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).

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.

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.

Everolimus for advanced pancreatic neuroendocrine tumors.

BACKGROUND: Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study. METHODS: We randomly assigned 410 patients who had advanced, low-grade or intermediate-grade pancreatic neuroendocrine tumors with radiologic progression within the previous 12 months to receive everolimus, at a dose of 10 mg once daily (207 patients), or placebo (203 patients), both in conjunction with best supportive care. The primary end point was progression-free survival in an intention-to-treat analysis. In the case of patients in whom radiologic progression occurred during the study, the treatment assignments could be revealed, and patients who had been randomly assigned to placebo were offered open-label everolimus. RESULTS: The median progression-free survival was 11.0 months with everolimus as compared with 4.6 months with placebo (hazard ratio for disease progression or death from any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<0.001), representing a 65% reduction in the estimated risk of progression or death. Estimates of the proportion of patients who were alive and progression-free at 18 months were 34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with placebo. Drug-related adverse events were mostly grade 1 or 2 and included stomatitis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash (49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23% vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyperglycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure to placebo by a factor of 2.3 (38 weeks vs. 16 weeks). CONCLUSIONS: Everolimus, as compared with placebo, significantly prolonged progression-free survival among patients with progressive advanced pancreatic neuroendocrine tumors and was associated with a low rate of severe adverse events. (Funded by Novartis Oncology; RADIANT-3 ClinicalTrials.gov number, NCT00510068.).

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.

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.

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.

Final results of a phase 2A study for the treatment of metastatic neuroendocrine tumors with a fixed activity of 90Y-DOTA-D-Phe1-Tyr3 octreotide.

BACKGROUND: The objective of this study was to assess the efficacy of (90)Y-DOTA-D-Phe1-Tyr3 octreotide ((90)Y-DOTATOC) therapy with a fixed activity of 2.56 GigaBequerels bimonthly in patients with advanced stage, well differentiated neuroendocrine carcinomas. METHODS: In total, 38 patients were enrolled in this phase 2A protocol. All patients had gastroenteropancreatic neuroendocrine tumors in sharp clinical and radiologic progression despite previous surgery, chemotherapy, and biotherapy. Their survival rate after therapy with (90)Y-DOTATOC was compared with a chronologic control group of patients who had received biotherapy and chemotherapy and with results from a previous similar study. The progression-free survival rate after peptide receptor radionuclide therapy with (90)Y-DOTATOC was determined for all patients until they had documented disease progression according to Response Criteria in Solid Tumors, tumor-related death, or censoring. RESULTS: Seventeen patients (43.6%) had a partial response, 10 patients (25.6%) had stable disease, and 11 patients (28.2%) had progressive disease. A statistically significant difference was observed (P < .001) between the response to (90)Y-DOTATOC treatment and the response to biotherapy with somatostatin analogs and chemotherapy and also between the current results and the results from a previous similar study (P < .05). At the time of the current evaluation with ongoing follow-up for 30 patients, the median progression-free survival was 22.3 months. CONCLUSIONS: The results from this phase 2 study indicated that the treatment of metastatic neuroendocrine tumors with fixed (90)Y-DOTATOC activity is useful and safe.

68Ga-labelled peptides for diagnosis of gastroenteropancreatic NET.

In the past few years, the introduction of novel PET tracers labelled with (68)Ga has changed the diagnostic approach to neuroendocrine tumours (NET) in specialized centres. Although somatostatin analogue tracers labelled with (111)In have represented the gold standard imaging modality for NET detection in past decades, the advantages offered by both labelling somatostatin analogues with (68)Ga and using PET/CT tomography for image acquisition, account for the increasing use of these tracers in clinical practice. There are an increasing number of reports of the higher accuracy of (68)Ga-DOTA peptide PET/CT for the detection of NET lesions as compared to morphological imaging procedures and somatostatin receptor scintigraphy. Moreover, the use of (68)Ga-DOTA peptides offers the possibility to noninvasively evaluate NET cells for the presence of somatostatin receptor expression, with direct therapeutic implications. Several practical advantages also favour the use of (68)Ga-DOTA peptides including the relatively easy and economic synthesis process and the fact that (68)Ga labelling can be performed in centres without an on-site cyclotron. We describe the advantages and limitations of (68)Ga-DOTA peptide PET/CT imaging for the assessment of gastroenteropancreatic NET referring to the available literature as well as to our experience, and finally highlight potential future perspectives.

Is 68Ga-DOTA-NOC PET/CT indicated in patients with clinical, biochemical or radiological suspicion of neuroendocrine tumour?

PURPOSE: In recent years, (68)Ga-DOTA-peptides positron emission tomography (PET)/CT has been increasingly used to study patients with neuroendocrine tumours (NET). However, performing specialized examinations in the appropriate contest is mandatory for both medical and economic reasons. The aim of the study is to evaluate the potential usefulness of (68)Ga-DOTA-NOC PET/CT in patients with suspected NET. METHODS: Among the patients undergoing (68)Ga-DOTA-NOC PET/CT at our centre, we reviewed those studied for suspected NET based on the presence of either clinical signs/symptoms or imaging or raised biochemical markers or a combination of these conditions. PET/CT results were compared with clinical and imaging follow-up of at least 1 year or pathology. RESULTS: Overall 131 suspected NET cases were included. The most common condition considered suspicious for NET was the increase of blood markers (66), followed by inconclusive findings at conventional imaging (CI, 41), clinical signs/symptoms (10), equivocal (18)F-fluorodeoxyglucose (FDG) PET (7) or somatostatin receptor scintigraphy (SRS, 4), or a combination of the above (3). PET/CT results were true-positive in 17 cases, true-negative in 112 and false-negative in 2 (overall sensitivity 89.5 %, specificity 100 %). Interestingly, increased blood markers and clinical signs/symptoms were associated with the lowest frequency of true-positive findings (1/66 and 1/10, respectively), while CI findings were confirmed in one third of the cases (13/41). Overall, the incidence of NET in the studied population was 14.5 % (19/131). CONCLUSION: Our data confirm the good accuracy (98 %) of (68)Ga-DOTA-NOC PET/CT in NET lesion detection. However, our results also suggest that (68)Ga-DOTA-NOC PET/CT may not be routinely recommended in patients with a suspicion of NET based on the mere detection of increased blood markers or clinical symptoms. Positive CI alone or in association with clinical/biochemical findings is on the contrary associated with a higher probability of true-positive findings.

Risk factors for disease progression in advanced jejunoileal neuroendocrine tumors.

BACKGROUND: Knowledge of clinical course in advanced jejunoileal neuroendocrine tumors (NETs) is poor. AIM: To investigate progression-free survival (PFS), overall survival (OS), and possible predictors for disease progression (DP) in advanced jejunoileal NETs. PATIENTS AND METHODS: We carried out a multicenter, retrospective analysis of incoming patients with sporadic advanced jejunoileal NETs. PFS and OS were assessed by Kaplan-Meier analysis. Risk factors for progression were analyzed by the Cox proportional hazards method. RESULTS: Of the 114 patients enrolled, 46.5% had functioning tumors, 93.9% had stage IV disease, and 57.3 and 42.7% were G1 and G2 tumors, respectively. During a median follow-up of 48 months (interquartile range 29-84 months), DP occurred in 61.4% of patients, after 19 months (interquartile range 10-41 months) from diagnosis. Median PFS was 36 months. The 2-year and 5-year PFS were 59 and 33%, respectively, while 5-year OS was 77.5%. Ki67 was the sole strong independent risk factor for unfavorable outcome according to multivariate analysis, being significantly associated with both PFS and OS. CONCLUSIONS: DP occurred in the majority of patients with advanced jejunoileal NETs, with median PFS being 36 months. Ki67 was a significant predictor of DP and should be considered in determining appropriate treatments and planning follow-up for these patients.

Clinicopathological features of pancreatic endocrine tumors: a prospective multicenter study in Italy of 297 sporadic cases.

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.

(68)Ga-DOTA-NOC PET/CT in comparison with CT for the detection of bone metastasis in patients with neuroendocrine tumours.

PURPOSE: To retrospectively evaluate the sensitivity, specificity and accuracy of (68)Ga-DOTA-NOC PET/CT and CT alone for the evaluation of bone metastasis in patients with neuroendocrine tumour (NET). METHODS: From among patients with NET who underwent (68)Ga-DOTA-NOC PET/CT between April 2006 and November 2008 in our centre, 223 were included in the study. Criteria for inclusion were pathological confirmation of NET and a follow-up period of at least 10 months. PET and CT images were retrospectively reviewed by two nuclear medicine specialists and two radiologists, respectively, without knowledge of the patient history or the findings of other imaging modalities. PET data were compared with the CT findings. Interobserver agreement was evaluated in terms of the kappa score. Clinical and imaging follow-up were used as the standard of reference to evaluate the PET findings. RESULTS: PET was performed for staging (49/223), unknown primary tumour detection (24/223), restaging (32/223), restaging before radioimmunotherapy (1/223), evaluation during therapy (12/223), equivocal findings on conventional imaging (4/223 at the bone level; 61/223 at sites other than bone), and follow-up (40/223). A very high interobserver agreement was observed. CT detected at least one bone lesion in only 35 of 44 patients with a positive PET scan. In particular, PET showed more lesions in 20/35 patients, a lower number of lesions in 8/35, and the same number in 7/35. The characteristics of the lesions (sclerotic, lytic, mixed) on the basis of the CT report did not influence PET reading. PET revealed the presence of at least one bone metastasis in nine patients with a negative CT scan. Considering patients with a negative PET scan (179), CT showed equivocal findings at the bone level in three (single small sclerotic abnormality in two at the spine level, and bilateral small sclerotic abnormalities in the humeri, femurs and scapula). Clinical follow-up confirmed the PET findings in all patients; thus there were no false-positive or false-negative findings. Considering all patients, PET detected more lesions than CT (246 vs. 194). As compared to CT, on a patient basis PET showed a higher sensitivity (100% vs. 80%), specificity (100% vs. 98%), positive predictive value (100% vs. 92%), and negative predictive value (100% vs. 95%). CONCLUSION: In conclusion, (68)Ga DOTA-NOC PET was more accurate than CT for the identification of bone lesions and led to a change in clinical management in nine patients with a negative CT scan.

Are there prognostic factors related to recurrence in pancreatic endocrine tumors?

AIMS: The aim of this study was to evaluate the rate, site, time of recurrence and prognostic factors related to the appearance of recurrences in patients affected by pancreatic endocrine tumors (PETs). METHODS: Data from 67 consecutive patients with PETs who underwent R0 resection were analyzed. The prognostic factors considered were: gender, age, type of tumor, presence of symptoms, size of tumor, tumor node metastasis (TNM) stage, WHO classification and adjuvant therapy. RESULTS: The recurrence rate was 24.6%, with a mean time of 7.3 +/- 4.5 years. The majority were in the liver (75% of cases) and were rarely local (25%). Univariate analysis of the prognostic factors showed that the risk of recurrences is significantly higher in PETs in MEN-1 syndrome, in tumor size > or =4 cm, in the presence of liver metastases, in TNM stages III-IV and, finally, in PD-Cas and WD-Cas. Multivariate Cox regression analysis showed that only MEN-1 syndrome and the WHO classification were independent predictors of an increased risk of recurrence. CONCLUSIONS: Several prognostic factors were related to recurrences in PETs. MEN-1 syndrome and the WHO classification can be considered independent factors of an increased risk of recurrence. and IAP.

Management of patients with gastrointestinal stromal tumor in clinical practice in Italy: a critical "event tree model" analysis of decision-making processes and outcomes.

AIMS AND BACKGROUND: Even though the standard treatment of patients affected by gastrointestinal stromal tumors has been well defined by clinical trials and clinical guidelines, in practice it may be different from those proposed in the literature. This paper reports and comments on a critical picture of the management of patients with gastrointestinal stromal tumors who received at least one treatment before arriving at our GIST Study Group. METHODS AND STUDY DESIGN: Attention was focused on 60 patients from various hospitals. Retrospective clinical data were recorded and analyzed with the "event tree" model, which describes the algorithm of all treatment options that each patient received before. Responses from first to fourth line of therapy, time to progression, and survival analysis were also analyzed. RESULTS: Starting from the diagnosis of disease, seven possible therapeutic event trees were identified: one for 7 unresectable patients and six different trees for 53 recurred patients who initially underwent surgery. The event trees describe the multitude of different treatments that patients with gastrointestinal stromal tumors received during the course of their disease. CONCLUSIONS: In clinical practice, the treatment of patients affected by gastrointestinal stromal tumor is still difficult, and the published recommendations often do not cover all therapeutic decisions for all clinical presentations of disease. Multidisciplinary dedicated teams are needed to offer the possibility to receive appropriate surgery and innovative medical therapies. The formation of formalized GIST Units is in progress in several parts of Italy. The GIST Units can be organized in a network to facilitate discussion and agreement for the wide variety of clinical presentation.

Value of both WHO and TNM classification systems for patients with pancreatic endocrine tumors: results of a single-center series.

OBJECTIVES: This study was designed to evaluate the clinical relevance of the World Health Organization (WHO) and tumor node metastasis (TNM) classifications in patients affected by pancreatic endocrine tumors. METHODS: Data from 76 consecutive patients with pancreatic endocrine tumors who underwent surgery were analyzed. RESULTS: Well-differentiated tumors were observed more frequently (57.9%) than well or poorly differentiated carcinomas (26.3% and 15.8%, respectively). The TNM stage was I in 27.6%, II in 39.5%, III in 19.7%, and IV in 13.2%. Univariate analysis of disease-specific survival showed that patients with stages I-II had a significantly better survival rate than those with stages III-IV (hazard ratio (HR), 12.46; 95% confidence interval (CI), 1.53-101.32; P = 0.018; HR, 25.74; 95% CI, 3.07-216.07; P = 0.003, respectively). Regarding the WHO classification, poorly differentiated carcinomas had the worst prognosis (HR, 79.13; 95% CI, 9.99-626.60; P < 0.001). Multivariate Cox regression analysis of disease-specific survival showed that the WHO classification is the only independent factors of improved survival: both poorly and well-differentiated carcinomas had an increased risk of death compared with WDTs (HR, 100.42; 95% CI, 12.16-829.40; P < 0.001; HR, 10.73; 95% CI, 1.12-104.17; P = 0.040, respectively). TNM classification and the WHO system are highly correlated (P < 0.001). CONCLUSIONS: TNM stage and the WHO classification seems to be equally reliable, even if TNM classification tends to understage the patients classified using the WHO system.

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.