Luca Landoni

Intraductal papillary mucinous neoplasms of the pancreas with multifocal involvement of branch ducts

INTRODUCTION The appropriate management of patients with branch-duct intraductal papillary mucinous neoplasm (BD-IPMN) with multiple involvements of branch ducts (multifocal BD-IPMN) remains challenging. PATIENTS AND METHODS Our database of patients affected by IPMN was queried to identify patients with a clinicoradiologic or a pathologic diagnosis of multifocal BD-IPMN between January 1990 and December 2006. RESULTS One hundred thirty-one patients (52 male and 79 female; median age 67 years) had a clinicoradiologic or a histopathologic diagnosis of multifocal BD-IPMN. Ten patients (7.6%) underwent surgery. After a median follow-up of 40 months (range 12 to 127) all the 121 patients conservatively managed are alive, and none underwent surgery during follow-up. One patient with invasive carcinoma developed hepatic metastases and died of disease 88 months after surgery. COMMENTS Patients with branch-side IPMN can be conservatively managed, but when multifocality is present follow-up may be problematic because of the number of lesions to be evaluated. The nonoperative management of well-selected patients with BD-IPMN, even in the multifocal setting, seems to be safe and reliable.

Multicenter, Prospective Trial of Selective Drain Management for Pancreatoduodenectomy Using Risk Stratification.

Objective: This multicenter study sought to prospectively evaluate a drain management protocol for pancreatoduodenectomy (PD). Background: Recent evidence suggests value for both selective drain placement and early drain removal for PD. Both strategies have been associated with reduced rates of clinically relevant pancreatic fistula (CR-POPF)—the most common and morbid complication after PD. Methods: The protocol was applied to 260 consecutive PDs performed at two institutions over 17 months. Risk for ISGPF CR-POPF was determined intraoperatively using the Fistula Risk Score (FRS); drains were omitted in negligible/low risk patients and drain fluid amylase (DFA) was measured on postoperative day 1 (POD 1) for moderate/high risk patients. Drains were removed early (POD 3) in patients with POD 1 DFA ⩽5,000 U/L, whereas patients with POD 1 DFA >5,000 U/L were managed by clinical discretion. Outcomes were compared with a historical cohort (N = 557; 2011–2014). Results: Fistula risk did not differ between cohorts (median FRS: 4 vs 4; P = 0.933). No CR-POPFs developed in the 70 (26.9%) negligible/low risk patients. Overall CR-POPF rates were significantly lower after protocol implementation (11.2 vs 20.6%, P = 0.001). The protocol cohort also demonstrated lower rates of severe complication, any complication, reoperation, and percutaneous drainage (all P < 0.05). These patients also experienced reduced hospital stay (median: 8 days vs 9 days, P = 0.001). There were no differences between cohorts in the frequency of bile or chyle leaks. Conclusions: Drains can be safely omitted for one-quarter of PDs. Drain amylase analysis identifies which moderate/high risk patients benefit from early drain removal. This data-driven, risk-stratified approach significantly decreases the occurrence of clinically relevant pancreatic fistula.

Anastomotic leakage in pancreatic surgery

IntroductionCurrently pancreaticoduodenectomy (PD) is thetreatment of choice for tumours of the periampullaryregion. PD is a complex, high-risk surgical procedure,considered to be one of the most binding operations or, maybe, the most binding in abdominal surgery[1 4].In 1979 Moossa defined PD as ‘the Cadillac ofabdominal surgery’ [5]. In the same period thein-hospital mortality rate after PD was 20 30% withan extremely high morbidity; severe, life-threateningcomplications were judged to be a part of theprocedure [6,7].Nowadays PD is a routine procedure in specializedhigh-volume centres and mortality has decreasedsignificantly in the last two decades. Many effortshave been made to gain better results; they must beidentified in preoperative and postoperative manage-ment and appropriate selection of patients, improvedsurgical skills, and development of multidisciplinaryteams dedicated to the care of pancreatic patients[8,9]. However, even if mortality is less than 3 5% inexperienced hands, the overall morbidity rate is stillhigh from 30% to 50% leading to prolonged in-hospital stay and increased costs [1 61].Anastomotic leakage and the subsequent pancreaticfistula (PF) are the most important complicationsafter PD. The pancreatic leakage is considered to bethe underlying phenomenon of other major complica-tions; the anastomotic dehiscence with autodigestionand destruction of surrounding tissue and vesselsfrom leaking activated pancreatic juice cancause peripancreatic collections, intra-abdominalabscess, delayed gastric emptying and postoperativehaemorrhage.The reported rate of PF is highly variable, rangingfrom 2% to 50% [1 61]. This wide range is due toseveral factors and, among these, the lack of auniversally accepted definition of PF [10 12].The aim of this paper is to review the causes, riskfactors, definitions, prevention and treatment ofanastomotic leakage in pancreatic surgery, with parti-cular regard to leakage of the pancreatico-entericanastomosis after PD.Pathophysiology and risk factorsThe most important pathophysiological factor in-volved in the development of a pancreatic fistula isthe pancreatic juice itself. In fact it is rich in proteasesthat, whenever activated, determine the digestion andthe destruction of the tissue leading to partial orcomplete anastomotic dehiscence. In addition, pan-creatic juice, through the fistulization of pancreatico-enteric anastomosis can cause inflammation and auto-destruction of the peripancreatic and retroperitonealtissues as well as the surrounding vessels and viscera,with possible dramatic vascular erosions. These phe-nomena can lead to haemorrhage, intra-abdominalabscess, peripancreatic and retroperitoneal collectionsand delayed gastric emptying which is, in most cases,an indirect sign of intra-abdominal complications.The presence of an intra-abdominal abscess isstrongly associated with the presence of a leak fromthe pancreatic anastomosis: at least 50 60% ofabscesses observed following PD are related topancreatic leakage [13 18]. All these complications

Pancreatic neuroendocrine neoplasms: Magnetic resonance imaging features according to grade and stage

AIM To describe magnetic resonance (MR) imaging features of pancreatic neuroendocrine neoplasms (PanNENs) according to their grade and tumor-nodes-metastases stage by comparing them to histopathology and to determine the accuracy of MR imaging features in predicting their biological behavior. METHODS This study was approved by our institutional review board; requirement for informed patient consent was waived due to the retrospective nature of the study. Preoperative MR examinations of 55 PanNEN patients (29 men, 26 women; mean age of 57.6 years, range 21-83 years) performed between June 2013 and December 2015 were reviewed. Qualitative and quantitative features were compared between tumor grades and stages determined by histopathological analysis. RESULTS Ill defined margins were more common in G2-3 and stage III-IV PanNENs than in G1 and low-stage tumors (P < 0.001); this feature had high specificity in the identification of G2-3 and stage III-IV tumors (90.3% and 96%, 95%CI: 73.1-97.5 and 77.7-99.8). The mean apparent diffusion coefficient value was significantly lower in G2-3 and stage III-IV lesions compared to well differentiated and low-stage tumors (1.09 × 10-3 mm2/s vs 1.45 × 10-3 mm2/s and 1.10 × 10-3 mm2/s vs 1.53 × 10-3 mm2/s, P = 0.003 and 0.001). Receiving operator characteristic analysis determined optimal cut-offs of 1.21 and 1.28 × 10-3 mm2/s for the identification of G2-3 and stage III-IV tumors, with sensitivity and specificity values of 70.8/80.7% and 64.5/64% (95%CI: 48.7-86.6/60-92.7 and 45.4-80.2/42.6-81.3). CONCLUSION MR features of PanNENs vary according to their grade of differentiation and their stage at diagnosis and could predict the biological behavior of these tumors.

Pancreatectomy with venous resection for pT3 head adenocarcinoma: Perioperative outcomes, recurrence pattern and prognostic implications of histologically confirmed vascular infiltration

BACKGROUND The outcomes of pancreatectomy with superior mesenteric vein (SMV) or portal vein (PV) resection have been mixed. This study investigated the morbidity and mortality profile after SMV-PV resection in comparison with standard pancreatectomy. Furthermore, we assessed whether tumors with histologically proven SMV-PV infiltration differ from other pT3 neoplasms in terms of recurrence pattern and survival. METHODS All patients with a pT3 head adenocarcinoma resected from 2000 to 2013 were analyzed retrospectively. In the SMV-PV resection group, information on venous wall status was obtained through pathologic reports. Standard statistical methods were used for data analysis. RESULTS The study population consisted of 651 patients, of whom 81 (12.4%) underwent synchronous SMV-PV resection. Venous resection was not associated with a higher rate of postoperative complications (60.5% versus 50.2%) and mortality (1.2% versus 1.1%) in comparison with standard pancreatectomy. Vascular infiltration was confirmed pathologically in 56/81 patients (69.1%). The median disease-specific survival of the entire population was 27 months (95% CI 24.6-29.3), with a 5-year survival rate of 20.5%. The median recurrence-free survival was 18 months (95% CI 15.0-20.9). On multivariate analysis, ASA score, preoperative pain, Ca 19-9 levels, tumor grade, R-status, lymph-vascular invasion, N-status, and adjuvant therapy resulted to be survival predictors. Similarly, Ca 19.9 levels, R-status, and N-status were predictors of recurrence. SMV-PV infiltration was not a significant prognostic factor. CONCLUSION Morbidity and mortality rates of pancreatectomy with SMV-PV resection are comparable with standard pancreatectomy. Pancreatic head adenocarcinoma with histologically confirmed SMV-PV infiltration does not segregate prognostically from other pT3 tumors.

The Evolution of Surgical Strategies for Pancreatic Neuroendocrine Tumors (Pan-NENs)

Objective: The objective of the present analysis is 2-fold: first, to define the evolution of time trends on the surgical approach to pancreatic neuroendocrine neoplasms (Pan-NENs); second, to perform a complete analysis of the predictors of oncologic outcome. Background: Reflecting their rarity and heterogeneity, Pan-NENs represent a clinical dilemma. In particular, there is a scarcity of data regarding their long-term follow-up after surgical resection. Methods: From the Institutional Pan-NEN database, 587 resected cases from 1990 to 2015 were extracted. The time span was arbitrarily divided into 3 discrete clusters enabling a balanced comparison between patient groups. Analyses for predictors of recurrence and survival were performed, together with conditional survival analyses. Results: Among the 587 resected Pan-NENs, 75% were nonfunctioning tumors, and 5% were syndrome-associated tumors. The mean age was 54 years (±14 years), and 51% of the patients were female. The median tumor size was 20 mm (range 4 to 140), 62% were G1, 32% were G2, and 4% were G3 tumors. Time trends analysis revealed that the number of resected Pan-NENs constantly increased, while the size (from 25 to 20 mm) and G1 proportion (from 65% to 49%) decreased during the study period. After a mean follow-up of 75 months, recurrence analysis revealed that nonfunctioning tumors, tumor grade, N1 status, and vascular invasion were all independent predictors of recurrence. Regardless of size, G1 nonfunctioning tumors with no nodal involvement and vascular invasion had a negligible risk of recurrence at 5 years. Conclusions: Pan-NENs have been increasingly diagnosed and resected during the last 3 decades, revealing reliable predictors of outcome. Functioning and nodal status, tumor grade, and vascular invasion accurately predict survival and recurrence with resulting implications for patient follow-up.

Are Cystic Pancreatic Neuroendocrine Tumors an Indolent Entity? Results from a Single Center Surgical Series

Introduction: Cystic pancreatic neuroendocrine tumors (CPanNETs) represent an uncommon variant of pancreatic neuroendocrine tumors (PanNETs). Due to their rarity, there is a lack of knowledge with regard to clinical features and postoperative outcome. Methods: The prospectively maintained surgical database of a high-volume institution was queried, and 46 resected CPanNETs were detected from 1988 to 2015. Clinical, demographic, and pathological features and survival outcomes of CPanNETs were described and matched with a population of 92 solid PanNETs (SPanNETs) for comparison. Results: CPanNETs accounted for 7.8% of the overall number of resected PanNETs (46/587). CPanNETs were mostly sporadic (n = 42, 91%) and nonfunctioning (39%). Two functioning CPanNETs were detected (4.3%), and they were 2 gastrinomas. The median tumor diameter was 30 mm (range 10-120). All tumors were well differentiated, with 38 (82.6%) G1 and 8 (17.4%) G2 tumors. Overall, no CPanNET showed a Ki-67 >5%. A correct preoperative diagnosis of a CPanNET was made in half of the cases. After a median follow-up of >70 months, the 5- and 10-year overall survival of resected CPanNETs was 93.8 and 62.5%, respectively, compared to 92.7 and 84.6% for SPanNETs (p > 0.05). The 5- and 10-year disease-free survival rates were 94.5 and 88.2% for CPanNETs and 81.8 and 78.9% for SPanNETs, respectively (p > 0.05). Conclusion: In the setting of a surgical cohort, CPanNETs are rare, nonfunctional, and well-differentiated neoplasms. After surgical resection, they share the excellent outcome of their well-differentiated solid counterparts for both survival and recurrence.

Common germline variants within the CDKN2A/2B region affect risk of pancreatic neuroendocrine tumors

Pancreatic neuroendocrine tumors (PNETs) are heterogeneous neoplasms which represent only 2% of all pancreatic neoplasms by incidence, but 10% by prevalence. Genetic risk factors could have an important role in the disease aetiology, however only a small number of case control studies have been performed yet. To further our knowledge, we genotyped 13 SNPs belonging to the pleiotropic CDKN2A/B gene region in 320 PNET cases and 4436 controls, the largest study on the disease so far. We observed a statistically significant association between the homozygotes for the minor allele of the rs2518719 SNP and an increased risk of developing PNET (ORhom = 2.08, 95% CI 1.05–4.11, p = 0.035). This SNP is in linkage disequilibrium with another polymorphic variant associated with increased risk of several cancer types. In silico analysis suggested that the SNP could alter the sequence recognized by the Neuron-Restrictive Silencer Factor (NRSF), whose deregulation has been associated with the development of several tumors. The mechanistic link between the allele and the disease has not been completely clarified yet but the epidemiologic evidences that link the DNA region to increased cancer risk are convincing. In conclusion, our results suggest rs2518719 as a pleiotropic CDKN2A variant associated with the risk of developing PNETs.

Can histogram analysis of MR images predict aggressiveness in pancreatic neuroendocrine tumors

ObjectivesTo evaluate MRI derived whole-tumour histogram analysis parameters in predicting pancreatic neuroendocrine neoplasm (panNEN) grade and aggressiveness.MethodsPre-operative MR of 42 consecutive patients with panNEN >1 cm were retrospectively analysed. T1-/T2-weighted images and ADC maps were analysed. Histogram-derived parameters were compared to histopathological features using the Mann-Whitney U test. Diagnostic accuracy was assessed by ROC-AUC analysis; sensitivity and specificity were assessed for each histogram parameter.ResultsADCentropy was significantly higher in G2-3 tumours with ROC-AUC 0.757; sensitivity and specificity were 83.3 % (95 % CI: 61.2–94.5) and 61.1 % (95 % CI: 36.1–81.7). ADCkurtosis was higher in panNENs with vascular involvement, nodal and hepatic metastases (p= .008, .021 and .008; ROC-AUC= 0.820, 0.709 and 0.820); sensitivity and specificity were: 85.7/74.3 % (95 % CI: 42–99.2 /56.4–86.9), 36.8/96.5 % (95 % CI: 17.2–61.4 /76–99.8) and 100/62.8 % (95 % CI: 56.1–100/44.9–78.1). No significant differences between groups were found for other histogram-derived parameters (p >.05).ConclusionsWhole-tumour histogram analysis of ADC maps may be helpful in predicting tumour grade, vascular involvement, nodal and liver metastases in panNENs. ADCentropy and ADCkurtosis are the most accurate parameters for identification of panNENs with malignant behaviour.Key Points• Whole-tumour ADC histogram analysis can predict aggressiveness in pancreatic neuroendocrine neoplasms.• ADC entropy and kurtosis are higher in aggressive tumours.• ADC histogram analysis can quantify tumour diffusion heterogeneity.• Non-invasive quantification of tumour heterogeneity can provide adjunctive information for prognostication.

Common genetic variants associated with pancreatic adenocarcinoma may also modify risk of pancreatic neuroendocrine neoplasms

Pancreatic neuroendocrine neoplasms (pNEN) account for less than 5% of all pancreatic neoplasms and genetic association studies on susceptibility to the disease are limited. We sought to identify possible overlap of genetic susceptibility loci between pancreatic ductal adenocarcinoma (PDAC) and pNEN; therefore, PDAC susceptibility variants (n = 23) from Caucasian genome-wide association studies (GWAS) were genotyped in 369 pNEN cases and 3277 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium to evaluate the odds associated with pNEN risk, disease onset and tumor characteristics. Main effect analyses showed four PDAC susceptibility variants-rs9854771, rs1561927, rs9543325 and rs10919791 to be associated with pNEN risk. Subsequently, only associations with rs9543325, rs10919791 and rs1561927 were noteworthy with false positive report probability (FPRP) tests. Stratified analyses considering age at onset (50-year threshold), showed rs2736098, rs16986825 and rs9854771 to be associated with risk of developing pNEN at a younger age. Stratified analyses also showed some single nucleotide polymorphisms to be associated with different degrees of tumor grade, metastatic potential and functionality. Our results identify known GWAS PDAC susceptibility loci, which may also be involved in sporadic pNEN etiology and suggest that some genetic mechanisms governing pathogenesis of these two entities may be similar, with few of these loci being more influential in younger cases or tumor subtypes.