Journal of the Endocrine Society最新文献

Context: Vosoritide is the first approved targeted therapy for achondroplasia (ACH) based on increased annualized growth velocity in clinical trials. The aim of our project was an assessment of the real-world setting and treatment with vosoritide.

Design: This was a 12-month, retrospective observational study on an inception cohort of 34 patients with ACH treated with vosoritide.

Patients and methods: Thirty-four patients with ACH (22 males; aged 2.8 to 15.3 years at treatment initiation) who received vosoritide treatment for at least 12 months at a specialized clinic for skeletal dysplasia in childhood were included in the analysis. Auxological measurements at baseline and after 12 months of therapy were converted into disease-specific (ACH) and general population [Centers for Disease Control and Prevention (CDC)] z-scores. Physical function assessed by a 6-minute walk test was converted into z-scores and compared to an unaffected reference cohort.

Results: After 12 months of treatment, both ACH and CDC height z-scores showed significant increases, with mean changes (mean ± SD) of 0.52 ± 0.35 and 0.38 ± 0.44, respectively (both P < .0001). The annualized growth velocity exceeded reference values for untreated children with ACH. No significant changes were observed in body mass index, upper to lower body segment ratio (sitting height/height), or head circumference. The 6-minute walking distance improved, with z-scores increasing from -2.00 ± 1.12 to -1.39 ± 1.23 (P = .0215).

Conclusion: In a real-world setting, children with ACH showed significant improvements in growth and physical function after 12 months of treatment with vosoritide.

Long-acting growth hormone (LAGH) has the potential to improve adherence and outcomes over daily somatropin in growth hormone deficiency (GHD). Whereas daily somatropin products are molecularly identical, LAGHs are molecularly distinct; additional moieties or mechanisms that prolong LAGH action confer unique pharmacodynamic/pharmacokinetic properties that could affect efficacy and safety. Only one LAGH available in the United States and Europe (lonapegsomatropin) delivers unmodified somatropin. With no head-to-head clinical trials of LAGHs available, this systematic literature review and network meta-analysis were conducted to compare the relative efficacy and safety of LAGHs in pediatric GHD. Five trials were eligible for inclusion in a Bayesian network meta-analysis; 3 contributed to the base case network, including 3 LAGHs (lonapegsomatropin, somapacitan, and somatrogon) and daily somatropin. Treatment with lonapegsomatropin was associated with statistically significantly higher annualized height velocity and change from baseline in height SD score (SDS) at week 52 compared to daily somatropin and somapacitan; no other significant differences in these outcomes were found. The change from baseline in average insulin-like growth factor-1 (IGF-1) SDS at week 52 was significantly higher for somatrogon vs all comparators and for lonapegsomatropin vs daily somatropin and somapacitan; average IGF-1 SDS was within normal range in all trials. No significant differences were seen in progression in bone age-to-chronological age ratio or serious adverse events (SAEs). Sensitivity analyses were consistent with the base case. In this network meta-analysis, lonapegsomatropin was the only LAGH associated with better growth outcomes. No significant differences were detected regarding SAEs; other safety outcomes could not be analyzed.

Hypothyroidism is a frequent disease, and oral levothyroxine is the mainstay of its treatment. However, more than 15% of levothyroxine-treated patients fail to achieve the recommended serum TSH level, and "refractory hypothyroidism" is due to either malabsorption, increased metabolism of thyroxine, or nonadherence to treatment. A levothyroxine absorption test must be used to differentiate true malabsorption from nonadherence or pseudo-malabsorption. We analyzed 166 levothyroxine absorption tests in 143 hypothyroid patients (109 women, mean age 43 ± 1 years) treated with oral levothyroxine. Despite a daily dose of 3.26 ± 0.09 g/kg/day, mean serum TSH concentration was 25.7 ± 3.7 mU/L. "Refractory hypothyroidism" was in the context of gastritis (24%), Helicobacter pylori infection (18%), drug interference with levothyroxine absorption (15.6%), nonadherence to treatment (10%), celiac disease (2.5%), or bariatric surgery (1.2%). After an overnight fast, patients orally took their daily dose of levothyroxine (220 ± 6 g), and blood samples were drawn before levothyroxine intake and every 2 hours for 24 hours. After levothyroxine intake, the mean total (basal = 7.64 ± 0.26 g/dL, peak 9.41 ± 0.28 g/dL), and free (basal = 12.58 ± 0.42 pg/mL, peak 15.77 ± 0.51 pg/mL) T4 levels increased (P < .001), total and free T4 peaks were observed at 4.2 ± 0.23 and 4.30 ± 9.27 hours, respectively. Levothyroxine absorption tests were well tolerated. In conclusion, in most patients with "refractory hypothyroidism," this clinical study revealed that the levothyroxine absorption test can be achieved via the absorption of the daily dosage of levothyroxine, and the evaluation of total or free T4 concentrations over 4- or 6-hour follow-up. The test is well tolerated without cardiovascular adverse events.

Meta-analyses of clinical trials have shown that vitamin D lowers the risk of progression from prediabetes to diabetes. Less is known about whether vitamin D promotes regression to normal glucose regulation (NGR). We conducted a systematic review and meta-analysis of clinical trials with vitamin D in adults with prediabetes that have reported on the outcome of regression to NGR. We searched Medline (through PubMed), Embase, and the trial registry ClinicalTrials.gov from inception to July 3, 2024, for randomized, controlled trials of at least 6 months' duration that reported on the effects of oral vitamin D supplementation on NGR in adults with prediabetes. The search identified 10 eligible trials, involving 4478 participants. The baseline characteristics of the study cohorts were: mean age range 20 to 74 years, mean body mass index range 24 to 38, mean blood 25-hydroxyvitamin D range 12 to 28 ng/mL. The median study duration range was 0.5 to 5 years. Across trials, 416 of 2253 (18.5%) participants randomly assigned to vitamin D reached NGR vs 312 of 2225 (14.0%) participants randomly assigned to placebo. In all trials, the relative risk of regression to NGR favored the vitamin D group, ranging from 1.09 to 12.6. After combining data, the summary relative risk of regression to NGR for vitamin D vs placebo was 1.27 (95% CI, 1.12-1.45), with no heterogeneity (I² = 1%). Sensitivity analyses did not change the result. Participant-level variables were not available, limiting meaningful subgroup analyses. In conclusion, vitamin D increases the likelihood of regression to normoglycemia in adults with prediabetes.

Context: Inflammatory markers may serve as potential biomarkers in predicting prognosis in patients with distant metastasis differentiated thyroid cancer (DM-DTC).

Objective: This study aimed to evaluate the predictive ability of inflammatory markers and clinicopathological features for disease progression (PD) in patients with DM-DTC.

Methods: A retrospective analysis was conducted on 230 DM-DTC patients from May 2016 to January 2022. Patients were divided into a training set and a validation set at a 7:3 ratio. Inflammatory markers were obtained within 1 week before the last ¹³¹I treatment. The primary outcome was progression-free survival (PFS). Univariable and multivariable Cox proportional hazards models identified significant prognostic factors, and a nomogram based on inflammatory markers and clinicopathological features was constructed and validated using R software.

Results: Multivariable Cox regression analysis showed that age (hazard ratio [HR] = 2.191; 95% CI, 1.387-3.462), histological type (HR = 2.030; 95% CI, 1.216-3.389), distant metastatic site (HR = 3.379; 95% CI, 1.832-6.233), T stage (HR = 6.061; 95% CI, 2.469-14.925), and LMR (HR = 2.050; 95% CI, 1.194-3.519) were identified as independent risk factors for the progression of DM-DTC. A predictive nomogram was constructed to estimate the probability of DM-DTC progression. The C-index of the PFS model was calculated to be 0.775 (0.749-0.802) for the training set and 0.731 (95% CI, 0.686-0.775) for the validation set. The calibration curve of the validation set closely approached the reference line. The decision curve analysis indicated that when the risk threshold was greater than 0.2, this nomogram model provided clinical net benefit.

Conclusion: The study identified significant inflammatory markers and clinical factors for predicting PD in DM-DTC patients, providing a robust prognostic model with potential clinical application.

Anaplastic thyroid cancer (ATC) is the rarest and most aggressive form of thyroid cancer, known for its highly variable nature and poor prognosis, primarily due to the lack of effective treatments. While conventional therapies have had limited success, there remains an urgent need for novel therapeutic approaches to combat this disease. ATC tumors are resistant to the standard radioiodine therapy because they lack the sodium/iodide symporter (NIS), which is necessary for iodine uptake. However, recent advances in theranostics targeting cell surface markers have opened new avenues for treating ATC. We used the PubMed database and Google search engine to identify relevant articles using combinations of specific keywords related to the topic of interest, focusing on each surface marker. This review explores multiple surface markers identified in ATC and their promising roles for delivering therapeutic agents into tumors, inducing cell death. Several promising markers, including prostate-specific membrane antigen, vitamin D receptor, IGF-1 receptor, programmed death-ligand 1, epidermal growth factor receptor, and L-type amino acid transporter 1 (LAT-1), have been found in ATC and could serve as effective targets for delivering therapeutic agents to tumors, inducing cell death. Restoring NIS expression is also explored as a potential therapy for ATC. Additionally, boron neutron capture therapy, which utilizes LAT-1 expression, is highlighted as a future therapeutic option due to its ability to selectively target tumor cells while minimizing damage to surrounding healthy tissue. These strategies offer the potential to overcome many of the challenges associated with ATC, improving patient outcomes and overall survival.

Context: The lack of a severity definition and standardized GH cutoff level for GH deficiency (GHD) diagnosis in children leads to ambiguity in the interpretation of GH stimulation tests and treatment recommendations.

Objective: To investigate treatment response differences among children with GHD treated with daily GH (somatropin) (year 1) or once-weekly somapacitan (years 1 and 2) based on GH peak concentrations assessed at diagnosis.

Methods: This was a subgroup analysis of 200 patients with GHD aged ≥2.5 years participating in the REAL4 randomized, phase 3 trial. Height velocity (HV; cm/year) and changes in height SD score (SDS) and IGF-I SDS from baseline were compared for 3 GH peak groups: ≤ 3, >3 to <7, and ≥7 to ≤10 μg/L.

Results: The ≤3 μg/L GH peak concentration group had the greatest HV at weeks 52 and 104. Mean change in height SDS ranged from 1.89 to 1.59, 1.17 to 1.06, and 0.92 to 1.07 at week 52 and 2.79 to 2.30, 1.64 to 1.54, and 1.33 to 1.51 at week 104 for the 2 treatment groups across the 3 GH peak concentrations, respectively. Mean change in IGF-I SDS ranged from 3.13 to 3.01, 2.11 to 1.96, and 1.87 to 2.26 at week 52 and from 2.81 to 2.11, 1.85 to 1.62, and 1.28 to 1.71 at week 104 for the 3 GH peak concentrations.

Conclusion: Patients with GHD in the ≤3 μg/L GH peak concentration group had greater HV and greater changes in height SDS and IGF-I SDS from baseline.

Context: Cells derived from neural crest populate several organs. A particular precursor cell, sympathogonia, gives rise to pheochromoblasts and neuroblasts. Due to common origin, tumors originating from pheochromoblasts, such as pheochromocytoma (PHEO) and paraganglioma (PGL), may rarely coexist with ganglioneuroma (GN).

Objective: We evaluated clinical, biochemical, and radiological characteristics of patients with composite PHEO/PGL and GN (PPGL-GN) and compared them to patients with PHEO.

Methods: In this retrospective, dual-center, observational, case-control study, we identified patients with PPGL-GN. Similarly, we identified a control group of patients with PHEO who underwent laparoscopic adrenalectomy. All diagnoses were confirmed on histology. Descriptive statistics were used to summarize demographic and clinical data.

Results: We identified 19 consecutive patients with PPGL-GN and 86 patients with PHEO. Patients with PPGL-GN, compared to those with PHEO, were younger (aged 46.0 vs 50.8 years; P = .03), had higher rate of underlying genetic disorders (47.4% vs 23.2%; P = .03), and had fewer functioning tumors (89.5% vs 100%; P = .002). There was no difference in the median radiological tumor size or the precontrast computed tomography density. Disease recurrence (at another site) was noted in 15.8% of PPGL-GN patients who had a median follow up of 14.6 months, as opposed to no disease recurrence in patients with PHEO. There was no documented recurrence at the tumor bed and no metastasis in both groups.

Conclusion: Patients with PPGL-GN were younger and had a higher occurrence of underlying genetic disorders compared to PHEO. However, PPGL-GN was radiologically indistinguishable from PHEO. The higher observed disease recurrence of PPGL-GN reinforces vigilant postoperative follow-up.