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Abstract 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.

Abstract 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.

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.

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.

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 [...]

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.

For many years, cell lines and animal models have been essential to improve our understanding of the basis of cell metabolism, signaling, and genetics. They also provided an essential boost to cancer drug discovery. Nevertheless, these model systems failed to reproduce the tumor heterogeneity and the complex biological interactions between cancer cells and human hosts, making a high priority search for alternative methods that are able to export results from model systems to humans, which has become a major bottleneck in the drug development. The emergent human in vitro 3D cell culture technologies have attracted widespread attention because they seem to have the potential to overcome these limitations. Organoids are unique 3D culture models with the ability to self-organize in contained structures. Their versatility has offered an exceptional window of opportunity to approach human cancers. Pancreatic cancers (PCs) patient-derived-organoids (PDOs) preserve histological, genomic, and molecular features of neoplasms they originate from and therefore retain their heterogeneity. Patient-derived organoids can be established with a high success rate from minimal tissue core specimens acquired with endoscopic-ultrasound-guided techniques and assembled into platforms, representing tens to hundreds of cancers each conserving specific features, expanding the types of patient samples that can be propagated and analyzed in the laboratory. Because of their nature, PDO platforms are multipurpose systems that can be easily adapted in co-culture settings to perform a wide spectrum of studies, ranging from drug discovery to immune response evaluation to tumor-stroma interaction. This possibility to increase the complexity of organoids creating a hybrid culture with non-epithelial cells increases the interest in organoid-based platforms giving a pragmatic way to deeply study biological interactions in vitro. In this view, implementing organoid models in co-clinical trials to compare drug responses may represent the next step toward even more personalized medicine. In the present review, we discuss how PDO platforms are shaping modern-day oncology aiding to unravel the most complex aspects of PC.

Background and study aims Feasibility of EUS-guided choledochoduodenostomy (EUS-CDS) using available lumen-apposing stents (LAMS) is limited by the size of the common bile duct (CBD) (≤ 12 mm, cut-off for experts; 15 mm, cut-off for non-experts). We aimed to assess the prevalence and predictive factors associated with CBD size ≥ 12 and 15 mm in naïve patients with malignant distal biliary obstruction (MDBO). Patients and methods This was a prospective cohort study involving 22 centers with assessment of CBD diameter and subjective feasibility of the EUS-CDS performance in naïve jaundiced patients undergoing EUS evaluation for MDBO. Results A total of 491 patients (mean age 69 ± 12 years) with mean serum bilirubin of 12.7 ± 6.6 mg/dL entered the final analysis. Dilation of the CBD ≥ 12 and 15 mm was detected in 78.8 % and 51.9 % of cases, respectively. Subjective feasibility of EUS-CDS was expressed by endosonographers in 91.2 % for a CBD ≥ 12 mm and in 96.5 % for a CBD ≥ 15 mm. On multivariate analysis, age (P

Pancreatic cystic lesions (PCLs) are a heterogenous group of lesions ranging from benign to malignant. There has been an increase in PCLs prevalence in recent years, mostly due to advances in imaging techniques, increased awareness of their existence and population aging. Reliable discrimination between neoplastic and non-neoplastic cystic lesions is paramount to ensuring adequate treatment and follow-up. Although conventional diagnostic techniques such as ultrasound (US), magnetic resonance imaging (MRI) and computer tomography (CT) can easily identify these lesions, assessing the risk of malignancy is limited. Endoscopic ultrasound (EUS) is superior to cross-sectional imaging in identifying potentially malignant lesions due to its high resolution and better imaging characteristics, and the advantage of allowing for cyst fluid sampling via fine-needle aspiration (FNA). More complex testing, such as cytological and histopathological analysis and biochemical and molecular testing of the aspirated fluid, can ensure an accurate diagnosis.

Background and study aims The aim of thi systematic review and consensus report is to standardize the practice of endoscopic ultrasound (EUS-guided needle-based confocal laser endomicroscopy (nCLE) for pancreatic cystic lesion (PCL) evaluation. Methods We performed an international, systematic, evidence-based review of the applications, outcomes, procedural processes, indications, training, and credentialing of EUS-nCLE in management of PCLs. Based on available clinical evidence, preliminary nCLE consensus statements (nCLE-CS) were developed by an international panel of 15 experts in pancreatic diseases. These statements were then voted and edited by using a modified Delphi approach. An a priori threshold of 80 % agreement was used to establish consensus for each statement. Results Sixteen nCLE-CS were discussed. Thirteen (81 %) nCLE-CS reached consensus addressing indications (non-communication PCL meeting criteria for EUS-FNA or with prior non-diagnostic EUS-FNA), diagnostic outcomes (improved accuracy for mucinous PCLs and serous cystadenomas with substantial interobserver agreement of image patterns), low incidence of adverse events (fluorescein-associated and pancreatitis), procedural processes (nCLE duration, manipulation of needle with probe), and training (physician knowledge and competence). Conclusion Based on a high level of agreement pertaining to expert consensus statements, this report standardizes the practice of EUS-nCLE. EUS-nCLE should be systematically considered when EUS-FNA is indicated for PCL evaluation.

Background The percutaneous approach allows for effective and safe treatment of liver lesions. But in case of subcapsular or left segments location, this approach seems to be less effective or unsafe. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a new technique used to treat pancreatic and neuroendocrine tumors in patients unfit for surgery. Methods Hereby, we describe the case of a 70-year-old patient with cirrhosis with a large subcapsular hepatocellular carcinoma (HCC) in II-III-IVb segments, in which surgery or percutaneous therapies were not feasible, treated with EUS-RFA. The HCC was treated using an EUS-RFA (EUSRA) system, which consists of a 19G water-cooled monopolar RFA needle and a dedicated generator system. Results After a multidisciplinary discussion, the lesion was ablated in two different sessions, which resulted in destruction of about 70 % of neoplastic tissue. A second step surgery was required but initially refused by the patient. Conclusions EUS-RFA could be an effective way to treat left hepatic lesions not manageable with conventional percutaneous methods. This case report does not highlight concerns about safety of this approach and this observation needs to be validated in a larger cohort of patients with cirrhosis.

Preliminary studies suggested a possible correlation of microbiota with Barrett's esophagus (BE) and esophageal adenocarcinoma (EAC), where the need for tools to ameliorate its poor prognosis is mandatory. We explored the potential signature of esophageal microbiota and its predicted functional profile along the continuous spectrum from BE to EAC. We analyzed through 16S-based amplicon sequencing the mucosal microbiota and the microbiota-related functional predictions in 10 BE and 6 EAC patients compared with 10 controls, exploring also potential differences between the metaplastic mucosa (BEM) and the adjacent normal areas of BE patients (BEU). BEM and EAC showed a higher level of α and β-diversity. BEM evidenced a decrease of Streptococcus and an increase of Prevotella, Actinobacillus, Veillonella, and Leptotrichia. EAC displayed a striking reduction of Streptococcus, with an increase of Prevotella, Veillonella and Leptotrichia. LefSe analysis identified Leptotrichia as the main taxa distinguishing EAC. BEM showed a decreased α-diversity compared with BEU and a reduction of Bacteroidetes, Prevotella and Fusobacterium. Functional predictions identified peculiar profiles for each group with a high potential for replication and repair in BEM; an upregulated energy, replication and signaling metabolisms, with the fatty-acids biosynthesis and nitrogen and D-alanine pathways down-regulated in EAC. Our pilot study identifies a unique microbial structure and function profile for BE and EAC, as well as for metaplastic and near-normal areas. It proposes a new concept for BE, which could be intended not only as the histological, but, also, as the microbial closest precursor of EAC. This requires further larger follow-up studies, but opens intriguing horizons towards innovative diagnostic and therapeutic options for EAC.

Background and study aims Endoscopic therapy for postoperative Bergmann type A bile leaks is based on biliary sphincterotomy ± stent insertion. However, recurrent or refractory bile leaks can occur. Patients and methods This was retrospective study including all consecutive patients who were referred to our center with a Bergmann type A bile leak refractory to previous conventional endoscopic treatments. Results Seventeen patients with post-cholecystectomy-refractory Bergmann type A bile leak were included. All had received prior endoscopic biliary sphincterotomy with biliary stent or nasobiliary catheter placement and all had a percutaneous or surgical abdominal drainage. Repeat endoscopic retrograde cholangiopancreatography (ERCP) confirmed a Bergmann type A bile leak and in all patients we observed that the abdominal drainage was placed adjacent to the origin of the fistula. Our treatment consisted of pulling the drain away from the fistulous site, with extension of the previous sphincterotomy when needed. The treatment was successful in all cases. Mild complications occurred in three patients. Conclusions Our retrospective study shows that refractory Bergmann type A bile leak may be a consequence of an unfavorable position of the abdominal drainage tube, which can be corrected by pulling the drain away from the origin of the fistula. This establishes a favorable pressure gradient that leads the bile flowing from the bile duct into the duodenum.

Background and study aims We report our experience in endoscopic ultrasound-guided gallbladder drainage performed emergently in 4 prohibitive surgical risk patients with concurrent coagulopathy or on anticoagulant therapy using an electrocautery enhanced lumen apposing self expanding metal stent (LA-SEMS).

Background Recently, a novel lumen-apposing fully covered self-expanding metal stent (LA-FCSEMS) mounted on an electrocautery-enhanced delivery system has been developed to perform endoscopic ultrasound (EUS)-guided transluminal drainage. From early experience, however, release of the proximal flange of the stent has mostly been done using endoscopic view guidance to ensure proper positioning. Aim We describe a new technique that we have named the Intra-Channel Stent Release Technique (ICSRT) to perform stent placement under complete EUS control, without the use of either fluoroscopic or endoscopic views. Material and methods Data on all consecutive patients who underwent EUS-guided drainage using the new ICSRT between June 2014 and April 2016 were retrospectively retrieved from two institution databases. All EUS procedures were performed by experienced endoscopists with the patient under conscious or deep sedation. The total procedure and stent deployment time, and adverse events related to stent positioning with the ICSRT were evaluated. Results One hundred consecutive patients (51 women; mean age ± SD, 66 ± 15.2 years, range 34 – 95) underwent EUS-guided transluminal drainage with the Hot AXIOS™ device using the new ICSRT. The procedure was technically successful in all but one patient (1 %). The mean total procedural time was 21.9 minutes (range 7 – 50), while the mean time for stent placement was 3.2 minutes (range 1 – 15). No major adverse events occurred. Discussion The ICSRT has been used to deploy the newly developed lumen-apposing FCSEMS under complete EUS guidance without fluoroscopic and/or endoscopic assistance. The technique appears to be safe and highly effective and should be learned by all interventional endosonographers in order to be able to perform drainage in all clinical scenarios.

Primary pancreatic lymphoma (PPL) is an extremely rare disease which occurs in pancreas, and accounts for less than 1% of extra-nodal malignant lymphomas and 0,5% of cases of pancreatic masses. We report the case of PPL in a 15 year-old boy suffering from Type I Diabetes Mellitus (DM) diagnosed at the age of 1 year. The patient achieved complete remission by immuno-chemotherapy. An association between type I DM and PPL has never been reported so far and could represent a new link between chronic autoimmune disease and primary extranodal lymphoma in a target tissue.

Primary pancreatic lymphoma (PPL) is an extremely rare disease which occurs in pancreas, accounts for less than 1% of extra-nodal malignant lymphomas and 0,5% of cases of pancreatic masses. We report the case of PPL in a 15 year-old boy suffering from Maturity onset Diabetes of the young type 3 (MODY3) diagnosed at the age of 1 year

Introduction: While outcomes of lumen-apposing metal stents (LAMS) placement in native anatomy have been reported, data on LAMS placement in surgically altered anatomy (SAA) is sparse. We aim to assess outcomes of LAMS placement in patients with SAA for different indications. Methods: This was an international multicenter retrospective observational study at 25 tertiary-care centers through November 2023. Consecutive patients with SAA who underwent LAMS placement were included. The primary outcome was technical success defined as correct placement of LAMS. Secondary outcomes were clinical success and safety. Results: Two hundred and seventy patients (125 males; average age 61 ± 15 years) underwent LAMS placement with SAA. Procedures included EUS-directed transgastric ERCP (EDGE) and EUS-directed transenteric ERCP (EDEE) (n=82), EUS-guided entero-enterostomy (n=81), EUS-guided biliary drainage (n=57), EUS-guided drainage of peri-pancreatic fluid collections (n=48), and EUS-guided pancreaticogastrostomy (n=2). Most cases utilized AXIOS stents (n=255) compared to SPAXUS stents (n=15). Overall, technical success was 98%, clinical success was 97%, and adverse event rate was 12%. Using AGREE classification, 5 events were rated as Grade II, 21 events as Grade IIIa, and 6 events as IIIb. No difference in adverse events were noted among stent types (P=0.52). Conclusion: This study shows that placement of LAMS is associated with high technical and clinical success rates in patients with SAA. However, the rate of adverse events is noteworthy and thus these procedures should be performed by expert endoscopists at tertiary centers.

Background and study aims: The overall diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) for subepithelial lesions (SELs) is suboptimal. The aim of this studywas to evaluate the diagnostic accuracy, defined as the proportion of correct diagnoses, obtained using the EUS-guided fine-needle tissue acquisition (FNTA) sampling technique performed with the newly developed forward-viewing EUS scope (FV-EUS). Patients and methods: This was a retrospective analysis of a prospectively collected database including all consecutive patients with SELs who underwent EUS-FNTA using the FV-EUS scope from 2007 to 2011 in a tertiary referral center. All procedures were performed by a single expert endoscopist. Results: A total of 121 consecutive patients with SELs (13 in the esophagus, 96 in the stomach, 10 in the duodenum, 2 in the rectum) underwent sampling of the lesion using the FV-EUS scope. The procedure was technically feasible in all but one patient, and no complication related to EUS- FNTA occurred. Full histological assessment including immunostaining could be completed in 93.4% (113/121) of the patients. Considering neoplastic vs. non-neoplastic diseases, the sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio were 92.8% (95 %CI 86.3-96.8), 100% (95 %CI 69.0-100%), infinity, and 0.07 (95% CI 0.04-0.14), respectively. Conclusions: EUS-FNTA performed in conjunction with the FV-EUS scope for sampling SELs of the gastrointestinal tract was safe and provided a very high diagnostic accuracy. Studies comparing FV-EUS with standard curved linear echoendoscopes are needed to clarify whether these results are due to the sampling technique or the type of scope utilized. [ABSTRACT FROM AUTHOR]

Abstract??Dilation of malignant esophageal strictures often is required to complete staging by endoscopic ultrasound (EUS). This study was designed to determine the successful dilation rate (ability to complete staging) and complication rate of through-the-scope (TTS) balloon dilation for malignant esophageal strictures during EUS. We retrospectively reviewed EUS reports for all cases of primary esophageal cancer staged at five centers between January 2002 and October 2004. All dilations were performed with TTS balloons. Among 272 endoscopic ultrasounds, dilation was required in 77 (28%) and was successful in 73 cases (95%). There was one esophageal perforation after dilation (1.3%; 95% confidence interval (CI), 0.2?7) and one esophageal perforation after EUS without dilation (0.5%; 95% CI, 0.1?2.8;P=0.48 by two-sided Fisher exact test). There were no other major complications. TTS balloon dilation is highly successful in permitting complete staging of obstructing tumors. The rate of complications after dilation with a TTS balloon dilator is low and similar to the baseline rate of EUS in this setting. [ABSTRACT FROM AUTHOR]

Biliary obstruction (BO) and gastric outlet obstruction (GOO) are frequent complications of pancreatobiliary and gastroduodenal neoplasia, which can severely impact oncological outcomes, patient survival and quality of life. Although endoscopic retrograde cholangiopancreatography (ERCP) remains the gold standard for biliary drainage, this may fail or be unfeasible because of duodenal/papillary infiltration or surgically-altered anatomy. Percutaneous transhepatic biliary drainage (PTBD) has been the standard rescue therapy in this setting, but is burdened by high morbidity and reduced quality of life. As for GOO, surgical gastroenterostomy and enteral stenting are limited by invasiveness and suboptimal long-term outcomes, respectively. Endoscopic ultrasound (EUS) has evolved from a diagnostic to a therapeutic modality, providing a safe and effective alternative for draining the pancreatobiliary tract into the stomach or duodenum. EUS-guided biliary drainage (EUS-BD) has already demonstrated similar efficacy, greater safety and fewer reinterventions compared to PTBD, and can be performed in the same session after ERCP failure. Further development of lumen apposing metal stents has paved the way towards the creation of EUS-guided anastomoses. EUS-guided gastroenterostomy (EUS-GE) is nowadays increasingly used to treat GOO, combining the minimal invasiveness of endoscopy with surgical-range efficacy. This review summarizes the technical details, current evidence and society recommendations contributing to EUS-BD and EUS-GE gaining ground in everyday practice or tertiary referral centers and becoming crucial in improving the multidisciplinary management of cancer-related symptoms., Competing Interests: Conflict of Interest: MB has consultancy agreements with Taewoong and Prion Medical and reports travel grants from Taewoong, Norgine and Prion Medical. RV reports consultancy agreement and research grant Boston-Scientific. AL has received consultancy fees from Boston Scientific and Pentax Medical, and educational fees from Taewoong Medical and receives research support from Medtronic. SvdM: co-chairs the Boston-Scientific Chair in Therapeutic Biliopancreatic Endoscopy, holds the Cook Medical chair in Portal Hypertension and holds consultancy agreements with Boston Scientific, Cook Medical and Pentax. All other Authors disclose no COI relevant for this article, (Copyright: © Hellenic Society of Gastroenterology.)

Since its initial report in 1992, endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has now been incorporated into the diagnostic and staging algorithm for the evaluation of benign and malignant diseases of the gastrointestinal tract and of adjacent organs. Its introduction constitutes a major breakthrough in the endoscopic field and has gradually transformed EUS from a pure imaging modality into a more interventional procedure. In addition, the possibility of collecting samples, providing a definitive cytological and/or histological evidence of the presence of malignancy, has strongly contributed to changing EUS from a subjective, highly operator dependant procedure into a more objective one. This article will review the instrumentation, technique and the most important clinical applications of EUS-FNA.