Toshiyuki Moriya

Phosphorylated Akt/PKB controls cell growth and apoptosis in intraductal papillary-mucinous tumor and invasive ductal adenocarcinoma of the pancreas.

Introduction Akt/PKB promotes cell proliferation and rescues cells from apoptosis. Aim To evaluate the role of Akt/PKB, a key molecule in phosphatidylinositol 3-OH kinase (PI3K) signaling, during the development of pancreatic duct neoplasias such as intraductal papillary–mucinous tumor (IPMT) and invasive ductal adenocarcinoma (IDAC) of the pancreas. Methodology and Results In PK-45H pancreatic cancer cells, the growth-inhibitory and apoptosis-inducing effects of LY294002, a PI3K inhibitor, were detected in a concentration-dependent manner, followed by the reduction of phosphorylated Akt levels. Immunohistochemical analyses revealed that frequent overexpression of phosphorylated Akt (Ser473) was detected in 10 (63%) of 16 IPMTs and 14 (70%) of 20 IDACs. It is interesting that the incidence of Akt phosphorylation closely correlated with Ki-67 immunoreactivity and had an inverse association with the number of cases of apoptotic bodies in both IPMT and IDAC. Although there was no good correlation with other clinicopathologic parameters, the two patients with recurrent IPMT had high levels of phosphorylated Akt. Conclusion Our findings suggest that activation of Akt plays an important role during the progression of these pancreatic duct neoplasias at the early stage. Furthermore, inhibition of the PI3K–Akt/PKB pathway may have therapeutic potential in the treatment of pancreatic duct tumors.

Spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein: techniques and its significance.

BackgroundPreservation of the spleen in distal pancreatectomy has recently attracted considerable attention. Since our first trial and success with spleen-preserving distal pancreatectomy with conservation of the splenic artery and vein for tumors of the pancreas and chronic pancreatitis, this procedure (Kimura’s procedure) has been performed very frequently.MethodsThe techniques for spleen-preserving distal pancreatectomy (SpDP) with conservation of the splenic artery and vein are clarified. The splenic vein is identified behind the pancreas and within the thin connective tissue membrane (fusion fascia of Toldt). The connective tissue membrane is cut longitudinally above the splenic vein. It is important to remove the splenic vein from the pancreas by working from the body of the pancreas toward the spleen (median approach), because it is very difficult to remove it in the other direction. The pancreas is removed from the splenic artery by proceeding from the spleen toward the head of the pancreas.ResultsPreservation of the spleen offers various advantages. The maximum platelet levels in blood serum are significantly lower in postoperative patients with splenic preservation than in those with splenectomy. The platelet count was maximal on postoperative day 10 in the 16 patients with SpDP and the count was maximal on postoperative day 13 in the 16 patients with distal pancreatectomy with splenectomy (DPS), and there was a smaller increase in the patients with SpDP than in the patients with DPS. Postoperative bleeding from an ablated splenic artery and vein in SpDP has not been encountered. Either DPS or spleen preservation without preservation of the splenic artery and vein may reduce the blood supply to the residual proximal stomach after distal gastrectomy, which is different from the findings in the Kimura procedure.ConclusionIn SpDP, a very slight elevation of the platelet count in serum may help to prevent infarction of the lungs and brain compared to DPS. Another advantage of SpDP performed according to our procedure is that the blood supply to the proximal stomach is conserved in patients with SpDP who undergo distal gastrectomy with resection of the left gastric artery. Benign lesions, as well as low-grade malignancy of the body and tail of the pancreas, may be indications for this procedure. Surgeons should know the techniques and significance of SpDP with conservation of the splenic artery and vein, which is a very safe and reliable method.

Intraductal Papillary-mucinous Neoplasms of the Gastric and Intestinal Types May Have Less Malignant Potential Than the Pancreatobiliary Type

Objectives: Intraductal papillary-mucinous neoplasms (IPMNs) of the pancreas are classified into 4 types-gastric, intestinal, pancreatobiliary, and oncocytic-on the basis of their morphology and immunohistochemistry. We classified IPMNs at our institute and used this classification to determine the clinicopathological features, prognosis, and malignant potential of the 4 types. Methods: Sixty-one patients with IPMN who underwent surgery between 2000 and 2007 were evaluated retrospectively. Results: There were 24 tumors of the gastric type, 22 intestinal, 12 pancreatobiliary, and 3 oncocytic. Patients with the intestinal or gastric type had a better prognosis than those with the pancreatobiliary type. The intestinal and pancreatobiliary types had almost the same frequencies of carcinoma, but the intestinal type tended to have a lower frequency of invasive carcinoma than the pancreatobiliary type. Patients with invasive carcinomas derived from intestinal-type IPMNs tended to have a better prognosis than those whose invasive carcinomas were derived from the pancreatobiliary type. Conclusions: Intraductal papillary-mucinous neoplasm of the gastric and intestinal types may have less malignant potential than that of the pancreatobiliary type. Invasive carcinomas derived from intestinal-type IPMNs may be less invasive and slower growing than those derived from the pancreatobiliary type.

Pancreatic schwannoma: Case report and an updated 30-year review of the literature yielding 47 cases

Pancreatic schwannomas are rare neoplasms. Authors briefly describe a 64-year-old female patient with cystic pancreatic schwannoma mimicking other cystic tumors and review the literature. Databases for PubMed were searched for English-language articles from 1980 to 2010 using a list of keywords, as well as references from review articles. Only 41 articles, including 47 cases, have been reported in the English literature. The mean age was 55.7 years (range 20-87 years), with 45% of patients being male. Mean tumor size was 6.2 cm (range 1-20 cm). Tumor location was the head (40%), head and body (6%), body (21%), body and tail (15%), tail (4%), and uncinate process (13%). Thirty-four percent of patients exhibited solid tumors and 60% of patients exhibited cystic tumors. Treatment included pancreaticoduodenectomy (32%), distal pancreatectomy (21%), enucleation (15%), unresectable (4%), refused operation (2%) and the detail of resection was not specified in 26% of patients. No patients died of disease with a mean follow-up of 15.7 mo (range 3-65 mo), although 5 (11%) patients had a malignancy. The tumor size was significantly related to malignant tumor (13.8 ± 6.2 cm for malignancy vs 5.5 ± 4.4 cm for benign, P = 0.001) and cystic formation (7.9 ± 5.9 cm for cystic tumor vs 3.9 ± 2.4 cm for solid tumor, P = 0.005). The preoperative diagnosis of pancreatic schwannoma remains difficult. Cystic pancreatic schwannomas should be considered in the differential diagnosis of cystic neoplasms and pseudocysts. In our case, intraoperative frozen section confirmed the diagnosis of a schwannoma. Simple enucleation may be adequate, if this is possible.

Biological similarities and differences between pancreatic intraepithelial neoplasias and intraductal papillary mucinous neoplasms

AbstractBackground: Ever since the classification of pancreatic intraepithelial neoplasia (PanIN) was published, studies on the precursor lesions of pancreatic cancer have been advancing along a new directions, using standardized terminology. There are few studies that have examined the biological differences between PanIN and intraductal papillary mucinous neoplasm (IPMN) in detail. Aims: PanIN and IPMN, which are similar in morphology, were compared using various indicators, with the aim of identifying the similarities and differences between the two. Methodology: A total of 46 PanINs and 37 ducts with IPMN were identified in 19 patients with invasive ductal carcinoma and 18 patients with IPMN. These PanINs and IPMNs were examined immunohistologically with respect to the expression patterns of HER2/neu, DPC4/Smad4, Akt/PKB, p53, cyclin A, Ki67, MUC1, and MUC2. Results: Significant differences in the expression of MUC1 and MUC2 were observed between IPMN-adenoma and PanIN-2 and between CIS and PanIN-3 (MUC1: p=0.001 and p=0.005, respectively; MUC2: p=0.002 and p<0.001, respectively). A significant difference in the p53 expression level was also observed between CIS and PanIN-3 (p=0.015). Conclusions: In both IPMN and PanIN, the grade of atypism increased with increasing expression of HER2/neu, DPC4/Smad4, and Akt/PKB, along with progression in the process of multistage carcinogenesis. Although the expression levels of these factors reflected the grade of atypism, they did not reflect any differences in the grade of biological malignancy between IPMN and PanIN. On the other hand, MUC1 and MUC2 may serve as indicators of the direction of differentiation, i.e., either progression to IDAC or IPMN. Positivity for MUC1 was believed to suggest differentiation into IDAC, and positivity for MUC2 appeared to be indicative of differentiation into IPMN. Such indication of the direction of differentiation seemed to appear in PanIN1-2, even before abnormalities of HER2/neu, Akt/PKB, DPC4/Smad4, p53, and cyclin A expression began to be detected.

Expression of MUC5AC and MUC6 in invasive ductal carcinoma of the pancreas and relationship with prognosis.

Aim/Background. MUC5AC and MUC6 are two major types of mucin that are abundantly present in the stomach; both of them form a gel of high viscosity that provides protection and lubrication. Expressions of MUC5AC and MUC6 are seen in pancreatic neoplasms, whereas the relationships between MUC5AC/MUC6 expression and clinicopathological factors and patient prognosis in invasive ductal carcinoma (IDC) of the pancreas have not been investigated. The aim of this study was to investigate MUC5AC and MUC6 expressions in IDC with special reference to clinicopathological factors and patient prognosis.Methods. Tissue samples were taken from 33 patients with IDC of the pancreas after radical surgical treatment. MUC5AC and MUC6 expressions were examined immunohistochemically.Results. The expressions of MUC5AC and MUC6 were observed in the cytoplasm of the tumor cells. MUC5AC and MUC6 immunoreactivities in the cancer tissues were found in 21 (63.6%) and 15 (45.5%) of 33 cases of IDC of the pancreas, respectively. MUC5AC-negative expression was associated significantly with lymphatic invasion, venous invasion, lymph node metastasis, and MUC5AC-positive patients showed significant better survival than those MUC5AC-negative patients. MUC6 expression was significantly related to tumor location, whereas MUC6 expression did not show significant relationship with patient survival.Conclusion. The results indicate that MUC5AC expression plays an important role in impacting tumor progression in IDC of the pancreas. MUC5AC expression is a benefit to better survival of patients with IDC of the pancreas. MUC6 expression is not involved in tumor progression in IDC of the pancreas.

Intrahepatic micrometastases around liver metastases from gastric cancer

BACKGROUND/PURPOSE We aimed to clarify the association between the presence of micrometastases around liver metastases from gastric cancer and the results of hepatic resection. In addition, we investigated the influence of E-cadherin and matrix metalloproteinase (MMP)-7 expression on the development of micrometastases. METHODS Micrometastases around liver metastases were examined microscopically in 31 metastatic liver tumor specimens resected from 17 patients who had undergone hepatic resection for liver metastases from gastric cancer. E-cadherin and MMP-7 expression in the primary gastric tumor, the liver metastases, and the micrometastases were examined immunohistochemically. RESULTS Hepatic micrometastases were present in around 48% of the liver metastases, accounting for 59% of the patients. The tumor recurrence rate in the remnant liver after hepatic resection was significantly higher, and survival significantly poorer, in patients with such micrometastases than in those without. Micrometastases tended to appear around the liver metastases that had reduced E-cadherin expression. Most of the micrometastases in the lymph ducts and sinusoids showed reduced E-cadherin expression. MMP-7 expression was not correlated with the presence of micrometastases. CONCLUSIONS About half of the hepatic metastases from gastric cancer had seeded off micrometastases, and the presence of these micrometastases was associated with a poorer result of hepatic resection. Reduced E-cadherin expression in metastatic liver tumors may be associated with the development of micrometastases.

Histopathological study of intraductal papillary mucinous tumor of the pancreas: special reference to the roles of Survivin and p53 in tumorigenesis of IPMT.

AbstractAim. In this study, we investigated the tissue expression of Survivin, p53, and Bcl-2 in intraductal papillary-mucinous tumor (IPMT) of the pancreas to identify their roles in tumorigenesis of IPMT, and examined their correlations with tumor cell apoptosis and proliferation in IPMT. The diagnostic values of the expression of Survivin, p53, and Bcl-2 and the apoptotic index (AI) and Ki-67 labeling index (Ki-67 LI) in IPMT were also examined. Methods. Twenty-two lesions from 17 patients with IPMT, including 12 benign (IPMT Adenoma) and 10 malignant (IPMT Carcinoma In Situ [CIS] (n=4) and Invasive IPMT (n=6) lesions, were immunostained for Survivin, p53, Bcl-2 and Ki-67. The apoptotic cells were detected by the Apop Tag® In Situ Oligo Ligation (ISOL) method. Results. The immunoreactivities for Survivin and p53 significantly increased in the transition from IPMT Adenoma to IPMT CIS (p<0.05 for both). This transition was associated with a significant decrease in tumor cell apoptosis (p<0.001). The expression of Survivin was significantly associated with AI in IPMT (p<0.01), but not with Ki-67 LI. The expressions of Survivin and p53, and AI and Ki-67 LI were also significantly different between benign IPMT and malignant IPMT. Bcl-2 was not expressed in IPMT. Conclusion. These results suggest that Survivin and p53 may play important roles in the transition from IPMT Adenoma to IPMT CIS. This transition is accompanied by a significant decrease in tumor cell apoptosis. Survivin is significantly associated with the change in AI in IPMT. The immunohistochemical detection of Survivin and p53 as well as the determination of the AI and Ki-67 LI have useful roles in the diagnosis of IPMT.

Postoperative hematological changes after spleen-preserving distal pancreatectomy with preservation of the splenic artery and vein.

Background: The aim of this study was to determine the early postoperative hematological changes after spleen-preserving distal pancreatectomy (SpDP) with preservation of the splenic artery and vein (PSAV). Methods: We reviewed 53 patients who underwent SpDP with PSAV (n = 21) or distal pancreatectomy with splenectomy (DPS; n = 32) for benign or low-grade malignant lesions between July 1998 and June 2010. Red and white blood cell (WBC) count, platelet count, serum hemoglobin, hematocrit, C-reactive protein, albumin level, and clinical factors were compared between the SpDP with PSAV and DPS. Results: There were no significant differences in the patient characteristics between the two groups. Platelet count on postoperative day (POD) 5 and WBC count on POD 3 were significantly higher in the DPS group, and these differences continued to be significant until the 3rd month after surgery. Serum hemoglobin and hematocrit in the 1st month after surgery were also significantly higher in the SpDP with PSAV group. Conclusion: The hematological benefits of SpDP with PSAV include reduction of postoperative hematological abnormalities in the early postoperative phase and recovery of the serum hemoglobin and hematocrit levels in the early postoperative phase.

Clinicopathologic study of the MIB-1 labeling index (Ki67) and postoperative prognosis for intraductal papillary mucinous neoplasms and ordinary ductal adenocarcinoma.

Objectives Intraductal papillary mucinous neoplasms (IPMNs) are pathologically classified as IPMN with low- or intermediate-grade dysplasia, IPMN with high-grade dysplasia, and IPMN with an associated invasive carcinoma. A stepwise carcinogenic pathway has been considered for IPMN. However, it is not obvious when surgical resection should be performed for IPMN. Methods We studied the MIB-1 labeling index in cases of IPMN and ordinary ductal adenocarcinoma (ODA). Moreover, IPMN with an associated invasive carcinoma was divided into 2, namely, carcinoma in situ and invasive components, and the respective MIB-1 labeling indexes were examined. Results The MIB-1 labeling index for IPMN with low- or intermediate-grade dysplasia (1.8%) was significantly lower than those for IPMN with high-grade dysplasia (14.2%), both the carcinoma in situ components (23.1%) and invasive components (19.2%) within the IPMN with an associated invasive carcinoma, and ODA (19.5%; P < 0.0001). The 5-year survival rates after resection were 100% for IPMN with low- or intermediate-grade dysplasia, 83.3% for IPMN with high-grade dysplasia, 53.8% for IPMN with an associated invasive carcinoma, and 10.3% for ODA. Conclusions MIB-1 might be useful for the classification of malignant potential in IPMN. Intraductal papillary mucinous neoplasm should be surgically resected when the tumor is diagnosed as IPMN with high-grade dysplasia.