Sex differences in carcinoid syndrome: A gap to be closed.

The incidence of neuroendocrine neoplasms and related carcinoid syndrome (CS) has markedly increased over the last decades and women seem to be more at risk than men for developing CS. Nevertheless, very few studies have investigated sex differences in clinical presentation and outcomes of CS. However, as per other tumours, sex might be relevant in influencing tumour localization, delay in diagnosis, clinical outcomes, prognosis and overall survival in CS. The present review was aimed at evaluating sex differences in CS, as they emerge from an extensive search of the recent literature. It emerged that CS occurs more frequently in female than in male patients with NENs and women seem to have a better prognosis and a slight advantage in overall survival and response to therapy. Moreover, the disease likely impacts differently the quality of life of men and women, with different psychological and social consequences. Nevertheless, sex differences, even if partially known, are deeply underestimated in clinical practice and data from clinical trials are lacking. There is urgent need to increase our understanding of the sex-related differences of CS, in order to define tailored strategies of management of the disease, improving both the quality of life and the prognosis of affected patients.

Current understanding of pathogenetic mechanisms in neuroendocrine neoplasms.

INTRODUCTION: Despite the fact that important advances in research on neuroendocrine neoplasms (NENs) have been made, consistent data about their pathogenetic mechanism are still lacking. Furthermore, different primary sites may recognize different pathogenetic mechanisms. AREAS COVERED: This review analyzes the possible biological and molecular mechanisms that may lead to NEN onset and progression in different organs. Through extensive research of the literature, risk factors including hypercholesterolemia, inflammatory bowel disease, chronic atrophic gastritis are evaluated as potential pathogenetic mechanisms. Consistent evidence is available regarding sporadic gastric NENs and MEN1 related duodenopancreatic NENs precursor lesions, and genetic-epigenetic mutations may play a pivotal role in tumor development and bone metastases onset. In lung neuroendocrine tumors (NETs), diffuse proliferation of neuroendocrine cells on the bronchial wall (DIPNECH) has been proposed as a premalignant lesion, while in lung neuroendocrine carcinoma nicotine and smoke could be responsible for carcinogenic processes. Also, rare primary NENs such as thymic (T-NENs) and Merkel cell carcinoma (MCC) have been analyzed, finding different possible pathogenetic mechanisms. EXPERT OPINION: New technologies in genomics and epigenomics are bringing new light to the pathogenetic landscape of NENs, but further studies are needed to improve both prevention and treatment in these heterogeneous neoplasms.

Recent advances and future challenges in the diagnosis of neuroendocrine neoplasms.

Neuroendocrine neoplasms (NEN) are a heterogeneous group of malignancies with increasing incidence, whose diagnosis is usually delayed, negatively impacting on patients' prognosis. The latest advances in pathological classifications, biomarker identification and imaging techniques may provide early detection, leading to personalized treatment strategies. In this narrative review the recent developments in diagnosis of NEN are discussed including progresses in pathological classifications, biomarker and imaging. Furthermore, the challenges that lie ahead are investigated. By discussing the limitations of current approaches and addressing potential roadblocks, we hope to guide future research directions in this field. This article is proposed as a valuable resource for clinicians and researchers involved in the management of NEN. Update of pathological classifications and the availability of standardized templates in pathology and radiology represent a substantially improvement in diagnosis and communication among clinicians. Additional immunohistochemistry markers may now enrich pathological classifications, as well as miRNA profiling. New and multi-analytical circulating biomarkers, as liquid biopsy and NETest, are being proposed for diagnosis but their validation and availability should be improved. Radiological imaging strives for precise, non-invasive and less harmful technique to improve safety and quality of life in NEN patient. Nuclear medicine may benefit of somatostatin receptors' antagonists and membrane receptor analogues. Diagnosis in NEN still represents a challenge due to their complex biology and variable presentation. Further advancements are necessary to obtain early and minimally invasive diagnosis to improve patients' outcomes.

Evaluation of Neutrophil-to-Lymphocyte Ratio (NLR), Platelet-to-Lymphocyte Ratio (PLR) and Systemic Immune-Inflammation Index (SII) as Potential Biomarkers in Patients with Sporadic Medullary Thyroid Cancer (MTC).

Medullary thyroid cancer (MTC) is a rare neuroendocrine neoplasm, and calcitonin is its main biomarker. An elevated neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) have been considered as negative prognostic factors in several neoplasms. The aim of this study is to evaluate the potential role of NLR, PLR and SII as biomarkers in MTC. Clinical data and tumor histological characteristics of patients with sporadic MTC, referred to the NET Unit of Federico II University of Naples (ENETS CoE) from 2012 to 2022, were retrospectively evaluated by analyzing preoperative and postoperative calcitonin, NLR, PLR and SII. We included 35 MTC patients undergoing total thyroidectomy. The mean preoperative NLR was 2.70 (±1.41, 0.93-7.98), the PLR was 121.05 (±41.9, 40.98-227.23) and SII was 597.92 (±345.58, 186.59-1628). We identified a statistically significant difference between pre- and post-thyroidectomy NLR (p = 0.02), SII (p = 0.02) and calcitonin (p = 0.0) values. No association with prognosis or tumor characteristics emerged. Elevated preoperative NLR and SII suggest a possible disease-associated inflammatory response, and their reduction after surgery may be related to debulking effects. Further studies are needed to define the role of NLR, PLR and SII as prognostic markers in MTC.

Vitamin D and Bone Metabolism in Adult Patients with Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is a genetic multisystemic autosomal dominant disorder determining reduced life expectancy due to higher risk of developing benign and malignant tumors. Low levels of vitamin D and reduced bone mineral density (BMD) have been reported in young patients with NF1. However, correlation between vitamin D and NF1 phenotype needs to be elucidated. Aim of this study was to assess vitamin D levels and bone metabolism in NF1 patients, analyzing potential correlations with clinical phenotype. A cross-sectional study was carried out in a monocentric series of NF1 patients, evaluating genotype, clinical phenotype, BMD, biochemical evaluation with focus on serum 25OH-vitamin D, parathyroid hormone (PTH), calcium and phosphate levels. Correlations between clinical manifestations, neurofibromas, and vitamin D status have been studied in comparison with healthy controls. 31 NF1 adult patients were matched for sex, age and body mass index with 31 healthy controls. A significantly difference in vitamin D level emerged in NF1 patients compared to controls. Interestingly low vitamin D levels correlated with a more aggressive phenotype and with a bigger size of neurofibromas. These data underline that vitamin D deficiency/insufficiency may play a role in clinical severity of neurofibromas in patients with NF1, suggesting the need to check bone status and replace vitamin D in these patients.

Therapeutic strategies for patients with neuroendocrine neoplasms: current perspectives.

INTRODUCTION: Neuroendocrine neoplasms (NENs) are a heterogeneous group of malignancies mainly arising in the gastroenteropancreatic (GEP) and bronchopulmonary systems, with steadily increasing incidence. The therapeutic landscape has widened and the therapeutic strategy should be based on new sequences and combinations, still debated. AREAS COVERED: Herein, we provide an overview of current approved pharmacological treatments in patients with NENs, with the aim to summarize evidence of efficacy of the main different options in GEP and pulmonary NENs, principally focusing on somatostatin analogs (SSAs), targeted therapy with everolimus and sunitinib, peptide receptor radionuclide therapy (PRRT) and chemotherapy. We discuss biological rationale and toxicities, including current indications according to differentiation and placement in the therapeutic algorithm, clinical trials, and combinations. Furthermore, we recommend areas for further research. EXPERT OPINION: Therapeutic management of patients with NENs represents a challenge for clinicians and the identification of effective sequences and combinations is of utmost importance. Major efforts should be directed to early identify and overcome resistance and to limit toxicity. The progress in the therapeutic management of NENs grows faster and the choice of the best approach should be based on randomized clinical trials, as well as on long-term, real-world data.

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.

Cardio-Metabolic Indices and Metabolic Syndrome as Predictors of Clinical Severity of Gastroenteropancreatic Neuroendocrine Tumors.

Background: Obesity, mainly visceral obesity, and metabolic syndrome (MetS) are major risk factors for the development of type 2 diabetes, cardiovascular diseases, and cancer. Data analyzing the association of obesity and MetS with gastroenteropancreatic neuroendocrine neoplasms (GEP-NEN) are lacking. Fatty liver index (FLI) is a non-invasive tool for identifying individuals with non-alcoholic fatty liver disease (NAFLD). Visceral adiposity index (VAI) has been suggested as a gender-specific indicator of adipose dysfunction. Both indexes have been proposed as early predictors of MetS. This study aimed to investigate the association of FLI VAI as early predictors of MetS with gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Methods: A cross-sectional, case-control, observational study was carried out at the ENETS Centers of Excellence Multidisciplinary Group for Neuroendocrine Tumors, University "Federico II". VAI and FLI were calculated. Results: We enrolled 109 patients with histologically confirmed G1/G2 GEP-NET (53 M; 57.06 ± 15.96 years), as well as 109 healthy subjects, age, sex- and body mass index-matched. Forty-four GEP-NET patients were G2, of which 21 were with progressive disease, and 27 patients had metastases. GEP-NET patients had a higher value of VAI (p < 0.001) and FLI (p = 0.049) and higher MetS presence (p < 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients (p < 0.001), in patients with progressive disease, and in metastatic vs non-metastatic patients (p < 0.001). In addition, higher values of VAI and FLI and higher MetS presence were significantly correlated with the worst clinical severity of NENs. The cut-off values for the FLI and MetS to predict high grading of GEP-NETs and the presence of metastasis were also provided. Conclusions: This is the first study investigating an association between VAI and FLI as early predictors of MetS and GEP-NET. Our findings report that the worsening of clinicopathological characteristics in GEP-NET is associated with higher presence of MetS, NAFLD, evaluated by FLI, and visceral adiposity dysfunction, evaluated by VAI. Addressing the clinical evaluation of MetS presence, NAFLD, and visceral adiposity dysfunction might be of crucial relevance to establish targeted preventive and treatment interventions of NEN-related metabolic comorbidities.

Role of FGF System in Neuroendocrine Neoplasms: Potential Therapeutic Applications.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of tumors originating from neuroendocrine cells dispersed in different organs. Receptor tyrosine kinases are a subclass of tyrosine kinases with a relevant role in several cellular processes including proliferation, differentiation, motility and metabolism. Dysregulation of these receptors is involved in neoplastic development and progression for several tumors, including NENs. In this review, we provide an overview concerning the role of the fibroblast growth factor (FGF)/fibroblast growth factor receptor (FGFR) system in the development and progression of NENs, the occurrence of fibrotic complications and the onset of drug-resistance. Although no specific FGFR kinase inhibitors have been evaluated in NENs, several clinical trials on multitarget tyrosine kinase inhibitors, acting also on FGF system, showed promising anti-tumor activity with an acceptable and manageable safety profile in patients with advanced NENs. Future studies will need to confirm these issues, particularly with the development of new tyrosine kinase inhibitors highly selective for FGFR.