Michiyoshi Hisanaga

Prognostic significance of angiogenesis in human pancreatic cancer.

SummaryTo evaluate whether angiogenic factors are of clinical relevance to actual human pancreatic cancers, we studied the intratumoral microvessel density (IMD), and PD-ECGF, VEGF protein expression in 40 pancreatic cancers using immunohistochemistry. We also investigated PD-ECGF and VEGF gene expression using reverse transcriptase-PCR (RT-PCR). Of the 40 pancreatic cancers studied, 30 carcinomas (75.0%) were evaluated to be PD-ECGF-positive and 10 carcinomas (25.0%) were determined to be PD-ECGF-negative. In contrast, 27 carcinomas (67.5%) were evaluated to be VEGF-positive, whereas 13 carcinomas (32.5%) were VEGF-negative. VEGF gene expression was moderately associated with an increase in the IMD (r2 = 0.181, P = 0.006), but no significant relationship was found between PD-ECGF gene expression and the IMD (r2 = 0.093, P = 0.059). However, tumours with positive expression for both PD-ECGF and VEGF had a higher IMD (P = 0.027). The results of the immunohistochemistry agreed well with the results of the quantitative RT-PCR. The median survival time of the hypervascular group was significantly shorter than that of the hypovascular group (P < 0.0001). In comparing the survival according to PD-ECGF and VEGF gene expression, the median survival time of the patients with positive PD-ECGF expression was significantly shorter than those with negative PD-ECGF expression (P = 0.040). Furthermore, the median survival time of the patients with positive VEGF expression was significantly shorter than those with negative VEGF expression (P = 0.048). However, the Cox multivariate analysis indicated that the IMD and VEGF expression were independent prognostic factors of the various clinicopathologic variables in pancreatic cancer patients (P = 0.0021 and P = 0.0443, respectively).

Significant influence of accompanying chronic hepatitis status on recurrence of hepatocellular carcinoma after hepatectomy. Result of multivariate analysis.

OBJECTIVE The aim of this study was to evaluate the correlation between the histologic status of accompanying chronic hepatitis and the recurrence rate of hepatocellular carcinoma (HCC) after hepatectomy by multivariate analysis. SUMMARY BACKGROUND DATA Recent studies have suggested that a considerable number of intrahepatic recurrence of HCC after hepatectomy might be the results of metachronous multicentric hepatocarcinogenesis. The authors hypothesized that the incidence of recurrence due to metachronous multicentric hepatocarcinogenesis would depend on the histologic status of accompanying chronic viral liver disease, which is a main promoter of HCC. METHODS One hundred ten patients with HCC who underwent curative resection were studied. Histologic status of accompanying chronic hepatitis was classified into the three categories: 1) normal liver or chronic persistent hepatitis (CPH, n = 13), 2) chronic aggressive hepatitis (CAH, n = 50), and 3) liver cirrhosis (LC, n = 47). RESULTS The Cox multivariate proportional hazard model showed that the accompanying chronic viral hepatitis status (p = 0.0133), extent of hepatectomy (p = 0.0078), and number of tumors (p = 0.0475) were significantly predictive variables for recurrence-free survival. By the log-rank test, recurrence-free survival rate in patients with CPH was significantly higher than those in patients with CAH (p = 0.0005) and LC (p = 0.0075). Patients with CAH had the lowest recurrence-free survival rate (vs. LC, p = 0.028). CONCLUSIONS The results of this study indicated the significant influence of histologic activity of hepatitis on recurrence of HCC. This might support the concept of significant contribution of multicentric hepatocarcinogenesis to recurrence of HCC after hepatectomy.

Transmembrane 4 superfamily as a prognostic factor in pancreatic cancer

Several members of the transmembrane 4 superfamily (TM4SF) have been reported to be related to tumor progression and metastasis. The aims of our study were to clarify the relationship between TM4SF and pancreatic cancer and to determine the prognostic significance of TM4SF in human pancreatic cancer. The mRNA levels for MRP‐1/CD9, KAI1/CD82 and ME491/CD63, which belong to the TM4SF gene family, were evaluated in 40 resectable pancreatic adenocarcinomas using reverse transcriptase‐PCR. MRP‐1/CD9 gene expression was associated with lymph node status, and with pathological status. Moreover, MRP‐1/CD9 expression was inversely associated with histo‐pathological grading. KAI1/CD82 gene expression was inversely associated with tumor status. ME491/CD63 gene expression, however, was conserved in all pancreatic cancers. The overall survival rate for the 22 patients whose tumors had decreased MRP‐1/CD9 gene expression was strikingly lower than that for the 18 patients with MRP‐1/CD9‐positive tumors. The overall survival rate of the 15 patients who were KAI1/CD82‐positive was significantly higher than that of the 25 patients with decreased KAI1/CD82 gene expression. In a multivariate analysis using the Cox proportional hazards model, MRP‐1/CD9 and KAI1/CD82 status was found to be the most significant Int. J. Cancer (Pred. Oncol.) 79:509–516, 1998.© 1998 Wiley‐Liss, Inc.

The Membrane-Anchored Matrix Metalloproteinase (MMP) Regulator RECK in Combination with MMP-9 Serves as an Informative Prognostic Indicator for Colorectal Cancer

Purpose: RECK, a membrane-anchored regulator of matrix metalloproteinases (MMPs), is widely expressed in healthy tissue, whereas it is expressed at lower levels in many tumor-derived cell lines. Studies in mice and cultured cells have shown that restoration of RECK expression inhibits tumor invasion, metastasis, and angiogenesis. However, the clinical relevance of these findings remains to be fully documented. Here we examined the expression of RECK and one of its targets, MMP-9, in colorectal cancer tissue. Experimental Design: The RECK and MMP-9 expression levels in colorectal cancer samples from 53 patients were determined by immunohistochemical techniques. The expression level of each protein was scored, and the patients were divided into two groups based on these scores. In 33 cases, we performed gelatin zymography to estimate the degree of MMP-2 and MMP-9 activation. Microvessel density and vascular endothelial growth factor (VEGF) expression were also evaluated histologically. Results: RECK protein was detected in 30 of 53 (56.6%) specimens. Importantly, patients with tumors expressing relatively high levels of RECK (high-RECK group) had a significantly lower risk of recurrence than did patients with tumors expressing relatively low levels of RECK (low-RECK group; P = 0.011). Moreover, RECK-dominant (RECK score ≥ MMP-9 score) patients showed a significantly lower incidence of recurrence than did MMP-9-dominant patients (P = 0.0003). Multivariate analysis revealed that the RECK/MMP-9 balance was an independent prognostic factor (P = 0.0122). The expression of VEGF and microvessel density were inversely correlated with the level of RECK expression. Conclusions: RECK/MMP-9-balance is an informative prognostic indicator for colorectal cancer. Our data also suggest that RECK suppresses tumor angiogenesis, probably by limiting the availability of VEGF in tumor tissues.

A novel small-molecule compound targeting CCR5 and CXCR3 prevents acute and chronic allograft rejection.

Background. Chemokines and chemokine receptors are critical in leukocyte recruitment, activation, and differentiation. Among them, CC chemokine receptor 5 (CCR5) and CXC chemokine receptor 3 (CXCR3) have been reported to play important roles in alloimmune responses and may be potential targets for posttransplant immunosuppression. Methods. Fully major histocompatibility complex (MHC)-mismatched murine cardiac and islet transplant models were used to test the effect in vivo of a novel, small-molecule compound TAK-779 by targeting CCR5 and CXCR3 in acute allograft rejection. An MHC class II mismatched cardiac transplant model was used to evaluate its efficacy in chronic allograft rejection. Intragraft expression of cytokines, chemokines, and chemokine receptors was measured by quantitative real-time polymerase chain reaction and by histological analysis. Results. Treatment of TAK-779 significantly prolonged allograft survival across the MHC barrier in two distinct transplant models. The treatment downregulated local immune activation as observed by the reduced expression of several chemokines, cytokines, and chemokine receptors. Thereby, the recruitment of CD4, CD8, and CD11c cells into transplanted allografts were inhibited. Furthermore, TAK-779 treatment significantly attenuated the development of chronic vasculopathy, fibrosis, and cellular infiltration. Conclusions. Antagonism of CCR5 and CXCR3 has a substantial therapeutic effect on inhibiting both acute and chronic allograft rejection. CCR5 and CXCR3 are functional in the process of allograft rejection and may be potential targets in clinical transplantation in the future.

Pattern of Recurrence after Resection for Intraductal Papillary Mucinous Tumors of the Pancreas

Abstract. The objective of this study was to clarify the patterns of recurrence and prognosis after resection of intraductal papillary mucinous tumors (IPMTs). Fourteen patients with IPMT were reviewed histologically; intraductal papillary adenocarcinoma was present in 12 cases and intraductal papillary adenoma in 2. Six patients were alive with no evidence of disease. Two patients died from other causes. Six patients had recurrences. The median survival time was 46 months. In the six recurrent cases, the median postoperative disease-free interval was 38 months. Four patients died of recurrence, and the median survival time after recurrence was 6 months. The major site of recurrence was the remnant pancreas. The other sites were the liver in two cases, peritoneum in two, and local in one. These results suggest the multicentric or metachronous oncogenesis of IPMT. Because of the low frequency of lymph node metastases, an operation to preserve pancreatic function may be recommended, especially for localized tumors such as the branch type. It is important to avoid an incomplete resection using intraoperative pancreatoscopy and ultrasonography. Long-term follow-up after surgery is necessary even for a curative resection. We should perform total pancreatectomy for recurrences without distant metastases.

Indefinite islet protection from autoimmune destruction in nonobese diabetic mice by agarose microencapsulation without immunosuppression.

Background. The recurrence of autoimmunity and allograft rejection act as major barriers to the widespread use of islet transplantation as a cure for type 1 diabetes. The aim of this study was to evaluate the feasibility of immunoisolation by use of an agarose microcapsule to prevent autoimmune recurrence after islet transplantation. Methods. Highly purified islets were isolated from 6- to 8-week-old prediabetic male nonobese diabetic (NOD) mice and microencapsulated in 5% agarose hydrogel as a semipermeable membrane. Islet function was evaluated by a syngeneic islet transplantation model, in which islets were transplanted into spontaneously diabetic NOD mice. Results. The nonencapsulated islet grafts were destroyed and diabetes recurred within 2 weeks after transplantation in all 12 mice. In contrast, 13 of the 16 mice that underwent transplantation with microencapsulated islets maintained normoglycemia for more than 100 days after islet transplantation. Histologic examination of the nonencapsulated islet grafts showed massive mononuclear cellular infiltration with &bgr;-cell destruction. In contrast, the microencapsulated islets showed well-granulated &bgr; cells with no mononuclear cellular infiltration around the microcapsules or in the accompanying blood capillaries between the microcapsules. Conclusions. Agarose microcapsules were able to completely protect NOD islet isografts from autoimmune destruction in the syngeneic islet transplantation model.

Serum Interleukin-6, Interleukin-8, Hepatocyte Growth Factor, and Nitric Oxide Changes during Thoracic Surgery

Abstract. Thoracic surgery creates a different environment from abdominal surgery in respect to the surgical procedure with pulmonary collapse under unilateral ventilation. Definitive evidence whether surgical trauma during thoracotomy is involved in postoperative pulmonary infections has not been clearly demonstrated. The objectives of this study were to evaluate the influence of surgical trauma during thoracotomy on postoperative infections and to investigate the clinical significance of postoperative humoral mediators in pulmonary infections after surgery. We measured serum interleukin-6 (IL-6), IL-8, hepatocyte growth factor (HGF), and nitric oxide (NO) levels in 27 patients undergoing thoracic surgery; the measurements were before and during thoracotomy, 60 minutes after reinflation, and after surgery. The patients were divided into three groups: lobectomy patients (group A), and esophagectomy patients without (group B) or with (group C) postoperative infections. The serum IL-6 and IL-8 levels in group C were markedly elevated 60 minutes after reinflation and were significantly higher than those in group A. The serum IL-8 levels during that period in group C were significantly higher than those in group B. The postoperative serum IL-6, IL-8, HGF, and NO levels were significantly higher in group C than in group B. Taken together, intraoperative hypercytokinemia, especially IL-8, following the thoracic procedure and subsequent reinflation preceded the clinical onset of postoperative infections. Hence postoperative serum IL-6, IL-8, and HGF levels may be useful predictors of infection after esophagectomy.

Repeat liver resection for hepatocellular carcinoma

BACKGROUND Although hepatectomy has been accepted as a therapeutic option for the primary tumor of hepatocellular carcinoma (HCC), what role the second liver resection will play in the clinical care of patients with intrahepatic recurrence of HCC after the initial resection has not been well evaluated. STUDY DESIGN In a retrospective review of the 6-year period between January 1991 and December 1996, records were examined of 94 patients who underwent curative liver resection for HCC. Of these, 57 patients had isolated recurrent disease to the liver; 12 of the 57 patients underwent repeat surgical resection and 45 patients received nonsurgical ablative therapy. Clinical data for these patients were reviewed for operative morbidity and mortality, survival, disease-free survival, and pattern of failure. RESULTS There were no perioperative deaths during repeat liver resections for recurrent HCC. Operative morbidity in the second resection was comparable to the initial resection. The disease-free survival rate after the second hepatectomy was 31% at 2 years, significantly lower than that after initial hepatectomy (62%) (p = 0.009). The overall survival rate after the second hepatectomy was 90% at 2 years, in contrast to 70% after nonsurgical ablative treatment for recurrent HCC (p = 0.253). CONCLUSIONS Although the second liver resection for recurrent HCC can be performed safely and may improve survival, the disease-free survival rate after such resection therapy is low. This likelihood of further recurrences encourages studies for the selection of patients who may benefit from repeat liver resection.

Analysis of risk factors for the development of gallstones after gastrectomy

The incidence of gallstones is higher in people who have undergone gastrectomy than in the general population, but the cause of this is unknown.