Search

Purpose: This paper outlines the consensus of the Italian Association for Neuroendocrine Tumors(Itanet), the Italian Association of Nuclear Medicine (AIMN), the Italian Society of Endocrinology (SIE), and the Italian Association of Medical Oncology (AIOM) on treating neuroendocrine neoplasms (NENs)with radioligand therapy (RLT)., Methods: A list of 10 questions regarding using RLT ingastroenteropancreatic neuroendocrine tumors (GEP-NETs) was addressed after a careful review of theavailable literature. compiling information from the MEDLINE database, augmented with expert opinionsand recommendations, aligns with the latest scientific research and the author's extensive knowledge.The recommendations are evaluated using the GRADE system, showcasing the level of evidence andthe strength of the recommendations., Results and Conclusions: Specifically, this paper focuses on thesubcategories of well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) thatexpress somatostatin receptors and are considered suitable for RLT, according to internationalguidelines., (© 2024. The Author(s).)

Purpose: Gastroenteropancreatic -neuroendocrine tumours (GEP-NETs) are commonly treated with surgical resection or long-term therapies for tumour growth control. Lutetium [ 177 Lu]-DOTA-TATE was approved for the treatment of GEP-NETs after the phase III NETTER 1trial demonstrated improved progression free survival, objective response rates and health-related quality of life (HRQoL) compared to high-dose somatostatin analogues. No real-world data exist on prescribing habits and clinically significant endpoints for [ 177 Lu]Lu-DOTA-TATE treatment in Italy. REAL-LU is a multicentre, long-term observational study in patients with unresectable/metastatic GEP-NETs progressing on standard therapies in Italian clinical practice. A pre-specified interim analysis was performed at the end of the enrolment period, data from which are described herein., Methods: Overall duration of REAL-LU will be approximately 48 months, with 12- and 36-month recruitment and follow-up periods, respectively. The primary objective is to evaluate [ 177 Lu]Lu-DOTA-TATE effectiveness in terms of progression-free survival. Secondary objectives include safety, impact on HRQoL, and identification of prognostic factors. This pre-specified interim analysis describes patient profiles, at the end of enrollment, of those prescribed [ 177 Lu]Lu-DOTA-TATE for GEP-NETs in Italy., Results: Among 161 evaluable patients, mean age was 64.7 ± 10.3 years at study entry, 83.8% presented with no clinical signs of disease at physical examination, and most had minor disease symptoms. All patients had metastatic disease, most commonly in the liver (83.9%) with a median of two metastatic sites. In 90.7% of patients, the disease was stage IV, and 68.3% had ≥ 1 target lesion. [ 177 Lu]Lu-DOTA-TATE was prescribed mainly as second-line therapy (61.6%) and following surgery (58.4%). HRQoL assessments revealed high levels of functioning and low levels of symptoms at baseline; 50.0% of patients were symptom-free at study entry., Conclusion: The characteristics of patients who received [177Lu]Lu-DOTA-TATE in Italy are similar to those of the GEP-NET population of NETTER 1 with trial but with a higher proportion of patients with a grade 2 (71%). With regard to the tumor grade profile, our study cohort appears to be closer to that of NETTER-2 study population which included patients with G2 or G3 advanced GEP-NETs (i.e. Ki-67 ≥ 10% and ≤ 55%). Further analysis of effectiveness and safety can be anticipated as REAL-LU data mature., Study Registration: ClinicalTrials.gov, NCT04727723; Study Registration Date: 25 January, 2021; https://clinicaltrials.gov/study/NCT04727723?cond=NCT04727723&rank=1., (© 2024. The Author(s).)

Metastatic pheochromocytomas and paragangliomas (PPGLs) are frequently associated with skeletal complications. Primary objective: to describe the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs). Secondary objectives: to 1) identify predictive and prognostic factors for SREs and 2) obtain information on the effectiveness of bone resorption inhibitors in reducing SRE risk and improving outcomes in term of survival and SREs time onset. In this retrospective multicenter, multinational study, 294 PPGL patients were enrolled. SREs occurred in 90 patients (31 %). Fifty-five patients (19 %) had bone fractures, 47 (16 %) had spinal cord compression, and 11 (4 %) had hypercalcemia. Twenty-two patients (7 %) had more than one SRE. Sixty-four patients (22 %) underwent surgery, and 136 (46 %) underwent radiotherapy. SREs occurred a median of 4.4 months after diagnosis of BM (range, 0-246.6 months). Independent factors associated with reduced risk of SREs in multivariable analysis were I-131-MIBG radionuclide therapy (hazard ratio [HR], 0.536 [95 % CI, 0.309-0.932]; P = .027) and absence of liver metastases (HR, 0.638 [95 % CI, 0.410-0.992]; P = .046). The median overall survival duration was 5.3 year. In multivariable analysis, age younger than 48 years at PPGL diagnosis (HR, 0.558 [95 % CI, 0.3877-0.806]; P = .002), absence of liver metastases (HR, 0.618 [95 % CI, 0.396-0.965]; P = .034), treatment with bisphosphonates or denosumab (HR, 0.598 [95 % CI, 0.405-0.884]; P = .010), and MIBG radionuclide therapy (HR, 0.444 [95 % CI, 0.274-0.718]; P = .001) were associated with a reduced risk of death. SREs occur frequently and early in bone-metastatic PPGL patients but do not negatively impact survival. MIBG radionuclide therapy and treatment with bone resorption inhibitors are associated with favorable outcome., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Resection of non-functioning pancreatic neuroendocrine tumours (NF-PanNETs) is curative in most patients. The potential benefits of neoadjuvant treatments have, however, never been explored. The primary aim of this study was to evaluate the safety of neoadjuvant 177Lu-labelled DOTA0-octreotate (177Lu-DOTATATE) followed by surgery in patients with NF-PanNETs., Methods: NEOLUPANET was a multicentre, single-arm, phase II trial of patients with sporadic, resectable or potentially resectable NF-PanNETs at high-risk of recurrence; those with positive 68Ga-labelled DOTA PET were eligible. All patients were candidates for neoadjuvant 177Lu-DOTATATE followed by surgery. A sample size of 30 patients was calculated to test postoperative complication rates against predefined cut-offs. The primary endpoint was safety, reflected by postoperative morbidity and mortality within 90 days. Secondary endpoints included rate of objective radiological response and quality of life., Results: From March 2020 to February 2023, 31 patients were enrolled, of whom 26 completed 4 cycles of 177Lu-DOTATATE. A partial radiological response was observed in 18 of 31 patients, and 13 patients had stable disease. Disease progression was not observed. Twenty-four R0 resections and 4 R1 resections were performed in 29 patients who underwent surgery. One tumour was unresectable owing to vascular involvement. There was no postoperative death. Postoperative complications occurred in 21 of 29 patients. Severe complications were observed in seven patients. Quality of life remained stable after 177Lu-DOTATATE and decreased after surgery., Conclusion: Neoadjuvant treatment with 177Lu-DOTATATE is safe and effective for patients with NF-PanNETs., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)

Metabolic alterations in cancers can be exploited for diagnostic, prognostic, and therapeutic purposes. This is exemplified by 18F-fluorodeoxyglucose (FDG)-positron emission tomography (FDG-PET), an imaging tool that relies on enhanced glucose uptake by tumors for diagnosis and staging. By performing transcriptomic analysis of breast cancer (BC) samples from patients stratified by FDG-PET, a 54-gene signature (PETsign) is identified that recapitulates FDG uptake. PETsign is independently prognostic of clinical outcome in luminal BCs, the most common and heterogeneous BC molecular subtype, which requires improved stratification criteria to guide therapeutic decision-making. The prognostic power of PETsign is stable across independent BC cohorts and disease stages including the earliest BC stage, arguing that PETsign is an ab initio metabolic signature. Transcriptomic and metabolomic analysis of BC cells reveals that PETsign predicts enhanced glycolytic dependence and reduced reliance on fatty acid oxidation. Moreover, coamplification of PETsign genes occurs frequently in BC arguing for their causal role in pathogenesis. CXCL8 and EGFR signaling pathways feature strongly in PETsign, and their activation in BC cells causes a shift toward a glycolytic phenotype. Thus, PETsign serves as a molecular surrogate for FDG-PET that could inform clinical management strategies for BC patients., (© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)

Background: Malignant pheochromocytomas (PCCs) and paragangliomas (PGLs) are rare tumors and available systemic therapies are limited., Aim: To explore the role of peptide receptor radionuclide therapy (PRRT) with Yttrium-90 ( 90 Y) and Lutetium-177 ( 177 Lu) peptides in pheochromocytomas (PCCs) and paragangliomas (PGLs)., Methods: We retrospectively analyzed more than 1500 patients with histologically proven neuroendocrine tumors treated with 177 Lu- or 90 Y-DOTA-TATE or -TOC between 1999 to 2017 at our Institute. Overall, 30 patients with confirmed malignant PCCs and PGLs matched inclusion/exclusion criteria and were considered eligible for this analysis., Results: Thirty (n = 30) patients were treated: 22 with PGLs and 8 with PCCs (12 M and 18 F, median age 47 [IQR: 35-60 years]). Eighteen patients (n = 18) had head and neck PGLs, 3 patients thoracic PGLs and 1 patient abdominal PGL. Sixteen patients (53%) had locally advanced and fourteen (47%) had metastatic disease. Twenty-seven (90%) patients had disease progression at baseline. Four (13%) patients were treated with 90 Y, sixteen (53%) with 177 Lu and ten (33%) with 90 Y +  177 Lu respectively. The median total cumulative activity from treatment with 90 Y- alone was 9.45 GBq (range 5.11-14.02 GBq), from 177 Lu- alone was 21.9 GBq (7.55-32.12 GBq) and from the combination treatment was 4.94 GBq from 90 Y- and 6.83 GBq from 177 Lu- (ranges 1.04-10.1 and 2.66-20.13 GBq, respectively). Seven out of 30 (23%) patients had partial response and 19 (63%) stable disease. Median follow up was 8.9 years (IQR: 2.9-12). The 5-y and 10-y PFS was 68% (95% CI: 48-82) and 53% (95% CI: 33-69), respectively, whereas 5-y and 10-y OS was 75% (95% CI: 54-87) and 59% (95% CI: 38-75), respectively. Grade 3 or 4 acute hematological toxicity occurred in three patients, two with leucopenia and one with thrombocytopenia, respectively., Conclusion: PRRT with 177 Lu- or 90 Y-DOTA-TATE or -TOC is feasible and well tolerated in advanced PGLs and PCCs., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Since most endocrine glands express ACE-2 receptors and can be infected by SARS-CoV-2 virus, this retrospective multicentre observational study aims to assess the metabolic activity of thyroid and adrenal glands of COVID-19 patients by 18 F-FDG PET/CT., Methods: We retrospectively evaluated the 18 F-FDG PET/CT scans of COVID-19 patients admitted by three different centres, either in a low-intensity department or in the intensive care unit (ICU). A visual assessment and a semi-quantitative evaluation of areas of interest in thyroid and adrenal glands were performed by recording SUVmax and SUVmean. The 18 F-FDG PET/CT uptake in COVID-19 patients was compared with those observed in normal age-matched controls., Results: Between March 2020 and March 2022, 33 patients from three different centres (twenty-eight patients in a low-intensity department and five patients in ICU), were studied by 18 F-FDG PET/CT during active illness. Seven of them were also studied after clinical remission (3-6 months after disease onset). Thirty-six normal subjects were used as age-matched controls. In the thyroid gland, no statistically significant differences were observed between control subjects and COVID-19 patients at diagnosis. However, at the follow-up PET/CT study, we found a statistically higher SUVmax and SUVmean ( p = 0.009 and p = 0.004, respectively) in the thyroid of COVID-19 patients. In adrenal glands, we observed lower SUVmax and SUVmean in COVID-19 patients at baseline compared to control subjects ( p < 0.0001) and this finding did not normalize after clinical recovery ( p = 0.0018 for SUVmax and p = 0.002 for SUV mean)., Conclusions: In our series, we observed persistent low 18 F-FDG uptake in adrenal glands of patients at diagnosis of COVID-19 and after recovery, suggesting a chronic hypofunction. By contrast, thyroid uptake was comparable to normal subjects at disease onset, but after recovery, a subgroup of patients showed an increased metabolism, thus possibly suggesting the onset of an inflammatory thyroiditis. Our results should alert clinicians to investigate the pituitary-adrenal axis and thyroid functionality at the time of infection and to monitor them after recovery.

Neuroendocrine neoplasms (NENs) are tumors originating from neuroendocrine cells distributed throughout the human body. With an increasing incidence over the past few decades, they represent a highly heterogeneous group of neoplasms, mostly expressing somatostatin receptors (SSTRs) on their cell surface. Peptide receptor radionuclide therapy (PRRT) has emerged as a crucial strategy for treating advanced, unresectable neuroendocrine tumors by administering radiolabeled somatostatin analogs intravenously to target SSTRs. This article will focus on the multidisciplinary theranostic approach, treatment effectiveness (such as response rates and symptom relief), patient outcomes, and toxicity profile of PRRT for NEN patients. We will review the most significant studies, such as the phase III NETTER-1 trial, and discuss promising new radiopharmaceuticals, including alpha-emitting radionuclide-labeled somatostatin analogs and SSTR antagonists.

Merkel cell carcinoma is a rare, aggressive skin malignancy, also known as neuroendocrine carcinoma of the skin, with high rates of recurrence and distant metastasis. In refractory metastatic Merkel cell carcinoma (mMCC), besides immunotherapy, chemotherapy, and radiation, peptide receptor radionuclide therapy (PRRT) may be a viable option since this type of tumor can express somatostatin receptors. Methods: We performed a comprehensive review of the literature to evaluate the efficacy of PRRT in mMCC patients. Results: Thirty-seven patients with mMCC received PRRT (1-5 cycles) with 177 Lu- or 90 Y-labeled somatostatin analogs (cumulative activity, 1.5-30 GBq). Radiographic response was available for 19 of 28 patients who received PRRT alone. Six (31.6%) of 19 patients showed objective responses, from partial to complete, and no severe adverse events were reported. Conclusion: Our analysis supports the use of PRRT in mMCC with sufficient somatostatin receptor uptake, although the quality of the available evidence is low. Prospective clinical trials are already in development and have started accruing in some parts of the world., (© 2023 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: To investigate the cause of lymphopenia in patients with newly diagnosed COVID-19, we measured [ 18 F]FDG uptake in several tissues, including the ileum, right colon, and caecum at diagnosis and after recovery and correlated these measurements with haematological parameters., Methods: We studied, by [ 18 F]FDG PET/CT, 18 newly diagnosed patients with COVID-19. Regions of interest were drawn over major organs and in the terminal ileum, caecum, and right colon, where the bowel wall was evaluable. Five patients were re-examined after recovery, and three of them also performed a white blood cell scan with 99m Tc-HMPAO-WBC on both occasions. Complete blood count was performed on both occasions, and peripheral blood lymphocyte subsets were measured at diagnosis. Data were analysed by a statistician., Results: Patients had moderate severity COVID-19 syndrome. Basal [ 18 F]FDG PET/CT showed focal lung uptake corresponding to hyperdense areas at CT. We also found high spleen, ileal, caecal, and colonic activity as compared to 18 control subjects. At recovery, hypermetabolic tissues tended to normalize, but activity in the caecum remained higher than in controls. Regression analyses showed an inverse correlation between CD4 + lymphocytes and [ 18 F]FDG uptake in the caecum and colon and a direct correlation between CD8 + lymphocytes and [ 18 F]FDG uptake in lungs and bone marrow. WBC scans showed the presence of leukocytes in the caecum and colon that disappeared at recovery., Conclusions: These findings indicate that lymphopenia in COVID-19 patients is associated with large bowel inflammation supporting the hypothesis that CD4 + lymphocytes migrate to peripheral lymphoid tissues in the bowel., (© 2022. The Author(s).)

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking., Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs)., Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias., Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy., Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors., Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31)., Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neoplasms that fall within the category of neuroendocrine tumors. In the last decade, their diagnostic algorithm has been modified to include the evaluation of molecular pathways, genotype, and biochemical phenotype, in order to correctly interpret anatomical and functional imaging results and tailor the best therapeutic choices to patients. More specifically, the identification of germline mutations has led to a three-way cluster classification: pseudo-hypoxic cluster, cluster of kinase receptor signaling and protein translation pathways, and cluster of Wnt-altered pathway. In this context, functional imaging gained a crucial role in the management of these patients in agreement with the ever-growing concept of personalized medicine. In this paper, we provide an overview of three specific molecular pathways targeted by positron-emitting tracers to image PCCs and PGLs: catecholamine metabolism, somatostatin receptors, and glucose uptake. Finally, we recommend different flow charts for use in the selection of tracers for specific clinical scenarios, based on sporadic/inherited tumor and known/unknown mutation status., (© 2022 S. Karger AG, Basel.)

Aims: The clinical significance of nonvisualized sentinel lymph nodes (non-vSLNs) is unknown. The authors sought to determine the incidence of non-vSLNs on lymphoscintigraphy, the identification rate during surgery, factors associated with non-vSLNs and related axillary management. Patients & methods:  A total of 30,508 consecutive SLN procedures performed at a single institution from 2000 to 2017 were retrospectively studied. Associations between clinicopathological factors and the identification of SLNs during surgery were assessed. Results: Non-vSLN occurred in 525 of the procedures (1.7%). In 73.3%, at least one SLN was identified intraoperatively. Nodal involvement was only significantly associated with SLN nonidentification (p < 0.001). Conclusion: Patients with non-vSLN had an increased risk for SLN metastasis. The detection rate during surgery was consistent, reducing the amount of unnecessary axillary dissection.

Grade 3 (G3) neuroendocrine tumors (NETs) are a novel category among digestive neuroendocrine neoplasms, characterized by Ki-67 >20% and a well-differentiated morphology, presenting high intra-tumor heterogeneity. We aimed to explore the role of dual-tracer PET imaging ( 68 Gallium (Ga)-DOTATOC and 18 Fluorodeoxyglucose (FDG)) as overall survival (OS) predictor in NET G3 patients. We performed a retrospective analysis in NET G3 patients treated at our institution between 2003 and 2021. Accordingly, 30 NET G3 patients were analyzed. 68 Ga-DOTA-TOC and 18 F-FDG uptake were assessed by tumor/non-tumor (T-nonT) ratio. We reported a slightly better OS for patients with ≥75% concordance between 68 Ga-DOTA-TOC and 18 F-FDG PET/CT ( p = 0.42). Among patients with discordant functional imaging, we reported a better 5-y OS rate for patients with a prevalent 68 Ga-DOTATOC vs. 18 F-FDG PET/CT ( p = 0.016). In positive 18 F-FDG PET/CT cases, we reported a better OS for <4 vs. ≥4 T/non-T ratio ( p = 0.021). Among upfront-NET G3 patients with concordant exams, 5-y OS rate was 83.3% (95% CI: 27.3-97.5). Among patients with discordant exams, 5-y OS rate was 81.3% (52.5-93.5), 100% for those with prevalent receptor expression, and 50% (11.1-80.4) for those with prevalent 18 F-FDG uptake. Our findings suggest that dual-tracer PET/CT can be considered as a predictor of patient outcome, able to stratify NET G3 patients with poorer prognosis.

Purpose: FDG-positive neuroendocrine tumors (NETs) have a poorer prognosis and exhibit shorter response duration to peptide receptor radionuclide therapy (PRRT). The aim of this prospective phase II study was to evaluate the efficacy and toxicity of PRRT with 177 Lu-DOTATATE associated with metronomic capecitabine as a radiosensitizer agent in patients with advanced progressive FDG-positive gastro-entero-pancreatic (GEP) NETs., Patients and Methods: Patients with advanced somatostatin receptor- and FDG-positive G1-G3 GEP-NETs (Ki67 < 55%) were treated with a cumulative activity of 27.5 GBq of 177 Lu-DOTATATE divided in five cycles of 5.5 GBq each every 8 weeks. Capecitabine (1000-1500 mg daily) was administered orally in the inter-cycle period between 177 Lu-DOTATATE treatments. Prior to commencing capecitabine, all patients were triaged with the dihydropyrimidine dehydrogenase (DPD) test. Only DPD-proficient individuals were enrolled. The primary objectives were disease control rate (DCR) and safety. Secondary aims included progression-free (PFS) and overall survival (OS). Treatment response was assessed per Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1). Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0., Results: From August 2015 to December 2016, 37 subjects were consecutively enrolled. A total of 25 (68%) were affected by pancreatic neuroendocrine tumors (P-NETs), and 12 (32%) had gastrointestinal neuroendocrine tumors (GI-NETs). By grading (WHO 2010 classification), 12 patients (32%) had G1 (Ki67 ≤ 2%), 22 (59%) had G2 (3% < Ki67 ≤ 20%), and 3 patients (9%) had G3 (Ki67 > 20%) NETs. Grade 3 (G3) or 4 (G4) hematological toxicity occurred in 16.2% of patients. Other G3-G4 adverse events were diarrhea in 5.4% of cases and asthenia in 5.4%. No renal toxicity was observed for the duration of follow-up. In 37 patients, 33 were evaluable for response. Objective responses included partial response (PR) in 10 patients (30%) and stable disease (SD) in 18 patients (55%), with a DCR of 85%. The median follow-up was 38 months (range 4.6-51.1 months). The median PFS was 31.4 months (17.6-45.4), and mOS was not reached., Conclusions: This study demonstrated that the combination of PRRT with 177 Lu-DOTATATE and metronomic capecitabine is active and well tolerated in patients with aggressive FDG-positive G1-G3 GEP-NETs. These data constitute the basis for a randomized study of PPRT alone vs. PRRT plus metronomic capecitabine., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objectives: Pleomorphic lung carcinoma (PLC) is a rare histotype of non-small cell lung cancer (NSCLC) characterized by aggressive clinical course, poor response to therapy and poor prognosis. Therefore, aim of our study is to analyze with 18F-FDG PET/CT a subset of patients affected by PLC to evaluate their metabolic characteristics in terms of SUVmax, MTV and TLG, in order to correlate them with overall survival (OS) and disease-free survival (DFS)., Material and Methods: We retrospectively analyzed 49 consecutive patients with histologically defined PLC occurred to our Institution between 2003 and 2014. All patients underwent F18-FDG PET-CT before surgery and primary tumor was automatically segmented using an isocontour threshold method. SUV threshold for tumor segmentation was defined as the 41 % of lesion SUVmax. Total volume of the segmented VOI (MTV, centimeters cubed) and average SUV (SUVavg, grams per milliliter) in the segmented VOI were measured., Results: In our population men were significantly more affected than women (42:7). According to Youden criteria, SUVmax, MTV41 and TLG41 best cut-off values to predict 2-year mortality were, 18.95, 27.89 and 290.45, respectively, with TLG41 showing best specificity (85 %) and positive predictive value (82.4 %). As concerning 2-year recurrence, SUVmax, MTV41 and TLG41 best cut-off values were 10.08, 27.89 and 134.85, with SUVmax showing best sensitivity (96.7 %) and negative predictive value (85.7 %). ROC curves confirmed that SUVmax, MTV41 and TLG41 were equally accurate to predict 2-year mortality and 2-year recurrence in our population., Conclusion: Metabolic biomarkers such as SUVmax, MTV and TLG can be used as a prognostic index for disease progression, recurrence and death in patients with PLC, independently from other clinical/pathological prognostic elements., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([ 18 F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus., Methods: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January-February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET., Results: Overall, [ 18 F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1)., Conclusions: A significant increase of interstitial pneumonia incidentally detected with [ 18 F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management.

The first "theragnostic model", that of radioiodine, was first applied both in diagnosis and therapy in the 1940s. Since then, many other theragnostic models have been introduced into clinical practice. To bring about the closest pharmacokinetic connection, the radiocompound used for diagnosis and therapy should be the same, although at present this is rarely applicable. Today, a widely applied and effective model is also the "DOTA-Ga-68/Lu-177", used with success in neuroendocrine tumors (NET). In this paper, we analyze the necessary steps from the in vitro evaluation of a target to the choice of radionuclide and chelate for therapy up to in vivo transition and clinical application of most employed radiocompounds used for theragnostic purposes. Possible future applications and strategies of theragnostic models are also highlighted.

Background: In neuroendocrine tumor (NET), complete surgery could better the prognosis. Radioguided surgery (RGS) with β - -radioisotopes is a novel approach focused on developing a new probe that, detecting electrons and operating with low background, provides a clearer delineation of the lesions with low radiation exposition for surgeons. As a first step to validate this procedure, ex vivo specimens of tumors expressing somatostatin receptors, as small intestine neuroendocrine tumor (SI-NET), were tested. Materials and Methods: SI-NET presents a high uptake of a beta-emitting radiotracer, 90 Y-DOTATOC. Five SI-NET patients were enrolled after performing a 68 Ga-DOTATOC positron emission tomography/computed tomography (CT) and a CT enterography; 24 h before surgery, they received 5 mCi of 90 Y-DOTATOC. Results: Surgery was performed as routine. Tumors and surrounding tissue were sectioned in different samples and examined ex vivo with the beta-detecting probe. All the tumor samples showed high counts of radioactivity that was up to a factor of 18 times higher than the corresponding cutoff value, with a sensitivity of 96% and a specificity of 100%. Conclusions: These first ex vivo RGS tests showed that this probe can discriminate very effectively between tumor and healthy tissues by the administration of low activities of 90 Y-DOTATOC, allowing more precise surgery.

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 (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients., Conclusion: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Introduction: In patients with positive lymph nodes (cN+) prior to neoadjuvant treatment (NAT), which convert to a clinically negative axilla (cN0) after treatment, the use of sentinel node biopsy (SNB) is still debatable, since the false-negative rate (FNR) is significantly high (12.6-14.2%). The objective of this retrospective mono-institutional study, with a long follow-up, aimed to evaluate the outcome in patients undergoing NAT who remained or converted to cN0 and received SNB independent of target axillary dissection (TAD) or the removal of at least 3 sentinel nodes (SNs)., Methods: This study analyzed 688 consecutive cT1-3, cN0/1/2 patients, operated at the European Institute of Oncology, Milan, from 2000 to 2015 who became or remained cN0 after NAT and underwent SNB with a least one SN found. Axillary dissection (AD) was not performed if the SN was negative. Nodal radiotherapy (RT) was not mandatory., Results: Axillary failure occurred in 1.8% of the initially cN1/2 patients and in 1.5% of the initially cN0 patients. After a median follow-up of 9.2 years (IQR 5.3-12.3), the 5- and 10-year overall survival (OS) were 91.3% (95% CI, 88.8-93.2) and 81.0% (95% CI, 77.2-84.2) in the whole cohort, 92.0% (95% CI, 89.0-94.2) and 81.5% (95% CI, 76.9-85.2) in those initially cN0, 89.8% (95% CI, 85.0-93.2) and 80.1% (95% CI, 72.8-85.7) in those initially cN1/2., Conclusion: The 10-year follow-up confirmed our preliminary data that the use of standard SNB is acceptable in cN1/2 patients who become cN0 after NAT and will not translate into a worse outcome., Competing Interests: Declaration of competing interest All the authors have no conflicts of interest in regards to the conflict of this manuscript., (Copyright © 2020 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Objective: To review the therapeutic strategy in Merkel cell carcinoma (MCC) treated with radiotherapy (RT) discussed in a multidisciplinary tumour board., Methods: Clinical records of patients with a diagnosis of MCC and with an indication to undergo RT at the European Institute of Oncology between 2003 and 2018 were reviewed retrospectively., Results: Twenty-six patients were included in the analysis (median age 65 years, range 42-87). Nineteen received adjuvant RT, 4 exclusive RT, and the remainder palliative RT. Intensity-modulated RT was used in 13 cases, a 3D conformal technique in 11 cases, and stereotactic RT in 2 cases. No major toxicities were recorded. The median relapse-free survival (RFS) after adjuvant RT was 20.5 months, while for unknown primary MCC, it was 23 months. In the adjuvant setting, median polyomavirus-positive RFS was 21.5 months (range 1-49) and median polyomavirus-negative RFS was only 14 months (range 4-45). Overall, RFS of polyomavirus-positive and polyomavirus-negative patients was 10.5 and 8 months, respectively. After adjuvant RT, only 1 out of 10 patients had a recurrence in the RT field. At the time of data collection, 16 patients were alive with no evidence of disease, 1 patient was alive with advanced status of disease, 8 patients died of disease progression, and 1 patient died of other causes., Conclusions: The management of unknown primary and polyomavirus-positive cases, which had a better prognosis in our series, may benefit from a multidisciplinary approach, given the limited data available regarding optimal treatment.

Objective: The aim of this case series is to describe our experience in diagnosis and management of oncological asymptomatic patients with COVID-19 who underwent 18 F-FDG PET/CT., Methods: From March 9 to March 31, 2020, we identified 5 patients who had PET/CT findings suspicious for COVID-19, but no symptom of infection., Results: The first three patients were administered an SARS-CoV-2 test in a COVID-dedicated center, while the fourth and fifth were tested in our institution, in accordance with a new internal procedure. The SARS-CoV-2 test yielded positive results in all five patients., Conclusion: In this COVID-19 emergency, our task as radiologists and nuclear medicine physicians is to be able to identify imaging findings suggestive of the disease and to manage patients without overloading the hospital system.

Purpose: PRELUDE aimed to assess use and effectiveness/safety of lanreotide autogel/depot (LAN) combined with 177 Lu-DOTATOC or 177 Lu-DOTATATE (LAN-peptide receptor radionuclide therapy [PRRT]) in patients with progressive neuroendocrine tumours (NETs)., Methods: International, non-interventional, retrospective, non-comparative analysis of medical records from patients with progressive metastatic or locally advanced grade 1 or 2 gastroenteropancreatic (GEP)- or lung-NETs. The primary endpoint was progression-free survival (PFS) at end of last LAN-PRRT cycle. Secondary endpoints included PFS at last available follow-up, best overall response, objective response rate (ORR), presence and severity of diarrhoea and flushing, and safety. Post-hoc analyses were conducted to determine pre-treatment tumour growth rate (TGR) cutoffs that best predicted the ORR during treatment., Results: Forty patients were enrolled (GEP-NETs, n = 39; lung-NETs, n = 1). PFS rates were 91.7% at end of last LAN-PRRT cycle and 95.0% at last available follow-up. In the full analysis set, best overall response among patients with GEP-NETs (n = 23) was stable disease (n = 14, 60.9%), partial response (n = 8, 34.8%) and progressive disease (n = 1, 4.3%). The ORR was 27.3% at end of last LAN-PRRT cycle and 36.8% at last available follow-up. Optimal baseline TGR cutoffs for predicting ORR at these time points were 1.18% and 0.33%, respectively. At baseline, 81.0% of patients had diarrhoea or flushing; both remained stable or improved in most cases. No increased adverse drug reactions were reported., Conclusion: Despite the major recruitment shortfall for the PRELUDE study, effectiveness data were encouraging in this selected population, highlighting the potential usefulness and feasibility of LAN combined with and after PRRT in patients with GEP-NETs. The study also identified challenges associated with evaluating clinical practice in a rare-disease setting and highlighted the need for standardisation of PRRT procedures., Trial Registration: Trial number: NCT02788578; URL: https://clinicaltrials.gov/ct2/show/NCT02788578.

Purpose: To assess the impact of baseline liver tumour burden, alkaline phosphatase (ALP) elevation, and target lesion size on treatment outcomes with 177 Lu-Dotatate., Methods: In the phase 3 NETTER-1 trial, patients with advanced, progressive midgut neuroendocrine tumours (NET) were randomised to 177Lu-Dotatate (every 8 weeks, four cycles) plus octreotide long-acting release (LAR) or to octreotide LAR 60 mg. Primary endpoint was progression-free survival (PFS). Analyses of PFS by baseline factors, including liver tumour burden, ALP elevation, and target lesion size, were performed using Kaplan-Meier estimates; hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression., Results: Significantly prolonged median PFS occurred with 177 Lu-Dotatate versus octreotide LAR 60 mg in patients with low (< 25%), moderate (25-50%), and high (> 50%) liver tumour burden (HR 0.187, 0.216, 0.145), and normal or elevated ALP (HR 0.153, 0.177), and in the presence or absence of a large target lesion (diameter > 30 mm; HR, 0.213, 0.063). Within the 177 Lu-Dotatate arm, no significant difference in PFS was observed amongst patients with low/moderate/high liver tumour burden (P = 0.7225) or with normal/elevated baseline ALP (P = 0.3532), but absence of a large target lesion was associated with improved PFS (P = 0.0222). Grade 3 and 4 liver function abnormalities were rare and did not appear to be associated with high baseline liver tumour burden., Conclusions: 177 Lu-Dotatate demonstrated significant prolongation in PFS versus high-dose octreotide LAR in patients with advanced, progressive midgut NET, regardless of baseline liver tumour burden, elevated ALP, or the presence of a large target lesion. Clinicaltrials.gov : NCT01578239, EudraCT: 2011-005049-11.

This paper provides a first insight of the potential of the β - Radio Guided Surgery (β - -RGS) in a complex surgical environment like the abdomen, where multiple sources of background concur to the signal at the tumor site. This case is well reproduced by ex-vivo samples of 90 Y -marked Gastro-Entero-Pancreatic Neuroendocrine Tumors (GEP NET) in the bowel. These specimens indeed include at least three wide independent sources of background associated to three anatomical districts (mesentery, intestine, mucose). The study is based on the analysis of 37 lesions found on 5 samples belonging to 5 different patients. We show that the use of electrons, a short range particle, instead of γ particles, allows to limit counts read on a lesion to the sum of the tumor signal plus the background generated by the sole hosting district.The background on adjacent districts in the same specimen/patient is found to differ up to a factor 4, showing how the specificity and sensitivity of the β - -RGS technique can be fully exploited only upon a correct measurement of the contributing background. This locality has been used to set a site-specific cut-off algorithm to discriminate tumor and healthy tissue with a specificity of 100% and a sensitivity, on this test data sample, close to 100%. Factors influencing the sensitivity are also discussed. One of the specimens set allowed us evaluate the volume of the lesions, thus concluding that the probe was able to detect lesions as small as 0.04 mL in that particular case., (Copyright © 2020 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Multiple synchronous (multifocal or multicentric) ipsilateral breast cancers with heterogeneous histopathology are a rare clinical occurrence, however, their incidence is increasing due to the use of MRI for breast cancer screening and staging. Some studies have demonstrated poorer clinical outcomes for this pattern of breast cancer, but there is no evidence to guide clinical practice. In this multidisciplinary review, we reflect on pathology and molecular characteristics, imaging findings, surgical management including conservation and reconstructive options and approach to the axilla, and the role of chemotherapy and radiotherapy. Multidisciplinary discussions appear decisive in planning an appropriate surgical choice and defining the correct systemic treatment tailored to each clinical condition.

Background: To assess the clinical usefulness of serum tumor markers for early detection of distant breast cancer recurrence using FDG-PET/CT., Methods: We retrospectively analyzed 561 consecutive patients who underwent surgery for invasive primary breast cancer and had increased tumor markers (CA 15-3 and CEA) after completion of locoregional therapy. FDG-PET/CT data were reviewed for all cases. CA 15-3 and CEA were evaluated both in a continuous and in a quartile (Q) distribution. The Wilcoxon rank-sum test and logistic regression models were used to evaluate the association between increased tumor marker values and the presence (and type) of distant metastases., Results: The median value of CA 15-3 was 35.0 U/mL (IQR, 29.5-43.0) in cases where no distant metastases were detected, and it was 58.9 U/mL (IQR, 40.0-108.0) in cases where metastases were detected (p < 0.001). The median value of CEA was 6.6 U/mL (IQR, 4.4-10.0) in cases of no metastases and 12.4 U/mL (IQR, 6.9-30.0) in cases of metastases (p < 0.001). Increased levels of both tumor markers (Q3 and Q4) were strongly associated with the presence of distant metastases. The association between CA 15-3 and bone/liver metastases was stronger compared with other types of metastases (p heterogeneity between odds ratios [ORs] = 0.03 for Q3 and <0.001 for Q4), while no relevant heterogeneity between ORs emerged for CEA., Conclusion: Increased tumor marker levels detected in asymptomatic breast cancer patients during adjuvant therapies and follow-up are significantly predictive of distant metastases identified on FDG-PET/CT., (© 2020 S. Karger AG, Basel.)

Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

Purpose: Radio-guided surgery with β - decays is a novel technique under investigation. One of the main advantages is its capability to detect small (⩽0.1 ml) samples after injecting the patient with low activity of radiopharmaceutical. This paper presents an experimental method to quantify this feature based on ex-vivo tests on specimens from meningioma patients., Methods: Patients were enrolled on the basis of the standard uptake value (SUV) and the tumour-to-non-tumour activity ratio (TNR) resulted from 68 Ga-DOTATOC PET exams. After injecting the patients with 93-167 MBq of 90 Y-DOTATOC, 26 samples excised during surgery were analyzed with a β - probe. The radioactivity expected on the neoplastic specimens was estimated according to the SUV found in the PET scan and the correlation with the measured counts was studied. The doses to surgeon and medical personnel were also evaluated., Results: Even injecting as low as 1.4 MBq/kg of radiotracer, tumour residuals of 0.1 ml can be detected. A negligible dose to the medical personnel was confirmed., Conclusions: Radio-guided surgery with β - decays is a feasible technique with a low radiation dose for both personnel and patient, in particular if the patient is injected with the minimum required activity. A correlation greater than 80% was observed between the measured counts and the expected activity for the lesion samples based on the individual SUV and the TNR. This makes identifiable the minimum injectable radiotracer activity for cases where 90 Y is the utilized radionuclide., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

Background: Neuroendocrine Tumors (NETs) are relatively rare tumors, mainly originating from the digestive system, that tend to grow slowly and are often diagnosed when metastasised. Surgery is the sole curative option but is feasible only in a minority of patients. Among them, pancreatic neuroendocrine tumors (pancreatic NETs or pNETs) account for less than 5% of all pancreatic tumors. Viable therapeutic options include medical treatments such as biotherapies and more recently Peptide Receptor Radionuclide Therapies (PRRT) with radiolabeled somatostatin analogues. Molecular imaging, with main reference to PET/CT, has a major role in patients with pNETs., Objective: The overexpression of specific membrane receptors, as well as the ability of cells to take up amine precursors in NET, have been exploited for the development of specific targeting imaging agents., Methods: SPECT/CT and PET/CT with specific isotopes such as [68Ga]-1,4,7,10-tetra-azacyclododecane- N,N',N'',N'''-tetra-acetic acid (DOTA)-somatostatin analogs, [18F]-FDG and [18F]-fluorodopa have been clinically explored., Results: To overcome the limitations of SSTR imaging, interesting improvements are connected with the availability of new radiotracers, activating with different mechanisms compared to somatostatin analogues, such as glucagon-like peptide 1 receptor (GLP-1 R) agonists or antagonists., Conclusion: This paper shows an overview of the RPs used so far in the imaging of pNETs with insight on potential new radiopharmaceuticals currently under clinical evaluation., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: Peptide receptor radionuclide therapy (PRRT) with 90 Y-labelled and 177 Lu-labelled peptides is an effective strategy for the treatment of metastatic/nonresectable neuroendocrine tumours (NETs). Dosimetry provides important information useful for optimizing PRRT with individualized regimens to reduce toxicity and increase tumour responses. However, this strategy is not applied in routine clinical practice, despite the fact that several dosimetric studies have demonstrated significant dose-effect correlations for normal organ toxicity and tumour response that can better guide therapy planning. The present study reviews the key relationships and the radiobiological models available in the literature with the aim of providing evidence that optimization of PRRT is feasible through the implementation of dosimetry., Methods: The MEDLINE database was searched combining specific keywords. Original studies published in the English language reporting dose-effect outcomes in patients treated with PRRT were chosen., Results: Nine of 126 studies were selected from PubMed, and a further five were added manually, reporting on 590 patients. The studies were analysed and are discussed in terms of weak and strong elements of correlations., Conclusion: Several studies provided evidence of clinical benefit from the implementation of dosimetry in PRRT, indicating the potential contribution of this approach to reducing severe toxicity and/or reducing undertreatment that commonly occurs. Prospective trials, possibly multicentre, with larger numbers of patients undergoing quantitative dosimetry and with standardized methodologies should be carried out to definitively provide robust predictive paradigms to establish effective tailored PRRT.

Background: Broncho-pulmonary neuroendocrine tumors (bpNETs) are rare malignancies and there is no consensus on therapeutical management of metastatic disease and follow-up after radical resection., Methods: Clinical records of patients with a cytological or histological diagnosis of bpNETs and distant metastases (metachronous or synchronous), evaluated at the European Institute of Oncology between 1997 and 2014, were retrospectively analyzed. Data on patient demographics, pathology, imaging exams, surgical and non-surgical treatments were collected. P value descriptive data, uni- and multi-variate survival analysis were generated for all variables., Results: With a median follow-up of 53 [9-215] months, 61 patients with metachronous and 47 with synchronous metastases were analysed. The most common tool of first recurrence detection was computed tomography. Liver (67%), lymph node (25%), bone (22%) and lung (16%) were the most common sites of relapse. Median time to recurrence was 5 years. Median overall survival (OS) was 72 months for the whole population, with no significant difference between patients with synchronous and metachronous metastases. Age, bone metastases, liver metastases and Ki-67 as a continuous variable all significantly correlated with prognosis at the multivariate analysis., Conclusions: This is one of the largest, single-centre, series of metastatic bpNETs. Among patients with metachronous metastases the pattern of recurrences was heterogeneous as were the follow-up exams used to detect them. The results of our analysis may represent solid bases for designing prospective clinical trials in homogeneous settings of bpNETs., Competing Interests: Conflicts of Interest: The authors have no conflicts of interest to declare.

The estimated annual incidence of R-NENs is 1.04 per 100,000 persons although the real incidence may be underestimated, as not all R-NEN are systematically reported in registers. Also the prevalence has increased substantially, reflecting the rising incidence and indolent nature of R-NENs, showing the highest prevalence increase among all site of origin of NENs. The size of the tumor reveals the behavior of R-NENs where the risk for metastatic spread increases for lesions > 10 mm. Applying the WHO 2010 grading system to whole NENs originating in the gastroenteropancreatic system, R-NENs are classified as Well-Differentiated Neuroendocrine Tumors (WD-NET), which contain NET G1 and NET G2, and Poorly-Differentiated Carcinomas (PD-NEC) enclosing only G3 neoplasms for which the term carcinoma is applied. The treatment is endoscopic resection in most cases: conventional polypectomy or endoscopic mucosal resection (EMR) for smaller lesions or endoscopic submucosal resection with a ligation device (ESMR-L), cap-assisted EMR (EMR-C) and endoscopic submucosal dissection (ESD). However it is important to know when the endoscopic treatment is not enough, and surgical treatment is indicated, or when the latter could be unnecessary. For PD-NECs, it has recently been demonstrated that chemoradiotherapy is associated with a similar long-term survival to that obtained with surgery. As well, new targeted-agents chemotherapy may be indicated for metastatic WD-NETs., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: Peptide receptor radionuclide therapy is a valid therapeutic option for pancreatic neuroendocrine neoplasms. The aim of this study was to describe an initial experience with the use of peptide receptor radionuclide therapy as a neoadjuvant agent for resectable or potentially resectable pancreatic neuroendocrine neoplasms., Methods: The postoperative outcomes of 23 patients with resectable or potentially resectable pancreatic neuroendocrine neoplasms at high risk of recurrence who underwent neoadjuvant peptide receptor radionuclide therapy (peptide receptor radionuclide therapy group) were compared with 23 patients who underwent upfront surgical operation (upfront surgery group). Patients were matched for tumor size, grade, and stage. Median follow-up was 61 months., Results: The size (median greatest width) of the primary pancreatic neuroendocrine neoplasms decreased after neoadjuvant peptide receptor radionuclide therapy (59 to 50 mm; P=.047). There were no differences in intraoperative and postoperative outcomes and there were no operative deaths, but the risk of developing a pancreatic fistula tended to be less in the peptide receptor radionuclide therapy group when compared to the upfront surgery group (0/23 vs 4/23; P < .02). The incidence of nodal metastases at the time of resection was also less in the peptide receptor radionuclide therapy group (n= 9/23 vs 17/23; P<.02). Neither median disease-specific survival (not reached in either group; P=.411) nor progression-free survival (52 vs 37 months; P>.2) differed between groups, but progression-free survival in the 31 patients who had an R0 resection seemed to be greater in the 15 patients in the peptide receptor radionuclide therapy group versus 16 patients the upfront group (median progression-free survival not reached vs 36 months; P<.05)., Conclusion: Neoadjuvant peptide receptor radionuclide therapy for resectable or potentially resectable pancreatic neuroendocrine neoplasms in patients with high-risk features of recurrence seems to be beneficial, but well-designed and much larger prospective trials are needed to confirm the safety and the oncologic value of this approach., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Oesophageal cancer is an aggressive disease. The possibility to early stratify patients as responsive and non-responsive with a non-invasive method is extremely appealing. The uptake of Fluorodeoxyglucose ( 18 F-FDG) in tumours, provided by positron emission tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT). In the last years, efforts have been focused on the possibility to use ad interim 18 F-FDG-PET/CT (PET int ) to evaluate response during radiation therapy. However, controversial findings have been reported, although some relevant results would support its use for individual therapeutic decision. The present review assembles the comprehensive literature of the last decade to evaluate whether and in which cases PET int may offer predictive potential in oesophageal cancer. All the analysed studies (13 studies, 697 patients) denoted PET int as a challenging examination for early assessment of outcomes during CRT. In particular, 8 studies advocated the predictivity of PET int , whilst 5 did not find any correlation between the interim variation of PET parameters and the pathological complete response and/or the clinical outcome. The reasons that possibly have caused contradictions among the studies demand further research with prospective and uniform protocols and methods of analysis to assess the predictive and prognostic value of PET int in oesophageal cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Mediastinal lymph node enlargement is common in the follow-up of patients with previously treated malignancies. The aim of this study is to assess the role of endobronchial ultrasound (EBUS) transbronchial needle aspiration (TBNA) for cyto-histological evaluation of positron emission tomography with 18 fluorodeoxyglucose (PET) positive mediastinal and hilar lymph nodes developed in patients with previous malignancies. All EBUS-TBNA cases performed from January 2012 to May 2016 were retrospective reviewed. Results of EBUS-TBNA in patients with mediastinal and/or hilar lymphadenopathies were analysed. Non-malignant cytopathologies were confirmed with surgical procedures or clinical and radiological follow-up. Among 1780 patients, 176 were included in the analysis. 103 of these (58.5%) had a diagnosis of tumour recurrence whereas 73 (41.5%) had a different diagnosis: 63 (35.8%) had a non-neoplastic diagnosis and 8 patients (4.6%) had a different cell type malignancy. Samples were false-negative in 5 (2.8%) out of 176 patients. The overall sensitivity, specificity, negative predicted value and diagnostic accuracy were 95.7% (95% CI 90.2-98.6%), 100% (95% CI 94.0-100%), 92.3% (95% CI 83.2-96.7%) and 97.2% (95% CI 93.5-98.8%), respectively. EBUS-TBNA demonstrated a pathological diagnosis different from the previous tumour in a large percentage of patients, confirming its strategic role in the management of patients with previously treated malignancies., Competing Interests: Conflict of interest: None declared.

Background: Non-Small Cell Lung Cancer (NSCLC) is characterized by aggressiveness and includes the majority of thorax malignancies. The possibility of early stratification of patients as responsive and non-responsive to radiotherapy with a non-invasive method is extremely appealing. The distribution of the Fluorodeoxyglucose ( 18 F-FDG) in tumours, provided by Positron-Emission-Tomography (PET) images, has been proved to be useful to assess the initial staging of the disease, recurrence, and response to chemotherapy and chemo-radiotherapy (CRT)., Objectives: In the last years, particular efforts have been focused on the possibility of using ad interim 18 F-FDG PET (FDG int ) to evaluate response already in the course of radiotherapy. However, controversial findings have been reported for various malignancies, although several results would support the use of FDG int for individual therapeutic decisions, at least in some pathologies. The objective of the present review is to assemble comprehensively the literature concerning NSCLC, to evaluate where and whether FDG int may offer predictive potential., Methods: Several searches were completed on Medline and the Embase database, combining different keywords. Original papers published in the English language from 2005 to 2016 with studies involving FDG int in patients affected by NSCLC and treated with radiation therapy or chemo-radiotherapy only were chosen., Results: Twenty-one studies out of 970 in Pubmed and 1256 in Embase were selected, reporting on 627 patients., Conclusion: Certainly, the lack of univocal PET parameters was identified as a major drawback, while standardization would be required for best practice. In any case, all these papers denoted FDG int as promising and a challenging examination for early assessment of outcomes during CRT, sustaining its predictivity in lung cancer.

Positron emission tomography (PET) is an imaging modality widely applied in oncology for tumor staging, volume delineation in radiation therapy planning, and therapy response assessment. F-18 fluorodeoxyglucose (FDG) PET combined with computed tomography plays a significant role in the management of locally advanced head and neck cancer patients in the pretreatment setting to predict outcome and prognosis and after chemoradiation therapy (CRT) to assess tumor response. This review aims to evaluate the use of FDG PET acquired during CRT, ad interim FDG (FDG int ), to identify tumor response at an early stage, modify the treatment plan if necessary, or set up alternative strategies to enhance the therapeutic ratio. Most of the studies confirmed the value of FDG int in predicting the response to CRT, whereas a few highlighted the poor predictive value of FDG int compared with FDG acquired 2 to 4 months after the end of CRT, which was well correlated with local and regional control and survival. Such findings deserve to be further analyzed in more homogeneous series with greater patient numbers according to the tumor site and CRT schedules. The best time to assess tumor response during radiation therapy remains a matter of debate, although 2 weeks seems most favorable, still providing the opportunity to adapt the treatment strategy., (Copyright © 2017 Elsevier Inc. All rights reserved.)

18 F-fluorodeoxyglucose PET/CT ( 18 F-FDG-PET/CT) is widely applied in oncology for disease staging, assessment of therapy response, relapse diagnosis, follow-up and target volume delineation. In particular, it can detect early response during chemoradiotherapy (interim) because functional modifications usually precede morphological ones. This ability is crucial to the radiation oncologist for the management of patients, to avoid persisting with ineffective therapy - often leading toxicity - and to shift to potentially more effective alternatives. Interim 18 F FDG-PET imaging in rectal and cervical cancer, the main malignancies of the pelvic district, has been applied and a broad literature is available, although some results are discordant. This systematic review summarizes the application of 18 F FDG-PET/CT during the chemoradiotherapy of locally advanced pelvic malignancies in order to clarify its capability to predict response and prognosis and its potential role to tailor therapy, which seems to be validated in rectal cancer, whilst less conclusive in cervical cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Purpose: Lu-DOTATATE (Lu-PRRT) is a valid therapeutic option in differentiated pancreatic neuroendocrine tumors (P-NETs). FDG PET seems to be an important prognostic factor in P-NETs. We evaluated the efficacy of Lu-PRRT and the role of FDG PET in 60 patients with advanced P-NETs., Methods: From March 2008 to June 2011, 60 consecutive patients with P-NETs were enrolled in the study. Follow-up lasted until March 2016. Eligible patients were treated with two different total cumulative activities (18.5 or 27.8 GBq in 5 cycles every 6-8 weeks), according to kidney and bone marrow parameters., Results: Twenty-eight patients received a mean full activity (FA) of 25.9 GBq and 32 a mean reduced activity (RA) of 18.5 GBq. The disease control rate (DCR), defined as the sum of CR+PR+SD was 85.7 % in the FA group and 78.1 % in the RA group. Median progression-free survival (mPFS) was 53.4 months in the FA group and 21.7 months in the RA group (P = 0.353). Median overall survival (mOS) was not reached (nr) in FA patients and was 63.8 months in the RA group (P = 0.007). Fifty-five patients underwent an FDG PET scan before Lu-PRRT, 32 (58 %) showing an increased FDG uptake in tumor sites. mPFS was 21.1 months in FDG PET-positive patients and 68.7 months in the FDG PET-negative group (P < 0.0002), regardless of the total activity administered., Conclusion: Both FA and RA are active in patients undergoing Lu-PRRT. However, an FA of 27.8 GBq of Lu-PRRT prolongs PFS and OS compared to an RA of 18.5 GBq. Our results indicate that FDG PET is an independent prognostic factor in this patient setting.