Dyslipidemia, lipid-lowering agents and neuroendocrine neoplasms: new horizons.

PURPOSE: Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies originating from cells with a neuroendocrine phenotype. The complex relationship between lipid metabolism and cancer is gaining interest and a potential anti-cancer effect of lipid lowering agents is being considered. This review aims to discuss the current understanding and treatment of dyslipidaemia in NENs, focusing on the role of lipid lowering agents, including new therapeutic approaches, and future perspectives as possible tool in cancer prevention and tumor-growth control. METHODS: We performed an electronic-based search using PubMed updated until December 2023, summarizing the available evidence both in basic and clinical research about lipid lowering agents in NENs. RESULTS: Dyslipidemia is an important aspect to be considered in NENs management, although randomized studies specifically addressing this topic are lacking, unlike other cancer types. Available data mainly regard statins, and in vitro studies have demonstrated direct antitumor effects, including antiproliferative effects in some cancers, supporting possible pleiotropic effects also in NENs, but data remain conflicting. Ezetimibe, omega 3-fatty acids, fibrates and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) may enhance the regulation of lipid homeostasis, as demonstrated in other cancers. CONCLUSIONS: Targeting dyslipidemia in NENs should be part of the multidisciplinary management and an integrated approach may be the best option for both metabolic and tumor control. Whether lipid lowering agents may directly contribute to tumor control remains to be confirmed with specific studies, focusing on association with other metabolic risk, disease stage and primary site.

Thyroid transcription factor-1 expression in lung neuroendocrine tumours: a gender-related biomarker?

PURPOSE: Thyroid transcription factor-1 (TTF-1) assessed by immunohistochemistry (IHC) is a specific biomarker for lung adenocarcinoma, and is commonly used to confirm the pulmonary origin of neuroendocrine tumours (NET). The majority of the available data suggest that TTF-1 is favourable prognostic biomarker for lung adenocarcinomas, whereas its role is more conflicting for lung NET. The main aim of this multicenter retrospective study was to investigate the potentially relevant associations between TTF-1 biomarker and clinical and pathological features of the study population, as well as determine TTF-1 prognostic effect on the clinical outcome of the patients. METHODS: A multicentre retrospective study was conducted on 155 surgically-removed lung NET, with available IHC TTF-1 assessment. RESULTS: Median age was 59.5 years (range 13-86), 97 patients (62.6%) were females, 31 cases (20%) were atypical carcinoids, 4 (2.6%) had TNM stage IV. Mitotic count ≥2 per 10 high-power field was found in 35 (22.6%) subjects, whereas necrosis was detected in 20 patients (12.9%). TTF-1 was positive in 78 cases (50.3%). The median overall survival was 46.9 months (range 0.6-323) and the median progression-free survival was 39.1 months (range 0.6-323). Statistically significant associations were found between (1) TTF-1 positivity and female sex (p = 0.007); and among (2) TTF-1 positivity and the absence of necrosis (p = 0.018). CONCLUSIONS: This study highlights that TTF-1 positivity differs according to sex in lung NET, with a more common TTF-1 positive staining in female. Moreover, TTF-1 positivity correlated with the absence of necrosis. These data suggest that TTF-1 could potentially represent a gender-related biomarker for lung NET.

Metabolomic profile of neuroendocrine tumors identifies methionine, porphyrin, and tryptophan metabolisms as key dysregulated pathways associated with patient survival.

OBJECTIVE: Metabolic profiling is a valuable tool to characterize tumor biology but remains largely unexplored in neuroendocrine tumors (NETs). Our aim was to comprehensively assess the metabolomic profile of NETs and identify novel prognostic biomarkers and dysregulated molecular pathways. DESIGN AND METHODS: Multiplatform untargeted metabolomic profiling (GC-MS, CE-MS, and LC-MS) was performed in plasma from 77 patients with G1-2 extra-pancreatic NETs enrolled in the AXINET trial (NCT01744249) (study cohort) and from 68 non-cancer individuals (control). The prognostic value of each differential metabolite (n = 155) in NET patients (P < .05) was analyzed by univariate and multivariate analyses adjusted for multiple testing and other confounding factors. Related pathways were explored by Metabolite Set Enrichment Analysis (MSEA) and Metabolite Pathway Analysis (MPA). RESULTS: Thirty-four metabolites were significantly associated with progression-free survival (PFS) (n = 16) and/or overall survival (OS) (n = 27). Thirteen metabolites remained significant independent prognostic factors in multivariate analysis, 3 of them with a significant impact on both PFS and OS. Unsupervised clustering of these 3 metabolites stratified patients in 3 distinct prognostic groups (1-year PFS of 71.1%, 47.7%, and 15.4% (P = .012); 5-year OS of 69.7%, 32.5%, and 27.7% (P = .003), respectively). The MSEA and MPA of the 13-metablolite signature identified methionine, porphyrin, and tryptophan metabolisms as the 3 most relevant dysregulated pathways associated with the prognosis of NETs. CONCLUSIONS: We identified a metabolomic signature that improves prognostic stratification of NET patients beyond classical prognostic factors for clinical decisions. The enriched metabolic pathways identified reveal novel tumor vulnerabilities that may foster the development of new therapeutic strategies for these patients.

Extrapulmonary Neuroendocrine Carcinomas: Current Management and Future Perspectives.

Neuroendocrine carcinomas (NECs) are poorly differentiated and highly aggressive epithelial neuroendocrine neoplasms. The most common primary site is the lung, but they may arise in every organ. Approximately 37% of extrapulmonary NECs (EP-NECs) occur in the gastroenteropancreatic (GEP) tract, followed by the genitourinary (GU) system and gynecological tract. As a result of their rarity, there is scant evidence to guide treatment recommendations, and a multidisciplinary approach is essential for the management of such patients. Platinum-based chemotherapy currently represents the standard of care for EP-NECs of any site, mirroring the management of small-cell lung cancer (SCLC), but further approaches are still under investigation. Indeed, ongoing trials evaluating targeted therapies, immune checkpoint inhibitors (ICIs), and radionuclide therapy could provide potentially breakthrough therapeutic options. Given the relative dearth of evidence-based literature on these orphan diseases, the aim of this review is to provide an overview of the pathology and current treatment options, as well as to shed light on the most pressing unmet needs in the field.

Predictive Factors of Response to Streptozotocin in Neuroendocrine Pancreatic Neoplasms.

Pancreatic neuroendocrine neoplasms (Pan-NENs) may exhibit a heterogeneous clinical course, ranging from indolent to progressive/metastatic behavior. In the latter scenario, streptozocin (STZ) is considered the cornerstone of systemic treatment; however, response to STZ-based chemotherapy may vary among individuals. In this narrative review, we aimed to identify the predictive factors of response to STZ in advanced Pan-NENs. We performed an extensive search in international online databases for published studies and ongoing clinical trials evaluating STZ in Pan-NENs. We found 11 pertinent studies evaluating 17 patient-, tumor-, or treatment-related factors. Age, CgA blood levels, tumor grade, Ki-67% index, anatomical location of the primary tumor, tumor stage, site of metastasis origin, liver tumor burden, extrahepatic spread, functional status, O6-methylguanine-methyltransferase (MGMT) status, line of therapy, and response to previous treatments were all statistically associated with radiological response and/or survival. The identified predictors may help clinicians make appropriate treatment decisions, in this way improving clinical outcomes in patients with advanced Pan-NENs.

Cell-based medicinal products approved in the European Union: current evidence and perspectives.

Advanced Therapy Medicinal Products (ATMPs) are innovative clinical treatments exploiting the pharmacological, immunological, or metabolic properties of cells and/or gene(s) with the aim to restore, correct, or modify a biological function in the recipient. ATMPs are heterogeneous medicinal products, developed mainly as individualized and patient-specific treatments, and represent new opportunities for diseases characterized by a high-unmet medical need, including rare, genetic and neurodegenerative disorders, haematological malignancies, cancer, autoimmune, inflammatory and orthopaedic conditions. Into the European Union (EU) market, the first ATMP has been launched in 2009 and, to date, a total of 24 ATMPs have been approved. This review aims at reporting on current evidence of cell-based therapies authorized in the EU, including Somatic Cell Therapies, Tissue Engineering Products, and Cell-based Gene Therapy Products as Chimeric Antigen Receptor (CAR) T-cells, focusing on the evaluation of efficacy and safety in clinical trials and real-world settings. Despite cell-based therapy representing a substantial promise for patients with very limited treatment options, some limitations for its widespread use in the clinical setting remain, including restricted indications, highly complex manufacturing processes, elevated production costs, the lability of cellular products over time, and the potential safety concerns related to the intrinsic characteristics of living cells, including the risk of severe or life-threatening toxicities, such as CAR-T induced neurotoxicity and cytokine release syndrome (CRS). Although encouraging findings support the clinical use of ATMPs, additional data, comparative studies with a long-term follow-up, and wider real-world evidences are needed to provide further insights into their efficacy and safety profiles.

Precision medicine in gastroenteropancreatic neuroendocrine neoplasms: Where are we in 2023?

Precision medicine describes a target-related approach to tailoring diagnosis and treatment of the individual patient. While this personalized approach is revoluzionizing many areas of oncology, it is quite late in the field of gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs), in which there are few molecular alterations to be therapeutically targeted. We critically reviewed the current evidence about precision medicine in GEP NENs, focusing on potential clinically relevant actionable targets for GEP NENs, such as the mTOR pathway, MGMT, hypoxia markers, RET, DLL-3, and some general agnostic targets. We analysed the main investigational approaches with solid and liquid biopsies. Furthermore, we reviewed a model of precision medicine more specific for NENs that is the theragnostic use of radionuclides. Overall, currently no true predictive factors for therapy have been validated so far in GEP NENs, and the personalized approach is based more on clinical thinking within a NEN-dedicated multidisciplinary team. However, there is a robust background to suppose that precision medicine, with the theragnostic model will yield new insights in this context soon.

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors: Alternatives to RECIST.

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06-3.40; p = .03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p = .91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. CLINICAL TRIAL REGISTRATION: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as "E-NETNET-L-E-CT" July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.

Proteasome inhibitors in medullary thyroid carcinoma: time to restart with clinical trials?

Introduction: Medullary thyroid cancer (MTC) is a rare thyroid tumour whose management in advanced stages is challenging, despite effective therapeutic options having expanded in recent years. Proteasome inhibitors (PrIn) have shown the ability to improve patient outcomes, including survival and quality of life, in several malignancies, due to their ability to impair cell proliferation and cause apoptosis through the inhibition of the proteasome activity. Consequently, these drugs could represent a useful tool, alone or in combination with other treatments, in MTC patients. Aim of the study: This review aims to summarize the available in vitro and in vivo data about the role of PrIn in MTC. Materials and methods: We performed an extensive search for relevant data sources, including full-published articles in international online databases (PubMed, Web of Science, Scopus), preliminary reports in selected international meeting abstract repositories, and short articles published as supplements of international meetings, by using the following terms: medullary thyroid carcinoma, proteasome inhibitors, bortezomib, carfilzomib, ixazomib, delanzomib, marizomib, oprozomib, and MG132. Additionally, we conducted with the same keywords, an in-depth search in registered clinical trials repositories. Results: Our search revealed in vitro studies in human and murine MTC cell lines, based on the use of PrIns, both alone and in combination with other anticancer drugs, and two pertinent clinical trials. Conclusion: We found a strong discrepancy between the evidence of PrIns effects in preclinical studies, and the scarcity or early interruption of clinical trials. We might speculate that difficulties in enrolling patients, as happens in other rare diseases, may have discouraged trials' implementation in favor of drugs already approved for MTC. However, given the concrete improvement in the comprehension of the molecular basis of PrIn effects in MTC, new clinical trials with accurate inclusion criteria of enrollment might be warranted, in order to ascertain whether this treatment, alone or in combination with other drugs, could indeed represent an option to enhance the therapeutic response, and to ultimately improve patients' outcome and survival.

COVID-19 in patients with neuroendocrine neoplasms: 2-year results of the INTENSIVE study.

We conducted a retrospective/prospective worldwide study on patients with neuroendocrine neoplasms (NENs) and a molecularly proven SARS-CoV-2 positivity. Preliminary results regarding 85 patients of the INTENSIVE study have been published in 2021. Now we are reporting the 2-year analysis.Here, we are reporting data from consecutive patients enrolled between 1 June 2020, and 31 May 2022. Among the 118 contacted centers, 25 were active to enroll and 19 actively recruiting at the time of data cut-off for a total of 280 patients enrolled. SARS-CoV-2 positivity occurred in 47.5% of patients in 2020, 35.1% in 2021, and 17.4% in 2022. The median age for COVID-19 diagnosis was 60 years. Well-differentiated tumors, non-functioning, metastatic stage, and gastroenteropancreatic (GEP) primary sites represented most of the NENs. COVID-19-related pneumonia occurred in 22.8% of the total, with 61.3% of them requiring hospitalization; 11 patients (3.9%) needed sub-intensive or intensive care unit therapies and 14 patients died (5%), in 11 cases (3.9%) directly related to COVID-19. Diabetes mellitus and age at COVID-19 diagnosis > 70 years were significantly associated with COVID-19 mortality, whereas thoracic primary site with COVID-19 morbidity. A significant decrease in both hospitalization and pneumonia occurred in 2022 vs 2020. In our largest series of NEN patients with COVID-19, the NEN population is similar to the general population of patients with NEN regardless of COVID-19. However, older age, non-GEP primary sites and diabetes mellitus should be carefully considered for increased COVID-19 morbidity and mortality. Relevant information could be derived by integrating our results with NENs patients included in other cancer patients with COVID-19 registries.

MicroRNA signature and integrative omics analyses define prognostic clusters and key pathways driving prognosis in patients with neuroendocrine neoplasms.

Neuroendocrine neoplasms (NENs) are mutationally quiet (low number of mutations/Mb), and epigenetic mechanisms drive their development and progression. We aimed at comprehensively characterising the microRNA (miRNA) profile of NENs, and exploring downstream targets and their epigenetic modulation. In total, 84 cancer-related miRNAs were analysed in 85 NEN samples from lung and gastroenteropancreatic (GEP) origin, and their prognostic value was evaluated by univariate and multivariate models. Transcriptomics (N = 63) and methylomics (N = 30) were performed to predict miRNA target genes, signalling pathways and regulatory CpG sites. Findings were validated in The Cancer Genome Atlas cohorts and in NEN cell lines. We identified a signature of eight miRNAs that stratified patients in three prognostic groups (5-year survival of 80%, 66% and 36%). Expression of the eight-miRNA gene signature correlated with 71 target genes involved in PI3K-Akt and TNFα-NF-kB signalling. Of these, 28 were associated with survival and validated in silico and in vitro. Finally, we identified five CpG sites involved in the epigenetic regulation of these eight miRNAs. In brief, we identified an 8-miRNA signature able to predict survival of patients with GEP and lung NENs, and identified genes and regulatory mechanisms driving prognosis in NEN patients.

Recurrence-Free Survival in Early and Locally Advanced Large Cell Neuroendocrine Carcinoma of the Lung after Complete Tumor Resection.

BACKGROUND: Large Cell Neuroendocrine Carcinoma (LCNEC) is a rare subtype of lung cancer with poor clinical outcomes. Data on recurrence-free survival (RFS) in early and locally advanced pure LCNEC after complete resection (R0) are lacking. This study aims to evaluate clinical outcomes in this subgroup of patients and to identify potential prognostic markers. METHODS: Retrospective multicenter study including patients with pure LCNEC stage I-III and R0 resection. Clinicopathological characteristics, RFS, and disease-specific survival (DSS) were evaluated. Univariate and multivariate analyses were performed. RESULTS: 39 patients (M:F = 26:13), with a median age of 64 years (44-83), were included. Lobectomy (69.2%), bilobectomy (5.1%), pneumonectomy (18%), and wedge resection (7.7%) were performed mostly associated with lymphadenectomy. Adjuvant therapy included platinum-based chemotherapy and/or radiotherapy in 58.9% of cases. After a median follow-up of 44 (4-169) months, the median RFS was 39 months with 1-, 2- and 5-year RFS rates of 60.0%, 54.6%, and 44.9%, respectively. Median DSS was 72 months with a 1-, 2- and 5-year rate of 86.8, 75.9, and 57.4%, respectively. At multivariate analysis, age (cut-off 65 years old) and pN status were independent prognostic factors for both RFS (HR = 4.19, 95%CI = 1.46-12.07, p = 0.008 and HR = 13.56, 95%CI 2.45-74.89, p = 0.003, respectively) and DSS (HR = 9.30, 95%CI 2.23-38.83, p = 0.002 and HR = 11.88, 95%CI 2.28-61.84, p = 0.003, respectively). CONCLUSION: After R0 resection of LCNEC, half of the patients recurred mostly within the first two years of follow-up. Age and lymph node metastasis could help to stratify patients for adjuvant therapy.

Chemotherapy in Well Differentiated Neuroendocrine Tumors (NET) G1, G2, and G3: A Narrative Review.

Neuroendocrine tumors (NETs) are rare neoplasms with a wide spectrum of clinical behavior, from the long survival of well-differentiated NETs to the dismal prognosis of high-grade neuroendocrine carcinomas (NECs), being G3 NETs a recently recognized intermediate entity. While the role of chemotherapy is well established in NECs, data on NETs mostly derives from small studies, experts' opinions, and extrapolating results from small-cell lung cancer studies. This narrative review aims to summarize available evidence about the use of chemotherapy in the setting of G1-2 NETs and G3 NETs. We performed literature research in PubMed Library for all articles published up to September 2022 about the efficacy of chemotherapy in NETs. Treatment regimens with STZ-5FU, CAPTEM, and anti-metabolite-based treatment are the most active and tolerated in gastroenteropancreatic NETs (GEP-NETs) G1-G2, while platinum-based regimens (FOLFOX/XELOX) and TEM/CAPTEM showed the best activity in thoracic NETs. Solid evidence about chemotherapy efficacy in G3 NETs is still lacking. Literature data support the use of chemotherapy in low-intermediate grade NETs after the failure of other therapies or if tumor shrinkage is needed. Studies assessing G3 NETs independently from NECs are needed to better understand the role of chemotherapy in this setting.

Efficacy and Safety of Lanreotide Autogel and Temozolomide Combination Therapy in Progressive Thoracic Neuroendocrine Tumors (Carcinoid): Results from the Phase 2 ATLANT Study.

INTRODUCTION: Lanreotide autogel (LAN) and temozolomide (TMZ) are guidelines-recommended monotherapies for thoracic neuroendocrine tumors (carcinoids; T-NETs), but prospective data for both combined and monotherapies are lacking. ATLANT (NCT02698410) evaluated efficacy and safety of LAN/TMZ in progressive T-NETs. METHODS: ATLANT was a 12-month, Italian, phase 2, single-arm, open-label, multicenter pilot study. Eligible patients had unresectable, locally advanced/metastatic, well-/moderately differentiated T-NETs with radiological progression. Patients received subcutaneous LAN 120 mg every 28 days and oral TMZ 250 mg/day for 5 consecutive days every 28-day cycle. Main endpoints are disease control rate (DCR) at 9 months (primary; investigator-assessed), median progression-free survival (PFS), biomarkers, and safety. RESULTS: The number of patients was 40; 60% were male. Primary tumor site was lung (90%) and thymus (10%). Carcinoid type was typical (20.0%) and atypical (52.5%). DCR at 9 months was 35.0% (95% confidence interval (CI) 20.63-51.68; nonacceptability threshold ≤10%, p < 0.0001; not significantly above clinically relevant threshold ≥30%, p = 0.2968). DCR between 7.5 and 10.5 months (sensitivity analysis) was 45.0% (95% CI: 29.26-61.51) and clinically relevant (p = 0.0320 at ≥30% threshold). Median PFS was 37.1 (95% CI: 24.1-52.9) weeks. No association was observed between biomarker variations (chromogranin A, neuron-specific enolase, somatostatin receptor type-2, Ki-67, 6-O-methylguanine-DNA-methyl-transferase) and DCR or PFS. Most patients (97.5%) had treatment-emergent adverse events (TEAEs); 72.5% had treatment-related TEAEs. TEAEs were mainly grade 1/2. No unanticipated TEAEs were reported. CONCLUSIONS: This study showed that the LAN/TMZ combination has promising efficacy in progressive T-NETs, and was well tolerated. Larger studies are warranted to support the clinical benefits of LAN/TMZ in patients with T-NETs.

Lipid Metabolism and Homeostasis in Patients with Neuroendocrine Neoplasms: From Risk Factor to Potential Therapeutic Target.

Lipid metabolism is known to be involved in tumorigenesis and disease progression in many common cancer types, including colon, lung, breast and prostate, through modifications of lipid synthesis, storage and catabolism. Furthermore, lipid alterations may arise as a consequence of cancer treatment and may have a role in treatment resistance. Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies with increasing incidence, whose mechanisms of cancer initiation and progression are far from being fully understood. Alterations of lipid metabolism may be common across various cancer types, but data about NENs are scattered and heterogeneous. Herein, we provide an overview of the relevant literature on lipid metabolism and alterations in NENs. The available evidence both in basic and clinical research about lipid metabolism in NENs, including therapeutic effects on lipid homeostasis, are summarized. Additionally, the potential of targeting the lipid profile in NEN therapy is also discussed, and areas for further research are proposed.

Angioside: The role of Angiogenesis and Hypoxia in Lung Neuroendocrine Tumours According to Primary Tumour Location in Left or Right Parenchyma.

Well-differentiated lung neuroendocrine tumours (Lu-NETs), classified as typical (TC) and atypical (AC) carcinoids, represent 30% of NETs. Angiogenesis plays an essential role in NET development and progression. A higher vascular network is a marker of differentiation, with positive prognostic implications. Materials and Methods: We retrospectively evaluated microvessel density (MVD) by CD34 immunohistochemical (IHC) staining and hypoxia by IHC staining for Hypoxia-inducible factor 1α (HIF-1α), comparing right- and left-lung parenchyma in 53 lung NETs. Results: The median age was 66 years (39−81), 56.6% males, 24.5% AC, 40.5% left-sided tumours and 69.8% TNM stage I. The mitotic count was <2/10 per 10 HPF in 79.2%, and the absence of necrosis in 81.1%, 39.6% with Ki67, was ≤2%. The MVD, the number of vessels and the average vessel area median values were significantly higher in the right than the left parenchyma (p: 0.025, p: 0.019, p: 0.016, respectively). Hypoxia resulted present in 14/19 (73.6%) left tumours and in 10/20 (50%) right tumours in the parenchyma (p: 0.129). Conclusions: This study suggests a biological rationale for a different angiogenesis and hypoxia according to the Lu-NETs' location. In our study, left primary tumours were less vascularized and most likely to present hypoxia than right primary tumours. This finding could have potentially useful prognostic and predictive implications for Lu-NETs.

Immunotherapy of Neuroendocrine Neoplasms: Any Role for the Chimeric Antigen Receptor T Cells?

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors with variable clinical presentation and prognosis. Surgery, when feasible, is the most effective and often curative treatment. However, NENs are frequently locally advanced or already metastatic at diagnosis. Consequently, additional local or systemic therapeutic approaches are required. Immunotherapy, based on chimeric antigen receptor T cells (CAR-T), is showing impressive results in several cancer treatments. The aim of this narrative review is to analyze the available data about the use of CAR-T in NENs, including studies in both preclinical and clinical settings. We performed an extensive search for relevant data sources, comprising full-published articles, abstracts from international meetings, and worldwide registered clinical trials. Preclinical studies performed on both cell lines and animal models indicate a significant therapeutic effect of CAR-T cells in NENs. Ongoing and future clinical trials will clarify the possible role of these drugs in patients with highly aggressive NENs.

Neuroendocrine Tumors: Challenges and Future Perspectives.

The awareness and interest of the scientific community towards Neuroendocrine tumors (NETs) has progressively increased in the last few decades [...].