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Pancreatic cancer is the fourth leading cause of cancer-related deaths in Japan. To identify risk loci, we perform a meta-analysis of three genome-wide association studies comprising 2,039 pancreatic cancer patients and 32,592 controls in the Japanese population. Here, we identify 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P, Previous genome-wide association studies have identified risk loci for pancreatic cancer but were centered on individuals of European ancestry. Here the authors identify GP2 gene variants associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Helicobacter pylori infection is a well-established risk factor for gastric cancer and has been linked to other gastrointestinal diseases, including pancreatic and biliary tract cancers; however, the relevance of enterohepatic non-H. pylori helicobacters to the pathophysiology of these diseases remains unclear.We estimated the prevalence of two enterohepatic non-H. pylori helicobacters (Helicobacter hepaticus and Helicobacter bilis) in the framework of a hospital-based case-control study involving 121 patients with biliary tract cancer, pancreatic cancer, or other gastrointestinal diseases. Bile and blood samples were collected from the patients undergoing endoscopic retrograde cholangiopancreatography. The presence of H. bilis, H. hepaticus, and other Helicobacter spp. was examined using bacterial culture, PCR-based detection, and serological tests.Culture of Helicobacter spp. from biliary brush samples was unsuccessful. Approximately 13.0% (15/115) of the bile samples collected from patients with a variety of gastrointestinal cancers, including pancreatic and biliary tract cancers, tested positive for one of the enterohepatic non-H. pylori helicobacter species as determined by PCR. Specifically, H. bilis and H. hepaticus DNA were detected in 11 and 4 bile samples, respectively. Approximately 20%-40% of the patients tested positive for serum non-H. pylori helicobacter IgG antibodies. The seroprevalence of H. bilis and H. hepaticus in the patients without evidence of H. pylori infection appeared to be higher in the pancreatic cancer group than in the control group.Our findings suggest a role for Helicobacter spp., especially H. bilis and H. hepaticus, in the etiology of pancreatic and biliary tract cancers.

The etiology of pancreatic cancer remains largely unknown. Here, we report the results of a meta-analysis of three genome-wide association studies (GWASs) comprising 2,039 pancreatic cancer cases and 32,592 controls, the largest sample size in the Japanese population. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P-8) and 4 suggestive loci (P-6) for pancreatic cancer. Of these risk loci, 16p12.3 is novel; the lead SNP maps to rs78193826 (odds ratio (OR)=1.46, 95% CI=1.29-1.66, P=4.28×10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant predicted to be highly deleterious. Additionally, the gene-based GWAS identified a novel gene, KRT8, which is linked to exocrine pancreatic and liver diseases. The identified GP2 gene variants were pleiotropic for multiple traits, including type 2 diabetes, hemoglobin A1c (HbA1c) levels, and pancreatic cancer. Mendelian randomization analyses corroborated causality between HbA1c and pancreatic cancer. These findings suggest that GP2 gene variants are associated with pancreatic cancer susceptibility in the Japanese population, prompting further functional characterization of this locus.

Background: We aimed to evaluate the role of genetic polymorphisms in tobacco carcinogen-metabolizing genes and their interactions with smoking in a hospital-based case-control study of Japanese subjects. Materials and Methods: We examine the associations of pancreatic cancer risk with genetic polymorphisms in GSTM1, GSTT1 and GSTP1, phase II enzymes that catalyze the conjugation of toxic and carcinogenic electrophilic molecules. The study population consisted of 360 patients and 400 control subjects, who were recruited from several medical facilities in Japan. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the associations between genotypes and pancreatic cancer risk. Results: Among the control subjects, the prevalence of the GSTM1-null genotype and the GSTT1-null genotype was approximately 56% and 48%, respectively. Cases and controls were comparable in terms of GSTM1 and GSTT1 genotype distributions. Neither of the deleted polymorphisms in GSTM1 and GSTT1 was associated with the risk of pancreatic cancer, with an age- and sex-adjusted OR of 0.99 (95%CI: 0.74-1.32) for the GSTM1-null genotype, and 0.98 (95%CI: 0.73-1.31) for the GSTT1-null genotype. The OR was 0.97 (95%CI: 0.64-1.47) for individuals with the GSTM1 and GSTT1-null genotypes compared with those with the GSTM1 and GSTT1present genotypes. No synergistic effects of smoking or GST genotypes were observed. Conclusions: Our results indicate no overall association between the GSTM1 and GSTT1 deletion polymorphisms and pancreatic cancer risk in the Japanese subjects in our study.

Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-174.

Background Evidence supporting the associations between folate metabolizing gene polymorphisms and pancreatic cancer has been inconclusive. We examined their associations in a case-control study of Japanese subjects. Methods Our case-control study involved 360 newly diagnosed pancreatic cancer cases and 400 frequency-matched, non-cancer control subjects. We genotyped four folate metabolizing gene polymorphisms, including two polymorphisms (rs1801133 and rs1801131) in the methylenetetrahydrofolate (MTHFR) gene, one polymorphism (rs1801394) in the 5-methyltetrahydrofolate-homocysteine methyltransferase reductase (MTRR) gene and one polymorphism (rs1805087) in the 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR) gene. Genotyping was performed using Fluidigm SNPtype assays. Unconditional logistic regression methods were used to estimate odds ratios (ORs) and 95 % confidence intervals (CIs) for the associations between folate metabolizing gene variants and pancreatic cancer risk. Results Overall we did not observe a significant association between these four genotypes and pancreatic cancer risk. For rs1801133, compared with individuals with the CC genotype of MTHFR C677T, the OR for those with the CT genotype and TT genotype was 0.87 (0.62-1.22) and 0.99 (0.65-1.51), respectively. For rs1801131, individuals with the CC genotype had approximately 1.2-fold increased risk compared with those with the AA genotype, but the association was not statistically significant. In analyses stratified by smoking and drinking status, no significant associations were noted for C677T genotypes. No significant interactions were observed with smoking and drinking with respect to pancreatic cancer risk. Conclusions Our data did not support the hypothesis that MTHFR polymorphisms or other polymorphisms in the folate metabolizing pathway are associated with pancreatic cancer risk.

To determine the recommended dose (RD) for full-dose S-1 and low-dose gemcitabine combined with radiotherapy in patients with non-metastatic advanced pancreatic cancer.Adult patients with non-metastatic advanced pancreatic cancer (Union for International Cancer Control T stage 3 or 4) were eligible. The weekly intravenous gemcitabine (level 0-1: 200 mg/ml,level 2: 300 mg/m on Days 1, 8, 15, 22, 29, 36) dose was escalated starting from level 1 in a 3+3 design along with full dose twice-daily oral S-1 (level 0: 60 mg/m2/day, level 1-2: 80 mg/ml/day), and was administered on the same days as radiotherapy (1.8 Gy x 28 days).Eight patients were included in this study. A dose-limiting toxicity (DLT) (grade 4 neutropenia) was observed in one of the first three patients in level 1, and three additional patients received the level 1 dose without any severe adverse events. DLTs (grade 3/4 neutropenia) were then observed in the first two patients given level 2 dose. Therefore, level 1 was designated as the RD. Common grade 3/4 toxicities included neutropenia (62.5%), anorexia (37.5%), and pneumonitis (12.5%).The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Objectives Autoimmune pancreatitis (AIP) and its extrapancreatic lesions seem to be clinical manifestations of organs involved in IgG4-related systemic disease. To clarify whether the stomach is a target organ, gastric function was evaluated in patients with AIP. Methods In 6 patients with AIP, gastric emptying was assessed by Carbon 13 (¹³C) acetate breath test before and after steroid therapy. Based on 4-hour breath samples, the half ¹³CO₂ excretion time (T(1/2)) and the time of maximal excretion (T(max)) were calculated as gastric emptying parameters. Data of 20 healthy volunteers were used as controls. The number of IgG4-positive plasma cells in gastrofiberscopic biopsy specimens was counted before and after steroid therapy. Results Both T(1/2) and T(max) in patients with AIP decreased significantly after steroid therapy (T(1/2): 1.89 ± 0.21 hours vs 1.69 ± 0.15 hours, P = 0.046; and T(max): 1.1 ± 0.2 hours vs 0.96 ± 0.2 hours, P = 0.027), and became similar to those of the controls (T(1/2): 1.69 ± 0.32 hours and T(max): 0.98 ± 0.2 hour). The number of IgG4-positive plasma cells infiltrating the gastric mucosa decreased after steroid therapy. Conclusions Gastric emptying was impaired in patients with AIP and improved to the reference range after steroid therapy. The stomach may be a target organ of IgG4-related systemic disease.

Objectives: Because the prevalence of carcinoma is high in main-duct intraductal papillary mucinous neoplasms (IPMNs) of the pancreas, surgical resection is recommended for all main-duct type IPMNs. This study aimed to investigate the clinical predictors of malignancy and natural history of main-duct IPMNs. Methods: Preoperative clinical characteristics reliably correlated with malignancy in 26 surgically resected patients with main-duct IPMN, and long-term outcome in 20 conservatively followed patients with main-duct IPMN was examined. Results: Age at diagnosis was significantly older in conservatively followed IPMN patients than in surgically resected IPMN patients. Main pancreatic duct (MPD) dilatation 10 mm or greater and mural nodules were significantly more frequent in malignant IPMNs. Obvious progression of dilatation of the MPD was detected in all 4 conservatively followed patients who developed invasive pancreatic carcinoma. The histology of IPMN at autopsy of 4 conservatively followed patients who died of other causes 21 to 120 months later was adenoma. Seven conservatively followed without malignant findings did not show obvious progression of MPD dilatation. Conclusions: Although surgical resection is indicated for many main-duct IPMNs, conservative follow-up may be an option for elderly asymptomatic patients with main-duct IPMNs with the MPD less than 10 mm, no obvious mural nodule, and negative cytology.

Objective To examine the short-term and long-term clinical courses of patients with autoimmune pancreatitis (AIP) who underwent different treatments and identify predictive factors for relapse of AIP after steroid therapy. Methods Clinical courses of 50 AIP patients followed up for more than 1 year (median 40 months, range: 12-173 months) were examined. Patients were subdivided according to initial treatments as follows: surgical procedures in 10 patients, supportive therapy in 11 patients, and steroid therapy in 29 patients. Results Of the surgically treated patients, two underwent steroid therapy later because of progressive extensive lymphadenopathy and retroperitoneal fibrosis, respectively. Five conservatively followed-up patients were later given steroid therapy because of exacerbation of AIP involving the bile duct. Steroid therapy was effective in all patients. Pancreatic endocrine and exocrine dysfunctions and salivary gland dysfunction improved after steroid therapy in 100, 85, and 75% of patients, respectively. AIP relapsed in five patients initially treated with steroid, and presence of hilar bile duct stenosis and elevated serum IgG4 levels were significantly associated with relapse. Two relapsed AIP patients developed a pancreatic stone 2 and 3 years later. Although seven patients died, no patient died of AIP-related diseases or developed pancreatic carcinoma. Conclusion Most AIP patients treated with steroid had good short-term and long-term outcomes clinically, morphologically, and functionally. Hilar bile duct stenosis and elevated serum IgG4 levels were predictors of AIP relapse after steroid therapy. As some patients developed pancreatic stone formation or a malignancy during or after steroid therapy, AIP patients should be rigorously followed up.

Background: Although pancreatic cancer has been extensively studied, few risk factors have been identified, and no validated biomarkers or screening tools exist for early detection in asymptomatic individuals. We present a broad overview of molecular epidemiologic studies that have addressed the relationship between pancreatic cancer risk and genetic polymorphisms in several candidate genes and suggest avenues for future research.Methods: A comprehensive literature search was performed using the PubMed database.Results: Overall, individual polymorphisms did not seem to confer great susceptibility to pancreatic cancer; however, interactions of polymorphisms in carcinogen-metabolizing genes, DNA repair genes, and folate-metabolizing genes with smoking, diet, and obesity were shown in some studies. The major problem with these studies is that, due to small sample sizes, they lack sufficient statistical power to explore gene–gene or gene–environment interactions. Another important challenge is that the measurement of environmental influence needs to be improved to better define gene–environment interaction. It is noteworthy that 2 recent genome-wide association studies of pancreatic cancer have reported that variants in ABO blood type and in 3 other chromosomal regions are associated with risk for this cancer, thus providing new insight into pancreatic cancer etiology.Conclusions: As is the case in other complex diseases, common, low-risk variants in different genes may act collectively to confer susceptibility to pancreatic cancer in individuals with repeated environmental exposures, such as smoking and red meat intake. Clarification of gene–gene and gene–environmental interaction is therefore indispensable for future studies. To address these issues, a rigorously designed molecular epidemiologic study with a large sample is desirable.

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Characteristic pancreatic duct changes on endoscopic retrograde pancreatography (ERP) have been described in autoimmune pancreatitis (AIP). The performance characteristics of ERP to diagnose AIP were determined.The study was done in two phases. In phase I, 21 physicians from four centres in Asia, Europe and the USA, unaware of the clinical data or diagnoses, reviewed 40 preselected ERPs of patients with AIP (n=20), chronic pancreatitis (n=10) and pancreatic cancer (n=10). Physicians noted the presence or absence of key pancreatographic features and ranked the diagnostic possibilities. For phase II, a teaching module was created based on features found most useful in the diagnosis of AIP by the four best performing physicians in phase I. After a washout period of 3 months, all physicians reviewed the teaching module and reanalysed the same set of ERPs, unaware of their performance in phase I.In phase I the sensitivity, specificity and interobserver agreement of ERP alone to diagnose AIP were 44, 92 and 0.23, respectively. The four key features of AIP identified in phase I were (i) long (1/3 the length of the pancreatic duct) stricture; (ii) lack of upstream dilatation from the stricture (5 mm); (iii) multiple strictures; and (iv) side branches arising from a strictured segment. In phase II the sensitivity (71%) of ERP significantly improved (p0.05) without a significant decline in specificity (83%) (p0.05); the interobserver agreement was fair (0.40).The ability to diagnose AIP based on ERP features alone is limited but can be improved with knowledge of some key features.

Genome-wide association studies (GWASs) have identified many single nucleotide polymorphisms (SNPs) that are significantly associated with pancreatic cancer susceptibility. We sought to replicate the associations of 61 GWAS-identified SNPs at 42 loci with pancreatic cancer in Japanese and to develop a risk model for the identification of individuals at high risk for pancreatic cancer development in the general Japanese population. The model was based on data including directly determined or imputed SNP genotypes for 664 pancreatic cancer case and 664 age- and sex-matched control subjects. Stepwise logistic regression uncovered five GWAS-identified SNPs at five loci that also showed significant associations in our case-control cohort. These five SNPs were included in the risk model and also applied to calculation of the polygenic risk score (PRS). The area under the curve determined with the leave-one-out cross-validation method was 0.63 (95% confidence interval, 0.60–0.66) or 0.61 (0.58–0.64) for versions of the model that did or did not include cigarette smoking and family history of pancreatic cancer in addition to the five SNPs, respectively. Individuals in the lowest and highest quintiles for the PRS had odds ratios of 0.62 (0.42–0.91) and 1.98 (1.42–2.76), respectively, for pancreatic cancer development compared with those in the middle quintile. We have thus developed a risk model for pancreatic cancer that showed moderately good discriminatory ability with regard to differentiation of pancreatic cancer patients from control individuals. Our findings suggest the potential utility of a risk model that incorporates replicated GWAS-identified SNPs and established demographic or environmental factors for the identification of individuals at increased risk for pancreatic cancer development.

Autoimmune pancreatitis (AIP) is considered to be a pancreatic lesion of IgG4-related systemic disease, but about 20% of AIP patients do not have elevated serum IgG4 levels. This study aimed to clarify the pathophysiology of AIP patients without elevated serum IgG4 levels. Fifty-eight AIP patients were divided into 2 groups: those with elevated serum IgG4 levels (>135 mg/dl; SIgG4-positive AIP) and those without (SIgG4-negative AIP). The 2 groups’ clinical, serological, radiological, and histological findings, as well as salivary and lacrimal gland function, were compared. Serum IgG4 levels were elevated in 45 AIP patients and normal in 13 patients. In SIgG4-negative AIP patients, the female ratio tended to be high; obstructive jaundice was less likely; abdominal pain and acute pancreatitis were more likely; segmental swelling of the pancreatic body and/or tail was more common; sclerosing extrapancreatic lesions, salivary and lacrimal gland dysfunction, and abundant infiltration of IgG4-positive plasma cells in the gastric mucosa were less likely; and conservative follow-up was sometimes implemented. Histological examination of the pancreas of SIgG4-negative AIP showed lymphoplasmacytic sclerosing pancreatitis (LPSP) rather confined to the pancreas (n = 4), inadequate material (n = 2), and pancreatic fibrosis showing infiltration of lymphocytes without infiltration of IgG4-positive cells or neutrophils (n = 2). Clinicopathological features of SIgG4-negative AIP differed from those of SIgG4-positive AIP. Some SIgG4-negative AIP cases are LPSP rather confined to the pancreas. SIgG4-negative AIP may include idiopathic duct-centric pancreatitis (IDCP) or sclerosing pancreatitis other than LPSP or IDCP, but further studies are needed to clarify this issue.

We sought to clarify the clinical utility of diffusion-weighted magnetic resonance imaging (DWI) for differentiating autoimmune pancreatitis (AIP) from pancreatic cancer.Thirteen AIP patients underwent DWI before therapy, and six of them underwent DWI after steroid therapy. The extent and shape of high-intensity areas were compared with those of 40 pancreatic cancer patients. Apparent diffusion coefficient (ADC) values were calculated in the AIP area before and after steroid therapy in pancreatic cancer patients and in a normal pancreatic body.On DWI, AIP and pancreatic cancer were detected as high-signal intensity areas. The high-intensity areas were diffuse (n=4), solitary (n=6), and multiple (n=3) in AIP patients, but all pancreatic cancer patients showed solitary areas (P0.001). A nodular shape was significantly more frequent in pancreatic cancer, and a longitudinal shape was more frequently found in AIP (P=0.005). ADC values were significantly lower in AIP (1.012+/-0.112 x 10(-3) mm(2)/s) than in pancreatic cancer (1.249+/-0.113 x 10(-3) mm(2)/s) and normal pancreas (1.491+/-0.162 x 10(-3) mm(2)/s) (P0.001). Receiver operating characteristic analysis yielded an optimal ADC cutoff value of 1.075 x 10(-3) mm(2)/s to distinguish AIP from pancreatic cancer. After steroid therapy, high-intensity areas on DWI disappeared or were markedly decreased, and the ADC values of the reduced pancreatic lesions increased almost to the values of normal pancreas.DWI is useful for detecting AIP and for evaluating the effect of steroid therapy. ADC values were significantly lower in AIP than in pancreatic cancer. An ADC cutoff value may be useful for distinguishing AIP from pancreatic cancer.

Background and Aim: The role of the accessory pancreatic duct (APD) in pancreatic pathophysiology has been unclear. We previously examined the patency of the APD in 291 control cases who had a normal pancreatogram in the head of the pancreas by dye-injection endoscopic retrograde pancreatography (ERP). APD patency was 43% and was closely related with the shape of the terminal portion of the APD. The present study aimed to clarify the clinical implications of a patent APD. Methods: Based on the underlying data, the patency rate of the APD was estimated from the terminal shape of the APD on ERP in 167 patients with acute pancreatitis. Results: In patients with acute pancreatitis, stick-type APD, spindle-type APD, and cudgel-type APD, which showed a high patency, were rare, and branch-type APD and halfway-type or no APD, which showed quite low patency, were frequent in acute pancreatitis patients. Accordingly, the estimated patency of the APD in acute pancreatitis patients was only 21%. There was no significant relationship between the estimated APD patency and etiology or severity of acute pancreatitis. Conclusions: The terminal shapes of the APD with low patency were frequent in acute pancreatitis patients, and estimated APD patency was only 21% in acute pancreatitis. A patent APD may function as a second drainage system to reduce the pressure in the main pancreatic duct and prevent acute pancreatitis.

Autoimmune pancreatitis (AIP) is a unique form of pancreatitis in which the pathogenesis is suspected to involve autoimmune mechanisms. AIP sometimes mimics pancreatic cancer in its presentation, but as AIP responds dramatically to steroid therapy, accurate diagnosis is necessary. AIP is currently diagnosed on the basis of a combination of characteristic clinical, serological, morphological and histopathological features. However, its diagnosis remains a clinical challenge and there are no internationally agreed diagnostic criteria. Another type of AIP called 'idiopathic duct-centric chronic pancreatitis' or 'AIP with granulocytic epithelial lesion' has been reported in Western countries. IgG4-related sclerosing disease is a systemic disease in which IgG4-positive plasma cells and T lymphocytes extensively infiltrate various organs. Organs with tissue fibrosis and obliterative phlebitis, such as the pancreas, salivary gland and retroperitoneum, show clinical manifestations; AIP seems to represent one manifestation of IgG4-related sclerosing disease. As a mass is formed in most cases of IgG4-related sclerosing disease, a malignant tumor is frequently suspected on initial presentation. Clinicians should consider IgG4-related sclerosing disease in the differential diagnosis to avoid unnecessary surgery.

Aim: To clarify the features of acute or chronic pancreatitis and pancreatic tumors associated with complete and incomplete pancreas divisum. Methods: Clinical features of pancreatic diseases associated with complete (n = 54) and incomplete (n = 50) pancreas divisum were examined. Results: Acute and chronic pancreatitis occurred more frequently in patients with complete pancreas divisum (22.2%: 12/54, and 18.5%: 10/54, respectively) than in controls (5.6%: 183/3,246, and 4.9%: 159/3,246, respectively; p < 0.01). In 8 patients with chronic pancreatitis, the dorsal pancreatic duct was irregularly dilated from the orifice to the tail, whereas the ventral pancreatic duct was not dilated (isolated dorsal pancreatitis). None of the 12 complete pancreas divisum patients with acute pancreatitis consumed heavy or moderate amounts of alcohol. Although 6 of 10 patients with chronic pancreatitis consumed heavy or moderate amounts of alcohol, 31 of 32 patients with this malformation who did not exhibit pancreatitis consumed little or no alcohol. Chronic pancreatitis occurred more frequently in patients with incomplete pancreas divisum (18.0%: 9/50) than in controls (4.9%: 159/3,246; p < 0.01). Of 54 patients with complete pancreas divisum, 6 patients (11.1%) were associated with pancreatic tumor. All tumors developed from the dorsal pancreas of pancreas divisum. Conclusions: Complete pancreas divisum can be the sole etiology of acute or chronic pancreatitis. The presence of another factor, such as alcohol abuse, may be required for chronic pancreatitis to develop in some patients with complete or incomplete pancreas divisum. In complete pancreas divisum, the dorsal pancreatic duct might be a factor that promotes oncogenesis.

Background/Aim: Pancreatitis is the most common and feared complication of endoscopic retrograde cholangiopancreatography (ERCP). We previously examined patency of the accessory pancreatic duct (APD) by dye injection endoscopic retrograde pancreatography (ERP). APD patency was found in 43% of 291 control cases who had no particular changes in the head of the pancreas compared to only 6% in patients with acute pancreatitis. APD patency was closely related with the shape of the terminal portion of the APD. This study aimed to clarify whether patency of the APD prevents post-ERCP pancreatitis. Methods:We examined retrospectively the terminal shape of the APD by ERP in 34 patients with post-ERCP pancreatitis. Based on these data, patency of the APD was estimated from its terminal shape in patients with post-ERCP pancreatitis. Results: The stick-type APD (p < 0.01), which indicated high patency, was less frequent, and the branch-type APD (p < 0.01) and halfway-type APD, or no APD (p < 0.01), which showed quite low patency, were more frequent in patients with post-ERCP pancreatitis compared with controls. Accordingly, the estimated patency of the APD in post-ERCP pancreatitis patients was only 16%, which was significantly lower than the 43% in controls. There was no significant relationship between the estimated APD patency and the severity of post-ERCP pancreatitis. Conclusions: The estimated APD patency was significantly lower in patients with post-ERCP pancreatitis. A patent APD may function as a second drainage system to reduce the pressure in the main pancreatic duct and prevent post-ERCP pancreatitis.

Objective Autoimmune pancreatitis (AIP) is frequently associated with various extrapancreatic lesions. The distribution and frequency of extrapancreatic lesions preceding or subsequent to AIP are unknown. The aim of this study was to investigate metachronous extrapancreatic lesions of AIP. Patients and Methods Extrapancreatic lesions were examined clinically, radiologically, and histologically in 56 AIP patients. Results Extrapancreatic lesions were associated in 25 (45%) of 56 AIP patients. Twenty-nine extrapancreatic lesions were detected synchronously with AIP in 18 patients, and 18 lesions were detected metachronously in 11 AIP patients. Fourteen patients had more than 2 extrapancreatic lesions. There was no significant difference in serum IgG4 levels between AIP patients with preceding extrapancreatic lesions and synchronous extrapancreatic lesions. Extrapancreatic lesions preceding AIP were sclerosing sialadenitis (n=8), cervical lymphadenopathy (n=4), swelling of the lacrimal glands (n=2), retroperitoneal fibrosis (n=1), and hilar lymphadenopathy (n=1). Retrospective histopathological examination confirmed that these lesions were compatible with IgG4-related sclerosing disease. Steroid therapy was not given for these initial lesions, and AIP occurred 3 to 48 months after these initial lesions. Swelling of the preceding extrapancreatic lesions persisted when AIP occurred. Extrapancreatic lesions subsequent to AIP were retroperitoneal fibrosis (n=1) and systemic lymphadenopathy (n=1), both of which occurred during follow-up of AIP without steroid therapy. All extrapancreatic lesions improved after steroid therapy. Conclusion Swelling of salivary or lacrimal glands, lymphadenopathy, and retroperitoneal fibrosis can precede AIP. Lymphadenopathy and retroperitoneal fibrosis can occur subsequent to AIP. Recognition of these findings will aid in the correct diagnosis of AIP.

Background/Aims: To clarify the anatomy of the pancreatic duct system and to investigate its embryology. Methods: We reviewed pancreatograms of 256 patients with a normal pancreatic head and 36 cases of complete pancreas divisum. Results: Accessory pancreatograms were divided into two patterns. The long-type accessory pancreatic duct (APD) forms a straight line and joins the main pancreatic duct (MPD) at the neck portion of the pancreas. The short-type APD joins the MPD near its first inferior branch. The short-type APD is less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the short- and long-type APD. The first long inferior branch from the long-type APD passes through the MPD near the origin of the inferior branch from the MPD. Immunohistochemically, in the short-type APD, the MPD between the junction of the short-type APD and the neck portion originated from the ventral pancreas. Conclusion: The long-type APD represents a continuation of the main duct of the dorsal pancreatic bud. The short-type APD is very likely formed by the proximal main duct of the dorsal pancreatic bud and its long inferior branch, with the main duct of the dorsal pancreatic bud at the point of connection with the main duct of the ventral pancreatic bud being obliterated and replaced by this additional communication.

Objective Autoimmune pancreatitis (AIP) is a peculiar type of pancreatitis of presumed autoimmune etiology. However, target antigens for AIP have not been detected. Furthermore, its preponderant occurrence in elderly men and the very dramatic response with no major residual deformity to oral steroid therapy within 2 weeks suggest that the pathogenesis of AIP might not involve autoimmune mechanism. Recently, it was reported that the immune reaction closely involved in the pathogenesis of allergic disorders was upregulated in the affected tissues of AIP. This study aimed to examine the allergic manifestations in AIP patients. Methods This case series consisted of 45 AIP patients. Present and/or past histories of allergic diseases, clinical findings, and laboratory data were reviewed. Results Twenty patients (allergic-type AIP) had histories of allergic diseases, such as acute allergic rhinitis (n= 11), including rose and hay fever, atopic dermatitis (n= 5), bronchial asthma (n= 3), drug allergy (n= 2), and hypersensitivity pneumonitis (n= 1). Serum IgE levels were elevated in only 12 allergic-type AIP patients, and they were significantly higher in allergic-type AIP patients than in AIP patients without allergic manifestations (P = 0.0001). The peripheral eosinophil count was significantly elevated in allergic-type AIP patients (P =0.048). With respect to initial symptoms, obstructive jaundice was less frequent in allergic-type AIP patients (P = 0.012), and abdominal pain was detected in only five patients with allergic-type AIP (P = 0.013). Allergic-type AIP occurred predominantly from September to February in 19 of 20 patients (P = 0.001). Conclusion Allergic manifestations were detected in about half of the AIP patients, and allergic mechanisms may be related to the occurrence of AIP in these patients.

Embryologically, the pancreatic duct system develops by the fusion between the dorsal and ventral pancreatic bud ducts. It has been suggested that the proximal part of the main dorsal pancreatic duct partially regresses to form the accessory pancreatic duct (APD). Aim of this study was to clarify the anatomy of the pancreatic duct system of the head of the pancreas and investigate the embryology of the normal pancreatic duct system.We reviewed endoscopic retrograde pancreatography of normal pancreatic heads (n = 256) and pancreas divisum (n = 36), focusing on long inferior branches arising from the APD and the main pancreatic duct (MPD). The accessory pancreatograms were divided into two patterns of course and shape, the long type (171 cases) and the short type (85 cases) according to the length of the MPD from the orifice to the junction with the APD. The long-type APD formed a straight line and joined the MPD at the neck portion of the pancreas. The short-type APD joined the MPD near its first inferior branch.The shape of the long-type APD was quite similar to that of the dorsal pancreatic duct of pancreas divisum. The short-type APD was less likely to have a long inferior branch arising from the APD. The length of the APD from the orifice to the first long inferior branch was similar in the long-type APD (19.4 +/- 4.0 mm) and in the short-type APD (18.8 +/- 4.2 mm). The first long inferior branch from the long-type APD passed though the MPD near the origin of the inferior branch from the MPD, whereas the short-type APD joined the MPD near its inferior branch.There are two types of APD. The long-type APD was quite similar to the shape of the dorsal pancreatic duct of pancreas divisum, and seems to represent a continuation of the main duct of the dorsal pancreatic bud. The short-type APD was less likely to have a long inferior branch, and seems to be formed by the most proximal part of the main duct of the dorsal pancreatic bud and its long inferior branch.

Background There are few endoscopic retrograde cholangiographic studies dealing with the relationship between the presence of a common channel and associated pancreaticobiliary diseases. Aims To endoscopically determine the incidence of common channels and assess whether the anatomy of the pancreaticobiliary ductal drainage into the duodenum has any bearing on pancreaticobiliary diseases. Patients and Methods We prospectively examined a common channel formation in 354 endoscopic retrograde cholangiographic cases. Cases with a common channel were divided into three groups: pancreaticobiliary maljunction, high confluence of pancreaticobiliary ducts with a common channel ≥6 mm in which the communication was occluded with the sphincter contraction, and common channel ≤5 mm in length. Results A common channel was observed in 131 cases (37.0%) including 11 with pancreaticobiliary maljunction and 13 with high confluence of pancreaticobiliary ducts. In cases with a common channel, the incidences of associated gallbladder carcinoma and acute pancreatitis were both 11.5%, which were significantly higher than 1.8% and 4.9% seen in cases without a common channel. In pancreaticobiliary maljunction cases, incidence of associated gallbladder carcinoma was 72.7%. Conclusion The presence of an obvious common channel was observed in 37.0%. A close relationship is suggested between the presence of a common channel and development of gallbladder carcinoma and acute pancreatitis.

Objective: To compare salivary gland function in autoimmune pancreatitis (AIP) patients with and without an elevated serum IgG4 concentration. Patients and Methods: We allocated 14 AIP patients into 2 groups: one group had high (>135 mg/dL) serum IgG4 and the other low serum IgG4. Sialochemistry and submandibular and parotid gland scintigraphy were done in these patients. Results: Serum IgG4 levels were elevated in 10 patients. Bilateral submandibular gland swelling was present in 5 patients with a high serum IgG4; there was no swelling in patients with a low serum IgG4. The salivary Na+ concentration was increased significantly in both patient groups (p

We genotyped 2 SNPs (rs3790844 T/C and rs3790843 G/A) in the NR5A2 gene that were identified in a genome-wide association study (GWAS) of pancreatic cancer in populations of mainly European ancestry and we examined their associations with pancreatic cancer risk in a case-control study of 360 patients and 400 control subjects in Japan. Unconditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). The SNPs were in linkage disequilibrium (r2 = 0.80). For rs3790843, the multivariable-adjusted OR was 0.75 (95% CI: 0.41–1.36) and 0.60 (95%CI: 0.33–1.08) for subjects with the AG and AA genotype, respectively, compared to subjects with the GG genotype. The per allele OR was 0.78 (0.62–0.99) (P = 0.046). For rs3790844, the multivariable-adjusted OR was 0.65 (95% CI: 0.37–1.14) and 0.47 (95%CI: 0.27–0.83) for subjects with the CT and CC genotype, respectively, compared to subjects with the TT genotype. The per allele OR was 0.70 (0.56–0.89) (P = 0.003). Our case-control study found that rs3790843 and rs3790844 in the NR5A2 gene are associated with pancreatic cancer risk in Japanese subjects. The direction of association is consistent with the prior findings from GWASs.

Background: Pancreaticobiliary maljunction (PBM) is characterized by a markedly long common channel. In this condition, the sphincter of Oddi does not functionally affect the junction of the pancreatic and bile ducts. Reflux of pancreatic juice into the biliary duct of patients with PBM occurs, resulting in a high incidence of carcinogenesis in the gallbladder. Hence, the gallbladder mucosa of PBM appears to be in a precancerous state. However, the relationship between a relatively long common channel and precancerous lesions of the gallbladder is unknown. The present study aimed to investigate histopathological changes in the gallbladder of patients with a relatively long common channel. Methods: High confluence of pancreaticobiliary ducts (HCPBD) was defined as presence of a common channel ≥ 6 mm in which communication between the pancreatic and bile ducts was disrupted with sphincter contraction. We histopathologically examined the resected or autopsied gallbladder specimens from patients with HCPBD (n = 20), PBM without biliary dilatation (n = 15) and controls (n = 10); focusing on mucosal height and hyperplastic change. Proliferation activity was also examined with Ki-67 immunostaining. Results: The gallbladder mucosa was significantly higher in PBM and HCPBD than in controls. Hyperplastic mucosal changes were detected more frequently in PBM (73.3%, P

Goals: To examine extrapancreatic lesions associated with autoimmune pancreatitis. Background: Autoimmune pancreatitis is a unique clinical entity proposed recently, and is reported to occasionally be associated with other autoimmune diseases. Study: Extrapancreatic lesions were examined clinically, radiologically, and histologically in 25 patients with autoimmune pancreatitis. Results: Stenosis of the bile duct was observed in 22 patients (lower bile duct [n = 19], upper bile duct [n = 1], intrahepatic bile duct [n = 2]). Marked extrapancreatic bile duct wall thickening not associated with obvious cholangiographic abnormality was seen on ultrasound in 3 patients. Enlargement of the salivary glands and cervical lymph nodes was detected in 4 patients. Abdominal lymphadenopathy was observed in 5 of 8 patients at laparotomy. Retroperitoneal fibrosis was noted in 2 patients. Obliterative phlebitis of the pancreatic and peripancreatic veins was observed histologically in all 6 resected specimens. Marked stenosis of the portal vein and encasement of the peripancreatic arteries was observed in 4 and 8 of 14 patients who underwent abdominal angiography, respectively. Diabetes mellitus was diagnosed in 13 patients. All associated extrapancreatic lesions except diabetes mellitus improved after steroid therapy. Conclusions: Extrapancreatic lesions found to be occasionally associated with autoimmune pancreatitis were stenosis of the bile duct, enlargement of the salivary glands, abdominal or cervical lymphadenopathy, retroperitoneal fibrosis, stenosis of the peripancreatic arteries or portal vein, and diabetes mellitus. It is possible that these lesions are induced by the same inflammatory mechanisms as autoimmune pancreatitis.

BACKGROUND AND STUDY AIMS Autoimmune pancreatitis (AIP) is a condition that has been proposed as a clinical entity only fairly recently. Its pathogenesis involves autoimmune mechanisms. Although the radiological findings in patients with AIP have been well evaluated, few studies have focused on the gastrointestinal findings in these patients. The aim of this study was to explore the endoscopic and histological findings in the gastrointestinal tract in patients with autoimmune pancreatitis. PATIENTS AND METHODS The endoscopic findings in the stomach (n = 10), the duodenum (n = 18), the major duodenal papilla (n = 18), and the colon (n = 5) in 24 patients with AIP were reviewed. These were compared with the results of histological examination of gastric mucosa (n = 13), duodenal mucosa (n = 9), the major duodenal papilla (n = 3), and colonic mucosa (n = 3) in these patients. All these specimens were subjected to immunohistochemical study using anti-IgG4 antibody. RESULTS Foci of slightly pale, thickened mucosa with loss of visible vascular pattern were observed in the stomach in four patients and in the colon in two patients on endoscopy. Slight or moderate swelling of the major duodenal papilla was detected in five patients. Slight to moderate lymphoplasmacytic infiltration was observed in the lamina propria of the gastric and colonic mucosa, and of the major duodenal papilla. Heavy infiltration with IgG4-positive plasma cells (>10 cells per high-power field) was observed in the lamina propria of the stomach in seven patients, of the colon in two patients, and of the major duodenal papilla in three patients; this was not observed in the control patients, who had other diseases. CONCLUSIONS Although there were no specific endoscopic findings in the stomach or colon in patients with autoimmune pancreatitis, foci of slightly pale, thickened mucosa with loss of visible vascular pattern were observed in some cases. This indistinct change seen on endoscopy appears to be due to heavy infiltration with IgG4-positive plasma cells, associated with CD4- or CD8-positive T lymphocytes, in the lamina propria of the gastric or colonic mucosa.

OBJECTIVES: In patients with pancreaticobiliary maljunction (PBM), reflux of pancreatic juice to the bile duct may contribute to carcinogenesis of the biliary tract. This study aimed to investigate the pancreatographic findings in patients with PBM and the relationship to their clinical findings in view of pancreatic juice flow. METHODS: Seventy-eight cholangiopancreatograms were reviewed. When the maximum diameter of the Santorini duct was almost equal to or greater than that of the ventral pancreatic duct, the relationship between the 2 ducts was defined as dorsal pancreatic duct (DPD) dominance. RESULTS: Pancreatographic findings were divided into 2 groups: a normal duct group (69 patients) and a DPD dominant group (9 patients). Although 40 patients (58%) with biliary carcinoma were identified in the normal duct group of PBM, only 1 gallbladder carcinoma (11%) occurred in DPD-dominant patients (P < 0.01). A large-caliber Santorini duct was noted to flow straight from the upstream DPD in all patients with DPD dominance. Concentration of amylase in the bile of DPD dominance was significantly lower than that of normal pancreatic duct system (P < 0.01). CONCLUSIONS: In PMB with DPD dominance, most pancreatic juice in the upper DPD is drained into the duodenum through the minor duodenal papilla, and reflux of pancreatic juice to the biliary tract might be reduced, resulting in reduced frequency of associated biliary carcinogenesis.

Background: Although there has been considerable controversy regarding pancreas divisum and pancreatitis, little discussion of this has taken place. The purpose of the present paper was to investigate the relationship between these two conditions. Methods: A retrospective investigation was undertaken of pancreatic tumors associated with pancreas divisum, in 650 cases of pancreatic carcinoma, 80 cases of intraductal papillary mucinous tumor of the pancreas and 32 cases of pancreas divisum. Results: Of these 32 cases, four (12.5%) were associated with pancreatic tumor: pancreatic carcinoma (n = 3) and intraductal papillary mucinous tumor (n = 1). All tumors developed from the dorsal pancreas of pancreas divisum. Periductal and interlobular fibrosis detected in the non-carcinomatous pancreas of the margin of distal pancreatectomy implied that chronic dorsal pancreatitis associated with pancreas divisum preceded carcinoma. Conclusions: Pancreatic tumors were detected in 12.5% of cases of pancreas divisum. In pancreas divisum, longstanding pancreatic duct obstruction caused by relative stenosis of the minor duodenal papilla might be a factor promoting oncogenesis. © 2005 Blackwell Publishing Asia Pty Ltd

Steroid therapy is currently common treatment for autoimmune pancreatitis (AIP); however, indications of steroid therapy have yet to be established, and the clinical course after steroid therapy is unknown.A total of 23 patients with AIP were subdivided into 4 groups according to the initial treatments undertaken. They were treated with pancreatoduodenectomy on suspicion of pancreatic tumor in 6 patients, choledochoduodenostomy with pancreatic biopsy in 4 patients, supportive therapy in 3 patients, and steroid therapy in 10 patients. Clinical course of AIP in each group was examined.Prognosis of the AIP patients is almost good except for the 2 patients who progressed to pancreatic insufficiency after resection. Two patients without jaundice improved spontaneously. Steroid therapy was effective in all patients treated, but pancreatic atrophy developed in 5 of these patients. Steroid therapy improved insulin secretion and glycemic control in 4 of 7 diabetes mellitus (DM) patients.To avoid futile surgery, in relatively elderly male patients with obstructive jaundice suggestive of pancreatic carcinoma, preoperative clinical suspicion of AIP is mandatory. Indications of steroid therapy for AIP are thought to be obstructive jaundice due to stenosis of the bile duct, other associated systemic autoimmune, and DM coincidental with AIP.

We sought to elucidate differences in the clinical characteristics of gallbladder carcinoma according to the histological degree of glandular formation.The subjects consisted of 66 autopsy cases out of 331 patients admitted for gallbladder carcinoma between 1975 and 2000. After identifying 49 tubular adenocarcinoma cases, we arbitrarily divided them into two categories: a well-differentiated type (group W; n=41; well or moderately differentiated tubular adenocarcinoma), and a poorly differentiated type (group P, n=8). The clinical features of the groups were compared.No significant differences were found with regard to sex, age, or serum carcinoembryonic antigen (CEA) levels between the two groups. Moreover, no intergroup difference was found in either the time interval from the initial symptoms to admission, or the grade of tumor progression on admission. Although the frequency of liver metastases on admission was similar in both groups, the frequency at autopsy was significantly higher in group W than in group P (73% vs 25%; P0.05). When survival was determined based on the duration after primary treatment, the longest and median periods were 48.7 months and 3.7 months, respectively, in group W, whereas none of the subjects in group P survived for over 2 months. This difference was statistically significant ( P0.001).Hematogenous metastasis was more prominent in group W. Poorly differentiated tubular adenocarcinoma can be closely associated with a poor prognosis.

The accessory pancreatic duct (APD) is sometimes developmentally obliterated near the duodenum. We evaluated patency of the APD by dye-injection endoscopic retrograde pancreatography (ERP). We injected 2–3 mL contrast medium containing indigocarmine into the main pancreatic duct (MPD) via a selectively cannulated endoscopic catheter. Patency of the APD was evaluated by observing the excretion of dye from the minor duodenal papilla. Of the 291 control cases studied, 43% demonstrated a patent APD. Patency of the APD in patients with acute pancreatitis was only 17%, significantly lower than that of controls (P

Except for pancreaticobiliary maljunction, the relationship between a relatively long common channel and gallbladder carcinoma is unknown.For purposes of this study, a high confluence of pancreaticobiliary ducts was defined as a common channel that is 6 mm or greater in length, together with occlusion of the communication between the pancreatic and bile ducts during sphincter contraction. Pancreaticobiliary maljunction and high confluence of the pancreaticobiliary ducts were detected in 69 (2.1%) and 54 (1.6%), respectively, of 3300 consecutive patients who underwent ERCP. Proliferation activity and genetic alteration were examined in the non-carcinomatous epithelium of the gallbladder in patients with these two radiographic findings at ERCP.The Ki-67 labeling index in the epithelium in cases of a high confluence of the pancreaticobiliary ducts and pancreaticobiliary maljunction without biliary dilatation was significantly greater than that in cases of gallbladder carcinoma without these anomalies (p0.01). Overexpression of p53 and K-ras mutations were detected in, respectively, 22.2% and 27.8% of cases of a high confluence of pancreaticobiliary ducts.A relatively long common channel may be an important risk factor for the development of gallbladder carcinoma. Vigilance for the development of gallbladder carcinoma is indicated in patients with a relatively long common channel, in addition to those with pancreaticobiliary maljunction.

We analyzed 144 patients with pancreatic adenocarcinoma who had received intraoperative radiation therapy (IORT) in combination with external beam radiation therapy (EBRT) within the past 20 years. The patients were divided into 2 groups: group 1 contained 65 patients with locally unresectable tumors who underwent bypass operations and group 2 contained 68 patients with resectable tumors who underwent pancreatic resection. As a pilot study, we performed additional arterial infusion chemotherapy after changing peripancreatic hemodynamics during EBRT in the remaining 11 patients. The 30 patients who received R0 resection had the best survival rates (3-year survival rate of 35.4%), while 3 patients with stage III disease survived more than 5 years. The survival of group 1 patients nearly equaled that of group 2 patients who underwent R1 or R2 resection (median survival, 10.9 vs. 11.1 months, respectively; P = 0.43). The 1-year survival rate for the 11 patients receiving arterial infusion chemotherapy was 45.4%, and 5 patients survived over 1 year without developing hepatic metastasis or regrowth of primary tumors. The survival benefits obtained using this form of radiotherapy are apparently limited. On the other hand, additional arterial infusion chemotherapy employing a new drug delivery system using hemodynamic change does appear promising.

Background/Aims: Few studies on Santorini’s duct dominance, in which the ventral pancreatic duct is narrower than and anastomoses with Santorini’s duct have been performed. We examined clinical and radiological findings in cases characterized by dominance of Santorini’s duct. Methods: We reviewed 3,800 cases of endoscopic retrograde cholangiopancreatography. Clinical and pancreatographic findings including caliber, course, terminal shape, and patency of Santorini’s duct were examined in cases of Santorini’s duct dominance. Results: Twenty-nine cases were diagnosed as Santorini’s duct dominant. Chronic pancreatitis, acute relapsing pancreatitis, pancreatic-type pain, and hyperamylasemia not associated with obvious pancreatitis were observed in 3, 1, 5, and 6 cases, respectively. Cholangiopancreatographic findings indicated congenital choledochal cyst (n = 2), branch fusion between the ventral and dorsal pancreatic ducts (n = 23), and normal pancreatic duct system characterized by a straight course through the body and tail to join the ventral pancreatic duct in the neck portion of the pancreas (n = 4). Regarding terminal shapes of Santorini’s duct, cudgel type (n = 9) and spindle type (n = 8), which showed frequent patency, were observed significantly more frequently than in controls. Patency of Santorini’s duct was observed in 90% (17/19). Conclusions: Many Santorini’s duct-dominant cases exhibited branch fusion between the ventral and dorsal pancreatic ducts. Although Santorini’s duct functions well in most cases in which it is dominant, pancreatitis or pancreatic-type pain occurs in half of such cases due to relative impairment of function of the minor duodenal papilla.

Whether advanced pancreatic carcinomas should be surgically removed has been a basic issue because performing an extended resection is futile if it has only a minimum impact on survival. The purpose of this study was to compare the results of pancreatic resection with those of a bypass operation for patients with stage III or IVA pancreatic carcinomas while applying intraoperative radiation therapy (IORT). The therapeutic outcomes of 132 patients who had received IORT for stage III or IVA carcinoma were analyzed retrospectively. The patients were divided into two groups: Group 1 included 68 patients with locally unresectable tumors who underwent a bypass operation; group 2 included 64 patients with resectable tumors who underwent pancreatic resection. Postoperative external beam radiation therapy (EBRT) was also delivered to 90 patients. Multivariate analysis indicated that strong independent predictors of increased survival were EBRT for group 1 ( p0.0001) and R0 resection for group 2 ( p = 0.017). Twenty patients who had been subjected to R0 resection showed the best survival, with a 3-year survival rate of 45%. The survival of group 1 patients receiving EBRT ( n = 47) nearly equaled that of group 2 patients undergoing R1 or R2 resection ( n = 44) ( p = 0.72); but group 1 patients with tumorsor= 6 cm ( n = 31) had a better survival rate than group 2 patients with tumors3 cm ( n = 28) ( p = 0.03). We concluded that postoperative EBRT is essential for improving the survival outcome, even after administering IORT. Patients with stage III lesions undergoing an R0 resection and receiving IORT demonstrated an excellent 3-year survival. A bypass operation plus IORT in combination with EBRT is preferred over IORT used as an adjuvant to R1 or R2 resection.

Background: Autoimmune pancreatitis is a unique clinical entity proposed recently, and is sometimes associated with inflammation of other organs. Aims: To examine the pathophysiology of the pancreas and other organs in patients with autoimmune pancreatitis. Patients and methods: We evaluated clinicopathological findings in six resected and one autopsied patient with autoimmune pancreatitis. The pancreas, peripancreatic tissue, bile duct, and gall bladder were examined histologically and immunohistochemically. Biopsied salivary gland and cervical lymph node of one patient were also examined. We also performed similar immunohistochemical examinations in pancreatectomy specimens from 10 patients with alcoholic chronic pancreatitis and biopsied salivary glands from five patients with Sjogren’s syndrome. Results: Stenosis of the extrahepatic bile duct was detected in all patients. Histological findings were characterised by diffuse lymphoplasmacytic infiltration with marked interstitial fibrosis and acinar atrophy, obliterated phlebitis of the pancreatic veins, and involvement of the portal vein. Immunohistochemically, diffusely infiltrating cells consisted predominantly of CD4 or CD8 positive T lymphocytes and IgG4 positive plasma cells. Similar inflammatory processes also involved the peripancreatic tissue, extrahepatic bile duct, gall bladder, and salivary gland. Lymph nodes were swollen with infiltration of IgG4 positive plasma cells. None of these findings was seen in alcoholic chronic pancreatitis or Sjogren’s syndrome. Conclusions: The development of the specific inflammations in extensive organs as well as the pancreas in patients with autoimmune pancreatitis strongly suggests a close relationship between autoimmune pancreatitis and multifocal fibrosclerosis.

It was reported that in only 19 (11%) of 173 patients was the common channel at the junction of the pancreatic and bile ducts found to be 6 mm or longer. Pancreaticobiliary maljunction (PBM) is defined as an anomaly with a markedly long common channel with the junction located outside the duodenal wall, so the action of the sphincter of Oddi does not functionally affect the junction. We defined high confluence of pancreaticobiliary ducts (HCPBD) as a length of the common channelor = 6 mm, in which the communication between the pancreatic and bile ducts was occluded when the sphincter was contracted. This study aims at investigating the clinical significance of HCPBD.2,980 consecutive cases with an adequate endoscopic retrograde cholangiopancreatography were reviewed. PBM and HCPBD were diagnosed according to the above definitions. PBM was divided into two groups: with or without biliary dilatation.PBM and HCPBD were detected in 63 (2.1%) and 50 (1.7%) cases, respectively. Biliary dilatation was detected in 30 cases having PBM. The incidences of gallbladder carcinoma associated with PBM with or without biliary dilatation and HCPBD were 13, 67, and 12%, being significantly higher than in controls (p0.05, p0.01, and p0.05). Pancreatic ductal reflux was detected in 11 (85%) of 13 patients with HCPBD in whom postoperative T tube cholangiograms were performed, and acute pancreatitis occurred in 14 (24%) of the 50 patients with HCPBD.HCPBD may be an intermediate variant of PBM. It is necessary to pay attention to an associated gallbladder carcinoma in patients with HCPBD as well as in those with PBM.

Rare pancreatic endocrine tumors consisting of both exocrine and endocrine components have been reported sporadically. We investigated the ductal and acinar differentiation in pancreatic endocrine tumors. In immunohistochemical studies of 28 pancreatic endocrine tumors, staining with anti-carcinoembryonic antigen (CEA) or CA19-9 antibody indicated ductal differentiation, while staining with anti-amylase or anti-trypsin antibody indicated acinar differentiation. K-ras gene mutations and p53 gene alterations also were studied. Ten tumors were immunoreactive for CEA or CA19-9. Five tumors diffusely immunoreactive for CEA or CA19-9, in addition to endocrine markers, were diagnosed as duct-endocrine cell tumors of the pancreas. Two tumors diffusely immunoreactive for CEA or CA19-9 and also for pancreaticogut hormones as well as endocrine markers were diagnosed as duct-acinarendocrine cell tumors. These tumors showed uniform histologic features and synchronous ductal, acinar, and endocrine differentiation, distinct from the coexisting different cellular populations seen in collision tumors. All tumors were malignant. These duct-endocrine cell tumors or duct-acinar- endocrine cell tumors of the pancreas may be derived from a stem cell that retains the capability of expressing either an exocrine or endocrine phenotype. Only one K-ras gene mutation and no p53 gene alterations were detected in these tumors, which suggests that they constitute an entity with a different origin than ductal carcinomas.