Domenico Tamburrino

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

CONTEXT Asymptomatic 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. OBJECTIVE The 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. EXPERIMENTAL DESIGN From 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. RESULTS Patients 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. CONCLUSIONS In 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.

Total pancreatectomy: Indications, different timing, and perioperative and long-term outcomes

BACKGROUND Total pancreatectomy (TP) has been performed rarely in the past because of its high morbidity and mortality. Because outcomes of pancreatic surgery as well as management of pancreatic insufficiency have improved markedly, enthusiasm for TP has an increased. METHODS Between 1996 and 2008, 65 patients (33 females, 32 males; median age, 63 years) underwent TP at a single, high-volume center. Indications, timing, and perioperative and long-term results were analyzed. RESULTS Twenty-five patients (38.5%) underwent a planned, elective TP and 25 patients underwent a single-stage unplanned TP after an initial partial pancreatectomy that required TP because of intraoperative hemorrhage (n = 1) or positive pancreatic resection margin (n = 24). The remaining 15 patients (23%) underwent a 2-stage pancreatectomy for tumor recurrence in the remnant. No completion TP for postoperative complications were performed. There was no mortality; the overall morbidity was 39% and the reoperation rate was 5%. Overall, 48% of patients had intraductal papillary mucinous neoplasms, and 29% pancreatic ductal adenocarcinoma. The R1 resection rate was 12%. Four of 23 patients (17%) who underwent single-stage, unplanned TP for positive resection margin had R1 resection (positive retroperitoneal margin). The median follow-up was 34 months. The overall 5-year survival was 71%. No deaths owing to hypoglycemia were observed. Median insulin was 32 U/d, and the median lipase was 80,000 U/d. CONCLUSION TP can be performed safely with no mortality and acceptable morbidity. Postoperative pancreatic insufficiency can be managed safely. To achieve an R0 during TP, both the resection and retroperitoneal margin should be evaluated intraoperatively. TP is an effective operation in selected patients.

Incidental diagnosis as prognostic factor in different tumor stages of nonfunctioning pancreatic endocrine tumors.

BACKGROUND Incidentally discovered nonfunctioning pancreatic endocrine tumors (NF-pNETs) increasingly are being detected, and their management is debated. Moreover, the prognostic importance of incidental diagnosis for locally advanced or metastatic NF-pNETs is unknown. The aim of this study is to analyze the outcomes of incidentally discovered/symptomatic NF-pNETs stratified by tumor stage. A preliminary experience with nonoperative treatment of incidental NF-pNETs is reported. METHODS Consecutive patients with symptomatic/incidental NF-PETs observed between 1990 and 2009 were analyzed, with different tumor stages considered. Nonoperative management of incidental NF-pNETs was evaluated. RESULTS Among 355 patients with NF-pNETs, the diagnosis was incidental in 124 (35%). Incidental NF-pNETs were associated more commonly with lower tumor stages compared with symptomatic tumors (P < .0001), but 30% of incidental NF-pNETs were stage III-IV. Incidental NF-pNETs had greater rates of radical resections and of R0 margins (P < .0001). Five-year progression-free survival (PFS) was 83% and 32% for incidental and symptomatic NF-pNETs, respectively (P < .0001). Five-year PFS was better for incidental NF-pNETs compared with symptomatic tumors for each tumor stage, including stage III (69% vs 27%, P < .0001) and stage IV (60% vs 17%, P = .112). After a median follow-up of 36 months, there was no tumor progression in 12 patients who underwent nonoperative management of incidental NF-pNETs. CONCLUSION A total of 30% of incidental NF-pNETs present with stage III-IV disease. PFS is much greater for incidental NF-pNETs compared with symptomatic patients, and this difference is evident also for stage III-IV tumors, suggesting that absence of symptoms may indicate a less-aggressive disease. Nonoperative management can be an alternative to surgery in selected incidental NF-pNETs.

Pancreatic Tumors and Immature Immunosuppressive Myeloid Cells in Blood and Spleen: Role of Inhibitory Co-Stimulatory Molecules PDL1 and CTLA4. An In Vivo and In Vitro Study

Background Blood and spleen expansion of immature myeloid cells (IMCs) might compromise the immune response to cancer. We studied in vivo circulating and splenic T lymphocyte and IMC subsets in patients with benign and malignant pancreatic diseases. We ascertained in vitro whether pancreatic adenocarcinoma (PDAC)-associated IMC subsets are induced by tumor-derived soluble factors and whether they are immunosuppressive focusing on the inhibitory co-stimulatory molecules PDL1 and CTLA4. Methodology and Principal Findings 103 pancreatic and/or splenic surgical patients were enrolled including 52 PDAC, 10 borderline and 10 neuroendocrine tumors (NETs). Lymphocytes and IMCs were analysed by flow cytometry in blood, in spleen and in three PDAC cell conditioned (CM) or non conditioned PBMC. PDL1 and CTLA4 were studied in 30 splenic samples, in control and conditioned PBMC. IMCs were FACS sorted and co-coltured with allogenic T lymphocytes. In PDAC a reduction was found in circulating CD8+ lymphocytes (p = 0.004) and dendritic cells (p = 0.01), which were reduced in vitro by one PDAC CM (Capan1; p = 0.03). Blood myeloid derived suppressive cells (MDSCs) CD33+CD14−HLA-DR− were increased in PDAC (p = 0.022) and were induced in vitro by BxPC3 CM. Splenic dendritic cells had a higher PDL1 expression (p = 0.007), while CD33+CD14+HLA-DR− IMCs had a lower CTLA4 expression (p = 0.029) in PDAC patients. In vitro S100A8/A9 complex, one of the possible inflammatory mediators of immune suppression in PDAC, induced PDL1 (p = 0.018) and reduced CTLA4 expression (p = 0.028) among IMCs. IMCs not expressing CTLA4 were demonstrated to be immune suppressive. Conclusion In PDAC circulating dendritic and cytotoxic T cells are reduced, while MDSCs are increased and this might favour tumoral growth and progression. The reduced CTLA4 expression found among splenic IMCs of PDAC patients was demonstrated to characterize an immune suppressive phenotype and to be consequent to the direct exposure of myeloid cells to pancreatic cancer derived products, S100A8/A9 complex in particular.

Long-term outcomes of surgical management of pancreatic neuroendocrine tumors with synchronous liver metastases

Background: The value of surgical resection in the management of pancreatic neuroendocrine tumors (PNET) with liver metastases (LM) is still debated. The aim of this study was to evaluate the outcomes of surgery of PNET with LM. Methods: Patients with PNET with synchronous LM between 2000 and 2011 from 4 high-volume institutions were included. The patients were divided into 3 groups: curative resection, palliative resection, and no resection. Results: Overall, 166 patients were included. Eighteen patients (11%) underwent curative resection, 73 patients (43%) underwent palliative resection, and 75 patients (46%) underwent conservative treatment. The median overall survival (OS) from the time of diagnosis was 73 months. Patients who underwent curative resection had a significantly better median OS from the initial diagnosis compared with those who underwent palliative resection and those who were conservatively treated (97 vs. 89 vs. 36 months, p = 0.0001). The median OS from the time of diagnosis in those patients who underwent radical or palliative resection was 97 months, with a 5-year survival rate of 76%. On multivariate analysis, factors associated with OS from the time of diagnosis were the presence of bilobar metastases, tumor grading, and curative resection in a first model. On a second model, curative or palliative surgery was an independent predictor of OS. Among 91 patients who underwent surgery, the presence of pancreatic neuroendocrine carcinoma G3 was the only factor independently associated with a poorer survival after surgery (median OS: 35 vs. 97 months, p < 0.0001). Conclusions: Patients with LM from PNET benefit from surgical resection, although surgery should be reserved to well- or moderately differentiated forms.

Evaluation of a predictive model for pancreatic fistula based on amylase value in drains after pancreatic resection

BACKGROUND Amylase value in drains (AVD) is a predictor of pancreatic fistula (PF). We evaluated the accuracy of an AVD-based model. METHODS Two hundred thirty-one patients underwent pancreatoduodenectomy with pancreaticojejunostomy (PDPJ) or pancreatoduodenectomy with duct-to-mucosa (PDDTM) and distal pancreatectomy (DP). Patients with AVD greater than 5,000 U/L on postoperative day (POD) 1 underwent AVD measurement on POD5. RESULTS Sensitivity and specificity of POD1 AVD greater than 5,000 in predicting PF were 71% and 90%, respectively. The sensitivity and specificity of POD5 AVD greater than 200 were 90% and 83%, respectively. AVD greater than 1,000 (for PDPJ) and 2,000 U/L (PDDTM and DP) represented the most accurate cutoffs on POD1. AVD greater than 200 (PDPJ), 300 (PDDTM), and 50 U/L (DP) represented the cutoffs with the highest sensitivity in predicting PF on POD5. CONCLUSION AVD-based model for predicting PF after pancreatic resection is an accurate tool, although AVD cutoffs should be evaluated for each type of operation.

Selection criteria in resectable pancreatic cancer: A biological and morphological approach

Pancreatic ductal adenocarcinoma (PDA) remains one of the most aggressive tumors with a low rate of survival. Surgery is the only curative treatment for PDA, although only 20% of patients are resectable at diagnosis. During the last decade there was an improvement in survival in patients affected by PDA, possibly explained by the advances in cancer therapy and by improve patient selection by pancreatic surgeons. It is necessary to select patients not only on the basis of surgical resectability, but also on the basis of the biological nature of the tumor. Specific preoperative criteria can be identified in order to select patients who will benefit from surgical resection. Duration of symptoms and level of carbohydrate antigen 19.9 in resectable disease should be considered to avoid R1 resection and early relapse. Radiological assessment can help surgeons to distinguish resectable disease from borderline resectable disease and locally advanced pancreatic cancer. Better patient selection can increase survival rate and neoadjuvant treatment can help surgeons select patients who will benefit from surgery.

Active Surveillance Beyond 5 Years Is Required for Presumed Branch-Duct Intraductal Papillary Mucinous Neoplasms Undergoing Non-Operative Management

Objectives:To evaluate the results of active surveillance beyond 5 years in patients with branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) without worrisome features (WF) and high-risk stigmata (HRS) undergoing non-operative management.Methods:Patients with a minimum follow-up of 5 years who underwent surveillance with at least yearly magnetic resonance imaging were included. New onset of and predictors of WF/HRS during follow-up as well as long-term survival were analyzed.Results:In all, 144 patients were followed for a median of 84 months. At diagnosis multifocal BD-IPMNs were found in 53% of cases and mean size of the largest cyst was 15.5 mm. Changes during follow-up were observed in 69 patients (48%). New onset of WF/HRS were observed in 26 patients (18%) but the rate of HRS was only 4%. WF and HRS developed after a median follow-up of 71 and 77.5 months from diagnosis, respectively, and without previous changes in 19/26 patients. Independent predictors of WF/HRS development were size at diagnosis>15 mm, increase in number of lesions, main pancreatic duct growth rate ≥0.2 mm/year, cyst growth rate >1 mm/year. Overall, the rate of pancreatic invasive malignancy was 2% and the 12-year disease-specific survival was 98.6%.Conclusions:Long-term nonoperative management is safe for BD-IPMNs without WF and HRS. Discontinuation of surveillance cannot be recommended since one out of six patients developed WF/HRS far beyond 5 years of surveillance and without previous relevant modifications. An intensification of follow-up should be considered after 5 years.

Molecular pathology of intraductal papillary mucinous neoplasms of the pancreas

Since the first description of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas in the eighties, their identification has dramatically increased in the last decades, hand to hand with the improvements in diagnostic imaging and sampling techniques for the study of pancreatic diseases. However, the heterogeneity of IPMNs and their malignant potential make difficult the management of these lesions. The objective of this review is to identify the molecular characteristics of IPMNs in order to recognize potential markers for the discrimination of more aggressive IPMNs requiring surgical resection from benign IPMNs that could be observed. We briefly summarize recent research findings on the genetics and epigenetics of intraductal papillary mucinous neoplasms, identifying some genes, molecular mechanisms and cellular signaling pathways correlated to the pathogenesis of IPMNs and their progression to malignancy. The knowledge of molecular biology of IPMNs has impressively developed over the last few years. A great amount of genes functioning as oncogenes or tumor suppressor genes have been identified, in pancreatic juice or in blood or in the samples from the pancreatic resections, but further researches are required to use these informations for clinical intent, in order to better define the natural history of these diseases and to improve their management.

The natural history of a branch-duct intraductal papillary mucinous neoplasm of the pancreas

IN FEBRUARY 2012 A 69-YEAR-OLD WOMAN presented with abdominal pain, steatorrhea, and weight loss. The patient had been well until 5 months before admission when upper abdominal pain and diarrhea developed. Upper gastrointestinal tract endoscopy and colonoscopy were negative. Her appetite decreased, and an unintentional weight loss of 10 kg occurred. In January 2012 abdominal pain became severe, and she reported an increasing abdominal girth with obvious steatorrhea. Twelve years before, she underwent an abdominal computed tomography (CT) for blunt trauma. As incidental findings, multiple cysts ranging from 5 to 25 mm in size were found in the entire pancreas. Larger cysts had a connection with a nondilated main pancreatic duct, suggesting a diagnosis of multifocal branch-duct intraductal papillary mucinous neoplasm (BD-IPMN). No additional diagnostic studies were performed. She underwent an abdominal ultrasound yearly for 4 years and then no further follow-up was performed since her pancreatic cysts showed no ‘‘worrisome features’’ at radiology. On examination she had a firm, palpable mass associated with upper abdominal pain. Her hemoglobin was 9.8 g/dL, alanine aminotransferase 67 U/L, glucose 141 mg/dL, and carbohydrate antigen 19.9 (19.9) 2,170 U/mL. Fecal elastase-