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Frederic Castinetti, Jean Baptiste De Freminville, Carole Guerin, Erika Cornu, Gabrielle Sarlon, and Laurence Amar

The question of systematic use of a pharmacological treatment before surgery in patients diagnosed with pheochromocytoma and paraganglioma (PPGL) remains highly controversial. While recent guidelines suggest that this should be used in all patients, some experienced teams consider it unnecessary in some cases, provided the surgery is performed in a dedicated center that has expert endocrinologists, cardiologists, surgeons, and anesthetists. This controversy is aimed at shedding light on the potential benefits and risks of such a treatment, focusing specifically on alpha blockers which are considered as the first-line medical treatments in patients with PPGL. After discussing the rationale for alpha blockers, hemodynamic instability, tolerance and acute cardiac complications will then be discussed in the first part of the manuscript, defending a systematic use. The second section will focus on blood pressure control, tolerance of alpha blockers and also the management of normotensive PPGL, examining the daily risks of PPGL, and arguing against the systematic use of a preoperative pharmacological treatment before surgery. Finally we will discuss the concept of expert centers and define the patients in whom the risk/benefit profile would favor use of this preoperative treatment.

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Mirko Parasiliti-Caprino, Fabio Bioletto, Chiara Lopez, Francesca Maletta, Marina Caputo, Valentina Gasco, Antonio La Grotta, Paolo Limone, Giorgio Borretta, Marco Volante, Mauro Papotti, Massimo Terzolo, Mario Morino, Barbara Pasini, Franco Veglio, Ezio Ghigo, Emanuela Arvat, and Mauro Maccario

Objective

Various features have been identified as predictors of relapse after complete resection of pheochromocytoma, but a comprehensive multivariable model for recurrence risk prediction is lacking. The aim of this study was to develop and internally validate an integrated predictive model for post-surgical recurrence of pheochromocytoma.

Methods

The present research retrospectively enrolled 177 patients affected by pheochromocytoma and submitted to radical surgery from 1990 to 2016, in nine referral centers for adrenal diseases. Cox regression analysis was adopted for model development, and a bootstrapping procedure was used for internal validation.

Results

Variables independently associated with recurrence were tumor size (hazard ratio (HR): 1.01, 95% CI: 1.00–1.02), positive genetic testing (HR: 5.14, 95% CI: 2.10–12.55), age (HR: 0.97, 95% CI: 0.94–0.99), and Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) (HR: 1.16, 95% CI: 1.04–1.29). The predictive performance of the overall model, evaluated by Somers’ D, was equal to 0.594, and was significantly higher than the ones of any single predictor alone (P  = 0.002 compared to tumor size; P  = 0.004 compared to genetic testing; P  = 0.048 compared to age; P  = 0.006 compared to PASS). Internal validation by bootstrapping techniques estimated an optimistic bias of 6.3%, which reassured about a small tendency towards overfit.

Conclusions

We proposed a multivariable model for the prediction of post-surgical recurrence of pheochromocytoma, derived by the integration of genetic, histopathological, and clinical data. This predictive tool may be of value for a comprehensive tailoring of post-surgical follow-up in radically operated pheochromocytoma patients.

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Evert F S van Velsen, Robin P Peeters, Merel T Stegenga, Uwe Mäder, Christoph Reiners, F J van Kemenade, Tessa M van Ginhoven, W Edward Visser, and Frederik Anton Verburg

Background

The joint Union International Contre le Cancer and American Joint Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-specific survival (DSS).

Methods

We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV.

Results

We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small.

Conclusions

The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although these two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable.

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

Objective

To evaluate the effect of a new care organization 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 pediatric services, personalizing 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

Two hundred two 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 vs 9 with the intervention (P  = 0.49). The percentage of honored consultation among those planned during 24 months was higher with intervention (P  = 0.0065). Patient satisfaction, physician trust, and 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 did not differ significantly, but indicators of a steadier follow-up were increased and the intervention appeared to be cost-effective.

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Sandeep Dhindsa, Husam Ghanim, Todd Jenkins, Thomas H Inge, Carroll M Harmon, Amit Ghoshal, Zengru Wu, Michael J McPhaul, Farid Saad, and Paresh Dandona

Objective

Obesity in adolescent males is associated with the lowering of total and free testosterone concentrations. Weight loss may increase testosterone concentrations.

Design and methods

We evaluated the changes in sex hormones following bariatric surgery in 34 males (age range: 14.6–19.8 years) with obesity. These participants were part of a prospective multicenter study, Teen-Longitudinal Assessment of Bariatric Surgery. The participants were followed up for 5 years after surgery. Total testosterone, total estradiol, luteinizing hormone, follicle-stimulating hormone, sex hormone-binding globulin, C-reactive protein, insulin and glucose were measured at baseline, 6 months and annually thereafter. Free testosterone, free estradiol and HOMA2-IR were calculated.

Results

Study participants lost one-third of their body weight after bariatric surgery, with maximum weight loss achieved at 24 months for most participants. Free testosterone increased from 0.17 (95% CI: 0.13 to 0.20) at baseline to 0.34 (95% CI: 0.30 to 0.38) and 0.27 nmol/L (95% CI: 0.23 to 0.32) at 2 and 5 years (P  < 0.001 for both), respectively. Total testosterone increased from 6.7 (95% CI: 4.7 to 8.8) at baseline to 17.6 (95% CI: 15.3 to 19.9) and 13.8 (95% CI: 11.0 to 16.5) nmol/L at 2 and 5 years (P  < 0.001), respectively. Prior to surgery, 73% of the participants had subnormal free testosterone (<0.23 nmol/L). After 2 and 5 years, only 20 and 33%, respectively, had subnormal free testosterone concentrations. Weight regain was related to a fall in free testosterone concentrations.

Conclusions

Bariatric surgery led to a robust increase in testosterone concentrations in adolescent males with severe obesity. Participants who regained weight had a decline in their testosterone concentrations.

Open access

Renato Cozzi, Maria Rosaria Ambrosio, Roberto Attanasio, Claudia Battista, Alessandro Bozzao, Marco Caputo, Enrica Ciccarelli, Laura De Marinis, Ernesto De Menis, Marco Faustini Fustini, Franco Grimaldi, Andrea Lania, Giovanni Lasio, Francesco Logoluso, Marco Losa, Pietro Maffei, Davide Milani, Maurizio Poggi, Michele Zini, Laurence Katznelson, Anton Luger, Catalina Poiana, and AME

Prolactinomas are the most frequent pituitary adenomas. Prolactinoma may occur in different clinical settings and always require an individually tailored approach. This is the reason why a panel of Italian neuroendocrine experts was charged with the task to provide indications for the diagnostic and therapeutic approaches that can be easily applied in different contexts. The document provides 15 recommendations for diagnosis and 54 recommendations for treatment, issued according to the GRADE system. The level of agreement among panel members was formally evaluated by RAND-UCLA methodology. In the last century, prolactinomas represented the paradigm of pituitary tumors for which the development of highly effective drugs obtained the best results, allowing to avoid neurosurgery in most cases. The impressive improvement of neurosurgical endoscopic techniques allows a far better definition of the tumoral tissue during surgery and the remission of endocrine symptoms in many patients with pituitary tumors. Consequently, this refinement of neurosurgery is changing the therapeutic strategy in prolactinomas, allowing the definitive cure of some patients with permanent discontinuation of medical therapy.

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Steinunn Arnardóttir, Jacob Järås, Pia Burman, Katarina Berinder, Per Dahlqvist, Eva Marie Erfurth, Charlotte Höybye, Karin Larsson, Oskar Ragnarsson, Bertil Ekman, and Britt Edén Engström

Objective

To describe the treatment and long-term outcomes of patients with acromegaly from all healthcare regions in Sweden.

Design and methods

Analysis of prospectively reported data from the Swedish Pituitary Register of 698 patients (51% females) with acromegaly diagnosed from 1991 to 2011. The latest clinical follow-up date was December 2012, while mortality data were collected for 28.5 years until June 2019.

Results

The annual incidence was 3.7/million; 71% of patients had a macroadenoma, 18% had visual field defects, and 25% had at least one pituitary hormone deficiency. Eighty-two percent had pituitary surgery, 10% radiotherapy, and 39% medical treatment. At the 5- and 10-year follow-ups, insulin-like growth factor 1 levels were within the reference range in 69 and 78% of patients, respectively. In linear regression, the proportion of patients with biochemical control including adjuvant therapy at 10 years follow-up increased over time by 1.23% per year. The standardized mortality ratio (SMR) (95% CI) for all patients was 1.29 (1.11–1.49). For patients with biochemical control at the latest follow-up, SMR was not increased, neither among patients diagnosed between 1991 and 2000, SMR: 1.06 (0.85–1.33) nor between 2001 and2011, SMR: 0.87 (0.61–1.24). In contrast, non-controlled patients at the latest follow-up from both decades had elevated SMR, 1.90 (1.33–2.72) and 1.98 (1.24–3.14), respectively.

Conclusions

The proportion of patients with biochemical control increased over time. Patients with biochemically controlled acromegaly have normal life expectancy, while non-controlled patients still have increased mortality. The high rate of macroadenomas and unchanged age at diagnosis illustrates the need for improvements in the management of patients with acromegaly.

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 non-alcoholic fatty liver disease (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 ten 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 s.c. adipose tissue FA metabolism and function, along with the plasma metabolome, was investigated.

Results

Twelve weeks of 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 s.c. 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 FA oxidation.

Open access

Lucie Canaff, Vito Guarnieri, Yoojung Kim, Betty Y L Wong, Alexis Nolin-Lapalme, David E C Cole, Salvatore Minisola, Cristina Eller-Vainicher, Filomena Cetani, Andrea Repaci, Daniela Turchetti, Sabrina Corbetta, Alfredo Scillitani, and David Goltzman

Objective

The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma.

Design

We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants.

Methods

Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses.

Results

A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter.

Conclusions

We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.