Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Pulmonary neuroendocrine (carcinoid) tumors: European Neuroendocrine Tumor Society expert consensus and recommendations for best practice for typical and atypical pulmonary carcinoids.

BACKGROUND: Pulmonary carcinoids (PCs) are rare tumors. As there is a paucity of randomized studies, this expert consensus document represents an initiative by the European Neuroendocrine Tumor Society to provide guidance on their management. PATIENTS AND METHODS: Bibliographical searches were carried out in PubMed for the terms 'pulmonary neuroendocrine tumors', 'bronchial neuroendocrine tumors', 'bronchial carcinoid tumors', 'pulmonary carcinoid', 'pulmonary typical/atypical carcinoid', and 'pulmonary carcinoid and diagnosis/treatment/epidemiology/prognosis'. A systematic review of the relevant literature was carried out, followed by expert review. RESULTS: PCs are well-differentiated neuroendocrine tumors and include low- and intermediate-grade malignant tumors, i.e. typical (TC) and atypical carcinoid (AC), respectively. Contrast CT scan is the diagnostic gold standard for PCs, but pathology examination is mandatory for their correct classification. Somatostatin receptor imaging may visualize nearly 80% of the primary tumors and is most sensitive for metastatic disease. Plasma chromogranin A can be increased in PCs. Surgery is the treatment of choice for PCs with the aim of removing the tumor and preserving as much lung tissue as possible. Resection of metastases should be considered whenever possible with curative intent. Somatostatin analogs are the first-line treatment of carcinoid syndrome and may be considered as first-line systemic antiproliferative treatment in unresectable PCs, particularly of low-grade TC and AC. Locoregional or radiotargeted therapies should be considered for metastatic disease. Systemic chemotherapy is used for progressive PCs, although cytotoxic regimens have demonstrated limited effects with etoposide and platinum combination the most commonly used, however, temozolomide has shown most clinical benefit. CONCLUSIONS: PCs are complex tumors which require a multidisciplinary approach and long-term follow-up.

Shortened interval of long-acting octreotide administration is effective in patients with well-differentiated neuroendocrine carcinomas in progression on standard doses.

BACKGROUND: In patients with well-differentiated (WD) neuroendocrine tumors (NET), long-acting octreotide (LAR), conventionally administered at a dose of 30 mg every 28 days, has well-documented anti-secretive but limited antiproliferative effects. AIM: The objective of this study was to evaluate a different schedule of LAR treatment consistent with a shorter interval between administrations (21 days) in WDNET patients with progressive disease at standard-dose interval. SUBJECTS AND METHODS: Twenty-eight patients followed for diagnosis and therapy of WDNET who had tumor progression during therapy with LAR 30 mg every 28 days were enrolled. Clinical, biological, and objective tumor response was evaluated after LAR 30 mg every 21 days. Time to progression was also evaluated after LAR 30 mg every 21 days and compared to LAR 30 mg every 28 days. RESULTS: The treatment with LAR 30 mg every 21 days resulted in complete and partial control of clinical symptoms in 40% and 60% of cases, respectively. Circulating neuroendocrine markers were significantly decreased in 30% of cases. A stabilization of disease was obtained in 93% and objective response in 7%. The median time to progression was significantly longer by using the shortened interval of LAR administration as compared to the standard one (30 vs 9 months, p<0.0001). The treatment was safe and well tolerated. CONCLUSIONS: The shortened schedule of LAR administration was able to re-institute control of clinical symptoms, to decrease level of circulating neuroendocrine markers and to increase time to progression in patients previously escaping from a standard schedule treatment.

Everolimus is an active agent in medullary thyroid cancer: a clinical and in vitro study.

Everolimus, an mTOR inhibitor, which has been demonstrated to induce anti-tumour effects in different types of neuroendocrine tumours, has never been evaluated in patients with medullary thyroid cancer (MTC). The aim of this study was to evaluate the in vitro and in vivo effects of everolimus in combination with octreotide in MTC. Two patients with progressive metastatic MTC and high calcitonin levels were treated with everolimus 5-10 mg/day. Both patients were under treatment with octreotide LAR at the study entry. An in vitro study was also performed to assess everolimus effects on MTC cell lines (TT and MZ-CRC-1 cells). A tumour response was observed in both patients. Serum calcitonin decreased by 86% in patient 1 and by 42% in patient 2. In TT and MZ-CRC-1 cells, everolimus induced a significant dose-dependent inhibition in cell proliferation. This effect seems to be related to a cell cycle arrest in G(0) /G(1) phase in both cell lines and to the induction of cellular senescence in TT cells. Everolimus in combination with octreotide may be active as anti-tumour therapy in patients with progressive metastatic MTC, suggesting to further evaluate this agent in MTC patients in a large prospective study.

Natural history of gastro-entero-pancreatic and thoracic neuroendocrine tumors. Data from a large prospective and retrospective Italian epidemiological study: the NET management study.

BACKGROUND: The few epidemiological data available in literature on neuroendocrine tumors (NET) are mainly based on Registry databases, missing therefore details on their clinical and natural history. AIM: To investigate epidemiology, clinical presentation, and natural history of NET. DESIGN AND SETTING: A large national retrospective survey was conducted in 13 Italian referral centers. Among 1203 NET, 820 originating in the thorax (T-NET), in the gastro-enteropancreatic tract (GEP-NET) or metastatic NET of unknown primary origin (U-NET) were enrolled in the study. RESULTS: 93% had a sporadic and 7% a multiple endocrine neoplasia type 1 (MEN1)-associated tumor; 63% were GEP-NET, 33% T-NET, 4% U-NET. Pancreas and lung were the commonest primary sites. Poorly differentiated carcinomas were <10%, all sporadic. The incidence of NET had a linear increase from 1990 to 2007 in all the centers. The mean age at diagnosis was 60.0 ± 16.4 yr, significantly anticipated in MEN1 patients (47.7 ± 16.5 yr). Association with cigarette smoking and other non-NET cancer were more prevalent than in the general Italian population. The first symptoms of the disease were related to tumor burden in 46%, endocrine syndrome in 23%, while the diagnosis was fortuity in 29%. Insulin (37%) and serotonin (35%) were the most common hormonal hypersecretions. An advanced tumor stage was found in 42%, more frequently in the gut and thymus. No differences in the overall survival was observed between T-NET and GEP-NET and between sporadic and MEN1-associated tumors at 10 yr from diagnosis, while survival probability was dramatically reduced in U-NET. CONCLUSIONS: The data obtained from this study furnish relevant information on epidemiology, natural history, and clinico-pathological features of NET, not available from the few published Register studies.

Secretive and proliferative tumor profile helps to select the best imaging technique to identify postoperative persistent or relapsing medullary thyroid cancer.

In patients with postoperative persistent medullary thyroid cancer (MTC), the tumor detection rate is generally low for most of the imaging techniques now available. The aim of this study was to investigate if the clinico-biological profile of the tumor may indicate which imaging technique to perform in order to identify postoperative persistent or relapsing MTC foci. Thirty-five consecutive MTC patients with detectable and progressively increasing postoperative serum concentrations of calcitonin were enrolled in the study. The detection rates of 18F-deoxy-d-glucose (FDG)-positron emission tomography (PET), somatostatin receptor scintigraphy (SRS), and 131I-metaiodobenzylguanidine scintigraphy (MIBG) were compared in relation with calcitonin and carcinoembryonic antigen serum concentrations, Ki-67 score and results of conventional imaging techniques (CIT). FDG-PET positivity was significantly associated with calcitonin serum concentrations >400 pg/ml and Ki-67 score >2.0% (P<0.05), while SRS positivity was associated with calcitonin serum concentrations >800 pg/ml (P<0.05). SRS positivity significantly correlated with tumor appearance at CIT (P<0.01), while FDG-PET was positive in nine CIT-negative patients. The secretive and proliferative tumor profile may guide the choice of the imaging technique to use in the follow-up of patients with MTC. A Ki-67 score >2.0% suggests to perform a FDG-PET in addition to conventional imaging. Calcitonin secretion predicts both FDG-PET and SRS uptake but SRS positivity is generally found only in patients with well defined MTC lesions that are also detectable at the conventional imaging examination. MIBG outcome is not predicted by any clinico-biological factors here investigated.

[Surgical treatment of well differentiated neuroendocrine tumours of the lung]. / Terapia chirurgica dei tumori neuroendocrini ben differenziati del polmone.

The bronchial tree represents the most frequent site of origin of carcinoids (around 25% of the total). The spectrum of differentiation of lung neuroendocrine tumors ranges from low-malignancy (carcinoids) to highly aggressive forms (small cell lung carcinoma) Diagnostic and therapeutic strategies therefore vary greatly. In well differentiated tumors (carcinoids) signs and symptoms are related to the airways obstruction in central forms, while peripheral forms are mostly discovered accidentally if asymptomatic. Clinical or subclinical paraneoplastic syndromes are associated in a minority of cases. Diagnostic work-up includes CT multislice, bronchial endoscopy and Octreoscan with chest Single Photon Emission Computed Tomography (SPECT). Further contribute may be added by the (68), Ga-DOTA-D-Phe(1)-Tyr(3)-ocreotide (DOTATOC) and 5-hydroxytryptophan (5-HTP) PET-CT, at present available only in a few centres, and by endobronchial ultrasound (EBUS), fluorescence bronchoscopy and virtual bronchoscopy. Surgery is the treatment of choice, while medical therapy is useful to treat the hypersecretion in paraneoplastic syndromes and to control tumor proliferation in metastatic or/and inoperable disease.

Diagnostic and prognostic implications of the World Health Organization classification of neuroendocrine tumors.

BACKGROUND: Neuroendocrine differentiation of tumors is often difficult to establish. In the same manner, the evaluation of the prognostic role of neuroendocrine differentiation may constitute a relevant clinical problem. Although different classifications are used for neuroendocrine tumors (NET) of different origin, the last World Health Organization (WHO) classification of NET, originally proposed for gastroenteropancreatic tumors, has proved to be a practical tool to allow pathologists to uniform the diagnoses and re-classify these tumors into 3 main categories. AIM: The present study was carried out in order to evaluate diagnostic and prognostic implications of NET reclassification according to the last WHO classification of NET. MATERIALS AND METHODS: Thirty-one tumors with an initial diagnosis referable to a NET achieved before 1999 were independently evaluated by 3 pathologists on the basis of the 2000 WHO classification of NET. Immunohistochemistry for panneuroendocrine markers and Ki-67 was also performed in all cases. RESULTS: Twelve, 14, and 4 tumors were respectively reclassified as well-differentiated NET, well-differentiated neuroendocrine carcinoma and poorly differentiated neuroendocrine carcinoma; 1 tumor was reclassified as mixed endocrine-exocrine tumor. Two or more neuroendocrine markers were expressed in all NET regardless of histotype, differentiation degree, and site of primary tumor. After revision, 10 of the 31 tumors under study (32%) changed histo-prognostic category when compared to the initial diagnosis. Ki-67 score was the best predictor of survival at the multivariate analysis. CONCLUSION: The WHO classification is suitable to accurately reclassify tumors with an initial diagnosis referable to a NET and to separate these tumors in 3 well-distinct histo-prognostic categories with relevant clinical implications. Ki-67 score seems to be a better predictor of survival than the degree of differentiation.

The biological characterization of neuroendocrine tumors: the role of neuroendocrine markers.

Neuroendocrine tumors (NET) may originate in different organs, from cells embryologically different but expressing common phenotypic characteristics, such as: the immuno-reactivity for markers of neuroendocrine differentiation (defined as "pan-neuroendocrine"), the capacity to secrete specific or aspecific peptide and hormones and the expression of some receptors, that are at the basis of the current diagnostic and therapeutical approach, peculiar to these tumors. NET have been conventionally distinguished in functioning, when associated with a recognized clinical endocrine syndrome, and non-functioning. However, this terminology may be misleading, since the great majority of NET may secrete neuroendocrine peptides, which can be employed as clinical markers for both diagnosis and follow-up. On the other hand, tissue immuno-reactivity for specific hormones does not always reflect secretory activity of the tumor cells. Finally, receptors and genetic markers are acquiring a relevant role in the characterization of NET, both improving knowledge of biology and physiopathology of NET, as well as in developing specific strategies to establish an early diagnosis and targeted therapies, to adopt prophylactic strategies in familial forms, and to identify more efficacious targets for therapy in the future.

Epidemiology of non-gastroenteropancreatic (neuro)endocrine tumours.

The widespread availability and reliability of immunohistochemical techniques in the last three decades have allowed researchers to identify cells with common neuroendocrine markers in virtually every organ. As a whole, these neuroendocrine cells form the so-called diffuse neuroendocrine system. Tumours arising from the cells of the diffuse neuroendocrine system are defined as (neuro)endocrine tumours (NETs). NETs have been increasingly described in recent years. However, despite the increase in the number of published papers focused on NET, we still lack adequate epidemiological data, particularly for non-gastroenteropancreatic (GEP) NETs. Furthermore, the real incidence of neuroendocrine differentiation for most sites is not completely known and is probably underestimated. As a consequence, data on the clinical features of many NET subgroups are not well known or confusing. For all of these reasons, we have attempted to evaluate the epidemiology of non-GEP NETs, reviewing the limited data available in the literature.

Clinical characterization of familial isolated pituitary adenomas.

CONTEXT: Familial pituitary adenomas occur rarely in the absence of multiple endocrine neoplasia type 1 (MEN1) and Carney complex (CNC). OBJECTIVE: Our objective was to characterize the clinical and genealogical features of non-MEN1/CNC familial isolated pituitary adenomas (FIPA). DESIGN AND SETTING: We conducted a retrospective study of clinical and genealogical characteristics of FIPA cases and performed a comparison with a sporadic population at 22 university hospitals in Belgium, Italy, France, and The Netherlands. RESULTS: Sixty-four FIPA families including 138 affected individuals were identified [55 prolactinomas, 47 somatotropinomas, 28 nonsecreting adenomas (NS), and eight ACTH-secreting tumors]. Cases were MEN1/PRKAR1A-mutation negative. First-degree relationships predominated (75.6%) among affected individuals. A single tumor phenotype occurred in 30 families (homogeneous), and heterogeneous phenotypes occurred in 34 families. FIPA cases were younger at diagnosis than sporadic cases (P = 0.015); tumors were diagnosed earlier in the first vs. the second generation of multigenerational families. Macroadenomas were more frequent in heterogeneous vs. homogeneous FIPA families (P = 0.036). Prolactinomas from heterogeneous families were larger and had more frequent suprasellar extension (P = 0.004) than sporadic cases. Somatotropinomas occurred as isolated familial somatotropinoma cases and within heterogeneous FIPA families; isolated familial somatotropinoma cases represented 18% of FIPA cases and were younger at diagnosis than patients with sporadic somatotropinomas. Familial NS cases were younger at diagnosis (P = 0.03) and had more frequently invasive tumors (P = 0.024) than sporadic cases. CONCLUSIONS: Homogeneous and heterogeneous expression of prolactinomas, somatotropinomas, NS, and Cushing's disease can occur within families in the absence of MEN1/CNC. FIPA and sporadic cases have differing clinical characteristics. FIPA may represent a novel endocrine neoplasia classification that requires further genetic characterization.

Early detection of insulin deprivation in continuous subcutaneous insulin infusion-treated patients with type 1 diabetes.

BACKGROUND: This study was performed to define the clinical relevance of early changes of capillary 3beta-hydroxybutyrate (3betaOHB), for detection of metabolic deterioration before occurrence of overt diabetic ketoacidosis following interruption of continuous subcutaneous insulin infusion (CSII). METHODS: An open clinical trial was performed with eight patients with type 1 diabetes on CSII therapy. After an overnight fast, at 8 a.m. (T0) CSII was interrupted for 4 h. At noon (T240) CSII was re-established, and at 4 p.m. (T480) the study was ended. Blood glucose (BG) and capillary and plasma 3betaOHB were measured at 30-min intervals, plasma insulin at 60-min intervals, and urinary ketones at 120-min intervals. RESULTS: After CSII interruption mean BG increased from 149.8+/-54.4 mg/dL at T0 to 224.8+/-56.2 mg/dL at T240 (P<0.05), and mean capillary 3betaOHB increased from 0.1+/-0.1 mmol/L at T0 to 0.9+/-0.6 mmol/L at T240 (P<0.001). The rate of increase of capillary 3betaOHB was faster and significantly more relevant than that of BG (P<0.05). The restoration of CSII produced a significant reduction of mean BG and capillary 3betaOHB (T480, 119.5+/-24 mg/dL and 0.2+/-0.2 mmol/L, respectively; P<0.05 for both vs. T240). The recovery of capillary 3betaOHB was significantly faster than that of BG (P=0.03). CONCLUSIONS: The dynamic evaluation of changes of capillary 3betaOHB levels can represent a useful support to home BG monitoring in the event of CSII interruption, providing faster information on early metabolic deterioration due to insulin deprivation and allowing preventative action for avoiding the evolution towards overt diabetic ketoacidosis. After reintroduction of insulin infusion the monitoring of the faster recovery of 3betaOHB relative to BG can provide useful information for the prevention of late hypoglycemia due to insulin overinfusion.

Thymic neuroendocrine carcinoma (carcinoid) in multiple endocrine neoplasia type 1 syndrome: the Italian series.

Neuroendocrine tumors may occur in the setting of multiple endocrine neoplasia type 1 (MEN1) syndrome. Among these, a probably underestimated prevalence of well differentiated neuroendocrine thymic carcinoma (carcinoid), a neoplasm characterized by very aggressive behavior, has been described. We report characterization of the seven Italian cases in which this association occurred among a series of 221 MEN1 patients (41 sporadic and 180 familial cases; prevalence, 3.1%). All of the patients were male, and six of seven (85%) were heavy smokers. No associated hormonal hypersecretion was detected. The first diagnosis was between the second and fifth decades. Familial clusters were present in three of seven (42.8%). No genotype-phenotype correlation was found. All seven cases were associated with hyperparathyroidism. In one patient, prophylactic thymectomy revealed a small nodular lesion suggestive of a thymic carcinoid, providing evidence that preventive thymectomy might prevent additional growth of an occult thymic carcinoid. These findings confirm that thymic carcinoids are associated with a very high lethality, with a near-total prevalence in smoker males. Therefore, prophylactic thymectomy should be considered at neck surgery for primary hyperparathyroidism in MEN1 male patients, especially for smokers, and, due to the frequent familial clusters distribution of this pathology, in subjects with affected relatives presenting this feature. Thus, we recommend screening every patient affected with a neuroendocrine thymic neoplasm for MEN1 syndrome.