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Background Functional dyspepsia (FD) is a disorder that presents with chronic dyspepsia, which is not only very common but also highly affects quality of life of the patients. In Japan, FD became a disease name for national insurance in 2013, and has been gradually recognized, though still not satisfactory. Following the revision policy of Japanese Society of Gastroenterology (JSGE), the first version of FD guideline was revised this time. Method Like previously, the guideline was created by the GRADE (grading of recommendations assessment, development and evaluation) system, but this time, the questions were classified to background questions (BQs, 24 already clarified issues), future research questions (FRQs, 9 issues cannot be addressed with insufficient evidence), and 7 clinical questions that are mainly associated with treatment. Results and Conclusion These revised guidelines have two major features. The first is the new position of endoscopy in the flow of FD diagnosis. While endoscopy was required to all cases for diagnosis of FD, the revised guidelines specify the necessity of endoscopy only in cases where organic disease is suspected. The second feature is that the drug treatment options have been changed to reflect the latest evidence. The first-line treatment includes gastric acid-secretion inhibitors, acetylcholinesterase (AChE) inhibitors (acotiamide, a prokinetic agent), and Japanese herbal medicine (rikkunshito). The second-line treatment includes anxiolytics /antidepressant, prokinetics other than acotiamide (dopamine receptor antagonists, 5-HT4 receptor agonists), and Japanese herbal medicines other than rikkunshito. The patients not responding to these treatment regimens are regarded as refractory FD.

A new automated diagnostic program for high-resolution esophageal manometry (HREM) has been developed. This diagnostic program could detect locations of landmarks and could make final diagnoses automatically. However, the accuracy of the program is not known. The aim of this study was to evaluate the accuracy of the automated diagnostic program for HREM. A total of 445 studies were enrolled. An HREM system (Starlet®) was used, and esophageal motility was diagnosed using the Chicago classification v3.0. First, the locations of the upper esophageal sphincter, transition zone, lower esophageal sphincter, esophago-gastric junction, crural diaphragm and stomach were determined, and each swallow was checked manually. Then, the parameters of the Chicago classification were calculated using an analytic program of the Starlet, and diagnoses were made by three experts. Second, all study raw data were analyzed again by the automated diagnostic program. Diagnoses made by the program were compared to those made by experts to evaluate the accuracy of the diagnoses. The new diagnostic program could identify the landmarks of each swallow, calculate the parameters and make a final diagnosis within 10 s. The diagnoses made by the automated diagnostic program were not matched to those made by experts in only 10 studies, and the overall accuracy of the new automated diagnostic program thus reached 97.8% (435/445). The new automated diagnostic program for HREM is clinically useful in terms of high diagnostic accuracy and time-saving.

Background/aimsFunctional dyspepsia (FD) is often comorbid with sleep disturbance. However, it is not fully understood how sleep disturbance affects the pathophysiology of FD. We aimed to investigate the relationship between FD and sleep disturbance.MethodsWe prospectively enrolled 20 FD patients with sleep disturbance between December 2018 and July 2019. Patients took sleep aids for 4 weeks and filled out questionnaires before and after taking sleep aids. Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), and Athens Insomnia Scale (AIS) were used to evaluate the severity of their sleep disturbance. Modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (mFSSG), Gastrointestinal Symptom Rating Scale (GSRS), and the Japanese version of Patient Assessment of Constipation Quality of Life (JPAC-QOL) were used to evaluate the severity of GI symptoms. Short-Form 36-Item Health Survey (SF-36) was used to evaluate QOL. Pre- and post-sleep medication values of questionnaires were compared.ResultsAmong 20 enrolled patients, 16 completed the study protocol. Zolpidem, eszopiclone, and suvorexant were administered to six, nine, and one patient, respectively. Each median total score of questionnaires (pre-/post-sleep medication, respectively) was as follows: PSQI, 10.0/8.5; ESS, 12.5/5.0; AIS, 10.0/4.0; mFSSG, 21.0/16.0; GSRS, 44.0/31.0 (Pain in GSRS, 11.0/5.0); JPAC-QOL, 26.0/15.5; SF-36, 63.9/71.9. All of these results showed statistically significant differences between pre- and post-sleep medication (p ConclusionsImprovement of sleep disturbance by administration of sleep aids resulted in improvement of GI symptoms and QOL in patients with FD. This effect may be related to pain modification.

Purpose of the guidelines The primary objective of these guidelines is to provide general clinicians with information that would guide them to make informed choices of the available diagnosis/treatment strategies for esophageal cancer (intended for malignant esophageal tumors of epithelial origin, not for any other non-epithelial malignant tumors of the esophagus or metastatic esophageal malignant tumors). Furthermore, these guidelines are also intended as an aid for healthcare professionals other than the physicians, patients, and patients’ family members, to obtain an understanding of the fundamental principles of the diagnosis and treatment of esophageal cancer. These guidelines are intended to allow physicians to undertake diagnosis and treatment of esophageal cancer by sharing the information contained in the guidelines and promote mutual understanding among the healthcare professionals, patients, and their family members.

We herein report a unique case of hepatitis C virus (HCV)-associated renal disease without cryoglobulinemia that showed proteinuria, hypoproteinemia, ascites, and edema. Due to combination therapy with daclatasvir and asunaprevir, the patient achieved sustained virological response at week 24 of the therapy. Furthermore, the therapy caused marked amelioration of her proteinuria, ascites, edema, and hypoalbuminemia, and finally improved her estimated glomerular filtration rate. There were no adverse events, and the combination therapy was well-tolerated. We recommend that HCV eradication with antiviral therapy using direct-acting antiviral agents be attempted first for all renal disease with HCV infection, regardless of cryoglobulinemia, considering the existence of resistance-associated variants.

Background The metabolism of many proton pump inhibitors is influenced by CYP2C19 genotype, which is a limitation of their use. Objectives To determine the efficacy and safety profile of Z-215 (azeloprazole sodium) as initial treatment for reflux esophagitis (RE), dose response, and optimal dose compared with rabeprazole sodium (RPZ). Methods We conducted an exploratory, multicenter, randomized, double-blind, parallel-group study in Japan. Patients with RE aged ≥20 years were enrolled and randomly assigned to receive 10, 20, or 40 mg Z-215 or 10 mg RPZ (1:1:1:1), and orally administered the respective drug for 8 weeks. The primary efficacy end point was the endoscopic healing rate after 8 weeks of treatment (at Week 8). We also assessed the effects of CYP2C19 genotype. Safety end points were the incidence of adverse events and adverse drug reactions. Results Five hundred three patients received the study drugs (10 mg Z-215: 125 patients, 20 mg Z-215: 126 patients, 40 mg Z-215: 126 patients, and 10 mg RPZ: 126 patients). The endoscopic healing rate at Week 8 was above 95% in all groups (10 mg Z-215: 95.2%, 20 mg Z-215: 96.8%, 40 mg Z-215: 95.2%, and 10 mg RPZ: 96.8%). The endoscopic healing rate and serum gastrin levels of the Z-215 groups were not influenced by CYP2C19 genotype. In patients with Grade C/D, the endoscopic healing rate at Week 4 was slightly higher in the 40-mg Z-215 group compared with the other groups. Incidences of adverse events/adverse drug reactions did not markedly differ between the Z-215 and 10-mg RPZ groups. Conclusions Z-215 was as effective and well tolerated as 10 mg RPZ in the treatment of RE in this selected population. CYP2C19 genotype status may not influence the efficacy and safety of Z-215. There were no clear dose–response effects between Z-215 doses in the endoscopic healing of RE. These findings suggest that Z-215 may be 1 option for the initial treatment of RE. ClinicalTrials.gov identifier: NCT 02463643.

Background The aim of this study was to evaluate the differences in upper gastrointestinal symptoms between generations and genders in relatively healthy Japanese subjects. Methods Altogether, 4086 healthy Japanese male and female (M/F) adults (M/F: 2244/1842) were analyzed. Among them, 3505 subjects (M/F: 1922/1583) were underwent a routine medical checkup at one of five hospitals in Saga, Japan from January 2013 to December 2013. The others were 581 (M/F: 322/259) healthy young volunteers at the Saga Medical School from April 2007 to March 2013. The participants were asked to complete the frequency scale for the symptoms of gastroesophageal reflex disease (FSSG) questionnaire, undergo upper gastrointestinal endoscopy, and submit to a rapid urease test to diagnose Helicobacter pylori infection. Among the 4086 subjects, the 2414 who had no H. pylori infection and no positive endoscopic findings were enrolled in the study. Results Subjects’ average age was 46.9 ± 12.2 years, with males’ and females’ ages being almost equivalent. The total FSSG score were high in females compared to males (P

Background Rabeprazole at 10 or 20 mg twice daily (b.i.d.) has been reported to be highly effective in the treatment of proton pump inhibitor (PPI)-resistant reflux esophagitis (RE) that is refractory to the standard once-daily PPI regimen. We evaluated the efficacy and safety of rabeprazole maintenance therapy at 10 mg once daily (q.d.) or b.i.d. for longer than 8 weeks. Methods Patients with RE refractory to standard PPI regimens for at least 8 weeks were enrolled. They were treated with rabeprazole at 10 or 20 mg b.i.d. for 8 weeks during the open-label treatment period. After endoscopic examination, those with confirmed healing entered the subsequent double-blind maintenance therapy. During this period, the subjects were randomized to receive rabeprazole 10 mg q.d. (control) or 10 mg b.i.d. The primary endpoint was the endoscopic no-recurrence rate at Week 52. Results In total, 517 subjects entered the treatment, and 359 subjects continued on maintenance therapy. The full analysis set for central assessment included 343 subjects. The no-recurrence rate at Week 52 was significantly higher in the b.i.d. group (73.9%; p 2 test) than in the q.d. group (44.8%). In particular, the b.i.d. regimen was more effective in all subgroups with Los Angeles Classification Grade B to D at treatment entry. Conclusions In the maintenance treatment of PPI-resistant RE, rabeprazole at 10 mg b.i.d. exerted a stronger recurrence-preventing effect than 10 mg q.d. over 52 weeks. No particular safety issues were noted during long-term administration. ClinicalTrials.gov number: NCT02135107.

Smoking cigarettes and drinking alcoholic beverages are considered very important risk factors for adverse health effects, such as many types of cancer and cardiovascular disease. In this study, we evaluated the influence of smoking and drinking cessation on risk of esophageal cancer, by means of meta-analysis. We extracted 205 studies by conducting a systematic literature search. Thirty-five studies that estimated risk reduction following smoking cessation and 18 studies conducted following drinking cessation were identified in the literature review. Former smokers had a significantly lower summary risk ratio (RR) than current smokers [RR 0.74, 95% confidence interval (CI) 0.68–0.80]. In subgroup analysis of Japanese smokers, squamous cell carcinoma, and adenocarcinoma, RRs for former smokers versus current smokers were 0.65 (95% CI 0.51–0.83), 0.60 (95% CI 0.50–0.72), and 0.93 (95% CI 0.84–1.03), respectively. The summary RR between former alcohol drinkers and current drinkers was not significant (RR 1.09, 95% CI 0.94–1.26). In our analysis of time since drinking cessation, drinkers who had stopped consuming alcohol for 5 years or more had a significantly lower summary RR than current drinkers (RR 0.78, 95% CI 0.66–0.93). Summary RR for drinkers who stopped for 10 years or more versus current drinkers was 0.65 (95% CI 0.57–0.74). Our investigation found that smoking cessation lowers esophageal cancer incidence. We also found that esophageal cancer incidence risk could be decreased in current drinkers by cessation of alcohol consumption for 5 years or more.

The administration of direct-acting antiviral agents (DAAs) to treat hepatitis C virus (HCV) infection has been reported to cause hepatitis B virus (HBV) reactivation. However, the actual conditions of HBV reactivation and the ideal timing of medical intervention have not been fully evaluated. We report the cases of two female patients dually infected with HBV and HCV. Both patients were inactive HBV carriers. Although the serum HCV RNA levels promptly decreased after the initiation of DAA-based therapy, the serum HBV DNA levels gradually increased during DAA-based therapy, with the peak serum HBV DNA levels observed at 16 weeks after the initiation of DAA-based therapy in both cases. Subsequently, we checked the serum HBV DNA levels closely every week several times. Fortunately, the serum HBV DNA levels gradually decreased without medical intervention. Neither case developed an alanine aminotransferase flare-up. The HCV genotypes were 2a and 1b, and the DAA-based therapies of Cases 1 and 2 were 12 weeks of sofosbuvir/ribavirin and ombitasvir/paritaprevir/ritonavir, respectively. The significance of our case reports is the demonstration of the existence of spontaneous remission of HBV reactivation that developed during DAA-based therapy, the avoidance of intervention of nucleot(s)ide analogs by frequent monitoring of serum HBV DNA levels, and development of HBV reactivation regardless of the viral genotype or class of DAA. In conclusion, the close monitoring of serum HBV DNA levels during and after DAA-based therapy is essential and medical intervention for HBV reactivation should be carefully considered on an individual basis.

This study aimed to evaluate the influence of Helicobacter pylori infection and its eradication on the upper gastrointestinal symptoms of relatively healthy Japanese subjects. A total of 3,005 subjects (male/female: 1,549/1,456) undergoing medical health checkups were enrolled in the present study, at five hospitals in Saga, Japan, from January to December 2013. They had no significant findings following upper gastrointestinal endoscopy. All subjects completed a questionnaire that addressed a frequency scale for symptoms of gastroesophageal reflux disease. The questionnaire comprised seven questions regarding reflux symptoms and seven regarding acid-related dyspepsia, which were answered with a score based on the frequency of symptoms. Helicobacter pylori infection was identified by a rapid urease test and/or H. pylori antibody titer, and an eradication history was confirmed by the subjects’ medical records. Helicobacter pylori infection was positive in 894 subjects out of 3,005 (29.8%). Eradication of Helicobacter pylori was successfully achieved in 440 subjects of 458 treated. Helicobacter pylori infection had no influence on the acid-related dyspepsia evaluated by the questionnaire, whereas the mean reflux score was relatively high in the Helicobacter pylori native negative subjects compared to Helicobacter pylori native positive. Eradication of Helicobacter pylori and time span after the eradication had no effect on the upper gastrointestinal symptoms evaluated by the questionnaire. Helicobacter pylori infection and history of eradication did not affect acid-related dyspepsia symptoms in Japanese healthy subjects.

We previously reported that cascade stomach was associated with reflux symptoms and esophagitis. Delayed gastric emptying has been believed to initiate transient lower esophageal sphincter relaxation (TLESR). We hypothesized that cascade stomach may be associated with frequent TLESR with delayed gastric emptying. Eleven subjects with cascade stomach and 11 subjects without cascade stomach were enrolled. Postprandial gastroesophageal manometry and gastric emptying using a continuous 13C breath system were measured simultaneously after a liquid test meal. TLESR events were counted in early period (0–60 min), late period (60–120 min), and total monitoring period. Three parameters of gastric emptying were calculated: the half emptying time, lag time, and gastric emptying coefficient. The median frequency of TLESR events in the cascade stomach and non-cascade stomach groups was 6.0 (median), 4.6 (interquartile range) vs 5.0, 3.0 in the early period, 5.0, 3.2 vs 3.0, 1.8 in the late period, and 10.0, 6.2 vs 8.0, 5.0 in the total monitoring period. TLESR events were significantly more frequent in the cascade stomach group during the late and total monitoring periods. In contrast, gastric emptying parameters showed no significant differences between the two groups. We concluded that TLESR events were significantly more frequent in persons with cascade stomach without delayed gastric emptying.

A 44-year-old woman with multiple sclerosis (MS) receiving interferon (IFN)-beta-1a treatment was admitted to a local hospital for severe icterus and liver injury. She was transferred to our university hospital because fulminant hepatitis (FH) was suspected. She was diagnosed with acute-type FH based on hepatic coma, severe liver injury and liver failure, and she received plasma exchange and continuous hemodiafiltration therapy. On hospital day 6, she died from liver failure despite intensive care. An autopsy revealed histological findings consistent with FH. Physicians should monitor the hepatic function of MS patients receiving IFN-beta-1a treatment, as serious events can occur in rare cases.

Background/Aims Twenty-four-hour esophageal impedance and pH monitoring allows detection of all types of reflux episodes and is considered the best technique for identifying gastroesophageal refluxes. However, normative data for the Japanese population are lacking. This multicenter study aimed to establish the normal range of 24-hour esophageal impedance and pH data both in the distal and the proximal esophagus in Japanese subjects. Methods Forty-two healthy volunteers (25 men and 17 women) with a mean ± standard deviation age of 33.3 ± 12.4 years (range: 22-72 years) underwent a combined 24-hour esophageal impedance and pH monitoring. According to the physical and pH properties, distal or proximal esophageal reflux events were categorized. Results Median 45 reflux events occurred in 24 hours, and the 95th percentile was 85 events. Unlike previous reports, liquid-containing reflux events are median 25/24 hours with the 95th percentile of 62/24 hours. Acidic reflux events were median 11/24 hours with the 95th percentile of 39/24 hours. Non-acidic gas reflux events were median 15/24 hours with the 95th percentile of 39/24 hours. Proximal reflux events accounted for 80% of the total reflux events and were mainly non-acidic gas refluxes. About 19% of liquid and mixed refluxes reached the proximal esophagus. Conclusions Unlike previous studies, liquid-containing and acidic reflux events may be less frequent in the Japanese population. Non-acidic gas reflux events may be frequent and a cause of frequent proximal reflux events. This study provides important normative data for 24-hour impedance and pH monitoring in both the distal and the proximal esophagus in the Japanese population.

Background Vonoprazan (V), a potassium-competitive acid blocker, has a more durable acid-inhibitory effect as compared with standard-dose proton pump inhibitors (PPIs) but has not been compared with 2-4 times higher daily PPI doses administered in two divided doses. Aims To evaluate the acid-inhibitory effect of V 10/20 mg once-daily (OD; V10/V20) vs rabeprazole (R) 10/20 mg twice-daily (BID; R20/R40) in healthy Japanese volunteers. Methods This multicentre, randomised, open-label, two-period, crossover study compared V10 or V20 vs R20, or V20 vs R40 using three cohorts of 10 healthy Japanese adults. Within each cohort, subjects were randomised to receive V or R for 7 days and, following a washout period ≥7 days, the other treatment for 7 days. On day 6 of each period, 24-hours multichannel gastric impedance-pH monitoring was performed. Percent times pH ≥ 3, ≥4 and ≥5 (pH 3, 4 and 5 holding time ratios [HTRs]) in 24 hours were evaluated as primary pharmacodynamic endpoints. Results Acid-inhibitory effect (24-hours pH 3 HTR) of V20 was greater than those of R20 (91.0% vs 65.3%; P = .0049) and R40 (98.5% vs 85.9%; P = .0073). Similar results were obtained for 24-hours pH 4 and 5 HTRs. V20 also achieved greater nocturnal pH 4 (91.5% vs 73.2%; P = .0319) and 5 HTRs (78.8% vs 62.2%; P = .0325) as compared with R40. One subject (20%) developed diarrhoea while receiving R40 which was considered treatment-related. Conclusions Compared with 2-4 times the standard daily dose of R, V20 exerts a more potent and durable acid-inhibitory effect. Trial identifier: UMIN000022198 (www.umin.ac.jp/ctr/index.htm).

The values of the parameters in the Chicago classification measured by a high-resolution manometry (HRM) system with the Unisensor catheter (Starlet) are significantly different from those measured by the ManoScan. The contraction vigor is categorized by values of the distal contractile integral (DCI) in the Chicago classification v3.0; however, reference values of the DCI in the Starlet and the clinical impact of the different reference values in the Starlet and ManoScan on diagnosing esophageal motility disorders are not known. We evaluated data from a previous report in which ManoScan and Starlet were compared in the same subjects. The DCI values in each system were compared and reference DCI values were calculated. Moreover, diagnoses assessed by Starlet using reference values in ManoScan were compared with those using calculated reference values and those assessed by ManoScan. There was a significant positive correlation between the DCI values measured by ManoScan and those measured by Starlet (r = 0.80, p

Monitoring of esophageal impedance is a technique for determining the physical characteris- tics (liquid, gas, or mixed) of refluxate, while impedance monitoring combined with pH recording makes it possible to assess the acidity of reflux(acid or non-acid). Assessment is usually performed by the total acid exposure time (%time pH4) and symptom-reflux asso- ciations including acidic and non-acidic reflux. This monitoring is quite useful for evaluation of proton pump inhibitor-resistant gastroesophageal reflux disease or non-erosive reflux disease. When normal acid exposure time and significant symptom-reflux associations are observed, a patient should be diagnosed as having hypersensitive esophagus. When normal acid exposure time and no significant symptom-reflux associations are observed, a patient should be diagnosed as having functional heartburn. Therefore, the result makes it possible to decide treatment strategy.

Background/Aim: We evaluated the efficacy of vonoprazan (VPZ), a novel potassium-competitive acid blocker, in patients with proton pump inhibitor (PPI)-refractory gastroesophageal reflux disease (GERD), exhibiting continued pathological esophageal acid exposure (EAE). Methods: Despite ≥8 weeks of appropriate PPI therapy, patients with ­persistent reflux symptoms and pathological EAE times (EAETs ≥4%) were invited to switch to VPZ treatment. After an 8-week-course of once-daily VPZ (20 mg), multichannel intraluminal impedance-pH (MII-pH) monitoring was repeated to compare gastric acid exposure times (GAETs), EAETs, and other reflux parameters relative to the baseline values. Before each MII-pH study, reflux symptom severities were scored using the Gastrointestinal Symptom Rating Scale; erosive esophagitis and fasting plasma gastrin levels were also assessed. Results: From among the 124 patients undergoing MII-pH monitoring, 13 patients (median age, 69 years; females, 64%) were monitored at baseline (while on PPI therapy) and after VPZ therapy. The median GAET associated with VPZ treatment (23.8%) was less than that for PPI treatment (41.1%; p = 0.01), including both daytime and nighttime measurements. VPZ therapy resulted in better median EAET values (4.5%) than did PPI therapy (10.6%) during the 24-h monitoring period (p = 0.055). EAE normalization was achieved in 46% of VPZ-treated patients and was associated with complete gastric acid suppression (p = 0.005). After switching to VPZ, reflux symptoms (p < 0.01) and erosive esophagitis (p = 0.01) improved. Conclusion: In patients with PPI-refractory GERD, VPZ provides more potent gastric acid suppression, more effective EAE control, enhanced symptom improvement, and better esophagitis healing than PPIs.

Aim To evaluate the clinical and virological features of acute hepatitis E (AH-E) in Gunma prefecture and focus on the hepatitis E virus (HEV) infection in immunocompromised patients. Methods A total of 30 patients with AH-E diagnosed at our Gunma University Hospital, and located in 3-39-15 Showa-machi, Maebashi, Gunma 371-8511 Japan, and its affiliated hospitals from 2004 to 2015, were studied. We evaluated the detailed medical histories, laboratory examinations and virological features of these participants. Results Of the 30 patients, 21 patients were men, with a median age of 61 years. Three of these patients had a history of recent oversea travel. A total of 14 patients had eaten raw or undercooked meat/viscera from animals, and two patients had contracted transfusion-transmitted AH-E. Eight patients were immunocompromised, including those with hematological disease, cancer receiving systemic chemotherapy and kidney transplant or connective tissue disease undergoing immunosuppressive medications. The alanine aminotransferase and total bilirubin levels were more significantly reduced in these immunocompromised patients than in the non-immunocompromised patients. Severe thrombocytopenia, an extra-hepatic manifestation of AH-E, occurred in one case. Among the 22 HEV strains whose subgenotype was determined, two were imported strains (1a and 1f), and 11 strains formed four distinct phylogenetic clusters within subgenotype 3b. The remaining nine strains differed from each other by 9.8–22.4%, and were classified into four subgenotypes (3a, 3b, 3e and 3f). Conclusion Markedly divergent HEV strains (3a, 3b, 3e and 3f) were found to circulate in Gunma. Although immunosuppression appears to play a crucial role in establishing chronic sequels, AH-E in eight immunocompromised patients, including transfusion-transmitted HEV infection in two patients, did not become chronic.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8 weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Background/Aims Upper gastrointestinal symptoms are more frequent and severe in female than in male outpatients in Japan. This study compared the upper gastrointestinal symptoms between healthy male and female young adult volunteers using a questionnaire. Methods In total, 581 third-grade medical students at Saga Medical School aged 22 to 30 years underwent upper gastrointestinal endoscopy and completed a questionnaire (frequency scale for symptoms of gastroesophageal reflux disease) from 2007 to 2013. Of these 581 students, 298 who were negative for Helicobacter pylori infection and had no particular lesions on endoscopic examination were enrolled in the present evaluation. A symptom was defined as positive when the subject evaluated the frequency of the symptom as sometimes, often, or always. Results The subjects comprised of 163 males (average age, 23.7 years) and 135 females (average age, 23.1 years). Upper gastrointestinal symptoms were more frequent in the females (75 of 135, 55.6%) than males (69 of 163, 42.3%; P < 0.05), with a high score for 4 symptoms (bloated stomach, heavy feeling in the stomach after meals, subconscious rubbing of the chest with the hand, and feeling of fullness while eating meals). Of the 144 subjects (69 males and 75 females) who complained of these symptoms, the females complained of dysmotility symptoms more often than did the males, but this was not true for reflux symptoms. Conclusions This study suggests that females develop upper gastrointestinal symptoms more frequently than do males among the young healthy Japanese population.

Various options are available to treat cervical esophageal cancer (CEC), including primary resection, neo-adjuvant therapy followed by surgery, and definitive chemoradiotherapy (dCRT). However, whether neo-adjuvant therapy or dCRT can improve larynx preservation rates in patients with CEC is unclear. This study investigated results of CEC treatment in clinical practice by a nationwide survey in Japan. We retrospectively investigated results of clinical practices for patients with resectable CEC treated between 2012 and 2014, using a mailed questionnaire as a nationwide survey to 308 institutions recognized by the Japan Esophageal Society and the Japan Broncho-Esophagological Society. We registered 792 patients from 93 institutions, of whom 11.1 % underwent endoscopic resection, 46.0 % underwent surgery, and 39.2 % underwent dCRT. Among patients with CEC who were considered to be poor candidates for laryngeal preservation at initial diagnosis, 24.5 % of the 139 patients treated with neo-adjuvant therapy, and 47.3 % of the 226 patients treated with dCRT preserved their larynxes. This questionnaire survey revealed that multimodality treatment for CEC could decrease laryngectomy rates, especially among patients who were not considered to be laryngeal preservation candidates. These treatment strategies can lead to both laryngeal preservation and postoperative quality of life, and should become more widely used.

A 54-year-old male consulted a local doctor with a chief complaint of systemic convulsions and muscle stiffness and was diagnosed with Isaacs' syndrome based on positive findings for antibodies against voltage-gated potassium channels in 2009. He subsequently experienced repeated hematemesis in 2013, at which time he was taken to our hospital by ambulance. Emergent endoscopy revealed esophageal varices with spurting bleeding. The bleeding was stopped with urgent endoscopic variceal ligation. Three days later, the patient developed sudden dyspnea with stridor during inspiration under sedation with an intravenous injection of low-dose flunitrazepam prior to receiving additional treatment and was aroused with intravenous flumazenil, after which his dyspnea immediately improved. Dyspnea may be induced by muscle cramps associated with Isaacs' syndrome exacerbated by sedation. Endoscopic variceal ligation was performed safely using multiple ligation devices in an awake state following pre-medication with hydroxyzine, without sudden dyspnea. Endoscopists should be cautious of the use of sedatives in patients with diseases associated with muscle twitching or stiffness, as in the current case. In addition, it is necessary to administer endoscopic treatment in an awake state or under conscious sedation in patients with a high risk of dyspnea.

Objective We retrospectively investigated the relationship between the tumor response and serial changes in α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) during hepatic arterial infusion of a cisplatin powder formulation (CDDP powder) in patients with advanced hepatocellular carcinoma (HCC). Methods Seventy-six advanced HCC patients were analyzed. All HCC patients received high-concentration cisplatin (1.43 mg/mL) via the haptic artery at a dose of 65 mg/m(2). AFP and DCP were measured at baseline and four to eight weeks after treatment, and the antitumor responses were evaluated according to the response evaluation criteria in solid tumours (RECIST) criteria after one or two courses of treatment. The patients were classified into two groups, a decreased group and a non-decreased group, according to the change in the serum levels of AFP and DCP at four to eight weeks compared to baseline. Results The response to treatment of the decreased group (n=16) and non-decreased group (n=60) was complete response/partial response/stable disease/progressive disease (CR/PR/SD/PD) in 4/4/5/3 and 1/11/8/40 patients, respectively. The response rate and disease control rate of the decreased group were significantly higher than those of the non-decreased group (p=0.016 and p

Background/Aims: This study aimed at (i) clarifying the factors associated with high scores on the modified frequency scale for the symptoms of gastroesophageal reflux disease (FSSG) among 3,505 relatively healthy subjects undergoing routine medical health checkups with gastrointestinal endoscopy and (ii) comparing risk factors for high FSSG scores between subjects with and without reflux esophagitis. Methods: In total, 3,505 subjects (male/female: 1,922/1,583) who underwent upper gastrointestinal endoscopy during health medical checkups at 5 hospitals in Saga, Japan from January 2013 to December 2013 were enrolled. All subjects completed a modified FSSG questionnaire, which comprised 7 questions regarding reflux symptoms and 7 questions regarding acid-related dyspepsia. Each question was assigned a score based on the frequency of symptoms. Results: Younger age, female gender, hiatal herniation, and endoscopic reflux esophagitis were risk factors for a FSSG score with a high total. Subjects with high scores but without esophagitis were women, and hiatal herniation and Barrett's esophagus were frequently seen in patients with reflux esophagitis. Conclusion: Younger age, female gender, hiatal hernia, and endoscopic esophagitis were risk factors for a high FSSG score, and women tended to complain of upper gastrointestinal symptoms more frequently than did men among subjects without endoscopic esophagitis.

There is a lack of critical evidence to justify the methods of follow-up after a curative esophagectomy or a complete response to definitive chemoradiotherapy (dCRT). Consequently, a wide variety of practices are in place throughout the world. A questionnaire concerning follow-up protocols was sent via electronic email for a nation-wide survey of the 117 Japanese hospitals that are recognized by the Japan Esophageal Society as training facilities for certified esophageal surgeons. Seventy-seven hospitals responded to the questionnaire. Most hospitals follow their patients for at least 5 years after esophagectomy or dCRT, usually at a frequency of more than 4 times per year with clinical visits and physical examinations in the 1st and 2nd year after treatment. About 65–75 and 40 % of the hospitals continue the follow-up until the 7th and 10th year after treatment, respectively. Most hospitals measure CEA and SCC-Ag and almost all hospitals utilize CT scans of the cervix, chest and abdomen for the follow-up. Most of the hospitals reported performing an upper gastrointestinal endoscopy at least once per year until the 5th year after treatment, more frequently for post-dCRT patients than for post-esophagectomy patients. Other imaging modalities such as FDG-PET/CT, cervical and abdominal USs, and chest and abdominal X-rays were incorporated at much lower rates. Follow-up protocols for patients who have been treated for esophageal cancer with curative intent vary among the hospitals in Japan. Based on these data, the most popular follow-up protocols in Japan are shown.

Although the prevalence of gastroesophageal reflux disease (GERD) used to be lower in East Asia as compared to Western countries, it has recently been increasing, most likely due to the socioeconomic development in the East. The prevalence of both GERD and functional gastrointestinal disorders (FGIDs) ranges between 10% and 25% worldwide and there are distinct subgroups of patients with overlapping of GERD and FGIDs. However, the true prevalence of an overlap between GERD and FGIDs can be determined only when a formal pathophysiological evaluation has been performed. Nocturnal reflux symptoms have a significant impact on patients' sleep quality and quality of life. Although proton pump inhibitors (PPIs) can improve both reflux and sleep-related symptoms, the relationship between nocturnal reflux events and sleep disturbance is not fully understood. GERD plays an important role in the pathogenesis of lung fibrosis, and PPIs or fundoplication may decrease the likelihood of pulmonary exacerbation or even improve pulmonary function. Refractory reflux symptoms without esophagitis have become one of the most common presentations of GERD in gastroenterology clinics. There are several new medical therapies, and endoscopic as well as laparoscopic techniques that have been increasingly used in these patients. The selection of options should be tailored and individualized based on the pathophysiology of refractory GERD.

BACKGROUND Functional dyspepsia (FD), a heterogeneous disorder, involves multiple pathogenetic mechanisms. Developing treatments for FD has been challenging. We performed a randomized, placebo-controlled, double-blind clinical trial to determine the efficacy of rikkunshito, a Japanese herbal medicine, in FD patients. METHODS FD patients (n = 192) who met the Rome III criteria without Helicobacter pylori infection, predominant heartburn, and depression were enrolled at 56 hospitals in Japan. After 2 weeks of single-blind placebo treatment, 128 patients with continuous symptoms were randomly assigned to 8 weeks of rikkunshito (n = 64) or placebo (n = 61). The primary efficacy endpoint was global assessment of overall treatment efficacy (OTE). The secondary efficacy endpoints were improvements in upper gastrointestinal symptoms evaluated by the Patient Assessment of Upper Gastrointestinal Disorders-Symptom Severity Index (PAGI-SYM), the Global Overall Symptom scale (GOS), and the modified Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (m-FSSG), and psychological symptoms evaluated by the Hospital Anxiety and Depression Scale (HADS). KEY RESULTS Rikkunshito increased OTE compared to placebo at 8 weeks (P = .019). Rikkunshito improved upper gastrointestinal symptoms (PAGI-SYM, GOS, and m-FSSG) at 8 weeks, especially postprandial fullness/early satiety (P = .015 and P = .001) and bloating (P = .007 and P = .002) of the PAGI-SYM subscales at 4 weeks and 8 weeks. Improvement of HADS at 8 weeks (P = .027) correlated with those of PAGI-SYM (r = .302, P = .001), GOS (r = .186, P = .044), and m-FSSG (r = .462, P

Patients with morbid obesity selected for bariatric surgery have a high prevalence of nonalcoholic steatohepatitis (NASH); however, the incidence is varied and depends on race. The prevalence of NASH in obese Japanese patients is unknown. We evaluated the prevalence of NASH in a prospective cohort of Japanese patients with morbid obesity. From October 2009 to July 2011, consecutive patients requiring bariatric surgery underwent a liver biopsy during the operation. The indications for bariatric surgery followed the guidelines of the Asia–Pacific Metabolic and Bariatric Surgery Society. One hundred two patients (55 males and 47 females, age 42.7 ± 10.7 years) were analyzed. The mean body mass index was 42.1 ± 8.2 kg/m2. Among the 102 patients, 84 patients (82.4 %) had nonalcoholic fatty liver disease and 79 patients (77.5 %) had NASH. The grading and staging of NASH by Brunt’s classification were as follows: grade 0 steatosis, one patient; grade 1 steatosis, 35 patients; grade 2 steatosis, 32 patients; grade 3 steatosis, 11 patients; stage 1 fibrosis, 25 patients; stage 2 fibrosis, 38 patients; stage 3 fibrosis, 16 patients, stage 4 fibrosis, no patients. The body weight, waist–hip ratio, visceral fat area, and aspartate aminotransferase, alanine aminotransferase, γ-glutamyl transpeptidase, fasting plasma glucose, fasting plasma insulin, C peptide, hemoglobin A1c, and homeostasis model assessment insulin resistance levels were significantly elevated in the NASH group in comparison with the non-NASH group. The platelet count was significantly decreased in the NASH group. The waist–hip ratio and the alanine aminotransferase, fasting plasma glucose, and homeostasis model assessment insulin resistance levels were found to be independent predictors of NASH in a multivariate analysis. The prevalence of NASH was 77.5 % in this prospective Japanese cohort. The prevalence of NASH in Japanese morbidly obese patients was extremely high, and early intervention should be undertaken.

Background This study aimed to evaluate risk factors for resistance to proton-pump inhibitor (PPI) therapy among patients with reflux esophagitis (RE) and nonerosive reflux disease (NERD) in gastroesophageal reflux disease (GERD) using a standardized questionnaire in Japan: the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG).

Endoscopic sphincterotomy (EST) dissects the sphincter of Oddi by cutting and/or causing the coagulation of the tissue using an electrosurgical current. Complications of EST include acute pancreatitis, hemorrhage, duodenal perforation, and sepsis.1–5 These complications occur in 5% to 10% of the population.1–5 Factors involved in the occurrence of complications of EST have been considered to be the Oddi dysfunction,6 types of electrosurgical current,7,8 specialist training, disinfection, drainage, and collaboration with surgical colleagues.4 The characteristics of the electrosurgical current may affect the frequency and extent of the complications of EST because the nature of the thermal tissue injury depends on the characteristics of the electrosurgical current used to perform EST.9,10 A pure cutting current achieves better cutting ability, whereas a low-voltage coagulating current that is not used solely gains better hemostasis in EST.1 A mixed current comprising mixed patterns of both pure cutting and coagulating currents is currently available for EST in 2 modes, which are the blended cut and the Endocut (E)-mode.1,11,12 The blended cut (C)-mode is comprised of cutting and coagulating currents delivered together in one waveform.13 The E-mode (ERBE, Marietta, GA) gains both the effects of cutting and coagulating because the cutting and coagulating currents are mixed together and applied in turn in short bursts with an intermittent pause.13 When compared with the conventional blended C-mode, the E-mode can give a well-defined and constant degree of coagulation of the incision margins for hemostasis by its automatic voltage regulation and controlled cutting speed, which prevents perforation of the superior part of the papilla of Vater based on an uncontrolled cutting speed, by its automatically fractionated cut.14 Thus, the E-mode may reduce complications of EST theoretically compared with the conventional blended C-mode. An EST with blended currents increases the rate of pancreatitis after EST compared with EST with a pure cutting current.7,8 There is, however, a contradictory report that EST with a pure cutting current has a similar pancreatitis rate, a higher rate of immediate hemorrhage, and poorer control of the incision than that with a blended current.15 A recent meta-analysis shows that the pure cutting current has a similar pancreatitis rate and more episodes of bleeding, primarily mild bleeding, than the mixed current.16 As for the comparison of mixed current modes, the results were controversial in the development of acute pancreatitis and clinically significant bleeding in multiple clinical trials comparing the E-mode with the blended C-mode.14,17–19 However, the problems in the previous studies, including small sample size and retrospective analysis, make it difficult to conclude the advantage of efficacy and safety of the E-mode. Our study aim was to evaluate whether the E-mode surpasses the conventional blended C-mode in safety and efficacy.

Background: Patients with proton pump inhibitor (PPI)-resistant nonerosive reflux disease (NERD) include subgroups that have markedly different pathophysiology. This study aimed to clarify the pathophysiology of NERD by esophageal manometry with 24-hour esophageal impedance and pH monitoring. Methods: Eighteen consecutive outpatients referred to our expert center for functional gastrointestinal motility with suspected PPI-resistant NERD were enrolled. Manometry was performed to detect esophageal motility disorders. Subsequently, 24-hour esophageal impedance and pH monitoring was done while patients were on PPI therapy. Results: Manometry revealed 1 case of achalasia, 1 case of nutcracker esophagus and 3 cases of diffuse esophageal spasm. Three patients had ineffective esophageal motility, with impedance and pH monitoring being performed in 2 of them. Esophageal acid exposure (%time pH Conclusion: A substantial percentage (28%) of patients with suspected PPI-resistant NERD had primary esophageal motility disorders. Both nonacidic reflux and weakly acidic reflux are important contributors to the symptoms of patients with PPI-resistant NERD. Esophageal manometry is required to exclude motility disorders, while 24-hour esophageal impedance and pH monitoring is invaluable for assessing symptom-reflux associations and the indications for fundoplication in patients with suspected PPI-resistant NERD.

Purpose These guidelines are intended for doctors who are engaged in the diagnosis and treatment of esophageal carcinoma, for the following purposes: (1) to present the standard practice for the diagnosis and treatment of esophageal carcinoma with a high regard for the principles of evidence-based medicine (EBM); (2) to improve the safety and results of treatment, thereby reducing the difference in treatment results among different institutions; (3) to reduce unnecessary costs and efforts; (4) help enable people to undergo treatment without anxiety. These guidelines provide only guidance on the indications for treatment and do not restrict or prohibit the use of any treatment deviating from those described herein.