Massimo Falconi

<h3>Background</h3> In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. <h3>Methods</h3> The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. <h3>Results</h3> Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former "grade A postoperative pancreatic fistula" is now redefined and called a "biochemical leak," because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. <h3>Conclusion</h3> This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.

The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results.In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation.The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors.Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

The international consensus guidelines for management of intraductal papillary mucinous neoplasm and mucinous cystic neoplasm of the pancreas established in 2006 have increased awareness and improved the management of these entities. During the subsequent 5 years, a considerable amount of information has been added to the literature. Based on a consensus symposium held during the 14th meeting of the International Association of Pancreatology in Fukuoka, Japan, in 2010, the working group has generated new guidelines. Since the levels of evidence for all items addressed in these guidelines are low, being 4 or 5, we still have to designate them "consensus", rather than "evidence-based", guidelines. To simplify the entire guidelines, we have adopted a statement format that differs from the 2006 guidelines, although the headings are similar to the previous guidelines, i.e., classification, investigation, indications for and methods of resection and other treatments, histological aspects, and methods of follow-up. The present guidelines include recent information and recommendations based on our current understanding, and highlight issues that remain controversial and areas where further research is required.

Non-inflammatory cystic lesions of the pancreas are increasingly recognized. Two distinct entities have been defined, i.e., intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN). Ovarian-type stroma has been proposed as a requisite to distinguish MCN from IPMN. Some other distinct features to characterize IPMN and MCN have been identified, but there remain ambiguities between the two diseases. In view of the increasing frequency with which these neoplasms are being diagnosed worldwide, it would be helpful for physicians managing patients with cystic neoplasms of the pancreas to have guidelines for the diagnosis and treatment of IPMN and MCN. The proposed guidelines represent a consensus of the working group of the International Association of Pancreatology.

Earlier detection is key to reducing cancer deaths. Here, we describe a blood test that can detect eight common cancer types through assessment of the levels of circulating proteins and mutations in cell-free DNA. We applied this test, called CancerSEEK, to 1005 patients with nonmetastatic, clinically detected cancers of the ovary, liver, stomach, pancreas, esophagus, colorectum, lung, or breast. CancerSEEK tests were positive in a median of 70% of the eight cancer types. The sensitivities ranged from 69 to 98% for the detection of five cancer types (ovary, liver, stomach, pancreas, and esophagus) for which there are no screening tests available for average-risk individuals. The specificity of CancerSEEK was greater than 99%: only 7 of 812 healthy controls scored positive. In addition, CancerSEEK localized the cancer to a small number of anatomic sites in a median of 83% of the patients.

The need for standards in the management of patients with endocrine tumors of the digestive system prompted the European Neuroendocrine Tumor Society (ENETS) to organize a first Consensus Conference, which was held in Frascati (Rome) and was based on the recently published ENETS guidelines on the diagnosis and treatment of digestive neuroendocrine tumors (NET). Here, we report the tumor-node-metastasis proposal for foregut NETs of the stomach, duodenum, and pancreas that was designed, discussed, and consensually approved at this conference. In addition, we report the proposal for a working formulation for the grading of digestive NETs based on mitotic count and Ki-67 index. This proposal, which needs to be validated, is meant to help clinicians in the stratification, treatment, and follow-up of patients.

Only advances that occurred from 2011–2014 that either strengthen the previous 2011 guidelines [1;2] or lead to changes or additional guidelines are reviewed here. Advances and modifications in the treatment of advanced metastatic disease is only briefly dealt with here as it is covered in a separate chapter, similar to the 2011 guideline format [3]. The format used here is the same as used in the 2011 guidelines with page references to the appropriate section inserted [1;2] and this document is meant as a supplement to these guidelines and does not reiterate all of the points made in the previous guidelines, only changes, supporting findings or modifications of the 2011 guidelines are thus covered here. As in the previous F-p-NET guidelines [1], the F-p-NETs will be considered in three groups: the more frequent gastrinomas and insulinomas considered independently and all the rare functional p-NETs (RFTs) considered together and as a separate category (Annex 1 and Table 1). Table 1 Functional Pancreatic endocrine tumors [F-p-NET] syndromes

The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study.After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

We investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies.Using a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas.Our data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis.These results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling. The genomes of 102 primary pancreatic neuroendocrine tumours have been sequenced, revealing mutations in genes with functions such as chromatin remodelling, DNA damage repair, mTOR activation and telomere maintenance, and a greater-than-expected contribution from germ line mutations. Pancreatic neuroendocrine tumours (PanNETs) are the second most common epithelial neoplasm of the pancreas. Aldo Scarpa, Sean Grimmond and colleagues report whole-genome sequencing of 102 primary PanNETs and present analysis of their mutational signatures as part of the International Cancer Genome Consortium. They find frequent mutations in genes with functions that include chromatin remodelling, DNA damage repair, activation of mTOR signalling, and telomere maintenance. They also identify mutational signatures, including one resulting from inactivation of the DNA repair gene MUTYH, and report a larger than expected germline contribution to PanNET development.

In Brief Objective: To describe clinical characteristics and outcomes of a large cohort of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas affecting the main pancreatic duct. Summary Background Data: IPMNs are being diagnosed with increasing frequency. Preoperative determination of malignancy remains problematic, and reported results of long-term survival following resection are conflicting. Methods: The combined databases from the Massachusetts General Hospital and the Pancreatic Unit of the University of Verona were analyzed. To avoid confusing overlap with mucinous cystic neoplasms, only patients with tumors of the main pancreatic duct (with or without side branch involvement) were included. A total of 140 tumors consecutively resected between 1990 and 2002 were classified as either benign (adenoma and borderline tumors) or malignant (carcinoma in situ or invasive cancer) to compare their characteristics and survival. Results: Men and women were equally affected (mean age 65 years). Seven patients (12%) had adenomas, 40 (28%) borderline tumors, 25 (18%) carcinoma in situ, and 58 (42%) invasive carcinoma. The median age of patients with benign IPMN was 6.4 years younger than those with malignant tumors (P = 0.04). The principal symptoms were abdominal pain (65%), weight loss (44%), acute pancreatitis (23%), jaundice (17%), and onset or worsening of diabetes (12%); 27% of patients were asymptomatic. Jaundice and diabetes were significantly associated with malignant tumors. Five- and 10-year cancer-specific survival for patients with noninvasive tumors was 100%, and comparable survival of the 58 patients with invasive carcinoma was 60% and 50%. Conclusions: Cancer is found in 60% of patients with main-duct IPMNs. Patients with malignant tumors are 6 years older than their benign counterparts and have a higher likelihood of presenting with jaundice or new onset diabetes. No patients with benign tumors or carcinoma in situ died of their disease following resection, and those with invasive cancer had a markedly better survival (60% at 5 years) than pancreatic ductal adenocarcinoma. These findings support both the concept of progression of benign IPMNs to invasive cancer and an aggressive policy of resection at diagnosis. Sixty percent of resected main-duct intraductal papillary mucinous neoplasms of the pancreas harbor either carcinoma in situ or invasive cancer. Compared with patients with benign tumors, these patients are older and have a higher likelihood of presenting with jaundice or diabetes, but 29% of them are asymptomatic. Resection can be done safely and long-term survival is excellent, with a low likelihood of recurrence in the remaining pancreas.

•This ESMO Clinical Practice Guideline provides key recommendations on the management of GEP-NENs.•Authorship includes a multidisciplinary group of experts from different institutions and countries in Europe.•Diagnostic and therapeutic recommendations include levels of evidence and grades of recommendations where applicable.

Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management.Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review.PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit.PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.

Purpose We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome. Patients and Methods Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays. Results Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines. Conclusion Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.

ENETS Consensus Guidelines for the Management of Patients with Digestive Neuroendocrine Neoplasms of the Digestive System : Well-Differentiated Pancreatic Non-Functioning Tumors

The earlier diagnosis of cancer is one of the keys to reducing cancer deaths in the future. Here we describe our efforts to develop a noninvasive blood test for the detection of pancreatic ductal adenocarcinoma. We combined blood tests for KRAS gene mutations with carefully thresholded protein biomarkers to determine whether the combination of these markers was superior to any single marker. The cohort tested included 221 patients with resectable pancreatic ductal adenocarcinomas and 182 control patients without known cancer. KRAS mutations were detected in the plasma of 66 patients (30%), and every mutation found in the plasma was identical to that subsequently found in the patient's primary tumor (100% concordance). The use of KRAS in conjunction with four thresholded protein biomarkers increased the sensitivity to 64%. Only one of the 182 plasma samples from the control cohort was positive for any of the DNA or protein biomarkers (99.5% specificity). This combinatorial approach may prove useful for the earlier detection of many cancer types.

In Brief Objective: Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods: Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results: MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4–233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions: This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate. The clinicopathologic characteristics and survival in 163 patients affected by mucinous cystic neoplasms (MCNs) defined by ovarian stroma were evaluated. Prevalence of invasive cancer was only 12%, and these patients were significantly older, had larger tumors, and had a higher prevalence of nodules. Five-year disease-specific survival was 100% and 57% for noninvasive and invasive MCNs, respectively. Surgery should be considered for all cases, but in low-risk MCNs (≤ 4 cm/no nodules), nonradical resections are appropriate.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas arising in branch ducts are thought to be less aggressive than their main-duct counterparts, and guidelines for their conservative management were recently proposed. This study describes the combined experience of 2 tertiary centers with branch-duct IPMNs aiming to validate these recommendations.A review of 145 patients with resected, pathologically confirmed, branch-duct IPMNs between 1990 and 2005 was conducted.Sixty-six patients (45.5%) had adenoma, 47 (32%) borderline tumors, 16 (11%) carcinoma in situ, and 16 (11%) invasive carcinoma. Median age was similar between benign and malignant subgroups (66 vs 67.5 years, respectively). Jaundice was more frequent in patients with cancer (12.5% vs 1.8%, respectively, P = .022) and abdominal pain in patients with benign tumors (45% vs 25%, respectively, P = .025). Forty percent of tumors were discovered incidentally. Findings associated with malignancy were the presence of a thick wall (P < .001), nodules (P < .001), and tumor diameter >or=30 mm (P < .001). All neoplasms with cancer were larger than 30 mm in size or had nodules or caused symptoms. After a mean follow-up of 45 months, the 5-year disease-specific survival for branch-duct IPMNs with noninvasive neoplasms was 100% and, for invasive cancer, was 63%.This large cohort of resected branch-duct IPMNs shows that cancer is present in 22% of cases and validates the recent guidelines that indicate absence of malignancy in tumors <30 mm, without symptoms or mural nodules.

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.

Both the European Neuroendocrine Tumor Society (ENETS) and the International Union for Cancer Control/American Joint Cancer Committee/World Health Organization (UICC/AJCC/WHO) have proposed TNM staging systems for pancreatic neuroendocrine neoplasms. This study aims to identify the most accurate and useful TNM system for pancreatic neuroendocrine neoplasms.The study included 1072 patients who had undergone previous surgery for their cancer and for which at least 2 years of follow-up from 1990 to 2007 was available. Data on 28 variables were collected, and the performance of the two TNM staging systems was compared by Cox regression analysis and multivariable analyses. All statistical tests were two-sided.Differences in distribution of sex and age were observed for the ENETS TNM staging system. At Cox regression analysis, only the ENETS TNM staging system perfectly allocated patients into four statistically significantly different and equally populated risk groups (with stage I as the reference; stage II hazard ratio [HR] of death = 16.23, 95% confidence interval [CI] = 2.14 to 123, P = .007; stage III HR of death = 51.81, 95% CI = 7.11 to 377, P < .001; and stage IV HR of death = 160, 95% CI = 22.30 to 1143, P < .001). However, the UICC/AJCC/WHO 2010 TNM staging system compressed the disease into three differently populated classes, with most patients in stage I, and with the patients being equally distributed into stages II-III (statistically similar) and IV (with stage I as the reference; stage II HR of death = 9.57, 95% CI = 4.62 to 19.88, P < .001; stage III HR of death = 9.32, 95% CI = 3.69 to 23.53, P = .94; and stage IV HR of death = 30.84, 95% CI = 15.62 to 60.87, P < .001). Multivariable modeling indicated curative surgery, TNM staging, and grading were effective predictors of death, and grading was the second most effective independent predictor of survival in the absence of staging information. Though both TNM staging systems were independent predictors of survival, the UICC/AJCC/WHO 2010 TNM stages showed very large 95% confidence intervals for each stage, indicating an inaccurate predictive ability.Our data suggest the ENETS TNM staging system is superior to the UICC/AJCC/WHO 2010 TNM staging system and supports its use in clinical practice.

To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.While several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.A total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).The 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.When compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.

Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS-TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS-TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases.

Since gastro-entero-pancreatic endocrine tumors are rare and heterogeneous diseases, their prognosis and long-term survival are not well known. This study aimed at identifying prognostic factors and assessing long-term survival in gastro-entero-pancreatic endocrine tumors. A total of 156 patients enrolled. Prognostic factors were determined by univariate/multivariate analysis; survival rates were assessed by the Kaplan–Meier method. The tumors were non-functioning in 59.6% of patients, and originated from the pancreas in 42.9%. At diagnosis, 64.3% of patients had metastases. The tumors were well differentiated in 89.6% of patients. Ki67 was &gt;2% in 39.6% of patients. Primary tumor size was &gt;3 cm in 49.6% of cases studied. For the univariate analysis, the negative prognostic factors were: pancreatic origin (rate ratio 4.64, P = 0.0002), poorly differentiated tumor (rate ratio 7.70, P = 0.0001), primary tumor size &gt;3 cm (rate ratio 4.26, P = 0.0009), presence of distant metastases (liver: rate ratio 5.88, P = 0.01; distant extra-hepatic: rate ratio 13.41, P = 0.0008). The pancreatic site, the poor degree of differentiation and the distant metastases were confirmed as negative prognostic factors at multivariate analysis. Overall 5-year survival rate was 77.5%. Survival rates differed according to: primary tumor site (62% for pancreatic vs 89.9% for gastrointestinal tract, P = 0.0001) and size (65.7% for &gt;3 cm vs 88.8% for ≤ 3 cm, P = 0.0003), degree of differentiation (22% for poor vs 86.8% for good, P &lt;0.0001), Ki67 (53.5% for &gt; 2% vs 90.1% for ≤ 2%, P = 0.003), metastases (96.1, 77, 73.3 and 50.1% for absent, local, liver and distant extra-hepatic metastases respectively), age at diagnosis (85.3% for ≤ 50 years vs 70.3% for &gt; 50 years, P = 0.03). Although 64.3% of gastro-entero-pancreatic endocrine tumors present metastases at diagnosis, the 5-year survival rate is 77.5%. Pancreatic site, a poor degree of tumor cell differentiation and distant extra-hepatic metastases are the major negative prognostic factors.

Background & AimsThe management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients.MethodsWe performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers.ResultsWe identified molecular markers and clinical features that classified cyst type with 90%−100% sensitivity and 92%−98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%.ConclusionsWe identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery. The management of pancreatic cysts poses challenges to both patients and their physicians. We investigated whether a combination of molecular markers and clinical information could improve the classification of pancreatic cysts and management of patients. We performed a multi-center, retrospective study of 130 patients with resected pancreatic cystic neoplasms (12 serous cystadenomas, 10 solid pseudopapillary neoplasms, 12 mucinous cystic neoplasms, and 96 intraductal papillary mucinous neoplasms). Cyst fluid was analyzed to identify subtle mutations in genes known to be mutated in pancreatic cysts (BRAF, CDKN2A, CTNNB1, GNAS, KRAS, NRAS, PIK3CA, RNF43, SMAD4, TP53, and VHL); to identify loss of heterozygozity at CDKN2A, RNF43, SMAD4, TP53, and VHL tumor suppressor loci; and to identify aneuploidy. The analyses were performed using specialized technologies for implementing and interpreting massively parallel sequencing data acquisition. An algorithm was used to select markers that could classify cyst type and grade. The accuracy of the molecular markers was compared with that of clinical markers and a combination of molecular and clinical markers. We identified molecular markers and clinical features that classified cyst type with 90%−100% sensitivity and 92%−98% specificity. The molecular marker panel correctly identified 67 of the 74 patients who did not require surgery and could, therefore, reduce the number of unnecessary operations by 91%. We identified a panel of molecular markers and clinical features that show promise for the accurate classification of cystic neoplasms of the pancreas and identification of cysts that require surgery.

Autoimmune pancreatitis is characterized by an inflammatory process that leads to organ dysfunction. The cause of the disease is unknown. Its autoimmune origin has been suggested but never proved, and little is known about the pathogenesis of this condition.

Background Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors. Methods All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed. Results Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease. Conclusion A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally. Tumor size is a criterion of staging in nonfunctioning pancreatic endocrine tumors as well as a predictor of outcome after curative resection. This study analyzes the correlation between tumor size and malignancy in patients with nonfunctioning pancreatic endocrine tumors. All patients with nonfunctioning pancreatic endocrine tumors who underwent curative resection (R0) at our institution between 1990 and 2008 were considered. Their clinicopathologic characteristics were compared among 3 different groups according to tumor size. Univariate and multivariable analyses were performed. Over the study period, 177 patients were identified. Overall, 90 patients (51%) had a tumor size ≤2 cm (group 1), 46 (26%) had tumor size between >2 cm and ≤4 cm (group 2), and 41 (23%) had tumor size >4 cm (group 3). Tumors ≤2 cm were more frequently incidentally discovered (group 1, 57% vs group 2, 51% vs group 3, 32%; P = .014) and benign (group 1, 81% vs group 2, 65% vs group 3, 5%; P < .0001). The presence of a nonfunctioning pancreatic endocrine tumor >2 cm and a nonincidental diagnosis of the tumor were independent predictors of malignancy at multivariable analysis. None of the 51 patients (29%) with a pancreatic endocrine tumor ≤2 cm that was incidentally diagnosed died of disease. A strict correlation between tumor size and malignancy in nonfunctioning pancreatic endocrine tumors was demonstrated. A nonoperative management could be advocated for tumors ≤2 cm when discovered incidentally.

The correlation of the amylase value in drains (AVD) with the development of pancreatic fistula (PF) is still unclear.The purpose of this study was to identify within the first postoperative day (POD1) the predictive role of different risks factors, including AVD, in the development of PF.We prospectively investigated 137 patients who underwent major pancreatic resections. PF was defined and graded in accordance with the International Study Group on PF.We considered 101 pancreaticoduodenectomies and 36 distal resections. The overall incidence of PF (A, B, and C grades) was 19.7% and it was 14.8% after pancreaticoduodenectomy and 33.3% after distal resection. All PF occurred in "soft" remnant pancreas. The PF developed in patients with a POD1 median AVD of 10,000 U/L, whereas patients without PF had a median AVD of 1222 U/L (P < 0.001). We established a cut-off of 5000 U/L POD1 AVD for univariate and multivariate analysis. The area under the receiver operating characteristic (ROC) curve was 0.922 (P < 0.001). The predicting risk factors selected in the univariate setting were "soft" pancreas (P = 0.005; odds ratio [OR]: 1.54; 95% CI: 1.32-1.79) and AVD (P < 0.001; OR: 5.66; 95% CI: 3.6-8.7; positive predictive value 59%; negative predictive value 98%), whereas in multivariate analysis the predicting risk factor was the POD1 AVD (P < 0.001; OR: 68.4; 95% CI: 14.8-315). Only 2 PFs were detected with AVD <5000 U/L and both were in pancreatogastric anastomosis (P = 0.053).AVD in POD1 > or =5000 U/L is the only significant predictive factor of PF development.

Mucin-producing neoplasms (MPNs) of the pancreas include mucinous cystic neoplasms (MCNs) and main-duct, branch-duct, and combined intraductal papillary mucinous neoplasms (IPMNs). MCNs and branch-duct IPMNs are frequently confused; it is unclear whether main-duct, combined, and branch-duct IPMNs are a different spectrum of the same disease. We evaluated their clinical and epidemiologic characteristics.Patients who underwent resection for histologically confirmed MPNs were identified (N = 557); specimens were reviewed and eventually reclassified.One hundred sixty-eight patients (30%) had MCNs, 159 (28.5%) had branch-duct IPMNs, 149 (27%) had combined IPMNs, and 81 (14.5%) had main-duct IPMNs. Patients with MCNs were significantly younger and almost exclusively women; 44% of patients with main-duct or combined IPMNs and 57% of those with branch-duct IPMNs were women. MCNs were single lesions located in the distal pancreas (95%); 11% were invasive. IPMNs were more frequently found in the proximal pancreas; invasive cancer was found in 11%, 42%, and 48% of branch-duct, combined, and main-duct IPMNs, respectively (P = .001). Patients with invasive MCN and those with combined and main-duct IPMNs were older than those with noninvasive tumors. The 5-year disease-specific survival rate approached 100% for patients with noninvasive MPNs. The rates for those with invasive cancer were 58%, 56%, 51%, and 64% for invasive MCNs, branch-duct IPMNs, main-duct IPMNs, and combined IPMNs, respectively.MPNs comprise 3 different neoplasms: MCNs, branch-duct IPMNs, and main-duct IPMNs, including the combined type. These tumors have specific clinical, epidemiologic, and morphologic features that allow a reasonable degree of accuracy in preoperative diagnosis.

a DRK Kliniken Westend, Berlin , Germany; b UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hopital Louis Mourier, Colombes , France; c Medicine and Surgery, General Surgery Section, MED/18 – General Surgery and d Department of Pathology, University of Verona, Verona , Italy; e Netherlands Cancer Centre, Amsterdam , and f Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam , The Netherlands;

Purpose Single-agent gemcitabine became standard first-line treatment for advanced pancreatic cancer after demonstration of superiority compared with fluorouracil. The Gruppo Italiano Pancreas 1 randomized phase III trial aimed to compare gemcitabine plus cisplatin versus gemcitabine alone (ClinicalTrials.gov ID NCT00813696). Patients and Methods Patients with locally advanced or metastatic pancreatic cancer, age 18 to 75 years, and Karnofsky performance status (KPS) ≥ 50, were randomly assigned to receive gemcitabine (arm A) or gemcitabine plus cisplatin (arm B). Arm A: gemcitabine 1,000 mg/m 2 weekly for 7 weeks, and, after a 1-week rest, on days 1, 8, and 15 every 4 weeks. Arm B: cisplatin 25 mg/m 2 added weekly to gemcitabine, except cycle 1 day 22. Primary end point was overall survival. To have 8% power of detecting a 0.74 hazard ratio (HR) of death, with bilateral α .05, 355 events were needed and 400 patients planned. Results Four hundred patients were enrolled (arm A: 199; arm B: 201). Median age was 63, 59% were male, 84% had stage IV, and 83% had KPS ≥ 80. Median overall survival was 8.3 months versus 7.2 months in arm A and B, respectively (HR, 1.10; 95% CI, 0.89 to 1.35; P = .38). Median progression-free survival was 3.9 months versus 3.8 months in arm A and B, respectively (HR, 0.97; 95% CI, 0.80 to 1.19; P = .80). The objective response rate was 10.1% in A and 12.9% in B (P = .37). Clinical benefit was experienced by 23.0% in A and 15.1% in B (P = .057). Combination therapy produced more hematologic toxicity, without relevant differences in nonhematologic toxicity. Conclusion The addition of weekly cisplatin to gemcitabine failed to demonstrate any improvement as first-line treatment of advanced pancreatic cancer.

<h3>Objectives</h3> Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. <h3>Design</h3> Retrospective multinational study including SCN diagnosed between 1990 and 2014. <h3>Results</h3> 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN9s related mortality was 0.1% (n=1). <h3>Conclusions</h3> After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. <h3>Trial registration number</h3> IRB 00006477.

Purpose Knowledge of clinical course of pancreatic endocrine carcinomas (PECs) is poor. This study aimed to determine the time to progression of advanced PECs, and to identify predictors capable of selecting subgroups with higher risk of progression. Patients and Methods In this multicenter retrospective analysis, patients with advanced PECs were enrolled. Staging was according to European Neuroendocrine Tumors Society guidelines. Grading was based on proliferation index using Ki67 immunohistochemistry. The primary end point was progression-free survival (PFS), which was assessed using the Kaplan-Meier method. The Cox regression proportional hazard model was used to identify predictors for tumor progression. Results Two hundred two patients with PECs were enrolled, including 172 with well-differentiated and 30 with poorly differentiated endocrine carcinomas. There were 34 patients with stage III and 168 with stage IV tumors. G1 tumors were present in 19.7% of patients, whereas 60.1% of patients had G2 tumors, and the remaining 20.2% had G3 tumors. Disease progression occurred in 166 patients (82.2%), at a median interval of 10 months (interquartile range, 5 to 22) from diagnosis. Median PFS was 14 months. Different PFS were observed depending on G grade (P &lt; .001) and tumor differentiation (P &lt; .001) and in patients who did not receive any antitumor treatment (P = .002). The major risk factor for progression was the proliferation index Ki67 (hazard ratio, 1.02 for each increasing unit; P &lt; .001). Overall 5-year survival was 44.1%. Conclusion The vast majority of patients with advanced PECs undergo disease progression. The major risk factor for progression is Ki67 index, which should lead physicians dealing with PECs to plan appropriate follow-up programs and therapeutic strategies.

The small intestine and pancreas are among the most frequent abdominal sites of origin of neuroendocrine tumours. Distinctive features of these forms are represented by the relatively low incidence and the wide heterogeneity in biological behaviour. In this light, it is difficult to standardize indications for surgery and the most appropriate approach. It would be helpful for surgeons managing patients with these tumours to have guidelines for surgical treatment of small intestinal neuroendocrine tumours and pancreatic neuroendocrine tumours. The proposed guidelines represent a consensus of the working group of the European Neuroendocrine Tumor Society (ENETS).

The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC).Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC.This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival.In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929).Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

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. 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. 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. 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. 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.

The importance of epigenetic modifications such as DNA methylation in tumorigenesis is increasingly being appreciated. To define the genome‐wide pattern of DNA methylation in pancreatic ductal adenocarcinomas (PDAC), we captured the methylation profiles of 167 untreated resected PDACs and compared them to a panel of 29 adjacent nontransformed pancreata using high‐density arrays. A total of 11,634 CpG sites associated with 3,522 genes were significantly differentially methylated (DM) in PDAC and were capable of segregating PDAC from non‐malignant pancreas, regardless of tumor cellularity. As expected, PDAC hypermethylation was most prevalent in the 5′ region of genes (including the proximal promoter, 5′UTR and CpG islands). Approximately 33% DM genes showed significant inverse correlation with mRNA expression levels. Pathway analysis revealed an enrichment of aberrantly methylated genes involved in key molecular mechanisms important to PDAC: TGF‐β, WNT, integrin signaling, cell adhesion, stellate cell activation and axon guidance. Given the recent discovery that SLIT‐ROBO mutations play a clinically important role in PDAC, the role of epigenetic perturbation of axon guidance was pursued in more detail. Bisulfite amplicon deep sequencing and qRT‐PCR expression analyses confirmed recurrent perturbation of axon guidance pathway genes SLIT2, SLIT3, ROBO1, ROBO3, ITGA2 and MET and suggests epigenetic suppression of SLIT‐ROBO signaling and up‐regulation of MET and ITGA2 expression. Hypomethylation of MET and ITGA2 correlated with high gene expression, which was associated with poor survival. These data suggest that aberrant methylation plays an important role in pancreatic carcinogenesis affecting core signaling pathways with potential implications for the disease pathophysiology and therapy.

Background Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. Methods We did this randomised, open-label, phase 2–3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18–75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I–II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 ≤5 × upper limit of normal [ULN] vs >5 × ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m2 on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m2 on days 1–28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630. Findings Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7–39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32–68) of 30 in group B and 19 (66%, 49–83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. Interpretation Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. Funding PERLAVITA ONLUS and MyEverest ONLUS.

Objective To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery. Methods In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. Results Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age &gt;70 years, atypical/malignant cyst fluid cytology, jaundice and MD &gt;15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p&lt;0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p&lt;0.0001). Conclusions In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

We aimed to assess the safety and efficacy of metformin for treating patients with metastatic pancreatic cancer and to identify endocrine and metabolic phenotypic features or tumor molecular markers associated with sensitivity to metformin antineoplastic action.We designed an open-label, randomized, phase II trial to assess the efficacy of adding metformin to a standard systemic therapy with cisplatin, epirubicin, capecitabine, and gemcitabine (PEXG) in patients with metastatic pancreatic cancer. Patients ages 18 years or older with metastatic pancreatic cancer were randomly assigned (1:1) to receive PEXG every 4 weeks in combination or not with 2 g oral metformin daily. The primary endpoint was 6-months progression-free survival (PFS-6) in the intention-to-treat population.Between August 2010 and January 2014, we randomly assigned 60 patients to receive PEXG with (n = 31) or without metformin (n = 29). At the preplanned interim analysis, the study was ended for futility. PFS-6 was 52% [95% confidence interval (CI), 33-69] in the control group and 42% (95% CI, 24-59) in the metformin group (P = 0.61). Furthermore, there was no difference in disease-free survival and overall survival between groups. Despite endocrine metabolic modifications induced by metformin, there was no correlation with the outcome. Single-nucleotide polymorphism rs11212617 predicted glycemic response, but not tumor response to metformin. Gene expression on tumor tissue did not predict tumor response to metformin.Addition of metformin at the dose commonly used in diabetes did not improve outcome in patients with metastatic pancreatic cancer treated with standard systemic therapy. See related commentary by Yang and Rustgi, p. 1031.

Pancreatic cystic lesions (PCLs) are frequent incidental findings. As most PCLs require costly diagnostic evaluation and active surveillance, it is important to clarify their prevalence in asymptomatic individuals. We therefore aimed at performing a systematic review and meta-analysis to determine it.a systematic search was conducted and studies meeting inclusion criteria were included. The prevalence of PCLs was pooled across studies. A random effect model was used with assessment of heterogeneity.17 studies, with 48,860 patients, were included. Only 3 were prospective; 5 studies were conducted in the US, 7 in Europe, 4 in Asia and 1 in Brazil. The pooled prevalence of PCLs was 8% (95% CI 4-14) with considerable heterogeneity (I2 = 99.5%). This prevalence was higher in studies of higher quality, examining older subjects, smaller cohorts, and employing MRCP (24.8% vs 2.7% with CT-scan). The pooled rate of PCLs was four times higher in studies conducted in the US than in Asia (12.6% vs 3.1%). 7 studies reported the prevalence of mucinous lesions, with a pooled rate of 4.3% (95% CI 2-10; I2 = 99.2%), but of 0.7% only for worrisome features or high risk stigmata.The rate of incidentally detected PCLs is of 8%. Mucinous lesions are the most common incidentally detected PCLs, although they rarely present with potential indication for surgery. The observed different rates in the US and other geographic Areas suggest that different protocols might be necessary to help balancing costs and effectiveness of follow-up investigations in asymptomatic subjects.

Abstract Background 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. Methods PubMed, Embase and the Cochrane Library were searched systematically for studies that compared the active surveillance of asymptomatic, sporadic, small NF-PNENs with surgical management. PRISMA guidelines for systematic reviews were followed. Results After screening 3915 records, five retrospective studies with a total of 540 patients were included. Of these, 327 patients (60·6 per cent) underwent active surveillance and 213 (39·4 per cent) had surgery. There was wide variation in the tumour diameter threshold considered as inclusion criterion (2 cm to any size). The median length of follow-up ranged from 28 to 45 months. Measurable tumour growth was observed in 0–51·0 per cent of patients. Overall, 46 patients (14·1 per cent) underwent pancreatic resection after initial conservative treatment. In most patients the reason was an increase in tumour size (19 of 46). There were no disease-related deaths in the active surveillance group in any of the studies. Conclusion This systematic review suggests that active surveillance of patients affected by sporadic, small, asymptomatic NF-PNENs may be a good alternative to surgical treatment.

Pancreatic cysts are common and often pose a management dilemma, because some cysts are precancerous, whereas others have little risk of developing into invasive cancers. We used supervised machine learning techniques to develop a comprehensive test, CompCyst, to guide the management of patients with pancreatic cysts. The test is based on selected clinical features, imaging characteristics, and cyst fluid genetic and biochemical markers. Using data from 436 patients with pancreatic cysts, we trained CompCyst to classify patients as those who required surgery, those who should be routinely monitored, and those who did not require further surveillance. We then tested CompCyst in an independent cohort of 426 patients, with histopathology used as the gold standard. We found that clinical management informed by the CompCyst test was more accurate than the management dictated by conventional clinical and imaging criteria alone. Application of the CompCyst test would have spared surgery in more than half of the patients who underwent unnecessary resection of their cysts. CompCyst therefore has the potential to reduce the patient morbidity and economic costs associated with current standard-of-care pancreatic cyst management practices.

Nuclear medicine plays an increasingly important role in the management neuroendocrine neoplasms (NEN). Somatostatin analogue (SSA)-based positron emission tomography/computed tomography (PET/CT) and peptide receptor radionuclide therapy (PRRT) have been used in clinical trials and approved by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA). European Association of Nuclear Medicine (EANM) Focus 3 performed a multidisciplinary Delphi process to deliver a balanced perspective on molecular imaging and radionuclide therapy in well-differentiated neuroendocrine tumours (NETs). NETs form in cells that interact with the nervous system or in glands that produce hormones. These cells, called neuroendocrine cells, can be found throughout the body, but NETs are most often found in the abdomen, especially in the gastrointestinal tract. These tumours may also be found in the lungs, pancreas and adrenal glands. In addition to being rare, NETs are also complex and may be difficult to diagnose. Most NETs are non-functioning; however, a minority present with symptoms related to hypersecretion of bioactive compounds. NETs often do not cause symptoms early in the disease process. When diagnosed, substantial number of patients are already found to have metastatic disease. Several societies' guidelines address Neuroendocrine neoplasms (NENs) management; however, many issues are still debated, due to both the difficulty in acquiring strong clinical evidence in a rare and heterogeneous disease and the different availability of diagnostic and therapeutic options across countries. EANM Focus 3 reached consensus on employing 68gallium-labelled somatostatin analogue ([68Ga]Ga-DOTA-SSA)-based PET/CT with diagnostic CT or magnetic resonance imaging (MRI) for unknown primary NET detection, metastatic NET, NET staging/restaging, suspected extra-adrenal pheochromocytoma/paraganglioma and suspected paraganglioma. Consensus was reached on employing 18fluorine-fluoro-2-deoxyglucose ([18F]FDG) PET/CT in neuroendocrine carcinoma, G3 NET and in G1-2 NET with mismatched lesions (CT-positive/[68Ga]Ga-DOTA-SSA-negative). Peptide receptor radionuclide therapy (PRRT) was recommended for second line treatment for gastrointestinal NET with [68Ga]Ga-DOTA-SSA uptake in all lesions, in G1/G2 NET at disease progression, and in a subset of G3 NET provided all lesions are positive at [18F]FDG and [68Ga]Ga-DOTA-SSA. PRRT rechallenge may be used for in patients with stable disease for at least 1 year after therapy completion. An international consensus is not only a prelude to a more standardised management across countries but also serves as a guide for the direction to follow when designing new research studies.

The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD).Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking.A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort.Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001).For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Traditionally viewed as poorly plastic, neutrophils are now recognized as functionally diverse; however, the extent and determinants of neutrophil heterogeneity in humans remain unclear. We performed a comprehensive immunophenotypic and transcriptome analysis, at a bulk and single-cell level, of neutrophils from healthy donors and patients undergoing stress myelopoiesis upon exposure to growth factors, transplantation of hematopoietic stem cells (HSC-T), development of pancreatic cancer and viral infection. We uncover an extreme diversity of human neutrophils in vivo, reflecting the rates of cell mobilization, differentiation and exposure to environmental signals. Integrated control of developmental and inducible transcriptional programs linked flexible granulopoietic outputs with elicitation of stimulus-specific functional responses. In this context, we detected an acute interferon (IFN) response in the blood of patients receiving HSC-T that was mirrored by marked upregulation of IFN-stimulated genes in neutrophils but not in monocytes. Systematic characterization of human neutrophil plasticity may uncover clinically relevant biomarkers and support the development of diagnostic and therapeutic tools.

Endoscopic ultrasound-guided radiofrequency ablation (EUS-RFA) is emerging as a safe and effective treatment for pancreatic neuroendocrine tumors. We aimed to compare EUS-RFA and surgical resection for the treatment of pancreatic insulinoma (PI).Patients with sporadic PI who underwent EUS-RFA at 23 centers or surgical resection at 8 high-volume pancreatic surgery institutions between 2014 and 2022 were retrospectively identified and outcomes compared using a propensity-matching analysis. Primary outcome was safety. Secondary outcomes were clinical efficacy, hospital stay, and recurrence rate after EUS-RFA.Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients).EUS-RFA is safer than surgery and highly effective for the treatment of PI. If confirmed in a randomized study, EUS-RFA treatment can become first-line therapy for sporadic PI.

This ENETS guidance paper aims to provide practical advice to clinicians for the diagnosis, treatment and follow-up of functioning syndromes in pancreatic neuroendocrine tumours (NET). A NET-associated functioning syndrome is defined by the presence of a clinical syndrome combined with biochemical evidence of inappropriately elevated hormonal levels. Different hormonal syndromes can be encountered in pancreatic NET patients, including insulinoma, gastrinoma as well as the rare glucagonoma, VIPoma, ACTHoma, PTHrPoma, carcinoid syndrome, calcitoninoma, GHRHoma and somatostatinoma. The recommendations provided in this paper focus on the biochemical, genetic and imaging work-up as well as therapeutic management of the individual hormonal syndromes in well-differentiated, grade 1-3, functioning NET with the primary tumour originating in the pancreas, and for specific subtypes also in the duodenum.

The aim of the present guidance paper was to update the previous ENETS guidelines on well-differentiated gastric and duodenal neuroendocrine tumours (NETs), providing practical guidance for specialists in the diagnosis and management of gastroduodenal NETs. Type II gastric NETs, neuroendocrine carcinomas (NECs), and functioning duodenal NETs are not covered, since they will be discussed in other ENETS guidance papers.

Pancreatic cancer (PC) is an aggressive disease, with a growing incidence, and a poor prognosis. Neoadjuvant treatments in PC are highly recommended in borderline resectable and recently in upfront resectable PC. PC is characterized by exocrine insufficiency and nutritional imbalance, leading to malnutrition/sarcopenia. The concept of malnutrition in PC is multifaceted, as the cancer-related alterations create an interplay with adverse effects of anticancer treatments. All these critical factors have a negative impact on the postoperative and oncological outcomes. A series of actions and programs can be implemented to improve resectable and borderline resectable PC in terms of postoperative complications, oncological outcomes and patients’ quality of life. A timely nutritional evaluation and the implementation of appropriate evidence-based nutritional interventions in onco-surgical patients should be considered of importance to improve preoperative physical fitness. Unfortunately, nutritional care and its optimization are often neglected in real-world clinical practice. Currently available studies and ERAS® guidelines mostly support the use of pre- or perioperative medical nutrition, including immunonutrition, in order to decrease the rate of postoperative infections and length of hospital stay. Further data also suggest that medical nutrition should be considered proactively in PC patients, to possibly prevent severe malnutrition and its consequences on disease and treatment outcomes. This narrative review summarizes the most recent data related to the role of prehabilitation, ERAS® program, medical nutrition, and the timing of intervention on clinical outcomes of upfront resectable and borderline PC, and their potential implementation within the timeframe of neoadjuvant treatments.

&lt;i&gt;Background:&lt;/i&gt; Pancreatic fistula (PF) is still regarded as a serious complication both in terms of frequency and sequelae. The incidence varies greatly in different reports because of the different definitions used. The aim of this study was to compare several definitions of PF encountered in the current literature and to demonstrate that the PF rate in the same group of patients treated in a high volume center is dependent upon the definition applied. &lt;i&gt;Methods:&lt;/i&gt; A Medline search of the last 10 years was performed as regards the definition of PF. A score was assigned to the reproducible definitions based upon two basic parameters: daily output (cm&lt;sup&gt;3&lt;/sup&gt;) and duration of the fistula represented by the number of days between the postoperative day of onset and the duration of the complication. Four definitions were formulated and were then applied to a group of 242 patients that underwent pancreatic head or intermediate resections with pancreatico-jejunal anastomosis in our Pancreatic Unit between November 1996 and December 2000. Statistical analysis was carried out using the Yates correct χ&lt;sup&gt;2&lt;/sup&gt; test with statistical significance set at p &lt; 0.05. &lt;i&gt;Results:&lt;/i&gt; Among 26 different definitions identified, 14 were found suitable for the applied score. We formulated four final definitions summarizing the current concepts of PF. The incidence of PF ranged between 9.9 and 28.5% according to the different definitions applied with highly statistical differences between them. &lt;i&gt;Conclusions:&lt;/i&gt; The PF rate after pancreatic resections is strictly dependent upon the definition used. An overall general agreement for an internationally accepted definition is urgently needed to correctly compare different experiences.

Anastomotic failure is still a significant problem that affects the outcome of pancreaticoduodenectomy. There have been many techniques proposed for the reconstruction of pancreatic digestive continuity, but there have been few prospective and randomized studies that compare their efficacy.In the current work, 144 patients who underwent a pancreaticoduodenectomy with soft residual tissue were assigned randomly to receive either a duct-to-mucosa anastomosis (group A) or a 1-layer end-to-side pancreaticojejunostomy (group B).The 2 treatment groups were found not to have any differences in regards to vital statistics, underlying disease, or operative techniques. The postoperative course was complicated in 54% of the 144 patients, with a comprehensive incidence of abdominal complications in 36% (group A, 35%; group B, 38%; P=not significant). The principal complication was pancreatic fistulas, which occurred in 14% of patients (group A, 13%; group B, 15%; P=not significant). Two patients (2%) required reoperation; the postoperative mortality rate was 1%.The 2 methods that were studied revealed no significant difference the rate of complications.

a Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam, The Netherlands; b Division of General Surgery, Department of Surgery, Medical University of Vienna, Vienna , Austria; c Hospices Civils de Lyon, Hopital Edouard-Herriot Service Central d‘Anatomie et Cytologie Pathologiques, Lyon , France; d Centre de Medecine Nucleaire, Universite Catholique de Louvain, Brussels , Belgium; e Department of Pathology, University of Kiel, Kiel , Germany; f B Unit of Surgery, Department of Surgery, University of Verona, Verona , Italy; g Department of Nuclear Medicine, Erasmus MC, Rotterdam , The Netherlands; h Department of Endocrine Oncology, University Hospital, Uppsala , Sweden; i Department of Internal Medicine, Division of Hepatology and Gastroenterology, Interdisciplinary Center of Metabolism and Endocrinology, Charite, Campus Virchow Hospital, University for Medicine Berlin, Berlin , Germany; j Service de Gastroenterologie-Pancreatologie, Pole des Maladies de l‘Appareil Digestif, Hopital Beaujon, Clichy , France; k Department of Pathology and Laboratory Medicine, Universita degli Studi, Parma, Italy; l Department of Endocrinology, Genoa University, Genoa , Italy

<b>Background:</b> Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are reported to be less aggressive than the main-duct type. Hence, less aggressive treatment has been proposed for the former. <b>Aim:</b> To evaluate the effectiveness of a follow-up protocol for BD-IPMNs. <b>Design:</b> Prospective study. <b>Setting:</b> An academic tertiary referral centre. <b>Patients:</b> From 2000 to 2003, 109 patients with BD-IPMNs underwent trans-abdominal ultrasound and magnetic resonance cholangiopancreatography with secretin. Patients who presented malignancy-related parameters (size &gt;3.5 cm, nodules, thick walls, carbohydrate antigen 19.9 level &gt;25 U/l, recent-onset or worsened diabetes) and/or complained of symptoms were submitted to surgery (arm A). All asymptomatic patients without suspicion of malignancy were followed up according to a 6-month clinical–radiological protocol (arm B). <b>Main outcome measures:</b> The effectiveness of conservative management of BD-IPMNs. <b>Results:</b> 20 (18.3%) patients underwent surgery (arm A); pathological diagnosis of BD-IPMNs was always confirmed. 89 (81.7%) patients were followed up for a median of 32 months (arm B); of these, 57 (64%) patients had multifocal disease. After a mean follow-up of 18.2 months, 5 (5.6%) patients showed an increase in lesion size and underwent surgery. The pathological diagnosis was branch-duct adenoma in three patients and borderline adenoma in two. <b>Conclusions:</b> Surgery is indicated in &lt;20% of cases of BD-IPMNs, and, in the absence of malignancy-related parameters, careful non-operative management seems to be safe and effective in asymptomatic patients. Although observation for a longer time is needed to confirm these results, our findings support the guidelines recently recommended by the International Association of Pancreatology.

Nonfunctioning pancreatic neuroendocrine tumors (NET) are defined by their histopathological differentiation. Neuroendocrine cells are characterized by the expression of marker molecules like neuron-specific enolase (NSE), an unspecific cytosolic marker or vesicle proteins like chromogranin A or synaptophysin, indicating large and dense hormone-storing core vesicles and neuropeptides- or small neurotransmitter-storing synaptic vesicles, respectively [1,2,3,4]. These proteins define the neuroendocrine origin of the tumor cells. The term ‘nonfunctioning’ refers to the absence of clinical symptoms of hormonal hypersecretion. However, nonfunctioning tumors may well show immunohistochemical positivity for hormones, neuropeptides or neurotransmitters. The WHO classifies nonfunctioning pancreatic NETs according to the uniform classification scheme for endocrine tumors, independent of the site of the primary: (1) well-differentiated endocrine tumor, with benign or uncertain behavior at the time of diagnosis; (2) well-differentiated endocrine carcinoma, with low-grade malignant behavior, and (3) poorly differentiated endocrine carcinoma, with high-grade malignant behavior [5] (table 1). Most (60–100%, according to the series) are classified as well-differentiated endocrine carcinomas [6, 7].Due to new and more sensitive imaging techniques, the number of neuroendocrine pancreatic incidentalomas has increased. The autoptic incidence is 1.6–10% per year [8], while the clinical incidence is 3.5–4/million/year [9]. Pancreatic endocrine tumors represent about 2–10% of all pancreatic tumors [9, 10]. In earlier series the percentage of nonfunctioning tumors out of all pancreatic endocrine tumors was estimated to be 18–66% [11,12,13,14,15,16,17]. In contrast, recent, large monocentric [7, 18, 19] or multicentric studies [20] classify 68–80% as nonfunctioning pancreatic neuroendocrine tumors. The peak incidence is during the fifth decade [6], with equal distribution among the sexes.Nonfunctioning pancreatic neuroendocrine tumors are defined by the absence of a hormone hypersecretion syndrome. The classification of the tumor as of neuroendocrine origin refers to the immunohistochemical positivity of chromogranin A and/or synaptophysin. Pathological grading is done according to the WHO classification of endocrine tumors; the majority are well-differentiated carcinomas. Pancreatic neuroendocrine tumors are rare.Due to the lack of symptoms related to hormonal hypersecretion, nonfunctioning pancreatic neuroendocrine tumors are diagnosed late in the course of the disease. The clinical signs and symptoms are due to the tumor mass, with local invasion and/or distant metastases. Abdominal pain is the major presenting symptom (35–78%), followed by weight loss (20–35%), anorexia and nausea (45%). The patient may present with intra-abdominal hemorrhage (4–20%), jaundice (17–50%) or a palpable mass (7–40%) [21,22,23,24,25]. Fifty-nine percent to 80% of the patients present with synchronous liver metastases at diagnosis [10, 25]. Given the mostly large primary (>5 cm), localizing the tumor at the head of the pancreas, followed by the body and tail, is straightforward [26].Most neuroendocrine pancreatic tumors are well-differentiated (WHO group 2) endocrine carcinomas (table 1) [27]. Overall 5-year survival is 30–63%, with a median survival from diagnosis of 72 months [12, 25, 28, 29]. Actuarial 5- and 10-year survival rates after diagnosis of liver metastases were 46 and 38%, respectively. [10]. However, aggressive treatment may increase 5-year survival to 63 or 82% [25, 30]. Rapid progression of liver metastases (more than 25% volume increase within 6–12 months) and the development of bone metastases confer a poor prognosis [10]. Histopathological staging (table 1), including tumor differentiation, tumor size, proliferation marker and angioinvasion, correlates with survival. All patients with low-risk tumors were alive after 47 months, 10% of those with intermediate-risk tumors had died after 94 months, while 35% of patients with low-grade malignant tumors died after a period of 42 months. Few patients with a high-grade malignant tumor were alive after 4 months [27].Nonfunctioning pancreatic neuroendocrine tumors present as large tumors, with signs and symptoms related to the tumor burden. At diagnosis, the prevalence of synchronous metastases is 80%. Prognosis depends on the presence or absence of liver/bone metastases and histopathological classification. Overall 5-year survival is 60%. MEN-1. Multiple endocrine neoplasia type 1 (MEN-1) is a hereditary tumor syndrome with autosomal inheritance and high penetrance. The main manifestations of the disease are primary hyperparathyroidism, pituitary adenomas and pancreatic neuroendocrine tumors. Nonfunctioning pancreatic neuroendocrine tumors occur besides functional tumors. MEN-1-related tumors occur at an earlier age and demonstrate a more benign course than do sporadic tumors. They may be multiple and vary in size from small microadenomas to large tumors. The malignant potential is related to the size of the tumor [31]. Recent data indicate a prevalence of 55% for nonfunctioning pancreatic neuroendocrine tumors in MEN-1 patients [32]. However, only a small number of patients (8%) with nonfunctioning pancreatic neuroendocrine tu- mors have MEN-1 syndrome [17]. Von Hippel-Lindau Disease (VHL). VHL is an autosomal-dominant disease with almost complete penetrance, characterized by the development of several types of neoplasia. Nonfunctioning pancreatic neuroendocrine tumors are part of the syndrome in up to 16% of the patients; frequently coexist with pheochromocytomas and may even precede the manifestation of other lesions [33,34,35,36].Tuberous Sclerosis. An association of nonfunctioning pancreatic NETs with tuberous sclerosis has also been suggested [37, 38].Nonfunctioning pancreatic neuroendocrine tumors are part of the MEN-1 syndrome. They occur at an earlier age than do sporadic pancreatic NETs, may precede other manifestations of the syndrome and determine the prognosis of the patients. Nonfunctioning pancreatic NET are a rare, but recognized part of von Hippel-Lindau disease and may be seen in patients with tuberous sclerosis.SRS has a sensitivity and specificity for pancreatic neuroendocrine tumors of 90 and 80%, respectively [39, 40]. SRS is the central modality for localization of the primary and definition of the extent of the disease. Whole-body imaging allows for detection of distant metastases and thus influences therapeutic decisions [41]. SRS is indicated as the first staging procedure and whenever the demonstration of extrahepatic metastases is necessary for therapeutic decisions. The following details indicate the recommended standard procedure: a double or triple head gamma-camera and a medium energy, parallel hole collimator, peaks at 172 and 245 keV with a window of 20%. 111In-octreotide 200 MBq for planar, 200–220 MBq for SPECT images. At an acquisition time of 15 min and 4 h post injection (p.i.) anterior and posterior abdominal views, at 24 h p.i. anterior and posterior views of the upper abdomen, head, chest and pelvis, as well as left and right lateral, anterior and posterior oblique views of the upper abdomen. Optional delayed images at 30– 48 h p.i. are recommended. Whole body imaging should be performed with a scanning speed of 3 cm/min. SPECT images should be acquired at 24 h p.i. with a 6° step rotation for 360°/40–60 s [42].Positron emission tomography (PET) and/or PET CT, using Ga-DOTATOC to visualize somatostatin receptors is a promising new tool. However sufficient data are still lacking [43,44,45]. Additional tracers used so far (11C-labelled L-Dopa, 18F-labelled L-Dopa and 11C-5-hydroxytryptophan) are not useful in nonfunctioning pancreatic NET [46, 47].With US, most, especially small lesions, appear hypoechoic [48,49,50], while larger lesions are more heterogeneous, due to the different degree of hyalinized stroma, hemorrhage and cystic degeneration [48, 50]. Cystic areas are hypoechoic to anechoic.Non-contrast-enhanced computed tomographic images (NCE-CT) display iso- or hypodense lesions compared to the adjacent pancreatic parenchyma. In addition, calcification and hemorrhage are accurately depicted on NCE-CT. With contrast enhancement, the hypervascularity of endocrine tumors is apparent and characteristic [48, 51, 52]. In addition areas of cystic degeneration are visualized as regions of reduced vascularity by contrast-enhanced CT. Images should be obtained with multidetector CT (2.5 mm section thickness) at the peak arterial phase of contrast enhancement and reconstructed at 1.25 mm thickness [42, 53, 54].MRT displays hypointense or hyperintense lesions compared to the adjacent pancreatic parenchyma on T1- or T2-weighted MRT images, respectively. Fat-saturated T1-weighted images during the injection of gadolinium chelates demonstrate the hypervascularity of endocrine tumors [48, 55, 56]. The hyperintensity is best depicted on fat-suppressed T2-weighted images. High-resolution, fat-saturated T2-weighted images, acquired during breath-hold acquisition, and volumetric T1-weighted images (3 mm slice thickness) at the peak arterial phase of contrast enhancement, using a high-field (1.5 T) MRT, employing high-performing gradients and phased array surface coils, are recommended. Injection rates of contrast material for the evaluation of hypervascular lesions average 3–5 ml/s. MRT with a hepatocyte-specific contrast agent may depict small (<1 cm) liver metastases and thus influence decision-making with respect to surgical therapy.To differentiate the hypervascular pancreatic neuroendocrine tumor from hypovascular pancreatic adenocarcinoma, contrast-enhanced techniques (multidetector CT or MRT) [53, 54, 57, 58] are useful. In addition, T2-weighted MR images differentiate the hyperintense neuroendocrine pancreatic tumor from the frequently scirrous, and thus hypointense, adenocarcinoma. Other helpful signs of differentiation are the mean larger volume, the occasionally cystic component and the lack of infiltration of peripancreatic fat and vessels of neuroendocrine tumors in comparison to the more aggressive growing adenocarcinoma [59, 60].In patients with a high degree of clinical suspicion but negative non-invasive imaging studies (US, CT and/or MRT), further diagnostic investigations may include contrast-enhanced US (sensitivity and specificity 94 and 96%, respectively) [61] or endoscopic ultrasound (EUS) with biopsies (sensitivity 82–86%) [62,63,64]. The sensitivity of CT and MR imaging is in the range of 75–79%, using comparable technical standards and equipment [65]. For follow-up, the technique which best visualizes the individual tumor should be used. However, with progressive disease and before therapeutic decisions, a thorough staging (SRS, US and CT/MRT) is recommended.US combined with state of the art contrast-enhanced CT/ MR imaging (including MRCP) is recommended. The decision whether to use CT or MRT depends on the preference, skill and expertise of the radiologist and the availability of the different techniques at each institution. Somatostatin receptor scintigraphy is the most sensitive, single screening method for extrahepatic disease manifestation. A possible algorithm is provided in figure 1.Chromogranin A (CgA) is a general tumor marker for neuroendocrine tumors [66]. Its concentration is supposed to correlate with the tumor mass. This correlation may be lost during SSA therapy [67]. In addition, basal and meal-stimulated pancreatic polypeptide (PP) may be useful for early detection of pancreatic involvement in MEN-1. The issue is controversial, as it has been demonstrated to substantiate the presence of a tumor in 75% of those tested [68], while others found no statistical difference between patients and controls for the meal-stimulated PP concentration [69].Nonfunctioning pancreatic neuroendocrine tumors may secrete hormones and/or neurotransmitters, with plasma concentrations clearly above the normal range (e.g. so-called ‘silent’ tumors), but they are insufficient to induce a hypersecretion syndrome. However, the clinical impact of silent tumors compared to non-secreting, nonfunctioning tumors is as yet unknown. Thus, extensive screening for secreted hormones is not justified.CgA is a recommended tumor marker, while the sensitivity and specificity of meal-stimulated PP are controversial. PP may be useful for early detection of pancreatic tumors in MEN-1. Extensive hormonal screening is not justified.Most nonfunctioning pancreatic neuroendocrine tumors present as well-differentiated tumors without distinctive histopathological features [5]. The growth pattern is usually of the nesting type. While fine needle aspiration cytology is not recommended as a standard diagnostic procedure, it may be useful in establishing the correct pre- or intraoperative diagnosis in the absence of a tissue specimen. New techniques, like monolayer cytology [70] or ‘cellblock’ sections, may improve the sensitivity of the procedure. Pre-operative histology is not required but is recommended. Histology is the gold standard in establishing a preoperative and definitive diagnosis. To demonstrate the endocrine nature of the neoplastic cells, immunohistochemical detection of CgA and synaptophysin are necessary and sufficient in most cases. To exclude tumors which may be confused with endocrine lesions, expression of vimentin, nuclear localization of beta-catenin for solid pseudopapillary tumors, and expression of trypsin for acinar cell carcinoma are useful [5]. While hormones/neurotransmitters like pancreatic polypeptide, glucagon, insulin, somatostatin, calcitonin and serotonin [5] may be expressed by silent neuroendocrine tumors, their immunohistochemical determination is not necessary for diagnosis and/or tumor subtyping. In contrast, the evaluation of the mitotic index is mandatory and that of the Ki67 index, at least in the primary tumor, is required. Germline DNA testing for hereditary tumor syndromes is only recommended in specific situations. These include a family history or clinical findings suggesting MEN-1 or von Hippel-Lindau disease (VHL), the presence of multiple tumors or the demonstration of precursor lesions, such as nesidioblastosis-like features or microadenomas, in the peritumoral pancreatic tissue [71, 72]. Mutational analysis should be performed to test for menin or VHL mutations.The pathological report should contain a detailed description of the macroscopic, microscopic and immunohistochemical findings, in order to support the diagnosis of an endocrine tumor and to allow for its correct classification, according to the current WHO criteria (table 2). Germline DNA testing, e.g. mutational analysis, is only justified in clinical situations strongly suggesting MEN-1 or VHL disease.According to the WHO classification, the size of the endocrine tumor correlates with malignant growth. Therefore, in localized tumors larger than 2 cm, aggressive surgery and, if required, resection of nearby organs (stomach, colon, kidney, adrenal gland) and/or major vessel resection, is indicated [73, 74]. In contrast, no data exist with respect to a positive effect of surgery on overall survival in small (<2 cm), possibly benign or intermediate-risk pancreatic endocrine tumors. Thus, the possibility of surgical cure has to be weighed against the operative morbidity, mortality and long-term complications associated with pancreatic surgery [75,76,77]. In patients with nonfunctioning pancreatic endocrine tumors as part of the MEN-1 syndrome, especially with small lesions, surgical intervention is still controversial [78,79,80].The type of surgery depends on the localization, the size and suspected malignancy of the tumor. Small, non-malignant, easily accessible tumors can be treated by local atypical resection (enucleation or middle pancreatectomy). Middle pancreatectomy is advisable for lesions in the pancreatic body and close to the Wirsung duct. With atypical resection, pancreatic parenchyma can be preserved, avoiding exocrine and endocrine pancreatic insufficiency, while on the other hand the risk of a postoperative pancreatic fistula is high [81,82,83]. Localization of the tumor in the pancreatic head or suspected malignancy require larger, more typical resections, i.e. pancreaticoduodenectomy or left pancreatectomy [84, 85]. Multiple nonfunctioning pancreatic NETs are part of MEN-1 and may cause up to 20% of MEN-1-related deaths [86,87,88,89]. Histopathological parameters cannot differentiate between benign and malignant disease in the absence of metastases or local invasion, and tumor size has no correlation to prognosis [31, 79, 90]. Careful microdissection of the pancreas demonstrates multiple, small (100 µm to 5 mm) microadenomas [72, 91], indicating clinically unapparent, yet histologically visible disease in MEN-1. While only a minority of the microadenomas acquire the potential to grow unrestrictedly, larger lesions may be genetically unstable; develop secondary mutations and will grow into clinically relevant lesions. While surgical resection of the visible tumors fails to cure the patient, prophylactic surgery aims to remove these lesions before malignancy develops. However, while recent data show that early diagnosis and surgery improve survival [92], others suggest a more conservative approach, as their data indicate, that only tumors larger than 2 cm are associated with an increased risk of malignancy [79]. Therapeutic strategies thus range from follow-up, to enucleation of visible lesions [86] or aggressive interventions with enucleation of tumors in the head of the pancreas combined with distal, subtotal (80%) pancreatic resection as prophylaxis against tumor recurrence [78, 93, 94].Localized, small, malignant tumors should be operated on aggressively, while in small (<2 cm) possibly benign tumors the surgical risk/benefit ratio should be carefully weighted. In MEN-1 patients with multiple tumors prophylactic surgery aims to remove the lesions before malignancy develops. Aggressive surgery, with curative intent for locally advanced nonfunctioning pancreatic NETs may prolong survival (5-year survival up to 80%, 72 and 77%, respectively) [75, 77, 85, 95]. However, all available data are retrospective analyses; most refer to a mixed – functioning and nonfunctioning – tumor cohort, and surgery is only part of a multimodal treatment approach. Thus, the effect of surgery alone is hard to estimate. In addition, surgery is mostly done in patients with less extensive disease and the prolonged survival of patients with debulking procedures may be primarily related to the stage of the tumor. Furthermore, most investigations give univariate survival analysis, which may be potentially misleading. Thus, the data are still inconclusive and only prospective randomized multicenter trials will provide an answer.No data support debulking procedures in unresectable, locally advanced nonfunctioning pancreatic NETs. With partial resection of the primary, the risk of bleeding is high, tumors recur and survival advantage is not supported by the data [75, 77, 90,95,96,97].Surgery of the Primary. In metastatic disease, resection of the primary alone fails to improve survival. In selected, low-risk patients with a low volume of liver metastases, but life-threatening or unbearable symptoms, surgery of the primary may prevent tumor related complications (gastrointestinal hemorrhage or biliary/gastric outlet obstruction) and allow for a more effective treatment by limiting the disease to the liver [77].Surgery for Liver Metastases. In the absence of extrahepatic disease, synchronous resection of the primary and liver metastases should be considered. The 5-year survival of patients treated with hepatic resection in recent series ranges from 47 to 76%, and this compares well with the 30–40% 5-year survival in untreated patients [98,99,100,101]. However, the rate of tumor recurrence is high, up to 76% [85, 98,102,103,104], and half of these are seen within 2 years after resection [102]. Surgery should only be undertaken if at least 90% of the tumor mass can be removed successfully. This may be possible in only up to 10% of the patients [98]. A prerequisite to hepatic surgery is sufficient hepatic reserve after resection. In addition, mortality and morbidity of palliative hepatic surgery should be less than 3–5% and 30%, respectively [103, 105, 106]. The type of surgery depends on the location of the metastases. The following procedures can be chosen: enucleation, one or more segmental resections, hemi-hepatectomy or extended hemi-hepatectomy. Intraoperative US must be performed for detection of all liver metastases. If feasible, the surgical procedure should include cholecystectomy to prevent possible side effects of somatostatin analogue or embolization therapy (gallstones or gallbladder necrosis, respectively).If radical resection is not achievable, biliary and gastric outlet obstruction should be treated by surgical bypass rather than endoscopic or percutaneous procedures. Long-term survival, even in the presence of liver metastases, makes the surgical approach preferable since the short-term patency of endoscopic stents is poor [58,107,108,109].Debulking of an unresectable primary is not recommended, with the exception of individual patients to avoid tumor-related complications. Surgery of liver metastases may be justified if at least 90% of the tumor mass can be reduced. This may be the case in only 10% of the patients. Surgery should only be performed in experienced centers with mortality, and morbidity less than 5 and 30%, respectively.Loco-regional ablative therapy is defined by a panel of mostly nonsurgical interventions, aiming at palliative reduction of hepatic lesions in patients without manifestation of extrahepatic disease. Locoregional ablative procedures have been used mainly in functioning metastatic NETs to reduce endocrine active tumor volume and thus improve symptoms of hypersecretion. There are insufficient data to define the role of loco-regional ablative strategies in nonfunctioning pancreatic NETs. Most investigations report on mixed tumor groups, the data are analyzed retrospectively and the procedure is part of a multimodal treatment. However, locoregional ablative therapies are widely used in clinical practice in patients who have failed systemic chemotherapy and/or are not candidates for other procedures, due to the extent of liver involvement. The following options are available: selective (chemo-)embolization, radiofrequency ablation, and radio-embolization. Selective embolization of peripheral arteries induces temporary, but complete ischemia. It has been suggested that embolization-induced ischemia sensitizes the tumor tissue to cytotoxic drugs, whose tumor concentration is increased by the slowing down of blood flow. The procedure can be performed repeatedly. Open questions are the type of drug (5-FU, doxorubicin and mitomycin C), dosage, intervals and timing of the procedure. Moreover, it has not been established whether chemo-embolization is more efficient than embolization alone. Results of (chemo-)embolization in 428 patients (14 trials, not all data are given in each trial) indicate a symptomatic response in 50–100%, biochemical response in 22–92%, and tumor volume response in 25–86% of the patients, overall median survival of 20–80 months and 5-year survival of 40–55% [110,111,112,113,114,115,116,117,118,119,120,121,122,123]. Positive prognostic factors are prior removal of the primary, metastatic liver involvement of less than 75%, diameter of the liver metastases < 5 cm and no extrahepatic metastasis [116, 123]. Mortality (0–3.3%) of the procedure is low; however, as morbidity may be significant, chemo-embolization should be performed in experienced centers. As it is not clear whether TACE prolongs survival, its main indication is the treatment of otherwise untreatable functionally active liver metastases [124].RFA is an alternative treatment limited to patients with no more than 8–10 lesions, and a diameter of the lesions below 4 cm. Depending on the tumor location, RFA can be performed laparoscopically or percutaneously [125,126,127,128,129,130]. Existing data report on all kinds of endocrine tumors. In the largest series so far (34 and 25 patients, 234 and 189 neuroendocrine metastases) symptomatic improvement occurred in 95 and 65%, partial or significant tumor volume reduction was observed in 65 and 68% of the patients, and median survival after RFA was 1.6 and 4.4 years, respectively. During the median follow-up of 1.6 years, 41% of the patients remained stable. Mortality was low and morbidity was 5–12% [131, 132]. In some patients, RFA may be used to convert an unresectable disease into a resectable one [105]. No data exist as to whether RFA has any effect on survival.Selective internal radiation therapy (SIRT) relies on the selective uptake by the tumor of yttrium-90 microspheres, following arterial hepatic injection. Due to the predominant arterial flow to liver tumors relative to normal liver tissue, the microspheres become trapped in capillary beds of tumorous lesions and deliver ionizing radiation to the tumor. Experience with this technique in NETs is lacking [133, 134]. An algorithm for the treatment of liver metastases is given in figure 2.(Chemo-)embolization and radiofrequency ablation have been used as loco-regional ablative therapy per se or as an adjunct to palliative surgery. Experience is limited, however, palliation seems possible in patients with a tumor burden of less than 75%, small metastases (<5 cm) and no extrahepatic metastases.In a few, highly selected cases liver transplantation may be an option. However, experience with liver transplantation is limited. Patients considered for transplantation have to be free of extrahepatic metastases, unresponsive to medical therapy, or not otherwise treatable. Patients with aggressive carcinomas should be excluded from liver transplantation. Most transplanted patients have recurrences within months to years, possibly due to postoperative immunosuppressive treatment and/or undiagnosed extrahepatic metastases prior to the procedure. Hence, improved methods for the detection of extrahepatic metastases are necessary before liver transplantation can be used or recommended [135,136,137,138,139,140,141,142,143,144,145,146].Liver transplantation may be an option in a patient without extrahepatic metastases, and low proliferation rate when all other therapeutic options have failed.Numerous studies have evaluated the effect of SSA or interferon on tumor proliferation. General conclusions should be interpreted with caution, as most studies report on a mixed tumor cohort. Demonstration of progressive disease before initializing somatostatin analogue/interferon therapy has been a prerequisite in only a small number of studies. No placebo group was included in any of the studies and most trials were performed in patients pre-treated with other therapeutic modalities. The duration of therapy was rather short in most trials, and standardized schemes for evaluating therapeutic efficacy had not been universally employed. There are only a small number of studies for SSA and none for interferon using a randomized, prospective, multicenter approach including only tumors with demonstrated progress. Most trials used secondary endpoints, such as tumor shrinkage or a decrease of tumor markers for the evaluation of drug efficacy. Endpoint analysis, i.e. time to progression or overall survival, was reported only in a minority of trials.In nonfunctioning pancreatic NETs somatostatin analogue (SSA) therapy aims at the stabilization of tumor growth. Partial and complete remission can be observed in fewer than 10% of the patients, while stabilization of tumor growth occurs in 24–57% of patients with documented tumor progress before somatostatin analogue therapy. Distant metastases and progressive disease during the first 6 months of therapy are negative predictors for a persistent stabilization of the disease [147]. SSA therapy should be initiated as first-line medical therapy, whenever tumor progress is documented and surgical or ablative treatment is no option (table 3). However, in low-differentiated tumors with a high Ki67 index (>15%) chemotherapy should be the first-line treatment strategy in patients without surgical or ablative therapeutic options. The tolerability of somatostatin analogues (nausea, newly developed diarrhea, abdominal pain) should be tested by initiating therapy with a short-acting analogue (e.g. octreotide). Thereafter, depot formulations, usually lanreotide-SR i.e. (every 2 weeks), lanreotide autogel s.c. or octreotide-LAR i.m. (every 4 weeks), are effective. The efficacy of lanreotide and octreotide is comparable [148,149,150]. Minor, initial side effects, usually subsiding within a few weeks, are abdominal discomfort, bloating and sometimes steatorrhea [148, 149, 151, 152]. In patients with steatorrhea, pancreatic enzyme supplementation may be of help. Major side effects are the development of gallstones (about 50%, rarely symptomatic). In a few cases, persistent steatorrhea resulting in malabsorption may occur [152, 153]. Follow-up of patients on SSA therapy should be performed in 6-month intervals. With documented, progressive disease during SSA therapy, SSA should be withdrawn.Interferon is given for the same indications as somatostatin analogues. However, data on interferon in nonfunctioning pancreatic NETs are rare. Results of 48 patients from 3 trials could be analyzed [28, 29, 154]. Progression has not usually been demonstrated before therapy and interferon was part of a multimodal therapeutic approach. Stabilization of the disease could be achieved in 23%, whereas partial r

Pancreaticoduodenectomy (PD) is still a difficult procedure with significant morbidity. We report 150 consecutive PDs performed during a 3-year period. All the cases have been prospectively evaluated with regard to the surgical outcome. Mortality in this series was 3/150 (2%) with a re-operation rate of 5/150 (3.3%); surgical complications were experienced in 57/150 (38%). The most frequent complications were collections in 25/150 (16.6%) and pancreatic fistulas in 16/150 (10.7%). The majority of these complications were conservatively managed: only one abscess and one fistula due to an anastomotic dehiscence required re-operation. The complication most responsible for mortality was haemorrhage secondary to arterial pseudoaneurysms in patients with severe post-operative pancreatitis. The continued high morbidity of PDs is compensated by the ability to treat complications non-operatively, resulting in a surgical risk that should now be considered medium to low in high volume centres.

In Brief Objective: To evaluate the indications, perioperative, and long-term outcomes of a large cohort of patients who underwent middle pancreatectomy (MP). Summary Background Data: MP is a parenchyma-sparing technique aimed to reduce the risk of postoperative exocrine and endocrine insufficiency. Reported outcomes after MP are conflicting. Methods: Patients who underwent MP between 1990 and 2005 at the Massachusetts General Hospital and at the University of Verona were identified. The outcomes after MP were compared with a control group that underwent extended left pancreatectomy (ELP) for neoplasms in the mid pancreas. Results: A total of 100 patients underwent MP. The most common indications were neuroendocrine neoplasms, serous cystadenoma, and branch-duct IPMNs. Comparison with 45 ELP showed that intraoperative blood loss and transfusions were significantly higher for ELP. The 2 groups showed no differences in overall morbidity, abdominal complications, overall pancreatic fistula, and grade B/C pancreatic fistula rate (17% in MP and 13% in ELP), but the mean hospital-stay was longer for MP patients (P = 0.005). Mortality was zero. In the MP group, 5 patients affected by IPMNs had positive resection margins and 3 had recurrence. After a median follow-up of 54 months, incidence of new endocrine and exocrine insufficiency were significantly higher in the ELP group (4% vs. 38%, P = 0.0001 and 5% vs. 15.6%, P = 0.039, respectively). Conclusions: MP is a safe and effective procedure for treatment of benign and low-grade malignant neoplasms of the mid pancreas and is associated with a low risk of development of exocrine and endocrine insufficiency. MP should be avoided in patients affected by main-duct IPMN. We evaluated indications, perioperative, and long-term outcomes of 100 patients who underwent middle pancreatectomy (MP) at 2 high-volume centers. The outcomes after MP were compared with a control group that underwent extended left pancreatectomy (ELP) for neoplasms in the mid pancreas. The incidence of new endocrine and exocrine insufficiency was significantly higher in the ELP group compared with MP one, with a 9-fold increase of new-onset diabetes (38% vs. 4%, P = 0.0001) and a 3-fold increase in exocrine insufficiency (15.6% vs. 5%, P = 0.039).

OBJECTIVES: Autoimmune pancreatitis (AIP) is a particular type of chronic pancreatitis that can be classified into diffuse and focal forms. The aim of this study was to analyze clinical and instrumental features of patients suffering from the diffuse and focal forms of AIP. METHODS: AIP patients diagnosed between 1995-2008 were studied. RESULTS: A total of 87 AIP patients (54 male and 33 female patients, mean age 43.4±15.3 years) were studied. Focal-type AIP was diagnosed in 63% and diffuse-type in 37%. Association with autoimmune diseases was observed in 53% of cases, the most common being ulcerative colitis (30%). Serum levels of IgG4 exceeded the upper normal limits (135 mg/dl) in 66% of focal AIP and in 27% of diffuse AIP (P=0.006). All patients responded to steroids. At recurrence non-steroid immunosuppressive drugs were successfully used in six patients. Recurrences were observed in 25% of cases, and were more frequent in focal AIP (33%) than in diffuse AIP (12%) (P=0.043), in smokers than in non-smokers (41% vs. 15%;P=0.011), and in patients with pathological serum levels of IgG4 compared to those with normal serum levels (50% vs. 12%;P=0.009). In all, 23% of the patients underwent pancreatic resections. Among patients with focal AIP, recurrences were observed in 30% of operated and in 34% of not operated patients. CONCLUSIONS: Focal-type and diffuse-type AIP differ as regards clinical symptoms and signs. Recurrences occur more frequently in focal AIP than in diffuse AIP. The use of non-steroid immunosuppressants may be a therapeutic option in relapsing AIP.

Pancreatic resections for benign diseases may lead to long-term endocrine/exocrine impairment. The aim of this study was to compare postoperative and long-term results after different pancreatic resections for benign disease.Between 1990 and 1999, 62 patients underwent pancreaticoduodenectomy (PD), 36 atypical resection (AR) and 64 left pancreatectomy (LP) for benign tumours. Exocrine and endocrine pancreatic function was evaluated by 72-h faecal chymotrypsin and oral glucose tolerance test.The incidence of pancreatic fistula was significantly higher after AR than after LP (11 of 36 versus seven of 64; P = 0.028). The long-term incidence of endocrine pancreatic insufficiency was significantly lower after AR than after PD (P < 0.001). Exocrine insufficiency was more common after PD (P < 0.001) and LP (P = 0.009) than after AR. The probability of developing both endocrine and exocrine insufficiency was higher for PD and LP than for AR (32, 27 and 3 per cent respectively at 1 year; 58, 29 and 3 per cent at 5 years; P < 0.001).Different pancreatic resections are associated with different risks of developing long-term pancreatic insufficiency. AR represents the best option in terms of long-term endocrine and exocrine function, although it is associated with more postoperative complications.

Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis.From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models.There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality.This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

Antibiotic prophylaxis in severe pancreatitis has recently yielded promising clinical results, with imipenem significantly reducing the incidence of infected necrosis compared with an untreated control group. On the bases of pefloxacin's spectrum of action and pancreatic penetration, we investigated whether such drugs represent a valid alternative to imipenem.In a multicenter study, 60 patients with severe acute pancreatitis with necrosis affecting at least 50% of the pancreas were randomly allocated to receive intravenous treatment for 2 weeks with pefloxacin, 400 mg twice daily (30 patients), or imipenem, 500 mg three times daily (30 patients), within 120 hours of onset of symptoms. Age, sex, body weight, Ranson and Apache II scores, C-reactive protein, etiology, and time from onset of symptoms to treatment were well matched in the two groups.The incidences of infected necrosis and extrapancreatic infections were 34% and 44%, respectively, in the pefloxacin group and 10% and 20% in the imipenem group. Imipenem proved significantly more effective in prevention of pancreatic infections (P </= 0.05). Mortality was not significantly different in the two groups.Despite its theoretical potential, pefloxacin is inferior to imipenem in the prevention of infections associated with severe pancreatitis.

Alterations of K-ras, p53, p16 and DPC4/Smad4 characterize pancreatic ductal cancer (PDC). Reports of inactivation of these latter two genes in pancreatic endocrine tumours (PET) suggest that common molecular pathways are involved in the tumorigenesis of pancreatic exocrine and endocrine epithelia. We characterized 112 primary pancreatic tumours for alterations in p16 and DPC4 and immunohistochemical expression of DPC4. The cases included 34 PDC, 10 intraductal papillary-mucinous tumours (IPMT), 6 acinar carcinomas (PAC), 5 solid-pseudopapillary tumours (SPT), 16 ampulla of Vater cancers (AVC) and 41 PET. All tumours were also presently or previously analysed for K-ras and p53 mutations and allelic loss at 9p, 17p and 18q. Alterations in K-ras, p53, p16 and DPC4 were found in 82%, 53%, 38% and 9% of PDC, respectively and in 47%, 60%, 25% and 6% of AVC. Alterations in these genes were virtually absent in PET, PAC or SPT, while in IPMT only K-ras mutations were present (30%). Positive immunostaining confirmed the absence of DPC4 alterations in all IPMT, SPT, PAC and PET, while 47% of PDC and 38% of AVC were immunonegative. These data suggest that pancreatic exocrine and endocrine tumourigenesis involves different genetic targets and that among exocrine pancreatic neoplasms, only ductal and ampullary cancers share common molecular events. © 2001 Cancer Research Campaign http://www.bjcancer.com

Chronic pancreatitis patients appear to present an increased incidence of pancreatic cancer. The aim of the study was to compare the incidence of cancer, whether pancreatic or extrapancreatic, in our chronic pancreatitis cases with that in the population of our region.We analyzed 715 cases of chronic pancreatitis with a median follow-up of 10 yr (7287 person-years); during this observation period they developed 61 neoplasms, 14 of which were pancreatic cancers. The cancer incidence rates were compared, after correction for age and gender, with those of a tumour registry.We documented a significant increase in incidence of both extrapancreatic (Standardized Incidence Ratio [SIR], 1.5; 95% confidence interval [CI], 1.1-2.0; p <0.003) and pancreatic cancer (SIR, 18.5; 95% CI, 10-30; p <0.0001) in chronic pancreatitis patients. Even when excluding from the analysis the four cases of pancreatic cancer that occurred within 4 yr of clinical onset of chronic pancreatitis, the SIR is 13.3 (95% CI, 6.4-24.5; p <0.0001). If we exclude these early-onset cancers, there would appear to be no increased risk of pancreatic cancer in nonsmokers, whereas in smokers this risk increases 15.6-fold.The risks of pancreatic and nonpancreatic cancers are increased in the course of chronic pancreatitis, the former being significantly higher than the latter. The very high incidence of pancreatic cancer in smokers probably suggests that, in addition to cigarette smoking, some other factor linked to chronic inflammation of the pancreas may be responsible for the increased risk.

Abstract A placebo-controlled double-blind multicentre study, with randomization into parallel groups, was performed to determine whether perioperative subcutaneous administration of octreotide 0·1 mg every 8 h reduces the rate of complications specifically related to pancreatic surgery. In all, 252 patients were evaluated (153 men, 99 women; mean(s.e.m.) age 53·1(0·8) years) who had pancreatic or periampullary tumour or other duodenal disease (157 patients) or chronic pancreatitis (95) and were undergoing elective pancreatic resection (100 Whipple's procedure, 60 distal resection, 12 others), pancreaticojejunostomy (66) or enucleation of pancreatic lesions (14). The proportion of patients with complications was significantly lower in the group treated with octreotide than in the placebo group (15·6 versus 29·2 per cent, P = 0·01). Octreotide thus appears to reduce substantially the risk of complications related to elective pancreatic surgery. Moreover, treatment acceptability was high.

The surgical strategy in patients with a pancreatic intraductal papillary mucinous tumour (IPMT) is still controversial. In this study the pathological findings in a series of patients were used to rationalize surgical choice.Fifty-one patients with IPMT were observed between 1988 and 1998 and treated by pancreatic resection. Factors evaluated included symptoms, tumour site, type of operation, histological findings and resection margins, tumour stage, follow-up and survival.Pancreaticoduodenectomy was the most frequent surgical treatment (33 patients; 65 per cent), followed by left pancreatectomy (ten), total pancreatectomy (five) and middle pancreatectomy (three). Histological assessment revealed the tumour to be an adenoma in 13 patients (25 per cent), a borderline tumour in ten (20 per cent) and a carcinoma in 28 (55 per cent), 19 of which were invasive. Mild to moderate dysplasia was present at the resection margin in 20 specimens (41 per cent), and carcinoma in one. Local recurrence was observed in four patients (8 per cent), all of whom underwent a second resection. The 3-year actuarial survival rate for benign and malignant disease was 94 and 69 per cent respectively (P = 0.03).These results suggest that resection should be the treatment for IPMT. Management of the resection margin could be crucial in avoiding tumour recurrence.

ENETS Consensus Guidelines for the Standards of Care in Neuroendocrine Tumors : Somatostatin Receptor Imaging with In-111-Pentetreotide

Standard resections for benign and borderline neoplasms of the pancreas are associated with a significant risk of long-term functional impairment, whereas enucleation preserves healthy parenchyma and pancreatic function. The aim of this study was to evaluate postoperative and long-term oncological and functional results after pancreatic enucleation.Data collected prospectively from 61 consecutive patients who underwent pancreatic enucleation were analysed.There were no deaths. A clinically significant pancreatic fistula was reported in 14 patients (23 per cent), and five patients (8 per cent) had a further operation for fistula-related complications. The most common indication for surgery was endocrine neoplasm (38 patients; 62 per cent) and two patients (3 per cent) had a final histopathological diagnosis of malignant neoplasm. At a median follow-up of 61 months no patient had developed tumour recurrence or exocrine insufficiency. Two elderly patients developed non-insulin-dependent diabetes.Enucleation is an effective procedure for the radical treatment of benign and borderline neoplasms of the pancreas, with good long-term outcomes.

Nonfunctioning pancreatic neuroendocrine tumors (NF-PanNETs) are often indolent neoplasms without lymph node (LN) metastasis at diagnosis. Therefore, in patients with low risk of LN metastasis, the extent of surgery and lymphadenectomy could be limited and follow-up adjusted to the very low risk of relapse.To construct a predicting model to assess the risk of pN+ prior to surgical resection for NF-PanNETs using preoperative retrievable variables.Retrospective review using multiple logistic regression analysis to construct predictive model of pN+ based on preoperatively available data.The combined prospective databases of the Surgical Departments of the University of Verona, Verona, Italy, and Beaujon Hospital, Clichy, France, were queried for clinical and pathological data.All patients with resected (R0 or R1), pathologically confirmed NF-PanNETs between January 1, 1993 and December 31, 2009.Risk of lymph node metastases in patients with pancreatic neuroendocrine tumors.Among 181 patients, nodal metastases were reported in 55 patients (30%) and were associated with decreased 5-year disease-free survival (70% vs 97%, P < .001). Multivariable analysis showed that independent factors associated with nodal metastasis were radiological nodal status (rN) (odds ratio [OR], 5.58; P < .001) and tumor grade (NET-G2 vs NET-G1: OR, 4.87; P < .001) (first model). When the tumor grade was excluded, rN (OR, 4.73; P = .001) and radiological tumor size larger than 4 cm (OR, 2.67; P = .03) were independent predictors of nodal metastasis (second model). The area under the receiver operating characteristic curve for the first and second models were 80% and 74%, respectively.Patients with NF-PanNET-G1 have a very low risk of pN+ in the absence of radiological signs of node involvement. When preoperative grading assessment is not achieved, the radiological size of the lesion is a powerful alternative predictor of pN+. The risk of pathological nodal involvement in patients with NF-PanNETs can be accurately estimated by a clinical predictive model.

IntroductionMalignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs.MethodsThe prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed.ResultsFifty-seven patients (male/female ratio = 1) with a median age of 58 years (33–78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ⩽0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR = 2.75) and a value of Ki67 >5% (HR = 3.39) were significant predictors of recurrence (P < 0.02).ConclusionsAfter resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials.

Background Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. Objective To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. Design Prospective cohort study. Setting Tertiary-care academic medical center. Patients Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. Intervention EUS-FNTA with a 19-gauge needle. Main Outcome Measurements Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. Results Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. Limitations Single center study with a single operator. Conclusion In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions. Preoperative determination of Ki-67 expression, an important prognostic factor for grading nonfunctioning pancreatic endocrine tumors (NF-PETs), remains an important clinical challenge. To prospectively evaluate the feasibility, yield, and clinical impact of EUS-guided fine-needle tissue acquisition (EUS-FNTA) with a large-gauge needle to obtain tissue samples for histologic diagnosis and Ki-67 analysis in patients with suspected NF-PETs. Prospective cohort study. Tertiary-care academic medical center. Consecutive patients with a single pancreatic lesion suspicious for NF-PET on imaging. EUS-FNTA with a 19-gauge needle. Feasibility and yield of EUS-FNTA for diagnosis and Ki-67 expression determination. Thirty patients (mean [± SD] age 55.7 ± 14.9 years), with a mean (± SD) lesion size of 16.9 ± 6.1 mm were enrolled. EUS-FNTA was successfully performed without complications in all patients, with a mean (± SD) of 2.7 ± 0.5 passes per patient. Adequate samples for histologic examination were obtained in 28 of the 30 patients (93.3%). Ki-67 determination could be performed in 26 of these 28 patients (92.9%, 86.6% overall), 12 of whom underwent surgical resection. Preoperative and postoperative Ki-67 proliferation indexes were concordant in 10 patients (83.3%), whereas 2 patients were upstaged from G1 to G2 or downstaged from G2 to G1, respectively. Single center study with a single operator. In patients with suspected nonfunctioning low-grade to intermediate-grade pancreatic neuroendocrine tumors (p-NETs), retrieval of tissue specimens with EUS-FNTA by using a 19-gauge needle is safe, feasible, and highly accurate for both diagnosis and Ki-67 determination. A Ki-67 proliferative index acquired through this technique might be of great help for further therapeutic decisions.

Background No data on chronic pancreatitis in Italy are available yet. Aim To evaluate demographic, clinical, diagnostic and therapeutic aspects in patients suffering from chronic pancreatitis. Patients and methods Eligible patients were prospectively enrolled from 2000 to 2005. Information concerning demographic data, lifestyle risk factors, family and clinical history, associated factors (alcohol, autoimmunity, cystic dystrophy of the duodenal wall, obstruction, genetic mutations) concomitant diseases, diagnostic findings, and pharmacological, endoscopic and surgical therapy were gathered. Results 893 patients (74% males, mean age 53.7 ± 15.2 years) were evaluated. 519/859 patients (60%) were drinkers and 555/840 (66%) were smokers. A strong positive correlation between drinking and cigarette consumption (R = 0.53; p < 0.0001) was found. Heavy alcohol consumption (>80 g of alcohol/day for more than 5 years) was considered the most important risk factor in 300 patients (34%), obstruction in 238 (27%), alcohol and obstruction in 82 (9%), autoimmunity in 34 (4%), cystic dystrophy of the duodenal wall/groove pancreatitis in 55 (6%), gene mutations in 36 (4%), and none (idiopathic) in 148 (17%). Bile stones were diagnosed in 287 patients (33%) and cholecystectomy was performed in 329 patients (38%). Pancreatic calcifications were diagnosed in 547/879 patients (62%). Pancreatic surgery was performed in 273 patients (31%). Endoscopic sphincterotomy was performed in 371 patients (42%). Exocrine and endocrine insufficiency were found, respectively, in 373/834 (45%) and 275/885 patients (31%). Conclusions An unexpected low frequency of alcohol abuse and new emerging associated risk factors for chronic pancreatitis were observed in Italy.

This paper gives practical guidelines for diagnosis and treatment of chronic pancreatitis. Statements have been elaborated by working teams of experts, by searching for and analysing the literature, and submitted to a consensus process by using a Delphi modified procedure. The statements report recommendations on clinical and nutritional approach, assessment of pancreatic function, treatment of exocrine pancreatic failure and of secondary diabetes, treatment of pain and prevention of painful relapses. Moreover, the role of endoscopy in approaching pancreatic pain, pancreatic stones, duct narrowing and dilation, and complications was considered. Recommendations for most appropriate use of various imaging techniques and of ultrasound endoscopy are reported. Finally, a group of recommendations are addressed to the surgical treatment, with definition of right indications, timing, most appropriate procedures and techniques in different clinical conditions and targets, and clinical and functional outcomes following surgery.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) represent a heterogenous group of tumors arising from a variety of neuroendocrine cell types. The incidence and prevalence of GEP-NENs have markedly increased over the last three decades. Symptoms are often absent in early disease, or vague and nonspecific even in advanced disease. Delayed diagnosis is thus common. Chromogranin A is the most commonly used biomarker but has limitations as does the proliferative marker Ki-67%, which is often used for tumor grading and determination of therapy. The development of a multidimensional prognostic nomogram may be valuable in predicting tumor behavior and guiding therapy but requires validation. Identification of NENs that express somatostatin receptors (SSTR) allows for SSTR scintigraphy and positron emission tomography imaging using novel radiolabeled compounds. Complete surgical resection of limited disease or endoscopic ablation of small lesions localized in stomach or rectum can provide cure; however, the majority of GEP-NENs are metastatic (most frequently the liver and/or mesenteric lymph nodes) at diagnosis. Selected patients with metastatic disease may benefit from advanced surgical techniques including hepatic resection or liver transplantation. Somatostatin analogs are effective for symptomatic treatment and exhibit some degree of antiproliferative activity in small intestinal NENs. There is a place for streptozotocin, temozolomide, and capecitabine in the management of pancreatic NENs, while new agents targeting either mTOR (everolimus) or angiogenic (sunitinib) pathways have shown efficacy in these lesions.

Pancreatic endocrine tumors (PETs) may be part of hereditary multiple endocrine neoplasia type 1 (MEN1) syndrome. While MEN1 gene mutation is the only ascertained genetic anomaly described in PETs, no data exist on the cellular localization of MEN1-encoded protein, menin, in normal pancreas and PETs. A total of 169 PETs were used to assess the i) MEN1 gene mutational status in 100 clinically sporadic PETs by direct DNA sequencing, ii) immunohistochemical expression of menin in normal pancreas and 140 PETs, including 71 cases screened for gene mutations, and iii) correlation of these findings with clinical–pathological parameters. Twenty-seven PETs showed mutations that were somatic in 25 patients and revealed to be germline in 2 patients. Menin immunostaining showed strong nuclear and very faint cytoplasmic signal in normal islet cells, whereas it displayed abnormal location and expression levels in 80% of tumors. PETs harboring MEN1 truncating mutations lacked nuclear protein, and most PETs with MEN1 missense mutations showed a strong cytoplasmic positivity for menin. Menin was also misplaced in a significant number of cases lacking MEN1 mutations. In conclusion, the vast majority of PETs showed qualitative and/or quantitative alterations in menin localization. In 30% of cases, this was associated with MEN1 mutations affecting sequences involved in nuclear localization or protein–protein interaction. In cases lacking MEN1 mutations, the alteration of one of the menin interactors may have prevented its proper localization, as suggested by recent data showing that menin protein shuttles between the nucleus and cytoplasm and also affects the subcellular localization of its interactors.

In Europe, cancer of the pancreas is the 10th most frequent cancer, accounting for some 2.6% of cancer in both sexes, and the eighth leading cause of cancer-related death with ∼65 000 deaths each year. In men, the annual incidence rates range between 8.7 (East) and 7.3 (North and West) per 100 000, and in women between 5.7 (North) and 4.5 (East). Men have approximately a half greater age-adjusted incidence rate than women. Incidence increases steeply with age from 1.5 per 100 000/year in patients 15–44 years of age to 55 per 100 000/year in patients >65 year of age. Pancreatic cancer is one of the most highly fatal cancers, with >95% of those affected dying of their disease. The high mortality rate is due to the high incidence of metastatic disease at diagnosis. No survival increases have been observed in the last years. There are three histological types of pancreatic cancer. Infiltrating ductal adenocarcinomas account for 90% of pancreatic neoplasms, the remaining 10% being represented by acinar cell carcinoma, accounting for <1% of pancreatic cancers (in this type overproduction of lipase may lead to metastatic fat necrosis syndrome, which includes peripheral fat necrosis, eosinophilia and polyarthralgias) and pancreatoblastoma (a tumour occurring mainly in children). More than 90% of pancreatic cancers carry mutations in the K-ras oncogene, a fact that negatively affects therapeutic use of EGFR blocking agents. Early detection of pancreatic cancer is unfortunately an infrequent situation at the present time. Consequently, there are no current screening programmes that can be recommended in the general population. However, some patients are at greater risk of developing a pancreatic cancer. The risk of pancreatic cancer is increased significantly (18-fold) in families with an affected first-degree relative. Pancreatic cancer is associated with several genetic syndromes including hereditary pancreatitis syndrome, hereditary non-polyposis colorectal cancer, hereditary atypical multiple mole melanoma syndrome, hereditary BRCA2-related breast and ovarian cancer and Peutz–Jeghers syndrome. For these patients specific programmes have been established in order to recognize pre-cancerous lesions. Clinical presentation is generally characterized by weight loss, pain and jaundice. Jaundice predominates in patients with cancer in the head of the pancreas, and pain in patients with tail and body tumours. In up to 10% of patients new onset of diabetes may be the first clinical feature. Pancreatitis may also be the first signal of a pancreatic neoplasia, especially in the elderly when there is no obvious cause such as gallstones or alcohol abuse. Another important feature of pancreatic cancer is weight loss. Currently CT scan is the preferred imaging modality used for the diagnosis and staging of pancreatic cancer. In addition to the assessment of the primary tumour localization and size, CT is used to evaluate major vessels adjacent to the pancreas for neoplastic invasion or thrombosis, as well as to evaluate hepatic or distant metastases, enlargement of peripancreatic regional lymph nodes, invasion of retroperitoneal structures and intraperìtoneal dissemination. Selected cases may benefit from MRI and laparoscopy. The actual role of ERCP is only therapeutic. At the present time, the rote of PET scanning in the management of patients with pancreatic cancer is under development. For small tumours endoscopic ultrasound (EUS) has been reported to be superior to CT. Because of this, it may be useful in family screening protocols. An additional aspect of the application of endoscopic technology includes the ability to combine EUS with fine needle aspiration cytological examination. Tumour markers such as CA19.9 are of limited diagnostic value (it is not specific for pancreas cancer and persons lacking the Lewis antigen are unable to synthesize CA19.9), although they are often taken as a baseline in order to guide treatment and follow-up. Pathological proof of malignancy is mandatory in unresectable cases or when preoperative treatment is planned. For patients expected to undergo surgery with radical intent, a previous biopsy is not necessary, and even preoperative percutaneous sampling should be avoided. In the presence of metastatic lesions they can be biopsied under ultrasound or CT guidance. The most widely used staging system for pancreatic cancer is the one developed by the TNM committee of the AJCC-UICC, and is presented in Table 1. Stage grouping of pancreatic cancer is presented in Table 2. A simpler staging system is often used, based on whether or not it is likely that the cancer can be removed surgically (Table 3). CT scan is the preferred and more diffuse imaging modality for staging. MRCP may add additional information about both the biliary and pancreatic ducts and the presence or absence of vascular invasion. Moreover it is able to distinguish better than CT a solid from a cystic mass and is indicated in the case of sever liver and renal failures. PET scanning is in development and it should not routinely be recommended at the present time as a staging procedure. EUS may provide useful information about vascular and nodal involvement. Moreover it represents a useful tool in any case in which pathological material is requested. While chest X-ray is usually recommended in the evaluation of patients, bone scan is not useful since only a few pancreatic patients present with bone involvement at diagnosis. Laparoscopy may detect small peritoneal and liver metastases changing the therapeutic strategy in <15% of patients. It can be suggested before resection in left-sided large tumours and/or with high CA19.9 levels or if neoadjuvant treatment is planned. However, from a practical standpoint, the extent of cancer spread in cancer of the pancreas can often be determined accurately only during surgery. Specific recommendations for the assessment of margins in surgical specimens, especially the superior mesenteric artery margin have also been published by the AJCC-UICC (sixth edition) and are present in the guidelines of the College of American Pathologists. The prognosis of patients who have undergone radical resection for pancreatic adenocarcinoma depends mainly on presence of negative resection margins. Tumour size, nodal involvement and histological grade are strong prognostic factors. Recently the prognostic role of post-resection CA19.9 has been confirmed. Less well-defined prognostic factors are the biological features of the tumour such as tumour DNA content. An important consideration is the previous experience of the hospital team and the skill of the surgeon. The treatment of pancreatic cancer is undertaken with two different aims. The first is radical surgery for patients with early stage of disease, mainly stage I and some stage II. In all other cases, the aim of treatment is the palliation of the several distressing symptoms related to this cancer. It is possible to define some treatment strategies according to the tumour stage. For this stage disease, the standard treatment option is radical pancreatic resection. For patients with pancreatic head tumours a pylorus-preserving pancreaticoduodenectomy is the procedure of choice which is a modified Whipple procedure preserving distal stomach and pylorus. The most common surgical approach for tumours of the pancreatic body and tail is a distal pancreatectomy which also routinely includes splenectomy. Postoperatively, six cycles of 5-fluorouracil (5-FU) or gemcitabine (GEM) chemotherapy may be suggested on the basis of two randomized trials. Recently, it was reported that there was no substantial differences in terms of disease-free survival or overall survival in a formal comparison between 5-FU and GEM as adjuvant therapy in pancreatic adenocarcinoma. The role of adjuvant chemoradiation (CT-RT) is controversial as reported in a few randomized Phase III trials. 5-FU-based chemoradiation following GEM chemotherapy as described in the RTOG 97-04 protocol may be an option for individual clinical use, especially in patients with tumours of the pancreatic head, large tumour diameter (>3 cm) and in patients with R1 resection as reported in a meta-analysis of adjuvant randomized trials. Most patients with stage II pancreatic cancer who have tumours that are technically unresectable may benefit from palliative bypass of intestinal obstruction followed by chemotherapy or chemoradiation as described for stages IIB and III. Nevertheless, when feasible, pancreatectomy can be considered a standard approach. Patients should be encouraged to participate in clinical trials for neoadjuvant treatment as recently published results from Phase II studies conducted on preoperative GEM-based chemoradiation seemed to indicate that the neoadjuvant approach can identify a subgroup of patients unlikely to benefit from surgical resection, without compromising survival in patients who ultimately undergo surgery. Recently the role of intraoperative radiotherapy (IORT) has been addressed in a joint analysis of European centres. The association of preoperative radiotherapy with IORT was associated with improved local control and overall survival, especially in patients with a lower trend to systemic disease spread. Nevertheless, at this time we cannot recommend it as a routine treatment in clinical practice. Indications for adjuvant chemotherapy or in combination with radiation therapy is similar to stage I. The majority of patients with stage IIB and III have tumours that encase blood vessels. Patients who present borderline resectable disease may benefit from preoperative therapy (chemoradiation or induction chemotherapy followed by chemoradiation) in order to increase the rate of R0 resections. In patients with unresectable disease 5-FU chemoradiation can be considered. However, two recent trials which compared chemoradiation with chemotherapy alone reported contradictory results. A relevant suggestion for the treatment of patients with locally advanced pancreatic cancer arose from a retrospective analysis of patients enrolled in the GERCOR studies and from a systematic review of trials of chemoradiation in locally advanced pancreatic cancer. In fact, patients treated with GEM and not progressing after 3 months of treatment and with a good performance status achieved an improvement in survival with the addition of chemoradiation. While treatment with GEM may be a reasonable choice, the use of a combination of GEM and other cytotoxic agents, such as 5-FU, irinotecan, cisplatin and oxaliplatin, is not supported by an advantage in survival apart from capecitabine. However, this combination showed a survival advantage in a trial although it was not confirmed in another one. A meta-analysis of randomized trials with a combination of GEM and platinum analogues seemed to suggest a role for this combination for young patients with good performance status. Nevertheless, the results of a large randomized trial comparing GEM alone with GEM plus cisplatin, presented at the last ASCO meeting, failed to show any benefit for the combination. Another therapeutic possibility is a combination of GEM and erlotinib, recently approved by the FDA and EMEA on the basis of a randomized trial from the NCI of Canada. However, the very modest survival gain (∼2 weeks) and the high economic costs of the treatment question the role of this combination in metastatic pancreatic cancer. At the moment there is no evidence supporting the use of either cetuximab or bevacizumab in the overall setting of pancreatic cancer. There is no standard chemotherapy for patients who have progressed in first-line treatment. The CONKO 003 study has shown a benefit in the second line setting therefore 5-FU/oxaliplatin should be considered as standard. Since the treatment results even in first line are still disappointing the enrolment in clinical trials should be considered not only for second line therapy but for all lines. Jaundice is common (70%–80%) in cancers involving the pancreatic head. For unresectable patients, endoscopic stent placement is the preferred procedure since it is associated with lower frequency of complications than percutaneous insertion and it is as successful as the surgical procedure but has a shorter hospital stay. Metal prostheses should be preferred for patients with a life expectancy of >3 months since they present fewer complications (occlusion) than plastic endoprostheses. Fewer than 5% of patients with pancreatic cancer present with duodenal obstruction, while gastric outlet obstruction may be more common during the course of disease. Neither chemotherapy nor radiotherapy provided palliation in this setting. In some cases, proximal obstruction may be overcome by the use of an expandable metalc stent. The role of prophylactic gastroenterostomy remains controversial. In fact, only 13%–15% of patients will require gastroenterostomy during the course of disease; it should not be performed as standard procedure but can be a reasonable choice for individual patients. Patients who present with severe pain must receive opioids. Morphine is generally the drug of choice. Usually, the oral route is preferred in routine practice. Parenteral routes of administration should be considered for patients who have impaired swallowing or gastrointestinal obstruction. Also hypofractionated radiotherapy may be delivered to these patients in order to improve pain control and reduce analgesic consumption. Percutaneous celiacoplexus blockade can be considered, especially for patients who experience poor tolerance of opiate analgesics. Analgesic response rates as high as 50%–90% are reported with 1 month to 1 year duration of effect. Patients should be followed at each cycle of chemotherapy for toxicity and evaluated for response to chemotherapy every 2 months. Clinical benefit and CA19.9 may be useful tools to assess the course of disease in the metastatic setting. Imaging procedures such as CT scan may be indicated mainly in locally advanced disease in order to rule out the presence of metastases and to add radiotherapy to the treatment plan. There is no possibility of cure, even for recurrences diagnosed early, so a follow-up schedule should be discussed with the patient and designed to avoid emotional stress and economic burden for the patient. In the case of elevated preoperative serum CA19.9 levels the assessment of this marker could be performed every 3 months for 2 years and an abdominal CT scan every 6 months. However, it is important to bear in mind that there is no advantage in an earlier detection of recurrences. Corrections to “Pancreatic cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up”Annals of OncologyVol. 21Issue 10PreviewAnn Oncol 2010; 21 (Supplement 5): v55–v58. Full-Text PDF Open Archive

Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. Patients and Methods We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. Results Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P &lt; .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P &lt; .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Conclusion Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.

<h3>Objective</h3>To analyze the characteristics and outcomes following enucleation and pancreatic resections of insulinomas.<h3>Design</h3>Retrospective cohort study; prospective database.<h3>Settings</h3>Academic, tertiary, and referral centers.<h3>Patients</h3>Consecutive patients with insulinomas (symptoms of hyperinsulinism and positive fasting glucose test) who underwent surgical treatment between January 1990 and December 2009.<h3>Main Outcome Measures</h3>Operative morbidity, tumor recurrence, and survival after treatment.<h3>Results</h3>A total of 198 patients (58.5% women; median age, 48 years) were identified. There were 175 (88%) neuroendocrine tumors grade G1 and 23 (12%) neuroendocrine tumors grade G2. Malignant insulinomas defined by lymph node/liver metastases were found in 7 patients (3.5%). Multiple insulinomas were found in 8% of patients, and 5.5% of patients had multiple endocrine neoplasia type 1. Surgical procedures included 106 enucleations (54%) and 92 pancreatic resections (46%). Mortality was nil. Rate of clinically significant pancreatic fistula was 18%. Enucleations had a higher reoperation rate compared with pancreatic resections (8.5% vs 1%; P = .02). Multiple endocrine neoplasia type 1 was significantly associated with younger age at onset (P &lt; .005) and higher rates of malignancies and multiple lesions. Median follow-up was 65 months. Six patients (3%; 5 patients had neuroendocrine tumors grade G2) developed tumor recurrence. Four patients (2%) died of disease. New exocrine (1.5%) and endocrine (4%) insufficiencies were associated only with pancreatic resections.<h3>Conclusions</h3>Outcomes following surgical resection of insulinomas are satisfactory, with no mortality and good functional results. Recurrence is uncommon (3%), and it is more likely associated with neuroendocrine tumors grade G2. Insulinomas in multiple endocrine neoplasia type 1 are at higher risk for being malignant and multifocal, requiring pancreatic resections.

OBJECTIVES: Information on pancreatic endocrine tumors (PETs) comes mostly from small, retrospective, uncontrolled studies conducted on highly selected patients. The aim of the study was to describe the clinical and pathological features of PETs in a prospective, multicenter study. METHODS: Newly diagnosed, histologically proven, sporadic PETs observed from June 2004 to March 2007 in 24 Italian centers were included in a specific data set. RESULTS: Two hundred ninety-seven patients (mean age 58.6±14.7 years, females 51.2%, males 48.8%) were analyzed. In 73 cases (24.6%), the tumor was functioning (F) (53 insulinomas, 15 gastrinomas, 5 other syndromes) and in 232 (75.4%) it was non-functioning (NF); in 115 cases (38.7%), the diagnosis was incidental. The median tumor size was 20 mm (range 2–150). NF-PETs were significantly more represented among carcinomas (P<0.001). Nodal and liver metastases were detected in 84 (28.3%) and 85 (28.6%) cases, respectively. The presence of liver metastases was significantly higher in the NF-PETs than in the F-PETs (32.1% vs. 17.8%;P<0.05), and in the symptomatic than in the asymptomatic patients (34.6% vs. 19.1%;P<0.005). At the time of recruitment, the majority of patients (251, 84.5%) had undergone surgery, with complete resection in 209 cases (83.3%). CONCLUSIONS: This study points out the high number of new cases of PETs observed in Italy, with a high prevalence of NF and incidentally discovered forms. The size of the tumor was smaller and the rate of metastasis was lower than usually reported, suggesting a trend toward an earlier diagnosis.

Neuroendocrine tumors of the small intestine are the most common causes of the carcinoid syndrome. Carcinoid heart disease occurs in more than half of the patients with the carcinoid syndrome. Patients with carcinoid heart disease who need to undergo surgery should also undergo preoperative evaluation by an expert cardiologist. Treatment with long-acting somatostatin analogs aims at controlling the excessive hormonal output and symptoms related to the carcinoid syndrome and at preventing a carcinoid crisis during interventions. Patients with a gastrinoma require pre- and postoperative treatment with high doses of proton pump inhibitors. Patients with a glucagonoma require somatostatin analog treatment and nutritional supplementation. Patients with a VIPoma also require somatostatin analog treatment and intravenous fluid and electrolyte therapy. Insulinoma patients generally require intravenous glucose infusion prior to operation. In patients with localized operable insulinoma, somatostatin analog infusion should only be considered after the effect of this therapy has been electively studied.

The documentation of patients with neuroendocrine tumors should include the most relevant data characterizing an individual patient from the first contact with their physician/hospital until their last presentation during follow-up. The documentation should be both simple but nevertheless as complete as possible and should include basic demographic details to identify a specific patient, tumor histology and biology, disease history, course of the disease, diagnostic tests and therapeutic interventions. This information is essential for treatment and follow-up strategies adjusted to the specific features of the tumor of the patient. Furthermore, standardized documentation acts as a key precondition to learn more about patients with specific tumor subtypes and regarding the impact of treatment modalities on the course of the disease. In the present clinical setting, the timing of data collection and content of documented data vary considerably. Therefore, comparison of data from different centers is frequently hampered by lack of data uniformity.During the ENETS Standards of Care Conference organized in Mallorca in 2007, a group of physicians with extensive experience in the clinical care of patients with benign and malignant gastro-entero-pancreatic (GEP) neuroendocrine tumors met to produce proposals for the unified collection of data and suggested time intervals for follow-up investigations. These guidelines recognize the diversity of tumor subtypes, the actual WHO and TNM tumor classifications, the individual clinical course of the disease as well as the resource implications relevant to the growing costs of the European healthcare systems. Particular attention was paid to recommend only those investigations which would have a significant impact on further therapeutic strategies.The panel agreed that the following 5 categories best define the different tumor entities observed in the clinical setting. The categories follow the recent WHO classification [1, 2] as well as the ENETS recommendations for TNM staging [3, 4] in order to better compare data from different centers.Insulinomas and small, benign tumors (T1 endocrine tumors of the stomach, rectum and appendix, ‘carcinoids’) were categorized separately. They belong to the most frequent benign endocrine tumor entities and require a less intensive follow-up compared to malignant variants.• Benign insulinoma (T1 <2 cm)• Endoscopically resectable benign (T1 <1 cm) neuroendocrine tumor (carcinoid) of the stomach, duodenum and rectum• Appendiceal carcinoid (T1 <2 cm)• T2 gastric neuroendocrine tumor >1 cm invading muscularis propria or subserosa• T2 (>1 cm) tumors of the duodenum/ampulla/proximal jejunum; duodenal gastrinomas and midgut carcinoids which are usually <1 cm (T1) and confined to the submucosa are frequently malignant and belong to category III.3• T2 (>2 cm) tumors limited to the pancreas• Appendiceal carcinoid 1–2 cm(a) G1: well-differentiated, Ki-67 <2%• T1–T2 duodenal gastrinomas• T1–T3 tumors of the lower jejunum, ileum• T2–T3 tumors of the appendix • T2–T3 tumors of colon and rectum• T2–T3 tumors of the stomach, duodenum, pancreas(a) G1: well-differentiated, Ki-67 <2%(b) G2: well-differentiated, Ki-67 2–20%(c) G3: poorly differentiated• All localizations(a) G1: well-differentiated, Ki-67 <2%(b) G2: well-differentiated, Ki-67 2–20%(c) G3: poorly differentiatedDocumentation of each patient should encompass:• Patient identification and basic demographic details• General health score (Karnofsky status)• Patient’s history: onset, extent and severity of tumor-specific symptoms, concomitant diseases, family history for endocrine tumors, metachronous or synchronous malignancies• Clinical diagnosis• Preceding biochemical and imaging procedures• Histopathological diagnosis including WHO and TNM classification and proliferation index Ki-67• Preceding treatment(s)Tumor-specific follow-up investigations are mainly based on imaging procedures and tumor markers. However, an expert physician who is in charge of an individual patient is able to judge the patient’s general health and even prognosis by a careful history and examination, assessment of weight loss, muscular mass and global heart function in cases of the carcinoid syndrome and possible carcinoid cardiac disease. However, these items are difficult to compare inter- and intra-individually and should be supported where possible by ‘objective’ procedures such as imaging methods and serum/plasma tumor markers.Current imaging procedures encompass abdominal ultrasound with or without contrast medium, endoscopy, endoscopic ultrasound, CT, MRI, octreotide scintigraphy (Octreoscan®) and in some centers PET imaging with different tracers. Procedure-specific expertise frequently determines the choice of imaging procedure. Accordingly, abdominal ultrasound may be recommended for follow-up if documentation allows one to compare findings obtained during different follow-up visits, although many would now rely on CT and MRI for their greater sensitivity and resolution. Octreoscan® is currently substituted in some nuclear centers by 68Gallium-DOTA-DOC PET/CT due to its higher sensitivity [5,6,7]. However, caution is recommended when comparing the number of tumor lesions detected by the Octreoscan and 68Gallium-DOTA-DOC PET/CT. Due to the higher sensitivity of 68Gallium-DOTA-DOC PET more lesions are detected with this technique, so it is essential to use the same technique when assessing for progression or regression. Currently, there are only limited data available which do not permit one to precisely define the significance of 68Gallium-PET for routine follow-up. In most centers and due to their reproducibility and high resolution, CT or MRI are the imaging procedures of choice for follow-up investigations both in the clinical setting as well as in prospective clinical studies. These techniques represent the ‘gold standard’ to define the tumor burden of a specific patient with a neuroendocrine tumor.At present, the most common tumor marker is chromogranin A (CgA) for patients with functioning neuroendocrine tumors of the midgut (carcinoid syndrome) and for non-functioning tumors of the midgut and pancreas as CgA reflects tumor mass and hence spread, and may be used to assess the speed of tumor growth [8,9,10]. Neurospecific enolase may act as additional marker in patients with poorly differentiated tumors. Since several assay kits exist, caution is recommended when comparing values from kits of different manufacturers [9]. 24-Hour urine 5-hydroxy-indol acetic acid (5-HIAA) as an established marker for patients with carcinoid syndrome has a diagnostic sensitivity as plasma CgA but requires 24-hour urine collection.With functioning pancreatic tumors (insulinoma, gastrinoma, glucagonoma, VIPoma, etc.) the respective hormones can be used as tumor markers as well. In patients with the carcinoid syndrome urinary 5-HIAA and plasma CgA levels are equally useful.In most metastatic hindgut tumors CgA is negative and no tumor markers are suitable for this tumor entity [8].Neuron-specific enolase has been shown to act as a valuable tumor marker in patients with poorly differentiated neuroendocrine tumors [9].Tumor markers should only be estimated in case of positive imaging; otherwise, unnecessary diagnostic procedures might be initiated without any useful impact on the patient’s prognosis.The time intervals for estimation of tumor markers should follow the suggestions given for imaging.For gastric type 1 endocrine tumors (carcinoids) CgA and gastrin are elevated but are not particularly helpful for follow-up.Levels of tumor markers like plasma CgA and urine 5-HIAA depend on the underlying diseases, concomitant medications and dietary settings. Plasma CgA is elevated in patients with type A chronic atrophic gastritis, patients with kidney insufficiency and patients taking acid-suppressing agents such as histamine H2 blockers or proton pump inhibitors. Urine 5-HIAA is influenced by a number of dietary factors, e.g. avocado, banana, tomato and others, and by drugs such as cumarine, paracetamol, phenacetin, aspirin and others.After curative resection of a sporadic insulinoma tumor-specific follow-up investigations are not indicated. Patients with an insulinoma which was not detected intraoperatively and therefore not removed should be referred on to a center with specific experience. The rare event of a relapsing insulinoma cannot be prevented by routine follow-up investigations.Following surgery, there may also be a place for procedure-specific surgical follow-up.For malignant insulinomas see: V.5 and V.6.80% of all gastric neuroendocrine tumors are type 1 tumors in the presence of type A gastritis. They usually occur as multiple lesions and are mostly smaller than 1 cm. They can easily be removed endoscopically by polypectomy. Rectal endocrine tumors (carcinoids) are solitary and rarely relapse.Follow-up endoscopies for gastric type 1 endocrine tumors should be performed at yearly intervals. Although often massively elevated, estimation of serum gastrin and plasma CgA has no impact on the prognosis and therefore does not influence the interval of follow-up endoscopies. These tumor markers should not be routinely included in routine follow-up programs. Follow-up endoscopy for a T1 rectal endocrine tumors is not indicated if endoscopic polypectomy was curative.Appendicectomy is the curative option for appendiceal endocrine tumors <1 cm (T1). Follow-up investigations are not routinely indicated. The optimal treatment of appendiceal endocrine tumors ≤2 cm (T2) invading the submucosa, muscularis propria and/or minimally (>3 mm) invading subserosa/mesoappendix is a matter of debate. Most surgeons recommend right-sided hemicolectomy. Following this procedure and providing that no metastatic lymph node involvement is present, no routine follow-up investigations are indicated. The beneficial effect of follow-up studies recommended in IV.4 for patients with a T2 endocrine tumor and simple appendicectomy remains controversial. There is no indication for tumor markers in patients with T1 or T2 appendiceal tumors.The respective tumors have been defined in III.2. In general, their grading is G1. After surgical tumor resection the following investigations are recommended.V.4.1.1 US/CT/MRI• 6 months postoperatively: US or CT or MRI (depending on availability and experience); if negative:• Repeat after further 6 months; if negative:• Repeat at yearly intervals postoperatively; the time intervals can be reconsidered according to (1) the tumor growth characteristics of an individual patient and/or when (2) tumor resection is Nx due to the lack of any nodal sampling at the time of surgery• In the case of stable disease, longer intervals may be justifiedV.4.1.2 Octreotide Scintigraphy (Octreoscan®)• At baseline, then every 2 years. Reconsider the time intervals according to the tumor growth characteristics of an individual patient. When the disease shows stability or no recurrence, according to US, CT or MRI, the octreotide scan may not be necessary. If a change in the strategy of treatment is considered a new scan may be justifiedV.4.1.3 Comments(a) There was no formal agreement in the panel discussion concerning the duration of follow-up investigations: 4 years – indefinitely(b) Octreoscan® may be substituted in future by 68Gallium-DOTA-DOC PET due to its higher sensitivity. See IV.2.Plasma CgA should only be determined in the presence of a tumor visualized by imaging, except in very occasional patients. In the presence of a tumor repeat every 6 months. For further comments see IV.2.2.The respective tumors have been defined in III.3. After surgical resection of a probably malignant tumor according to the WHO classification the following investigations are recommended.See recommendations suggested for V.4.V.5.2.1 General CommentTumors graded as G2 or G3 are much rarer than G1 tumors. In case of doubt with either very slow progression of tumors classified as G2 or G3 or very fast progression of tumors classified as G1 or G2 consider re-biopsy.V.5.2.2 ImagingV.5.2.2.1 US/CT/MRI. 3 months postoperatively US or CT or MRI (depending on availability and experience); if negative: repeat at 3-month intervals indefinitely.V.5.2.2.2 Octreoscan®. 3 months postoperatively; if negative: repeat 12 months postoperatively or if new lesions appear during US/CT/MRI imaging.For further comments see V.4.1.2.V.5.2.2.3 Comment. Octreoscan may be substituted in future by 68Gallium-DOTA-DOC PET due to its higher sensitivity. For further comment see IV.2.V.5.3.3 Tumor Markers• See V.4.2.• Intervals: 3 monthsThe respective tumors have been defined in III.3. Surgical intervention should always be considered as therapeutic option. For follow-up the following investigations are recommended.See recommendations suggested for V.4.In patients with carcinoid syndrome echocardiography should be performed at diagnosis. If positive at diagnosis repeat every 6 months; if negative, every 12 months.See recommendations suggested for V.5.2.In patients who are not members of a MEN-1 or VHL family but whose clinical spectrum of symptoms and pathohistological findings is suggestive of the MEN-1 or VHL syndromes, mutational analysis of the appropriate genes should be arranged. If positive, predictive genetic testing of family members should be performed according to the country-specific guidelines. Surveillance programs can be stopped in family members who are negative for the identified mutation, but biochemical and clinical surveillance is required for patients at risk. Patients with MEN-1 syndrome and patients with VHL disease should be referred to and followed up in specialized centers.In non-parathyroidectomized subjects: serum-calcium and plasma PTH levels at 12-month intervals. Most experts agree that in case of confirmed biochemical diagnosis of a primary hyperparathyroidism no further imaging studies are indicated to demonstrate the mostly asymmetric hyperplasia of the parathyroid glands.In patients with subtotal parathyroidectomy or with total parathyroidectomy and autotransplantation with or without substitution of calcium and 1,25-dihydroxycholecalciferol, the control of serum calcium should be determined according to the individual situation.Patients with recurrent hyperparathyroidism should be transferred to specialized centers with experience in MIBI scintigraphy and selective vein catheters.In general, pancreatico-duodenal neuroendocrine tumors are multiple. The resection of an insulinoma (usually pancreatic) should always be actively sought to avoid life-threatening hypoglycemic events.The resection of a gastrinoma (usually multiple and duodenal) is dependent on factors such as the patient’s individual situation (general health status, patient’s preference and the policy of the surgical institution). The consequences of hypergastrinemia can usually also be well managed by proton pump inhibitors, although high doses may need to be used.Most pancreatic neuroendocrine tumors are non-functioning and small tumors can be best visualized by endoscopic ultrasound, larger tumors by conventional ultrasound, CT and MRI. However, this will be contingent on the radiological expertise of the center. Follow-up investigations must be individualized and depend on the size and growth behavior of individual tumors. The same is true for metastatic tumors. In general, imaging intervals are between 1 and 2 years. Most experts agree that tumors >2 cm should be resected due to a ≈30% probability of metastatic spread.Tumor markers for pancreatic and duodenal tumors include plasma CgA and serum gastrin for gastrinoma. They can be used to detect a relapsing gastrinoma or tumor growth and should be determined during visits for imaging.In patients with and without adenomas of the hypophysis screening should be performed in intervals between 1 and 2 years.The follow-up investigations which should be documented to visualize the specific course of the disease in an individual patient are summarized in table 1.Göran Åkerström, Department of Surgery, University Hospital, Uppsala (Sweden); Bruno Annibale, University Sapienza Roma, Rome (Italy); Emilio Bajetta, Medical Oncology Unit B, Istituto Nazionale Tumori, Milan (Italy); Jaroslava Barkmanova, Department of Oncology, University Hospital, Prague (Czech Republic); Anne Couvelard, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Joseph Davar, Department of Cardiology, Royal Free Hospital, London (UK); Wouter de Herder, Department of Internal Medicine, Section of Endocrinology, Erasmus MC, Rotterdam (The Netherlands); Gianfranco Delle Fave, Ospedale S. Andrea, Rome (Italy); Barbro Eriksson, Medical Department, Endocrine Unit, University Hospital, Uppsala (Sweden); Diego Ferone, Departments of Internal Medicine and Endocrinological and Metabolic Sciences, University of Genoa, Genoa (Italy); Björn Gustafsson, Medisinsk avd, Gastroseksjon, St Olavs Hospital, Trondheim (Norway); Diana Ivan, Endocrinology and Diabetology, Klinikum der Philipps-Universität, Marburg (Germany); Gregory Kaltsas, G. Genimatas Hospital, Athens (Greece); Reza Kianmanesh, UFR Bichat-Beaujon-Louis Mourier, Service de Chirurgie Digestive, Hôpital Louis Mourier, Colombes (France); Günter Klöppel, Institut für Pathologie, TU München, Munich (Germany); Ulrich-Peter Knigge, Department of Surgery, Rigshospitalet, Copenhagen (Denmark); Paul Komminoth,Institute for Pathology, Stadtspital Triemli, Zürich (Switzerland); Dik Kwekkeboom, Department of Nuclear Medicine, Erasmus University Medical Center, Rotterdam (The Netherlands); Rachida Lebtahi, Nuclear Medicine Department, Bichat Hospital, Paris (France); Val Lewington, Royal Marsden, NHS Foundation Trust, Sutton (UK); Anne Marie McNicol, Division of Cancer Sciences and Molecular Pathology, Pathology Department, Royal Infirmary, Glasgow (UK); Emmanuel Mitry, Hepatogastroenterology and Digestive Oncology, Hôpital Ambroise-Paré, Boulogne (France); Ola Nilsson, Department of Pathology, Sahlgrenska sjukhuset, Gothenburg (Sweden); Kjell Öberg, Department of Internal Medicine, Endocrine Unit, University Hospital, Uppsala (Sweden); Juan O’Connor, Instituto Alexander Fleming, Buenos Aires (Argentina); Dermot O’Toole, Department of Gastroenterology and Clinical Medicine, St. James’s Hospital and Trinity College Dublin, Dublin (Ireland); Ulrich-Frank Pape, Department of Internal Medicine, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany); Mauro Papotti, Department of Biological and Clinical Sciences, University of Turin/St. Luigi Hospital, Turin (Italy); Marianne Pavel, Department of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany); Aurel Perren, Institut für Allgemeine Pathologie und Pathologische Anatomie der Technischen Universität München, Klinikum r.d. Isar, Munich (Germany); Marco Platania, Istituto Nazionale dei Tumori di Milano, Milan (Italy); Guido Rindi, Department of Pathology and Laboratory Medicine, Università degli Studi, Parma (Italy); Philippe Ruszniewski, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Aldo Scarpa, Department of Pathology, University of Verona, Verona (Italy); Klemens Scheidhauer, Klinikum rechts der Isar, TU München, Munich (Germany); Jean-Yves Scoazec, Anatomie Pathologique, Hôpital Edouard-Herriot, Lyon (France); Anders Sundin, Department of Radiology, Uppsala University Hospital, Uppsala (Sweden); Waldemar Szpak, Westville Hospital, Mayville (South Africa); Babs Taal, Netherlands Cancer Centre, Amsterdam (The Netherlands); Pavel Vitek, Institute of Radiation Oncology, University Hospital, Prague (Czech Republic); Marie-Pierre Vullierme, Service de Gastroentérologie, Hôpital Beaujon, Clichy (France); Bertram Wiedenmann, Department of Internal Medicine, Division of Hepatology and Gastroenterology, Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, Berlin (Germany).

Surgery for small intestinal neuroendocrine tumours (SI-NETs) is limited by metastatic disease in most patients. However, resection of the primary lesion alone has been advocated in patients with unresectable liver metastases. The present systematic review investigated the value of surgical resection of the primary lesion in patients with unresectable metastatic disease.MEDLINE was searched for studies reporting the outcome of patients with SI-NETs and unresectable liver metastases where there was an explicit comparison between resection of the primary lesion alone and no resection. The primary outcome was overall survival. Secondary outcomes were progression-free survival, treatment-related mortality and relief of symptoms.Meta-analysis was not possible, but six studies were analysed qualitatively to highlight useful information. Possible confounders in these studies were the inclusion of patients with other primary tumour sites, unknown primary tumour or non-metastatic disease. Bearing in mind these limitations, there was a clear trend towards longer survival in patients who underwent surgical resection in all studies; their median overall survival ranged from 75 to 139 months compared with 50-88 months in patients who did not have resection. The difference between the two groups was statistically significant in three studies. Data on symptomatic improvement were scarce and did not suggest a clear benefit of surgery. Surgery-related mortality seemed low.Available data suggest a possible benefit of resection of the primary lesion in patients with unresectable liver metastases, but the studies have several limitations and the results should therefore be considered with caution.

Abstract In pancreatic ductal adenocarcinomas (PDAC), lymphoid infiltrates, comprised mainly of Th2 cells, predict a poor survival outcome in patients. IL4 signaling has been suggested to stabilize the Th2 phenotype in this setting, but the cellular source of IL4 in PDAC is unclear. Here, we show that basophils expressing IL4 are enriched in tumor-draining lymph nodes (TDLN) of PDAC patients. Basophils present in TDLNs correlated significantly with the Th2/Th1 cell ratio in tumors, where they served as an independent prognostic biomarker of patient survival after surgery. Investigations in mouse models of pancreatic cancer confirmed a functional role for basophils during tumor progression. The recruitment of basophils into TDLN relied partly upon the release of chemokine CCL7/MCP3 by "alternatively activated" monocytes, whereas basophil activation was induced by T-cell–derived IL3. Our results show how basophils recruited and activated in TDLNs under the influence of the tumor microenvironment regulate tumor-promoting Th2 inflammation in PDAC, helping in illuminating a key element of the immune milieu of pancreatic cancer. Cancer Res; 76(7); 1792–803. ©2016 AACR.

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.

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. 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. 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. 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. 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.

New chemotherapeutic regimens have improved survival for stage IV pancreatic ductal adenocarcinoma and occasionally major response of liver metastases can be observed. Aim of this work is to analyze the outcomes of patients undergoing primary chemotherapy for liver metastases from pancreatic cancer and to evaluate the results of surgical resection.Retrospective analysis.patients with extra-hepatic metastases, patients with Eastern Cooperative Oncology Group performance status ≥3, patients undergoing supportive care alone.127 patients were identified. Liver metastases were unilobar in 28.5% of patients. Chemotherapy regimens included gemcitabine alone or in association with other agents (44%), oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX 8%), and cisplatin, gemcitabine plus capecitabine and epirubicin (PEXG) or capecitabine and docetaxel (PDXG) or epirubicin and fluorouracil (PEFG) (48%). 56 patients (44%) had a complete (7%) or partial response (37%). surgical resection was carried out in 11 patients (8.5%). Median overall survival was 11 months for the entire cohort and 15 months for those with partial/complete response. In this sub-group median survival was significantly longer (46 versus 11 months) for patients undergoing resection (P < 0.0001). Independent predictors of overall survival were chemotherapy with multiple agents (HR: 0.512), surgical resection (HR: 0.360), >5 liver metastases at diagnosis (HR: 3.515), and CA 19.9 reduction < 50% of baseline value (HR: 2.708).Surgical resection of primary pancreatic tumor with or without residual liver disease can be considered in selected cases after primary chemotherapy and it is associated with improved survival.

BackgroundMalignant potential of small (≤20 mm) nonfunctional pancreatic neuroendocrine tumors (sNF-PNET) is difficult to predict and management remain controversial. The aim of this study was to assess the prognosis of sporadic nonmetastatic sNF-PNETs.MethodsPatients were identified from databases of 16 centers. Outcomes and risk factors for recurrence were identified by uni- and multivariate analyses.ResultssNF-PNET was resected in 210 patients, and 66% (n = 138) were asymptomatic. Median age was 60 years, median tumor size was 15 mm, parenchyma-sparing surgery was performed in 42%. Postoperative mortality was 0.5% (n = 1), severe morbidity rate was 14.3% (n = 30), and 14 of 132 patients (10.6%) with harvested lymph nodes had metastatic lymph nodes. Tumor size, presence of biliary or pancreatic duct dilatation, and WHO grade 2–3 were independently associated with recurrence. Patients with tumors sized ≤10 mm were disease free at last follow-up. The 1-, 3- and 5-year disease-free survival rates for patients with tumors sized 11–20 mm on preoperative imaging were 95.1%, 91.0%, and 87.3%, respectively.ConclusionsIn sNF-PNETs, the presence of biliary or pancreatic duct dilatation or WHO grade 2–3 advocate for surgical treatment. In the remaining patients, a wait-and-see policy might be considered.

The aim of this study was to predict recurrence in patients with grade 1 or 2 nonfunctioning pancreatic neuroendocrine tumors (NF-pNET) after curative resection.Surgical resection is the preferred treatment for NF-pNET; however, recurrence occurs frequently after curative surgery, worsening prognosis of patients.Retrospectively, patients with NF-pNET of 3 institutions were included. Patients with distant metastases, hereditary syndromes, or grade 3 tumors were excluded. Local or distant tumor recurrence was scored. Independent predictors for survival and recurrence were identified using Cox-regression analysis. The recurrence score was developed to predict recurrence within 5 years after curative resection of grade 1 to 2 NF-pNET.With a median follow-up of 51 months, 211 patients with grade 1 to 2 NF-pNET were included. Thirty-five patients (17%) developed recurrence. The 5- and 10-year disease-specific/overall survival was 98%/91% and 84%/68%, respectively. Predictors for recurrence were tumor grade 2, lymph node metastasis, and perineural invasion. On the basis of these predictors, the recurrence score was made. Discrimination [c-statistic 0.81, 95% confidence interval (95% CI) 0.75-0.87] and calibration (Hosmer Lemeshow Chi-square 11.25, P = 0.258) indicated that the ability of the recurrence score to identify patients at risk for recurrence is good.This new scoring system could predict recurrence after curative resection of grade 1 and 2 NF-pNET. With the use of the recurrence score, less extensive follow-up could be proposed for patients with low recurrence risk. For high-risk patients, clinical trials should be initiated to investigate whether adjuvant therapy might be beneficial. External validation is ongoing due to limited availability of adequate cohorts.

This is a medical position statement developed by the Exocrine Pancreatic Insufficiency collaborative group which is a part of the Italian Association for the Study of the Pancreas (AISP). We covered the main diseases associated with exocrine pancreatic insufficiency (EPI) which are of common interest to internists/gastroenterologists, oncologists and surgeons, fully aware that EPI may also occur together with many other diseases, but less frequently. A preliminary manuscript based on an extended literature search (Medline/PubMed, Cochrane Library and Google Scholar) of published reports was prepared, and key recommendations were proposed. The evidence was discussed at a dedicated meeting in Bologna during the National Meeting of the Association in October 2012. Each of the proposed recommendations and algorithms was discussed and an initial consensus was reached. The final draft of the manuscript was then sent to the AISP Council for approval and/or modification. All concerned parties approved the final version of the manuscript in June 2013.

Surgery remains the only curative option for pancreatic neuroendocrine tumours (PNETs), but its indication is limited by metastatic disease in most patients. Indication for removing the primary lesion only in the setting of unresectable liver disease is controversial. The present systematic review aims at determining the potential bene- fits (survival, progression-free survival) or harms (morbidity, mortality) of surgical resection of the primary lesion only in patients with PNETs and unresectable metastases.Medline was queried for studies reporting the outcome of PNET patients with unresectable liver metastases whenever there was an explicit comparison between resection of the primary lesion only ('active treatment') and no resection ('non-active treatment'). The primary outcome was survival; possible secondary outcomes were progression-free survival, treatment-related mortality and morbidity, and relief of symptoms.Only 3 cohort studies found were eligible and analysed; no meta-analysis could be performed. The number of patients undergoing 'active treatment' varied from 16 to 20, with a percentage ranging from 17 to 39% of cohorts. Survival was longer in patients who received 'active treatment' in 2 studies, and the 5-year survival rate also seemed higher, without significant complications.Available data suggest a possible benefit of resection of the primary lesion only in this setting. However, a bias towards a more aggressive surgical approach in patients with a better performance status or less advanced disease seems likely, and no conclusion can be drawn except for the need of randomised trials. We calculated that such a trial would require at least 118 patients per arm.

To provide evidence-based recommendations for the management of exocrine pancreatic insufficiency (EPI) after pancreatic surgery.EPI is a common complication after pancreatic surgery but there is certain confusion about its frequency, optimal methods of diagnosis, and when and how to treat these patients.Eighteen multidisciplinary reviewers performed a systematic review on 10 predefined questions following the GRADE methodology. Six external expert referees reviewed the retrieved information. Members from Spanish Association of Pancreatology were invited to suggest modifications and voted for the quantification of agreement.These guidelines analyze the definition of EPI after pancreatic surgery, (one question), its frequency after specific techniques and underlying disease (four questions), its clinical consequences (one question), diagnosis (one question), when and how to treat postsurgical EPI (two questions) and its impact on the quality of life (one question). Eleven statements answering those 10 questions were provided: one (9.1%) was rated as a strong recommendation according to GRADE, three (27.3%) as moderate and seven (63.6%) as weak. All statements had strong agreement.EPI is a frequent but under-recognized complication of pancreatic surgery. These guidelines provide evidence-based recommendations for the definition, diagnosis, and management of EPI after pancreatic surgery.

An unconventional population of CD4+ signaling lymphocytic activation molecule family member 7-positive (SLAMF7+) cytotoxic effector memory T (TEM ) cells (CD4+ cytotoxic T lymphocytes [CTLs]) has been linked causally to IgG4-related disease (IgG4-RD). Glucocorticoids represent the first-line therapeutic approach in patients with IgG4-RD, but their mechanism of action in this specific condition remains unknown. We undertook this study to determine the impact of glucocorticoids on CD4+ CTLs in IgG4-RD.Expression of CD8α, granzyme A, perforin, and SLAMF7 within the effector memory compartment of CD45RO+ (TEM ) and CD45RA+ effector memory T (TEMRA ) CD4+ cells was quantified by flow cytometry in 18 patients with active IgG4-RD, both at baseline and after 6 months of glucocorticoid treatment. Eighteen healthy subjects were studied as controls. Next-generation sequencing of the T cell receptor α- and β-chain gene was performed on circulating CD4+ CTLs from patients with IgG4-RD before and after treatment and in affected tissues.Circulating CD4+ TEM and TEMRA cells were not expanded in IgG4-RD patients compared to healthy controls. CD4+SLAMF7+ TEM cells (but not TEMRA cells) were significantly increased among IgG4-RD patients. Within CD4+SLAMF7+ TEM cells, CD8α- cells but not CD8αlow cells were elevated in IgG4-RD patients. The same dominant clones of CD8α-CD4+SLAMF7+ TEM cells found in peripheral blood were also identified in affected tissue. CD8α- and CD8αlow CD4+SLAMF7+ TEM cells both expressed cytolytic molecules. Clonally expanded CD8α- but not CD8αlow CD4+SLAMF7+ TEM cells decreased following glucocorticoid-induced disease remission.A subset of CD8α-CD4+SLAMF7+ cytotoxic TEM cells is oligoclonally expanded in patients with active IgG4-RD. This TEM cell population contracts following glucocorticoid-induced remission. Further characterization of this cell population may provide prognostic information and targets for therapeutic intervention.

The benefit of adjuvant chemotherapy after resection of pancreatic cancer following neoadjuvant combination treatment with folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) is unclear.To assess the association of adjuvant chemotherapy with overall survival (OS) in patients after pancreatic cancer resection and neoadjuvant FOLFIRINOX treatment.This international, multicenter, retrospective cohort study was conducted from January 1, 2012, to December 31, 2018. An existing cohort of patients undergoing resection of pancreatic cancer after FOLFIRINOX was updated and expanded for the purpose of this study. All consecutive patients who underwent pancreatic surgery after at least 2 cycles of neoadjuvant FOLFIRINOX chemotherapy for nonmetastatic pancreatic cancer were retrospectively identified from institutional databases. Patients with resectable pancreatic cancer, borderline resectable pancreatic cancer, and locally advanced pancreatic cancer were eligible for this study. Patients with in-hospital mortality or who died within 3 months after surgery were excluded.The association of adjuvant chemotherapy with OS was evaluated in different subgroups including interaction terms for clinicopathological parameters with adjuvant treatment in a multivariable Cox model. Overall survival was defined as the time starting from surgery plus 3 months (moment eligible for adjuvant therapy), unless mentioned otherwise.We included 520 patients (median [interquartile range] age, 61 [53-66] years; 279 [53.7%] men) from 31 centers in 19 countries. The median number of neoadjuvant cycles of FOLFIRINOX was 6 (interquartile range, 5-8). Overall, 343 patients (66.0%) received adjuvant chemotherapy, of whom 68 (19.8%) received FOLFIRINOX, 201 (58.6%) received gemcitabine-based chemotherapy, 14 (4.1%) received capecitabine, 45 (13.1%) received a combination or other agents, and 15 (4.4%) received an unknown type of adjuvant chemotherapy. Median OS was 38 months (95% CI, 36-46 months) after diagnosis and 31 months (95% CI, 29-37 months) after surgery. No survival difference was found for patients who received adjuvant chemotherapy vs those who did not (median OS, 29 vs 29 months, univariable hazard ratio [HR], 0.99; 95% CI, 0.77-1.28; P = .93). In multivariable analysis, only the interaction term for lymph node stage with adjuvant therapy was statistically significant: In patients with pathology-proven node-positive disease, adjuvant chemotherapy was associated with improved survival (median OS, 26 vs 13 months; multivariable HR, 0.41 [95% CI, 0.22-0.75]; P = .004). In patients with node-negative disease, adjuvant chemotherapy was not associated with improved survival (median OS, 38 vs 54 months; multivariable HR, 0.85; 95% CI, 0.35-2.10; P = .73).These results suggest that adjuvant chemotherapy after neoadjuvant FOLFIRINOX and resection of pancreatic cancer was associated with improved survival only in patients with pathology-proven node-positive disease. Future randomized studies should be conducted to confirm this finding.

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.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.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.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.

To evaluate the outcome of pancreaticoduodenectomy (PD) versus non-PD resections for the treatment of gastrinoma in multiple endocrine neoplasia type 1.Gastrinoma in MEN1 is considered a rarely curable disease and its management is highly controversial both for timing and extent of surgery.Clinical characteristics, complications and outcomes of 27 prospectively collected MEN1 patients with biochemically proven gastrinoma, who underwent surgery, were analyzed with special regard to the gastrinoma type and the initial operative procedure.Twenty-two (81%) patients with gastrinoma in MEN1 had duodenal gastrinomas and 5 patients (19%) had pancreatic gastrinomas. At the time of diagnosis, 21 (77%) gastrinomas were malignant (18 duodenal, 3 pancreatic), but distant metastases were only present in 4 (15%) patients. Patients with pancreatic gastrinomas underwent either distal pancreatic resections or gastrinoma enucleation with lymphadenectomy, 2 patients also had synchronous resections of liver metastases. One of these patients was biochemically cured after a median of 136 (77-312) months. Thirteen patients with duodenal gastrinomas underwent PD resections (group 1, partial PD [n = 11], total PD [n = 2]), whereas 9 patients had no-PD resections (group 2) as initial operative procedure. Perioperative morbidity and mortality, including postoperative diabetes, differed not significantly between groups (P > 0.5). All patients of group 1 and 5 of 9 (55%) patients of group 2 had a negative secretin test at hospital discharge. However, after a median follow-up of 136 (3-276) months, 12 (92%) patients of group 1 were still normogastrinemic compared to only 3 of 9 (33%) patients of group 2 (P = 0.023). Three (33%) patients of group 2 had to undergo up to 3 reoperations for recurrent or metastatic disease compared to none of group 1.Duodenal gastrinoma in MEN1 should be considered a surgically curable disease. PD seems to be the adequate approach to this disease, providing a high cure rate and acceptable morbidity compared to non-PD resections.

<h3>Background</h3> IgG₄-related disease (IgG₄-RD) is a fibroinflammatory condition marked by rapid clinical improvement after selective depletion of B lymphocytes with rituximab. This feature suggests that B cells might participate in fibrogenesis and wound healing. <h3>Objective</h3> In the present work we aimed to demonstrate that B lymphocytes contribute directly to tissue fibrosis in patients with IgG₄-RD. <h3>Methods</h3> Total circulating CD19⁺ B lymphocytes, naive B cells, memory B cells, or plasmablasts from patients with IgG₄-RD were cultivated with human fibroblasts. Profibrotic soluble factors and collagen production in cocultures were assessed by using ELISAs and Luminex assays. RNA sequencing and quantitative RT-PCR were used to assess fibroblast activation in the presence of B cells, as well as induction of profibrotic pathways in B-cell subsets. Relevant profibrotic and inflammatory molecules were confirmed <i>in vitro</i> by using functional experiments and on IgG₄-RD tissue sections by using multicolor immunofluorescence studies. <h3>Results</h3> B cells from patients with IgG₄-RD (1) produced the profibrotic molecule platelet-derived growth factor B and stimulated collagen production by fibroblasts; (2) expressed enzymes implicated in extracellular matrix remodeling, such as lysyl oxidase homolog 2; (3) produced the chemotactic factors CCL4, CCL5, and CCL11; and (4) induced production of these same chemokines by activated fibroblasts. Plasmablasts expressed sets of genes implicated in fibroblast activation and proliferation and therefore represent cells with intrinsic profibrotic properties. <h3>Conclusion</h3> We have demonstrated that B cells contribute directly to tissue fibrosis in patients with IgG₄-RD. These unanticipated profibrotic properties of B lymphocytes, particularly plasmablasts, might be relevant for fibrogenesis in patients with other fibroinflammatory disorders and for wound-healing processes in physiologic conditions.