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.

Non-polypoid Colorectal Lesions Detection and False Positive Detection by Artificial Intelligence under Blue Laser Imaging and Linked Color Imaging.

Objectives: Artificial intelligence (AI) with white light imaging (WLI) is not enough for detecting non-polypoid colorectal polyps and it still has high false positive rate (FPR). We developed AIs using blue laser imaging (BLI) and linked color imaging (LCI) to detect them with specific learning sets (LS). Methods: The contents of LS were as follows, LS (WLI): 1991 WLI images of lesion of 2-10 mm, LS (IEE): 5920 WLI, BLI, and LCI images of non-polypoid and small lesions of 2-20 mm. LS (IEE) was extracted from videos and included both in-focus and out-of-focus images. We designed three AIs as follows: AI (WLI) finetuned by LS (WLI), AI (IEE) finetuned by LS (WLI)+LS (IEE), and AI (HQ) finetuned by LS (WLI)+LS (IEE) only with images in focus. Polyp detection using a test set of WLI, BLI, and LCI videos of 100 non-polypoid or non-reddish lesions of 2-20 mm and FPR using movies of 15 total colonoscopy were analyzed, compared to 2 experts and 2 trainees. Results: The sensitivity for LCI in AI (IEE) (83%) was compared to that for WLI in AI (IEE) (76%: p=0.02), WLI in AI (WLI) (57%: p<0.01), BLI in AI (IEE) (78%: p=0.14), and LCI in trainees (74%: p<0.01). The sensitivity for LCI in AI (IEE) (83%) was significantly higher than that in AI (HQ) (78%: p<0.01). The FPR for LCI (6.5%) in AI (IEE) were significantly lower than that in AI (HQ) (17.3%: p<0.01). Conclusions: AI finetuned by appropriate LS detected non-reddish and non-polypoid polyps under LCI.

Apomorphine Suppresses the Progression of Steatohepatitis by Inhibiting Ferroptosis.

The role of ferroptosis in steatohepatitis development is largely unknown. We investigated (1) whether hepatocyte ferroptosis occurs in a gene-modified steatohepatitis model without modifying dietary components, (2) whether ferroptosis occurs at an early stage of steatohepatitis, and (3) whether apomorphine, recently reported as a ferroptosis inhibitor, can ameliorate steatohepatitis. Hepatocyte-specific PTEN KO mice were used. Huh 7 and primary cultured hepatocytes isolated from the mice were used in this study. The number of dead cells increased in 10-week-old PTEN KO mice. This cell death was suppressed by the administration of ferroptosis inhibitor ferrostatin-1 for 2 weeks. Apomorphine also ameliorated the severity of steatohepatitis. Treatment with ferroptosis inhibitors, including apomorphine, decreases the level of lipid peroxidase. Apomorphine suppressed cell death induced by RSL-3 (a ferroptosis inducer), which was not suppressed by apoptosis or necroptosis inhibitors. Apomorphine showed a radical trapping capacity with much more potent activity than ferrostatin-1 and Trolox, a soluble form of vitamin E. In addition, apomorphine activated nrf2 and its downstream genes, including HO-1 and xCT. In conclusion, ferroptosis occurs in steatohepatitis from an early stage in PTEN KO mice. In addition, apomorphine ameliorates the severity of steatohepatitis by inhibiting ferroptosis.

Biologic therapy for ulcerative colitis associated with immune thrombocytopenia.

Ulcerative colitis (UC), a subtype of inflammatory bowel disease, occasionally manifests with extraintestinal manifestations. We present a 51-year-old male with refractory UC and immune thrombocytopenia (ITP) resistant to conventional treatments. The introduction of biologics, ustekinumab or adalimumab, resulted in clinical remission of colitis and improvements in platelet count. This case underscores the efficacy of biologics in managing refractory UC associated with ITP, emphasizing their potential to control intestinal inflammation and address concurrent thrombocytopenia, potentially avoiding surgical intervention.

2-Deoxy-D-Glucose Downregulates Fatty Acid Synthase Gene Expression Via an Endoplasmic Reticulum Stress-Dependent Pathway in HeLa Cells.

Fatty acid synthase (FASN) catalyzes the rate-limiting step of cellular lipogenesis. FASN expression is upregulated in various types of cancer cells, implying that FASN is a potential target for cancer therapy. 2-Deoxy-D-glucose (2-DG) specifically targets cancer cells by inhibiting glycolysis and glucose metabolism, resulting in multiple anticancer effects. However, whether the effects of 2-DG involve lipogenic metabolism remains to be elucidated. We investigated the effect of 2-DG administration on FASN expression in HeLa human cervical cancer cells. 2-DG treatment for 24 h decreased FASN mRNA and protein levels and suppressed the activity of an exogenous rat Fasn promoter. The use of a chemical activator or inhibitors or of a mammalian expression plasmid showed that neither AMPK nor the Sp1 transcription factor is responsible for the inhibitory effect of 2-DG on FASN expression. Administration of thapsigargin, an endoplasmic reticulum (ER) stress inducer, or 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a site 1 protease inhibitor, mimicked the inhibitory effect of 2-DG on FASN expression. 2-DG did not further decrease FASN expression in the presence of thapsigargin or AEBSF. Site 1 protease mediates activation of ATF6, an ER stress mediator, as well as sterol regulatory element-binding protein 1 (SREBP1), a robust transcription factor for FASN. Administration of 2-DG or thapsigargin for 24 h suppressed activation of ATF6 and SREBP1, as did AEBSF. We speculated that these effects of 2-DG or thapsigargin are due to feedback inhibition via increased GRP78 expression following ER stress. Supporting this, exogenous overexpression of GRP78 in HeLa cells suppressed SREBP1 activation and Fasn promoter activity. These results suggest that 2-DG suppresses FASN expression via an ER stress-dependent pathway, providing new insight into the molecular basis of FASN regulation in cancer.

Factors affecting complete stone removal and bile duct stone recurrence in patients with surgically altered anatomy treated by double-balloon endoscopy-assisted endoscopic retrograde cholangiography.

OBJECTIVES: This study assessed factors influencing the complete removal and recurrence of bile duct stones in patients with surgically altered anatomy (SAA) undergoing double-balloon endoscopy-assisted endoscopic retrograde cholangiography (DBERC). METHODS: A retrospective analysis of 289 patients with SAA treated for biliary stones with DBERC at Jichi Medical University Hospital (January 2007 to December 2022) was conducted. Evaluation of factors impacting complete stone removal was performed in 257 patients with successful bile duct cannulation. Logistic and Cox proportional hazards regression models were used to compute the odds ratios (ORs) and hazard ratios (HRs) at 95% confidence intervals (CIs). RESULTS: Of 257 patients, 139 (54.0%) and 209 (81.3%) achieved initial and complete removal, respectively. Recurrence occurred in 55 (21.4%) patients. Factors associated with initial complete stone removal included cholangitis (P < 0.01, OR 0.48, 95% CI 0.27-0.83), number of stones (P < 0.01, OR 0.31, 95% CI 0.18-0.54), and largest stone diameter (P < 0.01, OR 0.37, 95% CI 0.20-0.67). The size of the largest stone was associated with complete removal (P = 0.01, OR 0.24, 95% CI 0.13-0.76). Recurrence was associated with cholangitis (P = 0.046, HR 0.54, 95% CI 0.29-0.99), congenital biliary dilatation (P = 0.01, HR 2.65, 95% CI 1.21-5.80), and number of stones (P = 0.02, HR 1.96, 95% CI 1.12-3.41). CONCLUSIONS: Successful complete bile stone removal in patients with SAA depends on the stone diameter and number. Stone recurrence is influenced by the number of stones and history of congenital biliary dilatation.

International consensus on the management of large (≥20 mm) colorectal laterally spreading tumors: World Endoscopy Organization Delphi study.

OBJECTIVES: There have been significant advances in the management of large (≥20 mm) laterally spreading tumors (LSTs) or nonpedunculated colorectal polyps; however, there is a lack of clear consensus on the management of these lesions with significant geographic variability especially between Eastern and Western paradigms. We aimed to provide an international consensus to better guide management and attempt to homogenize practices. METHODS: Two experts in interventional endoscopy spearheaded an evidence-based Delphi study on behalf of the World Endoscopy Organization Colorectal Cancer Screening Committee. A steering committee comprising six members devised 51 statements, and 43 experts from 18 countries on six continents participated in a three-round voting process. The Grading of Recommendations, Assessment, Development and Evaluations tool was used to assess evidence quality and recommendation strength. Consensus was defined as ≥80% agreement (strongly agree or agree) on a 5-point Likert scale. RESULTS: Forty-two statements reached consensus after three rounds of voting. Recommendations included: three statements on training and competency; 10 statements on preresection evaluation, including optical diagnosis, classification, and staging of LSTs; 14 statements on endoscopic resection indications and technique, including statements on en bloc and piecemeal resection decision-making; seven statements on postresection evaluation; and eight statements on postresection care. CONCLUSIONS: An international expert consensus based on the current available evidence has been developed to guide the evaluation, resection, and follow-up of LSTs. This may provide guiding principles for the global management of these lesions and standardize current practices.

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.

Endoscopic Diagnosis of Small Bowel Tumor.

Recent technological advances, including capsule endoscopy (CE) and balloon-assisted endoscopy (BAE), have revealed that small intestinal disease is more common than previously thought. CE has advantages, including a high diagnostic yield, discomfort-free, outpatient basis, and physiological images. BAE enabled endoscopic diagnosis and treatment in the deep small bowel. Computed tomography (CT) enterography with negative oral contrast can evaluate masses, wall thickening, and narrowing of the small intestine. In addition, enhanced CT can detect abnormalities outside the gastrointestinal tract that endoscopy cannot evaluate. Each modality has its advantages and disadvantages, and a good combination of multiple modalities leads to an accurate diagnosis. As a first-line modality, three-phase enhanced CT is preferred. If CT shows a mass, stenosis, or wall thickening, a BAE should be selected. If there are no abnormal findings on CT and no obstructive symptoms, CE should be selected. If there are significant findings in the CE, determine the indication for BAE and its insertion route based on these findings. Early diagnosis of small intestinal tumors is essential for favorable outcomes. For early diagnosis, the possibility of small bowel lesions should be considered in patients with unexplained symptoms and signs after examination of the upper and lower gastrointestinal tract.

Multicenter prospective randomized controlled clinical trial comparing the pocket-creation method with and without single-clip traction of colonic endoscopic submucosal dissection.

BACKGROUND: The pocket-creation method (PCM) was developed to overcome the technical difficulties of endoscopic submucosal dissection (ESD), although opening the pocket remains challenging. We developed a novel technique of PCM with single-clip traction (PCM-CT), which uses a reopenable clip as a traction device to maintain stability during the procedure. No prospective study has compared the efficacy of PCM-CT and PCM. This study aimed to investigate the effectiveness of PCM-CT vs. PCM in a randomized controlled trial. METHODS: This randomized controlled clinical trial was conducted at four Japanese institutions. Patients with superficial colorectal neoplastic lesions were included following Japanese guidelines for colorectal cancer. Seven moderately experienced endoscopists performed the ESD procedures using either PCM-CT or PCM. RESULTS: 100 patients were enrolled in the study. Compared with PCM, PCM-CT achieved significantly faster mean (SD) dissection speed (21.4 [10.8] vs. 27.0 [14.5] mm2/min [95%CI 0.5 to 10.7], P = 0.03), and reduced the mean procedure time (81.8 [57.9] vs. 64.8 [47.6] minutes [95%CI -38.2 to 4.3], P = 0.12) and pocket-opening time (37.8 [33.0] vs. 30.0 [28.9] minutes [95%CI -20.2 to 4.6], P = 0.22). En bloc and R0 resection rates were not significantly different between the two groups (100% vs. 100%, P >0.99; 100% vs. 96%, P = 0.50, respectively). No significant differences were observed in adverse events between the two groups. CONCLUSION: ESD facilitated by the novel PCM-CT method appeared to be significantly faster than PCM. Both methods achieved high R0 resection rates.

Outcomes of Metastatic and Unresectable Small Bowel Adenocarcinoma in Japan According to the Treatment Strategy: A Nationwide Observational Study.

PURPOSE: Limited information is available regarding the characteristics and outcomes of stage IV small bowel adenocarcinoma (SBA) in Japan. This study examined the clinical and pathological characteristics and outcomes according to the treatment strategies in patients with stage IV SBA. METHODS: This retrospective observational study used the data of patients with jejunal or ileal adenocarcinoma collected by the Small Bowel Malignant Tumor Project of the Japanese Society for Cancer of the Colon and Rectum. Descriptive statistics were expressed as the mean (standard deviation) or median (range). Survival analysis was performed using Kaplan-Meier curves and pairwise log-rank tests. RESULTS: Data from 128 patients were analyzed. The treatment strategies were chemotherapy alone (26 of 128, 20.3%), surgery alone (including palliative surgery; 21 of 128, 16.4%), surgery + chemotherapy (74 of 128, 57.8%), and best supportive care (7 of 128, 5.5%). The median (range) overall survival was 16 (0-125) months overall, and 11 (1-38) months, 8 (0-80) months, 18 (0-125) months, and 0 (0-1) months for the chemotherapy, surgery, surgery + chemotherapy, and best supportive care groups, respectively. Three main categories of chemotherapeutic regimen were used: a combination of fluoropyrimidine and oxaliplatin (F + Ox), fluoropyrimidine and irinotecan (F + Iri), and single-agent fluoropyrimidine. Among patients treated with chemotherapy, the median (range) OS was 16 (1-106) months overall, and 17 (1-87) months, 29 (7-39) months, and 16 (1-106) months in patients treated with fluoropyrimidine, F + Iri, and F + Ox, respectively. CONCLUSION: Patients treated with surgery, chemotherapy, or both had a better prognosis than those who received best supportive care. Among patients who received chemotherapy, survival did not differ according to the chemotherapeutic regimen.

Clinicopathological features and prognosis of primary small bowel adenocarcinoma: a large multicenter analysis of the JSCCR database in Japan.

BACKGROUND: The clinicopathological features and prognosis of primary small bowel adenocarcinoma (PSBA), excluding duodenal cancer, remain undetermined due to its rarity in Japan. METHODS: We analyzed 354 patients with 358 PSBAs, between January 2008 and December 2017, at 44 institutions affiliated with the Japanese Society for Cancer of the Colon and Rectum. RESULTS: The median age was 67 years (218 males, 61.6%). The average tumor size was 49.9 (7-100) mm. PSBA sites consisted of jejunum (66.2%) and ileum (30.4%). A total of 219 patients (61.9%) underwent diagnostic small bowel endoscopy, including single-balloon endoscopy, double-balloon endoscopy, and capsule endoscopy before treatment. Nineteen patients (5.4%) had Lynch syndrome, and 272 patients (76.8%) had symptoms at the initial diagnosis. The rates for stages 0, I, II, III, and IV were 5.4%, 2.5%, 27.1%, 26.0%, and 35.6%, respectively. The 5-year overall survival rates at each stage were 92.3%, 60.0%, 75.9%, 61.4%, and 25.5%, respectively, and the 5-year disease-specific survival (DSS) rates were 100%, 75.0%, 84.1%, 59.3%, and 25.6%, respectively. Patients with the PSBA located in the jejunum, with symptoms at the initial diagnosis or advanced clinical stage had a worse prognosis. However, multivariate analysis using Cox-hazard model revealed that clinical stage was the only significant predictor of DSS for patients with PSBA. CONCLUSIONS: Of the patients with PSBA, 76.8% had symptoms at the initial diagnosis, which were often detected at an advanced stage. Detection during the early stages of PSBA is important to ensure a good prognosis.

Potential for expanding indications and curability criteria of endoscopic resection for early gastric cancer in elderly patients: results from a Japanese multicenter prospective cohort study.

BACKGROUND AND AIMS: Evidence for endoscopic resection (ER) in elderly patients with early gastric cancer (EGC) is limited. We assessed its clinical outcomes and explored new indications and curability criteria. METHODS: We analyzed data from a Japanese multicenter, prospective cohort study. Patients aged ≥75 years with EGC treated with ER were included. We classified eCuraC-2 (corresponding to noncurative ER, defined in the Japanese gastric cancer treatment guidelines) into elderly-high (>10% estimated metastatic risk) and elderly-low (EL-L) (≤10% estimated metastatic risk). RESULTS: In total, 3371 patients with 3821 EGCs were included; endoscopic submucosal dissection was the prominent treatment choice. Among them, 3586 lesions met the guidelines' ER indications, and 235 did not. The proportions of en bloc and R0 resections and perforations were 98.9%, 94.4%, and 0.8%, respectively, in EGCs within the indications. In EGCs beyond the indications, they were 99.5%, 85.4%, and 5.9%, respectively, for lesions diagnosed as ≤3 cm and 96.0%, 64.0%, and 18.0%, respectively, for those >3 cm. Curative ER and EL-L were observed in 83.6% and 6.2% of lesions within the indications, respectively, and in 44.2% and 16.8% of lesions <3 cm beyond the indications, respectively. The 5-year cumulative gastric cancer death rates after curative ER and elderly-high were 0.3% (95% confidence interval [CI], 0.2-0.6) and 3.5% (95% CI, 2.0-5.7), respectively. After EL-L, the rate was 0.9% (95% CI, 0.2-3.5) even without subsequent treatment. CONCLUSIONS: The usefulness of endoscopic submucosal dissection for elderly EGC patients was confirmed by their clinical outcomes. Lesions of ≤3 cm and EL-L emerged as new ER indication and curability criteria, respectively. (Clinical trial registration number: UMIN000005871.).

Advancements in endoscopic management of small-bowel polyps in Peutz-Jeghers syndrome and familial adenomatous polyposis.

Before the development of double-balloon enteroscopy (DBE), the standard management of small-bowel polyposis was surgical resection. This is an invasive procedure that could lead to short bowel syndrome. In the 21st century, several new enteroscopy techniques were distributed worldwide, including DBE, single-balloon enteroscopy, spiral enteroscopy, and motorized spiral enteroscopy. These devices enable the diagnoses and endoscopic interventions in the entire small bowel, even in patients with a history of laparotomy. In patients with Peutz-Jeghers syndrome (PJS), endoscopic ischemic polypectomy with clips or a detachable snare is the preferred method for managing pedunculated polyps because it is less likely to cause adverse events than conventional polypectomy. Although polyps in patients with PJS always recur, repeat endoscopic resection can reduce the total number and mean size of polyps in the long-term clinical course. Endoscopic reduction of small-bowel intussusception caused by PJS polyps can be successfully performed using DBE without surgery. A transparent hood is useful for securing a visual field during the treatment of small-bowel polyps, and minimal water exchange method is recommended to facilitate deep insertion. Familial adenomatous polyposis (FAP) is a genetic disorder that increases the risk of developing colorectal cancer. Because jejunal and ileal polyps in patients with FAP have the potential to develop into cancer via the adenoma-carcinoma sequence, periodical surveillance, and endoscopic resection are needed for them, not only polyps in the duodenum. In cases of multiple small-bowel polyps in patients with FAP, cold snare polypectomy without retrieval is an acceptable treatment option for polyps that are 10 mm or smaller in size. Additional good pieces of evidence are necessary to confirm these findings because this narrative review mostly includes retrospective observational studies from single center, case reports, and expert reviews.

Elevated luminal inorganic phosphate suppresses intestinal Zn absorption in 5/6 nephrectomized rats.

Zinc (Zn) is an essential trace element in various biological processes. Chronic kidney disease (CKD) often leads to hypozincemia, resulting in further progression of CKD. In CKD, intestinal Zn absorption, the main regulator of systemic Zn metabolism, is often impaired; however, the mechanism underlying Zn malabsorption remains unclear. Here, we evaluated intestinal Zn absorption capacity in a rat model of CKD induced by 5/6 nephrectomy (5/6 Nx). Rats were given Zn and the incremental area under the plasma Zn concentration-time curve (iAUC) was measured as well as the expression of ZIP4, an intestinal Zn transporter. We found that 5/6 Nx rats showed lower iAUC than sham-operated rats, but expression of ZIP4 protein was upregulated. We therefore focused on other Zn absorption regulators to explore the mechanism by which Zn absorption was substantially decreased. Because some phosphate compounds inhibit Zn absorption by coprecipitation and hyperphosphatemia is a common symptom in advanced CKD, we measured inorganic phosphate (Pi) levels. Pi was elevated in not only serum but also the intestinal lumen of 5/6 Nx rats. Furthermore, intestinal intraluminal Pi administration decreased the iAUC in a dose-dependent manner in normal rats. In vitro, increased Pi concentration decreased Zn solubility under physiological conditions. Furthermore, dietary Pi restriction ameliorated hypozincemia in 5/6 Nx rats. We conclude that hyperphosphatemia or excess Pi intake is a factor in Zn malabsorption and hypozincemia in CKD. Appropriate management of hyperphosphatemia will be useful for prevention and treatment of hypozincemia in patients with CKD.NEW & NOTEWORTHY We demonstrated that elevated intestinal luminal Pi concentration can suppress intestinal Zn absorption activity without decreasing the expression of the associated Zn transporter. Increased intestinal luminal Pi led to the formation of an insoluble complex with Zn while dietary Pi restriction or administration of a Pi binder ameliorated hypozincemia in chronic kidney disease model rats. Therefore, modulation of dietary Pi by Pi restriction or a Pi binder might be useful for the treatment of hypozincemia and hyperphosphatemia.