Correlation between endoscopic ultrasound features and exocrine pancreatic function in chronic pancreatitis.

BACKGROUND: Endoscopic ultrasound (EUS) is the most sensitive method for diagnosing chronic pancreatitis (CP) in its early stages, and Rosemont Classification (RC) is used for its evaluation. Data on the correlation between EUS features and pancreatic exocrine insufficiency (PEI) are limited. We investigated the correlation between the EUS findings and PEI. METHODS: This was a retrospective, monocentric cohort study involving patients prospectively enrolled from 2018 to 2022, with definite or probable CP according to the M-ANNHEIM criteria. All the patients underwent EUS and exocrine function investigations within 12 months of diagnosis. PEI was diagnosed using fecal elastase (FE) or when overt steatorrhea was reversed by pancreatic enzyme replacement therapy. Logistic regression analyses, rank correlation, ROC curve, and area under the curve (AUROC) were performed to evaluate the association between EUS features and PEI, and the accuracy of RC in predicting PEI. RESULTS: Among 128 patients examined (63.3 % male; mean age, 47 years), 69.5 % were diagnosed with PEI. In multivariate logistic regression among all the RC criteria, only lithiasis in the main pancreatic duct (MPD) was associated with increased risk of PEI (OR 2.92, 95 % CI 1.29-6.61; p = 0.01). Rank analysis showed a weak inverse correlation between RC and FE (Spearman's rho = -0.02; p = 0.03). The accuracy of RC was moderate (AUROC 0.62, p = 0.014). CONCLUSIONS: Among RC EUS features, lithiasis in the MPD is helpful for predicting the risk of PEI, while other findings are of limited utility in evaluating exocrine function.

Fully covered versus partially covered self-expandable metal stents for palliation of distal malignant biliary obstruction: a systematic review and meta-analysis.

BACKGROUND AND AIMS: Self-expandable metal stents (SEMSs) are standardly used for distal malignant biliary obstruction (dMBO). Although data suggest that covered versus uncovered SEMSs increase the time to recurrent biliary obstruction (TRBO), no data are available for fully covered (FC) versus partially covered (PC) designs. METHODS: PubMed, Scopus, and Cochrane databases were screened up to January 2023 for studies concerning dMBO treated by an FC- or PC-SEMS and describing adverse events (AEs), recurrences, or TRBO for specific design subpopulations. Pooled proportions or means were calculated using a random-effects model. Several subanalyses were preplanned, including a subanalysis restricted to prospective studies and unresectable diseases. Heterogeneity and publication bias were explored. Standardized differences (d-values) were calculated between groups. RESULTS: From 1290 records, 62 studies (3327 using FC-SEMSs and 2322 using PC-SEMSs) were included. FC- versus PC-SEMSs showed negligible differences in the rate of total AEs (12% vs 9.9%) and all specific AEs, including cholecystitis (2.5% vs 2.6%). In a subanalysis restricted to prospective studies and unresectable diseases, the rate of RBO was comparable between FC-SEMSs (27.3% [95% confidence interval {CI}, 23.7-31.2], I2 = 35.34%) and PC-SEMSs (25.3% [95% CI, 20.2-30.7], I2 = 85.09%), despite small differences (d-values between .186 and .216) in the rate of ingrowth (.5% vs 2.9%) favoring FC-SEMSs and migration (9.8% vs 4.3%) favoring PC-SEMSs. TRBO was shorter for FC-SEMSs (238 days [95% CI, 191-286], I2 = 63.1%) versus PC-SEMSs (369 days [95% CI, 290-449], I2 = 71.9%; d-value = .116). CONCLUSIONS: Despite considerable heterogeneity and small standardized differences, PC-SEMSs consistently exhibited longer TRBO than FC-SEMSs across analyses, without any other differences in AE rates, potentially proposing PC-SEMSs as the standard comparator and TRBO as the primary outcome for future randomized studies on dMBO. (Clinical trial registration number: CRD42023393965.).

Managing dysfunctions and reinterventions in endoscopic ultrasound-guided choledochoduodenostomy with lumen apposing metal stents: Illustrated technical review (with videos).

Endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) with lumen apposing metal stent is emerging both as a rescue strategy and a primary treatment for distal malignant biliary obstruction. The large-scale diffusion of the procedure and improved overall survival of patients with pancreatobiliary neoplasms is resulting in a growing population of long-term EUS-CDS lumen apposing metal stent carriers. Recent studies have reported a need for reintervention during follow-up as high as 55%, and the Leuven-Amsterdam-Milan Study Group classification has been developed, identifying five mechanisms of stent dysfunction and 11 possible rescue strategies aimed at restoring biliary drainage. This illustrated technical review aims to further dissect the recent classification through a comprehensive analysis of nine illustrative cases, offering insights into the pathophysiology underlying dysfunction and clinical reasoning behind rescue interventions, as well as technical considerations and practical tips and tricks. By exploring mechanisms of dysfunction, this review also assists clinicians in selecting the ideal candidates for EUS-CDS while identifying patients deemed high risk for dysfunction or clinical failure.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

EUS-guided gastroenterostomy for management of malignant gastric outlet obstruction: a prospective cohort study with matched comparison with enteral stenting.

BACKGROUND AND AIMS: Retrospective studies on malignant gastric outlet obstruction (mGOO) highlighted several advantages of EUS-guided gastroenterostomy (EUS-GE) over enteral stenting (ES). However, no prospective evidence is available. The aim of this study was to report on clinical outcomes of EUS-GE in a prospective cohort study, with a subgroup comparison versus ES. METHODS: All consecutive patients endoscopically treated for mGOO between December 2020 and December 2022 in a tertiary, academic center were enrolled in a prospective registry (Prospective Registry of Therapeutic Endoscopic Ultrasound [PROTECT]; NCT04813055) and followed up every 30 days to register efficacy/safety outcomes. EUS-GE and ES cohorts were matched according to baseline frailty and oncologic disease. RESULTS: A total of 104 patients were treated for mGOO during the study; 70 (58.6% male subjects; median age, 64 [interquartile range, 58-73] years; 75.7% pancreatic cancer, 60.0% metastatic cancer) underwent EUS-GE via the wireless simplified technique. Technical success was 97.1% and clinical success was 97.1% after a median of 1.5 (interquartile range, 1-2) days. Adverse events occurred in 9 (12.9%) patients. After a median follow-up of 105 (49-187) days, symptom recurrence was 7.6%. In the matched comparison versus ES (28 patients per arm), EUS-GE-treated patients experienced higher and faster clinical success (100% vs 75.0%, P = .006), reduced recurrences (3.7% vs 33.3%, P = .02), and a trend toward shorter time to chemotherapy. CONCLUSIONS: In this first, prospective, single-center comparison, EUS-GE showed excellent efficacy in treating mGOO, with an acceptable safety profile and long-term patency, and several clinically significant advantages over ES. While awaiting randomized trials, these results might endorse EUS-GE as first-line strategy for mGOO, where adequate expertise is available.

Same-session double EUS-guided bypass versus surgical gastroenterostomy and hepaticojejunostomy: an international multicenter comparison.

BACKGROUND AND AIMS: Gastric outlet and biliary obstruction are common manifestations of GI malignancies and some benign diseases for which standard treatment would be surgical gastroenterostomy and hepaticojejunostomy (ie, "double bypass"). Therapeutic EUS has allowed for the creation of an EUS-guided double bypass. However, same-session double EUS-guided bypass has only been described in small proof-of-concept series and lacks a comparison with surgical double bypass. METHODS: A retrospective multicenter analysis was performed of all consecutive same-session double EUS-guided bypass procedures performed in 5 academic centers. Surgical comparators were extracted from these centers' databases from the same time interval. Efficacy, safety, hospital stay, nutrition and chemotherapy resumption, long-term patency, and survival were compared. RESULTS: Of 154 identified patients, 53 (34.4%) received treatment with EUS and 101 (65.6%) with surgery. At baseline, patients undergoing EUS exhibited higher American Society of Anesthesiologists scores and a higher median Charlson Comorbidity Index (9.0 [interquartile range {IQR}, 7.0-10.0] vs 7.0 [IQR, 5.0-9.0], P < .001). Technical success (96.2% vs 100%, P = .117) and clinical success rates (90.6% vs 82.2%, P = .234) were similar when comparing EUS and surgery. Overall (11.3% vs 34.7%, P = .002) and severe adverse events (3.8% vs 19.8%, P = .007) occurred more frequently in the surgical group. In the EUS group, median time to oral intake (0 days [IQR, 0-1] vs 6 days [IQR, 3-7], P < .001) and hospital stay (4.0 days [IQR, 3-9] vs 13 days [IQR, 9-22], P < .001) were significantly shorter. CONCLUSIONS: Despite being used in a patient population with more comorbidities, same-session double EUS-guided bypass achieved similar technical and clinical success and was associated with fewer overall and severe adverse events when compared with surgical gastroenterostomy and hepaticojejunostomy.

Classification, risk factors, and management of lumen apposing metal stent dysfunction during follow-up of endoscopic ultrasound-guided choledochoduodenostomy: Multicenter evaluation from the Leuven-Amsterdam-Milan Study Group.

OBJECTIVES: Long-term outcomes of endoscopic ultrasound-guided choledochoduodenostomy (EUS-CDS) performed with lumen apposing metal stents (LAMS) have been poorly evaluated in small or retrospective series, leading to an underestimation of LAMS dysfunction. METHODS: All consecutive EUS-CDS performed in three academic referral centers were included in prospectively maintained databases. Technical/clinical success, adverse events (AEs), and dysfunction during follow-up were retrospectively analyzed. Kaplan-Meier analysis was used to estimate dysfunction-free survival (DFS), with Cox proportional hazard regression to evaluate independent predictors of dysfunction. RESULTS: Ninety-three patients were included (male 56%; mean age, 70 years [95% confidence interval (CI) 68-72]; pancreatic cancer 81%, metastatic disease 47%). In 67% of procedures, 6 mm LAMS were used. Technical and clinical success were achieved in 97.8% and 93.4% of patients, respectively, with AEs occurring in 9.7% (78% mild/moderate). Dysfunction occurred in 31.8% of patients after a mean of 166 days (95% CI 91-241), with an estimated 6 month and 12 month DFS of 75% and 52%, respectively; mean DFS of 394 (95% CI 307-482) days. Almost all dysfunctions (96%) were successfully managed by endoscopic reintervention. Duodenal invasion (hazard ratio 2.7 [95% CI 1.1-6.8]) was the only independent predictor of dysfunction. CONCLUSIONS: Endoscopic ultrasound-guided choledochoduodenostomy shows excellent initial efficacy and safety, although stent dysfunctions occurs frequently during long-term follow-up. Almost all stent dysfunctions can be managed successfully by endoscopic reinterventions. We propose a comprehensive classification of the different types of dysfunction that may be encountered and rescue procedures that may be employed under these circumstances. Duodenal invasion seems to increase the risk of developing EUS-CDS dysfunction, potentially representing a relative contraindication for this technique.

Endoscopic ultrasound-guided gastroenterostomy versus duodenal stenting for malignant gastric outlet obstruction: an international, multicenter, propensity score-matched comparison.

BACKGROUND: Endoscopic duodenal stenting is the current standard treatment for malignant gastric outlet obstruction (GOO) in patients with limited life expectancy. However, duodenal stenting is prone to stent dysfunction. Endoscopic ultrasound-guided gastroenterostomy (EUS-GE) is a novel technique with potentially superior stent patency. We compared clinical success, safety, and stent dysfunction of EUS-GE and duodenal stenting in patients with malignant GOO using propensity score matching. METHODS: This international, multicenter, retrospective study analyzed consecutive patients undergoing EUS-GE or duodenal stenting for GOO between 2015 and 2021 in three European centers. Primary outcomes were clinical success (GOO scoring system [GOOSS] ≥ 2) and stent dysfunction (GOOSS ≤ 1 after initial clinical success). A propensity score matching (1:1) analysis was performed using age, sex, underlying disease, disease stage, ascites, and peritoneal carcinomatosis as variables. RESULTS: 214 patients underwent EUS-GE (n = 107) or duodenal stenting (n = 107). After propensity score matching, 176 patients were matched and compared. Technical success rates for EUS-GE and duodenal stenting were 94 % (95 %CI 89 %-99 %) vs. 98 % (95 %CI 95 %-100 %), respectively (P = 0.44). Clinical success rates were 91 % (95 %CI 85 %-97 %) vs. 75 % (95 %CI 66 %-84 %; P = 0.008). Stent dysfunction occurred in 1 % (95 %CI 0-4 %) vs. 26 % (95 %CI 15 %-37 %) of patients (P < 0.001). Adverse event rate was 10 % (95 %CI 4 %-17 %) vs. 21 % (95 %CI 12 %-29 %; P = 0.09). CONCLUSION: EUS-GE had higher clinical success and lower stent dysfunction, with similar safety, compared with duodenal stenting, suggesting that EUS-GE may be preferred over duodenal stenting in patients with malignant GOO.

A novel two-component signaling system facilitates uropathogenic Escherichia coli's ability to exploit abundant host metabolites.

Two-component signaling systems (TCSs) are major mechanisms by which bacteria adapt to environmental conditions. It follows then that TCSs would play important roles in the adaptation of pathogenic bacteria to host environments. However, no pathogen-associated TCS has been identified in uropathogenic Escherichia coli (UPEC). Here, we identified a novel TCS, which we termed KguS/KguR (KguS: α-ketoglutarate utilization sensor; KguR: α-ketoglutarate utilization regulator) in UPEC CFT073, a strain isolated from human pyelonephritis. kguS/kguR was strongly associated with UPEC but was found only rarely among other E. coli including commensal and intestinal pathogenic strains. An in vivo competition assay in a mouse UTI model showed that deletion of kguS/kguR in UPEC CFT073 resulted in a significant reduction in its colonization of the bladders and kidneys of mice, suggesting that KguS/KguR contributed to UPEC fitness in vivo. Comparative proteomics identified the target gene products of KguS/KguR, and sequence analysis showed that TCS KguS/KguR and its targeted-genes, c5032 to c5039, are encoded on a genomic island, which is not present in intestinal pathogenic E. coli. Expression of the target genes was induced by α-ketoglutarate (α-KG). These genes were further shown to be involved in utilization of α-KG as a sole carbon source under anaerobic conditions. KguS/KguR contributed to the regulation of the target genes with the direct regulation by KguR verified using an electrophoretic mobility shift assay. In addition, oxygen deficiency positively modulated expression of kguS/kguR and its target genes. Taken altogether, this study describes the first UPEC-associated TCS that functions in controlling the utilization of α-ketoglutarate in vivo thereby facilitating UPEC adaptation to life inside the urinary tract.

FNR regulates expression of important virulence factors contributing to pathogenicity of uropathogenic Escherichia coli.

Uropathogenic Escherichia coli (UPEC) is responsible for the majority of urinary tract infections (UTIs), which are some of the world's most common bacterial infections of humans. Here, we examined the role of FNR (fumarate and nitrate reduction), a well-known global regulator, in the pathogenesis of UPEC infections. We constructed an fnr deletion mutant of UPEC CFT073 and compared it to the wild type for changes in virulence, adherence, invasion, and expression of key virulence factors. Compared to the wild type, the fnr mutant was highly attenuated in the mouse model of human UTI and showed severe defects in adherence to and invasion of bladder and kidney epithelial cells. Our results showed that FNR regulates motility and multiple virulence factors, including expression of type I and P fimbriae, modulation of hemolysin expression, and expression of a novel pathogenicity island involved in α-ketoglutarate metabolism under anaerobic conditions. Our results demonstrate that FNR is a key global regulator of UPEC virulence and controls expression of important virulence factors that contribute to UPEC pathogenicity.

EUS-directed transenteric ERCP with giant intrahepatic stone lithotripsy after a LAMS-in-LAMS rescue in response to a misdeployment.

Video 1LAMS-in-LAMS rescue of a misdeployment during EUS-directed transenteric ERCP. LAMS, Lumen-apposing metal stent.

Two clues make a proof: EUS-directed transgastric ERCP in twice-surgically altered anatomy-Roux-en-Y gastric bypass conversion of a sleeve gastrectomy.

Video 1EUS-directed transgastric ERCP in twice-surgically-altered anatomy: Roux-en-Y gastric bypass conversion of a sleeve gastrectomy.

VAC-Stent in the Treatment of Post-Esophagectomy Anastomotic Leaks: A New "Kid on the Block" Who Marries the Best of Old Techniques-A Review.

Esophagectomy, while a pivotal treatment for esophageal cancer, is not without adverse events. Among these, anastomotic leak (AL) is the most feared complication, threatening patient lives and incurring significant healthcare costs. The management of AL is complex and lacks standardization. Given the high morbidity and mortality rates associated with redo-surgery, which poses risks for already fragile patients, various endoscopic treatments have been developed over time. Self-expandable metallic stents (SEMSs) were the most widely used treatment until the early 2000s. The mechanism of action of SEMSs includes covering the wall defect, protecting it from secretions, and promoting healing. In 2010, endoscopic vacuum therapy (EVT) emerged as a viable alternative for treating ALs, quickly gaining acceptance in clinical practice. EVT involves placing a dedicated sponge under negative pressure inside or adjacent to the wall defect, aiming to clear the leak and promote granulation tissue formation. More recently, the VAC-Stent entered the scenario of endoscopic treatment of post-esophagectomy ALs. This device combines a fully covered SEMS with an integrated EVT sponge, blending the ability of SEMSs to exclude defects and maintain the patency of the esophageal lumen with the capacity of EVT to aspirate secretions and promote the formation of granulation tissue. Although the literature on this new device is not extensive, early results from the application of VAC-Stent have shown promising outcomes. This review aims to synthesize the preliminary efficacy and safety data on the device, thoroughly analyze its advantages over traditional techniques and disadvantages, explore areas for improvement, and propose future directions.

The Dual Lens of Endoscopy and Histology in the Diagnosis and Management of Eosinophilic Gastrointestinal Disorders-A Comprehensive Review.

Eosinophilic Gastrointestinal Disorders (EGIDs) are a group of conditions characterized by abnormal eosinophil accumulation in the gastrointestinal tract. Among these EGIDs, Eosinophilic Esophagitis (EoE) is the most well documented, while less is known about Eosinophilic Gastritis (EoG), Eosinophilic Enteritis (EoN), and Eosinophilic Colitis (EoC). The role of endoscopy in EGIDs is pivotal, with applications in diagnosis, disease monitoring, and therapeutic intervention. In EoE, the endoscopic reference score (EREFS) has been shown to be accurate in raising diagnostic suspicion and effective in monitoring therapeutic responses. Additionally, endoscopic dilation is the first-line treatment for esophageal strictures. For EoG and EoN, while the literature is more limited, common endoscopic findings include erythema, nodules, and ulcerations. Histology remains the gold standard for diagnosing EGIDs, as it quantifies eosinophilic infiltration. In recent years, there have been significant advancements in the histological understanding of EoE, leading to the development of diagnostic scores and the identification of specific microscopic features associated with the disease. However, for EoG, EoN, and EoC, precise eosinophil count thresholds for diagnosis have not yet been established. This review aims to elucidate the role of endoscopy and histology in the diagnosis and management of the three main EGIDs and to analyze their strengths and limitations, their interconnection, and future research directions.