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Background: Laparoscopic distal pancreatectomy (LDP) is a challenging operation due to technical complexity and tumor-related factors. Aim of this study was to identify preoperative risk factors affecting LDP difficulty. Methods: Consecutive patients who underwent LDP between 2015 and 2018 at San Raffaele Hospital and Policlinico S.Orsola-Malpighi Hospital were enrolled retrospectively. Three variables were used to define surgical difficulty: conversion to open, duration of surgery >3rd quartile and intraoperative blood loss >3rd quartile. The presence of ≥1 of these 3 variables was considered as another measure of difficulty. Results: Overall, 191 patients were included. Conversion to open was required in 25 patients (13%). At multiple regression analysis, tumor proximity to major vessels was the only independent predictor of conversion from laparoscopic to open (p < 0.001). No variables independently predicted an excessive duration of surgery. Male gender (p = 0.033) and increasing parenchymal thickness at resection line (p = 0.018) were independent predictors of excessive blood loss. Increasing parenchymal thickness at resection line (p = 0.014) and tumor proximity to major vessels (p = 0.002) were significant risk factors for the presence of ≥1 outcome of surgical difficulty. Conclusion: Male gender, increasing parenchymal thickness at resection line and tumor proximity to major vessels represent preoperative risk factors of LDP difficulty.

Aim To explore the potentiality of radiomics analysis, performed on 68Ga-DOTATOC and fluorine-18-fluorodeoxyglucose (18F-FDG) PET/computed tomography (CT) images, in predicting tumour aggressiveness and outcome in patients candidate to surgery for pancreatic neuroendocrine neoplasms (PanNENs). Patients and methods Retrospective study including 61 patients who underwent 68Ga-DOTATOC and 18F-FDG PET/CT before surgery for PanNEN. Semiquantitative variables [SUVmax and somatostatin receptor density (SRD) for 68Ga-DOTATOC PET; SUVmax and MTV for 18F-FDG PET] and texture features [intensity variability, size zone variability (SZV), zone percentage, entropy; homogeneity, dissimilarity and coefficient of variation (Co-V)] have been analysed to evaluate their possible role in predicting tumour characteristics. Principal component analysis (PCA) was firstly performed and then multiple regression analyses were performed by using the extracted principal components. Results Regarding 68Ga-DOTATOC PET, SZV, entropy, intensity variability and SRD were predictive for tumour dimension. Regarding 18F-FDG PET, intensity variability, SZV, homogeneity, SUVmax and MTV were predictive for tumour dimension. Four principal components were extracted from PCA: PC1 correlated with all 18F-FDG variables, while PC2, PC3 and PC4 with 68Ga-DOTATOC variables. PC1 was the only significantly predicting angioinvasion (P = 0.0222); PC4 was the only one significantly predicting lymph nodal involvement (P = 0.0151). All principal components except PC4 significantly predicted tumour dimension (P

Purpose: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. Methods: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. Results: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. Conclusions: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

Background Outcomes after surgery for sporadic pancreatic neuroendocrine neoplasms (Pan-NENs) were evaluated. Methods This multicentre study included patients who underwent radical pancreatic resection for sporadic non-functioning Pan-NENs. In survival analysis, the risk of mortality in this cohort was analysed in relation to that of the matched healthy Italian population. Relative survival (RS) was calculated as the rate between observed and expected survival. Factors related to RS were investigated using multivariable modelling. Results Among 964 patients who had pancreatic resection for sporadic non-functioning Pan-NENs, the overall RS rate was 91.8 (95 per cent c.i. 81.5 to 96.5) per cent. 2019 WHO grade (hazard ratio (HR) 5.75 (s.e. 4.63); P = 0.030) and European Neuroendocrine Tumour Society (ENETS) TNM stage (6.73 (3.61); P Conclusion A surgical approach seems without benefit for Pan-NECs, and unnecessary for small G1 sporadic Pan-NENs. Surgery alone may be insufficient for stage III–IV and G3 Pan-NENs.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with favorable pathological and clinical features may be considered as indolent lesions, and therefore be amenable to conservative management. According to the primary tumor site, different non-aggressive approaches, based on endoscopic resection or simple active surveillance, can be proposed to selected patients fulfilling specific criteria. Tumor size, Ki67 proliferative index and depth of invasion are markers that can be used in order to identify these subjects. Patients with type I gastric NENs

Overall survival (OS) is considered as the standard measure of outcome in oncology. However, considering that resectable pancreatic neuroendocrine neoplasms (Pan-NENs) usually have a long OS, the feasibility of prospective studies is questionable due to a long follow-up period needed. The primary endpoint was to validate the use of disease-free survival (DFS) as a surrogate measure of OS. The secondary endpoint was to calculate the gain in sample size using DFS instead of OS in hypothetical prospective studies with two parallel groups. A systematic review of studies reporting both OS and DFS in resected Pan-NENs was carried out. Multivariate linear regression analysis was used to evaluate if DFS predicts the OS in patients undergoing radical resection. Monte Carlo simulation was performed to estimate the gain in sample size, supposing the use of DFS instead of OS, to evaluate a hypothetical adjuvant treatment after surgery in a randomized trial. Six studies reporting data about seven cohorts of resected Pan-NENs were included, for a total of 1088 patients. The median OS and DFS were 144 (27–134) and 122 (50–267) months, respectively. There was a significant correlation between DFS and OS (R2 = 0.988; P = 0.035). Monte Carlo simulations showed that the number of patients needed to demonstrate a significant reduction of probability of a ‘target event’ in a hypothetical two-arm group exploring the hypothetical role of adjuvant therapy was reduced using DFS instead OS. This finding supports the legitimacy of using DFS as an acceptable surrogate for OS in surgical clinical trials.

Background: The cost-effectiveness of minimally invasive distal pancreatectomy (MIDP) is still a matter of debate. This study compares the cost-effectiveness of open (ODP), laparoscopic (LDP) and robotic distal pancreatectomy (RDP).Methods: Pubmed, Web of Science and Cochrane Library databases were searched. Studies comparing cost-effectiveness of ODP and MIDP were included.Results: A total of 1052 titles were screened and 16 articles were included in the study, 2431 patients in total. LDP resulted the most cost-efficient procedure, with a mean total cost of 14,682 +/- 5665 V and the lowest readmission rates. ODP had lower surgical procedure costs, 3867 +/- 768 V. RDP was the safest approach regarding hospital stay costs (5239 +/- 1741 V), length of hospital stay, morbidity, clinically relevant pancreatic fistula and reoperations.Conclusion: In this meta-analysis MIDP resulted as the most cost-effective approach. LDP seems to be protective against high costs, but RDP seems to be safer. (C) 2021 Elsevier Inc. All rights reserved.

Background The role of wrapping in the setting of pancreaticoduodenectomy (PD) is controversial. This study aimed to assess whether the use of omental or falciform ligament wrapping of pancreatic anastomosis and/or vessels could reduce the rate of POPF and postpancreatectomy hemorrhage (PPH) after PD. Methods Studies comparing PD with (PD-W) and without wrapping (PD-nW) were included. Primary outcomes were POPF and extraluminal PPH. Dichotomous variables were analyzed for risk ratios (RR) with 95% Confidence Intervals. Results Nine studies involving 4384 patients were considered. The risk of POPF and clinically relevant POPF (CR-POPF) was similar between patients with and without omental wrapping of pancreatic anastomosis when considered as overall. A significant benefit from wrapping in terms of CR-POPF (RR 0.14, P = 0.002) was reported for patients who underwent PD with pancreaticojejunostomy (PJ). The risk of extraluminal PPH was slightly lower in patients who underwent vessels wrapping compared to those who did not (RR 0.58, P = 0.020). Similar extraluminal PPH rates were reported for patients with and without wrapping of pancreatic anastomosis (P = 0.620). Discussion Data from low-evidence studies suggest that omental wrapping of PJ may reduce the incidence of CR-POPF, whereas vessels wrapping may have a slight effect for preventing extraluminal PPH.

Background: Surgery remains the only treatment for the cure of pancreatic neuroendocrine tumors (PanNETs). Biomarkers to identify the completeness of resection and predict recurrence are lacking. Objective: The aims of this study were to evaluate if the blood measurement of neuroendocrine gene transcripts (NETest) was diagnostic of PanNETs, and whether NETest blood levels could identify complete resection. We compared transcript analysis with the biomarker chromogranin A (CgA). Methods: This was a prospective, longitudinal, single-center study including 30 patients with a postoperative histological confirmation of PanNET. Blood for NETest and CgA was collected preoperatively and on postoperative day (POD)1, POD5, and POD30. Transcripts were measured by real-time quantitative reverse transcription polymerase chain reaction and multianalyte algorithmic analysis (NETest; normal < 20), and CgA was measured by enzyme-linked immunosorbent assay (ELISA; normal < 109ng/mL). Data are expressed as mean ± standard deviation (SD). Results: Pancreatic surgical resections (n = 30) were R0, 26; R1, 2; and R2, 2. Preoperatively, NETest score was elevated in all 30 patients (44.7 ± 27), but postoperatively, NETest scores significantly decreased (p = 0.006) to POD30 (24.7 ± 24). The proportion of patients (15/30) with an elevated score significantly decreased by POD30 (p < 0.0001). CgA levels were elevated preoperatively (184 ± 360ng/mL) in only 9/30 patients, but did not decrease significantly postoperatively at POD30 (260 ± 589ng/mL, p = 0.398). The number of patients with elevated CgA levels remained unchanged (9/30). Conclusions: The NETest is an accurate diagnostic biomarker for PanNETs (100%). A decrease in NETest levels after radical resection suggests this blood test provides early assessment of surgical efficacy. CgA had no clinical utility.

Purpose: PET with radiolabeled somatostatin receptors (SSTR) analogues, such as 68Ga-DOTATOC, is commonly used in all stages of gastroenteropancreatic neuroendocrine tumours (GEP-NETs). Magnetic resonance Imaging (MRI) has excellent soft-tissue contrast and it is mainly applied in this oncological setting for assessing liver disease. Simultaneous PET/MRI scanners allow the combined acquisition of PET and MRI data with improved patient comfort and reduced radiation dose. The aim of the present pictorial essay is to highlight the assets and limits of fully hybrid PET/MRI in the field of GEP-NETs, presenting significant clinical cases performed in our Centre. Technique and findings: PET/MRI protocol: simultaneous PET/MRI acquisition started approximately 60min after 68Ga-DOTATOC tracer injection; MR localizer was performed to define the number of table positions (PET-FOV) for PET/MRI whole-body acquisition. A dedicated MRI protocol was performed on the abdomen, following the whole-body PET/MRI scan. Conclusion: 68Ga-DOTATOC PET/MRI combines the high sensitivity and specificity of 68Ga-DOTATOC PET tracer and MR high-quality imaging, especially for the liver. The clinical setting of GEP-NETs represents an interesting setting of application of this imaging technique, although the pros and cons should be taken into account until further methodological improvements will occur, especially for the characterization of lung findings.

Objective:Despite heterogeneous biology, similar surveillance schemas are utilized after resection of all pancreatic neuroendocrine tumors (PanNETs). Given concerns regarding excess radiation exposure and financial burden, our aim was to develop a prognostic score for disease recurrence to guide individually tailored surveillance strategies.Methods:All patients with primary nonfunctioning, nonmetastatic well/moderately differentiated PanNETs who underwent curative-intent resection at 9-institutions from 2000 to 2016 were included (n = 1006). A Recurrence Risk Score (RRS) was developed from a randomly selected derivation cohort comprised of 67% of patients and verified on the validation-cohort comprised of the remaining 33%.Results:On multivariable analysis, patients within the derivation cohort (n = 681) with symptomatic tumors (jaundice, pain, bleeding), tumors >2cm, Ki67 >3%, and lymph node (LN) (+) disease had increased recurrence. Each factor was assigned a score based on their weighted odds ratio that formed a RRS of 0 to 10: symptomatic = 1, tumor >2cm = 2, Ki67 3% to 20% = 1, Ki67 >20% = 6, LN (+) = 1. Patients were grouped into low-(RRS = 0-2; n = 247), intermediate-(RRS = 3-5; n = 204), or high (RRS = 6-10; n = 9)-risk groups. At 24 months, 33% of high RRS recurred, whereas only 2% of low and 14% of intermediate RRS recurred. This persisted in the validation cohort (n = 325).Conclusions:This international, novel, internally validated RRS accurately stratifies recurrence-free survival for patients with resected PanNETs. Given their unique recurrence patterns, surveillance intervals of 12, 6, and 3 months are proposed for low, intermediate, and high RRS patients, respectively, to minimize radiation exposure and optimize cost/resource utilization.

Background International guidelines suggest a watchful strategy for small nonfunctioning pancreatic neuroendocrine tumors. The aim of this study was to evaluate the management and indications for surgery in patients with asymptomatic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm. Methods Patients with asymptomatic, incidental, sporadic nonfunctioning pancreatic neuroendocrine tumors ≤2 cm without nodal or distant metastases were included (2012–2016). A comparison between active surveillance and surgery groups was performed. Results Of the 101 included patients, 72% underwent active surveillanc and 28% were surgically treated. Patients submitted to surgery were significantly younger (53 vs 60 years, P = .013), had a higher incidence of positive 18F-fluorodeoxyglucose positron emission tomography (18% vs 50%, P = .003), and a higher incidence of cytologically determined G2 tumor (0% vs 14%, P = .008). Conservatively managed patients had a significantly smaller tumor size (12 vs 16 mm, P = .0001). The main reasons determining surgical choice were as follows: patient’s preference (32%), positive 18F-fluorodeoxyglucose positron emission tomography (21.5%), main pancreatic duct dilation (17.5%), cytologically determined G2 tumor (14.5%), and young age (14.5%). At a median follow-up of 40 months, all of the 73 patients conservatively managed were alive, with no evidence of distant metastases and none underwent surgery. Only 5 patients had a tumor growth >20%. Conclusion One-third of patients with asymptomatic small nonfunctioning pancreatic neuroendocrine tumors ≤2 cm underwent surgery. Patient’s preference, initial tumor size, and young age were the main determinants of surgical indication. Preoperative diagnostic workup, including 18F-fluorodeoxyglucose positron emission tomography and cytologic grading, seems to be poorly accurate in determining malignant features in these small lesions.

Purpose: In patients with neuroendocrine neoplasm (NEN), the diagnostic role of positron-emission tomography (PET) using somatostatin receptor-targeted tracers, such as 68Ga-DOTATOC and 68Ga-DOTATATE in combination with 18F-FDG to assess glucose metabolism, is still a matter of debate. This systematic review aims to examine all published data on the role ofcombined 68Ga DOTA-peptides and 18F-FDG PET in the diagnosis and management of patients with NEN. Methods: A systematic search of studies assessing the use of dual-tracer PET in patients with NEN has been carried out on PubMed, Web of Science and Scopus databases. PRISMA guidelines have been used to screen the suitable studies. Results: Overall, 13 articles (658 patients in total) were considered for the analysis. All but three studies included patients with NEN of different primary sites of origin and different histologic grades. Seven studies included patients at initial diagnosis, whereas the remaining six considered patients at first diagnosis and at restaging after therapy. The median sensitivity of 68Ga DOTA-peptide PET (68Ga-DOTATOC, 68Ga-DOTATATE and 68Ga-DOTANOC) and 18F-FDG PET was 93% (range 82–100%) and 58% (range 37–75%), respectively. The median sensitivity of combined examinations was 94% (range 92–100%). Conclusions: There is still very limited evidence supporting the role of a routine use of combined 68Ga DOTA-peptide and 18F-FDG PETs in the diagnostic work-up of NEN.

Purpose: To define an imaging risk profile in a population of patients affected by Pancreatic neuroendocrine neoplasms (PanNENs) candidates to surgery, by assessing the predictive role of 68Ga-DOTATOC and 18F-FDG PET/CT and PET/MR derived parameters in risk stratification, particularly regarding histological features of aggressive behaviour. Patients and methods: Retrospective study including 83 patients (53 males, 30 females; median age: 60 years, interquartile range 52–66.5), who underwent to 68Ga-DOTATOC (PET/CT: n = 77; PET/MR: n = 6) and, 68/83 patients, also to 18F-FDG PET (PET/CT: n = 65; PET/MR: n = 3) before surgery for PanNEN between 2011 and 2019, with available histological and follow-up data. The PET scans were interpreted with both qualitative (positive vs. negative) and semiquantitative measurements as follows: maximum and mean standardized uptake value (SUVmax and SUVmean) for both 18F-FDG and 68Ga-DOTATOC scans, metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) for 18F-FDG scans and somatostatin receptor density (SRD) and total lesion somatostatin receptor density (TLSRD) for 68Ga-DOTATOC PET. Receiver Operating Characteristics (ROC) curve analysis was used to investigate the performance of several PET parameters in predicting tumour stage or characteristic. For each PET parameter, the optimal cut-off was derived. Logistic regression analysis was used to assess if the PET parameters, categorized with the optimal cut-off values, were able to predict significantly the corresponding tumour stage or characteristic. Results: Overall, 29 (35%) patients had G1, 49 (59%) a G2 and five (6%) had a G3 PanNEN. The median Ki-67 index was 4% (interquartile range: 1–8%). SRD and TLSRD significantly discriminated between pT3 or pT4 PanNEN versus pT1 or pT2, as well as 18F-FDG MTV and TLG. 68Ga-DOTATOC SUVmax was able to significantly predict the presence of distant metastases with a threshold of 51.27 (sensitivity and specificity of 85.7 and 68.1%, respectively). 18F-FDG MTV and TLG were predictors of angioinvasion. The cut-off threshold for MTV was 7.98 (sensitivity and specificity of 69.7 and 82.4%, respectively) (p = 0.0004) whereas the cut-off for TLG was 32.4 (sensitivity and specificity of 69.7% and 82.4%, respectively) (p = 0.0004). Conclusion: Dual tracer 68Ga-DOTATOC and 18F-FDG PET scans provide relevant information regarding tumour behaviour and aggressiveness, implementing the diagnostic preoperative work-up.

Purpose: To assess the ability of radiomic features (RF) extracted from contrast-enhanced CT images (ceCT) and non-contrast-enhanced (non-ceCT) in discriminating histopathologic characteristics of pancreatic neuroendocrine tumors (panNET). Methods: panNET contours were delineated on pre-surgical ceCT and non-ceCT. First- second- and higher-order RF (adjusted to eliminate redundancy) were extracted and correlated with histological panNET grade (G1 vs G2/G3), metastasis, lymph node invasion, microscopic vascular infiltration. Mann–Whitney with Bonferroni corrected p values assessed differences. Discriminative power of significant RF was calculated for each of the end-points. The performance of conventional-imaged-based-parameters was also compared to RF. Results: Thirty-nine patients were included (mean age 55-years-old; 24 male). Mean diameters of the lesions were 24 × 27mm. Sixty-nine RF were considered. Sphericity could discriminate high grade tumors (AUC = 0.79, p = 0.002). Tumor volume (AUC = 0.79, p = 0.003) and several non-ceCT and ceCT RF were able to identify microscopic vascular infiltration: voxel-alignment, neighborhood intensity-difference and intensity-size-zone families (AUC ≥ 0.75, p < 0.001); voxel-alignment, intensity-size-zone and co-occurrence families (AUC ≥ 0.78, p ≤ 0.002), respectively). Non-ceCT neighborhood-intensity-difference (AUC = 0.75, p = 0.009) and ceCT intensity-size-zone (AUC = 0.73, p = 0.014) identified lymph nodal invasion; several non-ceCT and ceCT voxel-alignment family features were discriminative for metastasis (p < 0.01, AUC = 0.80–0.85). Conventional CT ‘necrosis’ could discriminate for microscopic vascular invasion (AUC = 0.76, p = 0.004) and ‘arterial vascular invasion’ for microscopic metastasis (AUC = 0.86, p = 0.001). No conventional-imaged-based-parameter was significantly associated with grade and lymph node invasion. Conclusions: Radiomic features can discriminate histopathology of panNET, suggesting a role of radiomics as a non-invasive tool for tumor characterization. Trial registration number: NCT03967951, 30/05/2019

The incidence gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) has dramatically risen over the last three decades, probably due to the increased detection of asymptomatic lesions. The diagnostic work-up for patients with suspected GEP-NENs is based on conventional imaging, endoscopy, pathology, and functional imaging, including 68Gallium-DOTATATE PET and 18F-FDG PET. The choice of the best treatment strategy should be based on the evaluation of tumor-related features and patient's characteristics. A conservative management, consisting of active surveillance or endoscopic resection, has been advocated for patients with small, incidentally discovered, nonfunctioning tumors without features of aggressiveness. On the other hand, surgery with lymphadenectomy, also with a minimally invasive approach, represents the gold standard for the curative treatment of localized disease. Moreover, surgical resection plays an important role also in the context of a multimodal treatment strategy for patients with advanced GEP-NENs. Finally, a wide range of medical therapies, comprising somatostatin analogues, peptide receptor radionuclide therapy, target therapies and several chemotherapy regimens, can be offered to patients with advanced GEP-NENs not amenable of surgical resection, according to the biological and molecular features of their disease.

Peptide Receptor Radionuclide Therapy (PRRT) is an emerging therapeutic option for pancreatic neuroendocrine tumors (PanNETs). A possible role for PRRT as a neoadjuvant agent is still largely undetermined, explored only in case reports or small case series. Likewise, the histopathological and immunophenotypic changes induced by PRRT are poorly characterized. In the present study, 24 patients who underwent neoadjuvant PRRT on the basis of their disease’s characteristics were retrospectively matched with 24 patients who underwent upfront surgery. A comprehensive morphological and immunohistochemical evaluation was conducted to identify the differences in the two groups. The most significant findings were that the total percentage of stroma increased significantly in patients who underwent PRRT (p < 0.0001) and the characteristics of the stroma were different in the two groups. The somatostatin receptors type 2A (SSTR2A) were retained in most patients (87%) after PRRT. The density of CD163+ M2-polarized macrophages was greater in the PRRT group (p = 0.022), and M2-polarized macrophages tended to assume an epithelioid morphology (p = 0.043). In the neoadjuvant PRRT group, none of the histological parameters considered were associated with progression-free survival (PFS). Neoadjuvant PRRT in PanNETs is associated with reduced tumor diameter, an increased percentage of stroma, preserved SSTR2A expression in most of the cases, and an increased CD163+ M2-polarized macrophages density.

Background: Oncological survival after resection of pancreatic neuroendocrine neoplasms (panNEN) is highly variable depending on various factors. Risk stratification with preoperatively available parameters could guide decision-making in multidisciplinary treatment concepts. C-reactive Protein (CRP) is linked to inferior survival in several malignancies. This study assesses CRP within a novel risk score predicting histology and outcome after surgery for sporadic non-functional panNENs. Methods: A retrospective multicenter study with national exploration and international validation. CRP and other factors associated with overall survival (OS) were evaluated by multivariable cox-regression to create a clinical risk score (CRS). Predictive values regarding OS, disease-specific survival (DSS), and recurrence-free survival (RFS) were assessed by time-dependent receiver-operating characteristics. Results: Overall, 364 patients were included. Median CRP was significantly higher in patients &gt, 60 years, G3, and large tumors. In multivariable analysis, CRP was the strongest preoperative factor for OS in both cohorts. In the combined cohort, CRP (cut-off &ge, 0.2mg/dL, hazard-ratio (HR):3.87), metastases (HR:2.80), and primary tumor size &ge, 3.0cm (HR:1.83) showed a significant association with OS. A CRS incorporating these variables was associated with postoperative histological grading, T category, nodal positivity, and 90-day morbidity/mortality. Time-dependent area-under-the-curve at 60 months for OS, DSS, and RFS was 69%, 77%, and 67%, respectively (all p &lt, 0.001), and the inclusion of grading further improved the predictive potential (75%, 84%, and 78%, respectively). Conclusions: CRP is a significant marker of unfavorable oncological characteristics in panNENs. The proposed internationally validated CRS predicts histological features and patient survival.

Background: The most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. Methods: A retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. Results: 157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. Conclusions: The number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs.

Background: Postoperative acute pancreatitis (POAP) can be a possible cause of postoperative pancreatic fistula (POPF). The present study aimed to evaluate the role of clinically-relevant POAP (CR-POAP), defined according to different cut-offs of postoperative amylase (AMS) values and C-reactive protein (CRP), in the development of clinically relevant POPF (CR-POPF) after pancreaticoduodenectomy (PD). Methods: Data from 610 patients who underwent PD (2015–2018) were analyzed. Patients were divided according to the upper limit (100 U/l) and 3-fold the upper limit (300 U/l) of serum POD1 AMS. Univariate and multivariable analysis of possible predictors of CR-POPF were performed. Results: Overall, 360 patients (59%) had POD1 serum AMS ≤100 U/l, 142 patients (23%) had POD1 serum AMS >100 U/l and ≤300 U/l, and 108 patients (18%) had POD1 serum AMS >300 U/l. Patients with POD1 serum AMS >300 had a higher frequency of soft pancreatic texture, complications, main pancreatic duct diameter ≤3 mm, and CR-POPF. POD1 serum AMS >100 U/l associated to POD2 CRP ≥180 mg/l (OR: 4.3, p < 0.001) was an independent predictor of CR-POPF. Conclusion: These results confirm that CR-POAP, defined as POD1 serum AMS >100 U/l and POD2 CRP ≥ 180 mg/l, is associated with an increased risk of CR-POPF.

Background Stage IV gastro-entero-pancreatic neuroendocrine neoplasms (GEP-NENs) G3 are the NENs with the worst prognosis. According to ENETS guidelines, platinum-based chemotherapy is the standard treatment for this population. Surgery is only considered in highly selected “resectable” NENs with usually lower Ki67. However, the role of surgery with curative intent has been poorly investigated. Objective To describe, in a retrospective series of stage IV GEP-NENs G3, overall survival (OS) and recurrence-free survival (RFS) rates after curatively intended surgery. Methods Multicenter analysis of stage IV GEP-NENs G3 receiving radical resection (R0/R1) from 2007 to 2017, with minimum post-surgical follow-up time of 3 months. Results Fifteen patients from 6 NEN referral centers, with median follow-up of 29 months (8-86), were included. Eight cases had a neuroendocrine carcinoma (NEC) and 7 a neuroendocrine tumor G3 (NET G3). Median OS after radical surgery was 59 months. All patients recurred, with a median RFS of 8 months. Conclusions Radical surgery might be considered for highly selected stage IV GEP-NENs G3. Larger series are needed to confirm these results.

Background The risk of recurrence after curative surgery for pancreatic neuroendocrine tumors is reported to be between 10% and 30%. Among the available locoregional and systemic treatments, there are no specific recommendations regarding the best option for treating recurrent disease. The aims of this study were to evaluate the pattern of recurrence after surgery performed with curative intent for nonfunctioning pancreatic neuroendocrine tumors and to analyze the impact of treatment on disease progression. Methods All patients submitted to curative surgery for sporadic, well-differentiated, nonfunctioning pancreatic neuroendocrine tumors at 2 Italian centers between 2001 and 2018, with evidence of disease recurrence during follow-up, were included (n = 46). Results The most frequent type of recurrence was distant metastases (n = 38, 83%), located in the liver in 100% of cases, whereas 8 patients (17%) had an isolated local recurrence. Therapy for first disease recurrence included both locoregional (n = 14) and systemic treatments (n = 32). A second disease recurrence/progression occurred in 28 patients (61%). Patients who underwent systemic treatment after the first disease recurrence had better progression-free survival (1-year progression-free survival 78%) compared with those submitted to a locoregional procedure (1-year progression-free survival 50%; P = .007). Independent predictors of shortened progression-free survival after the first disease recurrence were the type of treatment (locoregional, hazard ratio 4.452, P = .001), the presence of necrosis (hazard ratio 2.732, P = .022) and age (>60 year, hazard ratio 2.494, P = .040). Conclusion Upfront locoregional treatment of the first recurrence of nonfunctioning pancreatic neuroendocrine tumors after curative surgery should be avoided in favor of systemic therapy.

Pancreatic neuroendocrine neoplasms (PanNENs) are increasingly recognized entities, whose incidence has dramatically grown during the last two decades. Surgery plays a pivotal role in their management as it represents the only chance of cure. Since PanNENs display a wide range of aggressiveness, their surgical management needs to be tailored on tumor’s and patient’s characteristics. Currently, there are several open questions and burning issues in the field of PanNEN, such as the management of asymptomatic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNET) ≤ 2cm. An active surveillance of these small lesions has been demonstrated to be safe although the available evidences are only based on retrospective studies. On the other hand, formal pancreatic resection associated with lymphadenectomy represents the gold standard for patients with localized NF-PanNEN > 2cm or NF-PanNEN ≤ 2cm in the presence of symptoms, dilation of the main pancreatic duct or suspicion of nodal metastases. Surgery plays also an important role in the setting of metastatic disease. In particular, surgery is generally recommended in the presence of low-grade, resectable, metastatic disease, but several series have reported also a survival benefit of palliative primary tumor resection in patients with unresectable liver metastases. The role of surgery in PanNEN G3 is still controversial. Indeed, surgery is associated with an improved survival in patients with well-differentiated PanNET G3, whereas there is almost no survival benefit in case of poorly differentiated lesions.

Background: While platinum-based chemotherapy represents the standard treatment for advanced grade 3 (G3) neuroendocrine neoplasms (NENs) according to the European Neuroendocrine Tumor Society guidelines, the role of radical-intended surgery in these patients, as well as the use of adjuvant chemotherapy, are still controversial. The aim of the present work is to describe, in a retrospective series of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) G3, the overall survival (OS) rate and risk factors for death after radical surgery. Secondary aims are the description of median recurrence-free survival (RFS) and of the role of adjuvant chemotherapy. Patients and Methods: Multicenter analysis of a series of stage I–III GEP-NEN G3 patients receiving radical surgery (R0/R1) with/without adjuvant chemotherapy was performed. Results: Sixty patients from eight neuroendocrine tumor (NET) referral centers, with median follow-up of 23months (5–187months) were evaluated. While 28.6% of cases had NET G3, 71.4% had neuroendocrine carcinoma G3 (NEC G3). The 2-year OS rate after radical surgery was 64.5%, with a statistically significant difference in terms of Ki67 threshold (cut-off 55%, P = 0.03) and tumor differentiation (NEC G3 vs. NET G3, P = 0.03). Median RFS after radical surgery was 14months, and 2-year RFS rate was 44.9%. Use of adjuvant chemotherapy provided no benefit in terms of either OS or RFS in this series. Conclusions: Surgery with radical intent might represent a valid option for GEP-NEN G3 patients with locoregional disease, especially with Ki67 value ≤ 55%.

Background: Pancreatic neuroendocrine neoplasms (PanNEN) are ideal entities for minimally invasive surgery. The advantage of the laparoscopic approach in terms of complications, length of stay (LOS) and cosmetic results has been previously demonstrated. However, scarce data are available on long-term oncological outcomes. Aim of this study was to compare short-term postoperative outcomes, pathological findings and long-term oncological results of minimally invasive distal pancreatectomy (MIDP) and open distal pancreatectomy (ODP) for PanNEN. Methods: Patients who underwent ODP or MIDP for nonfunctioning PanNEN (NF-PanNEN) were retrospectively analyzed. Inverse probability of treatment weighting using propensity score was performed to compare the outcomes of MIDP and ODP. Results: Overall, 124 patients were included in the study: 84 underwent OPD, whereas 40 were submitted to MIDP. The rate of high-grade postoperative complications was significantly lower in the MIDP group (p = 0.005, grade of complication with highest estimated probability 0 vs 2) and the postoperative LOS was significantly shorter after MIDP (p < 0.001, estimated days 8 versus 10). The number of examined lymph nodes (ELN) in the ODP group was significantly higher (p = 0.0036, estimated number of ELN 13 vs 10). Similar disease-free survival and overall survival were reported for the two groups (p = 0.234 and p = 0.666, respectively). Conclusions: Although MIDP for PanNEN seems to be associated with a lower number of ELN, long-term survival is not influenced by the type of surgical approach. MIDP is advantageous in terms of postoperative complications and LOS, but prospective studies are needed to confirm the overall oncological quality of resection in this group of neoplasms.

Background: A fatty infiltration of the pancreas has been traditionally regarded as the main histological risk factor for postoperative pancreatic fistula, whereas the role of the secreting acinar compartment has been poorly investigated. The aim of this study was to evaluate the role of acinar content at pancreatic resection margin in the development of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis after pancreaticoduodenectomy. Methods: Data from 388 consecutive patients who underwent pancreaticoduodenectomy (2018–2019) were analyzed. Pancreatic section margins were histologically assessed for acinar, fibrosis, and fat content. Acinar content was categorized using median and third quartile as cut-offs. Univariate and multivariable analysis of possible predictors of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis were performed. Results: Acinar content was 80% in 66 patients (17.0%). The rate of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis was significantly higher in patients with acinar content >80% (39.4% and 33.3%, respectively) as well as in those with acinar content ≥60% and ≤80% (36.5% and 35.3%, respectively), compared with patients with acinar content 80%, odds ratio 2.93, P = .010) and clinically relevant postoperative acute pancreatitis (≥60% and ≤80%, odds ratio 9.42, P < .001; >80%, odds ratio 10.16, P < .001). Conclusion: An acinar content at pancreatic resection margin ≥60% is associated to an increased risk of clinically relevant postoperative pancreatic fistula and clinically relevant postoperative acute pancreatitis. Fat content was associated neither with clinically relevant postoperative pancreatic fistula nor with clinically relevant postoperative acute pancreatitis.

Purpose: The aim of this study was to quantify the impact of CT delineation uncertainty of pancreatic neuroendocrine neoplasms (panNEN) on Radiomic features (RF). Methods: Thirty-one previously operated patients were considered. Three expert radiologists contoured panNEN lesions on pre-surgical high-resolution contrast-enhanced CT images and contours were transferred onto pre-contrast CT. Volume agreement was quantified by the DICE index. After images resampling and re-binning, 69 RF were extracted and the impact of inter-observer variability was assessed by Intra-Class Correlation (ICC): ICC > 0.80 was considered as a threshold for “very high” inter-observer agreement. Results: The median volume was 1.3 cc (range: 0.2–110 cc); a satisfactory inter-observer volume agreement was found (mean DICE = 0.78). Only 4 RF showed ICC < 0.80 (0.48–0.73), including asphericity and three RFs (of five) of the neighborhood intensity difference matrix (NID). Conclusions: The impact of inter-observer variability in delineating panNEN on RF was minimum, with the exception of the NID family and asphericity, showing a moderate agreement. These results support the feasibility of studies aiming to assess CT radiomic biomarkers for panNEN.

Background/Aims: The annual incidence of pancreatic neuroendocrine tumors (PanNET) has been estimated to be around 0.8/100,000 inhabitants. The aim of this study was to determine the frequency of incidental histological diagnosis of PanNET in pancreatic specimen evaluation for a purpose other other than PanNET diagnosis. Methods: One thousand seventy-four histopathological examinations of pancreatic specimens performed in 3 centers in Italy were retrospectively reviewed. All cases with a main pathological diagnosis of PanNET were excluded. Results: An incidental associated diagnosis of PanNET was made in 41 specimens (4%). Among those 41 cases, 29 (71%) had a largest diameter p = 0.048). There was no association between incidental diagnosis of PanNET and age, gender, BMI, smoking habit, diabetes, and type of operation. Conclusions: The frequency of incidental histological diagnosis of PanNET is considerably high, suggesting that their real prevalence is probably underestimated. The present study suggests a possible correlation between the incidental occurrence of PanNET and IPMN.

Management of localized well-differentiated pancreatic neuroendocrine tumors (panNETs) is controversial and primarily dependent on tumor size. Upfront surgery is usually recommended for tumors larger than 2 cm in diameter since they frequently show metastatic potential, whereas smaller panNETs are generally characterized by an indolent clinical course, with a rate of relapse or metastasis below 15%. To explore whether increased tumor size is paralleled by genomic variations, we compared the rate and the mutational patterns of putative driver genes that are recurrently altered in these tumors by investigating differential cohorts of panNET surgical specimens smaller (n = 27) or larger than 2 cm (n = 29). We found that the cumulative number of mutations detected in panNETs >2 cm was significantly higher (p = 0.03) relative to smaller tumors, while mutations of DAXX were significantly more frequent in the cohort of larger tumors (p = 0.05). Moreover, mutations of DAXX were associated with features of malignancy including increased grade, nodal involvement and lymphovascular invasion, and independently predicted both relapse after surgery (p = 0.05) and reduced DFS in multivariable analysis (p = 0.02). Our data suggest that alterations of the DAXX/ATRX molecular machinery increase the malignant potential of panNETs, and that identification of mutations of DAXX/ATRX in small, nonfunctioning tumors can predict the malignant progression observed in a minority of them.

New systemic treatments have improved the therapeutic landscape for patients with metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs). While drugs such as everolimus, sunitinib, temozolomide and 177Lutetium-dotatate are appropriate for patients with widespread disease progression, local treatment approaches may be more appropriate for patients with unifocal progression. Surgical resection, radiofrequency ablation (RFA), hepatic arterial embolization (HAE) or radiation, can control discrete sites of progression, allowing patients to continue their existing therapy and sparing them toxicities of a new systemic treatment. We identified 69 patients with metastatic GEP-NETs who underwent a local treatment for focal progression in the setting of widespread metastases. Twenty-six percent underwent resection, 27% RFA, 23% external beam radiation and 23% selective HAE. With a median follow-up of 25 months, 42 (61%) patients subsequently progressed to the point of requiring additional intervention (12 locoregional, 30 systemic) for disease control. Median time to new systemic treatment was 32 months (95% CI, 16.5–47.5 months). Median time to any additional intervention was 19 months (95% CI, 8.7–25.3 months). Control of local sites of progression enabled the majority of patients to remain on their existing systemic treatment and avoid potential toxicities associated with salvage systemic therapy.

Neuroendocrine gastro-entero-pancreatic neoplasms (GEP-NENs) constitute a heterogeneous group of tumors, whose incidence has increased over the years. The most frequent site for primary disease is the stomach followed by small and large intestine, and pancreas. In the last decade, a dramatic growing in the incidence of small, incidental GEP-NENs has been recorded. In parallel, an increasing attitude toward more conservative approaches instead of surgical management has being widely spreading. This is particularly true for small, asymptomatic, pancreatic NEN as for these tumor forms an active surveillance has proven to be safe and feasible. Primary site and biological features of the neoplasms lead to different strategies and indications for surveillance and follow-up. This review focuses on the current evidence on modality and timing of surveillance and conservative treatment of incidentally discovered lesions.