Endoscopic findings and outcomes of gastric mucosal changes relating to potassium-competitive acid blocker and proton pump inhibitor therapy.

Gastric mucosal changes associated with long-term potassium-competitive acid blocker and proton pump inhibitor (PPI) therapy may raise concern. In contrast to that for PPIs, the evidence concerning the safety of long-term potassium-competitive acid blocker use is scant. Vonoprazan (VPZ) is a representative potassium-competitive acid blocker released in Japan in 2015. In order to shed some comparative light regarding the outcomes of gastric mucosal lesions associated with a long-term acid blockade, we have reviewed six representative gastric mucosal lesions: fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like gastric mucosal changes, gastric black spots, and stardust gastric mucosal changes. For these mucosal lesions, we have evaluated the association with the type of acid blockade, patient gender, Helicobacter pylori infection status, the degree of gastric atrophy, and serum gastrin levels. There is no concrete evidence to support a significant relationship between VPZ/PPI use and the development of neuroendocrine tumors. Current data also shows that the risk of gastric mucosal changes is similar for long-term VPZ and PPI use. Serum hypergastrinemia is not correlated with the development of some gastric mucosal lesions. Therefore, serum gastrin level is unhelpful for risk estimation and for decision-making relating to the cessation of these drugs in routine clinical practice. Given the confounding potential neoplastic risk relating to H. pylori infection, this should be eradicated before VPZ/PPI therapy is commenced. The evidence to date does not support the cessation of clinically appropriate VPZ/PPI therapy solely because of the presence of these associated gastric mucosal lesions.

The presence of hiatal hernia is a significant predictor for symptomatic recurrence after cessation of vonoprazan therapy for gastroesophageal reflux disease: a long-term observational study.

BACKGROUND: Gastroesophageal reflux disease (GERD) symptoms frequently recur after cessation of acid blockers. The presence of a hiatal hernia may worsen GERD symptoms and increase the risk of esophageal malignancy. The aim of this study is to clarify the timing and predictors for recurrence of GERD symptoms after cessation of vonoprazan (VPZ) therapy. METHODS: A retrospective observational study involved 86 patients who underwent cessation of VPZ therapy for symptomatic GERD. Collated data from medical record review included the endoscopic findings and Izumo scale score. RESULTS: The mean duration of continuous VPZ therapy before cessation was 7.9 months. GERD symptoms requiring the resumption of VPZ therapy recurred in 66 of 86 patients (77%). Kaplan-Meier analysis showed that overall recurrence-free rates at 6 months, one and two years after VPZ cessation were 44%, 32% and 23%, respectively. Alcohol use, the presence of a hiatal hernia and long-term therapy for more than six months were identified as significant positive predictors for symptomatic recurrence. Notably, hiatal hernia had the highest hazard ratio in both univariate and multivariate analyses. The recurrence-free rate in patients with a hiatal hernia was much lower at 6 months than in patients without a hiatal hernia (15% and 51%, respectively p = 0.002). After the symptomatic recurrence, GERD symptoms improved significantly after one-month VPZ therapy. CONCLUSION: The rate of symptomatic recurrence after VPZ cessation in patients with GERD is considerable. Cessation of acid suppression therapy should be cautious in patients with both a hiatal hernia and GERD.

Repeat bidirectional double-balloon enteroscopy 1 year later may be proper in Peutz-Jeghers patients with difficult-to-reach polyps.

Background and study aims Small-bowel polyps in patients with Peutz-Jeghers syndrome (PJS) are sometimes difficult to reach using double-balloon enteroscopy (DBE). However, they can induce intussusception, especially when ≧15 mm. This study aimed to review the outcomes of patients with such polyps. Patients and methods All patients with PJS with small-bowel polyps that bidirectional DBE failed to reach and were ≧5 mm as shown by DBE enterography at our institution from May 2006 to April 2022 were retrospectively evaluated. The endpoint was the earliest occurrence of symptomatic intussusception induced by the polyp, endoscopic removal by repeat DBE or intraoperative endoscopy, or the last medical record describing the patient's condition. Results This study included 27 polyps in 13 patients. All patients had extraluminal adhesions. None developed symptomatic intussusception, eight patients underwent endoscopic removal at repeat DBE without surgery, two patients underwent removal with intraoperative endoscopy, two patients were observed without polyp removal, and one patient had a polyp removed at repeat DBE and three unreachable polyps remained. Repeat DBE without surgery was able to remove 14 polyps (52%). Polyps ≧15 mm included 11 lesions in eight patients and were observed for a median of 14 months without symptomatic intussusception. Conclusions The difficult-to-reach polyps may have a low risk of immediate symptomatic intussusception, possibly due to limited bowel mobility by extraluminal adhesions, and the likelihood of reaching them at repeat DBE was substantial. Hence, repeat DBE 1 year later may be proper in such patients with PJS.

Vonoprazan Therapy is as Effective for Functional Dyspepsia without Heartburn as Acotiamide Therapy.

BACKGROUND AND AIMS: Acid suppression improves dyspepsia symptoms but the efficacy of vonoprazan for functional dyspepsia remains unclear. The aim of this study is to evaluate the effectiveness of vonoprazan therapy for functional dyspepsia without heartburn. METHODS: Patients receiving vonoprazan 10 mg once daily or acotiamide 100 mg three times daily for more than one month were included and retrospectively reviewed. Functional dyspepsia was diagnosed based on the ROME IV criteria. Patients with heartburn were excluded. Eighty-five patients were divided into vonoprazan (n=48) and acotiamide (n=37) groups. RESULTS: There were no significant differences at baseline between the vonoprazan and acotiamide groups. The functional dyspepsia score significantly improved in both groups (p<0.001). The degree of score reduction (55% vs 59%, p=0.559) and the resolution rates (21% vs 30%, p=0.345) were similar. Epigastric pain and postprandial distress scores were significantly improved in both groups, and the degree of improvement of each score was similar. Constipation and diarrhea scores were significantly improved in both groups, and the degree of improvement similar. CONCLUSION: These preliminary results suggest that vonoprazan is effective for the treatment of functional dyspepsia without heartburn in the short-term, with results similar to acotiamide therapy.

Maintenance of complete mucosal healing is associated with avoiding restenosis after endoscopic balloon dilation of Crohn's disease-related small intestinal strictures.

Background: Endoscopic balloon dilation (EBD) is an effective, minimally invasive treatment for Crohn's disease (CD) related intestinal strictures. However, restenosis frequently occurs and requires repetitive EBD or surgical resection. Since previous studies could not evaluate restenosis based on stricture diameter, factors affecting restenosis after EBD were unclear. This study aimed to identify these factors by precisely measuring the diameter of small intestinal strictures in patients with CD. Methods: This single-center retrospective study enrolled patients with CD with de novo small intestinal strictures who underwent two double-balloon enteroscopy sessions (EBD and follow-up) between January 2016 and October 2021. Clinical and endoscopic data were obtained from electronic medical records. A calibrated small-caliber-tip transparent hood was used to precisely measure stricture diameters. Multivariate analysis was performed to identify factors associated with restenosis. Results: Forty-eight patients (37 male) were analyzed. The total number of strictures detected decreased from 162 to 143. The mean diameter of all strictures and the narrowest stricture in each patient increased significantly from 8.6 to 9.8 mm and from 7.6 to 8.7 mm, respectively. Thirty-two (67%) patients developed endoscopic restenosis. Multivariate analysis showed that the presence of ulcers at the follow-up session was a risk factor for restenosis (odds ratio 9.4, p = 0.01). Patients with complete mucosal healing at both sessions (n = 21) showed significant improvement in the narrowest stricture (+1.7 mm, p = 0.001). Conclusions: Maintenance of complete mucosal healing is significantly associated with avoiding restenosis after EBD in CD-related small intestinal strictures.

Clinical Guidelines for Diagnosis and Management of Peutz-Jeghers Syndrome in Children and Adults.

BACKGROUND: Peutz-Jeghers syndrome (PJS) is a rare disease characterized by the presence of hamartomatous polyposis throughout the gastrointestinal tract, except for the esophagus, along with characteristic mucocutaneous pigmentation. It is caused by germline pathogenic variants of the STK11 gene, which exhibit an autosomal dominant mode of inheritance. Some patients with PJS develop gastrointestinal lesions in childhood and require continuous medical care until adulthood and sometimes have serious complications that significantly reduce their quality of life. Hamartomatous polyps in the small bowel may cause bleeding, intestinal obstruction, and intussusception. Novel diagnostic and therapeutic endoscopic procedures such as small-bowel capsule endoscopy and balloon-assisted enteroscopy have been developed in recent years. SUMMARY: Under these circumstances, there is growing concern about the management of PJS in Japan, and there are no practice guidelines available. To address this situation, the guideline committee was organized by the Research Group on Rare and Intractable Diseases granted by the Ministry of Health, Labour and Welfare with specialists from multiple academic societies. The present clinical guidelines explain the principles in the diagnosis and management of PJS together with four clinical questions and corresponding recommendations based on a careful review of the evidence and involved incorporating the concept of the Grading of Recommendations Assessment, Development and Evaluation system. KEY MESSAGES: Herein, we present the English version of the clinical practice guidelines of PJS to promote seamless implementation of accurate diagnosis and appropriate management of pediatric, adolescent, and adult patients with PJS.

Endoscopic treatment of intussusception due to small intestine polyps in patients with Peutz-Jeghers Syndrome.

Background and study aims Intussusception caused by intestinal polyps in patients with Peutz-Jeghers syndrome usually requires laparotomy. Patients following successful endoscopic reduction using double-balloon endoscopy (DBE) have been reported. The aim of this study was to evaluate the feasibility of endoscopic treatment of intussusception. Patients and methods We retrospectively reviewed patients who underwent DBE for intussusception due to small intestine polyps in patients with Peutz-Jeghers syndrome from January 2004 to June 2020. Results Twenty-seven (antegrade 22, retrograde 5) DBEs were performed in 19 patients with 25 sites of intussusception identified during the study period. If the intussusception remained once the endoscope reached the site, endoscopic reduction of the intussusception was performed as needed (15 sites). Ultimately, endoscopic resections (8 sites) or ischemic polypectomies (16 sites) of the polyp causing the intussusception were completed at 24 sites. Only one site could not be treated endoscopically and was treated surgically. The final per-site and per-patient success rates of endoscopic treatment were 96 % (24/25) and 95 % (18/19) respectively. Two patients developed mild acute pancreatitis and one patient developed intussusception after the procedures, both of which were treated non-operatively. Conclusions Endoscopic treatment of intussusception is feasible to avoid laparotomy in patients with Peutz-Jeghers syndrome.

Probiotics suppress nonalcoholic steatohepatitis and carcinogenesis progression in hepatocyte-specific PTEN knockout mice.

Nonalcoholic fatty liver disease (NAFLD), a hepatic characteristic of metabolic syndrome, received significant attention in clinical settings. The multiple-hit theory is one of the proposed mechanisms of NAFLD, and gut dysbiosis is considered a hit. Thus, controlling gut microbiota is a potential target in the management of NAFLD, and probiotics can be used as a treatment agent for NAFLD. The current study aimed to investigate the efficacy of probiotics against nonalcoholic steatohepatitis in a hepatocyte-specific PTEN knockout mouse model that mimics the characteristics of human NAFLD. Probiotics were administered to male knockout mice for 8 or 40 weeks. Next, we assessed hepatic inflammation, fibrosis, carcinogenesis, and oxidative stress. Probiotics were found to reduce serum transaminase levels, NAFLD activity score, and the gene expression of pro-inflammatory cytokines. In addition, they decreased liver fibrosis grade, which was examined via Sirius red staining, gene expression of fibrotic markers, and hydroxyproline. Furthermore, probiotics suppressed the number of liver tumors, particular in HCC. Probiotics reduced oxidative stresses, including glutathione levels, and anti-oxidative stress marker, which may be an underlying mechanism for their beneficial effects. In conclusion, probiotics treatment had beneficial effects against NAFLD and carcinogenesis in hepatocyte-specific PTEN knockout mice.

Long-term changes in serum gastrin levels during standard dose vonoprazan therapy.

BACKGROUND: Long-term acid suppression during vonoprazan therapy causes hypergastrinemia which may induce gastric mucosal changes such as fundic gland and hyperplastic polyps. The aim of this study is to clarify the long-term changes in serum gastrin levels and risk factors for hypergastrinemia. METHODS: From July 2016 to April 2020, 48 patients receiving vonoprazan 10 mg once daily for more than one year were reviewed. Serum gastrin level was evaluated by radioimmunoassay in a fasting condition (reference range 37-172 pg/ml). RESULTS: The baseline median gastrin level was 100 (range, 54-415) pg/ml. The gastrin level over 4 years was 700-1200 pg/ml, which plateaued at 1.5 years. Multivariate analysis revealed factors associated with gastrin levels 12 months after starting vonoprazan and identified severe gastric atrophy as a significant positive risk factor (p = .046). The gastrin level over 4 years in patients with severe gastric atrophy and no atrophy was approximately 900-1500 and 500-1000 pg/ml, respectively. Female gender was also identified as a positive factor, although it was not statistically significant (p = .087). The gastrin level over 4 years in females was approximately 900-1300 pg/ml, greater than in males (500-900 pg/ml). CONCLUSION: A continued increase in gastrin levels was not found during long-term vonoprazan therapy. Severe gastric atrophy is a significant risk factor for hypergastrinemia.

Multicenter epidemiological survey of pneumatosis intestinalis in Japan.

BACKGROUND: Pneumatosis intestinalis (PI) is a rare condition characterized by gas collection in the intestinal wall. We aimed to determine the etiology and affected segments associated with complications, treatment, and outcome. METHODS: We conducted a multicenter epidemiological survey using a standardized data collection sheet in Japan. Complicating PI was defined as strangulation or bowel necrosis, bowel obstruction, adynamic ileus, sepsis, shock, and massive gastrointestinal bleeding requiring blood transfusion. RESULTS: We enrolled 167 patients from 48 facilities. Multivariate analysis revealed that older age (adjusted OR, 1.05 and 95% confidence intervals [CI], 1.02-1.09, P = 0.0053) and chronic kidney disease (adjusted OR, 13.19 and 95% CI 1.04-167.62, P = 0.0468) were independent predictors of the small-bowel-involved type. Complicating PI was associated with the small-bowel-involved combined type (adjusted OR, 27.02 and 95% CI 4.80-152.01, P = 0.0002), the small-bowel-only type (adjusted OR, 3.94 and 95% CI 1.02-15.27, P = 0.0472), and symptomatic PI (adjusted OR, 16.24 and 95% CI 1.82-145.24, P = 0.0126). Oxygen therapy was performed in patients with a past history of bowel obstruction (adjusted OR, 13.77 and 95% CI 1.31-144.56, P = 0.0288) and surgery was performed in patients with complicating PI (adjusted OR, 8.93 and 95% CI 1.10-72.78, P = 0.0408). Antihypertensives (adjusted OR, 12.28 and 95% CI 1.07-140.79, P = 0.0439) and complicating PI (adjusted OR, 11.77 and 95% CI 1.053-131.526; P = 0.0453) were associated with exacerbation of PI. The complicating PI was the only indicator of death (adjusted OR, 14.40 and 95% CI 1.09-189.48, P = 0.0425). DISCUSSION: Small-bowel-involved type and symptomatic PI were associated with complications which were indicators of poor prognosis.

Images of laser and light-emitting diode colonoscopy for comparing large colorectal lesion visibility with linked color imaging and white-light imaging.

OBJECTIVES: In light-emitting diode (LED) and laser colonoscopy, linked color imaging (LCI) superiority to white-light imaging (WLI) for polyp detection is shown separately. We analyzed the noninferiority of LCI between LED and laser colonoscopy and that of WLI (LECOL study). METHODS: We prospectively collected nonpolypoid lesions with WLI and LCI using LED and laser colonoscopy from January 2021 to August 2021. All images were evaluated randomly by 12 endoscopists (six nonexperts and six experts in three institutions) using the polyp visibility score: 4, excellent; 3, good; 2, fair; and 1, poor. The comparison score (LED better/similar/laser better) for redness and brightness was evaluated for WLI and LCI pictures of each lesion. RESULTS: Finally, 63 nonpolypoid lesions were evaluated, and the mean polyp size was 24.5 ± 13.4 mm. Histopathology revealed 13 serrated lesions and 50 adenomatous/cancerous lesions. The mean polyp visibility scores of LCI pictures were significantly higher than those of WLI in the LED (3.35 ± 0.85 vs. 3.08 ± 0.91, P < 0.001) and the laser (3.40 ± 1.71 vs. 3.05 ± 0.97, P < 0.001) group, and the noninferiority of LCI pictures between LED and laser was significant (P < 0.001). The comparison scores revealed that the evaluation of redness and brightness (LED better/similar/laser better) were 26.8%/40.1%/33.1% and 43.5%/43.5%/13.0% for LCI pictures (P < 0.001) and 20.6%/44.3%/35.1% and 60.3%/31.7%/8.0% for WLI pictures (P < 0.001), respectively. CONCLUSION: The noninferiority of polyp visibility with WLI and LCI in LED and laser colonoscopy was shown. WLI and LCI of LED tended to be brighter and less reddish than those of laser.

A pilot study of micro-CT-based whole tissue imaging (WTI) on endoscopic submucosal dissection (ESD) specimens.

Endoscopic submucosal dissection can remove large superficial gastrointestinal lesions in en bloc. A detailed pathological evaluation of the resected specimen is required to assess the risk of recurrence after treatment. However, the current method of sectioning specimens to a thickness of a few millimeters does not provide information between the sections that are lost during the preparation. In this study, we have produced three-dimensional images of the entire dissected lesion for nine samples by using micro-CT imaging system. Although it was difficult to diagnose histological type on micro-CT images, it successfully evaluates the extent of the lesion and its surgical margins. Micro-CT images can depict sites that cannot be observed by the conventional pathological diagnostic process, suggesting that it may be useful to use in a complementary manner.

The effect of proton pump inhibitors and vonoprazan on the development of 'gastric mucosal redness'.

The safety of long-term proton pump inhibitor (PPI) and vonoprazan (VPZ) use is a relatively recent concern. Gastric mucosal redness was reported as a VPZ-associated lesion in a previous study. The aim of this study was to investigate the prevalence and risk factors for gastric mucosal redness. Between December 2020 and November 2021, 1,101 patients who underwent esophagogastroduodenoscopy were reviewed. The cohort was divided into four groups: Control (n=580), histamine-2 receptor antagonist (H2RA) (n=65), PPI (n=146) and VPZ groups (n=310). Gastric mucosal redness was present in 48/1,101 patients (4%). The prevalence in controls, H2RA, PPI and VPZ groups was 1.9% (11/580), 1.5% (1/65), 6.2% (9/146) and 8.7% (27/310), respectively. Both the PPI and VPZ groups had a significantly higher prevalence of gastric mucosal redness compared with the control group (P<0.001). In the multivariate analysis, PPI and VPZ use were significantly associated with gastric mucosal redness. Fundic gland polyps, gastric hyperplastic polyps, multiple white and flat elevated lesions, cobblestone-like mucosa, and stardust gastric mucosa were also significantly associated with PPI and VPZ use in the multivariate analysis. Back-to-back analysis showed that gastric mucosal redness was not seen before starting PPI/VPZ in most patients. The duration of treatment with VPZ was investigated to determine if it affected the prevalence of gastric mucosal redness. There were no significant differences in treatment duration among patients with and without gastric mucosal redness (mean ± standard deviation: 3.0±1.5 vs. 2.5±1.4 years, P=0.077). In conclusion, the prevalence of gastric mucosal redness was low but was associated with PPI and VPZ use.

Underwater Endoscopic Mucosal Resection of Small Rectal Neuroendocrine Tumors.

Background and Study Aims: The resection strategy for rectal neuroendocrine tumors (NET) < 10 mm is not uniform. We compared the utility of underwater endoscopic mucosal resection (UEMR) to endoscopic submucosal resection with a ligation device (ESMR-L) to resect rectal NETs. Patients and Methods: Patients with rectal NET < 10 mm treated with UEMR or ESMR-L were included. Their medical records were retrospectively reviewed. Results: Thirty-two patients were divided into a UEMR group (n = 7) and an ESMR-L group (n = 25). Histopathological diagnosis of NET by biopsy was known before resection in 43% (3/7) in the UEMR group and 68% (17/25) in the ESMR-L group, (p = 0.379). UEMR was performed on an outpatient basis for all patients, and 92% of ESMR-L (23/25) were performed as inpatient procedures (p < 0.001). The procedure time was significantly shorter in the UEMR group than in the ESMR-L group [median (IQR), min, 6 (5-8) vs. 12 (9-14), p = 0.002]. En bloc resection and R0 resection rates were 100% in both groups. Pathological evaluations were predominantly NET G1 in both groups (UEMR: 7/7, 100% and ESMR-L: 23/25, 92%). Two patients in the ESMR-L group developed delayed bleeding, controlled by endoscopic hemostasis. Device costs were significantly higher in the ESMR-L group than the UEMR group by approximately US$180 [median (IQR), $90.45 (83.64-108.41) vs. $274.73 (265.86-292.45), P < 0.001]. Conclusion: UEMR results in similar resection quality with shorter procedure time and lower costs compared to ESMR-L. We recommend UEMR for the resection of rectal NET < 10 mm.

Pathological Evaluation of Rectal Cancer Specimens Using Micro-Computed Tomography.

Whole-block imaging (WBI) using micro-computed tomography (micro-CT) allows the nondestructive reconstruction of a three-dimensional view of tissues, implying that WBI may be used for accurate pathological evaluation of patients with rectal cancer. HOWEVER, the clinical impact of this approach is unclear. We aimed to clarify the efficacy of WBI in the whole-mount specimens of locally advanced rectal cancer. A total of 237 whole-mount formalin-fixed paraffin-embedded blocks from 13 patients with rectal cancer who underwent surgical treatment were enrolled and scanned with micro-CT to generate three-dimensional images. WBI was evaluated following the conventional pathological review of the corresponding whole-slide imaging (WSI). WBI identified all tumor sites detected using WSI. Furthermore, WBI revealed one additional tumor site, which was not detected using WSI. Tumor resection margin was significantly closer to the soft-tissue edge when measured using WBI (7.7 mm vs. 6.6 mm, p < 0.01). Seventy-six percent of tumor deposits on WSI were changed according to the evidence of tumor interaction with the surrounding tissues confirmed using WBI. Furthermore, WBI revealed 25 additional lymph nodes, six of which were metastatic. The combination of conventional hematoxylin and eosin-stained imaging and WBI may contribute to an accurate pathological assessment.

Clinicopathological characteristics of colorectal serrated polyposis syndrome (SPS): results of a multicenter study by the SPS Study Group in Japan.

BACKGROUND: Serrated polyposis syndrome (SPS), a type of colorectal polyposis characterized by multiple serrated polyps, is associated with a high risk of colorectal carcinoma (CRC). This study aimed to clarify the clinicopathological characteristics of SPS in Japan. METHODS: We investigated the clinicopathological characteristics of patients with SPS from the "Multicenter Study on Clinicopathological Characteristics of SPS (UMIN 000032138)" by the Colorectal Serrated Polyposis Syndrome (SPS) Study Group. In this study, patients were diagnosed with SPS based on the 2019 World Health Organization (WHO) SPS diagnostic criteria. RESULTS: Ninety-four patients were diagnosed with SPS in 10 institutions between January 2001 and December 2017. The mean number (± standard deviation [SD]) of resected lesions per patient was 11.3 ± 13.8. The mean age at diagnosis of SPS was 63.3 ± 11.6 years, and 58 patients (61.7%) were male. Eighty-seven (92.6%) and 16 (17.0%) patients satisfied WHO diagnostic criteria I and II, respectively. Nine patients (9.6%) satisfied both criteria I and II. Carcinoma (T1-T4) were observed in 21 patients (22.3%) and 24 lesions. Of the 21 patients with CRC, 19 (90.4%) satisfied diagnostic criterion I, 1 (4.8%) satisfied diagnostic criterion II, and 1 (4.8%) satisfied diagnostic criteria I and II. There was no notable difference in the prevalence of CRC among patients who met diagnostic criterion I, II, and both I and II. CONCLUSIONS: Patients with SPS have a high risk of CRC and should undergo regular surveillance colonoscopy. Raising awareness of this syndrome is crucial.