Safety and efficacy of endoscopic ultrasound-guided radiofrequency ablation for pancreatic insulinoma: A single-center experience.

BACKGROUND/OBJECTIVES: Insulinomas are rare, functioning pancreatic neuroendocrine neoplasms (pNEN), whose gold standard therapy is surgical resection. Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is a recent technique that has emerged as a minimally invasive therapeutic option for patients with pancreatic lesions not eligible for surgery. In this study, we aimed to describe a series of patients with unresectable pancreatic insulinoma treated with EUS-RFA. METHODS: This is a single-center, retrospective study including all consecutive patients with functioning pancreatic insulinoma undergoing EUS-RFA for surgical unfitness or surgery refusal, between March 2017 and September 2021. Technical success (i.e., complete mass ablation), adverse event rate and severity, clinical and radiologic outcomes (i.e., symptom remission with a normal concentration of blood glucose, and the presence of intralesional necrosis), and post-procedural follow-up were assessed. RESULTS: A total of 10 patients (mean age: 67.1 ± 10.1years; F:M 7:3) were included. The mean size of insulinoma was 11.9 ± 3.3 mm. Technical success and clinical remission were achieved in 100% of patients. Only one (10%) patient was successfully treated with two RFA sessions. Two procedure-related early adverse events occurred, including two (20%) cases of mild abdominal pain. No major complications were observed. The complete radiologic response within 3 months after EUS-RFA was observed in all patients (100%). After a median follow-up of 19.5 (range12-59) months, symptom remission and persistent euglycemia were assessed in all the patients. CONCLUSIONS: Data from this case series suggest that EUS-RFA is a feasible and safe therapeutic approach for pancreatic insulinomas in patients unwilling or unable to undergo surgery with medium-term efficacy.

A multicenter randomized trial comparing a 25-gauge EUS fine-needle aspiration device with a 20-gauge EUS fine-needle biopsy device.

BACKGROUND AND AIMS: Several studies have compared EUS-guided FNA with fine-needle biopsy (FNB), but none have proven superiority. We performed a multicenter randomized controlled trial to compare the performance of a commonly used 25-gauge FNA needle with a newly designed 20-gauge FNB needle. METHODS: Consecutive patients with a solid lesion were randomized in this international multicenter study between a 25-gauge FNA (EchoTip Ultra) or a 20-gauge FNB needle (ProCore). The primary endpoint was diagnostic accuracy for malignancy and the Bethesda classification (non-diagnostic, benign, atypical, malignant). Technical success, safety, and sample quality were also assessed. Multivariable and supplementary analyses were performed to adjust for confounders. RESULTS: A total of 608 patients were allocated to FNA (n = 306) or FNB (n = 302); 312 pancreatic lesions (51%), 147 lymph nodes (24%), and 149 other lesions (25%). Technical success rate was 100% for the 25-gauge FNA and 99% for the 20-gauge FNB needle (P = .043), with no differences in adverse events. The 20-gauge FNB needle outperformed 25-gauge FNA in terms of histologic yield (77% vs 44%, P < .001), accuracy for malignancy (87% vs 78%, P = .002) and Bethesda classification (82% vs 72%, P = .002). This was robust when corrected for indication, lesion size, number of passes, and presence of an on-site pathologist (odds ratio, 3.53; 95% confidence interval, 1.55-8.56; P = .004), and did not differ among centers (P = .836). CONCLUSION: The 20-gauge FNB needle outperformed the 25-gauge FNA needle in terms of histologic yield and diagnostic accuracy. This benefit was irrespective of the indication and was consistent among participating centers, supporting the general applicability of our findings. (Clinical trial registration number: NCT02167074.).

Fully covered self-expandable metal stents to dilate persistent pancreatic strictures in chronic pancreatitis: long-term follow-up from a prospective study.

BACKGROUND AND AIMS: Symptomatic main pancreatic duct (MPD) strictures secondary to chronic pancreatitis (CP) may benefit from endoscopic insertion of single or multiple plastic stents. MPD stricture resolution after single plastic stent removal is uncommon. The use of removable fully covered, self-expandable metal stents (FC-SEMSs) to dilate MPD strictures secondary to CP was evaluated. METHODS: Patients with CP and symptomatic MPD stricture located in the head of the pancreas persisting for 3 months or more after placement of a single plastic stent were enrolled in a prospective single-arm trial. A nitinol FC-SEMS was inserted and removed after 6 months. The FC-SEMS diameter and length were chosen according to the stricture anatomy and MPD diameter above the stricture. Our primary objective was FC-SEMS removability. Secondary outcomes were MPD stricture resolution rate and adverse events. RESULTS: Between December 2012 and October 2014, 15 patients (10 male, mean age 60 years) were enrolled. Pancreatic calcifications were present in 6 (40%) patients. Four patients (27%) had a history of alcohol abuse. In 10 patients, the FC-SEMS was inserted through the major papilla, whereas 5 patients (3 pancreas divisum, 2 dominant dorsal duct) received the stent through the minor papilla. One patient developed cholangitis after 24 hours due to occlusion of the biliary sphincterotomy from the FC-SEMS; cholangitis resolved after insertion of a plastic biliary stent. Complete distal migration of the FC-SEMS was reported in 7 patients (47%) (5 asymptomatic, 2 symptomatic with recurrence of pancreatitis). All migrations occurred with the 3-cm-long FC-SEMS. Four patients (27%) developed de novo stricture induced by the FC-SEMS at the level of the flared end and were excluded from the follow-up; 1 patient with FC-SEMS migration had failed stricture resolution. One patient was lost to follow-up. Finally, 9 patients with MPD stricture resolution had a mean follow-up of 38.9 months (range, 5.3-55.3 months), and 89% were asymptomatic. CONCLUSIONS: FC-SEMS removability from the MPD in CP was feasible in all cases, and 90% of the patients were asymptomatic after 3 years. Migration seems more frequent with the 3-cm-long FC-SEMS. Occurrence of FC-SEMS-induced pancreatic strictures is a major issue and deserves further assessment. According to our experience, pancreatic FC-SEMSs have promising results, but a careful evaluation in the setting of clinical trials is needed.

Endoscopic ultrasound-through-the-needle biopsy in pancreatic cystic lesions: A multicenter study.

BACKGROUND AND AIM: Tissue acquisition in pancreatic cystic lesions (PCL) is the ideal method for diagnosis and risk stratification for malignancy of these lesions. Direct sampling from the walls of PCL with different devices has shown better results than cytology from cystic fluid. We carried out a retrospective, multicenter study to evaluate the feasibility, safety, and diagnostic yield of a micro-forceps, specifically designed to be used through a 19-gauge needle after endoscopic ultrasonography (EUS)-guided puncture of PCL. METHODS: We retrospectively collected data from patients who underwent EUS-through-the-needle biopsy (EUS-TTNB) in PCL at six referral centers. RESULTS: The sampling procedure was carried out in 56 patients (mean age 57.5 ± 13.1 years, M:F 17:39), and was technically successful in all of them (100%; 95% confidence interval [CI], 94-100%). Adverse events occurred in 9/56 (16.1%; 95% CI, 8-28%) patients, with self-limited intracystic hemorrhage the most common (7/56, 12.5%; 95% CI, 5-24%). All adverse events were mild, and resolved without any specific intervention. Specimens were considered adequate for histological diagnosis in 47/56 (83.9%; 95% CI, 72-92%). In two of these patients, despite the histological adequacy, a diagnosis could not be reached. In two other cases, a specimen sufficient for a cytological diagnosis was obtained. Overall diagnostic yield by combining cytological and histological samples was 47/56 (83.9%; 95% CI, 72-92%). CONCLUSION: EUS-TTNB with micro-forceps in PCL is feasible, safe, and has a high diagnostic yield. Future prospective studies are needed to better assess the clinical impact of EUS-TTNB on the management of PCL.

EUS-guided drainage of pancreatic fluid collections using a novel lumen-apposing metal stent on an electrocautery-enhanced delivery system: a large retrospective study (with video).

BACKGROUND AND AIMS: A lumen-apposing, self-expanding metal stent incorporated in an electrocautery-enhanced delivery system for EUS-guided drainage of pancreatic fluid collections (PFCs) recently has become available. The aim of this study was to analyze the safety and clinical effectiveness of this newly developed device in this clinical setting. METHODS: This was a retrospective analysis of all consecutive patients with PFCs who underwent EUS-guided drainage using the study device in 13 European centers. RESULTS: Ninety-three patients with PFCs (80% with complex collections) underwent drainage using the study device. Penetration of the PFC was accomplished directly with the study device in 74.2% of patients, and successful stent placement was accomplished in all but 1 patient, mostly without fluoroscopic assistance. Direct endoscopic necrosectomy (DEN) was carried out in 31 of 52 cases (59.6%) of walled-off necrosis and in 2 of 4 cases (50%) of acute peripancreatic fluid collection. Complete resolution of the PFC was obtained in 86 cases (92.5%), with no recurrence during follow-up. Treatment failure occurred in 6 patients because of persistent infection requiring surgery (n = 3), perforation and massive bleeding caused by the nasocystic drainage catheter (NCDC) (n = 2), and the need for a larger opening to extract large necrotic tissue pieces (n = 1). Major adverse events occurred in 5 patients (perforation and massive bleeding caused by the NCDC in 2 patients, 1 pneumoperitoneum and 1 stent dislodgement during DEN, and 1 postdrainage infection) and were mostly not related to the drainage procedure. CONCLUSIONS: EUS-guided drainage with the electrocautery-enhanced delivery system is a safe, easy to perform, and a highly effective minimally invasive treatment modality for PFCs.

Interobserver agreement and accuracy of preoperative endoscopic ultrasound-guided biopsy for histological grading of pancreatic cancer.

BACKGROUND AND STUDY AIM: Poorly differentiated/high grade pancreatic ductal adenocarcinoma (PDAC) is associated with an early unfavorable outcome, and patients with these tumors may be candidates for neo-adjuvant treatment. Endoscopic ultrasound-guided pancreatic fine-needle biopsy (EUS-FNB) may, in theory, allow preoperative assessment of PDAC histological grading. The aim of the current study was to assess the interobserver agreement and accuracy of preoperative PDAC grading from EUS-FNB specimens. METHODS: Data from 42 postsurgical PDAC patients who had undergone preoperative EUS-FNB were retrieved. Four experienced pathologists independently reviewed the EUS-FNB slides and reported tumor grading (well, moderately, or poorly differentiated). Agreement among pathologists for grading of preoperative EUS-FNB samples was expressed by using Cohen's or Fleiss' kappa statistic, as appropriate. Postsurgical PDAC grading was used as the gold standard to assess the cumulative accuracy of EUS-FNB for the preoperative prediction of PDAC grading. RESULTS: The kappa values for PDAC grading on EUS-FNB specimens ranged from 0.09 to 0.41. The total agreement among the four pathologists was only fair (κ = 0.27; 95 % confidence interval [CI] 0.14 - 0.38). When tumor grades were grouped as well or moderately differentiated vs. poorly differentiated, kappa values ranged from 0.19 to 0.50, with only a fair overall agreement (κ = 0.27; 95 %CI 0.21 - 0.49). The accuracy of preoperative grading from EUS-FNB was 56 % (75/134 readings; 95 %CI 40 % - 65 %), with mean sensitivity and specificity to detect a high grade, poorly differentiated tumor of 41 % (95 %CI 19 % - 54 %) and 78 % (53/68 readings; 95 %CI 60 % - 99 %), respectively. CONCLUSIONS: Preoperative EUS-FNB-based histological grading of PDAC is unreliable, and current results do not support the use of this information in clinical practice. This appears to be due to suboptimal interobserver agreement among pathologists and an overall low accuracy in predicting postsurgical grading.

Fine-needle tissue acquisition from subepithelial lesions using a forward-viewing linear echoendoscope.

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 study was 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.

Performance of the forward-viewing linear echoendoscope for fine-needle aspiration of solid and cystic lesions throughout the gastrointestinal tract: a large single-center experience.

BACKGROUND: A newly developed forward-viewing linear echoendoscope (FV-EUS) has recently become available. To date, however, only scanty data on the performance of the FV-EUS scope for fine-needle aspiration (FNA) of lesions throughout the gastrointestinal (GI) tract are available. This study aimed to evaluate the technical performance of the FV-EUS scope for FNA of solid and cystic lesions located throughout the GI tract in a large cohort of patients referred to a tertiary care center. METHODS: All patients who underwent endoscopic ultrasound (EUS)-guided FNA using the FV-EUS scope between January 2007 and December 2008 were included in this retrospective study. The performance of the FV-EUS scope for FNA was evaluated. RESULTS: During the study period, 285 patients with solid or cystic lesions throughout the GI tract underwent the procedure with the FV-EUS scope. A total of 300 FNAs were attempted, 6 (2%) of which could not be performed. Of the 294 successful EUS-FNA procedures, 130 (44.2%) were performed using a 22-gauge needle, 89 (30.3%) using a 25-gauge needle, and 75 (25.5%) using a 19-gauge needle. In all 67 cases of pancreatic cyst or dilated pancreatic duct, a specimen for cystic fluid analysis or cytologic examination could be obtained. Among the remaining 217 patients with solid lesion, a definitive diagnosis could be established for 211 patients (97.2%). The FV-EUS scope had a sensitivity of 74.7% (95% confidence interval [CI] 68.1-80.6%), a specificity of 100% (95% CI 89.9-100%), a positive likelihood ratio of infinity, and a negative likelihood ratio of 0.251 (95% CI 0.196-0.323). CONCLUSIONS: The FV-EUS scope is highly effective for FNA of solid and cystic lesions throughout the GI tract. Prospective studies comparing the FV-EUS scope and a curved linear scope are needed.

Pancreas as an Unusual Metastatic Site of Medullary Thyroid Carcinoma: A Case of Very Long-term Follow-up Under Prolonged Treatment with Somatostatin Analogues.

BACKGROUND: Pancreatic metastases from medullary thyroid carcinoma (MTC) are exceptional. Imaging and treatment based on somatostatin receptors may play a role, though the evidence is unconvincing. CASE PRESENTATION: We have, herein, documented a unique case of metastatic MTC, where pancreatic metastasis was identified by 68Ga-PET/CT, with the disease showing very slow progression during treatment with lanreotide autogel. A 51-year-old woman underwent total thyroidectomy for goiter in 2000, with a postoperative diagnosis of MTC. Due to persistent disease, somatostatin analogues (SSA) treatment commenced in 2005, following a positive acute octreotide test. In 2012, a pathology-confirmed pancreatic metastasis was diagnosed via 68Gallium-positron emission tomography (68Ga-PET/CT). The disease progressed very slowly over 17 years of SSA treatment. CONCLUSION: This uncommon case of pancreatic metastasis from MTC indicates that nuclear medicine techniques might offer valuable additional information. Extended treatment with lanreotide autogel appears to correlate with very slow disease progression in selected patients.

An alternative splicing signature defines the basal-like phenotype and predicts worse clinical outcome in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by extremely poor prognosis. PDAC presents with molecularly distinct subtypes, with the basal-like one being associated with enhanced chemoresistance. Splicing dysregulation contributes to PDAC; however, its involvement in subtype specification remains elusive. Herein, we uncover a subtype-specific splicing signature associated with prognosis in PDAC and the splicing factor Quaking (QKI) as a determinant of the basal-like signature. Single-cell sequencing analyses highlight QKI as a marker of the basal-like phenotype. QKI represses splicing events associated with the classical subtype while promoting basal-like events associated with shorter survival. QKI favors a plastic, quasi-mesenchymal phenotype that supports migration and chemoresistance in PDAC organoids and cell lines, and its expression is elevated in high-grade primary tumors and metastatic lesions. These studies identify a splicing signature that defines PDAC subtypes and indicate that QKI promotes an undifferentiated, plastic phenotype, which renders PDAC cells chemoresistant and adaptable to environmental changes.

Prevention of post-ERCP pancreatitis: current strategies and novel perspectives.

Endoscopic retrograde cholangiopancreatography (ERCP) is an advanced endoscopic procedure that might lead to severe adverse events. Post-ERCP pancreatitis (PEP) is the most common post-procedural complication, which is related to significant mortality and increasing healthcare costs. Up to now, the prevalent approach to prevent PEP consisted of employing pharmacological and technical expedients that have been shown to improve post-ERCP outcomes, such as the administration of rectal nonsteroidal anti-inflammatory drugs, aggressive intravenous hydration, and the placement of a pancreatic stent. However, it has been reported that PEP originates from a more complex interaction of procedural and patient-related factors. Appropriate ERCP training has a pivotal role in PEP prevention strategy, and it is not a chance that a low PEP rate is universally considered one of the most relevant indicators of proficiency in ERCP. Scant data on the acquisition of skills during the ERCP training are currently available, although some efforts have been recently done to shorten the learning curve by way of simulation-based training and demonstrate competency by meeting technical requirements as well as adopting skill evaluation scales. Besides, the identification of adequate indications for ERCP and accurate pre-procedural risk stratification of patients might help to reduce PEP occurrence regardless of the endoscopist's technical abilities, and generally preserve safety in ERCP. This review aims at delineating current preventive strategies and highlighting novel perspectives for a safer ERCP focusing on the prevention of PEP.

Endoscopic Ultrasound-Guided Fine Needle Biopsy in the Diagnostic Work-Up of Deep-Seated Lymphadenopathies and Spleen Lesions: A Monocentric Experience.

EUS-FNB has been introduced in clinical practice as a less invasive diagnostic approach with respect to surgery. We performed a single-center retrospective study on the diagnostic efficacy of EUS-guided FNB, including 171 patients with lymph nodes, splenic, and extranodal lesions that underwent EUS for FNB at our institution. Excluding 12 patients who did not undergo FNB and 25 patients with a previous diagnosis of a solid tumor, we included 134 patients with clinical/radiological suspect of a lymphoproliferative disease, including 20 patients with a previous history of lymphoma. Out of the 134 biopsies, material of diagnostic quality was obtained in 111 procedures (84.3%). Histological examination of the EUS-FNB samples produced an actionable diagnosis in 100 cases (74.6%). Among the patients without an actionable diagnosis, a second, different diagnostic procedure produced a further eight diagnoses of lymphoma. Therefore, the sensitivity of EUS-FNB for diagnosing lymphomas was calculated to be 86.4% (51/59). Assignment of lymphomas to WHO classification subtypes was possible in 47/51 (92%) of the cases. In conclusion, EUS-FNB is an effective procedure for the histological characterization of lesions that are suspected to be lymphoproliferative disease, allowing for an actionable diagnosis in 75% of cases.

The Gemelli Ultrasound Chronic Pancreatitis Score: A Non-invasive Tool for the Diagnosis of Chronic Pancreatitis.

A dedicated ultrasound (US) score, the Gemelli Ultrasound Chronic Pancreatitis (USCP) score, could be useful in the follow-up of patients with chronic pancreatitis (CP). However, its role in the diagnosis of CP has not been investigated. We aimed to evaluate the role of the Gemelli USCP score in the diagnosis of CP and the agreement with standard imaging techniques. Ninety-three patients clinically suspected of having CP and referred to the pancreatic outpatient clinic of A. Gemelli Hospital for endoscopic ultrasound (EUS) were prospectively enrolled. All patients underwent pancreatic US to calculate the Gemelli USCP score. A receiver operating characteristic curve analysis was also performed to assess the performance of the US score in CP diagnosis. The Gemelli USCP score was inversely related to the Rosemont score for both total value (p < 0.0001) and each parameter evaluated (p < 0.0001). This score was significantly higher in patients with CP with an excellent area under the receiver operating characteristic curve (0.946) and the optimal cutoff of 5. Moreover, we found a significant correlation between the Gemelli USCP score and laboratory parameters related to pancreatic exocrine insufficiency (p < 0.0001). The development of a dedicated ultrasound score could be useful as a non-invasive tool in the diagnosis of CP.

Pancreatic Cancer Patient-Derived Organoid Platforms: A Clinical Tool to Study Cell- and Non-Cell-Autonomous Mechanisms of Treatment Response.

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.

Personalized Endoscopy in Complex Malignant Hilar Biliary Strictures.

Malignant hilar biliary obstruction (HBO) represents a complex clinical condition in terms of diagnosis, surgical and medical treatment, endoscopic approach, and palliation. The main etiology of malignant HBO is hilar cholangiocarcinoma that is considered an aggressive biliary tract's cancer and has still today a poor prognosis. Endoscopy plays a crucial role in malignant HBO from the diagnosis to the palliation. This technique allows the collection of cytological or histological samples, direct visualization of the suspect malignant tissue, and an echoendoscopic evaluation of the primary tumor and its locoregional staging. Because obstructive jaundice is the most common clinical presentation of malignant HBO, endoscopic biliary drainage, when indicated, is the preferred treatment over the percutaneous approach. Several endoscopic techniques are today available for both the diagnosis and the treatment of biliary obstruction. The choice among them can differ for each clinical scenario. In fact, a personalized endoscopic approach is mandatory in order to perform the proper procedure in the singular patient.