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Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer caused by CDH1 mutation. HDGC causes multiple signet ring cell carcinomas (SRCCs) throughout the stomach. Few reports exist on the endoscopic findings during screening endoscopy, leading to the diagnosis of HDGC in its early stages. Recently, a new image-enhancement endoscopy technique, texture and color enhancement imaging (TXI), has been developed to improve the visibility of early gastric cancer. To the best of our knowledge, the use of TXI leading to HDGC diagnosis has not been reported. In this report, TXI contributed to the diagnosis of HDGC, and the patient was treated with total gastrectomy. A 27-year-old woman with a family history of gastric cancer underwent esophagogastroduodenoscopy, which revealed two pale lesions in the lower body of the stomach. Histological examination of the biopsy specimen revealed SRCC and the patient was referred to our hospital for treatment. Multiple lesions were found in the lower body using TXI, and a targeted biopsy confirmed other SRCCs. We suspected her disease to be HDGC, and the patient underwent a total gastrectomy. Histopathology showed multiple SRCCs (>60), but no lymph node metastases. Genetic testing revealed CDH1 mutations. The final pathological stage of the tumor was pT1a(m) N0M0 Stage I. TXI may be helpful in detecting multiple SRCCs in patients with HDGC. Endoscopists should be aware of HDGC, and careful investigation of the entire stomach is required for patients with diffuse-type gastric cancer before treatment., Competing Interests: All authors had full access to the data and had the final responsibility for the decision to submit for publication. No benefits in any form have been received or will be received from any commercial party directly or indirectly related to the subject of this study. Author Kazuki Sumiyama is the DEN Open's Deputy Editor‐in‐Chief., (© 2025 The Author(s). DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: We aimed to develop a chemoimmunotherapy regimen consisting of a novel Wilms' tumor 1 (WT1) peptide-pulsed dendritic cell (WT1-DC) vaccine and multiagent chemotherapy and to investigate the safety, clinical outcomes, and WT1-specific immune responses of patients with unresectable advanced pancreatic ductal adenocarcinoma (UR-PDAC) who received this treatment., Methods: Patients with UR-PDAC with stage III disease (locally advanced (LA-PDAC; n=6)), stage IV disease (metastatic (M-PDAC; n=3)), or recurrent disease after surgery (n=1) were enrolled in this phase I study. The patients received one cycle of nab-paclitaxel plus gemcitabine alone followed by 15 doses of the WT1-DC vaccine independent of chemotherapy. The novel WT1 peptide cocktail was composed of a multifunctional helper peptide specific for major histocompatibility complex class II, human leukocyte antigen (HLA)-A*02:01, or HLA-A*02:06 and a killer peptide specific for HLA-A*24:02., Results: The chemoimmunotherapy regimen was well tolerated. In the nine patients for whom a prognostic analysis was feasible, the clinical outcomes of long-term WT1 peptide-specific delayed-type hypersensitivity (WT1-DTH)-positive patients (n=4) were significantly superior to those of short-term WT1-DTH-positive patients (n=5). During chemoimmunotherapy, eight patients were deemed eligible for conversion surgery and underwent R0 resection (four patients with LA-PDAC, one patient with M-PDAC, and one recurrence) or R1 resection (one patient with M-PDAC), and one patient with LA-PDAC was determined to be unresectable. Long-term WT1-DTH positivity was observed in three of the four patients with R0-resected LA-PDAC. These three patients exhibited notable infiltration of T cells and programmed cell death protein-1+ cells within the pancreatic tumor microenvironment (TME). All patients with long-term WT1-DTH positivity were alive for at least 4.5 years after starting therapy. In patients with long-term WT1-DTH positivity, the percentage of WT1-specific circulating CD4+ or CD8+ T cells that produced IFN-γ or TNF-α was significantly greater than that in patients with short-term WT1-DTH positivity after two vaccinations. Moreover, after 12 vaccinations, the percentages of both circulating regulatory T cells and myeloid-derived suppressor cells were significantly lower in patients with long-term WT1-DTH-positive PDAC than in short-term WT1-DTH-positive patients., Conclusions: Potent activation of WT1-specific immune responses through a combination chemoimmunotherapy regimen including the WT1-DC vaccine in patients with UR-PDAC may modulate the TME and enable conversion surgery, resulting in clinical benefits (Online supplemental file 1)., Trial Registration Number: jRCTc030190195., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Aims: The need for mastering standard imaging techniques for convex EUS in the biliopancreatic regions has been increasing; however, large variations in the aptitude for achieving EUS competency hinder expert development. Therefore, we investigated the factors influencing the achievement of expert competency in EUS using a new assessment tool for multiple imaging items., Methods: Between January 2018 and February 2022, 3277 consecutive EUS procedures conducted by 5 beginners (EUS procedures <250), 7 intermediate trainees (250-749), and 2 experts (≥750) were prospectively evaluated. Immediately after each EUS procedure, the success or failure of imaging for each item was recorded using a newly developed EUS assessment tool that requires 17 items to be photographed. After correcting for missing values using multiple imputation, learning curves of EUS scores were created, and a competency was set based on expert scores. Finally, a comparative analysis between high and low performers was performed to extract factors influencing EUS scores., Results: Although 3 of 7 intermediates (43%; mean, 317 cases) achieved competency, none of the beginners achieved competency. During a comparative analysis, although no significant difference in the number of EUS procedures performed was observed between the high and low performers, the former had significantly higher scores in the written test (theoretical knowledge)., Conclusions: Our results showed that theoretical knowledge, rather than the number of EUS cases, may be a possible influencing factor for distinguishing high and low performers after treating 250 cases. (Clinical trial registration number: UMIN 000043271.)., (Copyright © 2023 American Society for Gastrointestinal Endoscopy. Published by Elsevier Inc. All rights reserved.)

Objectives: Selection criteria for self-expandable metal stents (SEMSs) with or without cover during palliative treatment of distal malignant biliary obstruction (DMBO) remain unclear. We evaluated factors associated with time to recurrent biliary obstruction (TRBO) in fully covered SEMSs (FCSEMSs) and uncovered SEMSs (UCSEMSs)., Methods: We retrospectively analyzed consecutive patients with DMBO who received a SEMS. TRBO was determined using the Kaplan-Meier analysis, and complications were compared between the FCSEMS and UCSEMS groups. After TRBO-associated factors were extracted using multivariate competing-risks regression (CRR), propensity score-adjusted CRRs were performed to verify their robustness., Results: There were 180 patients (66 FCSEMSs and 114 UCSEMSs) enrolled in this study. There was no significant difference between median TRBO in the FCSEMS and UCSEMS groups (275 vs. 255 days, p = 0.67). Complications were more frequent in the FCSEMS than UCSEMS group (21.2% vs. 8.8%; p = 0.023). Multivariate CRR for TRBO-associated factors revealed that "pancreatic ductal carcinoma (PDAC) treated with UCSEMS" was the only independent predictor of TRBO ( p = 0.03). Similarly, the propensity score-adjusted CRRs showed no significant difference in TRBO in "FCSEMS" vs "UCSEMS" ( p = 0.96); however, there was a significant difference in "PDAC using UCSEMS" vs "other" ( p = 0.043). In the palliative care group including any DMBO without chemotherapy, the first quartile of the TRBO of UCSEMS was 100 days., Conclusions: UCSEMSs are a possible option for both patients with DMBO arising from PDAC and for patients with any DMBO receiving palliative care who should avoid SEMS-related complications., Competing Interests: The author Kazuki Sumiyama is DEIC of DEN Open. The rest of the authors declare that they have no conflict of interest., (© 2022 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background: The utility of contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) alone in the biliopancreatic region appears to be limited because it is highly dependent on the experience and skill of the endoscopist. Therefore, the present study aimed to validate the efficacy of CH-EUS in clinical practice. Methods: Between January 2018 and March 2019, 301 consecutive patients who underwent CH-EUS were prospectively enrolled in this study. The diagnostic performance of CH-EUS was compared with that of dynamic computed tomography (CT), magnetic resonance imaging (MRI), and all combinations (i.e., CH-EUS, dynamic CT, and MRI) using a Bonferroni correction. A multiple logistic regression analysis was performed to extract each disease that allowed the CH-EUS diagnosis to be consistent with the final diagnosis. Results: In multiple comparisons of diagnostic performance, no significant differences were observed among dynamic CT, MRI, and CH-EUS (p = 1.00), but the diagnostic performance was significantly higher when all modalities were combined (p < 0.001). Moreover, only intraductal papillary mucinous neoplasm comprising adenoma or carcinoma (IPMN, n = 161) showed significance with respect to the agreement with the final diagnosis (p = 0.006). Conclusions: Our results showed that CH-EUS-based diagnosis of IPMN may be possible in clinical practice. On the contrary, to accurately diagnose biliopancreatic diseases other than IPMN, comprehensive diagnosis using multiple modalities may be necessary, rather than relying on CH-EUS alone.

Background: Post-ERCP pancreatitis (PEP) with trans-papillary approach remains a major issue, and the multi-factorial etiology can lead to the development of unpredictable PEP. Therefore, the early identification of PEP is highly desirable to assist with the health cost containment, the reduction in unnecessary admissions, earlier appropriate primary care, and intensive care for preventing progression of severe pancreatitis. This study aimed to establish a simplified predictive scoring system for PEP., Methods: Between January 1, 2012, and December 31, 2019, 3362 consecutive trans-papillary ERCP procedures were retrospectively analyzed. Significant risk factors were extracted by univariate, multivariate, and propensity score analyses, and the probability of PEP in the combinations of each factor were quantified using propensity score analysis. The results were internally validated using bootstrapping resampling., Results: In the scoring system with four stratifications using combinations of only five extracted risk factors, the very high-risk group showed 28.79% (95% confidence interval [CI], 18.30%-41.25%; P < 0.001) in the predicted incidence rate of PEP, and 9.09% (95% CI, 3.41%-18.74%; P < 0.001) in that of severe PEP; although the adjusted prevalence revealed 3.74% in PEP and 0.90% in severe PEP, respectively. The prediction model had an area under the curve of 0.86 (95% CI, 0.82-0.89) and the optimism-corrected model as an internal validation had an area under the curve of 0.81 (95% CI, 0.77-0.86)., Conclusions: We established and validated a simplified predictive scoring system for PEP using five risk factors immediately after ERCP to assist with the early identification of PEP., (© 2020. Springer Science+Business Media, LLC, part of Springer Nature.)

Endoscopic ultrasound-guided biliary drainage (EUS-BD) has become popular as a new drainage technique for malignant biliary strictures. Although EUS-BD has been reported to show high technical and clinical success rates, the rate of adverse events is 15%. In particular, peritonitis, which is generally caused by bile leakage from the aspiration side during the procedure and occurs within a few days after EUS-BD, needs to be considered as it can be fatal. In the present case, a jaundiced patient presented with unresectable pancreatic adenocarcinoma. Due to duodenal invasion, we performed EUS-guided hepaticogastrostomy for biliary drainage. After the procedure, jaundice improved, and abdominal computed tomography (CT) showed only a small amount of air in the intrahepatic bile duct. However, 7 days after the procedure, the patient developed fever, and clinical findings indicated peritonitis. Abdominal CT showed food in the stomach accompanied by the appearance of perihepatic free air, with increased air in the intrahepatic bile duct. The duodenal stent insertion settled the peritonitis and improved the perihepatic free air and the air in the intrahepatic bile duct through the discharge of food from the stomach. To date, no case of tardive peritonitis associated with air leakage after EUS-BD has been reported. We noted that even if there was no evidence of bile leakage after EUS-BD, the possibility of tardive peritonitis due to gradual air leakage from the stent implantation side of the stomach should be considered, and careful follow-up is needed., Competing Interests: All authors had full access to the data and had final responsibility for the decision to submit for publication. No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. Kazuki Sumiyama is a Deputy Editor‐in‐Chief of DEN Open., (© 2021 The Authors. DEN Open published by John Wiley & Sons Australia, Ltd on behalf of Japan Gastroenterological Endoscopy Society.)

Background and Aim: Fine-needle biopsy (FNB) needles obtain more core samples and support the shift from cytologic to histologic evaluation; however, recent studies have proposed a superior diagnostic potential for liquid-based cytology (LBC). This study compared the diagnostic ability of endoscopic ultrasound (EUS)-guided FNB histology with a 22-gauge Franseen needle (22G-FNB-H) and fine-needle aspiration (FNA) LBC with a conventional 25-gauge needle (25G-FNA-LBC)., Methods: We analyzed 46 patients who underwent both 22G-FNB-H and 25G-FNA-LBC in the same lesion during the same endoscopic procedure. This study evaluated the diagnostic ability of each needle, diagnostic concordance between needles, and incremental diagnostic effect of both needles compared to using each needle alone., Results: The agreement rate for malignancy between both techniques was 93.5% (kappa value = 0.82). There was no significant difference in the diagnostic ability of both methods. 22G-FNB-H and 25G-FNA-LBC provided an incremental diagnostic accuracy in two (4.3%) cases and one (2.2%) case, respectively., Conclusion: Our study demonstrated that the diagnostic accuracy of 25G-FNA-LBC and 22G-FNA-H for solid pancreatic lesions were comparable. A conventional 25-gauge needle that punctures lesions with ease can be used in difficult cases and according to the skill of the endoscopist., (© 2021 The Authors. JGH Open published by Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Aims: An antibiotic combination of amoxicillin, tetracycline and metronidazole (ATM) is effective for ulcerative colitis (UC), but this regimen is discontinued in some cases due to adverse events. This study aimed to assess a revised combination, namely, amoxicillin, fosfomycin and metronidazole (AFM), in UC patients with the goal of reducing side effects while maintaining therapeutic efficacy., Methods: A prospective open-label trial was undertaken in 104 adult UC patients. A combination of oral amoxicillin (1500 mg), fosfomycin (3000 mg) and metronidazole (750 mg) was administered to patients daily for 2-4 weeks in addition to their conventional medication. Clinical assessment was performed using the Lichtiger index before treatment and at 0, 3, 6, 9 and 12 months and 2 and 3 years. Endoscopic evaluation was performed using the Mayo score before treatment and at 3 and 12 months., Results: The compliance rate was 99.2%. Response and remission rates were 80.8% and 63.5% at completion, 73.1% and 64.4% at 3 months, and 39.4% for both at 12 months, respectively. Of the 41 patients who were in remission at 12 months, 63.4% maintained that status until the 2-year follow-up. Similarly, 69.2% of those in remission at 2 years remained relapse free at the 3-year follow-up. Side effects were observed in 44.2% of the participants. Fever occurred in one patient (1.0%), which was lower than the rate observed with ATM therapy., Conclusion: These results indicate that AFM therapy induces remission and is appropriate for long-term maintenance of UC while producing fewer and milder adverse events than ATM therapy., Clinical Trials: This study was registered in the University Hospital Medical Information Network (No. R000046546)., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2021.)

In endoscopic biliary drainage (EBD) for various benign and malignant biliary disorders, the appropriate timing to replace or change a plastic stent (PS) with a self-expandable metallic stent (SEMS) remains unclear. This study aimed to define the best period to replace or change a PS with a SEMS. Between January 1, 2012, and December 31, 2018, 1,887 consecutive EBD procedures, including 170 SEMS placements, were retrospectively identified. The period to recurrent biliary obstruction (PRBO) was estimated and compared between the malignant and benign groups and according to each disease using time to event analysis and competing risk analysis. Compared with the benign group, the malignant group had significantly shorter median PRBO with interquartile range (IQR) after PS placement [108 (39 - 270) vs. 613 (191 - 1,329) days, P < 0.001], even on multivariate analysis, with a subdistribution hazard ratio (SHR) of 3.58 (P < 0.001). The shortest PRBO distribution from the first quartile of the non-RBO period was seen in Mirizzi syndrome cases (25 days, P = 0.030, SHR = 3.32) in the benign group and in cases of pancreatic cancer (32 days, P = 0.041, SHR = 2.06); perihilar bile duct cancer (27 days, P = 0.006, SHR = 2.69); and ampullary cancer (22 days, P = 0.001, SHR = 3.78) in the malignant group. Our study supports that stent replacement for the benign group is feasible after 6 months, and the best period to replace or change a PS with a SEMS should be decided on the basis of the underlying disease to prevent RBO.

Background: Endoscopic biliary stenting (EBS) using a plastic stent is currently widely performed for preoperative biliary drainage for periampullary cancer. The aim of this study was to investigate the risk factors and surgical outcomes of stent dysfunction after EBS in patients who underwent pancreaticoduodenectomy (PD). Patients and Methods: The subjects were 85 patients who underwent PD after EBS using a plastic stent for malignant biliary obstruction between November 2008 and January 2019. We retrospectively investigated the relationship between perioperative patient characteristics and the incidence of stent dysfunction. Stent dysfunction was defined as insufficient biliary drainage and the presence of various symptoms, including high fever and abdominal pain, with elevated serum hepatobiliary enzyme levels or bilirubin level. Results: Stent dysfunction occurred in 38% of patients. In univariate analysis, serum total bilirubin before the initial EBS ≥15 mg/dL ( P  = .0244) and a stent diameter of 7 Fr ( P  = .0044) were significant predictors of stent dysfunction. In multivariate analysis, the only significant independent predictor of stent dysfunction was a stent diameter of 7 Fr ( P  = .0227). In the patients without stent dysfunction, duration from the initial EBS to the operation was significantly shorter than that in the patients with stent dysfunction ( P  = .0055). Operation time, intraoperative blood loss, postoperative pancreatic fistula, and bile leakage were comparable between the two groups. Conclusion: Seven French stent was the significant independent predictor of stent dysfunction after EBS in patients who underwent PD.

Pancreatic intraductal papillary mucinous neoplasm was originally regarded as a benign mucinous cystic tumor but certainly has a marked malignant potential. With the array of high-resolution imaging modalities that are now available, more frequent incidental asymptomatic intraductal papillary mucinous neoplasm patients can be diagnosed. Until now, our clinicians have been managing intraductal papillary mucinous neoplasm patients by referring to the international consensus guidelines which have been revised twice or American Gastroenterological Association guidelines. The aim of this review is to reassess the current guidelines for the management of malignancy in intraductal papillary mucinous neoplasm. Furthermore, we specifically discuss the problems to be solved for establishing more refined guideline for the early detection, risk stratification and better management of pancreatic cancer in intraductal papillary mucinous neoplasm patients., Competing Interests: Conflicts of Interest The authors declare that they have no conflicts of interest associated with this article.

Aim: To investigate the association of plasma levels of interleukin (IL)-6 and -8 with Wilms' tumor 1 (WT1)-specific immune responses and clinical outcomes in patients with pancreatic ductal adenocarcinoma (PDA) treated with dendritic cells (DCs) pulsed with three types of major histocompatibility complex class I and II-restricted WT1 peptides combined with chemotherapy., Methods: During the entire treatment period, plasma levels of IL-6 and -8 were analyzed by ELISA. The induction of WT1-specific immune responses was assessed using the WT1 peptide-specific delayed-type hypersensitivity (DTH) test., Results: Three of 7 patients displayed strong WT1-DTH reactions throughout long-term vaccination with significantly decreased levels of IL-6/-8 after vaccinations compared with the levels prior to treatment. Moreover, overall survival (OS) was significantly longer in PDA patients with low plasma IL-6 levels (< 2 pg/mL) after 5 vaccinations than in patients with high plasma IL-6 levels (≥ 2 pg/mL) (P = 0.025). After disease progression, WT1-DTH reactions decreased severely and were ultimately negative at the terminal stage of cancer. The decreased levels of IL-6/-8 observed throughout long-term vaccination were associated with WT1-specific DTH reactions and long-term OS., Conclusion: Prolonged low levels of plasma IL-6/-8 in PDA patients may be a prognostic marker for the clinical outcomes of chemoimmunotherapy.

Gemcitabine application for patients with impaired renal function or undergoing haemodialysis will increase if the efficacy and safety are proved as the treatment for pancreatic cancer of these patients. However, there is no guideline about the usage of gemcitabine in patients with impaired renal function or haemodialysis. We report the case of a 70-year-old man with advanced pancreatic cancer undergoing haemodialysis. After discontinuation of 100% or 80% dosage, 60% dose of gemcitabine was administered biweekly. Serum carbohydrate antigen 19-9 and carcinoembryonic antigen levels were marked by slight variations and abdominal computed tomography (CT) showed the tumour size hardly changed. We administered gemcitabine for the patient 14 times in total, and he survived over 8 months from the definitive diagnosis. These findings confirm the efficacy and safety of treatment with a biweekly 60% dose of gemcitabine for patients with advanced pancreatic cancer undergoing haemodialysis in the face of dose modification.

Background/aim: Chemoimmunotherapy has been used to treat intrahepatic cholangiocarcinoma (ICC). However, little is known about the phenomena underlying the immunomodulation of ICC cells elicited by chemoimmunotherapy., Materials and Methods: Primary ICC cells from a patient with ICC who received gemcitabine followed by 5-fluorouracil (5-FU), both combined with dendritic cells pulsed with Wilms' tumor 1 (WT1) peptides were cultured. ICC cells were treated with gemcitabine, 5-FU or interferon (IFN)-γ in vitro. The phenotype of the ICC cells was examined by flow cytometry and quantitative reverse transcription polymerase chain reaction., Results: Stimulation of the ICC cells with gemcitabine resulted in up-regulation of WT1 mRNA, programmed death receptor ligand-1 (PDL1) and calreticulin. Gemcitabine, 5-FU and IFN-γ induced up-regulation of mucin-1. Moreover, human leukocyte antigen (HLA)-ABC, HLA-DR and PDL1 were extremely up-regulated by IFN-γ., Conclusion: Chemoimmunomodulating agents alter the immunogenicity of ICC cells, resulting in complex clinical efficacy results., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Purpose: We performed a phase I trial to investigate the safety, clinical responses, and Wilms' tumor 1 (WT1)-specific immune responses following treatment with dendritic cells (DC) pulsed with a mixture of three types of WT1 peptides, including both MHC class I and II-restricted epitopes, in combination with chemotherapy., Experimental Design: Ten stage IV patients with pancreatic ductal adenocarcinoma (PDA) and 1 patient with intrahepatic cholangiocarcinoma (ICC) who were HLA-positive for A*02:01, A*02:06, A*24:02, DRB1*04:05, DRB1*08:03, DRB1*15:01, DRB1*15:02, DPB1*05:01, or DPB1*09:01 were enrolled. The patients received one course of gemcitabine followed by biweekly intradermal vaccinations with mature DCs pulsed with MHC class I (DC/WT1-I; 2 PDA and 1 ICC), II (DC/WT1-II; 1 PDA), or I/II-restricted WT1 peptides (DC/WT1-I/II; 7 PDA), and gemcitabine., Results: The combination therapy was well tolerated. WT1-specific IFNγ-producing CD4(+) T cells were significantly increased following treatment with DC/WT1-I/II. WT1 peptide-specific delayed-type hypersensitivity (DTH) was detected in 4 of the 7 patients with PDA vaccinated with DC/WT1-I/II and in 0 of the 3 patients with PDA vaccinated with DC/WT1-I or DC/WT1-II. The WT1-specific DTH-positive patients showed significantly improved overall survival (OS) and progression-free survival (PFS) compared with the negative control patients. In particular, all 3 patients with PDA with strong DTH reactions had a median OS of 717 days., Conclusions: The activation of WT1-specific immune responses by DC/WT1-I/II combined with chemotherapy may be associated with disease stability in advanced pancreatic cancer., (©2014 American Association for Cancer Research.)

Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/β-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy.

Aim: To investigate the association of procalcitonin (PCT) with ulcerative colitis (UC) activity., Methods: Serum PCT levels, C-reactive protein (CRP) levels, the erythrocyte sedimentation rate, and the white blood cell count were analyzed in 18 patients with UC and 11 healthy volunteers. Serum PCT levels were analyzed by an electrochemiluminescence immunoassay. Severity assessments were based on Truelove and Witts' severity index. Correlation of serum PCT and CRP levels with UC activity was examined. Moreover, we assessed serum PCT and CRP levels in patients with a Mayo endoscopic subscore., Results: Serum PCT levels in severe UC patients (n = 7) (0.096 ± 0.034 ng/mL) were significantly higher than in mild-to-moderate UC patients (n = 11) (0.033 ± 0.012 ng/mL) and healthy volunteers (n = 11) (0.035 ± 0.005 ng/mL) (P = 0.0005 and P < 0.0001, respectively). In addition, there was no difference in serum PCT levels between mild-to-moderate UC patients and healthy volunteers. Interestingly, patients with a Mayo endoscopic subscore of 3 points displayed significantly increased levels of serum PCT (0.075 ± 0.043 ng/mL) compared with patients with a subscore of 2 points (0.03 ± 0.011 ng/mL) (P = 0.0302). Moreover, CRP levels in patients with severe UC or a Mayo endoscopic subscore of 3 points were not significantly higher than in patients with mild-to-moderate UC or a Mayo endoscopic subscore of 3 points., Conclusion: Serum PCT levels were significantly correlated with UC activity., (© 2013 Baishideng Publishing Group Co., Limited. All rights reserved.)

The therapeutic efficacy of fusion cell (FC)-based cancer vaccine generated with whole tumor cells and dendritic cells (DCs) requires the improved immunogenicity of both cells. Treatment of whole tumor cells with ethanol resulted in blockade of immune-suppressive soluble factors such as transforming growth factor (TGF)-β1, vascular endothelial growth factor, and IL-10 without decreased expression of major histocompatibility complex (MHC) class I and the MUC1 tumor-associated antigen. Moreover, the ethanol-treated tumor cells expressed "eat-me" signals such as calreticulin (CRT) on the cell surface and released immunostimulatory factors such as heat shock protein (HSP)90α and high-mobility group box 1 (HMGB1). A dual stimulation of protein-bound polysaccharides isolated from Coriolus versicolor (TLR2 agonist) and penicillin-inactivated Streptococcus pyogenes (TLR4 agonist) led human monocyte-derived DCs to produce HSP90α and multiple cytokines such as IL-12p70 and IL-10. Interestingly, incorporating ethanol-treated tumor cells and TLRs-stimulated DCs during the fusion process promoted fusion efficiency and up-regulated MHC class II molecules on a per fusion basis. Moreover, fusions of ethanol-treated tumor cells and dual TLRs-stimulated DCs (E-tumor/FCs) inhibited the production of multiple immune-suppressive soluble factors including TGF-β1 and up-regulated the production of IL-12p70 and HSP90α. Most importantly, E-tumor/FCs activated T cells capable of producing high levels of IFN-γ, resulting in augmented MUC1-specific CTL induction. Collectively, our results illustrate the synergy between ethanol-treated whole tumor cells and dual TLRs-stimulated DCs in inducing augmented CTL responses in vitro by FC preparations. The alternative system is simple and may provide a platform for adoptive immunotherapy.

Induction of antitumor immunity by dendritic cell (DC)-tumor fusion cells (DC/tumor) can be modulated by their activation status. In this study, to address optimal status of DC/tumor to induce efficient antigen-specific cytotoxic T lymphocytes (CTLs), we have created various types of DC/tumor: 1) un-activated DC/tumor; 2) penicillin-killed Streptococcus pyogenes (OK-432; TLR4 agonist)-activated DC/tumor; 3) protein-bound polysaccharides isolated from Coriolus versicolor (PSK; TLR2 agonist)-activated DC/tumor; and 4) Combined OK-432- and PSK-activated DC/tumor. Moreover, we assessed the effects of TGF-β1 derived from DC/tumor on the induction of MUC1-specific CTLs. Combined TLR2- and TLR4-activated DC/tumor overcame immune-suppressive effect of TGF-β1 in comparison to those single activated or un-activated DC/tumor as demonstrated by: 1) up-regulation of MHC class II and CD86 expression on DC/tumor; 2) increased fusion efficiency; 3) increased production of fusions derived IL-12p70; 4) activation of CD4(+) and CD8(+) T cells that produce high levels of IFN-γ; 5) augmented induction of CTL activity specific for MUC1; and 6) superior efficacy in inhibiting CD4(+)CD25(+)Foxp3(+) T cell generation. However, DC/tumor-derived TGF-β1 reduced the efficacy of DC/tumor vaccine in vitro. Incorporating combined TLRs-activation and TGF-β1-blockade of DC/tumor may enhance the effectiveness of DC/tumor-based cancer vaccines and have the potential applicability to the field of adoptive immunotherapy.

Fusobacterium varium is an elusive pathogenic factor in ulcerative colitis (UC); conventional methods of fecal culture rarely recover F. varium. We have developed a nested culture method to recover Fusobacterium and we used it to investigate whether F. varium could be isolated from UC patients. We enrolled 50 consecutive patients in this study; 26 received combination antibiotic therapy that included amoxicillin, tetracycline, and metronidazole (ATM) for 2 weeks and were thus assigned to the ATM group, and the remaining 24 were assigned to the non-ATM group and did not receive any antibiotics. Stool samples were added to 10 ml of GAM broth that contained neomycin and crystal violet. The samples were vortexed and incubated under anaerobic conditions. The preincubated broth was streaked onto a Fusobacterium-selective agar plate and then incubated under anaerobic conditions. The species of the colonies isolated were identified using the Vitek Automated system and PCR analysis. We recoverd F. varium from 7 of the 24 non-ATM patients (29.2%) and none from the ATM patients (0%) (P = 0.0035). All of the F. varium isolates were susceptible to ATM. This study suggests that the recovery of F. varium is related to UC, which aligns with results from previous studies that used mucosal culture, immunostaining, real-time PCR, and serological studies.

Pancreatic cancer is a highly aggressive and notoriously difficult to treat. As the vast majority of patients are diagnosed at advanced stage of the disease, only a small population is curative by surgical resection. Although gemcitabine-based chemotherapy is typically offered as standard of care, most patients do not survive longer than 6 months. Thus, new therapeutic approaches are needed. Pancreatic cancer cells that develop gemcitabine resistance would still be suitable targets for immunotherapy. Therefore, one promising treatment approach may be immunotherapy that is designed to target pancreatic-cancer-associated antigens. In this paper, we detail recent work in immunotherapy and the advances in concept of combination therapy of immunotherapy and chemotherapy. We offer our perspective on how to increase the clinical efficacy of immunotherapies for pancreatic cancer.

We report a case of primary sclerosing cholangitis (PSC) with benign lymphadenopathy which was diagnosed with endosonography guided fine needle aspiration (EUS-FNA). A 65-year-old woman was admitted to Jikei University Hospital with severe jaundice. Although endoscopic retrograde cholangiography and liver biopsy revealed the findings consistent with PSC, abdominal computed tomography revealed numerous large perihepatic lymph nodes with a maximum diameter of more than 3 cm. Therefore, EUS-FNA was done in order to exclude malignant lymphadenopathy, and adequate specimens obtained by EUS-FNA showed reactive hyperplasia of lymph node. The patients were scheduled to undergo liver transplantation.

A 46-year-old man was admitted because of ileus. He had undergone an operation for lung carcinoma (stage IA) 8 years previously in another hospital. Because small bowel enema study showed widespread stricture of the ileum, we performed an operation. During the operation we diagnosed metastatic small bowel carcinoma. Because the resected sample of the small bowel carcinoma was similar to the lung carcinoma pathologically and detailed examination after the operation showed no other neoplasm, we considered this case to be small bowel metastasis of the lung carcinoma resected 8 years previously.

Background and Aim: A new argon plasma coagulation (APC) system was developed to improve the conduction characteristics of existing systems and to achieve a true non-contact procedure. We evaluated the new system in an ex vivo experiment and in two different clinical cases., Methods: Swine gastric walls were cauterized at various current settings and time intervals. The diameter and penetration depth of the cauterized areas were measured. We also describe the use of this method to treat patients with gastric hemorrhagic hereditary telangiectasias and a mucosal gastric cancer., Results: The ex vivo study revealed an improved maintenance of current conduction and greater control of the extent and penetration depth of the cauterization effects on tissue using the new APC system. In the clinical cases, hemorrhagic telangiectasias and an early stage gastric cancer were treated successfully without relapse using the new system., Conclusions: Improved current conduction and controllability of cauterization corresponding to emission time were demonstrated for the new APC. The new system allows expeditious superficial cauterization of a wide area without any contact with tissue. The therapeutic effect appeared favorable compared with previous APC devices for gastrointestinal applications.

Background: A newly developed narrow-band imaging (NBI) system, which uses modified optical filters, can yield clear images of microvessels and surface structure in gastric and colonic diseases. In the present study, we investigated the ability of magnifying endoscopy with NBI (MENBI) to diagnose and differentiate between benign and malignant ampullary tumors., Methods: Fourteen patients, whose ampullas were noted to be significantly enlarged or protruding with conventional endoscopy, were enrolled in the study. Specimens, which were obtained by forceps biopsy, endoscopic papillectomy, and/or surgery, were retrieved for histopathological examination. The correlation between MENBI images and histopathological findings was investigated. MENBI findings were classified as I, oval-shaped villi; II, pinecone/leaf-shaped villi; or III, irregular/nonstructured. In addition, tortuous, dilated, and network-like vessels noted on the ampullary lesions with MENBI were defined as abnormal vessels., Results: In 6 of 14 patients, the ampullary changes were proven to be inflammatory in forceps biopsy specimens, without any evidence of malignancy after more than 1 year of follow-up. In five patients, ampullary lesions were treated by endoscopic papillectomy, and in three, by pancreatoduodenectomy. All adenomas and adenocarcinomas had type II and/or type III surface structures, and patients whose ampulla had a type I surface structure had only inflammatory or hyperplastic changes. In addition, abnormal vessels were seen only in adenocarcinomas and never in adenomas., Conclusions: MENBI has the ability and potential to predict histological characteristics of ampullary lesions.