M. Falconi

European experts consensus statement on cystic tumours of the pancreas.

Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

Observational Study of Natural History of Small Sporadic Nonfunctioning Pancreatic Neuroendocrine Tumors

CONTEXTnAsymptomatic sporadic nonfunctioning, well-differentiated pancreatic neuroendocrine tumors (NF-PNETs) are increasingly diagnosed, and their management is controversial because of their overall good but heterogeneous prognosis.nnnOBJECTIVEnThe objective of the study was to assess the natural history of asymptomatic sporadic NF-PNETs smaller than 2 cm in size and the risk-benefit balance of nonoperative management.nnnEXPERIMENTAL DESIGNnFrom January 2000 to June 2011, 46 patients with proven asymptomatic sporadic NF-PNETs smaller than 2 cm in size were followed up for at least 18 months with serial imaging in tertiary referral centers.nnnRESULTSnPatients were mainly female (65%), with a median age of 60 years. Tumors were mainly located in the pancreatic head (52%), with a median lesion size of 13 mm (range 9-15). After a median follow-up of 34 months (range 24-52) and an average of four (range 3-6) serial imaging sessions, distant or nodal metastases appeared on the imaging in none of the patients. In six patients (13%), a 20% or greater increase in size was observed. Overall median tumor growth was 0.12 mm per year, and neither patients nor tumor characteristics were found to be significant predictors of tumor growth. Overall, eight patients (17%) underwent surgery after a median time from initial evaluation of 41 months (range 27-58); all resected lesions were European Neuroendocrine Tumor Society T stage 1 (n = 7) or 2 (n = 1), grade 1, node negative, with neither vascular nor peripancreatic fat invasion.nnnCONCLUSIONSnIn selected patients, nonoperative management of asymptomatic sporadic NF-PNETs smaller than 2 cm in size is safe. Larger and prospective multicentric studies with long-term follow-up are now needed to validate this wait-and-see policy.

Italian consensus guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms.

This report contains clinically oriented guidelines for the diagnostic work-up and follow-up of cystic pancreatic neoplasms in patients fit for treatment. The statements were elaborated by working groups of experts by searching and analysing the literature, and then underwent a consensus process using a modified Delphi procedure. The statements report recommendations regarding the most appropriate use and timing of various imaging techniques and of endoscopic ultrasound, the role of circulating and intracystic markers and the pathologic evaluation for the diagnosis and follow-up of cystic pancreatic neoplasms.

A systematic review on robotic pancreaticoduodenectomy

BACKGROUNDnRobotic surgery might have several advantages in respect of the laparoscopic approach since might make more feasible the execution of a complex procedure such as pancreaticoduodenectomy (PD). The aim of the present systematic review is to evaluate the current state of the literature on robotic PD.nnnMETHODSnA systematic literature search was performed, from January 1st 2003 to July 31st 2012, for studies which reported PDs performed for neoplasm and in which at least one surgical reconstructive or resective step was robotically performed.nnnRESULTSnThirteen studies, representing 207 patients, met the inclusion criteria. The definition of the robotic approach was heterogeneous since the technique was defined as robotic, robotic-assisted, robot-assisted laparoscopic and robotic hybrid. Resection and reconstruction steps of robotic PD were also heterogeneous combining sequentially different approaches: totally robotic technique, laparoscopic-robotic resection and robotic reconstruction, laparoscopic resection and robotic reconstruction, hand port-assisted laparoscopic resection and robotic reconstruction, laparoscopic-robotic resection and reconstruction through mini-laparotomy. As regard the type of PD 66% were classic Whipple operations and 34% pylorus-preserving pancreatoduodenectomies. The management of pancreatic stump was a pancreaticogastrostomy in 23%, end-to-side pancreaticojejunostomy in 67%, and fibrin glue occlusion of the main pancreatic duct in 10% of cases. The overall procedure failure (rates of conversion to open surgery) was 14%. The overall morbidity rate was 58% and the reoperation rate was 7.3%.nnnCONCLUSIONSnThere have been an increasing number of recent case series suggesting increased utilization of robotic PD over the past decade. The technical approach is heterogenous. For highly selected patient, robotic PD is feasible with similar morbidity and mortality compared to open or purely laparoscopic approaches. Data on cost analysis are lacking and further studies are needed to evaluate also the cost-effectiveness of the robotic approach for PD in comparison to open or laparoscopic techniques. The current state of the art analysis on robotic DP can be also useful in planning future trials.

Resection of the primary pancreatic neuroendocrine tumor in patients with unresectable liver metastases: possible indications for a multimodal approach.

BACKGROUNDnPancreatic neuroendocrine tumors (PNETs) present in more than 50% of cases with liver metastases as the only systemic localization. Liver metastases are unresectable in 80% of cases at diagnosis. In the context of a metastatic disease, the benefit of primary tumor removal in terms of survival is controversial.nnnMETHODSnA single-center series of patients with PNETs presenting with synchronous unresectable hepatic metastases and treated within a framework of a multidisciplinary team was analyzed retrospectively to assess the prognostic factors and the potential benefit of primary tumor resection on long-term survival.nnnRESULTSnAt the time of diagnosis, 12 of 43 patients (28%) underwent primary tumor resection. After a median follow-up of 5 years (range, 0.6-14 years), 22 disease-related deaths were observed. The corresponding 5-year survival and median disease-specific duration of survival were 58% and 77 months, respectively. In the operated and nonoperated patients the 5-year disease-specific survival was 82% and 50%, respectively (P = .027). At multivariate analysis, patients with primary tumor removed had an improved survival compared with patients who did not (hazard ratio 0.18; 95% CI 0.05-0.66; P = .010). Other important factors associated with improved survival at multivariate analysis were lesser age, lesser Ki-67 index, and 25% less liver tumor burden.nnnCONCLUSIONnIn the present series of patients with PNETs and unresectable liver metastases, resection of the primary tumor was associated with an improved survival. This observation suggests that resection of the primary tumor should be part of a global therapeutic strategy and its indication and timing should be discussed within a multidisciplinary team.

Systematic review of active surveillance versus surgical management of asymptomatic small non-functioning pancreatic neuroendocrine neoplasms

The incidence of asymptomatic, sporadic, small non‐functioning pancreatic neuroendocrine neoplasms (NF‐PNENs) has increased in recent decades. Conservative treatment has been advocated for these tumours. The aim of this study was systematically to evaluate the literature on active surveillance and to compare this with surgical management for asymptomatic sporadic small NF‐PNENs.

Sunitinib, pazopanib or sorafenib for the treatment of patients with late relapsing metastatic renal cell carcinoma.

PURPOSEnLate recurrence of renal cell carcinoma is not a rare event. In this retrospective study we investigate the clinicopathological features and the outcome of patients treated with sorafenib, sunitinib and pazopanib for late relapsing renal cell carcinoma.nnnMATERIALS AND METHODSnData were collected from 21 Italian centers involved in the treatment of metastatic renal cell carcinoma. Late relapse was defined as more than 5 years after initial radical nephrectomy.nnnRESULTSnA total of 2,490 patients were screened and 269 (11%) were included in the study. First line therapy was sunitinib in 190 patients (71%), sorafenib in 58 (21%) and pazopanib in 21 (8%). Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-not reported). On multivariate analysis MSKCC score and metastases to lymph nodes, liver and brain were associated with worst overall survival, while pancreatic metastases were associated with longer survival. Furthermore, age, MSKCC score and brain metastases were associated with worst progression-free survival.nnnCONCLUSIONSnPatients with late relapsing renal cell carcinoma seem to present a characteristic pattern of metastatic spread without showing significant differences in terms of progression-free survival among sorafenib, sunitinib and pazopanib.

Long-term outcomes and prognostic factors in neuroendocrine carcinomas of the pancreas: Morphology matters.

BACKGROUNDnLimited data are available for pancreatic neuroendocrine carcinomas (NEC) defined by 2010 World Health Organization (WHO) criteria (mitotic count >20 mitoses/10 high-power fields and/or a Ki67 index of >20%), because most studies encompass heterogeneous cohorts of extrapulmonary/gastrointestinal NEC. Our aim was to evaluate the clinicopathologic characteristics, treatment, and prognosis of patients with pancreatic NEC defined by the 2010 WHO criteria.nnnMETHODSnWe conducted a retrospective analysis of 59 patients with a histologic diagnosis of NEC between 1990 and 2012. All cases were re-reviewed and classified according to the WHO 2010 classification and the WHO 2000 criteria.nnnRESULTSnAll patients had stage III pancreatic NEC (n = 34; 58%) or IV pancreatic NEC (n = 25; 43%). Overall, 49 (83%) had poorly differentiated (PD) and 10 (17%) had a well-differentiated (WD) morphology. Fifteen patients (26%) were operated with curative intent (R0/R1), and 8 (14%) were R2 resections. Median disease-specific survival (DSS) for the entire cohort was 14 months. Median DSS did not differ between patient not undergoing resection and those undergoing R2 resection (10 vs 12 months; P > .46), but DSS was greater for patients who underwent R0/R1 resection compared with those with no resection/R2 resection (35 vs 11 months; P < .005). WD morphologic NEC had a greater survival than PD ones (43 vs 12 months; P = .004). Performance status, R2 resection/no resection, PD morphologic NEC, and no medical treatment were independent predictors of poor survival.nnnCONCLUSIONnPancreatic NEC constitute a heterogeneous group of tumors. Although NEC is an aggressive disease, curative resection in localized disease is associated with improved survival. Morphologic WD pancreatic NEC represents a subgroup with what seems to be a markedly improved survival. Within the NEC category, tumor treatment should be individualized considering tumor morphology as well as the other 2010 WHO criteria.

Risk of misdiagnosis and overtreatment in patients with main pancreatic duct dilatation and suspected combined/main-duct intraductal papillary mucinous neoplasms

BACKGROUNDnSegmental/diffuse dilatation of the main pancreatic duct (MPD) is the typical feature of combined/main-duct intraductal papillary mucinous neoplasms (CMD-IPMNs). MPD dilation in IPMNs may be also expression of mucus hypersecretion/obstructive chronic pancreatitis (OCP). The aim of this study was to evaluate the presence and extension of MPD involvement by tumor/OCP and assess the risk of overtreatment.nnnMETHODSnRetrospective analysis of suspected CMD-IPMNs resected between January 2009 and October 2014 were included. Pathologic correlations among MPD dilatation, IPMN, and OCP was searched.nnnRESULTSnOverall, 93 patients were resected for suspected CMD-IPMNs. At pathology, CMD-IPMNs were found in 69 patients (74%). Branch-duct IPMNs (BD-IPMNs) were found in 8 cases (9%), pancreatic ductal adenocarcinoma (PDAC) in absence of IPMN in 9 (10%), cystic neuroendocrine tumor (NET G2) in 1 (1%), serous cystadenoma in 2 (2%), and OCP alone/mucinous metaplasia in 4 patients (4%). Overall, 18 patients (19%) underwent an overtreatment because unnecessary (2 BD-IPMNs, 2 serous cystadenomas, and 4 OCPs only) or too extensive resections (9 CMD-IPMNs and 1 PDAC with associated OCP). In these, total pancreatectomy was the most common procedure (67%). Median size of MPD in IPMN-involved area was 12 mm compared with 7 mm when only OCP was found (P < .05).nnnCONCLUSIONnThere is a considerable risk of overtreatment in patients with a preoperative morphologic diagnosis of CMD-IPMNs. Partial pancreatectomy with margin examination should be performed instead of upfront total pancreatectomy. Radiologic observation can be considered in asymptomatic patients with worrisome MPD dilatation (5-9 mm) and lacking other high-risk stigmata.

Interaction between human mature adipocytes and lymphocytes induces T-cell proliferation

BACKGROUND AIMSnAdipose tissue is a critical organ that plays a major role in energy balance regulation and the immune response through intricate signals.nnnMETHODSnWe report on the inter-relation between mature adipocytes and lymphocytes in terms of adipocyte-derived T-cell chemo-attractants and adipocyte metabolic effects on lymphocytes.nnnRESULTSnDuring the culture time, mature adipocytes changed their structural and functional properties into de-differentiated cells. Isolated mature adipocytes expressed significantly higher levels of CIITA, major histocompatibility complex II (human leukocyte antigen [HLA]-DR) and costimulatory signal molecule CD80 compared with adipocytes after the de-differentiation process. Moreover, human leukocyte antigen-G, which may prevent the immune responses of mesenchymal stromal cells, was expressed at lower level in mature adipocytes compared with de-differentiated adipocytes. In line with these molecular data, functional results showed different immunoregulatory properties between adipocytes before and after the de-differentiation process. Mature adipocytes stimulated the proliferation of total lymphocytes and immunoselected cell populations CD3+, CD4+ and CD8+ in a direct contact-dependent way that involved the major histocompatibility complex I and II pathways. Moreover, adipocytes secreted potential chemo-attractant factors, but data showed that adipocyte-derived culture medium was not sufficient to activate lymphocyte proliferation, suggesting that a direct contact between adipocytes and immune cells was needed. However, specific mature adipocyte cytokines enhanced lymphocyte proliferation in a mixed lymphocyte reaction.nnnCONCLUSIONSnIn conclusion, cross-talk occurs between adipocytes and lymphocytes within adipose tissue involving T-cell chemo-attraction by mature adipocytes. Our findings, together with current observations in the field, provide a rationale to identify adipocyte-lymphocyte cross-talk that instigates adipose inflammation.