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Since telomerase expression is highly prevalent in human cancers, the quantitation of serum/plasma hTERT (human telomerase reverse transcriptase) mRNA levels may be useful for early detection of PCa (pancreatic cancer). To analyse the correspondence between exhTERT (extracellular hTERT) mRNA levels and hTERT expression, we designed a cell culture system to investigate factors modulating the extracellular levels of hTERT mRNA in media conditioned by eight PCa cell lines. We found that the level of exhTERT mRNA was dependent on cell growth rate. MIAPaCa-2, PANC-1, KLM-1 and PK-9 cells expressed high levels of exhTERT mRNA, independent of cell density, whereas proliferating PK-59, BxPC-3 and PK-45H cells released low levels of exhTERT mRNA. The augmented release of mRNA by spontaneous dead MIAPaCa-2 cells was further increased at postconfluence. In Capan-1 cells, low correspondence of marker was also due to RNase secretion. Upon reaching confluence, some PCa cell lines showed down-regulation of hTERT expression. Following cell-cell adhesion, as shown by E-cadherin engagement, PK-59 cells showed levels of extracellular message below the limits of detection, a loss not due to an increase in message degradation. These results suggest that the levels of exhTERT mRNA in the medium of PCa cell lines are altered not only in response to cell growth rate and cell destruction, but are responsive to extracellular cues such as RNases and cell density. A cell-free assay for exhTERT mRNA may therefore not be useful for early detection of PCa. © The Author(s) Journal compilation © 2012 International Federation for Cell Biology.

金沢大学医学部附属病院がん高度先進治療センター, We report a 48-year-old man with hepatocellular carcinoma (HCC) treated with hepatic arterial infusion (HAI) chemotherapy followed by proton beam therapy. The HCC lesion in this patient was 88 mm in diameter, with portal vein tumor thrombosis in the right lobe of the liver. He was first treated with 5-fluorouracil, cisplatin, and isovorin, administered by HAI, combined with interferon-α, and he was subsequently treated with epirubicin and mitomycin-C administered by HAI. However, no definite efficacy of either of these treatments was observed. Then, after 3 weeks' continuous administration of irinotecan by HAI, the tumor size decreased to 68 mm in diameter. However, 3 months after reduction of the tumor, the tumor had become enlarged to 100 mm in diameter and intrahepatic metastases were prominent. Angiographic findings indicated that the HCC was fed not only from the right hepatic artery but also from the left gastric and right and left subphrenic arteries. After rearrangement of the arteries, and 3 months' continuous HAI chemotherapy with irinotecan, plus hyperthermia, the tumor size had decreased to 50 mm in diameter. The reduction rate of the main tumor according to the Response Evaluation Criteria in Solid Tumors was 43%; therefore, the efficacy of this treatment was judged as a partial response. Two months after reduction of the tumor, the patient's serum alpha-fetoprotein (AFP) level was elevated, and so docetaxel was administered by HAI instead of irinotecan. The liver tumors showed gradual enlargement during the administration of docetaxel, although the AFP level was suppressed. Proton beam therapy was instituted and the liver tumors showed necrosis after this therapy. The patient died of hepatic failure and distant metastases 6 years after the onset of HCC. As far as we know, this is the first case report of HCC treated effectively with irinotecan administered by HAI followed by proton beam therapy in which tumor suppression and the long-term survival of the patient were observed. © 2009 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.

Because autoimmune pancreatitis (AIP) responds well to corticosteroids, many AIP patients are given this treatment. However, there is no consensus on the indications, dose, or duration of steroid treatment. The aim of this study was to establish the most appropriate steroid therapy regimen.We retrospectively reviewed morphological and serological improvement after steroid therapy and long-term outcome including relapse in 41 AIP patients who were given steroid therapy and were prospectively followed-up for more than 1 year.All patients responded to steroid therapy, which was given because of bile duct stenosis secondary to sclerosing cholangitis in 34 AIP patients. Pancreatic enlargement normalized within one month; however, 13 patients had incomplete resolution of pancreatic duct narrowing, and 14 patients had incomplete resolution of bile duct stenosis. There was no correlation between the degree of morphological improvement and the initial prednisolone dose (30 mg and 40 mg/day). In 58% of 19 patients, serum IgG4 elevation failed to normalize. Glucose intolerance improved in 38% of the 21 patients with diabetes mellitus. Nine patients who had complete morphological and serological resolution, stopped their medication, and none have relapsed. Thirty-two patients continued maintenance therapy, and 4 of these patients suffered relapse.The indications for steroid therapy in AIP patients include bile duct stenosis caused by sclerosing cholangitis and other systemic diseases, such as retroperitoneal fibrosis and diabetes mellitus. We recommend that oral prednisolone be used at an initial dose of 30 mg/day; maintenance therapy is required in cases without complete morphological and serological resolution.

Aberrant methylation of CpG islands is a common mechanism for the dysregulation of tumor suppressor genes in a variety of human malignancies. Preproenkephalin ppENK) hypermethylation is recognized in 90% of pancreatic carcinoma (PCa) tissues, but not in normal pancreas. We analyzed ppENK hypermethylation in pure pancreatic juice (PPJ) in patients with PCa, intraductal papillary mucinous neoplasms (IPMN), and chronic pancreatitis (CP), and elucidated its usefulness as a marker in the diagnosis of PCa compared with p53 mutation. PPJ was collected endoscopically from 28 patients with PCa, 15 patients with IPMN, and 20 patients with CP. DNA was extracted from the supernatant and the sediment of PPJ. Methylation-specific polymerase chain reaction was performed for hypermethylation analysis of ppENK. In addition, single-strand conformation polymorphism and direct sequencing were performed simultaneously to identify p53 mutations. The incidence of ppENK hypermethylation in the supernatant and/or the sediment of PPJ was 50% (14 of 28) in patients with PCa. In contrast, the incidence of ppENK hypermethylation was 26.7% (4 of 15) in patients with IPMN, and 5% (1 of 20) in patients with CP (P < 0.002). The incidence of p53 mutations in the PPJ was 42.9% (12 of 28) in patients with PCa and 0% (0 of 20) in patients with CP. Furthermore, the incidence of ppENK hypermethylation and/or p53 mutations in the PPJ was enhanced to 67.9% (19 of 28) in patients with PCa in the combination assay. These results suggest that ppENK hypermethylation in PPJ is specific for cancer, and the combination assay with p53 enhances the genetic diagnosis of PCa.

金沢大学がん研究所, Aim: To investigate the expression of genes involved in the gemcitabine-induced cytotoxicity in human pancreatic cancer cells. Methods: A human pancreatic cancer cell line, PANC-1, was cultured. 1 × 104 PANC-1 cells were plated in 96-well microtiter plates. After being incubated for 24 h, gemcitabine was added to the medium at concentrations ranging 2.5 -1 000 mg/L. The AlamarBlue dye method was used for cell growth analysis. DNA fragmentation was quantitatively assayed using a DNA fragmentation enzyme-linked immunosorbent assay (ELISA) kit. PAP and TP53INP1 mRNA expression was determined using the reverse transcription-polymerase chain reaction with semi-quantitative analysis. The expression of GSK-3β and phospho-GSK-3β proteins was examined with Western blot analysis. Results: The IC50 for the drug after a 48-h exposure to gemcitabine was 16 mg/L. The growth of PANC-1 cells was inhibited by gemcitabine in a concentration-dependent manner (P< 0.0001) and the cell growth was also inhibited throughout the time course (P

In the gene expression analysis of pancreatic carcinoma (PCa) using serial analysis of gene expression (SAGE) according to Ryu et al, the tag for the mesothelin mRNA transcript was present in 7 of 8 SAGE libraries derived from PCa but not in the 2 SAGE libraries derived from normal pancreatic duct epithelial cells. Mesothelin mRNA expression was confirmed with in situ hybridization in all 4 resected primary PCa tumors and with RT-PCR in 18 of 20 PCa cell lines, whereas mesothelin protein expression was confirmed with immunohistochemistry in all 60 resected primary PCa tissues by Argani et al. We evaluated mesothelin mRNA expression in pure pancreatic juice (PPJ) obtained from patients with PCa, chronic pancreatitis (CP), and intraductal papillary mucinous neoplasm (IPMN) of the pancreas.We evaluated mesothelin mRNA expression in the PPJ obtained from 21 patients with PCa, 22 with CP, and 11 with IPMN with reverse transcriptase PCR (RT-PCR). The PCR products were analyzed with agarose gel electrophoresis. DNase I treatment before RT-PCR and direct sequencing of the RT-PCR bands were performed for the analysis of the RT-PCR bands.Two products, of 308 and 226 bp, were obtained with RT-PCR, and the 308-bp RT-PCR product was confirmed as being that derived from the genomic DNA by direct DNA sequencing. Mesothelin mRNA expression was discovered using RT-PCR in 11 (52%) of 21 patients with PCa, 5 (45%) of 11 with IPMN, and 3 (14%) of 22 with CP. Fisher's exact test revealed significant differences between PCa and CP for mesothelin mRNA (P0.01). Moreover, the RT-PCR product (226 bp) of mesothelin mRNA in the PPJ samples with PCa was generally stronger than that in the PPJ samples with IPMN.Expression of mesothelin mRNA in PPJ was not strictly specific to PCa and was apt to be stronger in PCa than in IPMN. Quantitative detection of mesothelin mRNA in PPJ may have potential diagnostic implications for pancreatic tumors.

We developed and established a new dose-finding system, the individualized maximum repeatable dose (iMRD), suitable to induce prolonged TTP rather than tumor shrinkage.We applied this system in weekly gemcitabine therapy for 18 metastatic pancreas cancer patients. We determined the iMRD at the 5th week, after weekly dose adjustments. We started at 500 mg/m2 (1/2 maximum tolerated dose) of gemcitabine and repeated the treatment with an increase or a decrease of 100 mg/m each week, if toxicity was 0 or more than grade 1, respectively.The iMRD of weekly gemcitabine was 300 mg/m2 in 2 patients, 400 mg/m2 in 3 patients, 500 mg/m2 in 5 patients, 600 mg/m2 in 6 patients, and 700 mg/m2 in 2 patients, demonstrating significant differences among individual patients. Grade 3 marrow depression occurred in only 1 patient (5.6%). Of these 18 patients, 3 (16.7%), 13 (72.2%) and 2 (11.1%) patients showed partial response, stable disease, and progressive disease, respectively. The median of times to progressive disease and survival were 4.5 and 9.5 months, respectively. There were no significant differences in 1-year survival time and more than 50% reduction rate of serum CA19-9, a tumor marker for pancreatic cancer, between patients with lower (500 mg/m2 or less) and higher (600 mg/m2 or more) iMRD.These results suggest that iMRD is a simple method to determine an individual's tailored dose for chemotherapy and could be the optimal dose for patients with noncurable cancers such as metastatic pancreas cancer.

We report a rare case of an epidermoid cyst in an accessory spleen at the pancreatic tail with producing CA19-9. A 55-year-old female was admitted to our hospital, Cancer Research Institute, Kanazawa University, for close examination of a cystic lesion at the pancreatic tail and a high serum CA19-9-value (176 U/mL). There were almost no abdominal symptoms related to the cystic lesion. A cystic tumor approximately 3 cm in diameter and composed of multilocular cysts without a protruding portion of the inner surface was found at the pancreatic tail by ultrasound sonography, computed tomography, and magnetic resonance imaging. Endoscopic retrograde pancreatography revealed that the main pancreatic duct shifted at the pancreatic tail and there was no communication between the main pancreatic duct and cystic lesion. Based on a preoperative diagnosis of mucinous cystic tumor, distal pancreatectomy with splenectomy was performed. Histological findings suggested an epidermoid cyst (3.5 × 3.0 cm) originating from an intrapancreatic accessory spleen. Immunohistochemical analysis of CA19-9 in the epidermoid cyst showed clear staining of the inner epithelium of the cyst and amorphous or hyalinous cystic contents. The serum CA19-9 value was confirmed to decline to normal 2 months after resection. Physicians should not forget this disease during differential diagnosis related to pancreatic cystic lesions with elevated levels of serum tumor markers, such as CA19-9 or carcinoembryonic antigen, although this disease is extremely rare.

Background. Abnormalities of the tumor suppressor gene p16 have been reported in a variety of human tumors but are rare in pancreatic carcinoma except for cancer cell lines and xenografts. Their clinicopathological significance remains unknown. The purpose of this study was to examine immunohistochemical and genetic alterations of p16 in primary pancreatic carcinoma tissues and to investigate the relation between abnormalities of p16 and clinicopathological parameters to elucidate their clinicopathological significance. Methods. We investigated p16 expression in 60 pancreatic carcinoma cases by immunohistochemistry using a monoclonal antibody clone G175-405. In addition, we analyzed genetic alterations of the p16 gene using DNA extracted from microdissected tissue of pancreatic carcinoma, by polymerase chain reaction, nonradioisotopic single-strand conformation polymorphism (non-RI-SSCP), DNA sequencing, and hypermethylation analyses using restriction enzymes. We compared the abnormalities of p16 alterations with clinicopathological parameters to elucidate their significance. Results. On immunohistochemical study, staining for p16 protein was strongly positive in 22 (37%) of 60 pancreatic carcinoma cases, weakly positive in 24 (40%), and negative in 14 (23%). In contrast, p16 mutations were recognized in 9 (15%) of the 60 pancreatic carcinoma cases. The incidence of p16 mutations was 2 (9%) in 22 cases of pancreatic carcinoma with strongly positive staining, 4 (17%) in 24 with weakly positive staining, and 3 (21%) in 14 with negative staining. Hypermethylation of p16 was detected in the two pancreatic carcinoma cases with weakly positive staining, although homozygous deletions were not found in any case. There was no significant correlation between the expression of p16 protein and any of the clinicopathological parameters. However, there was a tendency for the tumor to be larger in patients with decreased expression of p16 protein than in those with normal expression levels. In contrast, the tumor was significantly larger and the survival period significantly shorter for patients with pancreatic carcinoma with p16 mutation or hypermethylation than for those with pancreatic carcinoma with an intact p16 gene (P ≪ 0.05). Conclusions. These findings suggest that p16 alterations may participate in the aggressiveness of pancreatic carcinoma.

Background: This study was performed to determine the echo layer structures of the normal gastric wall and early gastric cancer when visualized with a 30-MHz ultrasonic miniprobe. Methods: Twelve surgically resected gastric specimens were used for an ex vivo study. Eighteen normal sites and 12 early gastric cancer sites were scanned with an Olympus (XUM-S30-25R) probe with a frequency of 30-MHz. Endoscopic ultrasound images were compared with corresponding histopathologic sections stained with hematoxylin and eosin. Results: The normal mucosa was visualized as at least four alternating echo layers; the muscularis mucosa was delineated at all normal sites. Lymphoid aggregates within the mucosa could be seen. The submucosa was clearly visualized in most cases, but the muscularis propria and subserosa were seldom depicted due to attenuation of ultrasound waves. At the sites of gastric cancer, the layered architecture of the mucosa was disturbed by an irregular hypoechoic lesion. Minimal submucosal infiltration (400 and 750 μm) was clearly depicted in two cases, without ulceration at or around the tumor site. However, attenuation at the site of a deep ulcer scar prevented adequate visualization of the tumor extent in two other cases with ulceration. Conclusion: A 30-MHz ultrasonic miniprobe may provide additional imaging information of the gastric wall and could play a role in the assessment of early cancer lesions.

Pancreatitis-associated protein (PAP) is almost absent in normal pancreas, but is strongly induced in acute pancreatitis. PAP mRNA is also expressed in cancer cells, including pancreatic ductal adenocarcinoma. However, the clinicopathological significance of PAP in human pancreatic cancer is not clear. We examined PAP expression in pancreatic tissues from individuals with pancreatic ductal adenocarcinoma using immunohistochemistry. PAP was overexpressed in 79% (30 of 38) of pancreatic ductal adenocarcinoma, 19% (7 of 36) of chronic pancreatitis, and 29% (2 of 7) of mucinous cystadenoma. PAP was found in malignant ductular structures in pancreatic carcinomas as well as in benign proliferating ductules and acinar cells in chronic pancreatitis. It was not expressed in normal pancreas. The incidence of PAP overexpression was significantly higher in pancreatic cancer than in the other pancreatic diseases (P < 0.01). PAP overexpression was significantly correlated with nodal involvement, distant metastasis (P < 0.05), and short survival (P < 0.01) in pancreatic cancer. These results suggest that overexpression of PAP in human pancreatic ductal adenocarcinoma indicates tumor aggressiveness.

Clusterin, also known as apolipoprotein J, has been implicated in numerous processes, including active cell death. Clusterin is reported to be overexpressed in breast and prostate cancers. However, its expression in pancreatic cancer is yet to be reported.To examine clusterin expression and apoptosis in 52 pancreatic tissues, including specimens from 33 cases of pancreatic cancer, by immunohistochemistry.Clusterin was expressed in 49% (16) of 33 cases of pancreatic cancer, 50% (13) of 26 cases of chronic pancreatitis, and 67% (4) of 6 cases of mucinous cystadenoma. It was not expressed in normal pancreas. Clusterin mRNA was also expressed in the pancreatic cancer cell lines. Clusterin was significantly more highly expressed at stage I and II (well-differentiated and moderately differentiated cancers). Clusterin and apoptosis were localized in the same cells in pancreatic cancer. However, clusterin expression was not significantly associated with apoptosis in any pancreatic disease. Clusterin-positive patients with pancreatic cancer survived significantly longer.These results suggest that clusterin expression is induced in pancreatic cancer as well as chronic pancreatitis and that downregulation of clusterin may be involved in the progression of pancreatic cancer.

The sensitivity of bile cytology for the diagnosis of biliary tract carcinoma (BTCa) is still low. In addition, the incidence of detection of genetic mutations in the bile of BTCa is not satisfactory yet. To improve the molecular diagnosis of BTCa, we analyzed p53 and K-ras mutations in DNA extracted from not only the sediment but the supernatant of bile samples. Methods: Polymerase chain reaction-single-strand conformation polymorphism and direct sequencing were used for analyses of p53 mutations in exons 5 through 8. K-ras mutations at codon 12 were examined by mutant allele-specific amplification. Results: In bile supernatant from patients with BTCa, p53 and K-ras mutations were detected in 50.0% (15/30) and 56.7% (17/30) of cases, respectively. The incidence of p53 and K-ras mutations in the sediment was 33.3% and 43.3%, respectively. When a combination assay with both genes was used, molecular abnormalities were detected in 80.0% of cases, including 3 in which p53 alone was positive. In addition, either p53 or K-ras mutations were detected in 12 of 15 (80.0%) cases of BTCa in which the cytologic diagnoses were negative. p53 mutations were detected in neither supernatant nor sediment in 20 patients with cholelithiasis, although the incidence of K-ras mutations in the sediment was 20%. Conclusions: The incidence of p53 and K-ras mutations is higher in the supernatant than in the sediment, and simultaneous analyses of p53 and K-ras in the two bile fractions could enhance the genetic diagnosis of BTCa. Notably, the specificity of p53 mutations for cancer was very high in bile samples, and the sensitivity was also relatively high.

Background: This study aimed to evaluate a three-dimensional endoscopic ultrasonographic (3-D EUS) system in the assessment of the tumor invasion depth of early gastric carcinoma. Methods: Sixty-nine macroscopically early cancer lesions in 67 patients were recruited in an in vivo study. The surgically resected gastric specimens of 30 of them were re-examined in an ex vivo study. An Olympus 3-D EUS imaging system was employed in both studies. Diagnostic accuracy for tumor invasion depth was evaluated and compared with histopathological sections stained by H&E and Masson’s trichrome stain. Reconstructed surface-rendering images were evaluated and compared with the endoscopic and macroscopic findings. Results: Three-dimensional EUS allowed rapid tomographic assessment of the lesions in both the in vivo and ex vivo studies. The accuracy of 3-D EUS for the assessment of tumor invasion depth was 87% in the in vivo study. The accuracy rate was significantly lower (P = 0.03) for the cancer lesions associated with ulcer fibrosis (74%) than for those with no fibrosis (97%). In the 30 subjects who underwent both studies, the accuracy rates were higher in the ex vivo than the in vivo study (94%vs 77% for all the lesions, and 93%vs 74% for cancers associated with fibrosis), but were not statistically significant. The rates of good surface-rendering images were 64% and 94% in the in vivo and ex vivo studies, respectively. The differences were attributed to the clearer dual-plane reconstruction images obtained in the ex vivo study in absence of motion artifacts. Conclusions: Three-dimensional EUS is a promising imaging technique for the assessment of tumor invasion depth of early gastric cancer.

INTRODUCTION The pathogenesis of chronic pancreatitis (CP), especially of acinar cell injury, is still unclear. Interleukin (IL)-8 is a chemokine that is involved in various inflammatory diseases. AIM To examine whether IL-8 and other chemokines are expressed in experimental acinar cell injury. METHODOLOGY IL-8 expression was analyzed in spontaneous CP in the WBN/Kob rat and in rat pancreatic acinar AR4-2J cells treated with various stimuli using reverse transcription-polymerase chain reaction (semiquantitative) and immunohistochemistry. RESULTS Chronic pancreatitis developed at 12 weeks in the WBN/Kob rats. IL-8, macrophage chemoattractant protein-1, and macrophage inflammatory protein-2 mRNA was expressed from 4 weeks and peaked at 12 weeks. Immunohistochemistry showed a strong expression of IL-8 in acinar cells, proliferating ductular cells, and interstitial infiltrating cells. In contrast, normal pancreatic tissues lacked IL-8 expression. Further, IL-8 mRNA and protein were detectable in AR4-2J cells treated with the various stimuli, such as menadione, tumor necrosis factor-alpha and transforming growth factor beta1. CONCLUSION These results suggest that IL-8 is expressed in the pancreatic parenchyma and infiltrates in CP and that it plays a role in the initial pathogenesis of CP together with other chemokines and cytokines.

This study aimed to analyze the therapeutic effects of the carboxamide derivative IS-741 on spontaneous chronic pancreatitis (CP) in the WBN/Kob rat. Four-week-old male WBN/Kob rats were fed with MB-3, and IS-741 (0.012% in MB-3) was orally administered for 12 weeks. Cytokine-induced neutrophil chemoattractant (CINC), interleukin (IL) -6, pancreatitis-associated protein (PAP), and p8 mRNAs in the pancreas were detected with semiquantitative reverse transcription-polymerase chain reaction (RT-PCR). Histological examination of the pancreas showed that hemorrhage, interstitial edema, and inflammatory cell infiltration were markedly less severe at 12 weeks, while fibrosis and acinar degeneration were also milder at 16 weeks, in the IS-741-treated rats than in untreated rats. The above-mentioned genes were significantly suppressed in IS-741-treated rats at 12 weeks. Our results show that IS-741 exerts a potentially therapeutic effect on experimental CP by suppressing the expressions of the proinflammatory cytokines (IL-6 and CINC) and pancreatic acute phase proteins (PAP and p8).

A 22-year-old woman with Gardner's syndrome in whom long-term sulindac therapy, without surgical treatment, was effective in inducing complete regression of colonic adenomas is reported. One hundred milligrams of sulindac was administered twice daily after endoscopic polypectomy. Follow-up colonoscopy 6 months later revealed an encouraging regression of colonic adenomas. The tumors had disappeared after 40 months of sulindac treatment. A sustained effect was identified even after 51 months. Ten milligrams of famotidine was coadministered to prevent side effects of sulindac. Although the effect of sulindac on colorectal adenomas may be transient, this therapy may be useful for postponing prophylactic colectomy, especially for the sparse type of familial adenomatous polyposis.

Aims: To ascertain whether analysis of K-ras mutations at codon 12 (KRM) in the supernatant of pure pancreatic juice (PPJ) is more useful for the diagnosis of pancreatic carcinoma (PCa) than that in sediment, the authors analyzed KRM in DNA extract from not only the sediment but also the supernatant of PPJ and compared the results. Methodology: PPJ was collected endoscopically from 19 patients with PCa and 25 patients with chronic pancreatitis (CP). DNA was extracted from the supernatant and the sediment of PPJ. Mutant allele-specific amplification (MASA) was performed for KRM analysis with the DNA extracts from these samples. Results: The incidence of KRM in the supernatant of PPJ was 89% (17 of 19) in patients with PCa and 28% (7 of 25) in patients with CP, whereas that in the sediment was 79% (15 of 19) in patients with PCa and 20% (5 of 25) in patients with CP. Although there was no significant difference in KRM incidence between supernatant and sediment, the positive rate of KRM was higher in the former. Additionally, with regard to the PCa cases, KRM were found in the supernatant alone in four cases and in the sediment alone in two cases. Consequently, by a combination assay, all of the patients with PCa showed KRM in either the supernatant or sediment of PPJ. Although there was no relation between the incidence of KRM in PPJ and the location and size of tumor, and clinical stage of carcinoma in the patients with PCa, two patients with clinical stage I disease showed KRM in the supernatant. Conclusion: These results suggest that the positive rate of KRM in the supernatant is not lower than that in the sediment, and simultaneous analysis of KRM in the supernatant and sediment of PPJ enhances the genetic diagnosis of PCa.

An oral protease inhibitor, camostat mesilate (CM) has been used clinically for chronic pancreatitis (CP) in Japan, but it lacks enough scientific evidence of its effectiveness. The aim of this study was to analyze the effect of CM on the gene expressions of pancreatitis-associated protein (PAP), p8, and cytokines such as interleukin-6 and transforming growth factor-beta1 in spontaneous CP model (WBN/Kob rats). CM (10 mg/100 g body weight), mixed in MB-3 diet, was administered orally and gene expressions were analyzed by reverse transcription-polymerase chain reaction. In untreated WBN/Kob rats, the gene expressions of all the four factors peaked at 12 weeks, whereas they were significantly suppressed in the CM-treated rats. CM significantly increased the body weight and pancreatic wet weight, and it significantly inhibited inflammatory changes and fibrosis of the pancreas. These results suggest that CM inhibits pancreatic inflammation and fibrosis through the suppression of gene expressions of PAP, p8, and cytokines in CP.

In an attempt to clarify the mechanism of the effect of a herbal medicine, Saiko-keishi-to (TJ-10), which is a combination of Keishi-to (TJ-45) and Sho-saiko-to (TJ-9), we investigated the effects of these two herbal medicines and their components on pancreatic acinar cell injury models in vivo and in vitro.Four-week-old male WBN/Kob rats were fed an MB-3 pellet diet containing herbal medicine (TJ-9, TJ-10 and TJ-45). Expressions of pancreatitis-associated protein (PAP) and manganese superoxide dismutase (Mn-SOD) were analyzed with a reverse transcription-polymerase chain reaction (RT-PCR) and immunohistochemistry. The herbal medicines and two of their components, Keihi (Cinnamomi cortex) and Shakuyaku (Paeoniae radix alba), were tested in vitro using an arginine-treated rat pancreatic acinar AR4-2J cell injury model. The inducible nitric oxide synthase (iNOS) was assayed in in vitro experiments.TJ-45-treated WBN/Kob rats showed no evidence of pancreatitis whereas there were pathological changes of chronic pancreatitis in TJ-9-treated WBN/Kob rats. PAP was not expressed and Mn-SOD expression was increased in the TJ-10-, and TJ-45-treated rats. The herbal medicines and two components suppressed PAP mRNA expression and enhanced Mn-SOD and iNOS mRNA expression in arginine-treated AR4-2J cells.These results suggest that the herbal medicine TJ-45 is effective for chronic pancreatitis caused by pancreatic ischemia.

金沢大学医薬保健研究域医学系, A 43-year-old woman with a huge portal-systemic shunt accompanied by myxedema showed slow speech and behavior. Several imaging studies revealed a bold portal-systemic shunt from the splenic vein to the left renal vein. In addition, hypothyroidism caused by chronic thyroiditis was diagnosed, and synthesized thyroxine replacement was effective for the symptoms. However, the serum ammonia and indocyanin green retention remained in the abnormal range, nevertheless the portal vein pressure was normal and findings of liver cirrohsis were not recognized histologically. Surgical shunt closure was performed, resulting in normalized serum ammonia levels and serum branched chain amino acids/aromatic amino acids ratio, and improvement of the ammonia tolerance test.

Chronic pancreatitis is characterized by fibrosis. We reported an anti-inflammatory effect of the herbal medicine Saiko-keishi-to (TJ-10) on chronic pancreatitis. This study aimed to elucidate the antifibrotic effect of TJ-10. Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3) with or without TJ-10 (80 mg/100 g body weight) for 20 weeks. Pancreata were histopathologically examined at every 4 weeks, and the expression of fibrosis-related factors such as transforming growth factor beta1 (TGF-beta1), fibronectin (FN), alpha-smooth muscle actin (alpha-SMA), and type III collagen was analyzed. In untreated WBN/Kob rats, chronic pancreatitis developed at 12 weeks and progressed with marked fibrosis at 16 weeks, and the expression of TGF-beta1 and FN peaked at 12 weeks. However, in the TJ-10-treated rats, the rate of pancreatic fibrosis and the expression of TGF-beta1, FN, alpha-SMA, and type III collagen at 12 and 16 weeks decreased significantly compared to those in the untreated rats. These results suggest that TJ-10 inhibits the pancreatic fibrosis by the suppression of TGF-beta1 expression.

The p8 gene is barely expressed in the normal pancreas, but is overexpressed in acute pancreatitis. To elucidate the dynamic expression of p8 mRNA and its significance in the course of chronic pancreatitis, we investigated the p8 expression in spontaneous chronic pancreatitis in the WBN/Kob rat as well as in humans and arginine-treated rat pancreatic acinar AR4-2J cells. p8 mRNA was significantly increased at 12 weeks when chronic pancreatitis first appeared in the WBN/Kob rats. p8 was immunolocalized in the acinar cell nuclei. Acinar cell apoptosis was significantly increased at 12 and 20 weeks in the WBN/Kob rats. In AR4-2J cells, p8 mRNA was significantly induced at 4 hr after arginine addition. Apoptosis of AR4-2J cells was not increased during the strong expression of p8 mRNA. These results suggest that p8 is induced in the acinar cells during chronic pancreatitis as the self-defence mechanism against proapoptotic insults.

The Fas/Fas ligand (FasL) system is suggested to be correlated to the onset of inflammation and apoptosis in various diseases. However, whether Fas and FasL are expressed in chronic pancreatitis is unknown. The aim of this study was to examine the expression of the Fas/FasL system and to analyze its correlation with apoptosis in a spontaneous chronic pancreatitis model (the WBN/Kob rat). Four-week-old male WBN/Kob rats were fed a special pellet diet (MB-3). Different groups of rats were killed every four weeks, and pancreata were histopathologically examined. Fas and FasL mRNAs in the pancreas were detected with a reverse transcription-polymerase chain reaction method. The cellular localization of Fas and FasL mRNA and protein was determined with in situ hybridization (ISH) and immunohistochemistry (IHC). Apoptosis was detected with a terminal deoxynucleotidyltransferase-mediated method. Fas and FasL mRNA were expressed when the pancreas was still pathologically normal, and showed a biphasic peak at 12 and 20 weeks. ISH and IHC confirmed that Fas and FasL are expressed in the cytoplasm of acinar cells, ductal cells, and lymphocytes. An apoptotic index in acinar cells correlated to the expression of Fas and FasL mRNAs. These results suggest that the expression of the Fas/FasL system is involved in acinar cell apoptosis and the onset and progression of chronic pancreatitis in the WBN/Kob rat.

Pancreatitis-associated protein (PAP), the acute-phase protein of the pancreas, is overexpressed in acute pancreatitis. Serum PAP levels were reported to be useful as an indicator of the severity, prognosis and healing of acute pancreatitis. Although PAP was originally identified in pancreatic juice, there has been no clinical report on PAP levels in pancreatic juice. This study was conducted to determine levels of PAP in pancreatic juice (PJ-PAP) in various human pancreatic diseases.PAP levels in endoscopically aspirated PJ were measured by enzyme-linked immunosorbent assay in 86 patients with pancreatic diseases.55% of 22 patients with pancreatic cancer (PC) and 25% of 49 patients with chronic pancreatitis (CP) were positive (350 ng/ml) for PJ-PAP. PJ-PAP levels were significantly higher in PC than in CP, in which PJ-PAP was also significantly higher than in 15 control subjects. There was no significant correlation between PJ-PAP and serum PAP, and combination assay of serum PAP and/or PJ-PAP detected 80% of PC cases and 44% of CP cases.We have demonstrated that human PAP could be detected in pancreatic juice from patients with pancreatic diseases. Determination of PAP in pancreatic juice might be helpful for early detection of pancreatic injury.

A 55-year-old man with nonfunctioning islet cell carcinoma showing elevation of serum carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) levels is described with genetic analyses. Pathological examination of the resected specimen revealed two independent islet cell carcinomas, one in the body and the other in the tail of the pancreas. It was proved immunohistochemically that the tumor cells, particularly those in the tail, were immunoreactive to CEA and CA 19-9 and had the property of duct cells, as well as endocrine cells. Gastrin was demonstrated immunohistochemically in these tumor cells, although its level in serum was not elevated. Genetic analyses of the fresh specimens from the tumor in the body revealed K-ras codon 12 mutation and microsatellite instability. These findings are consistent with its progressive clinical course and strongly suggest that these tumors originate, not from the islet cells of Langerhans, but from protodifferentiated cells, capable of giving rise to all the pancreatic cell types.

Background. In an attempt to obtain evidence of the beneficial effects of TJ-10, we investigated the gene expression of PAP, an acute phase protein specific for pancreatitis in rat spontaneous chronic pancreatitis. Methods. Four-wk-old male WBN/Kob rats were fed with MB-3 pellet diet containing herbal medicine. There were two administration groups for each drug: the prophylactic group administered from 4–12 wk, and the therapeutic group administered from 12–20 wk. Untreated control rats were fed with MB-3 alone. Histopathologic changes and PAP gene expressions were analyzed at 12 and 20 wk. Results. In the prophylactic group, TJ-10-treated WBN/Kob rats showed no evidence of pancreatitis, and there was the amelioration of pancreatitis in the pancreata of the rats treated with other herbal medicines except TJ-24 at 12 wk. PAP mRNA was not expressed in the TJ-10-treated rats, and PAP gene expression was suppressed in rats treated with other drugs except TJ-107. In the therapeutic group, the amelioration of pancreatitis was seen only in TJ-10-treated rats, but PAP gene expression was significantly suppressed in the rats treated with all herbal medicines tested, compared with that in untreated control rats. Conclusion. An herbal medicine Saiko-keishi-to (TJ-10) delayed the onset of chronic pancreatitis in the WBN/Kob rat, and suppressed the pancreatitis-associated protein (PAP) gene expression more significantly than other herbal medicines.

Transforming growth factor-beta1 (TGF-β1) is suggested to be a mediator of fibrosis in chronic pancreatitis, but the serial change of TGF-β1 expression in the onset and progression of chronic pancreatitis is still unclear. We investigated the TGF-β1 expression in the spontaneous chronic pancreatitis model. Four-week-old male WBN/Kob rats were fed with special pellet diet (MB-3) for 20 weeks. TGF-β1 mRNA in the pancreas was detected by reverse transcription–polymerase chain reaction assay from four weeks, and its expression peaked at 12 weeks when the pancreatic fibrosis first appeared. The localizations of TGF-β1 mRNA and protein were confirmed in the cytoplasm of pancreatic acinar and ductal cells by in situ hybridization and immunohistochemistry, respectively. Although fibronectin expression peaked at 12 weeks and correlated with that of TGF-β1, its elevated expression tended to be prolonged. Pancreatic fibrosis peaked at 16 weeks after the peak of TGF-β1 expression. These results suggest that TGF-β1 expression may be a trigger of the fibrotic process of chronic pancreatitis in the WBN/Kob rat.

BACKGROUND K-ras mutations at codon 12 (KRM) have been detected in over 80% of tissues and pure pancreatic juice (PPJ) samples from patients with pancreatic carcinoma (PCa) and are promising genetic tumor markers. Aspirating PPJ not only requires technical skill, but is also exhausting for patients. The authors attempted to evaluate whether the detection of KRM in the duodenal aspirate (DA) obtained immediately after endoscopic retrograde cholangiopancreatography (ERCP), an easier sample-collecting method than collecting PPJ, could be useful for the diagnosis of PCa and biliary tract carcinoma (BTCa). METHODS DA was collected endoscopically without secretin stimulation immediately after the ERCP procedure from 160 patients: 38 patients with PCa, 38 with chronic pancreatitis (CP), 22 with BTCa, 20 with adenomyomatosis of the gallbladder (AGB), 22 with cholecystolithiasis (CCL), and 20 control subjects. Mutant allele specific amplification (MASA), which is a highly sensitive method for detecting KRM, was performed, with the DNAs extracted from these samples by phenol-chloroform. RESULTS The incidence of KRM in DA by MASA was 25 (66%) of the 38 PCa cases, 12 (32%) of the 38 CP cases, and 12 (55%) of the 22 BTCa cases. There was no patient with positive KRM in DA among the 20 cases of AGB, 22 of CCL, and 20 control subjects. The sensitivity was 62% and the specificity 88% in this study design. The KRM incidence was found to be relatively high for the patients with PCa and BTCa by MASA, which is a highly sensitive method, although the incidence of KRM in DA from the patients with PCa was not as high as the incidence in their PPJ with secretin stimulation. CONCLUSIONS MASA showed a relatively high incidence of KRM even in the DA, which was easily obtained from the patients with PCa and BTCa without secretin stimulation immediately after ERCP. These results suggest that the detection of KRM in the DA by MASA is useful for the screening of both PCa and BTCa. Cancer 1999;86:1441–8. © 1999 American Cancer Society.

p53 and Bcl-2 are two important factors related to apoptosis and tumorigenesis. In this study, a series of 52 cases of pancreatic carcinoma (PC) were investigated using an immunohistochemical assay to determine whether altered expression of Bcl-2 and p53 has an impact on the progression of this malignancy. Cytoplasmic immunoreactivity for Bcl-2 and nuclear staining of p53 was found in 12 (23.1%) and 32 (63.5%) cases of PC respectively. Furthermore, an inverse correlation between the expression of p53 and Bcl-2 existed in this series (P < 0.01). In a subgroup, the proportion of tumours showing that p53-positive and Bcl-2-negative staining was increased with increasing histological grade and clinical stage (P < 0.05), and moreover, the survival period of those patients whose tumour had this staining was shorter than those with other staining patterns of combined p53 and Bcl-2 (P < 0.05). Therefore, it is concluded that simultaneously aberrant expression of Bcl-2 and p53 may confer PC with more malignant clinicopathological characteristics. © 1999 Cancer Research Campaign

The serum levels of pancreatitis-associated protein (PAP) were measured in 196 patients with digestive diseases and 15 healthy subjects by an enzyme-linked immunosorbent assay. The serum PAP levels were significantly elevated in the patients with gastric, colorectal, biliary tract, hepatocellular, or pancreatic cancers compared with the healthy subjects. After curative resection of the tumor, serum PAP levels were significantly decreased. The serum PAP levels were not related to clinicopathological factors except for the tumor size of pancreatic cancer. There were some cases of PAP-positive and carcinoembryonic antigen (CEA) or carbohydrate antigen (CA) 19-9 -negative gastric and colorectal cancers. The serum PAP levels were also significantly elevated in the patients with acute pancreatitis compared with those in not only the healthy subjects but also the patients with chronic pancreatitis. The peak PAP levels were significantly correlated with the severity of acute pancreatitis and reflected the clinical healing of the disease. The peak of serum PAP was significantly delayed compared with those of other pancreatic enzymes. These results suggest that the increase of serum PAP levels in patients with gastrointestinal cancers reflects an ectopic expression of PAP in cancer cells and that increased serum levels of PAP in acute pancreatitis are correlated with the disease severity and are prolonged than those of other pancreatic markers.

Twenty-three patients with globus pharyngeus were treated with Koso-san (TJ- 70) at a dose of 7.5 g/day for at least 14 days. Symptoms disappeared in 18 cases and improved in 3 cases, therefore, the effective rate was 91.3% (21/23). The symptoms disappeared on average within 13.5 days. Terasawa qi-stasis scores were significantly decreased after the treatment. TJ-70 might thus be a remedy for globus pharyngeus with qi-stasis.

We report an 83-year-old man with pancreatic body cancer of 4.5 cm in diameter. Peripheral leukocyte count was 15,700/μl and the serum concentration of granulocyte-colony stimulating factor (G-CSF) was 123 pg/ml (normal, 6.0-21.9 pg/ml) on admission. Furthermore, not only K-ras codon 12 (GGT → GAT) but also p53 at codon 247 (CGG → CCG) mutations were identified in the pancreatic juice aspirated endoscopically. We performed chemotherapy with two courses of 5-fluorouracil, pirarubicin hydrochloride, and mitomycin-C, resulting in no beneficial effect. After the second course the patient developed interstitial pneumonia, probably caused by anti-cancer drugs, and died 4 months after the tumor was detected. In the autopsy tissue, the tumor macroscopically occupied the pancreas body and was 7 × 6 × 5 cm in size. Histopathologic diagnosis of the tumor was poorly differentiated adenosquamous carcinoma. Immunohistochemical staining of the autopsy tissue showed that pancreatic cancer cells were positive for G-CSF. This is the first case report of G-CSF-positive pancreatic cancer confirmed by immunohistochemistry.

Pancreatitis-associated protein (PAP) mRNA is expressed in some cases of gastric and colorectal cancers resulting from an ectopic expression in dedifferentiated cancer cells.The PAP gene is identical to the hepatoma-intestine-pancreas (HIP) gene, which is expressed in hepatoma. Expression in cancer might be another characteristic of PAP.Fresh surgical specimens of 100 gastrointestinal cancers, 14 benign digestive diseases, and six normal organs were studied with nonisotopic in situ hybridization (ISH) using biotin-labeled cDNA probe.PAP mRNA was detected in 10% (6/60) of gastric cancers, 21.4% (6/28) of colorectal cancers, 20.0% (1/5) of pancreatic cancers and 0% of biliary tract (three), esophageal (one), and hepatocellular cancers (three). Reverse transcription-polymerase chain reaction (RT-PCR) detected PAP mRNA in these ISH-positive cases. PAP mRNA was not detected in noncancerous portions, benign disease tissues, or normal organs except for the small intestine. There was no relationship between PAP mRNA expression and any clinicopathological factors.

Sclerosing pancreatitis might develop repeatedly or might rapidly extend to the whole pancreas with recurrent mass formation.Nothing is known concerning course or development of sclerosing pancreatitis.A 63-yr-old male was followed up for 2.5 yr.The patient was admitted because of a tumor in the body and tail of the pancreas. Serum pancreatic enzymes were transiently elevated, but tumor markers were all negative. Imaging studies showed a tumor 7 cm in size. The main pancreatic duct was normal in the head and obstructed at the body on endoscopic retrograde pancreatography (ERCP). The K-ras oncogene mutation was positive in pure pancreatic juice. Distal pancreatectomy was performed because pancreatic cancer was highly suspected. Pathological findings showed that the tumor was a densely fibrotic mass without malignant cells. Inflammatory cell infiltration was observed in the stroma. One year later, another mass 3 cm in size was noted in the remnant pancreatic head. ERCP revealed diffuse irregular narrowing of the main pancreatic duct, its branches, and the common bile duct. Liver dysfunction improved and an elevation of serum pancreatic enzymes subsided without any specific treatment, and the mass diminished in size. The patterns of various imaging studies on the second tumor were the same as those of the previous resected mass. Corticosteroid was not administered.

Four patients with liver cirrhosis and complaining of painful gynecomastia were treated with oral administration of Gegen-Tang (TJ-1). Pain disappeared in 3 patients in one week, and in one patient in 4 weeks. The size of gynecomastia did not change significantly on mammography, but palpable induration diminished or disappeared. The patients had been treated with Chaihu (saiko) group drugs for liver diseases, and TJ-1 was used in combination with these drugs. Serum levels of estrogen, progesterone, testosterone, and other sex hormones did not change significantly after TJ-1 treatment. These results suggest that TJ-1 could be used for the painful gynecomastia that is occasionally seen in cirrhotic patients.

The present study was undertaken to detect K‐ras oncogene point mutations at codon 12 in pure pancreatic juice (PPJ) by the hybridization protection assay (HPA) method for the diagnosis of pancreatic cancer (PC). This assay can be carried out within 30 min and can determine not only the presence of a mutation, but also the mutational type of K‐ras at codon 12. The minimal ratio of mutant DNA detectable by the HPA was 5–10% of the total DNA. PPJ was collected through a cannula under duodenal fiberscope control from 20 patients with PC and 20 patients with chronic pancreatitis (CP). Analysis of PPJ by the HPA revealed that the incidence of K‐ras point mutations at codon 12 was 55% (11/20) in patients with PC and 0% (0/20) in those with CP. Mutational types of K‐ras at codon 12 in PC were aspartic acid (Asp) in nine cases, both Asp and cysteine in one case, and arginine in one case. Analysis of K‐ras point mutations at codon 12 in PPJ using the HPA method seems promising as a new genetic test for the diagnosis of PC, because the HPA method is simple, and can easily determine the mutational type.

Endoscopic ultrasonography has become an important diagnostic procedure complementary to endoscopy and histopathological study in the preoperative evaluation of gastric carcinoma. Despite allowing visualization of tumoral infiltration with quite high accuracy, certain factors have limited the accuracy of this modality or even led to misinterpretation. We designed a prospective study to evaluate the accuracy of gastric carcinoma diagnosis with special reference to factors resulting in misdiagnosis. During a 22 month period, 86 patients with early and advanced gastric carcinoma underwent surgical or endoscopic resection on the basis of endosonographic findings. In all patients, endosonographic findings, location and macroscopic type of the tumor and histopathological characteristics including depth of invasion, malignant cell type and/or differentiation, and the presence/absence of ulceration in the tumor focus were recorded. The endosonographic and histopathological results were compared at the end of the study. Overall accuracy was 85% using the TNM staging system. There were no significant differences in accuracy in the location of the tumor, histological grading or macroscopic type of tumor, although the accuracy rate was lower for tumors located in the antrum. Ulceration in the tumor focus was a major factor leading to misinterpretation of the findings of early gastric cancer (p

We investigated the expressions of SLX, ST-439 and PLAP, which are regarded as having high specificity for cancer, in borderline lesions of the stomach to ascertain the significance of these potential markers in distinguishing between benign and malignant lesions. SLX, ST-439 and PLAP expressions in gastric biopsy specimens, from 73 patients with gastric lesions, were visualized using avidin-biotin-peroxidase. Although the prevalence of SLX in Group V was 90%. it was also high in intestinal metaplasia (40%) and adenoma (75%). The prevalences of ST-439 in intestinal metaplasia and adenoma grades l and 2 were 5, 23, and 17%. respectively. On the other hand, the prevalence of ST-439 was about 60% in adenoma grade 3 and in Groups IV and V. The prevalence and immunostaining range of ST-439 increased concomitantly with increasing grades of cytological and architectural atypia. The prevalence of PLAP in gastric biopsy materials was 30% overall, but was higher among the differentiated types. Moreover, PLAP was highly specific for cancer because of the negative immunostaining observed in benign lesions such as intestinal metaplasia and adenoma. These results suggest the following: 1) SLX is relatively non-specific for cancer and thus not useful in the pathological diagnosis of gastric lesions, and 2) borderline lesions with positive ST-439 mandate careful follow-up. Moreover, lesions with apparently extensive and intense ST-439 immunostaining may be gastric cancer and require urgent attention. Furthermore, 3) PLAP may provide additional diagnostic information useful for distinguishing between well-differentiated adenocarcinoma and borderline lesions including adenoma.

We analyzed 30 endoscopically treated patients with early gastric cancer in terms of the utility of endoscopic ultrasonography (EUS) and the evaluation of prognosis. Endoscopic therapy for early gastric cancer included strip biopsy, laser irradiation, and OK-432 injection. Examination of the depth of cancer invasion in the strip biopsy specimens showed that the diagnostic accuracy of EUS was 85.7%. Complete resection rate in strip biopsy was 82.8%, and the patients with incompletely resected cancer were successfully treated with laser irradiation and/or OK432 injection. The prognosis of the patients treated with strip biopsy was good. Three patients died of causes other than gastric cancer. Local recurrence and a heterochronous new lesion developed in six patients, but all of these cases were successfully treated with additional strip biopsy. All but one patient treated with laser irradiation and/or OK 432 injection survived during the study period. These results suggest that EUS is useful in determining the indication of endoscopic therapies and that prognosis is good in patients with early gastric cancer treated endoscopically.

The nucleotide (nt) sequence of the human cDNA encoding PAP, a pancreatic secretory protein induced during acute pancreatitis, was found to be identical with that of a gene activated in human primary hepatocellular cancer, designated HIP . To obtain insight into the expression of PAP/HIP , we characterized the gene organization, especially focusing on the 5 ′ -flanking region, and found that it spans about 3 kb and is composed of six exons. Exon 1 encodes the 5 ′ -noncoding sequence and exon 2 consists of three miniexons, 2a, 2b and 2c; the common exon 2c encodes the sequence including the start codon. Analysis by RT-PCR revealed the presence of at least three different types of 5 ′ -ends of human PAP/ HIP transcripts which were derived from alternative use of 5 ′ -exons. Although all three types of transcripts were expressed in both normal small intestine and pancreas, their gene expression was increased ectopically in gastric cancer, hepatocellular cancer and pancreatic acinar cell carcinoma. Furthermore, significant differences among the transcript types were detected between normal and tumor tissues, and especially between gastric and hepatocellular cancers, suggesting that PAP/HIP expression may vary with differences in 5 ′ -alternative splicing.

To compare the efficacy of lansoprazole and famotidine in the treatment of gastric ulcer, 24 patients with gastric ulcer were treated for 8 weeks. They were assessed by endoscopic ultrasonography (EUS), which provides cross-sectional images of the gastric wall as well as endoscopic images. Patients were randomly assigned to receive either lansoprazole 30 mg once daily (n = 12), or famotidine 20 mg twice daily (n = 12). The healing rate after 4 weeks of treatment was 80% in the lansoprazole group and 40% in the famotidine group. After 8 weeks of treatment, the respective healing rates were 100 and 72.7%. Healing to Sakita's S 2 stage of scarring occurred significantly more often in the lansoprazole group than in the famotidine group after 4 weeks (50% vs. 0% ; p < 0.05). After 4 weeks of treatment, the submucosal fibrous tissues detected by EUS were significantly less extensive in the lansoprazole-treated patients with deep ulcers (reaching the muscle layer or serosa) than in the famotidine-treated patients with deep ulcers (p < 0.01). These results suggest that lansoprazole may be more effective in ulcer healing than famotidine, particularly in patients with deep gastric ulcers.

Expressions of proliferating cell nuclear antigen (PCNA) in various liver diseases were investigated with an immunohistochemical method, using liver biopsy specimens. The disease category and the number of cases were as follows: nonspecific change 10, acute hepatitis 11, chronic inactive hepatitis 13, chronic active hepatitis without cirrhosis (CAH) 30, liver cirrhosis 10, and hepatocellular carcinoma 10. Significantly higher expression of PCNA was seen in chronic active hepatitis (CAH), compared to other disease groups. The PCNA expression in CAH was not correlated with the conventional histological evaluation of hepatitis activity or Knodell's hepatitis activity index. Among laboratory data, indocyanine green retention rate was negatively correlated with the PCNA expression ( r = −0.467 , P ). Significantly higher expression was also noted in acute hepatitis and hepatocellular carcinoma, compared with nonspecific change or liver cirrhosis. Although clinical significance of PCNA in chronic active hepatitis remains to be elucidated, PCNA might be a new histological marker of regeneration in benign liver disease.

An aberrant hepatic duct directly connected to the main pancreatic duct with anomalous arrangement of the pancreato-biliary ductal system is reported here, the first report of such a case, to our knowledge. A 53-year-old woman was admitted to our hospital because of cholecystolithiasis with abdominal pain in the right upper quadrant. Endoscopic retrograde cholangiopancreatography (ERCP) showed that an aberrant hepatic duct, which independently drained the right posterior segment of the liver, connected to the main pancreatic duct at a high insertion site distal to the sphincter area of the major papilla. The common bile duct (containing stones), on the other hand, united with the main pancreatic duct in a normal fashion. Cholecystectomy and bile duct lithotomy were performed. The aberrant hepatic duct was separated from the main pancreatic duct just above the junction, and was anastomosed side-by-side to the common hepatic duct. The embryologic development of this lesion is not clear, but is discussed in this report.

Two cases of mitomycin C nephropathy, which occurred after postoperative chemotherapy for advanced gastric cancer, were followed up for 6 (case 1) and 10 years (case 2). Hemolytic uremic syndrome developed 68 days (case 1) and 160 days (case 2) after the last administration of MMC with a total dose of 60 mg (case 1) and 40 mg (case 2). Serum creatinine levels were normalized in case 1 and they remained at about 2 mg/dl in case 2. Hyporeninemic hypoaldosteronism was transiently seen in case 2. These data suggest that recovery from the acute phase of hemolytic uremic syndrome leads to a good long-term prognosis in MMC nephropathy.

Biliary papillomatosis is a rare entity. A case of biliary papillomatosis associated with congenital choledochal cyst and intrahepatic gallstones is reported here. Percutaneous transhepatic cholangioscopy revealed multiple papillary lesions of the right intrahepatic duct and the common bile duct. Microscopically, the papillary mucosal lesion showed papillary proliferations of bile duct epithelial cells with mild atypia. Furthermore, a point mutation at codon 12 of the K-ras oncogene was found in the papillary lesion. To the best of our knowledge, this is the first case of biliary papillomatosis arising in congenital choledochal cyst. Although the pathogenesis of biliary papillomatosis in our case was unclear, biliary irritation associated with choledochal cyst may be related to biliary papillomatosis with point mutation at codon 12 of K-ras gene.

Expression of multidrug resistance gene ( mdr -1) mRNA was studied in cultured human hepatoma cells using non-isotopic in situ hybridization technique. The mdr -1 mRNA was detected in the cytoplasm of three hepatoma cell lines (PLC/PRF/5, Hep-G2, HuH-7) as well as in human epidermoid carcinoma cells KB-C-2 used as a positive control. The hepatoma cells SK-Hep-1 and epidermoid carcinoma cells KB-3-1 used as a negative control showed no signal of mdr -1 mRNA. Doxorubicin hydrochloride did not induce mdr -1 mRNA in SK-Hep-1 cells. These data suggest that some human hepatoma cells show resistance against chemotherapeutic agents through the expression of mdr -1 gene.

This study evaluated the diagnostic significance of concentrations of the cancer-associated carbohydrate antigen CA19-9 in pure pancreatic juice (PPJ) collected by endoscopic cannulation. We also attempted to elucidate the features and source of the increased CA19-9 concentration found in the pancreatic juice of patients with chronic pancreatitis (CP) by means of immunohistochemical staining. The mean output as well as the mean concentration of CA19-9 in each of the four fractions collected was highest in patients with pancreatic cancer (PC) and also was elevated significantly in patients with CP compared with controls. However, CA19-9 concentrations were not elevated in patients with cholecystolithiasis. When the cutoff value was set as the mean concentration + 2SD of the controls, significantly elevated concentrations of CA19-9 were found in the third fraction (secretory phase) in 90% of the patients with PC and 66% of the patients with CP. Immunohistochemical staining revealed that CA19-9 was expressed more widely in the ductal cells of CP tissues than in those of normal pancreatic (NP) tissues, with CP tissue showing more CA19-9-positive ductal cells per area than NP tissues. In NP tissue, CA19-9 was localized to the apical surface and supranuclear regions (apical type) in all the ductal cells stained by the antigen, while approximately 50% of cases with CP exhibited a cytoplasmic pattern showing a loss of polarity of the antigen expression. Moreover, this cellular localization pattern was more pronounced in the small ducts that had proliferated and aggregated following the destruction of lobules in CP.(ABSTRACT TRUNCATED AT 250 WORDS)