Introduction

One third of the world population is affected by obesity. Laparoscopic Sleeve Gastrecotomy (LSG) is the most widely used surgical treatment currently used to treat severe obesity. However, it appears to increase the risk of developing Gastro-Esophageal Reflux Disease (GERD) and its complications, such as Barrett's esophagus (Genco A. et Al, 2017).
Aim of this study was to evaluate possible impairment of the anti-reflux barrier function of the Esophageal-Gastric Junction (EGJ) in patients with severe obesity undergoing LSG by studying functional aspects of the EGJ by High Resolution Esophageal Manometry (HRM) with perfusion system and 24-hour pH-metry.

Aims & Methods

Forty-five obese patients, without evidence of hiatus hernia or GERD, undergoing LSG (34F 11M; 45±12 yrs) were compared with 21 overweight patients (10F 11M; 52±16 yrs) and 21 normal weight patients (17F 4M; 47±14 yrs) with GERD symptoms. Twenty-four of the obese patients (3M 21F; 45±11 yrs) were reevaluated after LSG.
The EGJ was evaluated by the EsophagoGogastic Junction–Contractile Integral (CI) on HRM, that integrates the inspiratory and expiratory pressures, the length and the duration of the contraction of the EGJ during three respiratory cycles at rest. It was calculated for Single Respiratory Cycle (EGG-CI SRC) and corrected for duration of the breathing (EGG-CI CRC). The findings were compared with normal ranges suggested in the literature (EGJ-CI-SRC 205.5±35.6 mmHg·cm·s and EGJ-CI-CRC 46.2±7.6 mmHg·cm) (Gor P. et Al, 2016).

Results

The 3 groups of patients, obese, overweight and normal weight, did not differ statistically for EGJ-CI SRC (120.3 ± 112.7 vs 116 ± 120 vs 103.7 ± 102.6 mmHg·cm·s, respectively) nor for EGJ-CI CRC (42.8 ± 31 vs 33.4 ± 28.2 vs 33.0 ± 28.5 mmHg·cm, respectively). After LSG a statistically significant decrease was observed for EGJ-CI CRC (46.7±36.8 vs 32.3±26.4 mmHg·cm, p=0.02), but not for EGJ-CI SRC (133.6±141 vs 115.2±103.6 mmHg·cm·s, n.s.). Twelve patients (50%) showed after LSG an acid exposure time above the normal limits and this result was related to the degree of reduction of EGJ-CI-CRC (r = 0.525; p = 0.01).The results of this study indicate that the esophagogastric barrier function of the EGJ is reduced in obese patients similarly to GERD patients regardless of BMI and appears to decrease further after LSG surgery, affecting its efficiency and probably favoring the onset of GERD.

Conclusion

In conclusion, the evidence that LSG affects the EGJ and may induce GERD suggests that HRM and 24-hour pH-mertry or 24-hour pH-impedancemetry could be useful in the work-up for bariatric surgery to identify subjects without or scarce reflux symptoms, but showing impaired functions that could worsen with surgery favoring the onset of GERD. It is possible that the functional characteristics of the GEG associated with other variables detected by HRM and pH-impedancemetry may in the future develop a predictive score for risk of MRGE in these patients.

References

Genco A, Soricelli E, Casella G, et al. Gastroesophageal reflux disease and Barrett’s esophagus after laparoscopic sleeve gastrectomy: a possible, underestimated long-term complication. Surg Obes Relat Dis 2017;13:568–74.
Gor P, Li Y, Munigala S, et al. Interrogation of esophagogastric junction barrier function using the esophagogastric junction contractile integral: an
observational cohort study. Dis esophagus Off J Int Soc Dis Esophagus 2016;29:820–8.

Disclosure

No conflict of interest

Introduction

Colonoscopy is highly effective yet inefficient at colorectal cancer (CRC) prevention with a prevalence of target (advanced adenomas) of only about 8%. Thus, finding a modality to risk-stratify for colonoscopy would be of public health implications One approach is to leverage field carcinogenesis, the concept that the gene/environmental interaction that predispose to neoplastic lesions are diffuse and thus rectal mucosa can predict risk of proximal neoplasia (1). Given the diffuse molecular alterations, our group has focused on transcriptional assessment through chromatin nano-architecture. While epigenetics such as methylation, histone acetylation etc will be reflected in chromatin nano-architecture, microRNAs (mIRs) provide an independent impact on gene expression. We, therefore, wanted to test whether chromatin + miR markers from the rectum would predict concomitant adenomas.

Aims & Methods

Chromatin Nano-architecture: We used a novel nanoscale optics technology, partial wave spectroscopic microscopy (PWS) which enables us to go quantify chromatin heterogeneity through pixel-to-pixel variability in refractive indices (2). The calculated marker correlated with fractal dimension (D).
Human Studies: We recruited patients undergoing screening/surveillance colonoscopy with IRB consent. Following colonoscopy 6 biopsies of endoscopically normal rectum. We had 104 controls and 53 advanced adenoma patients for these studies. Advanced adenomas were defined as size >10mm, >25% villous features or high grade dysplasia. Controls were those without adenomas/carcinomas.
miR: We used RT-PCR with internal controls. We used literature to identify 4 candidates miRs and used the delta delta approach to compute fold change of miR expression (case versus control).

Results

We analyzed D from the rectal biopsies with PWS from our clinical dataset and observed excellent diagnostic performance of area under receiver operator characteristic curve (AUC) of = 0.85 for those with and without advanced adenomas sensitivity = 0.74, specificity = 0.83.
The potential of our biomarker is also evaluated via combining with epigenetic regulators microRNAs (miR) in an independent pilot study. Evaluating the 4 oncomiRs in 20 human rectal biopsies (10 control, 10 advanced adenoma) had increased expressions in patients harboring advanced adenomas (fold changes were miR137=3.4, miR92a=5.97, miR-135b-5p=174 and miR361-5p=2.01).
With our PWS marker, the elevation of miR-92a, miR-135b-5p, and D was synergistic for discriminating patients with vs. without advanced adenomas to 0.9 increase in AUC compared to D alone. AUC) = 0.90, sensitivity = 0.88, specificity = 0.85.

Conclusion

We demonstrate, for the first time, that the chromatin nano-architectural parameter, D had excellent performance for identifying patients screen relevant neoplasia elsewhere in the colon. Furthermore, adding several miR markers to provide a more comprehensive epigenetic profile was synergistic diagnostics with D. Future studies will employ more miRs and combine with artificial intelligence to further improve the already strong performance for potential clinical impact.

References

Rebello D, Rebello E, Custodio M, Xu X, Gandhi S, Roy HK. Field carcinogenesis for risk stratification of colorectal cancer. Adv Cancer Res. 2021;151:305-344. doi: 10.1016/bs.acr.2021.03.004. Epub 2021 Mar 31. PMID: 34148616.
Gladstein S, Damania D, Almassalha LM, Smith LT, Gupta V, Subramanian H, Rex DK, Roy HK, Backman V. Correlating colorectal cancer risk with field carcinogenesis progression using partial wave spectroscopic microscopy. Cancer Med. 2018 May;7(5):2109-2120. doi: 10.1002/cam4.1357. Epub 2018 Mar 23. PMID: 29573208; PMCID: PMC5943438.

Disclosure

Hemant Roy, Vadim Backman, and Hariharan Subramanian are co-founders, have equity stakes, own IP and are on the Board of Directors for Nanocytomics LLC, a biomedical company providing cancer risk-stratification tests based on their proprietary biophotonics technology platform, partial wave spectroscopic (PWS) microscopy which is being utilized in this research. Sravya Prabhala is also an employee of Nanocytomics LLC.

Introduction

Despite the advancements in imaging modalities, diagnosis of biliary strictures remains challenging in some cases. Endoscopic retrograde cholangiopancreatography (ERCP) is the current gold standard for diagnosis. However, the pathological diagnosis via ERCP is limited due to the small specimen. Therefore, a novel device for the diagnosis of biliary stricture has been long-awaited. Although high sensitivity and specificity have been reported for probe-based confocal laser endomicroscopy (pCLE) for the diagnosis of biliary strictures using the Miami Classification, it remains uncertain whether confocal miniprobes can be properly applied to the target site with the use of pCLE under fluoroscopic guidance. The aim of the present study was to prospectively evaluate the clinical utility of pCLE under the direct view of peroral cholangioscopy (POCS) for the diagnosis of biliary strictures.

Aims & Methods

Consecutive patients with biliary strictures were included. All patients underwent imaging examination, such as computed tomography, magnetic resonance imaging, or endoscopic ultrasound, and were found to have biliary disorders. We investigated sensitivity, specificity, and accuracy to diagnose malignancy for: 1) ERCP alone, 2) POCS, 3) pCLE under the direct view of POCS, and 4) tissue sampling under the direct view of POCS. pCLE images were interpreted prospectively using the Miami Classification. We also evaluated other outcomes of pCLE under the direct view of POCS.

Results

A total of 30 patients (17 with malignant lesions) were prospectively enrolled.
1) ERCP alone showed 88.2% sensitive, 46.2% specific, and 70% (95% confidence interval [CI], 52.1%–83.3%) accurate.
2) POCS showed 100% sensitive, 76.9% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
3) pCLE under the direct view of POCS showed 94.1% sensitive, 92.3% specific, and 93.3% (95% CI, 78.7%–98.8%) accurate.
4) Tissue sampling under the direct view of POCS showed 82.4% sensitive, 100% specific, and 90% (95% CI, 74.4%–96.5%) accurate.
The POCS could not pass the biliary stricture in four patients, and we could not complete successful observation of the target area. Therefore, the success rate of pCLE under the direct view of POCS was 88.2% (30/34). The median procedural time for pCLE under the direct view of POCS was 42 min (interquartile range [IQR], 31.3–48 min). Accurate diagnosis rate of common bile duct and accurate diagnosis rate of hilar and intrahepatic bile duct were 86.7% (13/15), 100% (15/15) respectively. There was no significant difference among stricture locations (P=0.48). Adverse events occurred in three patients (one with mild pancreatitis, and two with mild cholangitis).

Conclusion

pCLE under the direct view of POCS provided highly accurate and sensitive characterization of biliary strictures and showed the potential for more diagnostic reliability and reduction of delays in diagnosis.

Introduction

The early diagnosis of pancreatic cancer has long been considered a major clinical challenge. Recently in Japan, imaging-based screening strategies focusing on indirect findings have ushered in a new era, enabling the detection of carcinoma in situ and high-grade pancreatic intraepithelial neoplasia (PanIN). This study aimed to elucidate the molecular evolutionary mechanisms of PanIN development and progression.

Aims & Methods

We conducted detailed histopathological analysis and multi-regional genomic sequencing on 33 lesions obtained from a single patient with a family history of pancreatic cancer. The patient initially underwent distal pancreatectomy for a branch duct-type intraductal papillary mucinous neoplasm (IPMN) accompanied by adjacent main pancreatic duct (MPD) stenosis, followed by remnant pancreatectomy four years later due to newly detected ductal irregularities. The analyzed lesions included 15 low-grade PanINs, 14 high-grade PanINs, two low-grade IPMNs, and two concomitant pancreatic ductal adenocarcinoma components. Molecular analyses included KRAS and GNAS mutation detection using droplet digital PCR, targeted sequencing using a pancreatic cancer-related gene panel, and whole-exome sequencing. Tumor phenotypes were assessed by immunohistochemistry.

Results

Among numerous low-grade PanINs harboring various KRAS mutations, four distinct multicentric high-grade PanINs arose in the pancreatic body and tail. These included a laterally spreading high-grade PanIN within the stenotic MPD, characterized by KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54; and three discrete high-grade PanINs located in branch ducts, all harboring KRAS G12V accompanied respectively by TP53 Y107D; TP53 S241F and ARID1A Q386X and S2096X; and TP53 G245S and ARID1A Q1066X. A low-grade gastric-type IPMN harboring KRAS G12R was determined to be clonally independent from the adjacent high-grade PanINs. A low-grade PanIN with KRAS G12D was identified at the pancreatic cut margin, though it showed no evidence of malignancy. In the remnant pancreatic head, a high-grade PanIN harboring KRAS G12D, TP53 deletion, and GATA6 Y83TfsX54—identical to the dominant clone in the pancreatic body—had extended along the MPD from the ductal stump to the ampulla. Two small invasive carcinoma foci were found to be continuous with this high-grade PanIN and shared identical KRAS, TP53, and GATA6 mutations, along with additional copy number variations affecting several genes. Another small high-grade PanIN with KRAS G12D and TP53 C275Y was identified in a neighboring branch duct. Furthermore, a germline CDKN2A H66R variant was detected, suggesting a potential hereditary predisposition to pancreatic tumorigenesis. The patient has remained recurrence-free for four years following the remnant pancreatectomy.

Conclusion

In high-risk individuals with a family history of pancreatic cancer or IPMN, PanINs may develop in large numbers, and multiple carcinomas in situ can arise simultaneously. Among these, clones exhibiting pronounced intraductal proliferation or progression toward invasion—thereby impacting clinical outcomes—may be selectively favored. This study provides novel insights into the clonal selection and molecular progression of multicentric high-grade PanINs. To our knowledge, this is the first report to comprehensively delineate the molecular trajectory of multifocal high-grade PanINs in a high-risk patient.

Introduction

Esophageal squamous cell carcinoma (ESCC) can be treated curatively with definitive chemoradiotherapy (CRT). However, local failure, characterized by residue just after CRT or recurrence after achieving complete response with CRT, occurs in 20-40% of patients who received this treatment. Salvage endoscopic therapy is one of the treatment options for cT1N0N0 local failure after CRT or radiotherapy (RT) for ESCC, but most reports on its outcomes are at single center.

Aims & Methods

This multicenter study aimed to clarify the short- and long-term outcomes of salvage endoscopic therapy (endoscopic resection [ER: EMR/ESD] and photodynamic therapy using Talaporfin Sodium [PDT]) for cT1N0M0 local failure after CRT/RT for ESCC, and to identify factors that influence the outcomes of salvage endoscopic therapy. Patients who underwent salvage endoscopic therapy (ER, PDT) for cT1N0M0 local failure after CRT/RT for ESCC at two institutions between December 2012 and August 2021 were retrospectively investigated. The patients were excluded if they were not followed up for more than three months after salvage therapy or had a history of salvage therapy. The selection of the procedure was primarily based on the depth of the tumor and the degree of submucosal fibrosis.

Results

A total of 168 patients were analyzed, of which 86 underwent ER (EMR/ESD = 15/71) and 82 underwent PDT. Among the patients, 140 were male, and the median age was 72 (range: 45-88) years. Lesion characteristics were as follows: The clinical T stage before CRT/RT; T1a/T1b/T2/T3/T4a/unknown = 5/78/24/48/9/4 cases. Local failure before salvage therapy; residual/local recurrent lesions = 107/61 cases. Clinical tumor depth before salvage therapy; EP-LPM/MM-SM1/SM2-SM3 = 54/35/79 cases. 53 of the 54 patients with a tumor depth of EP-LPM underwent ER, while 73 of the 79 patients with a tumor depth of SM2-SM3 underwent PDT. The local complete response rate in PDT was 62% (50/81 patients, 1 not evaluated), and the R0 resection rate in ER was 73% (63/84 patients, 2 not evaluated due to burn effect). One patient in the PDT group died from massive gastrointestinal bleeding due to esophageal-aortic fistula on the 69th day after PDT. The median observation period was 33.5 (2-109) months, and the three-year overall survival (OS), disease-specific survival, local recurrence-free survival (LRFS), and esophagectomy-free survival rates were 79% (95% confidence interval: 71-86%), 88% (80-93%), 54% (46-62%), and 76% (67-82%), respectively. Multivariate analysis revealed that age ≥75 years and residual lesion just after CRT were independent risk factors of OS (p = 0.039 and p = 0.024, respectively). Clinical tumor depth was not a significant risk factor for OS and LRFS. The clinical course after salvage treatment was as follows: 93 patients had no recurrence; 28 patients had lymph node and/or distant metastatic recurrence with/without local failure. Of the 53 patients with local failure (residual: 33, local recurrence: 20) after initial salvage endoscopic therapy, 46 underwent re-salvage therapy (ER: 11, PDT: 27, surgery: 8), and 24 of them are alive without the recurrence of ESCC, while 8 died from the primary disease.

Conclusion

Our results suggest that salvage endoscopic therapy including ER or PDT appears to be an effective treatment option for cT1N0M0 local failure after CRT/RT, regardless of clinical tumor depth, resulting in a certain number of patients achieving long-term survival without the primary disease and preserving their esophagus.

Introduction

The rise in obesity rates has triggered a surge in associated health issues, with metabolic syndrome (MS) affecting approximately 25% of populations in Western countries. Severe acute pancreatitis (AP) is associated with mortality rates as high as 50%. Prior research has linked components of MS to heightened complications and mortality in cases of AP.

Aims & Methods

This meta-analysis aims to elucidate potential risk factors and their combined effects on the outcomes of AP. We performed a systematic search of PubMed, Embase, and the Cochrane Library until November 1, 2023, identifying studies based on specified criteria. We investigated the influence of MS and its components (obesity, hypertension, diabetes mellitus, and hypertriglyceridemia) on AP outcomes, calculating pooled odds ratios (OR) with 95% confidence intervals (CIs). The study protocol was registered with PROSPERO under the identifier CRD42023471092.

Results

From an initial 15,904 records, 93 studies were included in the analysis. Overweight and obesity emerged as significant risk factors for complications (local OR: 2.677, 95%CI: 1.421-5.044; systemic OR: 2.404, 95%CI: 1.481-3.901) and the severity of AP (BMI≥30 kg/m², OR: 3.058, 95%CI: 1.369-6.829). Elevated triglyceride levels were linked to ICU admissions (OR: 2.546, 95%CI: 1.529-4.237) and severe AP (OR: 2.372, 95%CI: 1.275-4.413); hypertension correlated with increased mortality (OR: 2.135, 95%CI: 1.870-2.437), while diabetes was associated with higher odds of ICU admission (OR: 1.645, 95%CI: 1.358-1.992) and severe AP (OR: 1.49, 95%CI: 1.09-2.03). Our findings suggest that MS may elevate the likelihood of severe AP (OR=1.398, 95%CI: 0.918-2.129).

Conclusion

The individual components of metabolic syndrome are significant risk factors for complications, severity, and mortality related to acute pancreatitis. It is imperative to prioritize lifestyle counseling, education, and effective management for patients dealing with obesity.

Introduction

The duodenum plays a key role in regulating metabolism and is known to be dysfunctional early in the development of metabolic diseases such as type 2 diabetes (T2D). Duodenal mucosal resurfacing (DMR) is a non-pharmacologic, investigational, endoscopic treatment designed to hydrothermally ablate the duodenal mucosa to restore the metabolic functionality of the duodenum in people with T2D. DMR has a CE mark, reimbursement in select medical centres in Germany, and has been evaluated in over 300 patients to date with favorable safety and metabolic benefits observed. As part of the currently enrolling, global, pivotal Revitalize 1 trial for DMR, competency-based training and implementation have evolved to support scalable education of advanced-endoscopist investigators.

Aims & Methods

Here, we describe the current endoscopist training program for DMR, demonstrate its alignment with the European Society of Gastrointestinal Endoscopy¹ and the American Society for Gastrointestinal Endoscopy² training and effectiveness principles, and provide evidence that training methodology for DMR has led to acceptable and consistent safety outcomes in Revitalize 1. The training program consists of three core elements designed to enhance advanced-endoscopist proficiency toward safe and efficacious execution of the DMR procedure:
1) Structured didactic overview of the DMR system, procedure, and core competencies;
2) Initial hands-on tracking of the DMR catheter through the validated DMR training simulator; and
3) Hands-on live-patient cases focused on the successful execution of the DMR procedure and demonstration of core competencies.
The DMR simulator was developed and validated to complement the didactic component of the training program and recapitulate endoscopy skills necessary to perform the procedure as intended. Successful training was defined as completion of the full program with demonstration of competency in core DMR skills and troubleshooting techniques using the simulator. Procedural success was defined as performing ablations along the anatomical length of the duodenum from immediately beyond the ampulla of Vater to the Ligament of Treitz, while minimizing longitudinal gaps between areas of ablated mucosa.

Results

The DMR training program has been used to train therapeutic endoscopists in 6 centres in the EU and US as investigators in Revitalize 1. All centres successfully completed training in ~3 hours within 2 weeks of the first case. Nine open-label patients have been treated, to date, with 100% procedural success rate. Baseline characteristics were consistent with uncontrolled T2D despite multiple glucose‑lowering medications and insulin: 66.7% male, median (min, max), age 60 (45, 68) years, HbA1c 8.5% (7.6%, 9.1%), weight 96 (85, 128) kg, and diabetes duration 13 (7, 24) years. Adverse events (AEs) definitely or probably related to the device and/or procedure included sore throat (n=2), abdominal bloating (n=1), and abdominal pain (n=1). AEs were mild and resolved without sequalae. No observed long-term device- or procedure-related AEs, no device- or procedure-related SAEs, and no unanticipated AEs have been observed to date.

Conclusion

The three core elements of the DMR training program, inclusive of the DMR simulator, are scalable and have been reproducibly employed to train advanced therapeutic endoscopists to safely perform the DMR procedure. Results thus far suggest that DMR appears to be a safe, broadly accessible, and disease‑modifying approach to treat metabolic disease, such as T2D, via therapeutic endoscopy.

References

¹Boškoski et al. Curriculum for bariatric endoscopy and endoscopic treatment of the complications of bariatric surgery: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement. Endoscopy. 2023 Mar;55(3):276-293.
²Yang et al. The status of training in new technologies in advanced endoscopy: from defining competence to credentialing and privileging. Gastrointest Endosc. 2020 Nov;92(5):1016-1025.

Disclosure

IB: consultant–Apollo Endosurgery, Boston Scientific, Cook Medical, ERBE Elektromedizin; lecturer–Boston Scientific, Cook Medical, Microtech; grants–Apollo Endosurgery, Erbe Elektromedizin. CG: speaker–Intuitive Surgical (Proctor), BD, WL Gore, Medtronic. JV: consultant–Boston Scientific, Aspero Medical; research funding–Olympus America. MAG: research support/contracted research–Olympus America, Fractyl, Allurion Technologies; Consultant–Boston Scientific, Ambu. ES, KW, and HR: employees and shareholders of Fractyl Health, Inc. RS: Boston Scientific, Cook Medical, Intuitive Surgical.