bluuebunny/crossref_metadata_2025_split huggingface dataset:
Concordance of KRAS mutation detection between Illumina next generation gene sequencing (NGS) and CLIA-approved, clinical assays in metastatic colorectal cancer (mCRC).
Authors: Kothari Nishi , Yeatman Timothy Joseph , Schell Michael J. , Greenawalt Danielle , Hardwick James , Nebozhyn Michael , Loboda Andrey , Dai Hongyue , Kim Richard D. 
Published: February 2017

345 Background: It is well known that KRAS mutations limit the efficacy of anti-EGFR therapy in patients with mCRC. Therefore, accurate testing of KRAS is needed to ensure that appropriate patients receive anti-EFGR therapy. Most clinical institutions conduct KRAS testing in CLIA approved labs using standard DNA sequencing methods. The purpose of this study is to correlate KRAS mutation detection by Illumina KRAS gene sequencing to standard KRAS testing performed with CLIA. Methods: We analyzed tumor samples collected from 471 patients between 1998-2010. Patients were chosen randomly based on availability of sufficient tissue for DNA extraction. We performed targeted exome sequencing using an Illumina NGS platform with 50-100X coverage of KRAS. The BWA/GATK pipeline was used to identify variants and indels. Because matched normal samples were not available for comparison to identify somatic mutations, filtering of normal variants was performed using 1000 Genomes. Variants identified in 1000 Genomes with an MAF < 0.01 were filtered. Results: Out of 471 patients, 83 pts had KRAS testing done both by exome sequencing & CLIA approved labs. The concordance rate between the two testing methods was 89%. 39 pts (47%) were KRAS mutation negative (wild type) and 35 pts (46%) harbored KRAS mutation as determined by both methods. Of these, 31 pts had codon 12 mutations and 4 pts had codon 13 mutations. However, 6 pts (7%) were found to have no KRAS mutation using CLIA but were found to have KRAS mutations by NGS (two had A146V mutations, the others had Q61 mutations). In addition, 3 pts (4%) were KRAS mutants using CLIA but wild type by NGS. Thus, 10% of samples tested showed a discrepancy in outcome between the NGS & CLIA testing. Conclusions: Standard DNA sequencing methods (CLIA) was able to identify a majority of the KRAS mutants detected by NGS. However 10% of patients had either false positive or false negative results. The main explanation for this discrepancy is that CLIA approved labs generally only test for codons 12 & 13. The clinical role for NGS in tumor KRAS mutation detection should be further investigated to ensure that patients with mCRC receive appropriate therapy.
Impact of the recurrence score (RS) result and mismatch repair status (MMR) on agreement between oncologists (MDs) for stage II colon cancer (CC) recurrence risk (RR) assessment: A novel clinical utility endpoint for prognostic markers.
Authors: Kelley Robin Katie , Lopatin Margarita , Hwang Jimmy , Crager Michael , Brenner Adrienne A , Kuczma Jane , King Ashley , Chao Calvin , Lee Mark , Venook Alan Paul 
Published: February 2017

349 Background: Appropriate use of prognostic and predictive markers depends on quality of evidence for clinical utility in addition to clinical validity. In stage 2 CC, RR assessment is based traditionally on clinicopathologic factors (CP) with limited clinical validation and varies substantially across providers. We hypothesized that the validated Oncotype DX Colon Cancer RS and MMR tests may impact clinical decision-making by decreasing variation in RR assessment across MDs. We conducted a survey to compare the level of MD agreement on stage 2 CC RR assessment using CP alone vs CP+RS+MMR (CP+). Methods: A clinical trial database was randomly sampled for 100 cases of stage 2 CC stratified on T-stage, MMR and RS groups. Anonymous internet surveys asked each MD to assess 3-year RR for 10 cases with CP and 10 different cases with CP+. MDs were divided into panels of 5; all members of each panel reviewed the same cases. Agreement in RR among MDs was assessed using within-panel mean squared difference in RR assessments and analyzed using generalized linear models. Results: 30 community (C) and 20 university-based (U) MDs (Assoc of Northern California Oncologists or NCCN, respectively) completed evaluable surveys April-June 2012. For C vs U, median years in practice were 5 and 2; prior use of RS 13% vs 25%; and routine MMR use 21% vs 55%. The standard deviation of the differences (SDD) in RR assessments for CP alone was high overall (7%), and greater for U vs C MDs (8.2% vs 6.4%). CP+ produced higher agreement in RR assessments vs CP for both C (p<.001) and U (p=0.04) MDs, with 23% and 20% proportional reduction in SDD. ForT3 MMR-proficient (P) patients (n=70), CP+ produced higher agreement in RR for both C (p<0.001) and U (p=0.01) MDs with 37% and 29% reduction in SDD. Conclusions: Addition of RS+MMR to CP significantly increased MD agreement on RR assessment in stage 2 CC, including T3 MMR-P patients. Agreement was higher among C than U MDs. MD agreement on stage 2 CC RR assessment and Tx decision-making warrants consideration as a novel endpoint for clinical utility of RS, MMR, and other prognostic markers.
Anal intraepithelial neoplasia progression to squamous cell carcinoma.
Authors: Gami Bhavna , Ziprin Paul , Goldin Robert D , Osborn Michael , Greene Linda , Walsh John 
Published: February 2017

353 Background: In the U.K., the annual incidence of anal cancer is up to 1.5 per 100,000 per year. Anal intra-epithelial neoplasia (AIN) is believed to be a precursor to squamous cell carcinoma whose incidence is still undetermined. This cell transformation has been associated with human papillomavirus (HPV) infections, in particular HPV 16 and 18. Our aim was to determine the frequency of progression to squamous cell carcinoma (SCC) of the anus in patients with known AIN. Methods: Study subjects with diagnosis of AIN from January 1st 1997 to January 1st 2009 were identified from a prospective database in a single hospital trust. The incidence of a subsequent diagnosis of anal SCC was determined from the local pathology and anal cancer database and cross referenced with the regional cancer database, Thames Cancer Registry. Results: We identified 397 patients (303 males) diagnosed with AIN in the database and HPV infection was identified in n= 395 patients. 15 (4%) patients were diagnosed with anal SCC a median of 5 months, Interquartile range 27 (2- 29 months) after their initial diagnosis. The distribution of AIN 1, 2 and 3 at presentation was 2, 1 and 12 respectively. Of interest, number of patients developed other HPV related cancers during the study period, such as vulva (n=8), cervical (n=3) and penile cancers (n=1). Conclusions: The incidence of anal cancer is higher in patients with known AIN compared to the general population. This justifies surveillance of these patients for anal and other HPV related intraepithelial neoplasia, however the nature of this, anoscopy or clinical examination alone, has yet to be determined.
Impact of body mass index (BMI) and weight changes on recurrence and survival in stage III colon cancer (CC).
Authors: Vergidis Joanna , Alipour Sina , Cheung Winson Y. 
Published: February 2017

355 Background: Research suggests that physical activity can lower the risk of relapse and mortality from CC. However, it is unclear if such benefits are mediated through an effect on weight. Our aims were to (1) evaluate the impact of pre-treatment BMI on recurrence and survival in early stage CC, (2) examine how changes in weight from baseline may affect outcomes, and (3) explore if the effects of different body compositions are modified by adjuvant therapy (AT). Methods: Patients (pts) diagnosed with stage III CC from 2006 to 2008, evaluated at any 1 of 5 cancer centers in British Columbia, and who had their weights measured serially throughout their AT period were reviewed. Using Cox proportional hazards models, we compared outcomes among (a) BMI<25 [normal] vs. 25-30 [overweight] vs. >30 [obese] and (b) weight increase or decrease of < vs. >/=5% and < vs. >/=10%, while controlling for confounders. Results: A total of 821 pts were included: median age was 65 years, 50% were men, and 83% were ECOG 0/1. At baseline, 43, 37, and 20% were normal, overweight, and obese, respectively. Compared to pts with normal BMI, those who were overweight or obese did not show an increased risk of recurrence (HR 0.81, 95%CI 0.42-1.58 and HR 1.09, 95%CI 0.48-2.51, respectively, p trend=0.74) or death (HR 0.54, 95%CI 0.26-1.13 and HR 0.62, 95%CI 0.22-1.74, respectively, p trend=0.24). A number of pts experienced weight gain or loss during their AT period, but none of these weight changes affected outcomes (Table). Receipt of AT did not modify the effects of BMI or weight change on outcomes. In Cox models, advanced age and poor performance status were the main factors that consistently correlated with an increased risk of recurrence and death (p<0.05). Conclusions: Neither baseline BMI nor short-term weight changes during AT appear to affect outcomes in stage III CC. Physical activity likely exerts its benefit on relapse and survival by influencing long-term weight changes or by alternative mechanisms. [Table: see text]
Level of arterial ligation in sigmoid colon and rectal cancer surgery.
Authors: Yasuda Koji 
Published: February 2017

358 Background: Curative resection of sigmoid colon and rectal cancer includes "high tie" of the inferior mesenteric artery (IMA). However, IMA ligation compromises blood flow to the anastomosis, which may increase the leakage rate and it is unclear whether this confers a survival advantage. Accodingly, IMA may be ligated at a point just below the origin of the left colic artery (LCA) ("low tie"), with lymph node (LN) dissection around IMA. No study has investigated the detailed prognostic results between "high tie" and "low tie, with LN dissection around IMA". The aim of this study was to assess the utility of "low tie, with LN dissection around IMA" on survival in patients with sigmoid colon or rectal cancer. Methods: A total of 268 sigmoid colon or rectal cancer patients who underwent curative operation from 1998 to 2007 were enrolled in this study. The patient's medical records were reviewed to obtain information about operative method, the number of LN dissection, the number of metastatic LN, the site of metastatic LN, recurrence pattern, complication. Overall survival and relapse-free survival were calculated using the Kaplan-Meier method, with differences assessed using logrank test. Results: We divided all patients into three groups according to the ligation level of IMA. 41 patients were ligated at the level of IMA root (Group A: "high tie"). 164 patients were ligated just caudally to the origin of the LCA ("low tie"), with LN dissection around IMA. 63 patients were ligated at the level of superior rectal artery just caudally to the sigmoid artery. The significant difference was not observed in a complication rate in three groups. The significant difference was not observed in the survival rate and the relapse-free survival rate according to each stage in group A and group B either. Also, the significant difference was not observed in the survival rate and the relapse-free survival rate in node-positive cases in group A and group B. Conclusions: "Low tie,with lymph node dissection aroud IMA" is anatomically less invasive and is not inferior to the ligation in the IMA root ("hige tie") in prognostic point.
Clinical and preclinical evaluation of taxane sensitivity in gastric cancer (GC): Relevance of GC histology.
Authors: Galletti Giuseppe , Cleveland Kyle , Matov Alex , Hayes James E. , Klein Robert J. , Hassane Duane C. , Nicacio Leonardo V. , Giannakakou Paraskevi , Shah Manish A. 
Published: February 2017

37 Background: Docetaxel (D) is a standard treatment for advanced gastric cancer based on the TAX-325 study (van Cutsem, JCO 2006). We asked the question, do all subtypes of GC benefit equally from D therapy? Methods: We performed a post-hoc analysis of the TAX-325 study. We classified randomized patients as diffuse or non-diffuse histology and correlated histology with clinical outcomes using a Cox proportional hazards model. Preclinical studies involved 13 GC cell lines (4 intestinal subtype, 7 diffuse subtype, 2 unknown), assessed for D sensitivity using the Sulforhodamine B (SRB) cytotoxicity assay, microtubule bundling, mitotic arrest by immunofluorescence as evidence of drug-target engagement, and apoptosis assessment by Caspase 8, Caspase 3, and PARP cleavage by Western Blot. Results: In post hoc analysis of TAX-325, patients were classified as diffuse (n=206) or non-diffuse (n=239). Non-diffuse GC showed a significant improvement in overall survival with the addition of D (12.1 v 8.8 mo, p=0.002), whereas diffuse histology was not associated with an improvement in survival (8.3 v 8.5 mo, p=0.66). Preclinical studies similarly reveal that 5/7 diffuse GC cell lines were resistant to D by SRB assay compared with 1/4 intestinal GC cell lines (IC50 > 600 nM). To examine drug target engagement, a dynamic measure of D activity, 4/6 diffuse GC cell lines showed lack of D engagement on the microtubule network at physiologic D concentrations (0-100 nM). 5/6 diffuse cell lines demonstrated no apoptosis. Additionally, we found that 0/9 GC cell lines expressed P-glycoprotein, ruling out multidrug resistance as an etiology for diffuse GC resistance to D. Conclusions: In exploratory analysis, we observed diffuse GC to be resistant to the addition of D to standard chemotherapy in a random assignment phase III clinical trial. In vitro analyses support these clinical findings and demonstrate intrinsic D resistance in diffuse GC, unrelated to multidrug resistance. Ongoing mechanistic studies focus on the molecular basis of taxane sensitivity in GC to predict treatment efficacy. These findings will inform future clinical studies aimed at individualized therapy.
Colorectal cancer presentation in eastern Bay of Plenty, New Zealand.
Authors: Khan Afrasyab , Prasad Jagdish 
Published: February 2017

370 Background: New Zealand has a high incidence of colorectal cancer; the death rate is the highest amongst developed countries. New Zealand does not have a national screening program for colorectal cancer yet. This study was done in a region with a higher proportion Maori ethnicity. We hypothesized that there are differences in presentation and pathology of colorectal cancer between Maori and European people. Methods: A review of new cases of colorectal cancer presenting over a period of three years (2008-2011) at Whakatane Hospital was done. Data was collected from clinical records and entered into SPSS software. Results: 113 new cases of colorectal cancer were identified. Median age was 73 years. Maori patients were younger than the rest (median age 60 vs 74.5; p < 0.05). 95 patients were of European ethnicity and 15 were Maori. The predominant sign/symptom on presentation was PR bleeding (32%). Only 5 cases were asymptomatic and diagnosed on surveillance colonoscopy. The histologic type of tumor was adenocarcinoma in 111 cases. The most common site of the tumors was the rectum (18.6%). 34.5% cases had localized disease (stage 1, 2A) with no significant difference between Maori and the rest.18.6% cases had distant metastasis with no significant difference between Maori and the rest. Curative surgery was not done in 16 patients due to advanced disease, comorbidities or patient refusal. Conclusions: A higher proportion of patients were diagnosed with localized disease at presentation compared to the rest of New Zealand.. Fewer Maori patients had colorectal cancer in view of the higher proportion of Maori in the area (42-61%). The age of Maori was significantly lower than the rest. Colorectal cancer screening in New Zealand will likely detect cancer earlier. [Table: see text]
Characteristics of colorectal cancer in patients younger than 40 years compared to older patients.
Authors: Salem Mohamed E. , Arun Monica , Dyson Greg , Saad Chadi , Arbabi Cassra , Jain Tania , Taylor Stephanie , Kunz Sara , Choi Minsig , Shields Anthony Frank , Philip Philip Agop 
Published: February 2017

371 Background: The incidence of colorectal cancer (CRC) in younger patients (pts) is increasing. There is limited data on tumor characteristics and treatment outcome in this population. Methods: Patients with CRC treated at the Karmanos Cancer Center from 2005 to 2011 were studied. Younger (≤40 years) and older (>40 years) groups from a predominantly inner city population were compared for patient and tumor characteristics, treatment patterns, and survivals. T-tests and Fisher’s exact tests were used to determine statistical differences between age groups while the Kaplan-Meier method was used to estimate survival. Results: 42 pts were ≤ 40 (range, 17-40 years) and 96 pts were > 40 (range, 42-88 years). Mean ages for the groups were 33 and 60 years, respectively. There was no statistically significant difference in the distribution of race, gender, stage or KRAS mutation status between the two groups; however, older pts had a higher mean body mass index compared to younger pts (28 versus 23, p<0.001). Older pts were more likely to have a right colon primary (OR = 7.5, p = 0.04), while younger pts had higher likelihood of having sigmoid primary (OR = 3.4, p = 0.002) and worse grade (poorly differentiated) tumors (OR = 8.3, p <0.001). There were no significant differences between metastatic status or sites of metastases between the two groups. Significantly more young pts underwent surgery than older pts (92% versus 62%, p = 0.005). FOLFOX plus bevacizumab was the most commonly used first line treatment for both groups. The median survival estimates were 16.9 (8.1-23.9) and 17.1 months (13.3-31.0) for the younger and older pts, respectively. Importantly, the one-year survival rates were similar for both groups: 41% for both (p = 1). On the multivariate analysis, whether pts had a primary in the right or sigmoid colon was the only independent predictor of survival. Conclusions: Younger pts with colon cancer were diagnosed at a similar stage of the disease as older pts, but more likely to have poorly differentiated tumors. Younger pts were more likely to receive surgical interventions; however, both groups had equivalent one-year survivals. These results support the need for further prospective investigation in a larger population.
Uptake of genetic testing by relatives in Lynch syndrome: A systematic review.
Authors: Sharaf Ravi , Myer Parvathi , Stave Christopher , Diamond Lisa , Ladabaum Uri 
Published: February 2017

374 Background: Screening of persons with newly diagnosed colorectal cancer (CRC) for Lynch Syndrome (LS) can yield substantial population-level benefits at acceptable costs, presuming sufficient uptake of genetic testing by first-degree relatives (FDRs) of LS probands. We reviewed systematically the published literature addressing the frequency and predictors of uptake of genetic testing by FDRs of LS probands. Methods: A literature search was conducted in four electronic databases (CINAHL, PsycInfo, PUBMED, and SCOPUS) for articles published through May 2011 that reported the uptake of genetic testing by relatives of LS probands. Two investigators independently screened articles to determine whether they met inclusion criteria, and abstracted data inthree broad categories: study population, methodology, and uptake of genetic testing. A narrative, qualitative systematic review was performed. The data were not amenable to meta-analysis. Results: 1,258 potentially relevant articles were identified with 533 studies undergoing full text review. Eight articles met inclusion criteria. 52% or less of FDRs of LS probands underwent genetic testing. For each LS proband, 4.6 or fewer relatives underwent genetic testing. Demographic factors (age <50 years, female gender, parenthood, education level, employment, participation in past medical studies), psychological factors (lack of depressive symptoms), and family history (greater number of relatives with cancer) were associated with uptake of genetic testing. Conclusions: Genetic testing may be underutilized by FDRs at risk for LS. The economic feasibility of screening persons with CRC for LS depends on optimizing family-wide uptake of genetic testing. Future research and clinical efforts should focus on ways to overcome barriers to genetic testing.
Genomic classifiers (ColoPrint/MSI-Print) predict outcome and chemotherapy benefit in stage II and III colon cancer patients.
Authors: Kopetz Scott , Jiang Zhi-Qin , Overman Michael J. , Dreezen Christa , Tian Sun , Li Ying , Simon Iris , Chang George J. , Maru Dipen M 
Published: February 2017

378 Background: Although the benefit of chemotherapy in stage II and III colon cancer patients is significant, many patients might not need adjuvant chemotherapy because they have a good prognosis even without additional treatment. ColoPrint is a gene expression classifier that distinguish patients with low or high risk of disease relapse. It was developed using whole genome expression data and has been validated in public datasets, independent European patient cohorts and technical studies (Salazar 2011 JCO, Maak 2012 Ann Surg). Methods: In this study, the commercial ColoPrint test was validated in stage II (n=96) and III patients (n=95) treated at the MD Anderson Cancer Center from 2003 to 2009. Frozen tissue specimen, clinical parameters, MSI-status and follow-up data (median follow-up 64 months) were available. The 64-gene MSI-signature developed to identify patients with deficient mismatch repair system (Tian 2012 J Path) was evaluated for its accuracy to identify MSI patients and also for prognosis. Results: In this cohort, ColoPrint classified 56% of stage II and III patients as being at low risk. The 3-year Relapse-Free-Survival (RFS) was 90.6% for Low Risk and 78.4% for High Risk patients with a HR of 2.33 (p=0.025). In uni-and multivariate analysis ColoPrint and stage were the only significant factors to predict outcome. The MSI-signature classified 47 patients (24.6%) as MSI-H and most MSI-H patients were ColoPrint low risk (81%). Patients who were ColoPrint low risk and MSI-H by signature had the best outcome with a 3-year RFS of 95% while patients with ColoPrint high risk had a worse outcome independently of the MSI-status. Low risk ColoPrint patients had a good outcome independent of stage or chemotherapy treatment (90.1% 3-year RFS for treated patients, 91.4% for untreated patients) while ColoPrint high risk patients treated with adjuvant chemotherapy had 3-year RFS of 84%, compared to 70.1% 3-year RFS in untreated patients (p=0.026). Conclusions: The combination of ColoPrint and MSI-Print improves the prognostic accuracy in stage II and stage III patients and may help the identification of patients at higher risk who are more likely to benefit from additional treatment