bluuebunny/crossref_metadata_2025_split huggingface dataset:
Clinical significance of serum vascular cell adhesion molecule-1(VCAM-1) in colorectal cancer.
Authors: Ciftci Rumeysa , Aykan Nuri Faruk , Aksit Ece , Tilgen Yasasever Ceren , Vatansever Sezai , Yasasever Vildan 
Published: February 2017

550 Background: Vascular cell adhesion molecule-1 (VCAM-1) is a transmembrane glycoprotein, which is expressed on endothelium and contributes in leukocyte adhesion and extravasation during inflammation. It has been demonstrated that VCAM-1 is over-expressed on colorectal cancer (CRC) cells and plays role in metastasis development and angiogenesis. We aimed to compare serum VCAM-1 levels of CRC patients with heathy controls and evaluate its relationship with clinicopathologic parameters, treatment response and overall survival (OS). Methods: The study enrolled 111 patients with histopathologically confirmed CRC followed up between February 2010-September 2013 in Institute of Oncology, Istanbul University and 30 sex- and age-matched healthy controls. Pre-treatment serum VCAM-1 levels were determined by the solid-phase sandwich ELISA method. Results: The cancer localisation was rectum in 40% and colon in 60% of patients. Metastatic disease was present in 51.4%. Forty percent of 40 metastatic patients who received palliative chemotherapy (CT) was CT-responsive (partial or complete response). The median serum VCAM-1 level was significantly higher in CRC patients than controls (p<0.001). In addition, serum VCAM-1 level was significantly higher in diabetic CRC patients than those without diabetes (p=0.03). There was no significant relationship between other clinicopathologic parameters, stage, carcinoembrionic antigen (CEA), CA19.9 and VCAM-1. The median follow-up period was 12 (±8.2) months. Progression was observed in 16.2 % of patients and 18 % of patients had died at the time of analysis. The presence of metastasis (p<0.001) and elevated CEA level (p<0.001) were factors affecting OS significantly. Serum VCAM-1 did not have a significant impact on OS in both univariate (p=0.55) and multivariate analysis (p=0.23). Conclusions: Serum VCAM-1 level is significantly higher in patients with CRC than controls. However, it has no prognostic or predictive role for CT response. Studies randomising CRC patients in more homogenous treatment arms to evaluate the effect of systemic treatment on serum VCAM-1 with longer follow-up period are needed.
Treatment and outcomes of goblet cell adenocarcinomas (GCAs) of the appendix.
Authors: Tsang Erica , McConnell Yarrow Jean , Schaeffer David , Lee Lawrence , Zerhouni Siham , Schaff Kimberly , Speers Caroline , Kennecke Hagen F. 
Published: February 2017

551 Background: GCAs are rare mucinous neoplasms with mixed epithelial and endocrine differentiation, which behave more like mucinous adenocarcinomas than appendiceal neuroendocrine tumors. Optimal therapy is poorly described. Objectives of this study were to define prognostic factors and describe management of patients presenting with stage I-IV disease. Methods: Patients diagnosed with GCAs between 1990-2010 were identified from the British Columbia province-wide cancer registry and linked to an electronic pathology archive. Pathology was reviewed in 79 of 87 cases where archival tissue was available. Treatment and outcome data were obtained from the BC Cancer Agency, GI Cancer Outcomes Unit, and Provincial Pharmacy databases, combined with chart review. Kaplan Meier survival analysis was used to compare outcomes. There were insufficient events for robust multivariate analysis. Results: 87 cases of appendiceal GCAs were identified for an annual population incidence of 0.2/200,000. Median age was 54 (range 25-91) years, and 42 (48%) were male. There were no stage I patients. For stage II-III (n=68) and stage IV (n=19) patients, median overall survival (OS) was 42.8 and 15.4 months, respectively (p=0.009). Of stage II-III patients, 51 (76%) underwent right hemicolectomy and 9 (16%) received adjuvant chemotherapy: 5-FU (n=5), 5FU/oxaliplatin (n=4). Median recurrence-free survival (RFS) was 38.2 months (10 recurrences: 9 peritoneal, 1 hepatic). Univariate analysis demonstrated no prognostic effect of adjuvant chemotherapy, surgical approach (hemicolectomy vs. appendectomy), T4 tumors, number of nodes resected, or lymph node positivity. 5-year RFS was 90.2% in patients who presented with appendicitis, compared to 63.7% in those without appendicitis (p=0.016). Of 19 patients with stage IV disease, 10 (63%) received palliative chemotherapy including FOLFOX (n=4), FOLFIRI (n=1), FOLFIRI/bevacizumab (n=2), and capecitabine (n=2). Only high mitotic rate was associated with reduced OS. Conclusions: GCAs are rare tumors and the majority present with non-metastatic disease. Presentation with metastatic disease carries a poor prognosis and chemotherapy agents used for advanced colorectal tumors are most commonly applied.
Impact of liver fibrosis on effects and adverse effects of unresectable colorectal cancer under first line chemotherapy including CPT-11.
Authors: Yahagi Masashi , Tsuruta Masashi , Hasegawa Hirotoshi , Okabayashi Koji , Seishima Ryo , Takahashi Hidena , Matsui Shimpei , Yamada Toru , Kondo Takayuki , Shimada Takehiro , Matsuda Mutsuhito , Yoshikawa Yusuke , Asada Yusuke , Sugiura Kiyoaki , Suzuki Yoshiyuki , Tajima Yuki , Nakadai Junpei , Kitagawa Yuko 
Published: February 2017

556 Background: Liver dysfunction is one of the irritating adverse effects in chemotherapy for colorectal cancer. Polymorphisms of UGTIA1, which is related to metabolism of CPT-11 in the liver, cause severe adverse events. In addition, long-term induction of CPT-11 may involve steatohepatitis. Thus, it is critical to surrogate liver dysfunction in chemotherapy including CPT-11. In this current study, we evaluated whether NAHLD fibrosis score (NFS) which is liver fibrosis marker of nonalcoholic steatohepatitis, is feasible for predicting the effects and adverse events of chemotherapy including CPT-11 for colorectal cancer. Methods: From January 2007 to May 2013, of 118 patients who were diagnosed with unresectable advanced/recurrent colorectal cancer in our hospital, we retrospectively analyzed 89 patients who underwent first line chemotherapy including CPT-11. We statistically analyzed the value of the pretreatment NFS on response rate (RR), progression-free survival (PFS), and hematologic or non-hematologic toxicity of chemotherapy including CPT-11. Results: The median NFS was -1.302 (range=-5.158 to 2.62). Multivariate analysis revealed that NFS was an independent negative predictive marker for RR (coef -0.373 (-0.712 to -0.035), p = 0.031), although no contribution of NFS was observed to PFS (coef 0.958(0.786|1.168), p=0.672). In terms of the adverse events, high value of NFS is an independent risk factor in hematological toxicity (coef 0.93 (0.20 to 1.65), p = 0.012), while not in non-hematological toxicity (coef 0.198 (-0.218|0.613), p=0.351). Conclusions: The pretreatment NFS might be a feasible for predicting response and hematological toxicity in first line chemotherapy including CPT-11 against colorectal cancer.
Therapeutic drug monitoring of 5-fluorouracil (5-FU) in the treatment of patients with colorectal cancer (CRC).
Authors: Goel Gaurav , Sehgal Rajesh , Meisner Dennis James , Sun Min , Pasricha Gurleen , Chu Edward , Lee James J. 
Published: February 2017

563 Background: 5-FU continues to serve as the backbone of systemic combination chemotherapy for treatment of CRC in the adjuvant and metastatic disease settings. The dosing of 5-FU has traditionally been based on body surface area (BSA). Growing evidence suggests that BSA-based 5-FU dosing has several limitations, and that pharmacokinetic (PK)-guided dosing of 5-FU improves clinical efficacy with reduced toxicity. We conducted a QI study to evaluate the clinical feasibility of PK-guided 5-FU dose adjustment and its impact on clinical outcome. Methods: CRC patients treated with combination chemotherapy regimens containing infusional 5-FU who underwent PK-guided optimization of 5-FU dosing using an antibody-based immunoassay (OnDose or MyCare) were included in the analysis. Results: A total of 58 patients (34 males, 24 females) meeting the entry criteria have been identified to date. The median age was 61 years (range, 27-85). Fifteen patients had stage III disease, and the remaining 43 patients had stage IV disease. The 5-FU infusional regimens included mFOLFOX6 (n=45) and FOLFIRI (n=13). A total of 143 5-FU PK tests were performed for these 58 patients. The median number of tests performed per patient was 2 (range, 1-5). On initial testing, only 36% (n=21) patients had 5-FU systemic exposure, measured as area under the curve (AUC), within the suggested target range of 20-30 mg.hr/L. Fifty-five percent of the patients were below the target AUC while 9% (n=5) patients were above the target range. Of the 32 patients below the target range on 5-FU AUC test, the 5-FU doses were increased in 22 patients for the subsequent treatment cycle. The median number of dose modifications required to achieve the target AUC levels in these patients was 1 (range, 1-2). The majority of these patients (86%, n=19) tolerated the increased 5-FU dose well without worsening of 5-FU related toxicity. Conclusions: Our data provides further evidence that 5-FU dosing based on BSA results in sub-optimal 5-FU exposure levels for the majority of patients (64%). PK-guided dose adjustment of 5-FU appears to be a practical and feasible approach that can be applied in routine clinical practice.
Final analysis of the phase 2 APEC study: Overall survival (OS) data and biomarker subanalyses for first-line FOLFOX or FOLFIRI with cetuximab (cet) once every 2 weeks in patients (pts) with KRAS or RAS (KRAS and NRAS, exons 2-4) wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Cheng Ann-Lii , Cornelio Gerardo H. , Shen Lin , Price Timothy Jay , Yang Tsai-Sheng , Chung Ik-Joo , Dai Guanghai , Lin Jen-Kou , Sharma Atul , Yeh Kun-Huei , Ma Brigette , Zaatar Adel , Guan Zhongzhen , Masood Nehal , Srimuninnimit Vichien , Yau Thomas Cheung , Beier Frank , Chatterjee Sudipto , Lim Robert S.C. 
Published: February 2017

566 Background: The Asia-Pacific, multicenter, nonrandomized, phase II APEC study previously reported that first-line therapy for pts with KRAS ex 2 wt mCRC consisting of C once every 2 weeks combined with FOLFOX or FOLFIRI achieved efficacy and safety profiles comparable to those reported in analogous pivotal studies involving weekly C. This final analysis presents OS data from the KRAS wt intent-to-treat (ITT) population, as well as subgroup efficacy analyses stratified by BRAF, PIKC3A, and all RAS mutation status. Methods: Eligible pts received C once every 2 weeks (day 1 of each cycle, 500 mg/m2) with FOLFOX or FOLFIRI (investigator’s choice). Study treatment continued until disease progression, dose-limiting toxicity or consent withdrawal. The primary endpoint was best confirmed overall response as assessed by RECIST 1.0; progression-free survival (PFS) and OS were secondary endpoints. In the evaluable populations, the status of BRAF, PIK3CA, and all RAS mutations was assessed retrospectively by pyrosequencing. Results: 42 months after the last patient was enrolled, median OS in the KRAS wt population was 26.8 months (Table). There were no unexpected safety findings. Additional biomarker results—including objective response rate (ORR), PFS, and OS subgroup analyses stratified on BRAF, PIKC3A, and all RAS mutation status—will be presented. Conclusions: The observed median OS of 26.8 months in the KRAS wt population is comparable to that reported in prior pivotal studies involving weekly C plus FOLFOX or FOLFIRI in the first line. These results suggest that C plus FOLFOX or FOLFIRI in a once-every-2-weeks regimen is active and tolerable as first-line therapy in this Asia-Pacific study population and a convenient alternative to weekly administration. Clinical trial information: NCT00778830. [Table: see text]
Drug cost and outcome in metastatic colorectal cancer with emphasis on monoclonal antibodies.
Authors: Guirgis Helmy M. 
Published: February 2017

567 Background: Patients with wild type KRAS metastatic colorectal cancer (mCRC), treated with first-line cetuximab (Cet) or bevacizumab (Bev) and chemotherapy demonstrated similar overall survival (OS). In the Western world, costs of anticancer drugs ranged from $59,000 to $100,000 per life-year gain (LYG). Hazard ratios (HR) have rarely been integrated in cost/outcome evaluation. Objective: Weigh drug cost against survival and hazard ratio (HR) in mCRC with emphasis on monoclonal antibodies (MABs). Methods: Estimated costs in United States dollars (US$) were calculated for 70 kg or 1.7/m2 patients. Costs were divided by the reported median OS gain over control in days (OSg) and by probability of survival (PoS) calculated as (1.0 – HR). Relative values (RV) were computed as 100,000/cost/outcome. Results: There was no significant difference in cost/outcome of Pan and Cet in first-line wild KRAS mCRC. At 12 week (w), the cost/LYG of panitumumab (Pan), Cet, and Bev were $64,947, $82,224, and $36,919 with RVs of 1.54, 1.22 and 2.71 respectively. Using HRs, the corresponding PoS were $140,082, $137,040, and $42,524 with RVs of 0.71, 0.73, and 2.35. Wild RAS testing improved the cost/outcome of Pan by 25%. Increasing number of cycles increased the cost/outcome and decreased the RVs of all MOAs. Conclusions: In first-line wild KRAS mCRC at 12 w, the cost/outcome of Bev was approximately 30% to 57% that of Pan and Cet. Cost/outcome of Pan significantly improved in RAS wild type. The cost/outcome of MABs was determined by the number of cycles.
Prognostic clinical factors in pretreated colorectal cancer patients receiving regorafenib: Implications for clinical management.
Authors: Del Prete Michela , Giampieri Riccardo , Loupakis Fotios , Prochilo Tiziana , Salvatore Lisa , Faloppi Luca , Bianconi Maristella , Bittoni Alessandro , Aprile Giuseppe , Zaniboni Alberto , Falcone Alfredo , Scartozzi Mario , Cascinu Stefano 
Published: February 2017

591 Background: Most of the patients receiving regorafenib do not seem to benefit from this treatment approach and are therefore exposed to unnecessary toxicity. Angiogenesis and inflammation-related factors may have a relevant role in modulating the activity of anti-angiogenetic drugs such as regorafenib. In our study, we investigated LDH serum levels, platelet, neutrophil, and lymphocyte counts, and neutrophil-to-lymphocyte ratio (NLR) in predicting clinical outcomes for colorectal cancer patients receiving regorafenib. The final aim was to individuate an easy to use and reliable selection tool for these patients in the clinical practice. Methods: We collected LDH serum levels, neutrophil, lymphocyte, and platelet counts within one month before the start of regorafenib in 208 pretreated metastatic colorectal cancer patients. Cut-off values were calculated by ROC curve analysis. Survival analysis was performed by Kaplan-Meier method, and multivariate analysis by Cox method. Results: At multivariate analysis: high platelet count (p=0.0439), low lymphocyte count (p=0.0013), and high NLR (p=0.0237) were related to worse overall survival (OS); high neutrophil count and high NLR (p=0.0058) were related to worse progression free survival (PFS). Among 52 (25%) patients who were negative for all risk factors, a significant correlation was found with improved OS and PFS if compared with the group of patients with at least one risk factor. In particular, median OS was respectively 15.9 vs. 3.1 months (HR: 3.81, 95% CI: 2.32-4.82, p<0.0001) whereas median PFS was 5.9 vs. 2.1 months (HR: 2.62, 95% CI: 2.06-3.86, p<0.0001). Conclusions: We can speculate that colorectal cancer patients showing high neutrophil, high platelet, low lymphocyte count or high NLR may not be optimal candidates for regorafenib treatment. After confirmation in further prospective series, these clinical factors could play a role in the treatment strategy process.
K-RAS codon 13 mutation in advanced colorectal cancer: A single-center retrospective study investigating prognostic outcomes and treatment strategies.
Authors: Dadduzio Vincenzo , Basso Michele , Bensi Maria , Cona Silvia , Cerchiaro Eleonora , Strippoli Antonia , Campitiello Marco , Rossi Sabrina , Orlandi Armando , Plastino Francesca , Calegari Maria Alessandra , Cassano Alessandra , Barone Carlo , Semenova Diana 
Published: February 2017

633 Background: Ras genes are markers of resistance to anti-EGFR therapies. Emerging evidences suggest that each mutation, independently from its predictive role of response/resistance to specific treatments, may be expression of different diseases with different biologic behaviours. We collected data of mCRC patients harbouring K-Ras codon 13 mutation to evaluate response to therapy, PFS and OS. Methods: We retrospectively collected data of advanced colorectal cancer patients harbouring K-Ras codon 13 mutation treated at our Institution between 2004 and 2014. Results: A total of n.33 K-Ras codon 13 mutated patients were analysed. N.24 patients (72,7%) had synchronous metastatic disease. None of the patients received anti-EGFR treatment, while n.25 patients received anti-VEGF agent bevacizumab in association to chemotherapy with fluoropirimidines plus oxaliplatin and/or irinotecan (n.21 as frontline therapy, n.4 in second line). ORR was 51,5% (17/33) on first-line therapy, 22,2% (6/27) on second-line therapy and 16,6% (2/12) on third-line therapy. Median PFS was 14,1 months after first-line therapy, 9,3 months after second-line therapy, 6,4 months after third-line therapy. Median OS was 35,5 months (events: 19/33). N.14 patients received metastases surgery with radical intent. OS in this population has not been reached yet at a median follow-up of 38 months, even though all patients had a relapse. OS among patients undergone to systemic only strategy was 31 months. Conclusions: At our knowledge, this is the first report suggesting a favourable prognosis for K-ras codon 13 mutated patients, with a median overall survival even superior to pan-RAS wild-type patients. Indeed, the high percentage of advanced patients at diagnosis (72.7%), the high responsiveness to chemotherapy even in third line, the high percentage of patients converted to surgery (42.4%) in an unselected population, together with the high risk or relapse after surgery, suggest K-ras codon 13 mutated disease is probably a biologically aggressive disease. Nevertheless our data prompt that these patients may benefit aggressive strategies of treatment and multidisciplinary evaluation.
Polymorphism of the chemokine CXCR4 to predict treatment benefit of first-line bevacizumab-based chemotherapy in patients with metastatic colorectal cancer.
Authors: Matsusaka Satoshi , Loupakis Fotios , Zhang Wu , Cao Shu , Yang Dongyun , Ning Yan , Stremitzer Stefan , Sunakawa Yu , Yamauchi Shinichi , El-khoueiry Rita , Parekh Anish , Mizunuma Nobuyuki , Lenz Heinz-Josef 
Published: February 2017

635 Background: The chemokine receptor CXCR4 and its ligand CXCL12 promote angiogenesis and the migration of tumor cells into the metastatic sites in many cancers. CXCR4 expression on tumor cells is upregulated by hypoxia and angiogenic factors, such as vascular endothelial growth factor. Therefore, we analyzed the association between CXCR4/CXCL12 polymorphisms and prognosis in metastatic colorectal cancer (mCRC) patients underwent bevacizumab-based chemotherapy. Methods: This study included 144 Japanese patients (pts) for evaluation set and 424 patients from two clinical trials (204 of TRIBE arm A and 220 of PROVETTA) for validation set, with mCRC treated with bevacizumab-based chemotherapy as first line. A total of 144 Japanese pts with (male/female; 81/63, median age 61 years, median follow-up 4.2 years) and 424 pts (male/female; 252/172, median age 62 years; median follow-up time; 2.8 years) were enrolled in a pharmacogenomics translational study. Genomic DNA was extracted from the pts’ blood or tissue. One CXCR4 single nucleotide polymorphisms (SNP) (rs2228014) and two CXCL12 SNPs (rs1801157, rs3740085) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with the clinical outcome. Results: In univariate analysis, CXCR4 rs2228014 showed a significant difference in PFS [(G/G 15.3 months, any A allele 13.7 months, HR (95% CI) 1.64 (1.01-2.68), p=0.036)]. After multivariate analysis, CXCR4 rs2228014 remained to be a significant for PFS [HR (95% CI) 1.67 (1.01-2.78), p =0.046]. However, this polymorphism was not associated with tumor response and survival. In the validation cohort, pts with GG genotype had significantly longer PFS compared to those with any A allele (10.5 vs 9.6 months, HR (95% CI) 1.40 (1.02-1.93), p =0.035). CXCL12 polymorphisms were not associated with the clinical outcome. Conclusions: This study shows for the first time that CXCR4 rs2228014 may serve as a predictive marker in patients with mCRC treated with bevacizumab-based chemotherapy.
Potential predictive and prognostic biomarkers identified in baseline plasma samples from the VELOUR trial.
Authors: Sims Tasha Nicholle , Gao Bo , Phillips Robert , Lowy Israel 
Published: February 2017

638 Background: Biomarkers of resistance or susceptibility to vascular endothelial growth factor (VEGF) inhibition have not been validated. Ziv-aflibercept (ZALTRAP), a fusion protein that binds and neutralizes ligands of VEGFR1 and VEGFR2 (e.g., VEGFA, PLGF, and VEGFB), is approved for the treatment of metastatic colorectal cancer (mCRC) in combination with FOLFIRI in patients who have progressed after oxaliplatin therapy. We are currently analyzing plasma samples from VELOUR, the registration trial of FOLFIRI +/- ziv-aflibercept, in an effort to identify prognostic and predictive factors. Methods: VELOUR was a prospective, multicenter, multinational, randomized (1:1), double-blind, parallel-arm phase III study conducted in 1,226 patients. Retrospective analysis of circulating proteins from 553 baseline plasma samples was performed. Samples were analyzed for levels of 98 analytes using multiplex assays and ELISA. Biomarker values were dichotomized around the median value and analyzed with respect to overall survival (OS). Results: The biomarker study sub-population was similar to the overall VELOUR population. For OS, the hazard ratio (HR) was 0.809 in the plasma biomarker population vs. HR =0.817 in the overall VELOUR population. For PFS, the HR = 0.752 in the plasma biomarker population vs. HR = 0.758 in VELOUR. Patient demographics, including ECOG status, were similar between the groups. Several biomarkers were identified as potentially predictive or prognostic (or both) of OS, with a HR<0.7 (false discovery rate of 0.05 and interaction p < 0.10). No biomarker subset corresponded to worse OS with ziv-aflibercept treatment. Conclusions: Multiple potential prognostic and predictive biomarkers were identified in VELOUR and will be presented. These results are exploratory and require prospective studies for validation. Patient subsets with elevated expression of alternative angiogenic factors or increased pro-inflammatory markers may correlate with poor outcome overall, and in some cases are not improved by addition of ziv-aflibercept treatment. Further investigation of this dataset continues, including analysis of on-treatment plasma samples in a subset of patients.