A phase II, single-center, prospective, open-label study with high-dose somatostatin analogs (SSA) in patients with progressive neuroendocrine tumors (NET)

I tumori neuroendocrini (NET) rappresentano circa il 2% di tutti i tumori maligni e i dati epidemiologici mostrano un progressivo incremento di incidenza. La presentazione clinica, il comportamento biologico e la prognosi di questi tumori sono molto eterogenei. Spesso il decorso è indolente, per questo la diagnosi è tardiva e spesso associata alla presenza di metastasi. La chirurgia può essere curativa in casi selezionati, ma la maggior parte dei pazienti necessita di terapia medica. Gli analoghi della somatostatina (SSA) rappresentano il cardine della terapia medica per il controllo dei sintomi e anche della crescita tumorale, oltre a mostrare un buon profilo di sicurezza. Studi effettuati in pazienti acromegalici hanno mostrato che l’effetto antiproliferativo degli SSA potrebbe essere dose dipendente, così nella pratica clinica è comune l’impiego di aumentare il dosaggio o ridurre l’intervallo di tempo tra le somministrazioni di SSA. In pazienti affetti da NET sono stati pubblicati pochi dati, molto eterogenei e prevalentemente retrospettivi, sull’impiego di SSA ad alte dosi. Obiettivo principale di questo progetto è valutare l’efficacia di due diversi schemi terapeutici con SSA ad alte dosi (octreotide LAR 60 mg/28 giorni e lanreotide autogel 120 mg/21 giorni), in pazienti affetti da NET, in progressione di malattia durante terapia con SSA a dosi standard, afferenti presso l’Unità di Endocrinologia, Dipartimento di Medicina Clinica e Chirurgia, dell’Università degli Studi Federico II di Napoli. Obiettivi secondari sono la valutazione della risposta radiologica, clinica e biochimica, oltre all’analisi della sicurezza. In questo studio prospettico, monocentrico, di fase 2, in aperto, sono stati arruolati i 20 pazienti con diagnosi di NET confermata istologicamente, a sede di origine diversa, bene o moderatamente differenziati (G1, G2 secondo la classificazione WHO 2010), maggiorenni, trattati con SSA a dosi standard (octreotide LAR 30mg/28 giorni; lanreotide Autogel 120 mg/28 giorni) per almeno sei mesi, con evidenza di progressione di malattia (radiologica in accordo ai criteri RECIST 1.1 o con sindrome clinica non controllata, in caso di NET funzionante). I pazienti sono stati valutati clinicamente, radiologicamente e con esami biochimici. I pazienti sono stati rimasti in follow up per 29.9 mesi e l’efficacia della terapia con SSA ad alte dosi è stata evidenziata in 16 pazienti (80%). In un paziente (5%) è stata evidenziata risposta radiologica parziale, in 15 pazienti (75%) la malattia è rimasta stabile e in 4 (20%) è progredita. La mediana di sopravvivenza libera da malattia non è stata raggiunta. Tra i 12 pazienti asintomatici, è stata ottenuta risposta completa in 1 (8%), risposta parziale in 6 (50%), stabilità in 4 (34%) e progressione in 1 (8%). La risposta biochimica completa è stata ottenuta in 3 (15%) pazienti, 13 (65%) hanno mostrato risposta parziale e 3 (15%) stabilità e 1 (5%) progressione. Non sono stati evidenziati eventi avversi inattesi e nessun paziente ha dovuto sospendere la terapia per tossicità. La terapia con SSA ad alte dosi in pazienti affetti da NET in progressione durante terapia con dosi standard appare efficace e sicura. Sono necessari ulteriori studi su casistiche più ampie per validare questi dati ed evidenziare eventuali fattori predittivi di risposta

Immune checkpoint inhibitors in cancer therapy: The leading role of the endocrinologist

The endocrine, immune, and nervous systems have a close functional relation from the embryonic development until the end of life, nevertheless this important homeostasis can be altered by any stressors such as infections, autoimmune diseases, neoplasms or medications.             Immune checkpoint inhibitors (ICPi) have relatively recently emerged as a promising treatment option for several cancers, including advanced melanoma, non–small cell lung cancer, renal cell carcinoma, and colorectal cancer. ICPi target immune checkpoints, such as cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), programmed cell death 1 (PD-1) or its ligand (PD-L1). ICPi modulates the immune system with the aim of eradicating cancer cells, but despite their acknowledged anti-cancer efficacy, they can increase the risk of developing autoimmune disorders. In this fashion, the same mechanisms that support tumor regression may favor autoantigen-mediated cytotoxicity and the production of T-cell-dependent autoantibodies. Importantly, patients on ICPi may develop endocrine adverse events, even after months or years from the final dose of ICPi, affecting a wide variety of glands. These endocrine adverse events include hypophysitis, diabetes mellitus, hypo and hyperthyroidism, and, adrenal insufficiency. Such toxicities may complicate the clinical course and prognosis of patients, increasing morbidity and mortality if not promptly identified and treated, as they can be life threatening and irreversible

Natural History and Management of Familial Paraganglioma Syndrome Type 1: Long-Term Data from a Large Family

Head and neck paragangliomas are the most common clinical features of familial paraganglioma syndrome type 1 caused by succinate dehydrogenase complex subunit D (SDHD) mutation. The clinical management of this syndrome is still unclear. In this study we propose a diagnostic algorithm for SDHD mutation carriers based on our family case series and literature review. After genetic diagnosis, first evaluation should include biochemical examination and whole-body imaging. In case of lesion detection, nuclear medicine examination is required for staging and tumor characterization. The study summarizes the diagnostic accuracy of different functional imaging techniques in SDHD mutation carriers. 18F-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET)-computed tomography (CT) is considered the gold standard. If it is not available, 123I-Metaiodobenzylguanidine (MIBG) could be used also for predicting response to radiometabolic therapy. 18F-fluoro-2-deoxy-D-glucose (18F-FDG) PET-CT has a prognostic role since high uptake identifies more aggressive cases. Finally, 68Ga-peptides PET-CT is a promising diagnostic technique, demonstrating the best diagnostic accuracy in our and in other published case series, even if this finding still needs to be confirmed in larger studies. Periodic follow-up should consist of annual biochemical and ultrasonographic screening and biannual magnetic resonance examination to identify biochemical silent tumors early

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

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

BackgroundObesity, 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).MethodsA 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.ResultsWe 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.ConclusionsThis 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

Chronotype. what role in the context of gastroenteropancreatic neuroendocrine tumors?

Background Chronotype is defined as a trait determining the subject circadian preference in behavioral and biological rhythms relative to external light-dark cycle. Although individual differences in chronotype have been associated with an increased risk of developing some types of cancer, no studies have been carried out in gastroenteropancreatic neuroendocrine tumors (GEP-NET). Materials We investigate the differences in chronotype between 109 GEP-NET and 109 healthy subjects, gender-, age-, and BMI-matched; and its correlation with tumor aggressiveness. Results GEP-NET patients have a lower chronotype score (p = 0.035) and a higher percentage of evening chronotype (p = 0.003) than controls. GEP-NET patients with morning chronotype had lower BMI, waist circumference, and higher percentage of MetS (p < 0.001) than evening type. Interestingly, considering the clinical pathological characteristics, patients with the presence of metastasis, grading G2, and in progressive disease presented the lower chronotype score (p = 0.004, p < 0.001, and p = 0.002; respectively) compared to other categories. Chronotype score was negatively associated with anthropometric measurements, metabolic profile, percentage of MetS, and Ki67 index (p < 0.001 for all). Conclusions GEP-NET patients have an unhealthy metabolic profile and present more commonly an evening chronotype. These results support the importance of including the assessment of chronotype in an adjunctive tool for the prevention of metabolic alterations and tumor aggressiveness of GEP-NET

Gastrinomas and non-functioning pancreatic endocrine tumors in multiple endocrine neoplasia syndrome type-1 (MEN-1)

Purpose: Illustrate imaging findings of gastrinomas and non-functioning pancreatic endocrine tumors (NF-PNET) in a patient with multiple endocrine neoplasia type-1 (MEN-1) syndrome with a radiologic-pathologic correlation for both along with the results of a 13 yrs observational study. Methods: A 48 yrs old male patient with MEN-1 and a Zollinger-Ellison syndrome was submitted to a duodeno-cephalopancreatectomy (DCP) extended to the pancreatic body to remove several gastrinomas shown by an endoscopic-ultrasonography as well as a large (> 2 cm) hypo-vascular pancreatic nodule shown by a contrast-enhanced multi-detector CT (CE-MDCT). Further conventional (CT/MR) and functional imaging (68Ga-PET-DOTA-TOC) studies were performed over the next 13 years. Results: Up to 14 gastrin-positive NET-G1 (pT2,N1) as well as a single PNET-G2 (pT2,N0) were found at histo-pathology which also showed a NET-G1 in the uncinate process where CE-MDCT documented a 9 mm hyper-vascular nodule. A 7 mm pancreatic nodule with identical contrast-enhancement pattern was also shown at the level of the pancreatic tail which was left to preserve endocrine function. At this level, follow-up studies documented the occurence of a small (< 1 cm) hypo-vascular nodule which was metastatic at presentation and rapidly progressed under somastatin-analogs therapy whereas the hyper-vascular nodule remained stable over 13 years. Both the pancreatic lesion as well as the hepatic metastasis showed pathologic uptake of the radiotracer with a SUVmax of 6.3 and 29.5, respectively, allowing the patient to be scheduled for a Peptide Receptor Radionuclide Therapy performed with 29.6 GBq of 177Lu-Oxotreotide. Conclusions: Contrast-enhancement patterns are correlated with both the histological grade as well as the biological behaviour of PNETS

Pituitary function and morphology in Fabry disease.

Endocrine abnormalities are known to affect patients with Fabry disease (FD). Pituitary gland theoretically represents an ideal target for FD because of high vascularization and low proliferation rate. We explored pituitary morphology and function in a cohort of FD patients through a prospectic, monocentric study at an Academic Tertiary Center. The study population included 28 FD patients and 42 sex and age-matched normal subjects. The protocol included a contrast enhancement pituitary MRI, the assessment of pituitary hormones, anti-pituitary, and anti-hypothalamus antibodies. At pituitary MRI, an empty sella was found in 11 (39%) FD patients, and in 2 (5%) controls (p < 0.001). Pituitary volume was significantly smaller in FD than in controls (p < 0.001). Determinants of pituitary volume were age and alpha-galactosidase enzyme activity. Both parameters resulted independently correlated at multivariate analysis. Pituitary function was substantially preserved in FD patients. Empty sella is a common finding in patients with FD. The major prevalence in the elderly supports the hypothesis of a progressive pituitary shrinkage overtime. Pituitary function seems not to be impaired in FD. An endocrine workup with pituitary hormone assessment should be periodically performed in FD patients, who are already at risk of cardiovascular complications