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We attempted to determine the indications and limitations of steroid therapy as the first-line therapy in patients with autoimmune pancreatitis (AIP) with cyst formation (ACF).This Japanese multicenter survey was conducted to examine the merits/demerits of steroid treatment as the initial therapy for ACF.Data of a total of 115 patients with ACF were analyzed. Complete remission was achieved in 86% (86/100) of patients who had received steroid treatment, but only 33.3% (5/15) of patients who had not received steroids. Relapse after the remission (n = 86) occurred in 7.6% (6/86) of patients who had received steroid therapy, but 40% (2/5) of patients who had not received steroid therapy. Multivariate analysis identified adoption of the wait and watch approach without steroid treatment (odds ratio = 0.126, P .001) as a significant and independent negative predictor of remission of ACF. As for predictors of relapse, the presence of varix (odds ratio = 5.83, P = .036) was identified as an independent risk factor.Steroid therapy plays an important role as first-line therapy in AIP patients with pancreatic cyst formation, however, varix formation, besides the diameter of the cyst(s), is a risk factor for refractoriness to steroid therapy.

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss’ к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in > 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

Background The clinical characteristics of IgG4-related sclerosing cholangitis (IgG4-SC) especially without autoimmune pancreatitis (AIP) have not been investigated in a large cohort. Aims To clarify the clinical characteristics of IgG4-SC and IgG4-SC without AIP. Methods We retrospectively reviewed imaging, serology, other organ involvement (OOI) and histology of 872 patients with IgG4-SC who participated in a Japanese nationwide survey in 2019, and compared these items between IgG4-SC with and without AIP. Results AIP was present in 83.7% (730/872) of IgG4-SC. In IgG4-SC, bile duct wall thickening was observed on ultrasound (528/650; 81.2%), computed tomography (375/525; 71.4%) and magnetic resonance imaging or cholangiopancreatography (290/440; 65.9%). An elevated serum IgG4 level (≥ 135 mg/dL) was found in 88.0% (322/366). IgG4-related OOI other than AIP was observed in 25.2% (211/836). The proportion of females was significantly higher in IgG4-SC without AIP (28.9% vs. 20.1%; p = 0.025). Hilar stricture was the most common cholangiographic type in IgG4-SC without AIP (39/107; 36.4%).There were no significant differences between IgG4-SC with and without AIP in the rates of bile duct wall thickening, elevated serum IgG4 level, or IgG4-related OOI. Conclusions The clinical characteristics of IgG4-SC was similar between IgG4-SC with and without AIP in a large cohort.

The biopsy-based diagnosis of autoimmune pancreatitis (AIP) is difficult but is becoming imperative for pathologists due to the increased amount of endoscopic ultrasound-guided biopsy tissue. To cope with this challenge, we propose guidance for the biopsy diagnosis of type 1 AIP. This guidance is for pathologists and comprises three main parts. The first part includes basic issues on tissue acquisition, staining, and final diagnosis, and is intended for gastroenterologists as well. The second part is a practical guide for diagnosing type 1 AIP based on the AIP clinical diagnostic criteria 2018. Inconsistent histological findings, tips for evaluating IgG4 immunostaining and key histological features including the ductal lesion and others are explained. Storiform fibrosis and obliterative phlebitis are diagnostic hallmarks but are sometimes equivocal. Storiform fibrosis is defined as spindle-shaped cells, inflammatory cells and fine collagen fibers forming a flowing arrangement. Obliterative phlebitis is defined as fibrous venous obliteration with inflammatory cells. Examples of each are provided. The third part describes the differentiation of AIP from pancreatic ductal adenocarcinoma (PDAC), focusing on histological features of acinar-ductal metaplasia in AIP, which is an important mimicker of PDAC. This guidance will help standardize pathology reports of pancreatic biopsies for diagnosing type 1 AIP.

To clarify the clinicoepidemiological characteristics of immunoglobulin G4 (IgG4)-related disease (IgG4-RD) with malignancy, a nationwide epidemiological survey was conducted.Immunoglobulin G4-related disease patients with malignancy who had visited selected hospitals in Japan were surveyed. The study consisted of two stages: the number of IgG4-RD patients with malignancy was estimated by the first questionnaire and their clinicoepidemiological characteristics were assessed by the second questionnaire.The frequencies of autoimmune pancreatitis (AIP), IgG4-related sialadenitis, IgG4-related eye disease, IgG4-related kidney disease, and IgG4-related retroperitoneal fibrosis were 44.7%, 20.8%, 14.0%, 5.16%, and 5.12%, respectively. The overall prevalence of malignant disease in IgG4-RD cases was estimated to be 10 900 per 100 000 cases, which was significantly higher than that of malignant disease in the general population. The prevalence of malignant lymphoma in IgG4-RD cases was the highest and was estimated to be 1985 per 100 000 cases. IgG4-related kidney disease had the highest frequency of malignant disease (17.1%). In data from 200 patients, 61 (30.5%) cases of cancer were found 2 years or more before the IgG4-RD diagnosis, 92 cases (46%) during the 1 year preceding or following IgG4-RD diagnosis, and 62 cases of cancer (31%) 2 or more years following IgG4-RD diagnosis.The nationwide survey for IgG4-RD with malignancy in Japan showed that IgG4-RD may be related with malignant diseases.

The histological diagnosis of type 1 autoimmune pancreatitis (AIP) based on the findings obtained by an endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) is feasible, but the diagnostic consistency of this method has not been confirmed. We determined the interobserver agreement among 20 pathologists regarding the diagnosis of type 1 AIP, including the distinction from pancreatic ductal adenocarcinoma (PDAC) using large tissue samples obtained by EUS-FNB. After guidance for diagnosing AIP with biopsy tissues was provided, a round 2 was performed. The median sensitivity and specificity for diagnosing PDAC vs. non-neoplastic diseases were 95.2% and 100%, respectively. In groups of specialists (n = 7) and the generalists (n = 13), Fleiss' к-values increased from 0.886 to 0.958 and from 0.750 to 0.816 in round 2. The concordance was fair or moderate for obliterative phlebitis and storiform fibrosis but slight for ductal lesion of type 1 AIP. Discordant results were due to ambiguous findings and biopsy tissue limitations. Among the specialists, the ratio of cases with perfect agreement regarding the presence of storiform fibrosis increased in round 2, but agreement regarding obliterative phlebitis or ductal lesions was not improved. Although the histological definite diagnosis of type 1 AIP was achieved by most observers in 60% of the cases, the confidence levels varied. Because some ambiguities exist, the histological diagnostic levels based on the diagnostic criteria of type 1 AIP should not be taken for granted. Guidance is effective for improving accurate PDAC diagnoses (notably by recognizing acinar-ductal metaplasia) and for evaluating storiform fibrosis.

Summary Background IgG4-related disease is a newly recognised immunopathological entity that includes autoimmune pancreatitis, IgG4-related sialadenitis, and IgG4-related kidney disease. To understand the genetic landscape of IgG4-related disease, we did a genome-wide association study. Methods We did a genome-wide association study of Japanese individuals, initially screening 857 patients with IgG4-related disease at 50 Japanese research institutions and DNA samples from 2082 healthy control participants from the Nagahama Prospective Genome Cohort for the Comprehensive Human Bioscience. From Oct 27, 2008, to July 22, 2014, we enrolled 835 patients and used data from 1789 healthy participants. Only patients with confirmed diagnosis of IgG4-related disease according to the international diagnostic criteria were included. Genotyping was done with the Infinium HumanOmni5Exome, HumanOmni2.5Exome, or HumanOmni2.5 Illumina arrays, and genomic distributions were compared between case and control samples for 958 440 single nucleotide polymorphisms. The HLA region was extensively analysed using imputation of HLA alleles and aminoacid residues. Fine mapping of the FCGR2B region was also done. Associations between clinical manifestations of disease and the genetic variations identified in these two genes were examined. Findings We identified the HLA-DRB1 (p=1·1×10−11) and FCGR2B (p=2·0×10−8) regions as susceptibility loci for IgG4-related disease. We also identified crucial aminoacid residues in the β domain of the peptide-binding groove of HLA-DRB1, in which the seventh aminoacid residue showed the strongest association signal with IgG4-related disease (p=1·7×10−14), as has been reported with other autoimmune diseases. rs1340976 in FCGR2B showed an association with increased FCGR2B expression (p=2·7×10−10) and was in weak linkage disequilibrium with rs1050501, a missense variant of FCGR2B previously associated with systemic lupus erythematosus. Furthermore, rs1340976 was associated with the number of swollen organs at diagnosis (p=0·011) and IgG4 concentration at diagnosis (p=0·035). Interpretation Two susceptibility loci for IgG4-related disease were identified. Both FCGR2B and HLA loci might have important roles in IgG4-related disease development. Common molecular mechanisms might underlie IgG4-related disease and other immune-related disorders Funding The Japanese Ministry of Health, Labour, and Welfare, the Japanese Agency of Medical Research and Development, and Kyoto University Grant for Top Global University Japan Project.

Autoimmune pancreatitis (AIP) has the potential to transform into chronic pancreatitis with pancreatic stone involvement. This retrospective investigation sought to clarify the risk factors for stone formation in type 1 AIP.Questionnaires on patients with type 1 AIP were sent to 22 high-volume medical centers across Japan to compare the clinical features of patients with and without pancreatic stone formation.Of the completed records on 624 type 1 AIP patients, 31 (5%) had experienced pancreatic stones. Median follow-up duration was 1853 days. Bentiromide test values at diagnosis were significantly lower, and hemoglobin A1c values after corticosteroid treatment were significantly higher in patients with pancreatic stones. Imaging results disclosed that pancreatic atrophy and hilar or intrahepatic bile duct stenosis were significantly more frequent in patients with pancreatic stone formation. Pancreatic head swelling tended to be more frequent in this group as well. On the other hand, a shorter follow-up period was associated with the nonformation of pancreatic stones.The increased frequency of pancreatic head swelling in type 1 AIP patients exhibiting pancreatic stones indicated a propensity for pancreatic juice stasis with subsequent stone development and pancreatic dysfunction occurring over longer periods of disease duration.

Background Several years have passed since the clinical diagnostic criteria for IgG4-related sclerosing cholangitis 2012 were published. New findings and knowledge have accumulated since then. Methods The Research Committees for IgG4-related Diseases and for Intractable Diseases of the Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare of Japan and the Japan Biliary Association, have established a working group consisting of researchers specializing in IgG4-SC and have drawn up new clinical diagnostic criteria for IgG4-SC 2020. Results The diagnosis of IgG4-SC is based on a combination of the following six criteria: (1) narrowing of the intra- or extrahepatic bile duct, (2) thickening of the bile duct wall, (3) serological findings, (4) pathological findings, (5) other organ involvement, and (6) effectiveness of steroid therapy. Conclusion These new diagnostic criteria for IgG4-SC are useful in practice for general physicians and other non-specialists.

We report the two youngest cases of hepatocellular carcinoma (HCC) in non-alcoholic fatty liver disease (NAFLD) among our 119 NAFLD-HCC patients. A 36-year-old man was referred to our hospital due to a 5 cm in diameter liver tumor with elevation of α-fetoprotein and des-γ-carboxy prothrombin found at his annual health check. He had no symptoms other than 20 kg weight loss. He has been morbidly obese since he was a child. At the time of the diagnosis of NAFLD-HCC, blood chemistry showed FIB4-index 0.52, α-fetoprotein 11.1 ng/mL and des-γ-carboxy prothrombin 361 mAU/mL. He underwent curative operation. The non-cancerous lesion showed steatohepatitis with mild fibrosis. A 41-year-old man was diagnosed as having a huge liver tumor (15 cm in diameter) during medical examination for 10 kg weight loss. He had no clinical symptoms except weight loss. He has been morbidly obese since childhood. NAFLD was diagnosed at age 20. At the time of the HCC diagnosis, blood chemistry showed FIB4-index 1.42, α-fetoprotein 1974 ng/mL, and des-γ-carboxy prothrombin 82,602 mAU/mL. He underwent curative operation. We have to be aware that HCC can develop in young NAFLD patients without advanced fibrosis. Concerning tumor markers, elevation of des-γ-carboxy prothrombin was more sensitive than α-fetoprotein.

Germline BRCA1 and BRCA2 mutations are the most common gene mutations in familial pancreatic adenocarcinoma. Several reports have demonstrated the utility of platinum-based chemotherapy for treating cancer patients who harbour a BRCA mutation. Here we discuss a 47-year-old Japanese female with no relevant past history who presented with epigastralgia and fever in September 2016. A computed tomography scan revealed a low-density, low-enhanced tumour 15 mm in diameter in the head of the pancreas. The pathological diagnosis was a ductal pancreatic carcinoma. A 6 mm low-enhanced metastatic tumour was also detected in segment 4 of the liver. Because she had early onset of the disease and a family history—her mother died of pancreatic adenocarcinoma at age 48—we considered a diagnosis of familial pancreatic adenocarcinoma. She received modified FOLFIRINOX. Two months after starting chemotherapy, she was diagnosed with an invasive ductal carcinoma in the right breast. FOLFIRINOX was continued for 8 cycles (4 months); the primary pancreatic adenocarcinoma shrank and the liver metastatic foci disappeared, but the size of the breast tumour increased. Total right breast excision and sentinel lymph node dissection were performed. FOLFIRINOX was continued and after 12 cycles (6 months), both her pancreatic adenocarcinoma and liver metastasis were no longer visible using imaging. Pancreatoduodenectomy was performed and the primary tumour had shrunk to 2.5 mm. Genetic testing revealed a germline BRCA2 mutation. The FOLFIRINOX regimen showed dramatic effects on the collision pancreatic but not on the breast cancer.

A 61-year-old woman was referred to our hospital because of epigastric pain during chemotherapy for breast cancer recurrence. She was diagnosed with left breast cancer and underwent mastectomy with axillary lymph node dissection 13 years previously. The postoperative pathological examination result was luminal invasive lobular carcinoma. Hydronephrosis appeared after 1 month, which we diagnosed as ureter stenosis caused by radiation therapy for the lumbar metastasis and thus inserted an ureteralstent. After 1 month, computed tomography demonstrated expansion of the tumor into the stomach and duodenum. Upper gastrointestinalendoscopy demonstrated stenosis of the duodenum with intact mucosa. We diagnosed the duodenalstenosis due to the retroperitonealmetastasis of breast cancer and inserted duodenal, biliary, and pancreatic duct stents. The plural stent insertion was effective, and chemotherapy was administered with enforcement possibility for 7 months afterward.

BACKGROUND Sporadic autoimmune pancreatitis (AIP) cases showing remission without steroid treatment have been reported, however, the clinical course of these patients has not been clarified. This study sought to clarify the clinical course in AIP patients with hesitation for steroid treatment. METHODS We collected clinical data for AIP patients from high-volume centers in Japan. Data for AIP patients with and those without steroid treatment (steroid treatment vs. wait and see policy or W&S) were then compared. The primary point was the relapse-free survival rate (RFS) in patients with and those without steroid treatment, as determined using Kaplan-Meier curve. The secondary point was the identification of predictors of remission and risks of relapse in AIP patients without steroid treatment. RESULTS There were 510 AIP patients in the steroid treatment group and 97 patients in the W&S group. Overall, 55.7% (54/97) of type 1 AIP patients in the W&S group experienced transient remission without steroid treatment. The W&S group had a significantly higher patient age and significantly lower incidences of jaundice, diffuse pancreas swelling, proximal-type sclerosing cholangitis, and stent placement and a lower remission rate than the steroid treatment group (each P

Objective: We aimed to assess the usefulness of a novel guide-wire technique for repositioning without the use of a Nelaton tube and to compare this to the conventional technique. Subjects and Methods: A total of 50 patients who underwent endoscopic nasobiliary drainage (ENBD) at the Yachiyo Medical Center, Chiba, Japan, were enrolled into the study. The patients were randomly divided into 2 groups according to the use of a novel guide-wire technique (n = 28) or the conventional technique (n = 22). The ENBD catheters were repositioned from the mouth to the nose. The primary end point was the procedural time from the insertion of the Nelaton tube or guide wire into the nostril until the ENBD catheter had been repositioned in the nose. The secondary end point was the success rate of the procedure. Results: The mean procedure time of our technique (120.8 s) was shorter than the traditional technique (131.9 s), but this difference was not statistically significant (p = 0.56). Our technique did not involve the use of the Nelaton tube, and so could save the cost of USD 1.17 per patient. The novel technique did not require the removal of the mouthpiece with a laryngoscope or the use of a Nelaton tube, and no postural change was necessary. A single operator performed the novel procedure unassisted. No adverse events were observed relating to either the novel or the traditional technique. Conclusions: The novel guide-wire technique for repositioning ENBD catheters was effective and is recommended for use.

Stomach cancer can occur during chronic inflammation from Helicobacter pylori (HP) infection, and its occurrence can be suppressed by eradication of HP. However, the effects of suppressing stomach cancer by HP eradication are limited, and the cancer is known to recur even after eradication of this infection. Here, we report the case of a 56-year-old male patient with gastric cancer who, although undergoing HP eradication after treatment of early gastric cancer with endoscopy, experienced five metachronous cancer recurrences over a period of 13 years. Whether observation of patients who undergo eradication of HP due to peptic ulcers or chronic gastritis and patients who undergo eradication after endoscopic treatment for early gastric cancer should be performed at the same interval is an issue that must be addressed in the future. The appropriate observation period for each patient must be established while considering the burdens to the patient and from the medical economic perspective.

To evaluate the potential of diffusion kurtosis imaging (DKI) analysis with the breath-hold technique to assess the stage or classify hepatic fibrosis.Patients (n=67) suspected of having a disease of the hepatobiliary system examined by diffusion-weighted imaging (DWI) using a 3.0-T magnetic resonance imaging unit were enrolled in this study. To evaluate hepatic fibrosis, mean kurtosis, Mean apparent diffusion (MD) and apparent diffusion coefficient (ADC) values were compared between groups with varying fibrosis; F0-F1, F2-F3, and F4. The Steel-Dwass test was used for overall comparisons. Correlations between the fibrosis stage and mean kurtosis, MD or ADC values were assessed using Spearman's rank correlation. Discriminative capacities of DKI were evaluated using receiver operating characteristic (ROC) analysis.There were significant differences in ADC, MD and mean kurtosis values between non-cirrhosis and cirrhosis groups. Moreover, the mean kurtosis value was statistically different between the F0-F1 and F2-F3, F0-F1 and F4, and F2-F3 and F4 groups (all P0.05). MD value was statistically different between the F0-F1 and F4 groups, and F2-F3 and F4 groups (all P0.05). However, there was no significant difference in ADC values for all groups (all P0.05). In addition, mean kurtosis and MD values significantly correlated with the extent of hepatic fibrosis staging (Spearman's rank correlation coefficient, ρ=0.851 and -0.672; P0.0001). However, ADC values did not reveal a correlation with the extent of hepatic fibrosis staging (ρ=-0.227; P=0.078). According to the ROC analysis for the assessment of no fibrosis (F0), fibrosis (≥F1), and advanced fibrosis (≥F2) and liver cirrhosis, the DKI cut-off values were 0.923, 0.955, and 1.11, respectively.Using the DKI method with the breath-hold technique in the liver, the stage of hepatic fibrosis can be classified into normal and early hepatic fibrosis, substantial stages, and advanced hepatic fibrosis.

Published online: 25 March 2014, Article, JOURNAL OF GASTROENTEROLOGY. 49(5):765-784 (2014)

OBJECTIVES: We aimed to determine whether diffusion kurtosis imaging (DKI) analysis with the breath-hold technique can replace liver function results obtained from laboratory tests. METHODS: Patients (n = 79) suspected of having a hepatobiliary disease, and control group without liver diseases (n = 15) were examined with non-Gaussian diffusion-weighted imaging using a 3.0 T magnetic resonance imaging unit. Based on the findings of DKI, various blood serum parameters, including the indocyanine green (ICG) retention rate 15 min after an intravenous injection of ICG (ICG-R15) and mean kurtosis values and Child–Pugh and albumin–bilirubin (ALBI) scores, were calculated. In total, 17 patients were tested using ICG-R15. For evaluating liver function, correlations between the mean kurtosis value and the Child–Pugh score, ALBI score, and ICG-R15 value as indicators of liver function obtained from blood data were assessed using Spearman’s rank correlation. In apparent diffusion coefficient as well, we assessed correlations with these indicators. RESULTS: The mean kurtosis value correlated with the Child–Pugh score (Spearman’s rank-correlation coefficient, ρ = 0.3992; p < 0.0001). Moreover, the mean kurtosis value revealed a correlation with the ICG-R15 value (Spearman’s rank-correlation coefficient, ρ = 0.5972; p = 0.00114). The correlation between the mean kurtosis value and the ALBI score was the poorest among these (Spearman’s rank-correlation coefficient, ρ = 0.3395; p = 0.0008). CONCLUSION: Liver function correlating with the Child–Pugh score and ICG-R15 value can be quantitatively estimated using the mean kurtosis value obtained from DKI analysis. DKI analysis with the breath-hold technique can be used to determine liver function instead of performing laboratory tests. ADVANCES IN KNOWLEDGE: Previous studies have not evaluated liver function in vivo using DKI.

Background and Aim IgG4-related sclerosing cholangitis (IgG4-SC) must be precisely distinguished from primary sclerosing cholangitis and cholangiocarcinoma (CC) because the treatments are completely different. However, the pathological diagnosis of IgG4-SC is difficult. Therefore, highly specific non-invasive criteria such as serum IgG4 should be established. This study established a cut-off for serum IgG4 to differentiate IgG4-SC from respective controls using serum IgG4 levels measured in Japanese centers. Methods A total of 344 IgG4-SC patients were enrolled in this study. As controls, 245, 110, and 149 patients with pancreatic cancer, primary sclerosing cholangitis, and CC, respectively, were enrolled. IgG4-SC patients were classified into three groups: type 1 (stenosis only in the lower part of the common bile duct), type 2 (stenosis diffusely distributed throughout the intrahepatic and extrahepatic bile ducts), and types 3 and 4 (stenosis in the hilar hepatic region) with 246, 56, and 42 patients, respectively. Serum IgG4 levels were compared, and the cut-offs were established. Results The cut-off obtained from receiver operator characteristic curves showed similar sensitivity and specificity to that of 135 mg/dL when all IgG4-SC and controls were compared. However, a new cut-off value was established when subgroups of IgG4-SC and controls were compared. A cut-off of 182 mg/dL can increase the specificity to 96.6% (4.7% increase) for distinguishing types 3 and 4 IgG4-SC from CC. A cut-off of 207 mg/dL might be useful for completely distinguishing types 3 and 4 IgG4-SC from all CC. Conclusions Serum IgG4 is useful for the differential diagnosis of IgG4-SC and controls.

Some patients infected with hepatitis C virus (HCV) genotype 2 could be cured with treatment shorter than 24 weeks using peginterferon plus ribavirin, but there are still treatment-refractory patients. Direct-acting antivirals (DAAs) are not currently available for HCV genotype 2 patients, different from genotype 1 patients, in clinical practice. We investigated 29 HCV genotype 2-infected Japanese patients who had been previously treated and failed to clear HCV. We retreated them with peginterferon alfa-2a plus ribavirin and measured HCV RNA level to assess the efficacy and safety of this treatment in patients who had failed previous therapy. We found that retreatment of HCV genotype 2-infected Japanese patients with peginterferon alfa-2a plus ribavirin for 24-48 weeks led to 60 to 66.6% sustained virological response (SVR) in patients previously treated with (peg-)interferon monotherapy and to 69.9% SVR in relapsers previously treated with peginterferon plus ribavirin. Attention should be paid to certain patients with unique features. Selection of patients according to their previous treatment could lead to optimal therapy in HCV genotype 2 treatment-experienced patients.

The effect of maintenance steroid treatment (MST) in reducing the risk of relapse in patients with autoimmune pancreatitis (AIP) remains under debate. The aim of this study was to validate the effect of MST on AIP administered in accordance with the 2010 Japanese consensus guidelines.The clinical data of patients with (n = 510) from 22 high-volume centers in Japan were studied. The primary endpoints were the relapse rates (RRs) in patients administered MST versus those not administered MST. The secondary endpoints were the optimal dose and duration of MST in terms of steroid toxicity and the predictors of relapse.The RRs were 10.0% within 1 year, 25.8% within 3 years and 35.1% within 5 years. The RR in the steroid therapy group reached a plateau at 42.7% at 7 years. In terms of the optimal dosage, the overall RR in the MST 5 mg/day group was 26.1%, which was significantly lower than that in the group which had discontinued steroid therapy (45.2%; p = 0.023) or was receiving MST at 2.5 mg/day (43.4%, p = 0.001). The RRs in the group receiving MST at ≥5 mg/day versus the patient group receiving MST at5 mg/day were 10.6 vs. 10.3% within 1 year, 23.5 vs. 32.9% within 3 years and 32.2 vs. 41.3% within 5 years, respectively (log-rank, p = 0.028). The best cutoff value of the total steroid dose for serious steroid toxicity was 6405 mg, with a moderate accuracy of 0.717 determined using the area under the curve. Presence of diffuse pancreatic swelling [odds ratio OR) 1.745; p = 0.008) and MST at5 mg/day were identified as predictors of relapse (OR 0.483; p = 0.001).The RR could continue to increase for 7 years even under MST. Based on our analysis of the side effects of steroid therapy, MST at 5 mg/day for 2 (total 4625 mg) to 3 (total 6425 mg) years might be a rational and safe therapeutic strategy in terms of keeping the RR to30% while avoiding potential steroid toxicity.

AIM To examine the result of the use of 0.025-inch guidewire (GW) VisiGlide2TM as the first choice in the endoscopic retrograde cholangiopancreatography (ERCP)-related procedures without selecting the patient in a multicenter prospective study. METHODS ERCP using 0.025-inch GW VisiGlide2TM as the first choice was conducted in patients who have needed ERCP, and its accomplishment rate of procedure, procedural time, incidence of accidental symptoms were compared with those of ERCP using 0.025-inch GW VisiGlideTM. RESULTS The accomplishment rate of procedure was 97.5% (197/202), and procedural time was 23.930 ± 16.207 min. The accomplishment rate of procedure using 0.025-inch GW VisiGlideTM was 92.3% (183/195), and procedural time was 31.285 ± 19.122 min, thus the accomplishment rate of procedure was significantly improved and procedural time was significantly shortened (P < 0.05). Accidental symptoms by ERCP-related procedures were observed in 3.0% (6/202), and all were conservatively alleviated. CONCLUSION When 0.025-inch GW VisiGlide2TM was used for ERCP-related procedure as the first choice, it showed high accomplishment rate of procedure and low incidence of accidental symptoms, suggesting it can be used as the universal GW. Clinical Trial Registry (UMIN0000016042).

IgG4-sclerosing cholangitis (IgG4-SC) patients have an increased level of serum IgG4, dense infiltration of IgG4-positive plasma cells with extensive fibrosis in the bile duct wall, and a good response to steroid therapy. However, it is not easy to distinguish IgG4-SC from primary sclerosing cholangitis, pancreatic cancer, and cholangiocarcinoma on the basis of cholangiographic findings alone because various cholangiographic features of IgG4-SC are similar to those of the above progressive or malignant diseases. The Research Committee of IgG4-related Diseases and the Research Committee of Intractable Diseases of Liver and Biliary Tract in association with the Ministry of Health, Labor and Welfare, Japan and the Japan Biliary Association have set up a working group consisting of researchers specializing in IgG4-SC, and established the new clinical diagnostic criteria of IgG4-SC 2012. The diagnosis of IgG4-SC is based on the combination of the following 4 criteria: (1) characteristic biliary imaging findings, (2) elevation of serum IgG4 concentrations, (3) the coexistence of IgG4-related diseases except those of the biliary tract, and (4) characteristic histopathological features. Furthermore, the effectiveness of steroid therapy is an optional extra diagnostic criterion to confirm accurate diagnosis of IgG4-SC. These diagnostic criteria for IgG4-SC are useful in practice for general physicians and other nonspecialists.

The Tokyo Guidelines (TG) have enabled more accurate diagnosis of acute cholangitis (AC). This study was undertaken to develop a new prognostic scoring system to predict the need for urgent endoscopic retrograde cholangiopancreatography (ERCP) based on the clinical findings on admission. We prospectively reviewed 40 consecutive cases of AC and divided them into an urgent-ERCP group and an elective-ERCP group. Univariate analysis identified four factors that predicted the need for urgent ERCP: serum albumin level below 3.0 g/dl, blood urea nitrogen level above 20 mg/dl, platelet count below 120,000/μl, and the presence of systemic inflammatory response syndrome. These four predictors plus four predictors of organ dysfunction in the TG: shock, consciousness disturbance, respiratory failure, and prothrombin time/international normalized ratio >1.5, were used to devise a scoring system in which 1 point was assigned for the first four predictors and 2 points were assigned for the latter four predictors (maximum score possible: 12 points). The receiver-operator characteristic curve of the scores showed good test performance for predicting the need for urgent ERCP and for predicting a positive blood culture, and the areas under the concentration curves (AUCs) were 0.96 and 0.97, respectively. The optimal cut-off value for urgent ERCP was 2 points. This new simple scoring system allows identification of high-risk AC patients soon after admission to hospital.

Fibrogenic mesenchymal cells including fibroblasts and myofibroblasts play a key role in intestinal fibrosis, however, their precise role is largely unknown. To investigate their role in intestinal fibrosis, we analyzed the lesions of chronic colitis in C57BL/6 (B6) mice induced by dextran sulfate sodium (DSS). B6 mice exposed to single cycle administration of DSS for 5 days developed acute colitis that progressed to severe chronic inflammation with dense infiltrates of mononuclear cells, irregular epithelial structure, thickening of colonic wall, and persistent deposits of collagen. Increased mRNA expressions of proinflammatory cytokines are correlated with extensive cellular infiltration, and the mRNA expressions of collagen 1, transforming growth factor (TGF)-β, and matrix metalloproteinases were also enhanced in the colon. In the colon of chronic DSS colitis, fibroblasts (vimentin(+), α-smooth muscle actin (α-SMA)(-)) were increased in both mucosal and submucosal layers, while myofibroblasts (vimentin(+), α-SMA(+)) were increased in mucosal but not in submucosal layers. Primary mouse subcutaneous fibroblast cultures experiments revealed that exogenously added TGF-β 1 substantially augmented the expressions of both vimentin and α-SMA proteins with increased production of collagen. In conclusion, profibrogenic mesenchymal cells play an important role in the development of intestinal fibrosis in this chronic DSS-induced colitis model.

We have reviewed the endoscopic retrograde cholangiopancreatography (ERCP) images of patients with autoimmune pancreatitis (AIP) and pancreatic carcinoma (Pca) in an attempt to identify findings that would facilitate making a differential diagnosis between AIP and Pca.The study cohort consisted of 39 patients diagnosed with AIP and 62 patients diagnosed with Pca. The ERCP findings in the pancreatic duct and biliary tract were compared between the two groups.The ERCP images revealed that AIP patients had a higher prevalence of narrowing of the main pancreatic duct (MPD) for ≥ 3 cm of its length and a higher prevalence for the presence of side branches in the narrowed portion of the MPD than Pca patients (p0.001 and p0.001, respectively). In contrast, the prevalence of an upstream MPD having a maximal diameter ≥ 4 cm was significantly higher in the Pca patient group (p0.001). The discriminant analysis identified three significant factors: (1) whether or not side branches were present; (2) total length of the narrowed portion of the MPD; (3) maximal diameter of the upstream MPD. It was impossible to differentiate Pca from AIP in the two Pca patients in whom ERCP revealed both narrowing of the MPD for5 cm of its length and the presence of side branches.Among our patient cohort, the ERCP findings in terms of the length of the narrowed portion of the MPD, the presence of side branches, and maximal diameter of the upstream MPD enabled differential diagnosis between AIP and Pca in most of the cases. However, it must be borne in mind that some Pca patients have ERCP findings similar to those of AIP patients.

48歳女性．人間ドックの腹部超音波検査で肝血管腫を指摘され，近医で半年ごとに超音波検査にてフォローされていた．平成20年4月の検査で内部エコーの変化を指摘され，腹部造影CT上肝細胞癌を疑われたため当科紹介，入院となった．背景肝は正常で採血検査に異常値はなく，上部下部消化管内視鏡検査・胸部レントゲン検査では悪性所見を認めなかった．腹部超音波検査，CT検査，MRI検査，血管造影検査を行い多血性肝腫瘍を認めたが質的診断には至らず，確定診断のため超音波ガイド下で腫瘍生検を行った．腫瘍部は紡錘型平滑筋細胞が密に増生しており，脂肪組織はほとんど見られなかった．免疫染色で平滑筋細胞はHMB-45，melan-A陽性であり，肝血管筋脂肪腫と診断，外来で経過観察の方針となった．背景肝が正常で，肝炎ウイルスマーカー・腫瘍マーカー陰性，他臓器悪性腫瘍のない多血性肝腫瘍では，AMLの可能性を踏まえ積極的に腫瘍生検を考慮すべきと考えた．

To establish an appropriate steroid treatment regimen for autoimmune pancreatitis (AIP).A retrospective survey of AIP treatment was conducted in 17 centres in Japan. The main outcome measures were rate of remission and relapse.Of 563 patients with AIP, 459 (82%) received steroid treatment. The remission rate of steroid-treated AIP was 98%, which was significantly higher than that of patients without steroid treatment (74%, 77/104; p0.001). Steroid treatment was given for obstructive jaundice (60%), abdominal pain (11%), associated extrapancreatic lesions except the biliary duct (11%), and diffuse enlargement of the pancreas (10%). There was no relationship between the period necessary to achieve remission and the initial dose (30 mg/day vs 40 mg/day) of prednisolone. Maintenance steroid treatment was given in 377 (82%) of 459 steroid-treated patients, and steroid treatment was stopped in 104 patients. The relapse rate of patients with AIP on maintenance treatment was 23% (63/273), which was significantly lower than that of patients who stopped maintenance treatment (34%, 35/104; p = 0.048). From the start of steroid treatment, 56% (55/99) relapsed within 1 year and 92% (91/99) relapsed within 3 years. Of the 89 relapsed patients, 83 (93%) received steroid re-treatment, and steroid re-treatment was effective in 97% of them.The major indication for steroid treatment in AIP is the presence of symptoms. An initial prednisolone dose of 0.6 mg/kg/day, is recommend, which is then reduced to a maintenance dose over a period of 3-6 months. Maintenance treatment with low-dose steroid reduces but dose not eliminate relapses.

Background: The aim of the present study was to evaluate and compare 4-h post-endoscopic retrograde cholangiopancreatography (ERCP) hyperamylasemia and hyperlipasemia as predictors of post-ERCP pancreatitis. Methods: We reviewed 1631 consecutive cases consisting of 910 cases of diagnostic ERCP and 721 cases of therapeutic ERCP. Pancreatitis was diagnosed when abdominal pain persisted for 24 h after ERCP and the pain was associated with high serum amylase level and/or lipase level. Results: Pancreatitis developed in 69 (4.2%) of the 1631 cases. The receiver-operator characteristic (ROC) curve of both the 4-h amylase level and the 4-h lipase level after diagnostic ERCP showed good test performance, with area under the curve of 0.88 (95% CI: 0.85–0.91) and 0.94 (95% CI: 0.92–0.96), respectively. The ROC of both the 4-h amylase level and the 4-h lipase level after therapeutic ERCP also showed good test performance, with an area under the curve of 0.92 (95% CI: 0.90–0.93) and 0.96 (95% CI: 0.94–0.97), respectively. The optimal cut-off value for lipase after both diagnostic and therapeutic ERCP was 10-fold the upper limit of the normal range. The serum lipase value after both diagnostic ERCP (P = 0.025) and therapeutic ERCP (P = 0.035) was a more effective predictor of post-ERCP pancreatitis based on the areas under the ROC curve than was the serum amylase value. Conclusions: The 4-h post-ERCP lipase value is more useful for predicting pancreatitis after both diagnostic and therapeutic ERCP.

The present study was undertaken to identify the clinicopathological differences between sclerosing cholangitis with autoimmune pancreatitis (SC-AIP) and primary sclerosing cholangitis (PSC). We retrospectively compared the clinical, cholangiographic, and liver biopsy findings between 24 cases of PSC and 24 cases of SC-AIP. Patient age at the time of diagnosis was significantly lower in the PSC group than in the SC-AIP group. The peripheral blood eosinophil count was significantly higher in the PSC group than in the SC-AIP group, but the serum IgG4 level was significantly higher in the SC-AIP group. Cholangiography revealed band-like strictures, beaded appearance, and pruned-tree appearance significantly more frequently in PSC, whereas segmental strictures and strictures of the distal third of the common bile duct were significantly more common in SC-AIP. Liver biopsy revealed fibrous obliterative cholangitis only in the PSC specimens. No advanced fibrous change corresponding to Ludwig's stages 3 and 4 was observed in any of the SC-AIP specimens. IgG4-positive plasma cell infiltration of the liver was significantly more severe in SC-AIP than in PSC. Subsequent cholangiography showed no improvement in any of the PSC cases, but all SC-AIP patients responded to steroid therapy, and improvement in the strictures was observed cholangiographically. Based on the differences between the patients' ages and blood chemistry, cholangiographic, and liver biopsy findings, SC-AIP should be differentiated from PSC.

This paper deals with the buckling of a slender steel member with lateral bracing. The buckling phenomenon is buckling by a thermal load, not by an external force. The buckling quantities of interest are the buckling temperature and the buckling stress. A theoretical method to obtain the relations between these quantities and the bracing rigidity is shown in this paper.

The present study was undertaken to evaluate the prevalence of pancreatic and biliary tract tumors in pancreas divisum (PD).A retrospective single-center study was performed, and a total of 118 cases of complete PD and 7850 cases of fused pancreas were identified among the 8537 consecutive new endoscopic retrograde cholangiopancreatography (ERCP) examinations performed between 1980 and 2002. The prevalence of pancreatic cancer (PCA), intraductal papillary mucinous neoplasms (IPMNs), other pancreatic tumors, and biliary tract cancer in the patients with PD and the patients with a fused pancreas were compared.The prevalence of the pancreatic tumors in the PD patients was: PCA, 10%; IPMN, 5.1%; other pancreatic tumors, 2.5%. The prevalence of pancreatic tumors in the patients with a fused pancreas was: PCA, 4.8%; IPMN, 2.6%; and other pancreatic tumors, 1.1%. The prevalence of PCA was significantly higher in the patients with PD than in those with a fused pancreas (P = 0.008; OR, 2.24). The percentages of PD patients with PCA who had pancreatic-type pain and a serum pancreatic enzyme elevation were significantly higher than among the PD patients without PCA. The prevalence of biliary tract cancer was 0.8% in the PD group and 5.3% in the fused pancreas group, and it was significantly lower in PD than in fused pancreas (P = 0.031).The results of this study showed a significantly higher prevalence of PCA in PD than in fused pancreas. We concluded that patients with PD, especially patients presenting with pancreatic-type pain and pancreatic enzyme elevation, should be carefully followed up because of the risk of developing PCA.

Objective: We investigated the long-term outcome of autoimmune pancreatitis (AIP) including morphological changes in the pancreas, pancreatic duct, biliary tract, pancreatic function, and changes in the clinical manifestations after oral prednisolone (PSL) therapy. Patients and Methods: We prospectively followed 12 patients for a period of over 12 months (median follow-up period: 41 months; range: from 13 to 133 months). All twelve patients were treated with PSL. The morphological findings consisted of pancreatic enlargement (n=12), an irregularly narrowed main pancreatic duct (n=12), and bile duct stricture (n=10), and salivary gland swelling was observed in six patients. The initial dose of PSL was 30-40 mg/day, and it was subsequently tapered. Results: All 12 patients responded to PSL therapy. The enlargement of the pancreas and the irregularly narrowed main pancreatic duct improved to almost normal. Pancreatic atrophy developed in four of them (4/12, 33%), but no pancreatic calcification was observed in any of the patients. The bile duct stricture improved to various degrees in all 10 patients , but it persisted in the lower part of the bile duct in four of them (4/10, 40%). The salivary gland swelling also improved after PSL therapy. There was no recurrence of enlargement of the pancreas or irregularly narrowed main pancreatic duct after PSL therapy, but the bile duct stricture recurred in one case, and in three cases there was a relapse of salivary gland swelling that required a temporary increase in PSL dose during tapering. No deterioration of pancreatic exocrine function was detected in any of the patients. A malignant tumor was diagnosed in two patients during PSL therapy: early gastric cancer in one and rectal cancer in the other. All patients are alive. Conclusions: AIP treated with PSL has a favorable long-term outcome based on the morphological findings and assessments of pancreatic function. However, since two of the twelve patients developed a malignancy during PSL therapy, strict follow up should be part of the management of AIP.

Background We evaluated the severity assessment criteria for acute cholangitis (AC) of the Tokyo Guidelines 2013 (TG13) and developed a scoring system for predicting the need for urgent/early biliary drainage. Methods We retrospectively reviewed 66 AC cases prospectively managed based on the TG07 and divided into an urgent/early biliary drainage group (n = 30) and elective biliary drainage group (n = 36). Results There were 26 mild, 27 moderate, and 13 severe cases based on the TG13. The TG13 assessment in 12 of the 17 cases requiring early biliary drainage based on the TG07 was moderate, but underestimated the other five cases as mild AC. When five predictors (blood urea nitrogen >20 mg/dL, SIRS presence, platelet count