Kiyoaki Ouchi

Up-regulation of plasma membrane-associated ganglioside sialidase (Neu3) in human colon cancer and its involvement in apoptosis suppression

Human plasma membrane-associated sialidase (Neu3) is unique in specifically hydrolyzing gangliosides, thought to participate in cell differentiation and transmembrane signaling, thereby playing crucial roles in the regulation of cell surface functions. We have discovered levels of mRNA for this sialidase to be increased in restricted cases of human colon cancer by 3- to 100-fold compared with adjacent nontumor mucosa (n = 32), associated with significant elevation in sialidase activity in tumors (n = 50). In situ hybridization showed the sialidase expression in epithelial elements of adenocarcinomas. In cultured human colon cancer cells, the sialidase level was down-regulated in the process of differentiation and apoptosis induced by sodium butyrate, whereas lysosomal sialidase (Neu1) was up-regulated. Transfection of the sialidase gene into colon cancer cells inhibited apoptosis and was accompanied by increased Bcl-2 and decreased caspase expression. Colon cancer exhibited a marked accumulation of lactosylceramide, a possible sialidase product, and addition of the glycolipid to the culture reduced apoptotic cells during sodium butyrate treatment. These results indicate that high expression of the sialidase in cancer cells leads to protection against programmed cell death, probably modulation of gangliosides. This finding provides a possible sialidase target for diagnosis and therapy of colon cancer.

Therapeutic significance of palliative operations for gastric cancer for survival and quality of life.

Background and Objectives: There have been few reports on the objective assessment of quality of life (QOL) in patients with gastric cancer following palliative operations. The benefit of a palliative operation for survival and QOL of patients with gastric cancer is not clear.

Continuous removal of middle molecules by hemofiltration in patients with acute liver failure.

In patients with acute liver failure and hepatic coma, an increase in the abnormal “middle molecules” seen on the chromatograms of the sera is suspected of playing an etiologic role in the coma. A pilot study of continuous hemofiltration using a high-performance membrane was conducted in 16 such patients in an attempt to decrease the serum levels of the middle molecules. The procedure was used alternately with plasma exchange. High-performance liquid chromatography showed a notable removal of the substances in the filtrates and a sequential removal from the serum by hemofiltration. Eight (50%) of the 16 patients had amelioration in level of consciousness and were weaned successfully from hemofiltration. Although only three of the 16 patients survived the acute illness, 13 others lived an average of 15 days and five patients survived >3 wk. While the continuous removal of middle molecules from the serum may not reverse liver failure, this procedure used in conjunction with plasma exchange may provide a means of life support, e.g., for patients awaiting a liver transplant.

The development and extension of hepatohilar bile duct carcinoma: a three-dimensional tumor mapping in the intrahepatic biliary tree visualized with the aid of a graphics computer system

Computer‐assisted three‐dimensional (3D) reconstruction of the biliary tree including extrahepatic and intrahepatic parts was performed from surgical or autopsy materials from 12 patients with hepatohilar bile duct carcinoma in an effort to visualize three‐dimensionally the distribution of carcinoma and dysplasia. In each case, material including a hepatic lobe was reduced to serial slices 1 mm thick using a ham slicer, then the tumors, ducts with carcinoma in situ, and those with dysplasia were submitted to reconstruction. In a 3D map of the biliary tree reproduced on a display, a dysplastic zone was shown in most cases surrounding a focus of carcinoma, justifying the assumption of a dysplasia—carcinoma sequence. The carcinoma itself proved to form multiple foci along bile ducts in as many as 42% of the patients, in some of whom the foci were independent without any intervening dysplasia. These results suggest that as extensive a surgical measure as possible should be taken in designing a strategy against this tumor.

Recurrence of hepatocellular carcinoma in the liver remnant after hepatic resection

We analyzed the results of 19 patients who had intrahepatic recurrence of hepatocellular carcinoma (HCC) among 47 patients who were discharged from the hospital after having a hepatic resection in order to evaluate the factors affecting recurrence and survival. Recurrence-free survival rates were 80%, 44%, and 28% at 1, 3, and 5 years, respectively. Of the 19 patients with recurrence, 14 had multiple lesions, and 16 of the recurrences were detected within 3 years of surgery. None of the following factors correlated with recurrence: hepatic function; tumor size; presence of tumor capsule; capsular invasion; vascular invasion and intrahepatic metastasis; extent of hepatic resection; and resection with tumor-free margins. Patients having multiple recurrent HCCs, however, had larger-sized tumors at the time of resection than those with a solitary recurrence. The survival rates after recurrence were significantly better in patients with a solitary recurrence, and these patients were treated with transcatheter arterial embolization (TAE) therapy. Early detection as well as TAE for recurrent HCCs is necessary to improve long-term survival.

Histologic findings and prognostic factors in carcinoma of the upper bile duct

The histopathologic features of 34 resected carcinomas of the upper bile duct were reviewed. Patients with papillary adenocarcinoma showed a 3-year survival rate of 75 percent, which was better than those with poorly differentiated adenocarcinoma with no 2-year survivors. Infiltration to the serosa of the bile duct, lymph node metastasis, and vascular invasion were important prognostic factors, since the survival was better for the patients without than those with these factors. Among patients with papillary adenocarcinoma, none had hepatic infiltration and lymph node metastasis and most had no infiltration to the serosa. Patients with poorly differentiated adenocarcinoma, in contrast, had extensive association of those prognostic factors. Seventy-five percent of the patients with papillary adenocarcinoma and only 22 percent of patients with poorly differentiated adenocarcinoma were considered to have curative resection. These findings suggest that the histologic type strongly influenced the prognosis of the patients with carcinoma of the upper bile duct and can be used for the determination of the extent of this tumor.

Results of esophageal transection for esophageal varices: experience in 100 cases.

The results of transthoracic esophageal transection in 100 patients with esophageal varices are described. There were 11 operative deaths in this series, and the majority of patients died from hepatic failure. Esophageal varices disappeared completely in 81 percent of the patients and faded in 18 percent. Post-transection rebleeding was observed in six cases. There were 16 late deaths, caused mainly by hepatic failure and hepatoma. The 3 year and 5 year survival rates includine mortality rate, the efficacy in eliminating varices and the sufficient survival rate, it is presumed that esophageal transection is the most suitable operation for esophageal varices, even in poor risk patients.

Mitotic Index Is the Best Predictive Factor for Survival of Patients with Resected Hepatocellular Carcinoma

Background: In patients with hepatocellular carcinoma (HCC), tumor recurrence is not infrequent after resection. It is presumed that characteristics of the tumor such as cellular malignancy might influence the prognosis of the patients in association with tumor stage and radicality of the procedure. Methods: Univariate and multivariate analyses were used to retrospectively determine the clinicopathologic factors potentially related to survival in 40 patients who underwent hepatectomy for HCC. Results: In univariate analysis, tumor stage I or II, mitotic index of 4 or less/10 random high-power fields, solitary tumor, and curative resection were significantly correlated with better survival. In multivariate analysis, the mitotic index and surgical curability were independently significant variables influencing survival of patients, and the mitotic index was the best predictive factor. A highly significant correlation was found between the mitotic index and Ki-67 labeling index. Compared to tumors with a mitotic index of 4 or less, those with a mitotic index of 5 or more had a higher association with multiple tumors and advanced tumor stage, which preclude curative resection. Conclusion: Analysis of the mitotic index is quite simple, and the mitotic index could be a useful factor for predicting the long-term survival of patients with HCC following hepatic resection.

Prediction of recurrence and extratumor spread of hepatocellular carcinoma following resection

The prognosis of patients with hepatocellular carcinoma (HCC) undergoing hepatectomy depends mostly on tumor recurrence. Portal vein invasion (Vp) and intrahepatic metastasis (IM) might strongly reflect the invasiveness of HCC, but the number of patients in the present series in whom either of these factors were detected was small. In this study, we defined Vp and IM as the extratumor spread, and we focused on the relationship between recurrence in patients after hepatectomy and the extratumor spread and the mitotic activities of cancer cells, in the hope that careful monitoring of recurrence might be possible by simply analyzing histology of the resected specimens.

Palliative operation for cancer of the head of the pancreas: significance of pancreaticoduodenectomy and intraoperative radiation therapy for survival and quality of life.

Abstract. The benefits of a palliative operation and intraoperative radiation therapy (IORT) for survival and quality of life (QOL) of patients with cancer of the head of the pancreas are not clear. Survival and hospital-free survival (HFS), which are considered to be objective indicators of QOL, were studied in 13 patients who underwent palliative pancreaticoduodenectomy (PD) and 32 patients who underwent surgical bypass. Although there was no significant difference in the survival of patients who underwent PD or bypass (median survivals of 9 months and 7 months, respectively), HFS for 3 months or longer was achieved in 84.6% of the patients who underwent PD, which was significantly higher than that of the 53.1% in patients who underwent surgical bypass (p < 0.05). Among TNM stage III patients, a significant difference in survival was observed between surgical bypass associated with IORT and bypass alone (p < 0.05); the median survival time of the IORT group was 10 months, whereas that of the control group was 5 months. In addition, HFS of 3 months or longer was achieved in 83.3% of patients who underwent bypass with IORT but in only 25.0% of the patients who underwent surgery alone (p < 0.01). The addition of IORT to palliative PD neither prolonged survival nor improved HFS. These results show the beneficial effect of palliative PD on QOL, and the efficacy of IORT for survival and QOL was proved in cases with stage III pancreatic cancer who underwent surgical bypass. For patients subjected to palliative PD, however, IORT is not thought to be beneficial for either survival or QOL.