Ryushi Shudo

Selective cytotoxicity of farnesylamine to pancreatic carcinoma cells and Ki-ras–transformed fibroblasts

Farnesyl protein transferase (FPTase) catalyses the post‐translational modification of proteins by a farnesyl pyrophosphate. One of the substrates of this enzyme is p21ras, the product of the ras oncogene. We examined whether farnesylamine, one of the FPTase inhibitors (FTI), is selectively cytotoxic in pancreatic carcinoma cells and Ki‐ras–transformed fibroblasts. Furthermore, we investigated whether the cytotoxicity of farnesylamine is caused by the induction of apoptosis in these cells. Using the FPTase assay, we found that farnesylamine inhibited FPTase in vitro. Immunoprecipitation showed that farnesylamine inhibited farnesylation of p21ras in vivo. In addition, 24 and 5 μM farnesylamine were required to achieve 50% cytotoxicity in pancreatic carcinoma cells containing activated Ki‐ras and Ki‐ras–transformed NIH/3T3 cells, respectively. The parental NIH/3T3 cells were resistant to the cytotoxic effect of farnesylamine at concentrations less than 100 μM. After incubation with farnesylamine, DNA fragmentation was observed in both pancreatic carcinoma cells and Ki‐ras–transformed fibroblasts at cytotoxic doses of this compound but not in NIH/3T3 cells. These results indicate that the mechanism of cell death induced by farnesylamine is apoptosis, and this apoptosis occurred specifically in pancreatic carcinoma cells containing mutated Ki‐ras and the Ki‐ras–transformed cells. Because raf is downstream of ras (p21ras) in the ras–raf–mitogen‐activated protein kinase signaling pathway, we used c‐raf‐1–transformed fibroblasts, which proved to be resistant to apoptosis induced by farnesylamine. This supports the theory that inhibition of ras signaling may be related to the induction of apoptosis. These data further suggest that farnesylamine could be useful as a chemotherapeutic agent in cancers that very frequently contain a Ki‐ras oncogene mutation, e.g., pancreatic cancer. Mol. Carcinog. 21:93–99, 1998.

Association between anomalous pancreaticobiliary ductal union and adenomyomatosis of the gall‐bladder

A frequent association of biliary tract carcinoma and anomalous pancreaticobiliary ductal union (APBD) is well recognized, especially gall‐bladder carcinoma in undilated type APBD. However, little is known about the presence and incidence of adenomyomatosis (AMT) of the gall‐bladder, a presumed premalignant lesion, in patients with APBD. This retrospective study was conducted to elucidate the clinical features and incidence of AMT in APBD patients with relation to undilated type and dilated type APBD. We reviewed the clinicopathological records of 30 patients with APBD (28 women and two men) encountered during the past 10 years. Among them, 22 patients underwent cholecystectomy and the resected specimens were subjected to histopathological examinations. Eleven cases of APBD patients were undilated type and 11 cases were dilated type. Adenomyomatosis was found in six (55%) of 11 undilated type and one (9%) of 11 dilated type, and fundal type was predominantly observed in six (86%) of seven AMT. An overall incidence of AMT in APBD patients was 32%. An undilated type of APBD is frequently associated with AMT and we believe, therefore, that clinicians should be aware of a possible coexistence of APBD and AMT.

Duodenal erosions, a common and distinctive feature of portal hypertensive duodenopathy

OBJECTIVE:The aim of the present study was to assess the presence of duodenal erosion and its clinical characteristics on endoscopy in patients with portal hypertension who had undergone endoscopic injection sclerotherapy and/or endoscopic variceal ligation for esophagogastric varices.METHODS:The subjects were 440 patients with portal hypertension, 450 with chronic hepatitis as a related control group, and 450 who underwent upper endoscopic examination as part of their routine physical examination as the controls. The underlying hepatic disease, hepatic function, and endoscopic findings of duodenal erosion among the patients with portal hypertension were studied.RESULTS:Duodenal erosion was found in 68 patients with portal hypertension (68 of 440, 15.5%), four patients with chronic hepatitis (four of 450, 0.9%), and two controls (two of 450, 0.4%). The incidence of duodenal erosion among the patients with portal hypertension was significantly higher than that in the other two groups (p < 0.01, p < 0.01, respectively). The lesions commonly observed in duodenitis are speckle erosions mainly located in the duodenal bulb. However, the most frequently seen form of duodenal erosion among the patients with portal hypertension extended from the superior portion to the descending portion, and tended to show a circular alignment along the Kerckrings folds. The patients with portal hypertension with reduced hepatic reserve capacity had more severe duodenal erosion. Endoscopic ultrasonography revealed thickening of the duodenal wall and proliferation of vascular structures within and around the wall. The histological findings of the duodenal erosion included edema and vascular dilation in the mucosal and submucosal layers.CONCLUSIONS:The location of duodenal erosion in patients with portal hypertension differs from that in patients with ordinary duodenitis. Duodenal erosion in patients with portal hypertension is considered to be one of the lesions of portal hypertensive duodenopathy.

Pancreatic duct obstruction caused by malignant islet cell tumors of the pancreas.

Islet cell tumors of the pancreas represent 1% to 2% of all pancreatic tumors.1 Although diagnosis is highly accurate with imaging modalities such as CT and EUS,2-4 it is difficult to differentiate preoperatively between malignant and benign variants unless metastases and/or invasion of adjacent organs are present.5-7 ERCP continues to play a major role in the diagnosis of pancreatic diseases despite recent advances in and the widespread use of noninvasive diagnostic imaging modalities. There is, however, limited information available about the pancreatograms of islet cell tumors including findings that suggest whether the tumor is benign or malignant.7 Partial obstruction (stenosis) and complete obstruction of the main pancreatic duct are common findings that suggest pancreatic cancer; these occur in most cases of pancreatic malignancy but are unusual with islet cell tumors.8,9 If available, a clinical imaging finding highly suggestive of malignancy of islet cell tumor would be important in the preoperative assessment of patients without apparent metastasis. We encountered 2 cases of malignant islet cell tumors in which complete obstruction of the main pancreatic duct was demonstrated by ERCP.

α-Fetoprotein producing mucin-producing carcinoma of the pancreas: A case report with immunohistochemical study and lectin-affinity profile

a -Fetoprote in (AFP) is a fetal serum protein produced mainly in the fetal live r, yolk sac and, in small amounts, in the fetal gastrointe stinal tract (1). After birth, AFP rapidly disappe ars and is not detected in the serum of healthy persons. However, AFP often reappears in the serum of patients with live r cancer, germ-cell tumors such as yolk sac tumor, and some other malignancie s (2, 3). Along with live r cancer, cancers of the digestive organs are reported to produce AFP. However, pancreatic cancer with elevated serum AFP is rare (4 ± 11) . Mucin-producing tumor (MPT) of the pancreas has recently been increasingly recognize d as a clinical entity that is characte rized by unique clinicopathologic feature s distinct from those of a commono pancreatic ductal cell carcinoma (12± 14) . Dilation of the main pancreatic duct (MPD) and/or branch ducts with ® lling defects of mucin demonstrable by endoscopic retrograde pancreatography (ERP), as well as excretion of mucin through the patulous ori® ce of an enlarge d papilla of Vater, are diagnostic features of MPT, and this disease has a favorable prognosis following pancreatectomy. These feature s are attribute d to the excessive secretion of mucin by the tumor cells and, histopathologica lly, tumors consisted, for the most part, of intraductal papillary carcinoma and adenoma in the MPT and/or large branch ducts (13, 14) . Recently, we experienced a patient with mucinproducing carcinoma of the pancreas who had a high leve l of serum AFP. Mucin-producing carcinoma of the pancreas is seldom reported as an AFP-producing cancer. We reported a case of AFP-producing, mucin-producing carcinoma of the pancreas and used a immunohistochemical approach to determine the AFP-producing site in the resected specimen. In addition to these clinicopathologic characteristics, the bioche mical prope rty of AFP in the patient’ s serum, lectin-af® nity analysis, was also investigated. The literature of the pancreatic ductal cell carcinoma producing AFP is reviewed.

Endoscopic Variceal Ligation of Bleeding Rectal Varices: A Case Report

The incidence of ectopic varices in the rectum is likely to increase with improvements in the treatment and survival of patients with portal hypertension. If a patient with portal hypertension suffers massive lower gastrointestinal hemorrhage, it is important to perform a detailed endoscopic examination, as there is a possibility of rectal varices. Although a standard therapy for rectal varices has not been established, we encountered a case of rectal varices that was successfully treated with endoscopic variceal ligation alone. Endoscopic variceal ligation is minimally invasive, safe, effective, simple and reliable. Endoscopic variceal ligation is promising as a possible first line of therapy for rectal varices.

A CASE OF GASTRITIS CYSTICA POLYPOSA SHOWING A CHARACTERISTIC ENDOSCOPIC ULTRASONOGRAM

Littler reported on the torose polypoid lesion observed at the site of gastroenterostomy long after gastrectomy and called it gastritis cystica polyposa (GCP). Since then, much attention has been paid to hypertrophic lesions at the sites of gastroenterostomy, and many reports on GCP have been published. This lesion often develops in patients who had gastroenteroanastomosis. It was observed by the authors that a submucosal tumor developed at the cardiac part of the stomach in a patient who had no history of gastrectomy. Very few cases of GCP were observed in unoperated stomachs. The tumor was excised by endoscopic mucosal resection and diagnosed histopathologically as GCP. Endoscopic ultrasonography before the operation revealed the presence of a spongy body filled with anechoic areas of various sizes under the mucosa of the tumor. This finding is characteristic of this disorder and is detailed here with a discussion on related papers.

Combined effects of SN-38 and pentoxifylline on the induction of apoptosis through the activation of CPP-32 in pancreatic adenocarcinoma cell lines

AbstractBackground. Pentoxifylline (PENT) is a theophylline derivative that enhances cytotoxic effects against tumor cells pretreated with antitumor agents. It has also been reported that chemotherapy can induce apoptosis in some carcinoma cells. We investigated the effects of PENT on human pancreatic adenocarcinoma cells pretreated with SN-38, an active form of CPT-11 (a camptothecin analogue) and we also examined the participation of CPP-32, a member of the interleukin 1β-converting enzyme (ICE) family proteases, in chemotherapeutic agent-induced apoptosis. Methods. Human pancreatic adenocarcinoma cells (PK-1, PK-8) were cultured in RPMI 1640. Lethal effects were examined by MTT assay; DNA fragmentation was analyzed by agarose gel electrophoresis; and Western blot analysis was performed with anti-CPP-32 monoclonal antibody. Results. Pretreatment with SN-38 followed by PENT increased the cytotoxic effect compared with that seen for treatment with SN-38 alone. Isobologram analysis of the IC50 value revealed that PENT had supra-additive effects when administed after SN-38, but not when administered prior to or simultaneously with SN-38. Agarose gel electrophoresis showed typical DNA ladders in the DNA of cells treated with SN-38 and PENT. The acridine orange (AO) staining method was used to observe the morphological changes characteristic of apoptosis. Western blot analysis verified that activation of CPP-32 accompanied the development of apoptosis. In addition, SN-38-induced apoptosis was prevented by pretreatment with Ac-DEVD-CHO (DEVD), an inhibitor of CPP-32. Conclusions. These results indicate that the antitumor activity of SN-38 is attributable to apoptosis through the activation of CPP-32, and that combined treatment with PENT enhances the induction of apoptosis by SN-38. Accordingly, the use of PENT may provide a combined modality treatment for pancreatic cancer.

A rare ring-shaped anomaly of the main pancreatic duct accompanying a branch duct IPMN

The patient was a 74-year-old female. Screening computed tomography for examination of the abdomen showed a cystic mass in the pancreatic body. Close investigation using endoscopic retrograde cholangiopancreatography and magnetic resonance cholangiopancreatography revealed a very rare finding: the main pancreatic duct bifurcated at the pancreatic body, and these two ducts converged at the caudal side. A multilocular cystic mass in the pancreatic body and mucus discharge from the orifice of major papilla were observed. There was no protruded lesion in the main pancreatic duct. No findings suggested apparent malignancy. The patient was diagnosed as having hyperplastic intraductal papillary mucinous neoplasm of branch type showing a ring-shaped pancreatic duct, and was placed under follow-up.

Adrenal adenoma mimicking a submucosal tumor of the stomach

The widespread use of diagnostic imaging modalities has increased the incidental detection of adrenal masses. We experienced a case of adrenal adenoma that was detected incidentally on mass X‐ray examination of the stomach, with findings that were initially suggestive of a gastric submucosal tumor. Only a few cases of adrenal adenoma that resembles a gastric submucosal tumor on diagnostic imaging have been reported. In addition, only a few papers have described the endoscopic ultrasonography findings of adrenal tumors. As the preoperative endoscopic ultrasonography findings of the tumor in our patient correspond with the features of the cut surface of the resected tumor, endoscopic ultrasonography appears to be useful as a new imaging technique in the diagnosis of adrenal adenoma. As endoscopic ultrasonography is minimally invasive, it can be performed in an outpatient setting to collect useful information. As adrenal tumors can be visualized relatively easily, the presence of adrenal lesions should also be searched for when endoscopic ultrasonography is performed for biliary or pancreatic disorders.