佐田 尚宏

CONTEXT: Although rare, a pancreatic arteriovenous malformation can have serious consequences. A diagnosis of arteriovenous malformation requires evidence of aberrant communication between the arterial and the venous systems. This report describes a case where the use of multi-detector row CT and specific post-processing methods provided a diagnosis of arteriovenous malformation. This minimally invasive diagnostic approach resulted in a clear, precise and comprehensive visual representation of the pancreatic arteriovenous malformation. CASE REPORT: A 60-year-old man with right hypochondriac pain presented with a mass in the head of the pancreas. The hypochondriac pain resolved spontaneously and physical examination revealed no abnormal findings. A multi-detector row CT study was performed. The data obtained in the arterial phase demonstrated a high-contrast mass in the head of the pancreas and early enhancement of the portal vein. A maximum intensity projection method clarified the aberrant vascular communication. Changes in Hounsfield numbers were observed using a multi-planar reformation method. A volume-rendering method was used to create a 3D model which demonstrated the spatial relationship between the aberrant vascular communication and the surrounding tissue. An annual follow-up study using this technique showed no significant alteration. CONCLUSIONS: Multi-detector row CT with specific post-processing methods is a useful diagnostic tool for pancreatic arteriovenous malformation.

Retroperitoneal endoscopic adrenalectomy (EA) is recognized as a principal procedure for benign adrenal tumors. However, a limited visual field and a narrow working space make this approach difficult, particularly in cases of obese patients or small tumors. Using multidetector row CT (MD-CT), this study investigated the use of preoperative virtual simulation (PVS) to identify tumor and central vein locations for EA, and verified these findings during EA surgery. The study enrolled 11 cases comprising 10 adrenal adenomas and one ACTH-independent macronodular adrenal hyperplasia admitted to Jichi Medical University Hospital, Tochigi, Japan, between November 2003 and October 2006. Patients were evaluated in a lateral bending position using MD-CT. 3D PVS images of ribs, vertebrae, kidneys, and adrenal tumors were generated and compared with real images obtained during EA. The PVS images clearly showed the relative locations of the adrenal tumor, kidney, and adjacent anatomical structures. These locations were verified during EA. The central vein was identified in the PVS images in all cases. Information derived from the PVS images assisted in the performance of EA surgery. Preoperative 3D-simulation images using MD-CT contributed to the safety and efficiency of performing EAs.

BACKGROUND: Pancreatic carcinoma causes more than 20,000 deaths every year in Japan. The role of (neo-) adjuvant chemotherapy for pancreatic carcinoma is still controversial. METHODS: At the 34th Annual Meeting of the Japanese Society of Pancreatic Surgery in 2007, questionnaires were distributed regarding the use of (neo-) adjuvant chemo(radio)therapy for pancreatic carcinoma between 2001 and 2005. RESULTS: Sixty of the 146 member institutions responded to the questionnaires. There were a total of 1,846 cases of resected pancreatic carcinoma between 2001 and 2005. The study population had a greater proportion of males, and a mean age of 65.3 years (range 34-90 years). The lesion was located in the head of the pancreas in 1,204 cases (71.7%), in the body in 353 cases (21.0%), and in the tail in 111 cases (6.6%). Overall survival rates were 67.3% at 1 year, 36.0% at 2 years, and 23.9% at 3 years, respectively. Adjuvant chemotherapy (usually involving gemcitabine) was used in 66.0% of cases. The use of adjuvant chemotherapy was found to improve the overall survival rate. Interestingly, adjuvant chemotherapy only improved survival in late-stage (UICC stages IIB, III, and IV) but not early stage (IA, IB, and IIA) patients. Survival was treatment duration-dependent, with patients who received more than 12 months of therapy having a 3-year survival rate of 51.2%. CONCLUSION: This high volume retrospective data indicated the promising effect of gemcitabine-based adjuvant chemotherapy and the rational duration of adjuvant chemotherapy should be determined in the future prospective studies.

A 60-year-old man presented with melena and hematemesis in 1984. Esophagogastroduodenoscopy (EGD) detected a small protruding lesion in the duodenal bulb, which was diagnosed as Brunner's adenoma. No significant change was detected in subsequent annual EGD and biopsies for 10 years, after which the patient was not observed for 7 years. The patient presented with melena again in 2001. The lesion had changed shape to become a 10 mm sessile tumor with a central depression, and following a biopsy was diagnosed as an adenocarcinoma. The patient underwent partial resection of the duodenum. Histopathological assessment showed acidophilic cells with swollen nuclei, and clear cells forming a tubular or papillary tubule in the mucosal lamina propria and submucosal layer. The tumor cells stained positive for lysozyme, indicating that they arose from Brunner's gland. The patient showed no sign of recurrence and was disease-free for more than 34 months after surgery. The patient died of pneumonia. This is an extremely rare case of primary duodenal carcinoma arising from Brunner's gland in a patient observed for 17 years.

Recent advances in multidetector row computed tomography (MD-CT) technology provide new opportunities for clinical diagnoses of various diseases. Here we assessed CT virtual duodenoscopy, duodenography, and three-dimensional (3D) multicholangiography created by MD-CT for clinical diagnosis of duodenal malignant lesions. The study involved seven cases of periduodenal carcinoma (four ampullary carcinomas, two duodenal carcinomas, one pancreatic carcinoma). Biliary contrast medium was administered intravenously, followed by intravenous administration of an anticholinergic agent and oral administration of effervescent granules for expanding the upper gastrointestinal tract. Following intravenous administration of a nonionic contrast medium, an upper abdominal MD-CT scan was performed in the left lateral position. Scan data were processed on a workstation to create CT virtual duodenoscopy, duodenography, 3D multicholangiography, and various postprocessing images, which were then evaluated for their effectiveness as preoperative diagnostic tools. Carcinoma location and extent were clearly demonstrated as defects or colored low-density areas in 3-D multicholangiography images and as protruding lesions in virtual duodenography and duodenoscopy images. These findings were confirmed using multiplanar or curved planar reformation images. In conclusion, CT virtual duodenoscopy, doudenography, 3-D multicholangiography, and various images created by MD-CT alone provided necessary and adequate preoperative diagnostic information.

CONTEXT: Primary pancreatic lymphoma is a rare form of extranodal lymphoma originating in the pancreas. The present report describes a case of follicular lymphoma of the pancreas with unique CT and MRI findings. CASE REPORT: A 58-year-old male complained of sudden abdominal pain, and routine ultrasonography detected an 8 cm hypoechoic tumor in the head of the pancreas. The 3D image generated using multi-cholangiography and virtual duodenography provided the information necessary for a laparotomy. The tumor was enucleated for diagnosis. Follicular lymphoma is quite rare in the pancreas and gastrointestinal tract. A considerable number of pancreatic lymphoma subtypes have been reported. The expression "pancreatic lymphoma" has been used to describe both primary lymphoid neoplasms originating in the pancreatic parenchyma and tumors invading from a peri-pancreatic lymphadenopathy. The present case belongs to the latter, which might explain the unique imaging findings and histological type. These subtypes display different imaging findings and different clinical characteristics. In the future, primary pancreatic lymphoma should be discussed separately depending on the subtype. CONCLUSION: We propose a new subtype of primary pancreatic lymphoma. Multi-cholangiography and virtual duodenography provided the information necessary for a laparotomy in the present case. Enucleation is indicated for benign and low-grade malignant tumors of the pancreas, even if the tumor is located in the head of the pancreas.

Alcoholic chronic pancreatitis (CP) is not usually diagnosed until the end stage of the disease, and hence enormous medical and social resources are consumed in the treatment of established alcoholic CP. With the aim of early diagnosis and prevention of alcoholic CP, we here propose "alcoholic pancreatopathy" as a new category of pancreatic disorder induced by alcohol intake. In addition to a history of excessive alcohol intake (>80 g/day), the presence of at least one of the following conditions establishes the diagnosis of alcoholic pancreatopathy: 1. History of alcoholic acute pancreatitis. 2. Recurrent abdominal pain or gastrointestinal symptoms induced by alcohol intake. 3. Hyperamylasemia or a high serum level of any other pancreatic enzymes. 4. Abnormal findings in the pancreas by routine abdominal ultrasonography. Alcoholic pancreatopathy is a comprehensive concept that includes the early stage of pancreatic injury induced by alcohol, and is useful for detecting the preclinical stage of pancreatic injury induced by alcohol and hence for treating the early stage of the disease. Further assessments and well-designed studies for investigating the early stage of alcoholic CP are necessary, in which alcoholic pancreatopathy could play a key role.

BACKGROUND/AIMS: Current in vitro drug sensitivity tests have limitations and disadvantages. This study investigated the use of gene expression data to predict the sensitivity of pancreatic cancers to gemcitabine. MATERIALS AND METHODS: Cancer cells isolated from 14 pancreatic cancer patients were tested in vitro for gemcitabine sensitivity using the collagen droplet drug sensitivity test (CD-DST). On the basis of this test, 9 of the 14 cancers were identified as either gemcitabine-sensitive or gemcitabine-resistant. Total RNA was extracted from each of those nine cancers and used as a template to synthesize Cy3-labeled cDNA. Pancreatic RNA extracted from six normal individuals was used as a control. Labeled probes were hybridized to an Atlas Glass Human 1.0 Microarray chip, after which the chips were washed and scanned, and the data were analyzed using Microsoft Excel-embedded software. The expression profiles of selected genes were confirmed using real-time PCR analysis. RESULTS: Statistical analysis of the microarray data showed that four genes were differentially expressed in gemcitabine-sensitive cancers: microsomal glutathione S-transferase 1 (GSTT1), topoisomerase II alpha (TOP2A), caspase 3, and ATP-binding cassette and subfamily C member 2 (ABCC2). More than 20 other genes were additionally identified as possible candidate genes associated with drug resistance. CONCLUSIONS: Expression of drug resistance-related genes appeared to predict whether a cancer was gemcitabine-sensitive or -resistant. Further study will enable a drug resistance scoring system to be established on the basis of gene expression. Such a system will allow more efficient application of chemotherapy.

Hepatic amyloidosis complicated with Castleman's disease is quite rare. A 48-year-old woman was referred to our hospital with general fatigue, low-grade fever, anemia, thrombocythemia, and liver dysfunction. Physical examination revealed anemia and hepatomegaly and abdominal computed tomography showed marked hepatomegaly and right upper abdominal masses. Technetium-99m pyrophosphate (99mTc-PYP) scintigraphy revealed the diffuse abnormal uptake of the enlarged liver, suggesting amyloid deposition. Liver biopsy showed destruction of the liver structure and the massive deposition of AA type amyloid protein. Surgical resection was performed on the abdominal masses. Histological examination of the masses showed Castleman's disease (plasma cell type). After resection, her fever resolved and the liver size gradually decreased to within the normal range. This case shows that surgical resection of the main lesion is effective for hepatomegaly due to AA type amyloidosis associated with Castleman's disease.

We sought to validate computed tomographic virtual pancreatoscopy (CT-VP) created by multidetector row CT (MD-CT) in the clinical diagnosis of intraductal papillary mucinous neoplasm (IPMN) of the pancreas. Five cases of pancreatic IPMNs were included in this study. A nasopancreatic drainage tube was inserted and the pancreatic duct was filled with contrast medium, after which an upper abdominal scan was performed by MD-CT. CT-VP and three-dimensional (3D) CT pancreatographic images were created using a workstation and compared with images by conventional diagnostic techniques. All cases were evaluated by endoscopic retrograde pancreatography (ERP) and three cases of main duct type were assessed by intraoperative real pancreatoscopy (RP). In the main duct cases, papillary projections in the main pancreatic duct and branch orifices were clearly detected by CT-VP. These lesions and structures were confirmed by intraoperative RP, and the CT-VP images were clearer than RP images. In branch cases, a surface-rendering method allowed protruding lesions to be clearly detected in the dilated branches. Compared with conventional ERP or RP, CT-VP and 3D-CT pancreatographic images were finer in quality, and the procedures were less invasive, faster, and less expensive. The potential shown by CT-VP with 3D-CT pancreatography in the clinical diagnosis of pancreatic IPMNs suggests that this approach may replace ERP in the near future.

Although hand-assisted laparoscopic surgery (HALS) is very common in various laparoscopic procedures, it is rarely used for retroperitoneal endoscopic adrenalectomy because of the small working area. The authors evaluate HALS in endoscopic adrenalectomy with respect to its use as a rescue procedure in complicated cases. In their department, 47 patients underwent endoscopic adrenalectomies between 1998 and 2004. Mainly because of complicated anatomy, three primary aldosteronism cases were converted to retroperitoneal HALS. This involved making an additional 6 cm skin incision, into which the surgeon's left hand was inserted, with the palm used to create a sufficient visual field and working area. The fingers were used for tactile sensation and blunt resection. For these three cases, successful retroperitoneal HALS in endoscopic adrenalectomy resulted in no mortality or morbidity. These findings indicate that this procedure is a feasible technique for complicated benign adrenal tumor cases.

PURPOSE: We compiled a manual aimed at reducing preoperative cardiac assessment costs and defining the roles of surgeons and cardiologists. We tested prospectively and retrospectively if this manual achieved these goals. METHODS: Using the Guidelines for Perioperative Cardiovascular Evaluation for Noncardiac Surgery of the American College of Cardiology (ACC) / American Heart Association (AHA), and other articles as a reference, we compiled the Jichi Medical School Hospital (JMSH) Manual in September 2002. This manual contains a novel checklist and flowcharts and includes all past and present cardiac disorders, complications, abnormalities in electrocardiograms (ECGs) and chest X-rays, and evaluation of daily activity. Using this manual, we prospectively studied 1087 surgical candidates from September 2002 to August 2003, and retrospectively analyzed 927 surgical candidates from September 2001 to August 2002. RESULTS: In the prospective study, 39 (3.6%) patients were deemed to require further cardiac assessment and 4 (0.37%) suffered postoperative complications. In the retrospective study, 108 (11.7%) were deemed to require further cardiac assessment and 20 (2.2%) suffered postoperative complications. Using this manual reduced preoperative cardiac examination costs by 1323,600 Japanese yen, representing a 70.5% reduction. CONCLUSIONS: The JMSH Manual defines the roles of surgeons and cardiologists and is useful for assessing preoperative cardiac function and surgical risks. This manual dramatically reduced the costs associated with preoperative cardiac examinations.

BACKGROUND: Fistula formation has been reported in intraductal papillary-mucinous neoplasms (IPMNs) with or without invasion of the adjacent organs. The presence or absence of invasion is mostly determined by postoperative histological examination rather than by preoperative work-up. CASE PRESENTATION: A 72 year-old Japanese woman showed remarkable dilatation of the main pancreatic duct (MPD) in the distal region of the pancreas. Subsequent ERCP also showed MPD dilatation, after which the patient suffered moderate pancreatitis. A subsequent gastroscopy revealed a small ulceration that had not been observed in a gastroscopy performed 3 months prior. Mucinous discharge from the ulceration suggested it might be the orifice of a fistula connected to the MPD. En bloc resection including the distal region of the pancreas, spleen, stomach and part of the transverse colon was performed under the pre- and intraoperative diagnosis of an invasive malignant IPMN. However, histopathology revealed the lesion to be of "borderline malignancy" without apparent invasion of the stomach. Light microscopy showed inflammatory cellular infiltrates (mainly neutrophils) around the pancreatogastric fistula, but there was no evidence of neoplastic epithelia lining the fistulous tract. CONCLUSION: This case highlights that a pancreatogastric fistula can develop after acute inflammation of the pancreas in the absence of cancer invasion. Further information regarding IPMN-associated fistulae is necessary to clarify the pathogenesis, diagnosis, appropriate surgical intervention and prognosis for this disorder.

A novel recombinant human hepatic cell line, CYP3A4- and glutamine synthetase (GS, an enzyme which converts ammonium ion and glutamate to glutamine)-introduced HepG2 (HepG2-GS-CYP3A4), was established. Its usefulness in a large-scale culture with a circulatory bioreactor in vitro and in dog models of ischemic hepatic failure with acute diazepam (DZP, a substrate of CYP3A4) overdosage was further examined. HepG2-GS-CYP3A4 expressed about 9 times larger amounts of CYP3A4 protein than a control. After incubation with HepG2-GS-3A4 cells in a circulatory bioreactor for 24 h, ammonia and DZP concentrations in the culture medium significantly decreased by about 40%. Furthermore, this system improved the survival time and decreased serum concentrations of DZP, ammonia, and transaminase in dogs with ischemic hepatic failure plus acute DZP overdosage. The mean survival time with bioreactor with HepG2-GS-3A4 was 42.7 +/- 3.6 h, which was significantly longer than that without reactor, with reactor (no cells), and with HepG2-GS (23.4 +/- 2.8, 22.1 +/- 2.4, and 31 +/- 3.7 h, respectively). Therefore, it is concluded that this bioartificial liver could be a good tool for the treatment of dogs with hepatic failure and that it could potentially be a bridging procedure to liver transplantation.

The treatment of intraductal papillary mucinous tumors (IPMT) of the pancreas is still controversial. In this report we describe a single-branch resection of the pancreas (SBRP), which is a new method for the removal of branch-type IPMT of the head of the pancreas. A multilobular cystic lesion (50 x 40 mm) in the head of the pancreas was incidentally detected in an asymptomatic 40-year-old man who underwent a routine ultrasound examination. The tumor was carefully removed along the border of the cyst and the normal parenchyma, with complete preservation of the main pancreatic duct and the common bile duct. A pancreatic fistula developed during the postoperative period, but was well-controlled by endoscopic naso-pancreatic drainage. SBRP is a technically feasible procedure and this operation represents a minimally invasive alternative to any other segmental resection of the pancreas.

BACKGROUND: Small-cell neuroendocrine carcinoma in the duodenum is an extremely rare neoplasm with poor prognosis. CASE PRESENTATION: A 57-year-old man presented with sudden onset gastrointestinal bleeding and fainting attacks. Duodenoscopy and hypotonic duodenography revealed a 3 x 3 cm protruding tumor with ulcerations situated opposite the ampulla of Vater in the second part of the duodenum. Local excision of the tumor was performed, followed by adjuvant chemotherapy with 5-fluoro uracil and leucovorin. Examination of the tumor by immunohistochemistry and electron microscopy indicated it to be neuroendocrine in nature, expressing synaptophysin and AE1/AE3, and containing dense core granules. The patient showed no sign of recurrence and has been disease-free for more than 48 months after surgery. CONCLUSIONS: Most cases of small-cell neuroendocrine carcinoma in the duodenum show rapid progression of the disease, and even radical surgery with or without chemotherapy do not prevent death. We report a rare subtype of small-cell neuroendocrine carcinoma. This subtype appears to have a much better prognosis, and may be amenable to local excision, if the lesion is away from the ampulla of Vater.

OBJECTIVES: To investigate the effect of genistein on gene expression in Panc 1 cells using microarray technology. METHODS: Panc 1 cells were treated with 10 micromol/L genistein or DMSO (vehicle control) for 0, 1, 3, 6, or 12 hours. Total RNA from each sample was isolated, and biotin-labeled probes were hybridized to the human genome U133A chip, after which the chip was washed and scanned. Data were analyzed using DMT software (Affymetrix). For genes that showed large changes in expression due to genistein, these changes were confirmed using real-time PCR assays. RESULTS: Two independent microarray experiments showed that genistein significantly changed the expression of 47 genes: up-regulating of egr-1 and IL-8 and down-regulating of EGF-R AKT2, CYP1B1, NELL2, SCD, DNA ligase III, Rad as well as 18s and 28s rRNA and others. These alterations in expression were confirmed using real-time PCR, although the increase in change was not exactly the same in the 2 assays. CONCLUSIONS: Our data suggest the reported apparent ability of genistein to inhibit carcinogenesis may involve a number of pathways. The most obvious target is the EGF-R signaling pathway since the expression of 5 genes related to this pathway was reduced (EGFR, egr-1, AKT2, CYP1B1, and NELL2). Genistein may also act by disabling cancer cell self-protection by inhibiting expression of AKT2, CYP1B1, and DNA ligase III. Furthermore, genistein may inhibit car-cinogenesis by inhibiting expression of SCD. Finally, our data support findings indicating that genistein inhibits rRNA formation, which is an important mechanism by which genistein regulates tumor cell growth.

A 43-year-old Japanese man had an increasing level of serum CEA pointed out, by annual-physical checkups. No abnormal findings were detected,in the lungs or gastrointestinal tract. The only pathological lesions were a 1.5-cm-sized nodule in the pancreatic tail and a 5-cm-sized thyroid tumor. The thyroid tumor was shown to be Medullary carcinoma by aspiration cytology He underwent total thyroidectomy with extensive lymph node-dissection., After thyroid surgery,,the patient received distal pancreatectomy 2 weeks later. Pathological examination revealed the pancreatic tumor to be a metastasis of thyroid medullary carcinoma. The patient is alive and well without recurrence 5 years after thyroidectomy and pancreatectomy. The serum levels of CEA and calcitonin remain within normal limits. Thus, the patient seems to have had a solitary metastatic tumor from thyroid medullary cancer.

Pancreatic cancer has a dismal prognosis because most lesions are unresectable where as adjuvant and palliative chemotherapy exhibits poor results. Six patients with locally unresectable pancreatic cancer were treated with mitomycin-C (MMC) 8mg/m2 on day 1 and 5-FU 375mg/m2 and LV 20mg/m2 on days 1 to 5. Treatment cycles were repeated every four weeks if the patient's general condition permitted. All patients had measurable, histologically proven adenocarcinoma and had not undergone prior chemotherapy. Three patients underwent hepaticojejunostomy whilst choledochal stents were endoscopically inserted in two patients. No significant side effects of grade 3 or 4 were observed. Five of six patients who received an average of 5 treatment cycles died of their disease with a medial survival of 8.9 months. The remaining patient received 12 treatment cycles and 8 additional treatments without mitomycin-C and exhibited a complete remission for 36 months. Our data suggest that MMC plus 5-FU and leucovorin is a tolerable regimen and has promising effects. Further prospective studies are needed. Copyright © 2003 By PJD Publications Limited.

PURPOSE: This study was performed to evaluate the operative conditions for an abdominal wall-lifting laparoscopic cholecystectomy (ALLC) using a new preoperative grading system. METHODS: One hundred forty-five patients who underwent a cholecystectomy for cholecystolithiasis from January 1997 to December 1999 were retrospectively analyzed. Allotting 0-5 points for coexisting cholecystitis, past history, previous upper abdominal laparotomy, preoperative drainage, location of the stones, and body mass index, the total combined score was defined as the predictive score. The cases were graded into four risk groups according to the predictive score. The postoperative score, which evaluated the actual conditions of ALLC, was defined by allotting 0-8 points to operative factors: operation time, blood loss, additional trocars and procedures, conversion to open surgery, and postoperative complications. RESULTS: Ten cases (6.9%) were converted to open surgery and three cases (2.1%) had minor postoperative complications. The conversion rate for each risk group was 0% (minimum-risk group), 5.4% (low-risk group), 10.7% (intermediate-risk group), and 17.9% (high-risk group). The mean operation time was 63.0, 87.5, 89.0, and 120.2 min. The mean postoperative score was 1.08, 2.81, 3.96, and 6.36, and showed a respectively strong correlation with the predictive score (correlation coefficient: 0.997). CONCLUSIONS: Our preoperative grading system using the predictive score was found to be a reliable and feasible method for predicting the actual operative conditions for ALLC.

Background/Aims: Pancreatic cancer remains one of the most formidable tumors defying early detection and effective treatment. Long-term survivors, however, do exist after resection. We investigated the clinicopathologic features of patients with pancreatic cancer who survived more than 5 years to draw out some suggestions concerning the indication of surgical treatment. Methodology: We studied the clinicopathologic features of 13 patients with pancreatic cancer who survived more than 5 years after resection. We reviewed their clinical records to investigate preoperative symptoms, serum tumor markers, operative findings, postoperative adjuvant therapy, and modes of recurrence and survival periods. Information on the location, size, histology and spread of the primary tumors were mainly obtained from pathology reports. Results: Histologic types of the long survivors included ductal adenocarcinoma of common type in 4 patients, mucinous noncystic adenocarcinoma in 2, intraductal papillary-mucinous carcinoma (invasive) in 4, undifferentiated carcinoma in 1, endocrine tumor (islet cell carcinoma) in 1 and acinar cell carcinoma in 1. All 4 cases of ductal adenocarcinoma of the common type showed a moderate invasion either to the retroperitoneum, the portal vein or the duodenum. Two patients with mucinous noncystic carcinoma attained a long survival despite extensive invasion of the pancreatic stroma, although one died of peritoneal carcinomatosis. Two of 4 patients with intraductal papillary-mucinous cancer (invasive) died of peritoneal dissemination 6 and 11 years after resection, respectively. Three patients with cancer of other special histologic types, i.e., undifferentiated, well-differentiated endocrine carcinoma and acinar cell carcinoma, showed invasion of the portal vein and splenic artery, involvement of the retroperitoneum and a metastatic tumor in the liver, respectively. Conclusions: Whereas special histologic types including ductal variants tended to predispose to long-term survival, ductal adenocarcinoma of the common type had some chance of long survival even with invasion of the surrounding tissues.

The early diagnosis of pancreatic carcinoma is essential for increasing patient survival rates. In this study, 52 patients with suspected pancreatic diseases were examined to investigate the value of K-ras codon 12 point mutation, levels of carcinoembryonic antigen (CEA) and carbohydrate antigen (CA19-9), and cytology of pancreatic juice in the diagnosis of pancreatic carcinoma. Pancreatic juice was taken without secretin stimulation. K-ras mutation was detected by enriched polymerase chain reaction (PCR) restriction fragment length polymorphism (RFLP). K-ras mutation in pancreatic juice was more frequent in carcinoma than in benign diseases (P = 0.0448). The positive predictive value of K-ras mutation for the diagnosis of neoplastic disease was 83%. The CEA level in pancreatic juice in carcinoma was significantly greater than that in benign disease (P &lt 0.0001). When the cutoff level of CEA was set at 50ng/ml, its accuracy for the diagnosis of carcinoma was 85%. A multivariate analysis showed that K-ras mutation and CEA level in pancreatic juice, as well as serum CA19-9 level and age of the patient were independent variables for the diagnosis of carcinoma, and the accuracy of diagnosis by this analysis was increased to 90%. In conclusion, both K-ras mutation and CEA level in pancreatic juice may be valuable for the diagnosis of carcinoma. Better discrimination was possible with a multivariate analysis.

BACKGROUND/AIMS: A large, sustained increase in acinar [Ca2+](i) may play a key role in the pathogenesis of acute pancreatitis. Many mechanisms which lead to cell damage in vitro and pancreatitis in, vivo, such as free radicals or supraphysiological cerulein concentrations, cause a rapid increase in [Ca2+](i) in pancreatic acinar cells. Little is known about why [Ca2+](i) increases in some instances stimulate secretion and in other instances initiate cell death. So far, [Ca2+](i) increases were thought to represent physiological signals when they occurred as oscillations at the single cell level. METHODOLOGY: This paper reviews recent literature and our own original research about the role of calcium in the function of pancreatic acinar cells and the development of pancreatitis. RESULTS: Recent studies showed that exposure of acinar cells' to free radicals not only caused a bulk increase in [Ca2+](i) but also resulted in calcium oscillations which had a lower frequency than, but similar amplitude to oscillations occurring after physiological stimuli. The absolute increase in [Ca2+](i) did not definitely determine the cellular response. Instead, the duration of [Ca2+](i) increase may have been more important. In contrast to previous belief of a direct relationship between [Ca2+](i) oscillations and exocytosis, recent results show that radicals can induce [Ca2+](i) oscillations which do not exert exocytosis but inhibit the secretory response to physiological stimuli. Further experiments showed that the [Ca2+](i) release caused by radicals originates from thapsigargin-insensitive, ryanodine-sensitive stores. CONCLUSIONS: The origin and duration of [Ca2+](i) increases rather than their extent or oscillatory nature, determine whether the cell will secrete or die. An abnormal [Ca2+](i) increase can trigger trypsin activation, acinar cell damage and acute pancreatitis. This hypothesis is supported by studies which show that calcium chelators inhibit radical-induced trypsin activation as well as cell necrosis and apoptosis. Thus, an inhibition of pathological [Ca2+](i) release may have a therapeutic potential.

Activation of trypsinogen is thought to trigger the autodigestive process in acute pancreatitis. The lysosomal enzyme cathepsin B was suggested to cause the activation of trypsinogen because it is known that cathepsin B is able to activate trypsinogen in special circumstances and that lysosomal and digestive enzymes are colocalized within intracellular vacuoles in the early stage of pancreatitis, As yet this hypothesis has been difficult to prove because activated trypsin is difficult to quantify in pancreatitis by conventional enzymatic measurements. We therefore employed an ELISA for trypsin activating peptide (TAP), which is a small peptide cleaved during the activation of trypsinogen and can be determined reliably. Supraphysiological concentrations of cerulein (1 nM-1 mu M) resulted in a marked increase in TAP in freshly isolated pancreatic acinar cells, indicating activation of trypsinogen. This activation as determined by the TAP increase was significantly reduced by the serine protease inhibitor Fut-175 but not by the cathepsin B inhibitors E-64 and NCO-700. The concentrations of NCO-700 and E-64 abolished the cathepsin B activity of pancreatic acinar cells but did not significantly reduce the trypsin activity (after enterokinase preincubation); correspondingly the concentrations of Fut-175 used abolished the trypsin activity but did not reduce the cathepsin B activity. The results indicate that an autoactivation of trypsin rather than an activation of trypsinogen by cathepsin B triggers trypsin activation by supramaximal cerulein concentrations.

Peroxynitrite (0.5-50 mu M) induced does-dependent cytotoxic effects in rat pancreatic acinar AR4-2J cells. Glutathione (2 mM) and ebselen (10 mu M) partially reduced the cytotoxicity caused by 1-10 mu M concentrations of peroxynitrite. Higher concentrations (10-50 mu M) of peroxynitrite induced DNA smear suggestive of necrosis, while lower concentrations (2-5 mu M) induced DNA fragmentations suggestive of apoptosis. The effects of peroxynitrite on [Ca2+](i) showed a similar dose dependency. Peroxynitrite concentrations >10 mu M rapidly increased [Ca2+](i) in a dose-dependent manner, while concentrations <5 mu M did not affect [Ca2+](i). In contrast, the presentation of wild-type P53 was accelerated at lower concentrations of peroxynitrite (less than or equal to 10 mu M) but not at higher concentrations (50 mu M). The present study suggests that peroxynitrite at lower concentrations (2-5 mu M) induces wildtype P53 and apoptosis, which is potentially a protective response toward the DNA damage caused by peroxynitrite. On the other hand, higher concentrations of peroxynitrite (10-50 mu M) rapidly increase [Ca2+](i) and eventually induce necrosis.

This study evaluated the action of menadione on cell proliferation and integrity of the rot pancreatic acinar cell line, AR4-2J. Menadione at 1-20 mu M dose-and time-dependently inhibited cell proliferation of AR4-2J cells. In contrast, a high concentration of menadione (100 mu M) caused rapid cell death (> 90% of cells took up trypan blue within 4-h). While the high concentration of menadione (100 mu M) induced DNA smear in electrophoresis indicative of necrosis, lower concentrations (10-20 mu M) induced a DNA ladder indicative of apoptosis, Similar results were obtained using a DNA fragmentation ELISA. Glutathione (1 mM), the calcium chelator EGTA (500 mu M), and the cystein protease inhibitor NCO-700 (5 mM) partly inhibited the effect of 1-10 mu M menadione on cell proliferation and DNA fragmentation. Menadione at 1-20 mu M induced wild-type P53, whereas the 100 mu M menadione had a minor effect on wild-type P53. It is concluded that menadione induced necrosis at high concentrations and apoptosis at low concentrations in AR4-2J cells. Apoptosis induced by lower concentrations of menadione may be mediated by wild-type P53, intracellular calcium, and mechanisms which decrease the intracellular concentration of reduced glutathione. (C) 1997 Elsevier Science Inc.

A 55-year-old man with gallbladder cancer was surgically treated in our hospital in July 1988. The tumor was about 8 cm in diameter, replaced the entire gallbladder, and invaded the liver and the hepatoduodenal ligament. In addition, extensive tumor metastasis to lymph nodes, including those of the para-aortic area was noted (Stage IV). Extended cholecystectomy with resection of the liver and lymph node dissection were performed. Although all of the macroscopic tumors were removed surgically, toe believed that the tumor would recur in. the near future, since all of the excised para-aortic lymph nodes were involved by carcinoma histologically. After surgery, the patient received 5'-deoxy-5-fluorouridine (5'-DFUR) orally at a dose of 600mg per day. In December 1993, more than 5 years after the primary operation, cancer recurrence in para-aortic lymph nodes was demonstrated by computed tomography (CT). In June 1994, the patient underwent a second operation for treatment of recurrent tumor. The lymph nodes firmly adhered to both the aorta and left renal vein, and could not be removed. Since August 1994, he has received external radiation therapy, and there has been no further enlargement of the nodes. This is the first reported case of gallbladder cancer with para-aortic lymph node metastasis who survived more than, seven years after the primary extended radical operation with cholecystectomy, resection of the liver, and extended lymph node dissection.

Exocrine function was studied in anesthetized rats that had received two specific doses of caerulein (maximal stimulation and supramaximal stimulation). Male Wistar rats (body weight, 200-250 g) were divided into three groups: the control group (4-h saline infusion), the maximal stimulation group (0.25 mu g/kg per h caerulein for 4h), and the caerulein pancreatitis group (10 mu g/kg per h for 4h). Histologically, interstitial edema and cytoplasmic vacuolization were observed only in the caerulein pancreatitis group, with no abnormal findings in the other groups. The volume of pancreatic juice was significantly increased in both the maximal stimulation group and the caerulein pancreatitis group. The protein ouput and the amylase output in the 1st h of caerulein infusion were also significantly increased, to 459% and 338% in the maximal stimulation group, and to 925% and 1430% respectively, in the caerulein pancreatitis compared to the baseline values. We also found that the pancreatic juice of the caerulein pancreatitis group contained precipitated protein, and high trypsin activity, and protein degradation was confirmed by electrophoresis. These findings were not observed in the other groups. These results strongly suggest that hypersecretion and the appearance of trypsin activity in pancreatic juice plays an important role in the induction of histological changes in this pancreatitis model in anesthetized rats.

We report herein a rare case of malignant insulinoma which recurred as multiple liver metastasis 8 years after the initial resection, The patient was a 51-year-old Japanese man who originally presented in 1985 at the age of 43 years suffering from general malaise and syncope, The initial surgery in 1985 involved complete enucleation of a 15 X 13mm insulinoma located in the uncus of the pancreas, Histopathologically, the tumor was diagnosed as a benign adenoma (insulinoma) which was immunohistochemically stained with only the anti-insulin monoclonal antibody, Macroscopically, there were no signs of either invasion or metastasis. During the subsequent 7 years, he did not show any symptoms or significant abnormality in laboratory data, However, in 1993, the patient again experienced syncope with hypoglycemia and hyperinsulinemia. Ultrasonography revealed multiple echogenic lesions in the liver and a second laparotomy confirmed multiple hepatic metastases from insulinoma, the histopathological findings of which were similar to those of the primary tumor from 8 gears before, The patient is currently being treated with streptozotocin and 5-fluorouracil via a catheter in the hepatic artery.

Two cases of pancreatic cancer accompanied by pseudocyst are reported. Case 1 was a 60-year-old man who was admitted to our hospital complaining of left lower abdominal discomfort. A cystic lesion, about 3 cm in diameter, was found in the pancreatic tail by ultrasonography (US) and computed tomography (CT). No signs of chronic pancreatitis were found. At operation, an elastic, hard, white tumor, about 1 cm in diameter, was felt adjacent to the cystic lesion on the duodenal side. Histologically, this tumor was a duct cell carcinoma with an adjacent pseudocyst upstream of the pancreas. Case 2 was a 57-year-old man who complained of back pain and loss of body weight. US and CT examination revealed a cystic lesion, 11×7 cm in size, in the tail of the pancreas. Histological examination of the resected speciment revealed both a duct cell carcinoma, 3 cm in size, in the body of the pancreas and a pseudocyst, 9 cm in size. Pseudocysts accompanying carcinoma are thought to develop from obstruction of the pancreatic duct by the carcinoma, followed by intraductal high pressure and disruption of ductules upstream of the pancreas. Thus, we should pay careful attention to pseudocyst of the pancreas, especially when signs of diffuse chronic inflammation cannot be found, to help identify duct cell carcinoma in the early stage. Further detailed examinations of the cyst fluid or pancreatic juice, such as cytology, tumor marker determinations, or establishment of K-ras codon 12 mutation, are needed. © 1994 Springer-Verlag.

The intracellular distribution and action of a new synthetic protease inhibitor, E3123, were studied in cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by a 4-h iv infusion of a supramaximal dose of cerulein, and was treated by prophylactic (pretreatment) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophylactic treatment. A subcellular fractionation study showed that the activities of cathepsin-B and trypsin in the zymogen granule-enriched fraction of the cerulein-pancreatitis group were remarkably increased. Both prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied by amelioration of pancreatic histopathological features, including intracellular vacuolization and fat necrosis. A microscopic autoradiographic study using2H-labeled E3123 showed diffuse intracellular distribution of E3123, and the radioactivity of2H-E3123 in the posttreatment group was three times greater than that in the pretreatment group. This study provides the first experimental evidence that, even when administered therapeutically, exogenous protease inhibitors are transported into pancreatic acinar cells, thereby reducing the seventy of early intracellular alterations in cerulein-induced acute pancreatitis. © 1994 Humana Press Inc.

The intracellular distribution and action of a new synthetic protease inhibitor, E3123, were studied in cerulein-induced acute pancreatitis in rats. Acute pancreatitis was induced by a 4-h iv infusion of a supramaximal dose of cerulein, and was treated by prophylactic (pretreatment) or therapeutic (posttreatment) continuous administration of E3123. Pancreatic edema and hyperamylasemia were ameriolated only by prophylactic treatment. A subcellular fractionation study showed that the activities of cathepsin-B and trypsin in the zymogen granule-enriched fraction of the cerulein-pancreatitis group were remarkably increased. Both prophylactic and therapeutic treatment significantly prevented the elevation of these enzyme activities. These effects were accompanied by amelioration of pancreatic histopathological features, including intracellular vacuolization and fat necrosis. A microscopic autoradiographic study using H-3-labeled E3 123 showed diffuse intracellular distribution of E3 123, and the radioactivity of H-3-E3 123 in the posttreatment group was three times greater than that in the pretreatment group. This study provides the first experimental evidence that, even when administered therapeutically, exogenous protease inhibitors are transported into pancreatic acinar cells, thereby reducing the severity of early intracellular alterations in cerulein-induced acute pancreatitis.