[Show abstract][Hide abstract] ABSTRACT: Background:
Although bevacizumab plus FOLFOX is a standard treatment for metastatic colorectal cancer, oxaliplatin must be withdrawn in many patients because of cumulative neurotoxicity. We postulated that a reduced dose of oxaliplatin and modified treatment schedule would prolong the time to treatment failure and evaluated bevacizumab combined with a modified OPTIMOX1 regimen (mOPTIMOX1, oxaliplatin dose: 85 mg/m(2)).
Eligible patients had a histologically confirmed diagnosis of metastatic colorectal cancer and a performance status of 0-1. Patients were excluded if they had grade 1 or higher peripheral sensory neuropathy or had previously received chemotherapy for metastatic colorectal cancer. Patients received bevacizumab plus mFOLFOX6 every 2 weeks for 6 cycles, followed by 12 cycles of a simplified biweekly regimen of leucovorin and fluorouracil (sLV5FU2) plus bevacizumab. Oxaliplatin was then reintroduced, and bevacizumab plus mFOLFOX6 was continued until progressive disease.
The median duration of disease control was 11.7 months (95 % confidence interval [CI], 9.7-13.5 months). The median overall survival was 23.1 months (95 % CI, 18.8-27.9 months). The overall response rate according to both the RECIST and WHO criteria was 51.3 %. The most common grade 3 or 4 toxicities were neutropaenia (32.5 %), hypertension (17.5 %), leukocytopaenia, sensory neuropathy, and diarrhoea (10.0 %). There were no treatment-related deaths.
Bevacizumab plus mFOLFOX6 was well tolerated, and patients could continue chemotherapy for longer than with conventional FOLFOX regimens. This regimen might be an effective treatment option for patients with metastatic colorectal cancer.
Investigational New Drugs 05/2015; 33(4). DOI:10.1007/s10637-015-0239-1 · 2.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The molecular features of serrated polyps (SPs) with hyperplastic crypt pattern, also called Kudo's type II observed by chromoendoscopy, were evaluated.
The clinicopathological and molecular features of 114 SPs with a hyperplastic pit pattern detected under chromoendoscopy (five dysplastic SPs, 63 sessile serrated adenoma/polyps (SSA/Ps), 36 microvesicular hyperplastic polyps (MVHPs), and 10 goblet cell-rich hyperplastic polyps (GCHPs)) were examined. The frequency of KRAS and BRAF mutations and CpG island methylator phenotype (CIMP) were investigated.
Dysplastic SPs and SSA/Ps were frequently located in the proximal colon compared to others (SSA/Ps vs. MVHPs or GCHPs, P < 0.0001). No significant difference was found in the frequency of BRAF mutation among SPs apart from GCHP (60 % for dysplastic SPs, 44 % for SSA/Ps, 47 % for MVHPs, and 0 % for GCHPs). The frequency of CIMP was higher in dysplastic SPs or SSA/Ps than in MVHPs or GCHPs (60 % for dysplastic SPs, 56 % for SSA/Ps, 32 % for MVHPs, and 10 % for GCHPs) (SSA/Ps vs. GCHP, P = 0.0068). When serrated neoplasias (SNs) and MVHPs were classified into proximal and distal lesions, the frequency of CIMP was significantly higher in the proximal compared to the distal SNs (64 % vs. 11 %, P = 0.0032). Finally, multivariate analysis showed that proximal location and BRAF mutation were significantly associated with an increased risk of CIMP.
Distinct molecular features were observed between proximal and distal SPs with hyperplastic crypt pattern. Proximal MVHPs may develop more frequently through SSA/Ps to CIMP cancers than distal MVHPs.
[Show abstract][Hide abstract] ABSTRACT: Background
Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs).
We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance.
S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41).
We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.
PLoS ONE 08/2014; 9(8):e103822. DOI:10.1371/journal.pone.0103822 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Open Access Journal of Clinical Trials Dovepress submit your manuscript | www.dovepress.com Dovepress 37 M e T h O d O l O g y open access to scientific and medical research Open Access Full Text Article http://dx.doi.org/10.2147/OAJCT.S62272 Shin'ei Kudo 7 Masahiro Igarashi 8 hiroyasu Iishi 9 Kazuhiro Kaneko 1,10 Kinichi hotta 3,11,12 Nozomu Kobayashi 3,13 yuichiro yamaguchi 12 Kiyonori Kobayashi 8 hideki Ishikawa 14 yoshitaka Murakami 15 Tadakazu Shimoda 16 Takahiro Fujimori 17 yoichi Ajioka 18 hirokazu Taniguchi 16 hiroaki Ikematsu 1,3 5 hattori gI endoscopy and gastroenterology Clinic, Kumamoto, 6 Oda gI endoscopy and gastroenterology Clinic, Kumamoto, 7 digestive disease Center, Showa University Northern yokohama hospital, yokohama, 8 department of gastroenterology, Kitasato University east hospital, Sagamihara, 9 department of gastrointestinal Oncology, Osaka Medical Center for Cancer and Cardiovascular diseases, Osaka, 10 division of gastroenterology, department
[Show abstract][Hide abstract] ABSTRACT: A 60-year-old woman was referred to our hospital for further evaluation of a gastric submucosal tumor (SMT) on the lesser curvature in the supra-angular region of the stomach. Blood tests revealed elevation of the serum gastrin level and positive test results for intrinsic factor antibody and antiparietal cell antibody. Gastric endoscopy revealed evidence of mucosal atrophy from the fornix to the lower body of the stomach, but not in the antrum. The diagnosis of gastric SMT with type A gastritis was made. EUS revealed an internally heterogeneous hypoechoic tumor localized mainly in the fourth layer of the stomach. Since EUS-guided fine needle aspiration could not be performed successfully on account of the tumor location, we proposed three management options to the patient : observation with annual endoscopy, tumor biopsy using an ESD device, and surgical resection. She decided on surgical resection, and distal laparoscopic gastrectomy was performed. Histology of the resected specimen revealed an aberrant pancreas, Type 1 of Heirich’s classification and the serum gastrin level recovered to almost within the normal range.
[Show abstract][Hide abstract] ABSTRACT: Gastric cancers (GC) with methylation of multiple CpG islands have a CpG island methylator phenotype (CIMP) and they can have different biological features. The aim of this study was to investigate the DNA methylation status of GCs and its association with their clinicopathological features. We evaluated the methylation status of four genes (MINT1, MINT2, MINT25 and MINT31) in 105 primary GCs using bisulfite-pyrosequencing analysis. We classified tumors as CIMP-high (CIMP-H), CIMP-low (CIMP-L) or CIMP-negative (CIMP-N) based on the methylation of MINT1, MINT2, MINT25, and MINT31. Overall, the prevalence of CIMP-H, CIMP-L and CIMP-N was 22% (23/105), 52% (55/105) and 26% (27/105), respectively. We observed a significant difference in tumor stage (stages I-II vs. stages III-IV) between CIMP-H and CIMP-N tumors (P = 0.0435). No significant differences were observed in clinicopathological characteristics (gender, age, location and tumor differentiation) among the CIMP phenotypes. The prognoses of patients with a CIMP-H tumor is likely to be better than those with CIMP-L or CIMP-N tumors, but these differences are not statistically significant (P = 0.074 and P = 0.200). Our results suggest that CIMP may define a subgroup of GCs with distinct biological features.