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Colorectal micropapillary carcinoma has recently been reported as an aggressive variant of adenocarcinoma with a high incidence of lymph node metastasis, but has not been well investigated in terms of survival analysis. This study analyzed the clinicopathological characteristics, including survival data, of the patients with micropapillary carcinoma. We hypothesized that the aggressive features of micropapillary carcinoma might be related to the presence of more tumor cells with stem cell phenotype in colorectal cancer. Fifty-five (10%) micropapillary carcinoma cases were identified among 561 cases of colorectal cancer. We compared the clinicopathological characteristics, including survival data and immunohistochemical profiles of stem cell markers (SOX2, NOTCH3, CD44v6, CD166, ALDH1) of micropapillary carcinomas with those of randomly selected 112 conventional adenocarcinomas lacking micropapillary carcinoma components (non-micropapillary carcinoma) in the colorectum. To exclude the possibility of dilution of control group by patients with microsatellite instability-high carcinomas, we divided non-micropapillary carcinomas into microsatellite instability-high carcinoma and microsatellite stable tumors. Micropapillary carcinomas were characterized by more frequent lymphovascular invasion (Po0.0001) and lymph node metastasis (Po0.0001), higher pathological T and tumor node metastasis stages (P ¼ 0.047 and P ¼ 0.001), and more frequent SOX2 (P ¼ 0.038) and NOTCH3 expressions (P ¼ 0.005). Overall 5-year survival rate for patients with micropapillary carcinoma (37%) was significantly lower than for microsatellite instability-high carcinoma and microsatellite stable carcinoma patients (92 and 72%, Po0.0001). The presence of the micropapillary carcinoma component was shown to be associated with a significantly worse survival rate in univariate (Po0.0001) and multivariate (P ¼ 0.003, Cox hazard ratio 2.402) analyses. In conclusion, recognition of the micropapillary carcinoma component in colonic adenocarcinoma is very important, because the micropapillary carcinoma has been associated with a significantly worse prognosis. We also found a higher expression rate of cancer stem cell markers in micropapillary carcinomas, suggesting their potential contribution to the survival disadvantage of micropapillary carcinoma. Modern Pathology (2013Pathology ( ) 26, 1123Pathology ( -1131 doi:10.1038/modpathol.2012 published online 12 October 2012 Keywords: colorectum; micropapillary carcinoma; prognosis; stem cell marker; TNM stage Colorectal cancer is one of the leading causes of cancer deaths worldwide, and both the prevalence and the incidence rate in South Korea are rapidly rising. 1 For metastatic colorectal cancer, the 5-year survival rate is only about 10%. 2 Micropapillary carcinoma is a relatively uncommon and distinctive tumor characterized by small clusters of tumor cells in the clear lacunar spaces, mimicking lymphatic or vascular channels. 3 Micropapillary carcinoma has high potential to metastasize to the regional l...

Ginsenoside Re is a triol type triterpene glycoside and is abundantly present in ginseng berry. In the present study, we verified that ginsenoside Re can be transformed into less-polar ginsenosides, namely, Rg2, Rg6, and F4, by heat-processing. The products of heat-processed ginsenoside Re inhibited phosphorylation of CDK2 at Thr160 by upregulation of p21 level, resulting in S phase arrest. The products of heat-processed ginsenoside Re also activated caspase-8, caspase-9, and caspase-3, followed by cleavage of PARP, a substrate of caspase-3, in a dose-dependent manner. Concurrently, alteration of mitochondrial factors such as Bcl-2 and Bax was also observed. Moreover, pretreatment with Z-VAD-fmk abrogated caspase-8, -9, and -3 activations by the products of heat-processed ginsenoside Re. We further confirmed that the anticancer effects of the products of heat-processed ginsenoside Re in AGS cells are mainly mediated via generation of less-polar ginsenosides Rg6 and F4.

Activating KRAS and/or BRAF mutations have been identified as predictors of resistance to anti-epidermal growth factor receptor (EGFR) chemotherapy in colorectal cancer. But the status of KRAS and BRAF mutations and their clinicopathologic and prognostic significance has not been extensively evaluated in small intestinal adenocarcinomas. In this work, the KRAS and BRAF genes in 190 surgically resected small intestinal adenocarcinoma cases were sequenced and their association with various clinicopathologic variables, including survival of the patients, was analyzed. KRAS or BRAF mutations were observed in 63 (33%) cases. Sixty-one cases had KRAS mutations and 2 had BRAF mutations and the two types of mutation were mutually exclusive. The majority of KRAS mutations were G4A transition (43/61 cases, 71%) or p.G12D (31/61 cases, 51%). The patients with mutant KRAS tended to have higher pT classifications (P = 0.034) and more frequent pancreatic invasion (P = 0.020) than those with wild-type KRAS. Multivariate logistic regression analysis showed that certain mutated KRAS subtypes (G4A transitions and G12D mutations) were significantly correlated with higher pT classification (P = 0.015 and 0.004, respectively) than wild-type KRAS and other KRAS mutations. The patients with KRAS or BRAF mutation had a tendency to shorter overall survival than those with wild-type KRAS and BRAF (P = 0.148), but subgroup analysis demonstrated the patients with KRAS mutations showed worse survival (median, 46.0 months; P = 0.046) than those with wild-type KRAS (85.4 months) in lower pT classification (pT1-pT3) group. In summary, KRAS and, infrequently, BRAF mutations are observed in a subset of small intestinal adenocarcinomas, and are associated with higher pT classification and more frequent pancreatic invasion. KRAS mutation is a poor prognostic predictor in patients with lower pT classification tumors. Anti-EGFR targeted therapy could be applied to about two-thirds of small intestinal adenocarcinoma patients, namely those with wildtype KRAS and BRAF if they have metastatic disease, similar to colorectal cancer patients.

Epigallocatechin gallate (EGCG) and curcumin are well known to naturally-occurring anticancer agents. The aim of this study was to verify the combined beneficial anticancer effects of curcumin and EGCG on PC3 prostate cancer cells, which are resistant to chemotherapy drugs and apoptosis inducers. EGCG showed weaker inhibitory effect on PC3 cell proliferation than two other prostate cancer cell lines, LNCaP and DU145. Co-treatment of curcumin improved antiproliferative effect of EGCG on PC3 cells. The protein expressions of p21 were significantly increased by the co-treatment of EGCG and curcumin, whereas it was not changed by the treatment with each individual compound. Moreover, treatments of EGCG and curcumin arrested both S and G2/M phases of PC3 cells. These results suggest that the enhanced inhibitory effect of EGCG on PC3 cell proliferation by curcumin was mediated by the synergic up-regulation of p21-induced growth arrest and followed cell growth arrest. [BMB Reports 2015; 48(8): 461-466]

Small intestinal adenocarcinomas (SIACs) are rare, and their molecular pathogenesis is largely unknown. To define the roles of E-cadherin and β-catenin, we performed immunohistochemistry for E-cadherin and β-catenin in 194 surgically resected SIACs with tissue microarrays and compared the data with clinicopathologic factors, including survival rates of patients with SIAC. Loss of E-cadherin expression and aberrant β-catenin expression were observed in 41.8% (81/194 cases) and 40.7% (79/194 cases) of SIACs, respectively. Combined loss of E-cadherin and aberrant β-catenin expression was observed in 24.2% (47/194 cases) of SIACs, and this feature was most frequently observed in mucinous adenocarcinomas and signet ring cell carcinomas (P < .001), poorly differentiated and undifferentiated carcinomas (P < .001), and tumors with advanced pT classification (P = .03). Survival times for patients with SIAC with both loss of E-cadherin and aberrant β-catenin expression (median, 13.9 months) were significantly shorter than those for patients without aberrant expression of both proteins (49.9 months), as determined by univariate (P < .001) and multivariate (P = .01) analyses. In conclusion, loss of E-cadherin and aberrant β-catenin expression correlate with poorly differentiated tumors, advanced T classification, and decreased patient survival time; therefore, it could be a prognostic factor in patients with SIAC.

Background The aim of this study was to use immunohistochemistry (IHC) and silver in situ hybridization (SISH) to evaluate alterations in EGFR and HER2 in gastric cancer in order to determine the relationship with prognosis in gastric cancer patients following curative resection. Patients and methods In this study, we analyzed EGFR and HER-2 status by IHC and SISH in 254 stage I-III gastric cancer patients who underwent curative surgery. Results Thirteen cases (2.48 %) showed EGFR alteration by IHC or SISH. EGFR alteration was associated with older age (P = 0.021), intestinal type (P = 0.040) and higher stage disease (P \ 0.001). The patients with operable state gastric cancer who had EGFR alteration had an unfavorable prognosis, and multivariate analysis confirmed that EGFR alteration was an independent unfavorable prognostic factor. Twenty-seven cases (10.6 %) showed HER-2 alteration by IHC or SISH. HER-2 alteration was associated with older age (P = 0.006), well or moderately differentiated histology (P \ 0.001) and intestinal type (P = 0.002). Conclusion HER-2 alteration is not an independent prognostic factor for curatively resectable gastric cancer. We observed EGFR alteration in a subset of cases with operable state gastric cancer and determined that it was associated with an unfavorable prognosis.