P. Niccoli

Adrenal involvement in MEN1. Analysis of 715 cases from the Groupe d'étude des Tumeurs Endocrines database

OBJECTIVEnLimited data regarding adrenal involvement in multiple endocrine neoplasia type 1 (MEN1) is available. We describe the characteristics of MEN1-associated adrenal lesions in a large cohort to provide a rationale for their management.nnnMETHODSnAnalysis of records from 715 MEN1 patients from a multicentre database between 1956 and 2008. Adrenal lesions were compared with those from a multicentre cohort of 144 patients with adrenal sporadic incidentalomas.nnnRESULTSnAdrenal enlargement was reported in 20.4% (146/715) of patients. Adrenal tumours (>10u200amm in size) accounted for 58.1% of these cases (10.1% of the whole patient cohort). Tumours were bilateral and >40u200amm in size in 12.5 and 19.4% of cases respectively. Hormonal hypersecretion was restricted to patients with tumours and occurred in 15.3% of them. Compared with incidentalomas, MEN1-related tumours exhibited more cases of primary hyperaldosteronism, fewer pheochromocytomas and more adrenocortical carcinomas (ACCs; 13.8 vs 1.3%). Ten ACCs occurred in eight patients. Interestingly, ACCs occurred after several years of follow-up of small adrenal tumours in two of the eight affected patients. Nine of the ten ACCs were classified as stage I or II according to the European Network for the Study of Adrenal Tumors. No evident genotype/phenotype correlation was found for the occurrence of adrenal lesions, endocrine hypersecretion or ACC.nnnCONCLUSIONSnAdrenal pathology in MEN1 differs from that observed in sporadic incidentalomas. In the absence of relevant symptoms, endocrine biology can be restricted to patients with adrenal tumours and should focus on steroid secretion including the aldosterone-renin system. MEN1 is a high-risk condition for the occurrence of ACCs. It should be considered regardless of the size of the tumour.

Gender-related differences in MEN1 lesion occurrence and diagnosis: a cohort study of 734 cases from the Groupe d'étude des Tumeurs Endocrines

CONTEXTnMultiple endocrine neoplasia type 1 (MEN1) disease is an autosomal dominant syndrome that is believed to equally affect men and women. This assumption has never been confirmed.nnnOBJECTIVEnThe aims of this study were to evaluate the impact of gender on the prevalence of MEN1 lesions, on their lifetime probability of occurrence, and on the diagnosis of MEN1.nnnDESIGNnData regarding a study of 734 cases of MEN1 from the multicenter Groupe détude des Tumeurs Endocrines were analyzed.nnnRESULTSnThere were 57.8% females. The prevalence and probability of pancreatic tumors were higher in males than in females (P=0.06, P=0.0004). This difference was due to gastrinomas. The prevalence and probability of developing pituitary tumors were significantly greater in females (P<0.001, P<0.0001). Thymic tumors were exclusively found in men. There were no significant gender differences in the prevalence and the probability of developing hyperparathyroidism, or adrenal and bronchial tumors, or in the proportion of positive genetic tests. A family history of MEN1 was more frequently found in men than in women at the time of diagnosis (P=0.02). In the case of pituitary tumor, the proportion of patients diagnosed with MEN1 at the time of the first lesion was lower in women (44.2%) than in men (67.3%).nnnCONCLUSIONnThe phenotype expression of the MEN1 disease gene was different in males and females. In female patients, the possibility of MEN1 is not sufficiently taken into account. Any patient presenting a lesion that belongs to the MEN1 spectrum, such as a pituitary tumor, should be closely questioned about their family history and should be tested for hypercalcemia.

One-Year Progression-Free Survival of Therapy-Naive Patients With Malignant Pheochromocytoma and Paraganglioma

CONTEXTnThe natural history of malignant pheochromocytoma or paragangliomas (MPP) remain unknown.nnnOBJECTIVEnThe primary aim of this study was to define progression-free survival at 1 year in therapy-naive patients with MPP. Secondary objectives were to characterize MPP and to look for prognostic parameters for progression at 1 year.nnnDESIGN AND SETTINGnThe files of MPP followed up between January 2001 and January 2011 in two French Endocrine Networks were retrospectively reviewed. Therapy-naive patients were enrolled.nnnMAIN OUTCOME MEASURESnThe main outcome was progression-free survival at 1 year in therapy-naive MPP patients according to Response Evaluation Criteria In Solid Tumors 1.1 criteria.nnnRESULTSnNinety files (46 men, 44 women, mean age of 47.5 ± 15 years) were reviewed on site by one investigator. MPP characteristics were as follows: presence of an adrenal primary, a mitotic count exceeding 5 per high power field, hypertension, inherited disease, and presence of bone metastases in 50%, 22%, 60%, 49%, and 56% patients, respectively. Fifty-seven of the 90 patients with MPP (63%) were classified as therapy-naive. The median follow-up of these 57 patients was 2.4 years (range, 0.4-5.7). At 1 year, progression-free survival was 46% (CI 95: 33-59). Twenty-six of 30 (87%) patients with progression at 1 year had exhibited progressive disease at the first imaging workup performed after a median of 5.7 months. No prognostic parameter was identified.nnnCONCLUSIONSnHalf of the therapy-naive patients with MPP achieved stable disease at 1 year. In symptom-free patients with MPP, a wait-and-see antitumor policy seems appropriate as first line. Modality for a prospective follow-up is proposed.

MEN1 Disease Occurring Before 21 Years Old: A 160-Patient Cohort Study From the Groupe d'étude des Tumeurs Endocrines

CONTEXTnMultiple endocrine neoplasia Type-1 (MEN1) in young patients is only described by case reports.nnnOBJECTIVEnTo improve the knowledge of MEN1 natural history before 21 years old.nnnMETHODSnObtain a description of the first symptoms occurring before 21 years old (clinical symptoms, biological or imaging abnormalities), surgical outcomes related to MEN1 Neuro Endocrine Tumors (NETs) occurring in a group of 160 patients extracted from the Groupe détude des Tumeurs Endocrines MEN1 cohort.nnnRESULTSnThe first symptoms were related to hyperparathyroidism in 122 cases (75%), pituitary adenoma in 55 cases (34%), nonsecreting pancreatic tumor (NSPT) in 14 cases (9%), insulinoma in 20 cases (12%), gastrinoma in three cases (2%), malignant adrenal tumors in 2 cases (1%), and malignant thymic-NET in one case (1%). Hyperparathyrodism was the first lesion in 90 cases (56%). The first symptoms occurred before 10 years old in 22 cases (14%) and before 5 years old in five cases (3%). Surgery was performed before age 21 in 66 patients (41%) with a total of 74 operations: pituitary adenoma (n = 9, 16%), hyperparathyroidism (n = 38, 31%), gastrinoma (n = 1, 33%), NSPT (n = 5, 36%), and all cases of insulinoma, adrenal tumors, and thymic-NET. One patient died before age 21 due to a thymic-NET. Overall, lesions were malignant in four cases.nnnCONCLUSIONSnVarious MEN1 lesions occurred frequently before 21 years old, but mainly after 10 years of age. Rare, aggressive tumors may develop at any age. Hyperparathyroidism was the most frequently encountered lesion but was not always the first biological or clinical abnormality to appear during the course of MEN1.

Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d’étude des Tumeurs Endocrines (GTE) cohort study

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe détude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Sunitinib in Pancreatic Neuroendocrine Tumors: Updated Progression-Free Survival and Final Overall Survival From a Phase III Randomized Study

BackgroundnIn a phase III trial in patients with advanced, well-differentiated, progressive pancreatic neuroendocrine tumors, sunitinib 37.5u2009mg/day improved investigator-assessed progression-free survival (PFS) versus placebo (11.4 versus 5.5xa0months; HR, 0.42; Pu2009<u20090.001). Here, we present PFS using retrospective blinded independent central review (BICR) and final median overall survival (OS), including an assessment highlighting the impact of patient crossover from placebo to sunitinib.nnnPatients and methodsnIn this randomized, double-blind, placebo-controlled study, cross-sectional imaging from patients was evaluated retrospectively by blinded third-party radiologists using a two-reader, two-time-point lock, followed by a sequential locked-read, batch-mode paradigm. OS was summarized using the Kaplan-Meier method and Cox proportional hazards model. Crossover-adjusted OS effect was derived using rank-preserving structural failure time (RPSFT) analyses.nnnResultsnOf 171 randomized patients (sunitinib, nu2009=u200986; placebo, nu2009=u200985), 160 (94%) had complete scan sets/time points. By BICR, median (95% confidence interval [CI]) PFS was 12.6 (11.1-20.6) months for sunitinib and 5.8 (3.8-7.2) months for placebo (HR, 0.32; 95% CI 0.18-0.55; Pu2009=u20090.000015). Five years after study closure, median (95% CI) OS was 38.6 (25.6-56.4) months for sunitinib and 29.1 (16.4-36.8) months for placebo (HR, 0.73; 95% CI 0.50-1.06; Pu2009=u20090.094), with 69% of placebo patients having crossed over to sunitinib. RPSFT analysis confirmed an OS benefit for sunitinib.nnnConclusionsnBICR confirmed the doubling of PFS with sunitinib compared with placebo. Although the observed median OS improved by nearly 10xa0months, the effect estimate did not reach statistical significance, potentially due to crossover from placebo to sunitinib.nnnTrial registration numbernNCT00428597.

Pasireotide and octreotide antiproliferative effects and sst2 trafficking in human pancreatic neuroendocrine tumor cultures

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) raise difficult therapeutic problems despite the emergence of targeted therapies. Somatostatin analogs (SSA) remain pivotal therapeutic drugs. However, the tachyphylaxis and the limited antitumoral effects observed with the classical somatostatin 2 (sst2) agonists (octreotide and lanreotide) led to the development of new SSA, such as the pan sst receptor agonist pasireotide. Our aim was to compare the effects of pasireotide and octreotide on cell survival, chromogranin A (CgA) secretion, and sst2 phosphorylation/trafficking in pancreatic NET (pNET) primary cells from 15 tumors. We established and characterized the primary cultures of human pancreatic tumors (pNETs) as powerful preclinical models for understanding the biological effects of SSA. At clinically relevant concentrations (1-10u200anM), pasireotide was at least as efficient as octreotide in inhibiting CgA secretion and cell viability through caspase-dependent apoptosis during short treatments, irrespective of the expression levels of the different sst receptors or the WHO grade of the parental tumor. Interestingly, unlike octreotide, which induces a rapid and persistent partial internalization of sst2 associated with its phosphorylation on Ser341/343, pasireotide did not phosphorylate sst2 and induced a rapid and transient internalization of the receptor followed by a persistent recycling at the cell surface. These results provide the first evidence, to our knowledge, of striking differences in the dynamics of sst2 trafficking in pNET cells treated with the two SSAs, but with similar efficiency in the control of CgA secretion and cell viability.

Unraveling the intrafamilial correlations and heritability of tumor types in MEN1: a Groupe d'étude des Tumeurs Endocrines study

BACKGROUNDnMEN1, which is secondary to the mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Most studies demonstrated the absence of direct genotype-phenotype correlations. The existence of a higher risk of death in the Groupe détude des Tumeurs Endocrines-cohort associated with a mutation in the JunD interacting domain suggests heterogeneity across families in disease expressivity. This study aims to assess the existence of modifying genetic factors by estimating the intrafamilial correlations and heritability of the six main tumor types in MEN1.nnnMETHODSnThe study included 797 patients from 265 kindred and studied seven phenotypic criteria: parathyroid and pancreatic neuroendocrine tumors (NETs) and pituitary, adrenal, bronchial, and thymic (thNET) tumors and the presence of metastasis. Intrafamilial correlations and heritability estimates were calculated from family tree data using specific validated statistical analysis software.nnnRESULTSnIntrafamilial correlations were significant and decreased along parental degrees distance for pituitary, adrenal and thNETs. The heritability of these three tumor types was consistently strong and significant with 64% (s.e.m.=0.13; P<0.001) for pituitary tumor, 65% (s.e.m.=0.21; P<0.001) for adrenal tumors, and 97% (s.e.m.=0.41; P=0.006) for thNETs.nnnCONCLUSIONnThe present study shows the existence of modifying genetic factors for thymus, adrenal, and pituitary MEN1 tumor types. The identification of at-risk subgroups of individuals within cohorts is the first step toward personalization of care. Next generation sequencing on this subset of tumors will help identify the molecular basis of MEN1 variable genetic expressivity.

Is basal ultrasensitive measurement of calcitonin capable of substituting for the pentagastrin‐stimulation test?

To evaluate a second‐generation assay for basal serum calcitonin (CT) measurements compared with the pentagastrin‐stimulation test for the diagnosis of inherited medullary thyroid carcinoma (MTC) and the follow‐up of patients with MTC after surgery. Recent American Thyroid Association recommendations suggest the use of basal CT alone to diagnose and assess follow‐up of MTC as the pentagastrin (Pg) test is unavailable in many countries.

Patient-reported outcomes with lanreotide Autogel/Depot for carcinoid syndrome: An international observational study

BACKGROUNDnLanreotide Autogel/Depot effectively controls symptoms in patients with carcinoid syndrome associated with neuroendocrine tumours. Data on patient-reported outcomes are sparse.nnnAIMnTo evaluate the effect of lanreotide on patient-reported outcomes (PROs) with carcinoid syndrome.nnnMETHODSnThis was an international, open-label, observational study of adults with neuroendocrine tumours and history of diarrhoea, receiving lanreotide for >3 months for relief of carcinoid syndrome symptoms. The primary PRO measure was satisfaction with diarrhoea control. Secondary PRO measures included severity, change in symptoms and impact on daily life of diarrhoea; and patient satisfaction with flushing control.nnnRESULTSnOf 273 patients enrolled, 76% were completely or rather satisfied with diarrhoea control; 79% reported improvement in diarrhoea with lanreotide. The proportion of patients with mild, minimal, or no diarrhoea increased from 33% before treatment to 75% during treatment; 75% were unconcerned about the impact of diarrhoea on daily life. Satisfaction with flushing control amongst patients with significant flushing at treatment initiation was 73%.nnnCONCLUSIONSnLanreotide treatment was associated with improvements in symptoms as well as a range of PROs in patients with neuroendocrine tumours and carcinoid syndrome (ClinicalTrials.gov: NCT01234168).