Publications by authors named "Antongiulio Faggiano"

140 Publications

Ketogenic diet: a tool for the management of neuroendocrine neoplasms?

Crit Rev Food Sci Nutr 2020 Oct 14:1-11. Epub 2020 Oct 14.

Department of Experimental Medicine, University of Rome "La Sapienza," Rome, Italy.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms, whose incidence has rapidly increased in the last years. Nutrition plays an important role in their management; indeed, malnutrition negatively impacts on rates of complications, hospitalization, hospital stay, costs and mortality. Furthermore, it has been reported that a poor nutritional status could influence the outcome of patients with pancreatic NENs. Moreover, obesity, predisposing to insulin resistance and compensatory hyperinsulinemia, could stimulate the growth of these neoplasms. Ketogenic diet (KD), a high-fat, low-carbohydrate diet with adequate amounts of protein, has been reported to be a promising approach for the management of several types of cancer, mostly gynecological and neurological ones. Indeed, it appears to sensitize most cancers to standard treatment by exploiting the reprogramed metabolism of cancer cells and thus resulting in a promising candidate as an adjuvant cancer therapy. Thus, the aim of this review is to provide an overview on the importance of nutrition in cancer management and in particular in NENs' setting. Furthermore, we reported the current evidence on the efficacy of KD in the management of cancer and based on molecular mechanisms; we also hypothesize the potential use of this nutritional pattern in the management of NENs.
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http://dx.doi.org/10.1080/10408398.2020.1832955DOI Listing
October 2020

Immune Checkpoint Inhibitors: New Weapons Against Medullary Thyroid Cancer?

Front Endocrinol (Lausanne) 2021 14;12:667784. Epub 2021 Apr 14.

Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

Medullary thyroid carcinoma is a rare neuroendocrine neoplasm that originates from thyroid C cells. Surgery, with complete resection of the tumor, is the only curative approach. However, in most cases, the tumor recurs at locoregional or metastatic level. In this setting, the management remains challenging. In recent years, the immune checkpoint inhibitors have provided promise for changing the cancer treatment paradigm through the application of new approaches that enhance the body's natural antitumor defenses. The aim of this review is to summarize and discuss available data on efficacy and safety of the Food and Drug Administration-approved immune checkpoint inhibitors in patients with medullary thyroid carcinoma. After an extensive search, we found 7 useful data sources (one single-case report, one short article with very preliminary data, five ongoing registered clinical trials). Despite the lack of published evidence regarding the use of immune check point inhibitors, it must be considered that all the ongoing registered clinical trials saw first light in the last three years, thus indicating a growing interest of researchers in this field. Results coming from these trials, and hopefully, in the next future, from additional trials, will help to clarify whether this class of drugs may represent a new weapon in favor of patients with medullary thyroid carcinoma.
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http://dx.doi.org/10.3389/fendo.2021.667784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081349PMC
April 2021

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

Front Endocrinol (Lausanne) 2021 14;12:665631. Epub 2021 Apr 14.

Department of Clinical Medicine and Surgery, Federico II University of Naples, Naples, Italy.

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.
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http://dx.doi.org/10.3389/fendo.2021.665631DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8080021PMC
April 2021

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

Front Endocrinol (Lausanne) 2021 18;12:649496. Epub 2021 Mar 18.

Centro Italiano per la cura e il Benessere del paziente con Obesità (C.I.B.O), Endocrinology Unit, Department of Clinical Medicine and Surgery, University Medical School of Naples, Naples, Italy.

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 ( < 0.001) and FLI ( = 0.049) and higher MetS presence ( < 0.001) compared with controls. VAI and FLI values and MetS presence were higher in G2 than in G1 patients ( < 0.001), in patients with progressive disease, and in metastatic non-metastatic patients ( < 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.
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http://dx.doi.org/10.3389/fendo.2021.649496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8018238PMC
March 2021

Neuroendocrine Carcinomas with Atypical Proliferation Index and Clinical Behavior: A Systematic Review.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, 00189 Rome, Italy.

Background: Highly proliferative (G3) neuroendocrine neoplasms are divided into well differentiated tumors (NETs) and poorly differentiated carcinomas (NECs), based on the morphological appearance. This systematic review aims to evaluate the clinicopathological features and the treatment response of the NEC subgroup with a Ki67 labeling index (LI) < 55%.

Methods: A literature search was performed using MEDLINE, Cochrane Library, and Scopus between December 2019 and April 2020, last update in October 2020. We included studies reporting data on the clinicopathological characteristics, survival, and/or therapy efficacy of patients with NECs, in which the Ki67 LI was specified.

Results: 8 papers were included, on a total of 268 NEC affected patients. NECs with a Ki67 LI < 55% have been reported in patients of both sexes, mainly of sixth decade, pancreatic origin, and large-cell morphology. The prevalent treatment choice was chemotherapy, followed by surgery and, in only one study, peptide receptor radionuclide therapy. The subgroup of patients with NEC with a Ki67 LI < 55% showed longer overall survival and progression free survival and higher response rates than the subgroup of patients with a tumor with higher Ki67 LI (≥55%).

Conclusions: NECs are heterogeneous tumors. The subgroup with a Ki67 LI < 55% has a better prognosis and should be treated and monitored differently from NECs with a Ki67 LI ≥ 55%.
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http://dx.doi.org/10.3390/cancers13061247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999788PMC
March 2021

Foreword to the special issue on advances in neuroendocrine neoplasms.

Rev Endocr Metab Disord 2021 Mar 12. Epub 2021 Mar 12.

Endocrinology Unit, Department of Clinical and Molecular Medicine, Sant'Andrea Hospital, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1007/s11154-021-09639-zDOI Listing
March 2021

Primary Neuroendocrine Neoplasms of the Breast: Still Open Issues.

Front Endocrinol (Lausanne) 2020 26;11:610230. Epub 2021 Jan 26.

Endocrinology Unit, Department of Clinical Medicine and Surgery, University "Federico II", Naples, Italy.

Neuroendocrine breast tumors represent a rare subtype of breast cancer, accounting for less than 1% of all neuroendocrine neoplasms. Starting from their pathology definition, and going through their prevalence, prognosis and treatment, our knowledge is still really uncertain. In the present short review of the medical literature on this topic, we have evaluated in details their epidemiology, risk factors, pathogenesis, pathology, clinical presentation, radiographic aspects, prognosis, and therapy. We have thus been able to identify a number of open issues regarding primary neuroendocrine neoplasms of the breast that need to be clarified. Our ultimate aim was actually to try to understand whether neuroendocrine neoplasms of the breast can be considered a definite clinical entity and if neuroendocrine differentiation of breast tumors has a really clinical relevance.
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http://dx.doi.org/10.3389/fendo.2020.610230DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7874233PMC
January 2021

Emerging Therapies in Pheochromocytoma and Paraganglioma: Immune Checkpoint Inhibitors in the Starting Blocks.

J Clin Med 2020 Dec 29;10(1). Epub 2020 Dec 29.

Department of Clinical and Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Pheochromocytoma and paraganglioma are neuroendocrine neoplasms, originating in the adrenal medulla and in parasympathetic and sympathetic autonomic nervous system ganglia, respectively. They usually present as localized tumours curable with surgery. However, these tumours may exhibit heterogeneous clinical course, ranging from no/minimal progression to aggressive (progressive/metastatic) behavior. For this setting of patients, current therapies are unsatisfactory. Immune checkpoint inhibitors have shown outstanding results for several types of solid cancers. We therefore aimed to summarize and discuss available data on efficacy and safety of current FDA-approved immune checkpoint inhibitors in patients with pheochromocytoma and paraganglioma. After an extensive search, we found 15 useful data sources (four full-published articles, four supplements of scientific journals, seven ongoing registered clinical trials). The data we detected, even with the limit of the small number of patients treated, make a great expectation on the therapeutic use of immune checkpoint inhibitors. Besides, the newly detected predictors of response will (hopefully) be of great helps in selecting the subset of patients that might benefit the most from this class of drugs. Finally, new trials are in the starting blocks, and they are expected to shed in the next future new light on a therapy, which is considered a milestone in oncology.
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http://dx.doi.org/10.3390/jcm10010088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795591PMC
December 2020

Advances in the Management of Medullary Thyroid Carcinoma: Focus on Peptide Receptor Radionuclide Therapy.

J Clin Med 2020 Oct 29;9(11). Epub 2020 Oct 29.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

Effective treatment options in advanced/progressive/metastatic medullary thyroid carcinoma (MTC) are currently limited. As in other neuroendocrine neoplasms (NENs), peptide receptor radionuclide therapy (PRRT) has been used as a therapeutic option in MTC. To date, however, there are no published reviews dealing with PRRT approaches. We performed an in-depth narrative review on the studies published in this field and collected information on registered clinical trials related to this topic. We identified 19 published studies, collectively involving more than 200 patients with MTC, and four registered clinical trials. Most cases of MTC were treated with PRRT with somatostatin analogues (SSAs) radiolabelled with 90 yttrium (90Y) and 177 lutetium (177Lu). These radiopharmaceuticals show efficacy in the treatment of patients with MTC, with a favourable radiological response (stable disease, partial response or complete response) in more than 60% of cases, coupled with low toxicity. As MTC specifically also expresses cholecystokinin receptors (CCK2Rs), PRRT with this target has also been tried, and some randomised trials are ongoing. Overall, PRRT seems to have an effective role and might be considered in the therapeutic strategy of advanced/progressive/metastatic MTC.
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http://dx.doi.org/10.3390/jcm9113507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693147PMC
October 2020

ENDOCRINE TUMOURS: Calcitonin in thyroid and extra-thyroid neuroendocrine neoplasms: the two-faced Janus.

Eur J Endocrinol 2020 Dec;183(6):R197-R215

Department of Experimental Medicine 'Sapienza' University of Rome, Rome, Italy.

An increased calcitonin serum level is suggestive of a medullary thyroid cancer (MTC), but is not pathognomonic. The possibility of false positives or other calcitonin-secreting neuroendocrine neoplasms (NENs) should be considered. Serum calcitonin levels are generally assessed by immunoradiometric and chemiluminescent assays with high sensitivity and specificity; however, slightly moderately elevated levels could be attributable to various confounding factors. Calcitonin values >100 pg/mL are strongly suspicious of malignancy, whereas in patients with moderately elevated values (10-100 pg/mL) a stimulation test may be applied to improve diagnostic accuracy. Although the standard protocol and the best gender-specific cut-offs for calcium-stimulated calcitonin are still controversial, the fold of the calcitonin increase after stimulation seems to be more reliable. Patients with MTC show stimulated calcitonin values at least three to four times higher than the basal values, whereas calcitonin-secreting NENs can be distinguished from a C-cell disease by the absence of or
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http://dx.doi.org/10.1530/EJE-20-0506DOI Listing
December 2020

Quality of Life in Patients with Neuroendocrine Neoplasms: The Role of Severity, Clinical Heterogeneity, and Resilience.

J Clin Endocrinol Metab 2021 Jan;106(1):e316-e327

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Context: Although health-related quality of life (HRQoL) is a fundamental outcome in oncological clinical trials, its evaluation in the neuroendocrine neoplasm (NEN) research field is still limited.

Objectives: This study assessed the role of clinical severity (ie, presence or absence of metastasis and lines of therapies) and heterogeneity (ie, primary site, types of therapy, biology, and surgery) of NEN in relation to HRQoL, as well as resilience as a moderator between clinical severity and HRQoL.

Design: Cross-sectional multicentric study.

Setting: Italian university hospitals.

Patients: A total of 99 Italian patients (53 men and 46 women) with NEN and ranged in age from 22-79 years old.

Main Outcome Measure: Severity and heterogeneity of NENs, HRQoL, and resilience.

Results: The presence of metastasis and a greater number of therapies affected the global health and some physical symptoms. Resilience was associated with global health, functional status, and some physical symptoms, and it moderated the impact of metastases on constipation and of the multiple therapies on diarrhea and financial problems. Patients with NEN in districts other than the gastroenteropancreatic system and those in follow-up perceived fewer physical symptoms than their counterparts. Patients with a sporadic NEN perceived their functional status, global health, and disease-related worries as better than those with a hereditary NEN. Patients who underwent surgery were lower in constipation than their counterparts.

Conclusion: These findings highlight the need to assess the relationships between the clinical severity and heterogeneity of NEN with HRQoL and the role of resilience in improving patients' HRQoL.
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http://dx.doi.org/10.1210/clinem/dgaa760DOI Listing
January 2021

From microbiota toward gastro-enteropancreatic neuroendocrine neoplasms: Are we on the highway to hell?

Rev Endocr Metab Disord 2020 Sep 15. Epub 2020 Sep 15.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Gut microbiota is represented by different microorganisms that colonize the intestinal tract, mostly the large intestine, such as bacteria, fungi, archaea and viruses. The gut microbial balance has a key role in several functions. It modulates the host's metabolism, maintains the gut barrier integrity, participates in the xenobiotics and drug metabolism, and acts as protection against gastro-intestinal pathogens through the host's immune system modulation. The impaired gut microbiota, called dysbiosis, may be the result of an imbalance in this equilibrium and is linked with different diseases, including cancer. While most of the studies have focused on the association between microbiota and gastrointestinal adenocarcinomas, very little is known about gastroenteropancreatic (GEP) neuroendocrine neoplasms (NENs). In this review, we provide an overview concerning the complex interplay between gut microbiota and GEP NENs, focusing on the potential role in tumorigenesis and progression in these tumors.
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http://dx.doi.org/10.1007/s11154-020-09589-yDOI Listing
September 2020

Lanreotide Induces Cytokine Modulation in Intestinal Neuroendocrine Tumors and Overcomes Resistance to Everolimus.

Front Oncol 2020 7;10:1047. Epub 2020 Jul 7.

Department of Precision Medicine, University of Campania "Luigi Vanvitelli", Naples, Italy.

Somatostatin analogs mantain their major role in the treatment of patients with advanced neuroendocrine tumors (NETs) and have multiple modulatory effects on the immune system. Here, we evaluated the effects of lanreotide treatment on expression of Th1, Th2 cytokine patterns in serum of patients with NETs and in bronchial and pancreatic NET cell lines. Our results showed that lanreotide treatment promoted a Th1 cytotoxic immune-phenotype in patients with NETs originated by intestinal sites. Similar results were obtained also where lanreotide induced expression of Th1 cytokines only in pancreatic and not in bronchial-derived NET cell lines. It seems, therefore, that cytokinomics can represent a useful tool for the identification of tumor biomarkers for the early diagnosis and evaluation of the response to therapy in NET patients. To avoid the drug-resistance induced by everolimus (mTOR inhibitor), we made the pancreatic NET cell line resistant to this drug. After treatment with lanreotide we found that the drug reduced its viability compared to that of sensitive cells. These data may have direct implications in design of future translation combination trial on NET patients.
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http://dx.doi.org/10.3389/fonc.2020.01047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379869PMC
July 2020

Laryngeal Neuroendocrine Tumor With Elevated Serum Calcitonin: A Diagnostic and Therapeutic Challenge. Case Report and Review of Literature.

Front Endocrinol (Lausanne) 2020 16;11:397. Epub 2020 Jul 16.

Department of Experimental Medicine Sapienza University of Rome, Rome, Italy.

Laryngeal neuroendocrine neoplasms (NENs) are a rare group of NENs of the neck, which commonly show immunostaining for calcitonin. Laryngeal NENs with calcitonin hypersecretion and lymph node metastases represent a diagnostic and therapeutic challenge, which should be included in the differential diagnosis of medullary thyroid carcinoma (MTC). We report a complex case of laryngeal NEN with calcitonin hypersecretion and a review of the literature. A 59-year-old man presented with dysphagia, dyspnea, and lateral cervical mass; he was a smoker. At first imaging, a laryngeal lesion with lateral cervical lymphadenopathies was found, and it resulted as a moderately differentiated neuroendocrine tumor (G2), Ki67 = 5%, positive for calcitonin. Increased levels of serum calcitonin (50 pg/ml) were found. The patient started somatostatin analogs for lesions positivity to somatostatin receptor-based imaging. After 5 months, the disease progressed at 18F-fluorodeoxyglucose (F-FDG) PET-CT, and also new painful cutaneous lesions occurred. Considering high serum levels of calcitonin, differential diagnosis with MTC was required. Patient performed a thyroid color Doppler ultrasound, nodule fine needle aspiration, calcitonin dosage in fine needle washout fluid, and a calcium gluconate stimulation test. After multidisciplinary evaluation, we decided to perform a total thyroidectomy associated with lateral cervical lymphadenectomy and resection of skin metastases. No MTC was found. Two of the five resected lymph nodes, left upper parathyroid, and skin lesions were metastases of NEN G2, positive for calcitonin. After 2 months, new painful skin lesions occurred, and a target therapy with everolimus 10 mg/day was started. After 6 months of therapy, partial metabolic response with a reduction of 53.7% of radiotracer uptake at primary tumor was detected together with an improvement of patient's quality of life. The present case is the seventh described in the literature of laryngeal NEN associated with elevated serum calcitonin levels and the first case with parathyroid metastasis, suggesting the importance of a correct differential diagnosis between MTC and calcitonin-secreting laryngeal NEN, using an integrated approach of biochemistry and advanced imaging. This is also the first time that somatostatin analogs and then everolimus were used in this setting, resulting in clinical and partial metabolic response.
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http://dx.doi.org/10.3389/fendo.2020.00397DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7378381PMC
July 2020

Pancreatic Neuroendocrine Tumors in patients with Multiple Endocrine Neoplasia Type 1: Diagnostic Value of Different MRI Sequences.

Neuroendocrinology 2020 Jun 24. Epub 2020 Jun 24.

Background: Magnetic Resonance Imaging (MRI) is a useful imaging modality to assess the presence of Pancreatic Neuroendocrine Tumors (PNETs), allowing repeat monitoring examinations in MEN-1 patients.

Objectives: We aimed to compare the diagnostic accuracy of conventional MRI sequences identifying which better depict the presence of PNETs in MEN-1 patients.

Method: We performed a retrospective analysis of consecutive MEN-1 patients who underwent a conventional MRI protocol to monitor previously proven PNETs. MRI sequences T1-w Chemical-Shift (CS), T2-w HASTE, fat-suppressed (FS) T2-w HASTE, Diffusion Weighted Imaging (DWI), pre- and post-contrast FS T1-w sequences were independently analyzed by two experienced radiologists using a three-grade score (no lesion, uncertain lesion, certain lesion); lesion size and signal intensity were recorded. ANOVA Friedman and a Wilcoxon pairwise tests for the post-hoc analysis were used. The sensitivity of each sequence was measured; the results were analyzed with the Chi-squared test.

Results: We included 21 patients with a total of 45 PNETs proven by histology, EUS guided fine needle aspiration, CT and nuclear medicine studies. A statistically significant (p<0.01) difference was observed in the detection performance of each MRI sequence, particularly between both DWI (91%) and T2-w FS (85%) sequences in comparison to the others (T1-w CS, T2-w, pre- and post-contrast FS T1-w, ≤56% for all); no significant (p=0.5) difference was found between the detection performance of DWI and T2-w FS sequences. No correlation was observed between the qualitative score of each sequence and lesion tumor size.

Conclusions: DWI and T2-w FS sequences proved to be the most accurate in the detection of PNETs, thus suggesting a role for an abbreviated MRI protocol without contrast medium administration for monitoring MEN-1 patients.
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http://dx.doi.org/10.1159/000509647DOI Listing
June 2020

A Novel MAX Gene Mutation Variant in a Patient With Multiple and "Composite" Neuroendocrine-Neuroblastic Tumors.

Front Endocrinol (Lausanne) 2020 19;11:234. Epub 2020 May 19.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Pheochromocytomas (PCCs), paragangliomas (PGLs), ganglioneuroblastomas (GNBs), and ganglioneuromas (GNs) are neuroendocrine neoplasms (NENs) that were thought to share a common embryologic origin from neural crest cells. However, they rarely occur concurrently and recurrently. We describe the case of a 40-years-old woman with "composite PCC-GN" and multiple NENs and neuroblastic tumors. The patient was first referred to our department at the age of 15 years for paroxysmal hypertension, headache, sweating, and watery diarrhea. Her personal history included the diagnosis of a pelvic GNB with lumbar-aortic lymph node metastases at 11 months. Her family history was positive for cerebral glioblastoma multiforme (father). An abdominal ultrasound showed a right adrenal mass that histologically was a "composite adrenal PCC-GN." The symptoms disappeared after surgery. At the age of 20 years, the symptoms returned: computed tomography (CT) and 131I-metaiodobenzylguanidine (MIBG) scintigraphy showed an inter-aortocaval mass, found histologically to be an inter-aortocaval PGL. Her symptoms reappeared again at 28 years: CT and magnetic resonance imaging revealed four left adrenal gland nodules, found histologically to be multifocal PCCs with some atypia. Genetic screening for , and was negative. Mutational analysis of the gene revealed the presence of a novel heterozygous variant, c299G>C (p.Arg100Pro, NM_002382.5) that the bioinformatics prediction programs defined as noxious and causative of pathology. This report represents the first description of a co-occurrence of multiple composite PCC-GN and neuroblastic tumors. The long timeline of the presentation of the NENs/neuroblastic tumors from infancy to adulthood requires a lifelong follow-up for this patient. Moreover, the importance of this case lies in the presence of a novel gene variant deleterious, harmful, and causative of pathology, confirmed by Sanger sequencing and never been associated before with multiple composite PCC-GN. The present case underlines the importance of precision medicine and molecular diagnoses for hereditary pheochromocytomas and paragangliomas, suggesting that when they occur in early childhood, it is necessary to perform an extensive genetic investigation and a lifelong follow-up.
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http://dx.doi.org/10.3389/fendo.2020.00234DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7249266PMC
May 2020

Epidemiology of pancreatic neuroendocrine neoplasms: a gender perspective.

Endocrine 2020 08 28;69(2):441-450. Epub 2020 May 28.

Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.

Purpose: Pancreatic neuroendocrine neoplasms (PNENs) are a group of clinically rare and heterogeneous tumors of the pancreas. Currently there are no studies investigating the gender difference in PNEN susceptibility. Thus, the purpose of this study was aimed at examining how gender shapes risk factors, clinicopathological features, and comorbidities in PNENs.

Methods: The study design consisted of an Italian multicenter, retrospective study. The study included all consecutive patients with PNENs followed at the participating centers. Two hundred and twenty-nine patients (105 males,124 females, age 54 ± 0.98 years) with PNENs were enrolled at the participating centers. The clinicopathological features (age, gender, BMI, histology, tumor size, tumor grade, distant metastasis, hormonal function, and diagnostic circumstances), comorbidities (cardiovascular diseases (CVD), pancreatitis, type 2 diabetes (T2DM), and potential risk factors (smoking and drinking) were included in the analysis.

Results: Females were slightly prevalent (54.15%). PNENs were diagnosed at younger age in females compared to males (p = 0.04). The prevalence of CVD was significantly higher in males than in females (p = 0.006). In the female group, the presence of T2DM was significantly associated with higher tumor grade (p = 0.04) and metastatic disease (p = 0.02). The proportion of smokers and alcohol drinkers was significantly higher in the male group (p < 0.001). No significant gender differences were detected regarding the other parameters included in the analysis.

Conclusions: This study has identified gender differences of PNENs in terms of age at diagnosis, associated comorbidities, and potential risk factors. A gender-tailored approach could become a potential strategy to better understand the natural history of PNENs and improve the effectiveness of PNENs clinical management.
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http://dx.doi.org/10.1007/s12020-020-02331-3DOI Listing
August 2020

Bone Metabolism and Vitamin D Implication in Gastroenteropancreatic Neuroendocrine Tumors.

Nutrients 2020 Apr 8;12(4). Epub 2020 Apr 8.

Department of Clinical Medicine and Surgery, Federico II University, 80131 Naples, Italy.

Patients affected by gastroenteropancreatic-neuroendocrine tumors (GEP-NETs) have an increased risk of developing osteopenia and osteoporosis, as several factors impact on bone metabolism in these patients. In fact, besides the direct effect of bone metastasis, bone health can be affected by hormone hypersecretion (including serotonin, cortisol, and parathyroid hormone-related protein), specific microRNAs, nutritional status (which in turn could be affected by medical and surgical treatments), and vitamin D deficiency. In patients with multiple endocrine neoplasia type 1 (MEN1), a hereditary syndrome associated with NET occurrence, bone damage may carry other consequences. Osteoporosis may negatively impact on the quality of life of these patients and can increment the cost of medical care since these patients usually live with their disease for a long time. However, recommendations suggesting screening to assess bone health in GEP-NET patients are missing. The aim of this review is to critically analyze evidence on the mechanisms that could have a potential impact on bone health in patients affected by GEP-NET, focusing on vitamin D and its role in GEP-NET, as well as on factors associated with MEN1 that could have an impact on bone homeostasis.
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http://dx.doi.org/10.3390/nu12041021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230756PMC
April 2020

Diagnosis of Flier's syndrome in a patient with nondiabetic hypoglycemia: a case report and critical appraisal of the literature.

Endocrine 2020 07 9;69(1):73-78. Epub 2020 Apr 9.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy.

Purpose: Autoimmune hypoglycemia includes rare syndromes characterized by the presence of either anti-insulin antibodies (IAA) (Hirata's disease) or anti-insulin receptor (anti-ISR) antibodies (Flier's syndrome). Diagnosis is usually based on identification of the specific antibodies, in presence of the Whipple triad. However, most of these cases are classified as idiopathic diseases due to the difficulty to define the pathogenic culprit.

Methods: Basic research methodologies, including Western Blot and ELISA tests, have been used in this study.

Results: We describe a 21-year-old young woman (PT), non-obese and non-diabetic, with a positive history of autoimmune diseases, admitted to the hospital for recurrent episodes of severe symptomatic hypoglycemia. Counterregulatory response to hypoglycemia was normal as well as the fasting test, so excluding both hormone deficiencies and insulinoma. Since an autoimmune hypoglycemic syndrome was suspected, the hyperactivation of the insulin pathway was experimentally evaluated. At this purpose, human hepatocarcinoma (HepG2) cells were incubated with serum obtained from the patient (PT) and from control individuals. Interestingly, a significant increase of phosphorylation of insulin receptor, Akt, and ERK1/2 was observed in the HepG2 cells incubated with PT serum compared with the controls. ELISA tests revealed significantly increased levels of anti-ISR antibodies in PT serum, while IAA were similar both in PT and in control sera, supporting diagnosis of Flier's syndrome.

Conclusions: This study emphasizes the importance to identify new strategies for the differential diagnosis of hypoglycemia, not always possible with the routinely used diagnostic tests.
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http://dx.doi.org/10.1007/s12020-020-02287-4DOI Listing
July 2020

Pancreatic Neuroendocrine Neoplasms: Does Sex Matter?

Trends Endocrinol Metab 2020 09 26;31(9):631-641. Epub 2020 Mar 26.

Endocrinology Unit, Department of Clinical Medicine and Surgery, University 'Federico II', Naples, Italy.

Genetic and molecular disparities between men and women have a role in the differing incidence, pathophysiology, clinical signs, and treatment outcome of several cancers. Sex differences in cancer incidence are attributed to regulation at the genetic/molecular level and to sex hormones that in turn modulate gene expression in various cancers. Sex differences in the incidence of cancer, its aggressiveness, and the disease prognosis have been reported for several types of cancer but little is known for pancreatic neuroendocrine neoplasms (PNENs). The aim of this Opinion article is to provide an overview of sex differences in PNENs in terms of epidemiology, pathophysiology, treatment responses, prognosis, and survival. This overview might allow better tailoring of the management of PNENs.
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http://dx.doi.org/10.1016/j.tem.2020.02.010DOI Listing
September 2020

Biliary Stone Disease in Patients with Neuroendocrine Tumors Treated with Somatostatin Analogs: A Multicenter Study.

Oncologist 2020 03 6;25(3):259-265. Epub 2019 Nov 6.

NET Team Bologna ENETS Center of Excellence, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Bologna, Italy.

Background: Somatostatin analogs (SSAs) are the mainstay of neuroendocrine tumor (NET) treatment. Biliary stone disease is reported as a common side effect of SSAs, with a frequency ranging from 10% to 63%. Studies on SSA-treated patients for acromegaly report an increased incidence of biliary stone disease compared with the general population, whereas data on patients with NETs are few. Guidelines are based on weak evidence, thus resulting in conflicting recommendations. The aim of the study is to evaluate biliary stone disease incidence, complications, and risk factors in a large population of SSA-treated patients with NETs.

Materials And Methods: A retrospective analysis of a prospectively collected database was performed. Patients with a diagnosis of NET in seven dedicated centers from 1995 to 2017 were included at the time of SSA start.

Results: A total of 754 SSA-treated patients were evaluated. Patients with history of cholecystectomy or with known biliary stone disease were excluded; 478 patients were included. Among them, 118 patients (24.7%) received prophylactic ursodeoxycholic acid (UDCA). During the study period, 129 patients (27.0%) developed biliary stone disease; of them, 36 (27.9%) developed biliary complications. On multivariate analysis, primary gastrointestinal (GI)-NET (hazard ratio [HR] 1.76) and related surgery (HR 1.58) were independent risk factors for biliary stone disease.

Conclusion: We report a high incidence of biliary stone disease particularly in GI-NET or GI surgery. UDCA prophylaxis does not seem to have a protective role. Our data suggest that all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy; no conclusion could be drawn on the indication of prophylactic cholecystectomy in patients with primary pancreatic or thoracic NET for whom abdominal surgery is not planned.

Implications For Practice: The results of this study confirm an increased rate of gallstones development and related complications in patients with neuroendocrine tumors (NETs) treated with somatostatin analogs (SSAs). NETs of the gastrointestinal (GI) tract and related surgery are independent risk factors for biliary stone disease development. Therefore, all patients with primary GI-NET or undergoing abdominal surgery should be considered for prophylactic cholecystectomy. Data on other subgroups are not exhaustive, and management also evaluating additional clinical features (life expectancy, surgical and anesthesiological risks) should be considered. Prophylactic treatment with ursodeoxycholic acid does not seem to be a protective factor for SSA-related biliary stone disease.
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http://dx.doi.org/10.1634/theoncologist.2019-0403DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066710PMC
March 2020

Serotonin pathway in carcinoid syndrome: Clinical, diagnostic, prognostic and therapeutic implications.

Rev Endocr Metab Disord 2020 Dec;21(4):599-612

Department of Clinical Medicine and Surgery, Endocrinology Unit, University Federico II, Naples, Italy.

Carcinoid syndrome represents the most common functional syndrome that affects patients with neuroendocrine neoplasms. Its clinical presentation is really heterogeneous, ranging from mild and often misdiagnosed symptoms to severe manifestations, that significantly worsen the patient's quality of life, such as difficult-to-control diarrhoea and fibrotic complications. Serotonin pathway alteration plays a central role in the pathophysiology of carcinoid syndrome, accounting for most clinical manifestations and providing diagnostic tools. Serotonin pathway is complex, resulting in production of biologically active molecules such as serotonin and melatonin, as well as of different intermediate molecules and final metabolites. These activities require site- and tissue-specific catalytic enzymes. Variable expression and activities of these enzymes result in different clinical pictures, according to primary site of origin of the tumour. At the same time, the biochemical diagnosis of carcinoid syndrome could be difficult even in case of typical symptoms. Therefore, the accuracy of the diagnostic methods of assessment should be improved, also attenuating the impact of confounding factors and maybe considering new serotonin precursors or metabolites as diagnostic markers. Finally, the prognostic role of serotonin markers has been only evaluated for its metabolite 5-hydroxyindole acetic acid but, due to heterogeneous and biased study designs, no definitive conclusions have been achieved. The most recent progress is represented by the new therapeutic agent telotristat, an inhibitor of the enzyme tryptophan hydroxylase, which blocks the conversion of tryptophan in 5-hydroxy-tryptophan. The present review investigates the clinical significance of serotonin pathway in carcinoid syndrome, considering its role in the pathogenesis, diagnosis, prognosis and therapy.
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http://dx.doi.org/10.1007/s11154-020-09547-8DOI Listing
December 2020

Bone metabolism, bone mass and structural integrity profile in professional male football players.

J Sports Med Phys Fitness 2020 Jun 27;60(6):912-918. Epub 2020 Feb 27.

Department of Experimental Medicine, Sapienza University, Rome, Italy.

Background: Physical exercise plays an important role in bone mineralization as well as factors involved in bone metabolism influence the athletic performance. In European countries, soccer is the most popular sport. The aim of the study was to investigate bone metabolism, bone mass and structural integrity profile in professional male adult football players.

Methods: Sixteen professional male football players from a single team of the Second division Italian League (mean age 22.4±0.7 years) were enrolled. Bone biochemical parameters, including serum calcium, phosphorus, albumin, creatinine, alkaline phosphatase, intact plasma PTH, 25-hydroxy-vitamin D (25-OHD), 24-h urinary calcium and phosphorus, and calcaneal quantitative ultrasound (QUS), were evaluated at the beginning (October 2012) and at the end of the League (May 2013).

Results: 25-OHD levels were significantly lower at the end of the League compared to the beginning (27.1±5.9 vs. 36.6±9.5 ng/mL, fold change [FC]=0.25, P=0.008), and the prevalence of 25-OHD deficiency increased from 25% to 73%. Moreover, higher rate of previous bone, cartilage or ligament injuries correlated with 25-OHD deficiencies (P=0.014). T-score and Z-score were at the upper limits of the normality ranges, without significant difference between the beginning and end of the League. Phosphaturia was slightly decreased at the end of the League (691.0±364.5 vs. 934.0±274.3 mg/24h, FC=0.26, P=0.06). A significant correlation was found between phosphaturia and BQI (R2=0.28, P=0.03), and both T-s and Z-s (R2=0.28, P=0.03) at the beginning of the League.

Conclusions: With this pilot study, we demonstrated that vitamin D status significantly worsened at the end of the League. Therefore, vitamin D supplementation might be suggested in adult football players in order to prevent vitamin D deficiency and improve the athletic performance.
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http://dx.doi.org/10.23736/S0022-4707.20.09913-2DOI Listing
June 2020

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

J Clin Med 2020 Feb 21;9(2). Epub 2020 Feb 21.

Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy.

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.
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http://dx.doi.org/10.3390/jcm9020588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7074269PMC
February 2020

An incidental rectal neuroendocrine microcarcinoma ('micro-NEC') coexistent with a high grade adenoma.

Pathol Int 2020 05 20;70(5):300-302. Epub 2020 Feb 20.

Department of Advanced Biomedical Sciences, Pathology Section, Division of Endocrinology, University of Naples Federico II - Italy, Naples, Italy.

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http://dx.doi.org/10.1111/pin.12916DOI Listing
May 2020

Gastroenteropancreatic neuroendocrine neoplasms and inflammation: A complex cross-talk with relevant clinical implications.

Crit Rev Oncol Hematol 2020 Feb 23;146:102840. Epub 2019 Dec 23.

Department of Clinical Medicine and Surgery, University of Naples Federico II, Naples, Italy.

Neuroendocrine neoplasms (NENs) are a group of tumors originating from the neuroendocrine system. They mainly occur in the digestive system and the respiratory tract. It is well-know a strict interaction between neuroendocrine system and inflammation, which can play an important role in NEN carcinogenesis. Inflammatory mediators, which are produced by the tumor microenvironment, can favor cancer induction and progression, and can promote immune editing. On the other hand, a balanced immune system represents a relevant step in cancer prevention through the elimination of dysplastic and cancer cells. Therefore, an inflammatory response may be both pro- and anti-tumorigenic. In this review, we provide an overview concerning the complex interplay between inflammation and gastroenteropancreatic NENs, focusing on the tumorigenesis and clinical implications in these tumors.
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http://dx.doi.org/10.1016/j.critrevonc.2019.102840DOI Listing
February 2020

Vitamin D testing: advantages and limits of the current assays.

Eur J Clin Nutr 2020 02 6;74(2):231-247. Epub 2020 Jan 6.

Department of Medicine, Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, Boston, MA, USA.

Vitamin D deficiency and insufficiency has become a pandemic health problem with a consequent increase of requests for determining circulating levels of 25-hydroxyvitamin D [25(OH)D]. However, the analytical performance of these immunoassays, including radioimmunoassay and ELISA, is highly variable, and even mass spectrometric methods, which nowadays serves as the gold standard for the quantitatively determination of 25(OH)D, do not necessarily produce comparable results, creating limitations for the definition of normal vitamin D status ranges. To solve this problem, great efforts have been made to promote standardization of laboratory assays, which is important to achieve comparable results across different methods and manufacturers. In this review, we performed a systematic analysis evaluating critically the advantages and limits of the current assays available for the measure of vitamin D status, i.e., circulating 25(OH)D and its metabolites, making suggestions that could be used in the clinical practice. Moreover, we also suggest the use of alternatives to blood test, including standardized surveys that may be of value in alerting health-care professionals about the vitamin D status of their patients.
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http://dx.doi.org/10.1038/s41430-019-0553-3DOI Listing
February 2020

Evaluation of BRAF, RAS, RET/PTC, and PAX8/PPARg alterations in different Bethesda diagnostic categories: A multicentric prospective study on the validity of the 7-gene panel test in 1172 thyroid FNAs deriving from different hospitals in South Italy.

Cancer Cytopathol 2020 02 10;128(2):107-118. Epub 2019 Dec 10.

Department of Public Health, University of Naples Federico II, Naples, Italy.

Background: Thyroid fine-needle aspiration (FNA) is a reliable and cost-effective diagnostic tool for establishing the nature of thyroid nodules, although up to 30% of FNAs are still classified as "indeterminate." Molecular testing of FNAs could improve preoperative diagnosis, thereby reducing unnecessary surgery. In this multicenter prospective study the authors investigated, using a 7-gene assay, the distribution and diagnostic impact of BRAF, RAS, RET/PTC, and PAX8/PPARg, the most frequent genomic alterations occurring during thyroid oncogenesis.

Methods: In total, of 1172 routine FNAs from 7 centers in southern Italy were classified according to the Bethesda System for Reporting Thyroid Cytopathology. Each specimen was tested, and molecular data were compared with available histology or cytologic follow-up.

Results: In particular, for atypia of undetermined significance/follicular lesion of undetermined significance cases, the 7-gene test confirmed the high positive predictive value of BRAFV600E and BRAF-like mutations (80%) and the moderate positive predictive value of RAS-like alterations (32.4%), suggesting different surgical management, depending on the type of mutation. The rate of mutation-positive FNAs was strictly related to the risk of malignancy of each diagnostic class, supporting the identification of prognostically relevant diagnostic categories.

Conclusions: The 7-gene panel test improves the preoperative risk stratification of indeterminate thyroid FNAs, especially when considering the biologic significance of the different types of mutations. Moreover, the rate of mutation-positive FNAs is related to the risk of malignancy of each diagnostic class.
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http://dx.doi.org/10.1002/cncy.22217DOI Listing
February 2020

Prognostic impact of tumour burden in stage IV neuroendocrine neoplasia: A comparison between pancreatic and gastrointestinal localizations.

Pancreatology 2019 Dec 30;19(8):1067-1073. Epub 2019 Sep 30.

NET Team Bologna ENETS Center of Excellence, Department of Medical and Surgical Sciences, S. Orsola-Malpighi University Hospital, Alma Mater Studiorum University of Bologna, Italy.

Background: Although prognosis of NENs is affected by several features including tumour burden, the specific role of this factor in pancreatic NENs (PanNENs) and gastrointestinal NENs (GI NENs) is not well established.

Aim: To compare the prognostic role of tumour burden in PanNENs and GI NENs.

Patients And Methods: This study was a retrospective analysis of stage IV PanNENs and GI NENs. Tumours were classified based on liver tumour volume (<25% or >25%). Overall survival as assessed by Kaplan-Meier curves, and Cox proportional hazards method was used to perform risk factor analysis.

Results: The analysis included 300 patients, including 166 panNENs (55.3%) and 134 GI NENs (44.7%). A total of 158 patients (52.7%) had G2 tumours, 107 had G1 tumours (35.7%), and 35 had G3 tumours (11.6%). Tumour liver involvement >25% was observed in 187 patients (62.3%): 106 PanNENs (56.7%), and 81 GI NENs (43.3%) (p = 0.551). Bone metastases were present in 45 patients (15%): 22 PanNENs (13.2%) and 23 GI NENs (17.1%) (p = 0.416). Characteristics of the PanNENs, including: grading (G2 vs G1, HR = 3.7; G3 vs G1, HR = 16.40), liver involvement > 25% (HR = 3.09), and bone metastases (HR = 2.27) were independent predictors for poor survival, whereas the only significant risk factor in GI NENs was grading (G2 vs G1, HR = 4.36; G3 vs G1, HR = 8.60).

Conclusions: PanNENs and GI NENs have different risk profiles. Liver tumour volume and the presence of bone metastases significantly affect survival in patients with PanNENs but has no impact on the clinical outcomes of GI NENs.
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http://dx.doi.org/10.1016/j.pan.2019.09.015DOI Listing
December 2019

Lanreotide Therapy vs Active Surveillance in MEN1-Related Pancreatic Neuroendocrine Tumors < 2 Centimeters.

J Clin Endocrinol Metab 2020 01;105(1)

Department of Clinical Medicine and Surgery, Division of Endocrinology, University Federico II of Naples, Naples, Italy.

Purpose: Pancreatic neuroendocrine tumors (pNETs) are frequent in multiple endocrine neoplasia type 1 (MEN1) syndrome. They are usually not surgically treated unless larger than 1 to 2 cm or a growth rate > 0.5 cm per year. Somatostatin analogues represent one of the main therapeutic options in pNETs, but they have never been prospectively investigated in MEN1-related pNETs. The aim of this study was to prospectively evaluate the effectiveness of lanreotide in patients with MEN1-related pNETs < 2 cm.

Methods: MEN1 patients with 1 or more pNETs < 2 cm of maximal diameter were considered. Study design was prospective observational, comparing patients treated with lanreotide autogel 120 mg every 28 days (LAN group) and patients in active surveillance, not receiving any therapy (AS group).

Results: Forty-two patients were enrolled: 23 in LAN and 19 in AS group. Median follow-up was 73 months. Initial imaging identified a total of 91 pNETs. The median progression-free survival was significantly longer in the LAN than in the AS group (median not reached vs 40 months, P < 0.001). In the LAN group, 4 patients had an objective tumor response, 15 patients had stable disease, while 4 had tumor progression. In the AS group, 13 patients had pNET progression, while 6 were stable.

Conclusions: This is the first prospective study evaluating the efficacy of somatostatin analogues in MEN1-related pNETs. These findings highlight that lanreotide autogel is effective as antiproliferative therapy in MEN1-related pNETs < 2cm, suggesting the utility of somatostatin analogues to arrest the development of tumor lesions as well as to delay or avoid pancreatic surgery.
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http://dx.doi.org/10.1210/clinem/dgz007DOI Listing
January 2020