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Enora Le Roux, Agathe Turpin, Morgane Michel, Isabelle Tejedor, Florence Menesguen, Sabine Malivoir, Sandrine Bottuis, Hélène Mellerio, Michel Polak, and Philippe Touraine

Objective. To evaluate the effect of a new care organisation on multiple outcomes of transition success and its cost-effectiveness in patients with any endocrine or metabolic disease diagnosed during childhood and transferred to adult care.

Design. Non-randomized controlled trial in a French University Hospital.

Methods. Patients transferred to adult care during the control period (04/2014-08/2016) and the intervention period (09/2016-06/2018) were included. The intervention is based on case management involving liaising with paediatric services, personalising care pathways, and liaising with structures outside hospital (general practitioner, educational and social sector). The primary endpoint was the percentage of patients lost to follow-up at 24 months post transfer. Other outcomes were collected from medical files, consultation software, and questionnaires. A cost analysis was performed.

Results. 202 patients were included (101 per period) , the most represented pathologies were congenital and non-congenital hypopituitarism (respectively n=34 (17%) and n=45 (22%)) and thyroid diseases (n=21, 10%). Patients were aged 22.5 in median at 24 months post transfer where 12 were lost to follow up in the control group versus 9 with the intervention (p=0.49). The percentage of honoured consultation among those planned during 24 months was higher with intervention (p=0.0065). Patient satisfaction, physician trust, transfer delay did not differ between the groups. The incremental cost-effectiveness ratio was €179 per patient not lost to follow-up.

Conclusions. At 24 months post transfer the rate of lost to follow-up does not differ significantly, but indicators of a steadier follow-up are increased and the intervention appears to be cost-effective.

Free access

Rui M B Maciel and Ana Luiza Maia

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Free access

Andreas Ebbehoj, Per Løgstrup Poulsen, and Esben Søndergaard

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Frederic Castinetti, Philippe Caron, Isabelle Raingeard, Vincent Amodru, Frederique Albarel, Isabelle Morange, Philippe Chanson, Julie Calvo, Thomas Graillon, Karine Baumstarck, Henry Dufour, Jean Regis, and Thierry Brue

Introduction

Persistent growth hormone hypersecretion can be observed in roughly 50% of patients operated for somatotroph adenomas, requiring additional treatments. Despite its proven antisecretory efficacy, the use of Gamma Knife radiosurgery (GK) is limited probably due to the lack of data on long-term side effects, including potential cognitive consequences.

Methods

The LATe Effects of Radiosurgery in Acromegaly study was a cross-sectional exposed/unexposed non-randomized study. The primary objective was to determine the long-term neurocognitive effects of GK focusing on memory, executive functions, and calculation ability. Exposed patients had been treated by GK for acromegaly at least 5 years before inclusion. Unexposed patients (paired for age) had to be cured or controlled at last follow-up without any radiation technique. Patients of both groups were cured or controlled at the last follow-up.

Results

Sixty-four patients were evaluated (27 exposed and 37 unexposed). Mean follow-up after GK was 13 ± 6 years (including 24 patients followed for at least 10 years). While up to 23.8% of the patients of the whole cohort presented at least one abnormal cognitive test, we did not observe any significant difference in neurocognitive function between both groups. During the follow-up, 11 patients presented at least one new pituitary deficiency (P  = 0.009 for thyroid-stimulating hormone deficiency with a higher rate in exposed patients), two presented a stroke (1 in each group), and one presented a meningioma (12 years after GK).

Conclusions

While GK exposes patients to a well-known risk of pituitary deficiency, it does not seem to induce long-term cognitive consequences in patients treated for acromegaly.

Open access

Alexandra Dietz de Loos, Geranne Jiskoot, Annemerle Beerthuizen, Jan Busschbach, and Joop Laven

Context

Women with polycystic ovary syndrome (PCOS) have an increased risk of metabolic syndrome (MetS). Both PCOS and MetS are associated with excess weight.

Objective

To examine the effect of a three-component lifestyle intervention (LSI) with or without short message service (SMS+ or SMS−, respectively) on the prevalence and severity of MetS and metabolic parameters, compared to care as usual (CAU).

Design

Randomized controlled trial.

Methods

Women diagnosed with PCOS and a BMI >25 kg/m2 (n = 183) were either assigned to a 1-year three-component (cognitive behavioural therapy, diet, and exercise) LSI, with or without SMS support, or to CAU which provided weight-loss advice only. Main outcome measures included changes in the prevalence of MetS, the continuous MetS severity z-score (cMetS z-score), metabolic parameters, and the impact of weight loss.

Results

After 1 year, the decrease in the cMetS z-score was greater in the SMS+ group than the CAU group (−0.39, P  = 0.015). The prevalence of MetS changed with −21.6% (P  = 0.037), −16.5% (P  = 0.190), and +7.0% (P  = 0.509) in both LSI groups and CAU group, respectively. A post hoc analysis for both LSI groups combined vs CAU resulted in a MetS difference of −25.9% (P  = 0.046). Moreover, weight loss per se resulted in significantly favourable effects on all metabolic parameters.

Conclusions

This three-component LSI was more successful in improving metabolic health compared to CAU. Therefore, we recommend this intervention to women with PCOS and excess weight, provided that a clinically relevant weight loss is being pursued.

Open access

Charlotte J. Green, Thomas Marjot, John Walsby-Tickle, Catriona Charlton, Thomas Cornfield, Felix Westcott, Katherine E Pinnick, Ahmad Moolla, Jonathan M Hazlehurst, James McCullagh, Jeremy W Tomlinson, and Leanne Hodson

Objective:

Metformin is a first-line pharmacotherapy in the treatment of type 2 diabetes, a condition closely associated with NAFLD. Although metformin promotes weight loss and improves insulin sensitivity, its effect on intrahepatic triglyceride (IHTG) remains unclear. We investigated the effect of metformin on IHTG, hepatic de novo lipogenesis (DNL) and fatty acid (FA) oxidation in vivo in humans.

Design and Methods:

Metabolic investigations, using stable-isotope tracers, were performed in 10 insulin-resistant, overweight/obese human participants with NAFLD who were treatment naïve before and after 12-weeks of metformin treatment. The effect of metformin on markers of subcutaneous adipose tissue FA metabolism and function, along with the plasma metabolome were investigated.

Results:

Twelve weeks treatment with metformin resulted in a significant reduction in body weight and improved insulin sensitivity, but IHTG content and FA oxidation remained unchanged. Metformin treatment was associated with a significant decrease in VLDL-triglyceride (TG) concentrations and a significant increase in the relative contribution of DNL-derived FAs to VLDL-TG. There were subtle and relatively few changes in subcutaneous adipose tissue FA metabolism and the plasma metabolome with metformin treatment.

Conclusions:

We demonstrate the mechanisms of action of metformin whereby it improves insulin sensitivity and promotes weight loss, without improvement in IHTG; these observations are partly, explained through increased hepatic DNL and a lack of change in fatty acid oxidation.

Free access

Alexander A Leung, Janice L Pasieka, Hossein Sadrzadeh, and Gregory A Kline

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David J Handelsman, Reena Desai, Ann J Conway, Nandini Shankara-Narayana, Bronwyn Ga Stuckey, Warrick J Inder, Mathis Grossmann, Bu Beng Yeap, David Jesudason, Lam P Ly, Karen Bracken, and Gary Allen Wittert

Context: The time course of male reproductive hormone recovery after stopping injectable testosterone undecanoate (TU) treatment is not known.

Objective: To investigate rate, extent, and determinants of reproductive hormone recovery over 12 months after stopping TU injections.

Methods: Men (n=303) with glucose intolerance but without pathologic hypogonadism who completed a 2-year placebo(P)-controlled randomized clinical trial of TU treatment were recruited for a further 12 months while remaining blinded to treatment. Sex steroids (T, DHT, E2, E1) by LCMS, LH, FSH and SHBG by immunoassays and sexual function questionnaires (Psychosexual Diary Questionnaire (PDQ), International Index of Erectile Function (IIEF), SF-12) were measured at entry (three months after last injection) and 6, 12, 18, 24, 40 and 52 weeks later.

Results: In the nested cohort of TU-treated men, serum T was initially higher but declined to 12 weeks remaining stable thereafter with serum T and SHBG 11% and 13%, respectively, lower than P-treated men. Similarly, both questionnaires showed initial carryover higher scores in T-treated men, but after weeks 18 showed no difference between T and P treated men. Initially fully suppressed serum LH and FSH recovered slowly towards the participant’s own pre-treatment baseline over 12 months since last injection.

Conclusions: After stopping 2 years of 1000 mg injectable TU treatment, full reproductive hormone recovery is slow and progressive over 15 months since last testosterone injection but may take longer than 12 months to be complete. Persistent proportionate reduction in serum SHBG and T reflects lasting exogenous T effects on hepatic SHBG secretion rather than androgen deficiency.

Open access

Y S Elhassan, B Altieri, S Berhane, D Cosentini, A Calabrese, M Haissaguerre, D Kastelan, M C B V Fragoso, J Bertherat, A Al Ghuzlan, H Haak, M Boudina, L Canu, P Loli, M Sherlock, O Kimpel, M Laganà, A J Sitch, M Kroiss, W Arlt, M Terzolo, A Berruti, J J Deeks, R Libé, M Fassnacht, C L Ronchi, and the ENSAT

Objective

Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on the European Network for the Study of Adrenal Tumours stage and Ki67 index is limited. We aimed to demonstrate the prognostic role of a points-based score (S-GRAS) in a large cohort of patients with ACC.

Design

This is a multicentre, retrospective study on ACC patients who underwent adrenalectomy.

Methods

The S-GRAS score was calculated as a sum of the following points: tumour stage (1–2 = 0; 3 = 1; 4 = 2), grade (Ki67 index 0–9% = 0; 10–19% = 1; ≥20% = 2 points), resection status (R0 = 0; RX = 1; R1 = 2; R2 = 3), age (<50 years = 0; ≥50 years = 1), symptoms (no = 0; yes = 1), and categorised, generating four groups (0–1, 2–3, 4–5, and 6–9). Endpoints were progression-free survival (PFS) and disease-specific survival (DSS). The discriminative performance of S-GRAS and its components was tested by Harrell’s Concordance index (C-index) and Royston–Sauerbrei’s R2 D statistic.

Results

We included 942 ACC patients. The S-GRAS score showed superior prognostic performance for both PFS and DSS, with best discrimination obtained using the individual scores (0–9) (C-index = 0.73, R2 D = 0.30, and C-index = 0.79, R2 D = 0.45, respectively, all P < 0.01vs each component). The superiority of S-GRAS score remained when comparing patients treated or not with adjuvant mitotane (n = 481 vs 314). In particular, the risk of recurrence was significantly reduced as a result of adjuvant mitotane only in patients with S-GRAS 4–5.

Conclusion

The prognostic performance of S-GRAS is superior to tumour stage and Ki67 in operated ACC patients, independently from adjuvant mitotane. S-GRAS score provides a new important guide for personalised management of ACC (i.e. radiological surveillance and adjuvant treatment).

Free access

Jens O L Jørgensen, Gudmundur Johannsson, and Ariel Barkan