宮倉 安幸

Background: Incidence and clinical characteristics of synchronous colorectal cancer (sCRC) patients significantly vary among studies, likely due to differences in surveillance methodology. If remain undetected, sCRC can progress to more advanced stages seriously aggravating patient prognosis. We studied the incidence and clinicopathological characteristics of Japanese patients with sCRCs who underwent surgery for primary CRC and received exhaustive perioperative surveillance. Methods: We recruited 1005 patients with surgically resected CRCs between January 2007 and December 2011. The associations of clinical and pathological factors with sCRC development were assessed by univariate and multivariate logistic regression. Results: Eighty-four patients (8.4 %) developed sCRCs, 16 of them(19.0 %) harboring three or more cancers. Companion sCRCs were smaller and earlier stage than the index lesion (P < 0.0001). In multivariate analysis, advanced age (odds ratio (OR) 1.03 per year; P = 0.009) and left colon tumor location (OR 1.78; P = 0.013) are associated with higher risk of sCRCs, particularly in females. Overall survival did not differ between solitary CRC and sCRC (P = 0.62). Conclusions: Our results highlight the importance of perioperative colonoscopy examination to ensure the absence of sCRCs that, being small and early staged, are more difficult to detect. The incidence of sCRC, and notably of triple or more sCRCs, was higher than previously recognized. Because they are also significantly higher than expected by merely stochastic accumulation of individual cancerous lesions, we suggest that the occurrence of many sCRC reflects a hitherto uncharacterized predisposition condition.

Although epithelial-mesenchymal transition (EMT) has been implicated as the pivotal event in metastasis, there is insufficient evidence related to EMT in clinical settings. Intratumor heterogeneity may lead to underestimation of gene expression representing EMT. In the present study, we investigated the expression of EMT-associated genes and microRNAs in primary colorectal cancer while considering intratumor heterogeneity. One-hundred and thirty-three multiple spatially separated samples were obtained from 8 patients with metastatic colorectal cancers and 8 with non-metastatic colorectal cancers, from the tumor center (TC), invasive front (IF) and metastasis. Differences in gene and microRNA expression were investigated by microarray and quantitative reverse-transcription PCR. Gene expression microarray analysis detected 7920 sites showing differing levels of gene expression among the TC, IF and metastasis. Expression of the EMT-associated gene zinc-finger E-box-binding homeobox 1 (ZEB1) significantly increased in the IF (P<0.01). To exclude individual differences, the expression ratio between TC and IF in each tumor was applied to analysis. This approach enabled recognition of the activation of the VEGF and Wnt signaling pathways, which were involved in metastasis via promotion of EMT. While no activation of these pathways was seen at the TC, regardless of whether tumors were metastatic or non-metastatic, they were preferentially activated at the IF in metastatic tumors, where high ZEB1 expression was seen in connection with decreased miR-200c expression. Multiple sampling in a tumor revealed that heterogeneous ZEB1 expression induced by EMT-associated signaling pathways played a pivotal role in metastasis via regulation of miR-200c.

Intraductal papillary mucinous neoplasm (IPMN) has been associated with a high incidence of extrapancreatic malignancies (EPMs). However, it is controversial whether IPMN is prognostic for EPM. We aimed to help clarify the issue studying this association in patients with histologically proven IPMN. We reviewed 51 surgically resected IPMNs in Saitama Medical Center, Jichi Medical University between January 1991 and June 2012. Mean follow-up was 63.7 +/- 47.8 months. The observed EPM incidence was compared with the expected incidence of cancer in Japan. Of the 51 IPMNs, 14 were malignant and the rest benign. Seventeen EPMs developed in 15 patients (29.4%), nine of which occurred prior to IPMN diagnosis. For all IPMNs, the standardized incidence ratio (SIR) was significantly increased for the six types of reported EPMs (SIR=2.18, CI=1.31-3.42, P=0.004). Benign IPMNs showed no association with EPMs (SIR=0.92, CI=0.43-1,76, P=0.87). In contrast, malignant IPMNs showed a higher association (SIR=3.83, CI=1.87-7.03, P=0.0009). However, the association was mostly due to the prior EPMs, as removal of metachronous EPMs had no significant effect (SIR=3.63, CI=1.59-7.17, P=0.005). Thus, only malignant IPMNs drive the significant association with prior EPMs, showing a near 4-fold increased incidence compared to the general Japanese population. Histological characterization of IPMNs may offer clinical value for EPM patient management. We hypothesize that these observations may be explained if some patients with EPMs present a higher risk to develop IPMNs (and vice versa), possibly resulting from an uncharacterized multiple cancer predisposition condition.