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Background The genetic changes underlying carcinogenesis in patients with risk factors of gallbladder carcinoma (GBC) remains controversial, especially in patients with pancreaticobiliary maljunction (PBM). This study aimed to clarify the association between risk factors of GBC and genetic changes using next-generation sequencing (NGS). Methods We retrospectively analyzed resected tissues of 64 patients who were diagnosed with GBC (n = 26), PBM [with GBC (n = 8), without GBC (n = 20)], and chronic cholecystitis, used as a control group (n = 10). DNA was extracted from tumors and their surrounding tissues, which were precisely separated by laser-capture microdissection. Gene alterations of 50 cancer-related genes were detected by NGS and compared with clinical information, including PBM status. Results The most frequent gene alterations in GBC tissues occurred in TP53 (50%), followed by EGFR (20.6%), RB1 (17.6%), and ERBB2 (17.6%). Gene alterations that were targetable by molecular targeted drugs were detected in 20 cases (58.8%). Statistical analysis of gene alterations and risk factors revealed that TP53 alteration rate was higher in GBC patients with PBM than those without PBM (p = 0.038), and the TP53 mutation rates in the epithelium of control patients, epithelium of PBM patients without GBC, peritumoral mucosa of GBC patients with PBM, and tumor tissue of GBC patients with PBM were 10, 10, 38, and 75%, respectively (p Conclusions TP53 alteration more than KRAS mutation was revealed to underlie carcinogenesis in patients with PBM.

Although comprehensive gene analyses of pancreatic cancer provide new knowledge on molecular mechanisms, the usefulness and possibility of the analyses in routinely available clinical samples remain unclear. We assessed the possibility and utility of target sequencing of endoscopically obtained pancreatic cancer samples. Fifty‐eight pancreatic cancer patients who underwent EUS‐FNA or endoscopic biopsy were enrolled. The extracted DNA quantity was assessed and used for next‐generation sequencing (NGS) of 50 cancer‐related genes from which gene mutations, copy number alterations, and microsatellite instability (MSI) were extracted via secondary analysis. A median of 19.2 ng (3.8–228) of DNA was extracted from formalin‐fixed paraffin‐embedded samples. Gene alterations were detected in 55 of 58 samples (94.8%), including all samples with a DNA concentration below the detection limit (n = 11). Four frequently altered genes were KRAS (83%), TP53 (66%), SMAD4 (26%), and PTEN (17%), and molecular targetable genes were detected in 13 cases (22.4%). Five samples (8.6%) had many mutations and suspected MSI with impaired mismatch repair genes. A Cox regression analysis revealed that metastasis (p 5 ng/ml (p = 0.01, HR 2.86), ≤10 detected hotspot mutations (p = 0.03, HR 9.86), and intact Ras signaling (p, We performed next‐generation sequencing of endoscopically obtained formalin‐fixed paraffin‐embedded tissue samples from actual clinical samples of patients with pancreatic cancer to evaluate gene alterations and potential prognostic indicators. This targeted sequencing of cancer‐related genes was informative for predicting prognosis and selecting therapy.

Routinely available clinical samples of all stages of pancreatic cancer are used in the present study to elucidate its molecular mechanisms and identify novel therapeutic targets. We evaluated the use of next-generation sequencing (NGS) of endoscopically obtained pancreatic cancer tissues. We enrolled 147 patients who underwent endoscopic ultrasound-guided fine-needle aspiration or endoscopic biopsy. The quantity and quality of the extracted DNA was assessed. Tissue samples were used for NGS of 78 cancer-related genes, from which gene alterations and microsatellite instability (MSI) were extracted. NGS was successful in 141 out of 147 (96%) cases. Gene alterations were detected in 134 out of 141 (91%) samples, among which eight out of 10 samples with a DNA concentration below the detection limit had some type of gene alteration. Targetable genes were detected in 28 (19.9%) cases. MSI and germline mutations in homologous recombination repair associated genes were detected in 5% and 3% of cases, respectively. Cox regression analysis revealed that metastasis (P .005; hazard ratio [HR], 3.30) was associated with poor prognosis in all pancreatic cancer patients. In addition, fewer than three mutations (P = .03; HR, 2.48) and serum carcinoembryonic antigen levels5 ng/mL (P .005; HR, 3.94) were associated with worse prognosis in cases without and with metastasis, respectively. Targeted sequencing of all stages of pancreatic cancer using available samples from real clinical practice could be used to determine the relationship between gene alterations and prognosis to help determine treatment choices.

The aims of this study were to identify genetic characteristics of intraductal papillary mucinous neoplasm (IPMN)-associated pancreatic ductal carcinoma (PDC) and to detect these markers using pancreatic juice.From 76 cases, 102 tissues were obtained: 29 cases were noninvasive IPMN, 18 were PDC derived from IPMN (D-PDC; noninvasive part, n = 16; invasive part, n = 18), and 29 were PDC concomitant with IPMN (C-PDC; IPMN part, n = 10; PDC part, n = 29). Moreover, pancreatic juice samples from 28 cases were obtained (noninvasive IPMN, n = 13; D-PDC, n = 7; C-PDC, n = 8). Fifty-one cancer-related genes were analyzed by next-generation sequencing.TP53 mutation rates in D-PDC, C-PDC, and noninvasive IPMN were 67%, 66%, and 10%, respectively. Moreover, KRAS mutational patterns between 2 simultaneous tumors differed in 1 (6.3%) of the 16 D-PDC cases and in 8 (80%) of the 10 C-PDC cases (P = 0.0006). TP53 or multiple KRAS mutations were detected using pancreatic juice more frequently in C-PDC cases than in noninvasive IPMN cases (75% and 23%, respectively, P = 0.03).Multiple KRAS mutations along with TP53 mutation are genetic markers for C-PDC, which could be detected using pancreatic juice preoperatively.

Background and Aims. The insertion of the guidewires (GWs) into the pancreatic duct is technically difficult, and there is a risk of post-ERCP pancreatitis (PEP). The aim of this study was to evaluate the safety and efficacy of a small J-tipped guidewire for pancreatic duct endoscopic intervention. Methods. This single-site retrospective study was conducted to assess the procedural success rate and adverse events of endoscopic transpapillary interventions to the pancreatic duct in 114 cases using the small J-tipped GW and 180 cases using the angle-tipped GW. Results. The procedural success rate was significantly higher in the small J-tipped GW group compared with that in the angle-tipped GW group (76% versus 47%, P < 0.001). The procedural success-related factors were chronic pancreatitis (OR 0.43, 95% CI 0.22–0.82, P = 0.01), flexion angle of the pancreatic duct < 90° (OR 0.50, 95% CI 0.30–0.80, P = 0.01), and use of the small J-tipped GW (OR 4.63, 95% CI 2.61–8.20, P < 0.001). The rates of total post-ERCP pancreatitis were significantly lower in the small J-tipped GW group compared with that in the angle-tipped GW group (3.5% versus 12.2%, P = 0.01). Multivariate analysis of pancreatitis risk factors indicated that only the use of the small J-tipped GW was a factor in decreasing the risk of developing pancreatitis (OR 0.12, 95% CI 0.09–0.85, P = 0.02). Conclusions. Small J-tipped GWs increase the success rate of the pancreatic duct endoscopic intervention as well as a reduced risk of developing postoperative pancreatitis.

New biomarkers are needed to further stratify the risk of malignancy in intraductal papillary mucinous neoplasm (IPMN). Although microRNAs (miRNAs) are expected to be stable biomarkers, they can vary owing to a lack of definite internal controls. To identify universal biomarkers for invasive IPMN, we performed miRNA sequencing using tumor-normal paired samples. A total of 19 resected tissues and 13 pancreatic juice samples from 32 IPMN patients were analyzed for miRNA expression by next-generation sequencing with a two-step normalization of miRNA sequence data. The miRNAs involved in IPMN associated with invasive carcinoma were identified from this tissue analysis and further verified with the pancreatic juice samples. From the tumor-normal paired tissue analysis of the expression levels of 2792 miRNAs, 20 upregulated and 17 downregulated miRNAs were identified. In IPMN associated with invasive carcinoma (INV), miR-10a-5p and miR-221-3p were upregulated and miR-148a-3p was downregulated when compared with noninvasive IPMN. When these findings were further validated with pancreatic juice samples, miR-10a-5p was found to be elevated in INV (p = 0.002). Therefore, three differentially expressed miRNAs were identified in tissues with INV, and the expression of miR-10a-5p was also elevated in pancreatic juice samples with INV. MiR-10a-5p is a promising additional biomarker for invasive IPMN.

We aimed to evaluate a newly developed peroral cholangioscopy (POCS) classification system by comparing classified lesions with histological and genetic findings. We analyzed 30 biopsied specimens from 11 patients with biliary tract cancer (BTC) who underwent POCS. An original classification of POCS findings was made based on the biliary surface&rsquo, s form (F factor, 4 grades) and vessel structure (V-factor, 3 grades). Findings were then compared with those of corresponding biopsy specimens analyzed histologically and by next-generation sequencing to identify somatic mutations. In addition, the histology of postoperative surgical stumps and preoperative POCS findings were compared. Histological malignancy rate in biopsied specimens increased with increasing F- and V-factor scores (F1, 0%, F1, 25%, F3, 50%, F4, 62.5%, p = 0.0015, V1, 0%, V2, 20%, V3, 70%, p &lt, 0.001). Furthermore, we observed a statistically significant increase of the mutant allele frequency of mutated genes with increasing F- and V-factor scores (F factor, p = 0.0050, V-factor, p &lt, 0.001). All surgical stumps were accurately diagnosed using POCS findings. The F&ndash, V classification of POCS findings is both histologically and genetically valid and will contribute to the methods of diagnosing the superficial spread of BTC tumors.

The present study aimed to determine the ability of diagnosing malignancy and predicting malignant transformation in patients with IPMN using carcinoembryonic antigen (CEA) level in the pancreatic juice. We enrolled patients with IPMN who underwent endoscopic retrograde pancreatography (ERP) between 2002 and 2018. We examined the ability of diagnosing malignancy in 63 patients who underwent surgery (surgical group). Furthermore, we examined the value of predicting malignant transformation in 52 patients who underwent follow-up for over 1 year after ERP (follow-up group). In the surgical group, the overall sensitivity and specificity of CEA level (≥ 97 ng/ml) in the pancreatic juice for diagnosing malignancy were 45% and 100%, respectively. The specificity was excellent for all IPMN types; however, the sensitivity was highest in main duct type, followed by mixed type and branch duct type. In the follow-up group, malignant transformation was observed in four patients (7.7%) during the follow-up, and the median time until malignant transformation was 58 months. High CEA level in the pancreatic juice demonstrated a statistically significant difference in multivariate analysis and was found to be an independent predictor of malignant transformation (hazard ratio 17; P = 0.02). The cumulative malignant transformation rate was significantly higher in the high CEA group than that in the low CEA group (5-year cumulative malignant transformation rates, 69% vs. 0%, P

AIM To assess the role of ultrasonography of submandibular glands (SGs) in the diagnosis of type 1 autoimmune pancreatitis (AIP). METHODS Thirty-seven patients who were definitively diagnosed with type 1 AIP according to the international consensus diagnostic criteria (ICDC) for AIP at our institution between December 1990 and April 2016 were retrospectively reviewed. Findings by physical examination, ultrasonography, and scintigraphy of SGs were analyzed to reach a diagnosis based on the ICDC for AIP. The efficacy of corticosteroid treatment in the resolution of hypoechoic lesions in SGs was also evaluated by assessment with ultrasonography before and after treatment in 18 cases. RESULTS The sensitivity of multiple hypoechoic lesions in SGs by ultrasonography for the diagnosis of sialadenitis in type 1 AIP (84%) was higher than that of physical examination (46%), scintigraphy (28%), and SGs thickness (49%). Ultrasonographic evidence of hypoechoic lesions in SGs improved the definitive diagnosis of sialadenitis and type 1 AIP by the ICDC criteria in 11 (30%) and 2 (5.4%) cases, respectively. Multiple hypoechoic lesions in SGs were resolved or disappear by corticosteroid administration in 14 of 16 cases with hypoechoic lesions in SGs, whereas the ultrasonographic findings in the remaining 2 cases with hypoechoic lesions in SGs and the 2 cases with homogenous SG parenchyma remained unchanged after corticosteroid administration. CONCLUSION SG ultrasonography to detect multiple hypoechoic lesions might be useful for type 1 AIP diagnosis by improving diagnostic accuracy together with the ICDC sialadenitis criteria.

Background Self-expandable metal stents (SEMSs) are widely used for malignant biliary obstructions. Nitinol-covered SEMSs have been developed to improve stent patency. Currently, SEMSs may be uncovered, partially covered, or fully covered; however, there is no consensus on the best stent type for the management of malignant distal biliary obstruction (MDBO). Methods Patients with unresectable MDBO receiving SEMS (Wallflex™) were retrospectively analyzed. Time to recurrent biliary obstruction (TRBO) and survival time were compared among the three types of SEMSs. Univariate and multivariate analyses were performed to identify risk factors for stent dysfunction. Results In total, 101 patients received SEMSs for unresectable MDBO (44 uncovered, 28 partially covered, and 29 fully covered SEMSs). Median survival time was 200, 168, and 276 days in the uncovered, partially covered, and fully covered SEMSs groups, respectively. There were no differences in survival among the three groups. Median TRBO was 199, 444, and 194 days in the uncovered, partially covered, and fully covered SEMSs groups, respectively. Partially covered SEMSs had longer TRBO than uncovered (p = 0.013) and fully covered (p = 0.010) SEMSs. Tumor ingrowth occurred only with uncovered SEMSs and stent migration occurred only with fully covered SEMSs. Multivariate analyses confirmed that partially covered SEMSs have lower risk of dysfunction. Conclusions Partially covered SEMSs with a proximal uncovered flared end have longer patency than uncovered and fully covered SEMSs by preventing tumor ingrowth and stent migration.

The present study is aimed to clarify the utility of magnetic resonance cholangiopancreatography (MRCP) and the additional value of diffusion-weighted imaging (DWI) in diagnosing pancreatic ductal adenocarcinoma (PDAC) concomitant with intraductal papillary mucinous neoplasm (IPMN). This retrospective study involved 38 patients with PDAC concomitant with IPMN and 114 patients (control) who were randomly selected from 320 patients with IPMN without PDAC and were matched with cases for magnetic resonance imaging (MRI) strength (1.5 T/3.0 T). Two radiologists reviewed the 2 MR image sets with relevant clinical information blinded, first MRCP alone and then combined MRI set including DWI. Diagnostic capability and interobserver agreement were assessed by using receiver operating characteristics curve (Az) analysis and weighted κ statistics. Az values for the 2 observers were 0.834 and 0.821 for MRCP alone and 0.964 and 0.926 for the combined MRI (P

Patients with ulcerative colitis suffer from long term impairment of quality of life, especially when subjected to repeated hospitalization. We aimed to identify factors that may predict future hospitalization.We followed 139 consecutive patients with ulcerative colitis for average of 11.2 years (2.8 to 49.5 years) from the onset. Clinical and endoscopic stagings were determined by Japanese staging system, the extent of colitis by Montreal classification and endoscopic grading by Matts' grade.Overall hospitalization rate was 37% at 5 years, 47% at 10 years and 60% at 20 years from the onset. Of 5 parameters including demographic and staging scores, univariate analysis revealed clinical severity at onset (p = 0.003), total colonoscopic findings on severity (Matts' grade, p = 0.003), and total colonoscopic findings on sites of abnormality (p = 0.012) were significantly correlated with hospitalization. By multivariate analysis, total colonoscopic findings on sites of abnormality was the only baseline character significantly related to the need of hospitalization (p = 0.0007). In fact, 5/10/20 years hospitalization rates were only 18/26/33 percent for proctitis type, whereas those were 61/72/90 for total colitis type.The total colonoscopic finding on sites of abnormality at the onset is the only predictdr of hospitalization in patients with ulcerative colitis.

Background/aims In both SHARP and Asia-Pacific Study, sorafenib was proved to improve the overall survival of the patients with hepatocellular carcinoma. However, factors contributing to the improvement of overall survival of the patients treated by sorafenib have not been fully evaluated. In this study, patient-derived, background liver disease-derived and tumor-derived factors before treatment were evaluated whether they have contributed to the improvement of the overall survival. Methodology Forty-seven cases with HCC treated by sorafenib between Sept 2009 and Feb 2011 were included in this analysis. The survival of these cases was analyzed by Kaplan-Meier Method. Factors used for univariate analysis were two patient-derived parameters, two background liver disease-derived, five tumor-derived. Factors related to the over-all survival were analyzed by multivariate analysis using Cox regression model. Results In the multivariate analysis, only background liver disease-derived parameter Child-Pugh class A vs. B, (p=0.007, HR=0.21 (0.07-0.65)) was significant. No other parameters including tumor-derived factors were statistically significant by multivariate analysis. Conclusions We undertook the statistical analysis on the three categories. Surprisingly, no tumor derived parameter contributed to the overall survival. Background liver disease-derived parameter rather than tumor-derived parameter was found to define the prognosis of patients with advanced HCC treated by sorafenib.