Hideki Ura

Lack of Survival Benefit of Extended Lymph Node Dissection for Ductal Adenocarcinoma of the Head of the Pancreas: Retrospective Multi-institutional Analysis in Japan

Abstract. It has not been established that extended lymph node resection is necessary for ductal adenocarcinoma of the head of the pancreas. According to the general rules for the study of pancreatic cancer, a multiinstitutional, retrospective clinical study was undertaken to investigate the efficiency of extended lymph node dissection for this malignancy. Altogether 501 patients underwent resection of the pancreas between 1991 and 1994 at 77 medical facilities; the surgical procedures, staging, lymph node dissection, curability, and survival rate were analyzed retrospectively. Eighteen of the patients died within 30 postoperative days, leaving 483 patients to be studied. The resection was curative microscopically in 94 patients, resulting in a 3-year survival of 29%. Macroscopically curative resection resulted in a 3-year survival of 14%; noncurative resection produced a 3-year survival of 6%. Although extended lymph node dissection was performed on 38 patients in stage I, 42 patients in stage II, 206 patients in stage III, and 1 patient in stage IV, there was no improvement in survival when the results were compared to those seen after standard or palliative lymph node dissection. The extent of lymph node dissection has not affected the prognosis for ductal adenocarcinoma of the head of the pancreas at any stage of the course of the disease. Excessive lymph node dissection in advanced cases does not necessarily lead to a favorable prognosis. The patients who undergo a radical operation with an adequate lymph node dissection have longer survivals.

Separate functions of α2β1 and α2β1 integrins in the metastatic process of human gastric carcinomaintegrins in the metastatic process of human gastric carcinoma

The expression of α2β1 and α3β1 integrins was studied immunohistochemically in 110 resected human gastric carcinomas. Formalin-fixed and paraffin-embedded samples were serially sectioned and stained with monoclonal antibodies specifically against the α2 and α3 subunits of β1 integrins. Approximately 27% of the tumors expressed α3β1 integrin, and 20% expressed α3β1 integrin. The expression of α3β1 integrin was associated with lymph node and liver metastases (P<0.05 andP<0.05, respectively), and the expression of α3β1 integrin was associated with liver and peritoneal metastases (P<0.005 andP<0.0005, respectively). A multivariate analysis by the logistic regression model revealed that the expression of α3β1 and/or α3β1 integrins was an independent factor related to liver metastasis, and that the expression of α3β1 integrin was as strong an influence on the formation of peritoneal metastases as the depth of invasion. The expression of α3β1 integrin also correlated with increased invasiveness of the tumor; however, there was no correlation between α2β1 integrin expression and the invasiveness. These results suggest that α2β1 and α3β1 integrins have separate influences on the metastatic properties of cancer cells.

Carcinoma arising from ectopic pancreas in the stomach: Endosonographic detection of malignant change

We present a case of a submucosal tumor in the stomach that was suspicious for malignancy on preoperative endosonography. The resected tumor was histologically diagnosed as a ductal adenocarcinoma that originated in ectopic pancreatic tissue in the gastric wall. Although malignant transformation in ectopic pancreas is extremely rare, it remains an important consideration in the differential diagnosis of gastric submucosal masses.

Establishment and Characterization of Human Gastric Carcinoma Lines with High Metastatic Potential in the Liver: Changes in Integrin Expression Associated with the Ability to Metastasize in the Liver of Nude Mice

There is a need to establish animal models which are suitable for investigation of human gastric cancer metastasis to the liver. To this end, a human gastric carcinoma line, AZ521 was injected into the spleens of nude mice. Cells from the few liver metastatic foci of injected AZ521 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these procedures three times, we were able to obtain a cell line, designated as AZ‐M3c, with high metastatic potential in nude mice. Liver metastasis developed in 15 of 21 (71%) animals injected with AZ‐H3c, but in only 14% of those injected with parental AZ521. Further, AZ‐H3c caused faster tumor development than did AZ521. However, the primary AZ‐H3c tumors and liver metastatic AZ‐H3c tumors showed essentially the same histological appearance. We also analyzed the cell surface expression of adhesion molecules. The data showed that the expression of VLA‐1, VLA‐2, VLA‐3, VLA‐4, VLA‐5 was enhanced in AZ‐H3c. In contrast, the expression of VLA‐6, αvβ3, E‐cadherin, ICAM‐1 and LFA‐1 was reduced in this high‐metastatic line. These results suggest that β1 mtegrins play an important role in the liver metastasis of human gastric carcinoma cells. Our high‐metastatic line should be useful for studies aimed at the prevention of liver metastasis.

Septic Thrombophlebitis of the Portal and Superior Mesenteric Veins as a Complication of Appendicitis: Report of a Case

Pylephlebitis is extremely rare and associated with high mortality, even in this modern era. It usually occurs secondary to infection in the region drained by the portal systems or in the structure contiguous to the portal vein. We report a case of septic thrombophlebitis of the portal and superior mesenteric veins (SMV) with multiple liver abscesses caused by acute appendicitis with an abscess of the mesoappendix. We performed appendectomy and successfully removed the thrombi using a Fogarty catheter. Postoperative histopathological examination confirmed a diagnosis of appendicitis and septic thrombophlebitis of the portal vein and SMV. The patient recovered completely with appropriate medical and surgical treatment.

Surgical influence on Th1/Th2 balance and monocyte surface antigen expression and its relation to infectious complications

Malignancy and operation for it cause several alterations in immune function that are considered to be concerned with the development of infectious complications. Forty-three patients who underwent curative surgery for gastrointestinal malignancies were entered into this study and were divided into two groups, those with and those without postoperative infection. Changes in the proportion of Th1/Th2 subsets in CD4+ T cells and the expression of human leukocyte antigen (HLA)-DR and CD16a molecules on monocytes were measured by flow cytometry before and after surgery. We performed intracellular cytokine stainings to exactly detect Th1/Th2 subsets. The proportions of interferon-γ-producing CD4+ T (Th1) cells in the preoperative state were almost equal in the two groups, and the proportion decreased on postoperative day (POD) 1 in both groups. On POD 7, the proportion of Th1 cells recovered to the preoperative level in the noninfection group, while the suppression was further reinforced in the infection group (26.8% versus 18.3%, p < 0.005). In contrast, the proportion of interleukin-4-producing CD4+ T (Th2) cells in the infection group (11.3%) was already suppressed in the preoperative state when compared with the noninfection group (17.3%, p < 0.005). Changes in HLA-DR and CD16a expression on monocytes were similar to the changes in the proportion of Th1 cells. These results indicate that the suppression of Th1 cell and monocyte functions during the early phase of the postoperative course was directly related to the occurrence of infectious complications and that several immunological impairments have already occurred in the preoperative state in cancer patients.

Close Correlation between Increased Sialyl-Lewisx Expression and Metastasis in Human Gastric Carcinoma

Abstract. Expression of sialyl-Lewis x (sLe x ) antigen was studied immunohistochemically in 110 resected human gastric carcinomas using an anti-sLe x monoclonal antibody. Lymph node, liver, and peritoneal metastases were clearly more prevalent in tumors expressing high levels of sLe x than in those with no or low-level sLe x expression. No correlation was found between sLe x expression and histologic grade or histologic type of the Lauren classification. Among the tumors with lymph node metastasis, 44% expressed high levels of sLe x in both the primary tumor and involved lymph nodes, and 14% of the metastatic lesions demonstrated increased sLe x expression. The 5-year survival rate of the patients undergoing complete (R0) gastric resections was 60% in the sLe x high-expression group, which was significantly lower than that of the sLe x low-expression group (81%) and of the no-expression group (87%) (p < 0.05). These results suggest that high-level sLex expression is related to both an increased risk of metastasis and poor prognosis in gastric cancer patients.

A Novel Experimental Mouse Model of Peritoneal Dissemination of Human Gastric Cancer Cells: Different Mechanisms in Peritoneal Dissemination and Hematogenous Metastasis

We established a new cell line, AZ‐P7a, with high peritoneal‐metastatic potential in nude mice. AZ‐P7a cells were derived from the human gastric carcinoma line AZ‐521, which has low capacity for peritoneal dissemination. AZ‐P7a cells developed peritoneal metastasis in 11/14 (78.6%) mice, whereas the parental AZ‐521 cells developed metastasis in 2/6 (33.3%) mice. The metastatic foci in the peritoneum showed essentially the same histological appearance as those induced by parental cells. The tumorigenicity and the motile activity of AZ‐P7a cells were stronger than those of the parental AZ‐521 cells; in contrast, adhesion to the extracellular matrix and the production of vascular endothelial growth factor by AZ‐P7a cells were decreased. In fluorescence‐activated cell sorter (FACS) analysis, AZ‐P7a cells expressed significantly greater levels of integrins α2, α3, α5, α6 and αvβ5, as compared with AZ‐521 cells. However, α1, α4, αvβ3, hCD44H, hCD44v3, hCD44v6 and hCD44v10 were not expressed in either cell line. AZ‐P7a cells developed no liver metastasis when administered by the intrasplenic injection method, though the highly liver metastatic cell line AZ‐H5c showed the same rate of peritoneal dissemination as that exhibited by AZ‐P7a cells after intraabdominal injection. These findings suggested that the mechanism of peritoneal dissemination differed from that of hematogenous metastasis. Moreover, the latter appears to be controlled by more complex mechanisms than the former. Thus, this cell line might be useful for investigating the mechanism of peritoneal dissemination of human gastric cancer.

Establishment and characterization of human pancreatic carcinoma lines with a high metastatic potential in the liver of nude mice.

To investigate of human pancreatic cancer metastasis to the liver, a pancreatic carcinoma line, HPC-3, was injected into the spleens of nude mice. The cells from a few liver metastatic foci of the mice injected with HPC-3 were expanded in vitro and subsequently injected into the spleens of nude mice. By repeating these procedures, we were able to obtain a cell line, designated HPC-3H4. The mice were observed to have liver metastasis in 6 of 6 (100%) cases injected with HPC-3H4, whereas the rate was 0% at 3 weeks after the intrasplenic injection of HPC-3. The tumorigenicity of HPC-3H4 was more rapid than that of HPC-3. The motile activity of HPC-3H4 was also stronger than that of HPC-3, and the adhesion to the extracellular matrix of HPC-3H4 was stronger than that of HPC-3. We also analyzed the cell surface expression of the metastasis-related adhesion molecules. As a result, no substantial changes were observed in the expression level of adhesion molecules. These results suggest that HPC-3H4 is useful for studies aimed at the prevention of liver metastasis.

Liver Metastatic Model for Human Gastric Cancer Established by Orthotopic Tumor Cell Implantation

Abstract. We have established an orthotopic implantation model that is highly metastatic to the liver. A human gastric carcinoma cell line, AZ521, with low capacity for liver metastasis was implanted as a single-cell suspension in the stomach of nude mice. The tumor cells derived from a few liver metastatic foci were subsequently implanted orthotopically, and we established a cell line, AZH5G, by repeating the in vivo stepwise selection method. This metastasizing line (AZH5G) developed liver metastasis in seven of eight (87.5%) cases, whereas parental AZ521 developed in 3 of 20 (15.0%). The in vitro growth activities of AZH5G were lower than that of AZ521, although the in vivo tumorigenicity of AZH5G was clearly higher than that of AZ521. Motility assays demonstrated higher motility of AZH5G than of AZ521. Flow cytometric analysis demonstrated that the expression of α6-integrin significantly decreased in AZH5G (4.9% ± 4.1%) compared to in AZ521 (17.7% ± 8.1%) (p < 0.05). The adhesive activity of AZH5G cells to laminin was lower than that of AZ521 cells. In contrast, the adhesive activity of AZH5G cells to fibronectin was clearly higher than that of AZ521 cells. These findings suggested that changes in the expression of integrins on the cell surface might play an important role in metastatic ability. This well characterized line and its in vivo experimental model should be useful to investigate the mechanisms of liver metastasis and to develop a new therapeutic approach for human gastric cancer.