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Background and Aim: Sodium picosulfate plus magnesium citrate (SP + MC) is a well‐tolerated bowel preparation agent. However, Japan currently approves only two methods of taking SP + MC: the day‐before and split‐dose preparation, without approval of same‐day preparations. This study aimed to evaluate the efficacy and safety of same‐day SP + MC preparations. Methods: This was a multicenter, single‐arm, nonrandomized, open‐label study. We enrolled 145 Japanese patients between June and December 2023. The patients received two sachets of SP + MC dissolved in 300 ml of water and 1200 mL or more of clear liquid on the day of colonoscopy. Bowel cleansing efficacy, adverse events (AEs), and patient satisfaction were evaluated. Results: Of the enrolled patients, 137 underwent colonoscopy according to our protocol. Bowel preparation was adequate in 133 patients (97.1%). The mean total Boston Bowel Preparation Score was 8.3 ± 1.2. Five patients experienced AEs (3.6%): two (1.5%), abdominal pain; one (0.73%), ischemic enteritis; one (0.73%), vomiting or nausea; and one (0.73%), headache. All AEs were treated conservatively. None of the patients exhibited abnormal blood test results or clinical symptoms after receiving SP + MC. Regarding patient satisfaction, all patients were able to take SP + MC as directed; 136 (99.2%) expressed a preference for this bowel preparation for future colonoscopies. Conclusion: The same‐day SP + MC preparation showed high bowel‐cleansing efficacy and satisfaction in Japanese patients without serious AEs. [ABSTRACT FROM AUTHOR]

With the widespread use of immune checkpoint inhibitors (ICIs), liver injury (ICI‐induced liver injury) as an immune‐related adverse event has become a major concern in clinical practice. Because severe cases of liver injury require administration of corticosteroids, a comprehensive evaluation is crucial, including clinical course, blood and imaging tests, and if necessary, pathological examination through liver biopsy. As with liver injury induced by other drugs, classification of injury type by R‐value is useful in deciding treatment strategies for ICI‐induced liver injury. Histologically, the most representative feature is an acute hepatitis‐like hepatocellular injury, characterized by diffuse lobular inflammation accompanied by CD8‐positive T lymphocytes. Another condition that can cause liver injury during ICI treatment is cholangitis accompanied by non‐obstructive bile duct dilatation and bile duct wall thickening. Many cases of ICI‐induced cholangitis are classified as non‐hepatocellular injury type, and they have been reported to respond poorly to corticosteroids. It is essential that gastroenterologists/hepatologists and doctors in various departments work in cooperation to develop a system that achieves early diagnosis and appropriate treatment of ICI‐induced liver injury. [ABSTRACT FROM AUTHOR]

Aim: The IMbrave150 trial revealed that atezolizumab plus bevacizumab (AtezoBv) showed a higher objective response rate (ORR) in patients with advanced hepatocellular carcinoma (HCC). Although conversion therapy after AtezoBv has been recently reported, markers predictive of its efficacy, particularly radiological imaging markers, have not yet been identified. The present study focused on tumor morphological appearance on radiological imaging and evaluated whether it could be associated with AtezoBv efficacy. Methods: Ninety‐five intrahepatic lesions in 74 patients who were given AtezoBv for advanced HCC were recruited for evaluation. The lesions were divided into two groups, simple nodular (SN group) and non‐simple nodular (non‐SN group), based on the gross morphology on pretreatment imaging, and retrospectively evaluated for treatment response and other relevant clinical outcomes. Results: Assessing the size of individual tumors after treatment, waterfall plots showed that tumor shrinkage in the non‐SN group including 56 lesions was higher than that in the SN group comprising 39 lesions. The ORR was significantly higher in the non‐SN group (39.3% vs. 15.4%, p = 0.012). Additionally, the median time to nodular progression was longer in the non‐SN group (21.0 months vs. 8.1 months, p = 0.119) compared to the SN group. Six patients with non‐SN lesions underwent sequential local therapy. Conclusions: Atezolizumab plus bevacizumab may show increased therapeutic efficacy in patients with tumors with a higher potential for aggressive oncological behavior, such as non‐SN lesions. Treatment strategies focusing on conversion therapy may be crucial in patients with non‐SN lesions. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is one of the most refractory cancers with the worst prognosis. Although several molecules are known to be associated with the progression of PDAC, the molecular mechanisms underlying the progression of PDAC remain largely elusive. The Ror‐family receptors, Ror1 and Ror2, which act as a receptor(s) for Wnt‐family ligands, particularly Wnt5a, are involved in the progression of various types of cancers. Here, we show that higher expression of Ror1 and Wnt5b, but not Ror2, are associated with poorer prognosis of PDAC patients, and that Ror1 and Wnt5b are expressed highly in a type of PDAC cell lines, PANC‐1 cells. Knockdown of either Ror1 or Wnt5b in PANC‐1 cells inhibited their proliferation significantly in vitro, and knockout of Ror1 in PANC‐1 cells resulted in a significant inhibition of tumor growth in vivo. Furthermore, we show that Wnt5b‐Ror1 signaling in PANC‐1 cells promotes their proliferation in a cell‐autonomous manner by modulating our experimental setting in vitro. Collectively, these findings indicate that Wnt5b‐Ror1 signaling might play an important role in the progression of some if not all of PDAC by promoting proliferation. [ABSTRACT FROM AUTHOR]

Objectives: Endoscopic submucosal dissection (ESD) for superficial esophageal squamous cell carcinoma (ESCC) is performed for the treatment of lesions with varied backgrounds and factors. However, the predictive factors associated with the technical difficulty of ESD remain unknown in patients with varied lesions. Therefore, this study aimed to identify the predictive factors associated with the technical difficulty of ESD for ESCC using a retrospective cohort. Methods: This multicenter, retrospective study was conducted in 10 hospitals in Japan. Consecutive patients who underwent esophageal ESD between January 2013 and December 2019 were enrolled. Lesions of subepithelial tumors, adenocarcinoma, and adenoma were excluded. Difficult lesions were defined as ESD requiring a long procedure time (≥120 min), perforation development, piecemeal resection, or discontinued ESD. In the present study, the clinical factors were assessed to identify the technical difficulty of ESD using univariate and multivariate analyses. Results: Among 1708 lesions treated with esophageal ESD, eight subepithelial tumors, 44 adenocarcinomas, and two adenomas were excluded. Finally, 1505 patients with 1654 lesions were analyzed, and 217 patients with 217 lesions (13.1%) were classified as patients with difficult lesions. In multivariate analysis, the predictive factors associated with the technical difficulty of ESD were as follows: tumors with varices, tumors with diverticulum, antiplatelet use (discontinued), circumference of tumor (≥1/2), preoperative tumor size ≥30 mm, trainee, and nonhigh‐volume center. Conclusion: This multicenter retrospective study identified the predictive factors associated with the technical difficulty of ESD for ESCC with varied backgrounds and factors. [ABSTRACT FROM AUTHOR]

The prognosis of gallbladder cancer (GBC) remains poor, and a better understanding of GBC molecular mechanisms is important. Genome sequencing of human GBC has demonstrated that loss‐of‐function mutations of E74‐like ETS transcription factor 3 (ELF3) are frequently observed, with ELF3 considered to be a tumour suppressor in GBC. To clarify the underlying molecular mechanisms by which ELF3 suppresses GBC development, we performed in vivo analysis using a combination of autochthonous and allograft mouse models. We first evaluated the clinical significance of ELF3 expression in human GBC tissues and found that low ELF3 expression was associated with advanced clinical stage and deep tumour invasion. For in vivo analysis, we generated Pdx1‐Cre; KrasG12D; Trp53R172H; Elf3f/f (KPCE) mice and Pdx1‐Cre; KrasG12D; Trp53R172H; Elf3wt/wt (KPC) mice as a control and analysed their gallbladders histologically. KPCE mice developed larger papillary lesions in the gallbladder than those developed by KPC mice. Organoids established from the gallbladders of KPCE and KPC mice were analysed in vitro. RNA sequencing showed upregulated expression of epiregulin (Ereg) in KPCE organoids, and western blotting revealed that EGFR/mechanical targets of rapamycin complex 1 (mTORC1) were upregulated in KPCE organoids. In addition, ChIP assays on Elf3‐overexpressing KPCE organoids showed that ELF3 directly regulated Ereg. Ereg deletion in KPCE organoids (using CRISPR/Cas9) induced EGFR/mTORC1 downregulation, indicating that ELF3 controlled EGFR/mTORC1 activity through regulation of Ereg expression. We also generated allograft mouse models using KPCE and KPC organoids and found that KPCE organoid allograft tumours exhibited poorly differentiated structures with mTORC1 upregulation and mesenchymal phenotype, which were suppressed by Ereg deletion. Furthermore, EGFR/mTORC1 inhibition suppressed cell proliferation and epithelial–mesenchymal transition in KPCE organoids. Our results suggest that ELF3 suppresses GBC development via downregulation of EREG/EGFR/mTORC1 signalling. EGFR/mTORC1 inhibition is a potential therapeutic option for GBC with ELF3 mutation. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

M2 macrophages contribute to the progression of oesophageal squamous cell carcinoma (ESCC); however, the roles of M2 macrophages in early ESCC remain unclear. To clarify the biological mechanisms underlying the interaction between M2 macrophages and oesophageal epithelial cells in early‐stage ESCC, in vitro co‐culture assays between the immortalised oesophageal epithelial cell line Het‐1A and cytokine‐defined M2 macrophages were established. Co‐culture with M2 macrophages promoted the proliferation and migration of Het‐1A cells via the mTOR–p70S6K signalling pathway activated by YKL‐40, also known as chitinase 3‐like 1, and osteopontin (OPN) that were hypersecreted in the co‐culture supernatants. YKL‐40 and OPN promoted the above phenotypes of Het‐1A by making a complex with integrin β4 (β4). Furthermore, YKL‐40 and OPN promoted M2 polarisation, proliferation, and migration of macrophages. To validate the pathological and clinical significances of in vitro experimental results, immunohistochemistry of human early ESCC tissues obtained by endoscopic submucosal dissection (ESD) was performed, confirming the activation of the YKL‐40/OPN–β4–p70S6K axis in the tumour area. Moreover, epithelial expression of β4 and the number of epithelial and stromal infiltrating YKL‐40‐ and OPN‐positive cells correlated with the Lugol‐voiding lesions (LVLs), a well‐known predictor of the incidence of metachronous ESCC. Furthermore, the combination of high expression of β4 and LVLs or high numbers of epithelial and stromal infiltrating YKL‐40‐ and OPN‐positive immune cells could more clearly detect the incidence of metachronous ESCC than each of the parameters alone. Our results demonstrated that the YKL‐40/OPN–β4–p70S6K axis played important roles in early‐stage ESCC, and the high expression levels of β4 and high numbers of infiltrating YKL‐40‐ and OPN‐positive immune cells could be useful predictive parameters for the incidence of metachronous ESCC after ESD. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Objectives: Peroral endoscopic myotomy (POEM) is an effective treatment for esophageal motility disorders including achalasia and its variants. However, some surgeons have encountered challenging cases. This study aimed to develop a risk‐scoring system to predict challenging cases of POEM. Methods: Consecutive patients who underwent POEM between April 2015 and March 2020 at our hospital were included in this single‐center retrospective study. Challenging cases of POEM were defined as patients with any of the following: (i) procedure time ≥90 min; (ii) mucosal perforation; (iii) pneumothorax; and (iv) major bleeding. A risk‐scoring system for predicting challenging cases was developed based on multivariate logistic regression and internal validation was performed using the bootstrap method. Clinical usefulness was evaluated using a decision curve analysis. Results: Of the 467 patients, 59 (12.6%) had challenging POEM. A risk‐scoring system consisted of four variables: duration of symptoms ≥5 years (assigned score, 1 point), antithrombotics use (1 point), manometric diagnosis of achalasia variants (2 points), and dilation grade 3 (2 points). Our scoring system showed satisfactory discrimination (area under the receiver operating characteristic curve, 0.69; 95% confidence interval [CI] 0.61–0.77) and calibration (slope, 0.99; 95% CI 0.65–1.35). The decision curve analysis demonstrated its clinical usefulness. Conclusions: We established a risk‐scoring system to predict challenging cases of POEM. This scoring system may aid the selection of patients who require treatment from experienced surgeons. [ABSTRACT FROM AUTHOR]

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

Background and Aim: Regarding the gut–liver axis, fecal dysbiosis is implicated in the pathogenesis of non‐alcoholic fatty liver disease (NAFLD). The significance of mucosa‐associated microbiota (MAM, which is present in the mucin layer covering the intestinal mucosa) has not been well explored. We aimed to clarify the characteristics of MAM in patients with NAFLD. Methods: MAM were obtained from seven patients with early‐stage NAFLD and seven controls by colonoscopy in five locations (terminal ileum, cecum, ascending and sigmoid colon, and rectum) using mucosal brushes. The microbial 16S rDNA profiles of the MAM and fecal microbiota of patients in the NAFLD and control groups were analyzed. Results: α‐diversities of fecal microbiota were decreased in patients with NAFLD (observed species, Shannon index, and Chao1: 174.57 vs 134.86, 5.51 vs 4.65, and 206.34 vs 167.91; P = 0.048, 0.067, and 0.087, respectively), and microbial composition analyses by principal coordinate analysis differed between the fecal microbiota of patients with NAFLD and those of controls (permutational analysis of variance [PERMANOVA] of weighted and unweighted: Pseud‐F: 1.4179/P‐value: 0.05 and Pseud‐F: 2.1497/P‐value: 0.049, respectively). However, α‐diversities or microbial composition of MAM in most parts of the intestine did not differ significantly between the NAFLD and control groups. Unclassified Rikenellaceae, Oscillospira, Odoribacter, unclassified clostridiales, and Holdemania were decreased in the feces of patients with NAFLD (determined by linear discriminant analysis effect size), but five (except Holdemania) of the six genera were not decreased in the MAM of these patients. Conclusion: In early‐stage NAFLD, MAM was uniform and relatively stable throughout the intestine, even when fecal dysbiosis appeared. [ABSTRACT FROM AUTHOR]

Background and Aim: Pathological evaluation is essential for the diagnosis of biliary tract diseases. However, existing evaluation methods have various challenges in terms of operability and diagnostic performance. The present study aimed to evaluate the feasibility, utility, and safety of a novel device delivery system for bile duct biopsy. Methods: This study was conducted as a retrospective, descriptive analysis at a single center. Overall, 25 examinations in 14 consecutive patients who underwent transpapillary biopsies for biliary lesions using the novel device delivery system from July to November 2020 were reviewed. Number and time of biopsy, technical success rate, adequate tissue sampling rate, adverse events, and diagnostic performance of bile duct biopsies using the novel device were evaluated. Moreover, negative surgical margins were assessed in patients who underwent surgical resection after mapping biopsy. Results: The median number of biopsy samples was five (range: 2–13), with a median biopsy time of 11.6 min. The technical success rate was 100% (140/140), with an adequate sampling rate of 82.9% (116/140). These rates did not differ depending on the biopsy site or purpose. There were no serious adverse events related to the procedures. The diagnostic sensitivity, specificity, and accuracy of biliary stricture were 90%, 100%, and 92.3%, respectively. Negative surgical margins were confirmed in all patients undergoing surgical resection, including one patient with a surgical procedure changed based on the results of mapping biopsy. Conclusions: The novel device delivery system has potentials in diagnosing biliary tract diseases and determining appropriate treatment strategies. [ABSTRACT FROM AUTHOR]

Background and Aim: Post‐endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most serious adverse event of ERCP. Therefore, it is important to identify high‐risk patients who require prophylactic measures. The aim of this study was to develop a practical prediction model for PEP that identifies high‐risk patients. Methods: Patients who underwent ERCP at three tertiary hospitals between April 2010 and September 2012 were enrolled. The dataset was divided into a training set (two centers) and validation set (one center). Using the training set, univariable and multivariable analyses were performed to identify predictive factors for PEP. We constructed a scoring system and evaluated reproducibility using the validation set. Results: A total of 2719 ERCPs were analyzed. PEP developed in 133 cases (4.9%). Risk factors (adjusted odds ratios [OR]) in the training set were a history of PEP (OR: 4.2), intact papilla (OR: 2.4), difficult cannulation (OR: 1.9), pancreatic guidewire‐assisted biliary cannulation (OR: 2.2), pancreatic injection (OR: 2.1), pancreatic intraductal ultrasonography (IDUS)/sampling from the pancreatic duct (OR: 2.2), and biliary IDUS/sampling from the biliary tract (OR: 2.8). A scoring system was constructed using these seven clinical variables. The areas under the receiver‐operating characteristic curve of this model were 0.799 in the training set and 0.791 in the validation set. In the high‐risk group at a score of 3 or higher, the incidence of PEP was 13.4%, and all severe/fatal cases were in the high‐risk group. Conclusions: This scoring system helps to predict each patient's risk and select preventive measures. [ABSTRACT FROM AUTHOR]

Objective: Laparoscopic endoscopic cooperative surgery for duodenal tumors (D‐LECS) has been developed to prevent duodenal leakage by reinforcing the endoscopic submucosal dissection site. However, there has been no prospective trial showing the feasibility of D‐LECS. Herein, we conducted a single‐arm confirmatory trial to evaluate the safety of D‐LECS for non‐ampullary superficial duodenal neoplasms. Methods: This prospective single‐center single‐arm confirmatory trial analyzed patients with non‐ampullary superficial duodenal neoplasms who underwent D‐LECS. The primary endpoint was the incidence of any postoperative leakage occurring on the duodenal wall within 1 month postoperatively. The planned sample size was 20 patients, considering a threshold of 28% and one‐sided alpha value of 5%. Results: Between January 2015 and September 2018, 20 eligible patients were enrolled. Sixteen tumors were located in the second portion, three in the first portion, and one in the third portion of the duodenal region. The median operative time was 225 (134–361) min and the median blood loss was 0 (0–150) mL. Curative resection (R0) with negative margins was achieved in 19 cases. One case of postoperative leakage and one case of bleeding of grade 2 according to the Clavien–Dindo classification were observed in this series. The median duration of postoperative hospital stay was 9 (5–12) days. No local recurrence was observed in any patient during the median follow‐up of 15.0 (12.0–38.0) months. Conclusions: This trial confirmed the safety and feasibility of D‐LECS for non‐ampullary superficial duodenal neoplasms with respect to the low incidence of postoperative duodenal leakage. [ABSTRACT FROM AUTHOR]

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Objectives: This study compared the safety and efficacy of peroral endoscopic myotomy for esophageal motility disorders between octogenarians and non‐octogenarians. Methods: This retrospective observational study recruited 321 patients (28 octogenarians and 293 non‐octogenarians) who underwent peroral endoscopic myotomy from two institutions. Clinical success (postoperative Eckardt score ≤ 3), technical success (completion of gastric and esophageal myotomy), and perioperative adverse events were compared between octogenarians and non‐octogenarians. Perioperative adverse events were classified into major and minor adverse events based on the International Peroral Endoscopic Myotomy Survey criteria and were subdivided into technical and non‐technical adverse events according to the presence of a direct causal relationship with the procedure. Results: There were no significant differences in the rates of clinical success 1 year after treatment (100% vs. 97.3%, P = 0.64) and technical success (100% vs. 99.7%, P = 0.91) between octogenarians and non‐octogenarians. Octogenarians had a higher incidence of perioperative adverse events (28.6% vs. 10.2%, P = 0.00097), particularly major adverse events (25.0% vs. 3.0%, P < 0.0001). There were no significant differences in the incidence of minor adverse events (7.1% vs. 7.9%, P = 0.67). Although there was no difference in the incidence of technical adverse events (10.7% vs. 9.2%, P = 0.74), octogenarians had a significantly higher incidence of non‐technical adverse events (17.9% vs. 1.0%, P = 0.0002). Conclusions: There were no significant differences in short‐term clinical success and technical success between octogenarians and non‐octogenarians. However, octogenarians showed a significantly higher incidence of perioperative adverse events, particularly in major adverse events and non‐technical adverse events. Peroral endoscopic myotomy for octogenarians should be carefully applied. [ABSTRACT FROM AUTHOR]

Background and Aim: Upper gastrointestinal symptoms (UGSs), including reflux and dyspeptic symptoms (postprandial distress syndrome [PDS] and epigastric pain syndrome [EPS]), affect health‐related quality of life. However, the influence of sex on the relationship between body mass index (BMI) and UGSs remains controversial. This study investigates the influence of sex on this association in healthy subjects. Methods and Results: We utilized the database of a prospective, multicenter, cohort study of 7112 subjects who underwent upper endoscopy for health screening. A multivariable logistic regression analysis was conducted to assess the association between BMI and UGSs stratified by sex, adjusting for clinical features. The influence of sex on the association between the overlapping of UGSs and BMI in symptomatic subjects was also investigated. Reflux symptoms were significantly associated with high BMI (multivariable odds ratio [OR] 1.36; 95% confidence interval [CI] 1.10–1.67, P = 0.004). PDS symptoms were significantly associated with low BMI (OR 2.37; 95% CI 1.70–3.25; P < 0.0001), but EPS symptoms were not associated with BMI. The association between reflux symptoms and higher BMI was limited to men (men: OR 1.40; 95% CI 1.10–1.77; P = 0.005, women: P = 0.40). sex did not influence the association between the presence of PDS symptoms and lower BMI. The percentage of overlapping of all three symptoms (reflux, PDS, and EPS) was higher in women than in men (19.9% [58/292] vs 10.5% [49/468], P = 0.0002). Conclusions: The influence of BMI on the presence of UGSs was significantly different according to sex in this large‐scale cohort. [ABSTRACT FROM AUTHOR]

Background and Aim: One of the main concerns related to peroral endoscopic myotomy (POEM) is postoperative gastroesophageal reflux (GER). The two penetrating vessels (TPVs) that are found at the boundary between the circular and oblique muscles in the posterior cardia wall have been suggested to be a good indicator of the optimal distal extent of POEM. However, the effect of performing myotomy using the TPVs as an anatomical reference on the frequency of post‐POEM GER has not been studied. Methods: This study involved consecutive patients who underwent POEM for the treatment of achalasia between April 2015 and June 2017. All enrolled patients underwent POEM in the 5 o'clock position and were divided into two groups: the conventional line group (CL group, n = 31), in which the TPVs were not exposed during submucosal tunnel dissection in the cardia, and the TPVs line group (TPVs group, n = 83), in which the TPVs were exposed and gastric myotomy was performed along the right side of the TPVs to preserve the oblique muscle. Examinations for post‐POEM GER were conducted 3 months after the POEM. Results: The frequency of grade B or higher reflex esophagitis was 26/83 (31.3%) in the TPVs group and 18/31 (58.1%) in the CL group (P = 0.017). Nine of 83 patients (10.8%) had GER symptoms in the TPVs group, and six of 31 (19.4%) had GER symptoms in the CL group (P = 0.23). Conclusions: The novel myotomy method preserving oblique muscle using TPVs as anatomical landmarks significantly reduced the frequency of post‐POEM GER. [ABSTRACT FROM AUTHOR]

Achalasia is a rare benign esophageal motility disease caused by the impaired relaxation of the lower esophageal sphincter, which results from nerve damage. Patients with achalasia are known to have a high risk of esophageal cancer. Here, we present the case of a patient with achalasia and esophageal cancer in whom the Lugol‐voiding areas (LVAs) could be improved by pneumatic dilation and the extending area of esophagus cancer could become clear. In achalasia patients, LVAs are modified by inflammation and appear wider than their actual size. Moreover, some parts of LVAs in achalasia patients might be reversible by treatments that improve delayed emptying. When the spread of esophagus cancer is unclear due to the detection of numerous LVAs by Lugol chromoendoscopy, the treatments that improve delayed emptying first may be effective in accurately diagnosing the extending area of esophagus cancer. [ABSTRACT FROM AUTHOR]

Background and Aim: Cholecystitis is a major complication after self‐expandable metallic stent (SEMS) placement for malignant biliary obstruction. Ischemia is one of the risk factors for cholecystitis, but little is known about the influence of tumor invasion to the feeding artery of the gallbladder on the onset of cholecystitis after SEMS placement. The aim of the present study was to identify risk factors for cholecystitis after SEMS placement. Methods: Incidence and nine predictive factors of cholecystitis were retrospectively evaluated in 107 patients who underwent SEMS placement for unresectable distal malignant biliary obstruction at Kyoto University Hospital and Otsu Red Cross Hospital between January 2012 and June 2016. Results: Cholecystitis occurred in 13 of 107 patients (12.1%) after SEMS placement during the median follow‐up period of 262 days. Univariate analyses showed that tumor invasion to the feeding artery of the gallbladder and tumor involvement to the orifice of the cystic duct were significant predictors of cholecystitis (P = 0.001 and P < 0.001). Multivariate analysis confirmed that these two factors were significant and independent risks for cholecystitis with odds ratios of 22.13 (95% CI, 3.57–137.18; P = 0.001) and 25.26 (95% CI, 4.12–154.98; P < 0.001), respectively. Conclusions: This study showed for the first time that tumor invasion to the feeding artery of the gallbladder as well as tumor involvement to the orifice of the cystic duct are independent risk factors for cholecystitis after SEMS placement. [ABSTRACT FROM AUTHOR]

Background Few studies to date have investigated the antioxidant nutrients such as vitamin C (ascorbic acid), vitamin E (α-tocopherol), retinol and carotenoids in plasma from patients with pulmonary disease in Japan. To clarify the role of antioxidant nutrients such as vitamin C, vitamin E, retinol and various carotenoids in plasma of Japanese patients with chronic obstructive lung diseases (COPD), asthma-COPD overlap syndrome (ACOS) and/or bronchial asthma (BA), we compared to healthy elderly controls. Methods Ascorbic acid (AA), carotenoids (lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene and lycopene), retinol and α-tocopherol levels in plasma were determined by using a high performance liquid chromatography. Reduced glutathione (GSH), oxidised glutathione (GSSG) in whole blood and urinary 8-OHdG were also determined. Results Plasma AA level of COPD subjects was significantly lower than that of healthy elderly people. Conversely, ACOS and BA subjects showed no significant difference from healthy elderly people. Moreover, plasma lycopene and total carotenoid levels and GSH content in blood were significantly lower in COPD subjects than these in healthy elderly people. However, other redox markers such as GSSG, GSH/GSSG ratio and urinary 8-OHdG found no significant differences between COPD, ACOS and BA compared to healthy elderly people. Conclusions These results suggested that COPD of Japanese patients may develop partly because of oxidative stress derived from a shortage of antioxidant nutrients, especially of AA and lycopene, as well as GSH while this may not be the case in both ACOS and BA. [ABSTRACT FROM AUTHOR]

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Several previous studies reported that the neutrophil-to-lymphocyte ratio ( NLR) could be a promising prognostic factor for patients with cancer. We aimed to determine the prognostic value of NLR in patients with advanced pancreatic cancer ( APC) following palliative chemotherapy. We retrospectively reviewed 252 consecutive APC patients receiving palliative chemotherapy between January 2006 and December 2012. We classified the patients according to the pretreatment NLR values (≤5 or >5) into two groups and investigated the difference in treatment outcomes, including time to treatment failure ( TTF) and overall survival ( OS). A total of 212 patients had pretreatment NLR values of ≤5 (group A), while 40 patients had an NLR of >5 (group B). TTF and OS were significantly shorter in group B than in group A (3.1 vs. 8.7 months and 6.0 vs. 12.8 months, respectively; both P < 0.01). After adjustment for putative prognostic factors, including distant metastasis, status of recurrent/unresectable disease, pretreatment carbohydrate antigen 19-9 levels, and carcinoembryonic antigen levels using the Cox regression model, elevated pretreatment NLR remained an independent poor prognostic factor for OS (hazard ratio, 1.92; 95% confidence interval, 1.27-2.90; P < 0.01). In addition, patients in group B whose NLR dropped to ≤5 before the second cycle of chemotherapy showed longer TTF and OS compared with those whose NLR remained at >5. Our results support the idea that NLR can be a promising prognostic and predictive marker for APC patients receiving palliative chemotherapy. [ABSTRACT FROM AUTHOR]

Objective IgG4-related disease is a recently recognized entity affecting multiple organs, including the pancreas, biliary tracts, and salivary glands. Although IgG4-related disease is characterized by systemic IgG4 antibody responses and by infiltration of IgG4-expressing plasma cells, the innate immune responses leading to adaptive IgG4 antibody responses are poorly understood. The aim of this study was to clarify the innate immune responses leading to IgG4 antibody production. Methods IgG4 and cytokine responses to various nucleotide-binding oligomerization domain (NOD)-like receptor (NLR) and Toll-like receptor (TLR) ligands were examined using peripheral blood mononuclear cells (PBMCs) from healthy control subjects and patients with IgG4-related autoimmune pancreatitis. Results Activation of NOD-2 in monocytes from healthy control subjects induced IgG4 production by B cells in a BAFF-dependent and T cell-independent manner. In addition, PBMCs from patients with IgG4-related disease produced a large amount of IgG4 upon stimulation with NLR and TLR ligands; this enhanced IgG4 production was associated with the induction of BAFF by NLR and TLR ligands. Monocytes from patients with IgG4-related disease induced IgG4 production by B cells from healthy control subjects upon stimulation with NLR and TLR ligands. Conclusion The results of these studies suggest that abnormal innate immune responses against microbial antigens may underlie the immunopathogenesis of IgG4-related disease. [ABSTRACT FROM AUTHOR]

Non-alcoholic steatohepatitis (NASH) represents the progression of hepatic steatosis to streatohepatitis, fibrosis and cirrhosis. Three signaling pathways have been associated with this progression; Toll-like receptors, reactive oxygen species and Jun N-terminal kinase. This review will describe how activation of these three pathways is required for development of fibrosis in murine models of NASH. The three pathways are related and synergistic through intracellular cross-talk. Disruption of any of these pathways may inhibit NASH-induced fibrosis and are potential targets for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Acid sphingomyelinase (ASM) regulates the homeostasis of sphingolipids, including ceramides and sphingosine-1-phosphate (S1P). Because sphingolipids regulate AKT activation, we investigated the role of ASM in hepatic glucose and lipid metabolism. Initially, we overexpressed ASM in the livers of wild-type and diabetic db/db mice by adenovirus vector (Ad5ASM). In these mice, glucose tolerance was improved, and glycogen and lipid accumulation in the liver were increased. Using primary cultured hepatocytes, we confirmed that ASM increased glucose uptake, glycogen deposition, and lipid accumulation through activation of AKT and glycogen synthase kinase-3β. In addition, ASM induced up-regulation of glucose transporter 2 accompanied by suppression of AMP-activated protein kinase (AMPK) phosphorylation. Loss of sphingosine kinase-1 (SphK1) diminished ASM-mediated AKT phosphorylation, but exogenous S1P induced AKT activation in hepatocytes. In contrast, SphK1 deficiency did not affect AMPK activation. These results suggest that the SphK/S1P pathway is required for ASM-mediated AKT activation but not for AMPK inactivation. Finally, we found that treatment with high-dose glucose increased glycogen deposition and lipid/ accumulation in wild-type hepatocytes but not in ASM-/- cells. This result is consistent with glucose intolerance in/ ASM-/- mice. In conclusion, ASM modulates AKT activation and AMPK inactivation, thus regulating glucose and lipid metabolism in the liver. [ABSTRACT FROM AUTHOR]

RUNX3 is a candidate tumor suppressor gene localized in 1p36, a region frequently inactivated through hypermethylation, histone modulation, and other processes in various human tumors. In this study, to elucidate a causal link between RUNX3 expression and biliary tract cancer, we investigated 17 human biliary cancer specimens. In addition, to examine roles of RUNX3 in biliary tract cancer, we restored silenced RUNX3 in the human biliary cancer cell line Mz-ChA-2 using a histone deacetylase inhibitor. Thirteen of 17 human cancer specimens exhibited suppressed RUNX3 expression compared with normal biliary ducts. Moreover, the decreased RUNX3 expression was related to a lower accumulation of acetylated histone H3 associated with RUNX3. In in vitro experiments, vorinostat, a member of a new class of highly potent histone deacetylase inhibitors, restored RUNX3 expression in Mz-ChA-2 cells. Furthermore, vorinostat-induced RUNX3 significantly enhanced p21 expression and growth inhibition of Mz-ChA-2 cells through restoration of TGF-β signaling. These data suggest the significance of histone deacetylation-associated suppression of RUNX3 expression in biliary tract carcinogenesis. Furthermore, vorinostat might hold promise for treating biliary tract cancer through enhancement of TGF-β signaling by restoration of RUNX3. ( Cancer Sci 2011; 102: 776-783) [ABSTRACT FROM AUTHOR]

After the release of the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines in 2001 and update in 2003, its implementation in nine Asian countries was investigated. Questionnaire surveys involving thoraco-pulmonary physicians or internists investigated the awareness and consensus of the GOLD guidelines including the care and management of chronic obstructive pulmonary disease (COPD) patients in Asian. Two surveys were conducted, in June 2002 and March 2004, through questionnaires by direct mail in Japan and face-to-face interviews in the other countries. Approximately 600 questionnaires were returned with approximately 84% awareness of the publication and its update and nearly 90% appreciated the globalization efforts. The survey revealed great variances concerning the definition of COPD, its diagnosis, and use of computed tomography. As for the implementation, the majority answered the use of the combined local and GOLD guidelines in five of nine countries surveyed, while the GOLD guidelines were implemented mainly in Korea, suggesting the influence in daily practice for care and management of COPD patients. Implication of rehabilitation in clinical practice has not been standardized despite high evidence of its advantages. Most respondents stated the necessity of developing a local or regional guideline for best practice. Our survey revealed: (i) awareness of the GOLD guidelines was high and well accepted; (ii) the possibility of developing a uniform or standard guideline in Asia is low due to local characteristics; (iii) modifications of the GOLD guidelines may be more practical; and (iv) that the multidisciplinary pulmonary rehabilitation program needs to be further activated in GOLD implementation for the Asia–Pacific region. [ABSTRACT FROM AUTHOR]

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Collagen production by activated hepatic stellate cells (HSCs) is a key event in liver fibrosis, and a number of factors have been characterized that trigger HSC activation and collagen production. However, it remains unclear if these factors act locally at the site of injury or also affect HSCs distant to the site of injury. Methods: A model of partial bile duct ligation (PBDL) in which fibrogenesis can be compared between the injured ligated lobe and the non-ligated lobe. Results: After PBDL, HSCs showed an increased expression of procollagen type I α1 mRNA and collagen-reporter gene activity not only in the ligated lobe, but also in the non-ligated lobe, albeit at a lower level. In contrast, an increase in the number of desmin- and α-smooth muscle actin positive HSCs, and accumulation of inflammatory cells were observed only in the ligated lobe. Although transforming growth factor-β (TGF-β) mRNA was increased only in the ligated lobe, Smad2/3 were activated in the ligated and the non-ligated lobe. These data suggest that the systemic increase in profibrogenic mediators including TGF-β induces collagen transcription in the uninjured liver. Conclusion: Systemic profibrogenic mediators from the injury site affect the residual non-injured liver. [ABSTRACT FROM AUTHOR]

Objective: In clinical trials or experiments of gene therapy, airway administration of an adenoviral-based vector (E1A-deleted) elicits a dose-dependent inflammatory response with limitation in the duration of transgene expression. The purpose of this study was to evaluate the possibility that the adenoviral-based vector directly enhances IL-8 production independent of adenoviral E1A in normal human airway epithelial cells and to examine the different responses between primary human bronchial epithelial cells (HBE) and primary human small airway epithelial cells (HSAE) in production of IL-8 following exposure to an adenovirus vector. Methodology: Interleukin (IL)-8 levels were evaluated in the culture medium from HBE and HSAE treated with increasing doses of E1A-deleted adenoviral vector contained the Escherichia coli LacZ reporter gene (AdCMVLacZ). To clarify the mechanism of enhancing IL-8 production in airway epithelial cells by infection with adenovirus vector, αvβ5 agonistic antibody as an analogue of adenoviral capsid and adenoviral capsid vector denatured by exposure to ultraviolet (UV) light were used in the present study. Results: Inoculation of HBE with AdCMVLacZ at a multiplicity of infection (MOI) of between 1 and 200 resulted in a dose-dependent expression of LacZ, and maximal expression was observed at a MOI of 100. In contrast, inoculation of HSAE with AdCMVLacZ resulted in maximum expression of LacZ at a MOI of 10. Interleukin-8 levels in culture media from the same experiments revealed significantly greater production of IL-8 in HSAE inoculated with AdCMVLacZ at a MOI of 50, compared to HBE under the same conditions. The capsid-denatured adenoviral vector did not enhance IL-8 production, and αvβ5 agonistic antibody induced IL-8 enhancement. Conclusion: These results suggest that the adenoviral vector directly induces the expression of airway epithelial inflammatory cytokines in the pathogenesis of inflammation and that small... [ABSTRACT FROM AUTHOR]

Objective: The purpose of this study is to clarify the existing issues on the clinical diversity, natural history, and mode of disease progression of pulmonary lymphangioleiomyomatosis (LAM). Methodology: Eleven patients with LAM were reviewed retrospectively with special reference to serial changes in pulmonary function and radiological findings during the course of their disease, treatment, and outcome. All patients were female with a mean age of 33.8 years at presentation and the observation period ranged from 2.1 to 20.8 years (mean 7.4 years). Results: Four of six patients, treated with anti-hormone therapy, presented with exertional dyspnoea, marked airflow limitation (forced expiratory volume in 1 s/forced vital capacity, 23–38%), and severely impaired diffusing capacity (%DLCO, 21.4–36% of the predicted). The remaining two patients showed only a decreased diffusing capacity (70.6% and 59.4% of the predicted) which rapidly deteriorated with subsequent development of airflow limitation. Repeated chest computed tomographic (CT) examinations revealed increasing numbers of cysts with simultaneous loss of normal lung parenchyma in these two patients. In contrast, the five patients who received no anti-hormone therapy had no respiratory symptoms aside from pneumothorax at onset. Remarkable differences were noted, with pulmonary function being well maintained and slow progression of cystic changes on CT being observed in the latter group. Conclusions: Diverse clinical courses observed in patients with pulmonary LAM can be well delineated and assessed by periodic examinations including pulmonary function tests and chest CT imaging. Anti-hormone therapy is not always necessary for a certain group of LAM patients and they appear to have a stable course and favourable outcomes without anti-hormone treatment. [ABSTRACT FROM AUTHOR]

Objectives Methods Results Conclusion Early identification of patients needing hospital‐specific interventional care (HIC) following endoscopic treatment is valuable for optimizing postoperative hospital stays. We aimed to develop and validate a risk‐scoring system for predicting HIC in patients who underwent peroral endoscopic myotomy (POEM).This study included patients with esophageal motility disorders who underwent POEM at our hospital between April 2015 and March 2023. HIC was defined as any of the following situations: fasting for gastrointestinal rest to manage adverse events (AEs); intravenous administration of medications such as antibiotics and blood transfusion; endoscopic, radiologic, and surgical interventions; intensive care unit management; or other life‐threatening events. A risk‐scoring system for predicting HIC after postoperative day (POD) 1 was developed using multivariable logistic regression and was internally validated using bootstrapping and decision curve analysis.Of the 589 patients, 50 (8.5%) experienced HIC after POD1. Risk scores were assigned for four factors as follows: age (0 points for <70 years, 1 point for 70–79 years, 2 points for ≥80 years), preoperative prognostic nutritional index (0 points for >45, 1 point for 40–45, 4 points for <40), postoperative surgical site AEs on second‐look endoscopy (7 points), and postoperative pneumonia on chest radiography (6 points). The discriminative ability (concordance statistics, 0.85; 95% confidence interval, 0.78–0.91) and calibration (slope 1.00; 0.74–1.28) were satisfactory. The decision curve analysis demonstrated its clinical usefulness.This risk‐scoring system can predict the HIC after POD1 and provide useful information for determining discharge. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 38-year-old man who underwent subtotal gastrectomy for gastric cancer and later developed obstructive jaundice. It discusses the effectiveness of a novel approach for successful endoscopic ultrasoundguided hepaticogastrostomy using a double-guidewire technique.

The article presents a case study of a 63-year-old man with a history of alcoholic pancreatitis presented to our hospital with dyspnea. It discusses the Chest X-ray showed pleural effusion and magnetic resonance cholangiopancreatography showed that the pancreatic pleural effusion connected with a pancreatic pseudocyst through the mediastinum. It mentions the endoscopic nasopancreatic drainage reduced pancreatic duct leakage and the esophagobronchial fistula.