Masao Kobari

The mucus‐hypersecreting tumor of the pancreas. Development and extension visualized by three‐dimensional computerized mapping

Background. Mucus‐hypersecreting tumor of the pancreas appears as dilated ducts and cystic spaces filled with mucus. To determine where such tumors arise and how they extend, computer‐aided three‐dimensional reconstruction was done of the ductal system. This also was used to visualize the spatial relationships among epithelial hyperplasia, dysplasia, and carcinoma in situ (CIS).

Comparative Phenotypic Studies of Duct Epithelial Cell Lines Derived from Normal Human Pancreas and Pancreatic Carcinoma

We have investigated the mRNA/protein expression of several tyrosine kinase receptors, growth factors, and p16INK4A cyclin inhibitor in cell lines derived from normal human pancreatic duct epithelium (HPDE) and compared them with those of five pancreatic ductal carcinoma cell lines. Cultured HPDE cells express low levels of epidermal growth factor receptor (EGFR), erbB2, transforming growth factor (TGF)-alpha, Met/hepatocyte growth factor receptor (HGFR), vascular endothelial growth factor (VEGF), and keratinocyte growth factor (KGF). They also expressed high levels of amphiregulin but did not express EGF and cripto. The expression levels were similar in primary normal HPDE cells and those expressing transfected E6E7 genes of human papilloma virus-16, but their immortalization appeared to enhance the expression of EGFR and Met/HGFR. In comparison, pancreatic carcinoma cell lines commonly demonstrated overexpression of EGFR, erbB2, TGF-alpha, Met/HGFR, VEGF, and KGF, but they consistently showed marked down-regulation of amphiregulin mRNA expression. In contrast to all carcinoma cell lines that showed deletions of the p16 gene, HPDE cells consistently demonstrated normal p16 genotype and its mRNA expression. This is the first report that compares the phenotypic expression of cultured pancreatic ductal carcinoma cells with epithelial cell lines derived from normal human pancreatic ducts. The findings confirm that malignant transformation of human pancreatic duct cells commonly results in a deregulation of expression of various growth factors and receptors.

Frequent gain of copy number on the long arm of chromosome 20 in human pancreatic adenocarcinoma.

We have used comparative genomic hybridization (CGH) to survey genomic regions with aberrant copy numbers of DNA sequences in pancreatic adenocarcinoma. In 12 cell lines and 6 primary tumors from 18 patients with pancreatic adenocarcinomas, highly frequent losses (>60%) were observed on chromosome arms 6q, 9p, and 18q and the Y chromosome. Moderately frequent losses (40–60%) were observed on chromosome arms 3p, 4q, 8p, and 21q. Interestingly, these samples showed extremely high frequencies of increases in copy numbers of DNA sequences on the long arm of chromosome 20 (15/18, 83%). We further analyzed five cell lines by fluorescence in situ hybridization (FISH) with probes on chromosome 20 to define the increase in copy number more accurately, and we found that 20q was increased to between 5 and 8 copies per cell. These results suggest the existence of an oncogene or oncogenes on 20q that play a role in the development and/or the progression of pancreatic carcinogenesis. Genes Chromosom. Cancer 19:161–169, 1997.

Mode of progression of intraductal papillary-mucinous tumor of the pancreas: analysis of patients with follow-up by EUS

BackgroundWe investigated the mode of progression of intraductal papillary-mucinous neoplasm of the pancreas (IPMN) in patients who underwent follow-up in order to elucidate the characteristics of malignancy and to establish an effective treatment strategy.MethodsFifty-one patients with IPMN (branch-duct type, 47; main-duct type, 4) who had undergone follow-up study by endoscopic ultrasonography (EUS) were included (mean follow-up duration, 41.0 ± 32.3 months; average number of EUS examinations performed during follow-up, 4.4). Chronological changes in EUS findings and histological findings of resected specimens were evaluated.ResultsOf the patients with the branch-duct type, only 2% showed enlargement of the dilated branches. In the main-duct-type group, an increase in size of the main pancreatic duct (MPD) was observed in 75% of the patients. In 14 patients with papillary protrusions, an increase in size and lateral spread was observed in 71% and 43%, respectively. No patients developed invasive cancer. In 15 patients who had thick septum-like structures (TSS), the development of papillary protrusions and that of invasive cancer were observed in 53% and 13%, respectively. Twenty-nine patients who had thin septum-like structures showed no change. Two patients with dense multilocular large cysts and TSS developed invasive cancer without change in the cystic lesions. One patient developed carcinoma with multifocal stromal invasion.ConclusionsPatients with branch-duct type IPMNs without papillary protrusions or TSS are not immediate candidates for surgery. Those who have small papillary protrusions have a benign course. It is recommended that patients with the large branch-duct type with TSS should undergo surgery. Attention should be paid to the entire pancreas when performing follow-up examinations in patients with branch-duct type IPMN, as invasive ductal adenocarcinoma can develop at a site in the pancreas different from that of the IPMN.

The time of occurrence of liver metastasis in carcinoma of the pancreas

SummaryBy measuring the doubling time of liver metastasis, the authors investigated the possibility of occult liver metastasis at the time of pancreatectomy in patients with pancreatic carcinoma. We calculated tumor doubling times of liver metastases in six patients after pancreatectomy for periampullary carcinoma and compared with cell doubling times. We also calculated the diameters of the occult liver metastases at the time of pancreatectomy on the assumption that the growth rates of liver metastasis were constant. Tumor doubling times of liver metastases in six patients were 34, 32, 318, 108, 78, and 27 d, respectively. In two of these patients, tumor doubling times, compared with cell doubling times of 51 and 52 h for PK-36 and PK-59 established from the same patients with carcinoma of the pancreas, were about 15 times as long as those of cultured cell lines. The calculated sizes of the occult liver metastases at the time of pancreatectomy in these six patients were 2.4, 0.14, 19.0, 8.2, 3.5, and 4.2 mm. In five of these six patients, the calculated sizes were in the range between 10 μm and 1 cm. These results indicated occult liver metastases had already existed in patients with carcinoma of the pancreas at the time of pancreatectomy and were too small to be detected by imaging technique. We cannot improve survival rates in carcinoma of the pancreas by surgical management alone. For further improvement in survival rate of patients with carcinoma of the pancreas to occur, effective adjuvant therapies to prevent liver metastases must complement surgical management.

Pancreatectomy combined with superior mesenteric-portal vein resection for adenocarcinoma in pancreas

The aims of this study were to investigate morbidity, mortality, and survival of patients with ductal adenocarcinoma of the pancreas who underwent pancreatectomy without (group 1) or with (group 2) en bloc portal vein resection and to study the degree of carcinoma invasion of the portal vein in group 2. The medical records of 46 and 28 patients in groups 1 and 2, respectively, were reviewed. In addition, the degree of invasion of the wall of the portal vein was categorized histologically into three types: type I, transmural invasion involving the intima; type II, invasion of the wall of the vein without intimal involvement; and type III, compression of the wall of the vein by surrounding carcinoma without true invasion. The morbidity and mortality in group 1 (26% and 4%) were not different from those in group 2 (32% and 4%). Similarly, there was no difference in survival between the two groups. Survival tended to vary directly with the depth of invasion of the wall of the portal vein: type I 6.8 ± 1.9 months; type II 15.3 ± 6.4 months; type III 20.6 ± 13.0 months. These findings suggest that en bloc resection of the pancreas and the portal vein does not increase mortality and morbidity after pancreatectomy; survival after en bloc resection was similar to that of patients not requiring portal vein resection. Combined resection of the pancreas with the portal vein could be an option in the treatment of pancreatic cancer with direct invasion of the portal vein.

Genomic analysis of DUSP6, a dual specificity MAP kinase phosphatase, in pancreatic cancer

DUSP6 (alias PYST1), one of the dual-specificity tyrosine phosphatases, is localized on 12q21, one of the regions of frequent allelic loss in pancreatic cancer. This gene is composed of three exons, and two forms of alternatively spliced transcripts are ubiquitously expressed. Although no mutations were observed in 26 pancreatic cancer cell lines, reduced expressions of the full-length transcripts were observed in some cell lines, which may suggest some role for DUSP6 in pancreatic carcinogenesis.

Surgical Aspects and Management of Acute Necrotizing Pancreatitis : Recent Results of a Cooperative National Survey in Japan

A cooperative national survey between 1991 and 1994 recently clarified the status of acute necrotizing pancreatitis in Japan. The overall mortality rate was 20.8%; however, the mortality rate in patients with infection was 33.3%, and the mortality rate in patients who underwent surgery was 27.4%. With regard to surgical procedures, drainage procedures (mobilization of the pancreatic bed and retroperitoneal drainage) were performed most frequently, and one third of the patients who underwent drainage procedures needed reoperation. Although debridement of the necrotic tissue (necrosectomy or resection of the pancreas) was performed in 33.3%, the mortality rate was 35.3%. There was no difference in the mortality rate between early and delayed operation. Recently two new modalities have been advocated for the management of severe acute pancreatitis in Japan. One is continuous regional arterial infusion of protease inhibitor and antibiotics, and the other is continuous hemodiafiltration. Further work is needed to establish the most effective procedures for the management of acute necrotizing pancreatitis and debridement of pancreatic infection.

Pancreatic microcirculation in acute pancreatitis

We present a review of the microvascular morphology of the pancreas and microstructure of the pancreatic lobule, and report our experimental results of the investigation of pancreatic microcirculation following acute pancreatitis. Impairment of pancreatic microcirculation in the early phase of acute pancreatitis may play a key role in the progression of this disease. Possible contributory mechanisms include increased vascular permeability, reduced blood flow, leukocyte-endothelial cell interaction and intravascular thrombus formation. Using an in-vivo microscope system and off-line computer analysis, we achieved direct visualization and quantification of changes in microvascular permeability and leukocyte behavior in pancreas with acute pancreatitis. Bradykinin and oxygen radicals have been demonstrated to be involved in the increase of vascular permeability in the early stage of caerulein pancreatitis. Leukocyte adherence to the vessels in the pancreatic microcirculation is a secondary event following permeability changes in acute pancreatitis. Leukocyte infiltration during exacerbation of acute pancreatitis is mediated by leukocyte-endothelial cell interaction via leukocyte integrin CD11b/18.

The role of angiogenesis in the tumor growth of Syrian hamster pancreatic cancer cell line HPD-NR

BACKGROUND/AIMS New therapeutic approach is required for pancreatic cancer, one of the most intractable malignancies. The role of angiogenesis in the tumor growth of a Syrian hamster pancreatic cancer cell line HPD-NR, which closely resembles its human counterpart, was investigated. METHODS Angiogenic activity was measured as stimulation of growth of human umbilical vein endothelial cells (HUVEC), and angiogenic factors produced by HPD-NR cells were identified by reverse-transcription polymerase chain reaction and Northern blot analysis. Then in vitro and in vivo antitumor effects of a potent angiogenesis inhibitor, O-(chloroacetylcarbamoyl)fumagillol (AGM-1470), were examined. RESULTS The conditioned medium of HPD-NR cells stimulated the growth of HUVEC, and four hamster angiogenic factors were detected with an overexpression of transforming growth factor alpha and vascular endothelial growth factor messenger RNAs. AGM-1470 specifically inhibited the growth of HUVEC and that of HPD-NR tumors in vivo with decreased vascularity of the tumors but not the growth of HPD-NR cells in vitro. CONCLUSIONS The results suggest that angiogenesis plays an important role in tumor growth of HPD-NR cells and can be a new target of medical therapy for pancreatic cancer.