The incidence of papillary thyroid carcinoma (PTC) has increased over recent decades. This apparent epidemic has been attributed to the overdiagnosis of small PTC ≤10 mm in diameter (papillary ...thyroid microcarcinoma PTMC) incidentally detected on imaging for unrelated presentations. Although most PTMCs follow an indolent disease course, there is a small but significant proportion of cases that display more biologically aggressive features such as early metastasis and lymph node involvement. Management of PTMC diagnosed preoperatively should be distinguished from managing those PTMCs incidentally discovered after thyroidectomy. Here, we will focus on the challenge of managing the preoperative patient. Current guidelines recommend against routine biopsy of nodules ≤10 mm, even if they display highly suspicious features on ultrasound; however, it is not known how to identify those PTMCs at higher risk of disease progression. In view of their good prognosis even without surgical resection, active surveillance has emerged as an alternative to operative management for low‐risk PTMC without lymph node involvement or distant metastasis. This review aims to summarise active surveillance data for PTMC and identify clinical features that may differentiate the indolent majority from those PTMCs that exhibit early disease progression and metastasis.
Background
Indeterminate thyroid nodules (Bethesda III) are challenging to characterize without diagnostic surgery. Auxiliary strategies including molecular analysis, machine learning models, and ...ultrasound grading with Thyroid Imaging, Reporting and Data System (TI‐RADS) can help to triage accordingly, but further refinement is needed to prevent unnecessary surgeries and increase positive predictive values.
Design
Retrospective review of 88 patients with Bethesda III nodules who had diagnostic surgery with final pathological diagnosis.
Measurements
Each nodule was retrospectively scored through TI‐RADS. Two deep learning models were tested, one previously developed and trained on another data set, mainly containing determinate cases and then validated on our data set while the other one trained and tested on our data set (indeterminate cases).
Results
The mean TI‐RADS score was 3 for benign and 4 for malignant nodules (p = .0022). Radiological high risk (TI‐RADS 4,5) and low risk (TI‐RADS 2,3) categories were established. The PPV for the high radiological risk category in those with >10 mm nodules was 85% (CI: 70%–93%). The NPV for low radiological risk in patients >60 years (mean age was 100% (CI: 83%–100%). The area under the curve (AUC) value of our novel classifier was 0.75 (CI: 0.62–0.84) and differed significantly from the chance‐level (p < .00001).
Conclusions
Novel radiomic and radiologic strategies can be employed to assist with preoperative diagnosis of indeterminate thyroid nodules.
Beyond its established role in bone and mineral homeostasis, there is emerging evidence that vitamin D exerts a range of effects in skeletal muscle. Reports of profound muscle weakness and changes in ...the muscle morphology of adults with vitamin D deficiency have long been described. These reports have been supplemented by numerous trials assessing the impact of vitamin D on muscle strength and mass and falls in predominantly elderly and deficient populations. At a basic level, animal models have confirmed that vitamin D deficiency and congenital aberrations in the vitamin D endocrine system may result in muscle weakness. To explain these effects, some molecular mechanisms by which vitamin D impacts on muscle cell differentiation, intracellular calcium handling, and genomic activity have been elucidated. There are also suggestions that vitamin D alters muscle metabolism, specifically its sensitivity to insulin, which is a pertinent feature in the pathophysiology of insulin resistance and type 2 diabetes. We will review the range of human clinical, animal, and cell studies that address the impact of vitamin D in skeletal muscle, and discuss the controversial issues. This is a vibrant field of research and one that continues to extend the frontiers of knowledge of vitamin D's broad functional repertoire.
Abstract
Context
Thyroid dysfunction occurs commonly following immune checkpoint inhibition. The etiology of thyroid immune-related adverse events (irAEs) remains unclear and clinical presentation ...can be variable.
Objective
This study sought to define thyroid irAEs following immune checkpoint inhibitor (ICI) treatment and describe their clinical and biochemical associations.
Methods
We performed a retrospective cohort study of thyroid dysfunction in patients with melanoma undergoing cytotoxic T-lymphocyte antigen-4 (CTLA-4) and/or programmed cell death protein-1 (PD-1) based ICI treatment from November 1, 2009, to December 31, 2019. Thyroid function was measured at baseline and at regular intervals following the start of ICI treatment. Clinical and biochemical features were evaluated for associations with ICI-associated thyroid irAEs. The prevalence of thyroid autoantibodies and the effect of thyroid irAEs on survival were analyzed.
Results
A total of 1246 patients were included with a median follow-up of 11.3 months. Five hundred and eighteen (42%) patients developed an ICI-associated thyroid irAE. Subclinical thyrotoxicosis (n = 234) was the most common thyroid irAE, followed by overt thyrotoxicosis (n = 154), subclinical hypothyroidism (n = 61), and overt hypothyroidism (n = 39). Onset of overt thyrotoxicosis occurred a median of 5 weeks (interquartile range IQR 2-8) after receipt of a first dose of ICI. Combination immunotherapy was strongly associated with development of overt thyrotoxicosis (odds ratio OR 10.8, 95% CI 4.51-25.6 vs CTLA-4 monotherapy; P < .001), as was female sex (OR 2.02, 95% CI 1.37-2.95; P < .001) and younger age (OR 0.83 per 10 years, 95% CI 0.72-0.95; P = .007). By comparison, median onset of overt hypothyroidism was 14 weeks (IQR 8-25). The frequency of overt hypothyroidism did not differ between different ICI types. The strongest associations for hypothyroidism were higher baseline thyroid-stimulating hormone (OR 2.33 per mIU/L, 95% CI 1.61-3.33; P < .001) and female sex (OR 3.31, 95% CI 1.67-6.56; P = .01). Overt thyrotoxicosis was associated with longer progression free survival (hazard ratio HR 0.68, 95% CI 0.49-0.94; P = .02) and overall survival (HR 0.57, 95% CI 0.39-0.84; P = .005). There was no association between hypothyroidism and cancer outcomes.
Conclusion
Thyroid irAEs are common and there are multiple distinct phenotypes. Different thyroid irAE subtypes have unique clinical and biochemical associations, suggesting potentially distinct etiologies for thyrotoxicosis and hypothyroidism arising in this context.
Vitamin D deficiency is linked to a range of muscle disorders including myalgia, muscle weakness, and falls. Humans with severe vitamin D deficiency and mice with transgenic vitamin D receptor (VDR) ...ablation have muscle fiber atrophy. However, molecular mechanisms by which vitamin D influences muscle function and fiber size remain unclear. A central question is whether VDR is expressed in skeletal muscle and is able to regulate transcription at this site. To address this, we examined key molecular and morphologic changes in C2C12 cells treated with 25-hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D (1,25(OH)2D). As well as stimulating VDR expression, 25(OH)D and 1,25(OH)2D dose-dependently increased expression of the classic vitamin D target cytochrome P450, family 24, subfamily A, polypeptide 1 (CYP24A1), demonstrating the presence of an autoregulatory vitamin D-endocrine system in these cells. Luciferase reporter studies demonstrated that cytochrome P450, family 27, subfamily B, polypeptide 1 (CYP27B1) was functional in these cells. Both 25OHD and 1,25(OH)2D altered C2C12 proliferation and differentiation. These effects were related to the increased expression of genes involved in G0/G1 arrest (retinoblastoma protein Rb, 1.3-fold; ATM, 1.5-fold, both P < .05), downregulation of mRNAs involved in G1/S transition, including myc and cyclin-D1 (0.7- and 0.8-fold, both P < .05) and reduced phosphorylation of Rb protein (0.3-fold, P < .005). After serum depletion, 1,25(OH)2D (100nM) suppressed myotube formation with decreased mRNAs for key myogenic regulatory factors (myogenin, 0.5-fold; myf5, 0.4-fold, P < .005) but led to a 1.8-fold increase in cross-sectional size of individual myotubes associated with markedly decreased myostatin expression (0.2-fold, P < .005). These data show that vitamin D signaling alters gene expression in C2C12 cells, with effects on proliferation, differentiation, and myotube size.
Multiple endocrine neoplasia: an update McDonnell, Jane E.; Gild, Matti L.; Clifton‐Bligh, Roderick J. ...
Internal medicine journal,
August 2019, Letnik:
49, Številka:
8
Journal Article
Recenzirano
Odprti dostop
The multiple endocrine neoplasia (MEN) syndromes include MEN1, MEN2 (formerly MEN2A), MEN3 (formerly MEN2B) and the recently identified MEN4. Clinical presentations are varied and often relate to the ...overproduction of specific hormones. Understanding the genetics of each syndrome assists in determining screening timelines. Treatments for each manifestation are dependent on location, risk of recurrence or malignancy, hormone excess and surgical morbidity. Multidisciplinary management should include geneticists, genetic counsellors, endocrinologists and endocrine surgeons.
Abstract
Context
Checkpoint inhibitor–associated autoimmune diabetes mellitus (CIADM) is a rare illness, and little is known about its incidence, clinical features, or pathogenesis.
Case Series ...Description
Consecutive patients from a single quaternary melanoma center who developed new-onset insulin-requiring diabetes after commencing anti–programmed cell death-1 (PD-1) immunotherapy were studied to describe CIADM characteristics. Ten (1.9%) of 538 patients with metastatic melanoma treated with anti–PD-1–based immunotherapy from March 2015 to March 2018 developed CIADM. Nine patients had no history of diabetes, and one had pre-existing type 2 diabetes mellitus. Median time from immunotherapy start to CIADM diagnosis was 25 weeks interquartile range (IQR), 17.5 to 34.5 weeks. All patients had normal serum C-peptide shortly before CIADM onset and an inappropriately low level when measured soon after. At CIADM diagnosis, median hemoglobin A1c was 7.6% (IQR, 7.15% to 9.75%), median glucose level was 32.5 mmol/L (IQR, 21.6 to 36.7 mmol/L), and median C-peptide concentration was 0.35 nmol/L (IQR, 0.10 to 0.49 mmol/L). Type 1 diabetes (T1D)–associated autoantibodies (DAAs) were present in two patients (both of whom had anti–glutamic acid decarboxylase antibody); all were negative for insulin-associated protein 2, insulin, and ZnT8. Three patients were heterozygous for an HLA class II T1D-risk haplotype; two additional patients also carried protective haplotypes for T1D. All patients continued immunotherapy; eight (80%) had complete or partial oncological response, and all patients required ongoing insulin therapy.
Conclusion
CIADM is characterized by sudden permanent β-cell failure occurring after immunotherapy. It is distinct from T1D, usually lacks DAA or T1D-associated HLA-risk haplotypes, and is associated with difficult glycemic control from the onset. As such, CIADM represents a new model of auto-inflammatory β-cell failure.
CIADM represents a new class and increasingly common cause of autoimmune diabetes that is distinct from T1D in onset and cause; it is characterized by sudden complete β-cell failure after immune checkpoint inhibitor therapy.
Summary
Accompanying the high rates of vitamin D deficiency observed in many countries, there is increasing interest in the physiological functions of vitamin D. Vitamin D is recognized to exert ...extra‐skeletal actions in addition to its classic roles in bone and mineral homeostasis. Here, we review the evidence for vitamin D's actions in muscle on the basis of observational studies, clinical trials and basic research. Numerous observational studies link vitamin D deficiency with muscle weakness and sarcopaenia. Randomized trials predominantly support an effect of vitamin D supplementation and the prevention of falls in older or institutionalized patients. Studies have also examined the effect of vitamin D in athletic performance, both inferentially by UV radiation and directly by vitamin D supplementation. Effects of vitamin D in muscle metabolic function, specifically insulin sensitivity, are also addressed in this review. At a mechanistic level, animal studies have evaluated the roles of vitamin D and associated minerals, calcium and phosphate, in muscle function. In vitro studies have identified molecular pathways by which vitamin D regulates muscle cell signalling and gene expression. This review evaluates evidence for the various roles of vitamin D in skeletal muscle and discusses controversies that have made this a dynamic field of research.
Abuse of androgens and erythropoietin make hormonal doping the most effective and frequent class of ergogenic substances prohibited in elite sports by the World Anti-Doping Agency (WADA). At present, ...thyroid hormone (TH) abuse is not prohibited but its prevalence among elite athletes and non-prohibited status remains controversial. A corollary of prohibiting hormones for elite sports is that endocrinologists must be aware of a professional athlete's risk of disqualification for using prohibited hormones and/or to certify Therapeutic Use Exemptions, which allow individual athletes to use prohibited substances for valid medical indications. This narrative review considers the status of TH within the framework of the WADA Code criteria for prohibiting substances which requires meeting two of three equally important criteria of potential performance enhancement, harmfulness to health and violating the spirit of sport. In considering the valid clinical uses of TH, the prevalence of TH use among young adults, the reason why some athletes seek to use TH, the pathophysiology of sought-after and adverse effects of TH abuse together with the challenges of detecting TH abuse, it is concluded that, on present data, prohibition of TH in elite sport is neither justified nor feasible.
Diagnosis of pheochromocytoma or paraganglioma (PPGL) in pregnancy has been associated historically with high rates of materno-fetal morbidity and mortality. Recent evidence suggests outcomes are ...improved by recognition of PPGL before or during pregnancy and appropriate medical management with alpha-blockade. Whether antepartum surgery (before the third trimester) is required remains controversial and open to case-based merits. Women with PPGL in pregnancy are more commonly delivered by Caesarean section, although vaginal delivery appears to be safe in selected cases. At least some PPGLs express the luteinizing hormone/chorionic gonadotropin receptor (LHCGR) which may explain their dramatic manifestation in pregnancy. PPGLs in pregnancy are often associated with heritable syndromes, and genetic counselling and testing should be offered routinely in this setting. Since optimal outcomes are only achieved by early recognition of PPGL in (or ideally before) pregnancy, it is incumbent for clinicians to be aware of this diagnosis in a pregnant woman with hypertension occurring before 20 weeks’ gestation, and acute and/or refractory hypertension particularly if paroxysmal and accompanied by sweating, palpitations and/or headaches. All women with a past history of PPGL and/or heritable PPGL syndrome should be carefully assessed for the presence of residual or recurrent disease before considering pregnancy.
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