Morphometric studies in human pancreatic cancer argues against the etiological role of type 2 diabetes in pancreatic cancer.

BACKGROUND: To understand the role of islet amyloid polypeptide (IAPP) in type 2 diabetes and pancreatic cancer (PC), we investigated the patterns of its expression and its ratio to insulin, glucagon, somatostatin and pancreatic polypeptide cells by morphometry in tissues from these two diseases in comparison to the normal pancreas. MATERIALS AND METHODS: Pancreatic tissues from 11 donors (five without pancreatic disease and six with type 2 diabetes) and 11 surgical specimens from PC patients obtained from the cancer area (zone A) and the adjacent tumor-free area (zone B) were examined immunohistochemically. The size of islets, the number on beta-, alpha-, delta- pp- and IAPP-expressing cells and their ratios in the islets of these tissues were determined. RESULTS: In the normal pancreas, only 50% of the beta-cells while alpha- and delta-cells co-expressed IAPP only sporadically. In tissues from diabetics as well as in zone A, the number of the beta-cells and the IAPP-expressing cells was reduced significantly, while the number of alpha- and delta-cells was increased. In zone B, however, significantly more beta-cell and IAPP-expressing cells and a significantly lower number of alpha-cells were found compared to those in zone A. Significant differences were also found between the specimens from type 2 diabetics and pancreatic cancer relative to the ratios of IAPP/beta-cell, IAPP/alpha-cells and beta-cell/delta-cells. CONCLUSION: The morphometric data show a decrease rather than an increase in the number of IAPP-expressing cells in PC. Differences in abnormalities in type-2 diabetics and in zone B of PC tissue strongly argue against the role of type 2 diabetes in PC. Rather, the development of diabetes in subjects prone to pancreatic cancer could be a red flag for malignancy.

[Results of hepatic arterial infusion chemotherapy with 5-FU and leucovorin for unresectable liver metastases from colorectal cancer].

PURPOSE: Hepaticarterial infusional(HAI)5-FU chemotherapy, which involves the use of interventional radiology technique, has matured technically in Japan in the 1990's. The antitumor effect of 5-FU is enhanced by combination with leucovorin. This study was performed to evaluate the efficacy and toxicity of HAI 5-FU and leucovorin chemotherapy for patients with unresectable liver metastases from colorectal cancer. METHODS: Treatment was given to 20 patients with unresectable liver metastases from colorectal cancer. The chemotherapy regimen consisted of weekly HAI of 5-FU(1,000 mg/body)and leucovorin(250 mg/body)over five hours. The survival and response rates to the therapy were assessed according to RECIST. Hematologic and non-hematologic toxicity was assessed according to CTCAE v3.0. RESULTS: Combined HAI 5-FU and leucovorin therapy was carried out an average of 27 times. The response rate for liver tumors was 75%, and the median survival time was 22 months. The applied regimen caused only mild adverse events. There was no evidence of myelosuppression except for platelet decrease(grade 3)in a patient with chronic renal failure. CONCLUSION: This HAI approach using 5-FU and leucovorin was effective and the therapy for unresectable liver metastases from colorectal cancer was tolerated well. Therefore the HAI approach should be reconsidered as an effective therapy against this disease in Japan.

Distribution of pancreatic endocrine cells including IAPP-expressing cells in non-diabetic and type 2 diabetic cases.

There is a lack of agreement on the distribution of islet amyloid polypeptide (IAPP) in the pancreases of healthy and diabetic subjects. Therefore, a detailed morphometrical and immunohistochemical study was performed to obtain information on the distribution of cells expressing insulin, glucagon, somatostatin, pancreatic polypeptide (PP), and IAPP in the pancreases of non-diabetic (n=4) and diabetic individuals (n=6). In the non-diabetic cases, beta-cells contributed to approximately 64%, alpha-cells to 26%, delta-cells to 8%, PP cells to 0.3%, and IAPP cells to 34% of the islet cell population. The ratio of IAPP/insulin was approximately 1:2. In diabetic cases, beta-cells were decreased by 24%, and IAPP was decreased by 57%. The alpha- and delta-cells were increased by 40% and 58%, respectively. IAPP/insulin ratio was decreased by 41%. Thus, only 50% of the beta-cells in non-diabetics and only 30% in diabetics coexpressed IAPP. In diabetics, more delta-cells coexpressed IAPP than in non-diabetics. The results seem to argue against the notion that the secretion of IAPP is increased in diabetics. It is possible that an increase in somatostatin and glucagon plays a greater role in diabetes than IAPP.

Lower esophageal sphincter- and vagus-preserving proximal partial gastrectomy for early cancer of the gastric cardia.

PURPOSE: Proximal gastrectomy and lymph node dissection are often performed for T1 cancer of the gastric cardia; however, direct esophagogastrostomy is frequently complicated by reflux esophagitis. We describe a simple technique for preventing esophageal reflux and discuss its results. METHODS: This technique is indicated for T1 cancer of the gastric cardia without lymphadenopathy. Partial resection, including the lesion, is performed, preserving the vagus nerve and lower esophageal sphincter (LES). Lymph node dissection is done around the left gastric, celiac, and splenic arteries. The esophagus is then anastomosed to the anterior wall in the center of the remnant stomach. RESULTS: We evaluated the results of this procedure in eight patients. X-ray films showed no esophageal reflux in either the supine or the right decubitus position. None of the patients complained of reflux or other dyscrasic symptoms, and none had any feeling of microgastria. One patient had some localized erosion near the anastomosis. CONCLUSIONS: This simple and safe technique does not result in post-gastrectomy syndrome or microgastria, and the risk of leaving cancer cells is minimal.

Expression of Oct4, a stem cell marker, in the hamster pancreatic cancer model.

BACKGROUND: Oct4 has been shown to present a stem cell marker that is expressed in embryonic cells and in germ cell tumors. Recently, its expression in a few human tissues and cancer cells has been reported. Because in the hamster pancreatic cancer model most tumors develop from within islets presumably from stem cells, we investigated the expression of Oct4 in this model. METHODS: Two normal pancreases and 15 pancreatic cancers induced by N-nitrosobis(2-oxypropyl)amine (BOP) were processed for immunohistochemistry using a monoclonal Oct4 antibody at a concentration of 1:500. RESULTS: In the normal pancreas, Oct4 was expressed only in islet cells in a diffuse cytoplasmic pattern. No nuclear staining was found in any cells. In 14 of the pancreatic cancers, nuclear staining was detected in many cells or in small foci. Diffuse cytoplasmic but no nuclear staining was found in one tumor and a mixed Golgi type and nuclear staining in two cases. Nuclear staining was also identified in early intrainsular ductular and in Ca in situ lesions. CONCLUSIONS: BOP reactivates the Oct4 gene and can be considered an early tumor marker in this model.

In vitro detection of cross-resistant and non-cross-resistant agents with fluorouracil for patients with colorectal cancer.

BACKGROUND: Fluorouracil-based chemotherapy, such as that with 5-fluorouracil (5-FU)/leucovorin, is standard as first-line chemotherapy for advanced colorectal cancer (CRC) in Japan. However, the best agent for second-line chemotherapy after fluorouracil failure is yet to be determined. This study was undertaken to find an appropriate agent for second-line chemotherapy. METHODS: Seventy-five tumor specimens from CRC patients with no prior chemotherapy were obtained operatively and their chemosensitivity to five anticancer agents; i.e., 5-FU, mitomycin C (MMC), cisplatin, docetaxel, and an active metabolite of irinotecan (SN-38), was analyzed in an in vitro chemosensitivity test. In this method, the degree of chemosensitivity was expressed as the percent T/C ratio, where T was the total volume of the tumor colonies in the treated group and C was that of the control group. Pearson's correlation coefficients were used to assess the relationship between two agents. RESULTS: Fifty-eight specimens (colon, 28; rectum, 30) were successfully analyzed. Positive correlations with 5-FU chemosensitivity were verified for the chemosensitivity of MMC, cisplatin, and docetaxel. No correlation with 5-FU chemosensitivity was verified for SN-38 chemosensitivity. Although the functional mechanism of each of the agents differs from that of 5-FU, with the exception of irinotecan, they all had a spectrum closely similar to the 5-FU spectrum. CONCLUSION: Only irinotecan exhibited a spectrum independent of that of 5-FU, thus indicating that it could be an appropriate agent for second-line chemotherapy after fluorouracil failure.

Surgical oncotaxis--excessive surgical stress and postoperative complications contribute to enhancing tumor metastasis, resulting in a poor prognosis for cancer patients.

We investigated the relationship between surgical stress and tumor metastasis. The excessive surgical stress of a thoracolaparotomy enhanced tumor metastasis remarkably in an experimental model. We would like to propose that this phenomenon be termed "surgical oncotaxis". This effect has previously been attributed to some mechanisms of immunosuppression, excessive secretion of corticoids, and active oxygen production of granulocytes. An increase in lipid peroxide (LPO) in the liver was observed after a thoracolaparotomy, but a strong radical scavenger of a DL-alpha-tocopherol-L-ascorbic acid 2-0-phosphate diester (EPC-K1) restrained LPO levels in the liver and the effect of tumor metastasis in parallel. As clinical strategies for restraining the surgical oncotaxis, the control of any cytokine storm after surgery and/or the scavenging of active oxygen appears to be possible and hopeful, since it might be intermediated by cytokine. When pre-administration findings for EPC-K1 and methylpredonisolone were compared, EPC-K1 was found to be more suitable for restraining surgical oncotaxis, because serum LPO was only controlled with EPC-K1. The cytokine storm which occurs after surgery is augmented by a second stimulation, such as the administration of lipopolysaccharide, and no drug could control this well experimentally. Postoperative complications are a clinical model of a second stimulation (a so-called second attack). Our data showed the prognosis of a group with complications to be worse than that of a group without them even though no difference existed in the background of the esophageal cancer patients studied. Based on these results, safe surgery and the choice of minimally invasive surgery are the best ways to control surgical oncotaxis. Following a major surgical procedure, such as a thoracolaparotomy, the use of corticoids and/or radical scavengers can contribute to restraining surgical oncotaxis.

Detection of serum MMPs in tumor-bearing hamsters.

BACKGROUND/PURPOSE: Matrix metalloproteinases (MMPs) have been implicated as playing an important role in cancer invasion and metastasis. MMPs have been identified in various malignancies, including pancreatic duct adenocarcinomas. METHODS: We investigated the circulating level of MMP-2 and MMP-9 in sera from Syrian golden hamsters into which hamster pancreatic duct adenocarcinoma tissues had been transplanted subcutaneously (HPDt hamsters). Northern blot analysis and gelatin zymographic analysis were performed to detect the expression of MMPs and that of tissue inhibitors of metalloproteinases (TIMPs) in HPDt hamsters. RESULTS: Northern analysis revealed overexpression of MMP-2, MMP-9, and TIMP-2 mRNAs in subcutaneous tumors of HPDt hamsters as compared with normal pancreatic tissue. Sera from HPDt hamsters possessed significantly higher levels of serum MMP-2 and MMP-9 than control sera, as determined by gelatin zymographic analysis, and there was a significant correlation between tumor growth and serum MMP levels. CONCLUSIONS: These results indicate that overexpression of MMP mRNAs is involved in the progression of pancreatic duct adenocarcinomas, and that MMP protein expression in hamster sera is associated with the presence of pancreatic duct adenocarcinoma cells. The findings also suggest that serum MMPs could be useful markers for monitoring patients with pancreatic duct adenocarcinomas.