Among patients undergoing surgical resection for extrahepatic cholangiocarcinoma, invasive carcinoma at the ductal resection margins appears to have a significant relation to local recurrence and also a significant negative impact on survival, whereas residual carcinoma in situ does not. Discrimination whether carcinoma in situ or invasive carcinoma is present is important in clinical setting in which the resection margin at the ductal stump is positive.

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In recent years, due to the increasing prevalence of upper gastrointestinal endoscopy, there have been an increasing number of reports on duodenal adenoma and early stage cancer. However, endoscopic techniques for the resection of duodenal adenomas are difficult, due to the anatomical features of the duodenum, and the long distance to the lesion. There have only been a few reports on the use of endoscopic techniques for duodenal adenomas compared to those focused on the stomach and large intestine. For duodenal adenomas, we used a conventional endoscope for lesions proximal to the major duodenal papilla, and a short-type double balloon endoscope for lesions distal to the papilla. The en-bloc resection rate was 93.8%. There was only one case of microperforation. Endoscopic manipulation is considered difficult in the deep areas of the duodenum, but double balloon endoscopy enabled stable manipulation and successful resection of the tumor in the majority of cases.

Recent molecular studies have shown that the genetic profiles of differentiated-type adenocarcinomas of the stomach are associated with distinct cellular mucin phenotypes (gastric-intestinal-and mixed-phenotypes). Therefore, we examined whether these cellular mucin phenotypes reflect specific molecular genetic alterations, and whether the phenotypes can be used to help categorize the intramucosal neoplasias of gastric tumors. We subclassified tumors into four cellular phenotypes using immunohistochemical mucin analysis. In all, 62 early gastric carcinomas (gastric-phenotype, 13; intestinal-phenotype, 17; mixed-phenotype, 31; unclassifiedphenotype, 1) were examined using a combination of polymerase chain reaction microsatellite assays and immunohistochemical analysis in order to detect chromosomal allelic losses of multiple cancer-related chromosomal loci (1p, 3p, 4p, 5q, 8p, 9p, 13p, 17p, 18q and 22q), microsatellite instability (MSI), and overexpression of the p53 protein. In addition, we analyzed the relationship between MSI status and hMLH1 promoter hypermethylation, which is thought to be a cause of high MSI status. For gastric phenotype cancers, the frequency of 3p allelic loss was higher than that of other microsatellite markers, whereas 5q allelic loss was frequently found in intestinal phenotype cancers. The genetic profile of mixed phenotype cancers is comprised of two distinct genetic types: LOH and MSI types. In the former, 5q, 3p and 18q allelic losses are seen frequently in intramucosal carcinomas. On the other hand, 17p, 1p and 9p allelic losses are associated with the development of submucosal carcinomas. MSI was observed only in mixed phenotype cancers (six of 31 mixed phenotype cancers). Overexpression of the p53 protein is common in differentiated-type gastric cancers. In addition, the MSI status of the tumor cells was correlated with the extent of hypermethylation of the hMLH1 promoter. We suggest that the cellular mucin phenotypes of the differentiated-type adenocarcinomas result from distinct genetic alterations.

Loss of heterozygosity (LOH) and microsatellite instability (MSI) commonly occur in colorectal carcinomas. However, the role of these genetic alterations in determining DNA ploidy status of tumors (diploid, aneuploid and multiploid) remains unclear. In the present study, we attempted to clarify the relationship between genetic alterations and DNA ploidy status. Crypt isolation coupled with DNA cytometric sorting and polymerase chain reaction assay (17 microsatellite markers) were used to study allelic losses and MSI in 59 colorectal carcinomas (diploid, 15; aneuploid, 10 and multiploid, 34). Of the 15 diploid carcinomas, 6 exhibited MSI in which allelic losses were rarely found. The other 9 diploid tumors mostly exhibited allelic losses, but none displayed MSI status. Whereas allelic losses frequently occurred in the aneuploid carcinomas and the aneuploid populations of multiploid carcinomas, they were rarely detected in the diploid populations of multiploid carcinomas. MSI status was not observed in aneuploid carcinomas nor in either population of multiploid carcinomas. Although multiploid carcinomas genetically resemble aneuploid carcinomas in the expression of the severe LOH phenotype, the genetic alterations seen in the diploid populations of multiploid carcinomas may differ from those of diploid carcinomas. Furthermore, all diploid, aneuploid and both the diploid and aneuploid fractions of the multiploid tumors that were non‐MSI exhibited a high rate of LOH, suggesting that LOH is independent of the tumor's ploidy status. Int. J. Cancer 88:614–619, 2000. © 2000 Wiley‐Liss, Inc.

Histone deacetylase 6 (HDAC6) is a cytoplasmic enzyme that regulates many important biological processes, including cell migration, viral infection and autophagy. The aim of this study was to investigate the significance of HDAC6 in the invasion and metastasis activities of hepatocellular carcinoma (HCC). Three HCC cell lines and two primary cultures of hepatocytes were used for biological experiments. Immunohistochemistry for HDAC6 protein was also examined in 70 resected primary HCCs. Knockdown of the HDAC6 gene in the HCC cell lines was carried out by treatment with siRNA, and their migration and invasion activities were examined by the scratch assay and Matrigel invasion assay, respectively. HDAC6 expression was greater in all of the HCC cell lines compared to the primary cultures of hepatocytes. Knockdown of HDAC6 markedly downregulated the migration and invasion activities of all HCC cell lines (P<0.05). Overexpression of HDAC6 protein to a level higher than that in the corresponding normal hepatocytes was observed in 14 (20%) of the 70 primary HCCs, and was significantly correlated with high clinical stage, number of tumors, vascular invasion and intrahepatic metastasis (P<0.05). These results suggest that overexpression of the HDAC6 protein is involved in the migration and invasion activities of HCC cells, and may be a good biomarker for prediction of intrahepatic metastasis.

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The objective of this study was to evaluate the therapeutic usefulness of chemoradiotherapy (CRT) followed by surgery in patients with clinically T4 (cT4) esophageal cancer involving adjacent organs such as the trachea, main bronchi, and large vessels. Thirty-seven patients with cT4 squamous cell carcinoma of the thoracic esophagus were enrolled in this study. The CRT regimen comprised cisplatin (70 mg/m2) on day 1, 5-fluorouracil (700 mg/m2) on days 1-4 and external irradiation (200 cGy/day, total 30 Gy) on either days 8-26 (sequential schedule, n=15) or days 1-19 (concurrent schedule, n022). Two courses of CRT were given. The results of CRT were complete response in nine patients, partial response in 19, no change in three (minor response in two), and progressive disease in six patients. The median response duration in all responders was 172 days (range: 56-2469, n=19). After CRT, 13 patients received surgery. In 12 of these patients, tumors were completely resected. Histopathologic examination of the resected specimen revealed a discrepancy between clinical response and histopathologic effect. The median duration of survival and the 1-, 2- and 5-year survival rates were 304 days (84-3155), 45%, 35% and 23% in all patients, respectively, 866 days (190-3155), 83%, 83% and 57% in the 13 patients whose tumors were resected, and 187 days (84--2630), 25%, 5% and 5% in the 24 patients whose tumors were not resected. Grade 3 toxicity, especially hematological reactions, was noted in 13.5% (5/37) of the patients. There was one toxicity-related death (sepsis). A good outcome may be obtained with CRT, followed by surgery when feasible. However, CRT can cause toxic reactions, and close monitoring of patients is required.