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.

症例は65歳,男性.排便困難と肛門痛を主訴に近医を受診した.大腸内視鏡検査で下部直腸癌と診断され,当科を紹介受診.腹部CTで前立腺および肛門挙筋への浸潤,直腸周囲の膿瘍形成,側方リンパ節の腫脹を認めた.外来精査中にイレウスとなり,緊急で双孔式S状結腸人工肛門造設術を施行した.抗菌薬投与を行い炎症所見が消退した後,術前化学放射線療法(UFT 500mg/LV 75mg,総線量50.4Gy)を行い,腫瘍の著明な縮小を認め,骨盤内臓全摘術を施行した.術後に癒着性イレウスを発症したが保存的加療で軽快し,術後51日目に退院となった.切除標本では直腸病変は瘢痕化しており,病理組織学的検査では腫瘍細胞を認めず,化学放射線療法の効果はGrade3,病理学的完全奏効(pCR)と診断された.膿瘍形成を伴う高度進行直腸癌に対し術前化学放射線療法が奏効しpCRを得た症例を経験したので報告する.(著者抄録)

症例は65歳,男性.排便困難と肛門痛を主訴に近医を受診した.大腸内視鏡検査で下部直腸癌と診断され,当科を紹介受診.腹部CTで前立腺および肛門挙筋への浸潤,直腸周囲の膿瘍形成,側方リンパ節の腫脹を認めた.外来精査中にイレウスとなり,緊急で双孔式S状結腸人工肛門造設術を施行した.抗菌薬投与を行い炎症所見が消退した後,術前化学放射線療法(UFT 500mg/LV 75mg,総線量50.4Gy)を行い,腫瘍の著明な縮小を認め,骨盤内臓全摘術を施行した.術後に癒着性イレウスを発症したが保存的加療で軽快し,術後51日目に退院となった.切除標本では直腸病変は瘢痕化しており,病理組織学的検査では腫瘍細胞を認めず,化学放射線療法の効果はGrade3,病理学的完全奏効(pCR)と診断された.膿瘍形成を伴う高度進行直腸癌に対し術前化学放射線療法が奏効しpCRを得た症例を経験したので報告する.(著者抄録)

Purpose: Endocrine cell carcinoma, according to the Japanese classification criteria for colorectal cancer, corresponds to neuroendocrine carcinoma (NEC) and mixed adenoneuroendocrine carcinoma (MANEC), as defined in the 2010 World Health Organization (WHO) classification. We retrospectively reviewed the clinical features of patients with these tumors diagnosed and treated at our institution. Methods: The clinicopathological features of endocrine cell carcinomas of the colon and rectum diagnosed by neuroendocrine markers from January 2000 to December 2012 were retrospectively evaluated in 12 patients. Results: Surgical specimens were obtained from eight of the 12 patients. MANEC was diagnosed in six patients and NEC in one. One tumor was unclassifiable. The tumors were not resected in four patients, and all died within 3 months. Of the eight patients who underwent resection, four received an R0 resection, two of whom underwent adjuvant chemotherapy and survived more than 5 years. One patient who underwent an R2 resection and continuous chemotherapy survived for 53 months. One patient with NEC underwent surgery and radiotherapy, and died 17 months later. Conclusion: Most endocrine cell carcinomas of the colon and rectum reviewed were MANECs. Though their prognosis was generally poor, chemotherapy may be effective in some patients.

Background and aim: Patients with stage T3 or T4 rectal cancer are candidates for neoadjuvant chemoradiation therapy. The aim of this study is to clarify the usefulness of circumferential tumor extent determined by computed tomography (CT) colonography in differentiating T3 or T4 from T1 or T2 rectal cancer. Methods: Seventy consecutive rectal cancer patients who underwent curative-intent surgery were enrolled in this study. All patients underwent colonoscopy and CT colonography on the same day. The circumferential tumor extent was estimated in 10% increments. The pathological T stage was used as the reference. Results: The median circumferential tumor extent evaluated by colonoscopy for T1 (n = 6), T2 (n = 21), and T3/T4 (n = 43) were 10%, 30%, and 80%, respectively (T1/T2 vs. T3/T4, p < 0.0001). The median circumferential tumor extent evaluated by CT colonography for T1, T2, and T3/T4 is 10%, 30%, and 70%, respectively (T1/T2 vs. T3/T4, p < 0.0001). The correlation coefficient between colonoscopy and CT colonography was very high (0.94). By defining a circumferential tumor extent >= 50% by CT colonography as the criterion for stage T3 or T4, the sensitivity, specificity, positive predictive value and accuracy were 72%, 88%, 91%, and 79%, respectively. Conclusion: Circumferential tumor extent >= 50% determined by CT colonography is a simple and potentially useful marker to identify candidates for neoadjuvant chemoradiation therapy. Copyright (C) 2015, Asian Surgical Association. Published by Elsevier Taiwan LLC. All rights reserved.

Although size criteria have been proposed to identify lymph node metastases in patients with rectal cancer, size may not be an accurate predictor. Specimens from consecutive rectal cancer patients who underwent curative-intent radical surgery were examined. The long and short axes of lymph nodes were measured on the glass slides using micrometer calipers. The pathologic diagnosis was used as the reference. The diagnostic accuracy of metastatic status according to lymph node size was evaluated. Overall, 1283 lymph nodes from 78 patients were reviewed. The metastatic rate correlates with the length of both the long and short axes. However, metastases were present even in 1-mm lymph nodes, and the metastatic rate exceeds 5 per cent in lymph nodes measuring 3 mm along both axes. Cutoff values of >= 4 mm and >= 3 mm for the long and short axes result in a sensitivity of 76 per cent and 79 per cent, and a specificity of 36 per cent and 33 per cent, respectively, for each axis. Size criteria alone do not accurately predict the N-stage of rectal cancer. Diminutive lymph nodes, which are not seen on imaging studies, can contain metastatic disease.

Background: Methylation of the MLH1 promoter region has been suggested to be a major mechanism of gene inactivation in sporadic microsatellite instability-positive (MSI-H) colorectal cancers (CRCs). Recently, single-nucleotide polymorphism (SNP) in the MLH1 promoter region (MLH1-93G/A rs1800734) has been proposed to be associated with MLH1 promoter methylation, loss of MLH1 protein expression and MSI-H tumors. We examined the association of MLH1-93G/A and six other SNPs surrounding MLH1-93G/A with the methylation status in 210 consecutive sporadic CRCs in Japanese patients. Methods: Methylation of the MLH1 promoter region was evaluated by Na-bisulfite polymerase chain reaction (PCR)/single-strand conformation polymorphism (SSCP) analysis. The genotype frequencies of SNPs located in the 54-kb region surrounding the MLH1-93G/A SNP were examined by SSCP analysis. Results: Methylation of the MLH1 promoter region was observed in 28.6% (60/210) of sporadic CRCs. The proportions of MLH1-93G/A genotypes A/A, A/G and G/G were 26% (n = 54), 51% (n = 108) and 23% (n = 48), respectively, and they were significantly associated with the methylation status (p = 0.01). There were no significant associations between genotype frequency of the six other SNPs and methylation status. The A-allele of MLH1-93G/A was more common in cases with methylation than the G-allele (p = 0.0094), especially in females (p = 0.0067). In logistic regression, the A/A genotype of the MLH1-93G/A SNP was shown to be the most significant risk factor for methylation of the MLH1 promoter region (odds ratio 2.82, p = 0.003). Furthermore, a haplotype of the A-allele of rs2276807 located -47 kb upstream from the MLH1-93G/A SNP and the A-allele of MLH1-93G/A SNP was significantly associated with MLH1 promoter methylation. Conclusions: These results indicate that individuals, and particularly females, carrying the A-allele at the MLH1-93G/A SNP, especially in association with the A-allele of rs2276807, may harbor an increased risk of methylation of the MLH1 promoter region.