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Jens Otto L. Jorgensen, Gudmundur Johannsson, and Ariel Barkan

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

Objective: To examine factors associated with the reported incidence of pheochromocytoma and paraganglioma across studies.

Methods: The annual incidence of pheochromocytoma and paraganglioma was examined according to geographic altitude and year of detection.

Results: Although higher altitude and later year of detection were associated with a higher incidence of disease, these variables only accounted for a small degree of the between-study differences observed. There were large amounts of residual statistical heterogeneity after meta-regression. Other factors such as variable disease detection methods, data sources, and study quality were likely more important sources of statistical heterogeneity.

Conclusion: Variations in the incidence of pheochromocytoma and paraganglioma between studies were only partially explained by elevation and time of detection. Other factors, such as differences in study quality and the presence of clinical heterogeneity, likely impacted estimates of incidence.

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E M Ryhänen, A M Koski, E Löyttyniemi, M J Välimäki, U Kiviniemi, and C Schalin-Jäntti

Objective

In primary hyperparathyroidism (PHPT) with osteoporosis, bone mineral density (BMD) improves after parathyroidectomy. It is unclear whether combining surgery with postoperative bisphosphonate treatment can further improve bone health.

Design

This randomized, placebo-controlled study compared the effects of surgery alone and surgery combined with zoledronic acid on bone metabolism in PHPT with osteoporosis.

Methods

Fifty-six patients (f/m 47/9, mean age 68.4 years) with PHPT and osteoporosis were randomized 1–3 months after parathyroidectomy to receive a 2-year treatment of zoledronic acid or placebo. Dual-energy X-ray absorptiometry (DXA) and bone turnover markers (N-terminal propeptide of type 1 procollagen, C-terminal telopeptide of type 1 collagen, and alkaline phosphatase) were measured annually during the 2-year follow-up.

Results

Two years after parathyroidectomy, BMD was significantly higher in the zoledronic acid (ZOL) group compared with the placebo (PBO) group at the femoral neck (P = 0.045 for Z-score) and lumbar spine (P = 0.039 and 0.017 for T- and Z-scores, respectively). Bone turnover markers were significantly lower in the ZOL group (P < 0.001 for all markers). Of the 18 patients who had received bisphosphonates for >1 year before surgery, BMD improved significantly in the ZOL group both in the femoral neck and lumbar spine (n = 10; all P < 0.001–0.01), but in the PBO group, only in the lumbar spine (n = 8, P = 0.03), (P = 0.08–0.95 for between-group changes).

Conclusion

BMD increases after parathyroidectomy both with and without zoledronic acid but the increase is significantly higher with postoperative zoledronic acid.

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C A Lebbink, T P Ringers, A Y N Schouten-van Meeteren, L van Iersel, S C Clement, A M Boot, H L Claahsen-van der Grinten, G O Janssens, D G van Vuurden, E M Michiels, K S Han, A S P van Trotsenburg, W P Vandertop, L C M Kremer, and H M van Santen

Objective

Childhood brain tumor survivors (CBTS) are at risk to develop hypothalamic–pituitary (HP) dysfunction (HPD). The risk for HPD may vary between different age groups due to maturation of the brain and differences in oncologic treatment protocols. Specific studies on HPD in infant brain tumor survivors (infant-BTS, 0–1 years at diagnosis) or toddler brain tumor survivors (toddler-BTS, ≥1–3 years) have not been performed.

Patients and methods

A retrospective nationwide cohort study in CBTS was performed. Prevalence and risk factors for HPD were compared between infant-, toddler-, and older-BTS. Subgroup analysis was performed for all non-irradiated CBTS (n = 460).

Results

In total, 718 CBTS were included, with a median follow-up time of 7.9 years. Overall, despite the less frequent use of radiotherapy (RT) in infants, no differences in the prevalence of HPD were found between the three groups. RT (OR: 16.44; 95% CI: 8.93–30.27), suprasellar tumor location (OR: 44.76; 95% CI: 19.00–105.49), and younger age (OR: 1.11; 95% CI: 1.05–1.18) were associated with HP dysfunction. Infant-BTS and toddler-BTS showed more weight gain (P  < 0.0001) and smaller height SDS (P  = 0.001) during follow-up. In non-irradiated CBTS, infant-BTS and toddler-BTS were significantly more frequently diagnosed with TSH-, ACTH-, and ADH deficiency, compared to older-BTS.

Conclusion

Infant and toddler brain tumor survivors seem to be more vulnerable to develop HP dysfunction than older children. These results emphasize the importance of special infant and toddler brain tumor treatment protocols and the need for endocrine surveillance in children treated for a brain tumor at a young age.

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Guillaume Treiber, Ania Flaus Furmaniuk, Alice Guilleux, Samir Medjane, Oriane Bonfanti, Stéphane Schneebeli, Céline Bernard, Nathalie Le-Moullec, Faouzi Bakiri, Maryse Pholsena, Olivier Rollot, Camille Vatier, Eric Jarlet, Isabelle Jéru, Olivier Lascols, Françoise Darcel, Bhoopendrasing Domun, Adrien Venault, Sophie Venault, Marie-Line Jacquemont, Berenice Doray, Jean-Christophe Maiza, Muriel Cogne, Corinne Vigouroux, and Estelle Nobécourt

Aims

LMNA-linked familial partial lipodystrophy type 2 (FPLD2) leads to insulin resistance-associated metabolic complications and cardiovascular diseases. We aimed to characterise the disease phenotype in a cohort of patients carrying an LMNA founder variant.

Methods

We collected clinical and biological data from patients carrying the monoallelic or biallelic LMNA p.(Thr655Asnfs*49) variant (n =  65 and 13, respectively) and 19 non-affected relative controls followed-up in Reunion Island Lipodystrophy Competence Centre, France.

Results

Two-thirds of patients with FPLD2 (n = 51) and one-third of controls (n = 6) displayed lipodystrophy and/or lean or android morphotype (P  = 0.02). Although age and BMI were not statistically different between the two groups, the insulin resistance index (median HOMA-IR: 3.7 vs 1.5, P  = 0.001), and the prevalence of diabetes, dyslipidaemia, and non-alcoholic fatty liver disease were much higher in patients with FPLD2 (51.3 vs 15.8%, 83.3 vs 42.1%, and 83.1 vs 33.3% (all P ≤ 0.01), respectively). Atherosclerosis tended to be more frequent in patients with FPLD2 (P  = 0.07). Compared to heterozygous, homozygous patients displayed more severe lipoatrophy and metabolic alterations (lower BMI, fat mass, leptin and adiponectin, and higher triglycerides P ≤ 0.03) and tended to develop diabetes more frequently, and earlier (P  = 0.09). Dilated cardiomyopathy and/or rhythm/conduction disturbances were the hallmark of the disease in homozygous patients, leading to death in four cases.

Conclusions

The level of expression of the LMNA ‘Reunionese’ variant determines the severity of both lipoatrophy and metabolic complications. It also modulates the cardiac phenotype, from atherosclerosis to severe cardiomyopathy, highlighting the need for careful cardiac follow-up in affected patients.

Open access

Yasir S Elhassan, Barbara Altieri, Sarah Berhane, Deborah Cosentini, Anna Calabrese, Magalie Haissaguerre, Darko Kastelan, Maria Candida Barisson Villares Fragoso, Jerome Bertherat, Abir Al Ghuzlan, H.r Haak, Maria Boudina, Letizia Canu, Paola Loli, Mark Sherlock, Otilia Kimpel, Marta Laganà, Alice J Sitch, Matthias Kroiss, Wiebke Arlt, Massimo Terzolo, Alfredo Berruti, Jon Deeks, Rosella Libe, Martin Fassnacht, and Cristina L Ronchi

Objective: Adrenocortical carcinoma (ACC) has an aggressive but variable clinical course. Prognostic stratification based on ENSAT tumour 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: 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 (R)-status (R0=0; RX=1; R1=2; R2=3), Age (<50yr=0; ≥50yr=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 C-index and Royston-Sauerbrei’s R2D 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, R2D=0.30, and C-index=0.79, R2D=0.45, respectively, all P<0.01 vs 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).

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Betina Biagetti, Silvana Sarria-Estrada, Yiken Karelys Ng-Wong, Elena Martinez-Saez, Anna Casteràs, Esteban Cordero Asanza, Irene Hernandez, Marina Giralt-Arnaiz, and Rafael Simò

Objective

Transsphenoidal surgery (TSS) is mainly indicated in prolactinomas when dopamine agonist treatment fails. However, there is no established early predictor of cabergoline (CBG) response. The present study was aimed to identify predictors of CBG resistance in order to select patients who may benefit from early TSS.

Design

Retrospective longitudinal study.

Methods

We reviewed the medical record of patients diagnosed with prolactinoma after 2010. Inclusion criteria: macroprolactinomas under CBG treatment with serial prolactin levels and MRI before treatment and 3 and 12 months afterwards. The main outcome was tumour size shrinkage ≥ 50% (using the two largest diameters in sagittal view) after 12 months of CBG (TS_50). The capacity of the most important clinical and biochemical variables in predicting the main outcome was examined.

Results

A total of 185 prolactinomas where included: 124 (67.0%) were microadenomas and 61 (33.0%) were macroadenomas of which 27 patients meet de inclusion criteria; median age (42.5 years; (IQR: 28.0)). The median follow-up was (67.5 months; (IQR: 30.2)). Ten patients (37.0%) underwent surgery after more than 1 year of CBG. The volume reduction at the first MRI (3–4 months) was the unique valuable predictor: (OR: 1.16 (95% CI: 1.02–1.32)) of TS_50. A tumour volume shrinkage of ≥ 30% in the first 3–4 months of CBG therapy predicts TS_50 with an AUC (0.95 (CI: 0.76–0.99)).

Conclusion

Tumour shrinkage in the first 3–4 months after starting treatment with CBG is a good tool for predicting the long-term response and can help clinicians to take more appropriated and personalized decisions.

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Maria Cristina Vigone, Rita Ortolano, Gaia Vincenzi, Clara Pozzi, Micol Ratti, Valentina Assirelli, Sofia Vissani, Paolo Cavarzere, Alessandro Mussa, Roberto Gastaldi, Raffaella Di Mase, Mariacarolina Salerno, Maria Elisabeth Street, Jessica Trombatore, Giovanna Weber, and Alessandra Cassio

Objective. Oral solution and tablet formulations of Levo-Thyroxine (L-T4) are both used in the treatment of Congenital Hypothyroidism (CH). However, few studies and with a limited follow-up period have been published comparing these two formulations in children.

Design. The aim of this multicenter study was to compare the effectiveness of L-T4 oral solution (with ethanol as excipient) and tablet formulation in children with CH up to 3 years of age.

Methods. Children diagnosed with CH between 2006 and 2015 were enrolled and divided into two groups according to the L-T4 formulation used: solution in drops (Group D) or tablets (Group T). Auxological parameters, TSH and FT4 values and L-T4 dose were collected at diagnosis and at 15 days, 1, 3, 6, 12, 24 and 36 months of treatment. The Developmental Quotient at 1 and 3 years of age was evaluated using Griffiths’ Scale.

Results. 254 children were enrolled. 117 were treated with solution and 137 with tablets. Auxological parameters, dose and thyroid function values at diagnosis, 3, 6, 12, 24, 36 months were not significantly different. TSH at 15 days (p=0.002) and 1 month (p=0.009) was significantly reduced in group D. At 2-year follow-up, median TSH was significantly lower in group T (p=0.03). No statistical difference was detected between the median Developmental Quotient, however group D showed lower values in the language subscale at 12 months and in eye-hand coordination at 36 months.

Conclusions. Both therapeutic strategies are effective on treatment of CH. A higher risk of overtreatment in the first months of therapy seems to be associated with oral solution L-T4; therefore, a different strategy should be considered when starting and adjusting the dose. No negative effects in cognitive development were observed. The data obtained are encouraging but long-term follow-up is needed.

Open access

Giorgia Grassi, Iacopo Chiodini, Serena Palmieri, Elisa Cairoli, Maura Arosio, and Cristina Eller-Vainicher

Objective

Several studies showed the occurrence of vertebral fracture (VFx) in patients discontinuing denosumab (Dmab), suggesting the need of bisphosphonate (BPs) therapy to mitigate this VFx risk increase. However, the morphometric VFx (morphoVFx) incidence after Dmab discontinuation and the BPs effect on VFx risk in this setting are still a matter of debate.

Design

Retrospective, monocentric study.

Methods

In 120 patients (111 females) discontinuing Dmab, 19 have not been treated (non-treated group: 16 females, aged 63.5 ± 15.0 years) and 101 patients have been treated (treated group: 95 females, aged 70.0 ± 10.6 years) with BPs (28 alendronate (ALN); 73 zoledronate ZOL), single infusion), respectively. We evaluated the incidence of both clinical VFx and morphoVFx in treated group and non-treated group.

Results

Patients in treated group showed a 5.5% VFx incidence (n = 6, three clinical, three morpho VFx), which was anyway lower than non-treated group patients (n = 4, 21.1%, four clinical, three multiple, P = 0.029), despite a comparable FRAX score at the time of Dmab initiation. The logistic regression analysis showed that the VFx incidence was independently associated with the lack of BPs treatment (odds ratio: 13.9, 95% CI 1.7–111.1, P = 0.014), but not with the number of Dmab injections, age, duration of BPs before Dmab initiation, the BMD at Dmab withdrawal, and the prevalence of VFx at Dmab withdrawal.

Conclusions

The Dmab withdrawal is associated with an increased risk of clinical but not morphometric VFx. Therapy with ALN or with a single ZOL treatment is partially effective in reducing the increased VFx risk after Dmab withdrawal.

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Simone Kiel, Till Ittermann, Jette Steinbach, Henry Völzke, Jean-François Chenot, and Aniela Angelow

Objective

Thyroid disorders are common. Information on the long-term progression of morphologic disorders is scarce. The aim of this study was to describe the course of thyroid nodules and volume over a period of up to 10 years.

Design and Methods

Data from the population-based Study of Health in Pomerania were used for longitudinal analysis of 10 years, on average. Billing data from the Association of Statutory Health Insurance Physicians were matched to the data to exclude participants with thyroid surgery, radioiodine therapy and thyroid carcinoma. Changes in the number and size of thyroid nodules and thyroid volume were observed using ultrasound.

Results

A total of 1270 participants were included (53% female, median age at baseline 51 years). The proportion of subjects with at least one thyroid nodule increased from 34.9 to 47.5% after 10 years. The majority of participants had an unchanged or reduced number of nodules. About one-quarter had at least one nodule of size ≥ 1 cm. The proportion of participants with goitre increased from 35 to 37% after 10 years. Nevertheless, individual thyroid volume increased by < 1 mL (95% CI: 0.38–3.66) after adjusting for age and BMI irrespective of thyroid medication.

Conclusion

Thyroid nodules and goitre are common. After 10 years, the number of nodules did not increase in about 70% of people. This proportion did not differ substantially when excluding people with thyroid medication. Thyroid volume increased slightly over the follow-up period. These changes do not seem clinically relevant. Our results support a more restrictive approach regarding follow-up diagnostics in asymptomatic patients with thyroid nodules or minimally enlarged thyroid.