Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10-8), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10-7), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10-6) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10-5). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk.

Same-session endoscopic diagnosis and symptom palliation in pancreato-biliary malignancies: Clinical impact of rapid on-site evaluation (ROSE).

Background and study aims Besides increasing adequacy, rapid on-site evaluation (ROSE) during endoscopic ultrasound (EUS) or endoscopic retrograde cholangiopancreatography (ERCP) may impact choices and timing of subsequent therapeutic procedures, yet has been unexplored. Patients and methods This was a retrospective evaluation of a prospectively maintained database of a tertiary, academic centre with availability of ROSE and hybrid EUS-ERCP suites. All consecutive patients referred for pathological confirmation of suspected malignancy and jaundice or gastric outlet obstruction (GOO) between Jan-2020 and Sep-2022 were included. Results Of 541 patients with underlying malignancy, 323 (59.7%) required same-session pathological diagnosis (male: 54.8%; age 70 [interquartile range 63-78]; pancreatic cancer: 76.8%, biliary tract adenocarcinoma 16.1%). ROSE adequacy was 96.6%, higher for EUS versus ERCP. Among 302 patients with jaundice, ERCP-guided stenting was successful in 83.1%, but final drainage was completed in 97.4% thanks to 43 EUS-guided biliary drainage procedures. Twenty-one patients with GOO were treated with 15 EUS-gastroenterostomies and six duodenal stents. All 58 therapeutic EUS procedures occurred after adequate ROSE. With ERCP-guided placement of stents, the use of plastic stents was significantly higher among patients with inadequate ROSE (10/11; 90.9%) versus adequate sampling (14/240; 5.8%) P <0.0001; OR 161; 95%CI 19-1352). Median hospital stay for diagnosis and palliation was 3 days (range, 2-7) and median time to chemotherapy was 33 days (range, 24-47). Conclusions Nearly two-thirds of oncological candidates for endoscopic palliation require contemporary pathological diagnosis. ROSE adequacy allows, since the index procedure, state-of-the-art therapeutics standardly restricted to pathologically confirmed malignancies (e.g. uncovered SEMS or therapeutic EUS), potentially reducing hospitalization and time to oncological treatments.

Curriculum for diagnostic endoscopic ultrasound training in Europe: European Society of Gastrointestinal Endoscopy (ESGE) Position Statement.

The European Society of Gastrointestinal Endoscopy (ESGE) has recognized the need to formalize and enhance training in diagnostic endoscopic ultrasound (EUS). This manuscript represents the outcome of a formal Delphi process resulting in an official Position Statement of the ESGE and provides a framework to develop and maintain skills in diagnostic EUS. This curriculum is set out in terms of the prerequisites prior to training; the recommended steps of training to a defined syllabus; the quality of training; and how competence should be defined and evidenced before independent practice. 1: Trainees should have achieved competence in upper gastrointestinal endoscopy before training in diagnostic EUS. 2: The development of diagnostic EUS skills by methods that do not involve patients is advisable, but not mandatory, prior to commencing formal training in diagnostic EUS. 3: A trainee's principal trainer should be performing adequate volumes of diagnostic EUSs to demonstrate maintenance of their own competence. 4: Training centers for diagnostic EUS should offer expertise, as well as a high volume of procedures per year, to ensure an optimal level of quality for training. Under these conditions, training centers should be able to provide trainees with a sufficient wealth of experience in diagnostic EUS for at least 12 months. 5: Trainees should engage in formal training and supplement this with a range of learning resources for diagnostic EUS, including EUS-guided fine-needle aspiration and biopsy (FNA/FNB). 6: EUS training should follow a structured syllabus to guide the learning program. 7: A minimum procedure volume should be offered to trainees during diagnostic EUS training to ensure that they have the opportunity to achieve competence in the technique. To evaluate competence in diagnostic EUS, trainees should have completed a minimum of 250 supervised EUS procedures: 80 for luminal tumors, 20 for subepithelial lesions, and 150 for pancreaticobiliary lesions. At least 75 EUS-FNA/FNBs should be performed, including mostly pancreaticobiliary lesions. 8: Competence assessment in diagnostic EUS should take into consideration not only technical skills, but also cognitive and integrative skills. A reliable valid assessment tool should be used regularly during diagnostic EUS training to track the acquisition of competence and to support trainee feedback. 9: A period of supervised practice should follow the start of independent activity. Supervision can be delivered either on site if other colleagues are already practicing EUS or by maintaining contacts with the training center and/or other EUS experts. 10: Key performance measures including the annual number of procedures, frequency of obtaining a diagnostic sample during EUS-FNA/FNB, and adverse events should be recorded within an electronic documentation system and evaluated.

Glucose and lactate levels are lower in EUS-aspirated cyst fluid of mucinous vs non-mucinous pancreatic cystic lesions.

BACKGROUND: Distinguishing mucinous (M) pancreatic cystic neoplasms (PCNs) from non-mucinous (NM) is challenging but crucial. Low intracystic glucose level has shown diagnostic tool promise, however further investigation is needed to understand metabolic processes. AIMS: To compare the diagnostic accuracy of intracystic glucose and CEA levels in a large cohort and explore lactate levels as potential marker. METHODS: PCNs≥15 mm which underwent EUS-fine needle aspiration were prospectively enrolled. Glucose, CEA and lactate levels were measured. Diagnostic accuracy for M-PCN diagnosis was evaluated using surgical/cytology reports or multidisciplinary evaluations. RESULTS: 169 PCNs were included (64 % M-PCNs). Median intracystic glucose was significantly lower in M-PCNs (1 mg/dL) compared to NM-PCNs (101 mg/dL); mean intracystic CEA was significantly higher in M-PCNs (152.5 ng/mL) compared to NM-PCNs (0.3 ng/mL). ROC curve analysis revealed best glucose cut-off ≤58 mg/dL (accuracy 93.5 %) and CEA cut-off >2.5 ng/mL (accuracy 90.5 %) for M-PCNs. Intracystic lactates were significantly lower in M-PCNs correlating directly with glucose. Single glucose dosage evidenced best diagnostic accuracy respect markers combination. CONCLUSION: Intracystic glucose demonstrated high diagnostic utility for M-PCNs differentiation, surpassing CEA. Lactate levels correlated with glucose, suggesting their uptake by M-PCNs cells. These findings contribute to a better metabolic landscape understanding glucose use as diagnostic marker.

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.

Immunomodulatory Effects of Endoscopic Ultrasound-Guided Thermal Ablation in Patients with Pancreatic Ductal Adenocarcinoma.

Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1ß. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.

Approaching Small Neuroendocrine Tumors with Radiofrequency Ablation.

In recent years, small pancreatic neuroendocrine tumors (pNETs) have shown a dramatic increase in terms of incidence and prevalence, and endoscopic ultrasound (EUS) radiofrequency ablation (RFA) is one potential method to treat the disease in selected patients. As well as the heterogeneity of pNET histology, the studies reported in the literature on EUS-RFA procedures for pNETs are heterogeneous in terms of ablation settings (particularly ablation powers), radiological controls, and radiological indications. The aim of this review is to report the current reported experience in EUS-RFA of small pNETs to help formulate the procedure indications and ablation settings. Another aim is to evaluate the timing and the modality of the radiological surveillance after the ablation. Moreover, new studies on large-scale series are needed in terms of the safety and long-term oncological efficacy of RFA on these small lesions.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Genetic and non-genetic risk factors for early-onset pancreatic cancer.

BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Gastric cancer in 2022: Is there still a role for endoscopic ultrasound?

Gastric cancer (GC) represents the fourth leading cause of cancer death worldwide and many factors can influence its development (diet, geographic area, genetic, Helicobacter pylori or Epstein-Barr virus infections). High quality endoscopy represents the modality of choice for GC diagnosis. The correct morphologic classification during a high-resolution endoscopy is fundamental for oncologic diagnosis, staging and therapeutic decisions. Since its initial introduction in clinical practice the endoscopic ultrasound (EUS) has been considered a valuable tool for tumor (T-) and lymph nodes (N-) staging also in GC, in order to establish the best therapeutic strategy for the patient (e.g., upfront surgery vs neoadjuvant treatments). EUS tools as elastography, Doppler and contrast administration can improve diagnosis mainly in case of malignant lymph node evaluation. EUS has a marginal role in disease staging but has a fundamental role in case of a pre-endoscopic resection management and in the new era of endoscopic mucosal resection or submucosal dissection as minimally invasive surgery. Diagnosis and locoregional staging of GC with EUS are a method of inarguable value for the assessment of gastric wall involvement and presence of infiltrated paragastric lymph nodes. EUS can also have a role in disease restaging in those patients who have undergone neoadjuvant treatment. EUS can also have a role in the advanced phases of the disease, in facilitating palliative, minimally-invasive treatments, such as gastroenterostomy or biliary drainages. This review intends to discuss the modern role of EUS in GC topic.

Routine Molecular Profiling in Both Resectable and Unresectable Pancreatic Adenocarcinoma: Relevance of Cytologic Samples.

BACKGROUND & AIMS: Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease, for which it is crucial to promptly detect actionable and prognostic alterations to drive specific therapeutic decisions, regardless of tumor resectability status. Endoscopic ultrasonography-guided fine-needle aspiration (EUS-FNA) is of key importance for PDAC diagnosis and can contribute significantly to tumor molecular profiling. METHODS: Comprehensive genomic profile by targeted next-generation sequencing (NGS) was performed on 2 independent PDAC patient cohorts. Cohort 1 consisted of 77 patients with resectable PDAC for whom the histologic sample at the time of resection was available; for 56 patients cytologic specimens at the time of diagnosis also were obtained by EUS-FNA. Cohort 2 consisted of 20 patients with unresectable PDAC, for whom only the EUS-FNA cytologic sample was available. RESULTS: In cohort 1, a complete concordant mutational profile between the cytologic sample at diagnosis and the corresponding histologic specimen after surgery was observed in 88% of the cases, proving the ability to detect potential clinically relevant alterations in cytologic samples by NGS analysis. Notably, clinically actionable mutations were identified in 20% of patients. In cohort 2, comprehensive mutational profiling was obtained successfully for all samples. Consistent with the findings of cohort 1, KRAS, TP53, CDKN2A, and SMAD4 were the most altered genes. Most importantly, 15% of the patients harbored actionable mutations. CONCLUSIONS: Our findings show the feasibility of an NGS approach using both surgical specimens and cytologic samples. The model proposed in this study can be included successfully in the clinical setting for comprehensive molecular profiling of all PDAC patients irrespective of their surgical eligibility.

Ex-vivo investigation of radiofrequency ablation in pancreatic adenocarcinoma after neoadjuvant chemotherapy.

Objective: Endoscopic ultrasound (US)-guided radiofrequency ablation (RFA) has been investigated for pancreatic ductal adenocarcinoma (PDAC) but studies are limited and heterogeneous. Computed tomography (CT) scan features may predict RFA response after chemotherapy but their role is unexplored. The primary aim was to investigate the efficacy of ex-vivo application of a dedicated RFA system at three power on surgically resected PDAC in patients who underwent neoadjuvant chemotherapy. The secondary aim was to explore the association between pre-treatment CT-based quantitative features and RFA response. Methods: Fifteen ex-vivo PDAC samples were treated by RFA under US control at three power groups (10, 30, and 50 W). Short axis necrosis diameter was measured by two expert blinded pathologists as the primary outcome. Two radiologists independently reviewed preoperative CT images. Results: Eighty percent of specimens showed coagulative necrosis consisting of few millimeters: 5.7 ± 3.9 mm at 10 W, 3.7 ± 2.2 mm at 30 W, and 3.5 ± 2.4 mm at 50 W (p = 0.3), without a significant correlation between power setting and mean necrosis short axis (rho = -0.28; p = 0.30). Good agreement was seen between pathologists (k = 0.76; 95% confidence interval 0.55-0.98). Logistic regression analysis did not show associations between CT features and RFA response. Conclusions: RFA causes histologically evident damage with coagulative necrosis of a few millimeters in 80% of ex-vivo PDAC samples after chemotherapy and no clinical or pre-operative CT features can predict efficacy. Power settings do not correlate with the histological ablation area. These results are of relevance when employing RFA in vivo and planning clinical trials on its role in PDAC patients.

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.

Needle-Tract Seeding of Pancreatic Cancer after EUS-FNA: A Systematic Review of Case Reports and Discussion of Management.

Needle-tract seeding (NTS) has been sporadically reported as complication of Endoscopic Ultrasound (EUS)-guided aspiration (FNA) in pancreatic adenocarcinoma (PDAC). However, the evidence of its treatment and outcome is sparse. Adhering to PRISMA guidelines, we conducted a systematic review of EUS-FNA NTS cases of PDAC and analyzed their management and outcome. Up to September 2022, the search query retrieved forty-five cases plus an unpublished case from our center, for a total of forty-six; 43.6% were male, with a mean age of 68.6 years. Thirty-four patients (87.1%) underwent an initial surgical resection, with only 44.1% and 5.9% undergoing adjuvant and neoadjuvant chemotherapy, respectively, and 5.9% undergoing both. The NTS nodule was mostly located in the posterior gastric wall, developing at a median of 19 months after primary resection; 82.4% underwent surgical resection of the seeding, while for 17.6%, palliative chemotherapy treatment. Follow-up after NTS diagnosis and treatment was reported for only twenty-three patients: when NTS was treated with surgery, the median overall survival was 26.5 months compared to 15.5 if treated with radio/chemotherapy. NTS after EUS-FNA of PDAC occurs late and might be treated aggressively with good results. Interestingly, only a low number of patients developing NTS underwent chemotherapy for the primary cancer, suggesting its possible protective role.

EUS-guided ablation with the HybridTherm Probe as second-line treatment in patients with locally advanced pancreatic ductal adenocarcinoma: A case-control study.

Background and Objectives: Data on the clinical efficacy of EUS-guided ablation using the HybridTherm-Probe (EUS-HTP) in locally advanced pancreatic ductal adenocarcinoma (LA-PDAC) are lacking. The aim of the study was to assess the impact of EUS-HTP added to chemotherapy (CT) on overall survival (OS) and progression-free survival (PFS) of LA-PDAC patients with local disease progression (DP) after first-line therapy, compared to CT alone in controls. Methods: LA-PDAC cases, prospectively treated by EUS-HTP, were retrospectively compared to matched controls (1:2) receiving standard treatment. Study endpoints were the OS and PFS from local DP after first-line therapy, compared through log-rank test calculating hazard ratios and differences in restricted mean OS/PFS time (RMOST/RMPFST) within prespecified time points (4, 6, and 12 months). Results: Thirteen cases and 26 controls were included. Clinical, tumor, and therapy features before and after first-line therapy were case-control balanced. The median OS and PFS were not significantly improved in cases over controls (months: 7 vs. 5 and 5 vs. 3, respectively). At 4 and 6 months, the RMPFST difference was in favor of cases (P = 0.0001 and P = 0.003, respectively). In cases and controls not candidate to further CT (N = 5 and N = 9), the median OS and PFS were not significantly improved in cases over controls (months: 6 vs. 3 and 4 vs. 2, respectively), but the RMPFST difference was in favor of cases at 4 months (P = 0.002). Conclusions: In locally progressive PDAC patients experiencing failure of first-line therapy, EUS-HTP achieves a significantly better RMPFST up to 6 months compared to standard treatment, although without a significant impact on OS.

Radiation exposure during modern therapeutic endoscopic ultrasound procedures and standard alternatives.

Background and study aims Therapeutic EUS (t-EUS) is increasingly being adopted in clinical practice in tertiary referral centers; however, little is known about radiation exposure (RE) metrics and diagnostic reference limits for it. Methods Kerma-area product (KAP [Gy·cm 2 ]), Air Kerma and fluoroscopy time were retrospectively evaluated for all consecutive t-EUS procedures performed in San Raffaele Institute between 2019 and 2021. For EUS-guided choledochoduodenostomies (EUS-CDS) and gastroenterostomies (EUS-GE), an equal number of endoscopic retrograde cholangiopancreatographies (ERCPs) plus metal stenting and duodenal stents were included respectively for comparison. Results Data from 141 t-EUS procedures were retrieved (49 % pancreatic cancer, 38 % peripancreatic fluid collections). EUS-CDS (N = 44) were mainly performed fluoroless, while ERCPs required a significantly higher RE (KAP = 25 [17-55], P < 0.0001). Fluid collection drainage (EUS-FCD) with lumen apposing metal stents (LAMS, N = 26) were performed fluoroless, while EUS-FCD with double-pigtail plastic stents (DPPS, N = 28) required higher RE (KAP = 23 [13-45]). EUS-guided gallbladder drainage (EUS-GBD, N = 6) required scarce RE (KAP = 9 [3-21]) for coaxial DPPS placement. EUS-GE (N = 27) required higher RE than duodenal stenting (KAP = 44 [28-88] versus 29 [19-46], P = 0.03). EUS-guided hepaticogastrostomies (EUS-HGS, N = 10) had the highest RE among t-EUS procedures (KAP = 81 [49-123]). Procedure complexity or intervening complications were evaluated and resulted in higher RE within each procedure. Conclusions t-EUS procedures have different RE ( P  < 0.000001). EUS-CDS, EUS-GBD, and EUS-FCD with LAMS can be performed with no-to-mild radioscopy, unlike standard alternatives. However, radioscopy remains essential in case of technical difficulties or complications. EUS-GE and EUS-HGS involve a high RE. Endoscopists involved in t-EUS might experience RE higher than category standards, which indicates a need for increased awareness and personalized preventive measures.

Endoscopic ultrasound radiofrequency ablation of pancreatic insulinoma in elderly patients: Three case reports.

BACKGROUND: Endoscopic ultrasound (EUS)-guided radiofrequency ablation (RFA) has recently been proposed as a local treatment for functional pancreatic neuroendocrine neoplasms in patients unfit for surgery, in order to obtain clinical syndrome regression. Data on the safety and long-term effectiveness of this approach are scarce, and EUS-RFA procedures are not standardized. CASE SUMMARY: The present case series reports 3 elderly patients with a pancreatic insulinoma and comorbidities, locally treated by EUS-guided RFA with clinical success in terms of hypoglycemic symptoms. RFA procedures were performed during deep sedation, under EUS control with a 19 G needle, an electrode 5-mm in size at a power of 30 W and multiple RFA applications during the same session in order to treat the whole area of the lesions. Immediate relief of symptoms was evident in 2 patients after the first EUS-RFA, while in the third patient a second endoscopic treatment was needed. All 3 patients are symptom-free without need of medications after 24 mo of follow-up with imaging follow-up showing no disease recurrence. A single adverse event of intraprocedural bleeding occurred, which was successfully treated endoscopically. CONCLUSION: EUS-RFA represents an effective and safe alternative to surgery for the treatment of insulinomas in elderly patients at high surgical risk. However, larger multicenter studies with longer follow-up are needed in order to better assess its safety and clinical success.

Risk factors for the occurrence of ampullary tumors: A case-control study.

BACKGROUND: The incidence of ampullary tumors is increasing but data on association with an increased exposure to certain risk factors are scanty. OBJECTIVE: To investigate risk and protective factors associated with the occurrence of ampullary tumors and whether these factors differ between ampullary tumors of the intestinal and pancreatobiliary subtypes or between adenomas and carcinomas. METHODS: The association between a large set of exposome features and ampullary tumors occurrence was investigated in a bi-centric case-control study after ethic committee approval and power calculation. RESULTS: In 223 histologically confirmed patients and 446 controls, previous cholecystectomy (odd ratio [OR] = 2.07; 95% confidence interval [CI] = 1.34-3.20) and proton pump inhibitors use (OR = 1.66; 95% CI = 1.16-2.37) were associated with increased risk of ampullary tumors, aspirin use (OR = 0.57; 95% CI = 0.36-0.90) and light alcohol intake (OR = 0.54; 95% CI = 0.38-0.76) with reduced risk. A previous cholecystectomy was also associated with tumors of intestinal subtype and with both adenomas and carcinomas, and proton pump inhibitors use with adenomas only. Smoking, body mass index, family history of cancers, previous ulcer, diabetes and use of statins, insulin and metformin were not significant factors. CONCLUSION: This is the first case-control study specifically highlighting factors associated with the occurrence of ampullary tumors. We report factors that are novel and plausible, in keeping with mechanisms described for other gastrointestinal tumors and with potential clinical relevance.

A polymorphic variant in telomere maintenance is associated with worrisome features and high-risk stigmata development in IPMNs.

Intraductal papillary mucinous neoplasms (IPMNs) are nonobligatory precursor lesions of pancreatic ductal adenocarcinoma (PDAC). The identification of molecular biomarkers able to predict the risk of progression of IPMNs toward malignancy is largely lacking and sorely needed. Telomere length (TL) is associated with the susceptibility of developing cancers, including PDAC. Moreover, several PDAC risk factors have been shown to be associated with IPMN transition to malignancy. TL is genetically determined, and the aim of this study was to use 11 SNPs, alone or combined in a score (teloscore), to estimate the causal relation between genetically determined TL and IPMNs progression. For this purpose, 173 IPMN patients under surveillance were investigated. The teloscore did not show any correlation, however, we observed an association between PXK-rs6772228-A and an increased risk of IPMN transition to malignancy (HR = 3.17; 95%CI 1.47-6.84; P = 3.24 × 10-3). This effect was also observed in a validation cohort of 142 IPMNs even though the association was not statistically significant. The combined analysis was consistent showing an association between PXK-rs6772228-A and increased risk of progression. The A allele of this SNP is strongly associated with shorter LTL that in turn have been reported to be associated with increased risk of developing PDAC. These results clearly highlight the importance of looking for genetic variants as potential biomarkers in this setting in order to further our understanding the etiopathogenesis of PDAC and suggest that genetically determined TL might be an additional marker of IPMN prognosis.

Improving diagnostic accuracy and appropriate indications for surgery in pancreatic cystic neoplasms: the role of EUS.

BACKGROUND AND AIMS: Pancreatic cystic neoplasms (PCNs) represent a difficult preoperative diagnosis despite improvements in imaging. In this study, we compared preoperative and final pathologic diagnosis in a large cohort of resected PCNs, evaluating diagnostic accuracy with a specific focus on the value of EUS. METHODS: A retrospective analysis of patients undergoing resection between 2009 and 2019 for presumed PCNs was performed. Preoperative workup was reviewed by analyzing the role of imaging and EUS. Patients with a benign histology who did not show absolute indication were categorized as "delayable surgery." RESULTS: Of 585 patients who were retrospectively analyzed, in 108 (18.5%) final histology did not confirm preoperative diagnosis. EUS was associated with a lower rate of incorrect diagnosis (16%; P = .03), but the risk of overtreatment was similar regardless of instrumental diagnostic path (33/131 vs 68/328, P = .298). Dilatation of the main pancreatic duct and cytologic sampling were the only variables independently associated with a correct diagnosis (P < .001 and P = .041, respectively). Based on clinical presentation and final histology, pancreatic resection could have been spared or delayed in 101 of 459 patients (22%), and this was influenced by age (odds ratio [OR], .97; P = .002), cyst larger than 30 mm (OR, 1.89; P = .005), and type of operation (OR, 3.46 [P < .001] and 3.18 [P = .023] for distal pancreatectomies and other resections, respectively). CONCLUSIONS: The overall risk of unnecessary immediate surgery for PCNs is about 22% in a high-volume referral center. EUS with cytologic sampling is a useful procedure in the diagnostic management of PCNs, improving their diagnostic accuracy.