BackgroundThe Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated.MethodsWe used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the KEAP1 promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, NQO-1 and AKR1C1.ResultsDNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the KEAP1 promoter region. HT29 cells with a hypermethylated KEAP1 promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased KEAP1 mRNA expression. These result suggested that methylation of the KEAP1 promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of NQO-1 and AKR1C1 mRNA than Colo320DM cells. Aberrant promoter methylation of KEAP1 was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the KEAP1 promoter region, conferring a protective effect against cytotoxic anticancer drugs.ConclusionHypermethylation of the KEAP1 promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.

PurposeThe second planned interim analysis (median follow-up 12.5 months) in a phase III trial of postoperative adjuvant chemotherapy for stage III gastric cancer revealed significant improvement in relapse-free survival (RFS) for S-1 plus docetaxel over S-1 alone. Although enrollment was terminated on the recommendation of the independent data and safety monitoring committee, we continued follow-up and herein report on 3-year RFS, the primary endpoint. Patients and methods Patients with histologically confirmed stage III gastric cancer who underwent gastrectomy with D2 lymphadenectomy were randomly assigned to receive adjuvant chemotherapy with either S-1 plus docetaxel or S-1 alone. In the S-1 plus docetaxel group, S-1 was given orally for 2 weeks followed by 1 week of rest for seven courses, and docetaxel was given intravenously on day 1 of the second to seventh courses. The combination therapy was followed by S-1 monotherapy for up to 1 year. ResultsThe 3-year RFS rate of the S-1 plus docetaxel group was 67.7%. This was significantly superior to that of 57.4% in the S-1 group (hazard ratio [HR] 0.715, 95% CI 0.587-0.871, P = 0.0008). This translated into a significant benefit in the 3-year overall survival (OS) rate in the S-1 plus docetaxel group (77.7% versus 71.2%, HR 0.742, 95% CI 0.596-0.925, P = 0.0076). Conclusion On 3-year follow-up data, postoperative adjuvant therapy with S-1 plus docetaxel was confirmed to improve both RFS and OS and can be recommended as a standard of care for patients with stage III gastric cancer treated by D2 dissection.

Epstein-Barr virus (EBV) is detected in 20% to 30% of sporadic Burkitt lymphoma (sBL). However, only a few studies of EBV-positive (EBV) sBL have been reported, and its characteristics still remain controversial. To highlight the features of EBV sBL, we compared the clinicopathologic characteristics of 33 cases of EBV and 117 cases of EBV-negative (EBV) sBL in Japan. EBV sBL showed significantly higher age distribution (median, 42 vs. 13 y; P<0.0001) and higher frequency of patients older than 50 years (48% vs. 16%, P<0.0001). We also revealed the difference of the involved sites. The EBV group showed significantly higher incidence of involvement of tonsil (P=0.027), adrenal gland (P=0.011), and cervical lymph node (P=0.040). In addition, the EBV group tended to have higher incidence of nodal involvement (P=0.078) and involvement of para-aorta lymph node (P=0.084) and heart (P=0.050). In contrast, the gastrointestinal tract was less frequently affected in EBV sBL (P=0.024). In addition, the less positivity for MUM1 (P=0.020) of EBV sBL was highlighted. These results indicate that biological behavior and pathogenesis of EBV sBL might be different from those of EBV sBL. Our results demonstrate that EBV sBL has an aspect of age-related disease and is a distinct clinicopathologic subtype, which should be distinguished from EBV sBL.

Background and Aim: Genetic silencing by promoter methylation has attracted attention in the carcinogenesis of colorectal cancer. Methylation of the p16 INK4a gene has been found in primary colorectal cancer. Although the p15 INK4b gene displays high homology to the p16 INK4a gene in the amino acid sequence, methylation of p15 INK4b has not been fully studied. We investigated p15 INK4b methylation status in patients with colorectal cancer to verify the association between the methylation of p15 INK4b and clinicopathological features compared with p16 INK4a . Methods: DNA samples from the tissues of primary colorectal cancer and corresponding adjacent normal colon mucosa were obtained from surgical resections of 88 patients (47 males and 41 females, aged 29-83 years). Methylation-specific polymerase chain reaction was used to analyze p15 INK4b and p16 INK4a methylation status after bisulfite modification. Cumulative survival rates (mean follow-up period: 53.2 months) were calculated by the Kaplan-Meier analysis. Results: Methylations of p15 INK4b and p16 INK4a genes were detected in 23 (26.1%) and 20 (22.7%) colorectal cancers, respectively. Methylation of p15 INK4b was not associated with any clinicopathological features. Compared with normal mucosa, the methylation of p15 INK4b was more prominent in tumor tissue ( P < 0.001). Reverse transcription-polymerase chain reaction (RT-PCR) revealed that p15 INK4b methylaton decreased mRNA expression. Kaplan-Meier analysis showed that patients with stage I-II had a significant difference in survival rate between those with and without methylated p15 INK4b ( P = 0.018). Conclusions: Our results suggest that methylation of the p15 INK4b gene contributes to the process of carcinogenesis in colorectal cancer as well as p16 INK4a and is useful as a prognostic factor in the early stage.

Background:We aimed to compare the efficacy and safety of irinotecan/S-1 (IRIS) therapy with S-1 monotherapy in patients with gemcitabine-refractory pancreatic cancer.Methods:Patients were treated with oral S-1 (80–120 mg for 14 days every 4 weeks) plus intravenous irinotecan (100 mg m−2 on days 1 and 15 every 4 weeks; IRIS group) or oral S-1 group (80–120 mg daily for 28 days every 6 weeks). The primary endpoint was progression-free survival (PFS).Results:Of 137 patients enrolled, 127 were eligible for efficacy. The median PFS in the IRIS group and S-1 monotherapy group were 3.5 and 1.9 months, respectively (hazard ratio (HR)=0.77; 95% confidence interval (CI), 0.53–1.11; P=0.18), while the median overall survival (OS) were 6.8 and 5.8 months, respectively (HR=0.75; 95% CI, 0.51–1.09; P=0.13). Response rate was significantly higher in the IRIS group than in the S-1 monotherapy group (18.3% vs 6.0%, P=0.03). Grade 3 or higher neutropenia and anorexia occurred more frequently in the IRIS group.Conclusions:There was a trend for better PFS and OS in the IRIS group that could be a treatment arm in the clinical trials for gemcitabine-refractory pancreatic cancer.

This study is an evaluation of the effect of gastrointestinal cancer chemotherapy with short‐term periodic steroid premedication on bone metabolism. Primary endpoints were changes in bone mineral densities and metabolic bone turnover 16 weeks after initiation of chemotherapy.

Rapid TPAg is a useful diagnostic test for immediate and accurate determination of the results of H. pylori eradication therapy. The antigenicity of stool sample suspensions was preserved for 7 days in the collection devices.

Angioimmunoblastic T-cell lymphoma (AITL) is a distinct peripheral T-cell lymphoma entity exhibiting peculiar clinical features and poor prognosis. Its clinical characteristics and prognostic factors are not well established. To clarify the clinical characteristics and prognostic features of AITL, we conducted a multicenter, retrospective study. Fifty-six patients were enrolled. The median patient age was 68 years. Immunohistochemical examinations of tumor cells showed positivity for CD10 and T-cell markers, and chromosomal examination detected several types of abnormalities. More than 80 % of patients show advanced disease at diagnosis and poor prognostic scores. A high proportion of patients showed accompanying B symptoms, splenomegaly, and hepatomegaly at diagnosis. The 5-year overall survival (OS) rate was 48 % and progression-free survival was 25 %. Univariate analysis revealed higher age, fever, poor performance status, anemia, and low albumin level to be poor prognostic factors for OS. In addition to these factors, both IPI and PIT were also predictive of OS. Multivariate analysis indicated only a low level of serum albumin to be a significant prognostic factor for OS. Serum albumin may be one of the important prognostic factors for AITL. Further investigation is needed to confirm these results.