Correction to: Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database.

The original version of this article unfortunately contained a mistake in Table 2. The table 2 was truncated in the original publication. The full table 2 is given below.

Multiple endocrine neoplasia type 1: analysis of germline MEN1 mutations in the Italian multicenter MEN1 patient database.

PURPOSE: Multiple endocrine neoplasia type 1 (MEN1) is caused by germline inactivating mutations of the MEN1 gene. Currently, no direct genotype-phenotype correlation is identified. We aim to analyze MEN1 mutation site and features, and possible correlations between the mutation type and/or the affected menin functional domain and clinical presentation in patients from the Italian multicenter MEN1 database, one of the largest worldwide MEN1 mutation series published to date. METHODS: The study included the analysis of MEN1 mutation profile in 410 MEN1 patients [370 familial cases from 123 different pedigrees (48 still asymptomatic at the time of this study) and 40 single cases]. RESULTS: We identified 99 different mutations: 41 frameshift [small intra-exon deletions (28) or insertions (13)], 13 nonsense, 26 missense and 11 splicing site mutations, 4 in-frame small deletions, and 4 intragenic large deletions spanning more than one exon. One family had two different inactivating MEN1 mutations on the same allele. Gastro-entero-pancreatic tumors resulted more frequent in patients with a nonsense mutation, and thoracic neuroendocrine tumors in individuals bearing a splicing-site mutation. CONCLUSIONS: Our data regarding mutation type frequency and distribution are in accordance with previously published data: MEN1 mutations are scattered through the entire coding region, and truncating mutations are the most common in MEN1 syndrome. A specific direct correlation between MEN1 genotype and clinical phenotype was not found in all our families, and wide intra-familial clinical variability and variable disease penetrance were both confirmed, suggesting a role for modifying, still undetermined, factors, explaining the variable MEN1 tumorigenesis.

Everolimus in advanced, progressive, well-differentiated, non-functional neuroendocrine tumors: RADIANT-4 lung subgroup analysis.

In the phase III RADIANT-4 study, everolimus improved median progression-free survival (PFS) by 7.1 months in patients with advanced, progressive, well-differentiated (grade 1 or grade 2), non-functional lung or gastrointestinal neuroendocrine tumors (NETs) vs placebo (hazard ratio, 0.48; 95% confidence interval [CI], 0.35-0.67; P < .00001). This exploratory analysis reports the outcomes of the subgroup of patients with lung NETs. In RADIANT-4, patients were randomized (2:1) to everolimus 10 mg/d or placebo, both with best supportive care. This is a post hoc analysis of the lung subgroup with PFS, by central radiology review, as the primary endpoint; secondary endpoints included objective response rate and safety measures. Ninety of the 302 patients enrolled in the study had primary lung NET (everolimus, n = 63; placebo, n = 27). Median PFS (95% CI) by central review was 9.2 (6.8-10.9) months in the everolimus arm vs 3.6 (1.9-5.1) months in the placebo arm (hazard ratio, 0.50; 95% CI, 0.28-0.88). More patients who received everolimus (58%) experienced tumor shrinkage compared with placebo (13%). Most frequently reported (≥5% incidence) grade 3-4 drug-related adverse events (everolimus vs. placebo) included stomatitis (11% vs. 0%), hyperglycemia (10% vs. 0%), and any infections (8% vs. 0%). In patients with advanced, progressive, well-differentiated, non-functional lung NET, treatment with everolimus was associated with a median PFS improvement of 5.6 months, with a safety profile similar to that of the overall RADIANT-4 cohort. These results support the use of everolimus in patients with advanced, non-functional lung NET. The trial is registered with ClinicalTrials.gov (no. NCT01524783).

Multiple endocrine neoplasia syndrome type 1: institution, management, and data analysis of a nationwide multicenter patient database.

OBJECTIVE: The aim of this study was to integrate European epidemiological data on patients with multiple endocrine neoplasia type 1 by creating an Italian registry of this syndrome, including clinical and genetic characteristics and therapeutic management. METHODS: Clinical, familial and genetic data of patients with multiple endocrine neoplasia type 1, diagnosed, treated, and followed-up for a mean time of 11.3 years, in 14 Italian referral endocrinological centers, were collected, over a 3-year course (2011-2013), to build a national electronic database. RESULTS: The Italian multiple endocrine neoplasia type 1 database includes 475 patients (271 women and 204 men), of whom 383 patients (80.6%) were classified as familial cases (from 136 different pedigrees), and 92 (19.4%) patients were sporadic cases. A MEN1 mutation was identified in 92.6% of familial cases and in 48.9% of sporadic cases. Four hundred thirty-six patients were symptomatic, presenting primary hyperparathyroidism, gastroenteropancreatic neuroendocrine tumors and pituitary tumors in 93, 53, and 41% of cases, respectively. Thirty-nine subjects, belonging to affected pedigrees positive for a MEN1 mutation, were asymptomatic at clinical and biochemical screening. Age at diagnosis of multiple endocrine neoplasia type 1 probands was similar for both familial and simplex cases (mean age 47.2 ± 15.3 years). In familial cases, diagnosis of multiple endocrine neoplasia type 1 in relatives of affected probands was made more than 10 years in advance (mean age at diagnosis 36.5 ± 17.6 years). CONCLUSIONS: The analysis of Italian registry of multiple endocrine neoplasia type 1 patients revealed that clinical features of Italian multiple endocrine neoplasia type 1 patients are similar to those of other western countries, and confirmed that the genetic test allowed multiple endocrine neoplasia type 1 diagnosis 10 years earlier than biochemical or clinical diagnosis.

Risk factors of type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis. A retrospective, multicentre study.

The aim of this retrospective study was to evaluate the presence of risk factors for a type 1 gastric neuroendocrine neoplasia in a large cohort of patients with chronic atrophic gastritis. The study design consisted of an Italian multicentre, retrospective analysis. The study included all consecutive patients with chronic atrophic gastritis with or without type 1 gastric neuroendocrine neoplasias followed at the participating centres. Two hundred and twenty-nine patients with chronic atrophic gastritis were enroled at the participating centres. A total of 207 patients (154 female, 53 males, median age: 56.0 years) were included in the final analysis. One hundred and twenty-six patients had chronic atrophic gastritis without a gastric neuroendocrine neoplasia and 81 had a chronic atrophic gastritis with type 1 gastric neuroendocrine neoplasia. The median Chromogranin A level, evaluated in 141 patients, was 52.0 U/L. At upper gastrointestinal endoscopy, atrophy of the gastric mucosa was mild/moderate in 137 patients and severe in 68. Intestinal metaplasia of the corpus was present in 168 patients. At histological examination, 81 patients had a gastric neuroendocrine neoplasia (42 patients had a NET G1 and 33 a NET G2). The median Ki67 index was 2.0 %. At univariate and multivariate analysis, the risk factors for a gastric neuroendocrine neoplasia were: male gender, chromogranin A greater than 61 U/L, presence of intestinal metaplasia and age equal to or greater than 59 years. Chromogranin A greater than 61 U/L, the presence of intestinal metaplasia and male gender were independent risk factors for a type 1 gastric neuroendocrine neoplasia in patients with chronic atrophic gastritis.

Everolimus for the Treatment of Advanced Pancreatic Neuroendocrine Tumors: Overall Survival and Circulating Biomarkers From the Randomized, Phase III RADIANT-3 Study.

Purpose Everolimus improved median progression-free survival by 6.4 months in patients with advanced pancreatic neuroendocrine tumors (NET) compared with placebo in the RADIANT-3 study. Here, we present the final overall survival (OS) data and data on the impact of biomarkers on OS from the RADIANT-3 study. Methods Patients with advanced, progressive, low- or intermediate-grade pancreatic NET were randomly assigned to everolimus 10 mg/day (n = 207) or placebo (n = 203). Crossover from placebo to open-label everolimus was allowed on disease progression. Ongoing patients were unblinded after final progression-free survival analysis and could transition to open-label everolimus at the investigator's discretion (extension phase). OS analysis was performed using a stratified log-rank test in the intent-to-treat population. The baseline levels of chromogranin A, neuron-specific enolase, and multiple soluble angiogenic biomarkers were determined and their impact on OS was explored. Results Of 410 patients who were enrolled between July 2007 and March 2014, 225 received open-label everolimus, including 172 patients (85%) randomly assigned initially to the placebo arm. Median OS was 44.0 months (95% CI, 35.6 to 51.8 months) for those randomly assigned to everolimus and 37.7 months (95% CI, 29.1 to 45.8 months) for those randomly assigned to placebo (hazard ratio, 0.94; 95% CI, 0.73 to 1.20; P = .30). Elevated baseline chromogranin A, neuron-specific enolase, placental growth factor, and soluble vascular endothelial growth factor receptor 1 levels were poor prognostic factors for OS. The most common adverse events included stomatitis, rash, and diarrhea. Conclusion Everolimus was associated with a median OS of 44 months in patients with advanced, progressive pancreatic NET, the longest OS reported in a phase III study for this population. Everolimus was associated with a survival benefit of 6.3 months, although this finding was not statistically significant. Crossover of patients likely confounded the OS results.

Validation of the 2010 WHO classification and a new prognostic proposal: A single centre retrospective study of well-differentiated pancreatic neuroendocrine tumours.

BACKGOUND: In 2010, the World Health Organization (WHO) modified the classification for pancreatic neuroendocrine tumours (NETs). Recently, some modifications were proposed to improve its prognostic value. The aim of this study was to test the prognostic value of both the original and the modified 2010 WHO grading systems. METHODS: One hundred and twenty consecutive patients surgically resected for well-differentiated NETs were evaluated in multivariate Cox regression models. Age, sex, hormonal status, size, lymph node ratio, stage, margin status and grading were evaluated in order to predict disease-free survival (DFS). Four models were evaluated: model 1: grading according to the 2010 WHO; model 2: modified grading with cut-off at 5% of the Ki-67 index; model 3: modified grading in which the G2 category was divided into two subgroups (2-5% and 5-20%) and model 4: the Ki-67 index as a continuous variable. Decision curve analysis (DCA) was carried out to evaluate the clinical utility of the various cut-offs. RESULTS: All the grading systems remained independent factors in predicting DFS. Model 2 (c index = 0.814 and P = 0.012) and model 3 (c index = 0.865 and P = 0.015) showed higher predictive powers with respect to model 1 (c index = 0.799). Model 4 had a high predictive value (c index 0.848, P = 0.013). Decision curve analysis confirmed that biological behaviour represented the best prognostic parameter. CONCLUSION: This study presented some limitations: single centre, retrospective design and a long period of enrolment. The result showed that, by increasing the cut-off of the G2 category to 5% or by creating two subgroups in the G2 category, it was possible to obtain a better stratification of patients.

Risk and Protective Factors for Small Intestine Neuroendocrine Tumors: A Prospective Case-Control Study.

BACKGROUND: The incidence of small intestine neuroendocrine tumors (SI-NETs) is increasing, but few studies have investigated risk factors for their occurrence, suggesting that family history (FH) of any cancer, smoking and previous cholecystectomy are associated with an increased risk. Such studies investigated small series or examined cancer registries without direct interviews. AIM: We therefore aimed at clarifying risk and protective factors for the occurrence of sporadic SI-NETs. SUBJECTS AND METHODS: We performed a multicenter case-control study. Patients with a histologic diagnosis of SI-NETs were prospectively evaluated, excluding familial syndromes. Controls with non-neoplastic/non-chronic disorders seen at gastrointestinal outpatients clinics were matched for sex and age (4:1). All subjects were directly interviewed by means of a specific questionnaire on potential risk and protective factors. Cases and controls were compared by Fisher's test or Student's t test for categorical or continuous variables. Explanatory variables were analyzed by simple logistic regression analysis. A multiple logistic regression analysis was performed with an Enter model; p < 0.05 was considered significant. RESULTS: 215 SI-NET patients and 860 controls were enrolled. FH of colorectal cancer (CRC) (8.8 vs. 5.0%) and breast cancer (10.2 vs. 4.8%), heavy smoking (24.7 vs. 14.8%) and drinking >21 alcohol units per week (7.4 vs. 3.8%) were all significantly more frequent in SI-NET patients than in controls. Multivariate analysis showed that FH of CRC (OR 2.23, 95% CI 1.29-3.84, p = 0.003), FH of breast cancer (OR 2.05, 95% CI 1.13-3.69, p = 0.01) and smoking (OR 1.47, 95% CI 1.07-2.03, p = 0.01) and in particular heavy smoking (OR 1.94, 95% CI 1.29-3.84, p = 0.0008) were associated with an increased risk for carcinoid occurrence, while use of aspirin can be considered a protective factor (OR 0.20, 95% CI 0.06-0.65, p = 0.008). CONCLUSION: FH of colorectal and breast cancer as well as smoking seem to be risk factors for the development of SI-NETs, while use of aspirin might be a protective factor. These factors partially overlap with those associated with CRC, but are different from those previously associated with pancreatic neuroendocrine tumors. These findings may suggest that the mechanisms of carcinogenesis for endocrine cells in different sites can be specific and similar to those of their exocrine counterparts.

Clinical management of patients with gastric neuroendocrine neoplasms associated with chronic atrophic gastritis: a retrospective, multicentre study.

To provide data regarding clinical presentation, pathological features, management, and response to different treatments of patients with type I gastric neuroendocrine tumors in stages 0-2A. The study design consist of an Italian multicentre, retrospective analysis of patients with type I gastric neuroendocrine tumors managed with different therapeutic approaches: surgery, endoscopic surveillance, endoscopic resection, or somatostatin analog therapy. Among the 97 patients included, 3 underwent surgery, 45 (46.4%) radical endoscopic resection of the neoplastic lesions, 13 (13.4%) follow-up with upper endoscopy, and 36 (37.1%) somatostatin analog therapy. At the end of the follow-up, all patients were alive and there was no evidence of metastatic disease. Somatostatin analog therapy resulted in a complete response in 76.0% of the patients and stable disease in 24.0%. A prolonged period of therapy, the use of a full dose of somatostatin analogs and higher gastrin levels at diagnosis were related to a complete response to the therapy. The recurrence rate was 26.3% in patients treated with somatostatin analog therapy and 26.2% in patients treated with endoscopic resection, without a statistically significant difference in terms of disease-free survival. Regarding recurrence of the disease, no statistical difference was found according to type of therapy, number of neoplastic lesions, and 2010 WHO classification. The only risk factor for tumor recurrence was a short period of medical treatment. In conclusion, our study suggested that endoscopic surveillance, endoscopic resection and somatostatin analog therapy represent valid options in the management of patients with type I gastric neuroendocrine tumors in stages 0-2A.

Prognostic Value of 68Ga-DOTANOC PET/CT SUVmax in Patients with Neuroendocrine Tumors of the Pancreas.

UNLABELLED: This study was performed to investigate the role of (68)Ga-DOTANOC SUVmax as a potential prognostic factor in patients with pancreatic neuroendocrine tumor (pNET). METHODS: Among the patients who underwent (68)Ga-DOTANOC PET/CT, we retrospectively collected the data of those who had G1 or G2 pNET (2010 World Health Organization classification), presented with disease on PET/CT and CT, and had at least 6 mo of follow-up. Patients with multiple endocrine neoplasia were excluded. RESULTS: Overall, 43 patients were included. No significant differences in SUVmax were observed with respect to sex, tumor syndrome, stage, World Health Organization classification, or Ki-67. During follow-up (median, 20 mo), 11 patients (35.6%; median, 33 mo; interquartile range, 20-48 mo) had stable disease and 32 (74.4%; median, 19 mo; interquartile range, 14-26 mo) had progressive disease. SUVmax at 24 mo of follow-up was significantly higher (P = 0.022) in patients with stable disease than in patients with progressive disease. The best SUVmax cutoff ranged from 37.8 to 38.0. The major risk factors for progression included an SUVmax of no more than 37.8 (hazard ratio, 3.09; P = 0.003), a Ki-67 of more than 5% (hazard ratio, 2.89; P = 0.009), and medical therapy alone (hazard ratio, 2.36; P = 0.018). Advanced stage (IV) (P = 0.026), an SUVmax of less than 37.8 (P = 0.043), and medical therapy alone (P = 0.015) were also confirmed at multivariate analysis. Median progression-free survival was 23 mo. Significant differences in progression-free survival were observed in relationship to Ki-67 (median, 45 mo for Ki-67 ≤ 5% and 20 mo for Ki-67 > 5%; P = 0.005), SUVmax (<37.8 vs. >38.0: 16.0 vs. 27.0 mo; P = 0.002), and type of therapy (medical vs. peptide receptor radionuclide therapy: 16.0 vs. 26.0 mo; P = 0.014). CONCLUSION: (68)Ga-DOTANOC SUVmax is a relevant prognostic factor in patients with G1 and G2 pNET, and its routine use will improve disease characterization and management in these patients, who may present with atypical cases showing heterogeneous clinical behavior.

Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues.

In a randomized, double-blind, Phase III study, we compared pasireotide long-acting release (pasireotide LAR) with octreotide long-acting repeatable (octreotide LAR) in managing carcinoid symptoms refractory to first-generation somatostatin analogues. Adults with carcinoid tumors of the digestive tract were randomly assigned (1:1) to receive pasireotide LAR (60 mg) or octreotide LAR (40 mg) every 28 days. Primary outcome was symptom control based on frequency of bowel movements and flushing episodes. Objective tumor response was a secondary outcome. Progression-free survival (PFS) was calculated in a post hoc analysis. Adverse events were recorded. At the time of a planned interim analysis, the data monitoring committee recommended halting the study because of a low predictive probability of showing superiority of pasireotide over octreotide for symptom control (n=43 pasireotide LAR, 20.9%; n=45 octreotide LAR, 26.7%; odds ratio, 0.73; 95% confidence interval [CI], 0.27-1.97; P=0.53). Tumor control rate at month 6 was 62.7% with pasireotide and 46.2% with octreotide (odds ratio, 1.96; 95% CI, 0.89-4.32; P=0.09). Median (95% CI) PFS was 11.8 months (11.0 - not reached) with pasireotide versus 6.8 months (5.6 - not reached) with octreotide (hazard ratio, 0.46; 95% CI, 0.20-0.98; P=0.045). The most frequent drug-related adverse events (pasireotide vs octreotide) included hyperglycemia (28.3% vs 5.3%), fatigue (11.3% vs 3.5%), and nausea (9.4% vs 0%). We conclude that, among patients with carcinoid symptoms refractory to available somatostatin analogues, similar proportions of patients receiving pasireotide LAR or octreotide LAR achieved symptom control at month 6. Pasireotide LAR showed a trend toward higher tumor control rate at month 6, although it was statistically not significant, and was associated with a longer PFS than octreotide LAR.

WHO 2010 classification of pancreatic endocrine tumors. is the new always better than the old?

BACKGROUND: In 2010, the World Health Organization released a new classification system for endocrine pancreatic tumors. The new categories replaced those in the old classification. METHODS: To test the safety and accuracy of the new classification in stratifying patients, we retrospectively evaluated 64 consecutive patients, surgically R0 resected for pancreatic endocrine tumors. RESULTS: In our experience, only 19/31 (61.3%) patients classified as having well-differentiated tumors were included in the new neuroendocrine tumor G1 category while the remaining 12 (38.7%) shifted into the G2 category. Moreover, 10/33 (30.3%) patients classified as affected by a malignant endocrine neoplasm in the old system were considered as G1 tumors in the new one. These differences were statistically significant (P < 0.001) and changed the risk category in 22 (33.3%) patients with well-differentiated pancreatic endocrine tumors. Multiple multivariate models were produced and the poor stratification of the new system was found to be in the G2 category which presents too wide a range of the Ki 67 index (2 to 20%). We built a model in which the G2 category was divided into two subcategories: tumors with a Ki 67 index ≥2 and <5% and tumors with a Ki index ≥5 and <20%, partially modifying the new classification. In this model, the modified classification showed a superiority with respect to the European Neuroendocrine tumor Society-Tumor-Node-Metastasis staging system in stratifying patients for recurrence, with a relative risk of 19 (P < 0.001). CONCLUSION: The new G2 category seems too large because it includes both benign, low and high grade malignant tumors.

Real-world study of everolimus in advanced progressive neuroendocrine tumors.

Everolimus is a valid therapeutic option for neuroendocrine tumors (NETs); however, data in a real-world setting outside regulatory trials are sparse. The aim of this study was to determine everolimus tolerability and efficacy, in relation to previous treatments, in a compassionate use program. A total of 169 patients with advanced progressive NETs treated with everolimus were enrolled, including 85 with pancreatic NETs (pNETs) and 84 with nonpancreatic NETs (non-pNETs). Previous treatments included somatostatin analogs (92.9%), peptide receptor radionuclide therapy (PRRT; 50.3%), chemotherapy (49.7%), and PRRT and chemotherapy (22.8%). Overall, 85.2% of patients experienced adverse events (AEs), which were severe (grade 3-4) in 46.1%. The most frequent severe AEs were pneumonitis (8.3%), thrombocytopenia (7.7%), anemia (5.3%), and renal failure (3.5%). In patients previously treated with PRRT and chemotherapy, a 12-fold increased risk for severe toxicity was observed, with grade 3-4 AEs reported in 86.8% (vs. 34.3% in other patients). In addition, 63.3% of patients required temporarily everolimus discontinuation due to toxicity. Overall, 27.8% of patients died during a median follow-up of 12 months. Median progression-free survival (PFS) and overall survival (OS) were 12 months and 32 months, respectively. Similar disease control rates, PFS, and OS were reported in pNETs and non-pNETs. In the real-world setting, everolimus is safe and effective for the treatment of NETs of different origins. Higher severe toxicity occurred in patients previously treated with systemic chemotherapy and PRRT. This finding prompts caution when using this drug in pretreated patients and raises the issue of planning for everolimus before PRRT and chemotherapy in the therapeutic algorithm for advanced NETs.

Advanced digestive neuroendocrine tumors: metastatic pattern is an independent factor affecting clinical outcome.

OBJECTIVES: The objective of this study was to determine the impact of different metastatic spread patterns on outcome in advanced digestive neuroendocrine tumors (NETs). METHODS: This was a retrospective analysis of patients with stage IV NETs, classified as group 1 (unilobar liver metastases), group 2 (bilobar liver metastases), group 3 (extra-abdominal metastases). End points were overall survival (OS) and progression-free survival (PFS). Risk factor analysis was performed using Cox proportional hazard model. RESULTS: Of the 229 patients, 135 (58.9%) had pancreatic, and 94 (41.1%) small bowel NETs: 32 (13.9%) were included in group 1, 179 (78.2%) in group 2, and 18 (7.9%) in group 3. Median Ki67 was 4.5%. Overall, 5-year OS was 55%. Different OS was observed among the 3 groups: median survival not reached, 81 and 8 months, respectively (P < 0.001). Median PFS was 18 months. Both OS and PFS were significantly affected by Ki67 and metastatic spread pattern. CONCLUSIONS: The stratification of stage IV NET patients based on metastatic patterns, alongside Ki67, predicts the clinical outcome. The extent of metastatic disease is a previously unrecognized variable, which should be considered when evaluating the results of treatments in NET patients with advanced disease.

The role of lymph node ratio in recurrence after curative surgery for pancreatic endocrine tumours.

BACKGROUND: The prognostic role of lymph nodes metastasis in pancreatic neuroendocrine tumours is unclear. METHODS: Retrospective study of 53 patients who underwent a curative standard resection for pancreatic neuroendocrine tumours. The endpoint was to define the role of the lymph nodes ratio in recurrence after curative surgery. The following data were considered as possible factors for predicting the risk of recurrence: gender, age, presence of symptoms, hormonal status, site of tumours, type of resection, size of the tumours, radical resection, pathological T, N and M stage, the Ki67 index, the number of lymph nodes harvested, the number of metastatic lymph nodes and the lymph node ratio. Recurrence rate and time of recurrence were evaluated. RESULTS: Twelve (26.4%) patients developed a recurrence with a median time of 42.8 (1-305) months. At multivariate analysis, the only factors related to recurrence were: size of lesions (HR 1.1, C.I. 95% 1.0-1.1, P = 0.011), Ki67 ≥ 5% (HR 3.6, C.I. 95% 1.3-10, P = 0.014) and LNR > 0.07 (HR 5.2, C.I. 95% 1.1-25, P = 0.045). CONCLUSIONS: Our study confirmed that the lymph nodes ratio played an important role in the recurrence rate and suggested that a low number of metastatic lymph nodes reduced the disease free survival.

Radiolabelled somatostatin analogue treatment in gastroenteropancreatic neuroendocrine tumours: factors associated with response and suggestions for therapeutic sequence.

PURPOSE: Peptide receptor radionuclide therapy (PRRT) is a relatively new treatment modality for patients with unresectable or metastatic gastroenteropancreatic neuroendocrine tumours (GEP NETs). The aim of this study was to determine the time to progression of patients treated with PRRT and to identify the prognostic factors related to treatment response. METHODS: Patients with sporadic GEP NETs prospectively treated with PRRT were retrospectively analysed. The primary end point was progression-free survival (PFS). RESULTS: A total of 69 patients (37 men and 32 women; 45 with pancreatic and 24 with gastrointestinal lesion; 22 NET G1 and 41 NET G2) were treated with (90)Y or (177)Lu. The objective response rate was 27.5% (partial response, PR), while 50.7% had stable disease and 23.2% had progressive disease. Significant differences in PFS were observed in relationship to the stage of the disease (44 months for stage III, 23 months for stage IV), the evidence of a PR 6 months after the end of the PRRT (39 months in patients with a PR, 22 months in patients without a PR) and previous transarterial chemoembolization (TACE, yes 13 months vs no 31 months). Stage IV, NET G2 and previous TACE were found to be significant factors for tumour progression at multivariate analysis. CONCLUSION: Low tumour burden and a low proliferation index represent independent prognostic factors for long PFS, while previous chemoembolization techniques represent independent prognostic factors for early tumour progression and shorter PFS. Our data suggest that chemoembolization techniques to reduce the hepatic tumour burden should be avoided.

Contrast-enhanced ultrasound in the differential diagnosis of exocrine versus neuroendocrine pancreatic tumors.

OBJECTIVES: Contrast-enhanced ultrasound (CEUS) has been developed to better characterize the microvasculature of solid masses in several organs, including the pancreas. In this study, we assessed CEUS accuracy in differentiating exocrine from endocrine pancreatic tumors. METHODS: A total of 127 patients with single, undetermined pancreatic masses were prospectively examined with transabdominal ultrasound and CEUS, before surgical resection or percutaneous biopsy. RESULTS: Exocrine and endocrine pancreatic tumors showed different intralesional vascularization patterns: 98.9% (90/91) of exocrine tumors were hypoenhancing, whereas 95.8 % (23/24) of endocrine tumors had a hypervascular supply. A hypoenhancing pattern, indicative of ductal adenocarcinoma, had a significant (P < 0.001) diagnostic accuracy of 91.3% with a sensitivity of 96.8%, a specificity of 85.3%, a positive predictive value and a negative predictive value of 94.7% and 90.6%, respectively. The hyperenhancing pattern, indicative of endocrine tumors, had a significant (P = 0.031) diagnostic accuracy of 73.8% with a sensitivity of 83.3%, a specificity of 60.0%, a positive predictive value and negative predictive value of 83.3% and 60.0%, respectively. CONCLUSIONS: Contrast-enhanced ultrasound has a valuable diagnostic accuracy in differentiating exocrine from endocrine pancreatic tumors, which is a fundamental step to address appropriate histological evaluation, therapeutic approach, and follow-up.