Recent developments in the diagnosis of pancreatic neuroendocrine neoplasms.

INTRODUCTION: Pancreatic Neuroendocrine Neoplasms (PanNENs) are characterized by a highly heterogeneous clinical and biological behavior, making their diagnosis challenging. PanNENs diagnostic work-up mainly relies on biochemical markers, pathological examination, and imaging evaluation. The latter includes radiological imaging (i.e. computed tomography [CT] and magnetic resonance imaging [MRI]), functional imaging (i.e. 68Gallium [68 Ga]Ga-DOTA-peptide PET/CT and Fluorine-18 fluorodeoxyglucose [18F]FDG PET/CT), and endoscopic ultrasound (EUS) with its associated procedures. AREAS COVERED: This review provides a comprehensive assessment of the recent advancements in the PanNENs diagnostic field. PubMed and Embase databases were used for the research, performed from inception to October 2023. EXPERT OPINION: A deeper understanding of PanNENs biology, recent technological improvements in imaging modalities, as well as progresses achieved in molecular and cytological assays, are fundamental players for the achievement of early diagnosis and enhanced preoperative characterization of PanNENs. A multimodal diagnostic approach is required for a thorough disease assessment.

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.

Intraductal Papillary Mucinous Neoplasms in High-Risk Individuals: Incidence, Growth Rate, and Malignancy Risk.

BACKGROUND AND AIMS: In high-risk individuals (HRIs), we aimed to assess the cumulative incidence of intraductal papillary mucinous neoplasms (IPMNs) and compare IPMN growth, neoplastic progression rate, and the value of growth as predictor for neoplastic progression to these in sporadic IPMNs. METHODS: We performed annual surveillance of Dutch HRIs, involving carriers of germline pathogenic variants (PVs) and PV-negative familial pancreatic cancer kindreds. HRIs with IPMNs were compared with Italian individuals without familial risk under surveillance for sporadic IPMNs. RESULTS: A total of 457 HRIs were followed for 48 (range 2-172) months; the estimated cumulative IPMN incidence was 46% (95% confidence interval, 28%-64%). In comparison with 442 control individuals, IPMNs in HRIs were more likely to grow ≥2.5 mm/y (31% vs 7%; P < .001) and develop worrisome features (32% vs 19%; P = .010). PV carriers with IPMNs more often displayed neoplastic progression (n = 3 [11%] vs n = 6 [1%]; P = .011), while familial pancreatic cancer kindreds did not (n = 0 [0%]; P = 1.000). The malignancy risk in a PV carrier with an IPMN was 23% for growth rates ≥2.5 mm/y (n = 13), 30% for ≥5 mm/y (n = 10), and 60% for ≥10 mm/y (n = 5). CONCLUSIONS: The cumulative incidence of IPMNs in HRIs is higher than previously reported in the general population. Compared with sporadic IPMNs, they have an increased growth rate. PV carriers with IPMNs are suggested to be at a higher malignancy risk. Intensive follow-up should be considered for PV carriers with an IPMN growing ≥2.5 mm/y, and surgical resection for those growing ≥5 mm/y.

Managing complications of chronic pancreatitis: a guide for the gastroenterologist.

INTRODUCTION: Chronic pancreatitis is a heterogeneous and complex syndrome that, in most cases, causes pain as a cardinal symptom and affects both the morphology and function of the pancreas, leading to several serious complications. AREAS COVERED: The present review, based on a non-systematic PubMed search updated to June 2023, aims to present the current available evidence on the role of gastroenterologists in the diagnosis and treatment of both local and systemic complications by either endoscopic or medical treatments. EXPERT OPINION: At diagnosis and during chronic pancreatitis follow-up, particular care is needed to consider not only the clinically manifest signs and symptoms of the disease, such as pain, jaundice, gastrointestinal obstruction, and pseudocysts, which require multidisciplinary discussion to establish the best treatment option (endoscopic or surgical), but also less evident systemic complications. Pancreatic exocrine and endocrine insufficiency, together with chronic inflammation, addiction, and dysbiosis, contribute to malnutrition, sarcopenia, and osteopathy. These complications, in turn, increase the risk of infection, thromboembolic events, and death. Patients with chronic pancreatitis also have an increased risk of psychiatric disorders and pancreatic cancer onset. Overall, patients with chronic pancreatitis should receive a holistic evaluation, considering all these aspects, possibly through multidisciplinary care in dedicated expert centers.

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.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

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.

Endoscopic Ultrasound-guided Radiofrequency Ablation Versus Surgical Resection for Treatment of Pancreatic Insulinoma.

BACKGROUND & AIMS: Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI). METHODS: Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA. RESULTS: Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients). CONCLUSION: EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI.

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.

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.

Preoperative assessment of microvessel density in nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs).

BACKGROUND: Hypervascularization is a typical feature of pancreatic neuroendocrine tumors, and it frequently allows their recognition at imaging studies. However, the density of microvessels in pancreatic neuroendocrine tumors changes according to their biological behavior, and a low microvessel density is associated with higher disease aggressiveness. The primary aim was to investigate the relationship between microvessel density and aggressiveness of nonfunctioning pancreatic neuroendocrine tumors. The secondary aim was to evaluate the ability of contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound in predicting tumor microvessel density. METHODS: The patients who underwent surgery for nonfunctioning pancreatic neuroendocrine tumors (n = 66) with an available preoperative contrast-enhanced computed tomography (n = 39) and/or contrast-enhanced endoscopic ultrasound (n = 37) performed at San Raffaele Hospital (2016-2020) were included. The tumor vascularization was assessed by CD-34 staining, contrast-enhanced computed tomography, and contrast-enhanced endoscopic ultrasound. Median microvessel density (165 microvessels/mm2) was chosen as the cutoff to define low microvessel density and high microvessel density. RESULTS: The patients with a low microvessel density showed a significantly higher frequency of nodal metastases (P = .026), G2-G3 tumors (P = .022), and death domain-associated protein/α-thalassemia/mental retardation syndrome X-linked loss (P = .011) compared to patients with high microvessel density. The contrast-enhanced computed tomography tumor density in the arterial phase was significantly higher in patients with high microvessel density compared to those with low microvessel density (P = .016). The patients with a low microvessel density showed a significantly higher frequency of contrast-enhanced endoscopic ultrasound arterial hypoenhancement (P = .042) and late washout (P = .034). Contrast-enhanced computed tomography arterial hypoenhancement (P = .007) and contrast-enhanced endoscopic ultrasound late washout (P = .048) independently predicted a low microvessel density in the patients who underwent contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound, respectively. CONCLUSION: A low microvessel density represents a marker of aggressiveness in the patients with nonfunctioning pancreatic neuroendocrine tumors. Contrast-enhanced computed tomography and contrast-enhanced endoscopic ultrasound are reliable and easily available tools for preoperative assessment of microvessel density.

Reliability of grading preoperative pancreatic neuroendocrine tumors on EUS specimens: a systematic review with meta-analysis of aggregate and individual data.

BACKGROUND AND AIMS: Therapy and prognosis of pancreatic neuroendocrine tumors (PanNETs) are strictly related to the Ki-67 index, which defines tumor grading. The criterion standard for the assessment of grading of PanNETs is EUS-guided FNA (EUS-FBAFNA) or EUS-guided fine-needle biopsy sampling (EUS-FNB). Because data on diagnostic accuracy of EUS-FNA and EUS-FNB are heterogeneous, we aimed to analyze the variability in concordance between EUS grading and surgical grading. METHODS: The MEDLINE, SCOPUS, and EMBASE databases were searched until November 2021 to identify studies reporting the concordance rate between EUS grading and surgical grading. The study was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled events were calculated using a random-effects model and expressed in terms of pooled prevalence rates. A multivariate meta-regression was performed to find possible sources of heterogeneity. Where available, individual data were analyzed. RESULTS: Twenty-six studies with 864 patients undergone EUS-FNA or EUS-FNB and surgical resection for PanNETs were included. The pooled estimate rate for the overall concordance of EUS grading and surgical grading was 80.3% (95% confidence interval, 75.6-85.1). Undergrading (EUS grading < surgical grading) was significantly more frequent with respect to overgrading (14.7% vs 3.5%, P < .001). Individual data analysis showed that among nonconcordant patients, the median Ki-67 difference was 3% (interquartile range, 2-6.15). The type of World Health Organization classification adopted and the median lesion diameter were significantly associated with heterogeneity at meta-regression. CONCLUSIONS: EUS is an accurate technique in defining grading in patients with PanNETs, but a margin of error still exists, which should be the focus of future studies to minimize the risk of over- and/or undertreatment.

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.

Incidence of endocrine and exocrine insufficiency in patients with autoimmune pancreatitis at diagnosis and after treatment: a systematic review and meta-analysis.

BACKGROUND: Autoimmune pancreatitis (AIP) is a rare form of pancreatitis that may lead to endocrine and exocrine insufficiency if left untreated. AIP clinically responds to glucocorticoids (GCs) therapy, but multiple GCs courses are often required to maintain remission with detrimental effects on glycaemic control. OBJECTIVE: In this systematic review and meta-analysis, we aimed to assess the rate of endocrine and of exocrine insufficiency at diagnosis and at follow up in patients with AIP as well as the impact of GC therapy on pancreatic function in the long-term. METHODS: The MEDLINE, SCOPUS, and EMBASE databases were searched from inception to August 2021 to identify studies reporting data on endocrine and exocrine insufficiency in patients with AIP. Pooled events were calculated using a random-effect model and expressed in terms of pooled prevalence rates. RESULTS: A total of 6522 AIP patients and sixty-two studies were included in the analysis. The pooled estimate rate for the overall prevalence of diabetes in AIP at baseline was 37% (95% CI 32-42, I2 96%). The pooled prevalence rate of exocrine insufficiency was 45% (95%CI 32.9-57.4; I2 97%). The pooled estimate rate of diabetes at follow-up was 44% (95%CI 26.1-62.4) in studies where GCs were given to 100% of patients and 42% (95%CI 30.6-52.9) in studies where GCs were given to less than 100% of patients. CONCLUSION: A large proportion of patients with AIP displays concomitant exocrine and endocrine insufficiency at the time of diagnosis. The incidence of diabetes at the longest available follow up tends to increase in patients treated with GCs.

Differential EUS findings in focal type 1 autoimmune pancreatitis and pancreatic cancer: A proof-of-concept study.

Background and Objectives: Autoimmune pancreatitis (AIP) often mimics pancreatic cancer (PC), particularly if presenting as a focal lesion. EUS may orient the differential diagnosis between them. This study aims to identify EUS findings that might be useful to differentiate type 1 focal autoimmune pancreatitis (f-AIP1) and PC. Materials and Methods: F-AIP1 and PC patients were retrospectively collected, matched, and compared. EUS findings considered were: focal mass echogenicity, loss of lobularity, distal atrophy, peripancreatic hypoechoic margins (PHM), pancreatic duct dilation, duct-penetrating sign (DPS), pancreatic/common bile duct thickened walls (PD/CBD-TW), and vessel infiltration (VI). Elastography findings were also recorded. Variables with a P < 0.05 at univariate analysis were included in logistic multiple regression. Results: Fifteen patients with f-AIP and 60 with PC were studied. FE was hypoechoic in all patients from both groups. PHM was observed in 40% of f-AIP1 cases but not in PC ones (P < 0.001). DPS was found in 10/15 (66.7%) f-AIP1 and in 7/60 (11.7%) PC patients (P < 0.001). PD-TW and CBD-TW were observed in 66.7%/60% f-AIP1 cases and in 6.7%/13.6% PC patients, respectively (P < 0.001 for both comparisons). Pancreatic masses were significantly different at EUS elastography (elastic respectively in 71.4% f-AIP1 and 3.8% PC, P < 0.001). VI was suspected in 20% of f-AIPs and 85% of PCs (P < 0.001). At multiple regression, PD-TW, CBD-TW, elastic pattern, and the absence of VI independently supported a diagnosis of f-AIP1. Conclusions: Our results suggest that EUS findings deserve consideration in the diagnostic workup of AIP to improve the differential diagnosis with PC.

International external validation of a stratification tool to identify branch-duct intraductal papillary mucinous neoplasms at lowest risk of progression.

BACKGROUND: Identifying branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) at lowest risk of progression may allow for a reduced intensity of surveillance. OBJECTIVE: We aimed to externally validate the previously developed Dutch-American Risk stratification Tool (DART-1; https://rtools.mayo.edu/DART/), which identifies cysts at low risk of developing worrisome features (WFs) or high-risk stigmata (HRS). METHODS: Three prospective cohorts of individuals under surveillance for BD-IPMNs were combined, independent from the original development cohort. We assessed the performance (discrimination and calibration) of DART-1, a multivariable Cox-proportional logistic regression model with five predictors for the development of WFs or HRS. RESULTS: Of 832 individuals (mean age 77 years, SD 11.5) under surveillance for a median of 40 months (IQR 44), 163 (20%) developed WFs or HRS. DART-1's discriminative ability (C-statistic 0.68) was similar to that in the development cohort (0.64-0.72) and showed moderate calibration. DART-1 adequately estimated the risk for patients in the middle risk quintile, and slightly underestimated it in the lowest quintiles. Their range of predicted versus observed 3-year risk was 0%-0% versus 0%-3.7% for Q1; 0.3%-0.4% versus 3%-11% for Q2; and 2.6%-3% versus 2.4%-9.8% for Q3. The development of WFs or HRS was associated with pancreatic cancer (p < 0.001). Vice versa, in absence of WFs or HRS, the risk of malignancy was low (0.3%). CONCLUSIONS: The performance of DART-1 to predict the development of WFs or HRS in BD-IPMN was validated in an external international cohort, with a discriminative ability equal as in the development cohort. Risk estimations were most accurate for patients with BD-IPMNs in the middle risk quintile and slightly underestimated in the lowest quintiles.

Diagnostic accuracy of EUS-FNA in the evaluation of pancreatic neuroendocrine neoplasms grading: Possible clinical impact of misclassification.

BACKGROUND AND OBJECTIVES: Prognosis of pancreatic neuroendocrine neoplasms (PanNENs) mostly depend on tumor stage and grade, determined by Ki-67 labeling index. EUS-FNA is considered the gold-standard technique to obtain it. The aims of our study were to establish diagnostic accuracy of preoperative EUS-FNA Ki-67 evaluation considering final pathological assessment on surgical specimen as gold standard and to investigate the possible impact on prognosis of misclassification. METHODS: This is a retrospective study from a prospectively collected database. EUS-FNA grading (eG) and surgical one (sG) measured according to Ki-67 proliferative index values, according to 2017 WHO classification, were compared. eG-sG correlation was evaluated by Spearman index. Logistic regression investigated factors associated with misclassification. Prognostic difference in terms of progression-free survival was evaluated by Kaplan Meier method. RESULTS: One hundred and twelve PanNENs patients enrolled. In 13.4% of patients (15/112) EUS-FNA "undergraded" patients (eG1 vs. sG2), while in 12.5% (n = 14) it "overgraded" PanNENs (eG2 to sG1). No misclassifications in G3 patients. In patients with tumors <20 mm (n = 44), 2 (4.5%) eG1 and 10 (22.7%) eG2 were finally classified respectively as G2 and G1 at surgical histology. No factors, as i.e. the lesions' size or their morphological aspect, were associated with misclassification. In overgraded PanNENs, no progression occurred, while in patients correctly classified/undergraded the progression rate was 14.3%. CONCLUSIONS: This is the largest cohort of surgical PanNENs with preoperative EUS-FNA grading evaluation. Despite an acceptable eG-sG correlation, about 25% of patients are misclassified. Clinical impact of misclassification should be carefully considered especially in small tumors undergoing observation.