bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of DOCK6 with cancer stem cell development and as an independent prognostic factor of gastric cancer.
Authors: Wang Chia-Siu , Tsai Chung-Ying , Lee Kam-Fai , Kuo Liang-Mou , Lin Kwang-Huei 
Published: March 2017

68 Background: The prognosis of advanced gastric cancer (GC) remains poor, and the key players in molecular pathogenesis are predominantly unknown at present. Methods: In order to identify novel prognostic factor of GC, we compared the data of iTRAQ proteomics from 6 GC samples with that of Oncomine database from 86 GC samples to intersect 122 high-expression proteins in gastric cancer tissue. The candidate biomarkers were further characterized in fresh GC tumor tissues compared with adjacent non-tumor tissue by using Q-RT-PCR, immunohistochemical staining and western blot. GC cells with depletion of DOCK6 were examined to identify downstream molecules and establish their effects on cell motility, invasion and gastric cancer stem cell (CSC) markers. The possible signaling pathway of DOCK6 were also investigated. Results: DOCK6 is identified as one of the potential GC biomarkers in iTRAQ proteomics. Our data confirm the overexpression of DOCK6 in GC tumor tissue compared with adjacent non-tumor tissue. In addition, the clinical data shows higher DOCK6 expression was positive correlated to depth of invasion, lymph node metastasis, vascular invasion and pathological stage. Furthermore, higher DOCK6 expression represented significantly shorter cumulative survival both in univariate and multivariate analysis for survival outcome. Depletion of DOCK6 repressed the cell migration, proliferation, sphere formation, anchorage-independent growth and tumorigenicity as well as gastric cancer stem cell (CSC) markers. In order to explore the downstream effector of DOCK6, we correlated thousands of gene with DOCK6 in three GC dataset published in the literature. The DOCK6 positive-correlated genes were subsequently analyzed by Metacore. They were significantly involved in WNT/β-catenin signaling pathway. Our result demonstrates nuclear b-catenin, as well as CD44, was decreased accompanied by depleting DOCK6. Moreover, the interaction between DOCK6 and β-catenin was observed in GC cells. Conclusions: Our studies unveil the role of DOCK6 in the self-renewal of CSC and propose DOCK6 as an independent marker of tumor progression.
Factors predictive of receiving neoadjuvant versus adjuvant chemoradiotherapy in locally advanced rectal cancer and the impact on overall survival.
Authors: Coffman Alex Richard , Boothe Dustin , Frandsen Jonathan Evans , Gross Molly , Pickron Thomas Bartley , Scaife Courtney L. , Lloyd Shane 
Published: March 2017

686 Background: Neoadjuvant chemoradiotherapy (NCRT) is generally accepted as the optimal treatment strategy compared to adjuvant chemoradiotherapy (ACRT) for locally advanced rectal cancer due to improvement in local control and reduced toxicity. However, NCRT has not been shown to improve overall survival (OS). We investigated the effect of NCRT versus ACRT on OS as well as the impact of demographic factors and clinical stage for the selection of each treatment approach utilizing the National Cancer Data Base. Methods: Adult patients with stage II and stage III adenocarcinoma of the rectum diagnosed from 2004-2013 were included. Chi-square analysis was used to compare demographic variables and clinical stage between the NCRT and ACRT treatment groups. Univariate and multivariate logistic regression modeling was used to identify factors predictive of each treatment strategy. Kaplan Meier and log-rank analysis along with propensity score matching was performed to determine the effect on OS. Results: A total of 20,262 patients were identified: 17,737 (87.5%) received NCRT and 2,525 (12.5%) received ACRT. Utilization of NCRT increased over the study period (p < 0.01). Factors associated with receipt of NCRT on multivariate analysis include: treatment at an academic institution (OR 0.76, 95% CI 0.68-0.85), income greater than $46,000 (OR 0.79, 95% CI 0.67-0.92), and living greater than 50 miles from a treatment facility. Factors associated with receipt of ACRT on multivariate analysis include: female sex (OR 1.12, 95% CI 1.01-1.24), Charlson comorbidity index of 1 (OR 1.18, 95% CI 1.04-1.34), and radiotherapy dose greater than 5040 centigray (OR 1.76, 95% CI 1.56-1.98). Compared to ACRT, NCRT was associated with a decreased risk of death on multivariate analysis (HR 0.91, 95% CI 0.84-1.00), which persisted after propensity score analysis. Conclusions: The use of NCRT for locally advanced rectal cancer is increasing and is associated with an OS benefit compared to ACRT.
Application of the ASCO framework for assessing value in metastatic colorectal cancer clinical trials.
Authors: Ezeife Doreen Anuli , Parimi Sunil , Cusano Ellen R. , Smith Matthew K , Truong Tony H. , Raissouni Soundouss , Lin Yongtao , Monzon Jose Gerard , Li Haocheng , Tam Vincent C. , Tang Patricia A. 
Published: March 2017

687 Background: Phase III trials (P3T) in metastatic colorectal cancer (mCRC) have collectively led to incredible advancements in patient outcomes over the past thirty years. It is unknown how many of these trials have led to clinically relevant improvements based on clinical benefit, toxicity and cost. Our objective was to characterize the evolution of mCRC P3T with the ASCO Value Framework. Methods: P3T of systemic therapy for mCRC published between 1980 and 2015 were identified. Data regarding the trial sample size, journal year of publication, statistical significance, journal impact factor, and citation by the 2015 mCRC National Comprehensive Cancer Network (NCCN) guidelines were extracted. For each trial, the Net Health Benefit (NHB) score was calculated using the June 2015 (original) and May 2016 (revised) ASCO Value Advanced Disease Frameworks. Data were analyzed to identify associations using the Chi-square, Kruskal-Wallis, and t-tests. Results: There were 108 mCRC P3T eligible for calculation of the original and revised NHB score. Median NHB score was 4.1, range -30 to 43.5, using the revised framework. Only 13% of trials received at least 10 bonus points for palliation, quality of life, or tail of the curve. The revised framework demonstrated moderate correlation with the original framework (Pearson correlation coefficient = 0.63, p<0.0001). NHB scores were normally distributed with the revised framework, unlike the original framework. Trials with significant results had significantly higher revised NHB scores (median NHB score 23.1 vs 2.5, p < 0.0001). Clinical trials cited in NCCN had higher revised NHB scores than those not cited (median NHB score 7.6 vs 0, p = 0.03). In multivariate linear regression analysis, the only significant predictor of a high revised NHB score was a statistically significant improvement in the primary outcome. Conclusions: Median revised NHB score for mCRC P3T was 4.1. Higher NHB scores were associated with significant studies and citation by NCCN guidelines, a surrogate for practice-changing trials. The revised ASCO Value Framework can be a useful tool to assess the value of new mCRC treatments.
Does the addition of biologic agents to chemotherapy in patients with unresectable colorectal cancer metastases result in a higher proportion of patients undergoing resection? A systematic review and meta-analysis.
Authors: Bogach Jessica , Levine Oren Hannun , Ruo Leyo , Serrano Aybar Pablo Emilio 
Published: March 2017

690 Background: The likelihood of converting unresectable metastatic colorectal cancer (CRC) to operable disease with systemic therapy is unknown. The purpose of this study was to determine the proportion of patients with unresectable CRC metastases that become resectable on combination systemic therapy, and whether biologic agents (antiantiogenics, anti-EGFR and multitargeted agents) improve the rate of resection (primary outcome). Methods: We searched Medline, Embase, CENTRAL and PubMed for randomized controlled trials comparing chemotherapy and biologics (intervention) vs. combination chemotherapy alone (control) in patients with unresectable CRC metastases. Study selection, data abstraction, risk of bias and quality of the evidence assessment were carried out in duplicate. Secondary outcomes included overall survival (OS) and progression free survival (PFS). Risk of bias was assessed using the Cochrane tool. Statistical heterogeneity was calculated using chi-squared and I2. Clinical heterogeneity was explored via subgroup analyses. The quality of the evidence was assessed using GRADE. Protocol was published in PROSPERO. Results: Of 7954 abstracts retrieved, 12 studies were analyzed and 8 reported the primary outcome, with 2604 intervention and 2661 control patients. The proportion of patients resected was higher in the intervention group, Relative Risk 1.36, 95% confidence interval (CI) 1.08-1.69, p = 0.008. The absolute risk of undergoing resection was 48 per 1000 (control); compared to 65 per 1000 (intervention). There was no difference in OS, Hazard Ratio (HR) 0.91, 95% CI 0.82-1.01. PFS was better in the intervention group (HR 0.83, 95% CI 0.74-0.92). Overall the risk of bias for the included studies was low. Statistical test for heterogeneity was low (I2 was 0%, p = 0.72). There was significant clinical heterogeneity, which was not explained with subgroup analyses. The quality of the evidence (GRADE) was moderate. Conclusions: The addition of biologic agents to systemic chemotherapy in patients with unresectable CRC metastasis improves resectability and PFS but not OS.
Cost of colon cancer care: Results of nationwide inpatient sample (NIS) data.
Authors: Bansal Pranshu , Rabinowitz Ian , Boumber Yanis , Bansal Dhruv 
Published: March 2017

692 Background: Cost of cancer care including colon cancer continues to rise. Most of the recent advances in colon cancer inlcude biologics and targeted agents which are adminstered in an oupatient setting and more commonly thought to be responsible for increasing economic burden. Cost of care for cancer patients in an inpatient setting however continues to be a significant factor that needs to be identified better to help adopt cost effective quality improvement in future. Methods: We used NIS to extract data for patients hospitalized with primary diagnosis of colon cancer using clinical classification software code 14, and corresponding ICD9 codes for the years 2003-2013. ICD codes for colorectal and rectal cancer were eliminated. NIS is a nationally representative survey of hospitalizations conducted by the Healthcare Cost and Utilization Project. It represents 20% of all hospital data in US. Trend of rate of hospitalization, mean length of stay (LOS), mean cost of hospitalization and mean cost of hospitalization based on owner type- government, private not for profit (PNFP) and private for profit (PFP) was performed. Results: From the year 2003 to 2013 rate of hospitalizations for colon cancer decreased from 37.4 to 28.1 per 100,000 hospital admissions. Mean LOS declined from 9.06 to 7.76 between 2003-2013. In the same time period the mean cost of hospital stay increased from $39,430 to $73,219. The mean cost of hospitalization based on owner type in 2003 was government $33,507; PNFP $33,735 and PFP was $55,553 and in 2013 the mean costs were $63,194; $68,555 and $107,428 respectively. Conclusions: In the decade of 2003-2013 the rate of hospitalization decreased by approximately 25%, LOS decreased by 14% but the mean cost of hospitalization continued to increase throughout the decade with a mean increase of approximately 85% in hospital costs. The increase was observed across the spectrum of all owner types with the maximum increase of 104% in PNFP followed by PFP owner type at 93%, national inflation rate was 26% during this time. Progress made in decreasing LOS has not directly translated into reducing hospital costs and further studies focusing on factors in addition to cost of biologic agents that contribute to cancer care costs should be considered.
Impact of primary tumor sidedness on survival after resection of colorectal liver metastases (CRLM).
Authors: Lee-Ying Richard M. , Bosma Nicholas , Tang Patricia A. 
Published: March 2017

694 Background: The impact of primary tumour sidedness has recently been demonstrated in patients with metastatic colorectal cancer (mCRC). Differences in right (R) versus left (L) sided mCRC may be due to differences in consensus molecular subtyping. Clinically predictive mutations in ras, ( kras, nras and braf) may also help drive some of the differences in outcome. However, patients with mCRC who undergo surgical resection of CRLM often have a good prognosis. The aim of this study was to assess the impact of tumour sidedness on OS after resection of CRLM. Methods: Patients who underwent resection of CRLM in the province of Alberta, Canada were identified from 2004-2016. Tumour sidedness was determined by chart review, with R from the cecum to transverse and L from splenic flexure to sigmoid. Where available, ras mutational status was collected. OS was measured from the time of CRLM resection to death or last follow-up using the Kaplan-meier method. R and L were compared using the log-rank test and a Cox regression model. Results: 471 patients were identified who underwent resection of CRLM for mCRC, including 204 R and 267 L. Median age was 65, 63% male, with 54% synchronous metastatic disease, and 67% with a Charleson comorbidity index of 0. All ras wildtype was present in 22% of cases, any ras mutation was detected in 21% and 57% were unknown at the time of analysis. The median OS of R was 45 months, compared to 72 months for L, log-rank p = 0.01. After adjusting for potential confounders with a Cox-proportional hazard model, R compared to L remained significant, with a HR of 1.4 (95% CI 1.0-1.9, p = 0.02). ras mutational status was also significant for ras mutant, HR 2.4 (95% CI 1.7-3.3) and ras unknown HR 2.2 (95% CI 1.5-3.1) compared to ras wildtype p < 0.01. Conclusions: Primary tumour sidedness continues to have an impact on OS in mCRC, even when disease is managed surgically with resection of CRLM. Though limited by numbers, the impact remained significant even after controlling for potential confounders, including ras mutational status. Additional ras testing is underway. Further molecular classification may provide a biologic rationale for the observed differences.
Institutional variation in the thoroughness of pathologic assessment and pathologic complete response rates for locally advanced rectal cancers treated with neoadjuvant chemoradiation.
Authors: Chow Oliver S , Patil Sujata , Keskin Metin , Smith Jesse Joshua , Widmar Maria , Smith David D. , Avila Karin , Shia Jinru , Chu Peiguo , Garcia-Aguilar Julio 
Published: March 2017

696 Background: A pathologic complete response (pCR) after neoadjuvant therapy and surgical excision is associated with a better prognosis and guides the management of patients with locally advanced rectal cancer. It is not known whether the thoroughness of pathologic assessment correlates with the finding of pCR. Methods: We introduce a surrogate measure for the thoroughness of pathologic assessment by taking the ratio of maximum residual tumor size and the number of cassettes prepared from the tumor: the Tumor Size to Cassette Ratio (TSCR). We retrospectively reviewed pathology reports from 259 patients with Stage II/III rectal cancer enrolled in a multicenter prospective clinical trial to determine whether TSCR is associated with pCR. Results: Of 247 included patients, 71 (29%) had a pCR. The pCR rate ranged from 0-45% and TSCR ranged from 0.0004 to 1.67 across the twelve trial sites. TSCR was significantly associated with pCR on univariable analysis. On multivariable analysis, TSCR remained significantly associated with pCR (odds ratio of 0.05; 95% CI 0.008-0.302) after adjusting for clinical stage, tumor size, distance from anal verge, radiation dose, and the number of neoadjuvant cycles of FOLFOX received. Conclusions: Pathologists tend to assess rectal cancer specimens with a pCR more thoroughly, but the thoroughness of pathologic assessment of residual tumor specimens varies between institutions. The thoroughness of pathologic assessment is associated with pCR. This raises the need for further standardization in the assessment of rectal cancer specimens after neoadjuvant chemoradiation.
QTWIST analysis in the RECOURSE trial.
Authors: Tabernero Josep , Van Cutsem Eric , Ohtsu Atsushi , Amellal Nadia , Cadour Stéphanie , Fougeray Ronan , Haffemeyer Benjamin , Mayer Robert J. 
Published: March 2017

698 Background: RECOURSE showed that treatment with trifluridine/tipiracil in patients in patients (pts) with refractory metastatic colorectal cancer was associated with significantly improved survival vs placebo. As quality of life (QoL) was not captured in the trial, other methods were used to evaluate potential impact on QoL. Methods: We used the QTWIST method, i.e. quality-adjusted TWIST (time without symptoms of disease or toxicity), to explore survival adjusted for QoL with trifluridine/tipiracil vs placebo in the RECOURSE population. QTWIST incorporates a trade-off between time spent with treatment-related adverse events versus improvement in progression-free survival, and combines an estimate of the mean duration of each health state (TOX, TWIST, and RELAPSE [REL]), weighted by a utility coefficient, into a global QTWIST score. TOX represents time with grade 3/4 treatment-related adverse events that are expected to impact QoL (i.e. nausea, vomiting, diarrhea, fatigue/asthenia, anorexia, febrile neutropenia) before progression, TWIST represents time without symptoms or toxicity; and REL represents time from progression (as defined in the RECOURSE trial) until death. We applied a utility coefficient of 1 for TWIST and values of 0.5 for TOX and REL. A sensitivity analysis varied the utility coefficients for TOX and REL from 0 to 1. Results: 798 pts (533 trifluridine/tipiracil vs 265 placebo) were included with median follow-up time of 11.8 mo. The between-group difference in the global QTWIST score was 1.5 mo (95% CI, 1.49–1.52) in favor of trifluridine/tipiracil. Using varying utility coefficients for TOX and REL from 0 to 1 as a sensitivity analysis, the between-group difference in the global QTWIST score ranged from 1.3 to 1.7 mo, always in favor of trifluridine/tipiracil. Conclusions: The median overall survival benefit observed with trifluridine/tipiracil vs placebo in RECOURSE was 1.8 months. Consistently, patients' QoL as evaluated by QTWIST showed that quality-adjusted survival with Lonsurf is significantly improved by 1.5 months vs placebo. Clinical trial information: NCT01607957. [Table: see text]
Impact of country-specific health economic guidelines on cost-effectiveness (CE) estimates: An illustrative study of the CE of cetuximab in the first-line (1L) treatment of RAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Harty Gerard , Fujii Ronaldo Kenzou , Ostawal Amrita , Pescott Chris P 
Published: March 2017

702 Background: Adding cetuximab to conventional 1L chemotherapy (FOLFIRI or FOLFOX) improves survival outcomes in patients with RASwt mCRC. Conflicting evidence exists regarding the CE of cetuximab in mCRC, due in part to differences in country-specific health technology assessment (HTA) guidelines. Methods: CE estimates for the 1L treatment of RASwt mCRC with FOLFIRI or FOLFOX ± cetuximab were calculated for the UK (NICE), Brazil, Netherlands, and Belgium using a Markov cohort model populated with country-specific HTA requirement inputs and assumptions. Model outcomes were treatment costs, life-years (LY) or quality-adjusted LY (QALY) gained, and the incremental CE ratio (ICER). ICERs were compared against CE thresholds. Results: Country-specific HTA guidance resulted in differing CE outcomes for patients with RASwt mCRC receiving FOLFIRI or FOLFOX ± cetuximab (Table). Conclusions: We applied our Markov model to four markets, incorporating country-specific HTA requirements into our calculations. Although our analyses with similar comparators led to a varying range of CE estimates, they met the HTA threshold guidelines in the four markets. [Table: see text]
Treatment outcome and recovery from peripheral sensory neuropathy during a 3-year follow-up in patients receiving modified FOLFOX6 as adjuvant treatment for stage II/III colon cancer (JFMC41-1001-C2: JOIN Trial).
Authors: Manaka Dai , Kotaka Masahito , Shinozaki Katsunori , Touyama Tetsuo , Matsui Takanori , Ishigure Kiyoshi , Hasegawa Junichi , Inoue Keiji , Munemoto Yoshinori , Takagane Akinori , Ishikawa Hiroshi , Ishida Hideyuki , Ogata Yutaka , Oba Koji , Goto Koichi , Sakamoto Junichi , Saji Shigetoyo , Ohtsu Atsushi , Watanabe Toshiaki , Yoshino Takayuki 
Published: March 2017

703 Background: The JOIN Trial investigated safety and efficacy of modified FOLFOX6 (mFOLFOX6) in Japanese patients (pts) with stage II/III colon cancer. In the initial safety report, incidence of ≥ grade 3 (G3) peripheral sensory neuropathy (PSN) was 5.8% during treatment. Methods: Twelve cycles of mFOLFOX6 were given to pts with the following criteria: stage II/III curatively resected colon cancer; ECOG Performance Status (PS) of 0–1; age, ≥ 20 years; and adequate organ function. We report the treatment outcome results, including disease-free survival (DFS), relapse-free survival (RFS), overall survival (OS), and recovery from PSN during 3-year follow-up. Results: From November 2010 to March 2012, 882 pts were enrolled. In the efficacy group (N = 864; median follow-up, 3 years), pt characteristics were as follows: median age, 64 years; male, 53.8%; PS 0, 93.8%; stage II/IIIA/IIIB/IIIC (TNM), 18.5/7.3/52.5/21.6%; and lymph nodes examined, < 12/ > 12/unknown: 17.2/82.5/0.2%, respectively. Three-year DFS, RFS, and OS were 76.1, 77.3, and 92.7%, respectively. Favorable 3-year DFS, RFS, and OS were 92.1, 92.8, and 97.4% in stage II patients; 76.4, 77.9, and 93.8% in stage IIIA/B; and 61.6, 62.7, and 85.9% in stage IIIC, respectively. The main recurrent sites were liver (7.6%), lung (7.3%), and lymph nodes (5.2%). In multivariate Cox regression analysis, tumor histology, venous invasion, and lymph node metastatic ratio were statistically significant prognostic factors for DFS, RFS, and OS. Cumulative incidence of PSN during treatment was 47.8% in G1, 30.3% in G2, and 5.8% in G3. For those with G3 PSN during treatment, there was gradual recovery in 1.1% at 12 months after enrollment, 0.5% at 24 months, and 0.2% at 36 months. However, G1 and G2 residual PSN after 3 years was observed in 21.0% of pts (18.7%, G1; 2.3%, G2). Conclusions: Efficacy and safety of adjuvant mFOLFOX6 in pts with stage II/III colon cancer can be confirmed. Most pts successfully recovered from G3 PSN related to oxaliplatin, but G1 and G2 PSN was irreversible in one-fifth of pts at the 3-year follow-up. Clinical trial information: UMIN000004443.