Prevalence estimates of Helicobacter species infection in pancreatic and biliary tract cancers.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: Our findings suggest a role for Helicobacter spp., especially H. bilis and H. hepaticus, in the etiology of pancreatic and biliary tract cancers.

Glycoprotein 2 in health and disease: lifting the veil.

In 2020, we discovered glycoprotein 2 (GP2) variants associated with pancreatic cancer susceptibility in a genome-wide association study involving the Japanese population. Individuals carrying a missense coding variant (rs78193826) in the GP2 gene resulting in a p.V432M substitution had an approximately 1.5-fold higher risk of developing pancreatic cancer than those without this variant. GP2 is expressed on the inner surface of zymogen granules in pancreatic acinar cells, which are responsible for the sorting, storage and secretion of digestive enzymes. Upon neuronal, hormonal, or other stimulation, GP2 is cleaved from the membrane of zymogen granules and then secreted into the pancreatic duct and intestinal lumen. While the functions of GP2 remain poorly understood, emerging evidence suggests that it plays an antibacterial role in the gastrointestinal tract after being secreted from pancreatic acinar cells. Impaired GP2 functions may facilitate the adhesion of bacteria to the intestinal mucosa. In this review article, we summarize the role of GP2 in health and disease, emphasizing its functions in the gastrointestinal tract, as well as genetic variations in the GP2 gene and their associations with disease susceptibility. We hope that its robust genetic associations with pancreatic cancer, coupled with its emerging role in gastrointestinal mucosal immunity, will spur renewed research interest in GP2, which has been understudied over the past 30 years compared with its paralog uromodulin (UMOD).

Genome-wide association meta-analysis identifies GP2 gene risk variants for pancreatic cancer.

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 < 5.0 × 10-8), of which 16p12.3 has not been reported in the Western population. The lead single nucleotide polymorphism (SNP) at 16p12.3 is rs78193826 (odds ratio = 1.46, 95% confidence interval = 1.29-1.66, P = 4.28 × 10-9), an Asian-specific, nonsynonymous glycoprotein 2 (GP2) gene variant. Associations between selected GP2 gene variants and pancreatic cancer are replicated in 10,822 additional cases and controls of East Asian origin. Functional analyses using cell lines provide supporting evidence of the effect of rs78193826 on KRAS activity. These findings suggest that GP2 gene variants are probably associated with pancreatic cancer susceptibility in populations of East Asian ancestry.

Prediction model for pancreatic cancer risk in the general Japanese population.

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.

Associations between polymorphisms in folate-metabolizing genes and pancreatic cancer risk in Japanese subjects.

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.

Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese.

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 (r(2) = 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.

A Phase I Study of S-1 and Gemcitabine with Concurrent Radiotherapy in Patients with Non-Metastatic Advanced Pancreatic Cancer.

BACKGROUND/AIMS: 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. METHODOLOGY: 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). RESULTS: 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%). CONCLUSIONS: The combination of S-1 and gemcitabine with concurrent radiotherapy is a feasible regimen at the level 1 dose.

Case-control study of diabetes-related genetic variants and pancreatic cancer risk in Japan.

AIM: To examine whether diabetes-related genetic variants are associated with pancreatic cancer risk. METHODS: We genotyped 7 single-nucleotide polymorphisms (SNPs) in PPARG2 (rs1801282), ADIPOQ (rs1501299), ADRB3 (rs4994), KCNQ1 (rs2237895), KCNJ11 (rs5219), TCF7L2 (rs7903146), and CDKAL1 (rs2206734), and examined their associations with pancreatic cancer risk in a multi-institute case-control study including 360 cases and 400 controls in Japan. A self-administered questionnaire was used to collect detailed information on lifestyle factors. 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 association between these diabetes-associated variants and pancreatic cancer risk. RESULTS: With the exception of rs1501299 in the ADIPOQ gene (P = 0.09), no apparent differences in genotype frequencies were observed between cases and controls. Rs1501299 in the ADPIOQ gene was positively associated with pancreatic cancer risk; compared with individuals with the AA genotype, the age- and sex-adjusted OR was 1.79 (95%CI: 0.98-3.25) among those with the AC genotype and 1.86 (95%CI: 1.03-3.38) among those with the CC genotype. The ORs remained similar after additional adjustment for body mass index and cigarette smoking. In contrast, rs2237895 in the KCNQ1 gene was inversely related to pancreatic cancer risk, with a multivariable-adjusted OR of 0.62 (0.37-1.04) among individuals with the CC genotype compared with the AA genotype. No significant associations were noted for other 5 SNPs. CONCLUSION: Our case-control study indicates that rs1501299 in the ADIPOQ gene may be associated with pancreatic cancer risk. These findings should be replicated in additional studies.

Lack of associations between genetic polymorphisms in GSTM1, GSTT1 and GSTP1 and pancreatic cancer risk: a multi-institutional case-control study in Japan.

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 GSTT1- present 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.

Association between variations in the fat mass and obesity-associated gene and pancreatic cancer risk: a case-control study in Japan.

BACKGROUND: It is clear that genetic variations in the fat mass and obesity-associated (FTO) gene affect body mass index and the risk of obesity. Given the mounting evidence showing a positive association between obesity and pancreatic cancer, this study aimed to investigate the relation between variants in the FTO gene, obesity and pancreatic cancer risk. METHODS: We conducted a hospital-based case-control study in Japan to investigate whether genetic variations in the FTO gene were associated with pancreatic cancer risk. We genotyped rs9939609 in the FTO gene of 360 cases and 400 control subjects. An unconditional logistic model was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for the association between rs9939609 and pancreatic cancer risk. RESULTS: The minor allele frequency of rs9939609 was 0.18 among control subjects. BMI was not associated with pancreatic cancer risk. Compared with individuals with the common homozygous TT genotype, those with the heterozygous TA genotype and the minor homozygous AA genotype had a 48% (OR=1.48; 95%CI: 1.07-2.04), and 66% increased risk (OR=1.66; 95%CI: 0.70-3.90), respectively, of pancreatic cancer after adjustment for sex, age, body mass index, cigarette smoking and history of diabetes. The per-allele OR was 1.41 (95%CI: 1.07-1.85). There were no significant interactions between TA/AA genotypes and body mass index. CONCLUSIONS: Our findings indicate that rs9939609 in the FTO gene is associated with pancreatic cancer risk in Japanese subjects, possibly through a mechanism that is independent of obesity. Further investigation and replication of our results is required in other independent samples.

ABO blood type, long-standing diabetes, and the risk of pancreatic cancer.

AIM: To retrospectively study pancreatic cancer patients with respect to their ABO blood type and diabetes. METHODS: Our analysis included a cohort of 1017 patients with pancreatic ductal cancer diagnosed at our hospital in Tokyo. They were divided into two groups: 114 patients with long-standing type 2 diabetes (DM group, defined as diabetes lasting for at least three years before the diagnosis of pancreatic cancer) and 903 patients without diabetes (non-DM group). Multivariate analysis was performed to identify factors that are associated with long-standing diabetes. The DM group was further divided into three subgroups according to the duration of diabetes (3-5 years, 5.1-14.9 years, and 15 years or more) and univariate analyses were performed. RESULTS: Of the 883 pancreatic cancer patients with serologically assessed ABO blood type, 217 (24.6%) had blood type O. Compared with the non-DM group, the DM group had a higher frequency of blood type B [odds ratio (OR) = 2.61, 95%CI: 1.24-5.47; reference group: blood type A]. Moreover, male (OR = 3.17, 95%CI: 1.67-6.06), older than 70 years of age (OR = 2.19, 95%CI: 1.20-3.98) and presence of a family history of diabetes (OR = 6.21, 95%CI: 3.38-11.36) were associated with long-standing type 2 diabetes. The mean ages were 64.8 ± 9.2 years, 67.1 ± 9.8 years, and 71.7 ± 7.0 years in the subgroups with the duration of diabetes, 3-5 years, 5.1-14.9 years, and 15 years or more, respectively (P = 0.007). A comparison of ABO blood type distribution among the subgroups also showed a significant difference (P = 0.03). CONCLUSION: The association of pancreatic cancer with blood type and duration of diabetes needs to be further examined in prospective studies.

Strategy to differentiate autoimmune pancreatitis from pancreas cancer.

Autoimmune pancreatitis (AIP) is a newly described entity of pancreatitis in which the pathogenesis appears to involve autoimmune mechanisms. Based on histological and immunohistochemical examinations of various organs of AIP patients, AIP appears to be a pancreatic lesion reflecting a systemic "IgG4-related sclerosing disease". Clinically, AIP patients and patients with pancreatic cancer share many features, such as preponderance of elderly males, frequent initial symptom of painless jaundice, development of new-onset diabetes mellitus, and elevated levels of serum tumor markers. It is of uppermost importance not to misdiagnose AIP as pancreatic cancer. Since there is currently no diagnostic serological marker for AIP, and approach to the pancreas for histological examination is generally difficult, AIP is diagnosed using a combination of clinical, serological, morphological, and histopathological features. Findings suggesting AIP rather than pancreatic cancer include: fluctuating obstructive jaundice; elevated serum IgG4 levels; diffuse enlargement of the pancreas; delayed enhancement of the enlarged pancreas and presence of a capsule-like rim on dynamic computed tomography; low apparent diffusion coefficient values on diffusion-weighted magnetic resonance image; irregular narrowing of the main pancreatic duct on endoscopic retrograde cholangiopancreatography; less upstream dilatation of the main pancreatic duct on magnetic resonance cholangiopancreatography, presence of other organ involvement such as bilateral salivary gland swelling, retroperitoneal fibrosis and hilar or intrahepatic sclerosing cholangitis; negative work-up for malignancy including endoscopic ultrasound-guided fine needle aspiration; and steroid responsiveness. Since AIP responds dramatically to steroid therapy, accurate diagnosis of AIP can avoid unnecessary laparotomy or pancreatic resection.

Randomized phase II study of gemcitabine and S-1 combination versus gemcitabine alone in the treatment of unresectable advanced pancreatic cancer (Japan Clinical Cancer Research Organization PC-01 study).

PURPOSE: To evaluate the efficacy and safety of the combination of gemcitabine (GEM) and S-1 (GS) in comparison to GEM alone (G) for unresectable pancreatic cancer. METHODS: In this multicenter randomized phase II study, we randomly assigned unresectable pancreatic cancer patients to either the GS group or the G group. The GS group regimen consists of intravenous 1,000 mg/m(2) GEM during 30 min on days 1 and 8, combined with 80 mg/m(2) oral S-1 twice daily on days 1-14, repeated every 3 weeks. On the other hand, the G group regimen consists of intravenous 1,000 mg/m(2) GEM on days 1, 8, and 15, repeated every 4 weeks. The primary endpoint was objective response rate (ORR). Secondary end points included treatment toxicity, clinical response benefit, progression-free survival (PFS), and overall survival. RESULTS: We registered 117 patients from 16 institutions between June 2007 and August, 2010. The ORR of the GS group was 28.3%, whereas that of the G group was 6.8%. This difference was statistically significant (P = 0.005). The disease control rate was 64.2% in the GS group and 44.1% in the G group. Median PFS was 6.15 months in the GS group and 3.78 month in the G group. This was also statistically significant (P = 0.0007). Moreover, the median overall survival (OS) of the GS group was significantly longer than that of the G group (13.7 months vs. 8.0 months; P = 0.035). The major grade 3-4 adverse events were neutropenia (54.7% in the GS group and 22.0% in the G group), thrombocytopenia (15.1% in the GS group and 5.1% in the G group), and skin rash (9.4% in the GS group). CONCLUSIONS: The GS group showed stronger anticancer activity than the G group, suggesting the need for a large randomized phase III study to confirm GS advantages in a specific subset.

Utility of pancreatography for diagnosing autoimmune pancreatitis.

AIM: To identify pancreatographic findings that facilitate differentiating between autoimmune pancreatitis (AIP) and pancreatic cancer (PC) on endoscopic retrograde cholangiopancreatography (ERCP) and magnetic resonance cholangiopancreatography (MRCP). METHODS: ERCP findings of 48 AIP and 143 PC patients were compared. Diagnostic accuracies for AIP by ERCP and MRCP were compared in 30 AIP patients. RESULTS: The following ERCP findings suggested a diagnosis of AIP rather than PC. Obstruction of the main pancreatic duct (MPD) was more frequently detected in PC (P < 0.001). Skipped MPD lesions were detected only in AIP (P < 0.001). Side branch derivation from the narrowed MPD was more frequent in AIP (P < 0.001). The narrowed MPD was longer in AIP (P < 0.001), and a narrowed MPD longer than 3 cm was more frequent in AIP (P < 0.001). Maximal diameter of the upstream MPD was smaller in AIP (P < 0.001), and upstream dilatation of the MPD less than 5 mm was more frequent in AIP (P < 0.001). Stenosis of the lower bile duct was smooth in 87% of AIP and irregular in 65% of PC patients (P < 0.001). Stenosis of the intrahepatic or hilar bile duct was detected only in AIP (P = 0.001). On MRCP, diffuse narrowing of the MPD on ERCP was shown as a skipped non-visualized lesion in 50% and faint visualization in 19%, but segmental narrowing of the MPD was visualized faintly in only 14%. CONCLUSION: Several ERCP findings are useful for differentiating AIP from PC. Although MRCP cannot replace ERCP for the diagnostic evaluation of AIP, some MRCP findings support the diagnosis of AIP.

Incidence of and risk factors for developing pancreatic cancer in patients with chronic pancreatitis.

BACKGROUND/AIMS: Pancreatic cancer sometimes occurs during the course of chronic pancreatitis. This study aimed to identify risk factors for developing pancreatic cancer associated with chronic pancreatitis. METHODOLOGY: The incidence of pancreatic cancer developing in 218 patients with chronic pancreatitis and clinical features of the chronic pancreatitis patients who developed pancreatic cancer were studied. RESULTS: Nine patients developed pancreatic cancer. Average period from the diagnosis of chronic pancreatitis to the diagnosis of pancreatic cancer was 9.6 years. All pancreatic cancers were diagnosed at an advanced stage. Only 2 patients had been followed-up periodically. There were no significant differences between chronic pancreatitis patients who developed pancreatic cancer and those who did not in male/female ratio (3.5 vs. 8), average age on diagnosis (65.0 vs. 56.5), alcoholic/non-alcoholic chronic pancreatitis (1.6 vs. 2.6), smoking habits (62.5% vs. 70.7%), diabetes mellitus (77.8% vs. 54.4%), and continued alcohol drinking (37.5% vs. 53.1%). CONCLUSIONS: Over the period examined, 4% of chronic pancreatitis patients developed pancreatic cancer. Sex ratio, onset age, etiology, smoking habits, diabetes mellitus, and continued alcohol drinking were not significant risk factors for developing pancreatic cancer in chronic pancreatitis patients. Periodic follow-up due to the possibility of pancreatic cancer is necessary in chronic pancreatitis patients.

Endoscopic retrograde cholangiography does not reliably distinguish IgG4-associated cholangitis from primary sclerosing cholangitis or cholangiocarcinoma.

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 κ 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.

Gastric emptying in patients with autoimmune pancreatitis.

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.

Management strategies for autoimmune pancreatitis.

INTRODUCTION: Autoimmune pancreatitis (AIP) is a newly developed concept for a peculiar type of pancreatitis, and at present is recognized as a pancreatic lesion reflecting IgG4-related systemic disease. It is of utmost importance to differentiate AIP from pancreatic cancer to avoid unnecessary surgery. AREAS COVERED: The current management strategies for AIP, including its clinical features, diagnostic criteria, clinical subtypes, steroid therapy and prognosis are discussed, based on our 66 AIP cases and papers searched in PubMed from 1992 to March 2011, using the term 'autoimmune pancreatitis'. A new clinicopathological entity, an 'IgG4-related sclerosing disease' is also mentioned. EXPERT OPINION: AIP should be considered in the differential diagnosis in elderly male patients presented with obstructive jaundice and pancreatic mass. Steroids are a standard therapy for AIP, but their regimen including maintenance therapy should be evaluated in prospective trials.

Long-term follow-up of chronic pancreatitis patients with K-ras mutation in the pancreatic juice.

BACKGROUND/AIMS: Pancreatic cancer is known to occur during the course of chronic pancreatitis in some patients. This study aimed to identify a high risk group for developing pancreatic cancer associated with chronic pancreatitis, particularly the presence of K-ras mutations in the pancreatic juice. METHODOLOGY: K-ras mutation was analyzed by enriched polymerase chain reaction-enzyme linked mini-sequence assay in endoscopically-collected pancreatic juice of 21 patients with chronic pancreatitis between 1995 and 2000. All of them were followed-up for 6.0 +/- 3.8 (mean +/- SD) years (range, 2.1-14.2 years). RESULTS: K-ras point mutation was observed in the pancreatic juice of 11 patients with chronic pancreatitis (2+, n=2; 1+, n=6; +/-, n=3). Of these, 2 chronic pancreatitis patients with 2+K-ras point mutation developed pancreatic cancer 4.5 and 10.8 years, respectively, after the examination. CONCLUSIONS: Two chronic pancreatitis patients with K-ras mutation developed pancreatic cancer 4.5 and 10.8 years later. Semiquantitative analysis of K-ras mutation in endoscopically-collected pancreatic juice appears to be a useful tool for identifying chronic pancreatitis patients at high risk for developing pancreatic cancer.

[A case of fulminant ulcerative colitis initially presenting as fever of unknown origin].

A 40's man was referred to our hospital for the investigation of fever of unknown origin lasting for a month. The laboratory data showed a prominent inflammatory reaction and a high titer of PR3-ANCA. Despite the various imaging studies and bacteriological examinations, the cause of the fever could not be detected until he complained of abdominal pain with bloody stool that appeared during hospitalization and which prompted colonoscopy, resulting in the diagnosis of moderate ulcerative colitis of the descending colon. Although temporal improvement was achieved by mesalazine administration, the symptom exacerbated again. Then, a combination of steroid administration and the leukocytapheresis (LCAP) was performed, but it was also not effective. His rapidly deteriorating condition with the lesion extending to whole colon necessitated subtotal colectomy. He has been afebrile and in good condition since the operation, which indicates the cause of the fever was due to ulcerative colitis.