Meningiomas are common intracranial tumors with a female predominance. Their etiology is still poorly documented. The role of sexual hormones has long been evoked, and data have been conflicting ...across studies. However, a dose-dependent relationship between the incidence and growth of meningiomas and hormonal treatment with the progestin cyproterone acetate (CPA) has recently been established. CPA-associated meningiomas seem to be mainly located in the anterior and middle skull base, are more likely to be multiple, may harbor P1K3CA mutations in up to one-third of cases, and are more common with a longer duration of treatment. A similar but lower risk of meningiomas has been recently reported with the use of chlormadinone acetate and nomegestrol acetate as progestin treatments. Concerning hormonal replacement therapy (HRT) in menopausal patients, evidence from epidemiological studies seem to favor an increased risk of meningiomas in treated patients although a recent study failed to show an increased growth of meningiomas in HRT treated vs nontreated patients. Until larger studies are available, it seems wise to recommend avoiding HRT in patients with meningiomas. Evidence from published data does not seem to support an increased risk of meningiomas with oral contraceptive oral contraceptive (OR) use. Data are too scarce to conclude on fertility treatments. Based on studies demonstrating the expression of hormonal receptors in meningiomas, therapies targeting these receptors have been tried but have failed to show an overall favorable clinical outcome in meningioma treatment.
Pituitary neuroendocrine tumors (PitNETs) are common, with five main histological subtypes: lactotroph, somatotroph, and thyrotroph (POU1F1/PIT1 lineage); corticotroph (TBX19/TPIT lineage); and ...gonadotroph (NR5A1/SF1 lineage). We report a comprehensive pangenomic classification of PitNETs. PitNETs from POU1F1/PIT1 lineage showed an epigenetic signature of diffuse DNA hypomethylation, with transposable elements expression and chromosomal instability (except for GNAS-mutated somatotrophs). In TPIT lineage, corticotrophs were divided into three classes: the USP8-mutated with overt secretion, the USP8-wild-type with increased invasiveness and increased epithelial-mesenchymal transition, and the large silent tumors with gonadotroph transdifferentiation. Unexpected expression of gonadotroph markers was also found in GNAS-wild-type somatotrophs (SF1 expression), challenging the current definition of SF1/gonadotroph lineage. This classification improves our understanding and affects the clinical stratification of patients with PitNETs.
Display omitted
•Molecular classes of PitNETs are identified by integrated pangenomic analyses•PitNETs molecular classification mainly reflects pituitary lineage, driven by PIT1•Gonadotroph signatures are found in some corticotroph and somatotroph PitNETs•USP8-mutated corticotroph PitNETs correspond to a group with limited aggressiveness
By performing an unbiased multi-omics analysis of a large cohort of pituitary neuroendocrine tumors (PitNETs), Neou et al. generate a pangenomic classification that challenges the current histological classification of these tumors and has implications for the clinical management of the disease.
Abstract
Context
The behavior of locally advanced pheochromocytoma (LAP) remains unknown.
Objective
We characterized the population with LAP and recurrence-free survival (RFS).
Methods
This ...retrospective multicentric study was run within the ENDOCAN-COMETE network and French Group of Endocrine Tumors (GTE) from 2003 to 2018, including patients from 11 French referral centers with LAP as defined by capsular invasion, vascular invasion, adipose tissue invasion, and/or positive locoregional lymph nodes at diagnosis without evidence of distant metastasis. The main outcome measure was recurrence, defined as tumor reappearance, including local site and/or distant metastasis. The primary endpoint was RFS analysis; secondary endpoints were characterization, overall survival (OS), and prognostic factors of recurrence.
Results
Among 950 patients, 90 (9%) exhibited LAP criteria and 55 met inclusion criteria (median age, 53 years; 61% males; 14% with germline mutation; 84% with catecholamine excess). LAP was defined by 31 (56%) capsular invasions, 27 (49%) fat invasions, 6 (11%) positive lymph nodes, and 22 (40%) vascular invasions. After median follow-up of 54 months (range, 6-180), 12 patients (22%) had recurrences and 3 (5%) died of metastatic disease. Median RFS was 115 months (range, 6-168). Recurrences were local in 2 patients, distant in 2, and both local and distant in 8 patients. Median OS of patients was not reached. Size above 6.5 cm (P = 0.019) and Ki-67 > 2% (P = 0.028) were identified as independent significant prognostic factors in multivariate analysis.
Conclusion
LAP represents 9% of pheochromocytoma’s population and has a metastatic behavior. This study paves the way for future pathological TNM classification.
Somatostatin receptor ligands (SRL) are useful to control central hyperthyroidism in patients with thyrotropin-secreting pituitary adenoma (TSH pituitary adenoma). The aim of this study was to ...describe the frequency of thyrotropin deficiency (TSH deficiency) in patients with TSH pituitary adenoma treated by SRL.
Retrospective study.
Patients with central hyperthyroidism due to TSH pituitary adenoma treated by short or long-acting SRL were retrospectively included. TSH deficiency was defined by a low FT4 associated with non-elevated TSH concentrations during SRL therapy. We analysed the frequency of TSH deficiency and the characteristics of patients with or without TSH deficiency.
Forty-six patients were included. SRL were used as the first-line therapy in 21 of 46 patients (46%). Central hyperthyroidism was controlled in 36 of 46 patients (78%). TSH deficiency appeared in 7 of 46 patients (15%) after a median time of 4 weeks (4-7) and for a median duration of 3 months (2.5-3). The TSH deficiency occurred after one to three injections of long-acting SRL used as first-line therapy in 6/7 cases. There were no differences in terms of clinical and hormonal features, size of adenomas or doses of SRL between patients with or without TSH deficiency.
SRL can induce TSH deficiency in patients with central hyperthyroidism due to TSH pituitary adenoma. Thyrotropic function should be assessed before the first three injections of SRL in order to track TSH deficiency and reduce the frequency of injections when control of thyrotoxicosis rather than tumour reduction is the aim of the treatment.
Purpose
Bariatric surgery is associated with significant weight loss and improvement in comorbid conditions but in rare cases can expose to complications requiring intensive nutritional care (INC). ...INC in this context is poorly described and no data are available concerning long-term impact.
Materials and Methods
We retrospectively reviewed charts of bariatric patients who were hospitalized in our institution between 2013 and 2018. We identified patients with a postoperative complication requiring INC and we described their nutritional management (INC group). These patients were compared with controls matched to age, gender, preoperative BMI, and type of surgery selected from our database (control group). The primary endpoint was the percentage of total weight loss (%TWL) at 2.5 years. Secondary endpoints were improvement of co-morbidities, vitamin deficiencies, and depression/anxiety scores.
Results
The INC group consisted of 18 patients among which 77.8% had sleeve gastrectomy (SG). Half of these patients underwent revisional surgery. The most common complication was fistula formation (66.7%). Patients in the INC group, compared to the control group, showed a significantly higher %TWL at 2.5 years (33.6% vs 26.1%,
P
= 0.03). There was no significant difference in either reduction of preoperative comorbidities or depression/anxiety scores between the two groups. The number of patients with more than three nutritional deficiencies was similar in both groups. Thiamine deficiency was only observed in the INC group.
Conclusion
Complications requiring INC after bariatric surgery occur mainly after revisional surgery and may increase long-term %TWL but have no impact on nutritional deficiencies or symptoms of anxiety/depression.
Graphical abstract
Summary
Background
Genetic aberrations in various components of cAMP signalling pathway predispose to endocrine tumours. Mutations in the phosphodiesterases (PDEs) are involved in the predisposition ...to adrenocortical neoplastic conditions.
Objective
To screen for genetic variations in
PDE8B
among patients with different types of adrenocortical tumours.
Design and subjects
This is a case–control study followed by functional analyses. Two hundred and sixteen unrelated patients with different types of adrenocortical tumours and 192 healthy control individuals participated in the study.
Methods
Bidirectional Sanger sequencing, in vitro cell line transfection and in silico modelling are used in this study.
Results
Nine different
PDE8B
sequence changes, six novel and three previously reported, were identified in our patients and controls. Two of the variations, seen only in the patient group, showed significant potential to impair protein function, both in vitro and in silico.
Conclusion
PDE8B
is another PDE gene in which variations may contribute to predisposition of adrenocortical tumours.
Objective
Mitotane/Op'DDD is used in the treatment of adrenocortical carcinoma and for other causes of hypercortisolism. Mitotane inhibits cortisol secretion and displays adrenolytic and antitumor ...actions. This compound is a metabolite of the pesticide and endocrine disruptor DDT (dichlorodiphenyltrichloroethane) and is classified among teratogenic compounds worldwide. However, little is known about its effects on human development.
Design
The outcome of four children exposed to mitotane during their intrauterine life was examined.
Patients
Patients having conceived while taking mitotane, or with detectable mitotane plasma levels, were retrospectively recruited via the French COMETE and FIRENDO networks.
Measurements
Mitotane in maternal plasma, adrenocortical hormones in children.
Results
Three women treated with mitotane gave birth to four children. During early pregnancy, all patients had detectable mitotane plasma levels (0.9, 2.4 and 6.7 mg/L, respectively). During pregnancy, no foetal malformations were detected. The four exposed newborns presented at birth with apparently normal adrenal function and genitalia. One twin female had a low birthweight. Evaluation at birth and after 3 months, 2 years and 7 years of follow‐up showed no significant neurological abnormality. Evaluation of adrenocortical functions showed no cortisol deficiency.
Conclusions
Unexpectedly, exposure of these four children to mitotane during foetal life seemed to have no clear teratogenic effect. However, considering the sub‐therapeutic mitotane concentrations used here, the small number of cases, and because long‐term follow‐up is unknown, we strongly advise not to take mitotane during pregnancy and still recommend avoiding pregnancy, at least as long as mitotane plasma levels remain detectable.
Glomus tumors (GTs) are perivascular tumors mostly occurring in the distal extremities. Rare cases arise in the digestive tract and may be misdiagnosed with neuroendocrine or gastrointestinal stromal ...tumors. We aimed to specify the features of GT of the upper digestive tract. Clinical, histological, phenotypic, and molecular features of 16 digestive GTs were analyzed, of whom two underwent whole exome and RNA sequencing to search for gene alterations. RNA‐sequencing disclosed a t(1:5)(p13;q32) translocation, which resulted in the fusion of CARMN and NOTCH2 in two GTs. The fusion gene encoded a protein sequence corresponding to the NOTCH2 intracellular domain that functions as transcription factor. These finding was supported by high expression of genes targeted by NOTCH. The CARMN‐NOTCH2 translocation was detected in 14 out of 16 (88%) GTs of the upper digestive tract; but in only in two out of six cutaneous GTs (33%). Most digestive GT arose from the stomach (n = 13), and the others from duodenal (2) or oesophagous (1). Nuclear expression of NOTCH2 was detected in the 14 cases containing the fusion transcripts. The CARMN‐NOTCH2 fusion transcript may contribute to activation of the NOTCH2 pathway in GT and drive tumor development. The high frequency of this translocation in GT of the upper digestive track suggest that detection of nuclear NOTCH2 expression may be useful diagnostic biomarker of these tumors.
Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK ...and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis.
MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RASV12 or BRAFV600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAFV600E carcinoma cell lines.
BRAFV600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAFV600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAFV600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion.
Our results are in favor of a stronger activation of the MAPK pathway in BRAFV600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAFV600E PTC cell line models.
Leukocytosis is associated with increased cardiovascular disease risk in humans and develops in hypercholesterolemic atherosclerotic animal models. Leukocytosis is associated with the proliferation ...of hematopoietic stem and multipotential progenitor cells (HSPCs) in mice with deficiencies of the cholesterol efflux-promoting ABC transporters ABCA1 and ABCG1 in BM cells. Here, we have determined the role of endogenous apolipoprotein-mediated cholesterol efflux pathways in these processes. In Apoe⁻/⁻ mice fed a chow or Western- type diet, monocytosis and neutrophilia developed in association with the proliferation and expansion of HSPCs in the BM. In contrast, Apoa1⁻/⁻ mice showed no monocytosis compared with controls. ApoE was found on the surface of HSPCs, in a proteoglycan-bound pool, where it acted in an ABCA1- and ABCG1-dependent fashion to decrease cell proliferation. Accordingly, competitive BM transplantation experiments showed that ApoE acted cell autonomously to control HSPC proliferation, monocytosis, neutrophilia, and monocyte accumulation in atherosclerotic lesions. Infusion of reconstituted HDL and LXR activator treatment each reduced HSPC proliferation and monocytosis in Apoe⁻/⁻ mice. These studies suggest a specific role for proteoglycanbound ApoE at the surface of HSPCs to promote cholesterol efflux via ABCA1/ABCG1 and decrease cell proliferation, monocytosis, and atherosclerosis. Although endogenous apoA-I was ineffective, pharmacologic approaches to increasing cholesterol efflux suppressed stem cell proliferative responses.
PDF
