Establishing the optimal number of passes during EUS-FNB for diagnosis of pancreatic solid lesions: Prospective multicenter study.

Background and study aims The optimal number of needle passes during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) is not yet established. We aimed to perform a per-pass analysis of the diagnostic accuracy of EUS-FNB of solid pancreatic lesions using a 22G Franseen needle. Patients and methods Consecutive patients with solid pancreatic lesions referred to 11 Italian centers were prospectively enrolled. Three needle passes were performed; specimens were collected after each pass and processed individually as standard histology following macroscopic on-site evaluation (MOSE) by the endoscopist. The primary endpoint was diagnostic accuracy of each sequential pass. Final diagnosis was established based on surgical pathology or a clinical course of at least 6 months. Secondary endpoints were specimen adequacy, MOSE reliability, factors impacting diagnostic accuracy, and procedure-related adverse events. Results A total of 504 samples from 168 patients were evaluated. Diagnostic accuracy was 90.5% (85.0%-94.1%) after one pass and 97.6% (94.1%-99.3%) after two passes ( P =0.01). Similarly, diagnostic sensitivity and sample adequacy were significantly higher adding the second needle pass (90.2%, 84.6%-94.3% vs 97.5%, 93.8%-99.3%, P =0.009 and 91.1%, 85.7%-94.9% vs 98.2%, 95.8%-99.3%, P =0.009, one pass vs two passes, respectively). Accuracy, sensitivity, and adequacy remained the same after the third pass. The concordance between MOSE and histological evaluation was 89.9%. The number of passes was the only factor associated with accuracy. One case of mild acute pancreatitis (0.6%) was managed conservatively. Conclusions At least two passes should be performed for the diagnosis of solid pancreatic lesions. MOSE is a reliable tool to predict the histological adequacy of specimens.

Identification of spatially-resolved markers of malignant transformation in Intraductal Papillary Mucinous Neoplasms.

The existing Intraductal Papillary Mucinous Neoplasm (IPMN) risk stratification relies on clinical and histological factors, resulting in inaccuracies and leading to suboptimal treatment. This is due to the lack of appropriate molecular markers that can guide patients toward the best therapeutic options. Here, we assess and confirm subtype-specific markers for IPMN across two independent cohorts of patients using two Spatial Transcriptomics (ST) technologies. Specifically, we identify HOXB3 and ZNF117 as markers for Low-Grade Dysplasia, SPDEF and gastric neck cell markers in borderline cases, and NKX6-2 and gastric isthmus cell markers in High-Grade-Dysplasia Gastric IPMN, highlighting the role of TNFα and MYC activation in IPMN progression and the role of NKX6-2 in the specific Gastric IPMN progression. In conclusion, our work provides a step forward in understanding the gene expression landscapes of IPMN and the critical transcriptional networks related to PDAC progression.

Lumen-apposing metal stents for the treatment of pancreatic and peripancreatic fluid collections and bleeding risk: a propensity matched study.

INTRODUCTION: Endoscopic ultrasound (EUS)-guided drainage of symptomatic pancreatic fluid collections (PFCs) using the Hot-Axios device has recently been associated with a significant risk of bleeding. This adverse event (AE) seems to occur less frequently with the use of a different device, the Spaxus stent. The aim of the current study was to compare the rates of bleeding between the two stents. METHODS: Patients admitted for treatment of PFCs by EUS plus lumen-apposing metal stent in 18 endoscopy referral centers between 10 July 2019 and 28 February 2022 were identified and their outcomes compared using a propensity-matching analysis. RESULTS: 363 patients were evaluated. After a 1-to-1 propensity score match, 264 patients were selected (132 per group). The technical and clinical success rates were comparable between the two groups. Significantly more bleeding requiring transfusion and/or intervention occurred in the Hot-Axios group than in the Spaxus group (6.8% vs. 1.5%; P = 0.03); stent type was a significant predictor of bleeding in both univariate and multivariate regression analyses (P = 0.03 and 0.04, respectively). Bleeding necessitating arterial embolization did not however differ significantly between the two groups (3.0% vs. 0%; P = 0.12). In addition, the Hot-Axios was associated with a significantly higher rate of overall AEs compared with the Spaxus stent (9.8% vs. 3.0%; P = 0.04). CONCLUSION: Our study showed that, in patients with PFCs, bleeding requiring transfusion and/or intervention occurred significantly more frequently with use of the Hot-Axios stent than with the Spaxus stent, although this was not the case for bleeding requiring embolization.

Endoscopic ultrasound-guided gallbladder drainage as a first approach for jaundice palliation in unresectable malignant distal biliary obstruction: Prospective study.

OBJECTIVES: Endoscopic retrograde cholangiopancreatography (ERCP) represents the gold standard for jaundice palliation in patients with distal malignant biliary obstruction (DMBO). Biliary drainage using electrocautery lumen apposing metal stent (EC-LAMS) is currently a well-established procedure when ERCP fails. In a palliative setting the endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) could represent an easy and valid option. We performed a prospective study with a new EC-LAMS with the primary aim to assess the clinical success rate of EUS-GBD as a first-line approach to the palliation of DMBO. METHODS: In all, 37 consecutive patients undergoing EUS-GBD with a new EC-LAMS were prospectively enrolled. Clinical success was defined as bilirubin level decrease >15% within 24 h and >50% within 14 days after EC-LAMS placement. RESULTS: The mean age was 73.5 ± 10.8 years; there were 17 male patients (45.9%). EC-LAMS placement was technically feasible in all patients (100%) and the clinical success rate was 100%. Four patients (10.8%) experienced adverse events, one bleeding, one food impaction, and two cystic duct obstructions because of disease progression. No stent-related deaths were observed. The mean hospitalization was 7.7 ± 3.4 days. Median overall survival was 4 months (95% confidence interval 1-8). CONCLUSION: Endoscopic ultrasound-guided gallbladder drainage with the new EC-LAMS is a valid option in palliative endoscopic biliary drainage as a first-step approach in low survival patients with malignant jaundice unfit for surgery. A smaller diameter EC-LAMS should be preferred, particularly if the drainage is performed through the stomach, to avoid potential food impaction, which could result in stent dysfunction.

Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

INTRODUCTION: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before. METHODS: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195). RESULTS: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported. DISCUSSION: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time.

Acute cholecystitis management in high-risk, critically ill, and unfit-for-surgery patients: the Italian Society of Emergency Surgery and Trauma (SICUT) guidelines.

Dealing with acute cholecystitis in high-risk, critically ill, and unfit-for-surgery patients is frequent during daily practice and requires complex management. Several procedures exist to postpone and/or prevent surgical intervention in those patients who temporarily or definitively cannot undergo surgery. After a systematic review of the literature, an expert panel from the Italian Society of Emergency Surgery and Trauma (SICUT) discussed the different issues and statements in subsequent rounds. The final version of the statements was discussed during the annual meeting in Rome (September 2022). The present paper presents the definitive conclusions of the discussion. Fifteen statements based on the literature evidence were provided. The statements gave precise indications regarding the decisional process and the management of patients who cannot temporarily or definitively undergo cholecystectomy for acute cholecystitis. Acute cholecystitis management in high-risk, critically ill, and unfit-for-surgery patients should be multidisciplinary. The different gallbladder drainage methods must be tailored according to each patient and based on the expertise of the hospital. Percutaneous gallbladder drainage is recommended as the first choice as a bridge to surgery or in severely physiologically deranged patients. Endoscopic gallbladder drainage (cholecystoduodenostomy and cholecystogastrostomy) is suggested as a second-line alternative especially as a definitive procedure for those patients not amenable to surgical management. Trans-papillary gallbladder drainage is the last option to be reserved only to those unfit for other techniques. Delayed laparoscopic cholecystectomy in patients with percutaneous gallbladder drainage is suggested in all those patients recovering from the conditions that previously discouraged surgical intervention after at least 6 weeks from the gallbladder drainage.

Endoscopic Ultrasound Biliary Drainage in Pancreatic Cancer.

Endoscopic ultrasound (EUS) guided biliary drainage (BD) is an accepted salvage procedure in patients with distal malignant biliary obstruction (DMBO) when endoscopic retrograde cholangiopancreatography (ERCP) is unsuccessful. The potential advantages of EUS-BD include gastric or duodenal biliary access, utilization of novel biliary stents and stent placement away from the area of stenosis, resulting in longer stent patency. These features make EUS-BD very appealing as a primary procedure for biliary drainage. There is a growing body of evidence supporting the utilization of EUS as a primary drainage procedure instead of ERCP, with comparable outcomes.

The Role of Luminal Apposing Metal Stents on the Treatment of Malignant and Benign Gastric Outlet Obstruction.

Gastric outlet obstruction (GOO) is a clinical syndrome traditionally managed by surgical gastrojejunostomy or enteral stenting. The surgical approach is burdened with a high rate of adverse events (AEs), while enteral stenting has a limited long-term clinical effectiveness, with the need for repeat procedures. The availability of lumen-apposing metal stents (LAMSs) has resulted a shift in the treatment paradigm of GOO. Indeed, endoscopists are now able to create a stable anastomosis between the stomach and small bowel under endosonographic guidance. EUS-guided gastro-enteroanastomosis (EUS-GE) has the theoretical advantage of a durable luminal patency resulting from stent placement away from the site of obstruction, free from surgical-related AEs. This approach could be especially valuable in terminally ill patients with a limited life expectancy. The present paper reviews procedural techniques and clinical outcomes of EUS-GE in the context of both malignant and benign GOOs.

Mishaps with EUS-guided lumen-apposing metal stents in therapeutic pancreatic EUS: Management and prevention.

EUS-guided interventions have become widely accepted therapeutic management options for drainage of peripancreatic fluid collections. Apart from endosonographic skills, EUS interventions require knowledge of the endoscopic stenting techniques and familiarity with the available stents and deployment systems. Although generally safe and effective, technical failure of correct stent positioning or serious adverse events can occur, even in experts' hands. In this article, we address common and rare adverse events in transmural EUS-guided stenting, ways to prevent them, and management options when they occur. Knowing the risks of what can go wrong combined with clinical expertise, high levels of technical skills, and adequate training allows for the safe performance of EUS-guided drainage procedures. Discussing the procedural risks and their likelihood with the patient is a fundamental part of the consenting process.

Talniflumate abrogates mucin immune suppressive barrier improving efficacy of gemcitabine and nab-paclitaxel treatment in pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. This is due to its aggressive course, late diagnosis and its intrinsic drugs resistance. The complexity of the tumor, in terms of cell components and heterogeneity, has led to the approval of few therapies with limited efficacy. The study of the early stages of carcinogenesis provides the opportunity for the identification of actionable pathways that underpin therapeutic resistance. METHODS: We analyzed 43 Intraductal papillary mucinous neoplasms (IPMN) (12 Low-grade and 31 High-grade) by Spatial Transcriptomics. Mouse and human pancreatic cancer organoids and T cells interaction platforms were established to test the role of mucins expression on T cells activity. Syngeneic mouse model of PDAC was used to explore the impact of mucins downregulation on standard therapy efficacy. RESULTS: Spatial transcriptomics showed that mucin O-glycosylation pathway is increased in the progression from low-grade to high-grade IPMN. We identified GCNT3, a master regulator of mucins expression, as an actionable target of this pathway by talniflumate. We showed that talniflumate impaired mucins expression increasing T cell activation and recognition using both mouse and human organoid interaction platforms. In vivo experiments showed that talniflumate was able to increase the efficacy of the chemotherapy by boosting immune infiltration. CONCLUSIONS: Finally, we demonstrated that combination of talniflumate, an anti-inflammatory drug, with chemotherapy effectively improves anti-tumor effect in PDAC.

Endoscopic Ultrasound-Guided Locoregional Treatments for Solid Pancreatic Neoplasms.

Solid pancreatic neoplasms are one of the most diagnosed gastrointestinal malignancies thanks to the current and progressive advances in radiologic methods. Endoscopic ultrasound-guided techniques have over time gained a prominent role in the differential diagnosis and characterization of these pancreatic lesions, including pancreatic cancer, neuroendocrine tumors, and metastases. Recently, several endoscopic ultrasound-guided locoregional treatment techniques, which are divided into thermal ablative techniques and non-thermal injection techniques, have been developed and applied in different settings for the treatment of solid pancreatic neoplasms. The most common ablative techniques are radiofrequency, microwave, laser, photodynamic therapy and hybrid techniques such as hybrid cryothermal ablation. The most common injection techniques are ethanol injection, immunotherapy and brachytherapy. In this review, we update evidence about the efficacy and safety of endoscopic ultrasound-guided locoregional treatments for solid pancreatic neoplasms.

Repeated endoscopic ultrasound-guided fine-needle biopsy of solid pancreatic lesions after previous nondiagnostic or inconclusive sampling.

OBJECTIVES: Repeated endoscopic ultrasound (EUS)-guided tissue acquisition represents the standard practice for solid pancreatic lesions after previous nondiagnostic or inconclusive results. Since data are lacking, we aimed to evaluate the diagnostic performance of repeated EUS fine-needle biopsy (rEUS-FNB) in this setting. The primary outcome was diagnostic accuracy; sample adequacy, sensitivity, specificity, and safety were secondary outcomes. METHODS: Consecutive patients undergoing rEUS-FNB for solid pancreatic lesions at 23 Italian centers from 2019 to 2021 were retrieved. Pathology on the surgical specimen, malignant histology together with ≥6-month follow-up, and benign pathology together with ≥12-month follow-up were adopted as gold standards. RESULTS: Among 462 patients, 56.5% were male, with a median age of 68 (59-75) years, malignancy prevalence 77.0%. Tumor size was 26 (20-35) mm. Second-generation FNB needles were used in 89.6% cases. Diagnostic accuracy, sensitivity, and specificity of rEUS-FNB were 89.2%, 91.4%, and 81.7%, respectively (19 false-negative and 12 false-positive results). On multivariate analysis, rEUS-FNB performed at high-volume centers (odds ratio [OR] 2.12; 95% confidence interval [CI] 1.10-3.17; P = 0.03) and tumor size (OR 1.03; 95% CI 1.00-1.06; P = 0.05) were independently related to diagnostic accuracy. Sample adequacy was 94.2%. Use of second-generation FNB needles (OR 5.42; 95% CI 2.30-12.77; P < 0.001) and tumor size >23 mm (OR 3.04; 95% CI 1.31-7.06; P = 0.009) were independently related to sample adequacy. CONCLUSION: Repeated EUS-FNB allowed optimal diagnostic performance after nondiagnostic or inconclusive results. Patients' referral to high-volume centers improved diagnostic accuracy. The use of second-generation FNB needles significantly improved sample adequacy over standard EUS-FNB needles.

Study protocol for a multicenter randomized controlled trial to compare radiofrequency ablation with surgical resection for treatment of pancreatic insulinoma.

BACKGROUND: Insulinoma is the most common functional pancreatic neuroendocrine tumor and treatment is required to address symptoms associated with insulin hypersecretion. Surgical resection is effective but burdened by high rate of adverse events (AEs). Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) demonstrated encouraging results in terms of safety and efficacy for the management of these tumors. However, studies comparing surgery and EUS-RFA are lacking. AIMS: The primary aim is to compare EUS-RFA with surgery in term of safety (overall rate of AEs). Secondary endpoints include: (a) severe AEs rate; (b) clinical effectiveness; (c) patient's quality of life; (d) length of hospital stay; (e) rate of local/distance recurrence; (f) need of reintervention; (g) rate of endocrine and exocrine pancreatic insufficiency; (h) factors associated with EUS-RFA related AEs and clinical effectiveness. METHODS: ERASIN-RCT is an international randomized superiority ongoing trial in four countries. Sixty patients will be randomized in two arms (EUS-RFA vs surgery) and outcomes compared. Two EUS-RFA sessions will be allowed to achieve symptoms resolution. Randomization and data collection will be performed online. DISCUSSION: This study will ascertain if EUS-RFA can become the first-line therapy for management of small, sporadic, pancreatic insulinoma and be included in a step-up approach in case of clinical failure.

When Should We Adopt EUS-Guided Radiofrequency Ablation in Pancreatic Neuroendocrine Tumors?

Pancreatic neuroendocrine neoplasms (PanNENs) are rare and heterogeneous diseases that account for less than 2% of all cases of pancreatic cancer and only 30% of digestive neuroendocrine neoplasia, even if their incidence and prevalence continue to rise globally [...].

The Role of Lumen Apposing Metal Stents in the Palliation of Distal Malignant Biliary Distal Obstruction.

Malignant biliary obstruction (DMBO) has been traditionally managed by endoscopic retrograde cholangiopancreatography (ERCP). In the case of ERC failure, percutaneous transhepatic biliary drainage (PT-BD) has been widely utilized as a salvage procedure. However, over the last decade, endoscopic ultrasound-guided biliary drainage (EUS-BD) has gained increasing popularity, especially after the advent of electrocautery-enhanced lumen apposing metal stent devices (EC-LAMSs) which enable a one-step procedure, granting prevention of biliary leakage and minimizing occurrence of adverse events (AEs). In parallel, increasing evidence suggests a possible role of EUS-BD in the management of DMBO as a primary palliative drainage modality. In the current paper, we aim to review all the available evidence on the role of EUS-BD performed with EC-LAMSs and discuss salient technical aspects of this type of procedure.

Endoscopic ultrasound in the management of acute cholecystitis: Practical review.

Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) has emerged over the last years as an alternative procedure to percutaneous drainage (PT)-GBD in patients with acute cholecystitis (AC) at high surgical risk. This process has been driven by the advent of lumen-apposing metal stents (LAMS) with electrocautery-enhanced capability, which has rendered the drainage procedure easier to accomplish and safer. Studies and meta-analyses have proven the superiority of EUS-GBD over PT-GBD in high-surgical-risk patients with AC. Little evidence exists in the same setting that EUS-GBD compares equally with laparoscopic cholecystectomy (LC). Moreover, EUS-GBD might theoretically have a possible role in patients at high surgical risk with an indication to undergo cholecystectomy or with a high probability of conversion from LC to open cholecystectomy. Properly designed studies are needed to better clarify the role of EUS-GBD in these patient populations.

EUS-Guided Choledocho-duodenostomy Using Lumen Apposing Stent Versus ERCP With Covered Metallic Stents in Patients With Unresectable Malignant Distal Biliary Obstruction: A Multicenter Randomized Controlled Trial (DRA-MBO Trial).

BACKGROUND & AIMS: Several studies have compared primary endoscopic ultrasound (EUS)-guided biliary drainage to endoscopic retrograde cholangiopancreatography (ERCP) with insertion of metal stents in unresectable malignant distal biliary obstruction (MDBO) and the results were conflicting. The aim of the current study was to compare the outcomes of the procedures in a large-scale study. METHODS: This was a multicenter international randomized controlled study. Consecutive patients admitted for obstructive jaundice due to unresectable MDBO were recruited. Patients were randomly allocated to receive EUS-guided choledocho-duodenostomy (ECDS) or ERCP for drainage. The primary outcome was the 1-year stent patency rate. Other outcomes included technical success, clinical success, adverse events, time to stent dysfunction, reintervention rates, and overall survival. RESULTS: Between January 2017 and February 2021, 155 patients were recruited (ECDS 79, ERCP 76). There were no significant differences in 1-year stent patency rates (ECDS 91.1% vs ERCP 88.1%, P = .52). The ECDS group had significantly higher technical success (ECDS 96.2% vs ERCP 76.3%, P < .001), whereas clinical success was similar (ECDS 93.7% vs ERCP 90.8%, P = .559). The median (interquartile range) procedural time was significantly shorter in the ECDS group (ECDS 10 [5.75-18] vs ERCP 25 [14-40] minutes, P < .001). The rate of 30-day adverse events (P = 1) and 30-day mortality (P = .53) were similar. CONCLUSION: Both procedures could be options for primary biliary drainage in unresectable MDBO. ECDS was associated with higher technical success and shorter procedural time then ERCP. Primary ECDS may be preferred when difficult ERCPs are anticipated. This study was registered to Clinicaltrials.gov NCT03000855.