bluuebunny/crossref_metadata_2025_split huggingface dataset:
Il-8 as an underutilized prognostic factor in metastatic colorectal cancer.
Authors: Shah Manasi S , Fogelman David R. , Daniel-MacDougall Carrie , Raghav Kanwal Pratap Singh , Heymach John , Tran Hai T. , Jiang Zhi-Qin , Kopetz Scott 
Published: February 2017

409 Background: Cancer-associated inflammation has been identified as a key determinant of disease progression and survival in colorectal cancer. We investigated the association between circulating inflammatory cytokines and survival in metastatic colorectal cancer (mCRC) patients. Methods: Plasma levels of 47 cytokines were measured using multiplex-bead assays in a cohort of 168 previously untreated mCRC patients. Demographic, clinical-pathological features, body mass index, and mortality data were abstracted from patient medical records. Overall survival (OS) was evaluated by Kaplan-Meier analysis and Cox proportional hazards regression. Results: Using principal component analysis, we identified a subset of cytokines explaining the maximum variance in OS; and found interleukin (IL)-1b, IL-5, IL-8, IL-12 and VEGF to be significantly associated with OS. However, only IL-8 was significantly and independently associated with OS in multivariable-adjusted models. For each 100 pg/ml increase in the level of circulating IL-8, hazard rate for death increased by 1.6 (95% CI 1.24-1.97). IL-8 measurements ranged from <1 to 413 pg/ml with a median value of 22 pg/ml. Median uncensored survival was 26.5 and 15.5 months among patients with IL-8 levels below and above this value, respectively. ROC analysis of IL-8 demonstrated an AUC of 0.69 (95% CI 0.60-0.76), as compared to 0.52 for CEA (95% CI 0.46-0.59). Conclusions: We identified an association between IL-8 and OS in previously untreated mCRC patients, suggesting its potential role as a prognostic inflammatory biomarker. In this dataset, IL-8 outperformed CEA as a prognostic biomarker, a finding which requires validation in subsequent work. Appropriately identifying, monitoring and managing chronic inflammation and the host inflammatory response during colorectal cancer treatment may be important for improving long-term survival.
Coamplification of receptor tyrosine kinases and downstream targets in Japanese gastric cancers.
Authors: Silva Arnaldo Neves Santos , Coffa Jordy , Miyagi Yohei , Menon Varsha , Bottomley Daniel , Ward Lindsay C. , Aoyama Toru , Hayden Jeremy D. , Arai Tomio , Tan Iain BeeHuat , Deng NianTao , Chan Xiu Bin , Lin Suling Joyce , Tan Patrick , Yoshikawa Takaki , Zondervan Ilse , Savola Suvi , Grabsch Heike I. 
Published: February 2017

41 Background: Amplifications of receptor tyrosine kinases genes (RTKs), EGFR, ERBB2, FGFR2, MET, have been associated with the pathogenesis and progression of gastric cancer (GC). Recent studies have found that coamplifications of RTKs are rare in GC. Two phase III trials using RTK targeted therapy have failed to achieve survival benefit in GC patients. Co-amplification of RTKs and downstream targets genes (DSTs), PIK3CA, KRAS, MYC, CCNE1 may be related to resistance to RTK targeted therapy. We tested the hypothesis whether RTKs and DSTs genes are coamplified in GC. Methods: DNA and RNA were extracted from 221 GC from the Kanagawa Cancer Center Hospital (Yokohama, Japan). Copy number of EGFR, ERBB2, FGFR2, PIK3CA, KRAS, MYC, CCNE1 was investigated by a newly developed multiplex ligation dependent probe amplification (MLPA) assay. RNA expression of the same genes was measured using the NanoString platform and compared to DNA copy number status. The frequency of RTK and DST co-amplifications was established and related to KRAS mutation status. Results: RTK amplification was associated with high levels of RNA expression except MYC (all p<0.05). 68% of GC had no RTK amplification. 9% of GC had RTK amplification and no DST amplification. 10% of GC had RTKs co-amplified. 23% of GC had RTK and DST co-amplified. There was no overlap between KRAS mutations and amplifications of KRAS, PIK3CA, FGFR2 or MET. Conclusions: This is the first study reporting that RTK and DST co-amplification are more frequent than RTK co-amplification in GC. These results indicate that GC patients considered for RTK targeting therapy might require DNA copy number assessment of RTKs as well as key DSTs and KRAS mutation testing in order to identify those patients who benefit most from treatment.
Patient-reported sleep disruption as an independent prognostic factor for overall survival in metastatic colorectal cancer.
Authors: Ulusakarya Ayhan , Palesh Oxana , Bjarnason Georg A. , Deguzman Carl , Haitz Karyn , Giacchetti Sylvie , Spiegel David , Levi Francis , Innominato Pasquale F. 
Published: February 2017

410 Background: Sleep disruption is a prevalent problem among cancer patients and survivors, but clinical correlates of poor sleep are understudied, especially in colorectal cancer. We recently showed that metastatic breast cancer patients with poor sleep efficiency have a shorter overall survival. The primary study objective is to clarify the relationship between subjective sleep disruption and survival in patients with metastatic colorectal cancer (MCC). Methods: 240 pts (63% male, mean age=59; SD=11.0) treated for MCC in 1st to 5th line of 5-fluorouracil based chemotherapy completed the QOL Questionnaire (EORTC QLQ-C30). We considered sleep to be disrupted if patients reported little to severe trouble sleeping (scores >0 ). Multivariate Cox models included age, gender, site of primary tumor, stage at diagnosis, number of metastatic sites, performance status and prior chemotherapy. Results: 65.4% of the patients reported mild to severe sleep disruption according to EORTC QLQ-C30. Patients with trouble sleeping had poorer overall survival as compared to those without sleep disruption (HR: 1.47 [1.11 to 1.95]; p=0.008). Respective median survival times (months) were 14.2 [95% CI: 12.3 to 16.1] and 17.7 [10.0 to 25.3]. The survival benefit observed in patients without sleep disruption remained statistically significant after adjustment for other prognostic factors. The final multivariate prognostic model included subjective sleep disruption (HR: 1.49 [1.11 to 2.00]; p=0.009), number of metastatic sites (p<0.001), performance status (p=0.023), and prior chemotherapy (p<0.001). Conclusions: Our findings show that patients reported sleep disruption is an independent prognostic factor for overall survival in MCC. Future research is needed to determine the mechanisms of sleep disruption and its effect on survival, and whether treatment of sleep disruption can improve survival in MCC.
Genomic determinants of prognosis in esophageal adenocarcinoma: Using computational methods to account for gene-gene interactions.
Authors: Morgen Eric , Shen Xiaowei , Vaughan Thomas L. , Whiteman David , Wu Anna H. , Gammon Marilie D. , Chow Wong Ho , Stram Daniel O. , Romero Yvonne , Xu Wei , Liu Geoffrey ,   on behalf of the BEAGESS Investigators
Published: February 2017

42 Background: Methods of stratifying esophageal adenocarcinoma patients into prognostic groups are needed, as are new insights into genetic determinants of disease behaviour. Prognosis is likely to have non-negligible genetic influences, as mediated by host responses to tumor, resistance to therapeutic side-effects, and/or an influence on tumor development. Prior studies have used candidate-gene approaches. We took an alternative approach, using an unbiased, genome-wide approach, and novel analytic methods that may be better able to detect multi-gene interactions, which may contribute the majority of genetic effects for many clinical phenotypes. Methods: Germline DNA from a Toronto-based cohort of EAC patients (n=270) was analyzed by Omni1 Quad microarray as part of the BEAGESS initiative. Quality control and analysis was performed using PLINK, R, and GenABEL software packages. A Cox proportional hazards (CPH) model for progression-free survival tested each polymorphism for independent effects at a genome-wide significance level of P < 1E-07, adjusting for population stratification. While classical analysis has limited ability to detect gene-gene interactions, a Random Survival Forest algorithm was used to detect effects based on the complex interactions among top 1,000 polymorphisms by p-value ranking. Results: After data cleaning and standard GWAS quality control procedures, there were 735,309 SNPs and 245 patients remaining for analysis. The CPH model, adjusted for population stratification, produced a satisfactory Q-Q plot, and showed one SNP (rs7844673, Chr 8) that was significant at p=7.8E-8. In addition, Random Forest based variable selection produced a set of 20 polymorphisms that (1) reproduced 86% of the predictive ability of the full 1000 variables, and (2) also included the #3 ranked polymorphism by CPH modeling (rs9290822, Chr 3) upstream of the IGF2BP2 gene. Conclusions: A genome-wide approach has discovered two previously undescribed SNPs with a potential influence on EAC prognosis via a combination of independent and interactive effects. Validation in an independent cohort is currently being pursued.
Predicting the risk of gastrointestinal (GI) toxicity in early colon cancer (CC) patients (pts) treated with adjuvant chemotherapy: Developing a GI toxicity scoring system.
Authors: Gresham Gillian , Sidhu Jasleen , Malhi Navraj , Cheung Winson Y. 
Published: February 2017

420 Background: Baseline demographics and clinical factors may contribute to a pt’s overall risk for developing chemotherapy-related GI toxicity, such as nausea, vomiting, and diarrhea. We aimed to develop a GI toxicity scoring system to better stratify early CC pts who may be at higher risk of developing GI toxicity from adjuvant FOLFOX chemotherapy. Methods: Pts diagnosed with early CC from 2005 to 2008 and treated with FOLFOX at the British Columbia Cancer Agency were reviewed. GI toxicities of interest included (1) nausea/vomiting, (2) diarrhea, and (3) any GI side effects. Baseline variables that were analyzed consisted of age, sex, ECOG, time to adjuvant chemotherapy (TTAC), and laboratory parameters. Stepwise regression was used to develop a multivariate model for each toxicity and a weighted risk scoring system was subsequently devised based on the magnitude of the parameter estimates in the multivariate model. Results: In total, 475 pts were included: median age was 62 years (range 26-89), 16.2% were aged >70 years, and 54.5% were men. The majority (90.1%) was ECOG 0/1. Independent predictors for nausea/vomiting included age >70 years (OR 2.46, 95%CI 1.3-4.8, p=0.011), GFR <50 (OR 1.68, 95% CI 1.1-2.7, p=0.025), and TTAC >8 weeks (OR 1.33, 95% CI 0.9-2.1, p=0.14) whereas independent predictors for diarrhea included age >70 years (OR 1.44, 95% CI 0.79-2.62, p=0.12) and GFR <50 (OR 1.67, 95% CI 1.1-2.6, p=0.018). The multivariate model for the risk of any GI toxicity included age >70 years (OR: 2.61, 95% CI 1.1-6.1, p=0.049), GFR <50 (OR 1.69, 95% CI 1.1-2.6, p=0.0038), and TTAC >8 weeks (OR 1.79, 95% CI 1.2-2.7, p=0.0059). Points were assigned: 2 points for long TTAC and poor GFR and 1 point for advanced age. The study cohort was classified into their risk groups based on their score (Table). Conclusions: We developed a simple 5-point scoring system to stratify early CC pts receiving adjuvant FOLFOX into low and high risk groups for GI toxicity based on baseline clinical factors. Further validation of this scoring system is required. [Table: see text]
Dose intensity and survival outcomes with adjuvant FOLFOX for colon cancer.
Authors: Smoragiewicz Martin , Rasool Javaheri Khodadad , Yin Yaling , Gill Sharlene 
Published: February 2017

423 Background: Adjuvant FOLFOX chemotherapy for resected high-risk colon cancer is associated with a low risk of febrile neutropenia (FN). Nonetheless, neutropenia is a common cause of dose modification or delay with unknown consequences on outcomes. We examined the effect of neutropenia-related and other dose limiting toxicities (DLT), relative dose intensity (RDI) of oxaliplatin and 5-FU, on relapse-free (RFS) and overall survival (OS) in patients treated with FOLFOX chemotherapy for resected high-risk colon cancer. Methods: A chart review was conducted on patients treated at the British Columbia Cancer Agency with ≥ 1 cycle of FOLFOX chemotherapy for resected stage II or III colon cancer between January 1, 2006 and December 31, 2007. RFS and OS were analyzed by the Kaplan-Meier method and multivariate Cox proportional-hazards models. Results: 114 patients (median age 59.2 years, 43.8% male, 98% stage III, median follow-up 5.2 years) were included. 90% of patients experienced any DLT, while 58% of patients had a neutropenia related DLT. There were no documented episodes of FN. G-CSF was used in 9.6% of patients. Median RDI was 81% and 85% for oxaliplatin and 5-FU, respectively. Oxaliplatin and 5-FU RDI were not associated with RFS or OS when analyzed as continuous variable or categorically (Table). Conclusions: DLTs affect the majority of patients on adjuvant FOLFOX for high-risk colon cancer, but RFS and OS do not appear to be affected by the associated lower RDI of oxaliplatin and 5-FU. [Table: see text]
Are the cardiovascular side effects of bevacizumab caused by autonomic nervous system toxicity?
Authors: Oqab Zardasht , McIntyre William , Hammad Nazik , Biagi James Joseph , Seaborn Geoffrey , Hopman Wilma , Pal Raveen , Simpson Christopher , Baranchuk Adrian 
Published: February 2017

429 Background: Bevacizumab, a monoclonal antibody that inhibits the activity of vascular endothelial growth factor, has demonstrated activity against several malignancies. Reported adverse effects include hypertension, endothelial dysfunction, and heart failure. Animal models have suggested ANS toxicity as the mechanism. This pilot study investigates the effects of bevacizumab on short and long-term ANS function using a pre-post intervention design protocol. We report on the acute effects herein. Methods: Patients were recruited among those starting bevacizumab for colon cancer. A 10-minute ECG was recorded prior to, during, and following a first dose and analysed for heart rate variability (HRV), a marker of ANS dysfunction. The HRV values were compared using paired t-tests and repeated measures ANOVA. Plasma hormones were drawn before and after infusion and compared using paired t-tests. Results: Nine patients without a cardiac history were tested. Mean age was 63 years and 5 were male. All were in sinus rhythm with normal systolic function by echo. The Table reports changes in HRV indices and plasma hormones. Conclusions: Acute administration of bevacizumab produced a statistically significant decrease in plasma aldosterone and was associated with a trend towards decreases in plasma norepinephrine and the low/high frequency domain ratio of HRV. These changes may be signs of an early ANS imbalance. Both a larger patient series and longer follow-up are planned to characterize the effects of bevacizumab on the ANS. [Table: see text]
Expression of proliferation markers in colonic mucosa in normal volunteers with a high arginine-containing diet and effect of dietary grape ingestion.
Authors: Holcombe Randall F. , Martinez Micaela , Planutis Kestutis , Planutiene Marina 
Published: February 2017

431 Background: Resveratrol, which inhibits ODC and Wnt signaling, has colon cancer prevention activity in animal models. To assess the effects of a resveratrol-rich diet on the colon, 30 normal volunteers enrolled on a cancer prevention clinical trial (NCT00578396) involving the ingestion of 1/3, 2/3, or 1 pound of grapes per day for 14 days. Data analysis was stratified based on arginine intake because meat and dietary arginine have been linked to colon carcinogenesis. Methods: Patients were placed on a low-resveratrol diet 14 days prior to and during the grape ingestion period. Detailed dietary information and colonic biopsies were obtained before and after the grape intervention in a single-subject design. Tissue was processed for RNA for qRT- PCR analysis of genes implicated in colonic proliferation, Wnt signaling and colon carcinogenesis. The % of cells expressing Ki67 in the lower 1/3 of colonic crypts was determined by IHC. Results: Mean arginine consumption for the study population was 4.5 ± 2.27 gm/day. Participants with higher initial dietary arginine consumption (> 4.5gm) had higher levels of cyclinD1 (p = 0.022), c-myc (p = 0.0002), axin2 (p = 0.0065) and CD133 (p = 0.041) mRNA in the colonic mucosa than participants with lower initial arginine consumption. No differences in the % of base of the colonic crypt cells staining for Ki67 were seen. Grape ingestion led to a significant reduction in cyclinD1 expression in participants with higher initial arginine consumption (p = 0.0039), with levels falling to those seen in low arginine consumption participants. Conclusions: Normal volunteers with a high amount of daily arginine ingestion had elevated levels of markers indicative of cell proliferation (cyclinD1, c-myc), Wnt signaling (axin2), and colonic stem cells (CD133). Expression of each of these markers was reduced following grape ingestion, though only the reduction in cyclinD1 reached statistical significance. Significance: Dietary arginine adversely affects colonic mucosa and may predispose individuals to the development of colon cancer. The effects are reversed in part by a resveratrol-rich grape-containing diet. Clinical trial information: NCT00578396.
The influence of vitamin D and receptor status in colorectal cancer.
Authors: Paluri Ravi Kumar , Council Leona , Putcha Balananda Kumar , Jadav Trafina , Manne Upender , Posey James 
Published: February 2017

435 Background: Since vitamin D is a modifiable factor, we have proposed to evaluate vitamin D levels and cognate receptor expression in patients presenting with colorectal cancer (CRC). Previously, we retrospectively assessed vitamin D receptor (VDR) level in 98 CRC tumor tissues and noted a variation of expression with tumor stage (GI ASCO 2009 abs # 371). Methods: We prospectively evaluated 38 cases of CRCs newly diagnosed during 3 consecutive summers and assessed demographics, pathological characteristics and long-term clinical outcomes. Skin color was determined by the Fitzpatrick photo typing scale. At the time of enrollment, vitamin D levels were assessed, and a twenty point lifestyle assessment questionnaire was administered. Descriptive statistics were performed. Tumor and corresponding normal tissues are being evaluated to identify the patterns of VDR expression and expression of the Wnt/B-catenin inhibitors-Dickkopft 1(DKK-1) and Dickkoft-4 (DKK-4), which have been implicated in development of CRCs. Results: 38 patients diagnosed with CRC 24 were men and 14 were women with median age at diagnosis was 59 yrs (range, 28-78 yrs). Median follow up after diagnosis was 2.1 yrs (range, 0.06, 3.68 yrs). Histological grades of adenocarcinomas were well differentiated as well (13%), moderately differentiated (66%), and poorly differentiated (7%), and mucinous types (11%). Patients were staged as I (8%), II (39%), III (34%), or IV (19%). 81% of patients were treated with chemotherapy in an adjuvant or neo-adjuvant setting. The median serum total 25-hydroxy vitamin D level was 23 ng/ml (range, 6-87 ng/ml). There was no substantial difference in median vitamin D levels between lower and higher stages (25 vs 21). Lower stages of CRC were associated with lighter skin types (Fitzpatrick scale types I and II) and advanced stages with darker skin types (IV-VI); this could be a reflection of variable VDR expression. Conclusions: We are analyzing VDR expression as a covariate to compare to vitamin D levels, skin color, and stage. Results will be reported at the time of presentation. These studies were supported by a pilot project grant by the UAB Comprehensive Cancer center.
Prevalence and clinicopathologic features of hereditary nonpolyposis colorectal cancer (HNPCC) syndrome in Chinese American patients in south Brooklyn, New York.
Authors: Xiao Ying-Yi , Sun Yan Yu , Desani Jatin Karsandas , Clark Bradley , Win Khin Than , Huang Yiwu , Xu Yiqing 
Published: February 2017

441 Background: HNPCC is a hereditary disorder that predisposes to colorectal and other cancers before 50 years old and in multiple generations, with a prevalence of 2 to 5% in Caucasians. It is associated with mutations in DNA mismatch repair genes (MMR). The gold standard for diagnosis is genomic DNA sequencing. Immunohistochemical staining (IHC) is sensitive to predict but not diagnostic for HNPCC, as acquired hypermethylation of MLH1 promoter can present with negative IHC staining. We aimed to study the prevalence and clinicopathological features of HNPCC in Asian patients. Methods: IHC for 4 MMR protein expressions on tumor specimens, commercial MLH1 methylation studies and genomic sequencings were performed on eligible and selected patients diagnosed of colon, gastric or endometrial cancers. Results: 117 patients were identified (2000 to 2012), 55 M and 62 F, ranges from 23 to 92 years old. Seven cases of MMR deficiency were found: 5 with colon cancer (81 patients), 2 with gastric cancer (31 patients) and 0 with endometrial cancer (5 patients). Among the 81 colon cancer patients, 20 had cancer younger than 50 years old; and among them, 3 cases of MMR deficiency were confirmed by DNA sequencing. One patient was found to have a unique previously unreported suspected deleterious mutation. The other 2 patients had MLH1 promoter hypermethylation indicating acquired abnormality. 31 patients had gastric cancer, and 2 cases of MMR deficiency were found, including 1 MLH1 promoter hypermethylation and another isolated PMS2 deficiency by IHC. Conclusions: The prevalence of HNPCC in Chinese colon cancer patients in South Brooklyn is 3.7% (3/81). All cases were found in patients younger than 50 years old with a prevalence of 15% (3/20). Hypermethylation in MLH1 can be seen in both colon and gastric cancers. The screening in Chinese Americans for HNPCC is as important as in Caucasian population, and should be done also in Asian gastric cancer patients as well.