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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 Later-Ac 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 last follow-up.

Results: 64 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 TSH deficiency with a higher rate in exposed patients), 2 presented a stroke (1 in each group), and one, 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.

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Andreas Ebbehoj, Per Loegstrup Poulsen, and Esben Søndergaard

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Elina Peltola, Päivi Hannula, Heini Huhtala, Saara Metso, Juhani Sand, Johanna Laukkarinen, Mirja Tiikkainen, Jukka Sirén, Minna Soinio, Pirjo Nuutila, Leena Moilanen, David E Laaksonen, Tapani Ebeling, Johanna Arola, Camilla Schalin-Jäntti, and Pia Jaatinen

Objective

Insulinomas are rare functional pancreatic neuroendocrine tumours. As previous data on the long-term prognosis of insulinoma patients are scarce, we studied the morbidity and mortality in the Finnish insulinoma cohort.

Design

Retrospective cohort study.

Methods

Incidence of endocrine, cardiovascular, gastrointestinal and psychiatric disorders, and cancers was compared in all the patients diagnosed with an insulinoma in Finland during 1980–2010 (n = 79, including two patients with multiple endocrine neoplasia type 1 syndrome), vs 316 matched controls, using the Mantel–Haenszel method. Overall survival was analysed with Kaplan–Meier and Cox regression analyses.

Results

The median length of follow-up was 10.7 years for the patients and 12.2 years for the controls. The long-term incidence of atrial fibrillation (rate ratio (RR): 2.07 (95% CI: 1.02–4.22)), intestinal obstruction (18.65 (2.09–166.86)), and possibly breast (4.46 (1.29–15.39) and kidney cancers (RR not applicable) was increased among insulinoma patients vs controls, P  < 0.05 for all comparisons. Endocrine disorders and pancreatic diseases were more frequent in the patients during the first year after insulinoma diagnosis, but not later on. The survival of patients with a non-metastatic insulinoma (n = 70) was similar to that of controls, but for patients with distant metastases (n = 9), the survival was significantly impaired (median 3.4 years).

Conclusions

The long-term prognosis of patients with a non-metastatic insulinoma is similar to the general population, except for an increased incidence of atrial fibrillation, intestinal obstruction, and possibly breast and kidney cancers. These results need to be confirmed in future studies. Metastatic insulinomas entail a markedly decreased survival.

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Volha V Zhukouskaya, Inès Mannes, Catherine Chaussain, Peter Kamenický, Christelle Audrain, Anne-Sophie Lambert, Jérôme Nevoux, Philippe Wicart, Karine Briot, Federico Di Rocco, Séverine Trabado, Dominique Prié, Carolina Di Somma, Annamaria Colao, Catherine Adamsbaum, Anya Rothenbuhler, and Agnès Linglart

Purpose

To examine the MRI diagnostic performance in the assessment of therapeutic response to burosumab in children with X-linked hypophosphatemia (XLH).

Design

Prospective longitudinal open cohort.

Patients

Seventeen children with XLH, average age of 10.2 ± 2.7 years, had a knee MRI at baseline and after 1 year of burosumab.

Intervention

Children received burosumab at an average dose of 1.4 ± 0.5 mg/kg during 1 year for the treatment of severe rickets (the target serum phosphate ≥ 1.2 mmol/L (≥3.7 mg/dL). The primary endpoint was the change from baseline to 12 months in rachitic lesions on knee MRI. Secondary endpoints were changes in biochemical parameters of phosphate and alkaline phosphatase (ALP).

Results

One year of treatment with burosumab significantly reduced radiological disease activity on knee MRI (by 44 ± 29% in the transverse extent of widening) which was accompanied by a significant reduction in biochemical activity, namely in serum ALP activity, by 28 ± 17%. Additionally, MRI parameters after 1 year of treatment with burosumab (the maximum width of medial physis at 12 months and the change from baseline in the maximum width of lateral physis) were associated with ALP activity at 12 months.

Conclusion

We suggest that MRI is a valuable and quantitative tool to evaluate the therapeutic response to burosumab. MRI could be an excellent alternative to standard bone radiographs for evaluation of the rachitic lesions in a clinical setting avoiding repeated exposition to ionizing radiation.

Open access

Ploutarchos Tzoulis, Ashley B Grossman, Stephanie E Baldeweg, Pierre Bouloux, and Gregory Kaltsas

This review examines the prevalence, aetiology, pathophysiology, prognostic value, and investigation of dysnatraemia in hospitalised COVID-19 patients, taking into account all relevant studies published in PubMed and Cochrane Library studies until March 2021. Hyponatraemia is commonly observed in patients with bacterial pneumonia and is an independent predictor for excess mortality and morbidity. However, it remains unknown whether this association applies to coronavirus disease-2019 (COVID-19). Several studies reported a 20–35% prevalence for hyponatraemia and 2–5% for hypernatraemia in patients admitted with COVID-19. In addition, hyponatraemia on admission was a risk factor for progression to severe disease, being associated with an increased likelihood for the need for invasive mechanical ventilation, with an odds ratio (OR) of 1.83–3.30. Hyponatraemia seems to be an independent risk factor for mortality, with an OR of 1.40–1.50 compared to normonatraemia, while hypernatraemia is related to even worse outcomes than hyponatraemia. Furthermore, preliminary data show an inverse association between serum sodium and interleukin-6 levels, suggesting that hyponatraemia might be used as a surrogate marker for the risk of a cytokine storm and the need for treatment with interleukin antagonists. In conclusion, dysnatraemia is common and carries a poor prognosis in COVID-19 patients, indicating that it may play a future role in risk stratification and individualising therapy.

Free access

Mads R Andersen, Malte P Suppli, Jonatan I Bagger, Mikkel B Christensen, Gina L C Yosten, Filip K Knop, and Asger Lund

In 2008, the first evidence of a new hormone called neuronostatin was published. The hormone was discovered using a bioinformatic method and found to originate from the same preprohormone as somatostatin. This small peptide hormone of 13 amino acids and a C-terminal amidation was soon found to exert pleiotropic physiological effects. In animal studies, neuronostatin has been shown to reduce food intake and delay gastric emptying and gastrointestinal transit. Furthermore, neuronostatin has been shown to affect glucose metabolism by increasing glucagon secretion during situations when glucose concentrations are low. Additionally, neuronostatin has been shown to affect neural tissue and cardiomyocytes by suppressing cardiac contractility. The effects of neuronostatin have not yet been delineated in humans, but if the effects found in animal studies translate to humans it could position neuronostatin as a promising target in the treatment of obesity, hypertension and diabetes. In this review, we describe the discovery of neuronostatin and the current understanding of its physiological role and potential therapeutic applicability.

Open access

Lijuan Sun, Hui Jen Goh, Sanjay Verma, Priya Govindharajulu, Suresh Anand Sadananthan, Navin Michael, Yaligar Jadegoud, Christiani Jeyakumar Henry, S Sendhil Velan, Pei Shan Yeo, Yingshan Lee, Brenda Su Ping Lim, Huiling Liew, Chee Kian Chew, Timothy Peng Lim Quek, Shaikh A K K Abdul Shakoor, Wai Han Hoi, Siew Pang Chan, Daniel Ek Chew, Rinkoo Dalan, and Melvin Khee Shing Leow

Objective

Brown adipose tissue (BAT) controls metabolic rate through thermogenesis. As its regulatory factors during the transition from hyperthyroidism to euthyroidism are not well established, our study investigated the relationships between supraclavicular brown adipose tissue (sBAT) activity and physiological/metabolic changes with changes in thyroid status.

Design

Participants with newly diagnosed Graves’ disease were recruited. A thionamide antithyroid drug (ATD) such as carbimazole (CMZ) or thiamazole (TMZ) was prescribed in every case. All underwent energy expenditure (EE) measurement and supraclavicular infrared thermography (IRT) within a chamber calorimeter, as well as 18F-fluorodeoxyglucose (18F-FDG) positron-emission tomography/magnetic resonance (PET/MR) imaging scanning, with clinical and biochemical parameters measured during hyperthyroidism and repeated in early euthyroidism. PET sBAT mean/maximum standardized uptake value (SUV mean/max), MR supraclavicular fat fraction (sFF) and mean temperature (Tscv) quantified sBAT activity.

Results

Twenty-one (16 female/5 male) participants aged 39.5 ± 2.5 years completed the study. The average duration to attain euthyroidism was 28.6 ± 2.3 weeks. Eight participants were BAT-positive while 13 were BAT-negative. sFF increased with euthyroidism (72.3 ± 1.4% to 76.8 ± 1.4%; P < 0.01), but no changes were observed in PET SUV mean and Tscv. Significant changes in serum-free triiodothyronine (FT3) levels were related to BAT status (interaction P value = 0.04). FT3 concentration at hyperthyroid state was positively associated with sBAT PET SUV mean (r = 0.58, P = 0.01) and resting metabolic rate (RMR) (P < 0.01).

Conclusion

Hyperthyroidism does not consistently lead to a detectable increase in BAT activity. FT3 reduction during the transition to euthyroidism correlated with BAT activity.

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 one-year three-component (cognitive behavioural therapy, diet, 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 one 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 significant favourable effects on all metabolic parameters.

Conclusions

This three-component lifestyle intervention 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

Maria Fleseriu, Dagmar Führer-Sakel, Aart J van der Lely, Laura De Marinis, Thierry Brue, Joli van der Lans-Bussemaker, Judith Hey-Hadavi, Cecilia Camacho-Hubner, Michael P Wajnrajch, Srinivas Rao Valluri, Andrew Anthony Palladino, Roy Gomez, and Roberto Salvatori

Objective

To report the final long-term safety and efficacy analyses of patients with acromegaly treated with pegvisomant from the ACROSTUDY.

Design

Global (15 countries), multicentre, non-interventional study (2004–2017).

Methods

The complete ACROSTUDY cohort comprised patients with acromegaly, who were being treated with pegvisomant (PEGV) prior to the study or at enrolment. The main endpoints were long-term safety (comorbidities, adverse events (AEs), pituitary tumour volumes, liver tests) and efficacy (IGF1 changes).

Results

Patients (n = 2221) were treated with PEGV for a median of 9.3 years (range, 0–20.8 years) and followed up for a median of 7.4 years (range, 0–13.9 years). Before PEGV, 96.3% had received other acromegaly treatments (surgery/radiotherapy/medications). Before PEGV treatment, 87.2% of patients reported comorbidities. During ACROSTUDY, 5567 AEs were reported in 56.5% of patients and of these 613 were considered treatment-related (in 16.5% of patients) and led to drug withdrawal in 1.3%. Pituitary imaging showed a tumour size increase in 7.1% of patients; the majority (71.1%) reported no changes. Abnormal AST or ALT liver tests occurred in 3.2% of patients. IGF1 normalization rate improved over time, increasing from 11.4% at PEGV start to 53.7% at year 1, and reaching 75.4% at year 10 with the use of ≥30 mg PEGV/day in an increasing proportion of patients.

Conclusion

This comprehensive review of the complete cohort in ACROSTUDY confirmed the overall favourable benefit-to-risk profile and high efficacy of PEGV as mono- and combination therapy in patients with an aggressive course/uncontrolled/active acromegaly requiring long-term medical therapy for control.

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Ane Bayona, Patricia Benavent, Alfonso Muriel, Cesar Abuchaibe, Susan C Sharpe, Valentina Tarasova, Bryan McIver, and Pablo Valderrabano

Objective

To determine the proportion of aspirates reclassified into each Bethesda category and to assess the rates of malignancy in each of them on repeat fine-needle aspiration biopsy (RFNA) following an AUS/FLUS diagnosis.

Design

Systematic review and meta-analysis

Methods

On February 2019, Pubmed/MEDLINE, EMBASE, WoS, and the Cochrane Library were searched for articles published from January 1, 2007. All studies published in English describing RFNA outcomes in AUS/FLUS nodules were included. PRISMA and MOOSE guidelines were followed. Five investigators independently assessed the eligibility of the studies. Two investigators extracted summary data and assessed the risk of bias. Data were pooled using a random-effects model. The rate of malignancy was calculated on resected nodules only (upper limit of true value); and considering all unresected nodules were benign (lower limit of true value). The protocol was registered in PROSPERO (CRD42019123114).

Results

Of 2937 retrieved studies, 27 were eligible. The meta-analysis was conducted on summary data of 3932 AUS/FLUS thyroid nodules with RFNA. RFNA cytology would reclassify into categories I through VI of Bethesda: 4% (3%, 5%), 48% (43%, 54%), 26% (20%, 32%), 4% (3%, 6%), 5% (3%, 6%), and 2% (1%, 2%) of AUS/FLUS nodules. Malignancy rates of resected nodules were 24% (9%, 38%), 4% (1%, 7%), 40% (28%, 52%), 37% (27%, 47%), 79% (69%, 90%), and 99% (95%, 100%) for categories I through VI of Bethesda. There was high heterogeneity in these data.

Conclusions

RFNA reclassified two-thirds of the AUS/FLUS specimens into a more definitive cytological category, with a benign call rate of nearly 50% and a negative predictive value greater than 96%.