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Despite the clinical relevance of graft pancreatitis (GP) after pancreas transplantation (PT), a universally accepted definition is lacking. Aim of this scoping review was to provide a systematic overview of GP definitions reported in the literature. MEDLINE, Web of Science and Embase were searched for relevant articles. Prospective/retrospective studies reporting a GP definition were included. The included series (n = 20) used four main criteria (clinical, biochemical, radiological and pathological) to define GP. Overall, 9 studies defined GP using a single criterion (n = 8 biochemical, n = 1 pathological), 7 series using two criteria (n = 3 clinical + biochemical, n = 3 biochemical + radiological, n = 1 clinical + radiological), 3 series using three criteria (n = 3 clinical + biochemical + radiological), and 1 series using four criteria. Overall, 20 definitions of GP were found. GP rate was reported by 19 series and ranged between 0% and 87%. This scoping review confirms that a universally accepted definition of GP is absent, and there is no consensus on the criteria on which it should be grounded. Future research should focus on developing a validated definition of GP., Competing Interests: Declaration of competing interest The authors of this manuscript have no conflicts of interest to disclose as described by the Transplantation Reviews., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD)., Summary Background Data: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system., Methods: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades., Results: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001)., Conclusions: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The lack of preoperative prognostic factors to accurately predict tumour aggressiveness in non-functioning pancreatic neuroendocrine tumours may result in inappropriate management decisions. This study aimed to critically evaluate the adequacy of surgical treatment in patients with resectable non-functioning pancreatic neuroendocrine tumours and investigate preoperative features of surgical appropriateness., Methods: A retrospective study was conducted on patients who underwent curative surgery for non-functioning pancreatic neuroendocrine tumours at San Raffaele Hospital (2002-2022). The appropriateness of surgical treatment was categorized as appropriate, potential overtreatment and potential undertreatment based on histologic features of aggressiveness and disease relapse within 1 year from surgery (early relapse)., Results: A total of 384 patients were included. Among them, 230 (60%) received appropriate surgical treatment, whereas the remaining 154 (40%) underwent potentially inadequate treatment: 129 (34%) experienced potential overtreatment and 25 (6%) received potential undertreatment. The appropriateness of surgical treatment was significantly associated with radiological tumour size (P < 0.001), tumour site (P = 0.012), surgical technique (P < 0.001) and year of surgical resection (P < 0.001). Surgery performed before 2015 (OR 2.580, 95% c.i. 1.570 to 4.242; P < 0.001), radiological tumour diameter < 25.5 mm (OR 6.566, 95% c.i. 4.010 to 10.751; P < 0.001) and pancreatic body/tail localization (OR 1.908, 95% c.i. 1.119 to 3.253; P = 0.018) were identified as independent predictors of potential overtreatment. Radiological tumour size was the only independent determinant of potential undertreatment (OR 0.291, 95% c.i. 0.107 to 0.791; P = 0.016). Patients subjected to potential undertreatment exhibited significantly poorer disease-free survival (P < 0.001), overall survival (P < 0.001) and disease-specific survival (P < 0.001)., Conclusions: Potential overtreatment occurs in nearly one-third of patients undergoing surgery for non-functioning pancreatic neuroendocrine tumours. Tumour diameter emerges as the sole variable capable of predicting the risk of both potential surgical overtreatment and undertreatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Purpose: Accurate identification of lymph node (LN) metastases is pivotal for surgical planning of pancreatic neuroendocrine tumours (PanNETs); however, current imaging techniques have sub-optimal diagnostic sensitivity. Aim of this study is to investigate whether [ 68 Ga]Ga-DOTATOC PET radiomics might improve the identification of LN metastases in patients with non-functioning PanNET (NF-PanNET) referred to surgical intervention., Methods: Seventy-two patients who performed preoperative [ 68 Ga]Ga-DOTATOC PET between December 2017 and March 2022 for NF-PanNET. [ 68 Ga]Ga-DOTATOC PET qualitative assessment of LN metastases was measured using diagnostic balanced accuracy (bACC), sensitivity (SN), specificity (SP), positive and negative predictive values (PPV, NPV). SUVmax, SUVmean, Somatostatin receptor density (SRD), total lesion SRD (TLSRD) and IBSI-compliant radiomic features (RFs) were obtained from the primary tumours. To predict LN involvement, these parameters were engineered, selected and used to train different machine learning models. Models were validated using tenfold repeated cross-validation and control models were developed. Models' bACC, SN, SP, PPV and NPV were collected and compared (Kruskal-Wallis, Mann-Whitney)., Results: LN metastases were detected in 29/72 patients at histology. [ 68 Ga]Ga-DOTATOC PET qualitative examination of LN involvement provided bACC = 60%, SN = 24%, SP = 95%, PPV = 78% and NPV = 65%. The best-performing radiomic model provided a bACC = 70%, SN = 77%, SP = 61%, PPV = 60% and NPV = 83% (outperforming the control model, p < 0.05*)., Conclusion: In this study, [ 68 Ga]Ga-DOTATOC PET radiomics allowed to increase diagnostic sensitivity in detecting LN metastases from 24 to 77% in NF-PanNET patients candidate to surgery. Especially in case of micrometastatic involvement, this approach might assist clinicians in a better patients' stratification., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

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.

Insulinoma is a multifaceted disease that poses several challenges in terms of clinical presentation, diagnostic work-up, and surgical management. The aim of this study was to describe diagnostic work-up, surgical management, and postoperative outcomes of patients with insulinoma. All consecutive patients who underwent surgery for insulinoma at San Raffaele Hospital (Milan, Italy) between January 2008 and January 2022 were included. Overall, 98 patients were considered. The median delay between presenting symptoms and insulinoma diagnosis was 10 months (IQR, 4-21). Insulinoma diagnosis was made at our Institution in 45 patients, 20 of whom referred within 6 months from symptoms onset. In this subgroup, the median interval between symptoms presentation and insulinoma diagnosis was 4 months (IQR, 2-6), as compared to 14 months (IQR, 10-26) in patients (n = 25) who referred to our institution after 6 months from symptoms onset (p < .001). The insulinoma was localized preoperatively in all the cases. All patients underwent ≥1 high-quality imaging: computed tomography (CT: n = 87, sensitivity 84%), magnetic resonance imaging (MRI: n = 55, sensitivity 85%) and endoscopic ultrasound (EUS: n = 79, sensitivity 100%). MRI identified the tumor in eight patients with negative CT. EUS localized the insulinoma in three patients with negative CT and negative MRI. Parenchyma-sparing resections were performed in 41 patients. Contact with major vessels, lesion close to Wirsung duct and suspect of malignancy were the main reasons to perform a formal resection. An early referral to high-volume centers is important for reducing diagnostic delay in patients with insulinoma. The diagnostic work-up of insulinoma frequently requires several imaging modalities to be performed, with EUS being the most sensitive one. Parenchyma-sparing surgery for insulinoma should be performed whenever technically and oncologically feasible., (© 2023 British Society for Neuroendocrinology.)

Background: Pancreatic acinar content (Ac) has been associated with pancreas-specific complications after pancreatoduodenectomy. The aim of this study was to improve the prediction ability of intraoperative risk stratification by integrating the pancreatic acinar score., Methods: A training and validation cohort underwent pancreatoduodenectomy with a subsequent histologic assessment of pancreatic section margins for Ac, fibrosis (Fc), and fat. Intraoperative risk stratification (pancreatic texture, duct diameter) and pancreas-specific complications (postoperative hyperamylasemia [POH], postpancreatectomy acute pancreatitis [PPAP], pancreatic fistula [POPF]) were classified according to ISGPS definitions., Results: In the validation cohort (n= 373), the association of pancreas-specific complications with higher Ac and lower Fc was replicated (all P <0.001). In the entire cohort (n= 761), the ISGPS classification allocated 275 (36%) patients into intermediate-risk classes B (POH 32%/PPAP 3%/POPF 17%) and C (POH 36%/PPAP 9%/POPF 33%). Using the acinar score (Ac ≥60% and/or Fc ≤10%), intermediate-risk patients could be dichotomized into a low-risk (POH 5%/PPAP 1%/POPF 6%) and a high-risk (POH 51%/PPAP 9%/POPF 38%) group (all P <0.001). The acinar score AUC for POPF prediction was 0.70 in the ISGPS intermediate-risk classes. Overall, 239 (31%) patients were relocated into the high-risk group from lower ISGPS risk classes using the acinar score., Conclusions: The risk of pancreas-specific complications appears to be dichotomous-either high or low-according to the acinar score, a tool to better target the application of mitigation strategies in cases of intermediate macroscopic features., Competing Interests: The authors report no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose: Sleeve gastrectomy (SG) has become the most common bariatric procedure, but it is often characterized by the onset of postoperative gastroesophageal reflux disease (GERD). High-resolution manometry (HRM) is a useful tool to detect risk factors for GERD. The aim of this study was to evaluate preoperative manometric parameters as possible predictors of postoperative GERD., Materials and Methods: This was a monocentric retrospective study. We analyzed 164 patients, with preoperative esophagitis/GERD symptoms who underwent preoperative HRM and were submitted to SG (July 2020-February 2022)., Results: Postoperative GERD was observed in 60 patients (36.6%): 41 of them (68%) already had preoperative GERD symptoms, whereas the remaining 19 patients (32%) developed postoperative symptoms. Female patients developed postoperative GERD in a significantly higher fraction of cases as compared to male patients (82% versus 18%; p < 0.001). DCI (distal contractile integral) was identified as the only HRM parameter correlating with the presence of GERD. Patients with DCI ≤ 1623 mmHg*cm*s developed postoperative GERD in 46% of cases (n = 43/94), as compared to 24% of cases (n = 17/70) among patients with DCI > 1623 mmHg*cm*s (p = 0.005). At multivariable analysis, female sex (OR 3.402, p = 0.002), preoperative GERD symptoms (OR 2.489, p = 0.013), and DCI ≤ 1623 mmHg*s*cm (OR 0.335, p = 0.003) were identified as independent determinants of postoperative GERD., Conclusion: All the patients with preoperative risk factors for reflux, such as GERD symptoms or esophagitis on EGDS (esophagogastroduodenoscopy), should be considered for an HRM. Moreover, when a DCI ≤ 1623 mmHg*s*cm is found, a bariatric procedure different from SG might be considered., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Diabetes increases the risks related to surgery. At the same time, bariatric surgery improves diabetes. Glycated hemoglobin (A1C) is an index of diabetes severity. The purpose of this study is to evaluate A1C as a possible predictor of postoperative complications after Sleeve Gastrectomy (SG), focusing on leakage., Materials and Methods: Monocentric retrospective study considering all consecutive patients with obesity, with or without diabetes, who underwent bariatric surgical procedures, from January 2018 to December 2021. All patients had preoperative A1C values., Results: 4233 patients were considered. 522 patients (12.33%) were diabetics (A1C ≥ 6.5%). Of these, 260 patients (6.14%) had A1C ≥ 7% and 59 (1.39%) A1C ≥ 8%. 1718 patients (40.58%) were in a pre-diabetic range (A1C 5.7%-6.5%). Higher A1C values were associated with older age, male gender, higher BMI and increased rate of comorbidities. A longer operative time was observed for patients with A1C ≥ 7%, p = 0.027 (53 ± 20 vs 51 ± 18 min). The frequency of leakage was significantly higher when A1C ≥ 7% (3.8% vs 2.0%, p = 0.026). The frequency of leakage further increased when A1C ≥ 8% (5.1%), although this difference did not reach statistical significance., Conclusion: Patients with obesity and A1C ≥ 7% need to be referred to a diabetologist to treat diabetes before surgery and consequently decrease the risk of leakage., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Few studies analysed the impact of different venous resection techniques on recurrence in patients with pancreatic ductal adenocarcinoma (PDAC). Primary aim was to compare local recurrence rate and disease-free survival (DFS) between patients who underwent pancreatectomy with tangential versus segmental resection of portal vein/superior mesenteric vein., Materials and Methods: All consecutive patients who underwent pancreatectomy with venous resection for PDAC between 2009 and 2019 were included. A propensity score matching (PSM) was used to reduce the effect of treatment selection bias., Results: Overall, 120 patients (68%) underwent pancreatectomy with tangential venous resection and 57 patients (32%) were submitted to pancreatectomy with segmental venous resection. After a median follow-up of 24 months, local recurrence was comparable between the two groups (tangential: n = 32/120, 26.7% versus segmental: n = 10/57, 17.5%; p = 0.58). The median DFS was 17 months (IQR 9-31) in patients who underwent tangential resection, as compared to 12 months (IQR 5-21) in those who underwent segmental resection (p = 0.049). After PSM (n = 106), the median DFS was 18 months (IQR 9-26) in the tangential resection group, and 12 months (IQR 5-21) in the segmental resection group (p = 0.17). In the PSM population, lymph node ratio (HR 4.83; p = 0.028) and tumor size >25 mm (HR 3.26; p = 0.007) were identified as determinants of local recurrence., Conclusion: Tangential venous resections are not associated with a higher rate of local recurrence. Long-term outcomes are more related to tumors characteristics than to venous resection techniques. A step-up approach to vein resection, with tangential resection being performed whenever technically feasible, should be strongly encouraged., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Purpose: To evaluate the role of 68 Ga-DOTATOC PET parameters in predicting DAXX/ATRX loss of expression in patients with Pancreatic neuroendocrine tumors (PanNET) candidate to surgery., Methods: This retrospective study included 72 consecutive patients with PanNET (January 2018-March 2022) who underwent to 68 Ga-DOTATOC PET for preoperative staging. Image analysis: qualitative assessment and extraction of SUVmax, SUV mean, somatostatin receptor density (SRD), and total lesion somatostatin receptor density (TLSRD) from primary PanNET. Radiological diameter and biopsy information (grade, Ki67) were collected. Loss of expression (LoE) of DAXX/ATRX was assessed by immunohistochemistry on surgical specimen. Student t-test, univariate and multivariate logistic regression and ROC curves have been used to investigate the predictive value of PET parameters on DAXX/ATRX LoE., Results: Forty-two/72 patients had a G1, 28/72 a G2, and 2/72 a G3 PanNET. Seven/72 patients had DAXX LoE, 10/72 ATRX LoE, and 2/72 DAXX/ATRX LoE. SRD and TLSRD could predict DAXX LoE (p = 0.002, p = 0.018, respectively). By evaluating SRD in combination with radiological diameter, only SRD maintained statistical significance (multivariate logistic regression: p = 0.020, OR = 1.05), providing the best prediction (AUC-ROC = 79.01%; cut-off = 46.96; sensitivity = 77.78%; specificity = 88.89%). In the sub-analysis performed on 55 patients with biopsy availability, SRD demonstrated its role in providing useful and additional information (multivariate logistic regression: SRD p = 0.007; grade p = 0.040)., Conclusion: SRD has a predictive role on DAXX LoE in PanNETs, with higher probability of LoE at increasing SRD values. SRD provides complementary/additional information to grade assessed on biopsy material, and the combined use of these approaches might support patients' management by preoperatively identifying subjects with more aggressive diseases., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: To predict tumor grade (G1 vs. G2/3), presence of distant metastasis (M+), metastatic lymph nodes (N+), and microvascular invasion (VI) of pancreatic neuroendocrine neoplasms (PanNEN) based on preoperative CT radiomic features (RFs), by applying a machine learning approach aimed to limit overfit., Methods: This retrospective study included 101 patients who underwent surgery for PanNEN; the entire population was split into training (n = 70) and validation cohort (n = 31). Based on a previously validated methodology, after tumor segmentation on contrast-enhanced CT, RFs were extracted from unenhanced CT images. In addition, conventional radiological and clinical features were combined with RFs into multivariate logistic regression models using minimum redundancy and a bootstrap-based machine learning approach. For each endpoint, models were trained and validated including only RFs (RF&#95;model), and both (radiomic and clinicoradiological) features (COMB&#95;model)., Results: Twenty-five patients had G2/G3 tumor, 37 N+, and 14 M+ and 38 were shown to have VI. From a total of 182 RFs initially extracted, few independent radiomic and clinicoradiological features were identified. For M+ and G, the resulting models showed moderate to high performances: areas under the curve (AUC) for training/validation cohorts were 0.85/0.77 (RF&#95;model) and 0.81/0.81 (COMB&#95;model) for M+ and 0.67/0.72 and 0.68/0.70 for G. Concerning N+ and VI, only the COMB&#95;model could be built, with poorer performance for N+ (AUC = 0.72/0.61) compared to VI (0.82/0.75). For all endpoints, the negative predictive value was good (≥ 0.75)., Conclusions: Combining few radiomic and clinicoradiological features resulted in presurgical prediction of histological characteristics of PanNENs. Despite the limited risk of overfit, external validations are warranted., Key Points: • Histology is the only tool currently available allowing characterization of PanNEN biological characteristics important for prognostic assessment; significant limitations to this approach exist. • Based upon preoperative contrast-enhanced CT images, a machine learning approach optimized to favor models' generalizability was successfully applied to train predictive models for tumor grading (G1 vs. G2/3), microvascular invasion, metastatic lymph nodes, and distant metastatic spread. • Moderate to high discriminative models (AUC: 0.67-0.85) based on few parameters (≤ 3) showing high negative predictive value (0.75-0.98) were generated and then successfully validated., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

Background: The prognosis of nodal recurrence after surgery for non-functioning pancreatic neuroendocrine tumors (NF-PanNETs) and its predictors have been poorly investigated. This study aimed to compare clinicopathologic features and survival between patients with nodal relapse and those with distant relapse and to identify predictors of nodal relapse after surgery for NF-PanNETs., Methods: All patients (n = 321) submitted to surgery for NF-PanNETs were included. Nodal recurrence was defined as the presence of one or more enlarged LNs at high-quality radiologic examinations and always confirmed by 68 Ga-DOTA-PET or biopsy., Results: Altogether, 21 patients (6 %) experienced nodal (± distant) relapse, and 35 patients (11 %) had distant recurrence alone. Isolated nodal recurrence occurred for 23 % of patients with recurrence. Overall, 11 patients died of disease, one of whom (pT3N1G3) had an isolated nodal relapse. The rate of LN metastases (81 % vs 54 %; p = 0.044) and median number of positive LNs (PLN) (3 vs 0; p = 0.019) both were significantly higher for the patients with nodal (± distant) relapse than for those with distant relapse alone. Microvascular invasion (p = 0.046), T stage (p = 0.004), N stage (N1 [p = 0.049]; N2 [p = 0.001]), M stage (p < 0.001), and necrosis (p = 0.011) independently predicted nodal relapse. After distal pancreatectomy (n = 182), 13 patients experienced nodal recurrence, 9 of whom had left paraortic LNs involvement., Discussion: Lymph nodes are not rare sites of recurrence after surgery for NF-PanNETs. Lymph node involvement is a powerful determinant of nodal relapse. Nodal relapse frequently involves LNs that are not removed during standard lymphadenectomy., (© 2023. Society of Surgical Oncology.)

Background: Myositis ossificans (MO) is an uncommon disorder characterized by heterotopic ossification within soft tissues. Only a few cases of intra-abdominal MO (IMO) have been described in the literature. Histology could be difficult to understand and a wrong diagnosis could lead to an improper cure., Case Summary: We herein report the case of IMO in a healthy 69-year-old man. The patient presented with an abdominal mass in the left lower quadrant. A computed tomography scan showed an inhomogeneous mass with multiple calcifications. The patient underwent radical excision of the mass. Histopathological findings were compatible with MO. Five months later the patient showed a recurrence causing hemorrhagic shock due to intractable intralesional bleeding. The patients eventually died within three months since recurrence., Conclusion: The case described could be classified as post-traumatic MO that developed close to the previously fractured iliac bone. The subsequent surgical procedure was ineffective and the disease rapidly recurred. The misleading intraoperative diagnosis led to improper surgical treatment with a dramatic evolution., Competing Interests: Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article., (©The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights reserved.)

The incidence of well-differentiated non-functioning pancreatic neuroendocrine tumors (NF-PanNET) increased during the last decades. The risk of relapse after curative surgery, albeit low, is not negligible; moreover, adjuvant treatment is currently not an option and a reliable predictive model based on prognostic characteristics is urgently needed for tailoring a follow-up strategy. The histological classification of PanNET now relies only on the proliferative activity (mitosis and Ki67) and staging. In contrast to other endocrine neoplasms, the role of infiltrative growth pattern in NF-PanNET is not taken into consideration at present. In the current study, 247 consecutive patients who underwent surgical resection for a NF-PanNET were examined for the histological growth pattern of the tumor. Two distinct patterns (non-infiltrative vs. infiltrative) were described with the latter being further subclassified according to the type of structures invaded by the tumor (non-infiltrative: pattern 1; infiltration of adjacent pancreatic parenchyma and/or peripancreatic soft tissue: pattern 2; invasion of nearby organs and/or major vessels: pattern 3). The infiltrative growth resulted to be strongly associated with a poorer survival compared to a non-infiltrative growth (p < 0.001). In particular, the distinction between pancreatic parenchyma and/or peripancreatic soft tissue invasion versus adjacent organs and/or major vessels invasion was the most powerful predictor of recurrence after surgery at multivariate analysis (pattern 2 vs. pattern 1: HR 10.136, p = 0.028; pattern 3 vs. pattern 1: HR 15.775, p = 0.015). The infiltrative growth pattern could therefore provide additional prognostic information implementing the current grading and staging system., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Objective: To determine the accuracy of preoperative imaging, including contrast-enhanced computed tomography (CE-CT), endoscopic ultrasound (EUS), and 68 Gallium-DOTATOC positron emission tomography ( 68 Ga-DOTATOC PET), in identifying nodal metastases (N+) in sporadic nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs)., Background: An accurate preoperative identification of N+ in NF-PanNETs is critical for surgical planning. The accuracy of different imaging techniques in detecting lymph node (LN) metastases in NF-PanNETs has been poorly investigated., Methods: All consecutive patients undergoing surgery for sporadic NF-PanNETs (2018-2021) were enrolled in a prospective study (DETECTYON; NCT03918759). The accuracy of preoperative imaging techniques in detecting N+ was assessed through sensitivity, specificity positive and negative predictive values., Results: Overall, 100 patients with NF-PanNETs underwent CE-CT, EUS, and 68 Ga-DOTATOC PET before pancreatic resection. LN metastases were found in 42 cases (42%). Sensitivity, specificity, positive predictive value, and negative predictive value of different imaging techniques were 26%, 95%, 79%, 64% for CE-CT, 19%, 98%, 89%, 63% for EUS, and 12%, 95%, 63%, 60% for 68 Ga-DOTATOC PET, respectively. Radiologic tumor size >4 cm and the presence of radiologic N+ at ≥1 imaging were independent predictors of N+ at pathology. The identification of N+ at ≥1 imaging technique was associated with a higher number of positive LNs compared with negative imaging (4 vs 2) ( P =0.012)., Conclusions: CE-CT, EUS, and 68 Ga-DOTATOC PET are poorly sensitive in predicting nodal status in NF-PanNETs despite a high specificity., Competing Interests: The authors report no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

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/mm 2 ) 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., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: The aim of the current review is to summarize the available evidence to aid clinicians in the surveillance, treatment and follow-up of the different primary tumors developed by patients diagnosed with von Hippel-Lindau (VHL) syndrome., Methods: A non-systematic narrative review of original articles, meta-analyses, and randomized trials was conducted, including articles in the pre-clinical setting to support relevant findings., Results: VHL disease is the most common rare hereditary disorder associated with clear cell renal cell carcinoma. Affected individuals inherit a germline mutation in one VHL allele, and any somatic event that disrupt the other allele can trigger mutations, chromosomal rearrangements, or epigenetic regulations leading to oncogenesis. From a clinical perspective, patients continuously develop multiple primary tumors., Conclusion: Because VHL is considered a rare disease, very limited evidence is available for diagnosis, surveillance, active treatment with local or systemic therapy and follow-up., (© 2022 Editorial Office of Asian Journal of Urology. Production and hosting by Elsevier B.V.)

Background: The safety of observing small non-functioning pancreatic neuroendocrine tumours (NF-Pan-NETs) remains under debate., Methods: This was a multicentre retrospective study of patients with small incidental NF-Pan-NETs. Survival of patients who underwent upfront surgery versus active surveillance was compared. The risk of death was matched with that in the healthy population. The excess hazard rate and probability of a normal lifespan (NLP) were calculated. Propensity score matching (PSM) with a 1 : 1 ratio was used to minimize the risk of selection bias., Results: Some 222 patients (43.7 per cent) underwent upfront surgery and 285 (56.3 per cent) were observed. The excess hazard rate for the entire cohort was quantifiable as 0.04 (95 per cent c.i. 0 to 0.08) deaths per 1000 persons per year, and the NLP was 99.7 per cent. Patients in the active surveillance group were older (median age 65 versus 58 years; P < 0.001), and more often had co-morbidity (45.3 versus 24.8 per cent; P = 0.001), and smaller tumours (median 12 versus 13 mm; P < 0.001), less frequently located in the pancreatic body-tail (59.5 versus 69.6 per cent; P = 0.008, 59.3 versus 73.9 per cent; P = 0.001). Median follow-up was longer for patients who underwent upfront surgery (5.6 versus 2.7 years; P < 0.001). After PSM, 118 patients per group were included. The excess hazard rates were 0.2 and 0.9 deaths per 1000 persons per year (P = 0.020) for patients in the active surveillance and upfront surgery groups respectively. Corresponding NLPs were 99.9 and 99.5 per cent respectively (P = 0.011)., Conclusion: Active surveillance of small incidental NF-Pan-NETs is a reasonable alternative to resection., (© The Author(s) 2022. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Purpose: No single reliable biomarker is available for nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs). Vasostatin-1 (VS-1), the N-terminal fragment of chromogranin A (CgA), seems to be a more accurate biomarker compared to its precursor. Primary aim was to investigate the ability of VS-1, compared to total-CgA, to assess the effectiveness of surgical resection performed for NF-PanNETs. Secondary aim was to evaluate two additional CgA-derived fragments, pancreastatin (PST) and vasostatin-2 (VS-2), as possible biomarkers for NF-PanNETs., Methods: Consecutive patients who underwent surgery for NF-PanNETs at San Raffaele Scientific Institute were included (n = 35). Plasma levels of CgA and CgA-derived fragments were measured by Enzyme-Linked ImmunoSorbent Assay (ELISA), preoperatively and postoperatively., Results: Preoperative VS-1 was significantly higher compared to VS-1 measured on postoperative day 5 (POD5) (pre: 0.338 nM versus POD5: 0.147 nM, P < 0.001), whereas total-CgA significantly increased after surgery (pre: 1.123 nM versus POD5: 1.949 nM, P = 0.006). Overall, 24 patients showed ≥ 1 feature of tumor aggressiveness (T3-T4, nodal/distant metastases, Ki67 > 5%, microvascular/perineural invasion, necrosis). The median percentage decrease in VS-1 plasma levels was 63% (IQR 28-88%) among patients with aggressive tumors, compared to 13% (IQR 0-57%) in the remaining population (P = 0.033). No significant differences in terms of PST (P = 0.870) and VS-2 (P = 0.909) were observed between preoperative and postoperative time., Conclusion: VS-1 provides an early assessment of surgical efficacy in patients who undergo resection for NF-PanNETs, especially in those with aggressive neoplasms. Total-CgA, PST and VS-2 have no clinical utility in this setting., (© 2022. Italian Society of Endocrinology (SIE).)

Purpose: To explore the role of fully hybrid 68 Ga-DOTATOC PET/MR imaging and radiomic parameters in predicting histopathological prognostic factors in patients with pancreatic neuroendocrine tumours (PanNETs) undergoing surgery., Methods: One hundred eighty-seven consecutive 68 Ga-DOTATOC PET/MRI scans (March 2018-June 2020) performed for gastroenteropancreatic neuroendocrine tumour were retrospectively evaluated; 16/187 patients met the eligibility criteria ( 68 Ga-DOTATOC PET/MRI for preoperative staging of PanNET and availability of histological data). PET/MR scans were qualitatively and quantitatively interpreted, and the following imaging parameters were derived: PET-derived SUVmax, SUVmean, somatostatin receptor density (SRD), total lesion somatostatin receptor density (TLSRD), and MRI-derived apparent diffusion coefficient (ADC), arterial and late enhancement, necrosis, cystic degeneration, and maximum diameter. Additionally, first-, second-, and higher-order radiomic parameters were extracted from both PET and MRI scans. Correlations with several PanNETs' histopathological prognostic factors were evaluated using Spearman's coefficient, while the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was used to evaluate parameters' predictive performance., Results: Primary tumour was detected in all 16 patients (15/16 by 68 Ga-DOTATOC PET and 16/16 by MRI). SUVmax and SUVmean resulted good predictors of lymphnodal (LN) involvement (AUC of 0.850 and 0.783, respectively). Second-order radiomic parameters GrayLevelVariance and HighGrayLevelZoneEmphasis extracted from T2 MRI demonstrated significant correlations with LN involvement (adjusted p = 0.009), also showing good predictive performance (AUC = 0.992)., Conclusion: This study demonstrates the role of the fully hybrid PET/MRI tool for the synergic function of imaging parameters extracted by the two modalities and highlights the potentiality of imaging and radiomic parameters in assessing histopathological features of PanNET aggressiveness., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Duodenal gastric metaplasia (DGM) is considered a precancerous lesion. No data are available regarding its possible role as a risk factor for duodenal neuroendocrine neoplasms (dNENs)., Aims: To assess the prevalence of DGM in a cohort of dNENs., Methods: Subgroup analysis of a retrospective study including dNEN patients who underwent surgical resection between 2000 and 2019 and were observed at eight Italian tertiary referral centers., Results: 109 dNEN patients were evaluated. Signs of DGM associated with the presence of dNEN were reported in 14 patients (12.8%). Among these patients, nine (64.4%) had a dNEN of the superior part of the duodenum, one (7.1%) a periampullary lesion, three (21.4%) a dNEN located in the second portion of the duodenum, with a different localization distribution compared to patients without DGM ( p = 0.0332). Ten were G1, three G2, and in one patient the Ki67 was not available. In the group with DGM, six patients (35.7%) were classified at stage I, five (28.6%) at stage II, three (21.4%) at stage III, and no one at stage IV. In the group without DGM, 20 patients (31%) were at stage I, 15 (15%) at stage II, 42 (44%) at stage III, and 19 (20%) at stage IV ( p = 0.0236). At the end of the study, three patients died because of disease progression., Conclusions: our findings might suggest that DGM could represent a feature associated with the occurrence of dNEN, especially for forms of the superior part of the duodenum, which should be kept in mind in the endoscopic follow up of patients with DGM. Interestingly, dNEN inside DGM showed a more favorable staging, with no patients in stage IV. The actual relationship and the clinical relevance of this possible association require further clarification.

Background: Grade B postoperative pancreatic fistula represents the largest fraction of postoperative pancreatic fistula. A subclassification of grade B postoperative pancreatic fistula has been recently proposed and seems to better stratify postoperative pancreatic fistula clinical and economic burden. Aim of this study was to validate, from a clinical and economic standpoint, grade B postoperative pancreatic fistula subclassification in patients submitted to pancreaticoduodenectomy., Methods: All consecutive patients who underwent pancreaticoduodenectomy and developed biochemical leak or postoperative pancreatic fistula were included. Grade B postoperative pancreatic fistula was subclassified into 3 categories (B1: persistent drainage >21 days, B2: pharmacological treatments; B3: interventional procedures). Postoperative pancreatic fistula clinical and economic burden was assessed by evaluating postoperative complications, length of hospital stay, and overall hospital costs., Results: Overall, 289 patients developed biochemical leak or postoperative pancreatic fistula. Of these, 34 had biochemical leak (12%), 25 had grade B1 postoperative pancreatic fistula (9%), 91 had grade B2 postoperative pancreatic fistula (31%), 94 had grade B3 postoperative pancreatic fistula (32%), and 45 experienced grade C postoperative pancreatic fistula (16%). The severity of postoperative complications significantly increased across biochemical leak and postoperative pancreatic fistula categories (P < .001), but it was comparable between biochemical leak and grade B1 postoperative pancreatic fistula. There was no significant difference in terms of length of hospital stay between patients with biochemical leak and those with grade B1 postoperative pancreatic fistula (P = 1.000). Overall hospital costs were similar for patients with biochemical leak and those with grade B1 postoperative pancreatic fistula (P = 1.000), whereas they significantly increased across all the other postoperative pancreatic fistula subgroups., Conclusion: A subclassification of grade B postoperative pancreatic fistula can better stratify the increasing clinical burden and economic impact of postoperative pancreatic fistula after pancreaticoduodenectomy. Grade B1 postoperative pancreatic fistula has minimal clinical and economic consequences and can be considered closer to a biochemical leak than to a grade B2 postoperative pancreatic fistula., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Purpose: Patients submitted to curative surgery for non-functioning pancreatic neuroendocrine neoplasms (NF-PanNENs) exhibit a variable risk of disease relapse. Aims of this meta-analysis were to estimate the rate of disease recurrence and to investigate the risk factors for disease relapse in patients submitted to curative surgery for NF-PanNENs., Methods: Medline/Pubmed and Web of Science databases were searched for relevant studies. A meta-regression analysis was performed to investigate the source of recurrence rate heterogeneity. Pooled hazard ratios (HRs) and 95% confidence intervals (95% CI) were used to assess the effect of each possible prognostic factor on disease-free survival., Results: Fifteen studies, involving 2754 patients submitted to curative surgery for NF-PanNENs, were included. The pooled rate of disease recurrence was 21% (95% CI 15-26%). Study quality (Odds ratio, OR 0.94, P = 0.016) and G3-PanNENs rate (OR 2.18, P = 0.040) independently predicted the recurrence rate variability. Nodal metastases (HR 1.63, P < 0.001), tumor grade G2-G3 (G1 versus G2: HR 1.72, P < 0.001, G1 versus G3 HR 2.57, P < 0.001), microvascular (HR 1.25, P = 0.046) and perineural (HR 1.29, P = 0.019) invasion were identified as significant prognostic factors. T stage (T1-T2 versus T3-T4, P = 0.253) and status of resection margins (R0 versus R1, P = 0.173) did not show any significant relationship with NF-PanNENs recurrence., Conclusion: Disease relapse occurs in approximately one out of five patients submitted to curative surgery for NF-PanNENs. Nodal involvement, tumor grade, microvascular and perineural invasion are relevant prognostic factors, that should be taken into account for follow-up and for possible trials investigating adjuvant or neoadjuvant treatments., (© 2021. Italian Society of Endocrinology (SIE).)

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking., Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs)., Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias., Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy., Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors., Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31)., Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Several studies showed safety and feasibility of laparoscopic distal pancreatectomy (LDP) as compared to open distal pancreatectomy (ODP). Patients who underwent LDP or ODP (2015-2019) were included. A 1:1 propensity score matching (PSM) was used to reduce the effect of treatment selection bias. Aim of this study was to identify those factors influencing the loss of benefit (defined as a significantly better outcome compared to ODP) after LDP. Overall, 387 patients underwent DP (n = 250 LDP, n = 137 ODP). After PSM, 274 patients (n = 137 LDP, n = 137 ODP) were selected. LDP was associated with reduced intraoperative blood loss (median: 200 mL vs. 250 mL, p < 0.001), decreased wound infection rate (1% vs. 9%, p = 0.044) and shorter time to functional recovery (TFR) (median: 4 days vs. 5 days, p = 0.002). Consequently, TFR > 5 days and blood loss > 250 mL were defined as loss of benefit after LDP. In the LDP group, age > 70 years [Odds Ratio (OR) 2.744, p = 0.022] and duration of surgery > 208 min (OR 2.957, p = 0.019) were predictors of TFR > 5 days and intraoperative blood loss > 250 mL, respectively. No differences in terms of TFR were found between ODP and LDP groups in patients > 70 years (p = 0.102). Intraoperative blood loss was significantly higher in the ODP group, also when the analysis was limited to surgical procedures with operative time > 208 min (p = 0.003). In conclusion, LDP seems comparable to ODP in terms of TFR in patients aged > 70 years. This finding could be helpful in the choice of the best surgical approach in elderly patients undergoing potentially challenging DPs., (© 2021. Italian Society of Surgery (SIC).)

Purpose of Review: The aim of this review was to discuss how to select patients with gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) for surgery., Recent Findings: Surgical resection represents the mainstay for the curative treatment of GEP-NENs. Conservative strategies, such as endoscopic resection and active surveillance, have been recently advocated for the management of patients with small and asymptomatic GEP-NENs. On the other hand, patients with GEP-NENs showing features of aggressiveness should be managed by surgical resection with lymphadenectomy, when the surgical risk is considered acceptable. An accurate selection is important also in the setting of advanced disease, where surgery can provide a survival benefit in the context of a multimodal treatment strategy. Surgical and oncological risk should be always assessed in order to define indications for surgery in patients with GEP-NENs. Given the variety of available treatment options, surgical indication should be always shared with a dedicated multidisciplinary team., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Data on long-term actual survival in patients with surgically resected pancreatic ductal adenocarcinoma (PDAC) are limited. The aim of this study was to evaluate the actual 5-year disease-specific survival (DSS) and post-recurrence survival (PRS) in patients who underwent pancreatectomy for PDAC., Methods: Data from patients who underwent upfront surgical resection for PDAC between 2009 and 2014 were analyzed. Exclusion criteria included PDAC arising in the background of an intraductal papillary mucinous neoplasm and patients undergoing neoadjuvant therapy. All alive patients had a minimum follow-up of 60 months. Independent predictors of PRS, DSS, and survival > 5 years were searched., Results: Of the 176 patients included in this study, 48 (27%) were alive at 5 years, but only 20 (11%) had no recurrence. Median PRS was 12 months. In the 154 patients after disease recurrence, independent predictors of shorter PRS were total pancreatectomy, G3 tumors, early recurrence (< 12 months from surgery), and no treatment at recurrence. Median DSS was 36 months. Independent predictors of DSS were CA19-9 at diagnosis > 200 U/mL, total pancreatectomy, N + status, G3 tumors and perineural invasion. Only the absence of perineural invasion was a favorable independent predictor of survival > 5 years., Conclusion: More than one-quarter of patients who underwent upfront surgery for PDAC were alive after 5 years, although only 11% of the initial cohort were cancer-free. Long-term survival can also be achieved in tumors with more favorable biology in an upfront setting followed by adjuvant chemotherapy., (© 2021. Society of Surgical Oncology.)

Pancreatic neuroendocrine neoplasms are epigenetically driven tumors, but therapies against underlying epigenetic drivers are currently not available in the clinical practice. We aimed to investigate EZH2 (Enhancer of Zest homolog) expression in PanNEN and the impact of EZH2 inhibition in three different PanNEN preclinical models. EZH2 expression in PanNEN patient samples ( n = 172) was assessed by immunohistochemistry and correlated with clinico-pathological data. Viability of PanNEN cell lines treated with EZH2 inhibitor (GSK126) was determined in vitro. Lentiviral transduction of shRNA targeting EZH2 was performed in QGP1 cells, and cell proliferation was measured. Rip1TAG2 mice underwent GSK126 treatment for three weeks starting from week 10 of age. Primary cells isolated from PanNEN patients ( n = 6) were cultivated in 3D as islet-like tumoroids and monitored for 10 consecutive days upon GSK126 treatment. Viability was measured continuously for the whole duration of the treatment. We found that high EZH2 expression correlated with higher tumor grade ( p < 0.001), presence of distant metastases ( p < 0.001), and shorter disease-free survival ( p < 0.001) in PanNEN patients. Inhibition of EZH2 in vitro in PanNEN cell lines and in patient-derived islet-like tumoroids reduced cell viability and impaired cell proliferation, while inhibition of EZH2 in vivo in Rip1TAG2 mice reduced tumor burden. Our results show that EZH2 is highly expressed in high-grade PanNENs, and during disease progression it may contribute to aberrations in the epigenetic cellular landscape. Targeting EZH2 may represent a valuable epigenetic treatment option for patients with PanNEN.

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., (© 2021. Italian Society of Endocrinology (SIE).)

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 the 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 <60% in 166 patients (42.8%), ≥60% and ≤80% in 156 patients (40.2%), and >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 <60% (10.2% and 5.4%, respectively) (P < .001). Acinar content was identified as an independent predictor of clinically relevant postoperative pancreatic fistula (≥60% and ≤80%, odds ratio 2.51, P = .008; >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 the 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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 € and the lowest readmission rates. ODP had lower surgical procedure costs, 3867 ± 768 €. RDP was the safest approach regarding hospital stay costs (5239 ± 1741 €), 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., Competing Interests: None

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 < 0.001) were independent predictors of RS. The probability of a normal lifespan for patients with G1, G2, G3 Pan-NENS, and pancreatic neuroendocrine carcinomas (Pan-NECs) was 96.7, 54.8, 0, and 0 per cent respectively. The probability of a normal lifespan was 99.8, 99.3, 79.8, and 46.8 per cent for those with stage I, II, III, and IV disease respectively. The overall disease-free RS rate was 73.6 (65.2 to 79.5) per cent. 2019 WHO grade (HR 2.10 (0.19); P < 0.001) and ENETS TNM stage (HR 2.50 (0.24); P < 0.001) significantly influenced disease-free RS. The probability of disease-free survival was 93.2, 84.9, 45.2, and 6.8 per cent for patients with stage I, II, III, and IV disease, and 91.9, 45.2, 9.4, and 0.7 per cent for those with G1, G2, G3 Pan-NENS, and Pan-NECs, respectively., 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., (© The Author(s) 2021. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

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 × 27 mm. 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.

Background: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population., Aim: This study aimed to analyze the occurrence of second primary malignancies., Methods: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included., Results: Between 2000 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5- and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms., Conclusion: In NEN patients the prevalence of second primary malignancies was not negligible, suggesting a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy., Competing Interests: Declaration of Competing Interest The Authors have no conflicts of interest to declare., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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 68 Gallium-DOTATATE PET and 18 F-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., Competing Interests: Declaration of Competing Interest The Authors declare that there are no conflicts of interest associated with this publication and there has been no financial support for this work that could have influenced its outcome., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

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.

Molecular mechanisms underlying the development and progression of pancreatic neuroendocrine tumors (PanNETs) are still insufficiently understood. Efficacy of currently approved PanNET therapies is limited. While novel treatment options are being developed, patient stratification permitting more personalized treatment selection in PanNET is yet not feasible since no predictive markers are established. The lack of representative in vitro and in vivo models as well as the rarity and heterogeneity of PanNET are prevailing reasons for this. In this study, we describe an in vitro 3-dimensional (3-D) human primary PanNET culture system as a novel preclinical model for more personalized therapy selection. We present a screening platform allowing multicenter sample collection and drug screening in 3-D cultures of human primary PanNET cells. We demonstrate that primary cells isolated from PanNET patients and cultured in vitro form islet-like tumoroids. Islet-like tumoroids retain a neuroendocrine phenotype and are viable for at least 2 weeks in culture with a high success rate (86%). Viability can be monitored continuously allowing for a per-well normalization. In a proof-of-concept study, islet-like tumoroids were screened with three clinically approved therapies for PanNET: sunitinib, everolimus and temozolomide. Islet-like tumoroids display varying in vitro response profiles to distinct therapeutic regimes. Treatment response of islet-like tumoroids differs also between patient samples. We believe that the presented human PanNET screening platform is suitable for personalized drug testing in a larger patient cohort, and a broader application will help in identifying novel markers predicting treatment response and in refining PanNET therapy., (© 2020 S. Karger AG, Basel.)

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: The most appropriate nodal staging system for non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) remains unclear. Despite some evidence is available for pancreaticoduodenectomy, the adequate nodal staging is still unknown for distal pancreatectomy (DP). The aim of the present study was to evaluate the prognostic impact of the number of positive lymph nodes (PLNs) after DP for NF-PanNETs and to define the minimal number of lymph nodes to be harvested for an appropriate nodal staging., Methods: Data were retrospectively collected from patients who underwent DP with curative intent (R0-R1) for sporadic well-differentiated NF-PanNETs in 4 European high-volume centres. NF-PanNETs with nodal involvement (N+) were subclassified into N1 (1-3 PLNs) and N2 (4 or more PLNs). Univariate and multivariate analyses of disease-free survival (DFS) were performed., Results: Of 271 patients in the study, 62 (23%) had nodal involvement (N+). A higher probability of N+ was associated with the following factors: grading, resection margin status, perineural and microvascular invasion, and the number of examined lymph nodes. Three-year DFS rate for N0, N1, and N2 patients was 92, 72, and 50%, respectively (p < 0.001). At multivariate analysis, independent predictors of DFS were grading, T stage, presence of necrosis, and nodal status. For patients with ≥12 examined/resected lymph nodes, the N status remained a significant predictor of disease recurrence (p < 0.001), while it failed to predict recurrence in patients with <12 lymph nodes examined/resected (p = 0.116)., Conclusions: A minimal number of 12 nodes should be harvested in case of DP for NF-PanNET for an appropriate nodal staging. The number of positive lymph nodes is an independent predictor of DFS after DP for NF-PanNET, and the N0/N1/N2 nodal classification seems to be more relevant than the current N0/N+ staging., (© 2020 S. Karger AG, Basel.)

Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis. In vitro studies showed that PDAC cells can promote the cleavage of CgA C-terminal region by activating plasminogen to plasmin. Limited digestion of full-length CgA with plasmin abolished its anti-angiogenic activity and generated pro-angiogenic molecules. The fragmentation of CgA C-terminal region was increased also in murine models of PDAC. In these models, the inhibition of CgA fragmentation with aprotinin, an inhibitor of plasmin and other serine proteases, or the blockade of pro-angiogenic fragments with specific antibodies inhibited the growth of PDAC implanted subcutaneously in mice. Finally, administration of full-length CgA to mice bearing orthotopic PDAC reduced tumor perfusion, as measured by contrast-enhanced ultrasound. These findings suggest that PDAC can promote the cleavage of circulating CgA C-terminal region to generate fragments that regulate the tumor vascular biology and that may represent new potential therapeutic targets., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2020 Reni, Andreasi, Gasparri, Dugnani, Colombo, Macchini, Bianco, Dallatomasina, Citro, Assi, Protti, Esposito, Falconi, Curnis, Piemonti and Corti.)

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 <1 cm as well as those with non-ampullary duodenal NENs <1 cm with no associated syndrome can be safely managed by endoscopic resection. On the other hand, an active surveillance approach is preferred over surgery for patients with asymptomatic, non-functioning pancreatic NENs ≤2 cm without dilation of the main pancreatic duct or bile duct. As far as NENs of the appendix are concerned, appendectomy should be considered as curative when a R0 resection has been achieved in the presence of a tumor ≤1.5 cm, graded as G1 and without lymphovascular invasion. Finally, G1 rectal NENs ≤1 cm without invasion of the muscular layer can be safely treated by endoscopic resection. Therefore, surgeons should be aware of the existence of indolent GEP-NENs, in order to avoid unnecessary operations with associated postoperative complications., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)

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., (Copyright © 2020 Elsevier Inc. All rights reserved.)

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 < 109 ng/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 ± 360 ng/mL) in only 9/30 patients, but did not decrease significantly postoperatively at POD30 (260 ± 589 ng/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.

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., (Copyright © 2020 International Hepato-Pancreato-Biliary Association Inc. Published by Elsevier Ltd. All rights reserved.)