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CSES (China Seismo-Electromagnetic Satellite) is a Chinese–Italian scientific space mission dedicated to monitor the variations of the main parameters of the topside ionosphere (electric and magnetic fields, plasma parameters, charge particle fluxes) caused by either natural emitters – especially earthquakes – or artificial ones. The CSES satellite was successfully launched from the Jiuquan Satellite Launch Center located in the west of Inner Mongolia on February 2nd, 2018, and it is now orbiting under nominal conditions. The expected mission lifetime amounts to 5 years. CSES is the first element of a multi-satellite monitoring system; several satellites are scheduled for the next few years. The High-Energy Particle Detector (HEPD) is the main contribution of the Italian collaboration to the mission. It was designed and built in order to detect electrons in the energy range between 3 and 100 MeV, protons between 30 and 200 MeV, and light nuclei in the MeV energy window. The electronics of the detector was designed following stringent requirements on mechanical and thermal stability, power consumption, radiation hardness and double redundancy. The system successfully went through the space qualification tests. In this paper, we describe the HEPD electronics, the space qualification tests performed before launch, and the in-flight performance of the detector.

Mini-EUSO is a telescope launched on board the International Space Station in 2019 and currently located in the Russian section of the station. Main scientific objectives of the mission are the search for nuclearites and Strange Quark Matter, the study of atmospheric phenomena such as Transient Luminous Events, meteors and meteoroids, the observation of sea bioluminescence and of artificial satellites and man-made space debris. It is also capable of observing Extensive Air Showers generated by Ultra-High Energy Cosmic Rays with an energy above 10$^{21}$ eV and detect artificial showers generated with lasers from the ground. Mini-EUSO can map the night-time Earth in the UV range (290 - 430 nm), with a spatial resolution of about 6.3 km and a temporal resolution of 2.5 μs, observing our planet through a nadir-facing UV-transparent window in the Russian Zvezda module. The instrument, launched on 2019/08/22 from the Baikonur cosmodrome is based on an optical system employing two Fresnel lenses and a focal surface composed of 36 Multi-Anode Photomultiplier tubes, 64 channels each, for a total of 2304 channels with single photon counting sensitivity and an overall field of view of 44°. Mini-EUSO also contains two ancillary cameras to complement measurements in the near infrared and visible ranges. In this paper we describe the detector and present the various phenomena observed in the first year of operation.

Typical (TC) and atypical (AC) carcinoids are low-grade neuroendocrine tumors (NETs) of the lung and, are neglected diseases in respect of both high-grade NETs of the lung (i.e. small-cell lung cancer and large-cell neuroendocrine carcinoma) and gastroenteropancreatic (GEP)-NETs. AC and TC account for 2 and 0.2% of all thoracic malignancies, respectively, and have a 12.9% chance of metastatic spread at diagnosis, reaching up to 20% during disease history. There are very few trials specifically designed for lung NETs, and therapeutic options are mainly derived by studies carried out in patients with GEP-NETs. We report a case of a patient affected by AC progressed to available standard treatments who received off-label treatment with sunitinib, a well-known multitarget tyrosine-kinase inhibitor with marked antiangiogenic activity, used routinely for the treatment of GEP-NETs. During treatment, the patient required the administration of an alternative schedule to improve tolerability, with benefit, and achieved a partial response according to the RECIST criteria, which is unusual in NETs. We critically reviewed available data supporting the use of somatostatin analogs, chemotherapy, and target therapies (everolimus and sunitinib) in advanced lung NETs. In the review, ongoing trials in lung NETs and future developments in this research field are also discussed.

Background Gastric neuroendocrine neoplasias (gNEN) are defined as type I if associated with atrophic body gastritis and type III when tumour is sporadic. This classification, together with grading and size, plays a crucial prognostic role. Nevertheless, the impact of these features on clinical outcome is not clear. Aim To identify factors predicting poor outcome. Patients and methods Analysis of type I and type III gNEN. A composite endpoint was defined if tumour-related death or metastases or angioinvasion were observed. Results 156 gNENs were evaluated: 137 (87.8%) type I and 19 (12.2%) type III. Among type I, 103 were G1 (75.2%) and 34 (24.8%) were G2. In type III group, 8 were G1 (42.1%), 10 were G2 (52.6%), and 1 was G3 (5.3%). Negative endpoint occurred in 18 patients including 10 type III and 8 type I. Male gender (p = 0.032), tumour type (p = 0.003) and size >10 mm (p = 0.024) were predictors for poor outcome, whereas Ki67 was not confirmed on multivariate analysis (p = 0.192). 5-yr survival rates in type I and type III were 100% and 76.2%, respectively (p = 0.0002). Conclusions Tumour size, tumour type and gender affect clinical outcome in gNENs. In contrast to NENs rising from other sites, Ki67 plays a less important role.

BACKGROUND: Information on malignant pancreatic neuroendocrine neoplasms (pNENs) is mostly from retrospective studies in highly selected patients. The aim of this prospective, multicentre study was to assess treatment and outcomes of malignant pNENs in clinical practice. PATIENTS AND METHODS: Consecutive patients with newly diagnosed, histologically-proven pNENs were included and followed-up for 2 years. Tumours were defined as malignant when nodal or distant metastases were present or invasion of extrapancreatic structures/organs was evident. RESULTS: A total of 140 patients with malignant pNENs were included. Ninety-eight patients (70.0%) underwent a surgical resection (76 radical and 22 palliative). Other non-surgical treatments were used in 101 patients (72.1%): somatostatin analogues (n = 63), chemotherapy (n = 30), ablative treatments (n = 15) and peptide-receptor radionuclide therapy (n = 14). No relationship was observed between the 2010 WHO classification and type of treatment. A surgical resection was more often performed in incidentally detected tumours located in the pancreas body tail. Two-year progression-free survival was 63.8%: 82% after a radical resection, 44% after a palliative resection and 41% without a resection. A radical resection and Ki67 proliferative index >5% and >10% were the only significant prognostic determinants in multivariate analysis. CONCLUSIONS: A radical resection is the cornerstone treatment of malignant pNENs and represents, together with Ki67 assessment, the most powerful prognostic factor for 2-year outcomes.

Introduction The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. Methods A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 Results The main modification in the centers’ activity consisted of decreases in newly diagnosed NEN patients (− 76.8%), decreases in performed surgical procedures (− 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams’ activity (20.8%). A low proportion of centers (

Purpose: Pretreatment staging is the milestone for planning either surgical or endoscopic treatment in duodenal neuroendocrine neoplasms (dNENs). Herein, a series of surgically treated dNEN patients was evaluated to assess the concordance between the pre- and postsurgical staging. Methods: Retrospective analysis of patients with a histologically confirmed diagnosis of dNENs, who underwent surgical resection observed at eight Italian tertiary referral centers. The presurgical TNM stage, based on the radiological and functional imaging, was compared with the pathological TNM stage, after surgery. Results: From 2000 to 2019, 109 patients were included. Sixty-six patients had G1, 26 a G2, 7 a G3 dNEN (Ki-67 not available in 10 patients). In 46/109 patients (42%) there was disagreement between the pre- and postsurgical staging, being it understaged in 42 patients (38%), overstaged in 4 (3%). As regards understaging, in 25 patients (22.9%), metastatic loco-regional nodes (N) resulted undetected at both radiological and functional imaging. Understaging due to the presence of distal micrometastases (M) was observed in 2 cases (1.8%). Underestimation of tumor extent (T) was observed in 12 patients (11%); in three cases the tumor was understaged both in T and N extent. Conclusions: Conventional imaging has a poor detection rate for loco-regional nodes and micrometastases in the presurgical setting of the dNENs. These results represent important advice when local conservative approaches, such as endoscopy or local surgical excision are considered and it represents a strong recommendation to include endoscopic ultrasound in the preoperative tools for a more accurate local staging.

Background Outcomes after surgery for sporadic pancreatic neuroendocrine neoplasms (Pan-NENs) were evaluated. Methods This multicentre study included patients who underwent radical pancreatic resection for sporadic non-functioning Pan-NENs. In survival analysis, the risk of mortality in this cohort was analysed in relation to that of the matched healthy Italian population. Relative survival (RS) was calculated as the rate between observed and expected survival. Factors related to RS were investigated using multivariable modelling. Results Among 964 patients who had pancreatic resection for sporadic non-functioning Pan-NENs, the overall RS rate was 91.8 (95 per cent c.i. 81.5 to 96.5) per cent. 2019 WHO grade (hazard ratio (HR) 5.75 (s.e. 4.63); P = 0.030) and European Neuroendocrine Tumour Society (ENETS) TNM stage (6.73 (3.61); P Conclusion A surgical approach seems without benefit for Pan-NECs, and unnecessary for small G1 sporadic Pan-NENs. Surgery alone may be insufficient for stage III–IV and G3 Pan-NENs.

Background: Patients with sporadic neuroendocrine neoplasms may exhibit a higher risk of a second primary tumor than the general population. Aim: This study aimed to analyze the occurrence of second primary malignancies.Methods: A retrospective cohort of 2757 patients with sporadic lung and gastro-entero-pancreatic neuroendocrine neoplasms, managed at eight Italian tertiary referral Centers, was included.Results: Between 20 0 0 and 2019, a second primary malignancy was observed in 271 (9.8%) neuroendocrine neoplasms patients with 32 developing a third tumor. There were 135 (49.8%) females and the median age was 64 years. The most frequent locations of the second tumors were breast (18.8%), prostate (12.5%), colon (9.6%), blood tumors (8.5%), and lung (7.7%). The second primary tumor was synchronous in 19.2% of cases, metachronous in 43.2%, and previous in 37.6%. As concerned the neuroendocrine neoplasms, the 5and 10-year survival rates were 87.8% and 74.4%, respectively. PFS for patients with a second primary malignancy was shorter than for patients without a second primary malignancy. Death was mainly related to neuroendocrine neoplasms.Conclusion: In NEN patients the prevalence of second primary malignancies was not negligible, suggest ing a possible neoplastic susceptibility. Overall survival was not affected by the occurrence of a second primary malignancy. (C) 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.

Purpose To evaluate the antiproliferative activity and safety of nonconventional high doses of somatostatin analogs (HD-SSA) in patients with well-differentiated gastroenteropancreatic (GEP) neuroendocrine tumors (NET) with radiological disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria on a previous treatment. Methods A retrospective analysis of prospectively maintained databases from 13 Italian NET-dedicated centers was performed. Main inclusion criteria were: well-differentiated G1 or G2 GEP-NET, progressive disease on a previous treatment, and subsequent treatment with HD-SSA (either by increased administered dose [dose intensity] or shortened interval between administrations [dose density]). Main endpoints were progression-free survival (PFS) and safety. Results Of 198 patients, 140 matched inclusion criteria and were included in the analysis. Overall, median PFS was 31 months. Use of HD-SSA as second-line treatment was associated with reduced risk for progression or death compared with third- or further-line treatment (HR: 2.12; P = 0.004). There was no difference in PFS between HD-SSA by increased dose density (N = 133; 95%) or intensity (N = 7; 5%). Partial response according to RECIST criteria was observed in 12 patients (8.6%), and stable disease was achieved in 106 (75.7%) patients. Adverse events occurred in 21 patients (15.0%), 2 of whom had grade 3 biliary stone disease. No patients discontinued HD-SSA treatment due to adverse events. Conclusions HD-SSA is an active and safe treatment option in patients with progressive well-differentiated GEP-NET. The high rate of objective responses observed deserves prospective validation in ad hoc clinical trials.

Gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs) with favorable pathological and clinical features may be considered as indolent lesions, and therefore be amenable to conservative management. According to the primary tumor site, different non-aggressive approaches, based on endoscopic resection or simple active surveillance, can be proposed to selected patients fulfilling specific criteria. Tumor size, Ki67 proliferative index and depth of invasion are markers that can be used in order to identify these subjects. Patients with type I gastric NENs

Background Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA-treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA-treated patients with NETs. Materials and methods A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start. Results A total of 754 SSA-treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)-NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease. Conclusion We report a high incidence of biliary stone disease particularly in GI-NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned. Implications for practice The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease.

Overall survival (OS) is considered as the standard measure of outcome in oncology. However, considering that resectable pancreatic neuroendocrine neoplasms (Pan-NENs) usually have a long OS, the feasibility of prospective studies is questionable due to a long follow-up period needed. The primary endpoint was to validate the use of disease-free survival (DFS) as a surrogate measure of OS. The secondary endpoint was to calculate the gain in sample size using DFS instead of OS in hypothetical prospective studies with two parallel groups. A systematic review of studies reporting both OS and DFS in resected Pan-NENs was carried out. Multivariate linear regression analysis was used to evaluate if DFS predicts the OS in patients undergoing radical resection. Monte Carlo simulation was performed to estimate the gain in sample size, supposing the use of DFS instead of OS, to evaluate a hypothetical adjuvant treatment after surgery in a randomized trial. Six studies reporting data about seven cohorts of resected Pan-NENs were included, for a total of 1088 patients. The median OS and DFS were 144 (27–134) and 122 (50–267) months, respectively. There was a significant correlation between DFS and OS (R2 = 0.988; P = 0.035). Monte Carlo simulations showed that the number of patients needed to demonstrate a significant reduction of probability of a ‘target event’ in a hypothetical two-arm group exploring the hypothetical role of adjuvant therapy was reduced using DFS instead OS. This finding supports the legitimacy of using DFS as an acceptable surrogate for OS in surgical clinical trials.

The radiation belts in the Earth’s magnetosphere pose a hazard to satellite systems and spacecraft missions (both manned and unmanned), heavily affecting payload design and resources, thus resulting in an impact on the overall mission performance and final costs. The NASA AE9/AP9/SPM radiation models for energetic electrons, protons, and plasma provide useful information on the near-Earth environment, but they are still incomplete as to some features and, for some energy ranges, their predictions are not based on a statistically sufficient sample of direct measurements. Therefore, it is of the upmost importance to provide new data and direct measurements to improve their output. In this work, the AP9 model is applied to the China Seismo-Electromagnetic Satellite (CSES-01) orbit to estimate the flux of energetic protons over the South Atlantic Anomaly during a short testing period of one day, 1 January 2021. Moreover, a preliminary comparison with proton data obtained from the High-Energy Particle Detector (HEPD) on board CSES-01 is carried out. This estimation will serve as the starting ground for a forthcoming complete data analysis, enabling extensive testing and validation of current theoretical and empirical models.

Background: The optimal management of duodenal neuroendocrine neoplasms (dNENs) is unclear, and endoscopic resection is increasingly performed instead of surgery. Methods: This is a retrospective analysis of patients with histologically confirmed diagnosis of dNENs, managed at five Italian tertiary referral Centers in Italy. Results: From 2000 to 2017, 108 patients (69 males, 39 females, median age 59.5years) were included in this study. Seventy-one patients had G1, 21 G2, 4 G3 dNENs (12 Ki-67 not available). Fifty-four patients showed metastases at diagnosis, and 20 patients developed metachronous metastases. Thirty patients had a functioning dNEN (14 metastatic). Fifty-seven patients had the dNEN surgically resected, 16 endoscopically, 23 metastatic, received medical therapy + surgery or endoscopy. Seven patients underwent liver-directed therapies, and one patient had PRRT. Median OS was 187months. During a median follow-up of 76months, 20 patients died (19 of disease-related causes). At Cox’s multivariate proportional hazard regression, grading and age were the only variables independently related to OS. Median PFS was 170months. Grading and staging at the initial diagnosis were independently related to PFS. No differences in terms of OS and PFS were observed between patients treated surgically or endoscopically. Conclusions: dNENs prognosis may be highly variable. These tumors can be metastatic in up to 50% of cases at the time of first diagnosis and can develop metastases thereafter. Functioning neoplasms express high metastatic potential. Nuclear imaging should be performed to exclude distant metastases in all dNENs. Endoscopy and surgery play a primary role in the management of the disease. Further prospective studies are needed.

Introduction Besides data reported in a Phase-III trial, data on sunitinib in pancreatic Neuroendocrine Tumors (panNETs) are scanty. Aim To evaluate sunitinib efficacy and tolerability in panNETs patients treated in a real-world setting. Patients and methods Retrospective analysis of progressive panNETs treated with sunitinib. Efficacy was assessed by evaluating progression-free survival, overall survival, and disease control (DC) rate (stable disease (SD) + partial response + complete response). Data are reported as median (25th–75th IQR). Results Eighty patients were included. Overall, 71.1% had NET G2, 26.3% had NET G1, and 2.6% had NET G3 neoplasms. A total of 53 patients (66.3%) had received three or more therapeutic regimens before sunitinib, with 24 patients (30%) having been treated with four previous treatments. Median PFS was 10 months. Similar risk of progression was observed between NET G1 and NET G2 tumors (median PFS 11 months and 8 months, respectively), and between patients who had received ≥ 3 vs ≤ 2 therapeutic approaches before sunitinib (median PFS 9 months and 10 months, respectively). DC rate was 71.3% and SD was the most frequent observed response, occurring in 43 pts (53.8%). Overall, 59 pts (73.8%) experienced AEs, which were grade 1–2 in 43 of them (72.9%), grade 3 in 15 pts (25.4%), and grade 4 in one patient (1.7%). Six pts (7.5%) stopped treatment due to toxicity. Conclusions The present real-world experience shows that sunitinib is a safe and effective treatment for panNETs, even in the clinical setting of heavily pre-treated, progressive diseases.

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.

The China Seismo-Electromagnetic Satellite (CSES) aims to monitor electromagnetic, particle, and plasma perturbations in the iono-magnetosphere and inner Van Allen radiation belts originated by electromagnetic sources external and internal to the geomagnetic cavity, cosmic rays, and solar events. In particular, the objective of the space mission is to investigate lithosphere-atmosphere-ionosphere coupling mechanisms (including the effects of lightning, earthquakes, volcanoes, and artificial electromagnetic emissions) that induce perturbations of the top side of the ionosphere and lower boundary of the radiation belts. To this purpose, the mission has been conceived to take advantage of a multi-instrument payload comprising nine detectors for the measurement of electromagnetic field components, plasma parameters, and energetic particles, as well as X-ray flux. The Italian team participating in the CSES mission has built one of these devices, the High-Energy Particle Detector (HEPD), for high-precision observations of electrons, protons, and light nuclei. During its trip along the orbit, and thanks to the large set of detectors operated on board, CSES completely monitors the Earth, acting as an excellent instrument for space weather. The satellite was launched on 2018 February 2, with an expected life span of 5 yr. This article describes the CSES mission with a particular focus on the HEPD apparatus and its in-flight performance.

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 < .001) and tumor differentiation (P < .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 < .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.

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 90Y or 177Lu. 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.

Aim/Introduction: Digital PET/CT allows Q.Clear image reconstruction with different Beta (β) levels. However, no definitive standard β level for [68Ga]Ga-DOTANOC PET/CT has been established yet. As patient’s body mass index (BMI) can affect image quality, the aim of the study was to visually and semi-quantitatively assess different β levels compared to standard OSEM in overweight patients. Materials and methods: Inclusion criteria: (1) patients with NEN included in a prospective CE-approved electronic archive; (2) [68Ga]Ga-DOTANOC PET/CT performed on a digital tomograph between September2019/March2021; (3) BMI ≥ 25. Images were acquired following EANM guidelines and reconstructed with OSEM and Q.Clear with three β levels (800, 1000, 1600). Scans were independently reviewed by three expert readers, unaware of clinical data, who independently chose the preferred β level reconstruction for visual overall image quality. Semi-quantitative analysis was performed on each scan: SUVmax of the highest uptake lesion (SUVmax-T), liver background SUVmean (SUVmean-L), SUVmax-T/SUVmean-L, Signal-to-noise ratio for both liver (LSNR) and the highest uptake lesion (SNR-T), Contrast-to-noise ratio (CNR). Results: Overall, 75 patients (median age: 63years old [23–87]) were included: pre-obesity sub-group (25 ≤ BMI < 30, n = 50) and obesity sub-group (BMI ≥ 30, n = 25). PET/CT was positive for disease in 45/75 (60.0%) cases (14 obese and 31 pre-obese patients). Agreement among readers’ visual rating was high (Fleiss κ = 0.88) and the β1600 was preferred in most cases (in 96% of obese patients and in 53.3% of pre-obese cases). OSEM was considered visually equal to β1600 in 44.7% of pre-obese cases and in 4% of obese patients. In a minority of pre-obese cases, OSEM was preferred (2%). In the whole population, CNR, SNR-T and LSNR were significantly different (p < 0.001) between OSEM and β1600, conversely to SUVmean-L (not significant). These results were also confirmed when calculated separately for the pre-obesity and obesity sub-groups β800 and β1000 were always rated inferior. Conclusions: Q.Clear is a new technology for PET/CT image reconstruction that can be used to increase CNR and SNR-T, to subsequently optimise overall image quality as compared to standard OSEM. Our preliminary data on [68Ga]Ga-DOTANOC PET/CT demonstrate that in overweight NEN patients, β1600 is preferable over β800 and β1000. Further studies are warranted to validate these results in lesions of different anatomical region and size; moreover, currently employed interpretative PET positivity criteria should be adjusted to the new reconstruction method.

Purpose To assess and compare clinical outcomes and costs, to the Italian healthcare system, of three therapeutic options approved in the management of adult patients with gastro-enteropancreatic neuroendocrine tumours (GEP-NETs). Methods We compared the efficacy, safety, and costs of [177Lu]Lu-DOTA-TATE, everolimus (both originator and generic products), and sunitinib in patients with advanced GEP-NETs (NET G1 and G2) that had progressed following treatment with somatostatin analogs (SSAs). A cost-consequence model was developed and validated by a panel of clinical experts from three NET reference centres in Italy. The clinical outcomes included in the model were median progression-free survival and the incidence of grade 3 or 4 adverse events (AEs), as reported in pivotal clinical trials. The costs for acquisition and administration of each treatment, and of managing AEs, were calculated from the perspective of the Italian national health service. Treatment costs per progression-free month were calculated separately for patients with NETs of pancreatic (PanNETs; all three treatments) and gastrointestinal (GI-NETs; [177Lu]Lu-DOTA-TATE and everolimus only) origin. Results In patients with PanNETs, total costs per progression-free month were €2989 for [177Lu]Lu-DOTA-TATE, €4975 for originator everolimus, €3472 for generic everolimus, and €5337 for sunitinib. In patients with GI-NETs, total costs per progression-free month were €3189 for [177Lu]Lu-DOTA-TATE, €4990 for originator everolimus, and €3483 for generic everolimus. Conclusions [177Lu]Lu-DOTA-TATE was associated with lower costs per progression-free month versus relevant treatment options in patients with GI-NETs or PanNETs (NET G1–G2; progressed following SSA treatment), although acquisition and administration costs are higher. These findings provide further economic arguments in the overall context of treatment decision-making.

Purpose: Aim of the present review is to analyze the most relevant achievements of peptide receptor radionuclide therapy (PRRT) in neuroendocrine neoplasms (NENs) management, focusing on treatment efficacy as well as toxicity and taking into account the innovative applications and future perspectives. Methods: A comprehensive literature review of PubMed/Medline (last updated January 2021) was performed using a combination of the following keywords: PRRT, NEN/NET treatment, somatostatin analogues, PET/CT [68Ga]Ga-DOTA-peptides (DOTATATE, DOTATOC, DOTANOC), [18F]FDG. Case reports, editorials, letters to the editor and articles not specifically addressing PRRT achievements were excluded. Only papers in English were considered. Results: Published data showed that PRRT has been increasingly used for treatment of well-differentiated neuroendocrine tumours (NETs). Preliminary results from early studies were difficult to compare due to different treatment regimens in often small and heterogeneous patients’ populations. Recently, the regulatory agencies approved [177Lu]Lu-DOTA-TATE for treatment of well-differentiated gastro-entero-pancreatic neuroendocrine tumours G1-G2 (GEP-NET). Patients treated with PRRT show good response rates (range 66–95% considering total objective response and stable disease). Regarding toxicity, a significant reduction of renal absorbed dose (ranging from 9 to 53%) has been reported using kidney protection strategies. Moreover, the incidence of haematological long-term toxicity has been reported in many studies but toxicity is mild and transient in most patients while severe toxicity, such as acute leukemia (AL) and myelodysplastic syndrome (MDS), were reported in less than 3% of patients. However, several issues are still under debate including dose schemes personalization, selection of eligible patients, evaluation of treatment response and treatment sequencing. Conclusion: PRRT is now recognized as an effective treatment strategy for well-differentiated SSTR-positive NETs with a very high disease control and overall limited toxicity. Further optimization of PRRT employment is warranted to further increase efficacy and reduce toxicity.

International audience; The Extreme Universe Space Observatory on a Super Pressure Balloon 1 (EUSO-SPB1) instrument was launched out of Wanaka, New Zealand, by NASA in April, 2017 as a mission of opportunity. The detector was developed as part of the Joint Experimental Missions for the Extreme Universe Space Observatory (JEM-EUSO) program toward a space-based ultra-high energy cosmic ray (UHECR) telescope with the main objective to make the first observation of UHECRs via the fluorescence technique from suborbital space. The EUSO-SPB1 instrument is a refractive telescope consisting of two 1m$^{2}$ Fresnel lenses with a high-speed UV camera at the focal plane. The camera has 2304 individual pixels capable of single photoelectron counting with a time resolution of 2.5μ s. A detailed performance study including calibration was done on ground. We separately evaluated the properties of the Photo Detector Module (PDM) and the optical system in the laboratory. An end-to-end test of the instrument was performed during a field campaign in the West Desert in Utah, USA at the Telescope Array (TA) site in September 2016. The campaign lasted for 8 nights. In this article we present the results of the preflight laboratory and field tests. Based on the tests performed in the field, it was determined that EUSO-SPB1 has a field of view of 11.1$^{∘}$ and an absolute photo-detection efficiency of 10%. We also measured the light flux necessary to obtain a 50% trigger efficiency using laser beams. These measurements were crucial for us to perform an accurate post flight event rate calculation to validate our cosmic ray search. Laser beams were also used to estimated the reconstruction angular resolution. Finally, we performed a flat field measurement in flight configuration at the launch site prior to the launch providing a uniformity of the focal surface better than 6%.

Simple Summary The most effective and safest approach for the treatment of advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) remains unknown. A systematic review was done to clarify this point. A network meta-analysis was used to overcome the multiarm problem. Our study confirmed that somatostatin analogs (SSAs) alone remain the best choice for well-differentiated GEP–NENs. 177Lu-Dotatate plus SSA is a valid alternative for midgut NENs since it has been shown to be slightly more efficacious but yielding a higher risk for toxicity than SSAs. Abstract Several new therapies have been approved to treat advanced gastro-entero-pancreatic neuroendocrine neoplasms (GEP–NENs) in the last twenty years. In this systematic review and meta-analysis, we searched MEDLINE, ISI Web of Science, and Scopus phase III randomized controlled trials (RCTs) comparing two or more therapies for unresectable GEP–NENs. Network metanalysis was used to overcome the multiarm problem. For each arm, we described the surface under the cumulative ranking (SUCRA) curves. The primary endpoints were progression-free survival and grade 3–4 of toxicity. We included nine studies involving a total of 2362 patients and 5 intervention arms: SSA alone, two IFN-α plus SSA, two Everolimus alone, one Everolimus plus SSA, one Sunitinib alone, one 177Lu-Dotatate plus SSA, and one Bevacizumab plus SSA. 177Lu-Dotatate plus SSA had the highest probability (99.6%) of being associated with the longest PFS. This approach was followed by Sunitinib use (64.5%), IFN-α plus SSA one (53.0%), SSA alone (46.6%), Bevacizumab plus SSA one (45.0%), and Everolimus ± SSA one (33.6%). The placebo administration had the lowest probability of being associated with the longest PFS (7.6%). Placebo or Bevacizumab use had the highest probability of being the safest (73.7% and 76.7%), followed by SSA alone (65.0%), IFN-α plus SSA (52.4%), 177Lu-Dotatate plus SSA (49.4%), and Sunitinib alone (28.8%). The Everolimus-based approach had the lowest probability of being the safest (3.9%). The best approaches were SSA alone or combined with 177Lu-Dotatate.

Hyperammonemic encephalopathy represents a rare adverse effect of several chemotherapeutic agents, occurring in about 0.7% of patients treated with fluoropyrimidines, and it is independent from dihydropyrimidine dehydrogenase deficiency. Instead, its physiopathology is linked to the inhibition of Krebs cycle by fluoroacetate, leading to decreased ATP production, and to the inhibition of the urea cycle. Oxaliplatin seems to induce hyperammonemic encephalopathy in a similar way, acting on mitochondria. Here, we report the intriguing case of acute hyperammonemic encephalopathy in a 65-year-old patient with preserved liver function, who was treated with oxaliplatin and capecitabine for a metastatic, G1, atypical lung carcinoid. We reviewed the literature and found very few reports of oxaliplatin or capecitabineinduced hyperammonemic encephalopathy. Out of five cases of capecitabine-related hyperammonemic encephalopathy analyzed (four plus our case), median time to hyperammonemic encephalopathy onset was 6 days, with median serum ammonia levels of 213 μmol/L. Oxaliplatin-related hyperammonemic encephalopathy analyzed cases were three (two plus ours), with a median time to hyperammonemic encephalopathy of 11 days and median serum ammonia levels of 167 μmol/L. Identified predisposing factors for chemotherapy-induced hyperammonemia, such as dehydration, liver and renal impairment, infections, and sarcopenia were absent in our case. We hypothesize that the combination of a platinum-derivative and a fluoropyrimidine multiplies the risk of hyperammonemic encephalopathy, even in the absence of predisposing factors nor impaired liver function. We therefore suggest to always consider the risk of hyperammonemia when starting fluoropyrimidinesbased chemotherapy, especially combined with platinumderivatives, and to timely investigate neurologic symptoms monitoring ammonia serum levels. Anti-Cancer Drugs 31: 1103-1105.

There is scant evidence about optimal management of poorly differentiated neuroendocrine carcinoma of the bladder (BNEC). We performed a multicenter retrospective study on BNEC patients from 13 Italian neuroendocrine-dedicated centers to analyze strategies associated with better outcomes. Mixed adeno-neuroendocrine carcinomas (MANEC) were included. We analyzed overall survival (OS) in the overall cohort, relapse-free survival (RFS) in radically operated patients and progression-free survival (PFS) in patients who received chemotherapy for metastatic disease. Fifty-one BNEC patients were included (male: 46, median age: 70 years). Overall, median OS was 16.0 months, radical tumor resection was performed in 37 patients (72.5%) and 11 of these (29.7%) also received peri-operative platinum-etoposide chemotherapy. Median OS was longer in patients with better performance status (PS) and in those with stage I&ndash, III disease at diagnosis compared to stage IV. Among patients who underwent radical tumor resection (N = 37), RFS was longer in patients with better PS and showed a trend towards a longer RFS in those treated with peri-operative chemotherapy than with surgery alone (11 vs. 6 months, p = 0.078). Among 28 patients receiving chemotherapy for metastatic disease, PFS was 5.0 months and there was a trend towards improved PFS in patients receiving carboplatin-etoposide chemotherapy compared to other regimens. A multivariate model unmasked a significant association between carboplatin-etoposide chemotherapy and risk for disease progression or death (HR: 0.39 (95%CI: 0.16&ndash, 0.96) p = 0.040). Performance status might be associated with improved RFS in radically operated patients, while type of chemotherapy might affect PFS in patients receiving chemotherapy for metastatic BNEC.

Purpose: Temozolomide (TEM) has been reported to be active alone or in combination with capecitabine (CAP) in patients with neuroendocrine neoplasms (NENs). We retrospectively evaluated activity and toxicity of TEM-based chemotherapy in patients with advanced NENs and explored the potential correlation with clinical/biological factors. Methods: Patients received oral TEM alone or in combination with CAP. Objective response rate (ORR) [complete response + partial response (PR)], median progression-free survival (mPFS), and toxicity were calculated. The O6-methylguanine-DNA-methyltransferase (MGMT) gene inactivation status in tumor tissue was evaluated by pyrosequencing. Results: From September 2008 to April 2020, 170 patients (84% progressive on different therapies) were consecutively treated, 114 (67%) patients received TEM-CAP and 56 (33%) TEM alone. Primary tumor sites were: pancreas 98 (58%), gastrointestinal tract 21 (12%), lung 35 (21%), and unknown 16 (9%). The ORR was 28% for the whole population (33% for TEM-CAP and 18% for TEM as single agent). The median OS (mOS) and mPFS of the whole population were 35.6 months (32.6–48.7) and 14.7 months (10.1–18.3), respectively. There were 48% PR in the MGMT hypermethylated, mainly in pancreatic NENs. Vomiting and leukopenia were the most frequent grade 3/4 toxicity. Conclusions: This large retrospective analysis suggested that a TEM-based chemotherapy is active in advanced, pretreated NEN patients. It generated solid hypotheses that warrant a future prospective study in a biological homogeneous NEN population and clinical setting.

Purpose: Insulinomas are a rare type of neuroendocrine tumors, originating in the pancreas, difficult to diagnose and to treat. Due to its rarity, insulinomas are a not well-known pathological entity; thus, the diagnostic process is frequently a medical challenge with many possible differential diagnoses. The diagnostic process varies between non-invasive procedures, such as the fasting test or imaging techniques, and invasive ones. Insulinomas are rarely malignant, but the glycemic imbalance correlated with this tumor can frequently alter the quality of life of the patients and the consequent hypoglycemia can be extremely dangerous. Moreover, insulinomas can be associated with different genetic syndromes, such as Multiple Endocrine Neoplasia 1, accompanied by other specific symptoms. There are many different treatment strategies, depending on the need to control symptoms or control diseases progression, the only curative one being surgery. Methods and results: We reviewed the evidences present in the literature on insulinomas and reported its main clinical characteristics and management strategies. Conclusion: The aim of this review of the literature is to present the current knowledge on insulinomas, exploring the main clinical characteristics, the diagnostic tools, and the therapeutic strategies.

Introduction Management of malignant insulinomas is challenging due to the need to control both hypoglycaemic syndrome and tumor growth. Literature data is limited to small series. Aim of the study To analyze clinico-pathological characteristics, treatments and prognosis of patients with malignant insulinoma. Materials and methods Multicenter retrospective study on 31 patients (male: 61.3%) diagnosed between 1988 and 2017. Results The mean age at diagnosis was 48 years. The mean NET diameter was 41 ± 31 mm, and 70.8% of NETs were G2. Metastases were widespread in 38.7%, hepatic in 41.9% and only lymph nodal in 19.4%. In 16.1% of the cases, the hypoglycaemic syndrome occurred after 46 ± 35 months from the diagnosis of originally non-functioning NET, whereas in 83.9% of the cases it led to the diagnosis of NET, of which 42.3% with a mean diagnostic delay of 32.7 ± 39.8 months. Surgical treatment was performed in 67.7% of the cases. The 5-year survival rate was 62%. Overall survival was significantly higher in patients with Ki-67 ≤10% (P = 0.03), insulin level P = 0.015) and in patients who underwent surgery (P = 0.006). Peptide Receptor Radionuclide Therapy (PRRT) was performed in 45.1%, with syndrome control in 93% of patients. Conclusions Our study includes the largest series of patients with malignant insulinoma reported to date. The hypoglycaemic syndrome may occur after years in initially non-functioning NETs or be misunderstood with delayed diagnosis of NETs. Surgical treatment and Ki67 ≤10% are prognostic factors associated with better survival. PPRT proved to be effective in the control of hypoglycaemia in majority of cases.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine tumor of the skin whose incidence is rising. Multimodal treatment is crucial in the non-metastatic, potentially curable setting. However, the optimal management of patients with non-metastatic MCC is still unclear. In addition, novel insights into tumor biology and newly developed treatments (e.g., immune checkpoint inhibitors) that dramatically improved outcomes in the advanced setting are being investigated in earlier stages with promising results. Nevertheless, the combination of new strategies with consolidated ones needs to be clarified. We reviewed available evidence supporting the current treatment recommendations of localized MCC with a focus on potentially ground-breaking future strategies. Advantages and disadvantages of the different treatment modalities, including surgery, radiotherapy, chemotherapy, and immunotherapy in the non-metastatic setting, are analyzed, as well as those of different treatment modalities (adjuvant as opposed to neoadjuvant). Lastly, we provide an outlook of remarkable ongoing studies and of promising agents and strategies in the treatment of patients with non-metastatic MCC.

Purpose: The management of small (≤5 mm) rectal neuroendocrine neoplasms (r-NENs), incidentally removed during colonoscopy, still remains under debate. Methods: All consecutive patients affected by r-NENs from January 2013 to December 2017 were studied. The inclusion criteria were: (1) patients having an incidental pathological diagnosis of very small (≤5 mm) polypoid r-NENs; (2) patients treated with a standard polypectomy as first-line therapy and (3) patients treated by endoscopic submucosal dissection (ESD) as salvage therapy. The primary endpoint was to identify the factors related to residual disease after a standard polypectomy. The secondary endpoint was to calculate the accuracy of endoscopic ultrasound (EUS), grading and size in predicting residual disease. Results: Starting from a prospective database of 123 consecutive patients affected by r-NENs, only 31 met the inclusion criteria. A final pathological examination of an ESD specimen showed residual disease in 7 out of 31 patients (22.6%). A multivariate analysis showed that the size of the polyps was the only independent factor related to residual disease with an odds ratio of 8.7 ± 7.5 (P = 0.013) for each millimetre. The accuracy of EUS, grading and tumour size (3.1 mm cut-off point) and area under the curves were 0.661 ± 0.111, 0.631 ± 0.109 and 0.821 ± 0.109, respectively. Conclusions: When the r-NEN polyp was larger than 3 mm, ESD was indicated. Unlike the size of the tumour, grading and EUS features did not accurately predict residual disease.

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Purpose: The primary end-point was to evaluate the cure fraction. Secondary end-points were to investigate the time to cure, the excess of death risk, the probability of cure and the factors related to these parameters. Methods: Retrospective study of an ENETS database regarding patients affected by Si-NENs. For each patients, clinical, pathological and follow-up data were collected. The survival analysis was made using a novel approach: the cure model approach. Results: The cure fraction was 92.1%. The death risk, time to cure and the probability of cure were 6/1000 person-years, 3.6 years and 98.2%, respectively. The independent factors influencing these parameters were the grading and the R status (P = 0.041 and P = 0.017, respectively). Patients affected by Si-NENs G2 increased the death risk and time to cure respect to Si-NENs G1 (51 versus 6 per 1000 person-years and 5.1 versus 3.6 years, respectively) as well as patients not operated respect to those radically resected (R0/1) (66 versus 1 per 1000 person-years and 4.8 versus 0.4 years, respectively). The probability of cure decreased (88.1 versus 97.8% and 80.4 versus 99.7%, respectively). R2 resection shows better results than no resection. Conclusions: A large portion of patients affected by Si-NENs can be cured. The highest probability of cure regards patients with Si-NENs G1 who underwent to R0/R1 resection; the lower, those with Si-NENs G2 and no resection. R2 resection seems to be preferred respect to no resection.

Thymic tumors are a group of rare mediastinal malignancies that include three different histological subtypes with completely different clinical behavior: the thymic carcinomas, the thymomas, and the rarest thymic neuroendocrine tumors. Nowadays, few therapeutic options are available for relapsed and refractory thymic tumors after a first-line platinum-based chemotherapy. In the last years, the deepening of knowledge on thymus’ biological characterization has opened possibilities for new treatment options. Several clinical trials have been conducted, the majority with disappointing results mainly due to inaccurate patient selection, but recently some encouraging results have been presented. In this review, we summarize the molecular alterations observed in thymic tumors, underlying the great biological differences among the different histology, and the promising targeted therapies for the future.

Thymic epithelial tumors (TETs) are a group of rare thoracic malignancies, including thymic carcinomas (TC) and thymomas (Tm). Autoimmune paraneoplastic diseases are often observed in TETs, especially Tms. To date, chemotherapy is still the standard treatment for advanced disease. Unfortunately, few therapeutic options are available for relapsed/refractory TETs. In the last few years, the deepening of knowledge on thymus’ immunobiology and involved altered genetic pathways have laid the foundation for new treatment options in these rare neoplasms. Recently, the immunotherapy revolution has landed in TETs, showing both a dark and light side. Indeed, despite the survival benefit, the occurrence of severe autoimmune treatment-related adverse events has risen crescent uncertainty about the feasibility of immunotherapy in these patients, prone to autoimmunity for their cancer biology. In this review, after summarizing immunobiology and immunopathology of TETs, we discuss available data on immune-checkpoint inhibitors and future perspectives of this therapeutic strategy.

EUSO-Balloon is a pathfinder mission for the Extreme Universe Space Observatory onboard the Japanese Experiment Module (JEM-EUSO). It was launched on the moonless night of the 25th of August 2014 from Timmins, Canada. The flight ended successfully after maintaining the target altitude of 38 km for five hours. One part of the mission was a 2.5 hour underflight using a helicopter equipped with three UV light sources (LED, xenon flasher and laser) to perform an inflight calibration and examine the detectors capability to measure tracks moving at the speed of light. We describe the helicopter laser system and details of the underflight as well as how the laser tracks were recorded and found in the data. These are the first recorded laser tracks measured from a fluorescence detector looking down on the atmosphere. Finally, we present a first reconstruction of the direction of the laser tracks relative to the detector., 0, SCOPUS: ar.j, info:eu-repo/semantics/published

No validated prognostic tool is available for predicting overall survival (OS) of patients with well-differentiated neuroendocrine tumors (WDNETs). This study, conducted in three independent cohorts of patients from five different European countries, aimed to develop and validate a classification prognostic score for OS in patients with stage IV WDNETs. We retrospectively collected data on 1387 patients: (i) patients treated at the Istituto Nazionale Tumori (Milan, Italy; n = 515); (ii) European cohort of rare NET patients included in the European RARECAREnet database (n = 457); (iii) Italian multicentric cohort of pancreatic NET (pNETs) patients treated at 24 Italian institutions (n = 415). The score was developed using data from patients included in cohort (i) (training set); external validation was performed by applying the score to the data of the two independent cohorts (ii) and (iii) evaluating both calibration and discriminative ability (Harrell C statistic). We used data on age, primary tumor site, metastasis (synchronous vs metachronous), Ki-67, functional status and primary surgery to build the score, which was developed for classifying patients into three groups with differential 10-year OS: (I) favorable risk group: 10-year OS ≥70%; (II) intermediate risk group: 30% ≤ 10-year OS

Background. Neuroendocrine tumors (NETs) are characterized by having behavior and prognosis that depend upon tumor histology, primary site, staging, and proliferative index. The symptoms associated with carcinoid syndrome and vasoactive intestinal peptide tumors are treated with octreotide acetate. The PROMID trial assesses the effect of octreotide LAR on the tumor growth in patients with well-differentiated metastatic midgut NETs. The CLARINET trial evaluates the effects of lanreotide in patients with nonfunctional, well-, or moderately differentiated metastatic enteropancreatic NETs. Everolimus has been approved for the treatment of advanced pancreatic NETs (pNETs) based on positive PFS effects, obtained in the treated group. Sunitinib is approved for the treatment of patients with progressive gastrointestinal stromal tumor or intolerance to imatinib, because a randomized study demonstrated that it improves PFS and overall survival in patients with advanced well-differentiated pNETs. In a phase II trial, pasireotide shows efficacy and tolerability in the treatment of patients with advanced NETs, whose symptoms of carcinoid syndrome were resistant to octreotide LAR. An open-label, phase II trial assesses the clinical activity of long-acting repeatable pasireotide in treatment-naive patients with metastatic grade 1 or 2 NETs. Even if the growth of the neoplasm was significantly inhibited, it is still unclear whether its antiproliferative action is greater than that of octreotide and lanreotide. Because new therapeutic options are needed to counter the natural behavior of neuroendocrine tumors, it would also be useful to have a biochemical marker that can be addressed better in the management of these patients. Chromogranin A is currently the most useful biomarker to establish diagnosis and has some utility in predicting disease recurrence, outcome, and efficacy of therapy.

RATIONALE: to investigate the role of 68Ga-DOTA-NOC SUVmax as a potential prognostic factor in patients with pancreatic neuroendocrine tumour (pNET). METHODS: Among the patients who underwent 68Ga-DOTANOC PET/CT, we retrospectively collected data of those with pNET G1 or G2 (2010 WHO classification), presenting disease at PET/CT and CT, with at least 6 months follow-up. MEN patients were excluded. RESULTS: Overall, 43 patients were included. No significant differences in the SUVmax values were observed with respect to gender, tumour syndrome, stage, WHO classification and Ki67. During follow-up (median 20 months), 11 patients (35.6%; median: 33 months; IQR: 20-48 months) had stable disease (SD) while 32 (74.4%) had progressive disease (PD, median: 19 months; IQR, 14-26 months). SUVmax was significantly higher (P = 0.022) in patients with SD at 24 months follow-up as compared to patients with PD. The best SUVmax cut-off ranged from 37.8 to 38.0. The major risk factors for progression included a SUVmax ≤ 37.8 (HR=3.09, P = 0.003), Ki67>5% (HR=2.89, P = 0.009) and medical therapy alone (HR=2.36, P = 0.018). Advanced (IV) stage (P = 0.026), SUVmax5%; P = 0.005; ), SUVmax ( 38.0: 16.0 vs 27.0 months P = 0.002) and type of therapy (medical vs PRRT: 16.0 vs 26.0 months; P = 0.014). CONCLUSION: 68Ga-DOTA-NOC SUVmax is a relevant prognostic factor in patients with pNET G1 and G2 and its routine employment will improve the characterization and management of these patients that may present with a heterogenous clinical behaviour. 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 (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.

Purpose. To evaluate the role of the activation of mTOR (phosphorylated mTOR, p-mTOR) and the expression SSTR2A and IGF-1R as prognostic factor in well-differentiated neuroendocrine tumors. Methods. A retrospective study was conducted on data from patients with diagnosis of neuroendocrine tumor originated from pancreas (pNET) or gastrointestinal tract (stomach, appendix, and ileus; GI-NET) made between January 2003 and December 2004 and followed up at our institution. Archival material should be available for revision according to WHO 2010 neuroendocrine tumor classification and for p-mTOR, SSTR2A, and IGF-1R immunostaining, calculating a quantitative score (QS). We evaluated clinical, pathological, and immunohistochemistry features for association with the presence of advanced disease at diagnosis and disease relapse in patients who have undergone radical surgery. Results. Archival material from 64 patients was analyzed (37 pNETs and 27 GI-NETs). In these patients, G2 grading, low SSTR2A QS, and high p-mTOR QS were associated with advanced disease at diagnosis at multivariate analysis. Risk of recurrence in 49 patients with R0-resected tumors was higher for G2 grading, stage IIIB-IV, low IGF-1R QS, and high p-mTOR QS at univariate analysis. Conclusions. With the limits of retrospective data, activation of m-TOR is correlated with advanced disease at diagnosis and with shorter disease-free survival after R0 resection. Validation through prospective studies is needed.

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.

The preliminary results from measurements of deuteron fluxes in galactic cosmic rays (GCR) in the vicinity of the Earth in 2006–2009 are presented. The results are obtained by analyzing data from the PAMELA experiment aboard the Resurs DK-1 satellite. High-precision detection instruments provided an opportunity to identify GCR deuterons and measure their spectrum in the energy interval of 90–650MeV/nucleon. Spectra averaged over six-month intervals from the summer of 2006 to the summer of 2009 (the solar activity minimum) are presented. The influence of solar modulation on the observed spectrum is clearly seen in the results.

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 PAMELA space experiment is providing first direct observations of Solar Energetic Particles (SEPs) with energies from about 80 MeV to several GeV in near-Earth orbit, bridging the low energy measurements by other spacecrafts and the Ground Level Enhancement (GLE) data by the worldwide network of neutron monitors. Its unique observational capabilities include the possibility of measuring the flux angular distribution and thus investigating possible anisotropies associated to SEP events. The analysis is supported by an accurate back-tracing simulation based on a realistic description of the Earth's magnetosphere, which is exploited to estimate the SEP energy spectra as a function of the asymptotic direction of arrival with respect to the Interplanetary Magnetic Field (IMF). In this work we report the results for the May 17, 2012 event.

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.

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.