Society: ASGE

Background & Aim:
Non-variceal upper gastrointestinal bleeding (NVUGIB) accounts for a significant number of patient visits to emergency rooms and remains a major cause of mortality and morbidity worldwide. The re-bleeding rates of NVUGIB after endoscopic treatment within 72 hours have been reported to be up to 25%. re-UI-EWD is a newly developed novel endoscopic hemostatic powder UI-EWD(UI-EWD) that forms an adhesive hydropolymer when sprayed on the surface of the gastrointestinal tract. The aim of this study was to evaluate efficacy of UI-EWD on decreasing the re-bleeding rate after standard endoscopic treatment (SET) of acute NVUGIB.
Methods:
This prospective, multicenter, randomized controlled trial was conducted from December 2018 to November 2021. Consecutive patients with acute NVUGIB from high-risk lesions (Forrest classification Ia, Ib, and IIa) who achieved immediate hemostasis through SET were randomized in a 1:1 ratio to UI-EWD powder (P) with SET group (SET+P, test) vs SET only group (SET, control). Primary outcomes were defined as re-bleeding rate within 72 hours following treatment and secondary outcomes were re-bleeding rate within 30 days following treatment, as well as safety of UI-EWD.
Results:
A total of 348 patients were randomized into the test (n=175) vs control (n=173) groups. Baseline characteristics were not statistically different between groups. The classification of lesion type (test vs control: Forrest Ia and Ib, 115(66.8%) vs 113(67.3%), p=0.831), Glasgow-Blatchford bleeding score (test vs control: 10.7 vs 10.4, p=0.589) was not statistically different between groups. Re-bleeding rate within 3 days was statistically significantly lower in the test group than in the control group (2.9% (n=5) vs 11.3% (n=19), p=0.005). The 30-day cumulative re-bleeding rate was also lower in the test group than in the control group [7.0% (n=12) vs 18.5% (n=31), p=0.003] There was no reported UI-EWD related adverse events such as perforation, bowel obstruction, or gas embolization during the study period.
Conclusion:
This study demonstrates that UI-EWD application following SET significantly reduced 3-day and 30-day re-bleeding rates in patients treated for NVUGIB without any adverse reactions.

Introduction

The utilization of PuraStat® (3D Matrix Europe SAS, Caluire-et-Cuire, France), a viscous transparent gel which utilizes self-assembling peptide (SAP) technology, as a hemostatic agent has been reported in cardiac and sinus surgery. Recently, several studies have evaluated its use in acute gastrointestinal bleeding (GIB). To appraise the published literature further, we conducted a systematic review & meta-analysis of the efficacy and safety of PuraStat® in upper and lower GIB.

Methods

A systematic search of several databases was performed through November 2022 to identify studies assessing the utilization of endoscopically delivered PuraStat® as a primary or salvage hemostatic agent for upper and lower GIB. Endpoints assessed included technical success, defined as complete coverage of the lesion by the gel, initial hemostasis, defined as visual confirmation of bleeding cessation following application, and cumulative 7-day and 30-day rebleeding rates. Pooled proportions of outcomes assessed were calculated using the random-effects model. Heterogeneity was assessed using I² statistics. All p-values <0.05 were considered statistically significant.

Results

A total of 7 studies with 404 patients (256 males and 148 females) were included in the final analysis. The mean/median age ranged from 66.9 to 76 years. A variety of lesions and etiologies of high-risk (oozing/spurting) GIB including peptic ulcer disease (PUD), vascular lesions e.g., angiectasias, mucosal lesions e.g., Mallory-Weiss, refractory radiation proctitis as well as post-resection bleeding [endoscopic mucosal resection (EMR)/endoscopic submucosal dissection (ESD)], among others, were included. The overall pooled rate of technical success was 100% [95% Confidence Interval (CI) 0-100; I² 0%]. The pooled rate of initial hemostasis as primary and salvage therapy was 92.98% (95% CI 87.5-96.17; I² 32%) and 86.12% (95% CI 70.55-94.15; I² 81%), respectively. The quantity of PuraStat® needed to achieve hemostasis ranged from 1-6 mL and the average application time was 2 minutes (from 2 studies).

The pooled proportions of cumulative, 7-day, and 30-day rebleeding rates were 11.39% (95%CI 4.78-24.79; I² 84%), 10.56% (95%CI 1.53-47.29; I² 88%), 10.46% (95%CI 5.97-17.67; I² 54%), respectively. No adverse events were noted after PuraStat® application.

Conclusion

Our study demonstrates that application of PuraStat® to bleeding culprit gastrointestinal lesions is safe, technically feasible and is highly effective in achieving hemostasis as primary as well as salvage therapy. Furthermore, it can be applied quickly and significantly reduces the risk of delayed bleeding. Further studies are warranted to validate our findings.

Clinical outcomes for utilization of endoscopically delivered PuraStat® for upper and lower gastrointestinal bleeding.

Clinical outcomes for utilization of endoscopically delivered PuraStat® for upper and lower gastrointestinal bleeding.

Introduction
Exogenous insulin is the final treatment for controlling hyperglycemia in patients with type 2 diabetes (T2D) but contributes to weight gain and deterioration of metabolic health. Earlier studies have shown that duodenal mucosal ablation and regeneration (DMR) results in better glycemic control by improving insulin resistance, the root cause of T2D and metabolic syndrome. Pulsed Electric Field technology induces electroporation of the cell membrane by intermittent electric fields, causing apoptosis of affected cells. Re-Cellularization via Electroporation Therapy (ReCET™), is a novel endoscopic procedure that uses electroporation to elicit cell apoptosis and renewal while preserving tissue structure. In this study we aimed to eliminate insulin treatment in T2D patients with a single ReCET procedure combined with a GLP-1 receptor agonist (GLP-1RA). Safety, feasibility, and efficacy of the procedure were assessed.

Methods
Single arm, single center, first in human study in 14 T2D patients, between 28-75 years old, body mass index (BMI) 24-40 kg/m², with a glycosylated hemoglobin (HbA1c) ≤ 8.0%, basal insulin dose <1U/kg/day, C-peptide ≥ 0.2 nmol/l. All patients underwent the endoscopic ReCET procedure under deep sedation, followed by a 2 week post-procedural isocaloric liquid diet. Thereafter semaglutide (GLP-1RA) was started and titrated up to 1 mg/week. Primary feasibility endpoints (procedure time [time from catheter-in to catheter-out], technical success rate, % of patients tolerating GLP-1RA) and safety endpoints ((S)AEs, hypoglycemic events) were assessed. Primary efficacy endpoint was the number of subjects off insulin at 6 months with HbA1c ≤ 7.5%. Baseline and 6 months follow-up glycemic and metabolic data and treatment satisfactory scores were collected and assessed with Wilcoxon paired signed-rank test.

Results
All 14 patients underwent the ReCET procedure and completed 6 months follow-up. ReCET showed a technical success rate of 100% with a median axial treatment length of 12 centimeter (Table 1). Procedure time was 58 (IQR 49–79) minutes. The maximum dosage semaglutide was tolerated by 13 (93%) patients. No device related SAEs were observed. One patient experienced a hypoglycemic event without need for third party assistance. At 6 months, 12 (86%) patients were off insulin, yet showed a significant improvement in glycemic control (HbA1c, fasting plasma glucose, time in range of glucose values) and metabolic parameters with improvement of treatment satisfaction (Table 2).

Conclusion
These results suggest that the ReCET procedure is safe and feasible. ReCET in combination with semaglutide is a promising new therapeutic option that may effectively eliminate insulin therapy in selected T2D patients, while improving glycemic control and overall metabolic health.

Background & aims
Anti-reflux mucosectomy (ARMS) is effective to treat gastroesophageal reflux disease (GERD) with impaired gastroesophageal flap valve. However, the time to remodel the valve by healing is long and the risk of stricture. bleeding and perforation are also the concerns. Purse-string suturing with endoloop is applied to provide complete closure of defects in endoscopic intervention. We aimed to evaluate the efficacy and safety of a modified ARMS with purse-string suturing, called endoscopic gastroesophageal flap valvuloplasty.

Methods
From 1 November 2021 to 30 November 2022, 47 patients underwent endoscopic gastroesophageal flap valvuloplasty in the GERD center, Yuan-Sheng branch of Yuan-Rung Hospital, were analyzed retrospectively. All patients were diagnosed with pathological GERD by endoscopy, 24-hour pH-Impedance test, or 96-hour wireless capsule pH test and high-resolution impedance manometry.
Results
In total, 47 patients were analyzed and the mean follow-up days is 5.57 months. Remodeling the GEF valve to Hill grade I is 100% in the end of valvuloplasty and kept 78.9% and 100% for Hill grade II and III even more than two months later. The success rate of remodeling GEFV to Hill grade I in three patients with a previous history of Stretta or ARMS is 100% in longer than 2 months follow-up. The total procedure time is 84.5 ± 20.2 minutes including 54.3 ± 15.8 (ARMS procedure) and 30.2 ± 10.4 minutes (purse-string suturing). No dysphagia or chest pain was noted 2 weeks after valvuloplasty. No bleeding, infection, stricture, or perforation occurs during follow-up.
Conclusions
Endoscopic gastroesophageal flap valvuloplasty composed of ARMS and endoloop-assisted purse-string suturing, can remodel the impaired gastroesophageal flap vale effectively, instantly, and safely in pathological GERD patients.

Background: The pathophysiology of gastroparesis is poorly understood. ICC depletion and collagen fibrosis have been identified in surgical full-thickness biopsies of the pylorus/antrum. In this ongoing study, we seek to evaluate the feasibility of quantifying ICC and the degree of fibrosis from pyloric muscle biopsies during G-POEM.
Methods: Prospective evaluation of all consecutive patients with refractory gastroparesis who underwent G-POEM between December 1st 2021 and September 30th, 2022. After completion of the pyloromyotomy during G-POEM, biopsy of the pyloric muscle was performed using routine cold biopsy forceps. Endoscopy, 4-hour gastric emptying study (GES), endoscopic impedance planimetry (FLIP), and gastroparesis cardinal symptom index (GCSI) scores were all prospectively collected. Pyloric muscle biopsies were stained for hematoxylin and eosin, Masson’s trichome and CD117 immunoperoxidase. A biopsy specimen with at least 1 fragment of muscularis propria was deemed adequate. ICC was estimated using CD117 stain and Trichome stain was used to evaluate for fibrosis. Primary outcome was proportion of patients with adequate histopathological specimen for ICC and fibrosis quantification. Secondary outcome included characterization of pyloric muscle ICC and degree of fibrosis in patients undergoing G-POEM. ICC depletion was defined as ICC count < 10/high-power field (HPF).
Results: Thirty-one patients (mean age 56.3 ± 16.4 years, 64.5% women) with medically refractory gastroparesis (diabetes mellitus, n=8; post-surgical, n=12; idiopathic, n=11) underwent G-POEM during the study period. Mean baseline 4-hour retention percentage on GES and GCSI score were 43.4 ± 23.6 and 3.1 ± 1.3, respectively. G-POEM was successfully completed in all cases. Out of the 31 cases, adequate histological specimen for ICC quantification and grading of fibrosis was attained in 29 (93.5%) and 30 (96.8%) cases, respectively. There were no cases of post-procedural bleeding or perforation. The mean ICC count was 6.7 ± 3.1. Pyloric ICC was depleted in 24 out of the 29 cases (82.8%), whereas moderate/severe fibrosis was encountered in 16 out of 30 samples (53.3%). When compared to patients with ICC count >10/HPF, those with depleted ICC trended towards higher baseline 4-hour retention percentage on GES but this was not statistically significant (33 ± 24.4% vs 45.6 ± 23.3%, p=0.3).
Conclusion: Quantification of ICC and grading of fibrosis was both feasible and safe via pyloric muscle biopsies obtained during G-POEM. Our initial data shows that most patients referred for G-POEM have depletion of ICC and more than half endorse moderate to severe collagen fibrosis at the pylorus. Larger sample size from this ongoing prospective study may provide additional data on potential associations between histological findings and disease characteristics and outcomes of G-POEM.

Figure 1. Endoscopic view of biopsy forceps sampling of pyloric muscle during G-POEM (A). Interstitial cells of Cajal (cells with brown wavy cytoplasm) highlighted by CD117 stain (B). Grade 1 fibrosis (blue) among smooth muscle cells (red) stained with Masson's Trichome (C). Both at 200X magnification.

Figure 1. Endoscopic view of biopsy forceps sampling of pyloric muscle during G-POEM (A). Interstitial cells of Cajal (cells with brown wavy cytoplasm) highlighted by CD117 stain (B). Grade 1 fibrosis (blue) among smooth muscle cells (red) stained with Masson's Trichome (C). Both at 200X magnification.

Table 1. Baseline, Procedural and Histological Characteristics

Table 1. Baseline, Procedural and Histological Characteristics

BACKGROUND: Endoscopic full-thickness resection (EFTR) using the full-thickness resection device (FTRD) is effective at resection of colonic lesions not amenable to standard techniques. Data on the clinical efficacy and safety of endoscopic resection using the novel gastroduodenal (g)FTRD system for upper gastrointestinal (UGI) tract lesions is limited.

AIMS: To evaluate the efficacy and safety of a newly designed gFTRD for EFTR of UGI tract lesions.

METHODS: Consecutive patients >18 years who received EFTR of UGI tract lesion (6/2020-8/2022) with gFTRD were evaluated from eight U.S. centers. Primary endpoints included rates of technical success and R0 resection. Secondary endpoints were rates of en bloc resection, residual lesions at follow-up endoscopy, technical failure, and immediate/delayed adverse events.

RESULTS: Forty-four patients (mean age 60.9±15.8 years) received EFTR with mean pre- and post-resection size of 11.5±4.4 mm and 17.6±5.4 mm. Lesions were located in the stomach in 35 (80%) and duodenum in 9 (20%); 34 (77%) subepithelial and 10 (23%) were epithelial lesions. Technical success, en-bloc resection, and R0 resection were achieved in 43 (96%), 41 (91%), and 32 (71%) patients, respectively. Final pathologic diagnosis included neuroendocrine tumor in 14 (32%), gastrointestinal stromal tumor in 10 (23%), leiomyoma in 5 (11%), gastric cancer in 4 (9%), and adenoma with high grade dysplasia in 3 (7%). Minor immediate and delayed bleeding occurred in 17 (38%) and 2 (4%) patients. One patient had a delayed contained perforation managed without surgery. On follow-up endoscopy (mean of 160±104 days from resection), 19 (90%) of 21 patients had no evidence of residual lesion. On multivariate analysis, subepithelial compared to epithelial lesion was associated with R0 resection (p-value = 0.047).

CONCLUSION: In this large multicenter experience, the gFTRD system showed a high technical success rate with a high en-bloc resection rate for upper GI tract lesions, particularly subepithelial lesions. A significant number of patients showed immediate minor bleeding that required minimal intervention. The risk for major events was low. Our study suggests that gFTRD is a safe and effective therapeutic option for endoscopic resection of UGI tract lesions.

Introduction: Photoimmunotherapy with ASP-1929 (anti-EGFR antibody cetuximab conjugated to IRDye 700DX) and illumination of 690 nm visible red light is a combination therapy being investigated for selective cancer cell killing. Results from a phase IIa trial of photoimmunotherapy with RM-1929 (analogous to ASP-1929), showed a 43% objective response rate for recurrent head and neck squamous cell carcinoma (rHNSCC), and led to a conditional approval for ASP-1929 for rHNSCC in Japan. Meanwhile, PD-1 blockade reverses adaptive immune resistance, resulting in activation of tumor infiltrating lymphocytes after photoimmunotherapy in syngeneic mouse models. We aimed to investigate the safety and efficacy of photoimmunotherapy with ASP-1929 in combination with nivolumab for advanced gastric cancer.
Methods: The study was an open-label, single-arm, single-center, Phase Ib clinical trial. Eligible patients present with unresectable EGFR-positive gastric adenocarcinoma after standard chemotherapy. The dose escalation cohort was designed to determine the recommended dose (RD) of laser illumination energy density in a “3+3” design (50, 75, and 100 J/cm²). Nivolumab was administered at 240 mg on Day 1, ASP-1929 was administered at 640 mg/m² on Day 8 (Day 1 in the expansion cohort), and laser illumination was performed under endoscopy using the laser photoimmunotherapy unit and frontal diffuser or cylindrical light diffuser with centering balloon catheter on Day 9 (Day 2 in the expansion cohort). A maximum of 8 cycles of photoimmunotherapy was allowed if residual cancer is observed at primary site. The primary endpoint was proportion of incidence of dose-limiting toxicity (DLT), and other endpoints were treatment response and adverse events (AE). This study was registered at JapicCTI (JapicCTI-194969).
Results: From October 2019 to April 2022, 9 and 12 patients were enrolled into the dose escalation cohort and the expansion cohort, respectively. All 21 patients had received ≥ 2 previous lines of chemotherapy, and 7 patients had been previously treated with anti-PD-1 therapy. No DLT was observed in the dose escalation cohort, and the RD of laser illumination energy density was determined to be 100 J/cm². In total, 10 patients underwent 2 cycles or more of photoimmunotherapy. At the site of treatment, 1 patient achieved local partial response, 16 patients exhibited local stable disease and 4 patients were not evaluable by endoscopic assessment. Meanwhile, at distant metastases, 2 patients achieved partial response, 11 patients sustained stable disease, 3 patients were not evaluable, and 5 patients had disease progression according to RECIST criteria. With respect to AEs related to photoimmunotherapy with ASP-1929, one patient presented with grade 3 esophagitis.
Conclusion: Endoscopic photoimmunotherapy with nivolumab is feasible with an acceptable safety profile.

Akihiro Sato

Appearances