Takanobu Hayakumo

Clinical significance of cathepsin E in pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma.

Background: It has been reported that cathepsin E (CTSE) is a non‐secretory and intracellular aspartic proteinase found in the superficial epithelial cells of the stomach and that it is also expressed in pancreatic ductal adenocarcinoma. We evaluated the diagnostic value of CTSE in the pancreatic juice in the diagnosis of pancreatic ductal adenocarcinoma compared with that of CA19–9, carcinoembryonic antigen (CEA) and K‐ras mutations.

Expression of cathepsin E in pancreas: A possible tumor marker for pancreas, a preliminary report

Ductal cancers of the pancreas frequently express markers of gastrointestinal epithelial cells. Cathepsin E (CTSE) is a non‐secretory, intracellular, but non‐lysosomal proteinase found in the highest concentration in the superficial epithelial cells of the stomach. The aims of our study were to examine the expression of CTSE in the pancreas, to establish an assay system of CTSE and to evaluate the diagnostic usefulness of CTSE in the pancreatic juice. Eleven patients with pancreatic ductal adenocarcinoma, 10 with mucin‐producing adenoma, 3 with intraductal papillary hyperplasia and 43 with chronic pancreatitis were examined. Surgically resected pancreatic tissues were subjected to immunohistochemistry for CTSE. Pancreatic juice was collected from the patients and subjected to sandwich ELISA and Western analysis for detecting CTSE. Positive staining for CTSE was observed in pancreatic ductal adenocarcinoma by immunohistochemistry. CTSE was also expressed in mucin‐producing adenoma, intraductal papillary hyperplasia and mucinous hyperplasia. CTSE in the pancreatic juice was present in 8 of 11 patients with pancreatic ductal adenocarcinoma, 5 of 10 patients with mucin‐producing tumor, 1 of 3 patients with intraductal papillary hyperplasia and 4 of 43 patients with chronic pancreatitis. The detection frequency of CTSE in the pancreatic juice was significantly higher in the patients with pancreatic ductal adenocarcinoma than in the patients with chronic pancreatitis. Our findings suggest that the expression of CTSE is associated with the pathogenesis of pancreatic ductal adenocarcinoma, that CTSE in the pancreatic juice seems to be a useful marker for a definitive diagnosis and that CTSE may be expressed at a relatively early stage of multistep carcinogenesis in pancreatic lesions.

Proton-pump inhibitor-first strategy versus "step-up" strategy for the acute treatment of reflux esophagitis : a cost-effectiveness analysis in Japan

BackgroundGastroesophageal reflux disease (GERD) is a common condition, and acid-suppressing agents are the mainstays of treatment. For the acute medical management of GERD, two different strategies can be proposed: either the most effective therapy, i.e., proton-pump inhibitors (PPIs), can be given first, or histamine H2-receptor antagonists (H2RAs) can be attempted first (the “step-up” approach).MethodsA clinical decision analysis comparing the PPI-first strategy and the H2RA-first “step-up” strategy for the acute treatment of reflux esophagitis in Japan was performed, using a Markov chain approach.ResultsThe PPI-first strategy was consistently superior to the step-up strategy with regard to clinical outcomes for the patient and with regard to cost-effectiveness (direct cost per patient to achieve clinical success). This superiority was robust within the plausible range of probabilities according to the sensitivity analyses.ConclusionsThe PPI-first strategy is superior to the H2RA-first “step-up” strategy with regard to both efficacy and cost-effectiveness and therefore, the PPI-first strategy is the preferred therapeutic approach for the acute medical treatment of reflux esophagitis.

Metabolomic analysis to discover candidate therapeutic agents against acute pancreatitis.

Novel and effective drugs against acute pancreatitis are required. Therefore, we examined the changes in the metabolite levels in the serum and pancreatic tissue of mice with cerulein- and arginine-induced pancreatitis using gas-chromatography/mass-spectrometry (GC/MS) and investigated whether these alterations affected the severity of acute pancreatitis. In the cerulein-induced pancreatitis model, 93 and 129 metabolites were detected in the serum and pancreatic tissue, respectively. In the L-arginine-induced acute pancreatitis model, 120 and 133 metabolites were detected in the serum and pancreatic tissue, respectively. Among the metabolites, the concentrations of tricarboxylic acid (TCA) cycle intermediates and amino acids were altered in pancreatitis, and in pancreatic tissue, the levels of the intermediates involved in the initial part of the TCA cycle were increased and those of the intermediates involved in the latter part of the TCA cycle were decreased. Some metabolites exhibited similar changes in both pancreatitis mouse models, e.g., the levels of glutamic acid and O-phosphoethanolamine were significantly decreased in the pancreatic tissue. Supplementation with glutamic acid and O-phosphoethanolamine attenuated the severity of cerulein-induced acute pancreatitis. Our results suggest that GC/MS-based metabolomics is capable of accurately representing the status of acute pancreatitis, leading to the discovery of therapeutic agents for pancreatitis.

Quantification of Pregenomic RNA and Covalently Closed Circular DNA in Hepatitis B Virus-Related Hepatocellular Carcinoma

Pregenomic RNA (pgRNA) is generated from covalently closed circular DNA (cccDNA) and plays important roles in viral genome amplification and replication. Hepatic pgRNA and cccDNA expression levels indicate viral persistence and replication activity. This study was aimed to measure hepatic pgRNA and cccDNA expression levels in various states of hepatitis B virus (HBV) infection. Thirty-eight hepatocellular carcinoma (HCC) patients, including 14 positive for hepatitis B surface antigen (HBsAg) and 24 negative for HBsAg but positive for anti-hepatitis B core (anti-HBc) antibody, were enrolled in this study. In HBsAg-negative but anti-HBc-positive group, HBV-DNA was detected in 20 of 24 (83%) noncancerous liver tissues for at least two genomic regions based on polymerase chain reaction (PCR) analysis. pgRNA and cccDNA expression levels in occult HBV-infected patients were significantly lower than those in HBsAg-positive patients (P < 0.001). pgRNA and cccDNA in cancerous tissues were also detected without significant difference from those in noncancerous tissues. In conclusion, cccDNA and pgRNA are detected and represented HBV replication not only in noncancerous but also in cancerous liver tissues. In addition, the replication is shown in not only patients with HBsAg-positive but also occult HBV-infected patients, suggesting the contribution to HCC development.

Adherence to the preventive strategies for nonsteroidal anti-inflammatory drug- or low-dose aspirin-induced gastrointestinal injuries.

As the aging of the population advances, the use of nonsteroidal anti-inflammatory drugs (NSAIDs) and/or low-dose aspirin (LDA) is increasing. Their use is accompanied by a risk of serious complications, such as hemorrhage or perforation of the gastrointestinal tract. Therefore, gastroprotective strategies upon the prescription of NSAIDs/LDA are outlined in several guidelines or recommendations. Because all NSAIDs including cyclooxygenase (COX)-2 inhibitors have cardiovascular (CV) toxicity, recent guidelines are based on not only GI risks but also CV risks of NSAID users. Assessment of the adherence to evidence-based guidelines or recommendations for the safe prescription of NSAIDs/LDA in clinical practice is an important issue. Here, we summarize randomized controlled trials (RCTs) on the preventive effects of antisecretory drugs for NSAID- or LDA-induced peptic ulcers. Then, we describe preventive strategies upon the prescription of NSAIDs/LDA outlined in several guidelines or recommendations, and describe studies on adherence and outcomes of adherence to these preventive strategies. Finally, we discuss strategies to increase the adherence rate, and changing pattern of GI events associated with NSAIDs/LDA. In Japan, the preventive strategies upon the prescription of NSAIDs/LDA are expected to spread rapidly because the use of proton pump inhibitors for the prevention of recurrence of NSAID- or LDA-induced peptic ulcers and the use of COX-2 for the palliation of acute pain were recently approved under the national health insurance system. Further studies on adherence to the preventive strategies and the outcomes of adherence, which include both GI events and CV events, in the Japanese population are required.

Duodenal protrusion by carcinosarcoma of the extrahepatic bile duct

Carcinosarcoma is a rare tumor and is pathologically composed of a mixture of malignant epithelial and mesenchymal components. We report a rare case of carcinosarcoma of the bile duct in which the tumor extended from the bile duct to the second portion of the duodenum. A 71-year-old man was admitted to our hospital due to repeated cholangitis. Contrast enhanced computed tomography showed an obstruction of the common bile duct and duodenum by a huge tumor extending from the bile duct to the duodenum (Fig. 1). Endoscopic retrograde cholangiopancreatography revealed a huge tumor with bleeding at the papilla of Vater, and a stent was successfully placed into the common bile duct (Fig. 2). The patient underwent pancreaticoduodenectomy. Gross examination of the resected specimen revealed a huge polypoid tumor (75 ¥ 50 mm) extending from the common bile duct into the duodenum. Histology showed both sarcomatous and adenocarcinomatous components. The sarcomatous lesion was dominant, and a few carcinomatous components existed in the bile duct wall and at the invasive front of the tumor. Sarcomatous cells were negative both for epithelial and nonepithelial markers, indicating that the tumor had no particular differentiation. The tumor was finally diagnosed as carcinosarcoma of the bile duct. Ki-67 index of the sarcomatous cells was 40%. His postoperative course was uneventful. Solitary liver metastasis was detected 3 months after the operation, and he died 10 months after the operation. Carcinosarcoma of the bile duct is extremely rare and has a dismal prognosis with no knowledge about the effective chemotherapy and radiotherapy. The only recognized treatment for this tumor is surgery. Although this tumor is generally discovered as a big polypoid tumor within the bile duct, our case developed beyond the bile duct into the duodenum. The high Ki-67 index of this tumor was indicative of the high proliferative activity of this tumor.

A case of lymphoepithelial cyst of pancreas with unique “cheerios-like” appearance in EUS

Lymphoepithelial cyst (LEC) of the pancreas is a rare benign lesion, which is difficult to diagnose preoperatively. We describe a case of a 60-year-old male, incidentally diagnosed as having LEC of the pancreas, which was managed by laparoscopic distal pancreatectomy. Most of the reported cases of LEC were asymptomatic and diagnosed incidentally. A high index of suspicion under EUS may help in making a diagnosis and avoiding unnecessary surgery in asymptomatic patients. In particular, the unique “cheerios-like” appearance of the lesion in EUS, which was also found in this case, might be helpful in the differential diagnosis of pancreatic cystic lesions.

Point mutations in the c-K-ras 2 gene in multiple colorectal carcinomas

Abstract The c‐K‐ras 2 gene mutations were examined in colorectal tumours from patients with synchronous or metachronous tumours in order to investigate tumorigenesis. Sixty‐seven colorectal carcinomas from patients with a single lesion, 50 from patients with synchronous lesions, and 12 from patients with metachronous lesions were analysed for the presence of point mutations in codons 12 and 13 of c‐K‐ras proto‐oncogene. In the patients with metachronous or synchronous lesions, the finding of the mutation in one tumour was not associated with a greater frequency of the mutation in other carcinomas from the same patient. In the patients with tumours that each contained the mutation, the mutations were not always the same. In tumours from the patients with original and synchronous lesions, the mutation frequency was significantly lower in advanced carcinomas invading through the entire muscularis propria (10.5%) than in early carcinomas confined to the mucosa (47.8%), and the mutation frequency in carcinomas invading through the entire muscularis propria was significantly lower in patients with synchronous lesions (10.5%) than in patients with a single lesion (37.7%). These results suggest that the tumorigenesis of colorectal carcinomas from patients with synchronous lesions is different from that in patients with a single lesion.

What is the most adapted indication of prophylactic pancreatic duct stent within the high‐risk group of post‐endoscopic retrograde cholangiopancreatography pancreatitis? Using the propensity score analysis

Conducting randomized controlled trial (RCT) for each of the risk factors associated with prophylactic pancreatic duct stent (PPDS) for post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is difficult owing to the volume of cases and ethical considerations. In this study, we tried to reveal the degree of preventive effects of PPDS for each individual risk factor within the high‐risk group of PEP using the propensity score analysis.