Long-term outcome of regional cooperation pathway after endoscopic submucosal dissection for early detection of new gastric cancer.

OBJECTIVES: The Cancer Control Act requires the maintenance of regional cooperation pathways (RCP) for cancer treatment. In 2008, we started RCP for early detection of new gastric cancer after endoscopic submucosal dissection (ESD). In gastric cancer treatment, RCP after surgical resection had been widely used, but little is known about RCP after ESD. This study aimed to evaluate the effectiveness of RCP after ESD. METHODS: This study included 465 patients on whom our RCP was implemented from 2008 to 2018. A regional family physician performed surveillance endoscopy at 3 months and 1 year after ESD and annually thereafter. We retrospectively evaluated the cumulative incidence and treatment outcomes of new gastric cancer and compared them with previous reports. RESULTS: During a median follow-up period of 70.5 months (3-120 months), 58 patients developed new gastric cancers, and metachronous gastric cancer was detected in 55 patients more than 1 year after ESD. The 5-year cumulative incidence rate was 9.8%. Three patients did not want treatment. Among the remaining 55 patients, the initial treatment was ESD in 51 and surgical resection in 4. Eventually, 50 patients (48 in the ESD group and 2 in the surgical resection group) fulfilled the pathologic criteria for curative ESD. There were no deaths due to gastric cancer. CONCLUSION: Our study was the first to reveal the incidence of new gastric cancer after ESD using RCP. Most lesions were cured with ESD, and no patients died of gastric cancer. Therefore, we consider RCPs to be an option for surveillance after ESD.

Daikenchuto significantly improves stool consistency and lower gastrointestinal symptoms in patients with chronic constipation.

Background and Aim: A number of basic and clinical studies have confirmed that the traditional Japanese herbal medicine, Daikenchutou (DKT) has a pharmacological effect on cholinergic and serotonergic mechanisms with a favorable safety profile and an improving effect on lower gastrointestinal (GI) symptoms including abdominal pain or bloating. The purpose of this study is to evaluate the efficacy and safety of DKT on chronic constipation. Methods: This multicenter, randomized, placebo-controlled, double-blinded clinical trial enrolled 67 patients with chronic constipation fulfilling Rome III criteria. After a 2-week observation period, 63 patients with persistent symptoms were finally randomized to a 4-week course of treatment with DKT or placebo. The primary endpoint consisted of a global assessment of overall treatment effect (OTE), while the secondary endpoints consisted of improvements in stool consistency, spontaneous bowel movements, lower GI symptoms related to constipation, and quality of life. Factors associated with OTE were also investigated. Results: After 4 weeks administration of DKT, OTE was significantly higher than placebo. No side effects were observed. Significant improvement in stool consistency and lower GI symptoms was observed in the DKT group. The improvements in lower GI symptoms as well as stool consistency were associated with OTE. OTE was higher in patients with greater improvement in lower GI symptoms with mental component summary scores close to normal before treatment. Conclusion: DKT was effective and safe in treating chronic constipation, especially in patients having symptoms related to constipation with no impaired mental component summary score.

Uncontrolled, Open-Label Pre-Dinner Administration of Elobixibat in Japanese Adults with Chronic Constipation: A Retrospective Chart Review.

BACKGROUND: Elobixibat has been approved as a new therapeutic drug for chronic constipation. Only the pharmacological efficacy and safety profile of pre-breakfast administration of elobixibat had been previously demonstrated. OBJECTIVE: We evaluated the efficacy and safety profile of pre-dinner administration of elobixibat in patients with functional constipation in a retrospective observational study. METHODS: Patients aged 20 years or older diagnosed with functional constipation by the Rome IV criteria from June 1, 2018, to January 17, 2019. The evaluation time points were at the start and 1, 2, 4, and 8 weeks after treatment. The primary end point was frequency of spontaneous bowel movements per week. The secondary end points were changes in Bristol Stool Form Scale score, onset time required for spontaneous defecation after administration, percent of patients with spontaneous defecation within 24 hours and 48 hours after the first administration, improvement of abdominal pain or abdominal bloating evaluated by a visual analog scale, and total score and each subscore of the Japanese-Translated Version of Patient Assessment of Constipation Quality of Life Questionnaire. RESULTS: Pre-dinner administration of elobixibat was associated with significantly increased frequency of spontaneous bowel movements and improved Bristol Stool Form Scale score at 1, 2, 4, and 8 weeks after treatment. The mean onset time until spontaneous defecation after treatment was 4 to 5 hours, which was earlier than that by conventional constipation treatment drugs and almost constant within an individual during the treatment period. Spontaneous defecation was achieved by 85.4% within 24 hours and 90.2% within 48 hours after the first administration. Elobixibat also improved patients' quality of life, which was evaluated by the Japanese-Translated Version of Patient Assessment of Constipation Quality of Life Questionnaire without adverse events. CONCLUSIONS: Pre-dinner administration of elobixibat improved constipation, abdominal pain and bloating, and patient quality of life by management of fixed defecation. (Curr Ther Res Clin Exp. 2020; 81:XXX-XXX).

Difference in Defecation Desire Between Patients With and Without Chronic Constipation: A Large-Scale Internet Survey.

INTRODUCTION: Defecation desire (DD) is an important physiological component of normal defecation. However, knowledge of DD in the general population and in individuals with chronic constipation (CC) is lacking. We aimed to assess the prevalence of DD in the general population and individuals with CC and to understand the impact of treatment on DD among individuals with CC. METHODS: We conducted an online questionnaire survey targeting the Japanese general population in 2019. DD was reported as never, rarely, usually, or always. Individuals who self-reported constipation and met the Rome IV criteria for functional constipation but did not for irritable bowel syndrome were included in the CC group, while the same number of age-/sex-matched controls who met neither functional constipation nor irritable bowel syndrome criteria was included in the non-CC group. Individuals who reported DD as rarely or never were defined as having loss of DD (LODD). RESULTS: Of the 20,986 participants, 2,587 were included in the CC group (12.3%). LODD was significantly higher in the CC individuals than in the non-CC controls (57.4% vs 8.3%, respectively, P < 0.001, odds ratio 14.84 [95% confidence interval 12.65-17.42]). Satisfaction with treatment for constipation was lower in individuals with persistent LODD (25.9%) compared with those with improved LODD (56.5%) on treatment (P < 0.001, odds ratio 2.48 [1.39-4.43]). DISCUSSION: LODD is common in CC and is associated with decreased satisfaction to treatment. Greater attention should be paid to DD when treating patients with CC.

Clinical utility of salivary pepsin measurement in patients with proton pump inhibitor-refractory gastroesophageal reflux disease symptoms: a prospective comparative study.

BACKGROUND: Salivary pepsin measurement has been reported to be useful for diagnosing gastroesophageal reflux disease (GERD). This study aimed to clarify the usefulness of salivary pepsin measurement in patients with proton pump inhibitor (PPI)-refractory GERD symptoms without erosive esophagitis. METHODS: One hundred and two patients were included. Over seven days after terminating PPI treatment, all patients underwent a 24-h pH-impedance test and salivary pepsin measurement. In patients whose main symptoms included laryngopharyngeal symptoms, a hypopharyngeal multichannel intraluminal impedance (HMII) test was performed, whereas in other patients, a conventional combined multichannel intraluminal impedance-pH (MII-pH) test was performed. In the HMII tests, patients were divided into abnormal proximal exposure (APE) and non-APE groups. Salivary pepsin concentrations were compared according to acid exposure time (AET) values and were also compared between the APE and non-APE groups. RESULTS: The median salivary pepsin concentration in patients with AET > 6% was significantly higher than that in patients with AET ≤ 6% (345.0 [170.0-469.3] ng/mL vs. 120.0 [97.0-290.1] ng/mL, p < 0.01). The sensitivity, specificity, positive predictive value, and negative predictive value of a positive test (> 109 ng/mL) to diagnose patients with AET > 6% were 75.0%, 51.3%, 32.1%, and 86.9%, respectively. There was no significant difference between concentrations in the APE group and concentrations in the non-APE group. CONCLUSIONS: In patients with PPI-refractory nonerosive reflux disease, salivary pepsin measurement may help diagnose patients who have conclusive evidence of reflux, whereas it is not adequate for identifying patients with APE.

Esophageal Motility and Rikkunshito Treatment for Proton Pump Inhibitor-Refractory Nonerosive Reflux Disease: A Prospective, Uncontrolled, Open-Label Pilot Study Trial.

BACKGROUND: Only a few reports focused on esophageal motility in patients with proton pump inhibitor (PPI)-refractory nonerosive reflux disease (NERD) and there has been no established strategy for treatment. OBJECTIVE: To clarify the characteristics of esophageal motility in patients with PPI-refractory NERD, we evaluated esophageal function using combined multichannel intraluminal impedance and esophageal manometry (MII-EM). In addition, we evaluated the efficacy of rikkunshito (RKT), which is a gastrointestinal prokinetic agent. METHODS: Thirty patients with NERD were enrolled and underwent MII-EM. After 8 weeks of RKT (7.5 g/d) treatment, MII-EM was repeated on patients with PPI-refractory NERD. Symptoms were assessed by the Gastrointestinal Symptom Rating Scale. RESULTS: In patients with PPI-refractory NERD, measures of complete bolus transit, peristaltic contractions, and residual pressure of the lower esophageal sphincter during swallowing deviated from the standard values and esophageal clearance was found to be deteriorated. RKT significantly improved the peristaltic contractions (P < 0.05), the complete bolus transit (P < 0.01), and the residual pressure of lower esophageal sphincter (P < 0.05) in these patients. The overall score (P < 0.01) and the subscale scores of acid reflux syndrome (P < 0.05), abdominal pain (P < 0.05), and indigestion syndrome (P < 0.01) in the Gastrointestinal Symptom Rating Scale were significantly improved by the 8-week RKT treatment. CONCLUSIONS: In the pilot study, patients with PPI-refractory NERD had disorders of esophageal and lower esophageal sphincter motility that were improved by RKT. Further studies examining esophageal motor activity of RKT in PPI-refractory NERD are required. University hospital Medical Information Network (UMIN) Clinical Trial Registry identifier: UMIN000003092.

Clinical characteristics of elderly patients with proton pump inhibitor-refractory non-erosive reflux disease from the G-PRIDE study who responded to rikkunshito.

BACKGROUND: The incidence and severity of gastroesophageal reflux disease (GERD) in Japan tends to increase in elderly women. Rikkunshito (RKT), a traditional Japanese medicine, acts as a prokinetic agent and improves gastric emptying and gastric accommodation. Our previous prospective randomized placebo-controlled study showed that RKT combined with a standard-dose of rabeprazole (RPZ) significantly improved the acid-related dysmotility symptoms (ARD) in elderly patients with proton pump inhibitor (PPI)-refractory non-erosive reflux disease (NERD). This study aimed to evaluate clinical characteristics of elderly PPI-refractory NERD patients with ARD symptoms who responded to RKT. METHODS: Two hundred forty-two patients with PPI-refractory NERD were randomly assigned to 8 weeks of either RPZ (10 mg/q.d.) + RKT (7.5 g/t.i.d.) (RKT group) or RPZ + placebo (PL group). Among them, 95 were elderly (≥65 years) with ARD (RKT group: n = 52; PL group: n = 43). We analyzed the changes using the 12 subscale score of frequency scale for the symptoms of GERD (FSSG) and 15 items of the Gastrointestinal Symptom Rating Scale at 4 and 8 weeks and compared the therapeutic efficacy between the 2 groups. RESULTS: There were no marked differences in baseline demographic or clinical characteristics in the 2 groups except for rate of current smoking. The FSSG score (mean ± SD at 0, 4, and 8 weeks) in both the RKT (16.0 ± 7.0; 9.9 ± 8.4; 7.0 ± 6.4) and PL (15.1 ± 6.4; 10.9 ± 6.7, 11.1 ± 8.5) groups significantly decreased after treatment. However, the degree of improvement of total and ARD scores of FSSG after the 8-week treatment was significantly greater in the RKT group than in the PL group. Combination therapy with RKT for 8 weeks showed significant improvement in 3 subscale scores (abdominal bloating, heavy feeling in stomach and sick feeling after meals) of the ARD domain and 1 subscale score (heartburn after meals) of the reflux symptom domain. CONCLUSIONS: RKT may be useful for improving GERD symptoms in elderly PPI-refractory NERD patients with ARD. Thus, RKT was particularly effective for resolving postprandial GERD symptoms (heavy feeling in stomach, sick feeling, and heartburn after meals). TRIAL REGISTRATION: (UMIN000005880).

A randomized, placebo-controlled, double-blind clinical trial of rikkunshito for patients with non-erosive reflux disease refractory to proton-pump inhibitor: the G-PRIDE study.

BACKGROUND: The aim of this study was to investigate the efficacy of rikkunshito (RKT), a traditional Japanese medicine, combined with proton pump inhibitor (PPI) in patients with PPI-refractory non-erosive reflux disease (NERD). METHODS: Patients with PPI-refractory NERD (n = 242) were randomly assigned to the RKT group [rabeprazole (10 mg/day) + RKT (7.5 g/t.i.d.) for 8 weeks] or the placebo group (rabeprazole + placebo). After the 4- and 8-week treatments, we assessed symptoms and quality of life (QOL) using the Frequency Scale for the Symptoms of Gastroesophageal Reflux Disease (FSSG), Gastrointestinal Symptom Rating Scale (GSRS), and Short-Form Health Survey-8 (SF-8). RESULTS: There were no significant differences in FSSG and GSRS score improvement between these groups after the 4- and 8-week treatments. The mental component summary (MCS) scores of the SF-8 improved more in the RKT group (from 45.8 ± 8.1 to 48.5 ± 7.4) than in the placebo group (from 47.7 ± 7.1 to 48.4 ± 7.5) after the 4-week treatment (P < 0.05). The 8-week treatment with RKT was more effective for improvement of the degree of MCS score in patients with a low body mass index (<22) (P < 0.05) and significantly improved the acid-related dysmotility symptoms of FSSG in female and elderly patients (≥ 65 years). CONCLUSION: There were no significant differences in improvement of GERD symptoms in patients with PPI-refractory NERD between these groups. However, RKT may be useful for improving mental QOL in non-obese patients and acid-related dyspeptic symptoms, especially in women and the elderly.

Objective evaluation of visibility in virtual chromoendoscopy for esophageal squamous carcinoma using a color difference formula.

Computed virtual chromoendoscopy with flexible spectral imaging color enhancement (FICE) is a new dyeless imaging technique that enhances mucosal and vascular patterns. However, a method for selecting a suitable wavelength for a particular condition has not been established. The aim of this study is to evaluate the color difference method for quality assessment of FICE images of the intrapapillary capillary loop in magnifying endoscopy for esophageal squamous cell carcinoma. The color difference between 60 microvessels and background mucosa observed using the magnifying endoscope was 8.31±2.84 SD under white light and 12.26±3.14 (p=0.0031), 11.70±4.49 (p=0.0106), and 17.49±5.40 (p<0.0001) in FICE modes A, B, and C, respectively. The visibility scores for microvessels observed by medical students were 6.00±1.12 points under white light and 11.1±2.25 (p<0.0001), 8.65±2.06 (p=0.0001), and 12.55±2.56 (p<0.0001) in FICE modes A, B, and C, respectively. Furthermore, the measurement of color difference was correlated with the visibility score assigned by medical students (Pearson's correlation coefficient=0.583, p<0.0001) In conclusion, the color difference method corresponds to human vision and is an appropriate method for evaluation of endoscopic images.

Regionally differential effects of sennoside A on spontaneous contractions of colon in mice.

Sennosides, the most popular irritant laxatives, cause purgative actions in the intestine through biotransformation to rhein anthrone; however, the underlying mechanisms remain unclear. The purpose of this study was to define colonic motor actions of sennoside A with special reference to purgative action. Mice received a single oral dose of 30 mg/kg sennoside A, and the colon was removed about 6 hr later. Contractions of longitudinal and circular muscles were recorded using an isometric force transducer and a pressure transducer, respectively. In longitudinal muscle preparations, spontaneous contractions were augmented in distal colon compared to control. In circular muscle preparations, contractions were reduced in the proximal colon, but increased in the distal colon. Particularly in the proximal colon, the frequency of high-amplitude contraction was reduced. In the control group, non-adrenergic, non-cholinergic treatment decreased the amplitude of contractions in the proximal colon, but not in the distal colon. In the sennoside A group, non-adrenergic, non-cholinergic treatment only slightly depressed the amplitude of contractions in the proximal and distal colon. To confirm a causal relationship between luminal prostaglandin level and purgative action of sennoside A, the mice were treated with indomethacin. Significant changes induced by sennoside A were attenuated by indomethacin treatment. The present study indicates that spontaneous motility is inhibited by sennoside A in the proximal colon, but accelerated in the distal colon, and that effects are associated with luminal prostanoid level and only partially with cholinergic nerve mediation.

Mechanism of constipation in familial amyloid polyneuropathy: a case report.

Previously no functional study has been available for the mechanism of constipation in familial amyloid polyneuropathy (FAP). We performed a gut function test in a 78-year-old woman with transthyretin-type FAP who had severe constipation. The gut function test showed a prolonged colonic transit time, a low anal pressure at rest and upon squeezing, loss of the spontaneous phasic rectal contractions, and weak abdominal strain. All these abnormalities suggested a peripheral autonomic dysfunction, corresponding to the enteric neuropathy that was confirmed upon autopsy.

[Serotonin 5- HT4 receptor agonist (mosapride citrate)].

Irritable bowel syndrome is a functional gastrointestinal disorder characterized by abnormal sensation and motility in the lower gastrointestinal tract. In constipation-type irritable bowel syndrome, decreased bowel motility causes stagnation of feces and gas, resulting in enhanced pain sensation of the bowel. Mosapride citrate is a selective serotonin 5- HT4 receptor agonist and enhances propulsive activity throughout the gastrointestinal tract. Mosapride citrate was orally administered to 11 patients with constipation-type irritable bowel syndrome to investigate its effect on this disease. The result showed that mosapride citrate alleviated abdominal pain and abdominal distension, loosened stools, shortened bowel transit time, and decreased flatus in the bowel. The results suggest that mosapride citrate is useful for the treatment of irritable bowel syndrome.

Calcium polycarbophil improves constipation in non-traumatic spinal cord disorders.

Calcium polycarbophil shortened total colonic transit time (P < 0.05), increased bowel frequency and improved defecation difficulty in four patients with non-traumatic spinal cord disorders. Polycarbophil may be useful for the treatment of constipation.

Placement of the Bravo wireless pH monitoring capsule onto the gastric wall under endoscopic guidance.

BACKGROUND: The Bravo system was designed mainly to monitor esophageal pH, and there have been no reports on gastric pH monitoring using this system. OBJECTIVE: To place the Bravo capsule on the gastric wall and monitor gastric pH. DESIGN: Experimental clinical trial with the cooperation of volunteers. SETTING: Academic medical center. PATIENTS: Eleven volunteers (9 men, 2 women; mean age 38 years; 3 had symptoms of GERD). INTERVENTIONS: The Bravo system was introduced into the esophagus and stomach along a thin endoscope and capsules were attached, one each to the esophageal and gastric walls under direct vision through the endoscope. Esophageal and gastric pHs were simultaneously monitored. RESULTS: The 2 capsules were successfully placed in 10 of the 11 subjects, and both esophageal and gastric pHs were monitored for 48 hours in 9 subjects. Mild to moderate precordial pain was observed in 7 subjects, but no other complications or side effects were observed in this study. The gastric pH of 10 subjects increased after meals and returned to baseline pH 2 hours later. Decrease of esophageal pH was observed 1 hour after a meal in the symptomatic subjects and corresponded to the time when gastric pH decreased secondary to the increase of pH with meals. CONCLUSIONS: The Bravo capsule is easily placed on the gastric wall under endoscopic assistance and enables long ambulatory monitoring of gastric pH.

Evaluation of gastrointestinal motility by computerized analysis of abdominal auscultation findings.

BACKGROUND AND AIMS: To evaluate gastrointestinal motility by abdominal auscultation. METHODS: Abdominal auscultated sounds of 20 healthy adults and 10 diabetes mellitus patients with delayed gastric emptying were digitally recorded and then analyzed by computer while simultaneously monitoring the motility of the antrum of the stomach by ultrasonography. The auscultated sound, when the stomach wall was moving, was regarded as the gastroduodenal (GD) sound and when not moving as the intestinal (I) sound. The sound index (SI; the sum of the amplitude) was calculated to indicate the power of sound. Sounds were recorded for 15 min under fasting conditions and 60 min after a liquid meal. In six healthy adults, the gastroduodenal pressure was recorded under abdominal auscultation to detect any correlation between the motility index (MI; the sum of the area under the curve) and SI. RESULTS: A definite increase in the SI of the GD sound was observed after the liquid meal in comparison with that of the I sound. A positive correlation (r = 0.678) was observed between the SI of the GD sound and MI, thus, it was considered that the GD sound reflected the motility of the gastroduodenal wall. In the diabetes mellitus patients, the SI of the GD sound was significantly lower after food intake than in healthy adults. CONCLUSION: The results of the present study indicate that the abdominal auscultation test could be used as a new diagnostic method to detect any abnormality in gastrointestinal motility.

Objective assessment of the antispasmodic effect of shakuyaku-kanzo-to (TJ-68), a Chinese herbal medicine, on the colonic wall by direct spraying during colonoscopy.

AIM: To objectively evaluate the effect of TJ-68 on colonic spasms during colonoscopy. METHODS: One hundred and one patients subjected to screening colonoscopy were randomly assigned to two groups: TJ-68 in 51 subjects and saline as the control in 50. The endoscope was inserted into the sigmoid colon, then a spastic region was identified and the tip of the colonoscope was positioned at a distance of about 10 mm from the spastic region. The endoscopic view was recorded before and after direct spraying of the TJ-68 solution or warm saline. The intraluminal area of the spastic region was serially measured using a computer image analyzer and expressed as pixel counts. The area under the curve (AUC) was calculated from the pixel curve. Statistical significance was assessed by Wilcoxon's test and Mann-Whitney U test. RESULTS: The mean AUC of the spastic region before and after TJ-68 spraying was 29,128 and 121,943 pixels, respectively, while with saline, it was 31,635 pixels and 48,617 pixels, respectively. Thus, the AUC significantly increased after TJ-68 spraying compared with the spraying of saline (P<0.001). CONCLUSION: Direct spraying of TJ-68 on the colonic mucosa suppressed colonic spasm and it may be useful during colonoscopy when anticholinergic agents are contraindicated.