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Background: Molecular biomarkers capable of predicting recurrence patterns and prognosis are helpful for risk stratification and providing appropriate treatment to patients with hepatocellular carcinoma (HCC). In this study, we focused on G protein-coupled receptor 155 (GPR155), a cell surface signaling protein, as a candidate biomarker.Methods: We analyzed GPR155 expression, DNA methylation, and copy number in HCC cell lines. The clinical significance of GPR155 expression was evaluated using 144 pairs of surgically resected liver and normal tissues with subgroup analysis based on hepatitis virus infection.Results: GPR155 mRNA expression levels were differential and were decreased in 89% of HCC cell lines. No DNA methylation was detected, whereas copy number alterations were present in five (56%) HCC cell lines. GPR155 mRNA expression level was independent of background liver status and significantly lower in HCC tissues than corresponding normal liver tissues. The expression patterns of GPR155 protein by immunohistochemical staining were significantly associated with those of GPR155 mRNA. Downregulation of GPR155 was significantly associated with more aggressive HCC phenotypes including high preoperative α-fetoprotein, poor differentiation, serosal infiltration, vascular invasion, and advanced disease stage. Patients with downregulation of GPR155 were more likely to have worse prognosis after curative resection irrespective of hepatitis virus infection. Patients who experienced extrahepatic (distant) recurrences had significantly lower GPR155 expression than those with intrahepatic (liver confined) recurrences.Conclusions: Downregulation of GPR155 may serve as a prognosticator that also predicts initial recurrence sites independent of hepatitis virus infection. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to evaluate the efficacy and safety of CapeOX plus bevacizumab with a planned oxaliplatin stop-and-go strategy in Japanese patients with metastatic colorectal cancer (mCRC).Methods: Patients with untreated mCRC were treated with 4 cycles of CapeOX plus bevacizumab therapy, followed by capecitabine plus bevacizumab maintenance therapy. Reintroduction of oxaliplatin was scheduled after 8 cycles of maintenance therapy or upon tumor progression. The primary endpoint was progression-free survival (PFS), and secondary end points included overall survival (OS), objective response rate to each treatment, reintroduction rate of oxaliplatin, frequency of peripheral sensory neuropathy (PSN), and safety.Results: The 52 patients who received the protocol treatment were included in the evaluation of efficacy and safety. Median PFS and OS were 12.4 months (95% confidence interval [CI], 10.0-14.8) and 30.6 months (95% CI, 27.6-33.5), respectively. The objective response rates were 55.8% for the initial CapeOX plus bevacizumab therapy, 17.8% for capecitabine plus bevacizumab maintenance therapy, and 31.0% for reintroduced CapeOX plus bevacizumab therapy. The frequency of PSN was 63.5%, including 3.8% of patients with grade 3 PSN. No patients required treatment discontinuation because of PSN during the induction or maintenance therapy.Conclusions: CapeOX plus bevacizumab therapy with a planned oxaliplatin stop-and-go strategy is a feasible first-line treatment for Japanese patients with mCRC.Trial Registration: This trial is registered with the University Hospital Medical Information Network in 15 March 2010 ( UMIN000006478 ). [ABSTRACT FROM AUTHOR]

Background: Although number of elderly patients with metastatic colorectal cancer (mCRC) is rapidly increasing, this population is often underrepresented in clinical trials. Recently, a phase II trial demonstrated that capecitabine and oxaliplatin (XELOX) combined with bevacizumab XELOX plus bevacizumab was effective and well tolerated by elderly patients with mCRC who reside in Western countries. The aim of this study was to evaluate the safety and efficacy of XELOX plus bevacizumab for Japanese patients aged ≥ 75 years with mCRC.Methods: This prospective, open-label phase II trial recruited patients aged ≥ 75 years with previously untreated mCRC between March 2010 and January 2012. Treatment consisted of 7.5 mg/kg of intravenous bevacizumab and 130 mg/m(2) of oxaliplatin on day 1 of each cycle combined with 2000 mg/m(2) of oral capecitabine per day on days 1-14 of each cycle. Treatment was repeated every 3 weeks until disease progression or termination of the study. The primary endpoint was progression-free survival; the secondary endpoints were toxicity, overall response rate, time-to-treatment failure, and overall survival.Results: Thirty-six patients (male 58%; median age 78 years; colon cancer 67%) met all eligibility criteria and received at least one course of the planned treatment. The median time-to-treatment failure was 7.0 months. Twelve patients (33.3%) experienced adverse effects (AEs) ≥ grade 3 and frequent AEs ≥ grade 3, including neutropenia (22.2%) and neuropathy (13.9%). Hypertension was the most frequent AE ≥ grade 3 associated with bevacizumab (11.1%). Low baseline creatinine clearance associated significantly with the incidence of AEs ≥ grade 3. Response and disease control rates were 55.6 and 91.7%, respectively. Median progression-free and overall survival times were 11.7 months (95% confidence interval, 8.0-13.4 months) and 22.9 months, respectively.Conclusion: XELOX combined with bevacizumab was well tolerated by selected Japanese patients aged ≥ 75 years with mCRC patients, and controlled clinical trials are now required to determine the survival benefit. [ABSTRACT FROM AUTHOR]

Background Identification of novel molecular biomarkers will improve the management of patients with gastric cancer (GC). Prenyl diphosphate synthase subunit 2 (PDSS2) is required for coenzyme Q10 biosynthesis and acts as a tumor suppressor; however, the role and regulatory mechanisms of PDSS2 in GC are not understood. The aim of this study was to determine expression status and regulatory mechanisms of PDSS2 in GC. Methods Associations between expression and methylation of PDSS2 were evaluated using GC cell lines. The clinical significance of PDSS2 expression was evaluated using 238 pairs of surgically resected gastric tissues with subgroup analysis based on GC subtypes. Results The expression of PDSS2 mRNA was decreased in 73% of GC cell lines compared with the control non-cancerous cell. The PDSS2 promoter was hypermethylated in cells with decreased PDSS2 expression, and treating these cells with a methylation inhibitor reactivated PDSS2 expression. GC tissues expressed significantly lower mean levels of PDSS2 mRNA compared with adjacent normal tissues (P <0.001). The expression pattern of PDSS2 protein was consistent with that of its mRNA. The decrease of PDSS2 mRNA expression in GC tissues (less than half the level of expression detected in the corresponding normal adjacent tissues) correlated significantly with elevated levels of carbohydrate antigen 19-9 (P =0.015), lymph node metastasis (P =0.022), and shorter recurrence-free survival after curative resection (P =0.022). Further, multivariate analysis identified PDSS2 mRNA expression as an independent prognostic factor (hazard ratio 1.95, 95% confidence interval 1.22-3.09, P =0.005), and its expression pattern and prognostic significance were similar among three GC subtypes. Conclusions PDSS2 encodes a putative tumor suppressor, and we show here that its expression was regulated by hypermethylation of its promoter in GC cells. Inhibition of PDSS2 mRNA expression may serve as a novel biomarker of all types of GC. [ABSTRACT FROM AUTHOR]

Background Gastric cancer (GC) remains to have a poor prognosis via diverse process of cancer progression. Dihydropyrimidinase-like 3 (DPYSL3) is a cell adhesion molecule that has been reported to be involved in the metastatic process of tumor cells. The aim of this study was to identify a novel clinically-relevant biomarker of GC. Methods Expression analysis of DPYSL3 mRNA and protein levels was conducted using GC cell lines and 238 pairs of surgically resected gastric tissues. Correlations between expression status of DPYSL3 and clinicopathological parameters were investigated. Results DPYSL3 mRNA expression levels positively correlated with those of potentially interacting genes (VEGF, FAK and EZR) in GC cell lines. GC tissues from tumors with distant metastases (stage IV cancer) showed elevated expression levels of DPYSL3 mRNA. The DPYSL3 staining intensity in immunochemical staining was consistent with the mRNA expression patterns in GC tissues. High DPYSL3 mRNA expression in GCs was significantly associated with more malignant phenotypes and was an independent prognostic factor. Moreover, patients with high DPYSL3 mRNA expression had a significantly shorter recurrence free survival after curative resection. In subgroup analysis based on tumor histology, similar tendency was observed between patients with differentiated and undifferentiated GCs. Conclusions Expression status of DPYSL3 in GC tissues may represent a promising biomarker for the malignant behavior of GC. [ABSTRACT FROM AUTHOR]

Background Hepatocellular carcinoma (HCC) is one of the major causes of cancer-related death especially among Asian and African populations. It is urgent that we identify carcinogenesis-related genes to establish an innovative treatment strategy for this disease. Methods Triple-combination array analysis was performed using one pair each of HCC and noncancerous liver samples from a 68-year-old woman. This analysis consists of expression array, single nucleotide polymorphism array and methylation array. The gene encoding collagen type 1 alpha 1 (COL1A1) was identified and verified using HCC cell lines and 48 tissues from patients with primary HCC. Results Expression array revealed that COL1A1 gene expression was markedly decreased in tumor tissues (log 2 ratio -1.1). The single nucleotide polymorphism array showed no chromosomal deletion in the locus of COL1A1. Importantly, the methylation value in the tumor tissue was higher (0.557) than that of the adjacent liver tissue (0.008). We verified that expression of this gene was suppressed by promoter methylation. Reactivation of COL1A1 expression by 5-aza-2'-deoxycytidine treatment was seen in HCC cell lines, and sequence analysis identified methylated CpG sites in the COL1A1 promoter region. Among 48 pairs of surgical specimens, 13 (27.1%) showed decreased COL1A1 mRNA expression in tumor sites. Among these 13 cases, 10 had promoter methylation at the tumor site. The log-rank test indicated that mRNA down-regulated tumors were significantly correlated with a poor overall survival rate (P = 0.013). Conclusions Triple-combination array analysis successfully identified COL1A1 as a candidate survivalrelated gene in HCCs. Epigenetic down-regulation of COL1A1 mRNA expression might have a role as a prognostic biomarker of HCC. [ABSTRACT FROM AUTHOR]

Background: To detect genes correlated with hepatocellular carcinoma (HCC), we developed a triple combination array consisting of methylation array, gene expression array and single nucleotide polymorphism (SNP) array analysis. Methods: A surgical specimen obtained from a 68-year-old female HCC patient was analyzed by triple combination array, which identified doublecortin domain-containing 2 (DCDC2) as a candidate tumor suppressor gene of HCC. Subsequently, samples from 48 HCC patients were evaluated for their DCDC2 methylation and expression status using methylation specific PCR (MSP) and semi-quantitative reverse transcriptase (RT) PCR, respectively. Then, we investigated the relationship between clinicopathological factors and methylation status of DCDC2. Results: DCDC2 was revealed to be hypermethylated (methylation value 0.846, range 0-1.0) in cancer tissue, compared with adjacent normal tissue (0.212) by methylation array in the 68-year-old female patient. Expression array showed decreased expression of DCDC2 in cancerous tissue. SNP array showed that the copy number of chromosome 6p22.1, in which DCDC2 resides, was normal. MSP revealed hypermethylation of the promoter region of DCDC2 in 41 of the tumor samples. DCDC2 expression was significantly decreased in the cases with methylation (P = 0.048). Furthermore, the methylated cases revealed worse prognosis for overall survival than unmethylated cases (P = 0.048). Conclusions: The present study indicates that triple combination array is an effective method to detect novel genes related to HCC. We propose that DCDC2 is a tumor suppressor gene of HCC. [ABSTRACT FROM AUTHOR]