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The viral genome quasispecies composition of hepatitis C virus (HCV) could have important implications to viral pathogenesis and resistance to anti-viral treatment. The purpose of the present study was to profile the HCV RNA quasispecies. We developed a strategy to determine the full-length HCV genome sequences co-existing within a single patient serum by using next-generation sequencing technologies. The isolated viral clones were divided into the groups that can be distinguished by core amino acid 70 substitution. Subsequently, we determined HCV full-length genome sequences of three independent dominant species co-existing in the sequential serum with a 7-year interval. From phylogenetic analysis, these dominant species evolved independently. Our study demonstrated that multiple dominant species co-existed in patient sera and evolved independently.

Abstract EBV‐positive diffuse large B‐cell lymphoma (DLBCL), not otherwise specified (NOS), often affects the gastrointestinal tract. However, the prognostic significance of EBV associated with primary gastric DLBCL (gDLBCL) has not been established. This retrospective study included 240 patients with primary gDLBCL, diagnosed between 1995 and 2015. Tumor specimens were analyzed with EBER in situ hybridization. In 25 (10%) cases, tumor cells harbored EBV. The EBV+ group more frequently exhibited programmed death‐ligand 1 (PD‐L1) expression in microenvironment immune cells, but not tumor cells, compared to the EBV− group (86% vs 43%, P = .006). Among 156 patients that received rituximab‐containing chemotherapy, the EBV+ group had a significantly worse overall survival (OS) than the EBV− group (P = .0029). Multivariate analyses identified 3 independent adverse prognostic factors of OS: multiple gastric lesions (P = .002), EBER positivity (P = .003), and B symptoms (P = .018). These factors were combined to develop a gDLBCL prognostic (gDLP) model that significantly stratified the patients into 3 distinct risk groups (Scores: good = 0, intermediate = 1, and poor = 2/3, P

Abstract Background Prognosis of pancreatic cancer is poor with a 5-year survival rate of only 7%. Although several new chemotherapy treatments have shown promising results, all patients will eventually progress, and we need to develop newer chemotherapy treatments to improve response rates and overall survival (OS). HF10 is a spontaneously mutated oncolytic virus derived from a herpes simplex virus-1, and it has potential to show strong antitumor effect against malignancies without damaging normal tissue. We aimed to evaluate the safety and anti-tumor effectiveness in phase I dose-escalation trial of direct injection of HF10 into unresectable locally advanced pancreatic cancer under endoscopic ultrasound (EUS)-guidance in combination with erlotinib and gemcitabine administration. The mid-term results have been previously reported and here we report the final results of our study. Methods This was a single arm, open-label Phase I trial. HF10 was injected once every 2 weeks and continued up to four times in total unless dose-limiting toxicity (DLT) appears. A total of nine subjects in three Cohorts with dose-escalation were planned to be enrolled in this trial. The primary endpoint was the safety assessment and the secondary endpoint was the efficacy assessment. Results Twelve patients enrolled in this clinical trial, and ten subjects received this therapy. Five patients showed Grade III myelosuppression and two patients developed serious adverse events (AEs) (perforation of duodenum, hepatic dysfunction). However, all of these events were judged as AEs unrelated to HF10. Tumor responses were three partial responses (PR), four stable diseases (SD), and two progressive diseases (PD) out of nine subjects who completed the treatment. Target lesion responses were three PRs and six SDs. The median progression free survival (PFS) was 6.3 months, whereas the median OS was 15.5 months. Two subjects from Cohort 1 and 2 showed downstaging and finally achieved surgical complete response (CR). Conclusions HF10 direct injection under EUS-guidance in combination with erlotinib and gemcitabine was a safe treatment for locally advanced pancreatic cancer. Combination therapy of HF10 and chemotherapy should be explored further in large prospective studies. Trial registration: This study was prospectively registered in UMIN-CTR (UMIN000010150) on March 4th, 2013.

Abstract Background In Japan, approximately 0.9% and 1% of the whole population are infected with HBV and HCV, respectively. Doctors from departments other than gastroenterology often order viral hepatitis tests before an invasive examination or an operation. However, the notification of positive results to the patients and linkage to care is not appropriately performed. The in-hospital alert system was constructed to promote the notification and referral to gastroenterologists for patients with positive viral hepatitis tests, and its efficacy was evaluated. Methods The patients who tested HBsAg and anti-HCV antibody by chemiluminescent enzyme immunoassays and chemiluminescent immunoassays were investigated for whether they were notified of the positive results and if they were referred to gastroenterologists at our hospital. The notification and referral rate was compared before (from January to December 2014) and after the introduction of the alert system (from February to September 2016). Results HBsAg-positive rate was 1.1% (69/6543) before the introduction of the alert system and 0.8% (41/5403) after it. The notification rate has significantly improved from 46% to 73% (p = 0.0061) and the referral rate has improved from 16% to 27%, while not significant. Positive rate of anti-HCV antibody was 2.1% (139/6481) before the introduction of the alert system and 2.4% (128/5322) after it. The rate of notification and referral has significantly improved from 35% to 62% (p

Background and study aims Endoscopic submucosal dissection (ESD) enables en bloc removal of colorectal neoplasms regardless of size. Submucosal fibrosis is a significant factor for technical difficulty and poor outcomes. We assessed the predictive factors for severe submucosal fibrosis and the ESD outcomes. Patients and methods Patients undergoing ESD from January 2006 to September 2017 were retrospectively reviewed. The degree of submucosal fibrosis was classified into three types: no fibrosis (F0), mild fibrosis (F1), and severe fibrosis (F2). F0 and F1 cases were grouped as non-severe fibrosis for comparison with the severe fibrosis group. Predictors of severe submucosal fibrosis and ESD outcomes were evaluated. Results ESD was performed in 524 lesions (60 % male; mean age, 67.8 years). Eighty lesions with severe fibrosis (15.3 %) were observed. The overall en bloc resection rate and curative resection rate were 94.3 % and 77.7 %, respectively. Rates of en bloc resection (91.2 % vs. 94.8 %, P = 0.2) and perforation (7.5 % vs. 5.6 %, P = 0.45) were no different between severe fibrosis and non-severe fibrosis groups. However, incidences of non-curative resection and low resection speed were significantly higher in the severe fibrosis group. Among protruding lesions, tumor height and volume were significantly greater in the severe counterparts. A diameter ≥ 40 mm, endoscopic finding of the tumor beyond fold, and fold convergence were independent risk factors for severe fibrosis. Conclusions Severe submucosal fibrosis is a significant risk factor for non-curative resection and a long procedural time. Tumor size and morphology might help to predict the severity of fibrosis.

Commercially available lipid-based transfection reagents are widely used to deliver DNA to cells. However, these lipid-based transfection reagents show poor gene transfer efficiency in primary cells. Here, we demonstrate a simple method to improve gene transfer efficiency in primary fibroblasts and hepatoblasts using a combination of lipid-based transfection reagents. Our data show that combined use of Lipofectamine LTX and FuGENE HD increases the efficiency of gene transfer compared with the use of either reagent alone, and this combination achieves the best result of any pairwise combination of Lipofectamine LTX, FuGENE HD, TransFectin, and Fibroblast Transfection Reagent.

Background and study aims To decrease complications associated with preoperative endoscopic nasobiliary drainage (ENBD) for perihilar cholangiocarcinoma patients, we developed a modified 6-Fr ENBD catheter with multiple side holes (m-ENBD). The aim of this retrospective study was to compare the m-ENBD catheter with a conventional 7-Fr ENBD catheter (c-ENBD). Patients and methods This study involved 371 patients with suspected perihilar cholangiocarcinoma who underwent ENBD using a c-ENBD catheter or an m-ENBD catheter. The effectiveness of each catheter and the incidence of complications were evaluated. Univariate and multivariate analyses followed by propensity score matching were performed. Results In 145 patients with total bilirubin levels ≥ 2.0 mg/dL prior to drainage, these levels decreased to

Background and aims We have previously shown that the increase in blood flow volume in jejunum villi after spraying of 10 % dextrose solution correlates with pancreatic exocrine function (PEF). The aim of this study was to establish an objective method to evaluate the amount of jejunum villous blood flow using a novel image analysis system. Patients and methods The subjects were 26 patients who underwent upper gastrointestinal endoscopy with a newly developed small intestine endoscope (SIF-Y0007, Olympus, Tokyo, Japan). By defining the ratio of capillary occupancy in each villus at levels from 1 to 5, villous blood flow was evaluated subjectively on the villous blood flow scale (VBFS). Objective evaluation was performed based on luminance analysis. The morphological opening process was used to make images with leveled brightness. A histogram was prepared from the luminance information and the standard deviation was determined and defined as SDOV (Standard Deviation calculated from a histogram made by luminance analysis Of Villi). PEF was evaluated by measuring the BT-PABA (N-benzoyl-L-tyrosyl-p-aminobenzoic acid) excretion rate. Results There was a significant positive correlation between VBFS and SDOV (P

Background and study aims Endoscopic ultrasound (EUS) elastography (EUS-E) and contrast-enhanced harmonic EUS (CH-EUS) are useful methods for the diagnosis of pancreatic lesions. This study aims to compare the accuracy of combined EUS-E and CH-EUS with that of EUS-E or CH-EUS alone in the differential diagnosis of pancreatic solid lesions. Patients and methods One hundred thirty-six patients with solid pancreatic lesions underwent EUS with both EUS-E and CH-EUS were included. Diagnoses were classified as adenocarcinoma, neuroendocrine tumor (NET), and inflammatory pseudotumor in 95, 22, and 19 patients, respectively. EUS records in each case were rearranged into 3 groups: EUS-E, CH-EUS, and combination. Each modality was randomly reviewed by 3 reviewers with different levels of clinical experience. Sensitivity, specificity, and accuracy of each modality according to each diagnosis group were evaluated. For the combined diagnosis populations, the proportions of correct diagnoses among the 3 modalities were compared by using the multivariate logistic regression analysis. Results The accuracies of EUS-E, CH-EUS, and the combination of them were 68.4 %, 65.4 %, and 75.7 %, respectively, for adenocarcinoma group; 83.8 %, 82.4 %, and 86.8 % for NET group; 80.1 %, 78.7 %, and 81.6 % for inflammatory pseudotumor group. The multivariate logistic regression analysis for the combined diagnosis populations showed that the proportion of correct diagnoses when EUS-E and CH-EUS were combined was slightly higher than with the other 2 modalities, although the significant differences among them were not observed. Conclusion EUS-E and CH-EUS combined may improve differential diagnosis of solid pancreatic lesions compared with use of the individual modalities.

Objectives: Patients undergoing double-balloon enteroscopy require sedatives such as midazolam; however, patient’s body motion often hampers the outcome of double-balloon enteroscopy. Recently, dexmedetomidine has been used for endoscopic sedation and was reported to effectively reduce body motion. This study aimed to evaluate the efficacy and safety of sedation with dexmedetomidine in double-balloon enteroscopy (UMIN ID000015785). Methods: A prospective, observational study was conducted in 81 patients who underwent 111 double-balloon enteroscopy from July to December 2015 (dexmedetomidine group). The medical records of 112 patients who underwent 166 double-balloon enteroscopy with midazolam and pentazocine sedation from January 1 to October 31, 2014, were used for comparison (midazolam group). After propensity score matching, 182 double-balloon enteroscopy (91 double-balloon enteroscopy for each group) were analyzed. Results: There were 13 cases (11.7%) with body movements in the dexmedetomidine group. Comparison of the two groups matched by propensity score showed that the dexmedetomidine group had less body movement (12.1% vs 34.1%, p = 0.001) and less respiratory depression (50.5% vs 68.1%, p = 0.023). Hypotension (8.8% vs 4.4%, p = 0.232) and bradycardia (2.2% vs 0%, p = 0.497) were not significantly different in the two groups. Conclusion: Using dexmedetomidine for conscious sedation can reduce body motion and respiratory depression compared to our previous records.

Background Retention is the most common complication of capsule endoscopy (CE), and is reported to occur in 0–13% of cases. To avoid retention, a PillCam patency capsule (PC) is used in patients with suspected intestinal stenosis. However, a relatively low positive predictive value of the PC examination has been reported previously. The aims of this study were to clarify the accuracy of PC examination and to evaluate clinical factors related to cases of false-positive detection. Methods We performed a retrospective single-center study of 282 consecutive patients referred for PC examination. Patients in which the PC could not pass through the small bowel within 33 h were classified into the ‘no patency’ group. The ‘no patency’ group was investigated for evidence of significant stenosis upon further examinations, including CE, double-balloon endoscopy, and small bowel follow-through after PC examination. Clinical factors related to small bowel patency and false-positive cases were evaluated. Results We included 161 male (57.1%) and 121 female (42.9%) patients with a mean age of 47.5 ± 17.7 years. Of the 282 patients enrolled, 27 patients exhibited ‘no patency’ upon PC examination. Multivariate analysis showed that clinical factors related to ‘no patency’ included Crohn’s disease, abdominal symptoms, stenosis upon imaging, and previous abdominal surgery. Upon further examination, nine cases in the ‘no patency’ group had significant stenosis. Sensitivity, specificity, and negative and positive predictive values of PC examination for detecting small bowel stenosis were 93.8%, 96.6%, 99.6%, and 62.5%, respectively, and the only clinical factor related to false-positive cases was constipation ( p < 0.05). Conclusion We found a relatively low positive predictive value of PC examination and that constipation was related to false-positive results. To extend the implications of CE indications, clinical study focusing on these results is expected.

Background and study aims There have been few evaluations of the diagnostic ability of new narrow band light observation blue laser imaging (BLI). The present prospective study compared the diagnostic ability of BLI magnification and pit pattern analysis for colorectal polyps. Patients and methods We collected lesions prospectively, and the analysis of images was made by two endoscopists, retrospectively. A total of 799 colorectal polyps were examined by BLI magnification and pit pattern analysis at Nagoya University Hospital. The Hiroshima narrow-band imaging classification was used for BLI. Differentiation of neoplastic from non-neoplastic lesions and diagnosis of deeply invasive submucosal cancer (dSM) were compared between BLI magnification and pit pattern analysis. Type C2 in the Hiroshima classification was evaluated separately, because application of this category as an index of the depth of cancer invasion was considered difficult. Results We analyzed 748 colorectal polyps, excluding 51 polyps that were inflammatory polyps, sessile serrated adenoma/polyps, serrated adenomas, advanced colorectal cancers, or other lesions. The accuracy of differential diagnosis between neoplastic and non-neoplastic lesions was 98.4 % using BLI magnification and 98.7 % with pit pattern analysis. In addition, the diagnostic accuracy of BLI magnification and pit pattern analysis for dSM for cancer was 89.5 % and 92.1 %, respectively. When type C2 lesions were excluded, the diagnostic accuracy of BLI for dSM was 95.9 %. The 18 type C2 lesions comprised 1 adenoma, 9 intramucosal or slightly invasive submucosal cancers, and 8 dSM. Pit pattern analysis allowed accurate diagnosis of the depth of invasion in 13 lesions (72.2 %). Conclusions Most colorectal polyps could be diagnosed accurately by BLI magnification without pit pattern analysis, but we should add pit pattern analysis for type C2 lesions in the Hiroshima classification.

Background: Colon capsule endoscopy (CCE) is a procedure in which capsule swallowing facilitates observation of the lumen of the entire digestive tract. It does not require an air supply, and is a noninvasive procedure with a markedly low risk of adverse events in comparison with conventional colonoscopy (CS). It reduces patient stress, and may be acceptable to patients. A limitation of this procedure is that the entire colon observation rate (CCE excretion rate, completed CCE rate) is not 100%. In this study, we prospectively investigated clinical factors important to achieve observation of the entire colon on CCE. Methods: The participants were 70 patients for whom CCE was scheduled, and from whom written informed consent regarding participation in this study was obtained. We selected patient background/examination factors, and analyzed all factors involved in observation of the entire colon and factors for completion of the CCE within 4 h after the start of examination using multivariate analysis. Results: Of the 70 enrolled patients, 64 were analyzed, excluding 6. On multiple logistic analysis, only a water intake of ⩾12.0 ml/min during examination [ p = 0.025, odds ratio (OR): 46.753, 95% confidence interval (CI): 1.630–1341.248] was identified as an independent predictive factor involved in observation of the entire colon. With respect to factors involved in the completion of CCE within 4 h, multiple logistic analysis showed that a body mass index (BMI) of ⩾25 ( p = 0.039, OR: 13.723, 95% CI: 1.135–165.913), the absence of constipation ( p = 0.030, OR: 13.988, 95% CI: 1.287–152.047), and a water intake of ⩾12.0 ml/min during examination ( p = 0.004, OR: 12.028, 95% CI: 2.225–65.029) were independent predictive factors. Conclusions: Completion of a CCE was most closely related to water intake per hour. In addition to water intake, CCE-promoting factors included a high BMI and the absence of constipation.

We report a case of a 70-year-old man who presented with abdominal pain and weight loss, with initial imaging showing simultaneous mass lesions in the pancreas and lungs along with extensive lymphadenopathy in the thorax up to the left supraclavicular region. Core biopsies of the left supraclavicular lymph node showed squamous cell carcinoma, which required differentiation between secondary and primary pancreatic neoplasms. Endoscopic ultrasound-guided sampling using a novel fine needle biopsy system was key to making a definite histological diagnosis and determining the best treatment plan.

Background and study aims Diagnosis of Meckel’s diverticulum (MD) before surgery may be challenging; double-balloon endoscopy (DBE) facilitates identification of MD in the setting of a gastrointestinal bleeding; however, MD can be found incidentally without this condition. The purpose of this research was to determine specific characteristic of hemorrhagic MD and incidental MD at DBE. Patients and methods Ectopic gastric mucosa enclosed in the MD and/or ulceration were defined as “major findings”; ring-like scar surrounding the MD was defined as “minor finding”. We retrospectively reviewed the medical records of patients affected by MD and analyzed the findings that significantly affected the characterization of MD. Results MD was diagnosed in 33 patients. The axis of the diverticulum was longer in hemorrhagic MD compared to incidental MD (P = 0.031). The amount of transfusion was significantly higher (P = 0.018) in the hemorrhagic MD group. Hemorrhagic MD was significantly more correlated with major findings (P = 0.01) and minor findings (P

Objective. Dipeptidyl peptidase (DPP)-4 inhibitors inactivate glucagon-like peptide (GLP)-1, GLP-2, and other hormones by degradation. Administration of a DPP-4 inhibitor or GLP-2 analog stimulates intestinal growth and facilitates the restoration of mucosal damage caused by drug-induced colitis in mice. We studied the effect of GLP-2 deletion on morphological changes on gut and colitis recovery in mice deficient in proglucagon-derived peptides (PGDPs). Material and methods. Mice deficient in PGDPs were used. Eight-week-old male PGDPs−/− and PGDPs+/+ mice were sacrificed to examine the small intestine and colon morphology. To elucidate the effect of PGDP deletion on colitis, 12-week-old PGDPs−/− and PGDPs+/+ male mice were exposed to 2.5% dextran sulfate sodium (DSS) for 6 days. Colitis severity was assessed daily by disease activity index and body weight loss. Histological examinations were performed on days 7 and 21. Results. There were no differences in the height, width, and density of villous and the depth of crypt of small intestine, and the weight, length, and the crypt depth of colon between PGDPs−/− and PGDPs+/+. In DSS colitis, the decline and amelioration of disease activity index and body weight were not different between the PGDP−/− and PGDP+/+ mice. Histologically, the PGDP−/− mice showed significantly less recovery than showed by the PGDPs+/+ mice on day 21 (p

We report a case series of five patients with pancreatic acinar cell carcinoma who received surgical treatment and compared the preoperative contrast-enhanced endoscopic ultrasound (EUS) and EUS elastography patterns with the surgical specimens. The contrast-enhanced EUS indicated vascular tumors with gradual enhancement in four patients and a hypovascular tumor in one patient. The elastography indicated an elastic score of 3 (hard lesion with softer border) in two patients and a score of 5 (hard lesion, which included the surrounding area) in two patients. In tumors with an elastic score of 5, the pathology exhibited abundant hyalinizing fibrous stroma or massive tumor invasion to the surrounding tissue. We concluded that acinar cell carcinoma of the pancreas has various patterns of EUS contrast-enhancement and elastography, depending on the pathologic phenotype.

Background and study aims: Olympus recently developed a new algorithm called Omni mode that discards redundant video capsule endoscopy (VCE) images. The current study aimed to demonstrate the non-inferiority of the Omni mode in terms of true positives (TPs) and the superiority of the Omni mode with regard to reading time against a control (ordinary ES-10 system). Patients and methods: This multicenter prospective study included 40 patients with various small bowel diseases. VCE images were evaluated by 7 readers and 3 judging committee members. Two randomly allocated readers assessed the VCE images obtained using the 2 modalities for each patient. The order of the modalities was switched between the 2 readers and the interval between readings by the same reader was 2 weeks. The judging committee predefined clinically relevant lesions as major lesions and irrelevant lesions as minor lesions. The number of TPs for major and minor lesions and the reading times were compared between the modalities. The predefined non-inferiority margin for the TP ratio of the Omni mode compared with the control was 0.9. Results: The estimated TP ratios and 95 % confidence intervals for total, major, and minor lesions were 0.87 (0.80 – 0.95), 0.93 (0.83 – 1.04), and 0.83 (0.74 – 0.94), respectively. Although non-inferiority was not demonstrated, the rate of detection of major lesions was not significantly different between the modalities. The reading time was significantly lower when using the Omni mode than when using the control. Conclusions: The Omni mode may be only appropriate for the assessment of major lesions.

Background and study aims: Endoscopic resection is one treatment option for residual or locally recurrent esophageal cancer after definitive chemoradiotherapy or radiotherapy alone. However, little is known about the clinical benefit of salvage endoscopic resection for these lesions. Therefore, the effectiveness and prognostic factors of salvage endoscopic resection were investigated. Patients and methods: A total of 37 patients with esophageal squamous cell carcinoma (SCC) who underwent salvage endoscopic resection after definitive chemoradiotherapy or radiotherapy alone were reviewed. The method of salvage endoscopic resection was endoscopic mucosal resection using a cap (EMR-C), strip biopsy, or endoscopic submucosal dissection. The effectiveness and prognostic factors of salvage endoscopic resection were retrospectively analyzed. Results: A total of 37 patients with 49 lesions underwent salvage endoscopic resection. Baseline clinical stages were I in 23 patients, II in 3 patients, III in 9 patients, and IV in 2 patients. The number of locoregional recurrences and residual lesions were 35 and 14, respectively. The curative en bloc resection rate was 53.1 % (26/49). The total incidence of complications was 18.9 % (7/37); all were successfully managed conservatively. The 3-year and 5-year overall survival rates were 72.9 % and 53.3 %, respectively, with a median follow-up period of 54 months. Baseline clinical T1 – 2 and N0 were significant factors for good prognosis in terms of overall survival on univariate analysis. Conclusions: Salvage endoscopic resection, especially EMR-C, is a safe and feasible procedure to control residual or recurrent superficial esophageal SCC after definitive chemoradiotherapy or radiotherapy alone. The present results showed that baseline clinical T1 – 2 and N0 before chemoradiotherapy or radiotherapy were significant prognostic factors.

Background and study aims: Endoscopic tissue acquisition techniques using needle-knife and biopsy forceps allow abundant tissue acquisition from upper gastrointestinal subepithelial lesions; however, these techniques cannot capture real-time intratumor information. The aim of this study was to evaluate the feasibility of endoscopic ultrasound-guided forceps biopsy (EUS-FB) from upper gastrointestinal subepithelial lesions using a forward-viewing echoendoscope. Patients and methods: This study was a prospective case series. After mucosal cuts, several specimens were taken using a hot biopsy forceps under real-time EUS visualization. The incision was closed using hemoclips. Diagnostic yield, rate of diagnosable samples obtained under EUS visualization, procedure time, and adverse events were assessed. Results: Ten patients (median lesion size 16 mm, range 15 – 44 mm) underwent EUS-FB. The overall rate of histological diagnosis by EUS-FB was 100 % (10/10). The rate of diagnosable samples among all cases was 97.6 % (41/42). The median procedure times for EUS-FB and complete closure were 28.5 and 4.5 minutes, respectively. No adverse events occurred. Conclusions: This newly developed EUS-FB is feasible and allowed forceps biopsy from upper gastrointestinal subepithelial lesions. Study registration: UMIN000015364

Background. Although the usefulness of capsule endoscopy (CE) and double-balloon endoscopy (DBE) for the evaluation of Crohn’s disease (CD) is established, their capabilities in the differential diagnosis of small bowel stenosis have not been sufficiently addressed. The present study therefore aimed to retrospectively determine the types of patients for whom CE and DBE would confer the most benefit. Patients and Methods. We retrospectively reviewed data from 185 patients with established CD. A change of treatment based on CE or DBE results or successful DBE balloon dilation was defined as clinically useful indication. We then analyzed the factors significantly related to useful and poor indications. Results. CE results were assessed as useful indications in 28 (45%) of 62 patients. Multivariate analysis demonstrated that positive CRP and low IOIBD score are factors significantly related to a useful indication. DBE results were recognized as useful indications in 118 (77%) of 153 patients. Multivariate analysis indicated small bowel stenosis and abdominal pain as factors significantly associated with useful indications. All patients with a poor indication on CE had small bowel stenosis. Conclusions. CE was most useful for patients in clinical remission with positive CRP and without stenosis, whereas DBE was useful for patients with symptoms of stenosis.

Bevacizumab (BEV), a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, enhances the antitumor effectiveness of paclitaxel (PTX)-based chemotherapy in many metastatic cancers. A recent study in mice showed that VEGF receptor inhibitors can interfere with the neuroprotective effects of endogenous VEGF, potentially triggering the exacerbation of PTX-induced neuropathy. In clinical trials, exacerbation of neuropathy in patients who received PTX combined with BEV (PTX+BEV) has generally been explained by increased exposure to PTX owing to the extended duration of chemotherapy. We investigated whether the concurrent use of BEV is associated with the exacerbation of PTX-induced neuropathy.Female patients with breast cancer who had received weekly PTX or PTX+BEV from September 2011 through May 2016 were studied retrospectively. PTX-induced neuropathy was evaluated at the same time points (at the 6th and 12th courses of chemotherapy) in both cohorts. A multivariate Cox proportional-hazards model was used to assess the independent effect of BEV on the time to the onset of neuropathy.A total of 107 patients (median age, 55 years; range, 32-83) were studied. Sixty-one patients received PTX as adjuvant chemotherapy, 23 received PTX for metastatic disease, and 23 received PTX+BEV for metastatic disease. Peripheral sensory neuropathy was worse in patients who received PTX+BEV than in those who received PTX alone: at the 6th course, Grade 0/1/2/3 = 4/13/4/0 vs. 25/42/6/0 (P = 0.095); at the 12th course, 2/3/11/3 vs. 7/30/23/2 (P = 0.016). At the 12th course, the incidence of Grade 2 or higher neuropathy was significantly higher in patients treated with PTX+BEV than in those treated with PTX alone (74% vs. 40%; P = 0.017). In multivariate analysis, BEV was significantly associated with an increased risk of neuropathy (HR 2.32, 95% CI 1.21-4.44, P = 0.012).The concurrent use of BEV could worsen PTX-induced neuropathy in patients with breast cancer.

Trinitrobenzene sulfonic acid (TNBS) and oxazolone are used to induce colitis for the investigation of inflammatory reactions in the colon. Although these chemicals are presumed to bind proteins in the colonic mucosa and then induce colitis as haptens, hapten-protein formation has not yet been confirmed in the colonic mucosa. We developed a mouse model of colitis characterized by hapten-protein visualization, using 4-chloro-7-nitro-2,1,3-benzoxadiazole (NBD-Cl), which emits fluorescence after binding to proteins. The enema of 1 mg/mL NBD-Cl induced severe diarrhea, rectal bleeding, and body weight reductions in BALB/c mice. Mucosal signs indicative of colitis, such as redness and swelling observed under stereomicroscopy or inflammatory cell infiltration and crypt-epithelium destruction under microscopy, were manifested around NBD-proteins visualized with fluorescence. Fluorescence microscopy showed the infiltration of F4/80+ cells around areas of NBD-proteins, and flow cytometry indicated the uptake of NBD-proteins by CD11b+ cells. We also found critical roles for T cells and interleukin-6 in colitis induction with NBD-proteins. NBD-Cl-induced colitis presents a unique model to study the relevance between hapten-protein formation and inflammatory reactions and offers a method to assess experimental interventions on colitis induction in the mucosa, where hapten-protein formation is confirmed.

4-Nitro-7-(1-piperazinyl)-2,1,3-benzoxadiazole (NBD-PZ) reacts with carboxylic acids in the presence of condensing agents and is utilized for the fluorescence detection of the generated derivatives in high performance liquid chromatography or capillary electro-phoresis. Although the fluorescence intensity of derivatives of NBD-PZ–CH2CH2NH2 with carboxylic acids is elevated at low pH, the pH-dependent fluorescence of NBD-PZ itself has not yet been investigated. In this study, we determined the fluorescence spectra of NBD-PZ at various pH and found that the fluorescence intensity of NBD-PZ was elevated dramatically at pH ≤7.0. When NBD-PZ was applied to live HGC-27 cells, CW-2 cells, IEC-18 cells, and RAW264.7 cells, we observed that NBD-PZ clearly visualized lysosomes under fluorescence microscopy within 3 min. These findings indicate a novel application of NBD-PZ to visualize lysosomes in live cells, a strategy that offers substantial cost savings over commercially available lysosomal probes.

We evaluated the relationship between the early clinical response after 2 weeks of sorafenib therapy and the outcomes and anti-tumor response in patients with advanced hepatocellular carcinoma.Fifty-seven patients who had intrahepatic hypervascular hepatocellular carcinoma and Child-Pugh (CP) class A disease at baseline were enrolled in this prospective, multicenter, observational, non-interventional study. As an early clinical response after 2 weeks of sorafenib therapy, changes in intra-tumor blood flow on contrast-enhanced computed tomography (CE-CT), alpha-fetoprotein (AFP) levels, and remnant liver function were investigated.After 2 weeks of sorafenib therapy, there were 26 patients (45.6%) without disappearance of arterial tumor enhancement on CE-CT, 15 patients (26.3%) with an AFP ratio of >1.2, and seven patients (12.3%) with two or more increments in the CP score. Multivariate analysis showed that the absence of disappearance of arterial tumor enhancement on CE-CT, AFP ratio of >1.2, and two or more increments in the CP score after 2 weeks of sorafenib therapy were significant and independent predictors of worse survival. Upon scoring these three variables as "poor prognostic factors", patients with poor prognostic score 4, 3 or 2 (n = 17) had significantly worse outcomes and a significantly higher progressive disease (PD) rate based on modified Response Evaluation Criteria in Solid Tumors at 6 weeks after sorafenib therapy than those with poor prognostic score 1 or 0 (n = 40) (median overall survival: 194 days vs. 378 days; p = 0.0010, PD rate: 70.6% vs. 20.0%; p = 0.0003, respectively).Changes in intra-tumor blood flow on CE-CT, AFP levels, and remnant liver function after 2 weeks of sorafenib therapy may be useful for predicting the outcomes and anti-tumor response to sorafenib in patients with advanced hepatocellular carcinoma.

We showed previously that UBXD8 plays a key role in proteasomal degradation of lipidated ApoB in hepatocarcinoma cell lines. In the present study, we aimed to investigate the functions of UBXD8 in liver in vivo. For this purpose, hepatocyte-specific UBXD8 knockout (UBXD8-LKO) mice were generated. They were fed with a normal or high-fat diet, and the phenotypes were compared with those of littermate control mice. Hepatocytes obtained from UBXD8-LKO and control mice were analyzed in culture. After 26 wk of a high-fat diet, UBXD8-LKO mice exhibited macrovesicular steatosis in the periportal area and microvesicular steatosis in the perivenular area, whereas control mice exhibited steatosis only in the perivenular area. Furthermore, UBXD8-LKO mice on a high-fat diet had significantly lower concentrations of serum triglyceride and VLDL than control mice. A Triton WR-1339 injection study revealed that VLDL secretion from hepatocytes was reduced in UBXD8-LKO mice. The decrease of ApoB secretion upon UBXD8 depletion was recapitulated in cultured primary hepatocytes. Accumulation of lipidated ApoB in lipid droplets was observed only in UBXD8-null hepatocytes. The results showed that depletion of UBXD8 in hepatocytes suppresses VLDL secretion, and could lead to periportal steatosis when mice are fed a high-fat diet. This is the first demonstration that an abnormality in the intracellular ApoB degradation mechanism can cause steatosis, and provides a useful model for periportal steatosis, which occurs in several human diseases.

Liver fibrosis remains an important risk factor for hepatocarcinogenesis in patients with chronic hepatitis C even after the eradication of hepatitis C virus (HCV). However, it is difficult to estimate liver fibrosis based on liver biopsy after the eradication of HCV. We investigated the ability of laboratory indices to predict liver fibrosis in patients with sustained virologic response (SVR) to antiviral therapy. Three laboratory liver fibrosis indices (aspartate aminotransferase-platelet ratio index (APRI), FIB-4 index, and Forns index) were calculated based on data at the time of initial pretreatment liver biopsy and at second liver biopsy performed approximately 5 years after SVR in 115 patients who underwent serial liver biopsies. The indices at the time of initial biopsy were compared to histological degree of liver fibrosis in initial biopsy, and laboratory indices at the time of second liver biopsy were compared to the degree of fibrosis in second biopsy. In both comparisons, there were significant increases in all 3 indices with the increase of liver fibrosis grade as assessed in liver biopsy specimens. All 3 indices at the time of second biopsy were able to predict moderate to advanced (METAVIR score F2-4) and advanced (F3-4) fibrosis on liver biopsy, with the area under the receiver-operating characteristics curve >0.8 and the accuracy >70%. All 3 laboratory indices of fibrosis accurately reflected liver fibrosis in patients with SVR for 5 years despite the normalization of serum liver transaminase activity and the lack of liver inflammation.

BACKGROUND: Recent advances in the treatment of metastatic unresectable gastric cancers (MGC) include the development of new antitumor drugs and new regimens for their use. However, the selection of individually designed regimens by gastric cancer (GC) subtype remains problematic. Here, we investigated the clinical usefulness of programmed chemotherapy. METHODOLOGY/PRINCIPAL FINDINGS: MGC patients were classified into three groups by clinical condition. We implemented a chemotherapy program consisting of S-1 combination regimens. Median survival time (MST) of level 1 patients was 416 days (95% CI: 313-506 days), with an overall response rate of 47%. MSTs of level 2 and 3 patients were 208 (95% CI: 153-287 days) and 95 days (95% CI: 28-136 days), respectively. Grade 3-4 toxicities were neutropenia in 12% and anorexia in 6%. All treatment- related toxicities were resolved, and no treatment-related deaths occurred. CONCLUSIONS/SIGNIFICANCE: This program provided reasonable selection of case-matching regimens and may improve the survival of patients with MGC. Further, it may represent the first clinical tool to provide efficient chemotherapy course selection for MGC. Ongoing analysis of newly developed drugs and regimens will allow the efficacy of this chemotherapy program to be improved.

Cell migration is a critical cellular process that determines embryonic development and the progression of human diseases. Therefore, cell- or context-specific mechanisms by which multiple promigratory proteins differentially regulate cell migration must be analyzed in detail. Girdin (girders of actin filaments) (also termed GIV, Gα-interacting vesicle associated protein) is an actin-binding protein that regulates migration of various cells such as endothelial cells, smooth muscle cells, neuroblasts, and cancer cells. Here we show that Girdin regulates the establishment of cell polarity, the deregulation of which may result in the disruption of directional cell migration. We found that Girdin interacts with Par-3, a scaffolding protein that is a component of the Par protein complex that has an established role in determining cell polarity. RNA interference-mediated depletion of Girdin leads to impaired polarization of fibroblasts and mammary epithelial cells in a way similar to that observed in Par-3-depleted cells. Accordingly, the expression of Par-3 mutants unable to interact with Girdin abrogates cell polarization in fibroblasts. Further biochemical analysis suggests that Girdin is present in the Par protein complex that includes Par-3, Par-6, and atypical protein kinase C. Considering previous reports showing the role of Girdin in the directional migration of neuroblasts, network formation of endothelial cells, and cancer invasion, these data may provide a specific mechanism by which Girdin regulates cell movement in biological contexts that require directional cell movement.