菅野 敦

Pancreatic cancer is one of the life-threatening cancers due to the difficulty in the curative surgery and resistance against conventional therapeutic strategies. Recent studies indicated that cancer stem cells, which exist as a small number of cells within the entire cancer tissue, contribute to the disease progression. Cancer stem cells reveal resistance against conventional chemotherapy, which is derived from the high-expression of multiple transporter genes. Our previous study demonstrated the aggravating role of the homeobox gene MSX2 as an inducer of epithelial-mesenchymal transition, and MSX2 turned out to correlate with the chemoresistance in the current study. Comprehensive analysis of the MSX2-target gene has identified ABCG2 as the responsible gene. Since previous studies reported the pivotal role of ABCG2 as a determining factor of cancer stem cells, the detailed regulatory mechanism of ABCG2 expression by MSX2 was investigated. As a result, the MSX2 expression level in each cell line well correlated with the ABCG2 expression level, and alteration of the MSX2 expression level by over-expression or siRNA-based knockdown affected the ABCG2 expression accordingly. Finally, we identified the functional cooperation of MSX2 and SP1 in the transcriptional regulation of ABCG2 via the SP1 binding elements within the ABCG2 promoter. These findings clarified the intriguing regulatory mechanism of the cancer stem cell-related gene, and will delineate a novel therapeutic target in pancreatic cancer. J. Cell. Physiol. (C) 2011 Wiley Periodicals, Inc.

It is now clear that are two histological types (Type-1 and Type-2) of autoimmune pancreatitis (AIP). The histological pattern of Type-1 AIP or traditional AIP is called lymphoplasmacytic sclerosing pancreatitis (LPSP). The histological pattern of Type-2 AIR is characterized by neutrophilic infiltration in the epithelium of the pancreatic duct. In general, Type-2 AIR patients are younger, may not have a male preponderance, and rarely show elevation of serum IgG4 compared with Type-1 AIP patients. Unlike Type-1 AIP patients, Type-2 AIP patients rarely have associated sclerosing diseases, but they are more likely to have acute pancreatitis and ulcerative colitis. Although Type-2 AIP is sometimes observed in the USA and Europe, most AIP cases in Japan and Korea are Type-1. The international consensus diagnostic criteria for AIP comprise 5 cardinal features, and combinations of one or more of these features provide the basis for diagnoses of both Type-1 and Type-2 AIP Due to the fact that steroid therapy is clinically, morphologically, and serologically effective in AIP patients, it is the standard therapy for AIP The indications for steroid therapy in AIP include symptoms such as obstructive jaundice and the presence of symptomatic extrapancreatic lesions. Oral prednisolone (0.6 mg/kg/day) is administered for 2-4 weeks and gradually tapered to a maintenance dose of 2.5-5 mg/day over a period of 2-3 months. Maintenance therapy by low-dose prednisolone is usually performed for 1-3 years to prevent relapse of AIP

The epithelial-mesenchymal transition (EMT) is a critical step for pancreatic cancer cells as an entry of metastatic disease. Wide variety of cytokines and signaling pathways are involved in this complex process while the entire picture is still cryptic. Recently, miRNA was found to regulate cellular function including EMT by targeting multiple mRNAs. We conducted comprehensive analysis of miRNA expression profiles in invasive ductal adenocarcinoma (IDA), intraductal papillary mucinous adenoma, intraductal papillary mucinous carcinoma, and human pancreatic cancer cell line to elucidate essential miRNAs which regulate invasive growth of pancreatic cancer cells. Along with higher expression of miR-21 which has been shown to be highly expressed in IDA, reduced expression of miR-126 in IDA and pancreatic cancer cell line was detected. The miR-126 was found to target ADAM9 (disintegrin and metalloproteinase domain-containing protein 9) which is highly expressed in pancreatic cancer. The direct interaction between miR-126 and ADAM9 mRNA was confirmed by 30 untranslated region assay. Reexpression of miR-126 and siRNA-based knockdown of ADAM9 in pancreatic cancer cells resulted in reduced cellular migration, invasion, and induction of epithelial marker E-cadherin. We showed for the first time that the miR-126/ADAM9 axis plays essential role in the inhibition of invasive growth of pancreatic cancer cells. Mol Cancer Res; 10(1); 3-10. (C) 2011 AACR.

Intraductal tubulopapillary neoplasm (ITPN) is a recently recognized rare variant of intraductal neoplasms of the pancreas. Molecular aberrations underlying the neoplasm remain unknown. We investigated somatic mutations in PIK3CA, PTEN, AKT1, KRAS, and BRAF. We also investigated aberrant expressions of phosphorylated AKT, phosphatase and tensin homolog (PTEN), tumor protein 53 (TP53), SMAD4, and CTNNB1 in 11 cases of ITPNs and compared these data with those of 50 cases of intraductal papillary mucinous neoplasm (IPMN), another distinct variant of pancreatic intraductal neoplasms. Mutations in PIK3CA were found in 3 of 11 ITPNs but not in IPMNs (P = 0.005; Fisher exact test). In contrast, mutations in KRAS were found in none of the ITPNs but were found in 26 of the 50 IPMNs (P = 0.001; Fisher exact test). PIK3CA mutations were associated with strong expression of phosphorylated AKT (P < 0.001; the Mann-Whitney U test). Moreover, the expression of phosphorylated AKT was apparent in most ITPNs but only in a few IPMNs (P < 0.001; the Mann-Whitney U test). Aberrant expressions of TP53, SMAD4, and CTNNB1 were not statistically different between these neoplasms. Mutations in PIK3CA and the expression of phosphorylated AKT were not associated with age, sex, tissue invasion, and patients' prognosis in ITPNs. These results indicate that activation of the phosphatidylinositol 3-kinase pathway may play a crucial role in ITPNs but not in IPMNs. In contrast, the mutation in KRAS seems to play a major role in IPMNs but not in ITPNs. The activated phosphatidylinositol 3-kinase pathway may be a potential target for molecular diagnosis and therapy of ITPNs.

Objectives: The aim of this study was to clarify the pancreatic blood perfusion in patients with autoimmune pancreatitis (AIP) and the changes after steroid treatment. Methods: Perfusion computed tomography was performed in 11 patients with AIP and 12 control subjects. Pancreatic volumetric blood flow (F(V)), volume of distribution (V(D)), and blood transit time (T) were determined from a single-compartment kinetic model. Nine patients with AIP were reexamined by perfusion computed tomography after corticosteroid administration. Results: The pancreatic F(V) values of the 11 patients with AIP (82.7/min) were significantly lower than those of control subjects (163.5/min, P = 0.0006). On the other hand, the pancreatic V(D) and (T) values were not significantly different between AIP and normal. After steroid treatment, the F(V) values of 9 reexamined patients with AIP (76.2/min) were significantly elevated (109.8/min, P = 0.0391). However, the changes of the values after the treatment differed in degree among individuals. The values of 4 patients were dramatically elevated to greater than 100/min, whereas those of 4 other patients did not improve well. The value of the remaining patient whose initial FV value was normal (168.09/min) did not change after the treatment. Conclusions: Pancreatic volumetric perfusion was attenuated in AIP patients. The perfusion was improved after the steroid treatment.

Background/Aims: The feasibility of neoadjuvant chemoradiation therapy for cholangiocarcinoma, followed by conventional resection, has not been determined yet. Here, a phase I study of neoadjuvant chemoradiation therapy, named NACRAC, was performed to determine the maximum tolerated dose (MTD) and the recommended dose (RD) of gemcitabine when combined with external beam radiation therapy for resectable cholangiocarcinoma. Methodology: From August 2007 to June 2008, 12 patients provided informed consent. Preoperative radiation was administered in 1.8Gy daily fractions up to a total dose of 45Gy. Gemcitabine was administered at day land 8 every three weeks. The initial dose of gemcitabine was started from 400mg/m2(.) Results: One patient was not able to start treatment because of bleeding caused by a duodenal ulcer and cholangitis. At 800mg/m(2) of gemcitabine, one patient out of three failed to complete the treatment because of Grade 3 hematological toxicity. In another three cases of 800mg/m(2), the second case could not complete the treatment because of cholangitis. Then, 600mg/m(2) was determined to be the MTD, and the RD dose decided as 600mg/m(2). Conclusions: The RD of gemcitabine in NACRAC study was determined to be 600mg/m(2). NACRAC study should proceed to a phase II trial to evaluate the effectiveness.

BACKGROUND & AIMS: Distinction of immunoglobulin G4-associated cholangitis (IAC) from primary sclerosing cholangitis (PSC) or cholangiocarcinoma is challenging. We aimed to assess the performance characteristics of endoscopic retrograde cholangiography (ERC) for the diagnosis of IAC. METHODS: Seventeen physicians from centers in the United States, Japan, and the United Kingdom, unaware of clinical data, reviewed 40 preselected ERCs of patients with IAC (n = 20), PSC (n = 10), and cholangiocarcinoma (n = 10). The performance characteristics of ERC for IAC diagnosis as well as the kappa statistic for intraobserver and interobserver agreement were calculated. RESULTS: The overall specificity, sensitivity, and interobserver agreement for the diagnosis of IAC were 88%, 45%, and 0.18, respectively. Reviewer origin, specialty, or years of experience had no statistically significant effect on reporting success. The overall intraobserver agreement was fair (0.74). The operating characteristics of different ERC features for the diagnosis of IAC were poor. CONCLUSIONS: Despite high specificity of ERC for diagnosing IAC, sensitivity is poor, suggesting that many patients with IAC may be misdiagnosed with PSC or cholangiocarcinoma. Additional diagnostic strategies are likely to be vital in distinguishing these diseases.

Objectives: The aim of this study was to compare the benefits between endoscopic drainage and surgical drainage of the pancreatic duct for patients with chronic calcified pancreatitis. Methods: A total of 68 patients were classified into endoscopic (n = 34) or surgical (n = 34) treatment groups. Patients receiving endoscopic treatment were further divided into 2 subgroups: a short-period group, patients who could discontinue serial pancreatic stenting within 1 year (n = 19); and a long-period group, patients who needed pancreatic drainage by serial endoscopic stenting for more than 1 year (n = 15). The medical records of these patients were retrospectively analyzed. Results: Hospital stays, frequency of hospitalizations, and medical expense were similar between the short-period endoscopic treatment group and surgery group. On the other hand, patients in the long-period endoscopic treatment group required significantly longer hospital stays, more frequent hospitalizations, and had higher medical expenses than the short-period endoscopic treatment group as well as than the surgery group. Conclusions: Patients who underwent serial endoscopic stenting for more than 1 year showed no benefit compared with surgical treatment in terms of the frequency of hospital stays and medical costs.

Mucin-producing intraductal papillary neoplasm (adenocarcinoma/adenoma) in the bile duct is becoming recognized as a specific type of neoplasm. Since, it bears a striking similarity to intraductal papillary mucinous neoplasms of the pancreas with regard to its histopathologic features, the term "intraductal papillary mucinous neoplasms of the bile duct" (IPMN-B) is frequently used, although no definite terminology or definition has been decided by World Health Organization. This neoplasm lacks ovarian-like stroma and communicates with the bile ducts, unlike biliary mucinous cystic neoplasm (MCN). On the other hand, malignant IPMN-B is categorized as an intraductal-growth type of intrahepatic cholangiocarcinoma (ICC). In comparison to other types of ICC, such as the mass-forming type and periductal-infiltrating type that have poor resectability and an unfavorable prognosis, malignant IPMN-B can be resected and demonstrates a more favorable prognosis. Meanwhile, unlike biliary MCN that is usually confined in a closed cyst, IPMN-B can spread along the mucosal surface of the bile ducts, and it should be widely resected. Therefore, multimodality assessment is needed to ensure the correct diagnosis of IPMN-B. We herein review the imaging findings of IPMN-B with pathologic correlation.

Background: To distinguish cholangiocarcinoma from inflammatory disease remains difficult when stricture is present in the bile duct. Endoscopic brushing cytology is a convenient method for stricture in the bile duct, however, the diagnostic sensitivity of this method for malignancy is reported to be low (< 60%). Msh homeobox 2 is frequently expressed in carcinoma cells of epithelial origin but not in normal tissues. Aim: To assess whether MSX2 expression level in brushing samples allows differentiation of malignant from benign bile duct stricture. Patients and Methods: Cytological brushing specimens were obtained from strictures of the bile duct during endoscopic retrograde cholangiopancreaticography (ERCP) in 71 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. Results: MSX2 expression levels were significantly higher in malignant than in benign bile duct stricture (p=0.004). The sensitivity and specificity for cholangiocarcinoma of cytology and MSX2 expression in strictures of the bile duct were: 55.3% and 100%, and 72.3% and 58.3%, respectively. Conclusion: The sensitivity of MSX2 expression level for cholangiocarcinoma was much higher than that of cytology. This suggests that the evaluation of MSX2 level in ERCP brushing samples would be a useful tool to distinguish malignant from benign bile duct stricture.

Background and Aim Pancreatitis remains a serious complication after endoscopic retrograde cholangiopancreatography (ERCP). The efficacy of prophylactic pancreatic duct stent placement to prevent post-ERCP pancreatitis in patients at high risk has been established in several randomized controlled trials. The aim of this study was to investigate the frequency and risk factors of post-ERCP pancreatitis in patients who had undergone prophylactic pancreatic duct stenting. Patients and Methods Between July 2002 and January 2010, ERCP-related procedures were performed in 9192 cases of pancreatobiliary diseases at seven institutions. Among them, 414 patients (246 men, 168 women; mean age, 68 yr; age range, 22-91 yr) at high risk of post-ERCP pancreatitis who had undergone prophylactic pancreatic duct stenting were included in this study. The stent used in the present study was a 5-Fr stent with a single duodenal pigtail, which is made of soft polyethylene and has no flange (Pit-stent: Cathex, Co., Ltd., Tokyo, Japan). The pancreatic duct stent was placed via the channel of the duodenoscope over a guidewire with the assistance of fluoroscopy at the end of the procedure. The frequency and risk factors of post-ERCP pancreatitis were investigated. Post-ERCP pancreatitis was defined based on the consensus criteria. Results Therapeutic ERCP was performed in 52% of the patients. Indications for prophylactic pancreatic duct stenting were as follows: difficult cannulation of the bile duct, 192; pancreatic duct cytology/biopsy, 95; precut sphincterotomy, 40; pancreatic sphincterotomy, 29; female gender, 28; papillectomy, 25; sphincter of Oddi dysfunction, 12; history of pancreatitis, 10. Hyperamylasemia at 18-24 h after ERCP was observed in 64% (267 patients) of the patients. Pancreatitis occurred in 9.9% (41 patients: mild, 37; moderate, 2; severe, 2). Univariate analysis revealed intraductal papillary mucinous neoplasm (IPMN) of the pancreas to be the only significant risk factor for pancreatitis (OR 2.9, 95% CI 1.2, 7.1). Multivariate analysis also showed IPMN to be the only risk factor for pancreatitis (OR 3.1, 95% CI 1.2, 7.8). The mean diameter of the pancreatic head duct in patients with IPMN who developed post-ERCP pancreatitis was significantly smaller than that in those who did not develop pancreatitis (3.0 +/- 1 mm vs 4.7 +/- 2.6 mm, p=0.0037). Conclusion Post-ERCP pancreatitis developed in 9.9% of the patients at high risk who had undergone prophylactic pancreatic duct stenting. Since the majority of cases of post-ERCP pancreatitis were mild, pancreatic duct stenting may contribute to lessening the severity of pancreatitis. The present results suggest that IPMN without a dilated pancreatic head duct is a possible risk factor for post-ERCP pancreatitis after prophylactic pancreatic duct stenting.

We describe here a case of von Hippel-Lindau (VHL) disease with a serous cystic neoplasm of the whole pancreas. The patient was a 35-year-old woman suffering from a palpable abdominal tumor. She had a history of hemangioblastomas of the cerebellum. CT revealed large solid tumors in the pancreatic head and body, and multiple cystic lesions in the whole pancreas as well as a right renal tumor. When endoscopic retrograde cholangiopancreatography (ERCP) was performed, bleeding from the duodenal papilla was detected. Since she had some distinguishing clinical features, the diagnosis of VHL disease was made. The preoperative diagnosis of the pancreatic lesion was serous cystic neoplasms with hemosuccus pancreaticus and total pancreatectomy was performed. Histological examination of the specimen revealed serous cystic neoplasms which occupied the entire pancreas. VHL cases operated on for serous cystic neoplasms of the entire pancreas are very rare.

The incidence and mortality of cholangiocarcinoma are increasing despite improvements in the diagnostic method. Since the sensitivity of brushing cytology for cholangiocarcinoma is not satisfactory, a novel diagnostic marker needs to be established. A recent report has suggested upregulation of the calcium-binding protein S100P in cholangiocarcinoma. The expression status of S100P in normal bile duct and cholangiocarcinoma tissues was assessed by immunohistochemistry. The expression levels of S100P mRNA in the brushing cytology samples during endoscopic retrograde cholangiopancreatography (ERCP) from benign biliary strictures and cholangiocarcinoma were assessed by real-time reverse transcription-polymerase chain reaction (RT-PCR). The sensitivity and specificity of each diagnostic strategy was compared. S100P was frequently expressed in the cholangiocarcinoma tissues, but not in the normal bile duct. The brushing cytology samples from the cholangiocarcinoma cases revealed higher expression levels of S100P compared with the benign biliary strictures. The relative expression level of S100P could determine the cholangiocarcinoma at higher sensitivity than classical cytology, and the combination of the S100P expression level and cytology yielded a sensitivity of 90.0%, with a specificity of 92.0%. Calcium-binding protein S100P is a novel marker of cholangiocarcinoma. Detecting the S100P expression levels in brushing cytology samples has a diagnostic value, which will be helpful for better diagnosis of cholangiocarcinoma. (Cancer Sci 2011; 102: 150-156).

It is difficult to distinguish pancreatic ductal adenocarcinoma (PDAC) from chronic pancreatitis (CP) when stricture is present in the pancreatic duct. Endoscopic brushing cytology is a convenient method for investigating strictures in the pancreatic duct, however, the diagnostic sensitivity of this method for PDAC is reported to be low (40-70%). Recently, we revealed that MSX2 is frequently expressed in PDAC cells but not in normal cultured pancreatic duct or stellate cells. Thus, we analyzed MSX2 expression levels in brushing samples to examine whether this would differentiate PDAC from CP. Cytologic brushing specimens were obtained from pancreatic duct strictures during endoscopic retrograde cholangiopancreaticography in 82 patients. The brushing fluid was subjected to cytological diagnosis and RNA extraction. The expression level of MSX2 was evaluated by one-step real-time RT-PCR. MSX2 expression levels were significantly higher in PDAC than in CP (P = 0.0000007), and the expression level was associated with positive cytology (P = 0.013). The sensitivity, specificity, and diagnostic accuracy for PDAC of cytology and MSX2 expression in ductal strictures were: 47.4%, 100%, and 63.4%, and 73.7%, 84.0%, and 79.3%, respectively. The sensitivity and accuracy of MSX2 expression levels for diagnosis were much higher than those of cytology. This suggests that the evaluation of MSX2 levels in endoscopic retrograde cholangiopancreaticography brushing samples would be useful for distinguishing PDAC from CP. (Cancer Sci 2011; 102: 157-161).

下部胆管に発生した腺内分泌細胞癌の1例を報告する。症例は62歳、男性。全身倦怠感と皮膚黄染を主訴に来院した。入院時の血液検査所見は肝胆道系酵素の上昇を認めた。腹部CTでは下部胆管に造影効果のある腫瘍を認め、そこから肝側の胆管は拡張していた。ERCPでは、下部胆管に腫瘤影と一致した偏側性の欠損像を認めた。経乳頭的に生検を施行した結果、腺内分泌細胞癌の診断であった。遠隔転移を認めず、膵頭十二指腸切除術を施行した。術後gemcitabineの補助化学療法を施行したが、術後3ヵ月で多発性の肝転移が認められ、術後5ヵ月で永眠された。胆管原発の腺内分泌細胞癌は極めて稀であり、また術前の生検にて腺内分泌細胞癌と診断し得た症例の報告はなく貴重と考えられた。(著者抄録)

Endoscopic treatment associated with or without extracorporeal shock wave lithotripsy (ESWL) for chronic pancreatitis has been employed for about 20 years. Although two randomized control trials have revealed the greater effectiveness of surgery as compared to endoscopic treatment for chronic pancreatitis, a considerable number of patients have successfully obtained complete and long-term relief from pain by the less invasive endoscopic treatment. In this review, we discuss the indications, techniques and results of endoscopic treatment and ESWL for painful chronic pancreatitis. We also discuss the characteristic clinical features that are predictive of a good response to endoscopic treatment and ESWL.

A 50-year-old man with a cancer of the papilla of Vater underwent pylorus-preserving pancreatoduodenectomy reconstructed with pancreatogastrostomy in 2002. He began to complain of upper abdominal and back pain in April 2008. Abdominal CT scan revealed pancreatolithiasis with dilatation of the remnant main pancreatic duct. An upper intestinal endoscopy could not discern the orifice of the pancreatic duct. He was treated by transgastric EUS-guided drainage of the pancreatic duct several times, and ESWL for pancreatolithiasis. However, he had repeated pancreatitis. Surgical intervention was carried out to treat the obstructive pancreatitis in April 2009. Longitudinal pancreaticojejunostomy was performed without resection of the obstructive pancreatogastrostomy. The postoperative recovery was uneventful, and the patient remains asymptomatic after the second operation. We concluded that the longitudinal pancreaticojejunostomy is a safe and effective alternative for chronic pancreatitis after stenotic pancreatico-digestive tract anastomosis following pancreatoduodenectomy, especially for cases in which endoscopic stenting is ineffective.

Activated pancreatic stellate cells (PSCs) play a pivotal role in pancreatic fibrosis in chronic pancreatitis and pancreatic cancer. Recent studies have suggested a role of IL-33, a newly identified IL-1 family member, in fibrosis. We here examined the expression of IL-33 and the IL-33-mediated regulation of cell functions in PSCs. PSCs were isolated from human and rat pancreas tissues. The expression of IL-33 was examined by Western blotting, PCR, ELISA, and immunostaining. The roles of IL-33 in the regulation of PSC functions were examined by using recombinant IL-33 and small interfering RNA. Activated PSCs expressed IL-33 in the nucleus, and the expression was increased by IL-1 beta, TNF-alpha, PDGF-BB, and IFN-gamma, but not TGF-beta 1. Nuclear IL-33 expression was also observed in the pancreatic acinar and ductal cells. IL-1 beta induced IL-33 expression mainly through the activation of NF-kappa B and ERK pathways and partially through that of p38 MAP kinase, whereas PDGF-BB induced IL-33 expression mainly through the activation of ERK pathway. PSCs expressed soluble ST2, ST2L, and IL-1RAcP, but the expression level of ST2L was relatively low. Recombinant IL-33 did not stimulate key cell functions of PSCs. Decreased IL-33 expression by small interfering RNA resulted in decreased proliferation in response to PDGF-BB. In conclusion, activated PSCs expressed IL-33 in the nucleus. IL-33 might regulate the PDGF-induced proliferation in PSCs.

50歳男性、乳頭部癌に対し幽門輪温存膵頭十二指腸切除術(膵胃吻合)を施行され、6年後膵胃吻合部狭窄にともなう慢性膵炎、膵石症を併発した。超音波内視鏡下に膵管ステントを留置し症状が改善するも、9ヵ月後膵炎が頻回に再燃したため当科にて膵管空腸側々吻合(膵管ドレナージ術)を施行した。膵管空腸側々吻合術は膵頭切除後の慢性膵炎に対して有効で安全に施行し得、残膵機能温存の観点からも推奨される術式だと考えられた。(著者抄録)

Background Patients with branch duct type intraductal papillary mucinous neoplasm (BD-IPMN) without invasion usually show favorable prognosis. However, the prognosis becomes poor when the IPMN lesions give rise to invasive carcinoma cells. In addition, recent studies have revealed that BD-IPMN is frequently complicated by common type pancreatic ductal carcinoma. Thus, the prognosis of BD-IPMN depends on the occurrence of these two types of invasive carcinoma. However, little is known about the risk factors for the development of these invasive carcinomas in BD-IPMN. This study aims to identify the factors which predict the development of invasive carcinoma in BD-IPMN. Methods Invasive pancreatic carcinoma associating with BD-IPMN was classified as invasive IPMN group (invasive carcinoma derived directly from IPMN lesions) and concomitant group (common type of invasive carcinoma concomitant with BD-IPMN). The relation between the incidence of each type of invasive carcinoma in BD-IPMN and the clinicopathological parameters was retrospectively analyzed. Results There were 12 patients with invasive IPMN and 7 patients with concomitant cancer in 159 patients with BD-IPMN. Diameter of dilated branch (P < 0.001) or main pancreatic duct (MPD) (P = 0.001), size of mural nodule (P < 0.001), serum CEA level (P < 0.001) and serum CA19-9 level (P < 0.001) were factors associated significantly with invasive IPMN by univariate analysis. Among these factors, mural nodule with size larger than 6.5 mm [odds ratio 14.86 (95% CI 1.37-60.45); P = 0.02] and serum carcinoembryonic antigen (CEA) level over 5 ng/ml [odds ratio 6.91 (95% CI 1.17-54.13); P = 0.03] were found to be the factors independently associated with invasive IPMN. On the other hand, both univariate and multivariate analyses revealed that elevated carbohydrate antigen 19-9 (CA 19-9) levels were associated with the occurrence of concomitant ductal carcinoma in BD-IPMN [odds ratio 10.31 (95% CI 1.77-81.51); P = 0.01]. Conclusions Our results suggested that careful imaging study of the entire pancreas in addition to tumor lesions and measurement of serum CEA and CA19-9 would be required to find out the development of the two types of invasive carcinoma in BD-IPMN.

To distinguish malignant from benign branch duct (BD)-intraductal papillary mucinous neoplasm (IPMN) still remains difficult. Recently, we revealed that MSX2 was frequently expressed in pancreatic cancer and its expression was correlated with aggressive behavior of the cancer. The aim of this study was to assess the involvement of MSX2 in IPMN development and whether its expression would differentiate malignant from benign IPMN. Seventeen microdissected lesions and 45 IPMN tissues were used for quantitative real-time reverse-transcription polymerase chain reaction (RT-PCR) and immunohistochemistry, respectively. The role of MSX2 in the pancreatic duct cell was assessed by the induced expression of MSX2 in a normal human pancreatic duct epithelial cell line (HPDE). Malignant IPMN expressed significantly higher levels of MSX2 mRNA than benign IPMN lesions. MSX2 protein expression was frequently found in borderline and malignant lesions (20/29, 68.9%), while its expression was seen in only one of 16 benign IPMN tissues. Univariate analysis showed that nodules of 6 mm or more and MSX2 expression were significantly correlated with the malignancy of BD-IPMN (P = 0.022 and 0.0026, respectively), and multivariate analysis revealed that only MSX2 expression was identified as an independent factor to predict malignant BD-IPMN. HPDE cells expressing MSX2 showed increased cellular proliferation compared to control cells. Based on our results, MSX2 plays a pivotal role in the development of IPMN through growth stimulation of tumor cells, and its expression was identified as an independent predictive factor for malignancy of BD-IPMN.

慢性膵炎患者における膵癌発生の相対的危険度は4〜8といわれている.なかでも遺伝性膵炎や熱帯性膵炎では膵癌発生が極めて高率であるとされ,遺伝性膵炎では膵癌発症率が標準人口と比べて約50〜60倍である.大結石型の膵石で高度な膵管拡張を示す症例は,膵癌合併の危険性がより高いと考えられる.当科で経験した膵癌を合併した慢性膵炎症例について遺伝子解析を行った結果,熱帯性膵炎や若年性膵炎と関連がある膵分泌性トリプシンインヒビター(SPINK1)遺伝子変異を8例中3例に同定した.膵癌の高危険群を同定できれば,症状の出現前から膵に注目した検査が行われ,早期診断の可能性が高くなると考えられる.(著者抄録)

Granular cell tumors, also called Abrikossof's tumors, were originally described by Abrikossof A in 1926. The first case of a pancreatic granular cell tumor was described in 1975 and only 6 cases have been reported. We describe a case of granular cell tumor in the pancreas showing pancreatic duct obstruction. Because imaging studies showed findings compatible with those of pancreatic carcinoma, the patient underwent distal pancreatectomy. Histological examination showed that the tumor consisted of a nested growth of large tumor cells with ample granular cytoplasm and small round nuclei. The tumor cells expressed S-100 protein and were stained with neuron-specific enolase and periodic acid-Schiff, but were negative for desmin, vimentin, and cytokeratin. The resected tumor was diagnosed as a granular cell tumor. To our knowledge, this is the seventh case of Granular cell tumor of the pancreas to be reported. (C) 2010 Baishideng. All rights reserved.

This study aimed to clarify the association of the promoter variants in the CD14 gene with pancreatic diseases in Japan. Three hundred forty-six unrelated patients with acute pancreatitis (AP) (107 with severe and 239 with mild), 263 patients with chronic pancreatitis (CP), 264 patients with pancreatic neoplasm, and 319 healthy controls were genotyped for the single nucleotide polymorphisms at positions -260 and -651 from the AUG start codon in the CD14 gene by polymerase chain reaction-restriction enzyme digestion. The allele and genotype frequencies of the -260C/T and -651C/T polymorphisms did not differ between controls and patients with AP. In subgroup analyses, patients with severe AP had more -651C allele than controls [P = 0.005; odds ratio (OR) 1.71; 95% confidence interval (CI) = 1.18-2.49] or patients with mild AP (P = 0.001; OR 1.95; 95% CI = 1.33-2.85). Genotype -651CC was more common (P = 0.001 vs. controls and P = 0.001 vs. mild AP), and -651CT was less (P = 0.009 vs. controls and P = 0.007 vs. mild AP) in patients with severe AP than in healthy controls or patients with mild AP. The frequencies of pseudocyst development and requirement of surgery were higher in AP patients with -651CC than in those without this genotype. The -260C/T polymorphism was not associated with the severity of AP. The allele and genotype frequencies of both polymorphisms did not differ between controls and patients with CP or pancreatic neoplasm. -651C/T promoter polymorphism in the CD14 gene was associated with severity of AP in Japan.

慢性膵炎の疼痛に対する治療の手順として内科治療を第一選択として先行し、内科治療難渋例に対し手術を行うことが一般的である。しかし、膵管ステント交換等で入退院を繰り返さざるを得ない場合、どの時点で外科治療へ移行するべきか具体的な指針は示されていない。入院回数や費用などの患者負担に着目して内科治療群34症例と外科治療群34症例の比較を行ったところ、入院経費に有意差は無かったが、内科治療群は年間入院回数が有意に多かった。次に、内科治療群を膵管ステントの交換を繰り返しながら1年以上留置した群と膵管ステントが1年未満で不要になった群に分けて比較した所、前者は後者および外科治療群に比べ急性膵炎などのイベント発生率、入院回数、入院費用ともに成績が劣っていた。膵管ステントを継続的に1年以上留置することは患者の利益にならない。膵管ステントを継続しなければならない症例は、1年を目処に手術を考慮するべきである。(著者抄録)

Over a decade, there is accumulating evidence that activated pancreatic stellate cells (PSCs) play a pivotal role in the development of pancreatic fibrosis. In response to pancreatic injury or inflammation, quiescent PSCs are transformed (activated) to myofibroblast-like cells, which express α-smooth muscle actin. Activated PSCs proliferate, migrate, produce extracellular matrix components, such as type I collagen, and express cytokines and chemokines. Recent studies have suggested novel roles of PSCs in local immune functions and angiogenesis in the pancreas. If the pancreatic inflammation and injury are sustained or repeated, PSC activation is perpetuated, leading to the development of pancreatic fibrosis. In this context, pancreatic fibrosis can be defined as pathologic changes of extracellular matrix composition in both quantity and quality, resulting from perpetuated activation of PSCs. Because PSCs are very similar to hepatic stellate cells, PSC research should develop in directions more relevant to the pathophysiology of the pancreas, for example, issues related to trypsin, non-oxidative alcohol metabolites, and pancreatic cancer. Indeed, in addition to their roles in chronic pancreatitis, it has been increasingly recognized that PSCs contribute to the progression of pancreatic cancer. Very recently, contribution of bone marrow-derived cells to PSCs was reported. Further elucidation of the roles of PSCs in pancreatic fibrosis should promote development of rational approaches for the treatment of chronic pancreatitis and pancreatic cancer. © 2009 AGA Institute.

Objective: To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP). Methods: A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse. Results: Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p < 0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p=0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them. Conclusions: The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with lowdose steroid reduces but dose not eliminate relapses.

LIV-1 is a downstream target of STAT3 and is essential for the nuclear localization of Snail, a master regulator of epithelial to mesenchymal transition (EMT). Little is known about the association of LIV-1 with pancreatic carcinoma development, therefore, expression of LIV-1 mRNA was analyzed by real-time reverse transcriptase polymerase chain reaction (RT-PCR) in 9 cultured cell lines (8 carcinoma and I normal duct cell lines) and 24 pancreatic tissues (12 carcinoma and 12 normal tissues). Localization of this gene product was investigated by immunohistochemistry in 72 pancreatic carcinoma and the relation between its expression and clinicopathological findings was examined. To assess the function of LIV-1 in pancreatic carcinoma cells, stable siRNA expressing Panc-1 cells were generated. Higher expression of LIV-1 mRNA was found in both pancreatic carcinoma cell lines and pancreatic carcinoma tissues compared to normal duct cell line and histologically normal tissues, respectively. Immunohistochemical analysis revealed that LIV-1 expression was frequently found in 76.4% of pancreatic carcinoma tissues and its expression level was associated with tumor size and lymphatic infiltration. Down-regulated LIV-1 cells showed significant inhibition of anchorage-dependent or -independent proliferation and cell motility in vitro and reduction of tumor growth and metastasis in vivo. Furthermore, nuclear expression of Snail was decreased and E-cadherin expression was restored in LIV-1 siRNA expressing pancreatic carcinoma cells. These findings indicate that LIV-1 may be involved in acquisition of the aggressive phenotype of human pancreatic carcinoma cells through the induction of epithelial to mesenchymal transition.

症例は64歳・男性。検診にて肝左葉に腫瘤を指摘され、精査目的に当科を紹介された。腹部超音波検査、CT、MRIで肝S2に類円形の嚢胞内に増殖する乳頭状腫瘤を認めた。MRCPでは嚢胞はB2からの連続性が推測されたが、ERCPでは胆管と嚢胞の交通は確認できなかった。肝左葉切除を施行したところ、嚢胞内に少量の粘液と、充実性に発育する腫瘍を認めた。腫瘍は、卵巣様間質を認めず、pancreatobiliary typeの高分化型乳頭腺癌であった。中枢側の正常胆管と交通を示唆する部位を認め、また腫瘍より末梢の胆管の存在を認めなかった。以上から、末梢胆管に発生した胆管内乳頭状腫瘍(intraductal papillary neoplasm of the bile duct:IPNB)と診断した。IPNBは、症例数が少なく臨床的特徴が不明である。本症例は類円形の形態を呈した貴重な一例と考えられた。(著者抄録)

We have encountered cases of unusual intraductal pancreatic neoplasms with predominant tubulopapillary growth. We collected data on 10 similar cases of "intraductal tubulopapillary neoplasms (ITPNs)" and analyzed their clinicopathologic and molecular features. Tumor specimens were obtained from 5 men and 5 women with a mean age of 58 years. ITPNs were solid and nodular tumors obstructing dilated pancreatic ducts and did not contain any visible mucin. The tumor cells formed tubulopapillae and contained little cytoplasmic mucin. The tumors exhibited uniform high-grade atypia. Necrotic foci were frequently observed, and invasion was observed in some cases. The ITPNs were immunohistochemically positive for cytokeratin 7 and/or cytokeratin 19 and negative for trypsin, MUC2, MUC5AC, and fascin. Molecular studies revealed abnormal expressions of TP53 and SMAD4 in 1 case, but aberrant expression of P-catenin was not observed. No mutations in KRAS and BRAF were observed in the 8 cases that were examined. Eight patients are alive without recurrence, I patient died of liver metastases, and I patient is alive but had a recurrence and underwent additional pancreatectomy. The mitotic count and Ki-67 labeling index were significantly associated with invasion. All the features of ITPN were distinct from those of other known intraductal pancreatic neoplasms, including pancreatic intraepithelial neoplasia, intraductal papillary mucinous neoplasm, and the intraductal variant of acinar cell carcinoma. Intraductal tubular carcinomas showed several features that were similar to, those of ITPN, except for the tubulopapillary growth pattern. In conclusion, ITPNs can be considered to represent a new disease entity encompassing intraductal tubular carcinoma as a morphologic variant.

Since the rediscovery and definition of autoimmune pancreatitis (AIP) by Yoshida et al. in 1995, the disease has been attracting attention because of its unique clinical features and practical issues. This disease shows very impressive imaging findings, serological changes, and characteristic histopathology. It occurs most commonly in elderly males with painless jaundice or mild abdominal pain; resemblance in imaging findings between AIP and pancreatobiliary cancers poses an important practical issue of differentiation. With increasing recognition of AIP and accumulation of cases, another important feature of this disease has been revealed, i.e., association of extrapancreatic organ involvements. Initially misunderstood because it can be accompanied by other autoimmune disorders, such as Sjogren's syndrome or primary sclerosing cholangitis (PSC), AIP is now known to be associated with unique types of sialadenitis and cholangitis distinct from Sjogren's syndrome or PSC. Now the concept of "IgG4-related sclerosing disease" has become widely accepted and the list of organs involved continues to increase. With worldwide recognition, an emerging issue is the clinical definition of other possible types of autoimmune-related pancreatitis called "idiopathic duct-centric chronic pancreatitis (IDCP)" and "AIP with granulocyte epithelial lesion (GEL)" and their relation to AIP with lymphoplasmacytic sclerosing pancreatitis (LPSP). The time has arrived to establish clinical diagnostic criteria of AIP based on international consensus and to discuss regional and racial differences in the clinicopathological features of AIP. Consensus guidelines are also required for the ideal use of steroids in the treatment of AIP to suppress recurrence efficiently with minimal side effects. There are many issues to be settled in AIP; international collaboration of experts in the pancreas field is necessary to clarify the entire picture of this unique and important disease.

分枝型IPMNの手術適応基準を検討するため、分枝型IPMN159例を対象とし、さらに手術例45例と経過観察例114例に分けて、後ろ向きに調査した。経過観察例114例を対象に、国際診療ガイドラインの手術適応である拡張分枝膵管径30mmより大きい群とそれ未満で分け、予後に関してKaplan-Meier法によって比較したところ有意差を認めなかった(p=0.35)。次に分枝型IPMNの手術例45例からROC曲線を用いて良悪性を規定する因子として結節隆起高6mmを導きだし、結節隆起高6mmで経過観察例を分け、予後を比較したところ有意差を認めなかった(p=0.15)。さらに、経過観察例の結節隆起高を6mmから1mmずつ高く設定してそれより高い群と低い群の2群に分けて予後を比較したところ、9mmより高い群と低い群で有意差(p<0.05)が認められ、死亡例の死因はすべてIPMN由来浸潤癌であった。また、手術例の結節隆起高を調べると、9mmより大きい例はすべて悪性であった。以上から、確実に悪性と判定出来る結節隆起高9mmより大きい群を最初に手術適応とすることは、予後の観点からも妥当と考えられた。(著者抄録)