Congenital generalized lipodystrophy (CGL) is a rare, heterogeneous, autosomal recessive disorder characterized by near total absence of body fat with increased muscularity noticed at birth or in early infancy. Four distinct genetic subtypes of CGL have been reported to date. Types 1 and 2 are caused by biallelic variants in the 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2) and Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) genes, respectively, and are the most common subtypes (1). Types 3 and 4 are extremely rare and are caused by biallelic variants in the caveolin 1 (CAV1) (2), and Caveolae Associated Protein-1 (CAVIN1; also known as polymerase I and transcript release factor (PTRF)]) genes (3), respectively. Patients with all CGL subtypes are predisposed to metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia and hepatic steatosis; however, each subtype presents with some unique clinical features.
Sara Storvall, Helena Leijon, Eeva M Ryhänen, Tiina Vesterinen, Ilkka Heiskanen, Camilla Schalin-Jäntti, and Johanna Arola
Objective
Parathyroid carcinoma (PC), atypical parathyroid tumours (APT) and parathyroid adenoma (PA), all present with hypercalcemia. Diminished calcium-sensing receptor (CaSR) expression is reported in PC but is rare in benign tumours. Filamin A (FLNA) binds to the CaSR and activates the mitogen-activated protein kinase (MAPK) signalling pathway. FLNA is related to tumour aggressiveness in several cancers, but its role in parathyroid neoplasia is unknown.
Design
We examined FLNA, CaSR and parafibromin expression in PCs (n = 32), APTs (n = 44) and PAs (n = 77) and investigated their potential as diagnostic and/or prognostic markers.
Methods
Tissue microarray slides were immunohistochemically stained with antibodies for FLNA, CaSR and parafibromin. Staining results were correlated with detailed clinical data.
Results
All tumours stained positively for CaSR, with two tumours (one PC and one APT) showing diminished expression. Carcinomas were characterized by increased cytoplasmic FLNA expression compared to APTs and PAs (P = 0.004). FLNA expression was not correlated with Ki-67 proliferation index or loss of parafibromin expression. Cytoplasmic FLNA expression was also associated with higher serum calcium, PTH concentrations and male sex (P = 0.014, P = 0.017 and P = 0.049 respectively). Using a combined marker score, we found that parathyroid tumours with low FLNA expression and positive parafibromin staining were extremely likely to be benign (P < 0.001).
Conclusion
Cytoplasmic and membranous FLNA expression is increased in parathyroid carcinomas compared to benign tumours. A combined FLNA and parafibromin expression score shows potential as a prognostic predictor of indolent behaviour in parathyroid neoplasms.
Marga A G Helmink, Marieke de Vries, Frank L J Visseren, Wendela L de Ranitz, Harold W de Valk, and Jan Westerink
Objective
To identify determinants associated with insulin resistance and to assess the association between insulin resistance and cardiovascular events, vascular interventions and mortality in people with type 1 diabetes at high risk of cardiovascular disease.
Design
Prospective cohort study.
Methods
One hundred and ninety-five people with type 1 diabetes from the Secondary Manifestations of ARTerial disease (SMART) cohort were included. Insulin resistance was quantified by the estimated glucose disposal rate (eGDR) with higher eGDR levels indicating higher insulin sensitivity (i.e. lower eGDR levels indicating higher insulin resistance). Linear regression models were used to evaluate determinants associated with eGDR. The effect of eGDR on cardiovascular events, cardiovascular events or vascular interventions (combined endpoint) and on all-cause mortality was analysed using Cox proportional hazards models adjusted for confounders.
Results
In 195 individuals (median follow-up 12.9 years, IQR 6.7–17.0), a total of 25 cardiovascular events, 26 vascular interventions and 27 deaths were observed. High eGDR as a marker for preserved insulin sensitivity was independently associated with a lower risk of cardiovascular events (HR: 0.75; 95% CI: 0.61–0.91), a lower risk of cardiovascular events and vascular interventions (HR: 0.74; 95% CI: 0.63–0.87) and a lower risk of all-cause mortality (HR: 0.81; 95% CI: 0.67–0.98).
Conclusions
Insulin resistance as measured by eGDR is an additional risk factor for cardiovascular disease in individuals with type 1 diabetes. Modification of insulin resistance by lifestyle interventions or pharmacological treatment could be a viable therapeutic target to lower the risk of cardiovascular disease.
Marloes Nies, Eus G J M Arts, Evert F S van Velsen, Johannes G M Burgerhof, Anneke C Muller Kobold, Eleonora P M Corssmit, Romana T Netea-Maier, Robin P Peeters, Anouk N A van der Horst-Schrivers, Astrid E P Cantineau, and Thera P Links
Context
Whilst radioactive iodine (RAI) is often administered in the treatment for differentiated thyroid carcinoma (DTC), long-term data on male fertility after RAI are scarce.
Objective
To evaluate long-term male fertility after RAI for DTC, and to compare semen quality before and after RAI.
Design, setting, and patients
Multicenter study including males with DTC ≥2 years after their final RAI treatment with a cumulative activity of ≥3.7 GBq.
Main outcome measure(s)
Semen analysis, hormonal evaluation, and a fertility-focused questionnaire. Cut-off scores for ‘low semen quality’ were based on reference values of the general population as defined by the World Health Organization (WHO).
Results
Fifty-one participants had a median age of 40.5 (interquartile range (IQR): 34.0–49.6) years upon evaluation and a median follow-up of 5.8 (IQR: 3.0–9.5) years after their last RAI administration. The median cumulative administered activity of RAI was 7.4 (range: 3.7–23.3) GBq. The proportion of males with a low semen volume, concentration, progressive motility, or total motile sperm count did not differ from the 10th percentile cut-off of a general population (P = 0.500, P = 0.131, P = 0.094, and P = 0.500, respectively). Cryopreserved semen was used by 1 participant of the 20 who had preserved semen.
Conclusions
Participants had a normal long-term semen quality. The proportion of participants with low semen quality parameters scoring below the 10th percentile did not differ from the general population. Cryopreservation of semen of males with DTC is not crucial for conceiving a child after RAI administration but may be considered in individual cases.
Vin-Cent Wu, Shuo-Meng Wang, Kuo-How Huang, Yao-Chou Tsai, Chieh-Kai Chan, Shao-Yu Yang, Lian-Yu Lin, Chin-Chen Chang, Ching-Chu Lu, Yen-Hung Lin, Yun-Ming Chen, and Jeff S Chueh
OBJECTIVE:
Long-term outcomes (especially mortality and/or major cardiovascular events [MACE]) of the unilateral primary aldosteronism (uPA) patients who underwent medical or surgery targeted treatment, relative to those with essential hypertension (EH), have been scarcely reported.
DESIGN and SETTINGS:
Using the prospectively designed observational TAIPAI cohort, we identified 858 uPA cases among 1220 primary aldosteronism (PA) patients and another 1210 EH controls.
EXPOSURES
Operated uPA patients were grouped via their 1-year post-therapy statuses.
RESULTS
PASO clinical complete success (hypertension-remission) was achieved in 272 (49.9%) of 545 surgically-treated uPA patients. After follow-up for 6.3±4.0 years, both hypertension-remissive (HR, 0.54, p< 0.001) and not-cured (HR, 0.61, p< 0.001) uPA patients showed a lower risk of all-cause mortality than that of EH controls; whereas the not-cured group had a higher risk of incident MACE (sub-hazard ratio (sHR), 1.41, p= 0.037) but similar atrial fibrillation (Af) and congestive heart failure (CHF). Mineralocorticoid receptor antagonist (MRA)-treated uPA patients had higher risks of MACE (sHR, 1.38, p= 0.033), Af (sHR,1.62, p= 0.049) and CHF (sHR, 1.44, p= 0.048) than those of EH controls, with mortality as a competing risk. Using inverse probability of treatment-weighted matching and counting adrenalectomy as a time-varying factor, treatment with adrenalectomy was associated with lower risks of all-cause mortality (HR 0.57; p= 0.035), MACE (HR 0.67; p= 0.037) and CHF (HR 0.49; p= 0.005) compared to those of MRA therapy.
CONCLUSIONS :
Adrenalectomy, independent of post-surgical hypertension remission, was associated with lower all-cause mortality of uPA patients, compared to that of EH patients. We further documented a more beneficial effect of adrenalectomy over MRA treatment on long-term mortality, MACE, and CHF in uPA patients.
Jingjing Zhang, Xi Chen, Wei Liu, Chunlan Zhang, Yufei Xiang, Shiping Liu, and Zhiguang Zhou
Background
Obesity is associated with impaired immune function and chronic low-grade inflammation. Metabolic surgery is one of the most effective therapies for treating obesity and related metabolic disorders. We aimed to explore the pathophysiological roles of peripheral dendritic cells (DCs) and T lymphocytes in metabolic surgery.
Method
In this observational cohort study, a total of 106 individuals, including obese participants with or without T2DM, overweight subjects and normal controls, were recruited. All obese participants underwent laparoscopic sleeve gastrectomy surgery and returned for the evaluation of the clinical indicators after surgery. We evaluated the frequencies of circulating DCs subsets (myeloid (mDCs) and plasmacytoid (pDCs)), the pro-inflammatory (Th1 and Th17) and anti-inflammatory (Th2 and Treg) T cell subsets by flow cytometry.
Results
Compared with normal controls, the frequencies of mDCs, Th1 and Th17 cells increased, while Treg and Th2 cells decreased in the obese participants. The frequency of mDCs and Th1 cells consistently declined after surgery compared with baseline in the obese patients and were restored to the levels observed in the normal controls after surgery. Moreover, the frequency of Treg cells was increased at 6 months after surgery in the obese patients with T2DM, and Th17 cells declined at 6 months after surgery in the severely obese patients without T2DM.
Conclusion
This study indicates that metabolic surgery can effectively improve imbalanced immune cells in peripheral blood and restore the proportion of immune cells to a normal range during a 12-month follow-up.
Thierry Brue and Sally A Camper
Recent studies have shown a novel mechanism of combined pituitary hormone deficiency associated with mutations in POU1F1, altering the balance of alternative-splicing, which results in over-expression of the beta isoform of POU1F1. These studies underscore the need for biologists, in the context of routine molecular diagnosis of this condition, to investigate alternative splicing in POU1F1 as well as in other genes.
Maelle Le Bras, Hélène Leclerc, Olivia Rousseau, Pierre Goudet, Thomas Cuny, Frederic Castinetti, Catherine Bauters, Philippe Chanson, Antoine Tabarin, Sebastien Gaujoux, Sophie Christin-Maitre, Philippe Ruszniewski, Francoise Borson-Chazot, Isabelle Guilhem, Philippe Caron, Bernard Goichot, Albert Beckers, Brigitte Delemer, Isabelle Raingeard, Bruno Vergès, Sarra Smati, Matthieu Wargny, Bertrand Cariou, and Samy Hadjadj
Objective
Pituitary adenoma (PA) is one of the three major components of multiple endocrine neoplasia type 1 (MEN1). Recent studies have suggested that MEN1-associated PAs are less aggressive than initially estimated. We propose an analysis of the outcome of PAs with a standard of care treatment in a nationwide cohort of MEN1 patients.
Design
Retrospective observational nationwide cohort study using the MEN1 patient registry from the French Group of Endocrine Tumours (GTE).
Methods
The GTE database population consists of 1435 patients with MEN1. This analysis focused on 551 patients recruited after 2000 with at least 3 years of follow-up. The study outcome was tumour progression of PA defined by an increase in Hardy classification (HC) during follow-up according to referring physician regular reports.
Results
Among 551 MEN1 patients (index and related), 202 (36.7%) had PA, with 114 (56.4%) diagnosed by MEN1-related screening. PAs were defined according to HC as microadenoma (grade I) in 117 cases (57.9%), macroadenoma in 59 (29.2%) with 20 HC grade II and 39 HC grades III–IV and unspecified in 26 (12.8%). They were prolactinomas in 92 cases (45.5%) and non-secreting in 73 (36.1%). After a median follow-up of 3 years among the 137 patients with HC grades I–II, 4 patients (2.9%) presented tumour progression.
Conclusion
PAs in patients with MEN1 are less aggressive than previously thought. Tumour progression is rare with a standard of care monitoring and treatment, especially in related patients who mostly present non-secreting microadenoma. MRI monitoring for asymptomatic MEN1 patients should be reduced accordingly.
Bertrand Baussart, Chiara Villa, Anne Jouinot, Marie-Laure Raffin-Sanson, Luc Foubert, Laure Cazabat, Michèle Bernier, Fideline Bonnet, Anthony Dohan, Jerome Bertherat, Guillaume Assié, and Stephan Gaillard
Objective
Microprolactinomas are currently treated with dopamine agonists. Outcome information on microprolactinoma patients treated by surgery is limited. This study reports the first large series of consecutive non-invasive microprolactinoma patients treated by pituitary surgery and evaluates the efficiency and safety of this treatment.
Design
Follow-up of a cohort of consecutive patients treated by surgery.
Methods
Between January 2008 and October 2020, 114 adult patients with pure microprolactinomas were operated on in a single tertiary expert neurosurgical department, using an endoscopic endonasal transsphenoidal approach. Eligible patients presented with a microprolactinoma with no obvious cavernous invasion on MRI. Prolactin was assayed before and after surgery. Disease-free survival was modeled using Kaplan–Meier representation. A cox regression model was used to predict remission.
Results
Median follow-up was 18.2 months (range: 2.8–155). In this cohort, 14/114 (12%) patients were not cured by surgery, including ten early surgical failures and four late relapses occurring 37.4 months (33–41.8) after surgery. From Kaplan–Meier estimates, 1-year and 5-year disease free survival was 90.9% (95% CI: 85.6–96.4%) and 81% (95% CI: 71.2–92.1%) respectively. The preoperative prolactinemia was the only significant preoperative predictive factor for remission (P < 0.05). No severe complication was reported, with no anterior pituitary deficiency after surgery, one diabetes insipidus, and one postoperative cerebrospinal fluid leakage properly treated by muscle plasty.
Conclusions
In well-selected microprolactinoma patients, pituitary surgery performed by an expert neurosurgical team is a valid first-line alternative treatment to dopamine agonists.