bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multicenter trial for assessing cytokine promoter gene polymorphism as a predictive parameter of PSK responder for curatively resected stage II or III colorectal cancer.
Authors: Yoshino Shigefumi , Takumi Furuya , Sakata Koichiro , Shimizu Ryoichi , Okayama Naoko , Hazama Shoichi , Oka Masaaki 
Published: February 2017

619 Background: Polysaccharide-K (PSK), a protein-bound polysaccharide extracted from the mycelia of Coriolus versicolor, is an immunomodulator widely used in colorectal cancer in Japan. PSK has immunological actions including enhancement or inhibition of cytokine production. It has been reported that levels of cytokine production are influenced by polymorphisms in the promoters of cytokine genes. We hypothesized that cytokine promoter gene polymorphisms may be responsible for genetic susceptibilities to immunological effect of PSK. Methods: This is a multicenter prospective trial. One hundred and ten patients with stage II or III colorectal cancer were enrolled. All patients received adjuvant immnochemotherapy after curative resection using UFT (stage II) or UFT/LV (stage III) combined with PSK (3.0 g/day, p.o.) for 1 year. Post-operative survey of recurrence was followed with CT scan at 6-month intervals during the first 2 years after surgery and at 1-year intervals thereafter until 5 year after surgery. DNA was extracted from peripheral blood cells in all patients. The following polymorphisms of the patients were genotyped: TNF-α-1031T/C, IL-1ß-511C/T, IL-6-634C/G, IL-10-819T/C. Results: Twenty (6 in stage II, 14 in stage III) out of 110 patients showed recurrence after more than 5 years survey. Fifteen out of 74 patients with TNF-α-1031 TT genotype and 5 out of 36 with TNF-α-1031 CC or CT showed disease recurrence. Five out of 39 patients with IL-1ß-511 CC and 15 out of 71 with IL-1ß-511 CT or TT showed disease recurrence. Eleven out of 61 patients with IL-6-634 CC and 9 out of 49 with IL-6-634 CG or GG showed disease recurrence. No association between genotype frequency and disease recurrence was observed for TNF-α, IL-1ß, IL-6. Fifteen out of 61 patients with IL-10-819 CC or CT genotype showed disease recurrence, whereas only 5 out of 49 with IL-10-819 TT showed tumor recurrence (p=0.052). Especially, significant association with disease recurrence was found in stage III patients (12/30 vs 2/17, p=0.042). Conclusions: It is suggested that colorectal cancer patients with IL-10-819 TT genotype could be PSK responder after curative resection.
Macrophage polarization related gene variants to predict clinical outcome in metastatic colorectal cancer (mCRC) patients (pts) treated with bevacizumab (bev) in combination with FOLFIRI.
Authors: Sunakawa Yu , Stintzing Sebastian , Heinemann Volker , Loupakis Fotios , Cremolini Chiara , Cao Shu , Yang Dongyun , Zhang Wu , Parekh Anish , Yamauchi Shinichi , Ning Yan , Stremitzer Stefan , Matsusaka Satoshi , Mendez Angela , El-Khoueiry Rita Elie , Lenz Heinz-Josef 
Published: February 2017

621 Background: Macrophages, particularly M2, enhance tumor progression by stimulation of angiogenesis, acceleration of tumor invasion, and suppression of immunosurveillance. CCL2 promotes the polarization into M2 whereas histidine-rich glycoprotein (HRG) redirects M2 to M1. We hypothesized that single nucleotide polymorphisms (SNPs) in CCL2 and HRG may predict clinical outcome in mCRC pts treated with anti-VEGF drug in combination with chemotherapy. Methods: This study enrolled 4 pts cohorts treated with antibody drug plus FOLFIRI in prospective trials, A: KRAS exon 2 wild-type (KRAS wt) pts (n=84), B: mutant-type pts (n=89) from FOLFIRI-arm of TRIBE trial (NCT00719797), C: bev-arm (n=295), D: cetuximab-arm (n=297), served as negative control arm, from KRAS wt pts of FIRE3 trial (NCT00433927). Functionally significant SNPs, CCL2 rs4586, HRG rs9898, and HRGrs2228243, were analyzed by PCR-based direct sequencing for associations with response rate (RR), progression-free survival (PFS), and overall survival (OS) by uni- and multivariable analyses. Results: The minor G allele of HRG rs2228243 was significantly associated with better PFS, but not RR and OS, than the A/A genotype in both uni- and multivariable analyses (10.8 vs 9.3 months. HR: 0.62, p=0.048; HR: 0.57, p=0.040, respectively) in the cohort B while it was not associated in the other KRAS wt cohorts. In the cohort C, the minor C allele of CCL2 rs4586 correlated with significantly shorter OS, but not RR and PFS, in both uni- and multivariable analyses (22.3 vs 28.4 months. HR: 1.61, p=0.003; HR: 1.63, p=0.004, respectively). No significant association of CCL2 rs4586 was seen in the other cohorts although pts with the C allele of CCL2rs4586 had a negative marginal significant association in PFS and a shorter OS than pts with the T/T genotype (22.0 vs 30.8 months) in the cohort A. Conclusions: Our study provides evidence that SNPs in CCL2 and HRG may serve as a predictive or prognostic marker in mCRC pts treated with bev plus FOLFIRI. Our results also suggest that the impact of the SNPs on outcome may differ according to KRAS status. Prospective validation of this study is warranted.
Genetic analysis of colorectal cancers in young patients.
Authors: Abbott Andrea M. , Kothari Nishi , Teer Jamie K. , Srikumar Thejal , Kim Richard D. , Reed Damon R. , Shibata David 
Published: February 2017

632 Background: The incidence of colorectal cancer (CRC) is increasing in adults <50 years old and these cases may be associated with a worse prognosis. Despite our growing understanding of genetic conditions, a substantial number of CRC in young patients are classified as sporadic but may harbor unique molecular changes. We sought to compare profiles of genetic alterations between young and old patients who lack defects in known hereditary cancer genes. Methods: 283 CRC cases diagnosed between 1998 and 2010 were analyzed by targeted exome sequencing using the Illumina NGS platform with 50-100x coverage. Filtering of normal variants was performed using 1000 Genomes to enrich for somatic mutations which were then limited to those predicted to alter protein sequence. The younger and older cohorts were defined as ≤45 and ≥65 years old at diagnosis, respectively. Patients found to be MSI-high (n= 2 young, 50 old) or with a known hereditary syndrome (n=6) were excluded. For this preliminary screen, Fisher’s Exact test was used to detect differences in mutation frequencies. Results: A total of 195 older and 30 younger patients with median ages of 73 (range 65-93) and 42 (range 30-45) years respectively, were analyzed. We identified 57 genes with significant differential mutation frequencies. The top ten genes mutated with increased in frequency in the younger cohort are shown in Table 1. Conclusions: In this exploratory project, we identified mutations that occurred more frequently in younger CRC patients. Large scale validation of these findings and application of this approach may lead to novel screening and treatment strategies in younger patients [Table: see text]
Contribution of FOXC1 to the progression and metastasis and prognosis of human colon cancer.
Authors: Li Dawei , Li Qingguo , Zhuo Changhua , Xu Ye , Cai Sanjun 
Published: February 2017

636 Background: Distant metastasis remains the most common causes to death of colon cancer. Thus it is crucial to identify the molecular markers associated with the progression and metastasis of this disease. Recent evidence for overexpression of FOXC1 in several types of human cancer suggests that it might play a key role in tumor biology. However, the clinical significance of FOXC1 signaling in human colon cancer pathogenesis remains unknown. Methods: We investigated FOXC1 expression in 203 cases of primary colon cancer and matched normal colon tissue and lymph node matastasis in a tissue array. The underlying mechanisms of altered FOXC1 expression and the impact of this altered expression on colon cancer growth and metastasis was explored both in vitro and in vivo. Results: We found elevated expression of FOXC1 protein in cancereous tissue and lymph node metastases than adjacent normal colonic tissues. Overexpression of FOXC1 was associated with higher clinical stage, T stage, lymph node metastasis and presence of distant metastasis. FOXC1 served as an independent prognostic marker whose expression levels correlated with poorer metastasis-free survival (MFS) and poorer overall survival (OS). A Cox proportional hazards model revealed that FOXC1 expression was an independent prognostic factor in multivariate analysis. Experimentally, FOXC1 silencing significantly inhibited the growth and metastasis of colon cancer cells in vitro and in vivo. FOXC1 transcriptionally regulates SNAIL1, contributing to epithelial-to-mesenchymal transition and metastasis in colon cancer cells. Conclusions: Dysregulated expression of FOXC1 may play a critical role in colon cancer progression and metastasis. Thus, FOXC1 may serve as a candidate prognostic biomarker and therapeutically targeted.
Radiologic and pathologic prognostic factors after neoadyuvant chemotherapy for T3 rectal cancer (RC): 3-year update GEMCAD 0801-trial.
Authors: Machado Isidro , Brown Gina , Estevan Rafael , Salud Antonieta , Gil Mabel , Montagut Clara , Busto Marcos , Safont Maria Jose , Maurel Joan , Ayuso Juan Ramón , Aparicio Jorge , Feliu Jaime , Vera Ruth , Alonso Vicente , Gallego Javier , Martin Martha , Pericay Carles , Ballesteros Eva , Santos Jesus , Fernandez-Martos Carlos 
Published: February 2017

643 Background: Prognostic factors in RC treated only with neoadjuvant chemotherapy, have not been explored. We analized the prognostic value of clinical-radiological and pathological factors for disease-free, (DFS) and cumulative incidence of distant metastases (DM), for patients treated with preoperative capecitabine, oxaliplatin and bevacizumab (CAPOX-B) within our multicentre phase II GEMCAD 0801 trial. Methods: 46 patients were enrolled to evaluate safety and efficacy of neoadjuvant CAPOX-B followed by surgery. Results have been recently published (Oncologist 2014;19:1-2). Eligibility included baseline magnetic resonance (MR) showing a T3 tumour with mesorectal fascia potentially clear. Clinical, pathologic (ypN+, T or N downstaging, tumor regression grade [TRG], pathologic complete response [pCR]) and radiologic factors both at baseline (mr extramural venous invasion [EMVI]) and post neoadjuvant chemotherapy (ymr TRG, ymr lengh change [RECIST]), were analyzed. Univariate and multivariate analysis was performed. Results: With a median follow up of 36 months, fourteen patients experienced relapse (2 local, 11 distant, 1both). 3-year DFS was 69%. It was 95%/49% for T downstaging/no T downstaging (p=0.0009) and 95%/43% for mrEMVI positive/negative (p=0.0001), respectively. ymrTRG (Mandard) ranging from no regression, TRG 5, to complete response, TRG 1, p=0.0108 and ypN0/ypN+ (p=.02) were also significantly related to DFS in univariate analysis. The same factors and N-downstaging were also significant for cumulative incidence of DM. On Cox multivariate analysis, T downstaging and mrEMVI were the only independent prognostic factors for DM ( p=0.0363 and 0.0111 respectively) and DFS (p=0.0315 and 0.0277 respectively). Conclusions: T3 rectal cancer with MR detected EMVI positive and those without downstaging after neoadjuvant chemotherapy are associated with unfavourable prognosis. This suggests that future strategies for treatment intensification and surveillance could be based on EMVI and T staging. Clinical trial information: NCT00909987.
Genomic markers of panitumumab resistance including ERBB2/HER2 in a phase II study of KRAS wild-type (wt) metastatic colorectal cancer (mCRC).
Authors: Barry Garrett , Li-Chang Hector Hugo , Kennecke Hagen F. 
Published: February 2017

646 Background: Epidermal Growth Factor Receptor Inhibitors (EGFRi) are effective agents in the treatment of mCRC but up to one third of KRAS wt tumors do not respond. The primary objective was to identify a gene expression signature associated with primary resistance to panitumumab (Pmab) monotherapy and identify genomic markers associated with resistance. Methods: Patients with previously treated codon 12/13 KRAS wt mCRC were administered Pmab 6mg/kg IV q2weeks in a prospective phase II study. The primary endpoint was tumor response by RECIST and patients with progressive disease 8 weeks after initial Pmab were classified as resistant. Gene expression analysis was performed using a Nanostring-based assay with candidate genes implied in EGFRi resistance expression patterns. Differentially expressed genes were identified by Significance Analysis of Microarrays. Further interrogation of the HER2 signaling pathway was performed by immunohistochemistry and in situ hybridization. Illumina-based targeted resequencing was conducted on 20 cancer-implicated genes. Results: Of 34 patients treated with Pmab, 11 (32%) had progressive disease at 8 weeks and were classified Pmab resistant. A 5-gene expression signature was significantly associated with Pmab resistance (p = 0.001), including ERBB2, MLPH, IRX3, c11orf9, and KLK6. HER2 protein was overexpressed in 4/11 resistant and 0/21 responding cases (p = 0.035). Two (2) resistant tumors had ERBB2 gene amplification only, and one demonstrated both ERBB2 amplification and mutation. A non-codon 12/13 RAS mutation occurred in one treatment-resistant patient and was mutually exclusive with ERBB2 mutation, amplification, or HER2 overexpression. Four BRAF mutations were detected, two occurring in resistant patients. Conclusions: In this prospective study, a 5-gene signature including ERBB2 was associated with primary resistance to single agent Pmab. A subgroup of patients had evidence of aberrant HER2/ERBB2 signaling by protein over-expression and gene amplification. Results suggest a significant portion of KRAS wt tumors unresponsive to EGFRi may be identified by gene signature analysis. Clinical trial information: NCT00853931.
Phenotypic differences among RAS mutational variations in colorectal cancer (CRC): Analysis of 1,001 patients in single institute.
Authors: Shinozaki Eiji , Miki Yoshio , Ueno Masashi , Igarashi Masahiro , Suenaga Mitsukuni , Chin Keisho , Ozaka Masato , Ogura Mariko , Takahari Daisuke , Ichimura Takashi , Wakatsuki Takeru , Mizunuma Nobuyuki 
Published: February 2017

649 Background: RAS mutation has been reported as a predictor of benefit from anti EGFR therapies in the recent sub-analysis of some large prospective trials, PRIME, FIRE-3 and so on. On the other hand, some in vitro experiments had identified the differences of capability of GTP bounding and colony formation according to KRAS mutational variations. It remains unknown whether there are phenotypic differences clinically among RAS mutational variations as potentially negative predictive factors for anti EGFR treatments. This study aimed to reveal the prevalence and the phenotypic differences of these variations in a large cohort. Methods: Consecutive patients of 1,001 CRC from January 2012 to October 2013 were analyzed in this study. Multiplex genotyping of EGFR pathway was performed on archival samples using Luminex Assay (MABGEN and GENOSEARCH Mu-PACK, MBL) for KRAS including codons 61,146 and NRAS. We examined the correlation among mutation variations; KRAS G12D, G12V, G13D and other exon2, exon 3 and 4 and NRAS, and clinical phenotypic features. Statistical analysis was conducted by chi-square test. Results: The incidence of mutations; KRAS G12D, G12V, G13D, other exon2, exon 3 and 4, and NRAS were 16.2%, 10.0%, 6.4%, 7.0%, 4.6% and 3.5%, respectively. So called all RAS mutations were occupied in 47% in this cohort. There was no significant difference of prevalence among mutational variations according to clinical feature as follows; clinical stage, gender, age. In histopathology, moderately differentiated type of G12D was more frequent compared with other type of mutations. The respective proportion of KRAS exon 3 and 4, and NRAS mutations for left sided primary was relatively higher than those for right sided, although the frequency of other mutations were higher in right side. Conclusions: According to our analysis there were not so large phenotypic differences among these RAS mutational variations except histology and localization of primary. Futher follow up of this cohort will provide more information about treatment outcomes in near future.
Are circulating tumor cells (CTCs) a feasible tool for predicting disease recurrence and survival in nonmetastatic (M0) colorectal cancer (CRC)?
Authors: Bergamo Francesca , Rossi Elisabetta , Pucciarelli Salvatore , Rossi Giovanna , Facchinetti Antonella , Battaglin Francesca , Toppan Paola , Fiduccia Pasquale , Amadori Alberto , Lonardi Sara , Zamarchi Rita , Zagonel Vittorina 
Published: February 2017

650 Background: Based on the correlation between CTCs and clinical outcome of metastatic breast, prostatic and CRC cancer, CTCs might be an ideal model to investigate the individual risk to develop metastasis. On the other way, data on their significance in M0 CRC are still limited. In a previous study we investigated CRC cell death in the circulating compartment, finding high value of apoptotic CTCs (M30-positive) independently from the disease stage. Our aim was to evaluate the prognostic role of total and M30-positive CTCs in M0 CRC patients (pts). Methods: From January 2009 to December 2011, we prospectively enrolled 192 stage 0-III CRC pts (stage 0 identified rectal cancer pts with Tis or complete pathological response after neoadjuvant therapy). We used CellSearch assay to quantify total and M30-positive CTCs in peripheral blood of CRC pts candidate to curative resection at diagnosis, time of surgery and four months later. Multivariate survival analyses were conducted using a Cox-regression. Results: At baseline 81 out of 192 pts (43.3%) had at least 1 CTC/7.5 mL of peripheral blood, 40 pts (22.2%) had >2 cells and 20 pts (11.6%) had >3 cells. We found a weak association between OS and total CTCs number (p=0.069), a significant association with M30-positive CTCs (p=0.022) and no association between RFS and CTC status. Limiting the analysis to stage I-III (n=151), we found a strong association between OS and both CTCs number (p=0.021) and M30-positive cells (p=0.007). The multivariate analyses demonstrated a significant improvement of survival prediction adding baseline CTCs count to clinical and pathological characteristics (HR=1.51, 95% CI 1.16-1.96). Conclusions: We first demonstrated a significant association between OS and CTCs status in stage I-III CRC pts. This result is consistent with previous report in metastatic CRC. It highlights a potential advantage of CTCs count in stratifying CRC pts and identifying a subset of pts with a high metastatic risk that could benefit from an adjuvant therapy. Further studies are needed to explore this aspect, which might be particularly significant in stage II CRC where the indication for adjuvant therapy is still under debate.
The difference between the subjective and objective evaluation of oxaliplatin-induced vascular pain due to administer chemotherapy via peripheral vein.
Authors: Aisu Naoya , Yoshida Yoichiro , Yamada Teppei , Matsuoka Taisuke , Kojima Daibo , Tanimura Syu , Hoshino Seiichiro , Mogi Ai , Koganemaru Tomoko , Oda Mayumi , Fukuda Mahiru , Kiyomi Fumiaki , Noda Keita , Hirata Keiji , Tamura Kazuo , Yamashita Yuichi 
Published: February 2017

651 Background: We have reported the safety and effectiveness of chemotherapy via median cubital vein for metastatic colorectal cancer without implantation of a central venous port. However, vascular pain (VP) occasionally requires switching of the drip infusion route during chemotherapy for the administration of oxaliplatin via the peripheral vein. VP and phlebitis induced by intravenous infusion of antineoplastic agents reduces the rate of completion or continuation of chemotherapy. We also reported that addition of dexamethasone to oxaliplatin drip infusion controlled the vascular pain caused by administration of oxaliplatin via the peripheral vein (ASCO-GI2012). Pain is currently evaluated using subjective methods such as the visual analog scale (VAS). However, because the assessment of pain can greatly vary depending on the mood and physical state of the patient at the time of assessment, it is best to objectively evaluate pain. Pain Vision PS-2100 (PV) is an analytical instrument that was designed to quantitatively and objectively assess sense perception and nociception in a patient. Although it is used in the field of anesthesiology, there have been no reports concerning it for the assessment of oxaliplatin-induced VP. Methods: The present study examined the correlation of subjective and objective assessment results using VAS and PV, respectively, for cases of oxaliplatin-induced VP. Subjects comprised 57 patients with colorectal cancer who underwent chemotherapy at the Fukuoka University. Results: Both VAS and PV assessments of PN were performed 162 times in total, and partial correlation coefficient analysis adjusted by subject and gender. The VAS and PV mean values of VP were 24.8 (0–100) and 44.5 (0–596), respectively. The partial correlation coefficient was 0.350 (p= 0.0002). Conclusions: Although both assessments evaluated the same events, no strong correlation was observed between the results and a weak correlation was observed between VAS and PV. These results suggest that because VAS and PV each measure different factors, both subjective and objective assessments of drugs designed to ameliorate oxaliplatin-induced VP are necessary.
Highly sensitive quantitative detection of circulating tumor DNA in urine and plasma from advanced colorectal cancer patients in aid of early diagnosis of clinically relevant KRAS mutations.
Authors: Poole Jason C. , Vibat Cecile Rose T. , Benesova Lucie , Belsanova Barbora , Hancock Saege , Lu Timothy , Erlander Mark , Minarik Marek 
Published: February 2017

654 Background: Acquisition of point mutations in KRAS gene is causally associated with the onset of development of a resistance to anti-EGFR therapy in colorectal cancer. Newly acquired KRAS mutations can be detected in blood plasma months before radiographic detection. The objective of this study was to demonstrate feasibility of an ultrasensitive non-invasive method for detection of KRAS mutations in urine and plasma of patients with advanced colorectal cancer. Methods: Archived, matched urine and plasma samples (stored between 3-5 years prior to ctDNA extraction) from 20 treatment naïve, advanced stage cancer patients with known tumor tissue KRAS mutations determined by an accredited clinical laboratory, were used in a retrospective setting for a blinded concordance study. KRAS status in urine and plasma was compared to that in tumor tissue in order to assess clinical sensitivity of the ctDNA assay. An ultrashort-amplicon (31bp) assay for KRAS mutation enrichment and detection in highly fragmented urinary and plasma ctDNA was developed. The assay detected 1 copy of KRASG12A/C/D/R/S/V or G13D mutant allele in a background of wild-type DNA with a verified analytical sensitivity of 0.007% (7 copies per ~100,000 genome equivalents). Results: In a pilot study of 20 advanced stage colorectal cancer patients, 15 of 16 evaluable archived urine samples (94%) had KRAS mutation that was concordant with tissue biopsy. Of 20 archived plasma samples evaluated, 19 (95%) displayed the KRAS mutation concordant with tumor tissue. Of 16 paired urine and plasma samples, 15 (94%) had concordant KRAS mutation calls. Conclusions: This study demonstrates high clinical sensitivity (≥94%) of concordant KRAS mutation detection between urine, plasma and tissue specimens from advanced colorectal cancer patients. Early detection and monitoring of acquired KRAS mutations in circulating tumor DNA, and in particular urinary ctDNA, opens the possibility of a new paradigm for a truly non-invasive method of individualized care for colorectal cancer patients.