients, (113 mo vs 43.9 mo, p = .0154). For appendiceal cancer patients, there was no significant correlation between any of the biomarkers and OS, although the sample size was underpowered for such an analysis. Conclusions: Metastatic appendiceal cancer patients have significantly better outcomes than metastatic colon cancer patients. Molecular analyses reveal significant differences between these tumor types. Further molecular study of appendiceal cancer is needed, as this study and others suggest fundamental differences in biology from colon cancer.
Association of diabetes mellitus with increased mortality in patients receiving curative surgery for colon cancer.
Authors: Chen Kuo-Hsing , Shao Yu Yun , Yeh Yi-Chun , Shau Wen-Yi , Kuo Raymond Nienchen , Lin Zhong-Zhe , Chen Ho-Min , Yeh Kun-Huei , Cheng Ann-Lii , Lai Mei-Shu 
Published: February 2017

399 Background: Diabetes mellitus (DM) is associated with increased risk of colon cancer and has potential impact on its prognosis. This study aimed to investigate the association between DM and the prognosis of patients with early colon cancer who underwent curative surgery. Methods: We established the patient cohort of the study by searching the database of the population-based Taiwan National Cancer Registry. All patients who had newly diagnosed stage I or II colon cancer from 2004 to 2007 and underwent surgical resection with uninvolved surgical margins were enrolled. Information of DM, anti-DM medication, and other comorbidities was retrieved from the database of National Health Insurance, Taiwan. Colon cancer-specific survival (CSS) and overall survival (OS) were compared between patients with and without DM. The Cox proportional hazard model was used to estimate the adjusted hazard ratio (HR) of clinicopathologic variables in multivariate analysis. Results: A total of 5,525 patients were identified; 1,009 of them (18.9%) had DM and 4,325 of them (81.1%) had no DM. Patients with DM had an older median age at diagnosis (69.9 y vs. 66.8 y, p < 0.001), similar initial stage and grade, fewer adjuvant chemotherapy (26.5% vs. 31.2%, p = 0.003). Patients with DM had significantly poorer CSS and OS than patients without DM (Table). In multivariate analysis adjusting for age, gender, stage, adjuvant chemotherapy and comorbidities, DM remained an independent prognostic factor for poorer OS (adjusted HR: 1.45, p < 0.001). Among patients with DM, patients who used insulin had significantly poorer CSS and OS than patients who did not (5-year CSS: 79.5% vs. 85.5%, p = 0.047; 5-year OS: 50.9% vs. 70.4%, p < 0.001). Conclusions: In patients receiving curative surgery for early colon cancer, patients with DM had poorer OS than patients without DM. [Table: see text]
The relationship between tumour necrosis, circulating IL-6 concentrations, and inflammatory responses in patients undergoing curative resection for colorectal cancer.
Authors: Guthrie Graeme JK , Roxburgh Campbell SD , Richards Colin H , Horgan Paul G. , Mcmillan Donald C. 
Published: February 2017

404 Background: Cancer-associated inflammation, in the form of systemic and local inflammation, and tumour necrosis are known to have prognostic value in colorectal cancer (CRC). In addition, recent work has reported a direct relationship between the systemic inflammatory response and loss of skeletal muscle in patients with CRC. However, the inter-relationships between these inflammatory responses, tumour necrosis, metabolic upset and circulating biochemical mediators are unclear in CRC. Interleukin-6 and its downstream signalling cascades have been implicated in both cancer-associated inflammation and cancer-associated muscle wasting. The aim of the present study was to examine whether circulating IL-6 concentrations may link tumour necrosis, local and systemic inflammatory responses, and metabolic upset in patients undergoing curative resection for colorectal cancer. Methods: The study included 118 patients undergoing surgery for CRC between 2004 and 2009. Data were collected from pre-operative blood tests. Routine pathology specimens were scored for Klintrup criteria and tumour necrosis. Results: Tumour necrosis was associated with increased T-stage (p<0.01), reduced inflammatory cell infiltrate (p<0.05), increased IL-6 (p<0.001), IL-10 (p<0.01), and VEGF (p<0.001) and with markers of the systemic inflammatory response: mGPS (p<0.001), anaemia (p<0.05); increased white cell (p<0.001), neutrophil (p<0.05) and platelet (p<0.001) counts. Circulating IL-6 was associated with increased IL-10 (p<0.01), VEGF (p<0.001), increased mGPS (p<0.001), increased white cell (p<0.01) and platelet (p<0.01) counts and low skeletal muscle index (p<0.01). On Spearman rank correlation there were significant associations between circulating concentrations of IL-6 and IL-10 (rs= 0.39, p<0.001) and CRP (r= 0.42, p<0.001). Conclusions: Interleukin-6 appears to be associated with systemic inflammation, tumour necrosis, and sarcopenia in colorectal cancer. However, the lack of an association between IL-6 and the local inflammatory response suggests a more complex relationship with the tumour inflammatory cell infiltrate.